Cancer Part I: Prevention and Screening

From the 37th Annual Advances in Internal Medicine, presented by the University of California, San Francisco, School of Medicine

Educational Objectives

The goal of this program is to improve the effectiveness of cancer prevention stategies. After hearing and assimilating this program, the clinician will be better able to:

1.   Describe the current state of chemoprevention for cancer.

2.   Detail the limitations of population-based studies of chemopreventive strategies.

3.   Educate patients about primary, secondary, and tertiary prevention of cancer.

4.   Use evidence-based guidelines for identifying patients likely to benefit from screening for colorectal or breast cancer.

5.   Discuss the evidence for and against screening for prostate and lung cancers.

Faculty Disclosure

In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the plan­ning committee to disclose relevant financial relationships within the past 12 months that might create any personal con­flicts of interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial interest. For this program, the faculty and planning committee reported nothing to disclose.

Acknowledgements

Drs. Luce and Pérez-Stable were recorded at 37th Annual Advances in Internal Medicine, presented by the University of California, San Francisco, School of Medicine, and held May 18-22, 2009, in San Francisco, CA. The Audio-Digest Foun­dation thanks the speakers and UCSF School of Medicine for their cooperation in the production of this program.

Cancer Prevention

Judith A. Luce, MD, Clinical Professor of Medicine, Division of Hematology and Oncology, University of Cal­ifornia, San Francisco, School of Medicine

Cancer risk: increases with age; other factors  —  genetic defects (in eg, DNA repair mechanisms or cell-cycle control) and nongenetic events (eg, gene silencing by methylation or histone acetylation); consumption of environmental carcino­gens; certain gene polymorphisms affect metabolism of carcinogenic compounds, thereby increasing risk; viral agents may increase risk directly or indirectly (eg, by increasing inflammation); other contributing factors include hormones and secondary immunosuppression

Preventable cancer deaths: tobacco-related cancers responsible for 30% of cancer deaths in United States; cervical cancer, hepatocellular carcinoma, lung cancer, and Helicobacter pylori-related cancers important causes of mortal­ity worldwide; hormone-promoted cancers (breast and prostate) most common cancers in United States

Approach to intervention: primary prevention (eg, tobacco cessation, vaccination) has most potential for impact; secondary prevention (ie, screening) associated with decreased morbidity and mortality for some cancers; tertiary prevention may decrease risk for second malignancies; areas of focus  —  most common cancers; high-risk individu­als; older adults (have highest rates of cancer, but late in process of carcinogenesis)

Challenges for studying chemoprevention strategies: low individual annual risk; high number needed to treat (NNT); cost-effectiveness; risk-benefit ratio  —  depends on population (eg, higher-risk interventions may be accept­able in high-risk populations)

Population-based studies: epidemiologic and prospective cohort studies show associations between cancer risk and diet and lifestyle choices; problems include recall bias, lack of longitudinal data, and confounding variables; isolat­ing active compounds (eg, retinoids) from source (eg, green leafy vegetables) often problematic

Dietary supplements in smokers: epidemiologic data strongly suggested relationship between diet and risk for lung cancer; laboratory studies found that retinoids induce cellular differentiation; 5 major trials looked at b-carotene and/or retinoids; no benefit seen with supplementation (b-carotene supplementation appears to increase risk among current smokers)

Nonsteroidal anti-inflammatory drugs (NSAIDs) for preventing colorectal cancer: epidemiologic data suggested benefit of full-dose NSAIDs for reducing risk for colorectal cancer, but risk for gastrointestinal (GI) bleeding and other complications outweighs benefits in most patients; study shows high-dose therapy with cyclooxygenase (COX)-2 inhibitors associated with 50% reduction in new polyps, but other studies show increased risk for mortal­ity

Selenium and vitamin E for prostate cancer: case-control studies and other trials suggested benefit; second pros­tate cancer prevention trial (Selenium and Vitamin E Cancer Prevention Trial [SELECT]) found no benefits associ­ated with supplementation with selenium and/or vitamin E, compared to placebo; selenium supplementation seemed to increase risk for type 2 diabetes

Selective estrogen-receptor modifiers for breast cancer: »75% of women with breast cancer have estrogen-depen­dent disease; among women with breast cancer, treatment with estrogen-receptor modifiers reduces incidence of cancer in contralateral breast; Breast Cancer Prevention Trial  —  in women at high risk, tamoxifen therapy resulted in 50% decreased incidence of estrogen-receptor–positive breast cancer (no effect on estrogen-receptor–negative breast cancer); Study of Tamoxifen and Raloxifene  (STAR) —  raloxifene as effective as tamoxifen for preventing in­vasive breast cancer; raloxifene found to have better safety profile (tamoxifen associated with thrombotic risk and increased risk for endometrial cancer in postmenopausal women); cost-effectiveness study  —  universal prophylaxis (ie, for all women >50 yr of age) with tamoxifen not cost-effective

a-reductase inhibitors for prostate cancer: reduce tissue levels of dihydrotestosterone; finasteride  —  originally ap­proved for management of benign prostatic hyperplasia; reduces size of prostate gland and levels of prostate-spe­cific antigen (PSA); first Prostate Cancer Prevention Trial found finasteride associated with decreased incidence of prostate cancer but increased percentage of high-grade disease (possibly because finasteride reduces size of pros­tate, making biopsy more sensitive); also, high-grade cancers less hormone-sensitive; adverse effects (eg, erectile dysfunction) common; dutasteride  —  suppresses a₁- and a₂-reductases; more effective, potent, and long-lasting, compared to finasteride; 3 clinical trials (in progress)

Future research: directed by biology, not epidemiologic associations; genetic mutations  —  possible role of peroxi­some proliferator-activated receptor (PPAR)-inhibitors for patients with DNA repair defects (as seen in patients with mutations in BRCA1 or BRCA2 or hereditary nonpolyposis colon cancer); second hit to DNA repair process may cause death of affected (ie, cancerous) cells; possible role of epidermal growth factor receptor (EGFR) antag­onist in tobacco users with past oral malignancies or current preneoplastic lesions; numerous trials based on tumor biology in progress

Exercise: growing body of data from epidemiologic and cohort studies suggests exercise associated with reduced risk for prostate and breast cancers; action possibly mediated by weight reduction, reduced levels of hormones, insulin-like growth factor, or other mediators; potential confounding factors include other lifestyle issues (eg, diet, tobacco abstinence); questions include timing of initiation of exercise and whether breast cancer survivors who exercise have lower risk for relapse; prospective clinical trial in progress

Conclusions: public health interventions (eg, smoking cessation efforts, vaccination) have greatest potential for im­pact; chemoprevention complicated by issues of toxicity and cost; clinical practice  —  advise patients about healthy lifestyle choices; assess familial risk; screen patients based on age and other risk factors

Cancer Screening 2009:
Setting Evidence-based Priorities

Eliseo J. Pérez-Stable, MD, Professor of Medicine, Division of General Internal Medicine, University of Cali­fornia, San Francisco, School of Medicine

Criteria for screening: screening associated with decreased morbidity and mortality; disease must be prevalent and clinically significant and have detectable preclinical phase; treatment of preclinical phase more effective than treat­ment after symptoms develop; benefits of test must outweigh potential harms

Public opinion about screening: most Americans believe that cancer screening “good idea almost always” and that finding cancer early usually or always saves lives; 56% of those surveyed want screening, even for clinically irrele­vant cancers

Cancer incidence: women  —  breast, lung, and colorectal cancers most common; breast cancer more common in white women but more fatal (on average) in black women; Latina and Asian women have lowest rates; cervical, stomach, and liver cancers have infectious (ie, preventable) etiologies, and more common among immigrant groups; men  —  prostate cancer most common, particularly among blacks (twice as high as other groups; reasons unknown); other common cancers include lung (also higher in blacks), colorectal, stomach, and liver cancers

Colon Cancer

Evidence for screening: 3 large randomized trials using fecal occult blood testing (FOBT) or sigmoidoscopy for screening show 15% to 33% reduction in colon cancer mortality; United States Preventive Services Task Force (USPSTF) recommends screening individuals >50 yr of age and stopping screening at 75 yr of age; removing pol­yps reduces development of new polyps or advanced neoplasia by »50%

Screening options: recommendations  —  annual stool test (or every 2 yr); flexible sigmoidoscopy every 5 yr, with or without annual FOBT; double-contrast barium enema (rarely used for screening); colonoscopy every 10 yr (if no abnormal findings, no FOBT needed for 5 yr); computed tomography (CT) colonoscopy every 5 yr (Medicare may not cover); fecal DNA test (optimal interval unknown)

Fecal immunochemical tests: specificity 60% to 90% for detecting cancer and advanced adenomas; 1 or 2 samples sufficient; no special diet required; more expensive than guaiac-based tests, but fewer false positives; mortality benefit unknown; compared to colonoscopy  —  study compared findings from 6 immunochemical tests with those of colonoscopy; found tests have relatively low sensitivity and relatively high specificity

CT colonography: minimally invasive; performed in »10 min and does not require sedation; clinical trials show varying efficacy and no effect on mortality; 63% to 92% sensitive for detecting large lesions (likely will improve as technology improves); significant radiation exposure

Fecal DNA testing: detects alterations in DNA (indicating colorectal cancer); noninvasive test requires no prepara­tion and detects cancer occurring at any part of colon; high sensitivity and specificity for cancer and advanced polyps or neoplasia; test requires 30-g sample (on ice); expensive test

Colonoscopy: compared to sigmoidoscopy  —  higher sensitivity, because distal polyps (detectable by sigmoidos­copy) not always predictive of proximal neoplasia; adverse events  —  »2.8 serious events (eg, perforation) per 1000 screening colonoscopies; studies  —  clinical trial in progress; registry data suggest mortality benefit

Screening rates: 60% of adults >50 yr of age have had FOBT within 12 mo and/or endoscopy within 10 yr; lower rates among minorities, especially Asians and Latinos; rates also lower in areas of high poverty

Screening high-risk individuals: Polish study shows benefit of earlier screening (40-49 yr of age) in patients with family histories of colorectal cancer; other risk factors  —  history of polyp >1 cm, multiple adenomatous polyps, high dysplasia, or villous adenoma; follow-up depends on type of polyp detected; surveillance interval debated; Medicare covers repeat colonoscopy in 2 yr; family history  —  for patients with first-degree relative with colon can­cer or adenomatous polyp ³1 cm, begin screening at 40 yr of age or 10 yr earlier than diagnosis of relative

Breast Cancer

Epidemiology: 8.6% decrease in annual incidence among women ³50 yr of age, primarily in estrogen-receptor–pos­itive tumors (correlated with decreased use of hormone replacement therapy [HRT]); “westernization” of develop­ing countries may lead to increased incidence in those countries; lifetime risk, »1 in 8

Screening mammography: early detection associated with 25% decrease in mortality; for 2000 women screened, one cancer death prevented and 10 women overtreated (screening leads to more aggressive treatment, including treatment for ductal carcinoma in situ [no mortality benefit]); study found adding copayment decreased rate of screening; USPSTF recommendations  —mammography every 1 to 2 yr, beginning at 40 yr of age; self-examination not recommended (no mortality benefit); evidence for benefit  —  most clear in women 50 to 69 yr of age; no reduc­tion in mortality for women 40 to 49 yr of age; benefit in women 70 to 80 yr of age based on data extrapolated from younger group; questionable utility for women >80 yr of age; among women ³65 yr of age (group has highest inci­dence of breast cancer), screening associated with earlier detection of disease; disparities  —  low socioeconomic status and nonwhite race associated with decreased likelihood of screening or decreased quality of screening; black women have higher rates of high-grade tumors, regardless of history of screening; lower rates of breast cancer among Asian and American Indian women, and Latinas confirmed; accuracy  —sensitivity »80%; specificity »90%; positive predictive value (PPV) »4%, increases to »38% if radiologist recommends biopsy; registry data show highest accuracy in facilities that specialize in screening, use imaging specialists, have ³2 audits per year, and avoid double-reading; breast density  —  qualitative score; change (increase) in density associated with increased risk for breast cancer

Other screening options: magnetic resonance imaging (MRI)  —  study of women with unilateral breast cancer found benefit of screening contralateral breast with MRI; American Cancer Society recommends routine use of MRI for screening women at high risk; mammography plus ultrasonography  —associated with increased detection but higher rate of biopsy and lower PPV

Interventions to improve rate of screening: use of telephone management; web-based reminder system with tele­phone follow-up to nonresponders

Lung Cancer

Efficacy of screening: low-dose CT associated with false-positive rate of 5% to 40% (and unnecessary exposure to radiation); study of chest radiographs, with or without sputum cytology shows no benefit; CT more sensitive than radiographs, but benefit unknown; 3 trials in progress; study  — among current or former smokers, CT screening identified more cancers but did not affect mortality rate; recommendation  —  do not screen

Prostate Cancer

Screening: based on PSA testing and digital rectal examination (DRE); in United States, »80% of men between 50 and 80 yr of age have had PSA test

Risk: »15% lifetime risk; »30% of men have prostate cancer at autopsy (rate increases with age at death); morality rate »3%; risk factors  —  age; first-degree family history; race (blacks have highest risk; consider initiating screen­ing at 45 yr of age; Asian and American Indian men have lowest rates); elevated PSA  —common; likelihood of can­cer increases with level of PSA

Treatment: efficacy  —  studies show similar survival rates associated with watchful waiting and active therapy; mor­tality rates in United States and United Kingdom similar, despite differences in rates of screening and treatment; complications of radical prostatectomy  —  incontinence (8%); erectile dysfunction (60%); perioperative death (£1%)

Screening trials: arm of Prostate, Lung, Colon, and Ovarian Cancer Screening Trial randomized >76,000 men to an­nual screening (PSA test plus DRE) or usual care for 4 yr; screening associated with increased identification of can­cer but no difference in mortality; European Randomized Study of Screening for Prostate Cancer shows modest but statistically significant benefit associated with screening (PSA test with or without DRE) once every 4 yr

Recommendations: USPSTF  —  evidence insufficient to recommend for or against screening; shared decision mak­ing should include discussion of potential risks; interval  —  consider screening (PSA test plus DRE) every 4 yr; American Urological Association  —  initiate screening at 40 yr of age; American Cancer Society  —  initiate screen­ing at 50 yr of age for men at average risk and at 45 yr of age for men at high risk

Suggested Reading

Alkner S et al: Tamoxifen reduces the risk of contralateral breast cancer in premenopausal women: Results from a con­trolled randomised trial. Eur J Cancer Jun 15, 2009 [Epub ahead of print]; Andriole GL et al: Mortality results from a ran­domized prostate-cancer screening trial. N Engl J Med 360:1310, 2009; Bertagnolli MM et al: Five-year efficacy and safety analysis of the Adenoma Prevention with Celecoxib Trial. Cancer Prev Res (Phila) 2:310, 2009; Brandt A et al: Breast cancer risk in women who fulfill high-risk criteria: at what age would surveillance start? Breast Cancer Res Treat Jul 30, 2009 [Epub ahead of print]; Hundt S et al: Comparative evaluation of immunochemical fecal occult blood tests for colorectal adenoma detection. Ann Intern Med 150:162, 2009; Levin B et al: Screening and surveillance for the early detec­tion of colorectal cancer and adenomatous polyps, 2008. CA Cancer J Clin 58:130, 2008; Lippman SM et al: Effect of se­lenium and vitamin E on risk of prostate and other cancers: the Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA 301:39, 2009; Musquera M et al: The REDUCE trial: chemoprevention in prostate cancer using a dual 5alpha-reductase inhibitor, dutasteride. Expert Rev Anticancer Ther 8:1-73, 2008; Neuhouser ML et al: Dietary supple­ment use and prostate cancer risk in the Carotene and Retinol Efficacy Trial. Cancer Epidemiol Biomarkers Prev 18:2202, 2009; Schroeder FH et al: Screening and prostate-cancer mortality in a randomized European Study. N Engl J Med 360:1320, 2009; Smith-Bindman R et al: Does utilization of screening mammography explain racial and ethnic differ­ences in breast cancer? Ann Intern Med 144:541, 2006; Thompson IM et al: The influence of finasteride on the develop­ment of prostate cancer. N Engl J Med 349:215, 2003.