position statement testing for ovarian cancer on ... · position statement – testing for ovarian...

Position Statement – Testing for ovarian

cancer on asymptomatic women

Technical Report

February 2019

Position Statement – Testing for ovarian cancer in asymptomatic women: Technical Report was prepared and

produced by:

Cancer Australia

Locked Bag 3 Strawberry Hills NSW 2012 Australia

Tel: +61 2 9357 9400 Fax: +61 2 9357 9477

canceraustralia.gov.au

© Cancer Australia 2019.

ISBN Online: 978-1-74127-338-0

Recommended citation

Cancer Australia, 2019. Position Statement – Testing for ovarian cancer in asymptomatic women: Technical Report,

Cancer Australia, Surry Hills, NSW.

Position Statement – Testing for ovarian cancer in asymptomatic women: Technical Report can be downloaded from

the Cancer Australia website: canceraustralia.gov.au/resources

Copyright statements

Internet sites

This work is copyright. You may download, display, print and reproduce the whole or part of this work in unaltered form

for your own personal use or, if you are part of an organisation, for internal use within your organisation, but only if you or

your organisation do not use the reproduction for any commercial purpose and retain this copyright notice and all

disclaimer notices as part of that reproduction. Apart from rights to use as permitted by the Copyright Act 1968 or

allowed by this copyright notice, all other rights are reserved and you are not allowed to reproduce the whole or any

part of this work in any way (electronic or otherwise) without first being given the specific written permission from

Cancer Australia to do so. Requests and inquiries concerning reproduction and rights are to be sent to the Publications

and Copyright contact officer, Cancer Australia,

Locked Bag 3, Strawberry Hills, NSW 2012.

Disclaimer

Cancer Australia does not accept any liability for any injury, loss or damage incurred by use of or reliance on the

information. Cancer Australia develops material based on the best available evidence, however it cannot guarantee

and assumes no legal liability or responsibility for the currency or completeness of the information

http://www.canceraustralia.gov.au/

http://www.canceraustralia.gov.au/

iii Technical Report – Testing for ovarian cancer in asymptomatic women

Contents

Executive summary ......................................................................................................................................... 1

Population screening ............................................................................................................................................ 1 Surveillance in women at high risk of ovarian cancer .................................................................................... 1 Ongoing clinical studies........................................................................................................................................ 3 Emerging technologies ......................................................................................................................................... 3

1 Background ......................................................................................................................................... 4

Current Position Statements ................................................................................................................................. 4 Australian framework for population screening .............................................................................................. 4

2 Aim, objective and scope ................................................................................................................. 6

Aim……. ................................................................................................................................................................... 6 Objective ................................................................................................................................................................. 6 Scope of the review .............................................................................................................................................. 6

3 Methodology ....................................................................................................................................... 7

Clinical questions and PICOS criteria ................................................................................................................. 7 3.1.1 Population screening ............................................................................................................... 7 3.1.2 Surveillance of women at high risk ........................................................................................ 8

Search for clinical evidence ................................................................................................................................ 9 3.1.3 Search strategy ......................................................................................................................... 9 3.1.4 Study eligibility ......................................................................................................................... 10 3.1.5 Study selection ........................................................................................................................ 10 3.1.6 Quality appraisal of included evidence ............................................................................ 10

Search for clinical guidance ............................................................................................................................. 11 3.1.7 Search strategy ....................................................................................................................... 11 3.1.8 Eligibility criteria ....................................................................................................................... 11 3.1.9 Guideline selection ................................................................................................................. 11

Search for definitions of high risk population .................................................................................................. 11 3.1.10 Search strategy ....................................................................................................................... 12

Search for emerging technologies for screening or surveillance ............................................................... 12 3.1.11 Search strategy ....................................................................................................................... 12 3.1.12 Eligibility criteria ....................................................................................................................... 12

4 Results ................................................................................................................................................. 13

Review of evidence for population screening .............................................................................................. 13 4.1.1 Identified studies of screening effectiveness/harms ........................................................ 13 4.1.2 Data extraction – clinical studies ......................................................................................... 27 4.1.3 Data extraction – systematic reviews and HTAs ............................................................... 38

Review of evidence for surveillance of women at high risk ........................................................................ 47 4.1.4 Identified studies of surveillance effectiveness/harms .................................................... 47 4.1.5 Data extraction – clinical studies using ROCA-based CA125 evaluation ................... 59 4.1.6 Data extraction – clinical studies using single threshold CA125 .................................... 65 4.1.7 Data extraction – systematic reviews and HTAs ............................................................... 75

Review of clinical guidance .............................................................................................................................. 75 4.1.8 Identified guidelines ............................................................................................................... 75 4.1.9 Guidance relating to population screening ..................................................................... 77 4.1.10 Guidance relating to surveillance in women at high risk ................................................ 81

Review of definitions of high risk of ovarian cancer ..................................................................................... 84

Technical Report – Testing for ovarian cancer in asymptomatic women iv

4.1.11 Identified guidance that defines high risk .......................................................................... 84 4.1.12 Definitions of high risk of ovarian cancer ........................................................................... 84 4.1.13 Comparison of definitions with current Cancer Australia definition ............................. 88

Review of emerging technologies ................................................................................................................... 90

5 Synthesis of findings .......................................................................................................................... 95

Population screening .......................................................................................................................................... 95 5.1.1 Current clinical evidence ...................................................................................................... 95 5.1.2 Post-literature review publication – outcomes by histology ........................................... 97 5.1.3 Ongoing clinical studies......................................................................................................... 98 5.1.4 Impact of recent findings on evidence-informed guidance ......................................... 98 5.1.5 Emerging technologies .......................................................................................................... 98

Surveillance in women at high risk .................................................................................................................... 98 5.1.6 Current clinical evidence ...................................................................................................... 98 5.1.7 Ongoing clinical studies....................................................................................................... 102 5.1.8 Impact of recent findings on evidence-informed guidance ....................................... 102 5.1.9 Definitions of high risk of ovarian cancer ......................................................................... 102 5.1.10 Emerging technologies ........................................................................................................ 102

Appendices .................................................................................................................................................. 103

Appendix A Australian criteria for assessment of population screening ....................................... 103

Appendix B Literature search details .................................................................................................. 105

B.1 Clinical evidence .................................................................................................................. 105 B.2 Guidelines and position statements .................................................................................. 107 B.3 Emerging technologies ........................................................................................................ 110

Appendix C Evidence hierarchy ......................................................................................................... 111

Appendix D Included studies ............................................................................................................... 112

D.1 Population screening ........................................................................................................... 112 D.2 Surveillance in women at high risk ..................................................................................... 114

Appendix E Additional data extraction ............................................................................................. 116

E.1 Additional data extraction for population screening ................................................... 116 E.2 Additional data extraction for surveillance studies........................................................ 120

Appendix F Quality assessment .......................................................................................................... 122

Appendix G Membership of the Working Group .............................................................................. 130

Abbreviations and acronyms .................................................................................................................... 131

References……. ........................................................................................................................................... 134

v Technical Report – Testing for ovarian cancer in asymptomatic women

Tables

Table 1.1.1 2009 Cancer Australia guidance for ovarian cancer screening and surveillance ........................... 4

Table 3.1.1 PICOS criteria and additional considerations for population screening ............................................. 7

Table 3.1.2 PICOS criteria and additional considerations for surveillance of women at high risk ....................... 9

Table 3.2.1 Inclusion and exclusion criteria .................................................................................................................. 10

Table 3.2.2 Critical appraisal tools for specific study designs ................................................................................... 11

Table 4.1.1 Characteristics of included studies for population screening ............................................................. 15

Table 4.1.2 Cancer types included in primary and secondary analyses of the primary outcome in

PLCO and UKCTOCS – OC-specific mortality ......................................................................................... 20

Table 4.1.3 Terminology and definitions of select outcomes – PLCO and UKCTOCS .......................................... 21

Table 4.1.4 Key statistical analysis methods for mortality outcomes – population screening ............................ 22

Table 4.1.5 Key characteristics of systematic reviews relating to population screening for ovarian

cancer............................................................................................................................................................ 24

Table 4.1.6 Death due to ovarian cancer – primary outcome in PLCO and UKCTOCS ..................................... 27

Table 4.1.7 Death due to ovarian cancer – primary outcome analyses accounting for delayed

effects of screening in UKCTOCS .............................................................................................................. 29

Table 4.1.8 OC-specific mortality excluding prevalent cases, for ROCA triage versus no screening –

UKCTOCS ....................................................................................................................................................... 30

Table 4.1.9 All-other-cause mortality – PLCO and UKCTOCS ................................................................................... 30

Table 4.1.10 Mode of cancer detection in screening groups – PLCO and UKCTOCS .......................................... 31

Table 4.1.11 Ovarian cancer incidence – PLCO and UKCTOCS ............................................................................... 32

Table 4.1.12 Sensitivity of screening strategies – PLCO and UKCTOCS ..................................................................... 32

Table 4.1.13 False-positive surgery rates – PLCO and UKCTOCS ................................................................................ 33

Table 4.1.14 Cancer stage at diagnosis, all modes of detection – PLCO and UKCTOCS .................................... 34

Table 4.1.15 FIGO staging of ovarian cancer ............................................................................................................... 34

Table 4.1.16 Low versus high volume tumours at diagnosis, all modes of detection – UKCTOCS ....................... 35

Table 4.1.17 Complications associated with screening tests – PLCO and UKCTOCS ............................................ 37

Table 4.1.18 Complications associated with unnecessary surgery – PLCO and UKCTOCS .................................. 37

Table 4.1.19 Summary of evidence table from Henderson 2017 – effect on disease-specific mortality ........... 41

Table 4.1.20 Summary of evidence table from Henderson 2017 – harms ................................................................ 44

Table 4.1.21 Conclusions from systematic reviews relating to population screening for ovarian cancer ......... 46

Table 4.2.1 Characteristics of included studies using ROCA – surveillance of women at high risk of

ovarian cancer ............................................................................................................................................. 49

Table 4.2.2 Characteristics of included studies using single threshold CA125 – surveillance of women

at high risk of ovarian cancer .................................................................................................................... 50

Table 4.2.3 Inclusion/exclusion criteria – surveillance studies ................................................................................... 54

Table 4.2.4 Details of screening strategies – surveillance studies ............................................................................ 56

Table 4.2.5 Terminology and definitions – surveillance studies ................................................................................. 56

Table 4.2.6 Key characteristics of systematic reviews relating to surveillance of women at high risk .............. 58

Table 4.2.7 Mode of cancer detection – UKFOCSS Phase II ..................................................................................... 60

Table 4.2.8 False positive surgery rates – UKFOCSS Phase II ...................................................................................... 60

Table 4.2.9 Cancer stage at diagnosis – UKFOCSS Phase II ...................................................................................... 62

Technical Report – Testing for ovarian cancer in asymptomatic women vi

Table 4.2.10 Mode of cancer detection – CGN/GOG ............................................................................................... 64

Table 4.2.11 False-positive surgery rates – CGN/GOG ................................................................................................ 65

Table 4.2.12 Cancer stage at diagnosis – CGN/GOG ................................................................................................ 65

Table 4.2.13 Outcomes from PLCO RCT for women with at least one first degree relative with breast or

ovarian cancer ............................................................................................................................................. 66

Table 4.2.14 Outcomes from PLCO RCT for women with a personal history of breast cancer ............................ 67

Table 4.2.15 Mode of cancer detection – UKFOCSS Phase I ...................................................................................... 68

Table 4.2.16 Sensitivity of screening, with and without occult cancers – UKFOCSS Phase I ................................. 69

Table 4.2.17 False-positive surgery rates – UKFOCSS Phase I ...................................................................................... 70

Table 4.2.18 Cancer stage at diagnosis – UKFOCSS Phase I....................................................................................... 71

Table 4.2.19 Proportion of cancers diagnosed at ≥ Stage IIIC – UKFOCSS Phase I ................................................ 72

Table 4.2.20 Mode of cancer detection – UK-Netherlands-Norway study .............................................................. 73

Table 4.2.21 Cancer stage at diagnosis – UK-Netherlands-Norway study ............................................................... 73

Table 4.2.22 Key characteristics of systematic reviews relating to surveillance of women at high risk .............. 75

Table 4.3.1 Included clinical practice guidelines ....................................................................................................... 76

Table 4.3.2 Included position statements and other guidance ............................................................................... 77

Table 4.3.3 Relevant guidance from clinical practice guidelines – women at average risk ............................. 78

Table 4.3.4 Relevant guidance from other sources – women at average risk...................................................... 79

Table 4.3.5 Relevant guidance from clinical practice guidelines – surveillance of women at high risk .......... 82

Table 4.3.6 Relevant guidance from other sources – surveillance of women at high risk .................................. 83

Table 4.4.1 Definitions of women at high risk of ovarian cancer from guidelines and position

statements ..................................................................................................................................................... 84

Table 4.4.2 Definitions of women at high risk of ovarian cancer from included clinical studies........................ 87

Table 4.4.3 Current risk definition in Cancer Australia Position Statements............................................................ 89

Table 4.5.1 Potential ovarian cancer screening methodologies identified in literature search ........................ 92

Table 5.2.1 Identification of possible OC and diagnosis verification – surveillance studies............................. 121

Table AppA.1 Australian criteria for deciding whether a new screening program should be introduced

in a defined target population ............................................................................................................... 103

Table AppB.1 Search strategy to identify clinical evidence ...................................................................................... 105

Table AppB.2 Medline search string for ovarian cancer screening .......................................................................... 105

Table AppB.3 Medline search string for ovarian cancer surveillance in women at high risk ............................... 106

Table AppB.4 Study selection for the review of ovarian cancer population screening ....................................... 106

Table AppB.5 Study selection for the review of ovarian cancer surveillance in women at high risk ................. 107

Table AppB.6 Search strategy to identify guidelines and position statements ....................................................... 107

Table AppB.7 Medline search strings for guidelines and position statements ........................................................ 108

Table AppB.8 Selection for the review of guidelines and position statements ....................................................... 109

Table AppB.9 Search strategy to identify emerging technologies ........................................................................... 110

Table AppC.1 Designations of levels of evidence for interventional studies ........................................................... 111

Table AppD.1 Clinical trials of population screening for ovarian cancer ................................................................ 112

Table AppD.2 Systematic reviews of population screening for ovarian cancer .................................................... 113

Table AppD.3 Clinical studies of surveillance in women at high risk of ovarian cancer ....................................... 114

Table AppD.4 Systematic reviews of surveillance in women at high risk of ovarian cancer ................................ 115

Table AppE.1 ICD-10 codes interrogated for UKCTOCS study .................................................................................. 116

Table AppE.2 Case identification and verification – diagnosis or death due to OC ............................................ 117

Table AppE.3 Cancer stage at diagnosis, by tumour type grouping – UKCTOCS ................................................. 119

vii Technical Report – Testing for ovarian cancer in asymptomatic women

Table AppE.4 ROCA triage protocol – UKFOCSS Phase II ........................................................................................... 120

Table AppF.1 Systematic review quality assessment – Buhling 2017 ........................................................................ 122

Table AppF.2 Systematic review quality assessment – Guirguis-Blake 2017 ............................................................ 123

Table AppF.3 Systematic review quality assessment – Henderson 2017 .................................................................. 124

Table AppF.4 Systematic review quality assessment – Bloomfield 2014 .................................................................. 125

Table AppF.5 Systematic review quality assessment – Reade 2013 ......................................................................... 127

Table AppF.6 Systematic review quality assessment – Auranen 2011...................................................................... 128

1 Technical Report – Testing for ovarian cancer in asymptomatic women

Executive summary

Cancer Australia’s Position Statements on ‘Population screening and early detection of ovarian

cancer in asymptomatic women’ and ‘Surveillance of women at high or potentially high risk of

ovarian cancer’ were developed in 2009. Since that time, the evidence base for screening and

surveillance has grown, and the findings have been incorporated in recent clinical guidelines.

The objective of this high-level review is to identify and appraise recent clinical evidence and

recent national and international guidelines on ovarian cancer screening and surveillance. The

findings of the high-level review will be used to inform an update of the 2009 Cancer Australia

Position Statements.

Population screening

The Cancer Australia Position Statement on population screening refers to two large randomised

controlled trials (RCTs) of cancer antigen 125 (CA125) and transvaginal ultrasound (TVUS) in

asymptomatic women at average risk, namely the Prostate, Lung, Colorectal and Ovarian Cancer

Screening Trial (PLCO) and the United Kingdom Collaborative Trial of Ovarian Cancer Screening

(UKCTOCS). At the time, only preliminary results were available from these trials, and the final,

longer term results were much anticipated.

Since 2009, there have been 15 full text publications from these two large, well-conducted RCTs,

and there is ongoing debate about the relative strengths and weaknesses of each trial in light of

the inherent difficulties in designing and analysing a screening trial for a relatively rare and

heterogeneous cancer. Although disease-specific mortality is the key outcome for ovarian cancer,

false positive rates are also highly relevant as the screening strategy necessitates surgical removal

of ovaries for confirmation of diagnosis.

Based on a priori analyses, the evidence to date, which has adequate power to detect differences

in mortality, indicates there is no mortality benefit associated with population screening with any of

the implemented strategies. Pre-specified and post hoc secondary analyses are suggestive that a

delayed mortality benefit may be attributable to screening in the UKCTOCS study, but longer-term

follow up is necessary to confirm this. A post-hoc analysis of the PLCO trial was identified

subsequent to the literature search in this Review – no stage shift or mortality benefit was found for

Type II tumours, which were less likely to be detected by screening than other tumour types. Such

an analysis is yet to be report for the UKCTOCS trial. Follow up of UKCTOCS to 2018 has received

funding, and plans to continue to 2024 are reported. At that time, it may be necessary to re-

evaluate whether population screening is justified.

Overall, the current evidence does not support the implementation of screening in asymptomatic

women at average risk of ovarian cancer. Accordingly, recent national and international

guidelines do not recommend population screening for ovarian cancer based on the technologies

that have been trialled to date.

Surveillance in women at high risk of ovarian cancer

The Cancer Australia Position Statement on surveillance in high-risk women refers to two multicentre

prospective cohort studies that were underway at the time – the United Kingdom Familial Ovarian

Cancer Screening Study (UKFOCSS), and the Cancer Genetics Network and Gynecologic

Oncology Group (CGN/GOG) collaborative study.

Technical Report – Testing for ovarian cancer in asymptomatic women 2

Since 2009 there have been 10 full text publications relating to six studies of surveillance in women

at high risk of ovarian cancer: four prospective cohort studies (UKFOCSS Phase I, UKFOCSS Phase II,

CGN/GOG, UK-Netherlands-Norway study), one prospective cohort survey (Fox Chase Cancer

Centre study), and a post hoc analysis of a high-risk subgroup from the PLCO population screening

RCT (PLCO-HR). As random assignment to a no-surveillance arm is considered unethical in high-risk

women, no studies included a no-surveillance comparator group, instead relying on historical

controls or before/after comparisons within a cohort. While such comparisons may be considered

valid, and are likely the best approach available to investigate the effectiveness of surveillance,

the results of these studies should be considered in light of the inherent design flaws and inevitable

confounding that limit the opportunity to demonstrate statistically robust improvements in

outcomes. The low incidence rate for ovarian cancer also means that even in the largest studies,

the number of events are small, especially when subgroups such as stage at diagnosis are

examined, further reducing the certainty of the outcomes. Interpretation of the results of these

surveillance studies also requires consideration of the fact that risk-reducing salpingo-

oophorectomy (RRSO) is recommended as optimal management.

The PLCO-HR subgroup analysis overcomes many of the limitations described above. However, it

was not feasible to identify women in this study post hoc according to the usual array of criteria

that define high risk, and the more readily discernible group of women with a personal history of

breast cancer or family history of breast or ovarian cancer was used instead. Consequently, the

overall disease-specific risk in this subgroup would have been lower than in a typical high-risk

population.

The few surveillance studies that reported on mortality did not find any improvements associated

with surveillance. The PLCO subgroup analysis, however, did find significant improvements in

disease-specific survival with surveillance in a population with a higher-than-average risk, and an

absolute reduction in advanced-stage cancers. Stage shift trends were also discernible in the other

surveillance trials, and were statistically significant in the UKFOCSS trials. Event numbers were low in

all surveillance studies of high-risk cohorts, so it is not clear whether the failure to demonstrate a

corresponding improvement in mortality is due to limited statistical power or a fundamental failure

to improve mortality outcomes as a result of surveillance (i.e. early detection may not result in

improved mortality). Furthermore, these studies were limited by the lack of a balanced comparator

group (PLCO excepted), so the current lack of a demonstrated mortality benefit is not evidence

that surveillance cannot improve survival outcomes.

While stage shift may be of interest as a surrogate outcome for mortality, reduced volume of

disease is also a patient-relevant outcome in itself, with implications regarding rates of post-surgical

residual disease. So while the evidence may not be resounding for the use of surveillance as first-

line management in high-risk women, it appears there may be a role for surveillance of those

women wishing to postpone RRSO to complete childbearing or delay surgically induced

menopause. This suggests surveillance may be considered appropriate for some women to support

decision making around the timing of RRSO. This is likely to be a decision made at the clinical level,

but the evidence to date does not support a shift in current management recommendations

across all high-risk women.

No clinical practice guidelines or other guidance was identified that incorporates all recent

evidence relating to surveillance in women at high risk of ovarian cancer. In general, routine

surveillance is not recommended; however, some guidance documents advise that despite a lack

of strong evidence, surveillance using CA125 and TVUS may be considered in particular high-risk

populations from the age of 30 or 35, so long as patients are informed about the limited value of

these tools as an effective surveillance measure.


Ongoing clinical studies

The only ongoing study identified in the search of clinical trial databases was the long-term follow

up of UKCTOCS, which will use an updated classification of peritoneal cancers to reflect the revised

classification of tumours of the reproductive system from the World Health Organization (WHO) in

2014. After reclassification of these peritoneal cancers, the primary outcomes of UKCTOCS and

PLCO will be more closely aligned. The next censorship for UKCTOCS is planned for December 2018,

and final censorship for December 2024.

Although several clinical studies of new biomarkers and molecular screening tests were identified in

clinical trial databases, the viability of the clinical studies could not be verified. Several entries had

the following warning: “The recruitment status of this study is unknown. The completion date has

passed and the status has not been verified in more than two years.”

Emerging technologies

Given the absence of a single marker or screening device that is effective for ovarian cancer,

research is likely to increasingly aim to identify new markers and combinations of markers in

prediction models.

A number of methodologies were identified that are either currently available for prognosis or

diagnosis of ovarian cancer, or that are in clinical or scientific development for screening for

ovarian cancer. However, none of these technologies are likely to be introduced/recommended in

the short- to medium-term.

The recent Evidence Synthesis of screening for ovarian cancer prepared for the US Preventative

Services Task Force of the Agency for Healthcare Research and Quality (AHRQ; Henderson et al

2017) also identified no ongoing randomised trials of ovarian cancer screening using new screening

tools. The authors noted that while some tools in development may hold promise for the future (e.g.

microRNA), currently there are no new screening tools (i.e. biomarkers, instruments) exhibiting levels

of test performance beyond what is observed for the screening tools evaluated in trials.

In their recent review of the evolving paradigms in research and care for ovarian cancer, the

National Academies of Science, Engineering and Medicine (NASEM) claim that it is highly unlikely

that a single biomarker or imaging modality will be sufficient to aid in the early detection of all

ovarian cancer subtypes, given the marked heterogeneity of ovarian cancers and the incomplete

understanding of early disease development for each subtype (NASEM 2016). The authors note that

“while research on refining current methods may be fruitful, distinct multimodal approaches will

likely be needed to detect each of the various subtypes at their earliest stages”.


1 Background

Current Position Statements

In 2009, Cancer Australia developed Position Statements on ‘Population screening and early

detection of ovarian cancer in asymptomatic women’, and ‘Surveillance of women at high or

potentially high risk of ovarian cancer’. Table 0.1 lists the guidance provided in each Position

Statement.

Table 0.1 2009 Cancer Australia guidance for ovarian cancer screening and surveillance

Topic Statements

Population screening and early detection of ovarian cancer in asymptomatic women

There is currently no evidence that any test, including pelvic examination, CA125 or other biomarkers, ultrasound

(including transvaginal ultrasound), or combination of tests, results in reduced mortality from ovarian cancer.

There is no evidence to support the use of any test, including pelvic examination, CA125, or other biomarkers, ultrasound

(including transvaginal ultrasound), or combination of tests, for routine population based screening for ovarian cancer.

Further validation in large clinical trials is required before current or new biomarkers could be recommended for routine

use in a population screening setting.

Surveillance of women at high or potentially high risk of ovarian cancer

Ovarian cancer surveillance is not recommended for women at high or potentially high risk.

Evidence shows that ultrasound or CA125, singly or in combination, is not effective at detecting early ovarian cancer.

The most effective risk reducing strategy for ovarian cancer is bilateral salpingo-oophorectomy.

Definition of potentially high risk women

The category of potentially high risk of ovarian cancer covers less than 1% of the female population. As a group, lifetime

risk of ovarian cancer ranges between 1 in 30 and 1 in 2. This risk is more than 3 times the population average. Individual

risk may be higher or lower if genetic test results are known.1 Women who have had a genetic fault identified through

testing are regarded as being at high risk. Women have been defined as being at potentially high risk of developing

ovarian cancer1 if they:

Are at high or potentially high risk of breast cancer

Have one 1° relative diagnosed with epithelial ovarian cancer in a family of Ashkenazi Jewish ancestry2

Have one woman in the family with ovarian cancer at any age, and another with breast cancer before the

age of 50, where the women are 1° or 2° relatives of each other

Have two 1° or 2° relatives on the same side of the family diagnosed with epithelial ovarian cancer,

especially if one or more of the following features occurs on the same side of the family:

o additional relative(s) with breast or ovarian cancer

o breast cancer diagnosed before the age of 40

o bilateral breast cancer

o breast and ovarian cancer in the same woman

o breast cancer in a male relative

Have three or more 1° or 2° degree relatives on the same side of the family diagnosed with any cancers

associated with hereditary non-polyposis colorectal cancer (HNPCC): colorectal cancer (particularly if

diagnosed before the age of 50), endometrial cancer, ovarian cancer, gastric cancer, and cancers

involving the renal tract

Are a member of a family in which the presence of a high-risk ovarian cancer gene mutation has been

established.

Source: Cancer Australia website

Australian framework for population screening

The framework used to guide decision makers regarding the implementation of population

screening for cancer and other chronic diseases in Australia is outlined in Appendix A. The

Australian framework takes into account:

the need for a strong evidence base in making a decision about the introduction of a

screening program including evidence of the safety, reproducibility and accuracy of the

screening test and the efficacy of treatment; and

1 National Breast Cancer Centre 2006. Advice about familial aspects of breast cancer and epithelial ovarian cancer: a guide for health

professionals. National Breast Cancer Centre, Camperdown, NSW. 2 High-risk ovarian and breast cancer mutations are more common in people of Ashkenazi Jewish ancestry.


the requirement that a screening program offers more benefit than harm to the target

population.

The framework does not address surveillance in high risk populations, but it is necessary to consider

these patients when planning the coverage of screening programs.


2 Aim, objective and scope

Aim

The overall aim of this project is to provide the Australian community with up-to-date evidence-

based information on:

1. population screening and early detection of ovarian cancer in asymptomatic women, and

2. surveillance of women at high or potentially high risk of ovarian cancer.

Objective

The objective of this high-level review is to identify and appraise recent clinical evidence and

recent national and international guidelines on ovarian cancer screening and surveillance. The

findings of the high-level review will be used to inform an update of the 2009 Cancer Australia

Position Statements.

Scope of the review

The high level review includes the following components:

a review of the highest level clinical evidence for ovarian cancer screening and surveillance,

published from 2009 onwards

a review of clinical practice guidelines, position statements, and other evidence-based

guidance from Australia and other countries, published from 2011 onwards

a review of emerging technologies with potential for screening or surveillance.


3 Methodology

This section of the Technical Report describes the methodology used to identify and review recent

clinical evidence and guidelines on population screening for ovarian cancer and surveillance of

women at high or potentially high risk of ovarian cancer; the research questions, the PICOS criteria

used to guide the selection of eligible studies, the methodology used to search the published

literature and select relevant evidence and guidance.

Clinical questions and PICOS criteria

3.1.1 Population screening

3.1.1.1 Clinical question for population screen

The research question to focus the high-level review of the literature for ovarian cancer population

screening is:

What is the effectiveness (health benefits and harms) of routine population-based

screening for ovarian cancer?

3.1.1.2 PICOS criteria for population screening

PICOS criteria were developed to assist with evidence selection using information from the

literature. As shown in Table 0.1, these criteria define the following four elements in detail:

the target population for the intervention

the intervention being considered

the appropriate comparator

the outcomes that are most relevant to assess safety and effectiveness

the setting for the intervention.

Additional considerations are also noted (e.g. frequency of screening, duration of follow-up).

Table 0.1 PICOS criteria and additional considerations for population screening

PICOS criterion Description

Population Asymptomatic women who are at population risk of ovarian cancer.

Exclude children and adolescents, aged < 18 years, pregnant women, and symptomatic women.

Intervention Ovarian cancer screening using:

Pelvic examination

CA125

Other biomarkers (e.g. HE4)

Transvaginal ultrasound

Combination of above

Exclude examination or testing for diagnosis.

Comparator Usual care i.e. no population-based ovarian cancer screening.



Outcomes Detection outcomes

Ovarian cancer incidence

o all diagnoses

o by cancer site/grade/histology/stage

Number of interval cancers in screening group

Number of surgeries performed to detect one case of ovarian cancer

Rate of false-positive screening tests

Sensitivity

Mortality

Ovarian cancer specific mortality

o Time to ovarian cancer specific mortality

All-cause mortality

Adverse events

Complications associated with unnecessary surgery

QoL

Measures of worry or anxiety related to ovarian cancer risk

Quality of life (assessed using validated instruments)

Economic outcomes

Economic analysis (cost-effectiveness, cost-benefit, cost-minimisation)

Setting Developed countries, primary care outpatient setting (or similar)

Exclude settings not applicable to primary care

Additional considerations Frequency of screening/testing

Duration of follow-up

o stratify outcomes by follow-up time point (e.g. follow-up of 1-2 years versus >2 years) or use latest

reported time point for all outcomes

Menopausal status of women

Abbreviations: QoL, quality of life.

3.1.2 Surveillance of women at high risk

3.1.2.1 Clinical question for surveillance of women at high risk

For the review of surveillance in women at high risk of ovarian cancer, the research question is:

What is the effectiveness (health benefits and harms) of surveillance of women who

are at high or potentially high risk of ovarian cancer?

3.1.2.2 PICOS criteria for surveillance of women at high risk

PICOS criteria were developed to assist with evidence selection using information from the

literature. As shown in Table 0.2, these criteria define the following four elements in detail:

the target population for the intervention

the intervention being considered

the appropriate comparator

the outcomes that are most relevant to assess safety and effectiveness

the setting for the intervention.

Additional considerations are also noted (e.g. frequency of screening, duration of follow up).


Table 0.2 PICOS criteria and additional considerations for surveillance of women at high risk


Population Asymptomatic women who are at high or potentially high risk of ovarian cancer

Exclude children and adolescents, aged < 18 years, pregnant women, and symptomatic women

Intervention Ovarian cancer screening using:

Pelvic examination

CA125

Other biomarkers (e.g. HE4)

Transvaginal ultrasound

Combination of above

Exclude examination or testing for diagnosis

Comparator Usual care, including the option of risk-reducing surgery (salpingo-oophorectomy) i.e. no surveillance in

women at high or potentially high risk of ovarian cancer

Outcomes Detection outcomes


o all diagnoses

o by cancer site/grade/histology/stage

Number of interval cancers in screening group

Number of surgeries performed to detect one case of ovarian cancer

Rate of false-positive screening tests

Sensitivity

Mortality

Ovarian cancer specific mortality

o Time to ovarian cancer specific mortality

All-cause mortality

Adverse events


Complications associated with prophylactic surgery

QoL

Measures of worry or anxiety related to ovarian cancer risk

Quality of life (assessed using validated instruments)

Economic outcomes

Economic analysis (cost-effectiveness, cost-benefit, cost-minimisation)

Setting Developed countries, primary care outpatient setting (or similar)

Additional considerations Frequency of screening/testing

Duration of follow-up

o stratify outcomes by follow-up time point (e.g. follow-up of 1-2 years versus >2 years) or use latest

reported time point for all outcomes

Menopausal status of women

Study definition of high or potentially high risk

Search for clinical evidence

3.1.3 Search strategy

A comprehensive search of peer-reviewed scientific literature was undertaken 17 – 20 October

2017 for original publications of individual studies, health technology assessments (HTAs) or

systematic reviews providing clinical evidence of the effectiveness and safety of ovarian cancer

population screening, and surveillance of women at high or potentially high risk.

Briefly, the search strategy included:

a search of the Medline electronic database (using the Ovid interface),

a targeted search of the websites of peak cancer bodies and HTA agencies,

a search of clinical trial registries, and


snowballing for any additional relevant studies that might not have been identified in the

formal literature search (e.g. hand-searching reference lists; chasing up studies mentioned in

clinical practice guidelines).

The search strategy, including the websites targeted and Medline search string, is shown in

Appendix B (Section B.1).

3.1.4 Study eligibility

Study eligibility was based on the PICO criteria outlined above in Section 0, together with the

inclusion and exclusion criteria shown in Table 0.1. Eligible studies include RCTs, systematic reviews

and meta-analyses – that is, Level I and Level II evidence as described in the NHMRC Evidence

Hierarchy (Appendix C). For surveillance of women at high risk of ovarian cancer, lower levels of

evidence (Level III-1 or III-2) were eligible for inclusion, with prospective cohort studies taking priority

over retrospective studies.

In order to focus on recent developments (since publication of the Cancer Australia Position

Statements on ovarian cancer screening and surveillance), only studies published from 2009

onwards were considered for inclusion.

Table 0.1 Inclusion and exclusion criteria

Item Inclusion criteria Exclusion criteria

Publication types Published journal articles

Health technology assessments

Clinical trials

Conference abstracts

Letters and editorials

Opinion pieces and commentaries

Study types and

designs

Systematic reviews

Meta-analyses

Randomised controlled trials

Non-randomised trials

Single arm studies

Diagnostic studies

Study language English language articles only –

Publication date From 1 January 2009 –

3.1.5 Study selection

3.1.5.1 Population screening

The Medline search identified 248 unique records, of which 17 met the eligibility criteria for the

review. Appendix B (Section B.1.2) outlines the selection process. An additional seven records were

identified through targeted searches of websites and snowballing.

3.1.5.2 Surveillance in women at high risk

The Medline search identified 290 unique records, of which 11 met the eligibility criteria for the

review. The selection process is outlined in Appendix B (Section B.1.2). No additional records were

identified through targeted searches of websites and snowballing.

3.1.6 Quality appraisal of included evidence

Although formal assessment of the risk of bias associated with the included studies is out of scope

for the current work, the principles for assessing the risk of bias was based on one of the critical

appraisal tools listed in Table 0.2 that is appropriate for the study design.


Table 0.2 Critical appraisal tools for specific study designs

Level Study design Development Critical appraisal tool

I SR AMSTAR, Canada AMSTAR

II/III-1 RCTs/quasi-RCTs Cochrane Collaboration Risk of Bias (RoB) tool for RCTs

III-2 Non-randomised experimental trials,

cohort studies with concurrent control

group

Scottish Intercollegiate Guidelines

Network (SIGN)

Methodology Checklist 3 for

Cohort Studies

Search for clinical guidance


A comprehensive search was undertaken 17 – 20 October 2017 to identify national and

international clinical guidance (clinical practice guidelines and position statements) regarding

population screening for ovarian cancer in asymptomatic women, and surveillance of women at

high risk of ovarian cancer.


a search of the Medline electronic database (using the Ovid interface),

a search of clinical practice guideline databases, and

a targeted search of the websites of peak cancer bodies.

The search strategy, including the websites targeted and Medline search string, is shown in

Appendix B (Section B.2.1).

3.1.8 Eligibility criteria

Clinical practice guidelines and position statements were considered eligible if they provided

evidence-informed guidance on ovarian cancer screening and surveillance. Guidance developed

through a consensus process was only considered eligible in cases where evidence was found to

be insufficient. Guidelines published prior to 2011 were not eligible for inclusion on the basis that

they may not reflect current practice.

3.1.9 Guideline selection

The Medline search identified 200 unique records, of which nine met the eligibility criteria for the

review. The selection process is outlined in Appendix B (Section B.2.2). An additional 11 guidance

documents were identified through searches of clinical practice guideline databases and targeted

searches of websites.

Search for definitions of high risk population

Criteria for defining the population of women with an elevated risk of ovarian cancer typically

includes family history and genetic mutation status. The definition used in the 2009 Cancer Australia

Position Statement is shown in Table 0.1. A review of definitions used in clinical studies, clinical

practice guidelines, position statements and by peak cancer organisations will allow an assessment

of whether the definition requires any adaptation for the updated Cancer Australia Position

Statement.



A full and comprehensive, evidence-based assessment of the definition of the high-risk population

is beyond the scope of this Evidence Review and a specific search for definitions was not

undertaken. When searching for clinical studies and clinical guidance for other sections of the

report, the websites of peak cancer authorities were scanned for a definition of the population

considered to be at high or potentially high risk of ovarian cancer. Additionally, clinical studies,

guidelines and position statements considered eligible for inclusion in earlier sections of the report

were reviewed for criteria to define women with an elevated risk of ovarian cancer.

Search for emerging technologies for screening or surveillance


A targeted scanning search was undertaken 30 October – 3 November 2017 to identify promising

new tests and biomarkers for ovarian cancer.


a targeted search of the websites of HTA agencies

a targeted search of the websites of peak cancer bodies

a targeted search of horizon scan websites

a targeted search of 2016 and 2017 abstracts from key cancer conferences

a targeted search of clinical trial registries

a general web search

snowballing (e.g. hand-searching reference lists; chasing weblinks).

The search strategy, including the websites targeted, is shown in Appendix B (Section B.3.1).

3.1.12 Eligibility criteria

Tests/biomarkers were included if they were considered:

emerging – not yet available for use within the healthcare system but in development and

expected to be registered or launched within the next 2 years, or

new – tests that have been available for use for 5 years or less but not yet considered for use,

or are in the early phases of adoption.


4 Results

Review of evidence for population screening

4.1.1 Identified studies of screening effectiveness/harms

The literature searches identified a total of 24 eligible records for ovarian cancer population

screening: 19 clinical study publications/unpublished reports and five systematic reviews.

4.1.1.1 Key clinical studies

The 19 eligible clinical study publications and unpublished reports are listed in Appendix D (Section

D.1.1). They describe two RCTs:

The Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial

United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS).

For the PLCO trial, primary and secondary outcomes are reported in three publications, and two

publications describe post hoc analyses. One study that reports the results of the initial round of

screening was published prior to the 2009 cut-off date for the literature review, but this is also shown

in Appendix D. An additional two records describing study design were identified during a directed

search. The Cancer Data Access System website, hosted by the National Cancer Institute, is a

repository of information for this trial, and a link to the main page for this resource is also included.

For the UKCTOCS trial, primary and secondary outcomes are reported across five publications, and

an additional three publications describe post hoc analyses (two relate to cost-effectiveness).

Directed searching also identified a study protocol for the trial and another for the ongoing long

term follow up (entitled ‘Detailed Project Description’), which provides a brief overview of the

design of the original trial, mortality results so far, and the rationale for extending follow up.

Study characteristics

The study characteristics of the two RCTs of population screening are shown in Table 0.1. Key

differences between the trials include the following:

Menopausal status

PLCO – not excluded, but older participants (at least 55 years)

UKCTOCS – excluded pre-menopausal

Women with a high risk of ovarian cancer

PLCO – not excluded

UKCTOCS – excluded

Cancer antigen 125 (CA125) interpretation

PLCO – cutoff value of 35 U/mL

UKCTOCS – Risk of Ovarian Cancer Algorithm (ROCA) to analyse longitudinal CA125

(individual risk factors for each woman inform the ROCA in the calculation of personal risk)


Screening strategies

PLCO – single screening group with simultaneous CA125 and transvaginal ultrasonography

(TVUS) testing for first four years, then CA125 only for the final two years

UKCTOCS – two screening groups:

o TVUS only

o CA125 only unless levels elevated, then TVUS

Number of screening rounds

PLCO – 6

UKCTOCS – 7-11


Table 0.1 Characteristics of included studies for population screening

Item PLCO UKCTOCS

Country and setting United States – 10 screening centres under contract to the

National Cancer Institute

United Kingdom – 13 regional centres in NHS Trusts in England, Wales, and Northern Ireland, with the Queen Mary

University of London as the coordinating centre between 2001 and 2004 and then University College London from 2004

onwards

Trial number NCT00002540 NCT00058032

Inclusion criteria Women 55 to 74 years of age

Menopausal status not a criterion

Post-menopausal women, defined as either (a) >12 months amenorrhoea following a natural menopause or

hysterectomy, or (b) >12 months of HRT commenced for menopausal symptoms

50 to 74 years of age

Exclusion criteria Previous diagnosis of lung, colorectal, or ovarian

cancer

Previous oophorectomy (dropped in 1996)

Current tamoxifen use (dropped in 1999)

Increased risk of familial ovarian cancer not a criterion

Previous ovarian malignancy

History of bilateral oophorectomy

Active non-ovarian malignancy3

Increased risk of familial ovarian cancer4

Participation in other ovarian cancer screening trials

Study design RCT with two groups, randomised 1:1

CA125 and TVUS

no screening

RCT with three groups, randomised 1:1:2 respectively to:

multimodal screening (ROCA triage to repeat CA125 and/or TVUS)

TVUS

no screening

Period of study

Start date 16 Nov 1993 Apr 2001

Recruitment period Nov 1993 to Jul 2001 17 Apr 2001 to 29 Sep 20055

Randomisation period Nov 1993 to Jul 2001 1 Jun 2001 to 21 Oct 2005

Maximum no. of

annual screening

rounds

6 annual screening rounds

4 with CA125 plus TVUS, followed by

2 with CA125 only

Compliance per round:

CA125, 73-85%; TVUS, 78-84%

7-11 annual screening rounds, depending on date of randomisation (protocol change in 2008 increased number of

screening rounds from 6 to a maximum of 11)

Compliance across all rounds:

ROCA triage, 80.8%; TVUS, 78.0%

End of screening date NR, but planned for Sep 2006 (see Appendix E,

FigureAppE.1.1)

31 Dec 20116

3 Women who have a past history of malignancy are only eligible if (a) they have no documented persistent or recurrent disease and (b) have not received treatment for >12 months. The intention is to minimise false

positive CA125 results due to advanced stages of previously diagnosed malignancy. This exclusion did not include premalignant disease such as cervical intraepithelial neoplasia or use of tamoxifen to prevent

breast cancer recurrence. 4 Women with increased risk of familial ovarian cancer were eligible to enter the separate trial, the United Kingdom Familial Ovarian Cancer Screening Study (UKCTOCS) – the inclusion criteria for this study are listed in

the study characteristics table for studies of ovarian cancer surveillance in the following section of the current Report. 5 Of 1,243,282 women invited to participate, 205,090 were recruited and 202,638 (16.3%) were randomised. 6 The original trial protocol specified six annual screens and follow-up for 7 years from randomisation. In 2008, an analysis of overall and cause-specific standardised mortality in the no-screening group showed a lower

than expected mortality rate. Screening in the TVU and CA125 (±TVU) groups was therefore extended to Dec 31, 2011, resulting in women being offered 7–11 screens depending on the year of randomisation.


Item PLCO UKCTOCS

Person-years Screening: 371,833

No screening: 374,976

ROCA triage: 345,572

TVUS: 327,775

No screening: 1,097,089

End of follow-up 31 Dec 2012 Dec 2024

Length of follow up From randomisation through to

13 years of follow-up or

28 Feb 2010

whichever comes first.

From randomisation through to censorship

Dec 2014 (up to 14 years – 1 analysis)

Extended follow up, planned reporting:

Dec 2018 (up to 18 years)7

Dec 2024 (up to 24 years)

Participants randomised

Screening (method 1) Screening: 39,105 ROCA triage: 50,640

Screening (method 2) – TVUS: 50,639

Control No screening: 39,111 No screening: 101,359

Participants analysed

Screening (method 1) Screening: 34,253 ROCA triage: 50,624 (complete follow-up 50,084)

Screening (method 2) – TVUS: 50,623 (complete follow-up: 50,060)

Control No screening: 34,304 No screening: 101,299 (complete follow-up: 100,149)

Baseline characteristics The authors note that baseline characteristics were

balanced between study groups.

The authors note that baseline characteristics were balanced between study groups.

Median follow up

(years)

Primary analysis (28 Feb 2010)

12.4 (range 10.9-13.0)

Extended follow up (31 Dec 2012)

Screening: 14.72 (IQR 13.1, 16.4)

No screening: 14.65 (IQR 12.8, 15.7)

Primary analysis (31 Dec 2014)

11.1 (IQR 10.0–12.0)

7 Taken from NHS 2016 Detailed Project Description.


Item PLCO UKCTOCS

Screening methods CA125 interpretation

Threshold: ≥35 U/mL

Group 1 – CA125 + TVUS8

First 4 rounds of annual screening

CA125 and TVUS

Subsequent rounds (up to 2)

CA125 only

Bimanual examination of the ovaries was originally part of

the screening procedures but was discontinued in

December 1998 because no cancers were detected solely

by ovarian palpation.

CA125 interpretation

Risk of Ovarian Cancer Algorithm (ROCA)9

Group 1 – ROCA triage

Multimodal screening (MMS): annual serum CA125, with repeat CA125 alone or with TVUS, depending on results:

Level I screen

CA125 ROCA

Normal ROC – resume annual CA125 screening

Intermediate ROC – repeat CA125 in 12 weeks

Elevated ROC – Level II screen in 6-8 weeks, or earlier where suspicion is high

Level II screen

TVUS and repeat CA125 ROCA

Scan & ROC normal – resume annual CA125 screening

Scan normal but ROC elevated – repeat Level II scan in 12 weeks (sooner where suspicion is high)

Scan unsatisfactory (irrespective of ROC) – repeat Level II scan in 12 weeks (sooner where suspicion is high)

Scan abnormal (irrespective of ROC) – referral for clinical assessment with a view to surgery

Group 2 – TVUS

Annual TVUS scan, with repeat TVUS scans depending on results:

Level I screen

Scan normal – resume annual screening

Scan unsatisfactory – repeat scan in 12 weeks

Scan abnormal – repeat scan in 6-8 weeks (earlier where suspicion is high) = Level II

Level II screen

Scan normal – resume annual screening

Scan unsatisfactory – repeat scan in 6-8 weeks (earlier where suspicion is high) and triaged based on findings to

annual screening or clinical assessment

Scan abnormal – referral for clinical assessment with a view to surgery

8 Although TVUS was included in the first four screening rounds only, this intervention is referred to as CA125 +TVUS.

9 The first ROC determination is based on the absolute CA125 level and age-specific risk; subsequent ROC determinations are based on the absolute CA125 level and the rate of change in CA125.


Item PLCO UKCTOCS

UKCTOCS: strategies for ROCA ±TVUS (multimodal) and TVUS (ultrasound) screening

Source: NHS 2016 Figure 4, p11

Positive-screen follow-up

actions

Abnormal results for either test precipitated notification in

writing to the participant and their physician for standard

diagnostic and follow up procedures. If requested, referral

physicians were provided with standard-of-practice

guidelines for diagnostic procedures by the local PLCO

screening centre.

In both groups, women with persistent abnormalities had clinical assessment and additional investigations within the

NHS by a trial clinician.

On finding an adnexal abnormality, further evaluation was undertaken by a designated clinician, and included clinical

evaluation and investigations (serum CA125, repeat TVS and Doppler studies, CT/ MRI of the abdomen and pelvis and

occasionally assessment of other tumour markers) as appropriate. They had the option of conservative management in

cases where the features of the cyst were felt to be associated with a lower risk of EOC; the history included previous

hysterectomy/major pelvic surgery which could be responsible for the ultrasound appearance; or the participant was

asymptomatic and did not have other clinical findings suggestive of malignancy. The management plan took account

of the views of the individual woman, any significant comorbidity, the specific morphological features of the detected

lesion and history of a previous hysterectomy or major pelvic surgery that could be responsible for false-positive

ultrasound appearances. If surgery was not undertaken following clinical assessment, the women usually underwent

conservative management with follow-up and subsequent return to annual screening.

Comparator arm Usual care (no screening). Usual care (no screening).

Key outcomes reported Mortality due to OC


Cancer stage

Survival

Potential harms of screening

Mortality due to OC


Cancer stage

Physical morbidity due to surgical intervention attributable to screening

Psychological consequences of screening

Abbreviations: CT, computed tomography; EOC, epithelial ovarian cancer; HRT, hormone replacement therapy; IQR, interquartile range; MMS, multimodal screening; MRI, magnetic resonance imaging; NHS,

National Health Service; OC, ovarian cancer; PLCO, Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial; RCT, randomised controlled trial; ROC, risk of ovarian cancer; ROCA, Risk of Ovarian Cancer

Algorithm; TVS/TVUS, transvaginal ultrasound; UKCTOCS, United Kingdom Collaborative Trial of Ovarian Cancer Screening.


Cancer types included

Table 0.2 shows the ICD-10 codes for the three types of cancer included in the two RCTs of

population screening: ovarian cancer, fallopian tube cancer (FTC) and primary peritoneal cancer

(PPC). The UKCTOCS study included an additional category (undesignated) for cancers that were

either ovarian, tubal or peritoneal in origin, but could not be further delineated during the

interrogation of medical records.

The PLCO trial lists C56.9 as the ICD-10 code used for ovarian cancer while the UKCTOCS trial lists

the higher level code C56, under which sit C56.1 (left ovary), C56.2 (right ovary) and C56.9

(unspecified ovary). As described below, ascertainment of outcome in the PLCO trial involved

investigating all diagnoses of PLCO cancers, mostly via notifications from mailed surveys. Although

not stated, presumably all cancers described by respondents as ovarian were investigated,

regardless of which ICD-10 code may have been attributed to the malignancy. So it appears that

the use by the study authors of the specific C56.9 code to define ovarian cancer does not reflect

any limitation on the types of ovarian cancer included in this study.

The key difference between the trials regarding cancer types is the classification of borderline

tumours:

Invasive versus borderline epithelial ovarian tumours

PLCO – excludes epithelial ovarian borderline tumours (classified as false positives)

UKCTOCS – includes epithelial ovarian borderline tumours (classified as malignancies)

Nomenclature in this report:

ovarian cancer including borderline tumours – ovarian (all)

ovarian cancer excluding borderline tumours – ovarian (invasive).

Non-epithelial ovarian tumours

PLCO – does not specify inclusion or exclusion of non-epithelial ovarian tumours. In the current

Report, it is assumed that these tumours were not excluded in the PLCO trial, and that

reference to ‘primary invasive neoplasms of the ovary’ would include these cancers.

UKCTOCS – it is clearly stated that non-epithelial ovarian tumours are included as ovarian

cancer.

Cancer types included in analyses of the primary outcome

The primary analysis of the primary outcome in the UKCTOCS trial was restricted to ovarian cancers

and FTCs. The authors note that most peritoneal cancers are likely to be classified as tubal and

ovarian cancer ‘once wider acceptance of the World Health Organization (WHO) 2014 revision has

occurred’. Consequently, they also specified a secondary analysis of the primary outcome that

included all three cancer types.

The primary outcome in the PLCO trial included all three cancer types: invasive ovarian cancers,

FTCs and PPCs. In the report of extended follow up, an additional analysis was performed that

excluded peritoneal cancer, making this analysis more comparable to the primary outcome in the

UKCTOCS trial.


Table 0.2 Cancer types included in primary and secondary analyses of the primary

outcome in PLCO and UKCTOCS – OC-specific mortality

Code ICD-10 descriptor 1 analysis 2 analysis

PLCO UKCTOCS PLCO ext.

follow up

UKCTOCS

Ovarian

C5610 Malignant neoplasm of ovary

Fallopian tube

C57.0 Malignant neoplasm of fallopian tube

Peritoneal

C48.1/48.2 Malignant neoplasm of specified parts of

peritoneum/peritoneum, unspecified

Primary site undesignated

– Unable to delineate if primary site ovary or

fallopian tube or peritoneum

N/A N/A

Borderline tumours included as malignancy No Yes No Yes

Abbreviations: OC, ovarian cancer; N/A, not applicable; PLCO, Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial; UKCTOCS,

United Kingdom Collaborative Trial of Ovarian Cancer Screening.

Note: in the UKCTOCS study, ascertainment of outcome was performed on any women with one of 19 ICD-10 codes, who were reviewed for

re-classification into primary cancers of the ovary (C59), fallopian tube (C57.0), peritoneum (C48.1, C48.2), or undesignated (unclear whether

primary site is ovarian, tubal or peritoneal). In the PLCO study, ascertainment of outcome was performed on any women with any cancer

diagnosis. After censorship for the primary analysis (Feb 28th, 2010), no endpoint verification was performed, and the trial ascertained deaths

primarily through the National Death Index.

Notifications and ascertainment of outcomes

Key differences between the trials in the methods used to identify incident cancers and deaths

include the following:

Main sources for identification of ovarian cancer or death

PLCO – questionnaires mailed to participants (annual study update),11 supplemented with

searches of the National Death Index or, where possible, population-based cancer registries.

UKCTOCS – dataset linkage via NHS numbers allowed searches of cancer/death registries and

notifications by trial regional centres and treating hospitals. Supplemented with two mailed

questionnaires (3-5 years after randomisation and in April 2014).

Trigger for review of medical records for outcome verification

PLCO – ovarian cancer diagnosis or death indicated in returned questionnaire (annual study

update), or discovered in search of cancer or death registries.

UKCTOCS – discovery of any of 19 ICD-10 codes (Appendix E; Section E.1) in the linked cancer

or death registry records or medical records.

Definitions of select outcomes

A selection of definitions used in the two trials are shown in Appendix E (Section E.1). The key

differences between the two trials are:

10 C56.1, C56.2 and C56.9 are the three codes for malignant neoplasm of ovaries. While the PLCO study publication refers only to C56.9, the

mode of outcome ascertainment indicates all ovarian cancers would have been included. 11 Although one could expect substantially complete endpoint identification using the NDI, the PLCO trial uses an active approach as the

primary follow-up process to obtain more timely information and to promote contact with participants so as to enhance acquiring consent

and clinical follow-up information should a participant develop cancer or die.


Definition of prevalent cancers

PLCO – the terms ‘prevalent cancers’ or ‘prevalent screen’ are not used, but the number

diagnosed after the first round of screening were reported.

UKCTOCS – the term ‘prevalent cases’ is used, but does not refer to women diagnosed after

the first round of screening, but to women in the ROCA triage group estimated to have had

cancer prior to randomisation (backwards extrapolation of the ROCA).

Definition of false positives

PLCO – borderline ovarian cancers are false positives.

UKCTOCS – borderline ovarian cancers are malignancies (post hoc calculations also present

some results here for UKCTOCS with borderline ovarian cancer excluded i.e. false positive).

PLCO – any woman who proceeded to clinical assessment after a screen positive test but was

not diagnosed with ovarian cancer was regarded as a false positive, regardless of whether

surgery was undertaken (i.e. includes conservative management). However, false positives

who underwent surgery as part of the diagnostic workup were reported.

UKCTOCS – only women who underwent surgical intervention after a screen positive test but

were not diagnosed with ovarian cancer were regarded a false positive.

Table 0.3 Terminology and definitions of select outcomes – PLCO and UKCTOCS

Study ID Terminology

PLCO Cancers

True positives – diagnosed as a result of investigations initiated after a screening test with a positive result and without a

lapse in the diagnostic evaluation exceeding 9 months.

Prevalent cases – terminology not used, but category reported (detected as baseline screen).

Incident cases – terminology not used, but category reported (detected by screening at 1-5 years).

Interval cancers – cancers not detected by screening and diagnosed within 12 months of the woman’s last expected

screening examination.

Other Diagnoses

False positives – positive screening examination result that did not result in cancers detected by screening.

UKCTOCS Cancers

True positive – terminology not used.

Prevalent cases – cancers detected at first round of screening were not reported. Prevalent cases, defined as women

with ovarian cancer before screening started, were identified in the ROCA triage group for inclusion in a pre-specified

analysis by estimating whether the CA125 change point would have occurred prior to randomisation.

Incident cases – terminology not used, but screen positives was used to describe all screen-detected cancers, which

would include incident and prevalent cases.

Interval cancers (false negatives) – terminology not used, but category reported (detected in screen negatives < 1 year

from last test of screening episode).

Other diagnoses

False positive – benign adnexal pathology or normal adnexa in women who had screen-positive surgery.

Abbreviations: CA, cancer antigen; PLCO, Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial; ROCA, Risk of Ovarian Cancer

Algorithm; UKCTOCS, United Kingdom Collaborative Trial of Ovarian Cancer Screening.

Key statistical methods

The statistical analysis methods used for the primary outcome are shown in Table 0.4. The key

difference is the statistical test pre-specified in the statistical analysis plan for the for the primary

analysis:

PLCO – weighted log-rank test

UKCTOCS – Cox proportional hazard model.


The implications of these choices are discussed in Section 4.1.2.1 (data extraction) and Section

5.1.1 (synthesis of findings).

Table 0.4 Key statistical analysis methods for mortality outcomes – population screening

Analysis PLCO UKCTOCS

Participants included in

primary analysis

Intention to screen population, excluding women

with a pretrial history of bilateral oophorectomy

(eligible for enrolment only after a change in

protocol in 1996).

Modified intention to screen – all randomly

allocated women except for those who we later

came to know had a bilateral oophorectomy,

ovarian cancer, or exited the registry before

recruitment.

Primary outcome –

OC-specific mortality

Included cancers:

ovarian

fallopian tube

primary peritoneal

Primary analysis

weighted log-rank test

The test statistic was a weighted log-rank statistic

with weights linear in cumulative mortality. Choice

of this combination of boundary and weights was

based on power computation conducted using

simulation methods. For early termination with a

negligible effect, a stochastic curtailment

procedure was implemented. This procedure

makes allowance for non-proportional hazards,

frequently encountered in a screening trial.

Included cancers – primary analysis:

ovarian

fallopian tube

Included cancers – secondary analysis:

ovarian

fallopian tube

primary peritoneal

Primary analysis

Cox proportional hazards model

Prespecified secondary analysis

Royston-Parmar (RP) model

The RP method can model proportional and non-

proportional hazards due to delayed effects.

Post hoc analysis

weighted log-rank test

The pre-specified analytic approach did not take

into account the inherent delay from

randomisation to diagnosis and then death. Other

screening trials (such as the PLCO Trial) addressed

this delay by using a weighted log-rank test for the

primary outcome analysis. In view of this

precedent, it was decided to perform a single post

hoc analysis of the primary outcome, applying the

weighted log-rank test with the same choice of

weights proportional to pooled ovarian cancer

mortality as that used in the primary PLCO trial

analysis.

Subgroup analysis of primary

outcome –

OC-specific mortality,

excluding prevalent cases

NR Included cancers:

ovarian

fallopian tube

Excludes prevalent cases – CA125 change point

estimated to have occurred prior to

randomisation, indicating the cancer was present

before screening began.

Prespecified subgroup analysis

Royston-Parmar (RP) model

Abbreviations: CA, cancer antigen; OC, ovarian cancer; PLCO, Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial; UKCTOCS,


Ongoing studies of population screening


up of UKCTOCS. As described in the NHS 2016 report (Detailed Project Description for the long-term

follow up of UKCTOCS), the primary outcome will remain unchanged from the original RCT, but the

classification of peritoneal cancers will be updated to reflect the new criteria in the WHO 2014

definition. This process will involve re-examination of all cancers diagnosed as PPC, and it is

expected that cases evaluated using the WHO 2003 criteria are likely to be re-classified as primarily

ovarian or tubal cancers. Stage as per International Federation of Gynecology and Obstetrics

(FIGO) 2014 will also be re-assessed.


After reclassification of these peritoneal cancers, the primary outcomes of UKCTOCS and PLCO will

be more closely aligned, as the PLCO trial analysed all three primary cancer types together

(ovarian, tubal and peritoneal). The next censorship for UKCTOCS is planned for December 2018,

and final censorship for December 2024. A major secondary outcome for the long-term follow-up is

cost-effectiveness of screening.

4.1.1.2 Key systematic reviews and HTAs

Three systematic reviews examined screening of asymptomatic women for ovarian cancer (Buhling

2017; Henderson 2017; Reade 2013). An additional two systematic reviews examined routine pelvic

examination screening for gynaecologic cancers (including ovarian cancer) and other

gynaecologic conditions (Guirguis-Blake 2017; Bloomfield 2014). The list of citations for the published

systematic reviews is shown in Appendix D (Section D.1.2).

Characteristics of systematic reviews and included studies

The key characteristics and quality of the identified systematic reviews is summarised in Table 0.5.

The systematic review by Henderson et al (2017) was prepared for the US Preventative Services Task

Force of the Agency for Healthcare Research and Quality (AHRQ) and provides a comprehensive

assessment of screening for ovarian cancer in asymptomatic women, published up to January

2017. This good quality systematic review includes the PLCO and UKCTOCS RCTs, as well as two

smaller RCTs published in 1999 and 2007. The authors comment that the rarity of ovarian cancer

necessitated a focus on mortality from ovarian cancer rather than on overall mortality from all-

causes because the effects of screening on overall mortality would be minor given that ovarian

cancers represent a very small proportion of deaths overall. Because ovarian cancer is rare, large

trials are necessary to evaluate effects of screening on ovarian cancer morbidity and mortality in

average-risk women.


Table 0.5 Key characteristics of systematic reviews relating to population screening for ovarian cancer

Study ID

Qualitya

Study aim Literature

search

Study eligibility Included studies (no. of

patients)

Intervention &

comparator

Outcomes of interest

Screening for ovarian cancer

Henderson

2017

Good

quality

To update the previous

systematic review and inform the

USPSTF OC screening guidance.

The review addresses two

questions: 1). Does screening for

OC in asymptomatic women

using a single test or combined

algorithm (such as, but not limited

to, testing for serum CA125 and

ultrasonography) reduce all-

cause or disease-specific

morbidity and mortality? 2). What

are the harms of screening for

OC, including harms of the

screening test and of diagnostic

evaluation?

Narrative synthesis of results, with

grading of the overall body of

evidence for each question using

an adaptation of a system based

on GRADE. Prepared for AHRQ.

Medline,

PubMed

Publisher-

Supplied

Records,

Cochrane

Collaboration

Registry of

Controlled

Trials;

reference lists

Search Jan

2003 to Jan

2017

Inclusion

RCTs

asymptomatic women aged 45+ with

average (or unknown) risk of OC

reported health outcomes

primary care setting (including obstetrics

and gynaecology practices)

English language articles

Exclusion

screening explicitly in high-risk populations

reported screening accuracy and cancer

detection rates without reporting

morbidity, mortality or quality of life

screening tests not evaluated in clinical

trials

specialty practice settings, such as

oncology

4 RCTs, published in 17 articles

(N=293,587)b:

UKCTOCS, Jacobs 2016

(N=202,546; UK; good quality)

PLCO, Buys 2011 (N=68,557;

US; good quality)

QUEST, Andersen 2007

(N=549; US; fair quality)

UK Pilot, Jacobs 1999

(N=21,935; UK; good quality)

Intervention

Any screening for OC

(alone or as part of a

clinical examination).

Includes (but not

limited to): testing for

CA125, TVUS, and

combined screening

approaches or

algorithms

Comparator

Usual care or no

screening

Different screening

methods or programs

Question 1


all-cause mortality

cancer-related morbidity

quality of life

Question 2

surgery rate

FP screening results

complications of diagnostic

surgical procedures

health and psychological

effects of screening tests

Buhling

2017

Fair quality

To systematically analyse the

effect of TVUS in an

asymptomatic female population

as an annual screening

procedure with regard to

mortality data.

Studies evaluated descriptively

on their strengths and

weaknesses considering methods

and results.

PubMed,

Medline,

Embase

Search to

Dec 2015

Inclusion

RCTs with ethical approval

≥1 population-based intervention

screening group with annual TVS, ≥1 group

of post-menopausal women aged 45+

follow-up ≥3 years

no current symptoms associated with OC

no personal history of OC


Exclusion

inaccurate description of methodology &

results

history of bilateral oophorectomy

OC diagnosed before registration

Jadad score <3/5

3 RCTs (N=363,341)b:

PLCO, Buys 2011 (N=68,557;

USA, 1993-2001)

UKCTOCS, Jacobs 2016

(N=202,546; UK, 2001-2014)

SCSOCS, Kobayashi 2008

(N=82,487; Japan, 1985-2002)

Intervention

Annual TVUS ± CA125

Comparator

Usual care

Overview of outcomes

reported in included studies;

for example:

compliance

repeat testing

need for clinical evaluation

cancers detected

diagnostic performance

(sensitivity, specificity, PPV,

FP rate, surgeries to detect

one cancer)

deaths due to OC or other

causes

relative mortality reduction

stage at diagnosis


Study ID

Qualitya


search


patients)

Intervention &

comparator


Reade

2013

Good

quality

To determine the risks and

benefits of OC screening in

asymptomatic women, with a

focus on mortality and

unnecessary surgery and its

consequences.

Evaluated confidence in effect

estimates using GRADE system for

each outcome. Meta-analysis of

some outcomes.

Medline,

Cinahl,

Embase,

CENTRAL;

reference

lists;

contacted

expert for

ongoing or

unpublished

trials

Search to

Feb 2012

Inclusion

RCTs

asymptomatic women at high or low risk of

OC

any language articles

10 RCTs:

Parkes 1994 (N=7124 c; UK)

Tabor 1994 (N=950 c;

Denmark)

Jacobs 1999 (N=21,935 c; UK)

Taylor 2004 (N=432 c; USA)

ROCA trial, Menon

2005(N=13,472 c; UK)

Johnson 2006 (N=522 c; USA)

QUEST trial, Andersen 2007

(N=592 c; UK)

SCSOCS trial, Kobayashi 2008

(N=82,487 c; Japan)

UKCTOCS trial, Menon 2009

(N=202,638 c; UK)

PLCO trial, Buys 2011

(N=78,216 c; USA)

Intervention

Any form of screening

for OC

Comparator

No intervention, usual

care, or education

regarding signs &

symptoms of OC

all-cause mortality


surgeries performed to

detect one case of OC

FP screening tests

complications associated

with unnecessary surgery

OC diagnosed at an

advanced stage

worry or anxiety related to

OC risk

quality of life

Screening for gynaecologic cancers (including ovarian cancer)

Guirguis-

Blake 2017

Good

quality

To support the USPSTF in creating

its recommendation on the

periodic screening pelvic

examination.

The review addresses three

questions: 1) What is the direct

evidence for the effectiveness of

the pelvic examination in

reducing all-cause mortality,

cancer- and disease- specific

morbidity and mortality, and

improving quality of life? 2) What

are the test performance

characteristics of the pelvic

examination in screening for

gynecologic cancers and other

gynecologic conditions? 3) What

are the adverse effects of

screening using the pelvic

examination?

Qualitative synthesis prepared for

AHRQ.

Medline,

PubMed,

Cochrane

Central

Register of

Controlled

Trials;

reference

lists; grey

literature;

suggestions

from experts;

clinical trials

databases

Search to

Jan 2016

Inclusion

age ≥18 years, general unselected

females, asymptomatic, not pregnant,

women with or without hysterectomy, post-

menopausal women

primary care outpatient setting (or similar

applicable to primary care)

gynaecologic cancers and other

gynaecologic conditions

reported outcomes of interest

reported screening accuracy of the pelvic

examination in a single encounter or as a

periodic program of screening


developed countries

Exclusion

studies conducted solely in symptomatic

populations

studies rated as poor quality

cervical cancer, gonorrhea, chlamydia

For OC

4 studies in total (N=26,432):

1 RCT (good quality)

PLCO

3 prospective diagnostic

accuracy studies (fair quality):

Adonokis 1996

Grover 1995

Jacobs 1988

Intervention

Pelvic examination

(external inspection,

internal speculum

examination, bimanual

examination,

rectovaginal

examination) ± other

tests for screening

Comparator

No pelvic examination;

reference standard

all-cause mortality

cancer-specific mortality or

morbidity for included

cancers

disease-specific morbidity

for included conditions

quality of life

diagnostic accuracy

(sensitivity, specificity,

likelihood ratios, PPV, NPV)

unnecessary diagnostic

workup or treatment

physical pain/discomfort

psychological harms


Study ID

Qualitya


search


patients)

Intervention &

comparator


Bloomfield

2014

Fair quality

To evaluate the benefits and

harms of routine screening pelvic

examination in asymptomatic,

nonpregnant adult women for

indications other than sexually

transmitted infection screening

before provision of hormonal

contraception and cervical

cancer screening.

Findings summarised in narrative

and tabular form.

Medline;

Cochrane

databases;

reference

lists;

suggestions

from expert

panel and

peer

reviewers

Search to

Jan 2014

Inclusion

asymptomatic, nonpregnant, average-risk

women

outpatient settings

reported outcomes of interest

screening for noncervical cancer, PID, or

other gynecologic conditions

English language, full text articles

Exclusion

cervical cancer screening

For OC

3 diagnostic accuracy cohort

studies (N=5633 patients; high

quality):

Grover 1995

Jacobs 1988

Adonakis 1996

Intervention

Pelvic examination

Comparator


reference standard

diagnostic accuracy

(sensitivity, specificity, PPV,

NPV)

mortality or morbidity from

pathologic conditions

direct procedure-related

harms (physical

pain/discomfort)

indirect harms (false

reassurance, over-

diagnosis, over-treatment)

ancillary benefits

Abbreviations: AHRQ, Agency for Healthcare Research and Quality; CA, cancer antigen; FP, false positive; GRADE, Grading of Recommendations, Assessment, Development and Evaluation; NPV, negative

predictive value; OC, ovarian cancer; PID, pelvic inflammatory disease; PLCO, Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial; PPV, positive predictive value; QUEST, Quality of life, Education, and

Screening Trial; RCT, randomised controlled trial; SCSOCS, Shizuoka Cohort Study of Ovarian Cancer Screening; TVUS, transvaginal ultrasonography; UK, United Kingdom; UKCTOCS, UK Collaborative Trial of Ovarian

Cancer Screening; USA, United States of America; USPSTF, US Preventive Services Task Force.

a Quality was assessed using AMSTAR (see Appendix F).

b N refers to total number of patients included in the analysis.

c N refers to total number of patients randomised.


4.1.2 Data extraction – clinical studies

4.1.2.1 Mortality outcomes

Primary outcome – death due to ovarian cancer

Table 0.6 shows all deaths due to ovarian cancer (OC-specific death), regardless of mode of

cancer detection, in each group of the PLCO and UKCTOCS trials. The PLCO trial does not include

borderline tumours as ovarian cancer while UKCTOCS does. However, given the low malignant

potential of these tumours, mortality outcomes are not expected to differ with their inclusion or

exclusion. The PLCO trial included PPCs in all analyses, while UKCTOCS present data with

(secondary analysis) and without (primary analysis) peritoneal cancers, both of which are shown in

Table 0.6.

In women diagnosed with ovarian cancer throughout these trials, mortality was similar in the

screening and no-screening groups in both trials, with no statistical significance to the differences in

ovarian cancer death rates using the tests pre-specified for the primary analyses.

Table 0.6 Death due to ovarian cancer – primary outcome in PLCO and UKCTOCS

OC-specific

mortality

PLCO – primary analysis12

OC (invasive), FTC, PPC

Weighted log-rank test (0-13 y)

UKCTOCS – secondary analysis

OC (all), FTC, PPC

Cox proportional hazard (0-14 y)

UKCTOCS – primary analysis

OC (all), FTC

Cox proportional hazard (0-14 y)

CA125

+TVUS

No

screening

ROCA

triage

TVUS No

screening

ROCA

triage

TVUS No

screening

Participants, n 34,253 34,304 50,624 50,623 101,299 50,624 50,623 101,299

Person-years 381,574 382,502 548,533 548,825 1,097,089 548,533 548,825 1,097,089

Deaths, n 118 100 160 163 358 148 154 347

OC death rate

(per 10,000

person-years)13

3.1 2.6 2.9 3.0 3.3 2.7 2.8 3.2

Risk estimate

[95% CI]

RR 1.18

[0.82, 1.71]

– HR 0.89

[0.74, 1.08]

HR 0.91

[0.76, 1.09]

– HR 0.85

[0.70, 1.03]

HR 0.89

[0.73, 1.07]

–

% mortality

reduction [95%

CI], p value

NR – 11% [–8, 26]

p=0.23

9% [–9, 24]

p=0.31

– 15% [–3, 30]

p=0.10

11% [–7, 27]

p=0.21

–

Abbreviations: CA, cancer antigen; CI, confidence interval; FTC, fallopian tube cancer; HR, hazard ratio; NR, not reported; OC, ovarian

cancer; PLCO, Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial; PPC, primary peritoneal cancer; ROCA, Risk of Ovarian Cancer

Algorithm; RR, risk ratio; TVUS, transvaginal ultrasonography; UKCTOCS, United Kingdom Collaborative Trial of Ovarian Cancer Screening.

In ovarian cancer screening trials, there is an inherent delay between detection and death – as

only women without symptoms or a diagnosis of ovarian cancer can enter the study, the first

deaths will be observed after subsequent diagnosis and disease progression. Figure 0.1 shows

cumulative mortality results from the UKCTOCS trial, showing the no-screening group hazard rate

continuing to rise throughout the study period, the ROCA triage group hazard rate levelling off,

becoming substantially lower than that of the no-screening group at about 7 years, and the TVUS

hazard rate levelling off at about 9 years. The study authors note this appears to indicate a delayed

effect of screening.

12 Longer-term follow up to December 2012 extended the median by 2.3 years to 14.7 years (Pinsky 2016). This additional data was collected in

a subset of patients who re-consented to further follow up after Feb 2010. The number of patients in this group is not reported but the

mortality analysis (Pinsky 2016, Figure 1) shows the number at risk in the intervention arm fell from 12,805 to 2,631 in the last two years of follow

up (similar numbers reported for the control arm). The risk of ovarian cancer death at longer-term follow up was no different between arms,

either including PPC (RR 1.06 [95% CI 0.87, 1.30]) or excluding PPC (RR 1.08 [0.87, 1.33]). 13 Calculated post hoc for UKCTOCS


Figure 0.1 Kaplan-Meier cumulative OC-specific mortality with and without PPC – UKCTOCS

Ovarian (all), FTC, PPC Ovarian (all), FTC

Source: Jacobs 2016 Figure 2A and B.

Abbreviations: CI, confidence interval; FTC, fallopian tube cancer; HR, hazard ratio; MMS, multimodal screening; OC, ovarian cancer; PPC,

primary peritoneal cancer; UKCTOCS, United Kingdom Collaborative Trial of Ovarian Cancer Screening; USS, ultrasound screening.

The Cox proportional hazard model used for the primary analysis in the UKCTOCS trial assumes a

constant hazard event rate over time, and was considered by the study authors, in retrospect, to

be a poor choice of test for the primary analysis of mortality in a screening trial. Therefore, the

decision was made by the UKCTOCS investigators to conduct a post hoc analysis using the same

method as the PLCO study (weighted log-rank test).

An additional analysis of the primary outcome using the Royston-Parmer flexible parametric model

was pre-specified in the UKCTOCS protocol, and it also accounts for delayed effects. However, the

relative merits of each approach are beyond the understanding of the current Review authors.

These additional prespecified and post hoc analyses are shown in Table 0.7.

Again, these analyses are shown both with and without PPCs. When PPCs are included, neither the

Royston-Parmer model or weighted log rank test found a statistically significant difference between

no screening and either of the screening groups in UKCTOCS. When women with PPCs were

excluded from the analysis, statistically significance was achieved, showing screening improved

mortality rates for the following:

Royston-Parmer model for the period 7-14 years from randomisation – ROCA triage better

than no screening, in the detection of invasive ovarian cancer, borderline ovarian cancer

and FTC (23% reduction in mortality [95% CI: 1%, 46%]).

Weighted log-rank test (0-14 years from randomisation) – ROCA triage better than no

screening in the detection of ovarian cancer, borderline ovarian cancer and FTC (22%

reduction in mortality [95% CI: 3%, 38%], p=0.023).

Weighted log-rank test (0-14 years from randomisation) – annual TVUS better than no

screening in the detection of ovarian cancer, borderline ovarian cancer and FTC (20%

reduction in mortality [95% CI: 0%, 35%], p=0.049).


Table 0.7 Death due to ovarian cancer – primary outcome analyses accounting for

delayed effects of screening in UKCTOCS

OC-specific mortality UKCTOCS – secondary analysis

OC (all), FTC, PPC

UKCTOCS – primary analysis

OC (all), FTC

ROCA

triage

TVUS No

screening

ROCA

triage

TVUS No

screening

Participants, n 50,624 50,623 101,299 50,624 50,623 101,299

Deaths, n 160 163 358 148 154 347

Royston-Parmer model (pre-specified

analysis)

% reduction in mortality [95% CI]

p-value: 0-14 years

11% [–7, 28]

p=0.15

10% [–8, 27]

p=0.27

– 16% [–1, 33]

p=0.11

12% [–6, 29]

p=0.18

–

Split by time since randomisation

0-7 years 4% [–25, 27] 2% [–26, 26] – 8% [–20, 31] 2% [–27, 26] –

7-14 years 18% [–5, 40] 17% [–8, 38] – 23% [1, 46] 21% [–2, 42] –

Weighted log-rank test (post hoc

analysis)

% reduction in mortality [95% CI]

p-value: 0-14 years

18% [–1, 34]

p=0.064

17% [–3, 33]

p=0.097

– 22% [3, 38]

p= 0.023

20% [0, 35]

p=0.049

–

Abbreviations: CI, confidence interval; FTC, fallopian tube cancer; OC, ovarian cancer; PPC, primary peritoneal cancer; ROCA, Risk of

Ovarian Cancer Algorithm; TVUS, transvaginal ultrasonography; UKCTOCS, United Kingdom Collaborative Trial of Ovarian Cancer Screening.

These various analyses of mortality in the UKCTOCS trial are also illustrated in the form of forest plots

(Figure 0.2). A survival curve from the PLCO trial is shown in Appendix E (Section E.1).

Figure 0.2 Forest plot display of various mortality analyses for ROCA triage – UKCTOCS

ROCA triage TVUS

Source: NHS 2016, Figure 2, p8

Abbreviations: MMS, multimodal screening; NHS, National Health Service; ROCA, Risk of Ovarian Cancer Algorithm; TVUS, transvaginal

ultrasonography; UKCTOCS, United Kingdom Collaborative Trial of Ovarian Cancer Screening; USS, ultrasound screening.

Subgroup analysis of primary outcome – exclusion of prevalent cases in UKCTOCS

The UKCTOCS study prespecified a subgroup analysis of the primary outcome excluding cases of

ovarian cancer deemed to have developed prior to randomisation (i.e. prevalent cases). The

UKCTOCS study publication did not define prevalent cases as those identified in the first round of

screening. Instead, the serial levels of CA125 were analysed in the ROCA triage group in order to

estimate the time at which they are likely to have started to rise, and women deemed to have had

rising CA125 levels prior to randomisation were designated as prevalent cases. By excluding these

cases from the ROCA triage group, the study investigators were intending to assess mortality for

incident cases only, which may be more representative of ongoing screening.

Baseline CA125 levels were also available in 517 of the 63014 women with ovarian cancer, and

along with CA125 levels at diagnosis, women in the no-screening group appearing to have had

14 Ovarian cancer, including borderline, or FTC (i.e. excludes PPC)


rising CA125 levels prior to randomisation were designated as prevalent cases. No analysis of this

type was performed for the TVUS group. This process excluded an average of 19% of the 338 cases

of cancer in the ROCA triage group and an average of 18% of the 630 cases in the no-screening

group (for all cancers, excluding PPCs).

The Royston-Parmer model was used to derive hazard ratios for cumulative mortality up to 14 years

after randomisation (Table 0.8). Significant improvements in mortality were observed in the ROCA

triage group compared with no screening, both with peritoneal cancers (16%) and without

peritoneal cancers (20%).

Table 0.8 OC-specific mortality excluding prevalent cases, for ROCA triage versus no

screening – UKCTOCS

OC-specific mortality excluding

prevalent cases

UKCTOCS – 2 analysis

OC (all), FTC, PPC

UKCTOCS – 1 analysis

OC (all), FTC

ROCA triage No screening ROCA triage No screening

Participants, n 50,561 101,191 50,561 101,183

Deaths, n 131 298 120 281

% mortality reduction [95% CI]

Royston-Parmer model

0-14 years 16% [–6, 35]

p=0.047

– 20% [–2, 40]

p=0.021

Abbreviations: CI, confidence interval; FTC, fallopian tube cancer; OC, ovarian cancer; PPC, primary peritoneal cancer; ROCA, Risk of

Ovarian Cancer Algorithm; UKCTOCS, United Kingdom Collaborative Trial of Ovarian Cancer Screening.

Note: BOLD indicates statistically significant result.

All-other-cause mortality

In both the PLCO and UKCTOCS trials, all-cause mortality, excluding that due to ovarian cancer,

was no different between the no-screening and screening groups (Table 0.9).

Table 0.9 All-other-cause mortality – PLCO and UKCTOCS

Mortality over period of study PLCO UKCTOCS

CA125 +TVUS No screening ROCA triage TVUS No screening

Participants, n 34,253 34,304 50,624 50,623 101,299

All-other-cause mortality15

Deaths, n 2,924 2,914 3,376 3,262 6,658

Person-years 381,574 382,502 548,533 548,825 1,097,089

Mortality per 10,000 person-years16 76.6 76.2 61.5 59.4 60.7

Risk estimate [95% CI] RR 1.01

[0.96, 1.06]

– RR 0.9917

[CI NR] p = 0.65

–

Abbreviations: CA, cancer antigen; CI, confidence interval; NR, not reported; PLCO, Prostate, Lung, Colorectal and Ovarian Cancer

Screening Trial; ROCA, Risk of Ovarian Cancer Algorithm; RR, risk ratio; TVUS, transvaginal ultrasonography; UKCTOCS, United Kingdom

Collaborative Trial of Ovarian Cancer Screening.

4.1.2.2 Detection outcomes

Mode of detection

Table 0.10 shows the detection outcomes for the screening arms in the PLCO and UKCTOCS trials.

To allow a meaningful comparison with PLCO, the UKCTOCS data are presented with peritoneal

cancers included but borderline tumours excluded. The results for UKCTOCS including all

malignancies as defined by that study (i.e. including borderline tumours and PPCs) are also shown.

15 Excludes ovarian cancer, FTC and PPC. In PLCO also excludes colorectal and lung cancers. 16 Calculated post hoc for UKCTOCS. 17 RR for combined CA125 (±TVUS) and TVUS groups versus no screening.


Cancers for all women randomised to screening who attended at least one screening round are

shown by the phase of study in which diagnosis occurred: during the screening phase, or after the

screening phase. A larger proportion of these diagnoses were made during the screening phase in

UKCTOCS (83-87%), compared with PLCO (59%).

For cancers diagnosed during the screening phase, the proportion that were screen-detected (i.e.

not interval cancers) was around three quarters in the UKCTOC ROCA triage group, around two

thirds in the PLCO screening group, and around half in the UKCTOCS TVUS group. The UKCTOCS

study further classifies interval cancers into those detected within a year of a negative test and

those detected at a delayed routine trial screen (i.e. over a year between prior negative test and

abnormal test leading to diagnosis). Approximately half of the interval cancers in both UKCTOCS

screening groups were detected at a delayed trial screen.

Table 0.10 Mode of cancer detection in screening groups – PLCO and UKCTOCS

Detection outcomes

n (%)

PLCO


UKCTOCS


UKCTOCS

OC (all), FTC, PPC

CA125 +TVUS ROCA triage TVUS ROCA triage TVUS

Total cancers diagnosed, N (%) 212 310 271 354 324

Never attended screening 24 3 11 3 13

All diagnoses in women who attended

at least one screening round 188 (100) 307 (100) 260 (100) 351 (100) 311 (100)

Diagnosed during screening phase18 110 (59) 255 (83) 226 (87) 294 (84) 277 (89)

Diagnosed after screening phase 78 (41) 52 (17) 34 (13) 57 (16) 34 (11)

During screening phase 110 (100) 255 (100) 226 (100) 294 (100) 277 (100)

Screen-detected 73 (66) 188 (74) 116 (51) 212 (72) 164 (59)

Prevalent screen 20 NR NR NR NR

Subsequent screens 53 NR NR NR NR

Not screen detected – interval

cancers 37 (34) 67 (26) 110 (49) 82 (28) 113 (41)

Detected < 1 year since previous

trial screen NR 31 61 41 63

Detected >1 year since previous

trial screen i.e. delayed trial screen NR 36 49 41 50

Note: N and % calculated post hoc for many data in this table, using data reported in study publications.

Abbreviations: CA, cancer antigen; OC, ovarian cancer; PLCO, Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial; ROCA, Risk of


Incidence data are shown in Table 0.11, for the screening and no-screening groups of both trials.

Rates were similar between screening and no-screening groups.

18 Events up to one year after the last trial screen are included in the screening phase for UKCTOCS, and up to 9 months in the PLCO trial.


Table 0.11 Ovarian cancer incidence – PLCO and UKCTOCS

Detection outcomes

n (%)

PLCO


UKCTOCS


UKCTOCS

OC (all), FTC, PPC

CA125

+TVUS

No

screening

ROCA

triage

TVUS No

screening

ROCA

triage

TVUS No

screening

Total cancers detected,

N 212 176 310 271 583 354 324 645

Person-years 371,833 374,976 548 533 548,825 1,097,089 548 533 548,825 1,097,089

Incidence

Overall incidence per

10,000 person-years

[95% CI]

5.7

[NR]

4.7

[NR]

5.5

[4.8, 5.7]

4.7

[4.1, 5.3]

5.2

[4.8, 6.1]

6.2

[5.5, 6.8]

5.7

[5.1, 6.4]

5.7

[5.3, 6.2]

Risk estimate for

between-group

difference [95% CI]

RR 1.21

[0.99, 1.48] no statistical difference between groups no statistical difference between groups

Abbreviations: CA, cancer antigen; CI, confidence interval; NR, not reported; OC, ovarian cancer; PLCO, Prostate, Lung, Colorectal and

Ovarian Cancer Screening Trial; ROCA, Risk of Ovarian Cancer Algorithm; RR, risk ratio; TVUS, transvaginal ultrasonography; UKCTOCS, United

Kingdom Collaborative Trial of Ovarian Cancer Screening.

Sensitivity

Sensitivity estimates are shown for each of the screening groups in Table 0.12. Post hoc calculations

were performed to allow comparison between trials for invasive cancers. As expected, sensitivity is

reduced by the omission of borderline tumours in the UKCTOCS trial. The most sensitive test was the

UKCTOCS ROCA triage group.

Table 0.12 Sensitivity of screening strategies – PLCO and UKCTOCS

Outcome PLCO

OC (invasive),

FTC, PPC

UKCTOCS

OC (invasive), FTC, PPC OC (all), FTC PPC

CA125 +TVUS ROCA triage TVUS ROCA triage TVUS ROCA triage TVUS

Screen +ve

cancers, n 73 188 116 199 161 13 3

Interval cancers, n 37 67 110 38 60 3 3

Sensitivity % [95%

CI], n/N

66%

[NR]

73/

(73+37)

74%

[NR]

188/

(188+67)

51%

[NR]

116/

(166+110)

84%

[79, 88]

199/

(199+38)

73%

[66, 79]

161/

(161+60)

81%

[NR]

13/

(13+3)

50%

[NR]19

3/

(3+3)

Abbreviations: CA, cancer antigen; CI, confidence interval; FTC, fallopian tube cancer; NR, not reported; OC, ovarian cancer; PLCO,

Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial; PPC, primary peritoneal cancer; ROCA, Risk of Ovarian Cancer Algorithm; RR,

risk ratio; TVUS, transvaginal ultrasonography; UKCTOCS, United Kingdom Collaborative Trial of Ovarian Cancer Screening.

Note: sensitivity rates shown without confidence intervals were calculated post hoc using data in table.

False positives

Definitions for screen positive and false positive differed between the two trials. In both trials,

women who had a screen-positive test followed by surgery and a finding of no cancer were

deemed false positives, but in the PLCO trial, those women who underwent clinical assessment

after a screen-positive test and did not have surgery (i.e. conservative management, deemed not

to require further investigation) were also considered false positives. In the PLCO trial, 3,285 women

had false-positive testing results, of which 1,080 had received surgery.

Table 0.13 shows the number of screen-positive surgeries with benign or normal pathology (false-

positive surgeries) and the number of screen-positive surgeries with ovarian cancer, FTC or PPC

(screen-positive cancers). For PLCO, borderline tumours were counted as false-positive surgeries

19 The primary study publication (Jacobs 2016) reports this result as 3/10 peritoneal cancers were screen detected. However, this denominator

of 10 includes 4 cancers detected over a year after the last screening episode – such cancers were not included in the calculations of

sensitivity for any other groups.


and for UKCTOCS they were screen-detected cancers. To allow a meaningful comparison of false-

positive rates between trials, post hoc calculations were performed re-classifying borderline

tumours in UKCTOCS as false positives, reducing the number of screen detected cancers by 34 in

the ROCA triage group and 50 in the TVUS group.

When all borderline tumours are classified as false positives, the false-positive surgery rate was the

same in PLCO and the TVUS screening group of UKCTOCS (both 14.8 false-positive surgeries per

screen-detected cancer, corresponding to a low positive predictive value ([PPV] of 6.3%20). The

lowest rate was substantially lower; at 2.9 per screen-detected cancer, the ROCA triage arm of

UKCTOCS trial had a PPV of 25.4%21, exceeding the standard goal of 10% PPV (no more than nine

false positive surgeries per case of screen-detected cancer (NASEM 2016)).

Table 0.13 False-positive surgery rates – PLCO and UKCTOCS

Outcome PLCO


UKCTOCS

OC (all), FTC, PPC

UKCTOCS – reclassify borderline as

false positive as per PLCO22


CA125 +TVUS ROCA triage TVUS ROCA triage TVUS

Screen-positive surgeries, n 1,153 700 1,798 700 1,798

False positive surgeries23 1,080 488 1,634 522 1,684

Screen-detected cancers 73 212 164 178 114

Number of surgeries to detect

one case of cancer

15.8

(1,153/73)

3.3

(700/212)

11.0

(1,798/164)

3.9

(700/178)

15.8

(1,798/114)

Number of false positive

surgeries per screen-detected

cancer

14.8

(1,080/73)

2.3

(488/212)

10.0

(1,634/164)

2.9

(522/178)

14.8

(1,684/114)

Person-years of screening 371,833 345,572 327,775 345,572 327,775

Number of false positive

surgeries per 10,000 screens

2924 14 50 15 51

Abbreviations: CA, cancer antigen; FTC, fallopian tube cancer; OC, ovarian cancer; PLCO, Prostate, Lung, Colorectal and Ovarian Cancer

Screening Trial; PPC, primary peritoneal cancer; ROCA, Risk of Ovarian Cancer Algorithm; TVUS, transvaginal ultrasonography; UKCTOCS,


4.1.2.3 Tumour characteristics

Table 0.14 shows stage at diagnosis in both the PLCO and UKCTOCS trials. In each study group, the

majority of cancers were late stage (Stage III or Stage IV); 77-78% in the PLCO study and 55-69% in

UKCTOCS. When borderline epithelial ovarian cancers were excluded, the proportion of late-stage

tumours in UKCTOCS was reduced to 62-75% – closer to levels in the PLCO trial. Results for UKCTOCS

were calculated post hoc from stage-at-diagnosis data reported in the Jacobs 2016 online

supplement for the following four cancer groups: (1) invasive epithelial ovarian/ tubal/

undesignated cancer;25 (2) non-epithelial ovarian cancer; (3) borderline epithelial ovarian cancer;

and (4) peritoneal cancer (reproduced in Appendix E.1, Table AppE.3).

20 Calculated post hoc from data in Table 0.13. 21 Calculated post hoc from data in Table 0.13. 22 Borderline tumours excluded in post hoc calculations by current Review authors: ROCA triage n = 34; TVU n = 50. 23 Of 3,285 with false-positive results, 1,080 underwent surgery as part of the diagnostic workup. 24 Calculated post hoc. 25 Shown for Stages Ia-c, IIa-c and IIIa-c.


Table 0.14 Cancer stage at diagnosis, all modes of detection – PLCO and UKCTOCS

Tumours by

stage, n (%)

PLCO


UKCTOCS

OC (all), FTC, PPC

UKCTOCS

OC (invasive), FTC, PPC26

TVUS

No

screening

ROCA

triage TVUS

No

screening

ROCA

triage TVUS

No

screening

Total cancers

diagnosed 212 (100) 176 (100) 354 (100) 324 (100) 644 (100) 310 (100) 271 (100) 582 (100)

Stage at diagnosis

I 32 (15) 18 (10) 127 (36) 99 (31) 147 (23) 86 (28) 49 (18) 98 (17)

II 15 (7) 20 (11) 32 (9) 19 (6) 51 (8) 32 (10) 19 (7) 47 (8)

III 120 (57) 83 (47) 160 (45) 154 (48) 333 (52) 157 (51) 151 (56) 324 (56)

IV 43 (20) 54 (31)27 34 (10) 52 (16) 112 (17) 34 (11) 52 (19) 112 (19)

Unknown 2 (1) 1 (1) 1 (0) 0 (0) 2 (0) 1 (0) 0 (0) 1 (0)

Combined stages, known volume28

Early (I or II) 47 (22) 38 (22) 159 (45) 118 (36) 198 (31) 118 (38) 68 (25) 145 (25)

Late (III or IV) 163 (77) 137 (78) 194 (55) 206 (64) 445 (69) 191 (62) 203 (75) 436 (75)

Abbreviations: FTC, fallopian tube cancer; OC, ovarian cancer; PLCO, Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial; PPC,

primary peritoneal cancer; ROCA, Risk of Ovarian Cancer Algorithm; TVUS, transvaginal ultrasonography; UKCTOCS, United Kingdom

Collaborative Trial of Ovarian Cancer Screening.

Stage shift

The authors of the PLCO primary study publication concluded that screening did not result in a

stage shift for ovarian cancer diagnoses. They noted that the total number of advanced stage

cancers was greater in the screening group (n=163) than in the usual care group (n=137), and that

this was also the case when limiting the comparison to the screening phase of the trial. Considering

only screen-detected cancers in the screening group, 69% of cases were late stage compared to

the only ‘slightly higher’ 78% of the usual care group (no statistical analyses were reported).

The FIGO staging system classifies ovarian cancers according to the degree of spread, with early

stages confined to the ovaries or pelvis (Table 0.15). The UKCTOCS investigators have analysed

stage shift by comparing malignancies categorised according to the volume of metastatic

peritoneal disease, with cancers at Stage IIIa or less referred to as low volume and those more

advanced than Stage IIIa as high volume cancers.

Table 0.15 FIGO staging of ovarian cancer

Category Stage Characteristics of malignancy UKCTOCS

categories29

Early Stage I Confined to ovary

Low volume Stage II Spread to pelvis

Late

Stage III Peritoneal metastasis outside the pelvis

Stage IIIa Microscopic peritoneal metastasis (no macroscopic tumor)

Stage IIIb Macroscopic peritoneal metastasis (≤ 2 cm)

High volume Stage IIIc Macroscopic peritoneal metastasis (>2 cm and/or regional lymph node metastasis)

Stage IV Spread beyond abdominal organs

Abbreviations: FIGO, International Federation of Gynecology and Obstetrics; UKCTOCS, United Kingdom Collaborative Trial of Ovarian Cancer

Screening.

Table 0.16 shows UKCTOCS data for all cancers except non-epithelial ovarian cancer and

borderline epithelial ovarian cancer. It is for this population that the sole statistical analysis

26 Data calculated post hoc for this group of cancers, using data from the Jacobs 2016 online supplement. 27 Difference between TVUS and no screening in number of Stage IV cancers is not statistically significant. 28 Calculated post hoc from data reported in this table. 29 Categorisation as low or high volume taken from the UKCTOCS primary study publication (Jacobs 2016).


regarding potential stage shift is reported in this study. The authors found that significantly more

tumours were of low volume in the ROCA triage group compared to the no-screening group.

A systematic review prepared for the AHRQ (Henderson 2017) notes that statistically significant

stage shifts were observed for early stage disease (Stages I and II) and even at the localised stage

(Stage I; p<0.005). This was readily confirmed in Review Manager by the current Review authors for

the data in the table below and also for the other tumour type groups shown above in Table 0.15. It

is not clear why this was not reported in the UKCTOCS study publication.

Table 0.16 Low versus high volume tumours at diagnosis, all modes of detection – UKCTOCS

Tumours by stage, n (%) UKCTOCS

OC (invasive epithelial only30), FTC, PPC

ROCA triage TVUS No screening

Total cancers, n (%) 299 (100) 259 (100) 574 (100)

Early vs late stage at diagnosis31

Stage I or II 108 (36) 58 (22) 137 (24)

Stage III or IV or unstaged 191 (64)32 201 (78) 437 (76)32

Low vs high volume at diagnosis33

Stage I or II or IIIa 119 (40) 62 (24) 149 (26)

Stage IIIb or IIIc or IV or unstaged 180 (60) 197 (76) 425 (74)

Between-group differences for low vs high volume

ROCA triage vs no screening p < 0.0001 – –

TVUS vs no screening – p=0.57 –

Note: one cancer in the ROCA triage group and one cancer in the no screening group could not be staged. These cancers were excluded

from the early vs late stage analyses but included as high-volume cancers in the Jacobs 2016 analysis of low vs high volume.

Abbreviations: FTC, fallopian tube cancer; OC, ovarian cancer; PPC, primary peritoneal cancer; ROCA, Risk of Ovarian Cancer Algorithm;

TVUS, transvaginal ultrasonography; UKCTOCS, United Kingdom Collaborative Trial of Ovarian Cancer Screening.

Stage at diagnosis by phase of study

The PLCO study reported stage at diagnosis by phase of study (screening phase versus post-

screening phase). There was no significant association between study period and stage distribution;

76% of intervention group cases diagnosed during the screening phase of the study (years 0-5)

were Stage III or IV compared with 79% of those diagnosed during the post-screening phase.

4.1.2.4 Quality-of-life outcomes

The impact of an abnormal screen test result and surgery on anxiety, psychological morbidity

(Barrett 2014) and sexual functioning (Fallowfield 2017) was investigated in the UKCTOCS trial using

the following validated instruments:

State/Trait Anxiety Inventory (STAI) – score range 20 to 80

General Health Questionnaire 12 (GHQ-12) – score range 1 to 12, dichotomised with ≥4

signifying probable psychological morbidity

Fallowfield’s Sexual Activity Questionnaire (FSAQ) – 3 domains (range of scores): Pleasure

(0-18); Discomfort (0-6); Habit (0-3).

30 Excludes non-epithelial tumours as well as borderline tumours. 31 Data abstracted (with post hoc calculations) from results reported in Jacobs 2016 online supplement, Web Table 3. One tumour was not

able to be staged. 32 Includes one tumour not able to be staged. 33 Data abstracted (with post hoc calculations) from results reported in Jacobs 2016 study publication.


Each of the two screening interventions included two levels of follow-up testing:

ROCA triage

o Level 1 – repeat blood test

o Level 2 – repeat blood test and TVUS

TVUS

o Level 1 – repeat TVUS and by a senior ultrasonographer or consultant

o Level 2 – repeat TVUS or biopsy.

Among women recalled for repeat screening, the effect on anxiety was statistically significant

(mean difference 0.37 [95% CI: 0.23, 0.51; p< 0.01]) but with a range of scores from 20 to 80 with the

STAI, this was considered too small to be of clinical significance (the authors note the large size of

the study led to detection of very small changes). An effect on psychological morbidity was

evident when recalled for a Level 2 screen (chance of returning a GHQ-12 score ≥ 4: OR 1.28 [95%

CI: 1.18, 1.39)].

Surgery prompted by abnormal test results increased anxiety compared with routine screening, at

both 6 weeks (mean difference -1.1 [95% CI: -1.6, -0.59]) and 6 months (-1.23 [95% CI: -1.71, -0.75])

after surgery. Among women who returned to routine screening after surgery, anxiety levels

returned to normal after 6 months, but not surprisingly increased for women diagnosed with ovarian

cancer (3.21 [95% CI: 1.62, 4.80]).

Among women recalled for further tests, significant differences in sexual activity were found

between the ROCA triage group (n=12,810) and the annual TVUS group (n=10,156), with the TVUS

group having lower pleasure scores; mean difference -0.14, p=0.046 (instrument range 0-18).

Comparing all women in either screening group who were recalled for Level I screens only, those

recalled for Level II tests had significantly lower pleasure scores (-0.16, p=0.005).

The authors of these two studies concluded that screening for ovarian cancer does not increase

anxiety in general, especially when compared with the variation in anxiety levels that occur within

individuals. Psychological morbidity is slightly elevated by higher levels of secondary testing

following annual screening, and was unremitting for those diagnosed with ovarian cancer. They

found that ovarian cancer screening did not affect sexual activity and functioning unless a woman

had abnormal results and underwent repeated or higher level screening.

4.1.2.5 Safety outcomes

Complications associated with screening

In the PLCO trial, complications were reported separately for the two tests used in the single

screening group. The screening-related complication rate was higher for the CA125 blood test than

for TVUS, and is much higher than the rates in the UKCTOCS trial groups. It is possible that in the

PLCO trial, this outcome is actually the number of complications reported rather than the number

of women reporting complications. 34

34 The only data for this outcome is reported by the authors in the following statement: ‘Minor complications such as fainting and bruising

occurred at a rate of 58.3 per 10 000 women screened with CA125 and 3.3 per 10 000 women screened with transvaginal ultrasound’.


Table 0.17 Complications associated with screening tests – PLCO and UKCTOCS

Screening-related complications PLCO UKCTOCS

CA125 TVUS ROCA triage TVUS

Participants, n (%) 34,253 34,253 50,624 50,623

Number of women reporting a complication NR NR 30 (<1%) 61 (<1%)

Number of women reporting complications per 10,000

women screened35 58.3 3.3 0.86 1.86

Abbreviations: CA, cancer antigen; NR, not reported; PLCO, Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial; ROCA, Risk of



The proportion of women experiencing complications associated with false-positive surgery was

substantially greater in the PLCO study than in UKCTOCS. Insufficient information is available for the

PLCO study to compare the seriousness of the complications reported, which may account for

some of the difference.

Table 0.18 Complications associated with unnecessary surgery – PLCO and UKCTOCS

Unnecessary surgery outcomes PLCO UKCTOCS

CA125 +TVUS ROCA triage TVUS

Benign or normal pathology after screen positive surgery, n 1,080 488 1634

Number of women reporting complications 163 15 57

Number of complications reported36 222 NR NR

Proportion of women experiencing complications after

false-positive surgery, % [95% CI]

15%

[NR]

3.1%

[1.7, 5.0]

3.5%

[2.7, 4.5]

Complication rate associated with false-positive surgery,

(events per 100 surgical procedures) 20.6 NR NR

Abbreviations: CA, cancer antigen; CI, confidence interval; NR, not reported; PLCO, Prostate, Lung, Colorectal and Ovarian Cancer

Screening Trial; ROCA, Risk of Ovarian Cancer Algorithm; TVUS, transvaginal ultrasonography; UKCTOCS, United Kingdom Collaborative Trial of

Ovarian Cancer Screening.

Complication rates associated with surgery for benign or normal pathology were not reported for

the no screening groups of these trials. Major complications associated with ‘diagnostic

procedures’ was reported for PLCO, with 95/212 (45%) in the screening group and 91/176 (52%) in

the no-screening group experiencing at least 1 major complication (i.e. infection, blood loss, bowel

injury, cardiovascular events).

The UKCTOCS trial reported that outside of the trial, women had both ovaries or the only remaining

ovary removed for a range of indications and had benign pathology or normal adnexa, which

occurred at similar rates in all three study groups (0.8%-0.9%). Data for associated complication

rates for these surgeries were not available.

4.1.2.6 Economic analyses

Two economic analyses have been published on ovarian cancer population screening, both

evaluating the UKCTOCS trial. The study authors of both analyses conclude that longer follow up of

the UKCTOCS mortality data is necessary before screening could be recommended on economic

grounds.

35 For PLCO, this outcome may actually be the number of complications reported rather than the number of women reporting complications. 36 Some women reported more than one complication. In PLCO all complications are included in this analysis; in UKCTOCS only the most

serious complication was reported in women with more than one complication (i.e. the total number of complications associated with false-

positive surgery is not reported in UKCTOCS).


The authors of the model-based economic evaluation published by Kearns et al (2016) were from

the University of Sheffield and the University of Exeter. They based their model on information in the

public domain at the time, which included the primary study publication (Jacobs 2016).

The authors concluded the following:

Based on 11 years of follow-up we estimated that screening is not cost-effective, as

the mortality benefit is outweighed by the dis-benefits associated with both treating

false positives and earlier treatment of women with ovarian cancer. In contrast,

lifetime cost-effectiveness results are promising, with an estimated ICER comparing

[ROCA triage] with no screening of £8864 per [quality-adjusted life year] QALY (95%

confidence interval £2600 to £51,576).

They noted, however, that there was substantial uncertainty in the long-term effectiveness of ROCA

triage in reducing mortality, which is a key driver of cost-effectiveness (the non-significant effect on

mortality reported in the trial publication was used in the model).

The second economic evaluation was published by UKCTOCS investigators (Menon 2017), who

noted that the ‘long-lead time associated with establishing mortality benefit from ovarian cancer

screening has meant that the full benefits to be realised from such a programme have not been

established authoritatively’.

The following model estimates were reported:

Using a CA125–ROCA cost of £20, the within-trial results show [TVUS] to be strictly

dominated by [ROCA triage], with the [ROCA triage] vs [no screening] comparison

returning an incremental cost-effectiveness ratio (ICER) of £91,452 per life year

gained (LYG). If the CA125–ROCA unit cost is reduced to £15, the ICER becomes

£77,818 per LYG. Predictive extrapolation over the expected lifetime of the

UKCTOCS women returns an ICER of £30,033 per LYG, while Markov modelling

produces an ICER of £46,922 per QALY.

In the final conclusion they note the following:

Analysis suggests that, after accounting for the lead time required to establish full

mortality benefits, a national [ovarian cancer screening] programme based on the

[ROCA triage] strategy quickly approaches the current NICE thresholds for cost-

effectiveness when extrapolated out to lifetime as compared with the within-trial

ICER estimates.

A public health programme of screening for ovarian cancer could become cost-

effective within an NHS setting if the mortality benefit from screening continues to

increase over time. Any definitive conclusion as to whether [ROCA triage] could be

recommended on economic grounds would depend on the confirmation and size

of the mortality benefit at the end of ongoing follow-up of the UKCTOCS cohort.

When UKCTOCS long term follow up is reported, it is expected these analyses will be repeated.

4.1.3 Data extraction – systematic reviews and HTAs

The Henderson 2017 Evidence Synthesis prepared for the AHRQ is the most recent and

comprehensive of the published systematic reviews. The authors reanalysed the data reported in

the clinical trial publications to account for (1) the WHO revised classification of tumours of the

reproductive system37; (2) differences between RCTs in the calculation of false positive rates. The

37 In 2014, WHO revised the classification of tumours of the female reproductive system. Following these revisions, most cancers historically

classified as peritoneal cancer would be reclassified as ovarian and tubal cancers.


Evidence Synthesis considers data from four included RCTs: PLCO, UKCTOCS, UK Pilot, and QUEST.

The three larger trials (PLCO, UKCTOCS and the UK Pilot) were rated as good-quality. The smaller

QUEST trial, which only reported on psychological harms of screening, was rated as fair-quality. The

screening tests evaluated across the four trials were:

annual TVUS (UKCTOCS)

annual TVUS and CA125 serum testing (PLCO, QUEST)

annual CA125 testing (UK Pilot)

annual CA125 serum testing interpreted with an algorithm (ROCA) that incorporates changes

over time to inform triage and rescreening intervals (UKCTOCS).

The Shizuoka Cohort Study of Ovarian Cancer Screening and Shizuoka Cancer Registry (SCSOCS

trial) was not included in the Henderson 2017 Evidence Synthesis because health outcomes have

not been reported for that trial.

4.1.3.1 Mortality

The evidence summary in Table 0.19 relates to the Henderson 2017 Evidence Synthesis question:

Does screening for ovarian cancer in asymptomatic women using a single test or combined

algorithm (such as, but not limited to, testing for serum CA125 and ultrasonography) reduce all-

cause or disease-specific morbidity and mortality?

In summary, the three trials reporting mortality outcomes (PLCO, UKCTOCS, UK Pilot) had null

findings based on a priori per protocol statistical analyses testing four screening programs for

ovarian cancer. The PLCO and UKCTOCS were designed with statistical power to detect a 30 to 35

percent difference in mortality from this relatively rare but often fatal cancer, and had null findings

in primary analyses. The UK Pilot trial reported mortality outcomes, but was designed to examine the

feasibility of screening and was underpowered to detect a mortality difference.

The UKCTOCS investigators included statistical analyses suggestive of a possible long-term benefit

of the CA125 ROCA screening intervention on ovarian cancer mortality (excluding peritoneal

cancers) based on their observation that Kaplan-Meier cumulative mortality curves appear to

diverge approximately 10 years after randomisation. However, the Henderson 2017 Evidence

Synthesis did not focus on the secondary analysis because (1) they prioritised analyses with both

ovarian and peritoneal cancer included, since their presentation and treatment is not distinct in

clinical practice and because they are often difficult to distinguish pathologically; (2) they focused

on statistical tests that were specified a priori through publication of a protocol and trial registration,

using an intention-to-treat analysis of all participants, since these findings are more robust and

applicable to the implementation of a screening program and its cumulative effects; and (3) the

divergence of the trial arms later in the study period are more difficult to attribute to the original

randomised condition and screening per se, as the longer a study continues, the more

opportunities there are for measured and unmeasured differences in the study arms to accrue.

There were also substantially fewer women at risk included in the analyses beyond 10 years,

because women recruited into the study later have not yet accrued follow-up time for inclusion in

the analysis. Thus, data from the later years of the trial (>10 years) are based on incomplete data

and should be cautiously interpreted.

Henderson et al (2017) argue that differential reasons for censoring could lead to some divergence

in the ovarian cancer mortality curves as follow-up times lengthen. In the UKCTOCS trial, there were

no differences across arms in participant follow-up (censoring) or other causes of death, but there

may have been differences between arms and changes over time in the proportion of participants


in the trial with two ovaries intact. Those with both ovaries rather than just one, by definition, have

higher ovarian cancer risk. The usual-care screening arm may have had a net surplus of ovaries at

risk, despite a similar proportion of women at risk. Others have suggested that the potential

prophylactic effect of ovary and fallopian tube removal might influence the UKCTOCS results,

especially in the long term. To date, there is no overall difference in the incidence of ovarian

cancer by arm, suggesting that a prophylactic effect is not present, but as more years of follow-up

data are available for more of the enrolled participants, additional analysis of the cumulative

cancer incidence rate by study arm can be undertaken.


Table 0.19 Summary of evidence table from Henderson 2017 – effect on disease-specific mortality

Test # studies (k),

sample size

(n) Design

Summary of Findings by Outcome Consistency/

Precision

Reporting Bias Quality Body of Evidence

Limitations

Assessment of

Strength of Evidence

for key question

Applicability

CA125 k=2

n=173,858

RCT

OC mortality (k=2, n=173,858). Screening with

CA125 did not result in improved OC mortality

compared with no screening (UKCTOCS HR, 0.89

[95% CI, 0.74 to 1.08], U.K. Pilot RR, 0.5 [95% CI,

0.22 to 1.11])

Reasonably

consistent

Reasonably

precise

Undetected Good Follow-up data

incomplete

beyond 10 years

for a substantial

proportion of trial

participants

Moderate Trial evidence from the UK, where

screening occurred in specialised

trial settings and cancer treatment

was provided through the NHS,

which is a more centralised health

system relative to the US. Study

enrolled mostly white women.

UKCTOCS began in 2001. FDA does

not support ROCA screening

algorithm.

TVUS k=1

n=151,922

RCT

OC mortality (k=1, n=151,922). TVUS screening

did not result in improved OC mortality

compared with usual care (UKCTOCS HR, 0.91

[95% CI, 0.76 to 1.09])

Consistency

NA

Reasonably

precise

Undetected Good Follow-up data

incomplete

beyond 10 years

for a substantial

proportion of trial

participants

Moderate Trial evidence from the UK, where



provided through the NHS, which is

a more centralised health system

relative to the US. Study enrolled

few nonwhite participants.

CA125

+ TVUS

k=1

n=68,557

RCT

OC mortality (k=1, n=68,557). No reduction

found in OC mortality from combined TVUS and

CA125 screening compared with usual care

(PLCO RR, 1.18 [95% CI, 0.82 to 1.71])

Consistency

NA

Reasonably

precise

Undetected Good Changes to

protocol, ovarian

palpation

dropped after

first 4 trial years

Moderate US multisite trial with usual care

control condition and referral to

community clinicians for screen

positives. Majority white, non-

Hispanic study participants. Trial

begun in 1993.

Abbreviations: CA, cancer antigen; CI, confidence interval; FDA, US Food and Drug Administration; HR, hazard ratio; NA, not applicable; NHS, National Health Service; OC, ovarian cancer; PLCO, Prostate, Lung,

Colorectal and Ovarian Cancer Screening Trial; QUEST, Quality of life, Education, and Screening Trial; RCT, randomised controlled trial; ROCA, risk of ovarian cancer algorithm; RR, risk ratio; TVUS, transvaginal

ultrasonography; UK, United Kingdom; UKCTOCS, UK Collaborative Trial of Ovarian Cancer Screening, US, United States.


4.1.3.2 Stage shift and treatment findings

The Henderson 2017 Evidence Synthesis examined included studies for evidence of a cancer stage

or type shift. They focused the evaluation of stage shift on comparisons in the trial arms between

women diagnosed with localised disease (Stage I) and those with regional or distant disease

(stages II-IV).

Detection of a higher proportion of localised cancers in the screening arms compared with control

arms was reported in the two large trials. In UKCTOCS, a statistically significant (p<0.005) greater

proportion of cases was identified at the localised stage (Stage I) in the ROCA triage and TVUS

arms than in the control arm. The overall differences by arm and stage were also statistically

significant when comparing localised and regional cancers (stages I and II) to more advanced

stages (stages III and IV). However, this shift did not confer a statistically significant mortality benefit.

In PLCO, there was not a statistically significant difference in the proportion of cases identified at

the localised stage in the intervention versus usual care group. Furthermore, comparisons by stage

and arm also were not statistically different when comparing localised and regional cancer cases

to more advanced cancers. In addition, there were no differences in treatments (surgery plus

systemic therapy) by study arm in PLCO.

Overall, Henderson et al (2017) made the following observations:

‘The absence of a mortality benefit in these large, well-conducted trials has

generated a theory that late stage disease grows so rapidly that it cannot be

identified at an earlier stage. The stage shift in UKCTOCS trial would seem to counter

this, but the lack of mortality benefit may suggest that these “early stage” tumors

detected early are more aggressive tumor phenotypes that would not have

improved survival no matter when they were identified. Recent work to refine the

distinctions among ovarian cancer molecular, pathological, and clinical

characteristics highlight this point in noting that survival differences are more likely

attributable to type than to stage at diagnosis, with the most common Type II

cancers being particularly lethal regardless of stage, likely owing to microscopic

lesions that are not detectable before significant spread has occurred.’

4.1.3.3 Harms

Given evidence that there is no mortality benefit from routine ovarian cancer screening, Henderson

et al (2017) argue that the harms associated with screening merit extra consideration. Harms of

screening include surgery resulting from a false positive. These surgeries often result in the removal

of one or both ovaries and/or fallopian tubes, and can lead to major surgical complications.

The evidence summary in Table 0.20 relates to the question: What are the harms of screening for

ovarian cancer, including harms of the screening test and of diagnostic evaluation?

All four trials reported on the harms of ovarian cancer screening. False positive rates and surgical

harms were highest among screening programs including TVUS with or without CA125

measurement. Major surgical complications as estimated in the two largest trials occurred in

women with investigations from screening that did not lead to a cancer diagnosis, ranging from 3

to 15 percent of surgeries. The screening tests themselves resulted in minor complications, at rates

widely ranging based on study specific definitions from 0.86 to 58.3 per 10,000 screens/women for

CA125 test blood draws (e.g. fainting, bruising) and from 1.86 to 3.3 per 10,000 screens/women for

ultrasound testing (e.g. pain, discomfort, infection, bruising).

The UKCTOCS employed a more nuanced approach to CA125 testing and triage by using an

algorithm that assigns three levels of risk to direct surveillance and triage tests. This was aimed at


reducing rates of surgical investigation, which were lower in the ROCA triage arm than in the TVUS-

only arm of the trial. False positive surgery rates in the ROCA triage arm of UKCTOCS were markedly

lower than in PLCO (1% versus 3%), as were major complication rates for false positive surgery (just

over 3% in UKCTOCS versus 15% in PLCO). Henderson et al (2017) claim that differences in the study

settings could account in part for this difference, as all women referred for diagnostic testing in

UKCTOCS were seen at National Health Services tertiary care surgical centres, whereas diagnostic

testing in PLCO was conducted through referrals to women’s routine sources of care, and not

necessarily specialised tertiary care settings.


Table 0.20 Summary of evidence table from Henderson 2017 – harms

Test # studies (k),

sample size (n)

Design


Precision


Limitations

Assessment of


for key question

Applicability

CA125 k=3

n=242,415

RCT

FP rate from screening (k=2, n= 173,858). FP

rates over multiple rounds of screening ranged

from 4.2% to 44.3%.

Complications from screening (k=2, n= 220,480).

Complications from CA125 testing were

generally minor and ranged from 0.86 per

10,000 screens to 58.3 per 10,000 women.

FP surgery (k=2, n=173,858). FP surgeries

occurred in 0.2% to 1% of those screened with

CA125.

Complications from FP surgery (k=2, n=173,858).

One larger trial (n=151,923) reported

complications in 3.1% of FP surgeries. One

smaller trial (n=21,935) reported no surgical

complications.

Psychological effects of screening (k=1, n=

13,413). Psychological harms were reported in a

subset of 1 trial. No statistically significant

differences were found in psychological

outcomes between the screening and no-

screening arms.

Reasonably

consistent or

NA

Reasonably

precise

Undetected Good Psychological

harms measured

only for subsets

of trial

participants.

Moderate (Low for

psychological

harms).

Trial evidence from the UK, where



was provided through the NHS,

which is a more centralised health

system relative to the US.

TVUS k=2

n=220,479

RCT

FP rate and complications from screening (k=1,

n= 151,922). FP rate of 11.9% was reported in the

initial screening round.

Complications from screening (k=2, n= 220,479).

Complications from screening with TVUS ranged

from 1.86 per 10,000 screens to 3.3 per 10,000

women.

FP surgery (k=1, n=151,922). FP surgeries

occurred in 3.2% of those screened with TVUS.

Complications from FP surgery (k=1, n= 151,922).

Complications occurred in 3.5% of FP surgeries.

Psychological effects of screening (k=1,

n=10,716). Psychological harms were reported

in a subset of 1 trial. No statistically significant

differences were found in psychological

outcomes between the screening and no-

screening arms.

Reasonably

consistent or

NA

Reasonably

precise

Undetected Good Psychological

harms measured

only for subsets

of trial

participants

Data on

cumulative FP

rate not

reported.

Moderate (Low for

psychological

harms).

Screening conducted in specialised

trial centers.

Treatment for cancer (in all study

arms) was through the centralised

NHS system in UK and in community

care settings in US.


Test # studies (k),

sample size (n)

Design


Precision


Limitations

Assessment of


for key question

Applicability

CA125

+ TVUS

k=2

n=69,106

RCT

FP rate and complications from screening (k=1,

n=68,557). FP screening rate of 5.9% was

reported for the first round of screening and

9.8% for the entire screening program.

Complications from screening (see

complication rates for individual components).

FP rate for screen positive surgery (k=1,

n=68,557). FP surgeries occurred in 3.2% of those

screened.

Complications from FP surgery (k=1, n=68,557).

Complications occurred in 15.1% FP surgeries.

Psychological effects of screening (k=1, n=549).

Women with abnormal test results (n=32)

compared with women with no abnormal

results more likely to report cancer worry at 2

year follow-up (OR, 2.8 [95% CI, 1.1 to 7.2]).

Consistency

NA

Reasonably

precise

(except

psychological

harms

[imprecise])

Undetected Fair to

Good

Psychological

harms measured

only for subsets

of trial

participants.

Moderate (Low for

psychological

harms).

US-based, multisite trial.

Pragmatic trial with usual care

control condition and referral to

community clinicians for screen

positives.

Majority white, non-Hispanic

participants.

Abbreviations: CA, cancer antigen; CI, confidence interval; FP, false positive; NA, not applicable; NHS, National Health Service; OC, ovarian cancer; OR, odds ratio; RCT, randomised controlled trial; TVUS, transvaginal

ultrasonography; UK, United Kingdom; US, United States.


4.1.3.4 Conclusions from systematic reviews

Table 0.21 provides the conclusions reported in all of the published systematic reviews that assessed

screening interventions for ovarian cancer in asymptomatic women. Overall, the systematic reviews

were consistent in concluding that the body of evidence does not show a benefit for routine

screening over control in terms of a reduction in mortality; furthermore, the harms associated with

screening must be considered.

Table 0.21 Conclusions from systematic reviews relating to population screening for ovarian

cancer

Study ID

Qualitya

Intervention &

comparator

Conclusions

Screening for ovarian cancer

Henderson

2017

[AHRQ]

Good quality

Intervention


for OC

Comparator

Usual care or no

screening

Since the previous review for the USPSTF, results from a large trial conducted in the UK were

published

OC mortality did not differ between control and intervention screening conditions in any of

the included trials, including two good-quality studies with adequate power to detect

differences

Harms of screening include surgery following a false positive test, often resulting in removal

of one or both ovaries and/or fallopian tubes, and the potential for major surgical

complications

Reports from the UKCTOCS of a potential delayed effect of screening on OC mortality

require further follow-up data to evaluate, but the causal mechanism for a delayed

screening effect is unclear

Major trials of promising OC screening tools have null findings to date among healthy

average-risk women, and there are considerable harms associated with screening

Buhling 2017

Fair quality

Intervention

Annual TVUS ± CA125

Comparator

Usual care

An annual palpation does not offer the beneficial effect that might be expected from

patients who undergo this examination

The development of new ultrasound machines with higher image resolution in combination

with a well-standardised algorithm for OC in upcoming years might provide an improvement

in mortality

The current studies do not show a benefit in screening an asymptomatic population

annually with TVUS, but a significant change was observed in the MMS group after 7–14

years of follow-up with a 28% reduction in mortality

Nevertheless, all three heterogeneous RCTs have weaknesses in their methods and therefore

do not reflect a general recommendation, but at the same time cannot disprove

Reade 2013

Good quality

Intervention


for OC

Comparator

No intervention, usual

care, or education

RCTs evaluating screening [asymptomatic women for OC] do not show any benefit in

reduction of mortality or risk of diagnosis at an advanced stage

False-positive screening tests lead to unnecessary surgery and surgical complications, and

are associated with increased levels of worry for up to two years

This information should be considered for informed decision-making regarding OC screening

Screening for gynaecologic cancers (including ovarian cancer)

Guirguis-

Blake 2017

[AHRQ]

Good quality

Intervention

Pelvic examination

Comparator


reference standard

There is no direct evidence on the overall benefits and harms of the pelvic examination as a

one-time or periodic screening test

There is limited evidence regarding the diagnostic accuracy and harms of the routine

screening pelvic examination to guide practice in asymptomatic primary care populations

Bloomfield

2014

Fair quality

Intervention

Pelvic examination

Comparator


reference standard

No data supporting the use of pelvic examination in asymptomatic, average-risk women

were found

Low-quality data suggest that pelvic examinations may cause pain, discomfort, fear,

anxiety, or embarrassment in about 30% of women

Abbreviations: AHRQ, Agency for Healthcare Research and Quality; CA, cancer antigen; MMS, multimodal screening; OC, ovarian cancer;

RCT, randomised controlled trial; TVUS, transvaginal ultrasonography; UK, United Kingdom; UKCTOCS, UK Collaborative Trial of Ovarian Cancer

Screening; USPSTF. United States Preventative Services Task Force.



Review of evidence for surveillance of women at high risk

4.1.4 Identified studies of surveillance effectiveness/harms

The literature searches identified a total of 11 eligible records for surveillance of women at high risk

of ovarian cancer; 10 clinical study publications and one systematic review.

4.1.4.1 Key clinical studies

The 10 eligible clinical study publications are listed in Appendix D (Section D.2.1). They describe five

cohort studies and one post hoc analysis of the PLCO RCT. These studies are referred to in this

Review as:

The Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial – subgroup analysis

(PLCO-HR)

United Kingdom Familial Ovarian Cancer Screening Study – Phase I (UKFOCSS Phase I)

United Kingdom Familial Ovarian Cancer Screening Study – Phase II (UKFOCSS) Phase II)

o Partner study – Psychological evaluation of Familial Ovarian Cancer Screening (PsyFOCS)

Cancer Genetics Network and Gynecologic Oncology Group (CGN/GOG)

UK-Netherlands-Norway study

Fox Chase Cancer Centre

An additional record was found by directed searching – a protocol document for UKCTOCS

Phase II published online only.

A matched case-control study was also identified of 54 women with Lynch syndrome who

participated in any screening program using TVUS and CA125 for gynaecological cancers

(endometrial and ovarian; Stuckless 2013). This study, which found no improvement in early

detection, was excluded as it was retrospective.

A cohort study was identified that included women with increased risk of ovarian cancer within a

population screening trial (University of Kentucky Ovarian Cancer Screening Project; van Nagell

2011). Only true negatives were reported for this population, which is not an outcome of relevance

to this Review. Therefore, this study was not eligible for inclusion as a surveillance study (wrong

outcomes) nor as a population screening study (wrong study design – not an RCT).

An RCT was identified comparing screening modalities that triage women with CA125 testing,

either with or without the addition of HE4 testing (Karlan 2014). Positive predictive value was the

only outcome analysed, which is not eligible for inclusion in this Review, so this study was excluded.

Characteristics of included studies

Two of the six included studies used ROCA to evaluate CA125 levels:

UKFOCSS Phase II

CGN/GOG

The UKFOCSS Phase II evolved from the Phase I study, increasing the frequency of screening and

switching from single threshold to ROCA evaluation of CA125. The CGN/GOG study combined

data from the Cancer Genetics Network (CGN) and Gynecologic Oncology Group (GOG) studies,

which laid the groundwork for personalising the CA125 test with ROCA.

The characteristics of these studies are shown in Table 0.1.


The four other studies either used a single threshold for CA125 evaluation or were assumed to have

done so:

PLCO-HR

UKFOCSS Phase I


Fox Chase Cancer Centre study

The most recently published of these (PLCO-HR) is a post hoc analysis of high-risk women who

received routine annual screening in the PLCO population screening trial. Women in the UKFOCSS

Phase I trial also received annual screening with TVUS and single threshold CA125 testing. However,

between 2007 and 2009, phase II screening (ROCA once every 4 months, triaging to TVUS) was

introduced in response to concerns about the ability of annual screening to detect early-stage

disease.

An analysis of mostly published screening data from five cancer genetics centres in the UK, the

Netherlands and Norway was published in 2009 (UK-Netherlands-Norway). Information about the

screening interventions used, the definitions applied, and the cancers excluded were not reported

in detail, but it is assumed that a single threshold would have been used for CA125 evaluation.

A fourth study (Fox Chase Cancer Centre) did not report the details of screening, which served as a

control in an assessment of the impact of surgery on quality of life. However, the authors note that

screening options for high-risk women include serum CA125 evaluation and TVUS.

The characteristics of these five studies are shown in Table 0.2. The following sections include

information about eligibility criteria, details of the screening strategy, definitions used (e.g. interval

cancers, false positives), and methods for notification and ascertainment of outcomes.


Table 0.1 Characteristics of included studies using ROCA – surveillance of women at high risk of ovarian cancer

Item UKFOCSS Phase II CGN/GOG

Main publication ID Rosenthal 2017 Skates 2017

CA125 interpretation ROCA ROCA

Country and setting 42 centres in the UK (52% were UKFOCSS Phase I participants) CGN: 25 sites across US (NCT-00039559)

GOG-0199: 112 across US and Australia (NCT-00043472)

Key inclusion criteria

(see Table 0.3 for full list of criteria)

aged ≥35 years; median 45.5 (range 34.2, 84.8)

lifetime risk of OC ≥10%

aged > 30 years

subject or family member with BRCA1/2 mutation, or

multiple ovarian and/or breast cancers in 1st or 2nd degree relatives

Only difference in eligibility criteria is that women without ovaries were

ineligible for GOG-0199 but could be screened for PPC in CGN (excluded

from the analysis in the CGN/GOG analysis of these two studies).

Key exclusion criteria


test negative for mutation in an affected family member test negative for mutation in an affected family member

Study design, N Prospective, multicentre cohort study Combined analysis of two prospective, multicentre cohort studies

conducted by the CGN and GOG.

Recruited (N) N = 4,531 N = 3,818

CGN, N = 2,359; GOG-0199, N = 1,459

Analysed (N) N = 4,348 N = 3,449

CGN, N = 1,991; GOG-0199, N= 1,458

Cancers included invasive OC (i.e. not borderline)

FTC

PPC

invasive OC (i.e. not borderline)

FTC

PPC

Period of study

Start date Jun 2007 CGN 2001

GOG-0199 2003

End of recruitment May 2012 CGN 2011

GOG-0199 2006

Person-years screened 13,728 Total: 13,080

CGN 6,979

GOG-0199 6,101

Censorship 1 year after last UKFOCSS screen38 CGN: not reported, but all women were followed for at least a year after

the last screening test

GOG-0199: open-ended annual questionnaires after 5 years of screening

38 Dates reported for last cancer notifications from NHS digital were February 28, 2016 (England/Wales), May 15, 2016 (Scotland), and April 19, 2016 (Northern Ireland); the last death notifications were received on

March 14, 2016 (all countries).


Item UKFOCSS Phase II CGN/GOG

Median follow up

(years)

4.8 (range 0.1, 8.7) CGN 2.9 (range 0, 10.3)39

GOG-0199 5.0 (range 0, 6.9)

Screening method

(see Screening strategies section below for details)

HR ROCA triage

High-risk ROCA40 every 4 months for possible triage to additional CA125

and/or TVUS, and

TVUS annually

HR ROCA triage

High-risk ROCA40 every 3 months for possible triage to additional CA125

and/or TVUS, and

TVUS annually

Positive-screen follow-up actions Referral to a local gynaecologist for clinical assessment. Follow up with gynaecological oncologist or study site principal

investigator.

Key outcomes reported diagnoses by mode of detection

false positive surgeries

stage at diagnosis

mortality (reported but not analysed)

sensitivity

QoL outcomes

diagnosis by mode of detection


stage at diagnosis

sensitivity

Abbreviations: CA, cancer antigen; CGN, Cancer Genetics Network; FTC, fallopian tube cancer; GOG, Gynecologic Oncology Group; OC, ovarian cancer; PPC, primary peritoneal cancer; QoL, quality of life;

ROCA, risk of ovarian cancer algorithm; TVUS, transvaginal ultrasonography; UK, United Kingdom; UKFOCSS, United Kingdom Familial Ovarian Cancer Screening Study; US, United States.

Table 0.2 Characteristics of included studies using single threshold CA125 – surveillance of women at high risk of ovarian cancer

Item PLCO-HR UKFOCSS Phase I UK-Netherlands-Norway Fox Chase Cancer Centre

Main publication ID Lai 2016 Rosenthal 2013 Evans 2009 Fang 2009

CA125 interpretation Single threshold CA125 with TVUS Single threshold CA125 with TVUS Single threshold CA12541 with TVUS NR42 (likely CA125 and or TVUS)

Country and setting US – 10 screening centres under

contract to the National Cancer

Institute.43

37 centres in the UK Five cancer genetics centres44 in

UK – Edinburgh and Manchester

The Netherlands – Leiden

Norway – Oslo and Bergen45

Family Risk Assessment Program at Fox

Chase Cancer Centre, Philadelphia,

US

39 ‘0’ years indicates women who enrolled but were never screened. 40 The high-risk ROCA incorporated the higher a priori risk in this population and different reference levels for risk stratification for post-menopausal compared with pre-menopausal women (higher baseline CA125 and

variability in pre-menopausal women). 41 This study did not describe screening in detail, which was conducted in one of five European centres. However, a publication reporting results from the Netherlands that was cited by Evans 2009 for further

information regarding screening protocols reports using a single threshold cut-off of 35 U/mL. 42 The authors make the comment that ‘screening options for high-risk women include serum CA125 evaluation and TVU’. The screening group serves as a control for surgery in this QoL study. 43 Screening centres were located at the University of Colorado Health Sciences Center in Denver, Colorado; Georgetown University in Washington, DC; the Pacific Health Research Institute in Honolulu, Hawaii; Henry

Ford Health System in Detroit, Michigan; the University of Minnesota in Minneapolis, Minnesota; Washington University School of Medicine in St. Louis, Missouri; the Cancer Institute of Brooklyn at Maimonides Medical

Center in Brooklyn, New York (discontinued in 1997); the University of Pittsburgh Cancer Institute in Pittsburgh, Pennsylvania; the University of Utah Health Sciences Center in Salt Lake City, Utah; Marshfield Medical

Research and Education Foundation in Marshfield, Wisconsin; and the University of Alabama at Birmingham in Birmingham, Alabama. 44 These centres were among 10 centres involved in a European Biomed project funded in 1995 (there were insufficient data and cancers in the other centres to increase power). 45 Screening in Norway was performed in several local hospitals.



Key inclusion criteria


Family history:

aged 55 to 74

at least one first degree relative with

breast cancer or OC

Personal history:

a personal history of breast cancer

prior to enrolment

there were 2,708 participants (3.5%

of enrolees) identified for inclusion in

this subgroup

Menopausal status not a criterion.

age ≥ 35 years

estimated ≥ 10% lifetime risk of

OC/FTC

surveillance start ‘at age 30 or 35

years’46

‘Usually at least a 10% lifetime risk’ of

OC

age ≥25 years and considering

RRSO due to family history or

known mutation

Key exclusion criteria


Previous diagnosis of lung,

colorectal, or ovarian cancer

Previous oophorectomy (dropped in

1996)

Current tamoxifen use (dropped in

1999)

bilateral salpingo-oophorectomy NR NR

Study design, N Post hoc analysis of prospective PLCO

RCT of population screening –

subgroup analysis of high-risk women.

Family history subgroup N=22,355;

28.6% of enrolees in population

screening study

Personal history subgroup N = 2,708;

3.5% of enrolees

Prospective cohort study (N = 3,563) Prospective cohort study (N = 3,532) Prospective cohort survey (N = 75)

imminent surgery (n =38)

continue screening (n = 37)

Cancers included invasive OC

FTP

PPC

(borderline excluded – false positive)

epithelial OC

FTC

PPC (separately)

Non-epithelial OC and borderline

ovarian tumours were excluded.

‘PPC (defined according to

recognised pathologic criteria) is

unlikely to be amenable to early-stage

detection using current techniques;

however, data are presented both

including and excluding PPC from the

screening performance analysis.’

invasive epithelial OC

borderline OC

(FTC and PPC not mentioned)

N/A

46 According to a cited article reporting results from a multicentre study in the Netherlands that contributed to this study: ‘the minimum age of entry into the surveillance programme was 35 years or 5 years earlier

than the youngest age at diagnosis of ovarian cancer in the family.’



Period of study

Start date Nov 1993 May 2002 Jan 1991 Dec 1999

End date Jul 2001 (end of recruitment) Jan 2008 Mar 200747 Sep 2004

Person-years screened Not reported for subgroups 11,366 NR N/A

Censorship After 13 years of follow-up, or 28 Feb

2010; whichever comes first.

Participants were followed for a

minimum of 10 years.

Censored 1 year after withdrawal or

last trial screen. However, subsequent

diagnoses to March 2011 were

reported as diagnoses > 365 days after

last trial screen (post-censorship).

66.2% of women transferred to

UKFOCSS Phase II, which started in Jun

2007, and were censored 365 days

after the first Phase II screen. No

cancers were detected within this first

year of increased screening, so

sensitivity was not artificially increased.

1 Mar 2007 N/A

Median follow up

(years)

NR for subgroups (minimum 10 years) NR.

11,366 women-years of screening

(mean, 3.2 years per woman)

up to 16 years 1 year

Screening method

(see Screening strategies section below

for details)

Annual screening for 4 years with both:

TVUS

CA125

followed by 2 years of screening with

TVUS only.

Single threshold cut-off:

≥35 U/mL

Annual screening with both:

TVUS

CA125

Single threshold cut-offs:

pre-menopausal – 35 U/mL

post-menopausal – 30 U/mL

Annual screening with both:

TVUS

CA125

It is assumed CA125 was analysed with

a single threshold, but no further

description of the screening strategy

was reported.

Not reported.

Positive-screen follow-up actions Abnormal results for either test

precipitated notification in writing to

the participant and their physician for

standard diagnostic and follow up

procedures. If requested, referral

physicians were provided with

standard-of-practice guidelines for

diagnostic procedures by the local

PLCO screening centre.

Guidelines for management of results

were provided, but management

remained at the discretion of

collaborating gynaecologists.

NR NR

47 This period of time was variously reported as being the screening period or the recruitment period. Actual length of screening and recruitment is unclear, and may not have ceased at censorship.



Key outcomes reported OC incidence

stage at diagnosis

mortality due to OC

all-cause mortality

diagnoses by mode of detection


sensitivity

stage at diagnosis

mortality

diagnoses by mode of detection

stage at diagnosis

mortality (comparison of BRCA1/2

carriers and non-carriers)

QoL using four instruments, two of

which are validated:

Medical Outcomes Survey (MOS)

Short-Form Health Survey (SF-36)

Center for Epidemiological Studies-

Depression scale (CES-D)

Abbreviations: CA, cancer antigen; FTC, fallopian tube cancer; N/A, not applicable; NR, not reported; OC, ovarian cancer; PLCO, Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial; PPC, primary

peritoneal cancer; QoL, quality of life; RCT, randomised controlled trial; RRSO, risk-reducing salpingo-oophorectomy; TVUS, transvaginal ultrasonography; UK, United Kingdom; UKFOCSS, United Kingdom Familial

Ovarian Cancer Screening Study; US, United States.


Eligibility criteria

Table 0.3 Inclusion/exclusion criteria – surveillance studies

Study ID Inclusion/exclusion criteria including definition of high risk status

ROCA-based CA125 evaluation

UKFOCSS

Phase II

Inclusion criteria

The volunteer must be aged at least 35 years and should either have been affected by one of the following cancers or be

a first degree relative (FDR) of an affected family member (NB. Tubal & primary peritoneal cancers may be considered

equivalent to ovarian cancers)

Families with ovarian or ovarian & breast cancer

1) ≥2 individuals with OC who are FDR

2) One OC and 1 breast cancer <50 years who are FDR

3) One OC and 2 breast cancers <60 years who are FDR

4) Breast cancer in volunteer/ proband (≤45 years) and mother with both breast and ovarian cancer (in the same

person)

5) Breast cancer in volunteer/ proband (≤40 years) and sister with both breast and ovarian cancer (in the same person)

6) Criteria 1, 2, and 3 can be modified where paternal transmission is occurring (i.e. families where affected relatives are

related by second degree through an unaffected intervening male relative and there is an affected sister are

eligible).

Families with a known gene mutation

7) The family contains an affected individual with a mutation of one of the known OC predisposing genes e.g. BRCA1,

BRCA2, MLH1, MSH2, MSH6, PMS1 and PMS2.

Families with colorectal cancer (HNPCC or Lynch syndrome)

8) The family contains ≥3 individuals with a HNPCC related cancer#, who are FDR and ≥1 case is diagnosed before 50

years and the cancers affect ≥1 generation.

#HNPCC related cancers - colorectal, endometrial, small bowel, ureteric and renal pelvic cancers

Families with only breast cancer*

9) ≥4 breast cancers

10) 3 breast cancers related by FDR

a) one ≤30 years or

b) all ≤40 years or

c) one MBC (Male Breast Cancer) and one bilateral breast cancer

11) Breast cancer in volunteer/ proband (≤50 years) and

a) breast cancer in mother (age of onset being ≤30 years in one and ≤50 years in the other) or

b) bilateral breast cancer in mother (≤40 years onset) or

c) one MBC and one bilateral breast cancer

12) Two MBC (one <40 years) in the family and proband is a FDR of one of them.

Families with Ashkenazi Jewish ethnicity (additional criteria)*

Ashkenazi Jewish ethnicity and any one of the following:

13) Breast cancer (<40 years) or bilateral breast cancer (first cancer <50 years) in volunteer/ proband, irrespective of FH

(family history) of cancer

14) Breast cancer in volunteer/ proband (<50 years) and one FDR with breast cancer (<50years) or ovarian cancer (any

age) or MBC (any age)

15) Breast cancer in volunteer/ proband (<60 years) and one FDR with breast cancer (<40 years) or ovarian cancer (any

age) or MBC (any age)

16) One FDR with ovarian cancer (<50 years)

17) FDR with breast and ovarian cancer in the same woman (any age)

18) Two FDR with breast cancer (<40 years)

19) Two MBC (<60 years) in the family and proband is a FDR of one of them.

*Families in these categories negative on full BRCA1 and BRCA2 screening are ineligible.

Exclusion criteria

1) Past history of bilateral oophorectomy (women with one or both fallopian tubes still present are eligible)

2) Age <35 years

3) Women participating in other ovarian cancer research trials

4) Women who have tested negative for a pathological mutation found in an affected family member. Similarly, those

who obtain a negative result after recruitment need to be withdrawn

5) Breast cancer-only families (inclusion criteria 9-12) and Ashkenazi families (criteria 13-19) are not eligible if full gene

mutation screening has been done and no mutation found (such families are not thought to be at increased risk of

developing ovarian cancer)

6) Women should not be recruited if RRSO is imminent, but those with an intention to have RRSO at some (unspecified)

date in the future are eligible. Good clinical practice dictates that even if a woman is not recruited to UKFOCSS, she

should have a TVUS and CA125 performed shortly before RRSO to reduce the risk that an occult cancer only comes to

light at the time of surgery.


Study ID Inclusion/exclusion criteria including definition of high risk status

CGN/GOG Inclusion criteria

Eligibility criteria included the following, with “close relatives” defined as first- or second-degree blood relatives:

1. the subject or close relative (deleterious mutation in a first-degree relative confers a 50% prior probability of an

untested subject being a mutation carrier, while deleterious mutation in a second-degree relative confers a 25%

prior probability of an untested subject being a mutation carrier) had a known, deleterious BRCA1 or BRCA2

mutation; or

2. at least two ovarian or breast cancers (including DCIS) had been diagnosed among the subject or close

relatives within the same lineage; or

3. the subject was of Ashkenazi Jewish ethnicity, with one first-degree or two-second degree relatives with ovarian

or breast cancer; or

4. the subject was of Ashkenazi Jewish ethnicity and had a personal history of breast cancer; or

5. the probability of carrying a BRCA1 or BRCA2 mutation given family pedigree of breast and ovarian cancers as

calculated by BRCAPRO exceeded 20%.

When a diagnosis of breast cancer was required to meet any of these criteria, at least one breast cancer must have been

pre-menopausal or, if menopausal status was unknown at time of diagnosis, then age at diagnosis was required to be ≤50

years.

It has since become apparent that some of these women are now known to not be at increased risk for ovarian cancer –

e.g. women with a site-specific breast cancer family history whose families lack a deleterious BRCA1/2 mutation, but they

are nonetheless included in our analysis in line with the principle of “intention to treat.”

Exclusion criteria

The subject was excluded from study participation if she:

1. had a personal history of ovarian cancer, including low malignant potential cancers (LMP), or primary papillary

serous carcinoma of the peritoneum; or

2. had a close relative with a deleterious BRCA1/2 mutation and the subject had tested negative for the same

mutation; or

3. was less than 30 years of age; or

4. was currently pregnant or anticipating pregnancy during the study; or

5. was participating in other ovarian cancer early detection trials; or

6. had a current active malignancy (other than non-melanoma skin cancer); or

7. had been treated for metastatic malignancy within the prior five years (excluding hormonal therapies); or

8. had undergone intra-peritoneal surgery within the prior 3 months (laparoscopy or laparotomy); or

9. had a history of any medical conditions that would place the subject at risk related to phlebotomy, including but

not limited to hemophilia or other bleeding disorders, chronic infectious disease, emphysema or serious anemia.

Women who had clinical symptoms suggestive of ovarian cancer were also excluded.

Single threshold CA125 evaluation

PLCO-HR The current study defined a subgroup of participants who reported at least one first degree relative with breast cancer or

at least one first degree relative with ovarian cancer.

A separate subgroup of patients with a personal history of breast cancer prior to enrolment was also analysed.

Other inclusion and exclusion criteria as per the PLCO RCT for population screening.

UKFOCSS PI Inclusion criteria

The inclusion criteria originally defined a minimum 10% lifetime OC risk (Appendix, online only) on the basis of family history

or predisposing mutations, including LS-associated mutations. OC in the family was defined as epithelial OC, FTC, or PPC.

Exclusion criteria

Women were excluded if they had undergone bilateral salpingo-oophorectomy or were participating in

other OC screening trials.

UK-

Netherlands-

Norway

Inclusion criteria

Women assessed as being at increased risk of ovarian cancer (usually at least a 10% lifetime risk, requiring more than just a

single close relative with ovarian cancer). Screening started ‘at either 30 or 35 years of age’.

Exclusion criteria

None reported.

Fox Chase

Cancer

Centre

Inclusion criteria

Eligible women were ages 25 and older who were considering RRSO due to: 1) a family history of ovarian cancer, 2) a

family history suggestive of a hereditary breast/ovarian pattern, and/ or 3) the presence of a known disease-related gene

mutation in the family.

Exclusion criteria

None reported.

Abbreviations: CA, cancer antigen; CGN, Cancer Genetics Network; DCIS, ductal carcinoma in situ; FDR, first degree relative; FTC, fallopian

tube cancer; GOG, Gynecologic Oncology Group; HNPCC, hereditary nonpolyposis colorectal cancer; MBC, male breast cancer; OC,

ovarian cancer; PLCO, Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial; PPC, primary peritoneal cancer; RCT, randomised

controlled trial; ROCA, risk of ovarian cancer algorithm; RRSO, risk-reducing salpingo-oophorectomy; TVUS, transvaginal ultrasonography; UK,

United Kingdom; UKFOCSS, United Kingdom Familial Ovarian Cancer Screening Study.


Screening strategies

Table 0.4 Details of screening strategies – surveillance studies

Study ID Screening strategies


UKFOCSS

Phase II

ROCA every 4 months and annual TVUS (or within 2 months of an abnormal ROCA result). The ROCA was adjusted for the

high-risk population (HR ROCA).48

The first ROC value triaged women to one of the following three paths;

4-monthly routine screening (‘normal’)

TVUS within two months and repeat CA125 measurement after two months (‘intermediate’)*

referral for clinical assessment by collaborating centre gynaecologist (‘elevated’).

Subsequent TVUS and ROC results triggered one of the following paths;

return to routine screening

repeat CA125

repeat CA125 and TVUS

referral to rapid access gynaecologist, or

triage by coordinating centre study clinician if ROC was persistently intermediate or TVS unsatisfactory.

*from 13/05/2010 Intermediate results were sub-classified into High Intermediate and Low Intermediate.

In addition to this protocol, CA125 was repeated at coordinating centre clinicians’ discretion within 2 months if the ROC

was ‘normal’ but CA125 had increased by >50% since the prior test. Women referred but not undergoing surgery were, at

the coordinating centre clinicians’ discretion, transferred to ‘high-alert screening’, comprising repeat TVS and CA125 at 2,

6 and 10 months.

(Also see Table AppE.4 in Appendix E for a representation of the triage protocol.)

CGN/GOG ROCA every 3 months and annual TVUS

normal-risk women (<1% risk of having OC) returned in 3 months for the next CA125

those with an intermediate risk (1%–10%) were referred for TVUS

those with an elevated risk (>10%) received TVUS and evaluation by a gynaecologic oncologist or study site principal

investigator.


PLCO-HR In the screening arm, participants underwent a baseline pelvic ultrasound and serum CA125, with subsequent annual

pelvic ultrasound for an additional 3 years, and annual CA125 for 5 years. Abnormal screening was determined by a

CA125 greater than 35 U/mL, or any of the following abnormalities on pelvic ultrasound: ovarian volume greater than 10

mL, cyst volume greater than 10 mL, any solid area of papillary projection, or any cyst with mixed components.

UKFOCSS

Phase I

Annual TVUS and single threshold CA125 (cut-offs of 35 and 30 IU/mL in pre-menopausal and post-menopausal women,

respectively). Abnormalities triggered follow-up scans, but no further information was provided regarding timing or

combinations of tests performed during repeat screening. Protocols developed for Phase II of this study.

UK-

Netherlands-

Norway

This study did not describe screening in detail, which was conducted in one of five European centres. However, a

publication reporting results from the Netherlands that was cited by Evans 2009 for further information regarding screening

protocols reports using a single threshold cut-off of 35 U/mL.

Fox Chase

Cancer

Centre

Not described.

Abbreviations: CA, cancer antigen; CGN, Cancer Genetics Network; GOG, Gynecologic Oncology Group; HR, high-risk; OC, ovarian cancer;

PLCO, Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial; ROC, risk of ovarian cancer; ROCA, risk of ovarian cancer algorithm;

TVUS, transvaginal ultrasonography; UK, United Kingdom; UKFOCSS, United Kingdom Familial Ovarian Cancer Screening Study.

Terminology and definitions

Table 0.5 Terminology and definitions – surveillance studies

Study ID Definition


UKFOCSS

Phase II

Cancers

True positive – invasive epithelial OC/FTC diagnosed after screen-positive surgery.

Prevalent cases – diagnosed at first screen.

Incident cases – diagnosed after subsequent screens. For women who transferred from Phase I to Phase II, their first

Phase II screen was classified as incident.

48 The high-risk ROCA incorporated the higher a priori risk in this population and different reference levels for risk stratification for post-

menopausal compared with pre-menopausal women (higher baseline CA125 and variability in pre-menopausal women).


Study ID Definition

Interval cancers (false negatives) – presenting clinically < 365 days after the last screen.

Occult cancers – found in RRSO specimens < 365 days after the last annual screen (these can be classified as either false

negative or true positive as they would have been either missed or detected at the next routine screening if RRSO had not

taken place).49

Other diagnoses

False positive – all other diagnoses (including borderline and benign tumours) from surgery prompted by abnormal test

results.

Screening-related surgery – Cases in which a non-concerning test result (e.g. simple ovarian cysts, transiently raised

CA125) had contributed to the decision to undergo surgery.

True negative – last screen was normal, and no diagnosis of OC/FTC was made in the subsequent 365 days.

RRSO – asymptomatic women who had normal screening tests in the year before surgery and the recruiting center

indicated RRSO as the reason for withdrawal from the study.

CGN/GOG Cancers

True positive – term used but not defined.

Prevalent cases – existing but undetected at screening initiation.

Incident cases – arose during rather than before screening initiation.

Interval cancers – term not used; referred to as ‘clinically detected’, and not defined.

Occult cancers – term used but not defined.

Other diagnoses

False positive – term used but not defined.


PLCO-HR Taken from definitions extracted from PLCO RCT for population screening:

Cancers

True positives – diagnosed as a result of investigations initiated after a screening test with a positive result and without a

lapse in the diagnostic evaluation exceeding 9 months.

Prevalent cases – terminology not used, but category reported (detected as baseline screen).

Incident cases – terminology not used, but category reported (detected by screening at 1-5 years).

Interval cancers – cancers not detected by screening and diagnosed within 12 months of the woman’s last expected

screening examination.

Other Diagnoses

False positives – positive screening examination result that did not result in cancers detected by screening.

UKFOCSS PI Cancers

True positive – invasive epithelial OC/FTC diagnosed after screen-positive surgery.

Prevalent cases – diagnosed at first screen.

Incident cases – diagnosed after subsequent screens.

Interval cancers (false negatives) – presenting clinically < 365 days after the last screen.

Occult cancers – found in RRSO specimens < 365 days after the last annual screen (these can be classified as either false

negative or true positive as they would have been either missed or detected at the next routine screening if RRSO had not

taken place).49

Other diagnoses

False positive – all other diagnoses (including borderline and benign tumours) from surgery prompted by abnormal test

results.

Screening-related surgery – Cases in which a non-concerning test result (e.g. simple ovarian cysts, transiently raised

CA125) had contributed to the decision to undergo surgery.

True negative – last screen was normal, and no diagnosis of OC/FTC was made in the subsequent 365 days.

UK-

Netherlands-

Norway

Interval cancers: occurring symptomatically within 12–14 months of a previously normal screening round.

Incidence cancers: detected either by CA125, ultrasound or both after the initial prevalent round of screening.

Fox Chase

Cancer

Centre

As this study is reporting QoL outcomes only, findings from screening are not reported.

Abbreviations: CA, cancer antigen; CGN, Cancer Genetics Network; FTC, fallopian tube cancer; GOG, Gynecologic Oncology Group; HR,

high-risk; OC, ovarian cancer; PLCO, Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial; QoL, quality of life; RCT, randomised

controlled trial; ROCA, risk of ovarian cancer algorithm; RRSO, risk-reducing salpingo-oophorectomy; UK, United Kingdom; UKFOCSS, United

Kingdom Familial Ovarian Cancer Screening Study.

49 The authors therefore reported screening performance using both these scenarios, on the assumption that the true sensitivity of screening in

a population not undergoing RRSO falls between these two estimates.


Notifications and ascertainment of outcomes

Key differences between the trials in the methods used to identify incident cancers and deaths

include the following:

Main sources for identification of ovarian cancer or death

UKFOCSS Phase I and II – women were flagged at cancer registries using unique health

number identifiers.

CGN/GOG and PLCO-HR – followed up with questionnaires sent to participants.

Trigger for review of medical records for outcome verification

UKCFOCSS Phase I and II – review of all surgical records.

CGN/GOG – review of all surgical specimens.

PLCO-HR – ovarian cancer diagnosis or death indicated in returned questionnaire (annual

study update), or discovered in search of cancer or death registries.

4.1.4.2 Key systematic reviews and HTAs

Only one systematic review (Auranen et al 2011) evaluated the role of surveillance in women at

high risk of ovarian cancer. The specific focus of this systematic review was on women belonging to

hereditary nonpolyposis colorectal cancer (HNPCC, also known as Lynch syndrome) families. The

citation details for this review is shown in Appendix D (Section D.2.2).

Characteristics of systematic reviews

The characteristics of the systematic review are summarised in Table 0.6.

Table 0.6 Key characteristics of systematic reviews relating to surveillance of women at

high risk

Study ID

Qualitya


search

Study eligibility Included studies (no.

of patients)

Intervention &

comparator

Outcomes of

interest

Auranen

2011

Poor

quality

To evaluate the

role of

gynaecological

cancer

surveillance in

women who

carry a HNPCC

mutation or

belong to a

family that fulfils

the criteria for

HNPCC.

PubMed; a

clinical trials

registry

Search to

Feb 2010

Inclusion

women: a)

belonging to families

fulfilling Amsterdam II

criteria but the

families have not

been tested for

mutations; b)

belonging to families

with a known

HNPCC mutation but

the women have not

been tested; c)

carrying an HNPCC

mutation

reported a result of

any gynecological

intervention

Exclusion

reported

interventions other

than surveillance

For OC

1 prospective cohort

study:

Renkonen-Sinisalo

2006 (N=175;

Finland)

1 prospective

observational studies:

Gerritzen 2009

(N=100;

Netherlands)

1 retrospective

observational studies:

Rijcken 2003 (N=41;

Netherlands)

Intervention

Gynaecological

cancer

surveillance

Comparator

Not specified

cancers

detected at

screening

stage at

screening

cancer

precursor

states at

screening

interval

cancers

detected

stage of

interval

cancers

Abbreviations: HNPCC, hereditary nonpolyposis colorectal cancer; OC, ovarian cancer.



4.1.5 Data extraction – clinical studies using ROCA-based CA125 evaluation

A combined analysis of the CGN and GOG-0199 studies (Skates 2011) was the foundation work for

the development of ROCA for use in high risk women, which takes into account different baseline

levels in pre-menopausal and post-menopausal women, among other factors. The Skates 2017

study publication (CGN/GOG) reports diagnosis by mode of detection, false positive and stage at

diagnosis. Phase II of the UKFOCSS trial implemented a very similar screening strategy using the

high-risk ROCA for triage to TVUS.

4.1.5.1 UKFOCSS Phase II

Phase II of the UKFOCSS trial was instigated in response to concerns that annual screening with

CA125 (single threshold) and TVUS in the Phase I trial was not increasing the proportion of early

stage diagnoses (see Section 4.1.6.2 for the results of Phase I). Changes were made to Phase II of

the trial in an attempt to achieve rigorous adherence to screening schedules and swifter action on

abnormal results, and thereby optimise early detection:

screening frequency increased to once every 4 months

protocol driven threshold for, and timing of, repeat tests

CA125 assayed in a single laboratory to reduce inter-assay variability

ROCA for evaluating serial CA125 values

collaborators prompted to organise scans and referrals via an Internet-based database,

modelled on the successful UKCTOCS database.

Participants were recruited from the Phase I trial (52%) or by de novo recruitment (48%).

A before/after screening comparison is presented by the study authors, comparing outcomes

within a year of screening to those over a year after the last screen.

Detection outcomes

Mode of detection

The mode of cancer detection is shown in Table 0.7. A total of 37 cancers were detected, of which

around half (19) were detected within a year of trial screening. Of those, most were screen

detected (13) and the others were occult (i.e. no incident diagnoses prompted by symptoms within

a year of screening). This is in contrast to diagnosis over a year after the last trial screen, for which

13 of 18 (72%) were symptom-prompted.

Only one prevalent cancer was detected in Phase II, in a de novo recruit to Phase II. This is in

contrast to the Phase I trial, in which 9 of 37 cancers were prevalent. As half the participants in

Phase II had received ongoing screening immediately prior during Phase I, this result is not surprising.

Consequently, the results of Phase II are presented aggregated for prevalent or incident screen-

detected cancers.


Table 0.7 Mode of cancer detection – UKFOCSS Phase II

Detection outcomes with HR ROCA triage OC (invasive), FTC, PPC

n (%)

N=4,348

Total cancers detected 37 (100)

Detected <365 days after last trial screen (prior to censorship) 19 (51)

Detected >365 days after last trial screen (post-censorship) 18 (49)

Detected by screening 13 (35)

First screen (prevalent) 1 (3)

Subsequent screens (incident screen-detected) 12 (32)

Detected by other means <365 days after last trial screen 6 (16)

Surgery prompted by symptoms (interval cancers) 0 (0)

Occult cancers – discovered at RRSO unrelated to test results 6 (16)

Detected >365 days after last trial screen 18 (49)

Surgery prompted by symptoms 13 (35)

Occult cancers – discovered at RRSO 2 (5)

Detected at annual screening performed locally 3 (8)

Incidence (detected < 365 days from last screen)

Overall annual incidence (%) based on 13,728 person-years of trial screening 0.14

Abbreviations: FTC, fallopian tube cancer; HR, high risk; OC, ovarian cancer; PPC, primary peritoneal cancer; ROCA, risk of ovarian cancer

algorithm; RRSO, risk-reducing salpingo-oophorectomy; UKFOCSS, United Kingdom Familial Ovarian Cancer Screening Study.

Sensitivity

Occult cancers discovered during risk-reducing salpingo-oophorectomy (RRSO), unrelated to

screening, impacts on estimates of screening sensitivity. In an attempt to account for this, sensitivity

estimates were derived from modelling; the lower confidence interval for all screen detected

cancers of 75.3% was used as a conservative approximation of the proportion of occult cancers

that might have been screen detected had women not undergone RRSO.

Modelled sensitivity for ovarian cancer or FTC detection within 1 year was estimated at 94.7% (95%

CI: 74.0%, 99.9%).

False positives

Table 0.8 shows the number of false positive surgeries i.e. screen-positive surgeries resulting in any

diagnosis other than invasive ovarian cancer, FTC or PPC (borderline tumours were counted as

false positives). The number of false-positive surgeries per screen-detect cancer is substantially

higher in Phase II of UKFOCSS compared to Phase I (11.5 versus 2.4, respectively).

RRSO is currently recommended as optimal management for women at high risk of ovarian cancer,

but some women who would otherwise elect to have RRSO may decide to use surveillance if it

were recommended – especially prior to completion of childbearing. This impacts on the

implications of false positive surgery, as complications that may arise from false positive surgery

may also have occurred during prophylactic RRSO.

Table 0.8 False positive surgery rates – UKFOCSS Phase II

Outcome N (%)

Participants 4,348 (100)

Screen-positive surgeries 162 (3.7)

False positive surgeries 149 (3.4%)

Screen-detected cancers 13 (0.3%)

Number of surgeries to detect one case of cancer 12.5

Number of false positive surgeries per screen-detected cancer 11.5

Abbreviations: UKFOCSS, United Kingdom Familial Ovarian Cancer Screening Study.


Tumour characteristics

As described earlier in Table 0.15, FIGO staging of ovarian tumours is based on the degree of

spread, with early stage restricted to the ovaries or pelvis. The UKFOCSS Phase II study also reported

comparisons according to the volume of metastatic peritoneal disease, with cancers at Stage IIIa

or less referred to as low volume, and those more advanced than Stage IIIa as high volume

cancers. Table 0.9 shows all cancers diagnosed in this study by stage, and by detection mode.

Although a no-screening comparison group is not available, the authors note that a comparison

between diagnoses made during screening and after screening may be valid.

Screen-detected cancers are either prevalent or incident cases – these were shown combined as

only one case was detected at the prevalence screen.

Of 37 total diagnoses during the trial, 13 were screen detected, of which 5 (38.5%) were early stage

(95% CI: 13.9, 68.4) and 46% were low volume. Eighteen cancers were diagnosed >365 days after

the last UKFOCSS screen, most of which were flagged by symptoms. All of these post-censorship

diagnoses were late stage and high volume with the exception of one case found at Stage I during

RRSO unrelated to surgery (occult).

To investigate stage shift, the primary study publication reports a single statistical analysis,

comparing the proportion of high volume diagnoses made <365 days after the last screen (7/19;

36.8%) versus >365 days after the last screen (17/18; 94.4% [95% CI: 72.7, 99.9]), which was a

statistically significant difference (p<0.001).


Table 0.9 Cancer stage at diagnosis – UKFOCSS Phase II


Diagnoses by stage, n (%) All diagnoses

Detected <365 days after last trial screen Detected >365 days after last trial screen

Screen

detected

Occult – RRSO

unrelated to

screening

Prompted by

symptoms

All screening

phase

Local

annual

screening

Occult

– RRSO

Prompted by

symptoms

All post-

screening

phase

Total cancers detected 37 (100) 13 (100)50 6 (100) 0 (100) 19 (100) 3 (100) 2 (100) 13 (100) 18 (100)

Stage I 7 (19) 2 (15) 4 (67) 0 (0) 6 (32) 0 (0) 1 (50) 0 (0) 1 (6)

Stage II 4 (11) 3 (23) 1 (17) 0 (0) 4 (21) 0 (0) 0 (0) 0 (0) 0 (0)

Stage IIIa 2 (5) 1 (8) 1 (17) 0 (0) 2 (11) 0 (0) 0 (0) 0 (0) 0 (0)

Stage IIIb/c 21 (57) 7 (54) 0 (0) 0 (0) 7 (37) 3 (100) 1 (50) 10 (77) 14 (78)

Stage IV 3 (8) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 3 (23) 3 (17)

Early versus late stage

Early (I or II) 11 (30) 5 (38) 5 (83) 0 (0) 10 (53) 0 (0) 1 (50) 0 (0) 1 (6)

Late (III or IV) 26 (70) 8 (62) 1 (17) 0 (0) 9 (47) 3 (100) 1 (50) 13 (100) 17 (94)

Low versus high volume

Low volume (I or II or IIIa) 13 (35) 6 (46) 6 (100) 0 (0) 12 (63) 0 (0) 1 (50) 0 (0) 1 (6)

High volume (IIIb or IIIc or IV) 24 (65) 7 (54) 0 (0) 0 (0) 7 (37) 3 (100) 1 (50) 13 (100) 17 (94)

% low volume, <365 days vs >

365 days

p < 0.001

Abbreviations: FTC, fallopian tube cancer; OC, ovarian cancer; PPC, primary peritoneal cancer; RRSO, risk-reducing salpingo-oophorectomy; UKFOCSS, United Kingdom Familial Ovarian Cancer Screening Study.

50 Includes 1 case diagnosed in prevalence screen.


Mortality

Of the 37 women diagnosed with ovarian cancer, FTC or PPC, 5 (13%) were not alive at censorship

in March 2016.51 Of the 19 women diagnosed within a year of screening, 3 (16%) died. No survival

analysis was reported due to the low number of events observed.

Quality of life – PsyFOCS partner study

Outcomes from PsyFOCS, the partner study to UKFOCSS, used quality of life instruments to

investigate the impact of screening and reasons for withdrawal. All women entering Phase II of the

UKFOCSS trial were invited to participate in PsyFOCS, which used the following validated

instruments:

a revised Illness Perceptions Questionnaire (IPQ-R) – adapted to refer to ovarian cancer or

ovarian cancer risk52

the Hospital Anxiety and Depression Scale (HADS)

the Impact of Event Scale (IES) – used for ovarian cancer-specific distress.

Questionnaires were sent out at the following times:

T1 – one month before the first routine Phase II blood test

T2 – one week after women received their initial screening result

T3 –only for those recalled for further testing, sent one week after being returned to routine

screening

T4 – nine months after receiving a normal result or after return to routine screening following

recall for further tests due to an abnormal result.

Measures included cancer distress, general anxiety/depression, reassurance, and withdrawal from

screening.

Prior to screening

T1 was completed by 1,999 women, and these baseline psychological data were used in predictor

analyses of ovarian cancer-specific distress (Lancastle 2011; not reported here).

Factors associated with withdrawal from UKFOCSS Phase II prior to the first screen were investigated

(Lifford 2012); 110 of the 1,999 T1 survey respondents withdrew prior to their first Phase II screen, with

a majority (66%) deciding on RRSO. Logistic regression analysis of baseline (T1) findings from these

women and 1,868 women who continued with screening found the following were associated with

withdrawal prior to first screen:

prior annual (Phase 1) screening (OR=13.34, p<0.01)

past experience of recall for further tests (OR=2.37, p<0.01)

greater cancer-specific distress (OR=1.38, p<0.01)

belief in ageing as a cause of ovarian cancer (OR=1.32, p=0.05).

The authors concluded that both clinical and psychological factors were involved in the decision

to withdraw.

Impact of recall for further testing

Covariate analyses of data from all surveys (T1-T4) were used to indicate that women with

abnormal results reported significantly more ‘moderate cancer distress’ compared to women with

normal results (F=27.47, p≤0.001, η2=0.02) one week after their abnormal result, and were

51 It is assumed these women died from their disease, although this is not explicitly stated. This compares to 30% observed in the Phase I study. 52 Described in Lancastle 2011


significantly more likely to withdraw from screening (OR=4.38, p≤0.001). These effects were not

apparent at later follow up (once returned to routine screening, and nine months later). The effect

of screening results on general anxiety/depression or overall reassurance was not significant.

The authors report the following conclusion:

‘Women participating in frequent ovarian screening who are recalled for an

abnormal result may experience transient cancer-specific distress, which may

prompt reconsideration of risk management options. Health professionals and policy

makers may be reassured that frequent familial ovarian screening does not cause

sustained psychological harm’.

Semi-structured interviews were also conducted with women who had taken part in the UKFOCSS

study (Lifford 2013; not reported here) to ‘gain an in-depth understanding of women’s experiences

of participating in ovarian cancer screening’. Overall, the authors found that most women

considered surveillance screening to be an acceptable risk management strategy.

Safety outcomes

The primary publication for the UKFOCSS Phase II study did not report adverse events of screening

or surgery.

4.1.5.2 CGN/GOG

Detection outcomes

Mode of detection

Of the 19 cancers detected in the CGN/GOG combined studies, 9 were screen-detected; 4 at

prevalence screening and 5 at subsequent screening. One interval cancer and 9 occult cancers

were also diagnosed during the study. The authors did not report annual incidence. It is not clear

whether such an estimate is valid for the combined studies, but was calculated here post hoc to

compare with the Phase II UKFOCSS study – both were 0.14%.

Table 0.10 Mode of cancer detection – CGN/GOG

Detection outcomes with HR ROCA triage OC (invasive), FTC, PPC

n (%)

N=3,449

Total cancers detected 19

Detected by screening 9 (47)

First screen (prevalent) 4

Subsequent screens (incident screen-detected) 5

Detected by other means 10 (53)

Surgery prompted by symptoms (interval cancers) 1

Occult cancers – discovered at RRSO unrelated to test results 9

Incidence

Overall annual incidence (%) based on 13,080 person-years of trial screening 0.1453

Abbreviations: CGN, Cancer Genetics Network; FTC, fallopian tube cancer; GOG, Gynecologic Oncology Group; HR, high risk; OC, ovarian

cancer; PPC, primary peritoneal cancer; ROCA, risk of ovarian cancer algorithm; RRSO, risk-reducing salpingo-oophorectomy.

Sensitivity

Sensitivity was calculated as 83% based on 5 of the 6 incident cancers being screen detected. The

authors note that they focused sensitivity analysis on incident cases as they comprise the ‘best

metric for long-term screening’.

53 Calculated post hoc – annual incidence not reported in study publication.


This estimate does not take into account the 9 occult cancers discovered during 501 elective

RRSOs – had screening replaced these surgeries, a proportion of them may have been screen

detected. The UKFOCSS Phase I study accounted for the impact of occult cancers on sensitivity by

calculating upper and lower limits, and Phase II used modeling.

False positives

The false positive rate in the CGN/GOG was very high at 20.7 false positive surgeries performed for

every case of cancer detected.

Table 0.11 False-positive surgery rates – CGN/GOG

Outcome N (%)

Participants 3,449

Screen-positive surgeries 195

False positive surgeries 186

Screen-detected cancers 9



Abbreviations: CGN, Cancer Genetics Network; GOG, Gynecologic Oncology Group.


Table 0.12 shows the stage by diagnosis for all 19 cancers diagnosed in the CGN/GOG study. These

exclude borderline tumours. For incident cancers (both screen-detected and clinically detected), 3

of 6 (50%) were detected early (95% CI: 12%, 88%). Using historical rates, this represents a statistically

significant increase in early stage diagnosis compared to BRCA1 cases (10%; p=0.016) but not

normal risk cases (33.5%; p>0.1).

Table 0.12 Cancer stage at diagnosis – CGN/GOG


Diagnoses by stage, n (%)

Screen-detected Occult – RRSO

unrelated to

screening

Prompted by symptoms

(clinically detected

incident cancer) Prevalent Incident

Total cancers detected 4 5 9 1

Stage I - - 5 -

Stage II - 3 - -

Stage III 3 2 3 1

Stage IV 1 - - -

Other 1 STIC54


Stage I/II 0 3 5 0

Stage III/IV 4 2 3 1

Source: data extracted from Table 2 in Skates 2017.

Abbreviations: CGN, Cancer Genetics Network; FTC, fallopian tube cancer; GOG, Gynecologic Oncology Group; OC, ovarian cancer; PPC,

primary peritoneal cancer; RRSO, risk-reducing salpingo-oophorectomy.

Mortality

Mortality outcomes were not reported in this study.

4.1.6 Data extraction – clinical studies using single threshold CA125

4.1.6.1 PLCO-HR

This post hoc analysis of the PLCO RCT reported comparative results for two subgroups:

54 One lesion was reported as a serous tubal intraepithelial carcinoma (STIC) allocated Stage 0 and Grade 0.


women with a family history of breast or ovarian cancer (at least one first degree relative)

women with a personal history of breast cancer.

While these definitions are broader than the general definitions of high risk, it is of interest to

determine whether screening may be more effective in a population with a slightly elevated

overall risk compared to the general population.

All results reported in this study for women with a family history are shown in Table 0.13. A similar

number of cancers was diagnosed in each of the two study groups. While a higher proportion of

screened women were diagnosed with early stage cancers (Stages I or II), the difference was not

significant.

However, when classified as ≤Stage IIIb versus ≥Stage IIIc, a significant stage shift was observed in

screened versus unscreened women. The authors note this classification identifies women prior to

the ‘symptomatic phase’. The study authors conclude that these results indicate a trend towards

earlier stage diagnosis associated with screening, and a significant reduction in advanced bulky

disease at diagnosis.

Table 0.13 Outcomes from PLCO RCT for women with at least one first degree relative with

breast or ovarian cancer

OC (invasive), FTP, PPC

Outcomes

CA125 + TVUS

(N = 11,293)

No screening

(N = 11,062)

Risk ratio [95% CI]

Overall mortality NR NR 0.99 [0.93, 1.06]

Ovarian cancers detected, n 48 44 NR

OC-specific mortality, n 23 32 0.66 [0.39, 1.12]

OC-specific survival from enrolment55 NR NR 0.66 [0.47, 0.93]

Proportion diagnosed by stage

Diagnosed early (Stage I or II) 29% 17% p=0.085

Diagnosed prior to symptomatic phase (Stage I or II or IIIa/b) 48% 25% p=0.031

Abbreviations: CA, cancer antigen; CI, confidence interval; FTC, fallopian tube cancer; NR, not reported; OC, ovarian cancer; PLCO,

Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial; PPC, primary peritoneal cancer; RCT, randomised controlled trial; TVUS,

transvaginal ultrasonography.

OC-specific mortality and OC-specific survival from randomisation were both analysed, and while

a significant improvement in survival was observed for screened women (RR 0.66 [95% CI, 0.47 to

0.93]). Figure 0.1), this did not translate into a statistically significant improvement in disease-specific

mortality (RR 0.66 [0.39, 1.12]).

55 Cox proportional hazard regression test.


Figure 0.1 OC-specific survival in women with a family history of breast or ovarian cancer –

PLCO-HR

Source: Lai 2016, Figure 1.

Abbreviations: HR, high risk; OC, ovarian cancer; PLCO, Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial.

All results reported in this study for women with a personal history of breast cancer are shown in

Table 0.14. The number of events in the subgroup of women with a personal history of breast

cancer were too low to allow statistical analysis. The numbers diagnosed and the numbers that

died due to their diagnosis are shown. When combined with the results for the family history

subgroup, survival results remained statistically significant.

Table 0.14 Outcomes from PLCO RCT for women with a personal history of breast cancer

OC (invasive), FTP, PPC

Outcomes

CA125 + TVUS

N = 1,351

No screening

N = 1,357

Risk ratio [95% CI]

Ovarian cancers detected, n 6 5 Insufficient events

OC-specific mortality 3 4 Insufficient events

Abbreviations: CA, cancer antigen; CI, confidence interval; OC, ovarian cancer; FTC, fallopian tube cancer; PLCO, Prostate, Lung, Colorectal

and Ovarian Cancer Screening Trial; PPC, primary peritoneal cancer; RCT, randomised controlled trial; TVUS, transvaginal ultrasonography.

The study authors note that while trials of screening efficacy must demonstrate a reduction in

disease-specific mortality, secondary endpoints ‘may be useful, and may be indicative of a

potential benefit to screening’. It was noted that the increase in early stage cancers was

associated with a significant reduction in the absolute number of Stage IIIc and IV cancers (i.e. not

only an increase in the detection of nonlethal subclinical malignancies), and that cancers in the

screened group were similar to cancers in the control group with regard to histology and grade

(data not reported). The authors consider this to suggest a direct correlation between stage shift

and survival, rather than a ‘length-biased sampling’ effect.

The study authors concluded that this study found significant differences in the number of patients

presenting with advanced bulky disease, and in survival (but not mortality) in those diagnosed with

ovarian cancer. They consider that further investigation is warranted to assess the screening of

women with an increased risk of ovarian cancer.

The rate of false positive surgery was not reported in this study.


4.1.6.2 UKFOCSS Phase I

This UK study was initiated in 2002 and screened women at high risk of ovarian cancer with annual

single threshold CA125 and TVUS. A before/after screening comparison is presented by the study

authors, comparing outcomes within a year of screening to those over a year after the last screen.

After data abstraction, post hoc calculations (proportions) were performed so that outcomes

could be presented similarly to the Phase II study results, facilitating between-study comparisons.

Detection outcomes

Mode of detection

A total of 37 cancers were detected,56 of which the majority were screen detected (n=22; 59%). A

large proportion of those were prevalent at the start of the trial (n=9; 41% of screen-detected

cancers). Consequently, results are shown separately for prevalent cancers, which may be

expected to have different characteristics to those detected during the screening phase.

Detection is shown by time from last screen (<365 days vs >365 days from last screen). This screening

refers to screening that took place within the trial. A majority of women in Phase I of this study

transferred to Phase II, and they were censored one year after the first Phase II screen. No cancers

were diagnosed in Phase II within a year of transferring from Phase I. Therefore, the group of women

with cancers detected >365 days since their last screen would consist of:

women who did not attend all scheduled annual screens during Phase I, and

those who left Phase I but did not join Phase II.

Three cancers were detected after symptom-prompted surgery within a year of screening (interval

cancers). Symptom-prompted surgery also formed the majority of instances of cancers detected

over a year after surgery (6 of 10).

The overall annual incidence of ovarian cancer or FTC or PPC was higher in Phase I (0.24%) than in

Phase II (0.14%). The higher number of prevalent cases in Phase I accounts for this difference.

Table 0.15 Mode of cancer detection – UKFOCSS Phase I

Detection outcomes

n (%) with CA125 single threshold

N=3,563

OC (invasive), FTC,

PPC

OC (invasive), FTC PPC

Total cancers detected 37 (100) 33 (100) 4 (100)

Detected <365 days after last trial screen (prior to censorship) 27 (73) 26 (79) 1 (25)

Detected >365 days after last trial screen (post censorship) 10 (27) 7 (21) 3 (75)

Detected by screening <365 days after last trial screen 22 (59) 22 (67) 0 (0)

First screen (prevalent) 9 (24) 9 (27) 0 (0)

Subsequent screens (incident screen-detected) 13 (35) 13 (39) 0 (0)

Detected by other means <365 days after last trial screen 5 (14) 4 (12) 1 (25)

Surgery prompted by symptoms (interval cancers) 3 (8) 2 (6) 1 (25)

Occult cancers – discovered at RRSO unrelated to test results 2 (5) 2 (6) 0 (0)

Detected >365 days after last trial screen 10 (27) 7 (21) 3 (75)

Surgery prompted by symptoms 6 (16) 6 (18) 0 (0)

Occult cancers – discovered at RRSO 2 (5) 1 (3) 1 (25)

Detected by screening locally 2 (5) 0 (0) 2 (50)

56 Phase II also detected a total of 37 cancers – this is not a data extraction error.


Detection outcomes

n (%) with CA125 single threshold

N=3,563

OC (invasive), FTC,

PPC

OC (invasive), FTC PPC

Incidence (detected < 365 days from last screen)

Overall annual incidence (%) based on 11,366 person-years of

screening 0.24 0.2357 0.009

Abbreviations: CA, cancer antigen; OC, ovarian cancer; FTC, fallopian tube cancer; PPC, primary peritoneal cancer; RRSO, risk-reducing

salpingo-oophorectomy; UKFOCSS, United Kingdom Familial Ovarian Cancer Screening Study.

Sensitivity

As mentioned for Phase II of this study, occult cancers detected at RRSO, unrelated to screening,

impact on estimates of the sensitivity of screening. The Phase I study presented two analyses of

occult cancers; one treating them as false negatives (assumed all would have been detected in

the next round of screening) and the other treating them as true positives (assuming none would

be detected in the next round of screening), thus providing an upper and lower limit for the impact

of occult cancers on sensitivity. These analyses were also performed for subgroups according to

mutation status. While some estimates of sensitivity using the single threshold CA125 and TVUS for

annual screens are high, all have substantially wide confidence intervals.

Table 0.16 Sensitivity of screening, with and without occult cancers – UKFOCSS Phase I

Sensitivity estimated with two occult cancers

(diagnosed <365 days after last screen) either

excluded or included as a true positive

Prevalent Incident

OC (invasive), FTC

% [95% CI]

OC (invasive), FTC

% [95% CI]


% [95% CI]

Total screened population, (N=3,563)

Occult – false negative 90.0 [55.5, 99.8] 81.3 [54.3, 96.0] 76.5 [50.1, 93.2]

Occult – true positive 100 [69.2, 100] 87.5 [61.7, 98.5] 82.4 [56.6, 96.2]

BRCA1/2 mutation carriers (n=538)

Occult – false negative 85.7 [42.1, 99.6] 76.9 [46.2, 95.0] No PPC

Occult – true positive 100 [59.0, 100] 91.7 [61.5, 99.8] No PPC

Unknown mutation status at enrolment (n=3,065)

Occult – false negative None 91.7 [61.5, 99.8] 75.0 [19.4, 99.4]

Occult – true positive None 100 [73.5, 100] 75.0 [19.4, 99.4]

LS mutation of family history (n=99)

Occult – false negative 100 [29.2, 100] 100 [2.5, 100]58 No PPC

Occult – true positive 100 [29.2, 100] 100 [2.5, 100] No PPC

Abbreviations: CI, confidence interval; OC, ovarian cancer; FTC, fallopian tube cancer; PPC, primary peritoneal cancer; UKFOCSS, United


False positives

Table 0.17 shows the number of false positive surgeries i.e. screen-positive surgeries resulting in any

diagnosis other than invasive ovarian cancer, FTC or PPC (borderline tumours were counted as

false positives).

57 Calculated post hoc from 26 cancers detected <365 days from last screen. 58 As shown in Table 2 of Rosenthal 2013, all diagnoses in women with Lynch syndrome were detected at prevalent screen – it is unclear why

data are reported for incident cancers.


Table 0.17 False-positive surgery rates – UKFOCSS Phase I

UKFOCSS Phase I

Outcome

N (%)

Participants 3,563 (100)

Screen-positive surgeries 74

False positive surgeries 52

Screen-detected cancers (invasive OC, FTC, PPC diagnosed prior to censorship) 22



Note: data calculated post hoc from the reported number of false positive surgeries and the number of screen-detected cancers.

Abbreviations: OC, ovarian cancer; FTC, fallopian tube cancer; PPC, primary peritoneal cancer; UKFOCSS, United Kingdom Familial Ovarian

Cancer Screening Study.


Cancer stage at diagnosis is shown for all three cancer types diagnosed to March 2011 (Table

0.18). When considering cancers diagnosed within a year of screening, around half were

diagnosed late (Stage III or IV = 52%; Stage IIIa or later = 44%), while cancers diagnosed over a year

after the last trial screen were almost all late stage/high volume (90%), with 6 of 10 diagnoses

prompted by symptoms.

When restricted to incident screen-detected cancers, the frequency of late stage diagnoses was

higher (69% Stage III or IV; 62% high volume). In the prevalent screen, however, the majority of

cancers (67%) were detected at an early stage (Stage I or II). It is noted that the numbers analysed

are low. A single statistical comparison was reported, for ovarian cancer or FTC diagnosed within a

year of screening versus over a year after screening, excluding PPCs and women with Lynch

syndrome. This analysis is described below.


Table 0.18 Cancer stage at diagnosis – UKFOCSS Phase I


Diagnoses by stage, n (%) All

diagnoses

Detected <365 days after last trial screen Detected >365 days after last trial screen

Prevalent

screen

Incident screen Occult – RRSO

unrelated to

screening

Prompted by

symptoms

(interval)

All <1 year

after last

screen

Screening after

trial

Occult – RRSO Prompted by

symptoms

All >1 year

after last

screen

Total cancers detected 37 9 13 2 3 27 2 2 6 10

Stage I 10 (27) 5 2 1 1 9 (33) 0 1 0 1 (10)

Stage II 4 (11) 1 2 1 0 4 (15) 0 0 0 0 (0)

Stage IIIa 2 (5) 1 1 0 0 2 (7) 0 0 0 0 (0)

Stage IIIb 6 (16) 1 4 0 0 5 (19) 1 0 0 1 (10)

Stage IIIc 13 (35) 1 4 0 1 6 (22) 1 1 5 7 (70)

Stage IV 2 (5) 0 0 0 1 1 (4) 0 0 1 1 (10)


Early (I or II) 14 (38) 6 (67) 4 (31)59 2 (100) 1 (33) 13 (48) 0 (0) 1 (50) 0 (0) 1 (10)

Late (III or IV) 23 (62) 3 (33) 9 (69) 0 (0) 2 (67) 14 (52) 2 (100) 1 (50) 6 (100) 9 (90)

Low versus high volume

Low volume (I or II or IIIa) 16 (43) 7 (78) 5 (38) 2 (100) 1 (33) 15 (56) 0 (0) 1 (50) 0 (0) 1 (10)

High volume (IIIb or IIIc or IV) 21 (57) 2 (22) 8 (62) 0 (0) 2 (67) 12 (44) 2 (100) 1 (50) 6 (100) 9 (90)

Data abstracted from Rosenthal 2013 Table 3, with post hoc calculations of proportions.

Abbreviations: OC, ovarian cancer; FTC, fallopian tube cancer; PPC, primary peritoneal cancer; RRSO, risk-reducing salpingo-oophorectomy; UKFOCSS, United Kingdom Familial Ovarian Cancer Screening Study.

59 30.8%; 95% CI, 12.4% to 58.0%)


Table 0.19 shows the proportion of cancers that were Stage IIIc or later, which involves peritoneal

metastasis >2cm and/or regional lymph node metastasis, or spread beyond abdominal organs.

Proportions are shown for diagnoses made one year before and one year after the last screen trial.

Stepwise exclusion of primary peritoneal cases and women with Lynch syndrome is shown. For this

last comparison, diagnoses made within a year of screening were significantly less likely to be Stage

IIIc or Stage IV (Fisher’s test p=0.009).

Table 0.19 Proportion of cancers diagnosed at ≥ Stage IIIC – UKFOCSS Phase I

%, (n/N) or [95% CI] OC (invasive), FTC, PPC

(all 3 cancer types)

OC (invasive), FTC

(excl. PPC)

OC (invasive), FTC

(excl. PPC and Lynch

syndrome)

Detected <365 days after last trial screen 25.9%

(7/27)

23.1%

(6/26)

26.1%

[10.2, 48.4]

(6/23)

Detected >365 days after last trial screen 80.0%

(8/10)

85.7%

(6/7)

85.7%

[42.1, 99.6]

(6/7)

p=0.009

Abbreviations: CI, confidence interval; OC, ovarian cancer; FTC, fallopian tube cancer; PPC, primary peritoneal cancer; UKFOCSS, United


Mortality

All-cause mortality and OC-specific mortality were censored in March 2011. Of the 37 women

diagnosed with ovarian cancer, FTC or PPC, 11 died as a result of their disease (30%)60. All deaths

were due to ovarian cancer or FTC, but the number of deaths in women diagnosed within a year

of screening was not reported. However, there was no difference in OC-specific mortality between

women diagnosed within a year of last screen and those diagnosed over a year after last screen

(log-rank [Mantel-Cox] p=0.233).

4.1.6.3 UK-Netherlands-Norway study

The UK-Netherlands-Norway study reported the combined data from ovarian cancer screening at

five cancer genetics centres. The details of the screening protocol were not described, and may

well have differed between sites. The authors suggest the screening strategy would have involved

CA125 and TVUS, and this is certainly the case for at least the Netherlands centre, which used a

single threshold cut-off for CA125 evaluation.

Within this single cohort study, the authors made comparisons between cancers detected at

prevalence screening and post-prevalence screening (incident and interval cancers) with a view

to detecting a survival difference or a stage shift. False positive surgery and RRSO were not

reported. No quality of life or adverse event outcomes were reported.

60 This rate is higher than that observed in Phase II (13%).


Detection outcomes

Table 0.20 Mode of cancer detection – UK-Netherlands-Norway study

Detection outcomes

n (%)

UK-Netherlands-Norway

OC (invasive, borderline)

CA125/TVUS

Total cancers detected 64 (100)

Prevalent screen-detected (first screen) 26 (41)

Incident screen-detected (subsequent screens) 27 (42)

Interval cases (<12–14 months from negative screen) 11 (17)

Total post-prevalent cases (incident, incl. interval cancers) 38 (59)

Abbreviations: CA, cancer antigen; OC, ovarian cancer; TVUS, transvaginal ultrasonography; UK, United Kingdom.


Table 0.21 shows tumour stage by mode of detection (prevalent screen or post-prevalent screen)

for all cancers detected and also for all cancers in carriers of BRCA1/2 mutations. These groups

were not compared statistically, which is not surprising given the small sample sizes. The authors

noted that there is little difference in the number of late stage diagnoses (Stage III or IV) between

the prevalent and post-prevalent cases across all cancers, but when restricted to cancers in

women with BRCA1 or BRCA2 mutations, there is ‘some evidence of down staging’ (81% of

prevalent cases were late stage and 61% of post-prevalent cases were late stage).

Table 0.21 Cancer stage at diagnosis – UK-Netherlands-Norway study

OC (invasive, borderline)

Detection outcomes, n

All cancers All cancers BRCA1/2 carriers

Prevalent Post-prevalent Prevalent Post-prevalent

Total cancers detected 64 26 38 21 28

Stage I – borderline 5 4 1 0 0

Stage 1 – invasive 11 3 8 2 6

Stage II 7 2 5 2 5

Stage III or IV 41 17 24 17 17

Late stage diagnosis (% Stage III or IV)

Including borderline tumours 64 65 63 81 61

Excluding borderline tumours 70 77 65 N/A N/A

Abbreviations: OC, ovarian cancer; UK, United Kingdom.

Mortality

Kaplan–Meier survival analysis was used to compare survival to censorship61 in patients with

prevalent cases versus patients with post-prevalent cases. No difference was seen between

groups, either with borderline tumours included (log rank p=0.9363) or excluded (log rank

p=0.4428), or when restricted to patients with BRCA1/2 mutations (data not reported).

4.1.6.4 Fox Chase Cancer Centre

This prospective study surveyed women who were undergoing routine surveillance screening due

to an increased risk of ovarian cancer and were considering prophylactic RRSO. Participants

identified as either having surgery in the immediate future (N=38) were compared with those

choosing to continue with screening (N=37). Baseline characteristics were compared between

groups and were balanced overall.

61 Up to 16 years follow up, mean or median not reported.


Outcomes were assessed at 1 month, 6 months and 12 months after baseline assessment, which

was at surgery for women in the surgery group.

Quality of life

This study used the validated Medical Outcomes Survey (MOS) Short-Form Health Survey (SF-36)

and the Center for Epidemiological Studies-Depression scale (CES-D), which the authors note has

high reliability and internal validity and has been widely used. These two outcomes are reported

here. A further two instruments were also used: Sexual Activity Questionnaire and a 43-item

symptom checklist that was originally developed for the National Surgical Adjuvant Breast and

Bowel Project. Neither of these outcomes are reported here as they are not validated.

Short-Form Health Survey (SF-36)

Physical Component Summary (PCS) and Mental Component Summary (MCS) were analysed over

time from measures at baseline, 1 month, 6 months and 12 months, with surgery taking place at

baseline in the surgery group.

The surgery group reported significantly lower mean scores for physical wellbeing (PCS) at 1-month

follow-up compared with baseline (β=−5.61, p<0.02), whereas no such deficit was observed in the

screening group (Figure 0.2). No differences in MCS were observed between the two groups or

over time.

Figure 0.2 Mean PCS and MCS scores by group at each time point – Fox Chase Cancer

Centre

Source: Fang 2009, Figure 1.

Abbreviations: MCS, Mental Component Summary; PCS, Physical Component Summary.

The SF-36 subscales were also compared between the surgery and screening groups. At 1-month

follow up, women in the surgery group had significantly worse scores than at baseline for five

subscales: Physical Functioning, Role-Physical, Bodily Pain, Vitality, and Social Functioning. However,

these decrements were no longer apparent at 6-month and 12-month follow up. One exception

was bodily pain, with significantly lower scores, indicating greater pain, at 12-month assessment

(mean 69.00, SD 22.35) compared with baseline (mean 80.31, SD 22.51), β=−10.92, p=0.05.

Women in the screening group reported no significant decrements in these domains over time.

Center for Epidemiological Studies-Depression scale (CES-D)

No significant differences in depressive symptoms were observed over time or between the surgery

and screening groups.


The authors concluded that while deficits in physical functioning and other specific domains of

quality of life were observed following RRSO, they were short term, with most women recovering by

6 to 12 months after surgery.

4.1.7 Data extraction – systematic reviews and HTAs

The conclusions of the Auranen 2011 systematic review, which evaluated the role of

gynaecological cancer surveillance in women who carry a HNPCC mutation or belong to a family

that fulfils the criteria for HNPCC, are summarised in Table 0.22. As the literature search for this

systematic review was conducted in 2010, the results are not discussed any further in the current

report.

Table 0.22 Key characteristics of systematic reviews relating to surveillance of women at

high risk

Study ID

Qualitya

Intervention &

comparator

Conclusions

Auranen

2011

Poor quality

Intervention

Gynaecological

cancer surveillance

Comparator

Not specified

Currently available published studies on gynecological cancer surveillance in women with

HNPCC do not adequately allow for evidence-based clinical decisions.

No benefit was shown for OC surveillance. Of the five OCs diagnosed in the studies included

in the review, four were of endometrioid subtype and the subtype of the fifth patient was

not given. In the general population, approximately 15% of ovarian carcinomas are of

endometrioid subtype, and the majority are either serous or undifferentiated subtypes.

Abbreviations: HNPCC, hereditary nonpolyposis colorectal cancer; OC, ovarian cancer; TVUS, transvaginal ultrasound.


Review of clinical guidance

4.1.8 Identified guidelines

Nine clinical practice guidelines were identified with guidance relating to ovarian cancer

screening and/or surveillance, published from 2011 onwards (Table 0.1). The search also identified a

further 11 forms of guidance, which included position statements, regulatory safety

communications, committee opinions, policy recommendations, and practice bulletins (Table 0.2).


Table 0.1 Included clinical practice guidelines

Ref ID Title Developer/affiliation Brief description of

methodology

Paluch-

Shimon 2016

Prevention and screening in BRCA mutation

carriers and other breast/ovarian hereditary

cancer syndromes: ESMO Clinical Practice

Guidelines for cancer prevention and

screening

European Society of Medical

Oncology (ESMO)

Relevant literature selected by

expert authors. Levels of

evidence and grades as per

the Infectious Diseases Society

of America methodology

RACGP 2016 Guidelines for preventive activities in

general practice

Royal Australian College of General

Practitioners (RACGP)

Systematic review with quality

rating and grading using

NHMRC methodology

Llort 2015 SEOM clinical guidelines in hereditary breast

and ovarian cancer

Sociedad Española de Oncología

Médica (SEOM)

Used Infectious Diseases Society

of America-US Public Health

Service Grading System for

Ranking Recommendations in

Clinical Guidelines to determine

quality of evidence and

strength of recommendations

Singer 2015 Clinical Practice Guideline for the

prevention and early detection of breast

and ovarian cancer in women from HBOC

(hereditary breast and ovarian cancer)

families

Singer et al. (Austrian) NR

British

Columbia

2014

Genital tract cancers in females: ovarian,

fallopian tube, and primary peritoneal

cancers

Family Practice Oncology Network

and the Guidelines and Protocols

Advisory Committee

States that the guideline is

based on scientific evidence

current as of the effective date

Qaseem

2014

Screening Pelvic Examination in Adult

Women: A Clinical Practice Guideline From

the American College of Physicians

American College of Physicians (ACP) Systematic review and

evidence grading using GRADE

SIGN 2013 Management of epithelial ovarian cancer:

A national clinical guideline (SIGN 135)

Scottish Intercollegiate Guidelines

Network (SIGN)


rating using SIGN criteria.

Graded using SIGN criteria.

Morgan 2012 NCCN Guidelines Insights. Ovarian Cancer,

Version 3.2012. Featured updates to the

NCCN Guidelines

National Comprehensive Cancer

Network (NCCN)

NR but evidence-based

NBOCC 2011 Recommendations for management of

women at high risk of ovarian cancer. A

clinical practice guideline developed by

National Breast and Ovarian Cancer Centre,

September 2011

National Breast and Ovarian Cancer

Centre (NBOCC)62

Systematic review and level of

evidence using NHMRC criteria

62 Now Cancer Australia.


Table 0.2 Included position statements and other guidance

Ref ID Title Developer/affiliation Brief description of

methodology

AAFP 2017 Summary of Recommendations for Clinical

Preventive Services, July 2017

American Academy of Family

Physicians (AAFP)

Starting point is a review of

recommendations released by

USPSTF

ACOG 2017a Committee Opinion 716: The role of the

obstetrician-gynecologist in the early

detection of epithelial ovarian cancer in

women at average risk

American College of Obstetricians

and Gynecologists (ACOG)

Committee on Gynecologic

Practice and Society of

Gynecologic Oncology (SGO)

Not reported

ACOG 2017b Practice Bulletin No. 182: Hereditary breast

and ovarian cancer syndrome. Practice

Bulletin Number 182

American College of Obstetricians

and Gynecologists (ACOG)

Committee on Practice Bulletins–

Gynecology, Committee on

Genetics, and Society of

Gynecologic Oncology (SGO)

Systematic review and

evaluation and grading using

USPSTF criteria

ACR 2017 ACR Appropriateness Criteria Ovarian Cancer

Screening

American College of Radiology

(ACR)

Systematic review and

appropriateness rating using

RAND/UCLA Appropriateness

Method63

USPSTF 2017a

(draft)

Screening for ovarian cancer US Preventive Services Task Force

(USPSTF)


rating using USPSTF criteria.

Graded using USPSTF criteria.

USPSTF 2017b Screening for Gynecologic Conditions With

Pelvic Examination US Preventive Services Task

Force Recommendation Statement

US Preventive Services Task Force

(USPSTF)


rating using USPSTF criteria.

Graded using USPSTF criteria.

Zeimet 2017 AGO Austria recommendation on screening

and diagnosis of Lynch syndrome (LS)

Austrian Arbeitsgemeinschaft für

Gynäkologische Onkologie (AGO)

Not reported

FDA 2016 The FDA recommends against using screening

tests for ovarian cancer screening: FDA Safety

Communication

Food and Drug Administration (FDA) Not reported

GOC 2016 The Society of Gynecologic Oncology of

Canada (GOC) Opinion Statement regarding

the UK Collaborative Trial of Ovarian Cancer

Screening (UKCTOCS) results

Society of Gynecologic Oncology

of Canada (GOC)

Not reported

Wilt 2015 Screening for cancer: advice for high-value

care from the American College of Physicians

American College of Physicians

(ACP)

Review of clinical practice

guidelines

Moyer 2012 Screening for Ovarian Cancer: U.S. Preventive

Services Task Force Reaffirmation

Recommendation Statement

US Preventive Services Task Force Systematic review

4.1.9 Guidance relating to population screening

All guidance published in 2016 and 2017 considered evidence from the primary publication of the

UKCTOCS trial (Jacobs 2016). None of the clinical practice guidelines (Table 0.3) or other forms of

guidance (Table 0.4) recommend routine screening for ovarian cancer in asymptomatic or

average-risk women.

Consistent with this formal guidance, Cancer Research UK states that, “There is no national

screening programme for ovarian cancer in the UK because there is no test that reliably picks up

ovarian cancer at an early stage.”64

Likewise, the American Cancer Society states that, “Researchers continue to look for new tests to

help diagnose ovarian cancer early but currently there are no reliable screening tests.”65

63 Fitch K. The Rand/UCLA appropriateness method user's manual. Santa Monica: Rand; 2001. 64 Taken from the Cancer Research UK website, accessed October 2017. 65 Taken from the American Cancer Society website, accessed October 2017

http://www.cancerresearchuk.org/about-cancer/ovarian-cancer/getting-diagnosed/screening

https://www.cancer.org/cancer/ovarian-cancer/detection-diagnosis-staging/detection.html


Table 0.3 Relevant guidance from clinical practice guidelines – women at average risk

Ref ID

Developer

Guidance type Recommendation/evidence statement Level of evidence/

Grade66

Evidence base

RACGP 2016 Evidence-based Lower risk women: those who have used the oral contraception or carried a

pregnancy to term (risk of about half the population average)

No screening for ovarian cancer.

NR Jacobs 2016 [UKCTOCS], GOC 2016, CA 2015, Moyer

2012, CA 2009, Schorge 2010

British Columbia

2014

Evidence-based Routine screening of females, whether of high or average risk, is not recommended.

Studies have consistently failed to identify any reduction in the morbidity or mortality

from ovarian cancer in females screened with currently available technology such as

TVUS or CA125. The potential harms of screening are substantial and include false

reassurance, high recall rates for false positive results, and surgery for benign

conditions with the associated surgical risks.

NR Barton 2012 [AHRQ], Buys 2011 [PLCO], Horsman 2007,

BC Cancer Agency (date unknown),

Qaseem 2014

ACP

Evidence-based ACP recommends against performing screening pelvic examination [for cancer,

pelvic inflammatory disease or other benign conditions] in asymptomatic,

nonpregnant, adult women.

Moderate quality

evidence

Strong

recommendation

Related to ovarian cancer

Buys 2011 [PLCO]

SIGN 2013 Evidence-based Screening for ovarian cancer in the general population should not be performed

outside the research setting.

Grade A Buys 2011 [PLCO], Menon 2009 [UKCTOCS initial

screening round]

Morgan 2012

NCCN

Evidence-based Screening for ovarian cancer is not recommended by the NCCN Ovarian Cancer

Panel or by any major organisation.

Category 2A Smith 2012, Buys 2011 [PLCO], Clarke-Pearson 2009

Abbreviations: ACOG, American College of Obstetricians and Gynecologists; ACP, American College of Physicians; CA, cancer antigen; CT, computed tomography; FDA, US Food and Drug Administration; FDG-PET,

18F-fluorodeoxyglucose positron emission tomography; GOC, Society of Gynecologic Oncology of Canada; MRI, magnetic resonance imaging; NA, not applicable; NCCN, National Comprehensive Cancer Network;

NR, not reported; PLCO, Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial; RACGP, Royal Australian College of General Practitioners; SIGN, Scottish Intercollegiate Guidelines Network; TVUS, transvaginal

ultrasonography; UKCTOCS, UK Collaborative Trial of Ovarian Cancer Screening; US, United States; USPSTF, US Preventive Services Task Force.

NCCN: category I – high level of evidence with uniform consensus; category IIA – lower level of evidence with uniform consensus; category IIB – lower level of evidence without a uniform consensus but with no major

disagreement; and category III – any level of evidence but with major disagreement.

SIGN: Grade A: At least one meta-analysis, systematic review, or RCT rated as 1++, and directly applicable to the target population; or A body of evidence consisting principally of studies rated as 1+, directly

applicable to the target population, and demonstrating overall consistency of results; Grade B – A body of evidence including studies rated as 2++, directly applicable to the target population, and demonstrating

overall consistency of results; or Extrapolated evidence from studies rated as 1++ or 1+; Grade C – A body of evidence including studies rated as 2+, directly applicable to the target population and demonstrating

overall consistency of results; or Extrapolated evidence from studies rated as 2++; Grade D – Evidence level 3 or 4; or Extrapolated evidence from studies rated as 2+.

66 See table footnotes for description of different grading systems used.


Table 0.4 Relevant guidance from other sources – women at average risk

Ref ID

Developer


Grade67

Evidence base

ACOG 2017a Committee Opinion Currently, there is no strategy for early detection of ovarian cancer that reduces

ovarian cancer mortality. The use of TVUS and tumour markers (such as CA125), alone

or in combination, for the early detection of ovarian cancer in average-risk women

have not been proved to reduce mortality, and harms exist from invasive diagnostic

testing (e.g. surgery) resulting from false positive tests.

NA AOG 2016, Jacobs 2016 [UKCTOCS], OCRF/BCWG

2016, Menon 2015 [UKCTOCS], Bristow 2013, Moyer

2012, Buys 2011 [PLCO], Moore 2011, Ueland 2011, Van

Gorp 2011, Menon 2009 [UKCTOCS], Partridge 2009,

Menon 2005 [UKCTOCS], Skates 2003, Jacobs 1989,

Bast 1983,

ACR 2017 Evidence-based Ovarian cancer screening [using ultrasound, CT, MRI and FDG-PET] is not

recommended for average-risk pre-menopausal women.

Usually not

appropriate

No evidence base to support

Ovarian cancer screening [using ultrasound, CT, MRI and FDG-PET] is not

recommended for average-risk post-menopausal women, as randomised controlled

trials have not demonstrated a definitive mortality benefit in this population.

Usually not

appropriate

Jacobs 2016 [UKCTOCS], Lu 2013, Reade 2013, Dodge

2012, Buys 2011 [PLCO], van Nagell 2011, Pickhardt

2010, Partridge 2009, Kobayashi 2008, van Nagell 2007,

Menon 2005, Kinkel 2005, Jacobs 1999.

USPSTF 2017a

(draft)

Evidence-based68 The USPSTF recommends against screening for ovarian cancer in asymptomatic

women.

TVUS and serum CA125 testing are the most commonly suggested screening

modalities. Annual screening with TVUS and serum CA125 testing in women does not

decrease ovarian cancer mortality. Screening for ovarian cancer can lead to

important harms, including major surgical interventions in women who do not have

cancer. Therefore, the harms of screening for ovarian cancer outweigh the benefits.

Grade D Henderson 2017 AHRQ Evidence Synthesis Number

157: [UKCTOCS, PLCO]

USPSTF 2017b Evidence-based69 No recommendation. The USPSTF concludes that the current evidence is insufficient to

assess the balance of benefits and harms of performing screening pelvic

examinations70 [for gynaecologic conditions] in asymptomatic, nonpregnant adult

women.

I Statement (see

legend)

Guirguis-Blake 2017 AHRQ Evidence Synthesis Number

147: [PLCO]

FDA 2016 Safety

Communication for

physicians

Do not recommend or use tests that claim to screen for ovarian cancer in the general

population of women. Be aware that testing higher risk asymptomatic patients for

ovarian cancer has no proven benefit and is not a substitute for preventive actions

that may reduce their risk.

NA NR

GOC 2016 Opinion statement Based on the results of the two large randomised phase three trials, the recent

UKCTOCS trial (December 2015) and the previously published PLCO trial (2011), GOC

does not recommend screening for “ovarian” cancer at this time.

NA Jacobs 2016, [UKCTOCS] Buys 2011 [PLCO]

67 See table notes for description of different grading systems used. 68 Retrieved from USPSTF website. 69 Retrieved from USPSTF website. 70 May include any of the following components, alone or in combination: assessment of the external genitalia, internal speculum examination, bimanual palpation, and rectovaginal examination.

https://www.uspreventiveservicestaskforce.org/Page/Document/draft-recommendation-statement174/ovarian-cancer-screening1#citation15

https://www.uspreventiveservicestaskforce.org/Page/Document/UpdateSummaryFinal/gynecological-conditions-screening-with-the-pelvic-examination?ds=1&s=pelvic


Ref ID

Developer


Grade67

Evidence base

Wilt 2015 High-value care

advice

Clinicians should not screen average-risk women for ovarian cancer.

Based on a large RCT of screening, all organisations [ACOG, ACP, ACS, USPSTF]

recommend against pelvic examinations, CA125 blood tests, and TVUS for ovarian

cancer screening. Screening would lead to no benefits and would increase harms

and costs, including complications of invasive work-ups.

NA AAFP 2015; Smith 2015; Qaseem 2014; Moyer 2012;

Buys 2011 [PLCO]

AAFP 201271 Policy

recommendations

Asymptomatic women

The AAFP recommends against screening for ovarian cancer in women. (2012)

Grade: D

recommendation

[USPSTF]

Barton 2012 [AHRQ]; Danforth 2012 [AHRQ]; Buys 2011

[PLCO]; Menon 2009 [UKCTOCS initial screening

round]; Partridge 2009; Kobayashi 2008; Menon 2005;

Nelson 2004 [AHRQ]

Moyer 2012

USPSTF

Reaffirmation

Recommendation

Statement

Asymptomatic women without known genetic mutations that increase risk for ovarian

cancer – do not screen for ovarian cancer.

Grade D Barton 2012 [AHRQ]

Abbreviations: AAFP, American Academy of Family Physicians; ACOG, American College of Obstetricians and Gynecologists; ACP, American College of Physicians; ACS, American Cancer Society; AHRQ, Agency for

Healthcare Research and Quality; CA, cancer antigen; CT, computed tomography; FDA, US Food and Drug Administration; FDG-PET, 18F-fluorodeoxyglucose positron emission tomography; GOC, Society of

Gynecologic Oncology of Canada; MRI, magnetic resonance imaging; NA, not applicable; NCCN, National Comprehensive Cancer Network; NR, not reported; PLCO, Prostate, Lung, Colorectal and Ovarian

Cancer Screening Trial; RACGP, Royal Australian College of General Practitioners; RCT, randomised controlled trial; SIGN, Scottish Intercollegiate Guidelines Network; SR, systematic review; TVUS, transvaginal

ultrasonography; UKCTOCS, UK Collaborative Trial of Ovarian Cancer Screening; US, United States; USPSTF, US Preventive Services Task Force.

ACR: Usually not appropriate – The imaging procedure or treatment is unlikely to be indicated in the specified clinical scenarios, or the risk-benefit ratio for patients is likely to be unfavorable; May be appropriate – The

imaging procedure or treatment may be indicated in the specified clinical scenarios as an alternative to imaging procedures or treatments with a more favorable risk-benefit ratio, or the risk-benefit ratio for patients

is equivocal.

USPSTF: Grade A – The USPSTF recommends the service. There is high certainty that the net benefit is substantial; Grade B – The USPSTF recommends the service. There is high certainty that the net benefit is moderate,

or there is moderate certainty that the net benefit is moderate to substantial; Grade C – The USPSTF recommends selectively offering or providing this service to individual patients based on professional judgment and

patient preferences. There is at least moderate certainty that the net benefit is small; Grade D – The USPSTF recommends against the service. There is moderate or high certainty that the service has no net benefit or

that the harms outweigh the benefits; I statement: Insufficient evidence. Read the Clinical Considerations section of the USPSTF Recommendation Statement. If the service is offered, patients should understand the

uncertainty about the balance of benefits and harms.

71 AAFP guidance is dated 2017 but the relevant recommendation for asymptomatic women was developed in 2012.


4.1.10 Guidance relating to surveillance in women at high risk

Relevant guidance on surveillance of women at high or potentially high risk of ovarian cancer is

summarised below for clinical practice guidelines (Table 0.5) and other forms of guidance (Table

0.6).

None of the identified clinical practice guidelines incorporate the primary publications for

UKFOCSS, CGN/GOG or PLCO-HR, which were all published in 2016-2017. The recent American

College of Obstetricians and Gynecologists Practice Bulletin on hereditary breast and ovarian

cancer syndrome (HBOC; ACOG 2017b) incorporates evidence from UKFOCSS Phase II, but not

CGN/GOG or PLCO-HR. The recent American College of Radiology Appropriateness Criteria for

ovarian cancer screening (ACR 2017) incorporates the primary publication from PLCO-HR and

UKFOCSS Phase I, but not the UKFOCSS Phase II.

On the basis of the evidence considered, there was no strong support in guidelines for routine

surveillance of women at high risk. Five guidance documents advise that despite a lack of strong

evidence, surveillance with TVUS with or without CA125 may be considered in particular high-risk

populations (ACOG 2017b; ACR 2017; AGO 2017; Paluch-Shimon 2016; Llort 2015). One guideline

from Austria (Singer 2015) recommends annual TVUS and CA125 for the prevention and early

detection of ovarian cancer in women from HBOC families, noting that a potential benefit of

CA125 on the early detection of ovarian cancer has not been demonstrated.


Table 0.5 Relevant guidance from clinical practice guidelines – surveillance of women at high risk

Ref ID

Developer


Grade

Evidence base

Paluch-Shimon

2016

ESMO

Evidence-based Before risk-reducing salpingo-oophorectomy, 6-monthly, TVUS and measures of serum CA125 may

be considered from the age of 30; however, the limited value of these tools as an effective

screening measure should be communicated to individuals.

Studies without a

control group, case

reports, expert

opinion

Grade C

Menon 2015 [UKCTOCS post hoc analysis

of performance of a CA125 threshold

rule], Greene 2008

RACGP 2016 Evidence-based Higher risk women: family history of ovarian cancer, especially first-degree relatives and more than

one relative (risk of about 3 times the population average); presence of the genes BRCA1 or

BRCA2.

No screening for ovarian cancer.

NR Jacobs 2016 [UKCTOCS], USPSTF 2013,

Buys 2011 [PLCO]

Llort 2015

SEOM

Evidence-based Women with a BRCA1 or BRCA2 mutation who have not chosen salpingo-oophorectomy may

follow determination of CA125 and TVUS since age 35, but they should be informed that early

detection of ovarian cancer is not guaranteed.

IIC NR

Singer 2015 NR Female HBOC family members

Recommends TVUS and CA125 once a year. If applicable TVUS should be initiated 5 years prior to

the age at which the youngest family member has developed ovarian cancer. A potential benefit

of CA125 on the early detection of ovarian cancer has not been demonstrated.

NR NR

British Columbia

2014

Evidence-based Routine screening of females, whether of high or average risk, is not recommended. Studies have

consistently failed to identify any reduction in the morbidity or mortality from ovarian cancer in

females screened with currently available technology such as TVUS or CA125. The potential harms

of screening are substantial and include false reassurance, high recall rates for false positive

results, and surgery for benign conditions with the associated surgical risks.

NR Barton 2012, Buys 2011 [PLCO], Horsman

2007, BC Cancer Agency (date

unknown),

SIGN 2013 Evidence-based Screening for ovarian cancer in high risk groups should only be offered in the context of a

research study.

Grade D NCGSG 2009, Moller 2001, Taylor 2001,

Karlan 1999.

NBOCC 2011 Evidence-based For women at high/potentially high risk of ovarian cancer

Ovarian cancer surveillance is not recommended for women at high risk or potentially high risk.

Evidence shows that ultrasound or CA125, singly or in combination, is not effective at detecting

early ovarian cancer.

NR NBOCC 2009

Abbreviations: CA, cancer antigen; ESMO, European Society of Medical Oncology; HBOC, hereditary breast and ovarian cancer; NBOCC, National Breast and Ovarian Cancer Centre; NR, not reported; SEOM,

Sociedad Española de Oncología Médica; SIGN, Scottish Intercollegiate Guidelines Network; RACGP, Royal Australian College of General Practitioners; TVUS, transvaginal ultrasound.

ESMO: A – Strong evidence for efficacy with a substantial clinical benefit, strongly recommended, B – Strong or moderate evidence for efficacy but with a limited clinical benefit, generally recommended, C –

Insufficient evidence for efficacy or benefit does not outweigh the risk or the disadvantages (adverse events, costs, ...), optional, D – Moderate evidence against efficacy or for adverse outcome, generally not

recommended, E – Strong evidence against efficacy or for adverse outcome, never recommended.

SIGN: Grade A: At least one meta-analysis, systematic review, or RCT rated as 1++, and directly applicable to the target population; or A body of evidence consisting principally of studies rated as 1+, directly

applicable to the target population, and demonstrating overall consistency of results; Grade B – A body of evidence including studies rated as 2++, directly applicable to the target population, and demonstrating

overall consistency of results; or Extrapolated evidence from studies rated as 1++ or 1+; Grade C – A body of evidence including studies rated as 2+, directly applicable to the target population and demonstrating

overall consistency of results; or Extrapolated evidence from studies rated as 2++; Grade D – Evidence level 3 or 4; or Extrapolated evidence from studies rated as 2+.


Table 0.6 Relevant guidance from other sources – surveillance of women at high risk

Ref ID

Developer


Grade

Evidence base

ACOG 2017b Evidence-based

Practice Bulletin

In women with BRCA mutations or who have a personal history of ovarian cancer, routine ovarian

cancer screening with measurement of serum CA125 level or TVUS is generally not recommended.

TVUS or measurement of serum CA125 level may be reasonable for short-term surveillance in

women at high risk of ovarian cancer starting at age 30-35 years until the time they choose to

pursue risk-reducing bilateral salpingo-oophorectomy, which is the only proven intervention to

reduce ovarian cancer-specific mortality.

NR Rosenthal 2017 [UKFOCSS Phase II],

NCCN 2016, Nelson 2013, Oei 2006,

Olivier 2006, Stirling 2005,

ACR 2017 Evidence-based Ovarian cancer screening with pelvic ultrasound may be appropriate for some pre-menopausal

women at increased risk for ovarian cancer; however, strong evidence is not available for this

clinical scenario.

May be

appropriate

Jacobs 2016 [UKCTOCS], Rosenthal 2013

[UKFOCSS Phase I, Buys 2011 [PLCO], van

Nagell 2011, van der Velde 2009,

Gaarenstroom 2006, Olivier 2006, Stirling

2005, Hogg 2004.

Ovarian cancer screening with pelvic ultrasound may be appropriate for some post-menopausal

women at increased risk for ovarian cancer; however, strong evidence is not available for this

clinical scenario.

May be

appropriate

Lai 2016 [PLCO-HR], Rosenthal 2013

[UKFOCSS Phase I], van der Velte 2009,

Lacey 2006, Gaarenstroom 2006, Olivier

2006, Stirling 2005, Hogg 2004.

Zeimet 2017

AGO

Consensus-based Women who wish to avoid the risks of surgery and premature menopause and who understand

the risk of ovarian and endometrial cancer and the lack of efficient screening for early detection

of both cancers might nevertheless choose observation. As an alternative, the patient should be

offered the possibility of an annual endometrium biopsy (pipelle eventually complemented by an

office-hysteroscopy) together with TVUS examination from age 30/35 years.

NR Koh 2014, Koornstra 2009, Lindor 2006

FDA 2016 Safety

Communication for

physicians

Do not recommend or use tests that claim to screen for ovarian cancer in the general population

of women. Be aware that testing higher risk asymptomatic patients for ovarian cancer has no

proven benefit and is not a substitute for preventive actions that may reduce their risk.

NA NR

Abbreviations: ACOG, American College of Obstetricians and Gynecologists; ACR, American College of Radiology; AGO, Austrian Arbeitsgemeinschaft für Gynäkologische Onkologie; CA, cancer antigen; FDA, US

Food and Drug Administration; NA, not applicable; NBOCC, National Breast and Ovarian Cancer Centre; NR, not reported; TVUS, transvaginal ultrasound; US, United States.

ACR: Usually not appropriate – The imaging procedure or treatment is unlikely to be indicated in the specified clinical scenarios, or the risk-benefit ratio for patients is likely to be unfavorable; May be appropriate – The

imaging procedure or treatment may be indicated in the specified clinical scenarios as an alternative to imaging procedures or treatments with a more favorable risk-benefit ratio, or the risk-benefit ratio for patients

is equivocal.


Review of definitions of high risk of ovarian cancer

4.1.11 Identified guidance that defines high risk

Definitions of high risk populations were extracted from the guidance identified in Section 4.1.10,

and the studies identified in Section 4.1.4.

4.1.12 Definitions of high risk of ovarian cancer

Table 0.1 summarises the definitions of high risk that appear in identified clinical practice guidelines

and other position statements published from 2011 onwards. Table 0.2 summarises the criteria used

to recruit high risk women to the clinical studies that examined surveillance of women at high risk of

ovarian cancer.

In general, definitions include personal and family history of BRCA mutations, breast and ovarian

cancer, and Ashkenazi Jewish ancestry.

Table 0.1 Definitions of women at high risk of ovarian cancer from guidelines and position

statements

Ref ID/Developer

Country

Definition

Clinical practice guidelines

Paluch-Shimon 2016

ESMO

Europe

BRCA1 or BRCA2 germline mutation

Lynch syndrome genes: MLH1, MSH2, MSH6, EPCAM and PMS2 mutations

RAD51 mutation

BRIP1 mutation

RACGP 2016

Australia

‘Higher risk’ of OC:

Family history of OC, especially first-degree relatives and more than one relative (risk of about 3 times the

population average)

Presence of the genes BRCA1 or BRCA2

Also refers to breast cancer risk (see below), taken from Cancer Australia Familial Risk Assessment – Breast and

Ovarian Cancer (FRA-BOC) guidance.

Potentially high risk72 of breast cancer or carrying a mutation (<1% of the female population):

Women who are at potentially high risk of OC

Two first-degree or second-degree relatives on one side of the family diagnosed with breast or ovarian cancer,

plus one or more of the following features on the same side of the family:


o breast cancer diagnosed before age 40 years



o Ashkenazi Jewish ancestry


One first-degree or second-degree relative diagnosed with breast cancer aged <45 years plus another first-

degree or second-degree relative on the same side of the family with sarcoma (bone/soft tissue) aged <45

years

Member of a family in which the presence of a high-risk breast cancer gene mutation has been established

Llort 2015

SEOM

Spain

HBOC


Mismatch repair (MMR) genes, RAD51D, BRIP1

Singer 2015

Austria


72 More than three times the population average. Individual risk may be higher or lower if genetic test results are known.


Ref ID/Developer

Country

Definition

British Columbia 2014

Canada

For epithelial OC

personal or family history73 of cancer of breast, epithelial ovarian, fallopian tubes, primary peritoneal and/or

Lynch syndrome (also known as HNPCC)

personal or family history of confirmed breast cancer gene mutation (BRCA) 1 or 2

nulliparity and/or infertility

age

There may be other risk factors for ovarian cancer (e.g. use of fertility drugs, smoking); however, at present time

they are not well enough understood.

SIGN 2013

Scotland

Identifying women at high risk of developing ovarian cancer

Defining high risk groups using family history:

A woman is defined as being at high risk of ovarian cancer if she meets one of the following criteria:

she is a known carrier of relevant cancer gene mutations including BRCA1, BRCA2, MMR genes

she is an untested first degree relative of an individual with a mutation in BRCA1, BRCA2, RAD51C, RAD51D or

MMR genes

she is an untested second degree relative, through an unaffected man, of an individual with a mutation in

BRCA1, BRCA2, RAD51C, RAD51D or MMR genes

she has a first degree relative (mother, father, sister, brother, daughter or son) affected by cancer within a

family that meets one of the following criteria:

o two or more individuals with OC, who are first degree relatives of each other

o one individual with OC at any age, and one with breast cancer diagnosed under age 50 years, who are

first degree relatives of each other

o one relative with OC at any age, and two with breast cancer diagnosed under 60 years, who are

connected by first degree relationships

o three or more family members with colon cancer, or two with colon cancer and one with stomach,

ovarian, endometrial, urinary tract or small bowel cancer in two generations. One of these cancers must

be diagnosed under age 50 years and affected relatives should be first degree relatives of each other

o one individual with both breast and ovarian cancer

Defining high risk groups using genetic testing:

A high risk of ovarian cancer is associated with mutation in the tumour suppressor genes BRCA1 and BRCA2, in the

mismatch repair genes associated with HNPCC families, and rarely, in RAD51C and RAD51D.

NBOCC 2011

Australia

Definition of potentially high risk of ovarian cancer

Women have been defined as being at potentially high risk of developing OC if they:

Are a woman who is at high risk of breast cancer due to a gene fault e.g. in BRCA1 or BRCA2

Have one 1° or 2° relative diagnosed with epithelial OC in a family of Ashkenazi Jewish ancestry74

Have one 1° or 2° relative with OC at any age, and another with breast cancer before the age of 50, where

the women are 1° or 2° relatives of each other

Have two 1° or 2° relatives on the same side of the family diagnosed with epithelial OC, especially if one or

more of the following features occurs on the same side of the family:

1. additional relative(s) with breast or ovarian cancer

2. breast cancer diagnosed before the age of 40

3. bilateral breast cancer

4. breast and ovarian cancer in the same woman

5. breast cancer in a male relative

Have three or more 1° or 2° relatives on the same side of the family diagnosed with a family history suggestive

of Lynch syndrome (or HNPCC) e.g. colorectal cancer (particularly if diagnosed before the age of 50),

endometrial cancer, OC, gastric cancer, and cancers involving the renal tract

Are a member of a family in which the presence of a high-risk OC gene mutation has been established

If genetic test results are known, individual risk may be higher or lower. The category of potentially high risk of OC

covers less than 1% of the female population. As a group, lifetime risk of OC ranges between 1 in 30 and 1 in 2.

This risk is more than 3 times the population average.

73 Particularly in a patient’s close relatives, including: children, brothers, sisters, parents, aunts, uncles, grandchildren and grandparents on the

same side of the family. History of cancer in cousins and more distant relatives from the same side of the family may also be relevant. 74 High-risk ovarian and breast cancer gene mutations are more common in people of Ashkenazi Jewish ancestry.


Ref ID/Developer

Country

Definition

Other guidance

ACOG 2017b

United States

HBOC

Criteria for further genetic evaluation for HBOC:

Women affected with one or more of the following have an increased likelihood of having an inherited

predisposition to breast75 and ovarian, tubal, or peritoneal cancer and should receive genetic counseling and be

offered genetic testing:

breast cancer at age 45 years or less

breast cancer and have a close relative76 with breast cancer at age 50 years or less or close relative with

epithelial ovarian, tubal, or peritoneal cancer at any age

breast cancer at age 50 years or less with a limited or unknown family history77

breast cancer and have two or more close relatives with breast cancer at any age

breast cancer and have two or more close relatives with pancreatic cancer or aggressive prostate cancer

(Gleason score equal to or greater than 7)

two breast cancer primaries, with the first diagnosed before age 50 years

triple-negative breast cancer at age 60 years or less

breast cancer and Ashkenazi Jewish ancestry at any age

pancreatic cancer and have two or more close relatives with breast cancer; ovarian, tubal, or peritoneal

cancer; pancreatic cancer; or aggressive prostate cancer (Gleason score equal to or greater than 7)

Women unaffected with cancer, but with one or more of the following have an increased likelihood of having an

inherited predisposition to breast and ovarian, tubal, or peritoneal cancer and should receive genetic counseling

and be offered genetic testing:

a first-degree or several close relatives that meet one or more of the aforementioned criteria

a close relative carrying a known BRCA1 or BRCA2 mutation78

a close relative with male breast cancer

Genetic mutations associated with increased risk of ovarian cancer:


Lynch syndrome MMR genes (MSH2, MLH1, MSH6, PMS2, EPCAM)

BRIP1

RAD51C

RAD51D

STK11

ACR 2017

United States

OC screening – High risk (pre-menopausal or post-menopausal)

personal history or family history or known or suspected genetic predisposition or elevated CA125

Zeimet 2017

AGO

Austria

Lynch syndrome genes: MLH1, MSH2, MSH6, PMS2

FDA 2016

United States

“…women at high risk of developing ovarian cancer, including those with BRCA mutations,….”

USPSTF 201279 Women with BRCA1 and BRCA2 genetic mutations, the Lynch syndrome (HNPCC), or a family history of OC are

at increased risk for OC

Women with an increased-risk family history should be considered for genetic counselling to further evaluate

their potential risks

“Increased-risk family history” generally means having 2 or more first- or second-degree relatives with a history

of ovarian cancer or a combination of breast and ovarian cancer

o For women of Ashkenazi Jewish descent, it means having a first-degree relative (or 2 second-degree

relatives on the same side of the family) with breast or ovarian cancer

USPSTF 201680 Women with high-risk genetic syndromes, including BRCA1 and BRCA2 gene mutations, Lynch syndrome

(hereditary nonpolyposis colon cancer), Li-Fraumeni syndrome, and Peutz-Jeghers syndrome, are at high risk for

ovarian cancer.

Women with a family history of ovarian cancer are also at increased risk.

Abbreviations: ACOG, American College of Obstetricians and Gynecologists; ACR, American College of Radiology; AGO, Austrian

Arbeitsgemeinschaft für Gynäkologische Onkologie; CA, cancer antigen; ESMO, European Society of Medical Oncology; FDA, Food and Drug

Administration; HBOC, hereditary breast and ovarian cancer; HNPCC, hereditary non-polyposis colorectal cancer; NBOCC, National Breast

and Ovarian Cancer Centre; OC, ovarian cancer; SEOM, Sociedad Española de Oncología Médica; SIGN, Scottish Intercollegiate Guidelines

Network; RACGP, Royal Australian College of General Practitioners.

75 Invasive and ductal carcinoma in situ breast cancer. 76 Close relative is defined as first degree (parent, sibling, offspring), second degree (grandparent, grandchild, uncle, aunt, nephew, niece,

half-sibling), or third degree (first cousin, great-grandparent or greatgrandchild). 77 Limited family history includes fewer than two first-degree or second-degree female relatives surviving beyond age 45 years. 78 Or carrying another known actionable deleterious mutation associated with hereditary breast and ovarian cancer syndrome. 79 Final Recommendation Statement: Ovarian Cancer: Screening. U.S. Preventive Services Task Force. Current as of September 2012; Accessed

October 2017. 80 Draft Recommendation Statement: Ovarian Cancer Screening. U.S. Preventive Services Task Force. Accessed December 2017.

https://www.uspreventiveservicestaskforce.org/Page/Document/RecommendationStatementFinal/ovarian-cancer-screening

https://www.uspreventiveservicestaskforce.org/Page/Document/RecommendationStatementFinal/ovarian-cancer-screening

https://www.uspreventiveservicestaskforce.org/Page/Document/draft-recommendation-statement174/ovarian-cancer-screening1


Table 0.2 Definitions of women at high risk of ovarian cancer from included clinical studies

Ref ID Definition

UKFOCSS Phase II The UKFOCSS inclusion criteria were devised to include all women who have a ≥10% life time risk of OC. This

corresponds to a BRCA carrier probability of ≥25% in the volunteer and ≥50% in the first degree relative (FDR) of

the volunteer.

The volunteer should either have been affected by one of the following cancers or be a FDR of an affected

family member:

Families with ovarian or ovarian and breast cancer

1. ≥2 individuals with OC who are FDR

2. One OC and one breast cancer <50 years who are FDR

3. One OC and two breast cancers <60 years who are FDR

4. Breast cancer in volunteer/proband (≤45 years) and mother with both breast and ovarian cancer (in the same

person)

5. Breast cancer in volunteer/proband (≤40 years) and sister with both breast and ovarian cancer (in the same

person)

6. Criteria 1, 2, and 3 can be modified where paternal transmission is occurring i.e. families where affected

relatives are related by second degree through an unaffected intervening male relative and there is an affected

sister are eligible.

Families with a known gene mutation

7. The family contains an affected individual with a mutation of one of the known OC predisposing genes e.g.

BRCA1, BRCA2, MLH1, MSH2, MSH6, PMS1, PMS2.

Families with colorectal cancer (HNPCC or Lynch syndrome)

8. The family contains ≥3 individuals with a HNPCC related cancer81, who are FDR and ≥1 case is diagnosed

before 50 years and the cancers affect ≥1 generation.

Families with only breast cancer

9. ≥4 breast cancers

10. 3 breast cancers related by FDR: one ≤30 years, or all ≤40 years, or one male breast cancer (MBC) and one

bilateral breast cancer

11. Breast cancer in volunteer/proband (≤50 years) and: breast cancer in mother (age of onset being ≤30 years in

one and ≤50 years in the other), or bilateral breast cancer in the mother (≤40 years onset), or one MBC and one

bilateral breast cancer

12. Two MBC (one ≤40 years) in the family and the proband is a FDR of one of them.

Families with Ashkenazi Jewish ethnicity (additional criteria)82

13. Breast cancer (<40 years) or bilateral breast cancer (first cancer <50 years) in volunteer/proband, irrespective

of family history of cancer

14. Breast cancer in volunteer/proband (<50 years) and one FDR with breast cancer (<50 years) or OC (any age)

or MBC (any age)

15. Breast cancer in volunteer/proband (<60 years) and one FDR with breast cancer (<40 years) or OC (any age)

or MBC (any age)

16. One FDR with OC (<50 years)

17. FDR with breast and OC in the same woman (any age)

18. Two FDR with breast cancer (<40 years)

19. Two MBC (<60 years) in the family and proband is a FDR of one of them.

CGN/GOG Eligibility criteria included the following, with ‘close relatives’ defined as first- or second-degree blood relatives:

1. the subject or close relative (deleterious mutation in a FDR confers a 50% prior probability of an untested

subject being a mutation carrier, while deleterious mutation in a second-degree relative confers a 25% prior

probability of an untested subject being a mutation carrier) had a known, deleterious BRCA1 or BRCA2 mutation;

or

2. at least two ovarian or breast cancers (including DCIS) had been diagnosed among the subject or close

relatives within the same lineage; or

3. the subject was of Ashkenazi Jewish ethnicity, with one first-degree or two-second degree relatives with ovarian

or breast cancer; or

4. the subject was of Ashkenazi Jewish ethnicity and had a personal history of breast cancer; or

5. the probability of carrying a BRCA1 or BRCA2 mutation given family pedigree of breast and ovarian cancers as

calculated by BRCAPRO exceeded 20%.

When a diagnosis of breast cancer was required to meet any of these criteria, at least one breast cancer must

have been pre-menopausal or, if menopausal status was unknown at time of diagnosis, then age at diagnosis

was required to be ≤50 years.

It has since become apparent that some of these women are now known to not be at increased risk for OC – e.g.

women with a site-specific breast cancer family history whose families lack a deleterious BRCA1/2 mutation.

81 HNPCC cancers include colorectal, endometrial, ovarian, small bowel, ureteric and renal pelvic cancers. 82 Families in these categories negative on full BRCA1 and BRCA2 screening are ineligible.


Ref ID Definition

PLCO-HR The current study defined a subgroup of participants who reported at least one FDR with breast cancer or at least

one FDR with OC. A separate subgroup of patients with a personal history of breast cancer prior to enrolment was

also analysed.

The study population represents a heterogeneous group of patients, some with and some without genetic

mutations. As a whole, this may be construed as an intermediate or moderate risk group. Nonetheless, this was

seen as a clinically useful approach, as many patients with a positive family history will inquire about screening

but may not have the resources or desire to undergo genetic evaluation.

UKFOCSS Phase I Family history/mutation eligibility criteria

Eligibility was determined as follows: Participants were known carriers of one of the OC predisposing genes

(BRCA1, BRCA2, MLH1, MSH2, MSH6, PMS1, PMS2) or FDRs (mother, sister, daughter) of an affected member of a

high-risk family. High-risk families were those fulfilling any of the following criteria:

The family contained two or more individuals with OC who were FDRs

The family contained one individual with OC and one individual with breast cancer diagnosed at age < 50

years who were FDRs

The family contained one individual with OC and two individuals with breast cancer diagnosed at age < 60

years who were connected by first-degree relationships

The family contained an affected individual with a mutation of one of the known OC predisposing genes

(BRCA1, BRCA2, MLH1, MSH2, MSH6, PMS1, PMS2)

The family contained three individuals with colorectal cancer, at least one of whom was diagnosed at age <

50 years as well as one individual with OC, and all of these individuals were connected by first-degree

relationships

The first three criteria could be modified where paternal transmission occurred (i.e. families in which affected

relatives were related by second degree through an unaffected intervening male relative and in which the

proband had an affected sister were eligible)

UK-Netherlands-

Norway study

Women presenting to a cancer genetics centre had their family history documented, assessed and confirmed, as

far as practicable, by Clinical Genetic Services. Women assessed as being at increased risk of ovarian cancer

(usually at least a 10% lifetime risk, requiring more than just a single close relative with ovarian cancer) were

eligible to participate.

Fox Chase Cancer

Centre

Eligible women were ages 25 and older who were considering RRSO due to: 1) a family history of ovarian cancer,

2) a family history suggestive of a hereditary breast/ovarian pattern, and/ or 3) the presence of a known disease-

related gene mutation in the family.

Abbreviations: CGN/GOG, Cancer Genetics Network and Gynecologic Oncology Group; DCIS, ductal carcinoma in situ; FDR, first degree

relative; OC, ovarian cancer; PLCO, Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial; RRSO, risk-reducing salpingo-

oophorectomy; UK, United Kingdom; UKFOCSS, UK Familial Ovarian Cancer Screening Study;

4.1.13 Comparison of definitions with current Cancer Australia definition

The definition of high or potentially high risk from the 2009 Position Statements for ovarian cancer

surveillance is reproduced below. This definition is taken from a 2006 National Breast Cancer Centre

document, and is similar (but not identical) to the definition used in the 2011 guideline from the

same centre (see Table 0.1).83

83 In 2008, National Breast Cancer Centre (NBCC), incorporating the Ovarian Cancer Program, changed its name to National Breast and

Ovarian Cancer Centre (NBOCC). In 2011, NBOCC amalgamated with Cancer Australia to form a single national agency, Cancer Australia.


Table 0.3 Current risk definition in Cancer Australia Position Statements

Definition of high or potentially high risk women

The category of potentially high risk of ovarian cancer covers less than 1% of the female population. As a group, lifetime risk of ovarian

cancer ranges between 1 in 30 and 1 in 2. This risk is more than 3 times the population average. Individual risk may be higher or lower if

genetic test results are known.84 Women who have had a genetic fault identified through testing are regarded as being at high risk.

Women have been defined as being at potentially high risk of developing ovarian cancer185 if they:

Are at high or potentially high risk of breast cancer

Have one 1° relative diagnosed with epithelial ovarian cancer in a family of Ashkenazi Jewish ancestry86

Have one woman in the family with ovarian cancer at any age, and another with breast cancer before the age of 50, where

the women are 1° or 2° relatives of each other

Have two 1° or 2° relatives on the same side of the family diagnosed with epithelial ovarian cancer, especially if one or more

of the following features occurs on the same side of the family:


o breast cancer diagnosed before the age of 40




Have three or more 1° or 2° degree relatives on the same side of the family diagnosed with any cancers associated with

hereditary non-polyposis colorectal cancer (HNPCC): colorectal cancer (particularly if diagnosed before the age of 50),

endometrial cancer, ovarian cancer, gastric cancer, and cancers involving the renal tract

Are a member of a family in which the presence of a high-risk ovarian cancer gene mutation has been established

Source: Cancer Australia website

4.1.13.1 Family history criteria

Much of the family history criteria remain consistent with more recent guidance from other

jurisdictions. However, Ashkenazi Jewish ancestry could be extended to second degree relatives

(which is consistent with advice from NBOCC 2011 and USPSTF 201287).

In their review of the evolving paradigms in research and care for ovarian cancer, the National

Academies of Science, Engineering and Medicine (NASEM) recognises that relying on family history

alone may lead clinicians to overlook some women with germline mutations that put them at

higher risk for ovarian cancer (NASEM 2016). They claim that up to one-half of women with high risk

germline mutations do not have an apparent family history of breast or ovarian cancer. Also, family

history may not identify high risk for women with few female relatives, for women who were

adopted and do not know their biological family’s cancer history, or for women who otherwise do

not know the family health history of one or both parents.

4.1.13.2 Genetic testing criteria

In November 2017, two new Medical Benefits Schedule (MBS) items were listed for (i) genetic testing

of specific individuals affected by breast or ovarian cancer, and (ii) genetic testing of family

members of individuals who test positive according to the first item (i.e. ‘cascade testing’). For both

items, it is proposed that genetic testing be limited to the following genes: BRCA1, BRCA2, STK11,

PTEN, CDH1, PALB2, and TP53. While individuals known to have ovarian cancer are outside of the

scope of screening or surveillance, individuals who test positive following cascade testing represent

a subgroup of the population of women at increased risk of ovarian cancer.

As the introduction of an MBS item for cascade testing of BRCA1/2 and other specified mutations

might increase the number of women known to be at increased risk of ovarian cancer, it may be

worth considering whether the definition of high or potentially high risk could contain more explicit

advice about the genetic mutations that predispose to ovarian cancer (namely BRCA1/2, and

mutations associated with Lynch syndrome/HNPCC).

84 National Breast Cancer Centre 2006. Advice about familial aspects of breast cancer and epithelial ovarian cancer: a guide for health

professionals. National Breast Cancer Centre, Camperdown, NSW. 85 National Breast Cancer Centre 2006. Advice about familial aspects of breast cancer and epithelial ovarian cancer: a guide for health

professionals. National Breast Cancer Centre, Camperdown, NSW. 86 High-risk ovarian and breast cancer mutations are more common in people of Ashkenazi Jewish ancestry. 87 Note that the 2017 USPSTF Draft Recommendation Statement does not specifically mention Ashkenazi Jewish ancestry as a high risk

population.


The NASEM review of research and care for ovarian cancer (NASEM 2016) provides the following

examples of high-risk ovarian cancer susceptibility genes:

BRCA1, BRCA2 (HBOC syndrome)

MLH1, MSH2, MSH6, PMS2, EPCAM (Lynch syndrome)

TP53 (Li–Fraumeni syndrome)

STK11/LKB1 (Peutz–Jeghers syndrome, sex cord and mucinous tumours)

The American College of Obstetrics and Gynecology refers to several additional genetic mutations

associated with increased risk of ovarian cancer: BRIP1, RAD51C, RAD51D (ACOG 2017b).

4.1.13.3 Other criteria

The NASEM review of research and care for ovarian cancer (NASEM 2016) notes that the majority of

women with an ovarian cancer do not appear to have a known high-risk germline mutation or a

significant family history; as such, it is critical to also consider other potential risk factors. They state

that, “While several nongenetic factors are associated with either an increased or a decreased risk

for developing ovarian cancers, the patterns of association are inconsistent. For example, some risk

factors may affect risk in the same way for all subtypes, whereas other factors may increase risk for

some subtypes while decreasing risk for other subtypes. The strongest known risk factors to date are

those associated with the less common and less lethal subtypes”.

Review of emerging technologies

As discussed in earlier sections of the report, current approaches for early detection include

assaying for biomarkers (CA125), often in combination with imaging technologies. While the use of

these strategies in large screening trials has resulted in more ovarian cancers being detected at

earlier stages, to date these methods have not had a substantial impact on overall mortality.

The recent Evidence Synthesis of screening for ovarian cancer prepared for the US Preventative

Services Task Force of the AHRQ (Henderson 2017) notes the following:

“We identified no ongoing randomised trials of ovarian cancer screening using new

screening tools. While some tools in development may hold promise for the future

(e.g. microRNA), currently there are no new screening tools (i.e. biomarkers,

instruments) exhibiting levels of test performance beyond what is observed for the

screening tools evaluated in trials.

The UKCTOCS trialists are engaged in efforts to improve upon the ROCA algorithm,

adding other protein markers along with CA125 to new prediction models derived

using data from the UKCTOCS data. These models would require further validation

and testing to ascertain whether they truly represent improvements on the ROCA

algorithm that would potentially attain clinical benefits for ovarian cancer detection

and treatment. In any case, given the absence of a single marker or screening

device that is effective for ovarian cancer, research is likely to increasingly aim to

identify new markers and combinations of markers in prediction models.”

In the recent NASEM review of research and care for ovarian cancer (NASEM 2016), the committee

note that:

“Given the marked heterogeneity of ovarian cancers and the incomplete

understanding of early disease development for each subtype, it is highly unlikely

that a single biomarker or imaging modality will be sufficient to aid in the early


detection of all the subtypes. The committee concludes that current screening

strategies have not had a substantial impact on reducing mortality in the general

population and that while research on refining current methods may be fruitful,

distinct multimodal approaches will likely be needed to detect each of the various

subtypes at their earliest stages.”

The ensuing recommendation in the NASEM 2016 review is:

“Researchers and funding organisations should focus on the development and

assessment of early detection strategies that extend beyond current imaging

modalities and biomarkers and that reflect the pathobiology of each ovarian

cancer subtype.”

Table 0.1 identifies and notes methodologies that are either currently available for prognosis or


ovarian cancer (including ongoing trials). These findings suggest that there are no screening tests

for ovarian cancer that are likely to be introduced/recommended in the short- to medium-term.

The 2009 Cancer Australia Position Statement on surveillance in women at high risk of ovarian

cancer, and the 2010 horizon scanning report by the Australian and New Zealand Horizon Scanning

Network (ANZHSN 2010), mentioned OvPlex™, a then commercially available blood test developed

by HealthLinx Limited (Australia) that was marketed as a test for the early detection of ovarian

cancer. OvPlex was based on measurement of CA125 as well as four other biomarkers: C-reactive

protein (CRP), serum amyloid A (SAA), interleukin 6 (IL-6) and interleukin 8 (IL-8). In the Position

Statement it was noted that no data from prospective controlled trials had been reported for the

test, and this appears to still be the case. In addition, OvPlex appears to no longer be commercially

available, and HealthLinx Limited changed its name to Manalto Limited88 in 2015.

As recently as 2016, the US Food and Drug Administration (FDA) noted that they were “not aware of

any valid scientific data to support the use of any test, including using a test cleared or approved

by FDA for other uses, as a screening tool for ovarian cancer.”89 The FDA has specifically

recommended against the use of tests marketed for screening of ovarian cancer, with the

following recommendations made to physicians:90

“Do not recommend or use tests that claim to screen for ovarian cancer in the

general population of women. Be aware that testing higher risk asymptomatic

patients for ovarian cancer has no proven benefit and is not a substitute for

preventive actions that may reduce their risk.

Consider referring women at high risk of developing ovarian cancer, including those

with BRCA mutations, to a genetic counsellor or gynaecologic oncologist, or other

appropriate health care provider for more specialised care.”

In particular, the FDA stated that the ROCA algorithm has been marketed in the United States with

no data to support its claims for ovarian cancer detection and improved cancer survival. Following

this statement from the FDA in September 2016, the company marketing the ROCA test temporarily

suspended its commercial availability in the United States.

88 According to its Annual Report released on 30 October 2017, Manalto Limited is an “integrated technology company focusing on social

media and e-commerce solutions for SMBs [small and medium-sized businesses] and enterprises.” 89 Accessed from the FDA website on 8 November 2017. 90 Accessed from the FDA website on 8 November 2017.

https://www.fda.gov/MedicalDevices/Safety/AlertsandNotices/ucm519413.htm



Table 0.1 Potential ovarian cancer screening methodologies identified in literature search

Test/ combination

Company

(Source)

Description Components Approval Approved/studied use Approved for screening

Currently marketed

ROMA

Fujirebio Diagnostics

Software algorithm and

two analytes

Serum

CA125, HE4

Other

Menopausal status

FDA Assess whether a pre-menopausal or post-menopausal woman who

presents with an ovarian adnexal mass is at high or low likelihood of

finding malignancy on surgery

No – specifically noted that it

should not be used for

screening

OVA1

Vermillion

Software algorithm and

five analytes

Serum

CA125, transthyretin,

apolipoprotein A-1, Β2-

microglobulin, transferrin

FDA Further assess the likelihood that malignancy is present when the

physician’s independent clinical and radiological evaluation does not

indicate malignancy

No – specifically noted that it

should not be used for

screening

Currently under clinical investigation

Longitudinal MROCA

(Simmons 2016)91

Longitudinal algorithm

and four analytes

Serum

CA125, HE4, MMP-7, CA72-4

- Early detection of ovarian cancer -

Requiring clinical investigation

Proseek® Multiplex

Oncology Plates

(Boylan 2017)92

Twelve proteins Serum

CA125, HE4, MK, KLK6, hK11,

CXCL13, FR-alpha, IL-6,

TNFSF14, FADD, PRSS8, FUR

- Screening for detecting early stage ovarian cancer in the general

population

Plasma API

(Miyagi 2017)93

Index Plasma

Amino acid profile

- Distinguish epithelial ovarian malignant tumours from benign growths -

Novel risk model I

for Type I OC

(Russell 2017)94

Algorithm and three

analytes

Serum95

CA125, fibronectin, Protein Z

Other

Age, interaction term

between age and fibronectin,

interaction term between age

and Protein Z

- Early detection and screening for ovarian cancer -

91 According to the authors this panel is “now under validation in a large blinded retrospective study utilising longitudinal cases and controls specimens from the UKCTOCS trial, to establish final parameters for the

MROCA and to assess both lead times and CA125 complementarity. If either lead time or complementarity advantage is noted for the MROCA over the CA125 ROCA, a prospective trial will be conducted to

validate the multi-marker panel, interpreted with the MROCA algorithm to determine clinical utility for this screening methodology.” 92 The authors note that “Additional studies using a larger cohort of patients will allow for validation of these biomarkers and lead to the development of a screening tool for detecting early stage ovarian cancer

in the general population.” 93 The authors note that “a prospective clinical study is warranted to validate API for practical use in the future.”


Test/ combination

Company

(Source)


Novel risk model II

for Type II OC

(Russell 2017)96

Algorithm and three

analytes

Serum97

CA125, fibronectin, CRP

Other

Age, age*fibronectin

- Early detection and screening for ovarian cancer -

Scientific development

Protein biomarkers

(Boylan 2014)

Normal Pap test Core

Proteome

Residual Pap fluid

153 proteins

- Identification of proteins in residual Pap fluid of women with normal

cytology to identify biomarkers for gynaecological diseases

-

Multiplex methylation-

specific PCR assay

(Zhang 2013)

Multiplex methylation-

specific PCR assay to

identify methylation status

of one of seven genes

found in cell-free serum

DNA

Serum

APC, RASSF1A, CDH1, RUNX3,

TFPI2, SFRP5, OPCML98

- Improve early detection of ovarian cancer -

Ongoing trials

DOvEEgene

(NCT02288676;

Registered 2014)

Molecular screening test NR - Screening test for the early diagnosis of cancer of the endometrium,

fallopian tubes and ovaries

-

Biomarker identification

[NCT01787656;

Registered 2013]

Phase II biomarker

validation study

Unique peptides/protein –

unspecified

A Novel Method of Screening for Ovarian Cancer Using Gynecologic

Fluids and Mucus.

AminoIndex

(NCT02178462;

Registered 2014)

Metabolomic profiling of

amino acids

NR - To discriminate gynaecologic cancer from benign disease or healthy

subjects

-

94 The authors note that the models “require further validation in a larger, independent sample set, containing samples from patients with benign ovarian tumours and other diseases in order to add confidence in

their utility as screening tools.” 95 Samples collected from UKCTOCS. 96 The authors note that the models “require further validation in a larger, independent sample set, containing samples from patients with benign ovarian tumours and other diseases in order to add confidence in

their utility as screening tools.” 97 Samples collected from the UKCTOCS. 98 Tumorigenic function in epithelial ovarian cancer: APC = an antagonist of the Wnt pathway, involved in cell migration and adhesion, transcriptional activation, and apoptosis; RASSF1A = inhibit the accumulation of

cyclin D1, induce cell cycle arrest; RUNX3 = suppress the proliferation and tumorigenicity; CDH1 = Key role in EMT, loss of function is thought to increase proliferation, invasion, and/or metastasis; TFP12 = a Kunitz-type

serine proteinase inhibitor that inhibits transformation and proliferation; SFRP5 = inactivation leads to oncogenic activation of Wnt pathway and contributes to cancer progression and chemoresistance; OPCML =

Inhibit the proliferation and tumour growth, negatively regulating receptor tyrosine kinases (Zhang et al 2013).


Test/ combination

Company

(Source)


Lysophosphatidic acid

assay

(NCT00986206;

Registered 2009)99

Lysophosphatidic acid

assay

- - For the early detection of ovarian cancer (high risk women) -

Glycan analysis

(NCT00628654;

Registered 2008)

Glycan analysis - - Diagnosing cancer in women with ovarian epithelial cancer and in

healthy female participants

-

CA125 algorithm

(NCT00539162;

Registered 2007)

CA125 algorithm NR - Early detection of ovarian cancer in low risk women -

CAAb test

(NCT00327925;

Registered 2006)100

Ovarian cancer

associated antibodies test

- - Assess the effectiveness of the CAAb test with ovarian cancer patients

(primary purpose: screening)

-

Mesothelin

(NCT00155740;

Registered 2005)101

Mesothelin - - New tumour marker for ovarian cancer (primary purpose: screening) -

Abbreviations: CA, Cancer Antigen; CAAb, cancer associated antibodies; CRP, C-reactive protein; CXCL13, CXC motif chemokine 13; FADD, FAS-associated death domain protein; FR-alpha, folate receptor-alpha;

FUR, furin; HE4, human epididymis protein 4; hK11, kallikrein 11; IL-6, interleukin-6; KLK6, kallikrein 6; MK, midkine; MMP-7, matrix metalloproteinase-7; MROCA, multi-marker risk of ovarian cancer algorithm; NR, not

reported; OC, ovarian cancer; PCR, polymerase chain reaction; PRSS8, prostasin; ROMA, Risk of Ovarian Malignancy Algorithm; TNSF14, tumor necrosis factor superfamily member 14.

99 The ClinicalTrials.gov website notes that the recruitment status of this study is unknown. The completion date has passed and the status has not been verified in more than two years. 100 The ClinicalTrials.gov website notes that the recruitment status of this study is unknown. The completion date has passed and the status has not been verified in more than two years. 101 The ClinicalTrials.gov website notes that the recruitment status of this study is unknown. The completion date has passed and the status has not been verified in more than two years.


5 Synthesis of findings

Population screening

5.1.1 Current clinical evidence

The current clinical evidence for ovarian cancer screening in the general population indicates

there is no mortality benefit associated with screening with any of the implemented strategies,

based on a priori analyses in two large population screening trials: PLCO and UKCTOCS. In

summary, pre-specified and post hoc secondary analyses are suggestive that a delayed mortality

benefit may be attributable to screening in the UKCTOCS study, but longer-term follow up is

necessary to confirm this. Follow up to 2018 has received funding, and plans to continue to 2024

are reported.

The UKCTOCS statistical analysis plan nominated the Cox proportional hazard model for the primary

analysis of the primary outcome. This statistical approach assumes the hazard of disease-specific

death is proportional (i.e. constant) over time. However, there is an inherent delay in any potential

impact of screening on mortality due to the time from incident malignancy diagnosis through

disease progression to death. In the PLCO trial, a weighted statistic was chosen for the primary

analysis of the primary outcome because of ‘the presumed delay in effect of screening on ovarian

cancer mortality’. A weighted log-rank test was used, which differentially assigns weight to different

time points.

It is unclear why a method of analysis that relies on the proportional hazard assumption was chosen

for the primary analysis in the UKCTOCS trial. The authors of the primary study publication make the

following comment:

In retrospect, it would have been preferable to specify a primary analysis that was

weighted to reflect the predictable delay in mortality reduction in a screening trial

of this type.

They considered their failure to anticipate the late effect of screening in their statistical design as

the main limitation of the trial. The planned Cox proportion hazard statistic is reported as the

primary analysis, which found no mortality benefit to screening, so it was decided to perform a

single post hoc analysis using the weighted log-rank approach, which resulted in a statistically

significant reduction in ovarian cancer-specific mortality for the same population of tumours

analysed in the primary analysis (i.e. excluding peritoneal cancers).

When peritoneal cancers, which have very high mortality, are added to the weighted log-rank

analysis, statistical significance is lost. With the WHO definition of ovarian cancer having been

broadened in 2014 to include PPC, analyses including these cancers are more relevant for clinical

practice.

Another point of difference between the two RCTs is the treatment of borderline epithelial ovarian

cancers, which UKCTOCS included as malignancies but PLCO excluded as ‘low malignant

potential’ tumours. Since many of the detection outcomes were reported by cancer type in the

UKCTOCS study, a number of these outcomes were presented in this Review both with and without

these borderline tumours (post hoc calculations), which allows comparison of detection outcomes

and stage shift with the PLCO trial. Conversely, the systematic review by Buhling et al (2017)

examined the impact of re-classifying borderline tumours in the PLCO analysis as malignancies.

They found the risk ratio for ovarian cancer-specific death changed from 1.20 (p=0.0647) to a


statistically significant 1.22 (p=0.0463). They made the comment that borderline tumours ‘are

generally not malignant but have a high potential for transforming from benign to malignant’ and

this may be a reason to include them in the assessment of a screening process.

Stage shift was also investigated in this Review, as it is thought to be a necessary, although not

sufficient, requirement for reducing mortality. Some evidence of stage shift was reported in

UKCTOCS. The systematic review by Henderson et al (2017) conducted to inform U.S. Preventive

Services Task Force ovarian cancer screening guidance made the following observation about the

lack of a mortality benefit despite evidence of a stage shift:

‘The absence of a mortality benefit in these large, well-conducted trials has

generated a theory that late stage disease grows so rapidly that it cannot be

identified at an earlier stage. The stage shift in UKCTOCS trial would seem to counter

this, but the lack of mortality benefit may suggest that these “early stage” tumors

detected early are more aggressive tumor phenotypes that would not have

improved survival no matter when they were identified. Recent work to refine the

distinctions among ovarian cancer molecular, pathological, and clinical

characteristics highlight this point in noting that survival differences are more likely

attributable to type than to stage at diagnosis, with the most common Type II

cancers being particularly lethal regardless of stage, likely owing to microscopic

lesions that are not detectable before significant spread has occurred.’

This review also considered the following aspects of UKCTOCS that may have impacted on

mortality outcomes:

Data from the later years of the trial are based on incomplete data, with women randomised

late in the study yet to report full follow up (the current Review authors consider this data has

the potential to enhance screening-associated improvement in mortality if there is truly a

delayed mortality benefit in this trial).

The no-screening group may have had a surplus of ovaries, as removal of ovaries in false

positives will, over time, deplete the number of at-risk ovaries in the screening groups

(potentially prophylactic surgery in the screening groups would have the effect of decreasing

apparent mortality compared with the no-screening group).

The authors of the Henderson 2017 review also make the following comment:

Given the natural history of ovarian cancer, it is unclear how a screening

intervention aimed at identifying ovarian cancer and intervening at a more

treatable stage would have a delayed effect.

A delayed effect was expected by the PLCO trial investigators, who specified the weighted log-

rank test to account for non-proportional hazards. However, the length of the delay may be

puzzling (over 7 years). The current Review authors are not in a position to comment on this.

False positive rates are highly relevant in a screening strategy that necessitates surgical removal of

ovaries for confirmation of diagnosis. This is especially the case for population screening, the scale

of which will result in major negative impacts in a large number of women without elevated ovarian

cancer risk. The ROCA triage screening strategy reduced false positive rates substantially

compared to TVUS; when borderline tumours are considered false positives, ROCA triage resulted in

2.9 false positive surgeries per screen-detected cancer102 compared with 14.8 in the TVUS screening

groups in both the UKCTOCS and PLCO studies. Such unacceptably high rates of unnecessary

surgery with TVUS screening alone is likely to be a barrier to implementing population screening.

102 2.3 if borderline tumours are considered malignant.


However, another factor to be considered regarding the ROCA triage approach to screening,

should long term follow up suggest it does reduce mortality, is that around 20% of ovarian cancers

do not express CA125. This would result in these cancers evading screen detection, which is a

clinical limitation of the screening strategy in its current form.

Quality of life outcomes were examined in women taking part in UKCTOCS. The investigators found

that psychological morbidity is slightly elevated by higher levels of secondary testing following

annual screening, and that screening for ovarian cancer does not increase anxiety in general,

especially when compared with the variation in anxiety levels that occur within individuals. The

study authors did not appear to consider these findings to present a barrier to screening.

Overall, current evidence does not support the implementation of population screening. Results of

longer-term follow up in UKCTOCS will be reported in coming years, analysed with the pre-specified

Cox proportional hazard model, at which point it will be necessary to re-evaluate whether

population screening is justified.

5.1.2 Post-literature review publication – outcomes by histology

Type II tumours are the most common and most aggressive of the ovarian cancers with poorer

survival than other cancer types (Shih & Kurman 2004). Since the screening trials were initiated prior

to ‘a modern understanding of ovarian carcinogenesis’, neither specified Type II lesions as an

outcome of interest, and while the UKCTOCS study reported the proportion of diagnoses by

histological type for each of the study arms, neither screening trial reported outcomes by tumour

type. However, subsequent to the literature search for the current Review, a post hoc analysis of

the PLCO trial (Temkin 2017) was published that reports outcomes by tumour type. It should be

noted that around 20% of diagnoses are excluded from this retrospective analysis as they could not

be histologically characterised from limited information in earlier pathology reports.

In the PLCO screening arm, Type II tumours were less likely to be screen-detected than other

tumour types (sensitivity 64.8% versus 85.7%, respectively, p = 0.02). The majority of Type II tumours

were diagnosed post-screening (45.9%) or as interval cancers (15.7%). No stage shift was observed

for either Type II or other tumour types, with a majority of Type II tumours being diagnosed at a late

stage in both screening (85.8%) and non-screening (85.6%) arms. As expected, survival was

significantly different between Type II and other cancer type diagnoses (p<0.01), but no significant

difference was found in survival between the screening and non-screening groups for Type II

tumours (p = 0.74) or other cancer types (p = 0.32). The authors concluded that screening did not

result in a stage shift or mortality benefit for Type II cancers, and that:

‘The results of this study support the notion that non-Type II ovarian cancers tend to

remain in an early stage for some time, whereas Type II cancers tend to spread

rapidly and are more likely to be missed in the window of opportunity for early

detection afforded by a screening test.’

They noted the following:

‘Future studies of screening for ovarian cancer must incorporate a contemporary

understanding of the natural history of ovarian cancer and account for the diverse

biologic behaviour of the subtypes of this malignancy.’

The authors also noted that similar post hoc analyses of the UKCTOCS trial will be ‘crucial to a

modern understanding of the role of screening in ovarian cancer’.


5.1.3 Ongoing clinical studies


up of UKCTOCS, which will use an updated classification of peritoneal cancers to reflect the new

criteria in the WHO 2014 definition. After reclassification of these peritoneal cancers, the primary

outcomes of UKCTOCS and PLCO will be more closely aligned. The next censorship for UKCTOCS is

planned for December 2018, and final censorship for December 2024.

5.1.4 Impact of recent findings on evidence-informed guidance

All guidance published in 2016 and 2017 considered evidence from the primary publication of the

UKCTOCS trial (Jacobs 2016). None of the clinical practice guidelines or other forms of guidance

recommend routine screening for ovarian cancer in asymptomatic or average-risk women.

5.1.5 Emerging technologies

Given the absence of a single marker or screening device that is effective for ovarian cancer,

research is likely to increasingly aim to identify new markers and combinations of markers in

prediction models.

A number of methodologies were identified that are either currently available for prognosis or


ovarian cancer. However, none of these are likely to be introduced/recommended in the short- to

medium-term.

The UKCTOCS trialists are engaged in efforts to improve upon the ROCA algorithm, adding other

protein markers along with CA125 to new prediction models derived using data from the UKCTOCS

trial. These models would require further validation and testing to determine whether they truly

represent improvements on the ROCA algorithm that would potentially attain clinical benefits for

ovarian cancer detection and treatment.

OvPlex™ was mentioned in the 2009 Cancer Australia Position Statement as a commercial blood

test for early detection of ovarian cancer. No data from prospective controlled trials have been

reported for the test and it no longer appears to be commercially available.

Surveillance in women at high risk

5.1.6 Current clinical evidence

5.1.6.1 Design of studies and nature of comparisons presented

Justification for screening typically requires demonstration of a mortality benefit, which in the case

of surveillance in high risk women presents particular challenges. Random assignment to a no-

screening arm is considered unethical in high-risk women, so no studies restricted to this population

included a no-screening comparator group. Consequently, historical controls are called upon in

these studies, or before/after comparisons are made within the cohort of screened women. In the

case of UKFOCSS, follow up after the last trial screening test prior to diagnosis or at the end of the

screening period of the study was censored at 365 days for the purpose of recording events

associated with screening, but follow up continued after that to capture events after the end of

screening. In the CGN/GOG study, prevalent and incident cancers are compared, with the latter

considered to represent ongoing screening.

While such comparisons may be considered valid, and are likely the best approach available to

investigate the effectiveness of surveillance, the results of these studies should be considered in light

of the inherent design flaws and inevitable confounding that limit the opportunity to demonstrate


statistically robust improvements in outcomes. The low incidence rate for ovarian cancer also

means that even in the largest studies, the number of events are small, especially when subgroups

such as stage at diagnosis are examined, further reducing the certainty of the outcomes.

Interpretation of the results of these surveillance studies also requires consideration of a number of

factors involved in the management of high-risk women, including the fact RRSO is recommended

as optimal management.

An exception was the PLCO post hoc analysis of a subgroup that included high-risk women. The

PLCO population screening study did not exclude high-risk women, and randomised women to

usual care, so the PLCO-HR subgroup analysis overcomes many of the limitations described above.

However, it was not feasible to identify women in this study post hoc according to the usual array of

criteria that define high risk, and the more readily discernible group of women with a personal

history of breast cancer or family history of breast or ovarian cancer was used instead.

Consequently, the overall disease-specific risk in this subgroup would have been lower than in a

typical high-risk population.

Therefore, the findings of these trials are described in detail to allow the reader to better

appreciate the data being compared, and to visualise possible trends that may not have statistical

significance, especially for stage-at-diagnosis results. This required post hoc calculations, using the

published data, of proportions or ratios not reported in the study publications (e.g. early versus late

stage diagnosis, proportions of diagnoses by stage, incidence rates).

5.1.6.2 Overview of UKFOCSS studies

The UKFOCSS study began in 2002 with annual screening using a single threshold CA125

measurement and TVUS. A change in protocol in 2007 (Phase II) introduced more frequent testing,

evaluating CA125 every 4 months using ROCA to triage for TVUS. These two phases of the study are

reported separately in the results section of this Review, grouped with studies using similar methods

of CA125 evaluation. The findings of both Phase I and Phase II studies are discussed together here,

then compared with the other studies.

Mortality outcomes in the UKFOCSS studies

Both phases of the UKFOCSS study compared outcomes for women diagnosed within a year of

their last trial screen with those diagnosed over a year since their last trial screen.103 No difference in

survival was found between these two groups in Phase I of the study, and was not analysed in

Phase II due to the low number of events. The potential implications of other findings on mortality

are discussed later in this section.

The authors of the current Review note that a simple comparison of the proportion of all women

diagnosed by any means who died due to their disease was much greater in Phase I (30%) than in

Phase II (13%). These studies had a similar number of participants (Phase I, N=3,563; Phase II,

N=4,531), and a similar number of person-years of screening (Phase I, 11,366; Phase II, 13,728). The

two studies differed substantially with regard to screening strategies, which likely underlies the

observed differences in overall disease-specific mortality. Another contributing factor may be the

proportion of women continuing surveillance from a prior screening study (Phase I, 0%; Phase II,

48%). Fewer prevalent cases might be expected in this group at the first Phase II screen. Indeed, no

cancer diagnoses were made in the first year of Phase II in any of these women from Phase I,

whereas the prevalence screen in Phase I found 9 of the 22 screen-detected cancers in that study

(41%).

103 Women in the latter group may have undergone screening locally after withdrawal from trial.


Stage at diagnosis in the UKFOCSS studies

Prevalent cases in Phase I were more likely to be early stage than subsequently diagnosed cancers.

The study authors noted that three of the six early stage prevalent cancers were in women with

Lynch syndrome, with all three diagnosed at Stage I. They noted the prognosis of Lynch syndrome

ovarian cancer is better than that for BRCA1/2 carriers, possibly because of earlier stage at

diagnosis. The authors speculated that Lynch syndrome-associated tumours may have a ‘longer

sojourn time, explaining the high proportion of early-stage disease in the prevalence screen’. The

single statistical analysis of stage shift in the Phase I study excludes diagnoses in women with Lynch

syndrome, providing a more conservative estimate of any potential increase in early stage

diagnosis in screened women.

In the Phase I study, significantly fewer women were diagnosed with very late-stage tumours (Stage

≥IIIc, p=0.009) if screened in the year before diagnosis.104 The authors, however, lamented the

disappointing results regarding detection of Stage I disease, which did not increase with screening.

Phase II of the UKFOCSS study also reported a single statistical analysis of stage shift, finding women

screened within a year of diagnosis had a significantly higher proportion of low volume disease,

defined as ≤Stage IIIa (corresponding to less macroscopic peritoneal metastasis outside the pelvis;

p<0.001). The study also reported that the proportion of all cases with zero residual disease after

surgery (an important prognostic factor in ovarian cancer) was higher in women diagnosed within

one year of screening compared with women from the same cohort in whom cancer was

diagnosed more than one year after screening was completed, but this finding was not significant

(p = 0.09).

Around one third of these low-volume diagnoses made within a year of the last screen were occult

cancers discovered during RRSO unrelated to screening, and the study authors do state that the

significantly lower proportion of ‘high-volume’ disease is associated with the ROCA-based

screening ‘alongside reminders of the effectiveness of RRSO’. They conclude that their overall

findings suggest a screening-mediated reduction in disease volume.

Harms of surveillance

The foremost harm of screening for ovarian cancer is false-positive surgery. The number of false-

positive surgeries per screen-detected cancer in the Phase II study was 11.5, substantially higher

than in Phase I (2.9) or the ROCA triage arm of the UKCTOCS population screening study (also 2.9;

Table 0.13).105 Value judgements around false positive surgery are complex in women at increased

risk of ovarian cancer, as prophylactic surgery is the currently recommended optimal management

strategy for high-risk women.

Quality-of-life outcomes

A number of studies investigated the emotional and psychological impact of screening and

reasons for withdrawal. Both clinical and psychological factors influenced the decision to withdraw,

and while recall for further testing was shown to cause moderate cancer distress, these effects

were transient and did not increase general anxiety or depression. Most women found surveillance

an acceptable risk management strategy.

Conclusions from the UKFOCSS studies

For screening to impact on survival, a stage shift is thought to be necessary, but it is not sufficient on

its own to reduce mortality. While encouraging, the clinical significance of the observed screening-

mediated reduction in disease volume in Phase II of UKFOCSS is uncertain, and the study authors

104 This analysis also excluded PPC. 105 Counting borderline tumours as false positives.


note it remains unknown whether these outcomes would translate into improved survival in

screened high-risk women. They also note that the high rate of compliance observed in the study

may not be maintained outside a trial.

The Phase II study authors conclude, however, that screening using ROCA every 4 months and TVUS

(at an interval determined by the ROCA), along with continual consideration of RRSO, appears to

be a better approach than symptom awareness alone. They note the high negative predictive

value of surveillance (not reported here) is ‘relevant to this population of women, who may

undergo screening to delay RRSO to complete childbearing or delay surgically induced

menopause’, which suggests surveillance may be considered appropriate for some women to

support decision making around the timing of RRSO. This is likely to be a decision made at the

clinical level, but the evidence to date does not support a shift in current management

recommendations across all high-risk women.

5.1.6.3 High-risk ROCA studies

CGN/GOG and UKFOCSS Phase II

The only other screening studies to use the ROCA in women at high risk of ovarian cancer is the

combined analysis of the CGN and GOG-0199 studies (CGN/GOG) and UKFOCSS Phase II. The

screening protocol for UKFOCSS Phase II drew from CGN/GOG, and they included similar numbers

of participants and a similar number of person-years of screening; overall incidence of ovarian

cancer was similar in the two studies, at 0.14% per year.106

No survival or mortality analyses were performed in these studies. Stage shift associated with

screening was analysed only for UKFOCSS Phase II, and was found to be significantly lower for high

volume diagnoses (> Stage IIIa). A trend towards earlier diagnosis was observed in CGN/GOG

when prevalent and incident screen-detected cancers were compared, but events were very few

(n=4 and n=5, respectively). False positive rates were substantially higher in the CGN/GOG study, at

21.7 surgeries to detect one case of cancer compared with 12.5 in the UKFOCSS study.

The authors of the CGN/GOG study are ‘exploring opportunities’ to pool their results with those from

other ROCA studies of high-risk women such as the UKFOCSS study, which could improve statistical

power for sensitivity and positive predictive value estimates.

5.1.6.4 Other CA125 single threshold studies

The UKFOCSS Phase I study is discussed earlier with Phase II in Section 5.1.6.2.

PLCO-HR

The post hoc analysis of a subgroup in PLCO with personal or familial histories has the powerful

strengths of study design and size (RCT), and while not completely applicable to the typically

defined high-risk group, does provide evidence that outcomes of screening in women at higher-

than-average risk of ovarian cancer are different to those for the general population. A significant

improvement in ovarian cancer-specific survival with screening is encouraging, as is the significant

reduction in advanced-stage disease (Stage IIIc or IV) relative to earlier-stage disease, and a

significant reduction in the absolute number of Stage IIIc and IV cancers. Whether this demarcation

in disease stage is clinically relevant is unclear, and ovarian cancer-specific mortality was not

significantly improved.


The main focus of this study was comparative survival among women diagnosed with ovarian

cancer who were BRCA1 carriers, BRCA2 carriers, or ‘other’. However, prevalent and incident

106 Post hoc calculation by authors of the current Review for CGN/GOG.


(including interval) diagnoses were also compared in this study, which found no difference in

mortality but a non-significant trend towards down staging when restricting the analysis to BRCA1/2

carriers.

5.1.6.5 Overall findings of surveillance studies

The few surveillance studies that reported on mortality did not find any improvements associated

with screening. The PLCO subgroup analysis, however, did find significant improvements in disease-

specific survival with screening in a population with a higher-than-average risk, and an absolute

reduction in advanced-stage cancers – a necessary finding for effective screening. Stage shift

trends were also discernible in the other surveillance trials, and were statistically significant in the

UKFOCSS trials. Event numbers were low in all surveillance studies of high-risk cohorts, so it is not

clear whether the failure to demonstrate a corresponding improvement in mortality is due to limited

statistical power or a fundamental failure to improve mortality outcomes in screened individuals

(i.e. early detection may not result in improved mortality). Furthermore, these studies were limited

by the lack of a balanced comparator group (PLCO excepted), so the current lack of a

demonstrated mortality benefit is not evidence that surveillance cannot improve survival

outcomes.

While stage shift may be of interest as a surrogate outcome for mortality, reduced volume of

disease is also a patient-relevant outcome in itself, with implications regarding rates of post-surgical

residual disease. So while the evidence may not be resounding for the use of surveillance as first-

line management in high-risk women, it appears there may be a role for surveillance of those

women wishing to postpone RRSO.

5.1.7 Ongoing clinical studies

No ongoing clinical studies were identified in this population.

5.1.8 Impact of recent findings on evidence-informed guidance

No clinical practice guidelines or other guidance was identified that incorporates all recent

evidence relating to surveillance in women at high risk of ovarian cancer. In general, routine

surveillance is not recommended; however, some guidelines advise that surveillance using CA125

and TVUS may be considered in particular high-risk populations from the age of 30 or 35, so long as

patients are informed about the limited value of these tools as an effective screening measure.

5.1.9 Definitions of high risk of ovarian cancer

The criteria for defining women at high or potentially high risk of ovarian cancer typically contain

elements that are already included in the 2009 Position Statements, such as a personal and family

history of breast and ovarian cancer, genetic mutations, and Ashkenazi Jewish ancestry.

The recent introduction of an MBS item for cascade testing of BRCA1/2 and other specified

mutations has the potential to increase the number of women known to be at increased risk of

ovarian cancer. As such, it may be expected that any definition of a high risk population explicitly

mentions BRCA1/2 and other genetic mutations that predispose to ovarian cancer (e.g. mutations

associated with Lynch syndrome/HNPCC).

5.1.10 Emerging technologies

As for population screening (Section 5.1.5), there are no new biomarkers or other technologies that

are likely to be introduced/recommended in the short- to medium-term for surveillance of women

at high or potentially high risk of ovarian cancer.


Appendices

Appendix A Australian criteria for assessment of population screening

The framework used to guide decision makers regarding the implementation of population

screening for cancer and other chronic diseases in Australia is based on the principles outlined in

Table AppA.1. The framework has been adapted from the 1968 WHO criteria but takes into

account:

the need for a strong evidence base in making a decision about the introduction of a

screening program including evidence of the safety, reproducibility and accuracy of the

screening test and the efficacy of treatment; and

the requirement that a screening program offers more benefit than harm to the target

population.

The decision to introduce a screening program needs to also consider whether the outcomes in the

research setting can be reproduced in population screening settings.

The Australian Population Screening Framework is not designed to address targeted testing of high

risk groups. In planning the coverage of screening programs, however, steps must be taken to

ensure that consideration is given to those at high risk of developing the disease being screened

for, and that policies are in place for the appropriate identification and management of individuals

in these high risk groups.

Table AppA.1 Australian criteria for deciding whether a new screening program should be

introduced in a defined target population

Requirement Criteria to be met

Condition The condition:

is an important health problem

has a recognisable latent or early symptomatic stage

The natural history of the disease or condition, including, where relevant, the relationship between the risk

marker and the disease and the development from latent to declared disease is adequately understood.

Test The test:

is highly sensitive

is highly specific

is validated

is safe

has a relatively high positive predictive value

has a relatively high negative predictive value

is acceptable to the target population including important sub groups such as target participants who are

from culturally and linguistically diverse backgrounds, Aboriginal and Torres Strait Islander people, people

from disadvantaged groups, and people with a disability

There are established criteria for what constitutes positive and negative test results, where a positive test result

means that the person needs further investigations, and a negative test result means the person is rescreened

at the usual interval, where applicable.

Assessment Systems should be in place for evidence based follow up assessment of all people with a positive screening test

regardless of rurality, ethnicity, socio economic status or disadvantage status.

Treatment The treatment must be effective, available, easily accessible and acceptable to all patients with the

recognised disease or condition.


Requirement Criteria to be met

Screening program The Screening Program must:

respond to a recognised need

be clinically, socially, legally and ethically acceptable to health professionals, consumers and the Australian

public

have a clear definition of the objectives of the program and the expected health benefits

have scientific evidence of screening program effectiveness

identify the target population who stand to benefit from screening

clearly define the screening pathway and interval

ensure availability of the organisation, infrastructure, facilities and workforce needed to deliver the screening

program

have measures available that have been demonstrated to be cost effective to encourage high coverage

have adequate facilities available for having tests and interpreting them

have an organised quality control program across the screening pathway to minimise potential risks of

screening

have a referral system for management of any abnormalities found and for providing information about

normal screening tests

have adequate facilities for follow-up assessment, diagnosis, management and treatment

have evidence based guidelines and policies for assessment, diagnosis and support for people with a

positive test result

have adequate resources available to set up and maintain a database of health information collected for

the program

integrate education, testing, clinical services and program management

have a database or systems available capable of providing a population register for people screened that

can issue invitations for initial screening, recall individuals for repeat screening, follow those with identified

abnormalities, correlate with morbidity and mortality results and monitor and evaluate the program and its

impact

plan evaluation from the outset and ensure that program data are maintained so that evaluation and

monitoring of the program can be performed regularly

be cost-effective

ensure informed choice, confidentiality and respect for autonomy

promote equity and access to screening for the entire target population including important sub groups such

as participants who are from culturally and linguistically diverse backgrounds, Aboriginal and Torres Strait

Islander people, people from disadvantaged groups, and people with a disability

ensure the overall benefits of screening outweigh the potential harms, including psychological, physical,

social, cultural, ethical and legal harms

Treatment and ongoing

management

Treatment and management considerations:

Ongoing management referral protocols must be established for individuals who have the disease or

condition detected through the screening program

There needs to be an established policy for the management of individuals who are identified at high risk of

developing the disease or condition

Source: Population based screening framework 2016 downloaded from Department of Health, Standing Committee on Screening in

September 2017.

http://www.cancerscreening.gov.au/internet/screening/publishing.nsf/Content/population-based-screening-framework


Appendix B Literature search details

B.1 Clinical evidence

B.1.1 Search strategy

Table AppB.1 Search strategy to identify clinical evidence

Source of information Database/website Date limits and search terms

Electronic database Medline (Ovid)107 From 1 January 2009 to present.

See Table AppB.2 for search strings.

HTA websites AHRQ (https://www.ahrq.gov/)

CADTH (https://www.cadth.ca/)

EuroScan (http://www.euroscan.bham.ac.uk/)

HealthPACT (https://www.health.qld.gov.au/healthpact/html/tech-

evaluated)

MSAC (http://www.msac.gov.au/)

NICE (https://www.nice.org.uk/)

From 1 January 2009 to present.

Search terms will depend on the

complexity of the available search

engine. In the first instance, ‘ovarian

cancer’ combined with each

intervention.

Peak cancer authorities American Cancer Society (https://www.cancer.org/)

ASCO (http://www.asco.org/)

Cancer Care Ontario (https://www.cancercare.on.ca/)

Cancer Research UK (https://www.cancerresearchuk.org/)

EORTC (http://www.eortc.org/)

ESMO (http://www.esmo.org/)

IARC (http://www.iarc.fr/)

NCCN (https://www.nccn.org/)

NCI (https://www.cancer.gov/)

Society of Gynecologic Oncology (https://www.sgo.org/)




cancer’ combined with each

intervention.

Clinical trial registries Australian New Zealand Clinical Trials Registry

(http://www.anzctr.org.au/)

ClinicalTrials.gov (https://clinicaltrials.gov/)

EU Clinical Trials Register (https://www.clinicaltrialsregister.eu/ctr-

search/search)

World Health Organization International Clinical Trials Registry

Platform (http://apps.who.int/trialsearch/)

Recently completed (unpublished) and

ongoing trials only.




cancer’ combined with ‘screen’ or

‘detection’.

Abbreviations: AHRQ, Agency for Healthcare Research and Quality; ASCO, American Society of Clinical Oncology; CADTH, Canadian

Agency for Drugs and Technologies in Health; EORTC, European Organization for Research and Treatment of Cancer; ESMO, European

Society for Medical Oncology; EuroScan, European Information Network on New and Changing Health Technologies; HTA, Health Technology

Assessment; IARC, International Agency for Research on Cancer; MSAC, Medical Services Advisory Committee; NCCN, National

Comprehensive Cancer Network; NCI, National Cancer Institute; NICE, National Institute for Health and Care Excellence.

Table AppB.2 Medline search string for ovarian cancer screening

String

no.

Ovid MEDLINE(R) Epub Ahead of Print, In-Process & Other Non-Indexed Citations, Ovid MEDLINE(R) Daily and

Ovid MEDLINE(R) 1946 to Present. Searched 17 Oct 2017

Records

1 exp Ovarian Neoplasms/ 80,829

2 (ovar$ adj5 (Cancer$ or tumo?r$ or neoplas$ or carcinoma$ or malignan$)).ti,ot. 52,495

3 exp Mass Screening/ 120,562

4 exp Early Detection of Cancer/ 18,961

5 screen$.ti,ab,ot. 649,445

6 1 or 2 87,296

7 or/3-5 695,334

8 6 and 7 4,465

9 Randomized Controlled Trial/ 496,904

107 Includes Ovid MEDLINE(R) Epub Ahead of Print, In-Process & Other Non-Indexed Citations, Ovid MEDLINE(R) Daily and Ovid MEDLINE(R) 1946

to Present

https://www.ahrq.gov/

https://www.cadth.ca/

http://www.euroscan.bham.ac.uk/

https://www.health.qld.gov.au/healthpact/html/tech-evaluated

https://www.health.qld.gov.au/healthpact/html/tech-evaluated

http://www.msac.gov.au/

https://www.nice.org.uk/

https://www.cancer.org/

http://www.asco.org/

https://www.cancercare.on.ca/

https://www.cancerresearchuk.org/

http://www.eortc.org/

http://www.esmo.org/

http://www.iarc.fr/

https://www.nccn.org/

https://www.cancer.gov/

https://www.sgo.org/

http://www.anzctr.org.au/

https://clinicaltrials.gov/

https://www.clinicaltrialsregister.eu/ctr-search/search


http://apps.who.int/trialsearch/


String

no.



Records

10 randomi#ed controlled trial.pt. 496,904

11 controlled clinical trial.pt. 99,253

12 randomi#ed.ab. 519,298

13 placebo.ab. 202,740

14 clinical trials as topic.sh. 195,527

15 randomly.ab. 298,737

16 trial.ti. 195,716

17 or/9-16 1,243,082

18 8 and 17 494

19 limit 18 to yr="2009 -Current" 309

Table AppB.3 Medline search string for ovarian cancer surveillance in women at high risk

String

no.



Records

1 (famil$ or heredit$ or BRCA or high$ risk or elevated risk or increased risk).ti,ot,ab. 1,502,735


3 (ovar$ and (Cancer$ or tumo?r$ or neoplas$ or carcinoma$ or malignan$)).ti,ot. 54,588

4 2 or 3 88,365


6 (screen$ or surveillance or monitor or CA125 or CA-125 or CA 125 or human epididymis protein 4 or human

epididymal protein 4 or HE4 or HE 4 or transvaginal ultrasound or TVUS or tvs).ti,ot.

209,343

7 exp CA-125 antigen/ 4,580

8 5 or 6 or 7 273,813

9 1 and 4 and 8 700


B.1.2 Study selection

Table AppB.4 Study selection for the review of ovarian cancer population screening

Screening of records identified in Medline search on 17 October 2017 Records

Total records from population screening search 309

Duplicates 61

Unique records screened 248

Reasons for exclusion:

Wrong population 47

Wrong intervention 80

Wrong/no comparator 0

Wrong outcomes 76

Wrong publication type 29

Wrong study type 2

Not in English 0

Not in humans 0

Total excluded 234

Included records from population screening search in Medline 14

Records identified in Medline search for guidelines 3

Included records for population screening 17


Table AppB.5 Study selection for the review of ovarian cancer surveillance in women at high risk

Screening of records identified in Medline search on 17 October 2017 Records

Total records from ovarian cancer surveillance search 337

Duplicates 47


Reasons for exclusion:

Wrong population 22


Wrong/no comparator 5

Wrong outcomes 21


Wrong study type 19

Not in English 0

Not in humans 2

Total excluded at title/abstract review 279

Included records from ovarian cancer surveillance search in Medline 11

B.2 Guidelines and position statements


Table AppB.6 Search strategy to identify guidelines and position statements

Source of information Database/website Restrictions

Clinical practice

guideline databases

Australian Clinical Practice Guidelines Portal

(https://www.clinicalguidelines.gov.au/)

AHRQ's National Guideline Clearinghouse

(https://guideline.gov/)

Guidelines International Network

(http://www.g-i-n.net/library/international-guidelines-library)

SIGN (http://www.sign.ac.uk/)


Evidence-informed guidelines and

position statements published from 2011

onwards.

Search terms depend on complexity of

the search engine. In first instance try

‘ovarian cancer’.

Electronic databases Medline (Ovid) 108 Evidence-informed guidelines and

position statements published from 2011

onwards.

Peak cancer authorities American Cancer Society (https://www.cancer.org/)









Society of Gynecologic Oncology (https://www.sgo.org/)

Evidence-informed guidance/advice

published from 2011 onwards.

108 Includes Ovid MEDLINE(R) Epub Ahead of Print, In-Process & Other Non-Indexed Citations, Ovid MEDLINE(R) Daily and Ovid MEDLINE(R) 1946

to Present

https://www.clinicalguidelines.gov.au/

https://guideline.gov/

http://www.g-i-n.net/library/international-guidelines-library

http://www.sign.ac.uk/








http://www.iarc.fr/





To identify relevant guidance in the Medline database, a search string that includes broad terms

for the interventions was combined with a search filter for clinical practice guidelines and position

statements developed by the Canadian Agency for Drugs and Technologies in Health (CADTH).

Table AppB.7 Medline search strings for guidelines and position statements

String

no.

Ovid MEDLINE(R) Epub Ahead of Print, In-Process & Other Non-Indexed Citations, Ovid MEDLINE(R) Daily and Ovid

MEDLINE(R) 1946 to Present. Searched 17Oct 2017

Records


2 (ovar$ adj5 (Cancer$ or tumo?r$ or neoplas$ or carcinoma$ or malignan$)).ti,ab,kw. 85,947


4 exp Early Detection of Cancer/ 18,974

5 screen$.ti,ab,kw. 651,580

6 1 or 2 108,203

7 (3 or 4 or 5) and 6 6,333

8 (famil$ or heredit$ or BRCA or high$ risk or elevated risk or increased risk).ti,ab,kw. 1,525,861


10 (ovar$ and (Cancer$ or tumo?r$ or neoplas$ or carcinoma$ or malignan$)).ti,ab,kw. 104,015

11 9 or 10 123,264


13 (screen$ or surveillance or monitor or CA125 or CA-125 or CA 125 or human epididymis protein 4 or human

epididymal protein 4 or HE4 or HE 4 or transvaginal ultrasound or TVUS or tvs).ti,ab,kw.

922,898

14 exp CA-125 antigen/ 4,580

15 12 or 13 or 14 962,180

16 8 and 11 and 15 3,184

17 exp clinical pathway/ 6,128

18 exp clinical protocol/ 161,293

19 exp consensus/ 8,863

20 exp consensus development conference/ 11,567

21 exp consensus development conferences as topic/ 2,712

22 critical pathways/ 6,128

23 exp guideline/ 31,725

24 guidelines as topic/ 37,582

25 exp practice guideline/ 24,751

26 practice guidelines as topic/ 107,967

27 health planning guidelines/ 4,167

28 (guideline or practice guideline or consensus development conference or consensus development conference,

NIH).pt.

40,846

29 (position statement* or policy statement* or practice parameter* or best practice*).ti,ab,kf,kw. 25,608

30 (standards or guideline or guidelines).ti,kf,kw. 95,422

31 ((practice or treatment* or clinical) adj guideline*).ab. 32,939

32 (CPG or CPGs).ti. 5,447

33 consensus*.ti,kf,kw. 21,539

34 consensus*.ab. /freq=2 21,193

35 ((critical or clinical or practice) adj2 (path or paths or pathway or pathways or protocol*)).ti,ab,kf,kw. 17,345

36 recommendat*.ti,kf,kw. 35,508

37 (care adj2 (standard or path or paths or pathway or pathways or map or maps or plan or plans)).ti,ab,kf,kw. 46,971

38 (algorithm* adj2 (screening or examination or test or tested or testing or assessment* or diagnosis or diagnoses or

diagnosed or diagnosing)).ti,ab,kf,kw.

6,363

39 (algorithm* adj2 (pharmacotherap* or chemotherap* or chemotreatment* or therap* or treatment* or

intervention*)).ti,ab,kf,kw.

8,209

40 or/17-39 549,904

41 (7 or 16) and 40 469



B.2.2 Selection of guidelines and position statements

Table AppB.8 Selection for the review of guidelines and position statements

Screening of records identified in bibliographic database searches on 17 October 2017 Records

Total records from guidelines search 232

Duplicates 32


Title/abstract review exclusions:

Wrong population 4


Wrong outcomes 1


Wrong study type 11

Not in English 2

Not in humans 0

Total excluded at title/abstract review 183

Total records reviewed at full text 17

Full text review exclusions:

Superseded 2

Not in English 1

Wrong study type 5

Total excluded at full text review 8

Included records from Medline search for guidelines for ovarian cancer screening and surveillance 9

Records identified from other searches:

Medline search for studies of population screening 0

Medline search for studies of surveillance in women at high risk 2

Targeted and general web searches 11

Total guidelines and position statements 20


B.3 Emerging technologies


Table AppB.9 Search strategy to identify emerging technologies

Source of

information

Database/website Date limits and search terms

HTA websites AHRQ (https://www.ahtq.gov/)

CADTH (https://www.cadth.ca/)

EuroScan (http://www.euroscan.bham.ac.uk/)

HealthPACT (http://www.health.qld.gov.au/healthpact/html/tech-evaluated)

MSAC (http://www.msac.gov.au)


Published from 2009 onwards.

Search terms varied depending on

the complexity of the search

engine. Generally used ‘ovarian

cancer’.

Horizon scan

websites

ANZHSN (https://www.horizonscanning.gov.au/)

ISCRR (https://www.iscrr.com.au/evidence-data-and-research/evidence-

review-hub/horizon-scanning)

CADTH Horizon Scanning (http://www.cadth.ca/about-cadth/what-we-

do/products-services/horizon-scanning)

ECRI Institute (https://www.ecri.org/Pages/default.aspx)

The King’s Fund (http://www.kingsfund.org.uk/)

McGill Technology Assessment Unit (http://www.mcgill.ca/tau/)

The Medical Futurist (http://medicalfuturist.com/)

NICE Medtech Innovation Briefings (https://www.nice.org.uk/about/what-we-

do/our-orogrammes/nice-advice/medtech-innovation-briefings)

NIHR-DEC Horizon Scanning Programme

(https://www.oxfor.dec.nihr.ac.au/research/horizon-scanning-1)

NIHR-IO (https://www.io.nihr.ac.uk/)

NIHR-SATSU (https://www.york.ac.uk/satsu/




cancer’.

Peak cancer

authorities

ACS (https://www.cancer.org/)









Society of Gynecologic Oncology (https://www.sgo.org/




cancer’.

Clinical trial

registries

ANZCTR (https://www.anzctr.org.au/)

ClinicalTrials.gov (https://clinicaltrials.gov/)

EUCTR (https://www.clinicaltrialsregister.eu/ctr-search/search)

WHOICTRP (https://apps.who.int/trialsearch/

Recently completed or ongoing

trials




cancer’ and the following terms:

screening, surveillance, detection,

test, diagnostic and biomarker.

Conference

abstracts

Key cancer conferences:

ASCO (http://ascopubs.org/jco/meeting)

ESMO (http://www.esmo.org/Conferences/Past-Conferences

Abstracts/commentary from 2016

and 2017 conferences

Searched ‘ovarian cancer’ and

‘screening’ or ‘biomarker’.

Abbreviations: ACS, American Cancer Society; AHRQ, Agency for Healthcare Research and Quality; ANZHSN, Australia and New Zealand

Horizon Scanning Network; ASCO, American Society of Clinical Oncology; CADTH, Canadian Agency for Drugs and Technologies in Health;

DEC, Diagnostic Evidence Co-operative; EORTC, European Organisation for Research and Treatment of Cancer; ESMO, European Society for

Medical Oncology; EUCTR, European Union Clinical Trials Register; HealthPACT, Health Policy Advisory Committee on Technology; HTA, Health

Technology Assessment; IARC, International Agency for Research on Cancer; IO, Innovation Observatory; ISCRR, Institute for Safety,

Compensation and Recovery Research; MSAC, Medical Services Advisory Committee; NCCN, National Comprehensive Cancer Network; NCI,

National Cancer Institute; NICE, National Institute for Health and Care Excellence; NIHR, National Institute for Health Research; SATSU, Science

and Technology Studies Unit; WHOICTRP, World Health Organization International Clinical Trials Registry Platform.

https://www.ahtq.gov/

https://www.cadth.ca/

http://www.euroscan.bham.ac.uk/

http://www.health.qld.gov.au/healthpact/html/tech-evaluated

http://www.msac.gov.au/


https://www.horizonscanning.gov.au/

https://www.iscrr.com.au/evidence-data-and-research/evidence-review-hub/horizon-scanning

https://www.iscrr.com.au/evidence-data-and-research/evidence-review-hub/horizon-scanning

http://www.cadth.ca/about-cadth/what-we-do/products-services/horizon-scanning

http://www.cadth.ca/about-cadth/what-we-do/products-services/horizon-scanning

https://www.ecri.org/Pages/default.aspx

http://www.kingsfund.org.uk/

http://www.mcgill.ca/tau/

http://medicalfuturist.com/

https://www.nice.org.uk/about/what-we-do/our-orogrammes/nice-advice/medtech-innovation-briefings

https://www.nice.org.uk/about/what-we-do/our-orogrammes/nice-advice/medtech-innovation-briefings

https://www.oxfor.dec.nihr.ac.au/research/horizon-scanning-1

https://www.io.nihr.ac.uk/

https://www.york.ac.uk/satsu/







http://www.iarc.fr/




https://www.anzctr.org.au/

https://clinicaltrials.gov/


https://apps.who.int/trialsearch/

http://ascopubs.org/jco/meeting

http://www.esmo.org/Conferences/Past-Conferences


Appendix C Evidence hierarchy

The levels of evidence hierarchy for interventions, developed by the National Health and Medical

Research Council (NHMRC), is shown in Table AppC.1.

Table AppC.1 Designations of levels of evidence for interventional studies

Level Intervention Screening intervention

Ia A systematic review of Level II studies A systematic review of Level II studies

II A randomised controlled trial A randomised controlled trial

III-1 A pseudo-randomised controlled trial (i.e. alternate

allocation or some other method)

A pseudo-randomised controlled trial (i.e. alternate

allocation or some other method)

III-2 A comparative study with concurrent controls: A comparative study with concurrent controls:

Non-randomised, experimental trialb Non-randomised, experimental trial

Cohort study Cohort study

Case-control study Case-control study

Interrupted time series with a control group

III-3 A comparative study without concurrent controls: A comparative study without concurrent controls:

Historical control study Historical control study

Two or more single-arm studyc Two or more single-arm study

Interrupted time series without a parallel control group

IV Case series with either post-test or pre-test/post-test

outcomes

Case series

Source: National Health and Medical Research Council. NHMRC levels of evidence and grades for recommendations for developers of

guidelines. Canberra: National Health and Medical Research Council, 2009.

a A systematic review will only be assigned a level of evidence as high as the studies it contains, excepting where those studies are of Level II

evidence. Systematic reviews of Level II evidence provide more data than the individual studies and any meta-analyses will increase the

precision of the overall results, reducing the likelihood that the results are affected by chance. Systematic reviews of lower level evidence

present results of likely poor internal validity and thus are rated on the likelihood that the results have been affected by bias, rather than

whether the systematic review itself is of good quality. Systematic review quality should be assessed separately. A systematic review should

consist of at least two studies. In systematic reviews that include different study designs, the overall level of evidence should relate to each

individual outcome/result, as different studies (and study designs) might contribute to each different outcome.

b This also includes controlled before-and-after (pre-test/post-test) studies, as well as adjusted indirect comparisons (i.e. utilise A vs B and B vs

C, to determine A vs C with statistical adjustment for B).

c Comparing single-arm studies i.e. case series from two studies. This would also include unadjusted indirect comparisons (i.e. utilise A vs B and

B vs C, to determine A vs C but where there is no statistical adjustment for B).


Appendix D Included studies

D.1 Population screening

D.1.1 Clinical trials

Table AppD.1 Clinical trials of population screening for ovarian cancer

Trial Study ID Citation Main

outcome

PLCO: Prostate, Lung, Colorectal and Ovarian Cancer Screening RCT

Primary and secondary outcomes

Pinsky

2016

Pinsky PF, Yu K, Kramer BS, Black A, Buys SS, Partridge E, et al. (2016). Extended mortality

results for ovarian cancer screening in the PLCO trial with median 15years follow-up.

Gynecologic Oncology. 143(2):270-5.

Mortality –

longer term

follow up

Primary

publication

Buys 2011 Buys SS, Partridge E, Black A, Johnson CC, Lamerato L, Isaacs C, et al. (2011). Effect of

screening on ovarian cancer mortality: the Prostate, Lung, Colorectal and Ovarian

(PLCO) Cancer Screening Randomized Controlled Trial. JAMA. 305(22):2295-303.

Mortality

Partridge

2009

Partridge E, Kreimer AR, Greenlee RT, Williams C, Xu JL, Church TR, et al. (2009). Results

from four rounds of ovarian cancer screening in a randomized trial. Obstetrics &

Gynecology. 113(4):775-82.

False positive

surgery, stage

at diagnosis

Buys

2005109

Buys SS, Partridge E, Greene MH, Prorok PC, Reding D, Riley TL, et al. (2005). Ovarian

cancer screening in the Prostate, Lung, Colorectal and Ovarian (PLCO) cancer

screening trial: Findings from the initial screen of a randomized trial. American Journal of

Obstetrics and Gynecology. 193(5):1630-9.

Initial screen

Post hoc analyses

Pinsky

2013

Pinsky PF, Zhu C, Skates SJ, Black A, Partridge E, Buys SS, et al. (2013). Potential effect of

the risk of ovarian cancer algorithm (ROCA) on the mortality outcome of the Prostate,

Lung, Colorectal and Ovarian (PLCO) trial. International Journal of Cancer. 132(9):2127-

33.

Mortality

Nyante

2011

Nyante SJ, Black A, Kreimer AR, Duggan MA, Carreon JD, Kessel B, et al. (2011).

Pathologic findings following false-positive screening tests for ovarian cancer in the

Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening trial. Gynecologic

Oncology. 120(3):474-9.

Predictors of

false positive

results

Additional material

NIH –

National

Cancer

Institute

Cancer Data Access System. Online information for PLCO including a summary of trial

design, datasets and a list of study publications Accessed 31 Oct 2017

Data source

Prorok

2000

Prorok PC, Andriole GL, Bresalier RS, Buys SS, Chia D, Crawford ED, et al. (2000). Design of

the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. Controlled

clinical trials. 21(6 Suppl):273S-309S.

Study design

Simpson

2000

Simpson NK, Johnson CC, Ogden SL, Gamito E, Trocky N, McGuire C, et al. (2000).

Recruitment strategies in the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer

Screening Trial: the first six years. Controlled clinical trials. 21(6 Suppl):356S-78S.

Study design

109 This study was published prior to the 2009 date limit for the literature search, and was identified by hand searching.

https://biometry.nci.nih.gov/cdas/plco/


Trial Study ID Citation Main

outcome

UKCTOCS: UK Collaborative Trial of Ovarian Cancer Screening RCT

Primary and secondary outcomes

Fallowfield

2017

Fallowfield L, Solis-Trapala I, Menon U, Langridge C, May S, Jacobs I, et al. (2017). The

effect of ovarian cancer screening on sexual activity and functioning: results from the UK

collaborative trial of ovarian cancer screening RCT. British Journal of Cancer. 116(8):1111-

7.

Adverse

effects of tests

Primary

publication

Jacobs

2016

Jacobs IJ, Menon U, Ryan A, Gentry-Maharaj A, Burnell M, Kalsi JK, et al. (2016). Ovarian

cancer screening and mortality in the UK Collaborative Trial of Ovarian Cancer Screening

(UKCTOCS): a randomised controlled trial. Lancet. 387(10022):945-56. Supplementary

appendix available.

Mortality

Barrett

2014

Barrett J, Jenkins V, Farewell V, Menon U, Jacobs I, Kilkerr J, et al. (2014). Psychological

morbidity associated with ovarian cancer screening: results from more than 23,000

women in the randomised trial of ovarian cancer screening (UKCTOCS). BJOG: An

International Journal of Obstetrics & Gynaecology. 121(9):1071-9.

Adverse

effects of tests

Sharma

2012

Sharma A, Apostolidou S, Burnell M, Campbell S, Habib M, Gentry-Maharaj A, et al.

(2012). Risk of epithelial ovarian cancer in asymptomatic women with ultrasound-

detected ovarian masses: a prospective cohort study within the UK collaborative trial of

ovarian cancer screening (UKCTOCS). Ultrasound in Obstetrics & Gynecology. 40(3):338-

44.

False positive

surgery

Menon

2009

Menon U, Gentry-Maharaj A, Hallett R, Ryan A, Burnell M, Sharma A, et al. (2009).

Sensitivity and specificity of multimodal and ultrasound screening for ovarian cancer,

and stage distribution of detected cancers: results of the prevalence screen of the UK

Collaborative Trial of Ovarian Cancer Screening (UKCTOCS). Lancet Oncology. 10(4):327-

40.

Initial screen

Post hoc analyses

Menon

2017

Menon U, McGuire AJ, Raikou M, Ryan A, Davies SK, Burnell M, et al. (2017). The cost-

effectiveness of screening for ovarian cancer: results from the UK Collaborative Trial of

Ovarian Cancer Screening (UKCTOCS). British Journal of Cancer. 117(5):619-27.

Cost

effectiveness

Kearns

2016

Kearns B, Chilcott J, Whyte S, Preston L, Sadler S. (2016). Cost-effectiveness of screening

for ovarian cancer amongst postmenopausal women: a model-based economic

evaluation.[Erratum appears in BMC Med. 2017 Feb 3;15(1):31; PMID: 28158977]. BMC

Medicine. 14(1):200.

Cost

effectiveness

Menon

2015

Menon U, Ryan A, Kalsi J, Gentry-Maharaj A, Dawnay A, Habib M, et al. (2015). Risk

Algorithm Using Serial Biomarker Measurements Doubles the Number of Screen-Detected

Cancers Compared With a Single-Threshold Rule in the United Kingdom Collaborative

Trial of Ovarian Cancer Screening. Journal of Clinical Oncology. 33(18):2062-71.

Threshold

testing

Additional material

Jacobs

and

Menon

2015

Protocol for the United Kingdom Collaborative Trial of Ovarian Cancer Screening

(UKCTOCS) Version 7.1, April 2015 Accessed 31 Oct 2017

Study design

NHS 2016 Detailed Project Description: Long term impact of screening on ovarian cancer mortality

in the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS). Report. Accessed

31 Oct 2017.

Rationale for

extending

follow up

Abbreviations: PLCO, Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial; RCT, randomised controlled trial; NHS, National Health

Service; UK, United Kingdom; UKCTOCS, UK Collaborative Trial of Ovarian Cancer Screening.

D.1.2 Systematic reviews and HTAs

Table AppD.2 Systematic reviews of population screening for ovarian cancer

Study ID Citation

Buhling 2017 Buhling KJ, Lezon S, Eulenburg C, Schmalfeldt B. (2017). The role of transvaginal ultrasonography for detecting ovarian

cancer in an asymptomatic screening population: a systematic review. Archives of Gynecology & Obstetrics.

295(5):1259-68.

Guirguis-Blake

2017

Guirguis-Blake JM, Henderson JT, Perdue LA, Whitlock EP. (2017) Screening for Gynecologic Conditions With Pelvic

Examination: A Systematic Review for the U.S. Preventive Services Task Force. Evidence Synthesis No. 147. AHRQ

Publication No. 15-05220-EF-1. Rockville, MD: Agency for Healthcare Research and Quality.

Henderson 2017 Henderson JT, Webber E, Sawaya GF. (2017). Screening for Ovarian Cancer: An Updated Evidence Review for the U.S.

Preventive Services Task Force. Evidence Synthesis No. 157. AHRQ Publication No. 17-05231-EF-1. Rockville, MD: Agency

for Healthcare Research and Quality.

https://www.ucl.ac.uk/womens-health/research/womens-cancer/gynaecological-cancer-research-centre/ukctocs/files/ukctocs_protocol71

https://www.google.com.au/url?sa=t&rct=j&q=&esrc=s&source=web&cd=1&cad=rja&uact=8&ved=0ahUKEwjh6tr0mbDXAhVSy2MKHVACBSkQFggmMAA&url=https%3A%2F%2Fwww.ucl.ac.uk%2Fwomens-health%2Fresearch%2Fwomens-cancer%2Fgynaecological-cancer-research-centre%2Fukctocs%2Ffiles%2Fukctocs_protocol71&usg=AOvVaw1U3n6GoxyYxNJXsYQZQFTi



Study ID Citation

Bloomfield 2014 Bloomfield HE, Olson A, Greer N, Cantor A, MacDonald R, Rutks I, et al. (2014). Screening pelvic examinations in

asymptomatic, average-risk adult women: an evidence report for a clinical practice guideline from the American

College of Physicians. Annals of Internal Medicine. 161(1):46-53.

Reade 2013 Reade CJ, Riva JJ, Busse JW, Goldsmith CH, Elit L. (2013). Risks and benefits of screening asymptomatic women for

ovarian cancer: a systematic review and meta-analysis. Gynecologic Oncology. 130(3):674-81.

Abbreviations: HTA, health technology assessment; MA, meta-analysis; SR, systematic review.

D.2 Surveillance in women at high risk

D.2.1 Clinical studies

Table AppD.3 Clinical studies of surveillance in women at high risk of ovarian cancer

Study ID Citations Main outcome

UKFOCSS Phase II

Rosenthal

2017

Rosenthal AN, Fraser LSM, Philpott S, Manchanda R, Burnell M, Badman P, et al. (2017). Evidence of

Stage Shift in Women Diagnosed With Ovarian Cancer During Phase II of the United Kingdom

Familial Ovarian Cancer Screening Study. Journal of Clinical Oncology. 35(13):1411-20.

Performance

characteristics

Additional material

Jacobs 2010 The UK Familial Ovarian Cancer Screening Study (UK FOCSS) Phase II. Study Protocol. Accessed 10

Nov 2017.

Study design

PsyFOCS

Lifford 2013 Lifford KJ, Clements A, Fraser L, Lancastle D, Brain K, Psy FMG. (2013). A qualitative study of women's

experiences of familial ovarian cancer screening. Psycho-Oncology. 22(11):2576-84.

Quality of life

Brain 2012 Brain KE, Lifford KJ, Fraser L, Rosenthal AN, Rogers MT, Lancastle D, et al. (2012). Psychological

outcomes of familial ovarian cancer screening: no evidence of long-term harm. Gynecologic

Oncology. 127(3):556-63.

Quality of life

Lifford 2012 Lifford KJ, Fraser L, Rosenthal AN, Rogers MT, Lancastle D, Phelps C, et al. (2012). Withdrawal from

familial ovarian cancer screening for surgery: findings from a psychological evaluation study

(PsyFOCS). Gynecologic Oncology. 124(1):158-63.

Quality of life

Lancastle

2011

Lancastle D, Brain K, Phelps C. (2011). Illness representations and distress in women undergoing

screening for familial ovarian cancer. Psychology & Health. 26(12):1659-77.

Quality of life

CGN/GOG

Skates 2017 Skates SJ, Greene MH, Buys SS, Mai PL, Brown P, Piedmonte M, et al. (2017). Early Detection of

Ovarian Cancer using the Risk of Ovarian Cancer Algorithm with Frequent CA125 Testing in Women

at Increased Familial Risk - Combined Results from Two Screening Trials. Clinical Cancer Research.

23(14):3628-37.

Diagnostic

performance

PLCO-HR

Lai 2016 Lai T, Kessel B, Ahn HJ, Terada KY. (2016). Ovarian cancer screening in menopausal females with a

family history of breast or ovarian cancer. Journal of Gynecologic Oncology. 27(4):e41.

Mortality/

survival

UKFOCSS Phase I

Rosenthal

2013

Rosenthal AN, Fraser L, Manchanda R, Badman P, Philpott S, Mozersky J, et al. (2013). Results of

annual screening in phase I of the United Kingdom familial ovarian cancer screening study highlight

the need for strict adherence to screening schedule. Journal of Clinical Oncology. 31(1):49-57.110

Performance

characteristics


Evans 2009 Evans DG, Gaarenstroom KN, Stirling D, Shenton A, Maehle L, Dorum A, et al. (2009). Screening for

familial ovarian cancer: poor survival of BRCA1/2 related cancers. Journal of Medical Genetics.

46(9):593-7.

Survival in

BRCA1/2

carriers

Fox Chase Cancer Centre

Fang 2009 Fang CY, Cherry C, Devarajan K, Li T, Malick J, Daly MB. (2009). A prospective study of quality of life

among women undergoing risk-reducing salpingo-oophorectomy versus gynecologic screening for

ovarian cancer. Gynecologic Oncology. 112(3):594-600.

Quality of life

Abbreviations: CGN, Cancer Genetics Network; GOG, Gynecologic Oncology Group; PLCO, Prostate, Lung, Colorectal and Ovarian Cancer

Screening Trial; UK, United Kingdom; UKFOCSS, United Kingdom Familial Ovarian Cancer Screening Study.

110 Online appendix referred to be not available.

https://www.ucl.ac.uk/womens-health/research/womens-cancer/gynaecological-cancer-research-centre/ukfocss/UKFOCSS_Protocol_P2_v8_Oct_10_Website_20160525.pdf



D.2.2 Systematic review and HTAs

Table AppD.4 Systematic reviews of surveillance in women at high risk of ovarian cancer

Study ID Citations

Auranen 2011 Auranen A, Joutsiniemi T. (2011). A systematic review of gynecological cancer surveillance in women belonging to

hereditary nonpolyposis colorectal cancer (Lynch syndrome) families. Acta Obstetricia et Gynecologica Scandinavica.

90(5):437-44.


Appendix E Additional data extraction

E.1 Additional data extraction for population screening

FigureApp E.1.1 shows a timeline for the PLCO trial published in 2000. As this is the sole source of

information regarding the date that screening ended in this trial, this figure is reproduced here.

FigureApp E.1.1 Timeline for PLCO trial

Source: Prorok 2000 Figure 2.

Abbreviations: PLCO, Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial.

Table AppE.1 ICD-10 codes interrogated for UKCTOCS study

Code Description

C56 Malignant neoplasm of ovary

C57.0 Malignant neoplasm of fallopian tube

C57.4 Uterine adnexa, unspecified

C57.7 Other specified female genital organs

C57.8 Malignant neoplasm of overlapping lesion of female genital organs

C57.9 Malignant neoplasm of female genital organ, unspecified

C48.0 Retroperitoneum

C48.1 Specified parts of peritoneum

C48.2 Malignant neoplasm of peritoneum, unspecified

C48.8 Overlapping lesions of retroperitneum and peritoneum

C76.2 Malignant neoplasm of abdomen

C76.3 Malignant neoplasm of pelvis

C80 Malignant neoplasm without specification of site

D07.3 Carcinoma in situ of other/unspecified female genital organ

D28.2 Benign neoplasm of fallopian tube

D28.9 Benign neoplasm of female genital organ, unspecified

D36.9 Benign neoplasm of unspecified site

D39.1 Neoplasm of uncertain or unknown behaviour of ovary

D39.9 Neoplasm of uncertain or unknown behaviour of female genital organ, unspecified

Source: Jacobs 2016, supplementary appendix, p3.

Note: Medical records were obtained and interrogated for all women except those who had both an ICD10-C80 (malignant neoplasm of

uncertain origin) and another specific non-ovarian/ peritoneal cancer registration.

Abbreviations: ICD-10, International Statistical Classification of Diseases and Related Health Problems (10th revision); UKCTOCS, United

Kingdom Collaborative Trial of Ovarian Cancer Screening.


Table AppE.2 Case identification and verification – diagnosis or death due to OC

PLCO UKCTOCS

Identification of

possible cases of

ovarian cancer

Original analysis period (to 28 Feb 2010)

Incident cancers and deaths were ascertained primarily

through a mailed annual study update questionnaire

(ASU), which asked about type and date of cancer

diagnosed in the previous year.

Data pertaining to diagnosis and (at least initial)

treatment of all PLCO cancers were collected in both

the screened and control arms of the trial to enable

uniform staging and other prognostic criteria to be

applied. Incident cancers reported on the ASU were

verified by obtaining medical records and utilizing a

standardized abstracting process. Next of kin notified the

trial of deaths, which were verified by obtaining death

certificates; National Death Index (NDI) searches were

also used (screening centres compiled the information

necessary to search the NDI files, e.g. name, social

security number, date of birth). Population-based cancer

registries also were used when possible. Medical records

pertaining to diagnosed cancers were obtained by the

PLCO screening centers.

The screening centres actively tracked participants with

screening test abnormalities and actively sought,

collected, assembled, organized, and abstracted

medical record information related to diagnostic follow-

up and treatment.

Extended follow up (to 31 Dec 2012)

Going forward from the time of the original analysis

period, there was a structural change in the operation of

PLCO that affected the way cancer incidence and

mortality endpoints were ascertained. Specifically,

beginning in mid-2011, PLCO transitioned from a system

of follow-up performed at the individual screening

centers to a centralized approach in which Participants

were followed by a central data coordinating center

(CDCC). All participants were contacted, and those

willing to continue in the study were eligible for linkages

to the NDI and state cancer registries.

The coordinating centre (CC) was notified of new cases

of ovarian/fallopian tube cancer and possible ovarian

cancer by various sources. Volunteers’ NHS numbers

were used to link to various datasets and registries, and

the Health and Social Care Information Centre (HSCIC)

cancer registration and Death Certificates were two of

the most important sources of information.

Quarterly HSCIC updates were received electronically.

After each update, a query was run to identify potential

new cases of ovarian/tubal cancer. The query flags up a

list of the ICD-10 codes that could be related to a

diagnosis of ovarian or tubal cancer.

The cohort was also linked to the Hospital Episodes

Statistics (HES) administrative records in England. HES is a

comprehensive dataset of volunteers’ in- and out-

patient hospital admissions (2001-2009) and

corresponding disease codes (2003-2009). HES data on

the women was received by the CC in 2010. The clinical

diagnosis fields of the HES dataset were searched for any

of 19 relevant ICD-10 diagnosis codes (0, Table AppE.1).

For women who resided in England, data was also

obtained from the National Cancer Intelligence Network.

Another source of information was the trial regional

centres (RC), which would notify the CC of all new cases

of screen-detected OC, and possible OC, and forward

relevant medical notes to the UKCTOCS senior research

nurse or designated research associate. The RCs would

sometimes also notify the CC of screen negative and

control arm cases where these cases were known to

them. However, these volunteers did not always receive

treatment at the RC hospital and were therefore not be

identified through this method.

Other sources of notification were two postal follow-up

questionnaires (3-5 years after randomisation and April,

2014) and direct communication from trial participants,

their families, and physicians.

Verification of

diagnosis

Original analysis period (to 28 Feb 2010)

Data on the stage, histology, and grade of PLCO

cancers were abstracted by certified tumour registrars. In

addition, treatment information during the first year post-

diagnosis was abstracted.

Deaths potentially related to a PLCO trial cancer and

those of unknown or uncertain cause were reviewed by

at least 1 individual from a panel with appropriate

expertise (epidemiology, surgery, medicine, radiation

oncology); panel members were not otherwise affiliated

with the trial and reviewers were blinded to the

randomization group of the deceased participant.

Early on during the death review process, each death

had 2 independent reviews and discrepancies were

resolved by consensus after a third reviewer had

examined the records. After 2 years, the process was

streamlined. As a result, a primary reviewer considered

the record without having access to the death

certificate. If he or she recorded an underlying cause of

death different from that of the death certificate, a

second reviewer independently reviewed the record

together with the death certificate. Disagreement

between the reviewers resulted in another independent

Ascertainment of outcomes involved interrogating all

available data sources of women identified by the

notification process described above. All medical

records and notes related to cancer diagnosis/death

were obtained from the corresponding regional centres,

hospital(s) where treatment was received, GP surgeries,

hospices and cancer registries. For all screen-positive

surgeries, these included discharge summaries,

multidisciplinary team meeting notes, surgery notes, and

histopathology and/or cytology reports, along with

death certificates for cases of OC-specific death. 111

All data were reviewed by an outcomes review

committee (two pathologists and two gynaecological

oncologists) who were masked to the randomisation

group. They confirmed the final diagnosis, stage, and

morphology of any cancer and, when possible, they

classified invasive epithelial ovarian or tubal cancers into

Type I (low-grade serous, low-grade endometrioid,

mucinous, and clear cell cancers) or Type II (high-grade

serous, high-grade endometrioid, carcinosarcomas, and

undifferentiated carcinoma) cancers. Where it was not

possible to delineate whether the primary site was ovary,

fallopian tube, or peritoneum, the diagnosis was

classified as undesignated. Death due to ovarian cancer

111 This approach provided additional information for 99% (1757/1767) of women with regards to cancer diagnosis and 97% (876/900) with

regard to death diagnosis.


PLCO UKCTOCS

review, which was subsequently resolved by a meeting

or teleconference.

Extended follow up (to 31 Dec 2012)

Only mortality is reported to date for the extended

analysis. The trial ascertained deaths primarily through

the NDI, so medical records were not available to

perform endpoint verification. Therefore, for deaths

occurring after the original cut-off (Feb 28th, 2010), the

underlying cause of death from the NDI was used to

classify deaths as being from ovarian cancer or not and

no endpoint verification was performed.

Linkage with cancer registries to ascertain incident

ovarian cancers is ongoing, so complete incidence data

for the period after Feb 28th, 2010 are not currently

available.

was based on disease progression (appearance of new

lesions or increases in size of previously documented

lesions with imaging, clinical worsening, or rising

biomarker concentrations).

A final diagnosis was assigned by application of an

algorithm.

Abbreviations: ASU, annual study update; CC, coordinating centre; CDCC, central data coordinating center; GP, general practitioner; HES,

Hospital Episodes Statistics; HSCIC, Health and Social Care Information Centre; ICD, International Classification of Diseases; NDI, National

Death Index; OC, ovarian cancer; PLCO, Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial; RC, regional centres; UKCTOCS,


FigureApp E.1.2 Survival from randomisation in patients with ovarian (invasive), tubal or peritoneal

cancer – PLCO

Years from

randomisation 0 1 2 3 4 5 6 7 8 9 10 11 12 13

At risk

TVUS 212 210 207 201 195 183 168 153 140 125 95 69 47 16

No screening 176 176 173 167 160 148 135 123 114 98 72 54 35 15

Source: Buys 2011 online supplement, eFigure (last page).

Abbreviations: PLCO, Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial; TVUS, transvaginal ultrasonography.


Table AppE.3 Cancer stage at diagnosis, by tumour type grouping – UKCTOCS

Tumours by stage, n (%) UKCTOCS

OC (invasive), FTC, undesignated Peritoneal Non-epithelial ovarian Borderline epithelial ovarian

ROCA

triage TVUS

No

screening

ROCA

triage TVUS

No

screening

ROCA

triage TVUS

No

screening

ROCA

triage TVUS

No

screening

Total cancers detected, n 283 (100) 249 (100) 559 (100) 16 (100) 10 (100) 15 (100) 11 (100) 12 (100) 8 (100) 44 (100) 53 (100) 62 (100)

Stage at diagnosis

I 76 (27) 39 (16) 91 (16) 0 (0) 0 (0) 0 (0) 10 (91) 10 (83) 7 (88) 41 (93) 50 (94) 49 (79)

II 31 (11) 19 (8) 45 (8) 1 (6)112 0 (0) 1 (7)112 0 (0) 0 (0) 1 (13) 0 (0) 0 (0) 4 (6)

III 142 (50) 141 (57) 314 (56) 14 (88) 9 (90) 10 (67) 1 (9) 1 (8) 0 (0) 3 (7) 3 (6) 9 (15)

IV 33 (12) 50 (20) 108 (19) 1 (6) 1 (10) 4 (27) 0 (0) 1 (8) 0 (0) 0 (0) 0 (0) 0 (0)

Unknown 1 (0) 0 (0) 1 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 1 (2)

Abbreviations: FTC, fallopian tube cancer; OC, ovarian cancer; ROCA, risk of ovarian cancer algorithm; TVUS, transvaginal ultrasound; UKCTOCS, UK Collaborative Trial of Ovarian Cancer Screening.

112 Stage IIb.


E.2 Additional data extraction for surveillance studies

Table AppE.4 ROCA triage protocol – UKFOCSS Phase II

Note: Figure should be read from left to right.

Results classification:

ROC N = Normal; I = Intermediate*; E = Elevated

Scans N = Normal; U = Unsatisfactory; A = Abnormal

Action:

RS = Routine Screening (i.e. 4-monthly CA125 and annual scan)

CD = Clinical Decision

Refer = Referral for clinical assessment by local study centre gynaecologist.

Clinical Decision = management at discretion of study clinicians at coordinating centre. Clinical decisions will be to (i) refer the woman to a

gynaecologist for further investigation, (ii) return to routine screening or (iii) undergo repeat CA125 and or ultrasound sooner than routine

screening.

*from 13/05/10 Intermediate results were sub-classified into High Intermediate and Low Intermediate. Actions following these results were as

follows: High Intermediate – scan within 2 months and repeat CA125 after 2 months; Low Intermediate – repeat CA125 after 2 months.

Source: Rosenthal 2017 online supplement, Figure A3

Abbreviations: CA, cancer antigen; CD, clinical decision; ROC, risk of ovarian cancer; ROCA, risk of ovarian cancer algorithm; RS, routine

screening; UKFOCSS, United Kingdom Familial Ovarian Cancer Screening Study.


Table 0.1 Identification of possible OC and diagnosis verification – surveillance studies

Study ID Identification of possible cases of OC Verification of diagnosis


UKFOCSS

Phase II

Participants were flagged (by their unique NHS number)

with relevant cancer registries, which provided cancer

and/or death data. Collaborators notified the coordinating

centre when women withdrew before routine screening

ended (June 30, 2011). Women were observed through

cancer registries with censorship that was based on date of

death, last notification from the registry, or last contact if

they were lost to registry follow-up. Participants were sent

health questionnaires in January 2011 and April 2013

specifically asking about surgery that involved removal of

fallopian tubes/ovaries and cancer diagnosis.

Whenever women underwent salpingo-oophorectomy, the

coordinating centre obtained documentation of

indication, operation notes, and histopathology/

cytopathology reports. These were reviewed by a

gynaecologic oncologist and pathologist (blinded to the

clinical and previous pathology data) and were classified

according to the ICD-10.

Specific ICD codes were not mentioned: included cancers

were described as invasive ovarian, fallopian tube or

primary peritoneal cancers.

CGN/GOG Questionnaires sent to participants. Each study had central review of all ovarian surgical

specimens, including all 501 RRSOs, by central pathologists.


PLCO-HR OC diagnosis or death indicated in returned questionnaire

(annual study update), or discovered in search of cancer

or death registries (see Appendix E, Table AppE.2) for more

information about the PLCO RCT).

Deaths potentially related to a PLCO trial cancer and those

of unknown or uncertain cause were reviewed by at least 1

individual from a panel with appropriate expertise

(epidemiology, surgery, medicine, radiation oncology);

panel members were not otherwise affiliated with the trial

and reviewers were blinded to the randomisation group of

the deceased participant.

UKFOCSS

Phase I

All women were flagged with the relevant national cancer

registry (National Health Service Information Centre for

Health and Social Care, General Registrar Office for

Scotland, and Northern Ireland Cancer Registry).

Whenever women underwent salpingo-oophorectomy, the

Coordinating Centre obtained documentation explaining

surgical indication, whether CA125 and/or scan results had

prompted surgery, the operation note, and histopathology

and cytopathology reports. These data were reviewed by

a gynaecologic oncologist and pathologist.

UK-

Netherlands-

Norway

Hospital notes and cancer and other registries were used

to establish date at death and current vital status as of 1

March 2007.

More information may be available in one of five cited

records of prior publications of these screening

programmes.

Fox Chase

Cancer

Centre

N/A (screening outcomes not reported as only QoL

outcomes measured)

N/A

Abbreviations: CA, cancer antigen; CGN, Cancer Genetics Network; GOG, Gynecologic Oncology Group; HR, high-risk; N/A, not applicable;

NHS, National Health Service; OC, ovarian cancer; PLCO, Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial; QoL, quality of life;

RCT, randomised controlled trial; ROCA, risk of ovarian cancer algorithm; RRSO, risk-reducing salpingo-oophorectomy; UK, United Kingdom;

UKFOCSS, United Kingdom Familial Ovarian Cancer Screening Study.


Appendix F Quality assessment

Table AppF.1 Systematic review quality assessment – Buhling 2017

Question Answer

1. Was an 'a priori' design provided?

The research question and inclusion criteria should be established before the conduct of the review.

Note: Need to refer to a protocol, ethics approval, or pre-determined/a priori published research

objectives to score a “yes.”

Yes

2. Was there duplicate study selection and data extraction?

There should be at least two independent data extractors and a consensus procedure for disagreements

should be in place.

Note: 2 people do study selection, 2 people do data extraction, consensus process or one person checks

the other’s work.

Yes

3. Was a comprehensive literature search performed?

At least two electronic sources should be searched. The report must include years and databases used

(e.g. Central, EMBASE, and MEDLINE). Key words and/or MESH terms must be stated and where feasible the

search strategy should be provided. All searches should be supplemented by consulting current contents,

reviews, textbooks, specialized registers, or experts in the particular field of study, and by reviewing the

references in the studies found.

Note: If at least 2 sources + one supplementary strategy used, select “yes” (Cochrane register/Central

counts as 2 sources; a grey literature search counts as supplementary).

Yes

4. Was the status of publication (i.e. grey literature) used as an inclusion criterion?

The authors should state that they searched for reports regardless of their publication type. The authors

should state whether or not they excluded any reports (from the systematic review), based on their

publication status, language etc.

Note: If review indicates that there was a search for “grey literature” or “unpublished literature,” indicate

“yes.” SIGLE database, dissertations, conference proceedings, and trial registries are all considered grey for

this purpose. If searching a source that contains both grey and non-grey, must specify that they were

searching for grey/unpublished lit.

No

5. Was a list of studies (included and excluded) provided?

A list of included and excluded studies should be provided.

Note: Acceptable if the excluded studies are referenced. If there is an electronic link to the list but the link is

dead, select “no.”

No

6. Were the characteristics of the included studies provided?

In an aggregated form such as a table, data from the original studies should be provided on the

participants, interventions and outcomes. The ranges of characteristics in all the studies analyzed e.g. age,

race, sex, relevant socioeconomic data, disease status, duration, severity, or other diseases should be

reported.

Note: Acceptable if not in table format as long as they are described as above.

Yes

7. Was the scientific quality of the included studies assessed and documented?

'A priori' methods of assessment should be provided (e.g. for effectiveness studies if the author(s) chose to

include only randomized, double-blind, placebo controlled studies, or allocation concealment as inclusion

criteria); for other types of studies alternative items will be relevant.

Note: Can include use of a quality scoring tool or checklist, e.g. Jadad scale, risk of bias, sensitivity analysis,

etc., or a description of quality items, with some kind of result for EACH study (“low” or “high” is fine, as long

as it is clear which studies scored “low” and which scored “high”; a summary score/range for all studies is

not acceptable).

No

Used Jadad scale

as inclusion criteria

but no individual

Jadad score

reported. Reported

strengths and

weaknesses of

each study, but

not in terms of risk

of bias.

8. Was the scientific quality of the included studies used appropriately in formulating conclusions?

The results of the methodological rigor and scientific quality should be considered in the analysis and the

conclusions of the review, and explicitly stated in formulating recommendations.

Note: Might say something such as “the results should be interpreted with caution due to poor quality of

included studies.” Cannot score “yes” for this question if scored “no” for question 7.

No


Question Answer

9. Were the methods used to combine the findings of studies appropriate?

For the pooled results, a test should be done to ensure the studies were combinable, to assess their

homogeneity (i.e. Chi-squared test for homogeneity, I2). If heterogeneity exists a random effects model

should be used and/or the clinical appropriateness of combining should be taken into consideration (i.e. is

it sensible to combine?).

Note: Indicate “yes” if they mention or describe heterogeneity, i.e. if they explain that they cannot pool

because of heterogeneity/variability between interventions.

No

Data not pooled,

likely due to

heterogeneity but

not stated (also no

obvious assessment

of heterogeneity)

10. Was the likelihood of publication bias assessed?

An assessment of publication bias should include a combination of graphical aids (e.g. funnel plot, other

available tests) and/or statistical tests (e.g. Egger regression test, Hedges-Olken).

Note: If no test values or funnel plot included, score “no”. Score “yes” if mentions that publication bias

could not be assessed because there were fewer than 10 included studies.

No

11. Was the conflict of interest included?

Potential sources of support should be clearly acknowledged in both the systematic review and the

included studies.

Note: To get a “yes,” must indicate source of funding or support for the systematic review AND for each of

the included studies.

No

Not mentioned for

included studies

Table AppF.2 Systematic review quality assessment – Guirguis-Blake 2017

Question Answer





Yes



should be in place.


the other’s work.

Yes









Yes









Yes





Yes





reported.


Yes


Question Answer








not acceptable).

Yes






Yes








Yes






No



included studies.



No

Not mentioned for

included studies

Table AppF.3 Systematic review quality assessment – Henderson 2017

Question Answer





Yes



should be in place.


the other’s work.

Yes









Yes









No


Question Answer





Yes





reported.


Yes








not acceptable).

Yes






Yes








Yes






No

Publication bias

reported for studies

as undetected –

no test values were

given



included studies.



No

Not mentioned for

included studies

Table AppF.4 Systematic review quality assessment – Bloomfield 2014

Question Answer





Yes



should be in place.


the other’s work.

Yes


Question Answer









Yes









No





No





reported.


Yes








not acceptable).

Yes






No

Not explicit.

Limitations of

studies described

but not considered

in conclusions

particularly








No






No



included studies.



No

Not mentioned for

included studies


Table AppF.5 Systematic review quality assessment – Reade 2013

Question Answer





Yes



should be in place.


the other’s work.

Yes









Yes









Yes





No





reported.


Yes








not acceptable).

Yes

Quality assessment

for each outcome

investigated rather

than by individual

study






Yes








Yes




Note: If no test values or funnel plot included, score “no”. Score “yes” if mentions that publicat ion bias


No

Not mentioned for

included studies


Question Answer



included studies.



No

Not mentioned for

included studies

Table AppF.6 Systematic review quality assessment – Auranen 2011

Question Answer





Yes



should be in place.


the other’s work.

Can’t answer









No









No





No





reported.


Yes








not acceptable).

No

Methodological

quality assessment

was based on

reporting of

outcome measures

only






No


Question Answer








No

No explanation of

why results not

pooled






No



included studies.



No

Not mentioned for

included studies


Appendix G Membership of the Working Group

A Working Group was established to provide expert input into the development of the position

statement. The Working Group comprised members with clinical, academic and community

knowledge and experience. A list of the member of the Working Group is provided in the table

below.

Name Area of expertise Role

Professor Lyndal

Trevena

General Practitioner, NSW Chair

Associate Professor

Jane Armes

Pathologist, Royal College of Pathologists of Australasia

representative, NSW

Member

Dr Cheryl Bass Clinical Radiologist, Australian and New Zealand College of

Radiologists representative, VIC

Member

Associate Professsor

Alison Brand

Gynaecological Oncologist, NSW Member

Dr Rachel Delahunty Medical Oncologist, VIC Member

Dr Susan Jordan Epidemiologist, QLD Member

Associate Professor

Judy Kirk

Clinical Geneticist, NSW Member

Ms Karen Livingstone Consumer, VIC Member

Ms Ann-Maree

Mulders

Consumer, NSW Member

Dr Larissa Roeske General Practitioner, Royal Australian College of General

Practitioners representative, VIC

Member


Abbreviations and acronyms

AAFP American Academy of Family Physicians

ACOG American College of Obstetricians and Gynecologists

ACP American College of Physicians

ACR American College of Radiology

ACS American Cancer Society

AGO Austrian Arbeitsgemeinschaft für Gynäkologische Onkologie

AHRQ Agency for Healthcare Research and Quality

AMSTAR Assessing the Methodological Quality of Systematic Reviews

ANZHSN Australia and New Zealand Horizon Scanning Network

ASCO American Society of Clinical Oncology

CA cancer antigen

CAAb cancer associated antibodies

CADTH Canadian Agency for Drugs and Technologies in Health

CDCC central data coordinating centre

CGN Cancer Genetics Network

CGN/GOG Cancer Genetics Network and Gynecologic Oncology Group

CI confidence interval

CRP C-reactive protein

CT computed tomography

CXCL13 CXC motif chemokine 13

DCIS ductal carcinoma in situ

DEC Diagnostic Evidence Co-operative

EOC epithelial ovarian cancer

EORTC European Organisation for Research and Treatment of Cancer

ESMO European Society for Medical Oncology

EUCTR European Union Clinical Trials Register

EuroScan European Information Network on New and Changing Health Technologies

FADD FAS-associated death domain protein

FDA US Food and Drug Administration

FDG-PET 18F-fluorodeoxyglucose positron emission tomography

FDR first degree relative

FH family history

FIGO International Federation of Gynecology and Obstetrics

FP false positive

FR-alpha folate receptor-alpha

FTC fallopian tube cancer

FUR furin

GOC Society of Gynecologic Oncology of Canada

GOG Gynecologic Oncology Group

GP general practitioner

GRADE Grading of Recommendations Assessment Development and Evaluation

HADS Hospital Anxiety and Depression Scale

HBOC hereditary breast and ovarian cancer

HE4 human epididymis protein 4

HealthPACT Health Policy Advisory Committee on Technology

HES Hospital Episodes Statistics

hK11 kallikrein 11

HNPCC hereditary non-polyposis colorectal cancer

HR high risk

HRT hormone replacement therapy

HSCIC Health and Social Care Information Centre

HTA Health Technology Assessment


IARC International Agency for Research on Cancer

ICD International Classification of Diseases

ICD-10 International Statistical Classification of Diseases and Related Health Problems (10th revision)

ICER incremental cost-effectiveness ratio

IL-6 interleukin-6

IQR interquartile range

ISCRR Institute for Safety, Compensation and Recovery Research

KLK6 kallikrein 6

LMP low malignant potential

LS Lynch syndrome

LYG life year gained

MA meta-analysis

MBC male breast cancer

MBS Medical Benefits Schedule

MCS Mental Component Summary

MK midkine

MMP-7 matrix metalloproteinase-7

MMR mismatch repair

MMS multimodal screening ('ROCA triage')

MOS Medical Outcomes Survey

MRI magnetic resonance imaging

MROCA multi-marker risk of ovarian cancer algorithm

MSAC Medical Services Advisory Committee

NA not applicable

NASEM National Academies of Science, Engineering and Medicine

NBOCC National Breast and Ovarian Cancer Centre

NCCN National Comprehensive Cancer Network

NCI National Cancer Institute

NDI National Death Index

NHMRC National Health and Medical Research Council

NHS National Health Service

NICE National Institute for Health and Care Excellence

NIHR National Institute for Health Research

NPV negative predictive value

NR not reported

OC ovarian cancer

OR odds ratio

PCR polymerase chain reaction

PCS Physical Component Summary

PICOS population, intervention, comparator, outcomes, setting

PID pelvic inflammatory disease

PLCO Prostate Lung Colorectal and Ovarian Cancer Screening Trial

PPC primary peritoneal cancer

PPV positive predictive value

PRSS8 prostasin

PsyFOCS Psychological evaluation of Familial Ovarian Cancer Screening

QoL quality of life

QUEST Quality of life Education and Screening Trial

RACGP Royal Australian College of General Practitioners

RC regional centres

RCT randomised controlled trial

RoB risk of bias

ROC risk of ovarian cancer

ROCA risk of ovarian cancer algorithm

RP Royston-Parmar

RR risk ratio


RRSO risk-reducing salpingo-oophorectomy

RS routine screening

SCSOCS Shizuoka Cohort Study of Ovarian Cancer Screening

SEOM Sociedad Española de Oncología Médica

SIGN Scottish Intercollegiate Guidelines Network

STAI State/Trait Anxiety Inventory

SR systematic review

TVS/TVUS transvaginal ultrasound

UK United Kingdom

UKCTOCS UK Collaborative Trial of Ovarian Cancer Screening

UKFOCSS UK Familial Ovarian Cancer Screening Study

USPSTF United States Preventative Services Task Force

USS ultrasound screening (TVUS)

WHO World Health Organization

WHOICTRP World Health Organization International Clinical Trials Registry Platform


References

1. AAFP (2017) American Academy of Family Physicians. Summary of Recommendations for

Clinical Preventive Services. AAFP Policy Action November 1996, July 2017· Order No. 1968.

Available online.

2. ACOG (2017a). The American College of Obstetricians and Gynecologists. Committee

Opinion No. 716: The Role of the Obstetrician-Gynecologist in the Early Detection of

Epithelial Ovarian Cancer in Women at Average Risk. Obstet Gynecol. 130(3):e146-e149.

3. ACOG (2017b). The American College of Obstetricians and Gynecologists . Practice Bulletin

No 182: Hereditary Breast and Ovarian Cancer Syndrome. Obstet Gynecol. 130(3):e110-

e126.

4. ACR (2017). Pandharipande PV, Lowry KP, Reinhold C, Atri M, Benson CB, Bhosale PR, et al.

ACR Appropriateness Criteria® Ovarian Cancer Screening. J Am Coll Radiol. 14(11s):S490-s9.

5. Adonakis GL, Paraskevaidis E, Tsiga S, Seferiadis K, Lolis DE (1996). A combined approach for

the early detection of ovarian cancer in asymptomatic women. Eur J Obstet Gynecol

Reprod Biol. 65(2):221-225.

6. ANZHSN (2010). Australia and New Zealand Horizon Scanning Network. Horizon Scanning

Technology Prioritising Summary. Diagnostic tests for ovarian cancer. Prepared by Adelaide

Health Technology Assessment for the Health Policy Advisory Committee on Technology

(HealthPACT). © Commonwealth of Australia 2010. Available online.

7. Auranen A, Joutsiniemi T (2011). A systematic review of gynecological cancer surveillance in

women belonging to hereditary nonpolyposis colorectal cancer (Lynch syndrome) families.

Acta Obstetricia et Gynecologica Scandinavica. 90(5):437-444.

8. Barrett J, Jenkins V, Farewell V, Menon U, Jacobs I, Kilkerr J, et al (2014). Psychological

morbidity associated with ovarian cancer screening: results from more than 23,000 women

in the randomised trial of ovarian cancer screening (UKCTOCS). BJOG: An International

Journal of Obstetrics & Gynaecology. 121(9):1071-1079.

9. Barton MB, Lin K. (2012). Screening for ovarian cancer: Evidence update for the U.S.

Preventive Services Task Force Reaffirmation Recommendation Statement. AHRQ

Publication No. 12-05165-EF3. Rockville, MD: Agency for Healthcare Research and Quality.

10. Bloomfield HE, Olson A, Greer N, Cantor A, MacDonald R, Rutks I, et al (2014). Screening

pelvic examinations in asymptomatic, average-risk adult women: an evidence report for a

clinical practice guideline from the American College of Physicians. Annals of Internal

Medicine. 161(1):46-53.

11. Boylan KLM, Geschwind K, Koopmeiners JS, Geller MA, Starr TK, Skubitz APN (2017). A

multiplex platform for the identification of ovarian cancer biomarkers. Clin Proteomics.

14:34.

12. Boylan KL, Afiuni-Zadeh S, Geller MA, Hickey K, Griffin TJ, Pambuccian SE, et al (2014). A

feasibility study to identify proteins in the residual Pap test fluid of women with normal

cytology by mass spectrometry-based proteomics. Clin Proteomics. 11(1):30.

13. Brain KE, Lifford KJ, Fraser L, Rosenthal AN, Rogers MT, Lancastle D, et al. (2012).

Psychological outcomes of familial ovarian cancer screening: no evidence of long-term

harm. Gynecologic Oncology. 127(3):556-563.

http://www.aafp.org/dam/AAFP/documents/patient_care/clinical_recommendations/cps-recommendations.pdf

http://www.horizonscanning.gov.au/internet/horizon/publishing.nsf/Content/C8A5BA60BD01A93ECA257757000A2015/$File/FINAL%20PS%20%20re%20OvPlex%20updated%20April%202010.pdf


14. British Columbia (2014) Genital Tract Cancers in Females: Ovarian, Fallopian Tube, and

Primary Peritoneal Cancers. BCguidelines.ca. Available online.

15. Buhling KJ, Lezon S, Eulenburg C, Schmalfeldt B. (2017). The role of transvaginal

ultrasonography for detecting ovarian cancer in an asymptomatic screening population: a

systematic review. Archives of Gynecology & Obstetrics. 295(5):1259-1268.

16. Buys, SS, Partridge, E, Black, A, Johnson, CC, Lamerato, L, Isaacs, C, et al. (2011). Effect of

screening on ovarian cancer mortality: the Prostate, Lung, Colorectal and Ovarian (PLCO)

Cancer Screening Randomized Controlled Trial. JAMA. 305(22):2295-303.

17. Buys, SS, Partridge, E, Greene, MH, Prorok, PC, Reding, D, Riley, TL, et al. (2005). Ovarian

cancer screening in the Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening

trial: Findings from the initial screen of a randomized trial. American Journal of Obstetrics

and Gynecology. 193(5):1630-9.

18. Cancer Australia. (2015). Advice about familial aspects of breast and epithelial ovarian

cancer: A guide for health professionals. Surry Hills, NSW: Cancer Australia. Available online.

19. Cancer Australia. (2009). Population screening and early detection of ovarian cancer in

asymptomatic women. Surry Hills, NSW: Cancer Australia. Available online.

20. Evans DG, Gaarenstroom KN, Stirling D, Shenton A, Maehle L, Dorum A, et al. (2009).

Screening for familial ovarian cancer: poor survival of BRCA1/2 related cancers. Journal of

Medical Genetics. 46(9):593-597.

21. Fallowfield L, Solis-Trapala I, Menon U, Langridge C, May S, Jacobs I, et al. (2017). The effect

of ovarian cancer screening on sexual activity and functioning: results from the UK

collaborative trial of ovarian cancer screening RCT. British Journal of Cancer. 116(8):1111-

1117.

22. Fang CY, Cherry C, Devarajan K, Li T, Malick J, Daly MB. (2009). A prospective study of

quality of life among women undergoing risk-reducing salpingo-oophorectomy versus

gynecologic screening for ovarian cancer. Gynecologic Oncology. 112(3):594-600.

23. FDA (2016). U.S. Food & Drug Administration. The FDA recommends against using screening

tests for ovarian cancer screening: FDA Safety Communication. Issued September 7 2016.

Accessed November 2017.

24. GOC (2016). Society of Gynecologic Oncology of Canada. GOC Opinion Statement

regarding the UK Collaborative Trial Of Ovarian Cancer Screening (UKCTOCS) results.

Ottawa: Society of Gynecologic Oncology of Canada. Available at https://g-o-

c.org/publications/goc-position-statements/

25. Guirguis-Blake JM, Henderson JT, Perdue LA, Whitlock EP. (2017). Screening for Gynecologic

Conditions With Pelvic Examination: A Systematic Review for the US Preventive Services Task

Force. Evidence Synthesis No. 147. Rockville, MD: Agency for Healthcare Research and

Quality. AHRQ publication 15-05220-EF-1.

26. Henderson JT, Webber E, Sawaya GF. (2017). Screening for ovarian cancer: An updated

evidence review for the U.S. Preventive Services Task Force. Evidence Synthesis No. 157.

AHRQ Publication No. 17-05231-EF-1. Rockville, MD: Agency for Healthcare Research and

Quality.

27. Jacobs IJ, Menon U, Ryan A, Gentry-Maharaj A, Burnell M, Kalsi JK, et al. (2016). Ovarian

cancer screening and mortality in the UK Collaborative Trial of Ovarian Cancer Screening

(UKCTOCS): a randomised controlled trial. Lancet. 387(10022):945-956.

https://www2.gov.bc.ca/gov/content/health/practitioner-professional-resources/bc-guidelines/ovarian-cancers

http://canceraustralia.gov.au/sites/default/files/publications/advice-about-familial-aspects-breastcancer-and-epithelial-ovarian-cancer/pdf/2015_bog_familial_aspects_int.pdf

http://canceraustralia.gov.au/publications-and-resources/position-statements/population-screening-and-earlydetection-ovarian-cancer-asymptomatic-women


https://g-o-c.org/publications/goc-position-statements/

https://g-o-c.org/publications/goc-position-statements/


28. Jacobs IJ, Menon U. (2015). Protocol for the United Kingdom Collaborative Trial of Ovarian

Cancer Screening (UKCTOCS) Version 7.1, April 2015. Accessed 31 Oct 2017

29. Jacobs IJ. (2010). The UK Familial Ovarian Cancer Screening Study (UK FOCSS) Phase II.

Study Protocol. Accessed 10 Nov 2017.

30. Jacobs IJ, Menon U. (2004). Progress and challenges in screening for early detection of

ovarian cancer. Mol Cell Proteomics. 3:355-366.

31. Jacobs IJ, Skates SJ, MacDonald N, Menon U, Rosenthal AN, Davies AP, et al. (1999).

Screening for ovarian cancer: a pilot randomised controlled trial. Lancet. 353(9160):1207-

1210.

32. Jacobs I, Stabile I, Bridges J, Kemsley P, Reynolds C, Grudzinskas J, et al. (1988). Multimodal

approach to screening for ovarian cancer. Lancet. 1(8580):268-271.

33. Karlan BY, Thorpe J, Watabayashi K, Drescher CW, Palomares M, Daly MB, et al. (2014). Use

of CA125 and HE4 serum markers to predict ovarian cancer in elevated-risk women. Cancer

Epidemiology, Biomarkers & Prevention. 23(7):1383-1393.

34. Karlan BY, Baldwin RL, Lopez-Luevanos E, Raffel LJ, Barbuto D, Narod S, et al. (1990).

Peritoneal serous papillary carcinoma, a phenotypic variant of familial ovarian cancer:

implications for ovarian cancer screening. Am J Obstet Gynecol. 180(4):917-928.

35. Kearns B, Chilcott J, Whyte S, Preston L, Sadler S. (2016). Cost-effectiveness of screening for

ovarian cancer amongst postmenopausal women: a model-based economic

evaluation.[Erratum appears in BMC Med. 2017 Feb 3;15(1):31; PMID: 28158977]. BMC

Medicine. 14(1):200.

36. Kobayashi H, Yamada Y, Sado T, Sakata M, Yoshida S, Kawaguchi R, et al. (2008). A

randomized study of screening for ovarian cancer: a multicenter study in Japan. Int J

Gynecol Cancer. 18(3):414-420.

37. Lai T, Kessel B, Ahn HJ, Terada KY. (2016). Ovarian cancer screening in menopausal females

with a family history of breast or ovarian cancer. J Gynecol Oncol. 27(4):e41.

38. Lancastle D, Brain K, Phelps C. (2011). Illness representations and distress in women

undergoing screening for familial ovarian cancer. Psychology & Health. 26(12):1659-677.

39. Lifford KJ, Clements A, Fraser L, Lancastle D, Brain K, Psy FMG. (2013). A qualitative study of

women's experiences of familial ovarian cancer screening. Psycho-Oncology. 22(11):2576-

2584.

40. Lifford KJ, Fraser L, Rosenthal AN, Rogers MT, Lancastle D, Phelps C, et al. (2012). Withdrawal

from familial ovarian cancer screening for surgery: findings from a psychological evaluation

study (PsyFOCS). Gynecologic Oncology. 124(1):158-163.

41. Llort G, Chirivella I, Morales R, Serrano R, Sanchez AB, Teule A, et al. (2015). SEOM clinical

guidelines in Hereditary Breast and ovarian cancer. Clinical & Translational Oncology:

Official Publication of the Federation of Spanish Oncology Societes & of the National

Cancer Institute of Mexico 17(12): 956-961.

42. Lu, KH, Skates, S, Hernandez, MA, Bedi, D, Bevers, T, Leeds, L, et al. (2013). A 2-stage ovarian

cancer screening strategy using the Risk of Ovarian Cancer Algorithm (ROCA) identifies

early-stage incident cancers and demonstrates high positive predictive value. Cancer.

119(19):3454-3461.

https://www.ucl.ac.uk/womens-health/research/womens-cancer/gynaecological-cancer-research-centre/ukctocs/files/ukctocs_protocol71



43. Menon U, McGuire AJ, Raikou M, Ryan A, Davies SK, Burnell M, et al. (2017). The cost-

effectiveness of screening for ovarian cancer: results from the UK Collaborative Trial of

Ovarian Cancer Screening (UKCTOCS). British Journal of Cancer. 117(5):619-627.

44. Menon, U, Ryan, A, Kalsi, J, Gentry-Maharaj, A, Dawnay, A, Habib, M, et al. (2015). Risk

Algorithm Using Serial Biomarker Measurements Doubles the Number of Screen-Detected

Cancers Compared With a Single-Threshold Rule in the United Kingdom Collaborative Trial

of Ovarian Cancer Screening. Journal of Clinical Oncology. 33(18):2062-2071.

45. Menon, U, Gentry-Maharaj, A, Hallett, R, Ryan, A, Burnell, M, Sharma, A, et al. (2009).

Sensitivity and specificity of multimodal and ultrasound screening for ovarian cancer, and

stage distribution of detected cancers: results of the prevalence screen of the UK

Collaborative Trial of Ovarian Cancer Screening (UKCTOCS). Lancet Oncology. 10(4):327-

340.

46. Menon U, Skates SJ, Lewis S, Rosenthal AN, Rufford B, Sibley K, et al. (2005). Prospective study

using the risk of ovarian cancer algorithm to screen for ovarian cancer. J Clin Oncol.

23(31):7919-7926.

47. Miyagi E, Maruyama Y, Mogami T, Numazaki R, Ikeda A, Yamamoto H, et al. (2017).

Comparison of plasma amino acid profile-based index and CA125 in the diagnosis of

epithelial ovarian cancers and borderline malignant tumors. Int J Clin Oncol. 22(1):118-125.

48. Morgan, RJ, Jr., Alvarez, RD, Armstrong, DK, Burger, RA, Castells, M, Chen, LM, et al. (2012).

Ovarian cancer, version 3.2012. Journal of the National Comprehensive Cancer Network.

10(11):1339-1349.

49. Moyer VA. (2012). Screening for ovarian cancer: US Preventive Services Task Force

reaffirmation recommendation statement. Ann Intern Med. 157(12):900–904.

50. NASEM (2016). National Academies of Sciences, Engineering, and Medicine. Ovarian

cancers: Evolving paradigms in research and care. Washington, DC: The National

Academies Press.

51. National Breast Cancer Centre (2006). Advice about familial aspects of breast cancer and

epithelial ovarian cancer: a guide for health professionals. National Breast Cancer Centre,

Camperdown, NSW

52. NBOCC (2011). National Breast and Ovarian Cancer Centre. Recommendations for

management of women at high risk of ovarian cancer. ISBN: 978-1-74127-169-0 ©Cancer

Australia 2011. Available at Cancer Australia Guidelines.

53. NHS (2016). National Health Service Report. Detailed Project Description: Long term impact

of screening on ovarian cancer mortality in the UK Collaborative Trial of Ovarian Cancer

Screening (UKCTOCS). Accessed 31 Oct 2017.

54. Nyante SJ, Black A, Kreimer AR, Duggan MA, Carreon JD, Kessel B, et al. (2011). Pathologic

findings following false-positive screening tests for ovarian cancer in the Prostate, Lung,

Colorectal and Ovarian (PLCO) cancer screening trial. Gynecologic Oncology. 120(3):474-

479.

55. Paluch-Shimon, S, Cardoso, F, Sessa, C, Balmana, J, Cardoso, MJ, Gilbert, F, et al. (2016).

Prevention and screening in BRCA mutation carriers and other breast/ovarian hereditary

cancer syndromes: ESMO Clinical Practice Guidelines for cancer prevention and screening.

Annals of Oncology. 27(suppl 5):v103-v10.

56. Partridge, E, Kreimer, AR, Greenlee, RT, Williams, C, Xu, JL, Church, TR, et al. (2009). Results

from four rounds of ovarian cancer screening in a randomized trial. Obstetrics &

Gynecology. 113(4):775-782.

https://guidelines.canceraustralia.gov.au/guidelines/guideline_14.pdf



57. Pinsky PF, Yu K, Kramer BS, Black A, Buys SS, Partridge E, et al. (2016). Extended mortality

results for ovarian cancer screening in the PLCO trial with median 15 years follow-up.


58. Pinsky PF, Zhu C, Skates SJ, Black A, Partridge E, Buys SS, et al. (2013). Potential effect of the

risk of ovarian cancer algorithm (ROCA) on the mortality outcome of the Prostate, Lung,

Colorectal and Ovarian (PLCO) trial. International Journal of Cancer. 132(9):2127-2133.

59. Prorok PC, Andriole GL, Bresalier RS, Buys SS, Chia D, Crawford ED, et al. (2000). Design of the

Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. Controlled clinical

trials. 21(6 Suppl):273S-309S.

60. Qaseem A, Humphrey LL, Harris R, Starkey M, Denberg TD. (2014). Screening pelvic

examination in adult women: a clinical practice guideline from the American College of

Physicians. Ann Intern Med. 161(1):67-72.

61. RACGP (2016). The Royal Australian College of General Practitioners. Guidelines for

preventive activities in general practice. 9th edn. East Melbourne, Vic

62. Reade CJ, Riva JJ, Busse JW, Goldsmith CH, Elit L. (2013). Risks and benefits of screening

asymptomatic women for ovarian cancer: a systematic review and meta-analysis. Gynecol

Oncol. 130(3):674-681.

63. Rosenthal, AN, Fraser, L, Manchanda, R, Badman, P, Philpott, S, Mozersky, J, et al. (2013).

Results of annual screening in phase I of the United Kingdom familial ovarian cancer

screening study highlight the need for strict adherence to screening schedule. Journal of

Clinical Oncology. 31(1):49-57.

64. Rosenthal AN, Fraser LSM, Philpott S, Manchanda R, Burnell M, Badman P, et al. (2017).

Evidence of stage shift in women diagnosed with ovarian cancer during phase II of the

United Kingdom Familial Ovarian Cancer Screening Study. United Kingdom Familial Ovarian

Cancer Screening Study collaborators. J Clin Oncol. 35:1411–1420.

65. Russell MR, D'Amato A, Graham C, Crosbie EJ, Gentry-Maharaj A, Ryan A, et al. (2017).

Novel risk models for early detection and screening of ovarian cancer. Oncotarget.

8(1):785-797.

66. Sharma A, Apostolidou S, Burnell M, Campbell S, Habib M, Gentry-Maharaj A, et al. (2012).

Risk of epithelial ovarian cancer in asymptomatic women with ultrasound-detected ovarian

masses: a prospective cohort study within the UK collaborative trial of ovarian cancer

screening (UKCTOCS). Ultrasound in Obstetrics & Gynecology. 40(3):338-344.

67. Shih IM, Kurman RJ. (2004). Ovarian tumorigenesis. Am J Pathology 164(5):1511-1518.

68. SIGN (2013). Scottish Intercollegiate Guidelines Network (SIGN). Management of epithelial

ovarian cancer. Edinburgh: SIGN; 2013. (SIGN publication no. 135). [November 2013].

Available from URL: http://www.sign.ac.uk

69. Simmons AR, Clarke CH, Badgwell DB, Lu Z, Sokoll LJ, Lu KH, et al. (2016). Validation of a

Biomarker Panel and Longitudinal Biomarker Performance for Early Detection of Ovarian

Cancer. Int J Gynecol Cancer. 26(6):1070-1077.

70. Simpson NK, Johnson CC, Ogden SL, Gamito E, Trocky N, McGuire C, et al. (2000).

Recruitment strategies in the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer

Screening Trial: the first six years. Controlled clinical trials. 21(6 Suppl):356S-378S.

71. Singer, CF, Tea, MK, Pristauz, G, Hubalek, M, Rappaport, C, Riedl, CC, et al. (2015). Clinical

Practice Guideline for the prevention and early detection of breast and ovarian cancer in

http://www.sign.ac.uk/


women from HBOC (hereditary breast and ovarian cancer) families. Wiener Klinische

Wochenschrift. 127(23-24):981-986.

72. Skates SJ, Greene MH, Buys SS, Mai PL, Brown P, Piedmonte M, et al. (2017). Early Detection

of Ovarian Cancer using the Risk of Ovarian Cancer Algorithm with Frequent CA125 Testing

in Women at Increased Familial Risk - Combined Results from Two Screening Trials. Clinical

Cancer Research. 23(14):3628-3637.

73. Skates SJ, Mai P, Horick NK, Piedmonte M, Drescher CW, Isaacs C, et al. (2011). Large

prospective study of ovarian cancer screening in high-risk women: CA125 cut-point defined

by menopausal status. Cancer Prevention Research. 4(9):1401-1408.

74. Stuckless S, Green J, Dawson L, Barrett B, Woods MO, Dicks E, et al. (2013). Impact of

gynecological screening in Lynch syndrome carriers with an MSH2 mutation. Clinical

Genetics. 83(4):359-364.

75. Temkin SM, Miller EA, Samimi G, Berg CD, Pinsky P, Minasian L. (2017). Outcomes from

ovarian cancer screening in the PLCO trial: Histologic heterogeneity impacts detection,

overdiagnosis and survival. Eur J Cancer. 87:182-188.

76. USPSTF (2013). U. S. Preventive Services Task Force. Screening for ovarian cancer:

reaffirmation recommendation statement. American Family Physician. 87(10):Online.

77. van Nagell, JR, Jr., Miller, RW, DeSimone, CP, Ueland, FR, Podzielinski, I, Goodrich, ST, et al.

(2011). Long-term survival of women with epithelial ovarian cancer detected by

ultrasonographic screening. Obstetrics & Gynecology. 118(6):1212-1221.

78. USPSTF (2017a). Draft Recommendation Statement. Ovarian Cancer: Screening. Available

for public comment. Accessed November 2017.

79. USPSTF (2017b). Recommendation Summary. Gynecological Conditions: Periodic Screening

with the Pelvic Examination. March 2017. Accessed November 2017.

80. USPSTF (2016). U.S. Preventive Services Task Force. Final Recommendation Statement:

Ovarian Cancer: Screening. September 2012. Accessed November 2017.

81. Wilt TJ, Harris RP, Qaseem A (2015). Screening for cancer: advice for high-value care from

the American College of Physicians. Annals of Internal Medicine. 162(10):718-725.

82. Zeimet AG, Mori H, Petru E, Polterauer S, Reinthaller A, Schauer C, et al. (2017). AGO Austria

recommendation on screening and diagnosis of Lynch syndrome (LS). Archives of

Gynecology & Obstetrics 296(1): 123-127.

83. Zhang Q, Hu G, Yang Q, Dong R, Xie X, Ma D, et al. (2013). A multiplex methylation-specific

PCR assay for the detection of early-stage ovarian cancer using cell-free serum DNA.


https://www.uspreventiveservicestaskforce.org/Page/Document/draft-recommendation-statement174/ovarian-cancer-screening1#citation15

https://www.uspreventiveservicestaskforce.org/Page/Document/UpdateSummaryFinal/gynecological-conditions-screening-with-the-pelvic-examination?ds=1&s=pelvic

https://www.uspreventiveservicestaskforce.org/Page/Document/RecommendationStatementFinal/ovarian-cancer-screening#Pod1

position statement testing for ovarian cancer on ... · position statement – testing for ovarian...

Documents