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2: Screening and Health Maintenance

INTRODUCTION

PATIENT 1

Mr. S is a healthy 45-year-old white man who wants to be “checked for everything.”

How do you know when it is worthwhile to screen for a disease? Where do you find information on screening guidelines? How do you interpret screening guidelines?

It seems intuitive that it is best to prevent a disease from occurring at all and next best to diagnose and treat it early. However, there are risks and benefits to every intervention, and it is especially important to make sure an intervention is not going to harm a healthy individual. This chapter focuses on understanding the reasoning behind current screening practices.

Screening can be used to identify an unrecognized disease or risk factor in a seemingly well person.
Screening can be accomplished by collecting a thorough history, performing a physical examination, or obtaining laboratory tests.
Examples of screening include mammography and cholesterol testing.
1. Mammography can detect unrecognized, asymptomatic breast cancer.
2. Cholesterol testing can be used
  1. To identify high-risk individuals who do not yet have coronary disease (called primary prevention by clinicians).
  2. To prevent complications in patients with known coronary disease (called secondary prevention by clinicians, not actually screening).
The following criteria are helpful in determining whether screening for a disease is worthwhile:
1. The burden of disease must be sufficient to warrant screening.
  1. Screen only for conditions that cause severe disease, disability, or death.
  2. Consider prevalence of target disease and ability to identify high-risk group since the yield of screening is higher in high-risk groups.
2. The test used for screening must be of high quality.
  1. Screening tests should accurately detect the target disease when it is asymptomatic.
  2. Screening tests should have high sensitivity and specificity.
  3. Test results should be reproducible in a variety of settings.
  4. Screening tests must be safe and acceptable to patients.
  5. Ideally, screening tests should be simple and shown to be cost effective.
3. There should be evidence that screening reduces morbidity or mortality.
  1. There must be effective treatment for the target disease.
  2. Early detection followed by treatment must improve survival compared with detection and treatment at the usual time of presentation; in other words, people in whom the condition was diagnosed by screening should have better health outcomes than those in whom the condition was diagnosed clinically.
  3. The benefits of screening must outweigh any adverse effects of the screening test, treatment, or impact of early diagnosis.
  4. Ideally, benefits and harms are evaluated through a randomized trial of screening (Figure 2-1).
    - (1) The best outcome to measure is either all-cause mortality or disease-specific mortality, such as breast cancer or prostate cancer mortality.
    - (2) Outcomes such as cancer stage distribution (ie, whether there are more or fewer early-stage cancers found) and length of survival after diagnosis can be misleading because of lead time and length time biases.
      - (a) Lead time bias: If early treatment is not more effective than later treatment, the duration of time the individual lives with the disease is longer, but the mortality rate is the same (Figure 2-2).
      - (b) Length time bias: Cancers that progress rapidly from onset to symptoms are less likely to be detected by screening than slow-growing cancers, so that screening tends to identify a group with a better prognosis.
  5. Often, screening decisions are made based on less direct evidence, such as cohort or case-control studies. Given the biases inherent in these study designs, this is suboptimal and has led to the institution of screening programs that provide no benefit.

Figure 2-1.

Design for a randomized trial of screening.

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Figure 2-2.

Lead time bias. (The total survival times for the unscreened patient and the screened patient in whom early treatment is not effective are the same. The total survival time for the screened patient in whom early treatment is effective is lengthened.)

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Where do you find information on screening guidelines?

Because of the complexity and rapid evolution of the evidence underlying screening recommendations, most physicians rely on published guidelines to inform them about screening decisions. Guidelines are developed and updated by a variety of organizations. It is important to be familiar with different sources of guidelines and to understand how to access the most recent versions of guidelines.

The US Preventive Services Task Force (USPSTF)
1. Web site: http://www.uspreventiveservicestaskforce.org/
2. An independent panel of experts in primary care and prevention, now under the aegis of the Agency for Healthcare Research and Quality (AHRQ)
3. Supported by outside experts, several evidence-based practice centers, and university centers that help identify high-priority topics, produce systematic reviews, and draft guidelines.
4. USPSTF guidelines often form the basis of clinical guidelines developed by professional societies.
5. Highly evidence-based recommendations on when and how to screen
The National Guideline Clearinghouse (NGC)
1. Web site: http://www.guideline.gov/
2. A public resource for evidence-based clinical practice guidelines
3. Sponsored by the AHRQ and US Department of Health and Human Services
4. A way to access and compare a variety of guidelines, including those written by USPSTF, professional societies, and other private organizations
Professional/specialty societies
1. Often do their own independent reviews and issue their own guidelines regarding relevant diseases
2. Specific guidelines generally available through the society Web site or the NGC
3. Examples include
  1. Specialty societies (eg, American College of Physicians [internal medicine], American College of Obstetrics and Gynecology, American College of Surgery)
  2. Subspecialty societies (eg, American Thoracic Society, American College of Rheumatology, American Urologic Association, American College of Gastroenterology, American College of Cardiology)
  3. Others (eg, American Cancer Society, American Diabetes Association, National Osteoporosis Foundation, American Heart Association)

How do you interpret screening guidelines?

The USPSTF has developed a standardized system and vocabulary for evaluating the quality of the evidence addressing screening questions and for grading recommendations. The recommendation grade is based on a combination of the quality of the underlying evidence and an assessment of the size of the benefit. This general approach is often adopted by other organizations that make screening recommendations.

USPSTF levels of certainty regarding net benefit
1. High: Consistent results from well-designed studies in representative primary care populations that assess the effects of the preventive service on health outcomes; it is unlikely that these conclusions will change based on future studies.
2. Moderate: Evidence sufficient to determine the effects of the preventive service on health outcomes, but methodologic issues such as limited generalizability, inconsistent findings, or inadequate size or number of studies exist; these conclusions could change based on future studies.
3. Low: Insufficient evidence to assess effects on health outcomes, due to limited number or size of studies, flaws in study designs, inconsistency of findings, lack of generalizability.
Grades of recommendations
1. Grade A: The USPSTF recommends this service. There is high certainty that the net benefit is substantial.
2. Grade B: The USPSTF recommends this service. There is high certainty that the net benefit is moderate or there is moderate certainty that the net benefit is moderate to substantial.
3. Grade C: The USPSTF recommends selectively offering or providing this service to individual patients based on professional judgment and patient preferences. There is at least moderate certainty that the net benefit is small.
4. Grade D: The USPSTF recommends against the service. There is moderate or high certainty that the service has no net benefit or that the harms outweigh the benefits.
5. Grade I statement: The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of the service. Evidence is lacking, of poor quality, or conflicting, and the balance of benefits and harms cannot be determined.

Mr. S feels fine and has no medical history. He takes no medications, does not smoke currently, and drinks occasionally. However, he did smoke occasionally in college, and he estimates he smoked a total of 2–3 packs of cigarettes over 4 years. He exercises regularly by cycling 50–100 miles/week. His family history is notable for high cholesterol, hypertension, and a cerebrovascular accident (CVA) in his father; his mother was diagnosed with colon cancer at age 54. His physical exam shows a BP of 120/80 mm Hg and pulse of 56 bpm. His body mass index (BMI) is 22 kg/m². HEENT, neck, cardiac, pulmonary, abdominal, and extremity exams are normal. He refuses a rectal exam. Mr. S shows you a list of tests he wants done, derived from research he has done on the Internet: lipid panel, prostate-specific antigen (PSA), chest radiograph, and fecal occult blood test (FOBT). In addition, he shows you a letter from a company offering “vascular screening” with ultrasounds of the carotids and aorta and wants to know if he should have those tests done.

Should Mr. S be screened for prostate cancer with a PSA?

Prostate Cancer Screening

What is the burden of disease?
1. 240,000 new diagnoses of prostate cancer in 2011, with approximately 34,000 deaths
2. Second leading cause of cancer death in men in the United States
3. Lifetime risk of a prostate cancer diagnosis is about 15.9%; the lifetime risk of death is about 2.8%; autopsy studies suggest that 70% of men over age 70 have occult prostate cancer that did not impact their health status.
Is it possible to identify a high-risk group that might especially benefit from screening?
1. Older age increases the likelihood of prostate cancer but decreases the likelihood of death from prostate cancer (due to increased mortality from other causes).
  1. 200 cases/100,000 white men aged 50–59 compared with 900/100,000 men older than 70 years
  2. Mortality from untreated prostate cancer is 22–23% in men under the age of 71, 12% in men between the ages of 71 and 81, and only 4% in men older than 81 years.
2. African American race
  1. Higher prostate cancer incidence than white men: 217.5 vs 134.5 cases per 100,000
  2. Higher prostate cancer mortality than white men: 56.1 vs 23.4 deaths per 100,000
3. Family history: Relative risk of about 2 for men with a first-degree relative with prostate cancer; relative risk about 5 if 2 first-degree relatives affected.
What is the quality of the screening test?
1. Digital rectal exam (DRE)
  1. Sensitivity 59%
  2. Specificity unknown, but possibly as high as 94%; reproducibility poor
  3. Positive predictive value: 5–30%
  4. Neither sensitive nor specific enough to be used as a screening test, although may add to cancer detection when combined with PSA
2. PSA
  1. For a PSA ≥ 4.0 ng/mL, sensitivity is 68–80%, specificity 60–70%.
  2. Positive predictive values (PPVs) vary with PSA level.
    - (1) For a PSA of 4–10 ng/mL, the PPV is about 25%.
    - (2) For a PSA > 10 ng/mL, the PPV is 42–64%.
  3. Prostate cancer is found in some men even with very low PSA levels.
    - (1) PSA ≤ 0.5 ng/mL: cancer in 6.6% of men, 12% of which was high grade
    - (2) PSA 0.6–1.0 ng/mL: cancer in 10%
    - (3) PSA 1.1–2.0 ng/mL: cancer in 17%
    - (4) PSA 2.1–3.0 ng/mL: cancer in 24%, 19% of which was high grade
  4. PSA velocity (rate of change in PSA), PSA density (PSA per volume of prostate tissue measured on transrectal ultrasound or MRI), and free PSA (ratio of unbound to total PSA) are purported to increase PSA accuracy, but data are insufficient to recommend their use.
Does screening reduce morbidity or mortality?
1. Two large randomized controlled trials of PSA screening found lower grade cancers in the screened group.
2. The Prostate Lung Colorectal and Ovarian (PLCO) trial of 76,693 American men aged 55–74 years
  1. Annual PSA for 6 years and DRE for 4 years; 97% follow up at 7 years, 67% at 10 years
  2. 50% of control group screened outside of trial, biasing the results against a positive effect of screening
  3. Increased frequency of diagnosis, but no difference in prostate cancer mortality
3. European trial of 182,000 men aged 50–74 years
  1. PSA every 4 years; median follow-up 9 years
  2. Relative risk of prostate cancer death in screened group = 0.8 (95% CI, 0.67–0.98); absolute risk reduction = 0.7
  3. To prevent 1 prostate cancer death, 1410 patients would need to be screened and 48 cases diagnosed.
  4. In a separate analysis of just the Swedish patients in the trial, who were screened every 2 years, the relative risk of prostate cancer death was 0.56 (95% CI, 0.39–0.82), with an absolute risk reduction of 0.4; the number needed to screen was 293 and to diagnose was 12.
4. To compare benefits and risks of screening, consider 1000 men aged 55–69 screened with a PSA every 1–4 years.
  1. Prostate cancer will be diagnosed in 110.
  2. 100–120 will have at least 1 false-positive PSA requiring a biopsy.
  3. Erectile dysfunction due to treatment will develop in 29.
  4. Urinary incontinence due to treatment will develop in 18.
  5. 1 prostate cancer death will be avoided; without screening, 5 would die of prostate cancer; with screening, 4 would die of prostate cancer.
What are the current guidelines?
1. USPSTF (2012)
  1. Recommends against PSA screening for prostate cancer
  2. Grade D recommendation
2. American Cancer Society (2012)
  1. Asymptomatic men ≥ 50 years of age, with at least a 10-year life expectancy, should receive information on the issues regarding prostate cancer screening and then participate in informed decision making. Prostate cancer screening should not be done without an informed decision-making process.
  2. Men in higher risk groups should receive this information before age 50.
3. American College of Physicians (2012)
  1. Clinicians should inform men aged 50–69 years of the limited potential benefits and substantial harm of prostate cancer screening, and screen only those men who express a clear preference for screening.
  2. Clinicians should not screen average risk men under the age of 50, men over the age of 69, or men with a life expectancy of less than 10–15 years.
  3. Talking points to be used in discussions with patients can be found in Qaseem A et al (2012).
Table 2-1 summarizes information on staging, testing, histology, prognosis, and treatment of prostate cancer.

Table 2-1.Prostate cancer.

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Table 2-1. Prostate cancer.

Staging

Stage

IIA

IIB

III

Definition

Tumor confined within the prostate (T1–2); Gleason¹ ≤ 6; PSA < 10

Tumor confined within the prostate (T1–2); Gleason¹ ≤ 7; PSA < 20

Tumor confined within the prostate (T1–2); Gleason¹ ≥ 8; PSA ≥ 20

Tumor extends through the prostate capsule and can invade seminal vesicle (T3); any Gleason¹ and any PSA

Tumor invades structures other than the seminal vesicles (T4) or any regional lymph node involvement or any distant metastasis

Commonly used tests

For diagnosis:

Ultrasound-guided transrectal biopsy

For staging:

Abdominal/pelvic CT scan

Bone scan

PSA

Histology

Adenocarcinoma (95%)

Small cell tumors

Intralobular acinar carcinoma

Ductal carcinoma

Clear cell carcinoma

Mucinous carcinoma

Prognosis

100% 5-year survival for tumors confined to the prostate

28.7% 5-year survival for metastatic disease

Most men die of other diseases, rather than the prostate cancer

Treatment

Stage 1

• Watchful waiting

• Radical prostatectomy

• External-beam radiation therapy (EBRT)

• Implantation of radiation seeds directly into prostate

Stage 2

• Same options as Stage 1

• Additional option of adding hormonal therapy to EBRT

Stage 3

• Same as stage 2

• Consider orchiectomy as method to reduce hormonal stimulation of the cancer

Stage 4

• Palliative radiation or transurethral resection of the prostate

• Hormonal therapies

• Bisphosphonates

¹Gleason score: Gleason scoring for adenocarcinomas ranges from grade 1 (well-differentiated) to grade 5 (very poorly differentiated). The tumor is assigned a grade based on predominant histology and the second most predominant histology. These 2 numbers are scored yielding a total from 2 to 10. Example, predominant histology is well differentiated with areas of very poorly differentiated is reported as 1+5=8.

PSA, prostate-specific antigen.

You review the small potential benefit and significant potential harms of screening with Mr. S, also pointing out that none of the guidelines recommend even discussing PSA testing before age 50 in white men without an affected first-degree relative.

Should Mr. S be screened for colorectal cancer with fecal occult blood testing?

Colon Cancer Screening

What is the burden of disease?
1. Third most common cancer in the United States and second leading cause of death from cancer
2. About 102,900 diagnoses in 2010, with about 51,000 deaths each year
3. Americans have a 5% lifetime risk of developing colorectal cancer; 90% of cases occur after age 50
4. 80–95% of colorectal cancers arise from adenomatous polyps
  1. 10% of polyps > 1 cm become malignant in 10 years; 25% do so after 20 years
  2. Adenomas found in 40% of adults by age 60
  3. Advanced adenomas, defined as those ≥ 10 mm or having high-grade dysplasia or a villous component, are the most likely to develop into carcinoma.
Is it possible to identify a high-risk group that might especially benefit from screening? (Tables 2-2 and 2-3)
1. 20% of colorectal cancers occur in patients with specific risk factors.
  1. History of either colorectal cancer or adenomatous polyps in a first-degree relative, especially if diagnosed before age 60
  2. Personal history of adenomatous polyps
  3. Long-standing ulcerative colitis
2. 6% occur in patients with rare genetic syndromes, such as familial polyposis or hereditary nonpolyposis colorectal cancer (HNPCC).
  1. Colorectal cancer develops in 80% of patients with HNPCC by age 50 years.
  2. The mutation associated with HNPCC also increases the risk of cancer of the uterus, ovary, ureter, renal pelvis, stomach, small bowel, and bile duct.
  3. Familial polyposis patients have diffuse colonic polyps at an early age, and colorectal cancer will develop without intervention.
3. The remaining colorectal cancers occur sporadically.
What is the quality of the screening test?
1. Guaiac-based FOBT
  1. Two distinct samples of 3 different stools are applied to 6 test card panels.
  2. If Hgb is present, a blue color appears when hydrogen peroxide is added.
  3. False-negative tests can occur if the patient has ingested > 250 mg of vitamin C, and false-positive tests occur with use of aspirin, nonsteroidal antiinflammatory drugs (NSAIDs), and ingestion of red meat.
  4. “Low sensitivity” tests, such as Hemoccult II have a sensitivity of 25–38% and specificity of 98%.
  5. “High sensitivity” tests, such as Hemoccult SENSA, have a sensitivity of 64–80% and specificity of 87–90%.
  6. Annual screening detected 49% of cancers; biannual screening detected 27–39% of cancers.
  7. A single panel test after a DRE has a sensitivity of 9% and should never be considered an adequate screening test for colorectal cancer.
2. Immunochemical FOBT
  1. Requires 1–2 stool samples instead of 3; optimal interval for screening is not known.
  2. Several qualitative immunochemical FOBT tests are available in the United States; in general, they are more sensitive than guaiac-based FOBT with similar specificities; quantitative testing is not available in the United States.
3. Flexible sigmoidoscopy
  1. Examines approximately the first 60 cm of the colon; patients with polyps are referred for a full colonoscopy.
  2. Only 20–30% of proximal cancers are associated with a distal adenoma.
  3. However, sigmoidoscopy has been found to identify 66% of men with significant findings in the colon, assuming finding a polyp triggers a full colonoscopy; only 55% of lesions in women would be identified because cancers in women are more often proximal.
  4. Detects 7 cancers and about 60 large (> 1 cm) polyps/1000 examinations
  5. Bowel perforation rate is 0.88/1000 sigmoidoscopies
  6. Serious complication rate (deaths or events requiring hospital admission) 3.4/10,000 procedures
4. Combined FOBT and sigmoidoscopy
  1. 7 additional cancers/1000 examinations compared with sigmoidoscopy alone
  2. Did not improve yield at initial screening exam
5. Colonoscopy
  1. Miss rate of 5% for cancers, 2% for adenomas ≥ 1 cm, 13% for adenomas 6–9 mm, and 25% for those < 5 mm (based on studies of tandem colonoscopies by 2 examiners)
  2. Complication rates
    - (1) Major complications (perforation or bleeding) is 1/1000 procedures
    - (2) Perforation rate is 0.6/1000 procedures, with the risk being 4 times higher if polypectomy is performed.
    - (3) Bleeding occurs in 8.7/1000 colonoscopies with polypectomy.
6. Double-contrast barium enema
  1. Sensitivity = 48%
  2. Specificity = 85%
  3. Perforation rate = 1/25,000
7. CT colonography
  1. CT scanning with 2- and 3-dimensional image display
  2. Requires same bowel preparation as colonoscopy
  3. A small rectal catheter is inserted for air insufflation, but no sedation is required.
  4. Sensitivity for cancer = 96%
  5. Sensitivity for polyps ≥ 10 mm = 85–93%, with specificity 97%
  6. Sensitivity for polyps 6–9 mm = 70–86%, with specificity 86–93%
Does screening reduce morbidity or mortality?
1. Guaiac-based FOBT
  1. 3 large randomized trials show reduced colorectal cancer mortality.
  2. Relative risk reduction of colorectal cancer death: 15–33%
  3. Number needed to screen = 217 for annual screening, 344–1250 for biennial screening
2. Flexible sigmoidoscopy
  1. A meta-analysis of five randomized trials showed that the relative risk of colorectal cancer mortality was 0.72 in the screened group.
  2. The PLCO Screening Trial randomized nearly 155,000 persons aged 55–74 to sigmoidoscopy every 3–5 years or to usual care. The relative risk of colorectal cancer mortality was 0.74 in the screened group (absolute reduction from 3.9 to 2.9 colorectal cancer deaths/10,000 person years).
3. Combination guaiac-based FOBT and sigmoidoscopy
  1. In 1 randomized trial, more cancers were found with the combination of guaiac-based FOBT and sigmoidoscopy vs guaiac-based FOBT alone.
  2. Colorectal cancer mortality was not an endpoint.
4. Colonoscopy
  1. No randomized trial data
  2. 1 case-control study showed lower incidence of colon cancer (OR = 0.47) and lower colorectal cancer mortality (OR = 0.43).
  3. A 2009 case-control study found a reduction in death for colorectal cancers in the left colon (OR = 0.33) but not the right colon (OR = 0.99); other case-control studies have found similar reductions in both left- and right-sided late-stage cancers.
  4. Generally assumed that the mortality reductions seen in the FOBT trials is actually due to the follow-up colonoscopies.
5. Double-contrast barium enema: no outcome data available
6. CT colonography
  1. No randomized trial data available
  2. 1 nonrandomized study showed that rates of detection of advanced adenomas + cancers were similar in patients screened with CT colonography (3.2%) compared with conventional colonoscopy (3.4%).
7. Potential harms of screening include the complication rates noted previously, complications of sedation used for colonoscopy, radiation exposure, and patient discomfort.
What are the current guidelines?
1. USPSTF (2008)
  1. Strongly recommends screening average risk men and women beginning at age 50 years and continuing to age 75 years, using FOBT, sigmoidoscopy, or colonoscopy
    - (1) Grade A recommendation
    - (2) Insufficient data to assess the benefits and harms of CT colonography and fecal DNA testing as screening modalities (I recommendation)
  2. Recommends against routine screening in adults age 76–85 years (C recommendation)
  3. Recommends against screening in adults older than age 85 years (D recommendation)
2. American Cancer Society (2008)
  1. Begin screening at age 50
  2. Acceptable strategies include annual FOBT alone (either guaiac based or immunochemical), annual FOBT plus sigmoidoscopy every 5 yearas, sigmoidoscopy alone every 5 years, colonoscopy every 10 years, CT colonography every 5 years, or double-contrast barium enema every 5 years.
  3. Imaging procedures that can detect both adenomatous polyps and cancer are preferred over stool tests that primarily detect cancer.
3. American College of Gastroenterology (2009)
  1. Begin screening at age 50 in average risk adults and at age 45 in African-Americans; repeat every 10 years.
  2. Begin screening at age 40, repeating every 5 years, (or 10 years younger than the age of the youngest affected relative) in adults with
    - (1) 1 first-degree relative with colorectal cancer or an advanced adenoma (≥ 1 cm, high-grade dysplasia, villous elements) diagnosed at < 60 years of age.
    - (2) 2 first-degree relatives with colorectal cancer or advanced adenomas at any age.
  3. Colonoscopy is the preferred method; flexible sigmoidoscopy, CT colonography, and stool tests are acceptable alternatives.
  4. Surveillance after polypectomy (Table 2-4)
Table 2-5 summarizes information on staging, testing, histology, prognosis, and treatment of colon cancer.

Table 2-2.Questions that help identify patients at high risk for colorectal cancer.

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Table 2-2. Questions that help identify patients at high risk for colorectal cancer.

Has the patient had colorectal cancer or an adenomatous polyp?

Does the patient have an illness, such as inflammatory bowel disease, that increases the risk of colorectal cancer?

Has colorectal cancer or an adenomatous polyp been diagnosed in a family member?

Was it a first-degree relative (parent, sibling, or child)?

At what age was the cancer or polyp first diagnosed?

How many first-degree relatives have been diagnosed?

Table 2-3.Magnitude of risk for colorectal cancer.

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Table 2-3. Magnitude of risk for colorectal cancer.

Risk Factor

Approximate Relative Risk of Colorectal Cancer

None

Baseline risk = 5%

One first-degree relative with colon cancer

2–3

Two first-degree relatives with colon cancer

3–4

First-degree relative aged ≤ 50 at cancer diagnosis

3–4

One second- or third-degree relative with colon cancer

1.5

Two second-degree relatives with colon cancer

2–3

One first-degree relative > age 60 with an adenoma

1.8

One first-degree relative < age 60 with an adenoma

2.6

Table 2-4.Colonoscopic surveillance of polyps found at the baseline exam.

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Table 2-4. Colonoscopic surveillance of polyps found at the baseline exam.

Pathology

Recommended Surveillance Interval (years)

< 10 mm hyperplastic polyps

1–2 small (< 10 mm) tubular adenomas

5–10

Sessile serrated polyp(s) < 10 mm

3–10 tubular adenomas

> 10 adenomas

≥ 1 large (≥ 10 mm) tubular adenoma or sessile serrated polyp

≥ 1 villous adenomas

Adenoma with high-grade dysplasia

Table 2-5.Colon cancer.

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Table 2-5. Colon cancer.

Staging

Stage

Stage 0

Stage I

Stage II

Stage III

Stage IV

Definition

Confined to the innermost layer of the colon (carcinoma in situ)

Cancer is in the inner layers of the colon

Cancer has spread through the muscularis mucosa

Cancer has metastasized to the lymph nodes

Distant metastasis

Commonly used tests

For diagnosis:

Colonoscopy

For staging:

Abdominal/pelvic CT scan

Histology

Adenocarcinoma (> 90%)

• Well differentiated (10%)

• Moderately differentiated (70%)

• Poorly differentiated (20%)

Mucinous adenocarcinoma

Signet ring adenocarcinoma

Medullary carcinoma

Prognosis

Overall 1-year survival is 84%

Overall 5-year survival is 64%

Stage 1 5-year survival is 90%

Stage IV 5-year survival is 12%

Treatment

Local resection or polypectomy for stage 0

Resection of involved colon for stages I–II

Resection of involved colon possibly followed by chemotherapy for stage III

Resection of the involved colon and isolated metastases when possible, often followed by chemotherapy for stage IV

You explain to Mr. S that because colon cancer was diagnosed in his mother when she was 54 years old, his risk of developing colon cancer during his lifetime is increased from about 6% to somewhere between 12% and 18%. Although fecal occult blood testing alone is an acceptable screening strategy for low-risk individuals, all of the expert guidelines recommend screening colonoscopy for patients with his risk profile.

Should Mr. S be screened for hyperlipidemia with a lipid panel?

Cholesterol Screening

What is the burden of disease?
1. Coronary heart disease (CHD) is the leading cause of death in the United States.
2. Overall costs of CHD and stroke in 2003 estimated to be > $50 billion.
3. Lifetime risk of a CHD event, calculated at age 40 years, is 49% for men and 32% for women; nearly one-third of CHD events are attributable to total cholesterol > 200 mg/dL.
Is it possible to identify a high-risk group that might especially benefit from screening?
1. The low-density lipoprotein (LDL) and high-density lipoprotein (HDL) levels themselves are independent risk factors for CHD, with the increased risk being continuous and linear.
  1. For every 38 mg/dL increase in LDL above 118 mg/dL, the relative risk for CHD is 1.42 in men and 1.37 in women.
  2. For every 15.5 mg/dL increase in HDL above 40 mg/dL in men, the relative risk for CHD is 0.64.
  3. For every 15.5 mg/dL increase in HDL above 51 mg/dL in women, the relative risk for CHD is 0.69.
  4. Total cholesterol–HDL ratio
    - (1) In men, a ratio ≥ 6.4 was associated with a 2–14% greater risk than predicted from total cholesterol or LDL alone.
    - (2) In women, a ratio ≥ 5.6 was associated with a 25–45% greater risk than predicted from total cholesterol or LDL alone.
2. Patients with established atherosclerotic cardiovascular disease (ASCVD), defined as acute coronary syndrome, a history of myocardial infarction, stable angina, coronary or other arterial revascularization, stroke, transient ischemic attack, or peripheral arterial disease, are in the highest risk category.
3. Patients without established ASCVD should have a global risk score calculated.
  1. The American College of Cardiology/American Heart Association (ACC/AHA) 2013 guidelines recommend the Pooled Cohort Equations, a new risk assessment tool that estimates the 10-year risk of a first ASCVD event, defined as nonfatal myocardial infarction or coronary heart disease death or fatal or nonfatal stroke.
    - (1) Derived and validated in non-Hispanic whites and non-Hispanic African Americans
    - (2) Can use the equations developed for non-Hispanic whites in other populations, although risk assessments may not be as accurate
    - (3) Found at http://my.americanheart.org/cvriskcalculator
  2. The Framingham Risk Score is another commonly used calculator available at http://cvdrisk.nhlbi.nih.gov/calculator.asp.
    - (1) Validated in populations over age 40
    - (2) Unclear if it can be used in conjunction with the new ACC/AHA guidelines described below.
What is the quality of the screening test?
1. Total cholesterol and HDL are minimally affected by eating and can be measured in fasting or nonfasting individuals.
2. Triglycerides may be increased 20–30% by eating and must be measured in the fasting state.
3. LDL can be directly measured but is most commonly estimated using the following equation, which is valid only when the fasting triglycerides are less than 400 mg/dL: total cholesterol – (triglycerides/5 + HDL) = LDL.
4. Total cholesterol may vary by 6% in day-to-day measurements, with HDL varying as much as 7.5%; clinicians should obtain 2 measurements before starting therapy.
Does screening reduce morbidity or mortality?
1. In meta-analyses of primary prevention studies of statin drug therapy, including only patients without established coronary artery disease,
  1. All cause mortality is reduced by 14%, with a number needed to treat over 5 years of 138.
  2. Total cardiovascular disease events are reduced by 25%, with a number needed to treat over 5 years of 49.
  3. CHD events are reduced by 27%, with a number needed to treat over 5 years of 88.
2. No evidence that diet therapy reduces CHD events in primary prevention populations.
  1. Maximum expected cholesterol reduction with diet therapy is 10–20%.
  2. Most trials achieve an average reduction of about 5%.
What are the current guidelines?
1. USPSTF (2008)
  1. Screen all men at age 35 and women with risk factors at age 45.
    - (1) Grade A recommendation
    - (2) Good evidence that screening can identify asymptomatic people at increased risk for coronary artery disease and that lipid-lowering drug therapy decreases the incidence of CHD.
  2. Screen men aged 20–35 and women aged 20–45 if other risk factors are present.
    - (1) Grade B recommendation
    - (2) Other risk factors include diabetes, family history of cardiovascular disease before age 50 in male relatives or age 60 in female relatives, family history suggestive of familial hyperlipidemia, obesity (BMI ≥ 30 kg/m²), presence of multiple other risk factors (eg, hypertension, smoking).
  3. No recommendation regarding screening younger adults without risk factors (grade C recommendation).
  4. Screening should include measurement of total cholesterol and HDL.
  5. Optimal screening interval unclear
2. ACC/AHA (2013)
  1. The ACC/AHA issued updated risk assessment guidelines in 2013 for patients without ASCVD.
    - (1) Adults aged 20–79 should be assessed every 4–6 years for traditional ASCVD risk factors: total and HDL cholesterol, systolic BP, use of antihypertensive therapy, diabetes, current smoking.
    - (2) Adults aged 40–79 should have an assessment of ASCVD risk every 4–6 years, using the Pooled Cohort Equations.
    - (3) In selected individuals in whom there is uncertainty regarding initiation of pharmacologic therapy based on the Pooled Cohort Equations assessment, one can consider additional risk factors:
      - (i) Family history of premature cardiovascular disease (first-degree male relative < 55 years of age; first-degree female relative < 65 years of age)
      - (ii) High sensitivity C-reactive protein ≥ 2 mg/L
      - (iii) Coronary artery calcium score ≥ 300 Agatston units or ≥ 75th percentile for age, sex, and ethnicity
      - (iv) Ankle-brachial index < 0.9
  2. The 2013 treatment guidelines are summarized in Chapter 23, Hypertension.
3. American College of Physicians (2012)
  1. Screen all men ≥ 35 years of age and all women ≥ 45 years of age with a fasting lipid panel.
  2. Screen at an earlier age in patients with multiple risk factors, including obesity, or family history of premature coronary artery disease (clinical CHD before the age of 55 in a parent or grandparent).
  3. Repeat lipid screening every 5 years, or when the patient’s risk factor profile changes

You agree with Mr. S that a fasting lipid panel is an important screening test to do for men over 45, even in the absence of other risk factors.

Should Mr. S have a screening chest radiograph?

Lung Cancer Screening

What is the burden of disease?
1. Lung cancer is leading cause of cancer death in both men and women.
2. About 160,000 deaths from lung cancer in 2012, more than the number of deaths from breast, prostate, and colon cancer combined.
3. Prognosis of non-stage I lung cancers is poor.
Is it possible to identify a high-risk group that might especially benefit from screening?
1. Cigarette smoking is responsible for about 85% of lung cancers.
  1. Compared with nonsmokers, relative risk of developing lung cancer is about 20.
  2. A 65-year-old who has smoked 1 pack/day for 50 years has a 10% risk of developing lung cancer over the next 10 years.
  3. A 75-year-old who has smoked 2 packs/day for 50 years has a 15% risk.
2. Other risk factors include family history of lung cancer and exposure to asbestos, nickel, arsenic, haloethers, polycyclic aromatic hydrocarbons, and environmental cigarette smoke.
What is the quality of the screening test?
1. Chest radiograph: sensitivity = 60%, specificity = 94%
2. CT scan: sensitivity = 94%, specificity = 73%
Does screening reduce morbidity or mortality?
1. 6 randomized trials of chest radiography, with or without sputum cytology, failed to demonstrate a decrease in lung cancer mortality; all were limited by the control population undergoing some screening.
2. National Lung Screening Trial (NLST)
  1. Over 53,000 asymptomatic subjects aged 55–74 with ≥ 30 pack year smoking history; former smokers must have quit within the past 15 years
  2. Exclusions: previous lung cancer, other cancer within the last 5 years, CT scan within the last 18 months, metallic implants in the chest or back, home oxygen use, pneumonia, or other acute upper respiratory tract infection treated with antibiotics within the last 12 weeks
  3. Randomized to 3 annual screenings with low-dose CT scan or single view posteroanterior chest film; an abnormal screen was defined as a nodule ≥ 4 mm
  4. Lung cancer–specific mortality was significantly reduced in the low-dose CT group.
    - (1) CT group lung cancer mortality rate = 1.3%, compared to 1.6% in the chest film group
    - (2) Relative risk reduction = 20%; absolute risk reduction of 3 lung cancer deaths per 1000 patients screened with CT; number needed to screen to prevent 1 lung cancer death = 320
  5. Nearly 40% of participants had at least 1 positive CT result; 96% of these were false positives. Most false-positive results were resolved by follow-up CT scans, although some patients required biopsies.
What are the current guidelines?
1. USPSTF (2013)
  1. Annual screening with low-dose CT in adults ages 55–80 who have a 30 pack-year smoking history and currently smoke or have quit within the past 15 years.
  2. Screening should be discontinued once a person has not smoked for 15 years or develops a health problem substantially limiting life expectancy or ability to have curative lung surgery.
  3. Grade B recommendation
2. American College of Chest Physicians, American Cancer Society, and American Society of Clinical Oncology (2012): discuss screening with patients who meet the NLST eligibility criteria described above
Table 2-6 summarizes information on staging, testing, histology, prognosis, and treatment of lung cancer.

Table 2-6.Lung cancer.

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Table 2-6. Lung cancer.

Staging

Stage

IA (T1N0M0)

IB (T2N0M0)

IIA (T1N1M0)

IIB (T2N1M0 and T3 N0 M0)

IIIA (T3N1M0 and T1,2,3 N2 M0)

IIIB (T4 any N, M0; any T3 M0)

Stage IV

Definition

Tumor size ≤ 3 cm surrounded by lung parenchyma; no evidence of bronchial invasion

Tumors > 3 cm or any size that invades visceral pleura or main bronchus

Tumor size ≤ 3 cm with involvement of peribronchial or hilar lymph nodes

Tumor size > 3 cm with involvement of peribronchial or hilar lymph nodes

Tumors with localized, circumscribed extrapulmonary extension with involvement of peribronchial or hilar nodes or any tumor with involvement of ipsilateral mediastinal and subcarinal nodes

Extensive extrapulmonary tumor invasion of mediastinal structures

Any distant metastasis

Commonly used tests

For diagnosis:

Biopsy methods

• Bronchoscopy

• Mediastinoscopy

• Anterior mediastinotomy

For staging:

CT scan to the level of the adrenal glands (sensitivity 51%, specificity 86% for mediastinal nodes)

Positron emission tomography (sensitivity 74%, specificity 85% for mediastinal nodes)

Histology

Small cell (20–25%)

Non–small cell

• Squamous (25%)

• Adenocarcinoma (40%)

• Large cell adenocarcinoma (10%)

Prognosis

Based on stage at diagnosis

Overall 5-year survival is 16% because only 15% are diagnosed at a localized stage when the overall survival is 52%

Treatment

Resection for local disease

Adjuvant chemotherapy after resection for stages IIA–IIIA

Chemotherapy + radiation for nonresectable stage III

Chemotherapy + palliative care for stage IV

You explain to Mr. S that there have been no studies showing that screening chest radiographs reduce lung cancer deaths in smokers, much less in nonsmokers. You add that he does not meet NLST criteria and so should not be screened for lung cancer.

Should Mr. S be screened for abdominal aortic aneurysm and carotid artery stenosis with ultrasonography?

Abdominal Aortic Aneurysm (AAA) Screening

What is the burden of disease?
1. 4–8% of older men and 0.5–1.5% of older women have an AAA.
2. AAA accounts for about 9000 deaths per year in the United States.
  1. 1-year rupture rates are 9% for AAAs 5.5–5.9 cm, 10% for 6–6.9 cm, and 33% for AAAs ≥ 7 cm.
  2. Only 10–25% of patients with ruptured AAA survive to hospital discharge.
Is it possible to identify a high-risk group that might especially benefit from screening?
1. Age > 65, ever smoking (≥ 100 lifetime cigarettes), male sex, and family history are the strongest risk factors for an AAA > 4.0 cm.
  1. The OR increases by 1.7 for each 7-year age interval.
  2. Current or past smoking increases the risk of AAA by 3–5.
  3. The prevalence of AAA increases more rapidly with age in ever smokers than in never smokers.
  4. The prevalence of AAA > 4 cm in never smokers is < 1% for all ages.
  5. The OR is 1.94 for a positive family history.
  6. The OR is ∼1.3–1.5 for history of coronary artery disease, hypercholesterolemia, or cerebrovascular disease.
  7. The OR is 0.53 for black persons and 0.52 for patients with diabetes.
What is the quality of the screening test?
1. Ultrasonography has a sensitivity of 95% and specificity of 100% for the detection of AAA, defined as an infrarenal aortic diameter > 3.0 cm.
2. One-time screening is sufficient since cohort studies of repeated screening have shown that over 10 years, the incident rate for new AAAs is 4%, with no AAAs of > 4.0 cm found.
3. Abdominal palpation is not reliable.
Does screening reduce morbidity or mortality?
1. A meta-analysis of 4 randomized controlled trials of screening for AAA in men showed a reduction in mortality from AAA, with a pooled OR of 0.57 (95% CI, 0.45–0.74).
  1. Overall in-hospital mortality for open AAA repair is 4.2%; lower mortality is seen in high volume centers performing > 35 procedures/year (3% mortality vs 5.5% in low volume centers) and when vascular surgeons perform the repair (2.2% for vascular surgeons, 4.0% for cardiac surgeons, 5.5% for general surgeons).
  2. 30-day postoperative mortality is higher with open repair than with endovascular repair (2% absolute risk increase, number needed to harm = 50). There are no differences in long-term all-cause mortality or cardiovascular mortality, or in rates of stroke; therefore, endovascular repair is preferred.
2. There was no reduction in all cause mortality, or in AAA-specific mortality in women.
What are the current guidelines?
1. USPSTF (2005)
  1. One-time screening by ultrasonography in men age 65–75 who have ever smoked
  2. Grade B recommendation, based on good evidence of decreased AAA-specific mortality with screening
2. Society of Vascular Surgery (2009)
  1. One-time screening for all men over 65 (at 55 if family history is positive)
  2. One-time screening for women over 65 who have smoked or have a positive family history

Carotid Artery Stenosis (CAS) Screening

What is the burden of disease?
1. The estimated prevalence of significant CAS (60–99%) in the general population is about 1%.
2. The contribution of significant CAS to morbidity or mortality from stroke is not known, nor is the natural progression of asymptomatic CAS.
Is it possible to identify a high-risk group that might especially benefit from screening?
1. CAS is more prevalent in patients with hypertension or heart disease and in those who smoke.
2. There are no risk assessment tools that reliably identify patients with clinically important CAS.
What is the quality of the screening test?
1. For the detection of > 70% stenosis, carotid duplex ultrasonography has a sensitivity of 86–90% and a specificity of 87–94%.
2. For the detection of > 60% stenosis, the sensitivity is 94% and the specificity is 92%.
3. There is some variability in measurements done in different laboratories.
4. Screening for bruits on physical exam has poor reliability and sensitivity.
Does screening reduce morbidity or mortality?
1. There have been 2 randomized controlled trials of carotid endarterectomy for asymptomatic CAS, both of which showed about a 5% absolute reduction in stroke or perioperative death in the surgical group (∼5.5–6.5%), compared with the medically treated group (∼11–12%); the absolute risk reduction for disabling stroke was about 2.5%.
  1. These results may not be generalizable due to the highly selected participants and surgeons.
  2. The medical treatment was not well defined and did not include current standard care, such as aggressive control of BP and lipids.
2. All abnormal ultrasounds need to be confirmed by digital subtraction angiography, which has a stroke rate of 1%, or by magnetic resonance angiography or CT angiography, both of which are < 100% accurate.
3. 30-day perioperative stroke or death rates in asymptomatic patients range from 1.6% to 3.7%, with rates for women at the higher end of the range; in some states, rates are as high as 6%.
4. The perioperative myocardial infarction rate is 0.7–1.1%, going up to 3.3% in patients with more comorbidities.
What are the current guidelines?
1. USPSTF (2007)
  1. Recommends against screening for asymptomatic CAS in the general adult population
  2. Grade D recommendation, based on moderate certainty that the benefits of screening do not outweigh the harms.
2. The American Heart Association and the American Stroke Association (2011) do not recommend population-based screening.
3. Other societies, including the American College of Cardiology, the American College of Radiology, and the Society for Vascular Surgery do not recommend routine screening, although do recommend screening patients with bruits and to consider screening in patients with known atherosclerotic disease.

You explain to Mr. S that he should not invest in the “vascular screening.” Screening for CAS is not recommended for the general population, and since he is younger than 65 years with a minimal history of smoking, he does not need to be screened for AAA.

Mr. S has a second list for his wife, a 42-year-old similarly healthy woman who is scheduled to see you next: lipid panel, bone mineral density (BMD), Pap smear, and mammogram.

Mrs. S also has no medical history, except for 2 normal vaginal deliveries, the first at age 25. Her menses are regular. She does not smoke or drink, and she jogs regularly. She had 1 sexual partner before Mr. S and has been monogamous for 20 years. Her family history is negative, except for osteoporosis in her mother and grandmother. She has had a normal Pap smear every year since her first child was born. She weighs 125 pounds, her BP is 105/70 mm Hg, and her general physical exam, including breast exam, is entirely normal.

Should Mrs. S be screened for cervical cancer with a Pap smear?

Cervical Cancer Screening

What is the burden of disease?
1. About 12,200 new cases of cervical cancer and 4210 cervical cancer–related deaths in the United States in 2010
2. Incidence rates vary by race/ethnicity: 11.1 per 100,000 in Hispanic women; 10 per 100,000 in black women; 7.4/100,000 in white women; 7.3/100,000 in Asian women
3. Rates are considerably higher in countries where cytologic screening is not widely available; worldwide, cervical cancer is the second most common cancer in women and the most common cause of mortality from gynecologic malignancy.
4. Women with preinvasive lesions have a 5-year survival of nearly 100%, with a 92% 5-year survival for early-stage invasive cancer; only 13% survive distant disease.
Is it possible to identify a high-risk group that might especially benefit from screening?
1. 93–100% of squamous cell cervical cancers contain DNA from high-risk human papillomavirus (HPV) strains.
  1. Low- and high-risk subtypes
  2. Cervix especially vulnerable to infection during adolescence when squamous metaplasia is most active.
  3. Most infections cleared by the immune system in 1–2 years without producing neoplastic changes.
    - (1) 90% of low-risk subtypes resolve over 5 years
    - (2) 70% of high-risk subtypes resolve
  4. Women older than 30 years with HPV are more likely to have high-grade lesions or cancer than women younger than 30 with HPV.
2. Early-onset of intercourse (before age 17) and a greater number of lifetime sexual partners (> 2) are risk factors for acquiring HPV.
3. Cigarette smoking increases risk by 2- to 4-fold.
4. Immunocompromise and other sexually transmitted infections, such as herpes and HIV, also increase risk.
5. In utero exposure to diethylstilbestrol and previous treatment for high-grade lesions are also risk factors for cervical cancer.
What is the quality of the screening test?
1. Interpretation of Pap smears: the Bethesda Classification of Cervical Cytology
  1. Negative for intraepithelial lesion or malignancy
  2. Epithelial cell abnormalities: squamous cells
    - (1) Atypical squamous cells (ASC)
      - (a) ASC-US: of undetermined significance
      - (b) ASC-H: cannot exclude high-grade squamous intraepithelial lesion
    - (2) Low-grade squamous intraepithelial lesion
      - (a) Cellular changes consistent with HPV
      - (b) Same as mild dysplasia, histologic diagnosis of cervical intraepithelial neoplasia (CIN) 1
    - (3) High-grade squamous intraepithelial lesion
      - (a) Same as moderate/severe dysplasia, histologic diagnosis of CIN 2, CIN 3, CIS (carcinoma in situ)
      - (b) Should indicate if invasion suspected
    - (4) Squamous cell carcinoma
  3. Epithelial cell abnormalities: glandular cells
    - (1) Atypical (endocervical, endometrial, or glandular)
    - (2) Atypical, favors neoplastic
    - (3) Endocervical adenocarcinoma in situ
    - (4) Adenocarcinoma
2. Pap smear techniques
  1. Conventional Pap smear: cervical cells are spread on a glass slide and treated with a fixative by the examiner
  2. Liquid-based cytology: cervical cells are suspended in a vial of liquid preservative by the examiner, followed by debris removal and placement onto a slide in the laboratory
3. HPV testing
  1. A cervical specimen is placed into a transport medium or into the liquid preservative used for the liquid-based cytology Pap smear method.
  2. Specific RNA probes are added that combine with oncogenic DNA, and the DNA-RNA hybrids are detected by antibodies.
4. Test characteristics of conventional and liquid-based cytology are the same.
  1. Sensitivity for high-grade squamous intraepithelial lesion is ∼ 56%; for low-grade squamous intraepithelial lesion, ∼ 77%.
  2. Specificity for high-grade squamous intraepithelial lesion is ∼ 97%; for low-grade squamous intraepithelial lesion, ∼ 80%.
5. HPV testing is more sensitive but less specific for the detection of CIN 2 and CIN 3; false-positive rates are higher in women under 35 years of age.
Does screening reduce morbidity or mortality?
1. No randomized trial data demonstrate a reduction in cervical cancer mortality with screening.
2. Many observational studies show a decrease in both the incidence of cervical cancer (60–90%) and cervical cancer mortality (20–60%).
3. Many cervical cancers in the United States occur in women who have never been screened; modeling studies suggest than screening such women would reduce cervical cancer mortality by 74%.
4. Screening intervals are based on a combination of randomized trial data and modeling studies.
What are the current guidelines?
1. USPSTF (2012)
  1. Recommends screening women aged 21–65 with cytology (Pap smear) every 3 years; women aged 30–65 can be screened every 5 years with a combination of cytology and HPV testing (Grade A recommendation)
  2. Recommends against screening women older than 65 with a history of adequate recent screening, who are not otherwise at high risk
    - (1) Grade D recommendation
    - (2) Adequate screening is defined as 3 consecutive negative cytology results or 2 consecutive negative HPV results within 10 years of the cessation of screening, with the most recent test occurring within 5 years.
  3. Recommends against routine screening women who have had a total hysterectomy and no history of CIN 2, CIN 3, or cervical cancer (Grade D recommendation)
  4. Recommends against screening in women younger than 21 years (Grade D recommendation)
  5. Recommends against HPV testing in women younger than 30 years (Grade D recommendation)
2. American Cancer Society (2012) guidelines are similar to the guidelines of USPSTF.

You explain to Mrs. S that the combination of her sexual history and her history of 12 normal Pap smears in a row puts her at extremely low risk for cervical cancer. You point out that all expert guidelines consider it acceptable to perform Pap smears every 3 years in women with her history.

Should Mrs. S be screened for breast cancer with a mammogram?

Breast Cancer Screening

What is the burden of disease?
1. Most frequently diagnosed cancer in women
2. The overall lifetime risk of developing breast cancer is 12%
3. The 10-year risk at age 40 is 1.5%; at age 50, it is 2.4%; at age 60 it is 3.5%
4. In 2008, 182,460 cases of invasive cancer and 67,770 cases of in situ cancer were diagnosed, with 40,480 deaths.
Is it possible to identify a high-risk group that might especially benefit from screening?
1. Women who have a BRCA1/BRCA2 mutation are a special high-risk group, with a relative risk of developing breast cancer of 10.0–32.0; certain family history patterns are associated with an increased likelihood of BRCA mutations.
  1. For women of Ashkenazi Jewish descent: Any first-degree relative or 2 second-degree relatives on the same side of the family with breast or ovarian cancer
  2. For all other women:
    - (1) 2 first-degree relatives with breast cancer, at least 1 of whom was diagnosed at age 50 or younger
    - (2) 3 or more first- or second-degree relatives with breast cancer
    - (3) Both breast and ovarian cancer among first- and second-degree relatives
    - (4) A first-degree relative with bilateral breast cancer
    - (5) 2 or more first- or second-degree relatives with ovarian cancer
    - (6) A first- or second-degree relative with both breast and ovarian cancer
    - (7) Breast cancer in a male relative
2. Otherwise, age is the strongest risk factor (relative risk = 18 for women aged 70–74 compared with women aged 30–34).
3. Other risk factors are listed in Table 2-7.
4. Protective factors include > 16 months of breastfeeding, 5 or more pregnancies, exercise, postmenopausal BMI < 23 kg/m², oophorectomy before age 35.
5. A Breast Cancer Risk Assessment Tool has been developed.
  1. Available at http://www.cancer.gov/bcrisktool/
  2. Uses statistical methods applied to data from the Breast Cancer Detection and Demonstration Project, a mammography screening project conducted in the 1970s, to assess breast cancer risk
What is the quality of the screening test?
1. Digital and film mammography have similar overall test characteristics, but digital mammography is more sensitive in women under age 50 years, premenopausal women, and those with dense breasts.
  1. Overall sensitivity of digital = 70%; overall sensitivity of film = 66%; specificity 92% for both
  2. For women under 50 years of age, digital sensitivity = 78%, film sensitivity = 51%
2. About 23% of women have at least 1 false-positive mammogram requiring additional evaluation (additional imaging or biopsy).
3. The false-positive rate tends to be higher in younger women and those taking hormone replacement therapy due to increased breast density.
Does screening reduce morbidity or mortality?
1. Table 2-8 summarizes the results of meta-analyses of randomized trials of screening mammography.
2. Potential harms include anxiety about testing, overdiagnosis, radiation exposure, and false-positive mammograms.
  1. The rate of overdiagnosis (finding cancers that would never have become clinically significant) is unclear, with estimates ranging from 1% to 32%.
  2. There is a small risk of radiation-induced breast cancer (86 cancers and 11 deaths per 100,000 persons screened annually from age 40 to age 55 and then biennially).
3. Meta-analyses of trials of breast self-examination (randomized and nonrandomized) show no effect on breast cancer mortality.
What are the current guidelines?
1. USPSTF (2009)
  1. Recommends against routine screening in women aged 40–49 years (Grade C recommendation; should decide in context of patient's values and risk level)
  2. Screen women aged 50–74 every 2 years
    - (1) Grade B recommendation
    - (2) The 2-year interval is based on observations that reductions in breast cancer mortality were similar in studies using 18- to 33-month screening intervals and 12-month screening intervals; additionally, decision analyses using statistical models found that biannual screening resulted in 2 additional deaths/1000 women screened compared to annual screening.
  3. Current evidence is insufficient to assess benefits and harms of screening women aged 75 years or older (I statement).
  4. Recommends against teaching breast self-examination (D recommendation); evidence is insufficient regarding clinical breast exam (I statement).
2. American Cancer Society (2013)
  1. Begin annual mammography at age 40
  2. Clinical breast exam every 3 years from ages 20–39 and annually beginning at age 40
3. American College of Obstetrics and Gynecology (2009)
  1. Mammography every 1–2 years beginning at age 40; annually beginning at age 50
  2. Clinical breast exam annually beginning at age 20
Table 2-9 summarizes information on staging, testing, histology, prognosis, and treatment of breast cancer.

Table 2-7.Magnitude of risk for breast cancer.

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Table 2-7. Magnitude of risk for breast cancer.

Risk Factor

Approximate Relative Risk of Breast Cancer

50-year-old woman with no additional risk factors

10-year risk = 2.4%

BRCA1/BRCA2

10–32

Therapeutic radiation to the chest at age < 30 years

7.0–17.0

High breast density on mammography

5.0

Atypical ductal or lobular hyperplasia or lobular carcinoma in situ on previous biopsy

4.0

Mother or sister with breast or ovarian cancer

1.5–2.0

Postmenopausal obesity

1.2–1.9

Age at first birth > 30 years

1.2–1.7

White race

1.1–1.5

Age at menarche < 12 years or age at menopause > 55 years

1.2–1.3

Current use of hormone replacement therapy

1.2

> 2 drinks/day

1.2

Table 2-8.Efficacy of breast cancer screening.

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Table 2-8. Efficacy of breast cancer screening.

Age

RR Breast Cancer Death (95% CI)

Number Needed to Invite to Screening to Prevent 1 Breast Cancer Death¹

False-Positive Rate per 1000 Women Screened

40–49

0.85 (0.75–0.96)

1904

97.8

50–59

0.86 (0.75–0.99)

1339

86.6

60–69

0.68 (0.54–0.87)

377

79.0

70–79

1.12 (0.73–1.72)

68.8

¹Compliance with screening was 75–85%, so the number needed to screen to prevent 1 death would be 15–25% lower.

CI, confidence interval; RR, relative risk.

Table 2-9.Breast cancer.

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Table 2-9. Breast cancer.

Staging

Stage

Stage 0

Stage IA

Stage IB

Stage IIA

Stage IIB

Stage IIIA

Stage IIIB

Stage IIIC

Stage IV

Definition

Carcinoma in situ, including DCIS, LCIS, and Paget disease only involving the nipple

Tumor size ≤ 2 cm and localized to the breast

Tumor size ≤ 2 cm and focus of breast cancer cells < 2 mm is found in the lymph nodes

Tumor size ≤ 2 cm and a focus breast cancer cells > 2 mm is found in 1–3 axillary lymph nodes or in lymph nodes near the breast bone or tumor is > 2 cm and < 5 cm and has not spread to the lymph nodes

Tumor is > 2 cm and < 5 cm and a focus breast cancer cells < 2 mm is found in the lymph nodes or tumor is > 2 cm and < 5 cm and cancer has spread to 1–3 axillary lymph nodes or to lymph nodes near the breast bone or tumor is > 5 cm and has not spread to lymph nodes

Tumor is any size and cancer is found in 4–9 axillary lymph nodes or in lymph nodes near the breast bone or > 5 cm and a focus breast cancer cells < 2 mm is found in the lymph nodes or > 5 cm and cancer has spread to 1–3 axillary lymph nodes or to lymph nodes near the breast bone

Tumor is any size and has spread to the chest wall or skin of the breast and ulcerated and can have spread to 9 axillary lymph nodes or lymph nodes near the breast bone

Tumor is any size and has spread to the chest wall or skin of the breast and ulcerated and can have spread to ≥ 10 axillary lymph nodes or lymph nodes near the breast bone or supraclavicular lymph nodes

Any distant metastasis

Commonly used tests

For diagnosis:

Biopsy methods

Fine-needle aspiration (sampling with a thin needle)

Core biopsy (sampling with a wide needle

Incisional (part of mass is removed)

Excisional (all of mass is removed)

For staging:

Sentinel lymph node biopsy

Performed at the time of surgery

A radioactive blue dye is injected into the lymphatic system near the tumor

The first node to take up dye is removed and analyzed microscopically

If positive, other nodes may be removed

Histology

Noninvasive

• DCIS

Invasive

• Ductal (76%)

• Lobular (10–15%): often multiple and bilateral

• Medullary

• Inflammatory: dermal lymphatic invasion with skin changes (peau d’orange)

• Paget disease of the nipple

Prognosis

Based on the stage at the time of diagnosis

Overall 5-year survival is 90%

5-year survival for localized breast cancer is 98%

5-year survival for stage IV is 24%

Treatment

Surgery

• Approach determined by tumor size, patient preference

• Lumpectomy

• Segmental mastectomy

• Total mastectomy

• Modified radical mastectomy

• Breast reconstruction at time of surgery or later

Radiation therapy

• After lumpectomy and sometimes mastectomy

Hormonal therapy

• Works best in cancers with estrogen/progesterone receptors

• Aromatase inhibitors such as exemestane, anastrozole

• Selective estrogen response modifiers such as tamoxifen

Trastuzumab (Herceptin) for HER2/neu positive cancers

Chemotherapy indicated based on stage and biomarker profile

DCIS, ductal carcinoma in situ; LCIS, lobular carcinoma in situ.

You explain to Mrs. S that in women with no factors that increase the risk of breast cancer, the chance that she will have a false-positive mammogram is much larger than the chance a breast cancer will be found. Whether she should be screened prior to age 50 depends on her personal risk tolerance.

Should Mrs. S be screened for osteoporosis?

Osteoporosis Screening

What is the burden of disease?
1. In the United States, about 12 million people over the age of 50 have osteoporosis.
2. Osteoporotic fracture will occur in 50% of postmenopausal women.
  1. Hip fracture will occur in 15%, which is associated with loss of independence in up to 60% of patients and excess mortality of 10–20% within 1 year.
  2. Vertebral deformity will develop in 25%.
Is it possible to identify a high-risk group that might especially benefit from screening?
1. Low BMD itself is the strongest risk factor for fracture.
2. Increasing age is the strongest risk factor for low BMD; other risk factors include low body weight (< 132 pounds), lack of hormone replacement therapy use, family history of osteoporosis, personal history of fracture, ethnic group (white, Asian, Hispanic), current smoking, 3 or more alcoholic drinks/day, long-term corticosteroid use (≥ 5 mg of prednisone daily for ≥ 3 months).
3. The WHO Fracture Risk Algorithm (FRAX) calculates the 10-year probability of hip or major osteoporotic fracture using femoral neck BMD and clinical risk factors (available at http://www.shef.ac.uk/FRAX/).
  1. Although the full FRAX algorithm incorporates femoral neck BMD, it is possible to input just clinical risk factors to estimate the patient's clinical risk.
  2. Using just clinical risk factors, a 65-year-old woman with no additional positive answers has a 9.3% 10-year risk for any osteoporotic fracture.
What is the quality of the screening test?
1. Background
  1. Can measure bone density with a variety of methods (dual-energy x-ray absorptiometry, single-energy x-ray absorptiometry, ultrasonography, quantitative CT) at a variety of sites (hip, lumbar spine, heel, forearm)
  2. Current bone density is compared with peak predicated bone density and then reported as number of SD above or below peak predicted bone density.
  3. Osteoporosis is defined as a bone density “T score” at least 2.5 SD below peak predicted bone density (T score =–2.5 or more negative).
  4. Osteopenia is defined as a T score between –1.0 and –2.5.
  5. Normal is within 1 SD of peak predicted bone density.
2. Dual-energy x-ray bone absorptiometry is the gold standard test.
  1. Has been shown to be a strong predictor of hip fracture risk; femoral neck is best site to measure.
  2. The relative risk of hip fracture is 2.5 for each decrease of 1 SD in bone density at the femoral neck.
  3. The relative risk of vertebral fracture is 1.9 for each decrease of 1 SD in bone density at the femoral neck.
3. There are limited data regarding the optimal interval between screening exams.
  1. One study found that a repeat bone density 8 years after the initial test did not improve fracture risk prediction when compared with the initial test.
  2. Another study stratified patients by baseline bone density and then determined the estimated time interval for 10% of women in each cohort to develop osteoporosis or an osteoporotic fracture.
    - (1) For women with a normal BMD (T score, –1.0 or higher), the interval was 16 years.
    - (2) For women with mild osteopenia (T score, –1.01 to –1.49), the interval was 17 years.
    - (3) For women with moderate osteopenia (T score, –1.50 to –1.99), the interval was 5 years; for those with advanced osteopenia (T score, –2.0 to –2.49), the interval was 1 year.
Does screening reduce morbidity or mortality?
1. No studies of the effectiveness of screening in reducing osteoporotic fractures
2. Many studies show treatment substantially reduces fracture risk.
3. Potential harms of screening include misinterpretation of test results, increasing anxiety in patients, side effects of medications, and cost.
4. If 10,000 women aged 65–69 are screened, assuming a 12% prevalence of osteoporosis and that treatment reduces vertebral fracture by 50% and hip fracture by 66%
  1. The number needed to screen to prevent 1 vertebral fracture over 5 years is 233 and to prevent 1 hip fracture is 556.
  2. In women aged 60–64 (osteoporosis prevalence 6.5%), the number needed to screen for vertebral fracture is 435 and for hip fracture is 1000; in women aged 75–79 (osteoporosis prevalence 28%), the number needed to screen for vertebral fracture is 96 and for hip fracture is 238.
What are the current guidelines?
1. USPSTF (2011)
  1. Screen for osteoporosis in women aged 65 years or older and in younger women with a similar risk (> 9.3% 10-year risk based on the FRAX calculator).
    - (1) Grade B recommendation
    - (2) Good evidence that the risk of osteoporosis increases with age, that bone density measurements accurately predict fracture risk, and that treating asymptomatic women reduces fracture risk.
  2. Current evidence is insufficient to assess the balance of risk and benefits of screening in men (I recommendation).
2. National Osteoporosis Foundation (NOF) (2013)
  1. Screen women age 65 and older and men age 70 and older.
  2. Screen postmenopausal women and men age 50–69 based on risk factor profile.

You agree with Mrs. S that she is at increased risk for osteoporosis, but you explain that her 10-year risk is quite low, based on the FRAX calculator. There is no indication for BMD testing at this time. You discuss the importance of maintaining adequate calcium and vitamin D intake (1200 mg daily of calcium and 800–1000 international units daily of vitamin D).

CASE RESOLUTION

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Based on your discussion, Mr. S decides to forego the chest radiograph and PSA level. He agrees to be scheduled for a fasting lipid panel and a colonoscopy.

You discuss with Mrs. S that she has no additional risk factors for coronary disease, and expert guidelines disagree about when to start screening for hyperlipidemia in low-risk women.

Mrs. S opts to have a mammogram but is happy to let a Pap smear and lipid panel wait a couple of years. She leaves with a handout about the role of calcium and vitamin D intake in the prevention and treatment of osteoporosis.

Table 2-10 summarizes numbers needed to screen for commonly used tests.

Table 2-10.Numbers needed to screen (NNS).

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Table 2-10. Numbers needed to screen (NNS).

Disease

Test

Population

NNS

AAA

Ultrasonography

Ever smoking men, age 65–74

500 to prevent 1 AAA specific death over 5 years

Osteoporosis

DEXA

Women 75–79

Women 65–69

Women 60–64

238 to prevent 1 hip fracture; 96 to prevent 1 vertebral fracture

556 to prevent 1 hip fracture over 5 years; 233 to prevent 1 vertebral fracture

1000 to prevent 1 hip fracture; 435 to prevent 1 vertebral fracture

Breast cancer

Mammography

Women 60–69

Women 50–59

Women 40–49

320 to prevent 1 breast cancer death over 14 years

1138 to prevent 1 breast cancer death over 14 years

1618 to prevent 1 breast cancer death over 14 years

Colorectal cancer

Fecal occult blood testing

Annual screening, patients over 50

Biennial screening

217 to prevent 1 colorectal cancer death

344–1250 to prevent 1 colorectal cancer death

Lung cancer

Low-dose CT

Asymptomatic persons aged 55–74 with ≥ 30 pack year smoking history; former smokers must have quit within the past 15 years

320 to prevent 1 lung cancer death

Prostate cancer

PSA

Men 55–69

1410 to prevent 1 prostate cancer death

AAA, abdominal aortic aneurysm; DEXA, dual-energy x-ray bone absorptiometry; PSA, prostate-specific antigen.

REFERENCES

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Aberle DR, DeMello S, Berg CD et al.. Results of the two incidence screenings in the National Lung Screening Trial. N Engl J Med. 2013;369:920–31.

Boiselle PM. Computed tomography screening for lung cancer. JAMA. 2013;309:1163–70.

Greenland P, Alpert JS, Beller GA et al.. 2010 ACCF/AHA guideline for assessment of cardiovascular risk in asymptomatic adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2010;56:e50–103.

Hoffman RM. Screening for prostate cancer. N Engl J Med. 2011;365:2013–9.

Nelson HD, Maney EM, Dana T et al.. Screening for osteoporosis: an update for the U.S. Preventive Services Task Force. Ann Intern Med. 2010;153:99–111.

Nelson HD, Tyne K, Naik A et al.. Screening for breast cancer: an update for the U.S. Preventive Services Task Force. Ann Intern Med. 2009;151:727–37.

Porter N. Screening for dyslipidemia. (accessed 9/10/13) http://pier.acponline.org/physicians/screening/s367/s367.html.

Qaseem A, Barry MJ, Denberg TD et al.. Screening for prostate cancer: a guidance statement from the Clinical Guidelines Committee of the American College of Physicians. Ann Intern Med. 2012;158:761–69.

Qaseem A, Denberg TD, Hopkins RH et al.. Screening for colorectal cancer: a guidance statement from the American College of Physicians. Ann Intern Med. 2010;156:378–86.

Smith RA, Brooks D, Cokkinides V et al.. Cancer screening in the United States, 2013: a review of current American Cancer Society guidelines, current issues in cancer screening, and new guidance on cervical cancer screening and lung cancer screening. CA Cancer J Clin. 2013;63:88–105.

U. S. Preventive Services Task Force. (accessed 9/10/13) http://www.uspreventiveservicestaskforce.org/index.html.

Warner E. Breast cancer screening. N Engl J Med. 2011;365:1025–32.

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2: Screening and Health Maintenance

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INTRODUCTION

Figure 2-1.

Figure 2-2.

Prostate Cancer Screening

Colon Cancer Screening

Cholesterol Screening

Lung Cancer Screening

Abdominal Aortic Aneurysm (AAA) Screening

Carotid Artery Stenosis (CAS) Screening

Cervical Cancer Screening

Breast Cancer Screening

Osteoporosis Screening

CASE RESOLUTION

REFERENCES

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