management of ductal carcinoma in situ of the breast · 2020-01-23 · management of ductal...

Evidence-based Series 1-10 Version 3

A Quality Initiative of the

Program in Evidence-Based Care (PEBC), Cancer Care Ontario (CCO)

Management of Ductal Carcinoma in Situ of the Breast

Expert Panel on Ductal Carcinoma in Situ of the Breast

An assessment conducted in October 2019 deferred the review of Evidence-based Series (EBS) 1-10 Version 3. This means that the document remains current until it is assessed again next year. The PEBC has a formal and standardized process to ensure

the currency of each document (PEBC Assessment & Review Protocol)

EBS 1-10 is comprised of 4 sections. You can access the summary and full report here: https://www.cancercareontario.ca/en/guidelines-advice/types-of-cancer/276

Section 1: Clinical Practice Guideline (ENDORSED) Section 2: Systematic Review Section 3: Guideline Development and External Review Section 4: Document Assessment and Review

January 31, 2018

For information about the PEBC and the most current version of all reports, please visit the CCO website at http://www.cancercare.on.ca/ or contact the PEBC office at:

Phone: 905-527-4322 ext. 42822 Fax: 905-526-6775 E-mail: [email protected]

https://www.cancercareontario.ca/sites/ccocancercare/files/assets/CCOPEBCDARP.pdf

https://www.cancercareontario.ca/en/guidelines-advice/types-of-cancer/276

http://www.cancercare.on.ca/

mailto:[email protected]

PEBC Report Citation (Vancouver Style): Shelley W, McCready D, Holloway C, Trudeau M, Sinclair S; Breast Cancer Disease Site Group. Management of ductal carcinoma in situ of the breast. Eisen A, Rakovitch E, Walker-Dilks C, reviewers. Toronto (ON): Cancer Care Ontario; 2006 Sep 19 [ENDORSED 2018 Jan]. Program in Evidence-based Care Evidence-Based Series No.: 1-10 Version 3 ENDORSED. Journal Citation (Vancouver Style): Wright JR, Whelan TJ, McCready DR, O’Malley FP. Management of ductal carcinoma in situ of the breast. Cancer Prev Control. 1998;2(6):312-9.

Guideline Report History

GUIDELINE VERSION

SYSTEMATIC REVIEW PUBLICATIONS NOTES and KEY CHANGES Search

Dates Data

Original version 1998

Up to 1998

Full Report

Web publication

NA

Updated Version 2

September 2006

1998 to

2006

Full report

Updated web

publication

NA

Current

Version 3 January

2018

2006 to

June 2017

New data found in

Section 4: Document Summary and Review

Tool

Updated web

publication

2006

recommendations are ENDORSED

Table of Contents Section 1: Practice Guideline ................................................................................................... 1

Section 2: Systematic Review .................................................................................................. 6

Section 3: EBS Development Methods and External Review Process………………………34

Section 4: Document Assessment and Review………………………………………………….40

EBS 1-10 Version 3

PRACTICE GUIDELINE – page 1

Evidence-based Series 1-10 Version 3: Section 1

Management of Ductal Carcinoma in Situ of the Breast: A Clinical Practice Guideline

The Expert Panel on Ductal Carcinoma in Situ of the Breast



These guideline recommendations have been ENDORSED, which means that the recommendations are still current and relevant for decision making.

Please see Section 4 Document Review Summary and Tool for a summary of updated evidence published between 2006 and 2017,

and for details on how this Clinical Practice Guideline was ENDORSED.

January 31, 2018 Questions What is the optimal surgical management of ductal carcinoma in situ (DCIS) of the breast? Should breast irradiation be offered to women with DCIS, following breast-conserving

surgery (defined as excision of the tumour with microscopically clear resection margins)? Are there patients who could be spared breast irradiation post–breast-conserving surgery for DCIS?

What is the role of tamoxifen in the management of DCIS? Target Population

These recommendations apply to women with DCIS. They do not apply to women with DCIS with microinvasion. Recommendations and Key Evidence

Surgical Management

Women with DCIS of the breast who are candidates for breast-conserving surgery should be offered the choice of breast-conserving surgery or total mastectomy.

Mastectomy with the option for reconstruction remains an acceptable choice for women preferring to maximize local control.

EBS 1-10 Version 3


No randomized trials designed to compare total mastectomy with breast-conserving surgery for DCIS were found. The National Surgical Adjuvant Breast Project (NSABP) B-06 trial (1) involved women with invasive malignancy. However, a small number of women entered were found, on pathology review, to have only DCIS. An analysis based on this subgroup of DCIS patients (2) found a trend towards a much higher local recurrence rate in patients who received breast-conserving surgery alone (9/21; 43%), compared with those who received either breast-conserving surgery plus radiotherapy (2/27; 7%) or mastectomy (0/28; 0%). Two meta-analyses (3,4), consisting mainly of non-randomized trials, also demonstrated higher local recurrence in patients treated by breast-conserving surgery alone versus those treated by mastectomy. One reported no significant differences in local recurrence rates between patients treated by breast-conserving surgery followed by radiotherapy and mastectomy, whereas the second showed improved local recurrence rates with mastectomy. To date, no survival benefit for either type of surgery has been reported. The expert opinion of the Breast Cancer DSG is that this non-randomized data supports the recommendation that breast-conserving surgery followed by radiation or mastectomy are both acceptable treatment options.

Qualifying Statements

When breast-conserving surgery is performed, all mammographically suspicious calcifications should be removed and margins should be microscopically clear of DCIS.

Mastectomy, with the option of reconstruction, is recommended for those women who have an area of DCIS large enough that breast-conserving surgery would leave them with an unacceptable cosmetic result.

Added to the 2017 Endorsement:

A 2016 joint guideline from the Society of Surgical Oncology (SSO), American Society of Radiation Oncology (ASTRO), and American Society of Clinical Oncology (ASCO) recommends margins of at least 2 mm to reduce the risk of local recurrence (See Section 4 for details).

The ASTRO/ASCO recommendation (above) does not change the pathologic definition of a ―positive‖ margin. It remains entirely appropriate in pathology practice to report only DCIS at inked margin as ―positive,‖ and to provide distance to closest margin(s) when margins are negative.

For patients with DCIS treated with breast-conserving surgery and whole-breast irradiation, a positive margin (ink on DCIS) is associated with a significant risk of ipsilateral breast tumour recurrence (IBTR). A 2 mm margin minimizes the risk of IBTR compared with smaller negative margins. In patients with negative margins less than 2 mm, the need for re-excision should take into account other factors known to impact IBTR and routine mastectomy is discouraged.

Radiotherapy Women with DCIS who have undergone breast-conserving surgery should be offered adjuvant breast irradiation.

Randomized trials of post-lumpectomy radiation versus observation in patients at relatively low risk of recurrence following surgery alone are ongoing. Until the results of those studies are available, these patients should be referred to a radiation oncologist for a thorough discussion of what is currently known about the potential benefits and toxicities of post-lumpectomy radiation in their particular situation.

Three randomized trials (5-12) investigated the role of radiotherapy after breast-conserving surgery in patients with DCIS. In each, the risk of invasive and non-invasive ipsilateral recurrence was reduced with adjuvant radiotherapy. There were no significant differences in

EBS 1-10 Version 3


distant metastasis or overall survival.

Qualifying Statements Added to the 2017 Endorsement:

RCT evidence showed that radiotherapy after breast-conserving surgery reduced local failure compared with observation (RTOG 9804) (See Section 4 for details).

Emerging evidence exists on the use of hypofractionation and radiation boost (See Section 4 for details).

Tamoxifen

While there is some evidence to suggest that tamoxifen is effective in the reduction of ipsilateral recurrence and contralateral incidence in women with DCIS, the absolute benefit is small and the evidence is conflicting.

Women should be informed of the option of five years of tamoxifen therapy and of the potential toxicities and benefits associated with tamoxifen.

Two trials (12,13) investigated the role of tamoxifen versus no tamoxifen in addition to breast-conserving surgery and radiotherapy in the treatment of DCIS. The first demonstrated a significantly lower cumulative incidence of ipsilateral or contralateral breast malignancy for patients in the tamoxifen group versus those in the placebo group. In the second, tamoxifen treatment did not significantly reduce the incidence of either ipsilateral or contralateral breast malignancy.

Qualifying Statement In a subset analysis of one of the randomized studies (14), the beneficial effect of tamoxifen

was most apparent in the estrogen receptor-positive patients. Therefore, if it is felt that a patient might benefit from tamoxifen for one of the above reasons, hormone receptor assessment could be considered in order to aid in the decision regarding tamoxifen treatment.

Randomized studies suggest that women who are most likely to have a positive benefit/risk ratio with tamoxifen are those who are less than 50 years of age or who have positive resection margins and refuse further surgery. Women who have a contraindication to radiation or who refuse this treatment but still want to avoid mastectomy should also be considered for tamoxifen therapy.

Added to the 2017 Endorsement:

Systematic review and RCT data published since 2006 show increasing evidence supporting the use of tamoxifen in women with DCIS (NSABP B-24, UK/ANZ DCIS) (See Section 4 for details).

There is emerging evidence to support a role for aromatase inhibitors (NSABP B-35, IBIS II DCIS) (See Section 4 for details).

Related Guidelines Evidence Based Series #1-21: Optimal systematic therapy for early female breast cancer.

Funding The PEBC is supported by Cancer Care Ontario (CCO) and the Ontario Ministry of Health and Long-Term

Care. All work produced by the PEBC is editorially independent from its funding agencies.

EBS 1-10 Version 3


Copyright This evidence-based series is copyrighted by Cancer Care Ontario; the series and the illustrations herein

may not be reproduced without the express written permission of Cancer Care Ontario. Cancer Care Ontario reserves the right at any time, and at its sole discretion, to change or revoke this authorization.

Disclaimer

Care has been taken in the preparation of the information contained in this document. Nonetheless, any person seeking to apply or consult the evidence-based series is expected to use independent medical judgment in the context of individual clinical circumstances or seek out the supervision of a qualified

clinician. Cancer Care Ontario makes no representation or guarantees of any kind whatsoever regarding their content or use or application and disclaims any responsibility for their application or use in any way.

Contact Information

For further information about this series, please contact Dr. Wendy Shelley; Kingston Regional Cancer Centre, 25 King St W, Kingston ON, K7L 5P9; Telephone: 613-544-2631 x4502; Fax: 613-546-8209; E-

mail: [email protected].





EBS 1-10 Version 3


REFERENCES

1. Fisher B, Anderson S, Redmond CK, Wolmark N, Wickerham DL, Cronin WM. Reanalysis

and results after 12 years of follow-up in a randomized clinical trial comparing total mastectomy with lumpectomy with or without irradiation in the treatment of breast cancer. N Engl J Med. 1995;333(22):1456-61.

2. Fisher ER, Leeming R, Anderson S, Redmond C, Fisher B. Conservative management of intraductal carcinoma (DCIS) of the breast. J Surg Oncol. 1991;47(3):139-47.

3. Yin XP, Li XQ, Neuhauser D, Evans JT. Assessment of surgical operations for ductal carcinoma in situ of the breast. Int J Tech Ass Health Care. 1997;3:420-9.

4. Boyages J, Delaney G, Taylor R. Predictors of local recurrence after treatment of ductal carcinoma in situ: a meta-analysis. Cancer. 1999;85(3):616-28.

5. Julien JP, Bijker N, Fentiman IS, Peterse JL, Delledonne V, Rouanet P, et al. Radiotherapy in breast-conserving treatment for ductal carcinoma in situ: first results of the EORTC randomised phase III trial 10853. Lancet. 2000;355(9203):528-33.

6. Bijker N, Peterse JL, Duchateau L, Julien JP, Fentiman IS, Duval C, et al. Risk factors for recurrence and metastasis after breast-conserving therapy for ductal carcinoma-in-situ: analysis of European Organization for Research and Treatment of Cancer Trial 10853. J Clin Oncol. 2001;19(8):2263-71.

7. Fisher B, Costantino J, Redmond C, Fisher E, Margolese R, Dimitrov N, et al. Lumpectomy compared with lumpectomy and radiation therapy for the treatment of intraductal breast cancer. N Engl J Med. 1993;328(22):1581-6.

8. Fisher B, Dignam J, Wolmark N, Mamounas E, Costantino J, Poller W, et al. Lumpectomy and radiation therapy for the treatment of intraductal breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-17. J Clin Oncol. 1998;16(2):441-52.

9. Fisher B, Land S, Mamounas E, Dignam J, Fisher ER, Wolmark N. Prevention of invasive breast cancer in women with ductal carcinoma in situ: an update of the National Surgical Adjuvant Breast and Bowel Project experience. Semin Oncol. 2001;28(4):400-18.

10. Fisher ER, Costantino J, Fisher B, Palekar AS, Redmond C, Mamounas E. Pathologic findings from the National Surgical Adjuvant Breast Project (NSABP) Protocol B-17. Intraductal carcinoma (ductal carcinoma in situ). The National Surgical Adjuvant Breast and Bowel Project Collaborating Investigators. Cancer. 1995;75(6):1310-9.

11. Fisher ER, Dignam J, Tan-Chiu E, Costantino J, Fisher B, Paik S, et al. Pathologic findings from the National Surgical Adjuvant Breast Project (NSABP) eight-year update of Protocol B-17: intraductal carcinoma. Cancer. 1999;86(3):429-38.

12. Houghton J, George WD, Cuzick J, Duggan C, Fentiman IS, Spittle M. Radiotherapy and tamoxifen in women with completely excised ductal carcinoma in situ of the breast in the UK, Australia, and New Zealand: randomised controlled trial. Lancet. 2003;362(9378):95-102.

13. Fisher B, Dignam J, Wolmark N, Wickerham DL, Fisher ER, Mamounas E, et al. Tamoxifen in treatment of intraductal breast cancer: National Surgical Adjuvant Breast and Bowel Project B-24 randomised controlled trial. Lancet. 1999;353(9169):1993-2000.

14. Allred D, Bryant J, Land S, Paik S, Fisher ER, Julian T, et al. Estrogen receptor expression as a predictive marker of the effectiveness of tamoxifen in the treatment of DCIS: findings from NSABP protocol B-24. Breast Cancer Res Treat. 2002;76 Suppl 1:S36 [A30].

EBS 1-10 Version 3

SYSTEMATIC REVIEW – page 6


Management of Ductal Carcinoma in Situ of the Breast: A Systematic Review

W. Shelley, D. McCready, C. Holloway, M. Trudeau, S. Sinclair,

and the Breast Cancer Disease Site Group



Report Date: September 19, 2006 Replaces Original Report dated 1998

The 2006 guideline recommendations are

ENDORSED

This means that the recommendations are still current and relevant for decision making. Please see Section 4: Document Assessment and Review for a summary of updated evidence

published between 2006 and 2017, and for details on how this Clinical Practice Guideline was ENDORSED.

QUESTIONS

What is the optimal surgical management of ductal carcinoma in situ (DCIS) of the breast? Should breast irradiation be offered to women with DCIS, following breast-conserving

surgery (defined as excision of the tumour with microscopically clear resection margins)? Are there patients who could be spared breast irradiation post-breast-conserving surgery for DCIS?

What is the role of tamoxifen in the management of DCIS? INTRODUCTION

DCIS of the breast represents a heterogeneous group of diseases characterized by the proliferation of malignant epithelial cells that are confined within the basement membrane of the mammary ducts (1). The natural history of DCIS is poorly understood. Limited published information is available that is generalizable to current practice, because the clinical nature of DCIS has changed over the years. DCIS incidence increased significantly during the years that routine screening mammography became available. In the United States, the age-adjusted DCIS incidence rate increased from 2.4 per 100,000 women in 1973 to 15.8 per 100,000 women in 1992, an increase of 557% (2). At the present time, the vast majority of DCIS lesions are nonpalpable and are identified by microcalcifications discovered at the time of routine screening mammography.

EBS 1-10 Version 3


The management of DCIS has evolved with the changing clinical nature of the disease and the emergence of new evidence. Originally, mastectomy was the standard operative procedure for patients presenting with DCIS. However, there has been a shift towards breast-conserving surgery (BCS). Radiotherapy has been recommended for women with DCIS following BCS, but, more recently, the role of adjuvant radiation for all subgroups has been questioned. In addition, the role of adjuvant tamoxifen therapy in women with DCIS is unclear. Given the increasing incidence and the wide spectrum of management options, the Breast Cancer Disease Site Group (DSG) felt that DCIS of the breast was an appropriate topic for a practice guideline. METHODS

This systematic review was developed by Cancer Care Ontario’s Program in Evidence-Based Care (PEBC), using the methods of the Practice Guidelines Development Cycle (3). Evidence was selected and reviewed by three members of the PEBC Breast Cancer Disease Site Group (DSG), a radiation oncologist, a surgical oncologist, and a research methodologist.

This systematic review is a convenient and up-to-date source of the best available evidence on the management of DCIS of the breast. The body of evidence in this review is primarily comprised of randomized controlled trial data. That evidence forms the basis of a clinical practice guideline developed by the Breast Cancer DSG and published as Section 1 of this evidence-based series. The systematic review and companion practice guideline are intended to promote evidence-based practice in Ontario, Canada. The PEBC is editorially independent of Cancer Care Ontario and the Ontario Ministry of Health and Long-Term Care.

A practice guideline report on the management of DCIS of the breast was originally completed in January 1998 and published in Cancer Prevention and Control (4). Since the

publication of the 1998 guideline, the medical literature has been monitored, and the results of additional randomized clinical trials have become available that have an impact on treatment recommendations. Therefore, the Breast Cancer DSG felt that the original guideline document and the new evidence should be integrated. This systematic review, and the evidence-based series of which it is a part, reflect the evidence up to March 2005 and include revised recommendations based on that evidence. This evidence-based series replaces the original report. Literature Search Strategy

MEDLINE was searched to March 2006, using a disease-specific medical subject heading (MeSH) term (―carcinoma, intraductal, noninfiltrating‖) and treatment-specific MeSH terms (―radiotherapy‖, ―mastectomy‖, or ―tamoxifen‖). The Excerpta Medica database (EMBASE) was also searched up to March 2006, using a disease-specific Excerpta Medica Tree (EMTREE) term (―intraductal carcinoma‖) and the same treatment-specific EMTREE term as for the MEDLINE search.

Issue 5 (2004) of the Cochrane Library, the Physician Data Query database (http://www.cancer.gov/search/clinical_trials/), and conference proceedings from the American Society of Clinical Oncology (1998 to 2005), the American Society for Therapeutic Radiology and Oncology (1998 to 2005), and the San Antonio Breast Cancer Symposium (2001 to 2005) were also searched. The Canadian Medical Association Infobase (http://mdm.ca/cpgsnew/cpgs/index.asp) and the National Guidelines Clearinghouse (http://www.guideline.gov/) were searched for existing evidence-based practice guidelines. Relevant articles and abstracts were selected and reviewed by three reviewers, and the reference lists from these sources were searched for additional trials, as were the reference lists from relevant review articles. Inclusion Criteria

EBS 1-10 Version 3


Articles were selected for inclusion in this systematic review of the evidence if they met the following criteria: The management of DCIS of the breast was evaluated using a randomized controlled trial or

a meta-analysis of non-randomized and/or randomized trials. Reported outcomes included overall or disease-free survival, local recurrence (invasive or

non-invasive), breast conservation, distant recurrence, toxicity, or quality of life. Clinical trial results were reported in full papers or abstracts. Although data presented in

meeting abstracts may not be as reliable and complete as that from papers published in peer-reviewed journals, abstracts can be a source of important evidence from randomized trials and add to the evidence available from fully published studies. These data often appear first in meeting abstracts and may not be published for several years.

Evidence-based clinical practice guidelines addressing this topic were also eligible for inclusion. Exclusion Criteria

Articles were excluded if they met the following criteria: Trial results were published in a language other than English. Publication occurred prior to 1983. Because our understanding of DCIS biology has evolved

substantially since the maturation of screening mammography, trials published prior to this date are not relevant to current clinical practice.

Synthesizing the Evidence

Because the randomized trials on the management of DCIS of the breast were clinically heterogeneous, their results were not pooled. RESULTS Literature Search Results

The following publications were eligible for inclusion in the systematic review of the evidence: One subgroup analysis (5) of patients found to have DCIS on pathology review of a

randomized trial designed to address the role of BCS in early-stage invasive breast cancer (6). Two meta-analyses on the surgical management of DCIS, comprised predominantly of non-randomized prospective and retrospective studies (7,8).

Three randomized trials (reported in eight articles) that evaluated the use of adjuvant radiotherapy in patients who had undergone BCS for DCIS (9-16).

Two randomized trials (reported in three articles) that investigated the use of tamoxifen in patients with DCIS who had undergone BCS and adjuvant radiotherapy (13,16,17).

Six practice guidelines relevant to the management of DCIS of the breast (reported in seven sources) (18-24).

Outcomes

Mastectomy versus BCS for DCIS Unfortunately, no randomized trials designed to compare mastectomy with BCS for

DCIS were found. Data were available from the National Surgical Adjuvant Breast Project (NSABP) B-06 trial, a randomized trial designed to address the role of BCS in patients with early-stage invasive breast cancer (6). According to the pathology review, 76 patients with DCIS had been allocated to the three treatment groups, mastectomy, BCS only, and BCS with adjuvant radiation. These cases were followed, and results were published in a separate report (5). The majority of lesions were palpable, with an average size of 2.2 cm; only one lesion was found incidentally with mammography. At an average follow-up of 83 months, the rate of ipsilateral breast cancer recurrence was 43% (9/21) in the BCS only group and 7% (2/27) in the BCS plus radiotherapy group. There were no local failures in the mastectomy group (0/28).

EBS 1-10 Version 3


Radiotherapy following BCS was the only significant predictor of reduced local breast recurrence (p=0.01). There were two deaths due to breast cancer in the BCS-only group, no deaths in the BCS plus radiation group, and one death in the mastectomy group. Given that all patients were initially randomized in a trial of early invasive disease, this study may have limited generalizability. The small number of patients limits the power of this study to detect meaningful differences in survival.

A published meta-analysis by Peng Yin et al included 24 published reports, comprised mainly of clinical series, retrospective studies, and prospective non-randomized studies of patients with DCIS who were treated by mastectomy or BCS (7). Six of the 24 reports were published prior to 1983. The confidence profile method with the random effect hierarchical model was used to pool the data. The outcome of interest was the rate of local recurrence (defined as a chest wall recurrence for patients treated by mastectomy or a recurrence in the breast for patients treated by BCS) and death. New contralateral breast cancers were not included in the analysis. Local recurrence rates were corrected for the length of follow-up and compared for patients treated by mastectomy and BCS with and without irradiation. In total, 2,407 patients were included. At five years, local recurrence was higher for patients treated with BCS, with or without radiation, (21.5%; 95% confidence interval [CI], 14.0% to 30.7%) versus those treated by mastectomy (4.6%; 95% CI, 2.3% to 7.6%). In the studies reporting on patients treated by BCS plus radiation, the risk of local recurrence was 10.6% (95% CI, 5.6% to 16.9%). Mortality rates at five years were similar for patients treated by BCS or mastectomy (4.2%; 95% CI, 1.4% to 8.5% and 3.9%; 95% CI, 1.7% to 6.8%, respectively).

Similarly, Boyages et al conducted a meta-analysis of published reports of studies of patients with DCIS (8). Case series, retrospective studies, and prospective studies were included. Only one trial included in the BCS analysis (NSABP B-06, described above) and two trials included in the BCS plus radiotherapy analysis (NSABP B-06, described above and NSABP B-17, described below), were randomized. Six of the studies included were published prior to 1983. The summary recurrence rate and 95% confidence intervals for each treatment category were calculated using random and fixed effects models. The random effects model was employed where statistically significant heterogeneity between studies existed. Meta-analysis yielded statistically different summary local recurrence rates of 1.4%, 8.9%, and 22.5% in patients with DCIS treated by mastectomy, BCS plus radiotherapy, or BCS alone, respectively (Table 1).

Table 1. Pooled local recurrence rates by treatment (Boyages et al ) (8).

Treatment Number of

studies

Average of median

follow-ups per study (months)

Absolute local recurrence rate*

95% CI

Mastectomy 21 80 1.4% 0.7% to 2.1% BCS + radiotherapy 19 62 8.9% 6.8% to 11.0% BCS alone 17 68 22.5% 16.9% to 28.2%

Abbreviations: BCS, breast-conserving surgery; CI, confidence interval. *Patients with high-grade tumours, necrosis, comedo subtype, or positive margins were more likely to benefit from radiotherapy

following BCS.

Radiotherapy Following Breast-Conserving Surgery for DCIS

The European Organization for Research and Treatment of Cancer (EORTC) 10853 trial explored the role of radiotherapy after BCS for patients with DCIS. A peer-reviewed publication reported the results of this trial at a median follow-up of two years (9), but a more recent abstract reported results at a median follow-up of 10.2 years (25). A total of 1,010 women with DCIS measuring less than or equal to 5 cm were treated by BCS and were randomized to no

EBS 1-10 Version 3


further treatment or to radiotherapy, 5000 cGy in 25 daily fractions in five weeks. Resection margins were microscopically free of disease. Twenty-one percent were detected clinically, and the mean diameter was 21 mm (9). At a median follow–up of 10.2 years, the 10-year local relapse-free rate was 75% for patients receiving no further treatment compared with 85% for patients receiving adjuvant radiotherapy (hazard ratio [HR], 0.55; 95% CI, 0.41 to 0.73; log rank. p<0.0001).

At a median follow-up of two years, the radiotherapy group, relative to the no-further-treatment group, had a reduced risk of invasive recurrence from 8% to 4% (HR, 0.60; 95% CI, 0.37 to 0.97) and non-invasive recurrence from 8% to 5% (HR=0.65; CI, 0.41 to 1.03) (9). These differences continued to be significant at a median follow-up of 10.2 years (p=0.006 and p=0.009, respectively; exact risks not reported) (25). There were no significant differences in contralateral incidence, distant metastasis, death, or event-free survival. A multivariate analysis found a significant difference in the risk of local recurrence due to no further treatment as opposed to radiotherapy (HR, 1.74; 95% CI, 1.28 to 2.42), after controlling for young age, symptomatic detection, intermediately or poorly differentiated DCIS, solid or cribriform growth pattern, and doubtful margins.

A separate published report on a prognostic factor analysis in this study on a subset of 775 patients who had central pathology review confirmed DCIS without invasion (10). Median follow-up was 5.4 years. Treatment group, age, method of detection, nuclear grade, necrosis, architecture, size, margin status, histologic grade, and Van Nuy’s classification were the factors examined in a multifactor analysis. Under the Van Nuy’s classification system, low/moderate grade lesions (nuclear grade I or II) are split into two groups by the absence (Group I) or the presence (Group II) of comedo-type necrosis. High nuclear grade (grade III) is defined as Group III. Age ≤40 years, clinical detection, cribriform or solid/comedo architecture, close, involved or unknown margins, and no postoperative radiation were all risk factors for local recurrence.

Multivariate analysis was not done for each treatment group but, in the single factor analysis, all subgroups had an observed lower incidence of local recurrence in the radiated group compared to the non-radiated group. Two subgroups in the radiated group had local recurrence rates ≥20%—those ≤40 years of age, a 23% recurrence rate, and those with involved, close, or unspecified resection margins, a 20% recurrence rate.

The NSABP B-17 trial was also designed to evaluate the role of radiotherapy after BCS in women with DCIS (11-13). In this trial, 818 DCIS patients with microscopically clear resection margins after BCS were randomized to radiotherapy, 5000 cGy in 25 fractions in five weeks, or observation. Although the fact has been reported that approximately 90% of lesions were 2cm or less in size, with a mean size of 1.2cm, the debate has been whether size was accurately assessed on this study (26) or an underestimate. Only 8% were detected clinically. At a mean follow-up of 10.7 years, the 12-year cumulative incidence of invasive disease in the ipsilateral breast was reduced from 16.8% to 7.7% with radiotherapy (p=0.00001). The rate of non-invasive recurrence was also reduced from 14.6% to 8.0% with radiotherapy (p=0.001). There was no significant difference in overall survival for patients treated with BCS alone versus BCS plus radiotherapy (86% versus [vs.] 87%; RR, 0.95; 95% CI, 0.63 to 1.45; p=0.80).

The overall incidence of contralateral malignancy was only reported by treatment arm in the 1998 report after a median follow-up of eight years. At that time, the incidence of invasive or in situ contralateral disease was 5.4% in the lumpectomy group (4.9% invasive and 0.5% in situ) and 6.0% in the lumpectomy plus radiation group (3.6% invasive and 2.4% in situ). The 2001 report gave the rate of contralateral breast disease only as a first event rather than at any time, with the rate being 5.8 per thousand patients per year in the lumpectomy group and 8.4 in the radiation group (p=0.26).

The NSABP initially did a pathologic prognostic factor analysis after five years of follow-up (15) and updated this analysis after eight years of follow-up on a larger group of patients (N=623) who had had central pathology review (14). The pathologic factors examined were

EBS 1-10 Version 3


comedo necrosis, histologic type, margin status, lymphoid infiltrate, nuclear grade, focality, cancerization, stroma, and tumour size. In a multifactor analysis, only the presence of moderate to marked comedo necrosis was a significant predictor of breast recurrence. The average annual hazard rates for recurrence were lower for all nine pathologic characteristics in the radiated compared to the non-radiated group. When patients were subdivided according to the Van Nuy’s classification, again, recurrence rates were lower in all three groups if the patients had received radiation.

In the United Kingdom Coordinating Committee on Cancer Research (UKCCCR) trial, a complex, modified, 2x2 factorial design (Figure 1) was used to evaluate radiotherapy and tamoxifen in women with completely excised DCIS (16). Women were recruited from breast screening centres, and so the majority (90.5%) were over 50 years of age. Resection margins that were radiologically and histologically free of disease were required. Partway through the study, the decision was made to include patients with microinvasion (< 1 mm in diameter), and these patients made up 3% of the study population. Surgeons and their patients could either choose to enter the four-arm study (no postoperative treatment, tamoxifen alone, radiation alone, or radiation and tamoxifen) or to be randomized only to tamoxifen versus no tamoxifen or radiation versus no radiation. If a patient chose to participate only in the tamoxifen randomization, she could choose whether or not to receive radiation. Similarly, if she entered only the radiation randomization, she could choose whether or not to receive tamoxifen. For the purposes of the analyses, only the patients randomized to tamoxifen versus no tamoxifen were included in the tamoxifen comparison (i.e., patients who entered the radiation part of the study and chose to take tamoxifen were not included in the tamoxifen comparison). The same was true for the radiotherapy comparison.

A total of 1,694 eligible patients were entered into the study, 912 in the four-arm comparison, an additional 664 in the tamoxifen comparison (603 chose not to receive radiation and 61 chose radiation), and an additional 118 in the radiotherapy comparison (89 chose tamoxifen and 29 chose no tamoxifen). The results of the tamoxifen comparison are described in the following section, Tamoxifen and Radiotherapy versus Radiotherapy Alone.

EBS 1-10 Version 3


Figure 1: Design of the UKCCCR trial.

Abbreviations: UKCCCR, United Kingdom Coordinating Committee on Cancer Research.

Adapted from Houghton et al (16). Dotted lines indicate that allocations were by choice; solid lines indicate random allocation.

1694 entered in

study

912 chose 2x2 (4-way)

randomization

782 chose randomization to

one of the treatments (2-way randomization)

224 randomized to tamoxifen only

220 randomized to radiation only

226 randomised to no adjuvant treatment

664 entered only the tamoxifen

randomization

118 entered only the radiation randomization

30 chose radiation

298 chose no radiation

31 chose

radiation

305 chose no radiation

44 chose tamoxifen

16 chose no tamoxifen

45 chose to tamoxifen

13 chose no

tamoxifen

328 were randomized to tamoxifen

58 were randomized to

no radiation

60 were randomized to radiation

336 were randomized to

no tamoxifen

242 randomized to radiation and

tamoxifen

EBS 1-10 Version 3


A total of 1,030 patients are included in the radiation comparison (912 in the four-arm randomization and 118 in the two-arm randomization). Of these, 522 were randomized to receive radiation, 5000 cGy in 25 daily fractions in five weeks, and 508 were randomized to no radiation. Fifty-four percent in the group who received radiation and 51% in the group that did not receive radiation also received tamoxifen. After a median follow-up of 52.6 months, there was a significant decrease in ipsilateral DCIS and invasive disease and no significant difference in contralateral DCIS or invasive disease (Table 2). Table 2: Incidence of breast events in patients in the radiotherapy comparison (UKCCCR trial).

Type of event Randomized to

radiotherapy (%) Randomized to no radiotherapy (%)

HR (95% CI) p-value

Ipsilateral

Invasive 3 6 0.45 (0.24, 0.85) 0.01

DCIS 3 7 0.36 (0.19, 0.66) 0.0004

Invasive or DCIS 6 14 0.38 (0.25. 0.59) <0.0001

Contralateral

Invasive 2 1 1.50 (0.53, 4.22) 0.44

Invasive or DCIS 2 2 0.82 (0.34, 1.18) 0.65

Total invasive 5 7 0.62 (0.37, 1.04) 0.07

Total DCIS 3 9 0.31 (0.17, 0.56) <0.0001

Total invasive or DCIS 7 16 0.43 (0.29, 0.63) <0.0001

Abbreviations: DCIS, ductal carcinoma in situ; HR, hazard ratio; UKCCR, United Kingdom Coordinating Committee on Cancer Research.

Taken from Houghton et al (16).

Tamoxifen and Radiotherapy versus Radiotherapy Alone

The NSABP B-24 randomized trial investigated the role of tamoxifen, 20 mg daily for five years, versus placebo in addition to BCS and radiotherapy in the treatment of DCIS in 1,804 women (13,17). The majority of patients presented with mammographically detected DCIS (83%), tumours less than or equal to 1cm (84%) and negative margins (75%). Of the 1804 randomized patients, 564 (31.3%) did not complete the assigned therapy (269 on placebo and 295 on tamoxifen). Side effects of treatment was given as the reason for treatment discontinuation in 98 placebo patients and 146 tamoxifen patients. At a median follow-up of 6.9 years, the cumulative seven-year incidence of ipsilateral or contralateral breast malignancy was lower for patients in the tamoxifen group versus those in the placebo group (10.0% vs. 16.9%, p=0.0003). The lower incidence was seen primarily in invasive disease (4.4% vs. 8.5%, p=0.0009). Data broken down by ipsilateral recurrence and contralateral incidence are summarized in Table 3. Table 3: Cumulative incidence of breast cancer events at seven years (NSABP B-24 trial).

Type of recurrence Breast cancer events

Rate ratio (95% CI) P-value Placebo (%) Tamoxifen (%)

Ipsilateral Invasive 5.3 2.6 0.53 (0.32-0.86) 0.01 Non-invasive 5.8 5.0 0.85 (0.56-1.29) 0.48 Contralateral Invasive 3.2 1.8 0.64 (0.35-1.17) 0.16 Non-invasive 1.6 0.6 0.32 (0.09-0.93) 0.03

Abbreviation: NSABP, National Surgical Adjuvant Breast Project. Taken from Fisher et al (13).

EBS 1-10 Version 3


The overall seven-year survival rate was 95% for both groups. A substantial number of patients had positive (16%) or unknown (10%) margins for DCIS, and others were known to have residual suspicious calcifications. The recurrence rate in those with negative margins was lower and the effect of tamoxifen less. For those receiving tamoxifen versus placebo, the absolute risk of ipsilateral breast recurrence (invasive or DCIS) was 7.0% versus 8.8% in the margin-negative group and 10.6% versus 14.1% in the unknown or margin-positive group, respectively.

At five years of follow-up, two placebo patients had developed deep vein thrombosis compared with nine tamoxifen patients, and one placebo patient had suffered a non-fatal pulmonary embolus compared with two tamoxifen patients. At seven years of follow-up, three placebo patients had developed endometrial cancer compared with seven tamoxifen patients.

A subgroup analysis was done on the 628 patients for whom estrogen-receptor (ER) status was known (327 placebo and 301 tamoxifen) (27). Seventy-seven percent of the tumours were ER positive, and the risk ratio (RR) of recurrent or new breast pathology with tamoxifen was 0.41 in the ER-positive patients, (95% CI, 0.25-0.65; p=0.0002). In the ER- negative patients, the RR was 0.80 (p=0.5), but the authors point out that the number of events in the ER-negative group was too small (36) to rule out a clinically meaningful benefit (95% CI for RR, 0.41-1.56).

In the UKCCCR trial, 1,576 patients were included in the tamoxifen analyses, 912 in the four-arm randomization and 664 in the two-arm randomization (16). Seven hundred ninety-four patients were randomized to tamoxifen and 782 to no tamoxifen. Only 34% of the tamoxifen group and 32% of the no-tamoxifen group received radiation. Of the 794 patients randomized to receive tamoxifen, 86 (11%) stopped taking the drug before five years or took it for less than the time they were on the trial. After a median follow-up of 52.6 months, there was no statistically significant difference in the occurrence of ipsilateral or contralateral invasive carcinoma or DCIS (Table 4), but there was a difference in the overall incidence of DCIS (ipsilateral and contralateral combined). Table 4: Incidence of breast events in patients in the tamoxifen comparison (UKCCCR trial).

Type of event Randomized to tamoxifen (%)

Randomized to No tamoxifen (%)

HR (95% CI) p-value

Ipsilateral

Invasive 6 4 1.31 (0.84, 2.03) 0.23

DCIS 7 10 0.74 (0.52, 1.04) 0.08

Invasive or DCIS 13 15 0.90 (0.69, 1.17) 0.42

Contralateral

Invasive 1 2 0.66 (0.30, 1.46) 0.30

Invasive or DCIS 1 3 0.52 (0.25, 1.07) 0.07

Total invasive 7 6 1.11 (0.76, 1.63) 0.59

Total DCIS 7 11 0.68 (0.49, 0.96) 0.03

Total invasive or DCIS 14 18 0.83 (0.64, 1.06) 0.13

Abbreviation: DCIS, ductal carcinoma in situ; HR, hazard ratio; UKCCR, United Kingdom Coordinating Committee on Cancer

Research. Taken from Houghton et al (16).

In a comparison between NSABP B-24 and the UKCCCR results, the authors of the

UKCCCR noted that only 33% of the patients in their tamoxifen comparison also received radiation. Of these 523 patients who also received radiation, no difference was observed in the incidence of subsequent invasive cancer or DCIS between those who did and did not receive

EBS 1-10 Version 3


tamoxifen. In the 1,053 patients who did not receive radiation, the only difference was seen in the incidence of the combination of ipsilateral and contralateral DCIS (Table 5). Table 5: Incidence of breast events in patients in the tamoxifen comparison, stratified by whether or not they received radiotherapy (UKCCCR trial).

Type of event Randomized to tamoxifen (%)

Randomized to no tamoxifen

(%) HR (95% CI) p-value

Patients not receiving radiotherapy (N=1053)

Ipsilateral invasive 5 4 1.32 (0.81, 2.14) 0.26

Ipsilateral DCIS 6 9 0.73 (0.51, 1.06) 0.10

Total invasive 5 5 1.11 (0.72, 1.72) 0.64

Total DCIS 6 10 0.68 (0.47, 0.97) 0.03


Patients receiving radiotherapy (N=523)

Ipsilateral invasive 1 1 1.25 (0.43, 3.61) 0.68

Ipsilateral DCIS 1 1 0.75 (0.28, 2.02) 0.57

Total invasive 2 1 1.11 (0.50, 2.48) 0.80

Total DCIS 1 1 0.75 (0.28, 2.02) 0.57


Abbreviation: DCIS, ductal carcinoma in situ; HR, hazard ratio; UKCCR, United Kingdom Coordinating Committee on Cancer Research. Taken from Houghton et al (16).

In the UKCCCR study, only 9.5% of patients were less than 50 years of age, compared

with 33.5% of patients in the NSABP B-24 study. Data by age on the NSABP study was only available for ipsilateral breast malignancy. For this endpoint, the benefit of tamoxifen in both studies was more apparent in women 50 years of age or less (Table 6).

Table 6: Effect of tamoxifen in patients by age at randomization: a comparison of the UKCCCR and the NSABP B-24 trial results.

Randomized to tamoxifen

(%)

Randomized to no tamoxifen

(%) HR (95% CI)

p-value

≤ 50 years DCIS or invasive events Total UK events 18 26 0.62 (0.30, 1.28) 0.19 UK ipsilateral invasive or DCIS 13 22 0.52 (0.23, 1.20) 0.12 B-24 ipsilateral invasive or DCIS* 11 16 0.62 (0.41, 1.06) 0.09 >50 years DCIS or invasive events Total UK events 14 17 0.85 (0.65, 1.11) 0.24 UK Ipsilateral invasive or DCIS 13 14 0.95 (0.71, 1.26) 0.72 B-24 ipsilateral invasive or DCIS* 5 7 0.78 (0.49, 1.29) 0.36

Abbreviation: DCIS, ductal carcinoma in situ; HR, hazard ratio; NSABP, National Surgical Adjuvant Breast Project; UKCCR, United Kingdom Coordinating Committee on Cancer Research. Taken from Houghton et al (16).

* The UKCCCR authors calculated 95% CI and p-values for the B-24 trial by using binomial approximations.

The above studies provide some tamoxifen toxicity data, but the NSABP study P-1 provides detailed data, stratified by patient age, on a large sample of well women considered to be at higher than average risk of developing breast cancer (28). In order to determine if tamoxifen could decrease the likelihood of developing breast cancer, 13,388 women were

EBS 1-10 Version 3


randomized to placebo versus tamoxifen, 20 mg daily for five years.. Median follow-up was 54.6 months. The numbers of serious events by treatment arm and by age are given in Table 7, along with the risk ratios and 95% confidence intervals. The largest differences in the number of the serious adverse events appeared to be in women over 50 years of age, although the absolute number of adverse events is small with tamoxifen, as is the incremental risk.

Table 7: Toxicity on tamoxifen versus placebo, NSABP P-1 prevention trial.

Type of Event

Number of Events

RR RR 95% CI Placebo

(out of 6,707) Tamoxifen

(out of 6,681)

Endometrial cancer 15 36 2.53 1.35 to 4.97 Age≤49 8 9 1.21 0.41 to 3.60 Age≥50 7 27 4.01 1.70 to 10.90 Stroke 24 39 1.59 0.93 to 2.77 Age≤49 4 3 0.76 0.11 to 4.49 Age≥50 20 35 1.75 0.98 to 3.20 Pulmonary embolism 6 18 3.01 1.15 to 9.27 Age≤49 1 2 2.03 0.11 to 119.62 Age≥50 5 16 3.19 1.12 to 11.15 Deep vein thrombosis 22 35 1.60 0.91 to 2.86 Age≤49 8 11 1.39 0.51 to 3.99 Age≥50 14 24 1.71 0.85 to 3.58 Abbreviations: NSABP, National Surgical Adjuvant Breast Project; RR, relative risk.

Adapted from Fisher et al (28)

Practice Guidelines on the Management of DCIS Six relevant, evidence-based practice guidelines (reported in seven sources) were

identified (18-24). Table 8 summarizes the main recommendations or statements from each guideline, grouped according to surgical, radiation, or tamoxifen therapy. The fact that the tamoxifen recommendations/statements were made prior to the publication of the UKCCCR trial is important to note.

EBS 1-10 Version 3


Table 8: Clinical practice guidelines relevant to the management of DCIS.

Source (reference)

Country of Origin

Date last updated

Recommendation/statement

Surgical Radiation Tamoxifen

National Breast Cancer Centre (18)

Australia 2003

Excision must obtain clear margins. If margins are involved, further excision is required.

Radiotherapy after complete local excision reduces invasive recurrence. For women with good prognostic features, the overall clinical benefit may be small.

Not addressed.

National Comprehensive Cancer Network (19)

USA 2003

Women with DCIS that is not amenable to margin-free excision should receive mastectomy; otherwise BCS is recommended.

Whole breast irradiation with boost to tumour bed is recommended for women with negative margins. Selected patients with DCIS may be appropriately treated with BCS without irradiation.

Tamoxifen for five years should be considered for patients treated with BCS and radiotherapy or patients treated with BCS alone.

Canadian Breast Cancer Initiative (20,21)

Canada 2001

Mastectomy is recommended for those with large lesions where BCS would produce an unacceptable cosmetic effect or where there is persistent margin involvement after 2 or more attempts at excision.

BCS should usually be followed by radiotherapy, but in cases of small low-grade lesions with clear margins, radiotherapy may be omitted, after a careful discussion with the patient regarding options and risks.

Tamoxifen is a reasonable option for women who want to minimize their risk of recurrence and are willing to accept the risk of tamoxifen toxicity. The potential benefits and risks of tamoxifen for each individual patient should be discussed with that patient.

The Royal College of Radiologists (22)

United Kingdom

1999 Extensive or multifocal DCIS should be treated by mastectomy.

Radiotherapy after BCS reduces the rate of local recurrence, particularly in women with high-grade lesions or positive margins.

The role of tamoxifen remains conjectural.

The Scottish Intercollegiate Guideline Networks (23)

Scotland 1998

Mastectomy is recommended for patients with DCIS greater than 4cm or those with disease affecting more than one quadrant.

Radiotherapy should be considered following BCS with wide local excision.

Not addressed.

New Zealand Guidelines Group (24)

New Zealand

1997

Excision with clear margins is the treatment goal. To achieve this, either mastectomy or BCS may be performed.

Radiotherapy should normally be given following BCS.

Not addressed

Abbreviations: BCS, breast conserving surgery; DCIS, ductal carcinoma in situ.

EBS 1-10 Version 3


Additional Considerations for the Management of DCIS of the Breast

Evidence from randomized trials or meta-analyses is not available for a number of issues relevant to the management of DCIS. The following sections address these additional considerations, using expert opinion and non-randomized evidence from a non-systematic literature search. This information is intended to aid the practitioner and his/her patient in the management of DCIS of the breast and does not form the basis for the recommendations. Technical Factors for Breast-Conserving Surgery for the Treatment of DCIS

The management of DCIS lesions requires close cooperation between the surgeon, radiologist, and pathologist. At present, the majority of patients with DCIS will be identified by mammographic abnormality. Preoperative confirmation of the diagnosis is by core needle biopsy is desirable. A preoperative mammogram with magnification views will often delineate the extent of microcalcifications. In most cases, excision will require preoperative localization by the radiologist, using a hooked wire or a similar device. Bracketing wires may aid in marking the extent of the lesion.

Complete excision of the lesion should be achieved, as studies have shown that positive or indeterminate resection margins increase the risk of local recurrence (15,20,29). A specimen radiograph is recommended for those who have image-guided resections, to ensure that the lesion has been excised. Careful pathologic assessments of the margins should be made, as well as determination of the presence of comedo necrosis and grade, as these factors are predictive of risk for recurrence. If there is any doubt about the completeness of the excision, a postoperative mammogram is recommended. If the excision has been incomplete, a re-excision can be carried out.

With respect to the need for axillary dissection, retrospective data suggest that the incidence of occult microinvasion and positive nodes relates to the size of the primary lesion. Microinvasion is unlikely in lesions of <5 cm (30), and axillary dissection is not indicated. However, areas of DCIS >5.5 cm are associated with invasion in 48% of patients (31). Most women with such areas of DCIS will require a mastectomy for complete excision. Current guidelines for the management of invasive disease recommend axillary staging. If sentinel node biopsy is to be selected as the approach of choice for axillary staging, consideration should be given to sentinel node biopsy at the time of a mastectomy for extensive DCIS. Axillary staging performed after a mastectomy requires axillary lymph node dissection, as sentinel node biopsy is not feasible. If the final pathology after the mastectomy reveals DCIS only, there is no indication for treatment alterations, regardless of the finding of isolated tumour cells (metastases < 0.2 mm) in the sentinel node, since the excellent prognosis of these patients is unlikely to be improved. Clinicopathologic studies have not demonstrated a relationship between axillary micrometastases (<0.2 cm) and prognosis in pure DCIS (32).

As with invasive disease, there are a number of contraindications for BCS. Patients with large tumours or small breasts may not have a satisfactory cosmetic result and may be better served by a simple mastectomy with the option of breast reconstruction. Also, patients with DCIS >5cm were not included in the EORTC study (9), and only four patients in the NSABP B-17 study had lesions greater than 3 cm (12). In the NSABP B-24 study, only 4% of patients had lesions greater than 2 cm (17). Therefore, the local control rates reported in these studies may not be generalizable to patients with larger lesions. The presence of multiple tumours in the breast and the appearance of extensive microcalcifications are also relative contraindications to breast-conserving therapy.

EBS 1-10 Version 3


Dose and Fractionation Schedule of Breast Irradiation Following Breast-Conserving Surgery Dose/Fractionation schedule

All three randomized trials (9,11-13,16) in DCIS used the same dose, fractionation schedule, 5000 cGy in 25 fractions in five weeks. No randomized trials have compared different dose/fractionation schedules in DCIS. One published study compared two different fractionation regimens in women with resectable invasive breast cancer following lumpectomy. The Ontario Clinical Oncology Group randomized 1,234 women with invasive disease treated with BCS to a course of 5000 cGy in 25 fractions over five weeks or a course of 4250 cGy in 16 fractions over three weeks (33). At a median follow-up of 69 months, the five-year local recurrence-free, disease-free, and overall survival rates were 97.2% versus 96.8% (95% CI, -1.5% to 2.4%), 87.6% versus 91.0% (p=0.37), and 97.8% versus 96.1% (p=0.78) in the 16-fraction versus the 25-fraction arms, respectively. Cosmetic outcome was also comparable, with an excellent or good cosmetic outcome of 76.8% in the 16-fraction arm and 77.4% in the 25-fraction arm (absolute difference, -0.6%; 95% CI, -6.5% to 5.5%). Grade 2 or 3 skin toxicity was 66% in the 16-fraction arm and 60% in the 25-fraction arm (absolute difference, 6%; 95% CI, -0.3% to 10%). Four cases of radiation pneumonitis (two in each arm) and one case of rib fracture (in the 25-fraction arm) occurred. Boost

None of the DCIS studies used an additional ―boost‖ dose to the tumour bed, and no study compared breast radiation alone to breast radiation plus a boost in DCIS. Such studies have, however, been done in patients with invasive breast cancer. There have been four randomized trials in patients with resectable invasive disease, comparing whole breast irradiation to whole breast radiation plus a boost to the tumour bed. Three of these studies were in patients with microscopically clear resection margins, and the fourth included some patients with positive resection margins (34-37). Table 8 summarizes the studies and their results.

Three of the studies showed a statistically significant decrease in local recurrence with the addition of the boost (Table 9). The EORTC ―boost vs. no boost‖ (36) and Lyon trials (35) reported no significant difference in overall survival, and the Nice trial (34) reported no significant difference in cancer-specific survival. The Nice and Lyon trials did not report prognostic factor analyses. In a multivariate analysis, the Budapest boost trial (37) found age < 40 years, positive or close resection margins, and a high mitotic index to be predictive of local recurrence. The EORTC study found young age, a palpable tumour at presentation, and progesterone receptor-negative tumours to be predictive of local recurrence in a multivariate analysis, with ―young age‖ being the strongest predictor. Table 10 provides the five-year actuarial breast recurrence rates by treatment arm and age.

The Lyon, EORTC, and Budapest studies reported cosmetic outcomes. The Lyon study reported no cases of grade 3 telangiectasia and a 5.9% incidence of grade 1 or 2 telangiectasia in the no-boost arm and 12.4% in the boost arm (p=0.003). The physician assessment score was good to excellent in 85% of patients, and the patient self-assessment after two years was good to excellent in 90%, with no significant difference in the treatment arms for these outcomes. In the EORTC study, cosmetic assessment, based on photographs, was done in a subset of 731 patients by a panel (38). A relative breast retraction score was also calculated on 1,141 patients, again based on photographic assessment. A good to excellent score was give to 71% in the boost group and 86% in the no-boost group (p= 0.0001); the breast retraction score was 8.6% and 7.6%, respectively (p=0.04). The Budapest study reported 17.3% grade 2 or 3 late effects, according to the RTOG/EORTC scale, in those who received a boost and 7.8% in those who did not (p=0.03) and a good to excellent overall score of 85.6% in the boost group versus 91.3% in the no-boost group (p=0.14).

EBS 1-10 Version 3


Table 9: Randomized trials of whole breast irradiation versus whole breast irradiation with a boost in women with invasive breast cancer.

Lead author, year (ref).

Trial name

Margin status

Median follow-up (years)

Treatment arms

N

Crude breast recurrence rate (%)

p-value

Five-year breast recurrence rate (%)

p-value

Teissier et al, 1998 (34)

Nice trial Clear 6.1

50Gy/25 whole breast

664

6.8

0.13 NR NA

50Gy/25 whole breast +10Gy/5 boost (electron or proton)

4.3

Romestaing et al, 1997 (35)

Lyon trial Clear 3.3

50Gy/20/5wk whole breast

503 4.0

NR

4.5

0.044

50Gy/20/4wk +10Gy/4 boost (electron)

521 1.9 3.6

Bartelink et al, 2001 (36)

EORTC ―boost vs. no boost‖ trial

Clear 5.1


2,657 6.8

NR

7.3

<0.001

50Gy/25 whole breast +16Gy/8 boost (electron, proton, or implant)

2,661 4.1 4.3

Polgar et al, 2002 (37)

Budapest boost trial

some patients had positive margins

5.3 (min. 3 yrs)


103 15.5

NR

15.1

0.049 50Gy/25 whole breast +16Gy boost (electron or implant)

104 6.7 7.3

Abbreviations: EORTC, European Organization for Research and Treatment of Cancer; N, number of patients.

EBS 1-10 Version 3


Table 10: EORTC five-year actuarial breast recurrence rates by age group at randomization.

Age group Randomized to

no boost (%) Randomized to

boost (%) p-value

≤40 years 19.5 10.2 0.002

41-50 years 9.5 5.8 0.02

51-60 years 4.2 3.4 0.07

>60 years 4.0 2.5 0.14

Abbreviations: EORTC, European Organization for Research and Treatment of Cancer.

Adapted from Bartelink et al (36)

Omission of radiotherapy following breast-conserving surgery in low-risk patients

The two randomized trials (10,14) that analyzed prognostic factors did not identify a subgroup that had the same low recurrence rates with or without radiation. However, the numbers of patients in many of the subgroups were small, and the power to detect clinically meaningful differences or interaction was low. There are no published reports of studies that randomized patients at low risk of local recurrence to observation versus adjuvant radiation to determine if any patients might be treated without adjuvant radiation therapy. A number of non-randomized studies are available that attempt to describe a low-risk population.

In 1995, Silverstein reported on a series of 425 consecutive patients (including a retrospective series of 208 cases reported in 1990 (39)) to which a new pathologic classification (the Van Nuys DCIS classification, described above) was prospectively applied (30). Over the course of the study, non-randomized treatment options included, initially, mastectomy; then, BCS plus adjuvant radiation; and later, BCS alone. The option of follow-up only after BCS with clear margins became available in 1989, and most patients, when presented with this option, accepted it. The study presented results from these historical treatment cohorts with an overall median follow-up of 6.5 years. The disease-free survival at eight years was significantly different among all three groups: Group I (nuclear grade I or II without comedo-type necrosis), 93%; Group II (nuclear grade I or II with comedo-type necrosis), 84% (I vs. II, p=0.05); and Group III (high nuclear grade), 61% (II vs. III, p=0.003). Failures were primarily due to local recurrence. One patient in each of Groups II and III died of breast cancer (p=not stated OR non-

significant?). In 1996, Silverstein et al reported on another prognostic schema, the Van Nuys

Prognostic Index (VNPI) (40). In a cohort of 333 DCIS patients treated with BCS (195 by excision only and 138 by excision plus radiation therapy) at the Breast Centre, Van Nuys and the Children's Hospital, San Francisco, California, three independent risk factors for local recurrence were identified: tumour size (>4.1, 1.6-4.0, <1.5 cm); margin width (<1, 1-9, >10 mm), and the previously described Van Nuys pathologic classification (I, II, and III). Scores of 1 (best) to 3 (worst) were assigned for each of the three predictors and totalled to give an overall VNPI score ranging from 3 to 9. The scoring system was applied to the original cohort, and cut-off points were determined by statistical analysis to identify three separate risk groups: low, VNPI score 3 or 4; intermediate, VNPI score 5 to 7; and high, VNPI score 8 or 9. Table 11 shows the risks for recurrence, with and without radiotherapy following BCS.

EBS 1-10 Version 3


Table 11: Cumulative risk of ipsilateral breast recurrence (invasive and noninvasive) at eight years related to VNPI score.

VNPI Score

No Radiotherapy Radiotherapy

Number at risk

Rate of local recurrence (%)

Number at risk Rate of local

recurrence (%)

3,4 (low) 76 3 25 0 5-7 (intermediate) 106 32 103 15 8,9 (high) 13 100 10 65

Abbreviations: VNPI, Van Nuys Prognostic Index.

The results suggest that patients at a low risk of recurrence do not benefit from adjuvant radiation, those in the intermediate group do benefit, and those in the high-risk group benefit but remain at substantial risk of recurrence.

In 1999, Silverstein et al reported the pathological results for 469 women with DCIS, 213 who received radiotherapy after BCS and 256 who received no further treatment (41). For patients with margins >10 mm, there was no benefit from radiation therapy in terms of rates of recurrence at eight years (RR, 1.14; 95% CI 0.10 to 12.64; p=0.92), and for patients with margins ranging from 1 to <10 mm, there was no reported benefit from radiotherapy (RR, 1.49; 95% CI; 0.76 to 2.90; p=0.24). However, radiation therapy was of significant benefit for patients with margins <1 mm (RR, 2.54; 95% CI, 1.25 to 5.18; p=0.01). Table 12 summarizes the results of this analysis. Table 12: Influence of margin width on local control by patient radiotherapy status.

Margin width

No Radiotherapy Radiotherapy

Relative risk P-value # Patients

# Local recur.

# Patients # Local recur.

≥10mm 93 2 40 1 1.14 (0.10, 12.64) 0.92 1 to <10mm 124 23 100 15 1.49 (0.76, 2.90) 0.24 <1mm 39 13 73 21 2.54 (1.25, 5.18) 0.01 Abbreviations: recur., recurrences.

In 2003, Silverstein updated the prognostic index, based on an analysis of 706 DCIS

patients treated with breast-conserving therapy (42). In this analysis, age was also identified as an independent prognostic factor in the multivariate analysis, along with tumour size, margin width, and pathologic classification. Based on this new scoring system, women with scores of 4, 5, or 6 had no significant difference in 12-year local recurrence-free survival, whether or not they had radiation treatment. Those with scores of 7, 8, or 9 had improved local control rates when treated with radiation. Those with scores of 10, 11, or 12 had improved local control with radiation but still had an unacceptably high local recurrence rate of 50% at five years with BCS and radiation.

All four studies suggest that different risk groups, which require different management strategies, may be identified (30,40-42). The approach is technically demanding, requiring intensive tissue processing to document the size of the lesion and extent of margins. Specimens are resected en bloc, and the whole specimen is submitted for histologic examination. Each of the six margins is inked and the specimen is then serially sectioned at 2 mm to 3 mm intervals. The interpretation of the results was limited because of the non-randomized historical comparisons and small patient subgroups evaluated.

Other recent studies have attempted to identify and treat highly selected patients with BCS only. Several of these studies have demonstrated late recurrence, especially with low-grade lesions after longer follow-up. Lagios et al reported on a prospective series of 79 patients treated with local excision only (43). Patients were given the option of no further therapy if the

EBS 1-10 Version 3


original lesion was detected mammographically and found to be less than 25 mm in size, and postoperative mammograms confirmed no residual microcalcifications. The patients were accrued from 1972 to 1987. In an initial report after 48 months follow-up, a total of eight (10.1%) local recurrences were noted. After 124 months average follow-up, a total of 13 (17%) recurrences had developed, six invasive and seven non-invasive (44). While keeping in mind the limitations of comparisons across studies, in a similar cohort of patients treated with breast irradiation and followed for a similar period, no recurrences were noted in 20 patients (45).

Wong et al (46) reported a single-arm study of wide excision (1 cm) alone in DCIS

patients, grade 1or 2 with mammographic size 2.5 cm. Patients did not receive tamoxifen. The accrual goal was 200, but the study was stopped early with 158 patients accrued, because of a high local failure rate. At a median follow-up of 40 months, the actuarial five-year rate of local failure as first site of failure was 12% (13/158; crude recurrence rate, 8.2%). Nine patients recurred with DCIS and four with invasive disease.

The Radiation Therapy Oncology Group initiated a randomized trial (47) of post-lumpectomy radiation versus observation in patients felt to be at relatively low risk of recurrence with surgery alone (unicentric, non-palpable, <2.5 cm, nuclear grade 1 or 2, with necrosis in <1ducts,margins ≥ 3 mm, clinically node negative, plus or minus tamoxifen). The planned sample size was 1790, but accrual was slower than expected and was stopped in July 2006, after 636 patients had been accrued. Despite the smaller sample size, we should still obtain valuable information from this study as the data matures.

The Institute of Cancer Research in the United Kingdom started a similar study in 2004 with a planned sample size of 2000, accrued over five years. Those study results too will help clarify the role of post-lumpectomy radiation in this low-risk patient population (48) (See Table 13. Ongoing phase III trials). Pathologic Classification of DCIS

Several pathologic DCIS classification systems, based primarily on nuclear grade and/or necrosis, have been proposed to identify lesions more likely to recur or progress to invasive cancer in women treated by BCS (30,49,50). Evidence exists to support the clinical relevance of this approach, showing that high nuclear grade and/or necrosis, particularly extensive comedo necrosis are associated with a higher risk of early local recurrence following BCS (30,31,51). However, no classification system to date has been useful in predicting whether local disease is likely to recur as in situ or invasive carcinoma.

A Breast Health Institute-sponsored panel of experts representing the disciplines of surgical pathology, surgery, breast imaging (radiology), radiation oncology, and biostatistics was convened in 1997 to reach a consensus on the pathologic classification of DCIS (52). Although a single classification system for DCIS was not endorsed at this meeting, the recommendation was that the pathologist should clearly report the nuclear grade of the lesion and the presence or absence of necrosis. If a specific grading system for DCIS is used, this should be stated in the pathology report. The report should also include the architectural patterns present, since this may be clinically important. Studies have shown, for instance, that the micropapillary pattern, when present in pure form, tends to be more extensive (53-55).

The issue of consistency among pathologists in categorizing DCIS has been addressed in a few studies, using the newer classification systems (49,51,56-60). In general, the greatest consistency is achieved using classification systems based primarily on nuclear grade, particularly the Van Nuys scheme. Use of a synoptic report is recommended (52,61). DISCUSSION

In the surgical management of DCIS, the choice between mastectomy and BCS should be dependent upon patient preference and the results of clinical, mammographic, and pathologic evaluation. Mastectomy is indicated for patients at high risk of recurrence with BCS

EBS 1-10 Version 3


and radiation. High-risk factors include large size tumours (>5cm), particularly those with positive margins. While optimal margin widths for patients having BCS and radiation are not specifically known, close lateral margin widths of <1 mm have been associated with higher local

recurrence rates in some studies. Patients with smaller areas of DCIS with resection margins 1 mm or positive resection margins are also at a higher than average risk of recurrence. Mastectomy with the option of reconstruction is also an acceptable choice for women preferring to maximize local control. Given the importance of breast conservation for the patient and the potential for salvage, BCS and radiation is an equally acceptable option for eligible women with DCIS.

There are currently three prospective randomized trials (9-16) that support the routine use of radiation following BCS for patients with DCIS of the breast. Radiation resulted in reduced rates of breast recurrence (both invasive and non-invasive) and mastectomy. Patients should be made aware of the duration of radiation and its toxicity before making a choice between total mastectomy and BCS. All three studies used the dose-fractionation schedules of 5000 cGy in 25 fractions in five weeks, which should be considered the standard; however, the OCOG randomized trial in patients with invasive breast cancer showed that the shorter fractionation schedule of 4250 cGy in 16 fractions was as effective as and no more toxic than 5000 cGY in 25 fractions. We could find no radiobiological evidence to suggest that DCIS responds differently to radiation than invasive disease. The Breast Cancer DSG therefore felt it would be reasonable to offer this shorter fractionation schedule to those women with DCIS who preferred the convenience of a shorter overall treatment time.

None of the randomized studies in DCIS added a boost to the tumour bed. Randomized trials of boost versus no boost in patients with invasive disease (34-37) have shown a decrease in local recurrence rates when a boost of 1000 to 1600 cGy is added, particularly in younger women or those with close or positive resection margins. Some DCIS studies (29,41,62) have shown increased recurrence rates in younger women and those with close resection margins who received standard postoperative whole breast radiation without a boost. The Breast Cancer DSG therefore felt it reasonable to consider the addition of a boost to the tumour bed in those DCIS patients who are felt to be at higher than usual risk of recurrence with standard whole breast radiation alone, provided the patients are willing to accept the possibility of a somewhat poorer cosmetic outcome.

Identifying a group of patients treated with BCS for DCIS who do not require adjuvant radiotherapy is not yet possible. Current data (39-42) suggest that age, tumour size, margin status, grade, and comedo-type necrosis are important predictors for local recurrence. These studies suggest that there may be different risk groups for local failure (e.g., low, intermediate, and high) where different treatments may be more desirable—low risk, BCS alone; moderate risk, BCS plus radiation; and high risk, total mastectomy plus or minus reconstructive surgery. Further evidence is necessary before making firm recommendations and prospective randomized trials looking at this question are ongoing. Until then, it is recommended that pathologic descriptions including assessment of size, margin status, nuclear grade, and evidence of comedo necrosis be reported more consistently. Patients interested in BCS alone should be made aware of what is currently known about the potential benefits and toxicities of post-lumpectomy radiation.

The NSABP-24 study (13,17) showed an overall decrease in invasive and in situ disease with the addition of tamoxifen to surgical excision followed by radiation, but most of the benefit appeared to be in younger women and those with positive or unknown resection margins. The UKCCCR (16) study showed no benefit with the addition of tamoxifen, but the study population consisted mostly of women over 50 years of age with clear resection margins. There was an observed benefit in the subset of women less than 50 years of age and also in those who did not receive radiation. Therefore, the Breast Cancer DSG felt that five years of tamoxifen is an option for DCIS patients, particularly in women less than 50 years of age, those with positive

EBS 1-10 Version 3


resection margins who refuse further surgery, and those who refused or are unable to have radiation but want to avoid mastectomy. Patients and physicians need to consider the potential toxicities of tamoxifen as well as the possible benefits. ONGOING TRIALS

Table 13 lists ongoing randomized trials that were identified through a systematic search of the U.S. National Cancer Institute Clinical Trials Database and that address questions of interest in this systematic review. Additionally, one study of note, identified through a non-systematic search of the database, is the E5194 study, National Library of Medicine (NLM) identifier NCT00002934 (63). This study is a prospective cohort study designed to examine the role of local excision alone in low-risk patients with DCIS characterized by low- or intermediate-grade tumours less than 2.5 cm in size or high-grade tumours less than 1 cm in size that have been resected with greater than 3 mm margins. CONCLUSIONS

Women with DCIS of the breast who are candidates for BCS should be offered the choice of BCS or total mastectomy. Mastectomy with the option for reconstruction remains an acceptable choice for women preferring to maximize local control. Mastectomy, with the option of reconstruction, is recommended for those who have a large enough area of DCIS that BCS would leave the woman with an unacceptable cosmetic result. When BCS is performed, all mammographically suspicious calcifications should be removed, and margins should be microscopically clear of DCIS.

Women with DCIS who have BCS should be offered adjuvant breast irradiation to minimize the risk of recurrent neoplasia. Patients considered to be at relatively low risk of recurrence with surgery alone should be referred to a radiation oncologist for a thorough discussion of what is currently known about the potential benefits and toxicities of radiation in their particular situation.

While there is some evidence to suggest that tamoxifen is effective in the reduction of ipsilateral recurrence and contralateral incidence of neoplasia in women with DCIS, the absolute benefit is small and the evidence is conflicting. Women should be informed of the option of five years of tamoxifen therapy and of the potential toxicities and benefits associated with tamoxifen. Subset analyses of the randomized trials suggest that women who are most likely to have a positive benefit/risk ratio with tamoxifen are those who are less than 50 years of age or have positive or unknown resection margins, and this information can be considered in decision making. Those with positive estrogen-receptor tumours also seem to have the greatest benefit in the subset analysis of one of the studies. Therefore, if tamoxifen is felt to be of benefit for an individual patient, hormone-receptor assessment could be considered in order to aid in the decision regarding tamoxifen treatment. Postmenopausal women who opt for adjuvant tamoxifen should consider participating in the NSABP Trial B-35, comparing tamoxifen to anastrozole after lumpectomy and radiation. CONFLICT OF INTEREST

None of the authors declared any potential or actual conflict of interest. JOURNAL REFERENCE

The 1998 version of this systematic review was published as:

Wright JR, Whelan TJ, McCready DR, O’Malley FP. Management of ductal carcinoma in situ of the breast. Cancer Prev Control. 1998;2(6):312-9.

EBS 1-10 Version 3


ACKNOWLEDGEMENTS

The Breast Cancer DSG would like to thank Dr. Wendy Shelley, Dr. David McCready, Dr. Claire Holloway, Dr. Maureen Trudeau, Ms. Susan Sinclair, and Mr. Hans Messersmith for taking the lead in drafting this systematic review.

For a complete list of the Breast Cancer Disease Site Group members and the Report Approval Panel members, please visit the CCO Web site at http://www.cancercare.on.ca/

Funding

The PEBC is supported by Cancer Care Ontario (CCO) and the Ontario Ministry of Health and Long-Term Care. All work produced by the PEBC is editorially independent from its funding agencies.

Copyright

This evidence-based series is copyrighted by Cancer Care Ontario; the series and the illustrations herein may not be reproduced without the express written permission of Cancer Care Ontario. Cancer Care

Ontario reserves the right at any time, and at its sole discretion, to change or revoke this authorization.

Disclaimer Care has been taken in the preparation of the information contained in this document. Nonetheless, any person seeking to apply or consult the evidence-based series is expected to use independent medical judgment in the context of individual clinical circumstances or seek out the supervision of a qualified


Contact Information







EBS 1-10 Version 3


Table 13. Ongoing phase III trials. Protocol ID and NLM Identifier

First Published

Trial Sponsor Projected Accrual

Purpose

RTOG-9804, NCT00003857 (47)

June 1, 1999

NCI 1,790 within 6 years. Accrual Stopped in July 2006 after 636 patients randomized

Compare the efficacy of whole breast radiotherapy vs. observation with or without optional tamoxifen in decreasing or delaying the appearance of local failure (both invasive and in situ) and preventing the need for mastectomy in women with good-risk ductal carcinoma in situ (DCIS) of the breast.

Compare distant disease-free survival of patients treated with these regimens.

NSABP-B-35, NCT00053898 (64)

January 26, 2003

NCI 1,500 per arm within 5 years, accrual complete

Compare the value of anastrozole vs. tamoxifen, in terms of preventing recurrence (i.e., local, regional, and distant recurrences and contralateral breast cancer), after lumpectomy and radiotherapy in postmenopausal women with ductal carcinoma in situ (DCIS).

Compare subsequent disease occurrence, in terms of invasive breast cancer (local, regional, distant, or contralateral), ipsilateral and contralateral breast cancer (invasive and DCIS), and non-breast second primary malignancies, in patients treated with these drugs.

Compare quality of life and symptoms of patients treated with these drugs.

Compare quality-adjusted survival time of patients treated with these drugs.

Compare the occurrence of osteoporotic fractures in patients treated with these drugs.

Compare disease-free and overall survival of patients treated with these drugs.

CRUK-IBIS-II-DCIS, NCT00072462 (65)

October 25, 2003

Cancer Research UK

4,000 within 4 years

Compare the efficacy of adjuvant tamoxifen vs. anastrozole, in terms of local control and prevention of contralateral disease, in postmenopausal women with locally excised ductal carcinoma in situ.

Compare side effect profiles of these drugs in these patients.

EBS 1-10 Version 3


Protocol ID and NLM Identifier

First Published

Trial Sponsor Projected Accrual

Purpose

NSABP-B-39, NCT00103181 (66)

January 24, 2005

NCI 1,500 per arm within 2 years, 5 months

Primary Compare local tumour control in

women with ductal carcinoma in situ or stage I or II breast cancer treated with adjuvant whole breast vs. partial breast irradiation.

Secondary Compare overall survival, recurrence-

free survival, and distant disease-free survival in patients treated with these regimens.

Compare the cosmetic result in patients treated with these regimens.

Compare fatigue and treatment-related symptoms in patients treated with these regimens.

Compare perceived convenience of care in patients treated with these regimens.

Compare acute and late toxic effects of these regimens in these patients.

96/84 Graham, NCT00138814 (67)

NR St. George Hospital and Community Health Service, Sydney, New South Wales, Australia

NR Compare boost versus no boost radiotherapy. (Patient population includes DCIS if completely excised.)

OCOG-2005-RAPID, NCT00282035 (68)

NR Ontario Clinical Oncology Group

NR Determine if accelerated partial breast irradiation, using 3D CRT, is as effective as whole breast irradiation following BCS in with DCIS or invasive non-metastatic breast cancer.

ICR-DCIS-II, NCT00077168 (48)

January 23, 2004

Institute for Cancer Research, UK

1,000 per arm within 5 years

Primary

Compare ipsilateral tumour relapse and metastases in women with completely excised low-risk hormone receptor-positive DCIS who are receiving adjuvant tamoxifen or anastrozole and treated with adjuvant radiotherapy versus observation.

Compare quality of life. Secondary

Determine minimal surgical margins required to minimize local recurrence.

Identify molecular markers that predict ipsilateral tumour recurrence.

Abbreviations: DCIS, ductal carcinoma in situ; NCI, National Cancer Institute (USA); NR, not reported.

EBS 1-10 Version 3


REFERENCES 1. Harris JR, Lippman ME, Veronesi U, Willett W. Breast cancer (2). N Engl J Med.

1992;327(6):390-8. 2. Ernster VL, Barclay J, Kerlikowske K, Grady D, Henderson C. Incidence of and

treatment for ductal carcinoma in situ of the breast. JAMA. 1996;275(12):913-8. 3. Browman GP, Levine MN, Mohide EA, Hayward RS, Pritchard KI, Gafni A, et al. The

practice guidelines development cycle: a conceptual tool for practice guidelines development and implementation. J Clin Oncol. 1995;13(2):502-12.

4. Wright JR, Whelan TJ, McCready DR, O'Malley FP. Management of ductal carcinoma in situ of the breast. Cancer Prev Control. 1998;2(6):312-9.

5. Fisher ER, Leeming R, Anderson S, Redmond C, Fisher B. Conservative management of intraductal carcinoma (DCIS) of the breast. J Surg Oncol. 1991;47(3):139-47.

6. Fisher B, Anderson S, Redmond CK, Wolmark N, Wickerham DL, Cronin WM. Reanalysis and results after 12 years of follow-up in a randomized clinical trial comparing total mastectomy with lumpectomy with or without irradiation in the treatment of breast cancer. N Engl J Med. 1995;333(22):1456-61.

7. Yin XP, Li XQ, Neuhauser D, Evans JT. Assessment of surgical operations for ductal carcinoma in situ of the breast. Int J Tech Ass Health Care. 1997;3:420-9.

8. Boyages J, Delaney G, Taylor R. Predictors of local recurrence after treatment of ductal carcinoma in situ: a meta-analysis. Cancer. 1999;85(3):616-28.

9. Julien JP, Bijker N, Fentiman IS, Peterse JL, Delledonne V, Rouanet P, et al. Radiotherapy in breast-conserving treatment for ductal carcinoma in situ: first results of the EORTC randomised phase III trial 10853. Lancet. 2000;355(9203):528-33.

10. Bijker N, Peterse JL, Duchateau L, Julien JP, Fentiman IS, Duval C, et al. Risk factors for recurrence and metastasis after breast-conserving therapy for ductal carcinoma-in-situ: analysis of European Organization for Research and Treatment of Cancer Trial 10853. J Clin Oncol. 2001;19(8):2263-71.

11. Fisher B, Costantino J, Redmond C, Fisher E, Margolese R, Dimitrov N, et al. Lumpectomy compared with lumpectomy and radiation therapy for the treatment of intraductal breast cancer. N Engl J Med. 1993;328(22):1581-6.

12. Fisher B, Dignam J, Wolmark N, Mamounas E, Costantino J, Poller W, et al. Lumpectomy and radiation therapy for the treatment of intraductal breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-17. J Clin Oncol. 1998;16(2):441-52.

13. Fisher B, Land S, Mamounas E, Dignam J, Fisher ER, Wolmark N. Prevention of invasive breast cancer in women with ductal carcinoma in situ: an update of the National Surgical Adjuvant Breast and Bowel Project experience. Semin Oncol. 2001;28(4):400-18.

14. Fisher ER, Costantino J, Fisher B, Palekar AS, Redmond C, Mamounas E. Pathologic findings from the National Surgical Adjuvant Breast Project (NSABP) Protocol B-17. Intraductal carcinoma (ductal carcinoma in situ). The National Surgical Adjuvant Breast and Bowel Project Collaborating Investigators. Cancer. 1995;75(6):1310-9.

15. Fisher ER, Dignam J, Tan-Chiu E, Costantino J, Fisher B, Paik S, et al. Pathologic findings from the National Surgical Adjuvant Breast Project (NSABP) eight-year update of Protocol B-17: intraductal carcinoma. Cancer. 1999;86(3):429-38.

16. Houghton J, George WD, Cuzick J, Duggan C, Fentiman IS, Spittle M. Radiotherapy and tamoxifen in women with completely excised ductal carcinoma in situ of the breast in the UK, Australia, and New Zealand: randomised controlled trial. Lancet. 2003;362(9378):95-102.

EBS 1-10 Version 3


17. Fisher B, Dignam J, Wolmark N, Wickerham DL, Fisher ER, Mamounas E, et al. Tamoxifen in treatment of intraductal breast cancer: National Surgical Adjuvant Breast and Bowel Project B-24 randomised controlled trial. Lancet. 1999;353(9169):1993-2000.

18. National Breast Cancer Centre. The clinical management of ductal carcinoma in situ, lobular carcinoma in situ and atypical hyperplasia of the breast [monograph on the internet]. 1st ed. Camperdown (Australia): National Breast Cancer Centre; 2003. Available from: http://www.nbcc.org.au/bestpractice/resources/CMW_dcisbook.pdf

19. National Comprehensive Cancer Network Breast Cancer Panel. Clinical Practice Guidelines in Oncology. Breast Cancer [monograph on the Internet]. Version 2.2006. National Comprehensive Cancer Network; 2005 May 05 [cited 2005 Dec 16]. Available from: http://www.nccn.org/professionals/physician_gls/PDF/breast.pdf

20. The Steering Committee on Clinical Practice Guidelines for the Care and Treatment of Breast Cancer. The management of ductal carcinoma in situ (DCIS). Can Med Assoc J. 1998;158(Suppl 3):S27-S34.

21. Olivotto I, Levine M. Clinical practice guidelines for the care and treatment of breast cancer: the management of ductal carcinoma in situ (summary of the 2001 update). CMAJ. 2001;165(7):912-3.

22. Clinical Oncology Information Network Breast Cancer Working Group. Guidelines on the non-surgical management of breast cancer [monograph on the Internet]. Version 1. Godalming (UK): Springer-Verlag London; 1999 Jun [cited 2005 Dec 19]. Available from: http://www.rcr.ac.uk/docs/oncology/pdf/breast.pdf

23. Scottish Intercollegiate Guideline Network (SIGN). Breast cancer in women: a national clinical guideline recommended for use in Scotland [monograph on the Internet]. Edinburgh (Scotland): Scottish Intercollegiate Guidelines Network (SIGN), Scottish Cancer Therapy Network; 1998 [cited 2005 Dec 19]. Available from: http://www.sign.ac.uk/pdf/sign29.pdf

24. Council of the Royal Australasian College of Surgeons. Guidelines for the surgical management of breast cancer [monograph on the Internet]. Collins JP, Simpson JS, editors. New Zealand Guidelines Group Guideline Library; 1997 Sep 01 [cited 2005 Dec 19]. Available from:

http://www.nzgg.org.nz/guidelines/0082/Surgical_Management_Breast_Cancer.pdf 25. Bijker N, Meijnen PH, Bogaerts J, Peterse JL. Radiotherapy in breast-conserving

treatment for ductal carcinoma in situ (DCIS): ten-year results of European organization for research and treatment of cancer (EORTC) randomized trial 10853 [abstract]. Breast Cancer Res Treat 2005;94 Suppl 1:A7

26. Page DL, Lagios MD. Pathologic analysis of the National Surgical Adjuvant Breast Project (NSABP) B-17 Trial. Unanswered questions remaining unanswered considering current concepts of ductal carcinoma in situ. Cancer. 1995;75(6):1219-22.

27. Allred D, Bryant J, Land S, Paik S, Fisher ER, Julian T, et al. Estrogen receptor expression as a predictive marker of the effectiveness of tamoxifen in the treatment of DCIS: findings from NSABP protocol B-24. Breast Cancer Res Treat. 2002;76(Suppl 1):S36 [A30].

28. Fisher B, Constantino JP, Wickerham DL, Redmond CK, Kavanah M, Cronin WM. Tamoxifen for prevention of breast cancer: report of the national surgical adjuvant breast and bowel project P-1 study. J Natl Cancer Inst. 1998;90(18):1371-88.

29. Solin LJ, Fourquet A, Vicini F, Haffty B, Taylor M, McCormick B, et al. Mammographically detected ductal carcinoma in situ of the breast treated with breast-conserving surgery and definitive breast irradiation: long-term outcome and prognostic significance of patient age and margin status. Int J Radiat Oncol Biol Phys. 2001;50(4):991-1002.

EBS 1-10 Version 3


30. Silverstein MJ, Poller DN, Waisman JR, Colburn WJ, Barth A, Gierson ED, et al. Prognostic classification of breast ductal carcinoma-in-situ. Lancet. 1995;345(8958):1154-7.

31. Lagios MD. Duct carcinoma in situ. Pathology and treatment. Surg Clin North Am. 1990;70(4):853-71.

32. Lara JF, Young SM, Velilla RE, Santoro EJ, Templeton SF. The relevance of occult axillary micrometastasis in ductal carcinoma in situ: a clinicopathologic study with long-term follow-up. Cancer. 2003;98(10):2105-13.

33. Whelan T, MacKenzie R, Julian J, Levine M, Shelley W, Grimard L, et al. Randomized trial of breast irradiation schedules after lumpectomy for women with lymph node-negative breast cancer. J Natl Cancer Inst. 2002;94(15):1143-50.

34. Teissier E, Hery M, Ramaioli A, Lagrange JL, Courdi A, Bensadoun RJ, et al. Boost in conservative treatment: 6 year results of a randomized trial [abstract]. Breast Cancer Res Treat 1998;50:287 [A345]

35. Romestaing P, Lehingue Y, Carrie C, Coquard R, Montbarbon X, Ardiet JM, et al. Role of a 10-Gy boost in the conservative treatment of early breast cancer: results of a randomized clinical trial in Lyon, France. J Clin Oncol. 1997;15(3):963-8.

36. Bartelink H, Horiot JC, Poortmans P, Struikmans H, Van den BW, Barillot I, et al. Recurrence rates after treatment of breast cancer with standard radiotherapy with or without additional radiation. N Engl J Med. 2001;345(19):1378-87.

37. Polgar C, Fodor J, Orosz Z, Major T, Takacsi-Nagy Z, Mangel LC, et al. Electron and high-dose-rate brachytherapy boost in the conservative treatment of stage I-II breast cancer first results of the randomized Budapest boost trial. Strahlenther Onkol. 2002;178(11):615-23.

38. Vrieling C, Collette L, Fourquet A, Hoogenraad WJ, Horiot JC, Jager JJ, et al. The influence of the boost in breast-conserving therapy on cosmetic outcome in the EORTC "boost versus no boost" trial. EORTC Radiotherapy and Breast Cancer Cooperative Groups. European Organization for Research and Treatment of Cancer. Int J Radiat Oncol Biol Phys. 1999;45(3):677-85.

39. Silverstein MJ, Waisman JR, Gamagami P, Gierson ED, Colburn WJ, Rosser RJ, et al. Intraductal carcinoma of the breast (208 cases). Clinical factors influencing treatment choice. Cancer. 1990;66(1):102-8.

40. Silverstein MJ, Lagios MD, Craig PH, Waisman JR, Lewinsky BS, Colburn WJ, et al. A prognostic index for ductal carcinoma in situ of the breast. Cancer. 1996;77(11):2267-74.

41. Silverstein MJ, Lagios MD, Groshen S, Waisman JR, Lewinsky BS, Martino S, et al. The influence of margin width on local control of ductal carcinoma in situ of the breast. N Engl J Med. 1999;340(19):1455-61.

42. Silverstein MJ. The University of Southern California/Van Nuys prognostic index for ductal carcinoma in situ of the breast. Am J Surg. 2003;186:337-43.

43. Lagios MD, Margolin FR, Westdahl PR, Rose MR. Mammographically detected duct carcinoma in situ. Frequency of local recurrence following tylectomy and prognostic effect of nuclear grade on local recurrence. Cancer. 1989;63(4):618-24.

44. Lagios MD. Duct carcinoma in situ: Controversies in diagnosis, biology, and treatment. Breast Journal. 1995;1:66-78.

45. Solin LJ, Kurtz J, Fourquet A, Amalric R, Recht A, Bornstein BA, et al. Fifteen-year results of breast-conserving surgery and definitive breast irradiation for the treatment of ductal carcinoma in situ of the breast. J Clin Oncol. 1996;14(3):754-63.

46. Wong JS, Kaelin CM, Troyan SL, Gadd MA, Gelman R, Lester SC, et al. Prospective study of wide excision alone for ductal carcinoma in situ of the breast. J Clin Oncol. 2006;24(7):1031-6.

EBS 1-10 Version 3


47. PDQ [database on the Internet]. Phase III randomized study of whole breast radiotherapy versus observation with or without optional tamoxifen in women with good-risk ductal carcinoma in situ of the breast. Bethesda (MD): National Cancer Institute; 1999 Jun 01 [cited 2006 Jan 13]. Available from: http://www.cancer.gov/Search/SearchClinicalTrialsAdvanced.aspx

48. PDQ [database on the Internet]. Phase II randomized study of adjuvant radiotherapy versus observation in women with completely excised low-risk estrogen receptor- or progesterone receptor-positive ductal carcinoma in-situ of the breast receiving adjuvant tamoxifen or anastrozole. Bethesda (MD): National Cancer Institute; 2004 Jan 23 [cited 2006 Sep 20]. Available from:

http://www.cancer.gov/Search/SearchClinicalTrialsAdvanced.aspx 49. Holland R, Peterse JL, Millis RR, Eusebi V, Faverly D, van de Vijver MJ, et al. Ductal

carcinoma in situ: a proposal for a new classification. Semin Diagn Pathol. 1994;11(3):167-80.

50. Scott MA, Lagios MD, Axelsson K, Rogers LW, Anderson TJ, Page DL. Ductal carcinoma in situ of the breast: reproducibility of histological subtype analysis. Hum Pathol. 1997;28(8):967-73.

51. Badve S, A'Hern RP, Ward AM, Millis RR, Pinder SE, Ellis IO, et al. Prediction of local recurrence of ductal carcinoma in situ of the breast using five histological classifications: a comparative study with long follow-up. Hum Pathol. 1998;29(9):915-23.

52. Consensus conference on the classification of ductal carcinoma in situ. Hum Pathol. 1997;28(11):1221-5.

53. Patchefsky AS, Schwartz GF, Finkelstein SD, Prestipino A, Sohn SE, Singer JS, et al. Heterogeneity of intraductal carcinoma of the breast. Cancer. 1989;63(4):731-41.

54. Bellamy CO, McDonald C, Salter DM, Chetty U, Anderson TJ. Noninvasive ductal carcinoma of the breast: the relevance of histologic categorization. Hum Pathol. 1993;24(1):16-23.

55. Mack L, Kerkvliet N, Doig G, O'Malley FP. Relationship of a new histological categorization of ductal carcinoma in situ of the breast with size and the immunohistochemical expression of p53, c-erb B2, bcl-2, and ki-67. Hum Pathol. 1997;28(8):974-9.

56. Sloane JP, Amendoeira I, Apostolikas N, Bellocq JP, Bianchi S, Boecker W, et al. Consistency achieved by 23 European pathologists in categorizing ductal carcinoma in situ of the breast using five classifications. European Commission Working Group on Breast Screening Pathology. Hum Pathol. 1998;29(10):1056-62.

57. Douglas-Jones AG, Gupta SK, Attanoos RL, Morgan JM, Mansel RE. A critical appraisal of six modern classifications of ductal carcinoma in situ of the breast (DCIS): correlation with grade of associated invasive carcinoma. Histopathology. 1996;29(5):397-409.

58. Bethwaite P, Smith N, Delahunt B, Kenwright D. Reproducibility of new classification schemes for the pathology of ductal carcinoma in situ of the breast. J Clin Pathol. 1998;51(6):450-4.

59. Wells WA, Carney PA, Eliassen MS, Grove MR, Tosteson AN. Pathologists' agreement with experts and reproducibility of breast ductal carcinoma-in-situ classification schemes. Am J Surg Pathol. 2000;24(5):651-9.

60. Sneige N, Lagios MD, Schwarting R, Colburn W, Atkinson E, Weber D, et al. Interobserver reproducibility of the Lagios nuclear grading system for ductal carcinoma in situ. Hum Pathol. 1999;30(3):257-62.

61. Fitzgibbons PL, Connolly JL, Page DL. Updated protocol for the examination of specimens from patients with carcinomas of the breast. Cancer Committee. Arch Pathol Lab Med. 2000;124(7):1026-33.

EBS 1-10 Version 3


62. Vicini F, Recht A. Age at diagnosis and outcome for women with ductal carcinoma-in-situ of the breast: a critical review of the literature. J Clin Oncol. 2002;20(11):2736-44.

63. PDQ [database on the Internet]. Screening study following local excision in selected patients with ductal carcinoma in situ (DCIS) of the breast. Bethesda (MD): National Cancer Institute; 1997 Mar 01 [cited 2006 Jan 13]. Available from: http://www.cancer.gov/Search/SearchClinicalTrialsAdvanced.aspx

64. PDQ [database on the Internet]. Phase III randomized study of anastrozole versus tamoxifen in postmenopausal women with ductal carcinoma in situ of the breast undergoing lumpectomy and radiotherapy. Bethesda (MD): National Cancer Institute; 2003 Jan 26 [cited 2006 Jan 13]. Available from:

http://www.cancer.gov/Search/SearchClinicalTrialsAdvanced.aspx 65. PDQ [database on the Internet]. Phase III randomized study of adjuvant tamoxifen

versus anastrozole in postmenopausal women with ductal carcinoma in situ. Bethesda (MD): National Cancer Institute; 2004 Jan 20 [cited 2006 Jan 13]. Available from: http://www.cancer.gov/Search/SearchClinicalTrialsAdvanced.aspx

66. PDQ [database on the Internet]. Phase III randomized study of adjuvant whole breast versus partial breast irradiation in women with ductal carcinoma in situ or stage I or II breast cancer. Bethesda (MD): National Cancer Institute; 2005 Jan 24 [cited 2006 Jan 13]. Available from: http://www.cancer.gov/Search/SearchClinicalTrialsAdvanced.aspx

67. PDQ [database on the Internet]. Boost use in breast conservation radiotherapy. Bethesda (MD): National Cancer Institute; 2005 Dec 15 [cited 2006 Jan 13] Available from: http://www.cancer.gov/Search/SearchClinicalTrialsAdvanced.aspx

68. PDQ [database on the Internet]. RAPID: Randomized Trial of Accelerated Partial Breast Irradiation. Bethesda (MD): National Cancer Institute; 2006 Sep 20 [cited 2006 Sep 20]. Available from: http://www.cancer.gov/Search/SearchClinicalTrialsAdvanced.aspx

EBS 1-10 Version 3

DEVELOPMENT & METHODS – page 34


Management of Ductal Carcinoma in Situ of the Breast: Guideline Development and External Review –

Methods and Results

W. Shelley, D. McCready, C. Holloway, M. Trudeau, S. Sinclair, and the members of the Breast Cancer Disease Site Group



Report Date: September 19, 2006 Replaces Original Report dated 1998

THE PROGRAM IN EVIDENCE-BASED CARE

The Program in Evidence-Based Care (PEBC) is an initiative of the Ontario provincial cancer system, Cancer Care Ontario (CCO) (1). The PEBC mandate is to improve the lives of Ontarians affected by cancer, through the development, dissemination, implementation, and evaluation of evidence-based products designed to facilitate clinical, planning, and policy decisions about cancer care.

The PEBC supports a network of disease-specific panels, called Disease Site Groups (DSGs) and Guideline Development Groups (GDGs), mandated to develop the PEBC products. These panels are comprised of clinicians, other health care providers, methodologists, and community representatives from across the province.

The PEBC is well known for producing evidence-based practice guideline reports, using the methods of the Practice Guidelines Development Cycle (1,2). The PEBC reports consist of a comprehensive systematic review of the clinical evidence on a specific cancer care topic, an interpretation of and consensus agreement on that evidence by our DSGs and GDGs, the resulting clinical recommendations, and an external review by Ontario clinicians in the province for whom the topic is relevant. The PEBC has a formal standardized process to ensure the currency of each clinical practice guideline report, through the routine periodic review and evaluation of the scientific literature and, where appropriate, the integration of that literature with the original clinical practice guideline information. The Evidence-based Series: A New Look to the PEBC Practice Guidelines Each Evidence-based Series is comprised of three sections. Section 1: Clinical Practice Guideline. This section contains the clinical recommendations

derived from a systematic review of the clinical and scientific literature and its interpretation by the DSG or GDG involved and a formalized external review by Ontario practitioners.

EBS 1-10 Version 3


Section 2: Systematic Review. This section presents the comprehensive systematic review

of the clinical and scientific research on the topic and the conclusions reached by the DSG or GDG.

Section 3: Guideline Development and External Review: Methods and Results. This section

summarizes the guideline development process and the results of the formal external review by Ontario practitioners of the draft version of the clinical practice guideline and systematic review.

DEVELOPMENT OF THIS EVIDENCE-BASED SERIES Development and Internal Review

This evidence-based series was developed by the Breast Cancer DSG of CCO's PEBC. The series is a convenient and up-to-date source of the best available evidence on the management of ductal carcinoma in situ (DCIS) of the breast, developed through systematic review, evidence synthesis, and input from practitioners in Ontario.

Report Approval Panel

Prior to the submission of this Evidence-based Series report for external review, the report was reviewed and approved by the PEBC Report Approval Panel, which consists of two members, including an oncologist, with expertise in clinical and methodology issues. The Report Approval Panel did not identify any issues of concern and approved the report as submitted to them. External Review by Ontario Clinicians

Following the review and discussion of Sections 1 and 2 of this evidence-based series and review and the approval of the report by the PEBC Report Approval Panel, the Breast Cancer DSG circulated the clinical practice guideline and systematic review to clinicians in Ontario for review and feedback. Box 1 summarizes the draft clinical recommendations and supporting evidence developed by the panel.

BOX 1:

DRAFT RECOMMENDATIONS (approved for external review June 1, 2006) Target Population These recommendations apply to women with DCIS. Recommendations and Key Evidence Surgical Management

Women with DCIS of the breast who are candidates for breast-conserving surgery should be offered the choice of breast-conserving surgery or total mastectomy.

Mastectomy with the option for reconstruction remains an acceptable choice for women preferring to maximize local control.

No randomized trials designed to compare total mastectomy with breast-conserving surgery for DCIS were found. The National Surgical Adjuvant Breast Project (NSABP) B-06 trial (1) involved women with invasive malignancy. However, a small number of women entered were found, on pathology review, to have only DCIS. An analysis based on this subgroup of DCIS patients (2) found a trend towards a much higher local recurrence rate in patients who received breast-conserving surgery alone (9/21; 43%), compared with those who received either breast-conserving surgery plus radiotherapy (2/27; 7%) or mastectomy

EBS 1-10 Version 3


(0/28; 0%). Two meta-analyses (3,4), consisting mainly of non-randomized trials, also demonstrated higher local recurrence in patients treated by breast-conserving surgery alone versus those treated by mastectomy. One reported no significant differences in local recurrence rates between patients treated by breast-conserving surgery followed by radiotherapy and mastectomy, whereas the second showed improved local recurrence rates with mastectomy. The expert opinion of the Breast Cancer DSG is that this non-randomized data supports the recommendation that breast-conserving surgery followed by radiation is an acceptable treatment option, in addition to mastectomy.

Qualifying Statements

When breast-conserving surgery is performed, all mammographically suspicious calcifications should be removed and margins should be microscopically clear of DCIS.

Mastectomy, with the option of reconstruction, is recommended for those women who have an area of DCIS large enough that breast-conserving surgery would leave them with an unacceptable cosmetic result.

Radiotherapy

Women with DCIS who have had breast-conserving surgery should be referred to a radiation oncologist for a discussion regarding the role of radiation in their treatment.

Women with DCIS who have undergone breast-conserving surgery should be offered adjuvant breast irradiation. Women with small (less than 2.5 cm.) grade I or II tumours that are completely resected with resection margins clear

by 3mm should consider participating in the National Cancer Institute of Canada Radiation Therapy Oncology Group (NCIC/RTOG) clinical trial exploring radiation versus wide excision alone.

Three randomized trials (5-12) investigated the role of radiotherapy after breast-conserving surgery in patients with DCIS. In each, the risk of invasive and non-invasive ipsilateral recurrence was reduced with adjuvant radiotherapy. There were no significant differences in distant metastasis or overall survival.

Tamoxifen

While there is some evidence to suggest that tamoxifen is effective in the reduction of ipsilateral recurrence and contralateral incidence in women with DCIS, the absolute benefit is small and the evidence is conflicting.

Women should be informed of the option of five years of tamoxifen therapy and of the potential toxicities and benefits associated with tamoxifen. If post-menopausal women choose to accept adjuvant treatment, they should consider participation in the NSAPB study B-35, comparing tamoxifen to anastrozole following lumpectomy and radiation .

Two trials (9,12,13) investigated the role of tamoxifen versus no tamoxifen in addition to breast-conserving surgery and radiotherapy in the treatment of DCIS. The first demonstrated a significantly lower cumulative incidence of ipsilateral or contralateral breast malignancy for patients in the tamoxifen group versus those in the placebo group. In the second, tamoxifen treatment did not significantly reduce the incidence of either ipsilateral or contralateral breast malignancy.

Qualifying Statement

EBS 1-10 Version 3


In a subset analysis of one of the randomized studies (14), the beneficial effect of tamoxifen was most apparent in the estrogen receptor-positive patients. Therefore, if it is felt that a patient might benefit from tamoxifen for one of the above reasons, hormone receptor assessment could be considered in order to aid in the decision regarding tamoxifen treatment.

Randomized studies suggest that women who are most likely to have a positive benefit/risk ratio with tamoxifen are those who are less than 50 years of age or who have positive resection margins and refuse further surgery. Women who have a contraindication to radiation or who refuse this treatment but still want to avoid mastectomy should also be considered for tamoxifen therapy.

Methods

Feedback was obtained through a mailed survey of 109 practitioners in Ontario, including 54 surgeons, 31 radiation oncologists, and 24 medical oncologists. The survey consisted of items evaluating the methods, results, and interpretive summary used to inform the draft recommendations and whether the draft recommendations should be approved as a practice guideline. Written comments were invited. The survey was mailed out on June 23, 2006. Follow-up reminders were sent at two weeks (post card) and four weeks (complete package mailed again). The authors reviewed the results of the survey. Results

Forty-eight responses were received out of the 109 surveys sent (44.0% response rate). Responses include returned completed surveys as well as phone, fax, and email responses. Of the practitioners who responded, 38 (79.2%) indicated that the report was relevant to their clinical practice, and they completed the survey. Key results of the practitioner feedback survey are summarized in Table 1. Table 1. Responses to eight items on the practitioner feedback survey.

Item

Number (%)

Strongly agree or

agree

Neither agree nor disagree

Strongly disagree or

disagree

The rationale for developing a guideline, as stated in the ―Introduction‖ section of the report, is clear.

94.1% 2.6% 2.6%

There is a need for a guideline on this topic. 97.4% 0% 2.6%

The literature search is relevant and complete. 89.5% 7.9% 2.6%

The results of the trials described in the report are interpreted according to my understanding of the data.

92.1% 5.3% 2.6%

The draft recommendations in the report are clear. 92.1% 2.6% 5.3%

I agree with the draft recommendations as stated. 92.1% 2.6% 5.3%

This report should be approved as a practice guideline. 92.1% 2.6% 5.3%

If this report were to become a practice guideline, how likely would you be to make use of it in your own practice?

Very likely or likely

Unsure Not at all likely or unlikely

94.4% 5.6% 0%

Summary of Written Comments

Five respondents (13.2%) provided substantive written comments. The main points contained in the written comments, with the response of the authors, were:

SUMMARY – One respondent suggested that the recommendation regarding mastectomy and BCS should be modified to stress that no survival benefit has been

EBS 1-10 Version 3


found for either type of surgery. RESPONSE – A statement was added to the key evidence of the recommendation to this effect.

SUMMARY – Two respondents pointed out that the NCIC/RTOG trial was no longer open, and that a recommendation that patients should be enrolled in it was not valid. RESPONSE – This portion of the recommendation was removed. The recommendation regarding radiation was also changed to address the management of those at relatively low risk of recurrence with surgery alone, given that this randomized trial is no longer open to accrual.

SUMMARY – One respondent suggested that the document should strongly recommend the use of post-excision radiographs to rule out residual disease. RESPONSE – The writing committee did not feel that a strong recommendation for the use of post-excision radiographs was necessary. The committee felt that, if current state-of-the-art preoperative and specimen radiography was utilized and the specimen radiograph and microscopic examination was supportive of complete excision, a post-excision radiograph was not necessary. The committee felt that the sentence under the Technical Factors section on page 14, which reads, ―If there is any doubt about the completeness of excision, a postoperative mammogram is recommended.‖ was sufficient. No change was made to the document, based on this comment.

SUMMARY – One respondent stated that prescriptive recommendations with respect to the available trial were questionable, and the data supporting no ―XRT‖ was soft. RESPONSE – As above for the comments regarding the closure of this study.

SUMMARY – One respondent asked whether there was any data on compliance in the Tamoxifen studies. RESPONSE – Data on compliance was included in the relevant section of the Systematic Review.

Funding The PEBC is supported by Cancer Care Ontario (CCO) and the Ontario Ministry of Health and Long-Term

Care. All work produced by the PEBC is editorially independent from its funding agencies.

Copyright This evidence-based series is copyrighted by Cancer Care Ontario; the series and the illustrations herein

may not be reproduced without the express written permission of Cancer Care Ontario. Cancer Care Ontario reserves the right at any time, and at its sole discretion, to change or revoke this authorization.

Disclaimer

Care has been taken in the preparation of the information contained in this document. Nonetheless, any person seeking to apply or consult the evidence-based series is expected to use independent medical judgment in the context of individual clinical circumstances or seek out the supervision of a qualified


Contact Information







EBS 1-10 Version 3


REFERENCES

1. Browman GP, Levine MN, Mohide EA, Hayward RSA, Pritchard KI, Gafni A, et al. The practice guidelines development cycle: a conceptual tool for practice guidelines development and implementation. J Clin Oncol. 1995;13:502-12.

2. Browman GP, Newman TE, Mohide EA, Graham ID, Levine MN, Pritchard KI, et al. Progress of clinical oncology guidelines development using the practice guidelines development cycle: the role of practitioner feedback. J Clin Oncol. 1998;16(3):1226-31.

EBS 1-10 Version 3

DOCUMENT ASSESSMENT AND REVIEW – page 40

Evidence-Based Series 1-10 Version 3: Section 4

Management of Ductal Carcinoma in Situ of the Breast

Guideline Review Summary

A. Eisen, E. Rakovitch, C. Walker-Dilks, and Members of the Expert Panel on Management of

Ductal Carcinoma in Situ of the Breast

January 31, 2018

The 2006 guideline recommendations are

ENDORSED

This means that the recommendations are still current and relevant for

decision making

The original version of this guidance document was released by Cancer Care Ontario’s Program in Evidence-based Care in 1998, and updated in 2006.

In March 2016, this document was assessed in accordance with the PEBC Document Assessment and Review Protocol and was determined to require a review. As part of the review, a PEBC methodologist (CWD) conducted an updated search of the literature. Two clinical experts (AE and ER) reviewed and interpreted the new eligible evidence and proposed the existing recommendations could be endorsed, with the addition of new qualifying statements. An expert panel (See Appendix 1 for membership) endorsed the recommendations found in Section 1 (Clinical Practice Guideline) on January 31, 2018. DOCUMENT ASSESSMENT AND REVIEW RESULTS Questions Considered

1. What is the optimal surgical management of ductal carcinoma in situ (DCIS) of the breast?

2. Should breast irradiation be offered to women with DCIS, following breast-conserving surgery (defined as excision of the tumour with microscopically clear resection margins)?

3. Are there patients who could be spared breast irradiation post–breast-conserving surgery for DCIS?

4. What is the role of tamoxifen in the management of DCIS?

EBS 1-10 Version 3


Literature Search and New Evidence The literature search strategy is shown in Appendix 2. The updated search (2006 to June 2017) yielded 9 practice guidelines, 16 systematic reviews, and 18 reports of 9 RCTs. An additional search for ongoing studies on Clinicaltrials.gov and the WHO International Clinical Trials Registry Platform yielded 12 potentially relevant ongoing clinical trials. The evidence is summarized below in Tables 1 to 4. Impact on the Guideline and Its Recommendations

The new evidence essentially supports the existing recommendations. No changes to treatment of DCIS are proposed and the main messages of the guideline remain the same. The evidence suggests that more details can be included regarding fractionation schedule and margins. Furthermore, oncotype and molecular profiling should be mentioned despite the lack of mature evidence available on this issue. Aromatase inhibitors are also becoming a potential treatment option. The clinical experts proposed that the existing recommendations should be endorsed, with accompanying statements to clarify the above mentioned aspects of DCIS management.

With respect to surgical margins, the original recommendations stated that in women for whom breast-conserving surgery is performed, all mammographically suspicious calcifications should be removed and margins should be microscopically clear of DCIS. A recent joint guideline from the Society of Surgical Oncology (SSO), American Society of Radiation Oncology (ASTRO), and the American Society of Clinical Oncology (ASCO) provided more specific guidance about margin width and recommended that margins of at least 2 mm reduce the risk of local recurrence (1). The SSO-ASTRO-ASCO guideline was based on a meta-analysis of 20 studies (2). A qualifying statement was added to Section 1 of this guideline to highlight the new guidance on margin width.

The original guideline indicated that identifying a group of patients treated with BCS for DCIS who do not require adjuvant radiotherapy was not yet possible. The use of biomarkers in guiding targeted therapy is increasing, and may improve the identification of women with a low risk of local recurrence after BCS who derive a small benefit from RT (3-5).

A 2015 meta-analysis compared hypofractionation versus standard RT and boost versus no boost in women with DCIS (6). No statistically significant benefit was observed for hypofractionation; in women with positive margins, boost RT reduced the risk for local recurrence. A European guideline indicated a need for further evidence to support hypofractionation or boost RT (7). However, a retrospective analysis of pooled individual patient data found a reduction in local recurrence rates with boost (8). Furthermore, the results of a trial comparing hypofractionation with conventional fractionation with or without boost RT (TROG) are pending. A qualifying statement was added to Section 1 of this guideline.

Since 2006, mature data have emerged that strengthen the recommendation on the use of tamoxifen (9-14). Furthermore, early evidence points to aromatase inhibitors as a potential treatment option (15-17). Qualifying statements have been added to Section 1 of this guideline.

The Breast Cancer DSG ENDORSED the 2006 recommendations (with additional qualifying statements) on the management of DCIS.

EBS 1-10 Version 3


Document Review Tool

Number and Title of Document

under Review

1-10 Management of Ductal Carcinoma in Situ of the Breast

Original Report Date September 19, 2006

Date Assessed (by DSG or

Clinical Program Chairs)

March 23, 2016

Health Research Methodologist Cindy Walker-Dilks

Clinical Expert Dr. Andrea Eisen and Dr. Eileen Rakovitch

Approval Date and Review

Outcome (once completed)

ENDORSE

January 31, 2018

Original Question(s):

1. What is the optimal surgical management of ductal carcinoma in situ (DCIS) of the breast?

2. Should breast irradiation be offered to women with DCIS, following breast-conserving surgery (defined as excision of the tumour with microscopically clear resection margins)?

3. Are there patients who could be spared breast irradiation post–breast-conserving surgery for DCIS?

4. What is the role of tamoxifen in the management of DCIS?

Target Population:

Women with DCIS.

Study Selection Criteria:

Inclusion Criteria: Articles were selected for inclusion in this systematic review of the evidence if they met the following criteria:

The management of DCIS of the breast was evaluated using a randomized controlled trial or a meta-analysis of non-randomized and/or randomized trials.

Reported outcomes included overall or disease-free survival, local recurrence (invasive or non-invasive), breast conservation, distant recurrence, toxicity, or quality of life.

Clinical trial results were reported in full papers or abstracts. Although data presented in meeting abstracts may not be as reliable and complete as that from papers published in peer-reviewed journals, abstracts can be a source of important evidence

EBS 1-10 Version 3


from randomized trials and add to the evidence available from fully published studies. These data often appear first in meeting abstracts and may not be published for several years.

Evidence-based clinical practice guidelines addressing this topic were also eligible for inclusion.

Exclusion Criteria: Articles were excluded for the following reasons:

Trial results were published in a language other than English.

Publication occurred prior to 1983. Because our understanding of DCIS biology has evolved substantially since the maturation of screening mammography, trials published prior to this date are not relevant to current clinical practice.

Search Details:

2006 to June 2017 (MEDLINE and EMBASE)

Cochrane Database of Systematic Reviews

Clinical practice guideline providers: National Guideline Clearinghouse, SAGE, NICE, SIGN, CMA, AHRQ

ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform

Summary of new evidence:

Of 1189 total hits from MEDLINE and EMBASE + 22 hits from clinical practice guideline providers, 9 practice guidelines, 16 systematic reviews, and 18 reports of 9 RCTs were included. 12 ongoing trials were identified. Clinical Expert Interest Declaration:

Dr. Eisen and Dr. Rakovitch both reported that they received research funding from Genomic

Health.

1. Does any of the newly identified

evidence contradict the current

recommendations? (i.e., the current

recommendations may cause harm or

lead to unnecessary or improper

treatment if followed)

No

2. Does the newly identified evidence

support the existing

recommendations?

Yes

EBS 1-10 Version 3


3. Do the current recommendations

cover all relevant subjects addressed

by the evidence? (i.e., no new

recommendations are necessary)

Yes

Review Outcome as

recommended by the

Clinical Expert

ENDORSE

If outcome is UPDATE,

are you aware of trials

now underway (not yet

published) that could

affect the

recommendations?

N/A

DSG/Expert Panel

Commentary

EBS 1-10 Version 3


Evidence Tables Table 1. Summary of Relevant Guidelines

Citation (ref) Search dates Recommendations

National Institute for Health and Care Excellence (NICE) 2009 (18)

Varies depending on search topic. Searches run from databases’ inception to 2006 to 2008. This guideline was reviewed in 2015 and will be updated.

Surgery Recommendations • For all patients treated with breast conserving surgery for DCIS a minimum of 2 mm radial margin of excision is recommended with pathological examination to NHSBSP reporting standards. Re-excision should be considered if the margin is less than 2 mm after discussion of the risks and benefits with the patient. • Enter patients with screen-detected DCIS into the Sloane Project (UK DCIS audit). • All breast units should audit their recurrence rates after treatment for DCIS. Qualifying statement: The evidence from observational studies shows that there is no single size of clear margin that is the optimum for reduced local recurrence rate. These recommendations are based on GDG consensus. Recommendations • Do not perform SLNB routinely in patients with a preoperative diagnosis of DCIS who are having breast conserving surgery, unless they are considered to be at a high risk of invasive disease. Qualifying statement: There was insufficient evidence to support the routine use of SLNB in patients with DCIS. There was GDG consensus that patients at a high risk of having unsuspected invasive disease would benefit from SLNB. • Offer SLNB to all patients who are having a mastectomy for DCIS. Qualifying statement: This recommendation was based on GDG consensus. Adjuvant Systemic Therapy Recommendation • Do not offer adjuvant tamoxifen after breast conserving surgery to patients with DCIS. Qualifying statement: There is conflicting evidence to support the use of tamoxifen in reducing local recurrence particularly when surgery is adequate (although the GDG recognises that there is a small reduction in the incidence of contralateral breast cancers).

EBS 1-10 Version 3



Adjuvant Radiotherapy Recommendation • Offer adjuvant radiotherapy to patients with DCIS following adequate breast conserving surgery and discuss with them the potential benefits and risks. Qualifying statement: There is good quality randomised controlled trial evidence that radiotherapy reduces absolute risk of further recurrence. There was GDG consensus that there may be a subgroup of patients with DCIS who have a low risk of recurrence and thus for whom the addition of radiotherapy may not be justified, namely patients with small and low grade DCIS.

Scottish Intercollegiate Guidelines Network (SIGN) 2013 (19)

2003 to 2011 Surgery • Women with DCIS who are undergoing breast surgery should be offered the choice of breast conservation surgery or mastectomy. • In women with DCIS undergoing conservation surgery the radial margins must be clear (≥1 mm). Radiotherapy • All patients with ductal carcinoma in situ should be considered for breast radiotherapy following breast conservation surgery.

Alberta Health Services 2015 (20)

Database inception to 2008, with updates to 2015

Adjuvant RT for patients with DCIS BCS • Adjuvant whole breast radiotherapy (WBRT) recommended Partial breast RT investigational as part of clinical trial if available • For positive margins (ink on margin), re-excision recommended (close margin at fascia is an exception) Pathologic/radiologic correlation required with margin width less than 2 mm; re-excision may be considered if there is discordance and based on individual case details For close margins not treated with re-excision, the role of RT boost is not well defined Mastectomy • No adjuvant RT recommended, even if resection margins close. Adjuvant RT can be considered when margin positive but benefit not defined

Visvanathan 2013 American Society of Clinical Oncology (9)

From the June 2007 update through June 2012.

Tamoxifen Recommendation • Tamoxifen (20 mg per day orally for 5 years) should be discussed as an option to reduce

EBS 1-10 Version 3



the risk of invasive breast cancer, specifically ER-positive breast cancer, in premenopausal women who are age ≥35 years with a 5-year projected absolute breast cancer risk ≥1.66%, according to the NCI Breast Cancer Risk Assessment Tool (or equivalent measures), or with lobular carcinoma in situ (LCIS). Agent indication: FDA approved for the treatment of metastatic breast cancer and adjuvant treatment of breast cancer and to reduce the risk of invasive breast cancer in premenopausal or postmenopausal women with DCIS and/or women at high risk of developing breast cancer.

Biganzoli 2012 International Society of Geriatric Oncology (SIOG) and European Society of Breast Cancer Specialists (EUSOMA) (21)

Consensus process; no lit search details

• There are no strong data available for treatment of older women with DCIS. Healthy older women with localized DCIS should be considered for BCS and postoperative RT.

Moran 2014 Society of Surgical Oncology-American Society for Radiation Oncology (22)


Question: What is the absolute increase in risk of ipsilateral breast tumor recurrence (IBTR) with a positive margin? Can the use of radiation boost, systemic therapy, or favorable tumor biology mitigate this increased risk? Recommendation • Positive margins, defined as ink on invasive cancer or DCIS, are associated with at least a two-fold increase in IBTR. This increased risk in IBTR is not nullified by: delivery of a boost, delivery of systemic therapy (endocrine therapy, chemotherapy, biologic therapy), or favorable biology Question: What is the significance of an extensive intraductal component (EIC) in the tumor specimen, and how does this pertain to margin width? Recommendation • An EIC identifies patients who may have a large residual DCIS burden after lumpectomy. There is no evidence of an association between increased risk of IBTR when margins are negative

Morrow 2016 Society of Surgical

MEDLINE, EMBASE, and evidence-based

Positive margins Question: Are positive margins associated with an increased risk of ipsilateral breast

EBS 1-10 Version 3



Oncology-American Society for Radiation Oncology-American Society of Clinical Oncology (1)

databases (up to Oct 2014). Based on the Marinovich 2016 meta-analysis.

tumour recurrence (IBTR)? Can the use of whole breast radiotherapy (WBRT) mitigate this increased risk? Recommendation • A positive margin, defined as ink on DCIS, is associated with a significant increase in IBTR. This increase risk is not nullified by the use of WBRT. Negative margin widths Question: What margin width minimizes the risk of IBTR in patients receiving WBRT? Recommendation • Margins of at least 2 mm are associated with a reduced risk of IBTR relative to narrower negative margin widths in patients receiving WBRT. The routine practice of obtaining negative margin widths wider than 2 mm is not supported by the evidence. Treatment with excision alone Question: Is treatment with excision alone and widely clear margins equivalent to treatment with excision and WBRT? Recommendation • Treatment with excision alone, regardless of margin width, is associated with substantially higher rates of IBTR than treatment with excision and WBRT, even in predefined low-risk patients. The optimal margin width for treatment with excision alone is unknown, but should be at least 2 mm. Some evidence suggests lower rates of IBTR with margin widths wider than 2 mm. Endocrine therapy Question: What are the effects of endocrine therapy on IBTR? Is the benefit of endocrine therapy associated with negative margin width? Recommendation • Rates of IBTR are reduced with endocrine therapy, but there is no evidence of an association between endocrine therapy and negative margin width. Patient and tumour features Question: Should margin widths greater than 2 mm be considered in the presence of unfavorable

EBS 1-10 Version 3



factors such as comedonecrosis, high grade, large size of DCIS, young patient age, negative ER status, or high risk multigene panel scores? Recommendation • Multiple factors have been shown to be associated with the risk of IBTR in patients treated with and without WBRT, but there are no data addressing whether margin widths should be influenced by these factors. Radiation delivery Question: Should margin width be taken into consideration when determining WBRT delivery technique? Recommendation • Choice of WBRT delivery technique, fractionation, and boost dose should not be dependent upon negative margin width. There is insufficient evidence to address optimal margin widths for accelerated partial breast irradiation. DCIS in the presence of invasive cancer Question: Should DCIS with microinvasion be considered as invasive carcinoma or DCIS when determining optimal margin width? Recommendation • DCIS with microinvasion, defined as no invasive focus >1 mm in size, should be considered as DCIS when considering the optimal margin width.

Souchon 2014 German Society of Radiation Oncology (DEGRO) (7)

2008 to 2012 Surgery • Complete resection should be achieved. Simple mastectomy and BCS with adjuvant RT are both effective to achieve local control. • Mastectomy should be considered in patients with large lesions or positive margins after re-excision. • SLN excision is considered unnecessary. • Diagnostic axillary lymph node excision is considered unnecessary. • The optimal minimal tumour-free margin width has not been ultimately defined. Systemic treatment

EBS 1-10 Version 3



• Chemotherapy is not part of DCIS management. • No mature data available on the effectiveness of aromatase inhibitors. • Trastuzumab in addition to RT in HER2-positive patients with DCIS is being investigated. RT • Patients of all ages with all clinical and histological subtypes of DCIS benefit from BCS followed by whole breast irradiation (WBI). WBI should be confined to the breast tissue without encompassing thoracic wall and regional lymphatics. • Boost irradiation is not recommended at this time. Further evidence is needed to investigate a possible benefit of boost in younger women. • The role of hypofractionation in DCIS is unclear. • The use of accelerated partial breast irradiation (APBI) is discouraged outside of clinical trials.

Kaufman 2015 ACR Appropriateness Criteria® (23)


• Breast conservation therapy (consisting of breast-conserving surgery to achieve negative margins, followed by adjuvant radiation therapy to the whole breast) is an acceptable treatment alternative to mastectomy for women with localized ductal carcinoma in situ (DCIS) wishing to conserve their breast. • In selected older patients with fully excised, low-grade disease, observation may be considered after conservative surgery. • When a mastectomy is desired or required, most surgeons will simultaneously perform a sentinel lymph node biopsy. • Conventionally fractionated whole-breast radiation for DCIS consists of 45-50.4 Gy in 25-28 fractions, with or without a boost to the tumor bed. • Although there are currently no phase III data to support the use of a boost in DCIS, most radiation oncologists will deliver a boost dose of 10-16 Gy, depending on patient age and margin status. • Partial breast irradiation may be used in appropriately selected patients but should be delivered on protocol. • Tamoxifen should be considered in estrogen receptor-positive patients with DCIS. • DCIS with microinvasion is managed similarly to DCIS, except that SLNB is often used and regional nodal radiation therapy may be considered in selected cases. • Hypofractionated whole-breast radiation for DCIS is being investigated in ongoing phase III studies, but it may be considered in appropriately selected patients.

EBS 1-10 Version 3



• The use of MRI for DCIS remains unclear but may be considered in selected patients for whom there are concerns regarding additional disease that would alter the planned management.

Table 2. Summary of Relevant Systematic Reviews

Citation (ref) Search details Inclusion criteria Intervention/comparison Results Included studies

Overviews

Virnig 2009 (24)

MEDLINE, Scirus, Cochrane databases, Web sites of the Sloane Project and of the International Breast Cancer Screening Network 1965 to 2009.

As a state-of-the-science report, studies were not excluded by level of evidence. Studies of invasive breast cancer only, non-breast ductal cancers were excluded. Question 4: In Patients With DCIS, What Is the Impact of Surgery, Radiation, and Systemic Treatment on Outcomes?

BCS + RT vs BCS

Addition of RT to BCS was associated with a reduction of local DCIS or invasive carcinoma recurrence of 45% to 55%; no effect on br ca mortality or all-cause mortality.

EORTC 10853 (Bijker 2006) SweDCIS (Holmberg 2008) NSABP B-17 (Fisher 1993, 2001)

BCS + RT + Tam vs BCS + RT Tamoxifen was associated with a 50% reduction in contralateral disease and of br ca mortality but no effect on all-cause mortality.

UKCCCR ANZ (Houghton 2003) NSABP B-24 (Fisher 2001)

No RCTs comparing mast with BCS or BCS + RT

Observational studies show women having mast less likely than women having BCS or BCS + RT to experience local DCIS or invasive recurrence.

Kane 2010 (25) Same as Virnig, 1965 to 2009.

Same as Virnig. BCS + RT vs BCS Br ca mort: Effect 1.09 (95% CI 0.67 to 1.79 Overall mort: Effect 0.96 (95% CI 0.77 to 1.20)

EORTC 10853 (Bijker 2006) SweDCIS (Holmberg 2008) NSABP B-17 (Fisher 1999,

EBS 1-10 Version 3



2001)

BCS + RT + Tam vs BCS + RT Br ca mort: Effect 0.50 (95% CI 0.17 to 1.46) Overall mort: Effect: 0.95 (95% CI 0.63 to 1.44)

NSABP B-24 (Fisher2001)

Petrelli 2011 (26) MEDLINE (1975 to 2007) Retrospective and prospective studies and meta-analyses

RCTs: BCS + RT vs BCS BCS + RT + Tam vs BCS + RT

Local recurrence: BCS + RT vs BCS alone: NSABP-B17 RR 0.43 EORTC RR 0.53 SweDCIS RR 0.33 RT + Tam vs RT NSABP B-24 RR 0.69 RT +/- Tam vs no RT UKCCCR RR 0.38 RT + Tam vs RT alone UKCCCR RR 0.69

EORTC 10853 (Julien 2000, Bijker 2006) SweDCIS (Emdin 2006, Ringberg 2007) NSABP B-17 (Fisher 1993, 1999, 2001) UKCCCR ANZ (Houghton 2003) NSABP B-24 (Fisher 1999, Fisher 2001)

Stuart 2015 (10)

MEDLINE, Evidence-Based Medicine Reviews databases and hand-searching up to August 2013. Individual patient data from 26 studies (including 4 RCTs)

(1) all patients had pure DCIS, with no evidence of invasion or nodal involvement; (2) had a minimum median or mean follow-up of 10 years, (3) provided descriptions and proportions by surgery-type; (4) ipsilateral local recurrence (LR) (breast or chest wall) was a minimum reported outcome; (5) outcome data (LR and breast cancer deaths) were documented in relation to surgery-type, and RT delivery for BCS; and (6) minimum of five eligible patients per study were reported.

Treatments: Mastectomy BCS + RT (+/- Tam) BCS w/o RT (+/- Tam) Biopsy only

Total local recurrence rate (10-y adjusted meta-regression): Mast 2.6% BCS + RT 13.6% BCS 25.5% Biopsy only 27.8% Mast vs each of the other groups (P<0.0001) Among patients receiving conservation surgery Local recurrence: BCS + RT + Tam 9.7% BCS + RT 14.1% BCS + Tam 24.7% BCS 25.1% BCS + RT vs BCS alone (P<0.0001)

4 RCTs included NSABP B-17 (Fisher 2001) EORTC 10853 (Bijker 2006) UKCCCR ANZ (Cuzick 2011) NSABP B-17 & B-24 (Wapnir 2011)

EBS 1-10 Version 3



Invasive local recurrence: BCS + RT + Tam 4.7% BCS + RT 7.2% BCS + Tam 11.0% BCS 11.3% BCS vs BCS + RT (P<0.0001) BCS vs BCS + RT + Tam (P<0.0001) Meta-regression analysis of br ca death rate at 10 years was similar for the Mast, BCS + RT and BCS patients (1.3% to 2.0%) but not statistically significantly different from biopsy only (2.7%) (P=0.0685)

King 2017 (27) MEDLINE, PsycInfo, CINAHL, EMBASE, and Scopus (up to Nov 2015), reference lists, and experts in the field.

Studies of women with DCIS that described patient-reported outcomes (PROs) by direct patient report (qualitative studies) or quantitative studies of ≥10 patients that performed a regression analysis, described PROs cross-sectionally or longitudinally, and PROs were collected with a self-reported questionnaire.

Psychological morbidity: 6 studies; mixed results. Risk perceptions: 5 studies; persistent, exaggerated risk of death perceptions in women with DCIS. Health-related quality of life: 9 studies; mixed results, but tendency for women to have poor HRQOL scores initially and improved scores in the longer term. Sexuality and body image: 6 studies; sexual problems were related to worse body image, surgical side effects, and more depression.

4 qualitative studies and 19 quantitative studies were included. Reporting only quantitative studies.

RT

Viani 2007 (28) MEDLINE 1966 to 2006, RCTs comparing adjuvant Adjuvant RT vs no RT Overall mort EORTC 10853 (Julien

EBS 1-10 Version 3



Cancerlit 1998 to 2006, ASCO conference proceedings, and manual searches.

RT with BCS in women with primary diagnosis of DCIS.

OR 1.08 (95% CI 0.65 to 1.78)

2000) SweDCIS (Emdin 2006) NSABP B-17 (Fisher 1993) UKCCCR ANZ (Houghton 2003)

Ipsilateral DCIS recurrence OR 0.40 (95% CI 0.31 to 0.53)

EORTC 10853 (Julien 2000) SweDCIS (Emdin 2006) NSABP B-17 (Fisher 1993) UKCCCR ANZ (Houghton 2003)

Ipsilateral invasive br ca recurrence OR 0.45 (95% CI 0.33 to 0.60)


Distant metastases OR 1.04 (95% CI 0.57 to 1.91)

EORTC 10853 (Julien 2000) SweDCIS (Emdin 2006) NSABP B-17 (Fisher 1993)

Contralateral br ca recurrence OR 1.53 (95% CI 1.05 to 2.24)


Polgar 2008 (29) MEDLINE 1975 to 2007. Not described. Retrospective and prospective trials and meta-analyses included.

Adjuvant RT vs no RT (no meta-analysis)

12 y local recurrence: 15.7% vs 31.7%, p<0.000005 12 y OS: 87% vs 86%

NSABP B-17 (Fisher 1993, Fisher [Cancer] 1999, Fisher 2001)

10 y local recurrence: 15% vs 26%, p<0.0001 10 y OS: 95% vs 95%

EORTC 10853 (Julien 2000, Bijker 2001, Bijker 2006)

5 y local recurrence: 7% vs 22%, p<0.0001

SweDCIS (Emdin 2006, Ringberg 2007)

RT vs no RT 4.4 y local recurrence: 5.6% vs 13.6%, p<0.0001

UKCCCR ANZ (Houghton 2003)

Tam vs no Tam 4.4 y local recurrence: 12.8% vs 14.6%, p=NS

UKCCCR ANZ (Houghton 2003)

EBS 1-10 Version 3



RT + Tam vs RT 7 y local recurrence: 7.7% vs 11.1%, p=0.02 7 y OS: 95% vs 95%

NSABP B-24 (Fisher [Lancet] 1999, Fisher 2001)

EBCTCG 2010 (30) Central review of RCTs in early br ca every 5 years since 1985. Individual patient data of trials with results up to Sep 2006.

BCS + RT vs BCS Any ipsilateral event at 5 y: 7.6% vs 18.1% Any ipsilateral event at 10 y: 12.9% vs 28.1% Rate ratio 0.46, P<0.00001 RT effective regardless of age, local excision, or tamoxifen

EORTC 10853 (Julian 2000, Bijker 2001 [Br J Ca]), Bijker 2001 [JCO], Bijker 2006) SweDCIS (Emdin 2006, Ringberg 2007, Holmberg 2008) NSABP B-17 (Fisher 1993, Fisher 1998, Fisher 1999) UKCCCR ANZ (Houghton 2003)

Goodwin 2013 (31) Cochrane Br Ca Group Specialised Register, MEDLINE, EMBASE, WHO International Clinical Trials Registry (to 2011), Cochrane Central Register (2008); St. Gallen, ASCO, and ESMO conference proceedings.

Any trial in which RT was the primary treatment comparison after BCS in women with 1st time DCIS.

BCS + RT vs BCS All ipsilateral recurrence: HR 0.49 (95% CI 0.41 to 0.58)

EORTC 10853 (Bijker 2006) SweDCIS (Holmberg 2008) NSABP B-17 (Fisher 2001) UKCCCR ANZ (Houghton 2003)

Ipsilateral invasive recurrence: HR 0.50 (95% CI 0.32 to 0.76)

NSABP B-17 (Fisher 2001) UKCCCR (Houghton 2003)

Ipsilateral DCIS recurrence: 0.61 (95% CI 0.39 to 0.95)

NSABP B-17 (Fisher 2001) UKCCCR ANZ (Houghton 2003)

Skandarajah 2013 (32) MEDLINE (1965 to 2011). Studies investigating RT in breast conservation in women with DCIS. Minimum level 2 evidence.

BCS + RT vs BCS Ipsilateral new events: 13% vs 32%, HR 0.41, P<0.0001

UKCCCR ANZ (Cuzick 2011)

Ipsilateral new events: 13% vs 31%

NSABP B-17 (Fisher 1999)

Ipsilateral new events: 15% vs 26%

EORTC 10853 (Bijker 2006 [JCO], Bijker 2002 [Br J Ca])

Ipsilateral new events: 7% vs 22%, HR 0.33, (95% CI

SweDCIS (Emdin 2006)

EBS 1-10 Version 3



0.24 to 0.47, P<0.0001)

Dunne 2009 (33) MEDLINE, EMBASE, Cochrane Central Register (up to 2007).

Randomized and nonrandomized trials and prospective and retrospective series of patients with DCIS treated with BCS and RT.

Ipsilateral breast tumour recurrence (IBTR) for differing margin status when compared with a negative margin. BCS + RT

IBTR for negative vs positive margins: 20 studies; OR 0.36 (95% CI 0.27 to 0.47) IBTR for negative vs closed margins: 7 studies; OR 0.59 (95% CI 0.42 to 0.83) IBTR for negative vs unknown margins: 13 studies; OR 0.56 (95% CI 0.36 to 0.87)

22 trials (n=4660; 806 from RCTs)

Wang 2012 (34) PubMed (1970 to 2010). RCTs and observational studies with >100 patients with DCIS. Ipsilateral breast tumour recurrence had to be reported separately for women treated with BCS alone and BCS + RT. Studies had to provide subgroup data based on different margin widths.

Positive vs negative margins. Different margin widths

IBTR for negative vs positive margins in patients receiving BCS+RT: 13 studies; OR 0.45 (95% CI 0.36 to 0.57) IBTR for negative vs positive margins in patients receiving BCS alone: 13 studies; OR 0.34 (95% CI 0.25 to 0.46) Negative margin of at least 10 mm was associated with a lower risk of IBTR compared with 2 mm (OR 0.46, 95% CI 0.29 to 0.69)

24 studies (n=7564)

Nilsson 2015 (6) MEDLINE, Cochrane Library (up to 2014); ASCO & San Antonio Breast Cancer Symposium proceedings

Studies comparing hypofractionated (any schedule) with standard (50 Gy, 25 fractions) RT or RT boost with no boost in patients with DCIS. Outcome was local recurrence.

Hypofractionated vs standard RT Boost vs no boost RT

Local recurrence: Hypofractioned vs standard RT: 4 studies; OR 0.78 (95% CI 0.58 to 1.03), p=0.08 Boost vs no boost: 12 studies; OR 0.91 (95% CI 0.77 to 1.08), p=0.28 Patients with positive margins after surgery with boost RT had reduced risk for local recurrence compared with no boost:

13 retrospective cohort studies

EBS 1-10 Version 3



6 studies; OR 0.56 (95% CI 0.36 to 0.87), p=0.01)

Marinovich 2016 (2) MEDLINE, EMBASE (up 29 Oct 2014). Evidence base for the Society of Surgical Oncology-American Society for Radiation Oncology-American Society of Clinical Oncology consensus guideline (Morrow 2016).

Studies of women with DCIS undergoing BCS that provided calculation of the local recurrence rate according to microscopic margin status and the threshold distance to declare a negative margin.

BCS Local recurrence: Negative vs positive/close margin status: OR 0.53 (95% CI 0.45 to 0.62), p<0.001 Local recurrence also associated with margin distance: 2 mm: OR 0.51 (95% CI 0.31 to 0.85) 3 to 5 mm: OR 0.42 (95% CI 0.18 to 0.97) 10 mm: OR 0.60 (95% CI 0.33 to 1.08 Network meta-analysis: Negative vs positive margins: OR for local recurrence 0.45 (95% CrI 0.30 to 0.62)

20 studies (n=8651)

Tamoxifen

Staley 2012 (11) Cochrane Breast Cancer Specialised Register, Cochrane Central, WHO international Clinical Trials Registry (up to Aug 2011)

RCTs of women receiving tamoxifen or not after surgery for DCIS with or without adjuvant RT

BCS + Tam vs BCS Ipsilateral recurrence: HR 0.75 (95% CI 0.61 to 0.92)

UKCCCR ANZ (Houghton 2003, Cuzick 2011) NSABP B-24 (Fisher 1999, Fisher 2001)

Contralateral recurrence: RR 0.50 (95% CI 0.28 to 0.87)


New primary invasive carcinoma ipsilateral: HR 0.79 (95% CI 0.62 to 1.01)


New primary invasive carcinoma contralateral: RR 0.57 (95% CI 0.39 to 0.83)


EBS 1-10 Version 3



All-cause mortality: RR 1.11 (95% CI 0.89 to 1.39)


Kinsey-Trotman 2016 (12) MEDLINE (1990 to Feb 2015)

RCTs, observational studies, or comparative studies of women with DCIS receiving tamoxifen or AIs

BCS + Tam vs no Tam All breast cancer recurrence: Mixed RT and no prior RT: RR 0.69 (95% CI 0.60 to 0.79), p<0.005 Prior RT only: RR 0.67 (95% CI 0.55 to 0.81) Contralateral breast recurrence: Mixed RT and no prior RT: RR 0.54 (95% CI 0.39 to 0.75), p<0.05 Prior RT only: RR 0.63 (95% CI 0.44 to 0.91) Noninvasive breast events: Mixed RT and no prior RT: RR 0.73 (95% CI 0.60 to 0.90), p<0.05 Prior RT only: RR 0.78 (95% CI 0.58 to 1.05) Invasive breast events: Mixed RT and no prior RT: RR 0.68 (95% CI 0.54 to 0.84), p<0.05 Prior RT only: RR 0.63 (95% CI 0.47 to 0.84)

NSABP B-24 (Fisher 2001) UKCCCR ANZ (Cuzick 2011) WISC (Sprague 2012) (Cohort study)

BCS + AIs 5 RCTs comparing AIs with placebo showed a reduction in invasive breast cancer or breast cancer recurrence with AIs, however no subgroup analyses were done of DCIS-only patients.

IBIS II (Cuzick 2014) NCIC CTG MAP.3 (Goss 2011) NCIC CTG MA.17 (Ingle 2008) NSABP B-33 (Mamounas 2008) ABCSG (Jakesz 2007)

EBS 1-10 Version 3


Table 3. Summary of Relevant RCTs

Trial Name Citations (ref)

Population Arms / Dose (n) Outcomes Follow-up

Results

Comparison: BCS + RT vs BCS EORTC 10853 Donker 2013 (35) (15 years) Bijker 2006 (36) (10 years) Donker 2012ab (37) (abstract)

Women had complete local excision for DCIS (n=1010)

RT: 50 Gy in 25 fractions over 5 weeks to the whole breast. 5% of patients received a boost (n=507). No further treatment (n=503)

Primary: Time to local recurrence (LR) in the ipsilateral breast. Secondary: Regional recurrence, contralateral breast cancer, distant metastasis, breast cancer specific survival, overall survival

Median 15.8 years

15-year LR-free rate: 82% vs 69%; HR 0.52, 95% CI 0.40 to 0.68, p<0.001 Pure DCIS LR-free rate: 92% vs 84%; HR 0.49, 95% CI 0.33 to 0.73, p=0.003 Invasive LR-free rate: 90% vs 84% HR 0.61, 95% CI 0.42 to 0.87, p=0.007 Regional recurrence: HR 0.46, 95% CI 0.21 to 1.02, p=0.051 Contralateral breast cancer: 10% vs 7%; HR 1.36, 95% CI 0.89 to 2.10, p=0.157 Distant metastasis: HR 0.99, 95% CI 0.61 to 1.61, p=0.982 Breast cancer specific survival: 96% vs 95%, HR 1.07, 95% CI 0.60 to 1.91, p=0.814 Overall survival: 88% vs 90%, HR 1.02, 95% CI 0.71 to 1.44, p=0.931

SweDCIS Warnberg 2014 (38) (20 years) Holmberg 2008 (39) (8 years) Emdin 2006 (40) (5.2 years)

Women had BCS for DCIS (n=1067)

RT: 50 Gy in 25 fractions over 5 weeks (n=534) No RT (n=533)

Primary: Ipsilateral breast events (new DCIS and invasive cancers). Secondary: Contralateral breast events, breast cancer specific death, all death.

Median 204 months (17 years)

20-year ipsilateral breast event risk: 20% vs 32%; ARR 12%, 95% CI 6.5 to 17.7; RRR 37.5% DCIS: ARR 10%, CI 6 to 14; RRR 67% Invasive breast cancer: ARR 2%, 95% CI -3 to 7; RRR 13% Contralateral breast events: 67 vs 48 events DCIS: HR 1.2, 95% CI 0.50 to 2.90 Invasive breast cancer: HR 1.42, 95% CI 0.94 to 2.14 Breast cancer specific death: 4.1% vs 4.2% All death: 22.8% vs 27%

EBS 1-10 Version 3




Results

NSABP B-17 Wapnir 2011 (13)


RT: 50 Gy at 10 Gy/wk (n=413) No RT (n=405)

Primary: Event-free survival defined as time from surgery to recurrence (invasive ipsilateral breast tumour recurrence [IBTR], DCIS IBTR or other [local, regional, or distant]), contralateral breast invasive or DCIS tumours, second primary cancer, or death before any of these events. Secondary: All-cause mortality and breast cancer-specific mortality.

Median 207 months (17.25 years)

RT vs no RT Invasive IBTR: 10.7% vs 19.6%, HR 0.48, 95% CI 0.33 to 0.69, p<0.001 DCIS IBTR: 9.0% vs 15.4%, HR 0.53, 95% CI 0.35 to 0.80, p<0.001 Contralateral breast cancer: 9.3% vs 7.9%, p=NS No difference between groups in local, regional, or distant recurrence; second primary cancer; or death before these events. All-cause mortality: 17.1% vs 15.8%; HR 1.08, 95% CI 0.79 to 1.48 Breast cancer-specific mortality: 4.7% vs 3.1%; HR 1.44, 95% CI 0.71 to 2.92

Comparison: BCS + RT + Tamoxifen vs BCS + RT NSABP B-24 Wapnir 2011 (13)


RT: 50 Gy at 10 Gy/wk; a boost of 10 Gy to the lumpectomy cavity was permitted (n=902) RT + Tamoxifen: 20 mg/d for 5 years (n=902)

Primary: Event-free survival defined as time from surgery to recurrence (invasive IBTR or DCIS IBTR; and local, regional, or distant), contralateral breast invasive or DCIS tumours, second primary cancer, or death before any of these events. Secondary: Endometrial cancer, all-cause mortality, and breast cancer-specific mortality.

Median 163 months (13.6 years)

RT+Tam vs RT Invasive IBTR: 6.6% vs 9.0%, HR 0.68, 95% CI 0.49 to 0.95, p=0.025 DCIS IBTR: 6.7% vs 7.6%, HR 0.84, 95% CI 0.60 to 1.19, p=0.33 Contralateral breast cancer: 4.9% vs 8.1%, HR 0.68, 95% CI 0.48 to 0.95, p=0.023 No difference between groups in local, regional, or distant recurrence; second primary cancer; or death before these events. Endometrial cancer: 15 vs 7 events; HR 2.09, 95% CI 0.85 to 5.13 All-cause mortality: 14.4% vs 17.1%; HR 0.86, 95% CI 0.66 to 1.11

EBS 1-10 Version 3




Results

Breast cancer-specific mortality: 2.3% vs 2.7%; HR 0.81, 95% CI 0.43 to 1.50

Comparison: RT, Tamoxifen, Both, Neither UK/ANZ DCIS (UKCCCR ANZ) Cuzick 2011 (14)

2x2 factorial Women had locally excised DCIS (n=1701; 1694 analyzed) 912 patients chose to enter 2x2 randomization 782 patients chose randomization to one of the treatments

RT: 50 Gy in 25 fractions over 5 weeks (n=267) Tamoxifen: 20 mg/d for 5 years (n=567) RT + Tam (n=316) No adjuvant treatment (n=544)

Primary: Invasive ipsilateral breast events (RT); any new breast event, including contralateral disease and DCIS (Tam)

Median 12.7 years

RT vs no RT All new breast events: 10.6% vs 23.2%; HR 0.41, 95% CI 0.30 to 0.56, p<0.0001 Ipsilateral invasive: 3.3% vs 9.1%; HR 0.32, 95% CI 0.19 to 0.56, p<0.0001 Ipsilateral DCIS: 3.8% vs 9.7%; HR 0.38, 95% CI 0.22 to 0.63, p<0.0001 Contralateral breast cancer: 3.3% vs 4.1%; HR 0.84, 95% CI 0.45 to 1.58, p=0.6 Tam vs no tam All new breast events: 18.1% vs 24.6%; HR 0.71, 95% CI 0.58 to 0.88, p=0.002 Ipsilateral invasive: 6.8% vs 6.9%; HR 0.95, 95% CI 0.66 to 1.38, p=0.79 Ipsilateral DCIS: 8.6% vs 12.1%; HR 0.70, 95% CI 0.51 to 0.86, p=0.03 Contralateral breast cancer: 1.9% vs 4.2%; HR 0.44, 95% CI 0.25 to 0.77, p=0.005 RT+Tam vs no treatment All new breast events: 9.5% vs 27%; HR 0.31, 95% CI 0.19 to 0.49, p<0.0001 Ipsilateral invasive: 3.7% vs 10.1%; HR 0.30, 95% CI 0.14 to 0.65, p=0.002 Ipsilateral DCIS: 2.9% vs 11.1%; HR 0.24, 95% CI 0.10 to 0.56, p=0.001 Contralateral breast cancer: 2.9% vs 4%; HR 0.59, 95% CI 0.24 to 1.41, p=0.2 RT+Tam vs RT All new breast events: 9.5% vs 12.4%; HR 0.77, 95% CI 0.44 to 1.32, p=0.3 Ipsilateral invasive: 3.7% vs 2.7%; HR 1.37, 95% CI 0.49 to 3.84, p=0.6

EBS 1-10 Version 3




Results

Ipsilateral DCIS: 2.9% vs 5.0%; HR 0.57, 95% CI 0.22 to 1.48, p=0.2 Contralateral breast cancer: 2.9% vs 4.1%; HR 0.80, 95% CI 0.31 to 2.08, p=0.7 RT+Tam vs Tam All new breast events: 9.5% vs 19.7%; HR 0.45, 95% CI 0.28 to 0.74, p=0.002 Ipsilateral invasive: 3.7% vs 8.5%; HR 0.43, 95% CI 0.19 to 0.95, p=0.04 Ipsilateral DCIS: 2.9% vs 8.5%; HR 0.33, 95% CI 0.14 to 0.79, p=0.01 Contralateral breast cancer: 2.9% vs 1.8%; HR 1.49, 95% CI 0.49 to 4.55, p=0.5 No significant difference in death rate across treatment groups.

Comparison: Anastrozole vs Tamoxifen IBIS-II DCIS Forbes 2016 (15)

Postmenopausal women with DCIS (n=2980). RT permitted according to local practice. Patients with mastectomy were excluded.

Anastrozole: 1 mg/day (n=1471) Tamoxifen: 20 mg/day (n=1509)

Primary: Breast cancer (invasive cancers and new or recurrent DCIS): local recurrence (all ipsilateral disease), distant recurrence (node-positive contralateral disease and recurrences at distant sites), or isolated contralateral events. Secondary: ER status, breast cancer mortality, other cancers, CVD, fractures, non-breast cancer deaths.

Median 7.2 years

All new breast cancer: 5% vs 5%; HR 0.83, 95% CI 0.59 to 1.18, p=0.31 Invasive: 3% vs 3%; HR 0.72, 95% CI 0.46 to 1.14, p=0.16 DCIS: 2% vs 2%; HR 0.98, 95% CI 0.57 to 1.69, p=0.95 No differences were seen between groups in ipsilateral or contralateral invasive or DCIS. For ER positive women, breast cancer recurrence 2% vs 4%; HR 0.55, 95% CI 0.35 to 0.86, p=0.008 For ER negative women, breast cancer recurrence 1% vs <1%; HR 1.34, 95% CI 0.65 to 2.75, p=0.43. Death: 33 vs 36 deaths; HR 0.93, 95% CI 0.58 to 1.50, p=0.78 Breast cancer death: 1 vs 3 deaths Other cancer: 61 vs 71 other cancers; OR 0.88, 95% CI 0.61 to 1.26, p=0.47

EBS 1-10 Version 3




Results

Side effects Fracture: 9% vs 7%; OR 1.36, 95% CI 1.03 to 1.80, p=0.027 Any musculoskeletal: 64% vs 54%; OR 1.49, 95% CI 1.28 to 1.74, p<0.0001 Any vasomotor or gynecological: 61% vs 69%; OR 0.69, 95% CI 0.59 to 0.80, p<0.0001 Major thromboembolic: <1% vs 2%; OR 0.30, 95% CI 0.11 to 0.71, p=0.0028 Any cardiovascular: 6% vs 6%; OR 1.15, 95% CI 0.84 to 1.57, p=0.38

NSABP B-35 Margolese 2016 (16) Margolese 2015ab (41) (abstract)

ER or PR positive postmenopausal women with DCIS (n=3104). Patients had undergone BCS with clear margins and negative nodes and whole breast RT.

Anastrozole: 1 mg/day (n=1552) Tamoxifen: 20 mg/day (n=1552)

Primary: Any breast cancer event (local, regional, or distant recurrence; contralateral breast cancer; invasive disease; or DCIS). Secondary: Disease-free survival, second primary cancer, death from any cause, ipsilateral breast cancer, contralateral breast cancer, non-breast second primary cancer, osteoporotic fracture, overall survival, quality of life.

Median 9.0 years

All new breast cancer: 90 vs 122 events; HR 0.73, 95% CI 0.56 to 0.96, p=0.0234 Invasive: 43 vs 69 events; HR 0.62, 95% CI 0.42 to 0.90, p=0.0123 DCIS: 47 vs 53 events; HR 0.88, 95% CI 0.59 to 1.30, p=0.52 All new ipsilateral recurrence: 46 vs 55 events; HR 0.83, 95% CI 0.56 to 1.22, p=0.34 Ipsilateral invasive: 17 vs 22 events; HR 0.76, 95% CI 0.40 to 1.43, p=0.39 Ipsilateral DCIS: 29 vs 33 events; HR 0.87, 95% CI 0.53 to 1.43, p=0.59 All new contralateral breast cancer: 39 vs 60 events; HR 0.64, 95% CI 0.43 to 0.96, p=0.0322 Contralateral invasive: 21 vs 40 events; HR 0.52, 95% CI 0.31 to 0.88, p=0.0148 Contralateral DCIS: 18 vs 20 events; HR 0.90, 95% CI 0.47 to 1.69, p=0.73 Disease-free survival: 5-year estimate 91.6% vs 91.5%; 10-year estimate 77.9% vs 82.7%. Non-breast second primary cancer: 107 vs 102 events; risk ratio 1.04, 95% CI 0.78 to 1.37 Osteoporotic fracture: 69 vs 50 events; risk ratio 1.38, 95% CI 0.95 to 2.03

EBS 1-10 Version 3




Results

Death: 98 vs 88 deaths; HR 1.11, 95% CI 0.83 to 1.48, p=0.48 Overall survival: 5-year estimate 97.9% vs 98.0%; 10-year estimate 92.5% vs 92.1% A statistically significant interaction was seen between treatment and age group (p=0.0379) showing benefit of anastrozole only in women less than 60 years of age.

NSABP B-35 Ganz 2016 (17)

1193 women completed the quality of life substudy.

Anastrozole (n=592) Tamoxifen (n=601)

Instruments: Medical Outcomes Study-Short Form 12 (SF-12) SF-36 Vitality Scale Breast Cancer Prevention Trial (BCPT) symptom checklist Center for Epidemiologic Studies Depression Scale (CES-D) Medical Outcomes Study (MOS) Sexual Problems Scale Overall health rating scale Primary outcomes: Physical and mental health component scale scores (SF-12) Vasomotor symptoms (BCPT) Secondary outcomes: vaginal symptoms and sexual functioning. Exploratory outcomes: other symptoms, vitality, depression

5 years Mean severity scores with treatment difference from mixed modelling (positive means greater severity with anastrozole, negative means greater severity with tamoxifen) SF-12 physical component: 45.85 vs 46.72; difference -0.21, 95% CI -1.30 to 0.88, p=0.38 SF-12 mental component: 51.48 vs 52.38; difference -0.71, 95% CI -1.85 to 0.43, p=0.93 Vasomotor symptoms: 1.17 vs 1.33; difference -0.26, 95% CI -0.37 to -0.15, p=0.011 Musculoskeletal pain: 1.72 vs 1.50; difference 0.29, 95% CI 0.18 to 0.40, p=0.0006 Vaginal problems: 0.86 vs 0.76; difference 0.12, 95% CI 0.01 to 0.24, p=0.035 Bladder control problems: 0.80 vs 0.96; difference -0.18, 95% CI -0.28 to -0.08, p=0.0002 Cognitive problems: 0.92 vs 0.89; difference -0.02, 95% CI -0.11 to 0.06, p=0.72 Weight problems: 1.17 vs 1.15; difference -0.05, 95% CI -0.16 to 0.06, p=0.48 Gynecological symptoms: 0.18 vs 0.29; difference -0.12, 95% CI -0.16 to -0.07, p<0.0001 MOS Vitality score: 57.54 vs 58.34; difference -0.25, 95% CI -2.38 vs 1.88, p=0.86

EBS 1-10 Version 3




Results

CES Depression score: 6.39 vs 6.19; difference 0.11, 95% CI -0.43 to 0.40, p=0.46 Sexual functioning score: 45.29 vs 43.65; difference 0.067, 95% CI -2.58 to 2.72, p=0.56 Younger age (<60 years) was associated with increased vasomotor symptom severity, vaginal symptoms, weight problems, and gynecological symptoms.

Comparison: RT vs Observation RTOG 9804 McCormick 2015 (42) McCormick 2012ab (43) (abstract) McCormick 2012abB (44) (abstract)

Women had BCS for low or intermediate grade DCIS (n=636)

RT: 50 Gy in 25 fractions or 50.4 Gy in 28 fractions (n=314) No RT (n=317) Tamoxifen was allowed if started within 4 weeks from the diagnosis of DCIS.

Primary: Local failure (biopsy-proven invasive or DCIS recurrence). Secondary: Overall survival, contralateral breast failure, distant failure, salvage mastectomy failure.

Median 7.17 years

5-year local ipsilateral local failure: 0.4% vs 3.5%; 7-year local ipsilateral local failure: 0.9% vs 6.7%; HR 0.11, 95% CI 0.03 to 0.47, p<0.001 7-year contralateral breast failure: 3.9% vs 4.8%; HR 1.07, 95% CI 0.48 to 2.39, p=0.86 7-year overall survival: 91.7% vs 95.1%; HR 1.56, 95% CI 0.81 to 3.01, p=0.18 7-year disease-free survival: 88% vs 80.4%; HR 0.84, 95% CI 0.53 to 1.32, p=0.44 7-year incidence of mastectomy 1.5% vs 2.8%

Comparison: RT Boost vs No Boost Multivariate analysis of NSABP B-24 Julian 2011ab (45) (abstract)

Women with DCIS treated with BCS and RT (n=1804).

Tamoxifen (n=902) Placebo (n=902) Boost RT was optional; 613 received boost therapy ranging from 1 Gy to 20 Gy, with 81.5% receiving 10 Gy.

Ipsilateral breast tumor recurrence (IBTR)

Mean 161 months

IBTR: HR 0.87, 95% CI 0.66 to 1.15, p=0.33 Invasive IBTR: HR 0.86, 95% CI 0.58 to 1.27, p=0.44 Noninvasive IBTR: HR 0.89, 95% CI 0.60 to 1.33, p=0.56

Comparison: MarginProbe device vs no device Boolbol 2011ab (46) (abstract)

Women with DCIS and mixed (DCIS & invasive)

MarginProbe device [provides real-time

Primary: complete surgical resection (CSR) – the

DCIS patients: Successful CSR: 69% vs 17%, p<0.0001

EBS 1-10 Version 3




Results

Boolbol 2011abB (47) (abstract)

tumour types receiving BCS (n=596) DCIS patients: n=161

intraoperative detection of cancerous tissues at the margins of excised specimens] (n=83) No MarginProbe (n=78)

correct intraoperative identification and resection of all positive margins on the main lumpectomy specimen.

Candidates for re-excision: 13% vs 37%, p=0.0005

EBS 1-10 Version 3


Table 4. Ongoing Trials

ClinicalTrials.gov and WHO International Clinical Trials Registry Platform

Protocol ID Title and details of the trial Status

NCT00769379 Radiation Therapy With or Without Trastuzumab in Treating Women With Ductal Carcinoma In Situ Who Have Undergone Lumpectomy This randomized phase III trial studies radiation therapy to see how well it works with or without trastuzumab in treating women with ductal carcinoma in situ who have undergone lumpectomy. Monoclonal antibodies, such as trastuzumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Radiation therapy uses high-energy x-rays to kill tumor cells. It is not yet known whether radiation therapy is more effective with or without trastuzumab in treating ductal carcinoma in situ.

Ongoing

NCT01112254 Evaluation of the Diagnostic Performance of MRI±Biopsy to Optimize Resection of Ductal Carcinoma In Situ (DCIS) Breast Cancer (IRCIS) The purpose of this study is to evaluate the diagnostic performance of MRI±biopsy to optimize resection of Ductal Carcinoma In Situ (DCIS) breast cancer.

Completed

NCT00470236 Radiation Doses and Fractionation Schedules in Non-low Risk Ductal Carcinoma In Situ (DCIS) of the Breast (DCIS) The addition of tumour bed boost after BCS in women with non-low risk DCIS reduces the risk of local recurrence (invasive or intraductal recurrence in the ipsilateral breast). The risk of local recurrence in the shorter fractionation arm is not worse than that for the standard fractionation arm. A molecular signature predictive of invasive recurrence of DCIS will be detectable and the molecular signature may eventually have clinical utility for therapy individualization. To improve the outcome of women with non-low risk DCIS treated with breast conserving therapy. To individualize treatment selection for women with DCIS to achieve long term disease control with minimal toxicity.

Ongoing

NCT00003857 Radiation Therapy With or Without Optional Tamoxifen in Treating Women With Ductal Carcinoma in Situ Radiation therapy uses high-energy x-rays to damage tumor cells. Estrogen can stimulate the growth of breast cancer cells. Hormone therapy using tamoxifen may fight breast cancer by blocking the uptake of estrogen by the tumor cells. It is not yet known if radiation therapy is more effective than observation, with or without tamoxifen, in treating ductal carcinoma in situ. This randomized phase III trial compares the effectiveness of radiation therapy with that of observation, with or

Ongoing

EBS 1-10 Version 3


without tamoxifen, in treating women who have ductal carcinoma in situ.

NCT00907868 Breast-Conserving Surgery and Whole-Breast Radiation Therapy With or Without Additional Radiation Therapy to the Tumor in Treating Women With Ductal Carcinoma in Situ Radiation therapy uses high-energy x-rays to kill tumor cells. Giving radiation therapy after surgery may kill any tumor cells that remain after surgery. It is not yet known whether whole-breast radiation therapy is more effective when given with or without additional radiation therapy to the tumor in treating patients with ductal carcinoma in situ. This randomized phase III trial is studying breast-conserving surgery followed by whole-breast radiation therapy to see how well it works when given with or without additional radiation therapy to the tumor in treating women with ductal carcinoma in situ.

Unknown status Last recruitment status was Recruiting updated in 2009

NCT00072462 Adjuvant Tamoxifen Compared With Anastrozole in Treating Postmenopausal Women With Ductal Carcinoma In Situ (IBIS-II DCIS) Estrogen can stimulate the growth of breast cancer cells. Hormone therapy using either tamoxifen or anastrozole may fight breast cancer by blocking the use of estrogen. It is not yet known whether tamoxifen is more effective than anastrozole in preventing breast cancer after surgery for ductal carcinoma in situ. This randomized phase III trial is studying how well adjuvant tamoxifen works compared to anastrozole in treating postmenopausal women who have undergone surgery to remove ductal carcinoma in situ.

Ongoing

NCT00262899 Genetic Counseling or Usual Care in Helping Women With Newly Diagnosed Ductal Carcinoma In Situ or Stage I, Stage II, or Stage IIIA Breast Cancer Make Treatment Decisions Genetics education and counseling may help patients make treatment decisions. It is not yet known how genetic counseling or usual care influence patient treatment decisions for breast cancer. This randomized clinical trial is studying how well genetic counseling works compared to usual care in helping patients with newly diagnosed ductal carcinoma in situ, stage I, stage II, or stage IIIA breast cancer make treatment decisions.

Completed

NCT00438659 Mometasone Furoate in Preventing Radiation Dermatitis in Patients Undergoing Radiation Therapy to the Breast or Chest Wall for Invasive Breast Cancer or Ductal Carcinoma in Situ Steroid therapy, such as mometasone furoate, may prevent radiation dermatitis caused by radiation therapy. It is not yet known whether mometasone furoate is more effective

Completed

EBS 1-10 Version 3


than a placebo in preventing radiation dermatitis. This randomized phase III trial is studying mometasone furoate to see how well it works compared to a placebo in preventing radiation dermatitis in patients undergoing radiation therapy to the breast or chest wall for invasive breast cancer or ductal carcinoma in situ.

NCT02492607 LORD

Management of Low-risk DCIS (LORD) A substantial number of DCIS lesions will never form a health hazard, particularly if it concerns slow-growing low-grade DCIS. This implies that many women might be unnecessarily going through intensive treatment resulting in a decrease in quality of life and an increase in health care costs, without any survival benefit. This study is a randomized, international, multicenter, phase III non-inferiority trial, and aims to determine whether screen-detected low-grade DCIS can safely be managed by an active surveillance strategy or that the conventional treatment, being either WLE alone, WLE + RT, or mastectomy, and possibly HT, should remain the standard of care.

Not yet open for recruitment

NCT00402519 APBI Versus EBRT Therapy After Breast Conserving Surgery for Low-risk Breast Cancer To assess the role of interstitial brachytherapy alone compared to whole breast irradiation in a defined low-risk group of invasive breast cancer or ductal carcinoma in situ concerning local failure (all ipsilateral local recurrences) to affirm the hypothesis that local control rates in each arm are equivalent.

Ongoing

NCT00282035 RAPID

Randomized Trial of Accelerated Partial Breast Irradiation To determine if Accelerated Partial Breast Irradiation, using 3D CRT, is as effective as Whole Breast Irradiation following breast conserving surgery in women with an new histological diagnosis of ductal carcinoma in situ only or invasive breast cancer without evidence of metastatic disease. Effectiveness will be determined by the rate of ipsilateral breast tumour recurrence. General objective is to improve the convenience and quality of life of female patients who receive breast irradiation.

Ongoing

ACTRN12606000510549 ANZ 9002 (DCIS): Protocol for the management of screen detected ductal carcinoma in situ (DCIS) of the breast This phase III randomized controlled trial aims to compare 3 arms measuring disease-free survival as primary outcome. Arm A: Complete local excision/lumpectomy (surgical removal of the tumour) with no further initial local or systemic therapy Arm B: Complete local excision/lumpectomy followed by oral tamoxifen 20 mg daily for 5 years

Ongoing

EBS 1-10 Version 3


Arm C: Complete local excision/lumpectomy followed by supervoltage radiotherapy to the residual breast tissue to a dose of 50Gy in 25 fractions over 5 weeks (or its equivalent) Arm D: Complete local excision/lumpectomy followed by both radiotherapy to a dose of 50Gy in 25 fractions over 5 weeks (or its equivalent) and oral tamoxifen 20 mg daily for 5 years

EBS 1-10 Version 3


References

1. Morrow M, Van Zee KJ, Solin LJ, Houssami N, Chavez-MacGregor M, Harris JR, Horton J, Hwang S, Johnson PL, Marinovich ML, Schnitt SJ, Wapnir I, Moran MS. Society of Surgical Oncology-American Society for Radiation Oncology-American Society of Clinical Oncology Consensus Guideline on Margins for Breast-Conserving Surgery With Whole-Breast Irradiation in Ductal Carcinoma In Situ. J Clin Oncol. 2016 Nov 20;34(33):4040-4046.

2. Marinovich ML, Azizi L, Macaskill P, Irwig L, Morrow M, Solin LJ, Houssami N. The Association of Surgical Margins and Local Recurrence in Women with Ductal Carcinoma In Situ Treated with Breast-Conserving Therapy: A Meta-Analysis. Ann Surg Oncol. 2016 Nov;23(12):3811-3821.

3. Rakovitch E, Nofech-Mozes S, Hanna W, Baehner FL, Saskin R, Butler SM, Tuck A, Sengupta S, Elavathil L, Jani PA, Bonin M, Chang MC, Robertson SJ, Slodkowska E, Fong C, Anderson JM, Jamshidian F, Miller DP, Cherbavaz DB, Shak S, Paszat L. A population-based validation study of the DCIS Score predicting recurrence risk in individuals treated by breast-conserving surgery alone. Breast Cancer Res Treat. 2015 Jul;152(2):389-98.

4. Rakovitch E., Nofech-Mozes S., Hanna W., Sutradhar R., Baehner F.L., Miller D.P., Fong C., Gu S., Tuck A., Sengupta S., Elavathil L., Jani P.A., Bonin M., Chang M.C., Slodkowska E., Anderson J.M., Cherbavaz D.B., Shak S., Paszat L. Multigene expression assay and benefit of radiotherapy after breast conservation in ductal carcinoma in situ. J Natl Cancer Inst. 2017;109 (4) (no pagination).

5. Solin LJ, Gray R, Baehner FL, Butler SM, Hughes LL, Yoshizawa C, Cherbavaz DB, Shak S, Page DL, Sledge GW Jr, Davidson NE, Ingle JN, Perez EA, Wood WC, Sparano JA, Badve S. A multigene expression assay to predict local recurrence risk for ductal carcinoma in situ of the breast. J Natl Cancer Inst. 2013 May 15;105(10):701-10.

6. Nilsson C, Valachis A. The role of boost and hypofractionation as adjuvant radiotherapy in patients with DCIS: a meta-analysis of observational studies. Radiother Oncol. 2015 Jan;114(1):50-5.

7. Souchon R, Sautter-Bihl ML, Sedlmayer F, Budach W, Dunst J, Feyer P, Fietkau R, Haase W, Harms W, Wenz F, Sauer R; Breast Cancer Expert Panel of the German Society of Radiation Oncology (DEGRO). DEGRO practical guidelines: radiotherapy of breast cancer II: radiotherapy of non-invasive neoplasia of the breast. Strahlenther Onkol. 2014 Jan;190(1):8-16.

8. Moran MS, Zhao Y, Ma S, Kirova Y, Fourquet A, Chen P, Hoffman K, Hunt K, Wong J, Halasz LM, Freedman G, Prosnitz R Jr, Yassa M, Nguyen DHA, Hijal T, Haffty BG, Wai ES, Truong PT. Association of Radiotherapy Boost for Ductal Carcinoma In Situ With Local Control After Whole-Breast Radiotherapy. JAMA Oncol. 2017 Aug 1;3(8):1060-1068.

9. Visvanathan K, Hurley P, Bantug E, Brown P, Col NF, Cuzick J, Davidson NE, Decensi A, Fabian C, Ford L, Garber J, Katapodi M, Kramer B, Morrow M, Parker B, Runowicz C, Vogel VG 3rd, Wade JL, Lippman SM. Use of pharmacologic interventions for breast cancer risk reduction: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol. 2013 Aug 10;31(23):2942-62.

10. Stuart KE, Houssami N, Taylor R, Hayen A, Boyages J. Long-term outcomes of ductal carcinoma in situ of the breast: a systematic review, meta-analysis and meta-regression analysis. BMC Cancer. 2015 Nov 10;15:890.

11. Staley H, McCallum I, Bruce J. Postoperative tamoxifen for ductal carcinoma in situ. Cochrane Database Syst Rev. 2012 Oct 17;10:CD007847.

EBS 1-10 Version 3


12. Kinsey-Trotman S, Shi Z, Fosh B. Breast Ductal Carcinoma In Situ: A Literature Review of Adjuvant Hormonal Therapy. Oncol Rev. 2016 Dec 7;10(2):304.

13. Wapnir IL, Dignam JJ, Fisher B, Mamounas EP, Anderson SJ, Julian TB, Land SR, Margolese RG, Swain SM, Costantino JP, Wolmark N. Long-term outcomes of invasive ipsilateral breast tumor recurrences after lumpectomy in NSABP B-17 and B-24 randomized clinical trials for DCIS. J Natl Cancer Inst. 2011 Mar 16;103(6):478-88.

14. Cuzick J, Sestak I, Pinder SE, Ellis IO, Forsyth S, Bundred NJ, Forbes JF, Bishop H, Fentiman IS, George WD. Effect of tamoxifen and radiotherapy in women with locally excised ductal carcinoma in situ: long-term results from the UK/ANZ DCIS trial. Lancet Oncol. 2011 Jan;12(1):21-9.

15. Forbes JF, Sestak I, Howell A, Bonanni B, Bundred N, Levy C, von Minckwitz G, Eiermann W, Neven P, Stierer M, Holcombe C, Coleman RE, Jones L, Ellis I, Cuzick J; IBIS-II investigators. Anastrozole versus tamoxifen for the prevention of locoregional and contralateral breast cancer in postmenopausal women with locally excised ductal carcinoma in situ (IBIS-II DCIS): a double-blind, randomized controlled trial. Lancet. 2016 Feb 27;387(10021):866-73.

16. Margolese RG, Cecchini RS, Julian TB, Ganz PA, Costantino JP, Vallow LA, Albain KS, Whitworth PW, Cianfrocca ME, Brufsky AM, Gross HM, Soori GS, Hopkins JO, Fehrenbacher L, Sturtz K, Wozniak TF, Seay TE, Mamounas EP, Wolmark N. Anastrozole versus tamoxifen in postmenopausal women with ductal carcinoma in situ undergoing lumpectomy plus radiotherapy (NSABP B-35): a randomised, double-blind, phase 3 clinical trial. Lancet. 2016 Feb 27;387(10021):849-56.

17. Ganz PA, Cecchini RS, Julian TB, Margolese RG, Costantino JP, Vallow LA, Albain KS, Whitworth PW, Cianfrocca ME, Brufsky AM, Gross HM, Soori GS, Hopkins JO, Fehrenbacher L, Sturtz K, Wozniak TF, Seay TE, Mamounas EP, Wolmark N. Patient-reported outcomes with anastrozole versus tamoxifen for postmenopausal patients with ductal carcinoma in situ treated with lumpectomy plus radiotherapy (NSABP B-35): a randomised, double-blind, phase 3 clinical trial. Lancet. 2016 Feb 27;387(10021):857-65.

18. National Institute for Health and Care Excellence (2009). Early and locally advanced breast cancer: diagnosis and treatment. NICE guideline (CG 80).

19. Scottish Intercollegiate Guidelines Network (SIGN). Treatment of primary breast cancer. Edinburgh: SIGN; 2013.

20. Alberta Health Services. Adjuvant radiation therapy for ductal carcinoma in situ. Clinical Practice Guideline BR-006 Version 4; May 2015.

21. Biganzoli L, Wildiers H, Oakman C, Marotti L, Loibl S, Kunkler I, Reed M, Ciatto S, Voogd AC, Brain E, Cutuli B, Terret C, Gosney M, Aapro M, Audisio R. Management of elderly patients with breast cancer: updated recommendations of the International Society of Geriatric Oncology (SIOG) and European Society of Breast Cancer Specialists (EUSOMA). Lancet Oncol. 2012 Apr;13(4):e148-60.

22. Moran MS, Schnitt SJ, Giuliano AE, Harris JR, Khan SA, Horton J, Klimberg S, Chavez-MacGregor M, Freedman G, Houssami N, Johnson PL, Morrow M. Society of Surgical Oncology-American Society for Radiation Oncology consensus guideline on margins for breast-conserving surgery with whole-breast irradiation in stages I and II invasive breast cancer. Ann Surg Oncol. 2014 Mar;21(3):704-16.

23. Kaufman SA, Harris EE, Bailey L, Chadha M, Dutton SC, Freedman GM, Goyal S, Halyard MY, Horst KC, Novick KL, Park CC, Suh WW, Toppmeyer D, Zook J, Haffty BG. ACR Appropriateness Criteria® Ductal Carcinoma in Situ. Oncology (Williston Park). 2015 Jun;29(6):446-58, 460-1.

EBS 1-10 Version 3


24. Virnig BA, Shamliyan T, Tuttle TM, Kane RL, Wilt TJ. Diagnosis and management of ductal carcinoma in situ (DCIS). Evid Rep Technol Assess (Full Rep). 2009 Sep;(185):1-549.

25. Kane RL, Virnig BA, Shamliyan T, Wang SY, Tuttle TM, Wilt TJ. The impact of surgery, radiation, and systemic treatment on outcomes in patients with ductal carcinoma in situ. J Natl Cancer Inst Monogr. 2010;2010(41):130-3.

26. Petrelli F, Barni S. Tamoxifen added to radiotherapy and surgery for the treatment of ductal carcinoma in situ of the breast: a meta-analysis of 2 randomized trials. Radiother Oncol. 2011 Aug;100(2):195-9.

27. King MT, Winters ZE, Olivotto IA, Spillane AJ, Chua BH, Saunders C, Westenberg AH, Mann GB, Burnett P, Butow P, Rutherford C. Patient-reported outcomes in ductal carcinoma in situ: A systematic review. Eur J Cancer. 2017 Jan;71:95-108.

28. Viani GA, Stefano EJ, Afonso SL, De Fendi LI, Soares FV, Leon PG, Guimarães FS. Breast-conserving surgery with or without radiotherapy in women with ductal carcinoma in situ: a meta-analysis of randomized trials. Radiat Oncol. 2007 Aug 2;2:28.

29. Polgár C, Kahán Z, Orosz Z, Gábor G, Hadijev J, Cserni G, Kulka J, Jani N, Sulyok Z, Lázár G, Boross G, Diczházi C, Szabó E, László Z, Péntek Z, Major T, Fodor J. The role of radiotherapy in the conservative treatment of ductal carcinoma in situ of the breast. Pathol Oncol Res. 2008 Jun;14(2):179-92.

30. Early Breast Cancer Trialists' Collaborative Group (EBCTCG), Correa C, McGale P, Taylor C, Wang Y, Clarke M, Davies C, Peto R, Bijker N, Solin L, Darby S. Overview of the randomized trials of radiotherapy in ductal carcinoma in situ of the breast. J Natl Cancer Inst Monogr. 2010;2010(41):162-77.

31. Goodwin A, Parker S, Ghersi D, Wilcken N. Post-operative radiotherapy for ductal carcinoma in situ of the breast. Cochrane Database Syst Rev. 2013 Nov 21;(11):CD000563.

32. Skandarajah AR, Bruce Mann G. Selective use of whole breast radiotherapy after breast conserving surgery for invasive breast cancer and DCIS. Surgeon. 2013 Oct;11(5):278-85.

33. Dunne C, Burke JP, Morrow M, Kell MR. Effect of margin status on local recurrence after breast conservation and radiation therapy for ductal carcinoma in situ. J Clin Oncol. 2009 Apr 1;27(10):1615-20.

34. Wang SY, Chu H, Shamliyan T, Jalal H, Kuntz KM, Kane RL, Virnig BA. Network meta-analysis of margin threshold for women with ductal carcinoma in situ. J Natl Cancer Inst. 2012 Apr 4;104(7):507-16.

35. Donker M, Litière S, Werutsky G, Julien JP, Fentiman IS, Agresti R, Rouanet P, de Lara CT, Bartelink H, Duez N, Rutgers EJ, Bijker N. Breast-conserving treatment with or without radiotherapy in ductal carcinoma In Situ: 15-year recurrence rates and outcome after a recurrence, from the EORTC 10853 randomized phase III trial. J Clin Oncol. 2013 Nov 10;31(32):4054-9.

36. EORTC Breast Cancer Cooperative Group; EORTC Radiotherapy Group, Bijker N, Meijnen P, Peterse JL, Bogaerts J, Van Hoorebeeck I, Julien JP, Gennaro M, Rouanet P, Avril A, Fentiman IS, Bartelink H, Rutgers EJ. Breast-conserving treatment with or without radiotherapy in ductal carcinoma-in-situ: ten-year results of European Organisation for Research and Treatment of Cancer randomized phase III trial 10853--a study by the EORTC Breast Cancer Cooperative Group and EORTC Radiotherapy Group. J Clin Oncol. 2006 Jul 20;24(21):3381-7.

37. Donker M, Litiere S, Werutsky G, Julien JP, Fentiman IS, Agresti R, Rouanet P, Tunon De Lara C, Rutgers EJT, Bijker N. Adjuvant radiotherapy after breast-conserving

EBS 1-10 Version 3


surgery for ductal carcinoma in situ-fifteen-year results of the EORTC randomized phase III trial 10853. European Journal of Cancer. 2012;48:S106. Conference Abstract.

38. Wärnberg F, Garmo H, Emdin S, Hedberg V, Adwall L, Sandelin K, Ringberg A, Karlsson P, Arnesson LG, Anderson H, Jirström K, Holmberg L. Effect of radiotherapy after breast-conserving surgery for ductal carcinoma in situ: 20 years follow-up in the randomized SweDCIS Trial. J Clin Oncol. 2014 Nov 10;32(32):3613-8.

39. Holmberg L, Garmo H, Granstrand B, Ringberg A, Arnesson LG, Sandelin K, Karlsson P, Anderson H, Emdin S. Absolute risk reductions for local recurrence after postoperative radiotherapy after sector resection for ductal carcinoma in situ of the breast. J Clin Oncol. 2008 Mar 10;26(8):1247-52.

40. Emdin SO, Granstrand B, Ringberg A, Sandelin K, Arnesson LG, Nordgren H, Anderson H, Garmo H, Holmberg L, Wallgren A; Swedish Breast Cancer Group. SweDCIS: Radiotherapy after sector resection for ductal carcinoma in situ of the breast. Results of a randomised trial in a population offered mammography screening. Acta Oncol. 2006;45(5):536-43.

41. Margolese RG, Cecchini RS, Julian TB, Ganz PA, Costantino JP, Vallow L, Albain KS, Whitworth PW, Cianfrocca ME, Brufsky A, Gross HM, Soori GS, Hopkins JO, Fehrenbacher L, Sturtz K, Wozniak T, Seay TE, Mamounas EP, Wolmark N. Primary results, NRG Oncology/NSABP B-35: A clinical trial of anastrozole (A) versus tamoxifen (tam) in postmenopausal patients with DCIS undergoing lumpectomy plus radiotherapy. J Clin Oncol. 2015;33(18 Suppl 1). Conference Abstract.

42. McCormick B, Winter K, Hudis C, Kuerer HM, Rakovitch E, Smith BL, Sneige N, Moughan J, Shah A, Germain I, Hartford AC, Rashtian A, Walker EM, Yuen A, Strom EA, Wilcox JL, Vallow LA, Small W Jr, Pu AT, Kerlin K, White J. RTOG 9804: a prospective randomized trial for good-risk ductal carcinoma in situ comparing radiotherapy with observation. J Clin Oncol. 2015 Mar 1;33(7):709-15.

43. McCormick B. RTOG 9804: A prospective randomized trial for "good risk" ductal carcinoma in situ (DCIS), comparing radiation (RT) to observation (OBS). J Clin Oncol. 2012;30(15 Suppl May 20):1004. Conference Abstract.

44. McCormick B, Moughan J, Hudis C, Kuerer H, Rakovitch E, Smith B, Sneige N, Shah A, Germain I, White J. Low-risk Breast Ductal Carcinoma In Situ (DCIS): Results From the Radiation Therapy Oncology Group 9804 Phase 3 Trial. Int J Radiat Oncol Biol Phys. 2012;84(3S Suppl):S5. Conference Abstract.

45. Julian TB, Vicini FA, Costantino JP, Arthur DW, Kidwell KM, Land SR, Mamounas EP, Wolmark N. Boost Radiation Therapy Not of Value in Reducing IBTR of Invasive or Noninvasive Breast Cancers for Patients with DCIS: Results from the NSABP B-24 Trial. Cancer Res. 2011;71(24 Suppl):P3-13-01. Conference Abstract.

46. Boolbol SK, Cocilovo C, Tafra L. Intra-Operative Margin Assessment of Diffuse Disease with MarginProbe” as an Adjunct to Standard of Care, Results from a Randomized Prospective Multi Center Study. Cancer Res 2011;71(24 Suppl): P3-12-02. Conference Abstract.

47. Boolbol SK, Cocilovo C, Tafra L. Use of a novel device to reduce positive margins for ductal carcinoma in situ. J Clin Oncol. 2011;29(27 Suppl): 87. Conference Abstract.

EBS 1-10 Version 3


Appendix 1. Members of the Expert Panel

Name Affiliation Declarations of Interest

Amanda Hey Regional Primary Care Lead, Northeast Cancer Centre, Health Sciences North

None

Brian Pinchuk Surgical Oncology, North York General Hospital

None

Francisco Perera Radiation Oncology, London Health Sciences Centre

Been a principal investigator for a clinical trial involving any of the objects of study, regardless of the source of funding (Previously in the early 1990s, I was local principal investigator for the London Regional Cancer Program for NSABP protocol B-17); Given present data, the chance is very low that my income from our local business partnership could be affected by guideline recommendations (example: A group of patients with DCIS for whom radiation is presently recommended are felt to no longer require radiation)

Glykeria Martou Plastic Surgery, Kingston Regional Cancer Centre

None

Ian Dayes Radiation Oncology, Juravinski Cancer Centre

Professional income could increase or decrease by substantially more than $10,000 per year, depending on the outcome of the guideline (ie, increased or decreased indications for RT)

Kathleen Bell Genetic Counselling, Diagnostic Assessment Program Lead, Juravinski Cancer Centre

None

Leta Forbes Provincial Head, Systemic Treatment Program; Medical Oncology, Lakeridge Health

None

Martin Chang Pathology, Mount Sinai Hospital

None

Maureen Trudeau Medical Oncology, Odette Cancer Centre

Stocks, bonds, or stock options valued at $5,000 or more in a relevant business

EBS 1-10 Version 3


entity (RNA Diagnostics); Received any grants or other research support, either as principal or co-investigator, in any amount, from a relevant business entity (Pfizer, Amgen, Genomic Health, Roche , Essai, Novartis, Astra Zeneca , Astellas - fellow support and/or clinical trial per patient support); Had managerial responsibility for an organization or department that has received $5,000 or more in a single year from a relevant business entity, even if you did not personally benefit (Pfizer, Amgen, Genomic Health, Roche , Essai, Novartis, Astra Zeneca , Astellas - fellow support and/or clinical trial per patient support was head of division of medical oncology and hematology until Aug 2015)

Derek Muradali Radiologist-in-Chief, Prevention and Cancer Control; Radiology, St. Michael’s Hospital

None

Angel Arnaout Surgical Oncology, The Ottawa Hospital

None

EBS 1-10 Version 3


Appendix 2. Search Strategy: Systematic reviews and guidelines Database: Embase <1996 to 2017 June 5>, Ovid MEDLINE(R) Epub Ahead of Print, In-Process & Other Non-Indexed Citations and Ovid MEDLINE(R) without Revisions 2013 to Daily Update Search Strategy: -------------------------------------------------------------------------------- 1 (systematic adj (review: or overview:)).mp. 2 (meta-analy: or metaanaly:).mp. 3 (pooled analy: or statistical pooling or mathematical pooling or statistical summar: or mathematical summar: or quantitative synthes?s or quantitative overview:).mp. 4 (exp review literature as topic/ or review.pt. or exp review/) and systematic.tw. 5 (cochrane or embase or psychlit or psyclit or psychinfo or psycinfo or cinhal or cinahl or science citation index or scisearch or bids or sigle or cancerlit or pubmed or pub-med or medline or med-line).ab. 6 (reference list: or bibliograph: or hand-search: or handsearch: or relevant journal: or manual search:).ab. 7 or/1-6 8 (selection criteria or data extract: or quality assess: or jadad score or jadad scale or methodologic: quality).ab. 9 (stud: adj1 select:).ab. 10 (8 or 9) and review.pt. 11 7 or 10 12 (guideline or practice guideline).pt. 13 exp consensus development conference/ 14 consensus/ 15 (guideline: or recommend: or consensus or standards).ti. 16 or/12-15 17 11 or 16 18 (systematic adj (review: or overview:)).mp. 19 (meta-analy: or metaanaly:).mp. 20 (pooled analy: or statistical pooling or mathematical pooling or statistical summar: or mathematical summar: or quantitative synthes?s or quantitative overview:).mp. 21 (exp review literature as topic/ or review.pt. or exp review/) and systematic.tw. 22 (cochrane or embase or psychlit or psyclit or psychinfo or psycinfo or cinhal or cinahl or science citation index or scisearch or bids or sigle or cancerlit or pubmed or pub-med or medline or med-line).ab. 23 (reference list: or bibliograph: or hand-search: or handsearch: or relevant journal: or manual search:).ab. 24 (selection criteria or data extract: or quality assess: or jadad score or jadad scale or methodologic: quality).ab. 25 (stud: adj1 select:).ab. 26 (24 or 25) and review.pt. 27 or/18-23 28 26 or 27 29 consensus development conference/ 30 practice guideline/ 31 *consensus development/ or *consensus/ 32 *standard/ (2101) 33 (guideline: or recommend: or consensus or standards).kw. 34 (guideline: or recommend: or consensus or standards).ti. 35 or/29-34 36 28 or 35 37 17 or 36 38 exp carcinoma, intraductal, noninfiltrating/ 39 intraductal carcinoma/ 40 ductal carcinoma in situ.tw. 41 dcis.tw. 42 38 or 39 or 40 or 41 43 exp mastectomy/

EBS 1-10 Version 3


44 exp tamoxifen/ 45 exp radiotherapy/ 46 43 or 44 or 45 47 42 and 46 48 37 and 47 49 (2006: or 2007: or 2008: or 2009: or 2010: or 2011: or 2012: or 2013: or 2014: or 2015: or 2016:).ed. 50 (2006: or 2007: or 2008: or 2009: or 2010: or 2011: or 2012: or 2013: or 2014: or 2015: or 2016:).dd. 51 (48 and 49) or (48 and 50) 52 remove duplicates from 51 53 limit 52 to english language 54 (2016: or 2017:).dd. 55 (2016: or 2017:).ed. 56 (48 and 54) or (48 and 55) 57 remove duplicates from 56 58 limit 57 to english language

Appendix 3. Search Strategy: RCTs Search run 6 Jun 2017 Database: Embase <1996 to 2017 June 5>, Ovid MEDLINE(R) Epub Ahead of Print, In-Process & Other Non-Indexed Citations and Ovid MEDLINE(R) without Revisions 2013 to Daily Update Search Strategy: -------------------------------------------------------------------------------- 1 exp carcinoma, intraductal, noninfiltrating/ 2 intraductal carcinoma/ 3 ductal carcinoma in situ.tw. 4 dcis.tw. 5 1 or 2 or 3 or 4 6 exp mastectomy/ 7 exp tamoxifen/ 8 exp radiotherapy/ 9 6 or 7 or 8 10 5 and 9 11 (2006: or 2007: or 2008: or 2009: or 2010: or 2011: or 2012: or 2013: or 2014: or 2015: or 2016:).ed. 12 (2006: or 2007: or 2008: or 2009: or 2010: or 2011: or 2012: or 2013: or 2014: or 2015: or 2016:).dd. 13 (10 and 11) or (10 and 12) 14 exp Randomized Controlled Trial/ or Clinical Trial, Phase III/ or Clinical Trial, Phase IV/ or Phase 3 Clinical Trial/ or Phase 4 Clinical Trial/ or ((exp Clinical Trial/ or Prospective Study/ or Prospective Studies/) and Random$.tw.) or exp Randomized Controlled Trials as topic/ or Clinical Trials, Phase III as Topic/ or Clinical Trials, Phase IV as Topic/ or exp "Randomized Controlled Trial (Topic)"/ or "Phase 3 Clinical Trial (Topic)"/ or "Phase 4 Clinical Trial (Topic)"/ or ((exp Clinical Trials as Topic/ or exp "Clinical Trial (Topic)"/) and random$.tw.) or Random Allocation/ or Randomization/ or Single-Blind Method/ or Double-Blind Method/ or Single Blind Procedure/ or Double Blind Procedure/ or Triple Blind Procedure/ or Placebos/ or Placebo/ or ((singl$ or doubl$ or tripl$) adj3 (blind$3 or mask$3 or dummy)).tw. or (random$ control$ trial? or rct or phase III or phase IV or phase 3 or phase 4).tw. or (((phase II or phase 2 or clinic$) adj3 trial$) and random$).tw. or (placebo? or (allocat$ adj2 random$)).tw. or (random$ adj3 trial$).mp. or "clinicaltrials.gov".mp. 15 13 and 14 16 remove duplicates from 15 17 limit 16 to english language 18 (2016: or 2017:).ed.

EBS 1-10 Version 3


19 (2016: or 2017:).dd. 20 (10 and 18) or (10 and 19) 21 14 and 20 22 remove duplicates from 21 23 limit 22 to english language

EBS 1-10 Version 3


DEFINITIONS OF REVIEW OUTCOMES

1. EDUCATION AND INFORMATION – EDUCATION AND INFORMATION means that a Clinical

Expert and/or Expert Panel has reviewed new evidence pertaining to the guideline topic

and determined that the guideline is out of date or has become less relevant. The

document will no longer be tracked or updated but may still be useful for academic or

other informational purposes. The document is moved to a separate section of our

website and each page is watermarked with the words “EDUCATION AND INFORMATION.”

2. ENDORSED – ENDORSED means that a Clinical Expert and/or Expert Panel has reviewed

new evidence pertaining to the guideline topic and determined that the guideline is still

useful as guidance for clinical decision making. A document may be endorsed because the

Expert Panel feels the current recommendations and evidence are sufficient, or it may

be endorsed after a literature search uncovers no evidence that would alter the

recommendations in any important way.

3. UPDATE – UPDATE means the Clinical Expert and/or Expert Panel recognizes that the

new evidence pertaining to the guideline topic makes changes to the existing

recommendations in the guideline necessary but these changes are more involved and

significant than can be accomplished through the Document Assessment and Review

process. The Expert Panel advises that an update of the document be initiated. Until that

time, the document will still be available as its existing recommendations are still of

some use in clinical decision making, unless the recommendations are considered

harmful.

management of ductal carcinoma in situ of the breast · 2020-01-23 · management of ductal...

Documents