The RTI-UNC Evidence-based Practice Center (EPC), together with members of the current U.S. Preventive Services Task Force (USPSTF), sought to clarify issues concerning chemoprevention to prevent breast cancer by performing a systematic review of the relevant scientific literature on this topic.
The systematic evidence review (SER) on this topic (available on the AHRQ Web site at www.ahrq.gov/clinic/uspstfix.htm) examines the evidence for chemoprevention to prevent breast cancer among women who have never had breast cancer. Figure A-1 (9 KB) presents a comprehensive analytic framework for this topic.
The analytic framework begins on the left side with the population at risk. Several different populations should be considered:
In addition, because of the effect of tamoxifen or other chemopreventive agents on potentially serious conditions other than breast cancer, women with particularly increased (or decreased) risk of thromboembolic events, bone fractures, or endometrial cancer should be considered separately.
Moving to the right in the analytic framework, the "chemoprevention" arrow points to a box labeled "incidence of breast cancer." Moving downward from the chemoprevention arrow is an "adverse effects/costs" arrow. Some of the adverse effects of tamoxifen or raloxifene are deep vein thromboembolism, pulmonary embolism, stroke, endometrial cancer, hot flashes, and cataracts.
Possible benefits from tamoxifen or raloxifene chemoprevention include reduced risk of heart disease and bone fractures. These are listed together in a separate box: "other beneficial effects."
Farther to the right is a "treatment" arrow, leading to a box labeled "health outcomes," which includes mortality and/or morbidity from breast cancer. We also consider "incidence of breast cancer" to be a health outcome worthy of consideration in its own right.
Leading downward from the "treatment" arrow is another "adverse effects/costs" arrow. Included here are adverse effects from chemotherapy, surgery, and radiation therapy used to treat breast cancer.
Finally, an "overarching" arrow for chemoprevention leads directly to reduced mortality and morbidity from breast cancer.
The primary, overarching question, shown as the topmost line in Figure A-1 (9 KB), is the following:
The secondary questions (i.e., linkage questions), shown in the body of Figure A-1 (9 KB), are the following:
No clinical trial has been large or long enough to examine the impact of chemoprevention on mortality from breast cancer (Key Question 1). In addition, the effectiveness of treatment for breast cancer is clear and has been examined in a continuing rigorous meta-analysis. The adverse effects of treatment are also well documented.
Therefore, this review focuses on Key Questions 2 through 5. We consider in these questions evidence about issues of dose and duration of chemoprevention.
We prospectively established inclusion and exclusion criteria for the key questions. For key questions 2-4, we required randomized controlled trials (RCTs) of chemoprevention agents in populations of women without breast cancer in which the outcome measures included breast cancer incidence and/or mortality. Because the only agents we found that met these criteria were selective estrogen-receptor modulators (SERMs), we specifically searched for studies of these agents.
We operationalized the inclusion and exclusion criteria into the search criteria given in Table A-1. We searched the MEDLINE® database for studies of the appropriate study design in humans. Our search strategy yielded 635 potentially useful articles (Table A-2). We added another 65 articles from searching reference lists of reviews, the Cochrane library, and guidelines.
Our evaluation strategy involved two phases. The first phase used broad search terms and review criteria for all 700 article abstracts; the aim was to maximize the probability that all articles that could be useful in any way came to our attention (Table A-3). Four EPC staff independently reviewed the titles and abstracts of the 700 articles identified by the literature searches and excluded those that they agreed clearly did not meet eligibility criteria. When the initial reviewers disagreed or were uncertain, the articles were carried forward to the next review stage in which EPC team members reviewed the full articles and made a final decision about inclusion or exclusion by consensus. A total of 70 articles were examined in phase 2 (Table A-4).
The second phase used more stringent review criteria for full review of the articles themselves to focus our attention on those papers that most directly answered the key questions (Table A-3). Only four studies met all inclusion criteria from phase 2 (Table A-4). We abstracted these four studies into an evidence table, evaluating their quality in detail. Where appropriate in the other parts of the review, we cite articles that are not in the evidence tables; these studies or materials may not directly address the key questions, but they do assist in interpretation of the articles in the evidence tables.
Select Figure A-2 (6 KB) for flowchart on selecting articles.
To characterize the quality of the included studies, we rated the internal and external validity for each article in the evidence table using criteria developed by the USPSTF Methods Work Group. We then rated the aggregate internal validity and external validity as well as the coherence (consistency or agreement of the results of the individual studies) for each of the key questions in the analytic framework.
In all these steps, EPC staff collaborated with two members of the USPSTF who acted as liaisons for this topic. The collaboration took place chiefly by electronic mail and conference calls. Steps in the development of the SER on this topic were presented at USPSTF meetings in May and September 1999 and February 2000 where the EPC staff and Task Force liaisons also were able to discuss the analytic framework and key questions, literature search strategy, results, and implications of the findings.