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
Cancer fear is real.
• 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
Cancer fear is real.
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
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
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
Sturgeon, Lai, Duffy BMJ 2009;339:b3527
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*
Sturgeon, Lai, Duffy BMJ 2009;339:b3527
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
Sturgeon, Lai, Duffy BMJ 2009;339:b3527
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
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
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
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
*Thompson IM et al N Engl J Med. 2004;350(22):2239
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
*Thompson IM et al N Engl J Med. 2004;350(22):2239
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
(probability) of a disease
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
(probability) of a disease
-ve Lower risk
(probability) of a disease
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
(probability) of a disease
-ve Lower risk
(probability) of a disease
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
(probability) of a disease
-ve Lower risk
(probability) of a disease
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?
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