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

Transcription

1 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

2 Is it practical for? Detecting early cancer? or prevent death from cancer? Allaying patient s anxiety? ( after all, patient can afford the test!)

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

4 Cancer fear is real. Marker research: Harris Interactive

5 Cancer fear is real. Survey of 13,351 general adults in the eligible age range in participating 506 General Practices with a return rate of 59.7% Of all the diseases there are, I am most afraid of Cancer It makes me uncomfortable to think about cancer 52% 59% I worry a a lot about cancer 25% 0% 50% 100% Other studies: ranged from 35-62% Vrinten et al. BMC Cancer 2014, 14:597

6 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

7 What is offered publically

8 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.

9 Evidence for tumour markers? Facts of tumour markers: what liteature says

10 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 Diagnosis or case Prognosis (with Detecting Monitoring early detection finding other factors) recurrence 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) Human chorionic gonadotrophin Colorectal cancer No No Yes Yes Yes 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

11 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 Diagnosis or case Prognosis (with Detecting Monitoring early detection finding other factors) recurrence 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) Human chorionic gonadotrophin Colorectal cancer No No Yes Yes Yes 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

12 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 Diagnosis or case Prognosis (with Detecting Monitoring early detection finding other factors) recurrence 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) Human chorionic gonadotrophin Colorectal cancer No No Yes Yes Yes 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

13 Raised tumour markers in other malignant conditions Sturgeon, Lai, Duffy BMJ 2009;339:b3527

14 Factors that may influence interpretation of tumour markers* 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 Cystoscopy Digital rectal examination Prostatic needle biopsy Prostatic massage Prostate ultrasonography Transurethral prostatic biopsy PSA PSA PSA (in some men) PSA PSA PSA PSA Sturgeon, Lai, Duffy BMJ 2009;339:b3527

15 Benign conditions that contribute to raised 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 Sturgeon, Lai, Duffy BMJ 2009;339:b3527

16 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

17 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

18 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 noncancer 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

19 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 noncancer in 91% of patients without cancer Disease No Disease Total Test Positive Negative Total Sensitivity Specificity 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

20 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 noncancer in 91% of patients without cancer 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 Asymptomatic (screening) with normal DRE Risk/prevalence sensitive prediction Negative Predictive values if < 4ng/ml Meaning 85%* Patient has 85% chance of NOT having 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

21 Proportion with cancer from biopsy % of them have high grade cancer 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 25% of them have high grade cancer 0 <= to to to to 4.0 PSA level: ng/ml *Thompson IM et al N Engl J Med. 2004;350(22):2239

22 RCTs on prostate cancer screening using PSA on hard outcomes Absolute difference: ERSPC: +3.6% PLCO: +1.1% Absolute difference: ERSPC: -0.11% PLCO: Hayes JH. JAMA. 2014;311(11):

23 CEA Colorectal cancer; Breast; gastric; lung; mesothelioma; oesophageal; pancreatic Using an upper limit of normal of 2.5 mg/l, sensitivity of 36% specificity of 87% in screening for Dukes A and B colorectal cancer 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:

24 CA 19-9 Pancreatic cancer; Colorectal; gastric; hepatocellular; oesophageal; ovarian Author, year n CA 19-9 (>37 U/mL) Pancreatic cancer, n (%) Sensitivity (%) Specificity (%) Satake et al., ,840(1) 0.2% 4 (0.03) PPV (%) NPV (%) 4,506 (2) 4.3% 85(1.98) Kim et al., , % 4(0.01) Chang et al., , % 2(0.04) =Asymptomatic individuals, 2=symptomatic individuals; Satake s study was based on registry and incomplete data was reported A very low prevalence disease, thus, inefficient in screening Useful for prognostic, survival, treatment response marker Ballehaninna UK. J Gastrointest Oncol 2012;3(2):

25 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 Screening (PLOC) Review , % 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),

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

27 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% Jacobs IJ et al. Lancet 2016; 387:

28 α-fetoprotein Hepatocellular, colorectal, lung, germ cell 80% of HCC are related to either HBV or HCV. (McGlynn KA, 2011) Cut off of AFP level Sensitivity Specificity PPV NPV +LR US AFP 20 & US AFP 200 & US 5.85 Biannual US and serum AFP: mortality reduction of 37% in Hep B group. (Zhang BH, et al, 2004)

29 Diagnostic accuracy of tumour markers in individual patients

30 Fear is important to address in a positive way Pressure to screen: Evidence can only show what is the average benefit The guidelines say no! Clinician has to decide whether it is beneficial to individual The cliché of tailor to individual needs But, the patient want this, this and that!

31 Process of screening Screening aims to identify asymptomatic population who are at higher risk of a disease. Higher risk individual Test: +ve Higher risk (probability) of a disease Higher chance of falling into false +ve Confirmatory test General Population Test Lower risk individual Imperfect validity -ve Lower risk (probability) of a disease Higher chance of false ve

32 Process of screening Screening aims to identify asymptomatic population who are at higher risk of a disease. Higher risk individual Test: +ve Higher risk (probability) of a disease Higher chance of falling into false +ve Confirmatory test General Population Test Lower risk individual Imperfect validity -ve Lower risk (probability) of a disease Higher chance of false ve

33 Process of screening Screening aims to identify asymptomatic population who are at higher risk of a disease. Higher risk individual Test: +ve Higher risk (probability) of a disease Higher chance of falling into false +ve Confirmatory test General Population Test Lower risk individual Imperfect validity -ve Lower risk (probability) of a disease Higher chance of false ve

34 Process of screening Screening aims to identify asymptomatic population who are at higher risk of a disease. Higher risk individual Test: +ve Higher risk (probability) of a disease Higher chance of falling into false +ve Confirmatory test General Population Test Lower risk individual Imperfect validity -ve Lower risk (probability) of a disease Higher chance of false ve Focus of counseling

35 Process of screening Different population has different complications and benefit from screening test. Complications from test procedure Benefit of diagnosis on overall mortality Older and fragile More prone Smaller General Population Test Confirmatory test Younger and healthier More resistant Larger Wilson JA 2010

36 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) No screening screening

37 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

38 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?