Concepts in Cancer Management

Educational Objectives

The goal of this program is to improve screening for and management of cancer. After hearing and assimilating this program, the clinician will be better able to:

1.   Counsel women about self-breast examination and mammography.

2.   Describe current and newer screening tools for colorectal cancer.

3.   Utilize guidelines about screening for breast and colorectal cancer.

4.   Recognize men who may benefit from prostate cancer screening, based on current guidelines.

5.   Discuss treatment decisions for localized prostate cancer.

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. Dr. Potter presents information in his lecture that is related to off-label or investigative use of a therapy, product, or device.

Acknowledgements

Dr. Potter spoke in San Francisco, CA, at Annual Review in Family Medicine: Controversies and Challenges in Pri­mary Care, presented April 19-21, 2009, by the University of California, San Francisco, School of Medicine. Dr. Warlick was recorded in Minneapolis, MN, on November 21, 2008, at the University of Minnesota Medical School’s Internal Medicine Review and Update 2008. The Audio-Digest Foundation thanks the speakers and the sponsors for their cooperation in the production of this program.

Cancer Screening: New Tests, New Choices

Michael B. Potter, MD, Professor of Clinical Family and Community Medicine, University of California, San Francisco, School of Medicine

Introduction: in United States, »1.4 million new cases of cancer and 500,000 deaths per year; 1 in 4 deaths cancer-related; most deaths due to lung cancer, with colorectal cancer second leading cause of cancer deaths overall; since 1975, cancer death rate higher in men than in women (likely due to higher rates of tobacco smoking in men); slight decline in death rates since »1990 may be due to healthier lifestyles, better screening and early detection, better treatment, and less use of hormone replacement therapy in women; effective screening tests should be easy, safe, accurate, inexpensive, and widely available

Breast cancer screening: self-breast examination (SBE)  —  3 large studies show no mortality benefit, even though many women do find cancers; American Cancer Society (ACS) suggests teaching women how to perform SBE may be beneficial; optional; clinical breast examination (CBE)  — mortality benefit not well established; takes »5 min; according to United States Preventive Services Task Force (USPSTF), insufficient evidence for SBE or CBE; standard of care to discuss evidence with patients; ACS recommends performing CBE and suggests teach­ing how to perform SBE

Mammography: women 40 to 49 yr of age  —  controversial until past few years; baseline risk for breast cancer death, 1 in 500 (mammography reduces risk by »17%); mammography every 1 to 2 yr may save 1 in 2000 women; recommended to offer mammography to patients; discuss risk to help patients make informed deci­sion; women 50 to 69 yr of age  —  baseline risk for breast cancer death, 1 in 100 (mammography reduces risk by »30%); regular mammography saves 1 in 300 lives; USPSTF and ACS guidelines  —  mammography recom­mended every 1 to 2 yr after 40 yr of age, continuing as long as woman healthy

Digital mammography: less radiation than conventional film mammography; image can be manipulated to en­hance contrast; twice as expensive as film mammography; study showed improved breast cancer detection (and possibly outcomes) in women <50 yr of age, women with dense breasts on mammography, and pre- or peri­menopausal women

Breast magnetic resonance imaging (MRI): highly sensitive; high risk for false positives and overdiagnosis; re­cently recommended by ACS for women with >20% lifetime risk for breast cancer as defined by breast cancer risk assessment tools; usually not recommended for breast cancer follow-up; unclear when to start or stop; con­sult breast cancer specialist before ordering

Breast thermography: detects heat and infrared energy emitted from breasts; potentially less invasive than mam­mography; fairly sensitive; may replace or become adjunct to mammography

Colorectal cancer: most cancers take »10 yr to progress from normal to detectable adenomas and cancers; screening tests  —  annual fecal occult blood tests (FOBTs); flexible sigmoidoscopy every 5 yr; double-contrast barium en­ema every 5 yr; colonoscopy every 10 yr; high-sensitivity guaiac FOBT (HSgFOBT)  —  sensitivity high (70%), but lower specificity results in more colonoscopies; <$5 per test; fecal immunochemical test (FIT)  —  specific for human globin (no dietary changes required; results in fewer false positives); 2 samples probably more sensitive than 1 sample, but 1 sample probably still more sensitive than 3-sample FOBT; slightly more expensive; FOBT  —  in-office testing never proven effective for colon cancer screening; stool DNA testing  —  “not ready for prime time”; not shown more sensitive than FIT; costs >$300; computed tomography colonography (CTC)  —  less invasive and risky than conventional colonoscopy; requires preparation; risk for perforation lower (nearly zero, compared to 1 in 1000 with conventional colonoscopy); sensitivity for cancers and polyps similar to that of colo­noscopy; costs ³$1000; 20% to 25% of patients have polyps (or other finding) on first screening, and require sec­ond procedure (ie, colonoscopy); frequency of use, training, and management of extracolonic findings uncertain; radiation risk highest in younger people (at age >50 yr, risk of developing cancer after 1 abdominal CT study, 1 in 10,000)

Guidelines: USPSTF  —  preferred choices include 1) colonoscopy every 10 yr; 2) flexible sigmoidoscopy every 5 yr with newer FOBT (ie, HSgFOBT or FIT); 3) annual newer FOBT alone; use clinical judgment on patients >75 yr of age; do not screen patients >85 yr of age; CTC and stool DNA testing not recommended; less evidence for double-contrast barium enema, compared to newer tests; ACS, American College of Radiology, and United States Multi-Society Task Force  —  preferred options include 1) colonoscopy every 10 yr; 2) flexible sigmoidoscopy ev­ery 5 yr with or without HSgFOBT or FIT; 3) double-contrast barium enema or CTC every 5 yr; acceptable to perform annual stool testing; stool DNA testing optional; do not screen patients who cannot tolerate treatment or benefit clinically from early detection; USPSTF decision analysis  —  mortality reduction similar between colo­noscopy every 10 yr in patients ages 50 to 75 yr, annual FIT (or high-sensitivity guaiac FOBT; between ages 50-75 yr), or flexible sigmoidoscopy every 5 yr with FIT or HSgFOBT every 3 yr; caveats include failure to consider costs and risks of procedure, failure to evaluate newer tests, assumption that all FITs and HSgFOBTs same, and that all tests followed up thoroughly, completely, and on schedule

Colonoscopy: study suggests limited reduction in mortality from right-sided cancers; enhancements  —  magnification endoscopy; narrow-band imaging endoscopy; confocal microscopy endoscopy

Prostate cancer: »4% reduction in mortality per year in United States since 1992; sensitivity and specificity of digi­tal rectal examination (DRE) low; prostate-specific antigen (PSA)  —cutoff, ³4 ng/mL; misses some aggressive cancers and detects many nonaggressive cancers; US study  —  annual PSA and DRE on 77,000 men 55 to 74 yr of age saw no difference in mortality, but »50% of men in control group underwent PSA testing; European study  —  PSA testing every 4 yr; biopsy if PSA >3 ng/mL; slight mortality benefit; number needed to screen to prevent 1 death in 10 yr, 1410; number needed to treat (NNT), 50; controversial

Reducing overtreatment: informed decision-making; use age-specific cutpoints for biopsy (lower threshold for men 50-60 yr of age); follow PSA velocity (in men with PSA of 3-5 ng/mL, recheck PSA 6-12 mo later; rapid in­crease may indicate aggressive cancer); consider percentage of free PSA in patients with PSA levels 4 to 10 ng/mL (in cancer, free PSA lower [<20%]); consider active surveillance for patients whose tumors have low Gleason score

Proteomic screening tests: identify more aggressive tumors with higher sensitivity and specificity; could lead to fewer biopsies

Lung cancer screening: studies in 1970s showed no mortality benefit of sputum cytology and x-rays in tobacco smokers, although more cancers detected; 10% of lung cancers not smoking-related; untreated stage 1 cancers likely to progress, but benefits of detection still uncertain; randomized trials show screening might improve mortal­ity, but side effects and risks uncertain; be cautious about offering lung cancer screening; consider offering tests to patients with eg, extremely high risk or chronic cough and progressive symptoms with weight loss

Prostate Cancer

Christopher A. Warlick, MD, PhD, Assistant Professor of Urologic Surgery, University of Minnesota Medical School, Minneapolis

Introduction: consider life expectancy and comorbidities when making decisions about treatment of prostate cancer; in United States, prostate cancer most common noncutaneous cancer diagnosed in men; in 2006, »230,000 new cases and 27,000 deaths; 1975 to early 1990s  —  incidence of prostate cancer slowly and steadily increased, marked by spike in early 1990s (start of PSA screening); mortality began increasing, but slowly and steadily decreased since start of PSA screening; incidence and mortality disproportionately higher in black men; decrease in mortality may be due to improved treatment (eg, nerve-sparing surgical techniques; radiation therapy); no definitive data about effect of PSA screening on mortality rates

PSA screening: can provide early diagnosis, but can also burden patients with diagnosis that ultimately may not af­fect their lives (consider age and comorbidities); overdiagnosis  —diagnosis of prostate cancer that would have been clinically silent in absence of screening; models suggest £30% of patients overdiagnosed; treating all men 65 to 69 yr of age diagnosed with Gleason 6 disease results in vast overtreatment; most patients diagnosed by PSA screen­ing (adds lead time of 6-10 yr in natural history of disease)

Changes in PSA values: elevated PSA levels can be due to benign prostatic hyperplasia (BPH), prostatitis, cancer, inflammation, trauma, urinary catheterization, and ejaculation; use of 5-a reductase inhibitors (eg, finasteride, dutasteride) for >6 mo reduces PSA level by 50% (when evaluating PSA in these patients, multiply value by 2); el­evated PSA does not equal cancer diagnosis; in men with normal digital rectal examination and elevated PSA (2.5-10.0 ng/mL), rate of cancer detection 25% to 30% on biopsy; PSA sensitive but not specific

PSA screening guidelines: American Academy of Family Physicians, American College of Physicians, American College of Preventive Medicine, and American Medical Association  —do not advocate PSA screening; recommend discussing risks and benefits of screening and individualizing approach for men >50 yr of age with life expectancy of >10 yr; American Urologic Association and ACS  —  strong proponents of screening; for white men >50 yr of age with no family history, annual PSA screening and DRE recommended; black men and men with first-degree rela­tive with prostate cancer should be screened starting at age 40 yr; PSA screening does not replace DRE (detection rates highest when both used); USPSTF  —  stated that men >75 yr of age should not be screened due to “moderate certainty that the harms of screening outweigh the benefits”, and benefits of screening in men <75 yr of age un­clear; speaker’s comments  —  benefits of screening men >75 yr of age “little to none,” but men with abnormal DRE likely to have sequelae; perform annual DREs, even in men not having annual PSA; as population ages, age-spe­cific cutoffs may be adjusted; standard screening “across the board” probably not helpful

Improving specificity of PSA screening: use of age-specific cutoffs, percentage of free PSA, and PSA density; PSA velocity  —  powerful predictor of disease; PSA increases of >2 ng/mL per year during year before diagnosis associ­ated with increased risk for death from prostate cancer, even after therapy; patients with relatively dramatic rise in PSA (eg, 1.5 ng/mL to 3.7 ng/mL), and patients with consistent increases (eg, >0.7 ng/mL per year) over 12 to 18 mo should be referred to urologist for biopsy

PSA screening interval: annual screening currently recommended, but recent data suggest screening every 4 yr may be as beneficial; PSA values obtained more frequently than every 3 mo not recommended due to significant vari­ability (in patients with rapid spike in PSA, giving antibiotics for 30 days and rechecking PSA reasonable)

Future of PSA screening: likely to be done earlier (ie, at age 30-40 yr) and less often; early history of PSA helps es­tablish rates of change over time; more frequent screening of men with initially high levels, and less frequently for men with low levels

Treatment decisions for localized prostate cancer: observation  —  1) watchful waiting; for older men or men with too many comorbidities to require active therapy; 2) active surveillance; for men young and healthy enough to ben­efit from therapy; consider whether disease severe enough to warrant therapy; actively follow with PSA screening and DREs every 6 mo; annual surveillance biopsy to check for changes in disease characteristics; surgery  —  open or robotically assisted surgery; side effects include incontinence and erectile dysfunction; radiation therapy  —  side effects include incontinence, erectile dysfunction, and changes to bladder and rectum; onset of side effects vary be­tween treatment modalities

Watchful waiting vs prostatectomy: studies  —  1) in nonscreen-detected population, risk for prostate cancer deaths at 10 yr decreased from 15% to 10%; supports active treatment; in subset analysis (men >65 yr of age), absolute risk reduction only 0.3%; NNT to prevent 1 prostate cancer death at 10 yr, >300; 2) in patients 65 to 80 yr of age, overall mortality decreased, but decrease in prostate cancer deaths minimal; NNT, 200; some methodologic ques­tions and concerns about selection bias; considerations  —  life expectancy (ie, age and comorbidities); clinical pa­rameters of disease (not all men with prostate cancer [particularly low-risk disease] benefit from therapy; men with high-risk disease likely to benefit); personal experience with illness; experience of family and friends; wishes of family and friends; patient’s anxiety level; patient’s priorities and willingness to tolerate side effects; physician opinion

Life expectancy: 10-yr mortality rate of low-risk prostate cancer, 5%; in man 65 yr of age in average health, gain in life expectancy after treatment, »2 yr; in man 70 yr of age, »1 yr; in man 80 yr of age, “matter of months”; discuss significance of gain in life expectancy with each patient; important to clarify what patient has to gain and lose; nor­mal life expectancy curve can be adjusted for other comorbidities (eg, diabetes, heart disease)

Summary: prostate cancer heterogeneous disease with variable natural history; continuous risk for prostate cancer with increasing PSA levels; utility of PSA screening becomes less clear with increasing age and comorbidities; pri­mary care physician in unique position to help assess patient’s comorbidities and life expectancy

Question and Answer

Gleason score: grading of prostate cancer; assessment of relative aggressiveness of disease; score comprised of sum of number (3, 4, or 5) referring to most common pattern seen on biopsy and number (3, 4, or 5) referring to second most common pattern; 3 signifies most well-differentiated and least aggressive pattern, 4 for more aggressive pat­terns, and 5 for most aggressive patterns); Gleason score of 8-10 indicates aggressive disease; Gleason score of 6 most indolent; Gleason score of 7 (ie, 4 + 3) indicates intermediate disease

Suggested Reading

Adam BL et al: Serum protein fingerprinting coupled with a pattern-matching algorithm distinguishes prostate cancer from benign prostate hyperplasia and healthy men. Cancer Res 62:3609, 2002; Bill-Axelson A et al: Radical prostatectomy ver­sus watchful waiting in early prostate cancer. N Engl J Med 352:1977, 2005; Brenner DJ et al: Computed tomography--an increasing source of radiation exposure. N Engl J Med  357:2277, 2007; Gonzalgo ML et al: Update on PSA testing. J Natl Compr Canc Netw 5:737, 2007; Levin B et al: American Cancer Society Colorectal Cancer Advisory Group, US Multi-So­ciety Task Force; American College of Radiology Colon Cancer Committee. Screening and surveillance for the early detec­tion of colorectal cancer and adenomatous polyps, 2008: a joint guideline from the American Cancer Society, the US Multi-Society Task Force on Colorectal Cancer, and the American College of Radiology. CA Cancer J Clin 58:130, 2008; Pisano ED et al: Digital Mammographic Imaging Screening Trial (DMIST) Investigators Group. Diagnostic performance of digital versus film mammography for breast-cancer screening. N Engl J Med 353:1773, 2005; Ross KS et al: Comparative effi­ciency of prostate-specific antigen screening strategies for prostate cancer detection. JAMA 284:1399, 2000; U.S. Preven­tive Services Task Force: Screening for colorectal cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 149:627, 2008; Wong YN et al: Survival associated with treatment vs observation of localized prostate cancer in elderly men. JAMA 296:2683, 2006; Zauber AG et al: Evaluating test strategies for colorectal cancer screening: a decision analysis for the U.S. Preventive Services Task Force. Ann Intern Med 149:659, 2008.