Alfred O. Berg

Screening for Colorectal Cancer in Adults at Average Risk: A Summary of the Evidence for the U.S. Preventive Services Task Force

The U.S. Preventive Services Task Force (USPSTF) last considered its recommendations regarding colorectal cancer screening in 1996 (1). At that time, the available evidence included one randomized, controlled trial showing that fecal occult blood testing (FOBT) reduced mortality rates (2); a casecontrol study showing that persons having sigmoidoscopy were less likely to die of colorectal cancer (3); and one nonrandomized, controlled trial of FOBT combined with rigid sigmoidoscopy that suggested some benefit from the two tests together (4). On the basis of this evidence, the USPSTF recommended screening for colorectal cancer with FOBT, sigmoidoscopy, or both (a grade B recommendation) but did not recommend for or against other means of screening (digital rectal examination, double-contrast barium enema, or colonoscopy) because the available evidence was insufficient. (See the companion article in this issue for a description of the USPSTF classification of recommendations.) The Task Force also recommended that FOBT be performed yearly but did not specify an interval for sigmoidoscopy. Since 1996, important new evidence has emerged regarding the effectiveness of colorectal cancer screening. We performed an updated systematic review to help the USPSTF evaluate new evidence on the effectiveness of different colorectal cancer screening tests as it updated its previous recommendation. We examined the evidence concerning the effectiveness of screening in adults older than 50 years of age who are at average risk for colorectal cancer. The effectiveness, accuracy, and adverse effects of digital rectal examination (with or without a single office-based FOBT), traditional three-card FOBT (hereafter referred to as FOBT), sigmoidoscopy, FOBT with sigmoidoscopy, double-contrast barium enema, and colonoscopy were examined. Other tests or combinations of tests have not been well evaluated and are not discussed here. A more detailed report of our review can be found on the Web site of the U.S. Agency for Healthcare Research and Quality (www.ahrq.gov/clinic/uspstfix.htm) (5). The USPSTFs updated recommendations for colorectal cancer screening recommendations can be found in the companion article in this issue (6). Methods To identify the relevant literature, we used the Guide to Clinical Preventive Services, 2nd edition (1); existing systematic reviews; focused MEDLINE literature searches from 1966 through September 2001; and hand searches of key articles. When available, systematic reviews were used to identify older relevant studies. Literature searches were used to identify newer studies. Detailed descriptions of the literature searches can be found in the Appendix. To identify relevant studies, one reviewer examined the abstracts of the articles identified in the initial search. A second reviewer examined the excluded articles. Disagreements about inclusion were resolved by consensus. Two reviewers examined the full text of the remaining articles to determine final eligibility. We used evidence from randomized, controlled trials or observational studies that measured patient outcomes, particularly changes in colorectal cancer mortality rates and incidence. When such data were not available, we included indirect information on the accuracy of screening tests. Details about study inclusion are available in the Appendix. We rated the quality of the included articles by using the criteria developed by the USPSTF Methods group (7), which are described in the accompanying article in this issue (6). We used the final set of eligible articles to create evidence tables and a draft report. The draft report was extensively peer reviewed by the USPSTF, experts in the field, governmental agencies, and nongovernmental organizations. Role of the Funding Source This evidence report was funded through a contract to the Research Triangle InstituteUniversity of North Carolina Evidence-based Practice Center from the Agency for Healthcare Research and Quality. Staff of the funding source contributed to the study design, reviewed draft and final manuscripts, and made editing suggestions. Results Our general search identified 719 articles published since 1995 on colorectal cancer screening. We retained 19 of these articles in our final document. Specific searches from 1966 through 2001 for articles about the accuracy of barium enema and complications of screening yielded 621 and 839 articles, respectively. After review, we retained 13 articles about barium enema and 19 articles about complications of screening. We also included 15 articles identified from the previous USPSTF review or from hand searches of other articles. Table 1 our findings. Table 1. Characteristics of Screening Tests for Colorectal Cancer Digital Rectal Examination Effectiveness A casecontrol study from the Kaiser Permanente Medical Care Program in northern California examined the effect of screening with digital rectal examination on death from colorectal cancer (8). The investigators identified patients 45 years of age and older who died of distal rectal cancer between 1971 and 1986 and selected matched controls from the patient membership. They examined medical records to determine whether the patients and controls had undergone screening digital rectal examination within a year of cancer diagnosis. Investigators found no difference between groups after controlling for potential confounders, although the confidence interval was wide (odds ratio, 0.96 [95% CI, 0.56 to 1.7]). Accuracy The potential sensitivity of screening digital rectal examination is low; fewer than 10% of cases of colorectal cancer are within reach of the examining finger (28). The specificity of positive results on digital rectal examination has not been examined in outpatients at average risk for colorectal cancer. In-Office Fecal Occult Blood Testing after Digital Rectal Examination Effectiveness No studies have examined the effect of a single in-office FOBT after digital rectal examination on colorectal cancer incidence or mortality rates. Accuracy A single in-office FOBT is likely to be less sensitive than the traditional three-card FOBT performed at home because only one sample is taken (9). In a large study from Japan, Yamamoto and Nakama (10) found that the first test card detected only 58% of cancer found after a three-card test. The single in-office FOBT may be less specific than a properly performed three-card FOBT because the in-office test does not allow degradation of the vegetable peroxidases that sometimes produce false-positive results (9). In addition, the potential trauma from the in-office examination itself may also result in lower specificity (9). Two studies of poor to fair quality that used existing data to retrospectively compare the specificity of the single in-office FOBT and the three-card home FOBT (11, 12) found little difference in specificity between the two groups. However, the validity of these studies is limited because neither could ensure that similar patient samples received each test. Fecal Occult Blood Testing Effectiveness In addition to an older randomized trial performed in Minnesota (2), which was available to the USPSTF in 1996, two newer randomized, controlled trials have examined the effectiveness of biennial FOBT for reducing death from colorectal cancer (13, 14). These more recent trials, from the United Kingdom (13) and Denmark (14), found 15% and 18% reductions in mortality rates, respectively, with biennial testing. Neither trial used slides that were rehydrated before development (Table 2). Table 2. Trials of Fecal Occult Blood Testing The Minnesota trial compared annual and biennial testing with no screening and rehydrated most test cards (83%). Cumulative colorectal cancer mortality rates after 18 years of follow-up were 33% (CI, 17% to 49%) lower among persons randomly assigned to undergo annual FOBT than in a control group that was not offered screening (absolute rates, 9.5 deaths per 1000 participants vs. 14.1 deaths per 1000 participants; difference, 4.6 deaths per 1000 participants) (2). Biennial screening, which did not show a reduction in mortality rates at 13-year follow-up, produced a 21% (CI, 3% to 38%) reduction in mortality rate at 18 years (15). The 18-year follow-up also showed that the incidence of colorectal cancer decreased by 20% (CI, 10% to 30%) and 17% (CI, 6% to 27%) in the groups screened annually and biennially, respectively, compared with controls (16). Because of differences in hydration, test frequency, duration, and effect size, the results of these trials could not be combined in a meta-analysis. Accuracy A systematic review from 1997 found that the sensitivity of a single unrehydrated FOBT for cancer was approximately 40%; its specificity seems to range from 96% to 98%. Rehydration was found to increase sensitivity to between 50% and 60% but decreased specificity to 90% (9, 29). In a recent study, Lieberman and colleagues (17) found that the sensitivity of rehydrated FOBT for cancer was 50% (CI, 30% to 70%). For advanced neoplasia (cancer and polyps that are large, villous, or dysplastic), sensitivity was 24% (CI, 19% to 29%) and specificity was 94% (CI, 93% to 95%). In the annual screening arm of the 13-year Minnesota trial, which primarily used rehydrated test cards and had a high initial rate of participation (approximately 90%), 49% of patients who developed colorectal cancer were identified through screening. Thirty-eight percent of all patients had had at least one colonoscopy (2). Biennial screening detected 39% of patients with cancer in the intervention group, and 28% of patients required colonoscopy. Compared with the Minnesota trial, the two European trials were population-based, lasted 8 to 10 years, used only biennial testing, and had lower participation rates (60% to 70% of patients completed the first screening). Screening detected 27% of patients in the intervention group who developed colorectal cancer, a

The Evaluation of Genomic Applications in Practice and Prevention (EGAPP) initiative: methods of the EGAPP Working Group

The Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Initiative, established by the National Office of Public Health Genomics at the Centers for Disease Control and Prevention, supports the development and implementation of a rigorous, evidence-based process for evaluating genetic tests and other genomic applications for clinical and public health practice in the United States. An independent, non-federal EGAPP Working Group (EWG), a multidisciplinary expert panel selects topics, oversees the systematic review of evidence, and makes recommendations based on that evidence. This article describes the EGAPP processes and details the specific methods and approaches used by the EWG.

Recommendations from the EGAPP Working Group: genetic testing strategies in newly diagnosed individuals with colorectal cancer aimed at reducing morbidity and mortality from Lynch syndrome in relatives

Summary of Recommendations: The Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group found sufficient evidence to recommend offering genetic testing for Lynch syndrome to individuals with newly diagnosed colorectal cancer to reduce morbidity and mortality in relatives. We found insufficient evidence to recommend a specific genetic testing strategy among the several examined.Rationale: Genetic testing to detect Lynch syndrome in individuals with newly diagnosed colorectal cancer (CRC) is proposed as a strategy to reduce CRC morbidity and mortality in their relatives (see Clinical Considerations section for definition of Lynch syndrome). The EGAPP Working Group (EWG) constructed a chain of evidence that linked genetic testing for Lynch syndrome in patients with newly diagnosed CRC with improved health outcomes in their relatives. We found that assessing patients who have newly diagnosed CRC with a series of genetic tests could lead to the identification of Lynch syndrome. Relatives of patients with Lynch syndrome could then be offered genetic testing, and, where indicated, colorectal, and possibly endometrial, cancer surveillance, with the expectation of improved health outcome. The EWG concluded that there is moderate certainty that such a testing strategy would provide moderate population benefit.Analytic Validity: The EWG found adequate evidence to conclude that the analytic sensitivity and specificity for preliminary and diagnostic tests were high.Clinical Validity: After accounting for the specific technologies and numbers of markers used, the EWG found at least adequate evidence to describe the clinical sensitivity and specificity for three preliminary tests, and for four selected testing strategies. These measures of clinical validity varied with each test and each strategy (see Clinical Considerations section).Clinical Utility: The EWG found adequate evidence for testing uptake rates, adherence to recommended surveillance activities, number of relatives approachable, harms associated with additional follow-up, and effectiveness of routine colonoscopy. This chain of evidence supported the use of genetic testing strategies to reduce morbidity/mortality in relatives with Lynch syndrome. Several genetic testing strategies were potentially effective, but none was clearly superior. The evidence for or against effectiveness of identifying mismatch repair (MMR) gene mutations in reducing endometrial cancer morbidity or mortality was inadequate.Contextual Issues: CRC is a common disease responsible for an estimated 52,000 deaths in the United States in 2007. In about 3% of newly diagnosed CRC, the underlying cause is a mutation in a MMR gene (Lynch syndrome) that can be reliably identified with existing laboratory tests. Relatives inheriting the mutation have a high (about 45% by age 70) risk of developing CRC. Evidence suggests these relatives will often accept testing and increased surveillance.

Methodological standards and patient-centeredness in comparative effectiveness research: The PCORI perspective

Rigorous methodological standards help to ensure that medical research produces information that is valid and generalizable, and are essential in patient-centered outcomes research (PCOR). Patient-centeredness refers to the extent to which the preferences, decision-making needs, and characteristics of patients are addressed, and is the key characteristic differentiating PCOR from comparative effectiveness research. The Patient Protection and Affordable Care Act signed into law in 2010 created the Patient-Centered Outcomes Research Institute (PCORI), which includes an independent, federally appointed Methodology Committee. The Methodology Committee is charged to develop methodological standards for PCOR. The 4 general areas identified by the committee in which standards will be developed are (1) prioritizing research questions, (2) using appropriate study designs and analyses, (3) incorporating patient perspectives throughout the research continuum, and (4) fostering efficient dissemination and implementation of results. A Congressionally mandated PCORI methodology report (to be issued in its first iteration in May 2012) will begin to provide standards in each of these areas, and will inform future PCORI funding announcements and review criteria. The work of the Methodology Committee is intended to enable generation of information that is relevant and trustworthy for patients, and to enable decisions that improve patient-centered outcomes.

National Institutes of Health State-of-the-Science Conference Statement: Family History and Improving Health

The role of obtaining family history information in the primary care setting, the validity of such information, and whether the information affects health outcomes must be clarified. Accordingly, t...

Recommendations from the EGAPP Working Group: testing for cytochrome P450 polymorphisms in adults with nonpsychotic depression treated with selective serotonin reuptake inhibitors

This statement summarizes the Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group recommendations regarding CYP450 genetic testing in adult patients beginning treatment with selective serotonin reuptake inhibitors (SSRIs), and the supporting scientific evidence. EGAPP is a project developed by the National Office of Public Health Genomics at the Centers for Disease Control and Prevention to support a rigorous, evidence-based process for evaluating genetic tests and other genomic applications that are in transition from research to clinical and public health practice in the United States. A key goal of the EGAPP Working Group is to develop conclusions and recommendations regarding clinical genomic applications and to establish clear linkage to the supporting scientific evidence. The Working Group members are nonfederal experts in genetics, laboratory medicine, and clinical epidemiology convened to establish methods and processes; set priorities for review topics; participate in technical expert panels for commissioned evidence reviews; publish recommendations; and provide guidance and feedback on other project activities.Summary of Recommendation The EGAPP Working Group found insufficient evidence to support a recommendation for or against use of CYP450 testing in adults beginning SSRI treatment for non-psychotic depression. In the absence of supporting evidence, and with consideration of other contextual issues, EGAPP discourages use of CYP450 testing for patients beginning SSRI treatment until further clinical trials are completed.Rationale: The EGAPP Working Group found no evidence linking testing for CYP450 to clinical outcomes in adults treated with SSRIs. While some studies of a single SSRI dose in healthy patients report an association between genotypic CYP450 drug metabolizer status and circulating SSRI levels, this association was not supported by studies of patients receiving ongoing SSRI treatment. Further, CYP450 genotypes are not consistently associated with the patient outcomes of interest, including clinical response to SSRI treatment or adverse events as a result of treatment. No evidence was available showing that the results of CYP450 testing influenced SSRI choice or dose and improved patient outcomes, or was useful in medical, personal, or public health decision-making. In the absence of evidence supporting clinical utility, it is not known if potential benefits from CYP450 testing will outweigh potential harms. Potential harms may include increased cost without impact on clinical decision making or improvement in patient outcomes, less effective treatment with SSRI drugs, or inappropriate use of genotype information in the management of other drugs metabolized by CYP450 enzymes.

Newborn screening technology: proceed with caution.

The American College of Medical Genetics (ACMG) recommends a significant expansion in the number of conditions targeted by newborn screening (NBS) programs.1 In this commentary we advocate a more cautious approach. NBS dates to the early 1960s, when the technology developed to conduct large-scale testing on dried blood spots for phenylketonuria (PKU).2 PKU remains the paradigm condition for NBS because of features of the disease and its treatment, which are particularly advantageous to population screening. It is a condition that silently causes neurologic devastation but is amenable to early detection and effective prevention with a diet of moderate burden and complexity.3 Many children affected with PKU and their families have benefited from state screening programs over the past 4 decades because of collaboration between health departments, families, primary care providers, and metabolic specialists. However, PKU screening is not an unmitigated success.4,5 There was initial uncertainty about whether children with variant forms of hyperphenylalaninemia required treatment and about whether affected children require life-long dietary management.6 Indeed, some children with benign conditions were seriously harmed from unnecessary restrictions in their diets.5 In addition, long-term studies demonstrate decrements in cognitive function for affected children and adolescents who are not fully adherent to the diet,7,8 yet adherence to the diet is challenging because of its poor palatability, high cost, and limits on insurance coverage in many policies. Affected women who are off the diet are at high risk of bearing severely neurologically impaired children.9 Only recently have many programs begun tracking affected women to enable notification, education, and management. These difficulties by no means negate the value of NBS for PKU, but they highlight the problems with the successful implementation of a population-based screening program even when a model condition is targeted. … Address correspondence to Jeffrey R. Botkin, MD, MPH, Research Administration Building, 75 South 2000 East #108, Salt Lake City, UT 84112-8930. E-mail: jeffrey.botkin{at}hsc.utah.edu

Recommendations from the EGAPP Working Group: Can tumor gene expression profiling improve outcomes in patients with breast cancer?

Summary of Recommendations: The EGAPP Working Group (EWG) found insufficient evidence to make a recommendation for or against the use of tumor gene expression profiles to improve outcomes in defined populations of women with breast cancer. For one test, the EWG found preliminary evidence of potential benefit of testing results to some women who face decisions about treatment options (reduced adverse events due to low risk women avoiding chemotherapy), but could not rule out the potential for harm for others (breast cancer recurrence that might have been prevented). The evidence is insufficient to assess the balance of benefits and harms of the proposed uses of the tests. The EWG encourages further development and evaluation of these technologies.Rationale: The measurement of gene expression in breast tumor tissue is proposed as a way to estimate the risk of distant disease recurrence in order to provide additional information beyond current clinicopathological risk stratification and to influence decisions about treatment in order to improve health outcomes. Based on their review of the EGAPP-commissioned evidence report, Impact of Gene Expression Profiling Tests on Breast Cancer Outcomes1 and other data summaries, the EWG found no direct evidence linking tumor gene expression profiling of women with breast cancer to improved outcomes, and inadequate evidence to construct an evidence chain. However, further evaluation on the clinical utility of some tests and management algorithms, including well-designed randomized controlled trials, is warranted.Analytic Validity: Some data on technical performance of assays were identified for MammaPrint and Oncotype DX, though estimates of analytic sensitivity and specificity could not be made. Published performance data on the laboratory developed Quest H:I Test were limited. Overall, the EWG found the evidence to be inadequate.Clinical Validity: The EWG found adequate evidence regarding the association of the Oncotype DX Recurrence Score with disease recurrence and adequate evidence for response to chemotherapy. The EWG found adequate evidence to characterize the association of MammaPrint with future metastases, but inadequate evidence to assess the added value to standard risk stratification, and could not determine the population to which the test would best apply. The evidence was inadequate to characterize the clinical validity of the Quest H:I Test.Clinical Utility: The EWG found no evidence regarding the clinical utility of the MammaPrint and Quest H:I Ratio tests, and inadequate evidence regarding Oncotype DX. These technologies have potential for both benefit and harm.Contextual Issues: The EWG reviewed economic studies that used modeling to predict potential effects of using gene profiling, and judged the evidence inadequate.

Evaluation of a physician education intervention to improve primary care for low-back pain i: Impact on physicians

In an effort to improve the cost-effectiveness of primary care for low-back pain, we developed, implemented, and evaluated a physician education intervention. The program was designed to provide family physicians with specific information, tools, and techniques that our previous studies and the literature suggested should be associated with more satisfying and cost-effective care for low-back pain. The in-clinic educational intervention included feedback of the findings of our previous studies of care for back pain (comparing family physicians and chiropractors), an up-to-date summary of scientific knowledge relevant to the management of back pain in primary care, a videotape contrasting ineffective and effective patient encounters, and a clinical assessment form for low-back pain. The back pain-related beliefs, attitudes, and behaviors of 15 primary care providers in a large health maintenance organization clinic and of 14 family physicians in six group practices were assessed before and after the intervention. Significant increases were noted in the proportions of providers who felt confident they knew how to manage low-back pain, who believed their patients were satisfied, and who claimed they reassured patients that they did not have serious disease. The intervention, however, had little impact on the prevalence of negative feelings about patients with back pain or frustration with patients who wanted their doctor to “fix” their problem. The intervention had a similar impact on health maintenance organization and fee-for-service physicians.

Recommendations from the EGAPP working group: Can UCT1A1 genotyping reduce morbidity and mortality in patients with metastatic colorectal cancer treated with irinotecan?

Summary of Recommendations: The Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group found that the evidence is currently insufficient to recommend for or against the routine use of UGT1A1 genotyping in patients with metastatic colorectal cancer who are to be treated with irinotecan, with the intent of modifying the dose as a way to avoid adverse drug reactions (severe neutropenia).Rationale: The EGAPP Working Group (EWG) found no intervention trials showing that targeted dosing of irinotecan based on UGT1A1 genotyping could reduce the rates of two specific adverse drug events, severe (Grade 3–4) neutropenia or diarrhea. Observational studies indicate a significant association between UGT1A1 genotypes, particularly *28/*28 and *1/*28, and the occurrence of severe neutropenia. Observational studies also indicate a possible association between severe diarrhea and these UGT1A1 genotypes, but the association is not statistically significant. An additional finding was the suggestion that reducing irinotecan dose may result in patient harms due to diminished effectiveness of treatment in highest risk individuals (*28/*28 homozygotes), and that a higher dose might be warranted among individuals at lower risk of adverse drug events (*1/*1 and *1/*28 genotypes). This review did not consider higher risk patients (e.g., having previous adverse reactions to irinotecan or additional risk factors for neutropenia).Analytic Validity: The EWG found adequate evidence to conclude that analytic sensitivity and specificity were high for the commonly tested alleles, but evidence was inadequate for rarer alleles.Clinical Validity: The EWG found adequate evidence of a significant association between UGT1A1 genotype and the incidence of severe neutropenia at standard doses of irinotecan. The EWG found adequate evidence of a possible association between genotype and severe diarrhea, but the effect was smaller and not statistically significant. The EWG found adequate evidence of a significantly higher rate of tumor response to standard irinotecan dosing among individuals with the genotype at highest risk of adverse drug events (*28/*28).Clinical Utility: The EWG found no evidence to support clinical utility in the proposed clinical scenario. Preliminary modeling suggests that, even if targeted dosing were to be highly effective, it is not clear that benefits (reduced adverse drug events) outweigh harms (unresponsive tumors).Contextual Issues: Addressing patient preferences regarding risk of side effects and quality of life, versus aggressive treatment to potentially improve effectiveness, is expected practice. In addition, a recent study reported that risk for neutropenia was lower at lower irinotecan doses. For treatment regimens utilizing lower irinotecan doses, UGT1A1 genotype may not be a useful indicator of risk for adverse drug events. Further rigorous evaluation of UGT1A1 genotyping using current and promising irinotecan treatment protocols is warranted.