The Washington Manual of Oncology, 3 Ed.

Cancer Screening

Megan E. Wren • Aaron M. Goodman

 I. GENERAL PRINCIPLES

1. The benefit of screening depends on the prevalence of the disease, the sensitivity and specificity of the screening test, the acceptability of the test to the patient, and, most importantly, the ability to change the natural course of disease with treatment.
2. Studies of the benefits of screening are susceptible to several forms of bias including lead time bias, length bias, overdiagnosis, and volunteer bias.
3. Research evidence has often been inadequate to reach definitive conclusions regarding how, when, whom, and whether to screen for various cancers. The guidelines below are a synthesis of the recommendations of the major organizations (Table 41-1).
4. BREAST CANCER SCREENING
5. Breast cancer is the most commonly diagnosed invasive cancer in US women. About 1 in 8 (12.5%) will develop breast cancer by age 90.
6. Many women greatly overestimate their risk of breast cancer. In one study (Patient Educ Couns 2005;57:294), 89% of women overestimated their risk with an average estimate of 46% lifetime risk.
7. Breast cancer mortality has declined approximately 30% over the past two decades. It is unclear whether it is related to more aggressive screening or improved treatment options.
8. The benefits of screening are best proven for mammography in women aged 50 to 69.
9. Women aged 40 to 49 have a lower incidence of breast cancer and denser breasts (thus lower sensitivity and specificity of screening), leading to lower predictive values.
10. The United States Preventive Services Task Force (USPSTF) review stated that “for biennial screening mammography in women aged 40 to 49 years, there is moderate certainty that the net benefit is small.” They emphasized the lower incidence in this group and the adverse consequences of screening (Ann Intern Med 2009;151:716).
11. Data are limited for women age 70 and over, and older women have competing causes of mortality, limiting the benefit of cancer screening.
12. Randomized trials have shown that teaching breast self-examination (BSE) does not save lives (J Natl Cancer Inst 2002;94:1445), so many now endorse teaching “breast self-awareness” rather than formal BSE.
13. Clinical breast exam (CBE) may modestly improve cancer detection rates if experienced clinicians use very careful technique (JAMA 1999;282:1270).
14. Recommendations of some major groups are as follows.
15. The USPSTF issued updated recommendations in 2009.
16. Women aged 50 to 74 years should have mammography every 2 years.
17. Screening mammography should not be done “routinely” for women aged 40 to 49 years. Women and their doctors should base the decision to start mammography before age 50 years on the risk for breast cancer and preferences about the benefits and harms.
18. Current evidence is insufficient to assess the benefits and harms of the CBE or screening mammography in women 75 years or older.
19. The USPSTF recommends against teaching patients BSE.
20. The American Cancer Society (ACS) recommends
21. Age 20 to 39: CBE every 3 years.
22. Age 40 and over: annual CBE and annual mammography.
23. Optional BSEs.
24. The age to stop screening is not specified but should be individualized based on the potential benefits and risks in the context of overall health status.

3. American Congress of Obstetricians and Gynecologists (ACOG) recommends:
4. Age 20 to 39: CBE every 1 to 3 years.
5. Age 40 and over: annual CBE and annual mammography.
6. Over age 75 the decision to screen should be individualized.
7. “Breast self-awareness should be encouraged and can include BSE.”
8. BRCA1 and BRCA2 germline mutations substantially increase the risk that a woman will develop breast cancer over her lifetime (J Natl Cancer Inst 2013;11:812).
9. BRCA 1 carriers have a 60% cumulative risk of breast cancer by age 70.
10. BRCA2 carriers have a 55% cumulative risk of breast cancer by age 70.
11. The USPSTF makes no recommendations for screening women at high risk.
12. The ACS recommends women that very high risk (>20% lifetime risk) or with BRCA1 or BRCA 2 gene mutation should undergo magnetic resonance imaging (MRI) screening and mammography every year. For most women at high risk, screening with MRI and mammograms should begin at age 30. Women at moderately increased risk (15% to 20% lifetime risk) should talk to their physicians about the benefits and limitations of MRI screening in addition to yearly mammography.
13. ACOG recommends women at very high risk (>20% lifetime risk) should have “enhanced screening” with annual mammography, CBE every 6 to 12 months, instruction in BSE, and possibly MRI.
14. The National Comprehensive Cancer Network (NCCN) recommends the following for BRCA-positive women who have not undergone risk reducing mastectomy:
15. Consideration of monthly BSE starting at age 18.
16. CBE every 6 to 12 months beginning at age 25.
17. Annual mammography and breast MRI beginning at age 25.

 III. CERVICAL CANCER SCREENING

1. The effectiveness of cervical cancer screening has never been studied in a randomized trial but is supported by strong epidemiologic evidence. Most cases of cervical cancer occur in unscreened or inadequately screened women.
2. Cervical cytologic screening may be done with the conventional Pap smear or with liquid-based tests (method does not change screening frequency).
3. HPV vaccination does not change the screening guidelines.
4. The ACS, USPSTF, and ACOG have similar recommendations, as summarized below.
5. Do not begin screening until age 21 years regardless of sexual history.
6. Under age 21, cervical cancer is quite rare (1 to 2 per million), while HPV infection is common and dysplasia may occur, but both usually spontaneously remit.
7. Women aged 21 to 29 years should be screened every 3 years with cytology only. (HPV testing would detect many transient infections without carcinogenic potential.)
8. Women aged 30 and older may be screened by cytology plus HPV cotesting every 5 years (preferred), or with cytology alone every 3 years.
9. Women who have had a total hysterectomy (including removal of the cervix) for benign disease may stop cervical cancer screening.
10.  Screening may be stopped at age 65 in women who have had adequate screening (three consecutive negative Pap tests or two consecutive negative HPV/Pap cotests within past 10 years, and most recent test within 5 years).
11.  Risk factors and special cases:
12. In women with HIV infection, the CDC recommends cervical cytology screening twice in the first year after diagnosis and annually thereafter, while ACOG recommends annual cytology starting at age 21.
13. ACOG recommends that women with a history of high-grade dysplasia or cancer should continue routine age-based testing for 20 years, even past age 65.
14. More frequent screening may be required in women with a history of prenatal exposure to diethylstilbestrol (DES) and women who are immunocompromised (such as organ transplantation).

 IV. COLORECTAL CANCER SCREENING

1. Colorectal cancer (CRC) is the second most common cause of cancer deaths in the United States. Screening is associated with decreases in incidence as well as mortality, due to removal of premalignant adenomatous polyps, but only about two-thirds of Americans have been screened adequately (N Engl J Med 1993;329:1977).
2. Screening strategies fall into two main categories:
3. Stool-based tests that primarily detect cancer: guaiac-based fecal occult blood testing (gFOBT), fecal immunochemical test (FIT), or stool DNA testing.
4. Tests that detect both cancer and adenomatous polyps, thus permitting polyp removal for cancer prevention: flexible sigmoidoscopy (FSIG), colonoscopy, barium enema, or CT colonography.
5. For any test other than colonoscopy, any abnormalities must be followed up with a full colonoscopy, not just repeat testing.
6. A brief summary of screening tests and recommended intervals includes the following:
7. Annual gFOBT has modest sensitivity and specificity, but has been shown in randomized controlled trials to lower CRC mortality. It should be done with a high-sensitivity test such as Hemoccult SENSA on three specimens collected at home (in-office rectal exam is not an acceptable stool test for CRC screening).
8. Annual FIT that detects human globin from lower GI bleeding (globin from upper GI sources is digested) and is therefore more specific.
9. Stool DNA test, interval uncertain.
10. FSIG every 5 years has been shown to lower CRC mortality despite only examining the distal colon. It requires a limited bowel prep, and no sedation is required. Colonic perforation is rare (<1 in 20,000).
11. Air contrast barium enema (ACBE) every 5 years has only half the sensitivity of colonoscopy. It requires a full bowel prep, no sedation is used, and the test may be uncomfortable.
12. Computed tomography colonography (CTC) or “virtual colonoscopy” every 5 years.
13. Requires a full bowel prep and air insufflation.
14. Sensitivity is probably comparable to colonoscopy.
15. Patients with large polyps must be referred for colonoscopic resection, but uncertainty exists about management of small (<6 mm) polyps.
16. Colonoscopy every 10 years.
17. Requires a full bowel prep and sedation.
18. Regarded as the gold standard, but may miss 5% to 12% of lesions >1 cm.
19. Lesions can be resected during the procedure.
20. Risk of colonic perforation is about 1 in 1,000; can also cause bleeding and cardiovascular complications.
21. Current guidelines were published in 2012 by the American College of Physicians (ACP) (Annal Intern Med 2012;156:378), in 2008 by the USPSTF (Annal Intern Med 2012;156(5):378), and in 2008 by a joint guideline (CA Cancer J Clin 2008;58:130) published by ACS, the United States Multi-Society Task Force on Colorectal Cancer, and the American College of Radiology.
22. The USPSTF recommendations include the following:
23. Screen adults aged 50 to 75 using annual high-sensitivity gFOBT, or FSIG every 5 years combined with high-sensitivity gFOBT every 3 years, or colonoscopy every 10 years.
24. Do not routinely screen those aged 76 to 85 years, but there may be considerations that support screening in an individual patient.
25. Screening is not recommended >85 years of age.
26. The ACP recommends that
27. Clinicians perform individualized assessment of risk for CRC in all adults.
28. Average-risk adults should start CRC screening at age 50, using annual gFOBT, annual FIT, FSIG every 5 years, or colonoscopy every 10 years.
29. High-risk adults should start screening with colonoscopy at age 40 or 10 years younger than the age at which the youngest affected relative was diagnosed with CRC.
30. Screening should stop at age 75 or if life expectancy is <10 years.
31. The joint guideline recommends that
32. Screening for CRC in average-risk, asymptomatic adults should begin at age 50.
33. CRC screening is not appropriate if the patient is not likely to benefit from screening due to life-limiting comorbidity.
34. Colon cancer prevention should be the primary goal of screening. Preferred tests detect adenomatous polyps and can prevent cancer: FSIG every 5 years, ACBE every 5 years, CT colonography every 5 years, or colonoscopy every 10 years.
35. Other acceptable screening tests include annual gFOBT with a high-sensitivity test, annual FIT, or stool DNA test, interval uncertain.
36.  High-risk persons need earlier and/or more frequent screening. These include those with a personal history of CRC or adenomatous polyps, inflammatory bowel disease, endometrial cancer before age 50, a hereditary CRC syndrome, or a strong family history of CRC or polyps.
37. Those with CRC or adenomatous polyps in a first-degree relative <60 years of age or in two first-degree relatives of any age should be screened with colonoscopy every 5 years beginning at age 40, or 10 years before the youngest case in the immediate family, whichever is earlier.
38. For those with CRC or adenomatous polyps in a first-degree relative at 60 or older, or two second-degree relatives with CRC, screening should begin at age 40 with any recommended form of testing at the usual intervals.
39. LUNG CANCER SCREENING
40. Lung cancer is the most common cause of cancer death in the United States.
41. Multiple randomized trials have demonstrated no mortality benefit to screening with chest X-ray (CXR), with or without sputum cytology.
42. Observational trials in the late 1990s showed that low-dose single-breath-hold, helical CT (LDCT) scans could detect early stage lung cancers more effectively than CXRs.
43. The National Lung Screening Trial (NLST) published in 2011 was the first randomized trial to show a statistically significant benefit to CT screening for lung cancer (N Engl J Med 2011;365:395).
44. The trial compared LDCT to CXR for 3 years in more than 50,000 people aged 55 to 74; participants had at least 30 pack-years of smoking, including current smokers and former smokers who had quit within 15 years.
45. At a median follow-up of 6.5 years, there was a relative mortality reduction of 20% for lung cancer deaths and 6.7% reduction in all-cause mortality in the LDCT group.
46. To prevent one lung cancer death, the number needed to screen with LDCT was 320.
47. Abnormal screening tests occurred in 24% of the LDCT group and 6.9% of the CXR group, >90% of which were false positives. Most only required additional imaging but some required invasive procedures. Complications from the diagnostic workup were uncommon: about 1.5% of the participants who had abnormal screening tests.
48. The USPSTF issued updated guidelines in December of 2013:
49. The USPSTF recommends annual screening for lung cancer with low-dose CT in adults aged 55 to 80 years with a 30 pack-year smoking history and who currently smoke or have quit within the past 15 years.
50. Screening should be discontinued once a person has not smoked for 15 years or develops a health problem that substantially limits life expectancy or the ability or willingness to have curative lung surgery.
51. A number of expert organizations have issued updated guidelines, including the ACS (CA Cancer J Clin 2013;63:107), the NCCN, and the American College of Chest Physicians (Chest 2013;143(5 Suppl):e78S).
52. They support LDCT screening in individuals similar to those in the NLST:
53. Age 55 to 74
54. At least 30 pack-years of smoking.
55. Current smoker or quit within the past 15 years.
56. Screening is not appropriate for patients with severe comorbidities that limit life expectancy or would preclude potentially curative treatment.
57. The decision to start screening should be preceded by a process of informed and shared decision making, with discussion of the potential benefits, limitations, and harms associated with screening.

 VI. PROSTATE CANCER SCREENING

2. Although 17% of men will be diagnosed with prostate cancer, only 2.4% will die of it. Screening for prostate cancer (PrCA) is a controversial topic as trials have shown small or no survival benefit in screened groups and many men die “with” rather than “of” prostate cancer. Treatment has potential harms, including erectile dysfunction, urinary incontinence, and bowel problems.
3. The USPSTF (Annal Intern Med 2012;157:120) recommends against PSA testing, concluding that screening produces more harms than benefits.
4. The ACS (CA Cancer J Clin 2010;60:70) stresses the need for informed decision making.
5. This information should be provided starting at age 50 (at 40 to 45 in higher-risk men).
6. Men with <10-year life expectancy should not be offered prostate cancer screening (at age 75, only about half of men have a life expectancy of 10 years or more).
7. Key discussion points include the following:
8. Screening may reduce the risk of dying from PrCA, but the evidence is conflicting, and experts disagree about the value of screening.
9. Not all men whose PrCA is detected through screening require immediate treatment. It is not currently possible to predict which men are likely to benefit from treatment.
10. Treatment for PrCA can lead to urinary, bowel, sexual, and other health problems.
11. The PSA and DRE may produce false-positive or -negative results.
12. Abnormal results require prostate biopsies that can be painful, may lead to complications, and can miss clinically significant cancer.
13. If screening is elected, the ACS recommends PSA with or without DRE.
14. Initial PSA <2.5 ng/mL: screen every 2 years.
15. Initial PSA 2.5 ng/mL or greater: screen annually.
16. PSA >4.0 ng/mL: refer for biopsy (2.5 to 4.0: individualized assessment).
17. The ACP recommends that PSA testing should only be done in patients with a clear preference for screening (Annal Intern Med 2013;158:761).
18. Clinicians should inform men aged 50 to 69 about the limited potential benefits and substantial harms of screening for prostate cancer.
19. Screening should not be done in average-risk men aged <50 or >69, nor those with a life expectancy of <10 to 15 years.
20. The American Urological Association (AUA) published its guideline online in 2013 (Carter HB, Albertsen PC, Barry MJ, et al. Early Detection of Prostate Cancer: AUA Guideline. 2013. Accessed July 5, 2013 www.auanet.org/education/guidelines/prostate-cancer-detection.cfm).
21. Men <40 years of age should not be screened.
22. Average-risk men <55 years of age should not be routinely screened.
23. For men 40 to 55 years of age who are at higher risk (family history or African American), decisions should be individualized.
24. For men aged 55 to 69, they strongly recommend shared decision making, based on a man’s values and preferences after weighing the benefits against the known potential harms associated with screening and treatment. They estimate that one prostate cancer death is averted for every 1,000 men screened for a decade.
25. Men should not be routinely screened if they are >70 years of age or have a life expectancy <10 to 15 years.
26. If men choose screening, an interval of 2 years or more may be preferred over annual screening as this preserves the majority of the benefits and reduces overdiagnosis. Intervals for rescreening can be individualized based on baseline PSA level.
27. There is no evidence that DRE is beneficial as a primary screening test.

 VII. OVARIAN CANCER SCREENING

1. Ovarian cancer is uncommon (2% lifetime risk) but often lethal because only 15% are diagnosed while still localized to the ovary (CA Cancer J Clin 2013;63:87).
2. Patients at the highest risk for ovarian cancer are those with inherited cancer syndromes: the BRCA1 gene mutation conveys a lifetime risk of about 40%, and the BRCA2 gene mutation conveys a lifetime risk of about 20%.
3. Pelvic examination is not effective for screening due to poor sensitivity and specificity.
4. Ovarian cancer is occasionally found incidentally on a Pap smear (sensitivity <30%).
5. The tumor marker CA125 has limited sensitivity and specificity.
6. Only about half of early ovarian cancers have elevated levels of CA125.
7. False positives are too common (about 1%) for an effective screening test. Levels vary with the menstrual cycle, age, ethnicity, and smoking, and CA125 can be increased with endometriosis, uterine leiomyomata, cirrhosis, ascites from any cause, and a variety of cancers.
8. Transvaginal ultrasound (TVU) has limited sensitivity and specificity for screening.
9. A large randomized trial in the United States showed that screening with CA125 and TVU did not improve ovarian cancer mortality (relative risk 1.18, screened vs. usual care) (JAMA 2011;305:2295). The positive predictive value was only about 1%, and for every screen-detected ovarian cancer about 20 women underwent surgery; 20% of those surgeries resulted in major complications.
10. Other studies are ongoing.
11.  No organization recommends screening average-risk women for ovarian cancer.
12. The USPSTF specifically recommends against screening due to lack of benefit, and potential harms by leading to unnecessary surgeries (Annal Intern Med 2012;157:900).
13. ACOG concluded that currently there is no effective strategy for ovarian cancer screening (Obstet Gynecol 2011;117:742).
14. Clinicians should have a high index of suspicion when women present with symptoms commonly associated with ovarian cancer: pelvic or abdominal pain, increase in abdominal size or bloating, and difficulty eating or feeling full.
15. High-risk women may be offered the combination of pelvic examination, TVU, and CA125 testing.
16. The NCCN recommends consideration of twice yearly ovarian cancer screening with TVU and serum CA125 levels beginning at age 30, or 5 to 10 years earlier than the earliest age of first diagnosis of ovarian cancer in the family.
17. Owing to the lack of efficacy of ovarian cancer screening modalities, many organizations recommend bilateral salpingo-oophorectomy for high risk women at age 35 to 40 years or once the patient no longer wishes to bear more children.

VIII. TESTICULAR CANCER

1. USPSTF recommends against screening for testicular cancer because the incidence is low and testicular germ cell tumors are one of the most curable solid neoplasms. No evidence has shown that routine screening would improve health outcomes.
2. The AUA recommends monthly testicular self-exams.

 IX. SCREENING FOR OTHER CANCERS

1. Routine population screening is not recommended for the following cancers: endometrial, bladder, thyroid, oral cavity, or skin. Clinicians should be vigilant for early symptoms of possible cancer in those sites.
2. The ACS recommends that “the cancer-related checkup should include examination for cancers of the thyroid, testicles, ovaries, lymph nodes, oral cavity, and skin, as well as health counseling about tobacco, sun exposure, diet and nutrition, risk factors, sexual practices, and environmental and occupational exposures.”

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