Cancer Screening 2009: Setting Evidence-based Priorities

Transcription

1 Cancer Screening 2009: Setting Evidence-based Priorities Eliseo J. Pérez-Stable, MD Professor of Medicine Department of Medicine Division of General Internal Medicine University of California, San Francisco April 6, 2009 Declaration of full disclosure: No conflict of interest Principles of Cancer Screening Screening for cancer associated with decreased morbidity and mortality Disease is prevalent, serious and has a detectable preclinical phase Treatment of pre-symptomatic disease is more effective than treatment after symptoms develop Benefits of the test should outweigh potential harms Enthusiasm for Cancer Screening in the United States: National Survey 87% Good Idea Almost Always 74% Most or All the Time Finding Cancer Early Saves Lives 56% Want to be tested for cancers which would never cause problems during the persons lifetime 73% Would prefer to receive a total-body CT scan instead of receiving $1000 JAMA. 2004; 291:

2 Cancer Incidence by Site in Women White African Latina Asian American Breast Lung Colorectal Cervix Stomach Liver *Rates per 100,000 age-adjusted to the US 2000 population ** SEER Registries: 12 SEER areas Cancer Incidence by Site in Men White African LatinoAsian American Prostate Lung Colorectal Stomach Liver 6.2 ` *Rates per 100,000 age-adjusted to the US 2000 population from 12 SEER Registries Colon Cancer Screening Early Detection and Primary Prevention 2

3 Screening for Colon Cancer 3 large randomized trials have shown that screening with fecal occult blood test (FOBT) or sigmoidoscopy is associated with a 15% to 33% reduction in colon cancer mortality U.S. Preventive Services Task Force recommends screening persons over 50 y 90% of cases occur after age 50 Benefits outweigh potential harms Stop screening at age 75 Screening for Colon Cancer Trials Minnesota UK Denmark N age, y frequency annual/biennialbiennial biennial rehydration yes no no adherence 1 90% 60% 67% Ransohoff, AIM1997; 126:811 Screening for Colon Cancer: FOBT Randomized Controlled Trials Minnesota UK Denmark Follow-up, y % Positive rate / /1.7 PPV: 1st / rescreen / /8-16 RR reduction, % Ransohoff, AIM1997; 126:811 3

4 Colon Cancer Screening Multi-society Task Force Annual stool test (Every 2 years is OK; FIT) Flexible sigmoidoscopy every 5 years Annual FOBT plus sigmoidoscopy every 5 y Double-contrast barium enema +/- Flex Sig every 5 years (no one does this) All positive tests lead to colonoscopy Colonoscopy every 10 years (no FOBT x 5 y) American College of Gastroenterology recommends colonoscopy every 10 years as the preferred strategy Colon Cancer Screening 2008 American Cancer Society, The U.S. Multi-Society Task Force on Colorectal Cancer, and the American College of Radiology re-endorsed previous list and added two new options: Computed Tomography Colonography every 5 years (CMS may not pay for this) Fecal sdna test for cancer at unknown intervals American College of Gastroenterology dissented Ca Cancer J Clin 2008 Fecal Immunochemical Tests Similar specificity to guaic based FOBT detects human globin Sensitivity of 61% to 91% for cancer, and advanced adenomas better One or two samples sufficient No special diet needed More expensive but decreases false positives; no upper GI source No clinical trials of effectiveness J Natl Cancer Inst Oct 3;99(19):

5 Comparison of Immunochemical Fecal Occult Blood Tests Practice-based study of 1319 patients undergoing screening colonoscopy in Germany Tested stool with 6 tests and compared to findings 10% had advanced adenomas Sensitivity: 27% (CI 20%-35%) Specificity: 97% (CI 95%-98%) Hundt S, Ann Intern Med 2009; 150: CT Colonography Every 5 Years CT colonography remains promising but has limitations Wide variation in clinical trials with no effect on mortality; quality control needed Sensitivity 63-92% for large lesions technology evolving 10% of patients require a 2nd procedure On list of 2008 guidelines as option Technology will improve and may become standardized radiation exposure? Fecal DNA Testing DNA alterations in colorectal cancer found Non-invasive and no preparation Detection along entire length of colon Studies showed Fecal DNA testing for mutations in tumor suppressor genes had high sensitivity (91%) and specificity (93%) for both cancer and advanced neoplasia (82% / 93%) Recommended in 2008 guidelines, interval uncertain Very expensive to run the panel 5

6 Colon Cancer Screening Rates 2006 FOBT within 12 months and/or endoscopy within 10 years? 60% Lower for Non-Whites Lower for Latinos Lower in areas of high poverty Is Colonoscopy Better? Colonoscopy showed lesions that would have been missed by sigmoidoscopy alone Distal polyps are not always predictive of proximal neoplasia 80% of high risk lesions would have been detected 2.8 per 1000 screening colonoscopies result in serious harm Effectiveness of colonoscopy overrated Case Control Study of Colonoscopy and Death from Colon Cancer Canadian population-based registry 10,292 cases age y died from CRC by 12/ ,460 controls (5:1) random sample Colonoscopy done in 719 (7%) cases and 5031 (9.8%) controls Completed colonoscopy reduced death from CRC: OR = 0.63 ( ); benefit limited to left side: OR 0.33 ( ) Baxter NN, Annals Int Med 2009; 150:1-8 6

7 Evidence for 10 Year Interval for Screening Colonoscopy Retrospective cohort of 35,975 persons in Manitoba, 41% women Normal colonoscopy at baseline and followed through system Lower than expected risk of developing colon cancer at 2, 5 & 10 y Benefit varies from 30% to 75% reduction in expected cancer cases Right sided colon lesions more common Singh JAMA 2006; 295: National Polyp Study Removing Polyps Reduces Colon Cancer Risk Expected (Mayo) Expected (SEER) Observed: NPS % risk years Should We Screen for Colon Cancer in Persons 80 y and Older? Current recommendations offer no limit Cost benefit modeling data show no benefit if over 80 years old Consider life expectancy (> 6 y) in decision-making Comparison of findings among 1,034 persons between the ages of y, y, and over 80 y find more abnormalities in older adults 7

8 What Happens If We Screen for CRC in Persons 80 and older? Age Any Neoplasia Advanced Neoplasia % 3% % 5% % 14% Life expectancy benefit was reduced among patients 80+ to 15% of benefit among those aged y. Lin JAMA 2006; 295: National Colonoscopy Screening Program in 50,148 Patients, Poland Screening program with 66% of those 40 to 49 having a family history of CRC and 13% 50 to 66 Age Cancer Advanced Any % 3.4% 9.5% % 5.9% 14.9% Men twice as likely to have abnormalities OR= 2.08 ( ) Family history increases yield by about 30% in women and 50% in men OR = 2.49 for two relatives with CRC Rate of complications was 0.1%; no deaths Regula, et al. NEJM 2006; 355: Screening in High Risk Individuals People who have a polyp >1 cm or multiple adenomatous polyps or high dysplasia, or villous adenoma should repeat colonoscopy at 3 years Subsequent follow-up depends on the type of polyps detected Tubular adenomas less than 1 cm: repeat colonoscopy in 5 years Interval for surveillance debated Medicare pays for repeat in 2 years! 8

9 Colon Cancer and Family History If single first-degree relative under age 60 years has a history of colon cancer or a 1 cm adenomatous polyp begin screening at age 40 ACG: colonoscopy every ten years starting age 40 or ten years earlier than the diagnosis of relative with CRC Consider ASA 325 mg daily (not recommended by Preventive task Force) Vitamin D and calcium? Estrogen? Colon Cancer Screening: Conclusions Any colon cancer screening better than no screening colonoscopy is the best option if available Increase awareness of the importance of colon cancer screening CT colonography and fecal DNA testing may have a role in the future Breast Cancer Screening Mammography at 40 MRI for High Risk? Breast Exams 9

10 Breast Cancer: Incidence Mortality African American American Indian Asian Latino White *Rates per 100,000 age-adjusted to the US 2000 population ** SEER Registries: 12 SEER areas Breast Cancer Incidence Declines SEER Registries for % Decrease in annual incidence Only in women 50 years and older Most evident in Estrogen Receptor Positive Tumors Temporal relation to WHI results and decrease use of HRT Westernization in lower-income countries may lead to more breast CA NEJM 2007; 356: Breast Cancer Screening NCI estimates about 1 in 8 women will develop breast cancer Benefit of early detection and 25% decrease in mortality Meta-analysis concluded that screening mammography did not reduce mortality (Olsen, Lancet 2001;358:1340-2) Screening leads to more aggressive treatment Co-pay of $10 led to 8.3% lower rate of biennial screening (Trivedi, NEJM 2008;358:375) 10

11 United States Preventive Services Task Force Breast Cancer Screening Recommendations Recommends mammography with or without clinical breast examination every 1-2 years for women > 40 Breast Self-Exam shows no reduction in mortality not recommended Data most clear for women aged 50-69: 20-30% reduction in breast cancer mortality For women in their 40s there is no mortality reduction: PPV = 4% vs. 13% in y Benefit to women aged 70 to 80 y if the life expectancy not compromised by co-morbid disease Long-term effect of mammograms age y: Pooled Analysis Screened Not screened 16% How much is due to screening age 50? Estimates: ~ half Mammograms after 70? 10 yr risk of breast cancer at various ages yr risk (%) Age 11

12 Screening Mammography in Women Age 65 Almost 50% of new cases of breast cancer and 67% of deaths occur in older women Breast cancer screening q 2 y after age 65 reduces mortality at reasonable costs for women without co-morbidities Mammography lowers risk of metastatic breast cancer and increased likelihood of localized cancer in women aged years Medicare analyses showed that wealthier ($100k+ net worth) women are more likely to get screened if 5 year survival is 90% (82% vs. 68%) or < 50% (48% vs. 32%) Ann Int Med 2003;139: ; Arch Intern Med 2008; 168: Breast Cancer Risk and Mammography Use, National Health Interview Survey 6002 women, 45 to 75 y Mammography Use Perceived risk: low 63% Medium or high 68% Gail Model estimated risk in 5 y < 0.086% 51% 0.086% to 1.17% 64% 1.17% to 1.57% 68% > 1.57% 76% Younger age, obesity, smoking, depression, family history, previous abnormal mammogram and early age at menarche associated with higher perceived risk. Gross JGIM 2006; 21: Screening Mammography Differences May Explain Breast Cancer Disparities Mammography Registry Cohort: 1,010,555 women, 40+ y, from , 17,558 diagnosed with breast cancer Non-white women were 20%-40% more likely to receive inadequate mammography screening African American women had higher rates of high-grade tumors regardless of screening Lower rates of cancer among Asian, American Indian, Latinas Smith-Bindman, AIM 2006; 144:

13 Mammography Facility Characteristcis and Accuracy of Screening 44 facilities, , mammograms, 2686 cancers Sensitivity: 79.6% (74.3% %) Specificity: 90.2% (88.3% %) PPV = 4.1% (3.5% to 4.7%) Biopsy recommended, PPV = 38.8% Specificity varied among facilities Screening only, imaging specialist, 2 audits /yr, no double reading Taplin S, JNCI 2008; 100: Mammogram Breast Density and Breast Cancer Risk Mammography registries consortium 301,955 women, 2 mammograms, 2,639 cancers in follow up BI-RADS 1 = Least dense BI-RADS 4 = Most dense Rate of Breast Cancer by change: BI-RADS 1 to 2: 5.6 (4.7 to 6.9) BI-RADS 1 to 3: 9.9 (6.4 to 15.5) BI-RADS 1 No Change: 3.0 (2.3 to 3.9) JNCI 2007; 99: MRI Screening for Breast Cancer 969 Women with unilateral breast cancer diagnosed, mean age of 53 y MRI Screen of contra lateral breast after normal mammogram and clinical exam 30 occult breast cancers found (3.1%) 121 biopsies done (12.5%) 18 invasive cancers; 12 DCIS MRI screen all women with diagnosis? Finding occult cancers of unknown significance? NEJM 2007; 356:

14 Mammography plus Ultrasound for Women at Elevated Risk 2809 women with dense breast tissue examined with mammography plus ultrasound in random order Yield additional 1 to 7 cancers per 1000 women Three times more biopsies recommended with lower PPV of 8.9% vs. 22.6% JAMA 2008; 299: Telephone Care Management to Improve Cancer Screening in NYC Randomized Trial of 1,413 women in care at 11 community clinics in Intervention: 4 telephone calls from Prevention Care Manager vs. usual care Outcomes were measured from Medical records Telephone Care Management Improves Use of Cancer Screening Tests Telephone Rx Usual Mammography 58% to 68% 56% to 58% PAP 71% to 78% 71% to 71% CRC Screen 39% to 63% 39% to 50% Dietrich AIM 2006; 144:

15 Proactive System to Improve Breast Cancer Screening Web-based system: Preventive Care Reminder System (PRECARES) Women y randomized to usual care or intervention managed by assistant 2 monthly letters, 3 months before due date and telephone call to nonresponders Chaudry R. Arch Intern Med 2007; 167: PRECARES Outcomes Usual Care Intervention N (3339) (3326) p Mammography 55.3% 64.3% <.001 PAP Smear 63.8% 62.8% NS Colon sc reen 74.7% 73.8% NS ArchIntern Med2007; 167: WISER Randomized Trial Risk-tailored messages on mammography in diverse women 899 randomized and F/U 18 months No effect on screening rates 72.6% vs 74.2% Subgroup analysis of Worriers (often or all the time) showed benefit (85% vs. 63.5%) Bodurtha J, J Women s Health 2009; 18: 41 15

16 Lung Cancer Screening Not Recommended Lung Cancer Screening Low-dose computed tomography used with False positive rate ranging from 5% - 41% Chest radiographs with or without sputum cytology showed no lung cancer mortality benefit in RCT Chest CT more sensitive than chest radiographs, but unknown benefit 3 trials in high-risk patients with mortality outcomes are in progress CT Screening for Lung Cancer 3,246 current or former smokers screened for lung cancer starting in 1998 and followed for 3.9 y Annual CT scans at 2 academic centers 144 persons diagnosed 44 expected cases RR = 3.2 ( ) 38 deaths observed; 38 deaths expected Screen only in clinical research studies JAMA 2007;297:

17 International Early Lung Cancer Action Program Study Study in October 2006 NEJM: 90% 10 year survival of stage 1 lung cancer when detected by CT scan screening Advocacy group lobbying to fund screening in absence of evidence No Control group: Over diagnosis Lack of unbiased outcome measure: lead time bias Ignored previous studies with CXR Ignored harms of screening Henschke, et al; NEJM 2006; 355: ; Welch et al; JAMA 2007; 167: Lung Cancer Screening: Summary of Recommendation USPSTF concludes that the evidence is insufficient to recommend for or against screening asymptomatic persons for lung cancer with chest CT, chest radiographs, sputum cytology, or combination of these tests Ann Intern Med 2004;140:738-9 Prostate Cancer Screening Is There Benefit? 17

18 Prostate Cancer Risks 15% lifetime risk; 30% of men have prostate cancer at autopsy; 3% risk of dying from CA Risk factors Age First degree Family history Race: African American men have highest incidence rates of prostate cancer in the world and twice as likely to die from it than are other Americans (consider start to screen at age 45) Asian and American Indian men have the lowest rates Prostate Cancer 2000 Incidence Mortality African American American Indian Asian Latino White *Rates per 100,000 age-adjusted to the US 2000 population from 12 SEER Registries Prostate Cancer Screening? Prostate cancer benign disease in many Similar survival of observation vs. initial treatment (surgery or radiation) in cohort Similar risk of prostate cancer deaths in U.S and U.K. screening differences Prostate cancer mortality declined following the introduction of PSA and TURP Complications of radical prostatectomy 8% incontinent 60% impotent (nerve-sparing procedure better) 0.5-1% perioperative death Prostate Cancer Outcomes Study: JAMA

19 Prostate Cancer Screening Trial: PLCO 76,693 men randomized to annual screening (PSA for 6 y and DRE for 4 y) vs. usual care from PSA done in 85% screened and 40% to 52% of usual care men More cancers found: 116 vs. 95 per 10,000 person-years No mortality difference: 50 vs. 44 deaths Rate ratio = 1.13 (95% CI = ) Andriole GL, et al NEJM 2009; 360: Prostate Cancer Screening Trial: ERSPC 182,000 men randomized to screening PSA once every 4 y vs. no screening PSA done in 82% screened and 40% to 52% of usual care men More cancers found with cumulative incidence 8.2% vs. 4.8% Prevent one death: number needed to screen = 1410; 48 new cases would need treatment Rate ratio = 0.80 (95% CI = ) Schröder FH, et al NEJM 2009; 360: Digital Rectal Examination (DRE) One-third of prostate cancers occur in areas which can be reached by DRE Higher sensitivity performed by urologists Abnormal DRE increases the likelihood of prostate cancer Negative exam does NOT change the likelihood of significant prostate CA No decreased risk of metastatic cancer 19

20 Prostate-Specific Antigen Serum levels depends on prostate size (higher in BPH and prostatitis) Level >4.0 detects about two-thirds of prostate cancer Digital rectal examination before PSA measurement does not elevate it Cancer increases bound PSA (decreased % free) PSA Screening 15% men age > 50 have elevated PSA Higher PSA, more likelihood of prostate cancer PSA ng/dl: 12% had prostate cancer PSA 4-10 ng/dl: 22% have prostate cancer PSA >10 ng/dl: 66% have prostate cancer Other tests: PSA density, PSA velocity, % free PSA, but none of these proven superior to PSA alone Proportion of prostate cancers diagnosed at early and curable stage increased from 66% to >90% since PSA Screening with the PSA test Should the threshold for biopsy be lowered? Current PSA testing (4.0 level) misses 82% of prostate cancers in men < 60 years of age 65% of prostate cancers in men > 60 years of age Conclusions: A lower threshold level of PSA to >2.5 for recommending prostate biopsy, particularly in younger men & African Americans & those with a family history, may improve the clinical value of the PSA test. N Engl J Med 2003;349:

21 U.S. Preventive Services Task Force Recommendations The evidence is insufficient to recommend for or against routine screening for prostate cancer using PSA or DRE PSA can detect early prostate cancer, but inconclusive evidence about whether early detection improves health outcomes Harms include frequent false positives and unnecessary anxiety, biopsies, and potential complications of treatment Prostate Cancer Screening Options Screen all men as routine - annual or every 4 years Discuss potential benefits and harms of screening and individualize decision to screen - shared decision ACS/AUA: Men who ask their doctor to make the decision on their behalf should be tested annually Discouraging testing not appropriate Not offering testing inappropriate Screen for Ovarian Cancer? Not Yet 21

22 Ovarian Cancer: Should We Screen? Lifetime risk of ovarian cancer No affected relatives 1.2% One affected relative 5% 2 affected relatives 7% Hereditary syndrome 40% Other risk factors: Older Age, nulliparity, Whites, History of breast, colon or uterus cancer Protective factors: breast feeding, pregnancy >1, OCP (37% reduction) Ovarian Cancer: Screening Techniques No evidence for pelvic exam Serum CA-125 assay Trans-vaginal ultrasound Serum CA-125 plus ultrasound Ovarian cancer limited to the ovaries is associated with a much higher survival rate Non-specific symptoms Ovarian Cancer Screening: Clinical Trial 22,000 women in the UK Annual screening vs none for 3 y Screening protocol: CA-125 yearly Ultrasound - elevated CA-125 Surgical evaluation if US abnormal 7 year follow-up 22

23 Ovarian Cancer Screening: Results 468 women had elevated CA women had surgery: 6 had cancer and 10 developed it in 7 years 20 cancers in controls Mean survival longer in screened group: 73 months vs 42 months No significant difference in ovarian cancer mortality 18 deaths vs 9 deaths Ovarian Cancer Screening: Recommendations UK clinical trial: slight increase in mean survival (73 vs. 42 months) but no difference in mortality Low disease prevalence, many must be screened to detect a few cases, small increase in survival NIH Consensus Conference and USPSTF: no evidence for widespread screening high risk women (two or more relatives) should be referred to and screened Aspirin for Cancer Prevention Cancer Prevention Study II Nutrition Cohort compared 5Y daily use 325 mg ASA vs. no use 76,303 women participated 7,196 women diagnosed with cancer Overall cancer incidence: RR = 0.86 (0.73 to 1.03) Breast cancer incidence: RR = 0.83 (0.63 to 1.10) Colon cancer incidence: RR = 0.68 (0.52 to 0.90) JNCI 2007; 99:

24 Summary of Recommendations Any colon cancer screening better than no screening for reducing mortality all are cost effective Women aged 50 to 69 should undergo mammography every 1-2 years Physicians should discuss the pros and cons of mammography screening with women aged and over age 70 Summary of Recommendations Screening for ovarian cancer is not recommended in average risk women, but may be considered in women at high risk There is no evidence that screening for lung cancer reduces mortality Discuss screening for prostate cancer in all men 50 to 69 years of age; discourage screening in older men Sources for Information US Preventive Services Task Force: Cancer in Women of Color: Center to Reduce Cancer Health Disparities: SEER cancer statistics: 24