Recent Controversies in Cancer Screening Recommendations

US Pharm. 2010;35(11)(Oncology suppl):3-8.

ABSTRACT: Recent modifications in screening recommendations for breast, cervical, and prostate cancer have generated much disagreement among clinicians and patients. In November 2009, the United States Preventive Services Task Force announced its recommendations for breast cancer mammography screening, which differed from current recommendations of the American Cancer Society (ACS). A few days later, the American Congress of Obstetricians and Gynecologists announced its recommendations for cervical cancer screening, which also were different from those of the ACS. Not long afterward, prostate cancer screening was questioned because of conflicting evidence from two large, randomized trials.

Recent changes in screening recommendations for breast, cervical, and prostate cancer have sparked a great deal of controversy among clinicians and patients. The American Cancer Society (ACS) recommends annual mammography screening for breast cancer starting at age 40 years for women at average risk.¹ In November 2009, the United States Preventive Services Task Force (USPSTF) announced its recommendation against routine mammography screening for women aged 40 to 49 years.² Days after the USPSTF made its controversial announcement, the American Congress of Obstetricians and Gynecologists (ACOG) advised that cervical cancer screening be initiated later and conducted less frequently than recommended by the ACS.³ Finally, with regard to prostate cancer, it is unclear how much benefit early detection and screening confer. Two recent large, randomized trials revealed conflicting data, which led the ACS to modify its screening recommendations.^4-6

^{Breast Cancer}

^{Breast cancer is the most commonly diagnosed cancer in women, accounting for approximately 28% (207,090 new cases) of all cancers in 2010; it is also the second leading cause of cancer death (39,840 cases).7} In November 2009, the USPSTF made recommendations that differed from the ACS endorsement of annual mammography starting at age 40 years in women at average risk.¹ Instead, the USPSTF--an independent panel of physicians and scientists that makes recommendations to the U.S. Department of Health and Human Services (DHHS)--suggested initiating biennial mammography screening in women aged 50 years and older.^2,8

This recommendation was based on a meta-analysis of eight mammography screening trials.^2,8-14 Randomly screened women aged 39 to 49 years had a pooled relative risk of 0.85 (95% credible interval, 0.75-0.96) for breast cancer mortality and a 15% reduction in breast cancer mortality.^2,8 (Credible interval, a term used in Bayesian inference, is similar to confidence interval [CI], but also incorporates information from the prior distribution [previous studies]; CIs are based solely on data in one study.¹⁵) In comparison, women who began mammography screening in their 50s had a 14% reduction in risk. This means that 1,904 women aged 40 to 49 years and 1,339 women aged 50 to 59 years must be screened to prevent 1 breast cancer death 11 to 20 years later.^2,8 The USPSTF concluded that the benefit of initiating screening at age 40 years versus 50 years did not sufficiently outweigh the harms associated with early screening.

Additionally, resource allocation associated with early screening was considered. Data from the Breast Cancer Surveillance Consortium, which consists of five mammography registries and two affiliated sites with linkages to pathology and tumor registries across the U.S., showed that, for every case of invasive breast cancer detected by mammography screening in women aged 40 to 49 years, 556 women will have mammography, 47 will undergo additional imaging, and five will undergo biopsy.⁸

Limitations of the Analysis: Limitations of the meta-analysis must be considered. The meta-analysis measured the effectiveness of an invitation to screening, not the screening itself. For example, in the Age trial, only 68% of patients invited for screening went for screening.¹⁶ The meta-analysis also included trials with effective protocols and ineffective protocols. For example, the Swedish Two-County trial was limited to women aged under 50 years.¹¹ Other ineffective protocols include long screening intervals (³24 months) and single-view (rather than dual-view digital) mammography.

While some studies support ACS or USPSTF recommendations, others have been inconclusive.^2-10,12-14 Most notably, the UK Trial of Early Detection of Breast Cancer and the Swedish Two-County Trial support the ACS recommendation of annual mammography screening starting at age 40 years.^11,17 On the other hand, the Edinburg trial, the Canadian National Breast Screening Study (NBSS)-1, NBSS-2, and the Health Insurance Plan of Greater New York study support the USPSTF recommendation of biennial mammography screening starting at age 50.^10,13,18,19 A study by Moss et al, as well as the Gothenburg Breast Screening Trial, concluded that further research needs to be conducted and that future decisions on screening policies should consider factors such as harms, costs, and benefits.^9,12

Harms of Mammography: One of the most common potential harms of mammography screening is a false-positive result, which can cause short-term psychological distress and anxiety and necessitate additional imaging studies and invasive procedures such as biopsy and fine-needle aspiration.^1,2 An increase in the number of biopsies may also increase a woman's breast cancer risk score as determined by the Gail model.¹ False-positive results and additional imaging studies are more likely in younger women (40-49 years).^1,2 Radiation exposure may increase the risk of breast cancer, but the amount of exposure during mammography is minimal.^1,2 Overdiagnosis--detection of cancer that would not have become clinically apparent during the patient's lifetime in the absence of screening--may also occur, usually leading to overtreatment.^1,2 Mammography involves breast compression to create uniform density, reduce breast thickness, and flatten overlying skin. It can be a painful process, but few women in one study said that this pain would affect future screening.⁸ The effects of these potential harms are hard to measure.

After reviewing the USPSTF report, the DHHS did not alter its recommendations; it continues to endorse annual mammography screening starting at age 40 years for women at average risk. The USPSTF did not measure years of potential life lost due to death from breast cancer before age 50 years, which was an important factor in the ACS recommendation.²⁰

It is important to remember that mammography screening saves lives by detecting disease early and reducing the chance of progression. It is recommended that women be informed of the potential harms, such as false-positive results and the fear and anxiety that accompany additional testing, as well as the benefits of mammography screening.^1,2 The advantages of annual versus biennial screening are an important area of continued research.

There is currently no debate about screening recommendations for women at increased risk. Women at high risk include those with breast cancer gene BRCA1 or BRCA2; two or more relatives with breast or ovarian cancer; a relative with breast cancer occurring before age 50 years; relatives with both breast and ovarian cancer; one or more relatives with two cancers other than breast and ovarian; a male relative with breast cancer; and Ashkenazic Jewish heritage.¹ High-risk patients should consider initiating screening at 30 years, have shorter screening intervals (6 months), and undergo additional MRI and ultrasound screening. Shared decision-making between patient and provider is recommended after a review of the benefits, harms, and limitations of the different options. Screening decisions in women older than 70 years also should be individualized, taking into consideration current health status and estimated life expectancy.

Cervical Cancer

Cervical cancer commonly develops in women who have been infected with human papillomavirus (HPV). HPV is acquired through vaginal intercourse, but is usually cleared by the immune system within 1 to 2 years without developing neoplastic changes.²¹

Screening Recommendations: Since 2002 and 2003, respectively, the ACS and the ACOG have recommended cervical cancer screening with the Papanicolaou (Pap) test beginning approximately 3 years after the start of sexual intercourse or annually by age 21 years.^3,15,21 Women aged 30 years and older should have a Pap smear every 2 to 3 years.^3,21

The ACS recommends that screening be stopped at age 70 years after three negative tests in the last 10 years; the ACOG does not provide an upper age limit.^3,21 In November 2009, however, the ACOG revised its recommendations to include biennial screening starting at age 21, regardless of age at onset of sexual activity.³ Women older than 30 years who have three consecutive negative cervical cytology screening tests; are HIV-negative; have no history of grade 2 or 3 cervical intraepithelial neoplasia; are not immunocompromised; and were not exposed to diethylstilbestrol in utero may extend the screening interval to once every 3 years.³

The ACOG recommendations are based on the fact that 0.1% of cervical cancer cases occur before age 21 years.³ The ACOG recommends this more conservative approach because screening earlier than this may increase anxiety, morbidity, and testing expense. Also, because women under 21 years have most or all of their childbearing years ahead of them, it is important to avoid unnecessary cervical procedures. Annual cytology examinations provide little benefit over screening at 2- or 3-year intervals.^3,22-25

^{HPV Vaccines: Gardasil and Cervarix are two FDA-approved HPV vaccines.26,27} Cervarix is a bivalent vaccine with activity against HPV types 16 and 18, which is approved for prevention of cervical cancer in females aged 10 to 25 years.²⁷ Gardasil is a quadrivalent HPV vaccine with activity against types 6, 11, 16, and 18 that is approved for males and females aged 9 to 26 years.²⁶ Vaccination is necessary prior to HPV exposure, but it is, of course, unknown at what age a patient will become sexually active.

The ACS recommends HPV vaccination in females aged 11 to 18 years.²¹ There is insufficient evidence for or against vaccinating those aged 19 to 26 years. Patients should speak to a health care provider about the benefits of vaccination, as well as its harms (i.e., injection-site reactions, fever, headache, nausea, fainting).^21,26,27 The ACOG recommends vaccination in females aged 9 to 26 years, with the initial vaccination to target those aged 11 to 12 years.³

As mentioned, Cervarix and Gardasil are effective against HPV types 16 and 18, which account for about 70% of cervical cancers, but Gardasil also is effective against HPV types 6 and 11, which cause approximately 90% of genital warts.^3,21 The vaccination schedule comprises three doses. The second dose should be given 2 months after the first dose, and the third dose given 6 months after the first dose.^26,27 Females should be advised to continue regular Pap screening after receiving the HPV vaccine.

^{Prostate Cancer}

^{Prostate cancer is the most common cancer diagnosed in U.S. men (217,730 cases) and the second leading cause of cancer death (32,050) in this population.7} Results of two large, prospective, randomized trials that examined prostate-specific antigen (PSA) screening--the European Randomized Study of Screening for Prostate Cancer (ERSPC) and the U.S.-based Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO)--were published in 2009.^4-6 Results were conflicting; PLCO showed no benefit to PSA screening, whereas ERSPC showed a 20% reduction in prostate cancer mortality associated with screening.^4-6

PLCO Results: PLCO randomized 76,693 patients aged 55 to 74 years at 10 U.S. centers to either usual care (n = 38,350) or annual serum PSA screening for 6 years and digital rectal examination (DRE) for 4 years (n = 38,343).⁵ Prostate biopsy was recommended for patients whose PSA exceeded 4 ng/mL or whose DRE revealed a suspicious nodule. Patients were followed for at least 7 years. The incidence of death per 10,000 person-years was 2.0 (50 deaths) in the screening group and 1.7 (44 deaths) in the usual-care group. The difference in prostate cancer-specific mortality between groups was not significant.

It is important to consider the trial's limitations. Forty-four percent of patients underwent up to two PSA tests prior to randomization, which may have reduced the number of prevalent prostate cancers in the study population. Also, there was a poor compliance rate for physician-recommended biopsy: Only 40% of patients advised to undergo biopsy followed through, and this decreased to 30% by the third round of screening. PLCO found no significant difference in mortality between patients routinely screened for prostate cancer and those not screened.

ERSPC Results: This trial, conducted in seven European centers, enrolled 162,243 patients aged 55 to 69 years.⁶ Patients were randomized to receive either PSA screening every 4 years or no screening. Prostate biopsy was recommended for patients whose PSA exceeded 4 ng/mL, but many centers lowered the PSA cutoff to 3 ng/mL midstudy, and DREs were not routinely performed. No ERSPC patients were screened for prostate cancer prior to randomization. A total of 85.8% of patients with a positive PSA underwent biopsy.

There was a 20% reduction in prostate cancer mortality after an average follow-up of 9 years. After adjustment for contamination (failure to screen in the screening arm and nonattendance), there was a 31% reduction in mortality. This means that, in order to prevent one death from prostate cancer, 1,410 men must be screened and 48 must be treated. Patients in the screening arm who were diagnosed with prostate cancer were more likely to receive treatment at a university hospital, where therapy tended to be modern and more intense. Other potential confounding factors were that many centers lowered the PSA cutoff to 3.0 ng/mL and eliminated DRE midstudy.

ACS Recommendations: After reviewing the PLCO and ERSPC results, the ACS revised its prostate cancer screening recommendations.²⁸ Previously, the ACS advised annual PSA screenings for men aged 50 years and older. The revised recommendations for asymptomatic men with at least a 10-year life expectancy include the patient making an informed decision with his health care provider about prostate cancer screening. Average-risk men should begin informed decision-making at age 50, while high-risk patients (having African American heritage or a 1st-degree relative diagnosed with prostate cancer at age <65 years) should begin at age 45. Men at appreciably higher risk (multiple 1st-degree relatives diagnosed with prostate cancer at age <65 years) should begin informed decision-making at age 40. Risks that should be considered with prostate cancer screening include possible overdiagnosis, overtreatment and anxiety because of a false-positive result, and risk of bleeding and infection from biopsy.

Current evidence on the effectiveness of prostate cancer screening to reduce mortality is conflicting. The ACS recommends informed decision-making between patient and provider.²⁸ The patient's age, family history, and personal values should be considered, and the patient should be educated about the risks, benefits, and uncertainties associated with prostate cancer screening.

Additional Screening Information

Guidelines and additional information about cancer screening are available to the interested reader.²⁰

References

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