Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Can Biomarkers be Used in Screening for Cancer? Professor Joe Duffy St Vincent’s University Hospital and School of Medicine & Medical Science, University College, Dublin. Approaches to Controlling Disease Prevention Develop better treatments Early detection by screening Established Risk Factors for Cancer Smoking UV light Obesity Approaches to Controlling Disease Prevention Develop better treatments Early detection by screening Concept of Cancer Screening is Appealing Catch it early Remove it Cure “A stitch in time saves nine” “An ounce of prevention is worth a pound of cure” Cancer Screening is Widely Sold Endorsed by celebrities Politicians use it to get votes Promoted by certain “cancer help groups” Cancer Screening is Superficially a Win:Win Situation If test is positive: patient and doctor feel gratified that disease was caught early If negative, patient and doctor feel reassured If diagnostic workup causes complications, patients feels the price is worth it for survival Ransohoff D, et al. Am J Med 2002;113:663 Three quarters of the US population would chose a total body CT scan over 1000$ gift voucher Schwartz, JAMA 2004;291:71 Screening for Cancer The aim of screening is to detect early malignancy or a premalignant condition in healthy subjects It is assumed that early detection results in a better outcome Ideally, only tests shown to reduce mortality in a large randomized trial should be used in screening Recommended Cancer Screening Tests Cancer Breast CRC Cervical Technique Mammography FOBT/colonoscopy PAP Survival Yes Yes Yes Advantages of Biomarkers as Cancer Screening Tests Biomarkers can be measured in biological fluids (blood, urine) that can be obtained with minimal inconvenience. This in turn should lead to high compliance rates. For many biomarkers, automated assays are available, allowing the processing of large numbers of samples in a relatively short period of time. Advantages of Biomarkers as Cancer Screening Tests Tests for biomarkers provide quantitative results with objective endpoints. Assays for biomarkers are relatively cheap. Biomarkers Investigated for Cancer Screening PSA: prostate cancer CA 125: ovarian cancer FOBT: colorectal cancer PSA as a Screening Test for PCa Vast majority of cancers detected via PSA screening are organconfined Use of PSA has potential to detect PCa up to 10 years before clinical evidence of disease PSA as a Screening Test for PCa PCa detected with PSA screening have lower stage and are more differentiated than those detected outside of screening Since the introduction of PSA screening, death rates from PCa have declined PCa Screening is Controversial PSA alone is less than an ideal screening test for PCa Screening may lead to overdiagnosis and thus overtreatment Definitive therapy for localised PCa unclear Unknown if screening for PCa reduces mortality Prevalence of PCa in Relation to PSA level PSA level (ug/L) % PCa <0.5 6.6 0.6-1.0 10.1 1.1-2.0 17 2.1-3.0 23.9 3.1-4.0 26.9 Thompson, N Engl J Med 2005;350:2239 Prevalence of High Grade PCa in Relation to PSA level PSA level (ug/L) % High Grade PCa <0.5 12.5 0.6-1.0 10.0 1.1-2.0 11.8 2.1-3.0 19.1 3.1- 4.0 25.0 Thompson, N Engl J Med 2005;350:2239 Prevalence of PCa in Relation to PSA level Only approximately 1 in 4 men with a PSA level 4-10 ug/L will have a positive biopsy Overdiagnosis Term used when a condition is diagnosed that would otherwise not go on to cause symptoms or death May result from 2 possibilities: a) cancer never progress or may regress b) cancer progresses so slowly that the patient dies of other causes before cancer becoming symptomatic Overdiagnosis Overdiagnosis is a particularly serious problem for PCa because of the disparity between the histological evidence of disease and deaths from the disease Overdiagnosis > 50% of men > 50 yr have histological evidence of prostate cancer Approx 16% diagnosed with the disease Life-time risk of dying from the disease is 3% Overdetection of PCa by PSA Screening For a single screen At 55 yrs of age: Overdetection rate, 27% At 75 yrs of age, Overdetection rate, 56% For annual screening between 55-67 yr: Overdetection rate: 50% and Lifetime risk of PCa diagnosis increased by 80% Draisma et al. JNCI 2003;95:868 Definite or best therapy for men with localised PCa is unknown Treatment: Implications of Screening A prerequisite for any disease screening programme is that there should be effective and definitive treatment for the screened disease Treatment Options for PCa Radical prostatectomy Radiotherapy, Brachytherapy Androgen deprivation Observation/Active surveillance Side Effects of Treatments for Early PCa (ERSPC) Radical prostatectomy 80-90% erectile dysfunction 39-49% urinary incontinence Radiotherapy 41-55% erectile dysfunction 6-7% incontinence 30-35% bowel problems Madalinska et al, J Clin Oncol 2001:19:1619 Radical Prostatectomy vs Watchful Waiting RP reduced formation of metastasis by 6.7% RP reduced death rates from PCa by 5.4% Reduction in metastasis and death confined to men <65 years of age Overall mortality was not significantly different Bill-Axelson et al. JNCI 2008;17:1797 RADICAL PROSTATECTOMY vs WATCHFUL WAITING: Side Effects Erectile dysfunction (80 vs 45%) and urinary leakage (49 vs 21%) more common after RP whereas urinary obstruction (28 vs 44%) was less common. Subjective quality of life was similar in the 2 groups. Steinbeck et al, N Eng J Med 2002;347:790 Unknown if screening for PCa reduces mortality PSA as a Screening Test for PCa: Way Forward Perform a large prospective randomised trial comparing patient outcome and quality of life in screened and control groups. Trial would require approx 200,000 men and a time period of approx 10 yr Randomized Trials Evaluation PSA in Screening for PCa, in Progress European Randomized Screening for Prostate Cancer (ERSPC) Prostate, Lung, Colorectal and Ovarian Cancer (PLCO) End of 2001, >215,000 subjects randomized. de Koning et al. IJC 2002;97:237 PCa Screening: PLCO Cancer Screening Trial 77, 000 men randomized to screening or no screening Annual PSA testing for 6 yr and DRE for 4 yr After 7-10 yr follow-up, similar rates of death in 2 groups Andriole et al, NEJ Med 2009;13:1310 Cumulative deaths from prostate cancer in the intervention and control arms from year 1 to year 13. Andriole G L et al. JNCI J Natl Cancer Inst 2012;104:125-132 PCa Screening: ERSPC 182 000 men randomized to screening or no screening PSA testing every 4 yr, on average PSA screening reduced rate of death from prostate cancer by 20% Schroder et al, NEJ Med 2009;360:1320 PCa Screening: ERSPC To prevent one death from PCa, 1410 men would have to be screened and 48 patients treated Schroder et al, NEJ Med 2009;360:1320 ERSPC Trial: Follow-up, 11 yr PSA screening decreased rate of death from PCa by 21% No difference in all-cause mortality between screened and control groups Schroder et al, N Engl J Med 2012;366:981 Screening for Prostate Cancer: Systematic Review and Meta-analysis Systematic review of the literature identified 6 randomized prospective controlled trials of PCa screening Total no of patients: 387,286 Screening was associated with a significant increase probability (46%) of being diagnosed with PCa Djulbegovic et al. BMJ 2010;341 Screening for Prostate Cancer: Systematic Review and Meta-analysis Screening had no significant impact on deaths from PCa Screening had no significant impact on overall mortality Djulbegovic et al. BMJ 2010;341 Complications of Prostate Biopsy Complication % Affected Pain 44 Fever 18 Haematuria 66 Hematochezia 37 Haemoejaculate 93 Rosario et al, BMJ 2012;344:d7894 PSA Population-Based Screening: Recommendation by Expert Panels American Cancer Society: Yes American Urological Society: Yes European Urological Society: Yes European Group on Tumor Markers: No European Society of Med Oncology: No Nat Academy of Clin Biochemistry: No Nat Institute of Clinical Excellence: No US Preventive Service Task Force: No Screening for Prostate Cancer: ASCO PCO In men with a life expectancy < 10 yr, screening should be discouraged as harms seem to outweigh benefits In men with a life expectancy of > 10 yr, doctors should discuss with their patients if PSA testing is appropriate. PSA testing may save lives but is associated with harm, including complications from unnecessary biopsy, surgery, or radiation Basch et al, JCO 2012 Screening for Prostate Cancer: ASCO PCO It is recommended that information written in lay language be available to clinicians and their patients to facilitate the discussion of the benefits and harms associated with PSA testing before the routine ordering of a PSA test. Basch et al, J Clin Oncol 2012 Ovarian Cancer > 70% diagnosed with advanced disease 5-yr survival for women with advanced disease: 20-30% For women diagnosed with early disease: 5-yr survival: 80% Traditional View of Ovarian Cancer Referred to as “the silent disease” Prevailing view was that there were usually no symptoms until advanced disease was present, ie, when prognosis was dire Ovarian Cancer is not so Silent: Ovarian Cancer Symptom Index Pelvic pain/Abdominal pain Urinary urgency/Urinary frequency Increased abdominal size/bloating Difficulty in eating/feeling full Index positive: if any of those 6 symptoms occurred >12 times per mo for < 1 yr Goff et al. Cancer 2007:109:221 Screening for Ovarian Cancer UKCTOCS Trial PLCO Trial (USA) Screening for Ovarian Cancer (UKCTOCS Trial) Involves CA 125 and TVU > 200,000 women randomized Sensitivity for ovarian cancer: 89% Specificity for ovarian cancer: 99.8% PPV for ovarian cancer: 35% Approx 50% of cancer detected had early disease Menon et al. Lancet Oncol 2009 PLCO Screening Trial for Ovarian Cancer 78,216 women randomised to screening or usual care Screened group had annual CA 125 measurements for 6 yr & TVU for 4 yr Median follow-up: 12 .4 yr Buys et al. JAMA 2011;305:2295 Effect of Screening on Disease Stage at Diagnosis Stage Screened (no, %) Controls (no, %) I 32 (15%) 18 (10%) II 15 (7%) 20 (11%) 111 120 (57%) 83 (47%) IV 43 (20%) 54 (31%) Buys et al, JAMA 2011;305:2295 Effect of Screening on Cumulative Cases and Deaths Buys, S. S. et al. JAMA 2011;305:2295-2303 Complications Resulting from Screening False positive screening tests: 3285 Resulting surgeries: 1080 Serious complications: 163 Buys et al. JAMA 2011;305:2295 CA 125 in Women with Symptoms Suggestive of Ovarian Cancer Measure serum CA125 in primary care in women with symptoms that suggest ovarian cancer If serum CA125 > 35 IU/ml, arrange an US scan of the abdomen and pelvis. If US suggests ovarian cancer, refer woman urgently for further investigation. NICE Guidelines 2011 Tumor Markers in Early Diagnosis of Ovarian Cancer Measure serum CA125 in secondary care in all women with suspected ovarian cancer, if this has not already been done in primary care. In women under 40 with suspected ovarian cancer, measure levels of AFP beta-hCG as well as serum CA125, to help identify women with germ cell tumours. NICE Guidelines, 2011 Does Early Referral Affect Outcome? 1318 women with symptoms of ovarian cancer presented to a medical practitioner: 50% within 1 mo 70% within 2 mo 90% within 6 mo 10% after 6 mo Nagle et al, J Clin Oncol 2011;29:2253 Does Early Referral Affect Outcome? No significant relationship found between time to diagnosis and stage of disease at diagnosis or survival Nagle et al, J Clin Oncol 2011;29:2253 Attempts at Early Diagnosis of Ovarian Cancer 1455 patients with symptoms of ovarian cancer 22 gynecological cancers detected 11/22 were ovarian cancer (ie, a prevalence of 1 in 132 (0.7%) Gilbert et al, Lancet Oncol 2012 Characteristics of Ovarian Cancers Detected Tumor Trial patients Clinic patients P value Stage 1 &2 4 (36%) 17 (23%) NS Stage 3 & 4 7 (65%) 58 (77%) NS CA 125 level (Median) 72 888 <0.01 High grade serous 9 (82%) 51 (89%) NS Gilbert et al, Lancet Oncol 2012 FOBT in screening for colorectal cancer Status of CRC Screening 43 organized schemes were identified, based in 24 different countries Of 35 in operation for > 1 yr, 26 were population-based screening programmes, 9 pilot Benson et al, IJC 2012;130;122:2961 CRC Screening: Available Tests Bowel visualisation Colonoscopy, Computed tomographic colonography, Flexible sigmoidoscopy Biochemical FOBT Stools DNA Serum markers Screening Tests Being Used Across the World gFOBT: 16 FIT: 9 Endoscopy: 9 Benson et al, IJC 2012;130;122:2961 Advantages of FOBT vs Bowel Visualisation Tests Safe, non-invasive No bowel preparation necessary Less expensive to perform Can be done in privacy of ones home Best validated CRC screening test Impact of CRC Screening with FOBT in Reducing Mortality 4 large prospective randomized trials performed Involved > 320,000 subjects Meta-analysis: 16% reduction in mortality in the screened group When corrected for non-attendance, reduction in mortality was 25% Cochrane Systematic Review, 2007 Types of FOBTs Guaiac-based (gFOBT) which detects the pseudoperoxidase activity of the haem moiety in haemoglobin Faecal immunochemical test (FIT or iFOBT) which detects the globin moiety in intact human haemoglobin or its early degradation products gFOBT vs FIT: Advantages of FIT FITs have increased analytical sensitivity and specificity Use of FITs leads to higher uptake rates FITs can be automated FITs are quantitative or semi-quantitative FITs provide an adjustable cut-off point With FITs, no dietary or medication restriction Duffy et al. Int J Cancer 2011;128:3 gFOBT vs FIT: Disadvantages of FIT FITs are more expensive to perform Samples for FITs less stable after collection of stools FITs are less well clinically validated EGTM Recommendations for FOBT in CRC Screening A quantitative FIT with an adjustable cut-off point is recommended Duffy et al, Int J Cancer 2011;128:3 FIT vs Colonoscopy in Screening for CRC Criteria Colonoscopy FIT P value Uptake 24.6% 34.2% < 0.001 Cancer detection 0.5% 0.3% NS Adv adenoma detection 9.7% 2.4% < 0.001 Eary adenoma detection 22.1% 1.1% <0.001 Complications 0.5% 0.1% <0.001 Quintero et al. N Engl J Med 2012;366:697 Markers Under Evaluation or Previously Evaluated for Cancer Screening Cancer Marker(s) Neuroblastoma HCC* Prostate Ovarian Stomach Colorectal VMA/HVA AFP PSA CA 125 Pepsinogen FOBT Survival No Yes ? ? ? Yes *In patients infected with hepatitis B or C Thank you US vs European Trial Parameter USA trial PSA assay Beckman European trial Beckman Cut-off 4 ug/L 3 ug/L (most) Frequency Annual X 6 yr Every 4 yr DRE Yes No (most) fPSA No Only at 1 site PLCO PCa Screening Trial: Possible Reasons for Negative Findings Cut-off point of 4 ug/L too high PSA screening in control group negating impact on test group Excess PSA screening had occurred prior to start of study Andriole et al, N Eng J Med 2009;360:13 PLCO PCa Screening Trial: Possible Reasons for Negative Findings Improvement in therapy resulted in fewer deaths in both groups and blunted a potential benefit of screening Follow-up might not have been long enough to see a benefit of early detection in the screened group Andriole et al, N Eng J Med 2009;360:13 Prostate Cancer Screening: The Reality Doubles the risk of a lifetime diagnosis of prostate cancer with little of any decrease in the risk of dying from the disease Prostate Cancer Screening: The Reality In 1985 before PSA screening in the US, a man had an 8.7% lifetime risk of being diagnosed with PCa and a 2.5% risk of dying from the disease In 2005, he had a 17% lifetime risk of being diagnosed with PCa and a 3% risk of dying from it Boyle et al. CA C J Clin 2009;59:220 ERSPC Trial Results: Implications Screening doubled the risk if being diagnosed with PCa Decreased the probability of dying from PCa by 20%, ie, from 3% to 2.4% Boyle et al. CA Cancer J Clin 2013;59:220