screening of tumour marker: is it practical? · tumour marker relevant cancer currently recommended...

Tumour Markers as screening tests for cancer: is it practical?

Dr Tong SF MBBS (UM) MMed (Fam Med) (UKM) PhD (Sydney)

Department of Family Medicine

Faculty of Medicine

UKM

Is it practical…for?

• Detecting early cancer? … or prevent death from cancer?

• Allaying patient’s anxiety?

(…after all, patient can afford the test!)

May be these are done for reasons that we do not know.

Cancer fear is real.

http://www.webmd.com/alzheimers/news/20110223/americans-worry-about-getting-alzheimers

Marker research: Harris Interactive


• Survey of 13,351 general adults in the eligible age range 55-64 in

participating 506 General Practices with a return rate of 59.7%

• Other studies: ranged from 35-62%

Vrinten et al. BMC Cancer 2014, 14:597

25%

52%

59%

0% 50% 100%

I worry a a lot about cancer

It makes me uncomfortable to think aboutcancer

Of all the diseases there are, I am most afraidof Cancer


In Malaysia, a FGD about cardiovascular screening….

“I believe everyone is more worried about cancer. So I feel what you

said about stroke, those heart diseases, these, they are probably not so

bother about”

45-year-old account executive

Cheong AT, et al. AP WONCA 2015

What is offered publically…

Fear is important to address in a positive way

• Pressure to screen:

Evidence can only show what is the average benefit

Clinician has to decide whether it is beneficial to individual

The guidelines say no to tumour markers! I want to be tested.

Facts of tumour markers: what liteature says

Evidence for tumour markers?

Tumour marker Relevant cancer Currently recommended clinical recommendations

Screening or

early detection

Diagnosis or case

finding

Prognosis (with

other factors)

Detecting

recurrence

Monitoring

treatment

α fetoprotein Germ cell/testicular tumour No Yes Yes Yes Yes

Hepatocellular carcinoma Yes* Yes† Yes Yes Yes‡

Calcitonin Medullary thyroid carcinoma No Yes No Yes Yes

Cancer antigen 125 (CA125) Ovarian cancer Under

evaluation§

Yes¶ Yes Yes Yes**

Cancer antigen 15-3 (CA15-3) Breast cancer No No No Yes†† Yes‡‡

Cancer antigen 19-9 (CA19-9) Pancreatic cancer No Yes§§ Yes Yes Yes¶¶

Carcinoembryonic antigen

(CEA)

Colorectal cancer No No Yes Yes‡ Yes‡

Human chorionic

gonadotrophin

Germ cell and testicular cancers;

gestational trophoblastic neoplasia

No Yes Yes Yes Yes

Paraproteins B cell proliferative disorders No Yes No Yes Yes

Prostate specific antigen Prostate cancer No Yes Yes Yes Yes

Thyroglobulin Thyroid cancer No No No Yes Yes

Sturgeon, Lai, Duffy BMJ 2009;339:b3527

Commonly requested serum tumour markers and the current recommendations of the National Academy of Clinical Biochemistry

Raised tumour markers in other malignant conditions


Factor Tumour marker Lifestyle

Smoking CEA—minor increase in some assays Cannabis use Human chorionic gonadotrophin—transient increase

Medication 5 α reductase inhibitors PSA—median decrease of about 50%

Medical investigation/intervention Chemotherapy Most tumour markers, especially with bulk disease, transient Laparoscopy CA125

Catheterisation PSA† Cystoscopy PSA‡ Digital rectal examination PSA (in some men)‡ Prostatic needle biopsy PSA§ Prostatic massage PSA‡ Prostate ultrasonography PSA‡ Transurethral prostatic biopsy PSA§

Factors that may influence interpretation of tumour markers*


CA19-9 Acute cholangitis Acute and/or chronic pancreatitis Cholestasis Chronic liver diseases

o such as cirrhosis, chronic active hepatitis

Diabetes Irritable bowel syndrome Jaundice Pancreatitis CA15-3 Acute hepatitis Chronic liver diseases

o such as cirrhosis, chronic active hepatitis

Chronic renal failure Colitis Dermatological conditions

CA125 Acute hepatitis Acute and/or chronic pancreatitis Acute urinary retention Arthritis/osteoarthritis/rheumatoid arthritis Chronic liver diseases—such as cirrhosis, chronic active hepatitis Chronic renal failure Colitis Congestive heart failure Cystic fibrosis Diabetes Diverticulitis Endometriosis Heart failure Irritable bowel syndrome Leiomyoma Menstruation Non-malignant ascites Ovarian hyperstimulation Pancreatitis Pericarditis Peritoneal inflammation Pregnancy Recurrent ischaemic strokes in patients with metastatic cancer Respiratory diseases—such as pleural inflammation, pneumonia Sarcoidosis Systemic lupus erythematosus

PSA Acute urinary retention Benign prostatic hyperplasia Prostatitis Urinary tract infection

CEA Chronic liver diseases—such as

cirrhosis, chronic active hepatitis

Chronic renal failure Colitis Diverticulitis Irritable bowel syndrome Jaundice Respiratory diseases—such as

pleural inflammation, pneumonia

Human chorionic gonadotrophin Chronic renal failure Menopause Pregnancy α fetoprotein Liver regeneration Pregnancy


Benign conditions that contribute to raised “tumour” markers

What are the messages from these tables?

From the perspective of the test:

• Might be sensitive • Test might pick up many diagnoses

• But, they are generally not accurate • Too many conditions or factors are associated with the raised cancer markers

What are the messages from these tables?

From the perspective of the test:

• Might be sensitive • Test might pick up many diagnoses

• But, they are generally not accurate • Too many conditions or factors are associated with the raised cancer markers

From the perspective of diagnostic usefulness for patients:

• What is the chances of patients having cancer (or negative)? • The predictive values…

PSA – a careful interpretation

Cut off of 4ng/ml Meaning

Sensitivity 21% for any grade, 51% for high grade Test has the ability in correctly identify cancer in 21% (or 51%) of patient with cancer

Specificity 91% for any grade Test has the ability in correctly identify non-cancer in 91% of patients without cancer

American Cancer Society guideline for the early detection of prostate cancer: update 2010

*Thompson IM et al N Engl J Med. 2004;350(22):2239







Positive

Negative

Total

Test

DiseaseNo

Disease Total

Sensitivity Specificity

90

85

15

10

105

95

100 100

.85.90






Pre-test condition Positive Predictive values if > 4ng/ml

Meaning

Asymptomatic (screening) 30% Patient has 30% chance of cancer

Abnormal DRE 50% Patient has 50% chance of cancer

Pre-test condition Negative Predictive values if < 4ng/ml

Meaning

Asymptomatic (screening) with normal DRE

85%* Patient has 85% chance of NOT having cancer


Risk/prevalence sensitive

prediction

0

5

10

15

20

25

30

<=0.5 0.6 to1.0 1.1 to 2.0 2.1 to 3.0 3.1 to 4.0

Pro

po

rtio

n w

ith

can

cer

fro

m b

iop

sy

PSA level: ng/ml

The proportion of men with prostate cancer among 2,950 men who never had a PSA level of more than 4.0 ng per milliliter or an abnormal

digital rectal examination after 7 years of follow up

12.5% of them have high grade cancer

25% of them have high grade cancer


Absolute difference: ERSPC: -0.11% PLCO: +0.03

Absolute difference: ERSPC: +3.6% PLCO: +1.1%

RCTs on prostate cancer screening using PSA on hard outcomes

Hayes JH. JAMA. 2014;311(11):1143-1149.

CEA

• Using an upper limit of normal of 2.5 mg/L, • sensitivity of 36%

• specificity of 87%

• Only rarely, benign diseases give rise to serum values of > 10 mg/L

• Disadvantage of not able to localise the lesions

• Have other better modalities with good evidence, i.e. iFOBT, colonoscopy

• Non-CRC cancers are rare: considering the low validity of the test, the predictive values will be poor

Duffy MJ. Clin Chem 2001;47:624 –30.

in screening for Dukes’ A and B colorectal cancer

Colorectal cancer; Breast; gastric; lung; mesothelioma; oesophageal; pancreatic

CA 19-9

Author, year n CA 19-9

(>37 U/mL)

Pancreatic

cancer, n

(%)

Sensitivity

(%)

Specificity

(%)

PPV

(%)

NPV

(%)

Satake et al., 1994

12,840(1) 0.2% 4 (0.03) - - - -

4,506 (2) 4.3% 85(1.98) - - - -

Kim et al., 2004 70,940 1.5% 4(0.01) 100 98.5 9 100

Chang et al., 2006 5,343 7.2% 2(0.04) 100 92.8 5 100

1=Asymptomatic individuals, 2=symptomatic individuals; Satake’s study was based on registry and incomplete data was reported

Ballehaninna UK. J Gastrointest Oncol 2012;3(2):105-119

Pancreatic cancer; Colorectal; gastric; hepatocellular; oesophageal; ovarian

• A very low prevalence disease, thus, inefficient in screening • Useful for prognostic, survival, treatment response marker

CA 125 Ovarian cancer; Breast; cervical; endometrial; hepatocellular; lung; non-Hodgkin’s lymphoma; pancreas; peritoneal; uterus

n Elevated

CA 125(%)

Sensitivity

(%)

Specificity

(%)

PPV

(%)

NPV (%)

Women with

adnexal mass

Review 61-90 35-91 35-91 67 -91

Screening

(PLOC)

28,000+ 1.4 55 99 3.98% 99.95%

PLOC: 26 ovarian cancer case found (≈0.1%) • Some patients were subjected to exploratory laparotomy • 1 cancer was found for every 3.9 surgeries • 14 out of 16 patients diagnosed because of elevated CA 125 were in

advanced stage ACOG; 2007 SS Buys et al. Am J Obstet Gynecol 193 (5), 1630-1639. 11 2005

Jacobs IJ et al. Lancet 2016; 387: 945–56

Ovarian cancer screening and mortality in the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS)

• 202 638 (>99.9% of follow-up) • Median follow up 11 years • Ovarian cancer 0.6%

• MMS: 0·7% • USS : 0·6% • Control: 0·6%

High number of undetected cases

Jacobs IJ et al. Lancet 2016; 387: 945–56

Ovarian cancer screening and mortality in the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS)

At censorship, mortality rate: 0.32%

Control: 0.34%

MMS: 0.29%

USS: 0.30%

𝛂-Fetoprotein

• 80% of HCC are related to either HBV or HCV. (McGlynn KA, 2011)

• Biannual US and serum AFP: mortality reduction of 37% in Hep B group. (Zhang BH, et al, 2004)

Hepatocellular, colorectal, lung, germ cell

Cut off of AFP level Sensitivity Specificity PPV NPV +LR

20 49-71 49-86 1.28-4.03

200 4-31 76-100 1.13-54.25

US 40-81 80-100 77.4

AFP 20 & US 99.2 68.3 2.45

AFP 200 & US 5.85

Diagnostic accuracy of tumour markers in individual patients

Fear is important to address in a positive way

• Pressure to screen:

Evidence can only show what is the average benefit

Clinician has to decide whether it is beneficial to individual The cliché of “tailor to individual needs”

The guidelines say no! But, the patient want this, this and that!

Process of screening Screening aims to identify asymptomatic population who are at higher risk of a disease.

General Population

Test: +ve Higher risk

(probability) of a disease

-ve Lower risk


Confirmatory test

Test

Higher risk individual

Lower risk individual

Higher chance of falling into false +ve

Higher chance of false – ve

Imperfect validity

Process of screening Screening aims to identify asymptomatic population who are at higher risk of a disease.

General Population

Test: +ve Higher risk


-ve Lower risk


Confirmatory test

Test

Higher risk individual

Lower risk individual

Higher chance of falling into false +ve

Higher chance of false – ve

Imperfect validity

Focus of counseling

Process of screening

Different population has different complications and benefit from screening test.

General Population Confirmatory test Test

Older and fragile

Younger and healthier

Wilson JA 2010

Complications from test procedure

More prone

More resistant

Benefit of diagnosis on overall mortality

Smaller

Larger

Cancer – a unique disease

• Lead time bias Apparent increase in survival – a significant issue if treatability is questioned (including whether patient will adhere to proven treatment)

(e.g Ovarian cancer)

• Length time bias Detection of less aggressive cancer

- over diagnosis

- over treatment

(e.g Prostate cancer)

http://www.cancer.gov/newscenter/qa/2002/nlstqaQA

Noscreening

screening

Ethical consideration of cancer screening with tumour markers: the non-maleficence principle

• Patient coming for screening is “healthy” to start with.

• Justifying harm caused by screening is more difficult than justifying harm caused by treatment of symptomatic patients.

Healthy person coming for screening

A sick patient seeking treatment

Are tumour markers practical for…?

• Detecting early cancer? … or prevent death from cancer? - data do not support this…but that is from a public health perspective

• Allaying patient’s anxiety? For individual patients - ultimate benefit versus harm:

Most people will not benefit from it.

But, what is your risk? How much you can take on the harms of screening?

screening of tumour marker: is it practical? · tumour marker relevant cancer currently recommended...

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