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Originally published as JCO Early Release 10.1200/JCO.2002.06.020 on July 1 2002 © 2002 American Society for Clinical Oncology
American Society of Clinical Oncology Technology Assessment on the Use of Aromatase Inhibitors as Adjuvant Therapy for Women With Hormone Receptor–Positive Breast Cancer: Status Report 2002ByFrom the American Society of Clinical Oncology, Alexandria, VA. Address reprint requests to American Society of Clinical Oncology, Health Services Research Department, 1900 Duke St, Suite 200, Alexandria, VA 22314; email: guidelines{at}asco.orgThis article was published online ahead of print at www.jco.org.
OBJECTIVE: To conduct an evidence-based technology assessment to determine whether the routine use of anastrozole or any of the aromatase inhibitors in the adjuvant breast cancer setting is appropriate for broad-based conventional use in clinical practice. POTENTIAL INTERVENTIONS: Anastrozole, letrozole, and exemestane. OUTCOMES: Outcomes of interest include breast cancer incidence, breast cancer-specific survival, overall survival, and net health benefit. EVIDENCE: A comprehensive, formal literature review was conducted for relevant topics and is detailed in the text. Testimony was collected from invited experts and interested parties. The American Society of Clinical Oncology (ASCO)–prescribed technology assessment procedure was followed. BENEFITS/HARMS: The ASCO panel recognizes that a woman and her physician’s decision regarding adjuvant hormonal therapy is complex and will depend on the importance and weight attributed to information regarding both cancer and non–cancer-related risks and benefits. CONCLUSION: The panel was influenced by the compelling, extensive, and long-term data available on tamoxifen. Overall, the panel considers the results of the Arimidex (anastrozole) or Tamoxifen Alone or in Combination (ATAC) trial and the extensive supporting data to be very promising but insufficient to change the standard practice at this time (May 2002). A 5-year course of adjuvant tamoxifen remains the standard therapy for women with hormone receptor–positive breast cancer. The panel recommends that physicians discuss the available information with patients, and, in making a decision, acknowledge that treatment approaches can change over time. Individual health care providers and their patients will need to come to their own conclusions, with careful consideration of all of the available data. (Specific questions addressed by the panel are summarized in Appendix 3.) VALIDATION: The conclusions of the panel were endorsed by the ASCO Health Services Research Committee and the ASCO Board of Directors. SPONSOR: American Society of Clinical Oncology.
THERE HAS BEEN growing research and clinical interest in the use of third-generation aromatase inhibitors in the treatment of breast cancer. In December 2001, the results of the multinational, randomized Arimidex (anastrozole) or Tamoxifen Alone or in Combination (ATAC) study were presented at the San Antonio Breast Cancer Symposium. In the months since the ATAC results were presented, there has been considerable discussion within the oncology community, by both health care providers and patients, about how the results should be applied to clinical practice. The current dilemma for oncologists and their patients is whether the promising preliminary results from the ATAC trial justify the routine use of anastrozole or any of the aromatase inhibitors in the adjuvant setting. At the request of the American Society of Clinical Oncology (ASCO) President and Board of Directors in January 2002, the ASCO Health Services Research Committee convened a multidisciplinary panel of experts to conduct a technology assessment. The panel was asked to review the data on the adjuvant use of aromatase inhibitors and to make recommendations to health care providers and patients.
Adjuvant hormonal therapy can prevent recurrences and improve survival in women with operable breast cancer whose tumors are positive for hormone receptors.1 Tamoxifen received Food and Drug Administration approval for adjuvant therapy in postmenopausal women with positive nodes in 1986, and in pre- and postmenopausal women with node-negative disease in 1990. As demonstrated in multiple randomized trials and an individual patient data meta-analysis, adjuvant tamoxifen reduces the risk of disease recurrence and improves overall survival.1-3 Tamoxifen is beneficial in women of all age groups, and the benefits are similar regardless of whether a woman has received chemotherapy. Multiple randomized trials have addressed the optimal duration of tamoxifen therapy. The results of these trials have shown that a 5-year course of tamoxifen is superior to 1 or 2 years,1,4 although a 10-year course of treatment has not been shown to be better than 5 years.5,6 In women who have taken tamoxifen for 5 years, the benefits persist beyond the completion of therapy, including a lower risk of recurrence and a decreased likelihood of death for at least 5 years after discontinuing tamoxifen compared with women who never took tamoxifen. In absolute terms, a 5-year course of tamoxifen results in an improvement in survival at 10 years of 5.6% in patients with negative axillary nodes and 10.9% in those with positive nodes. Tamoxifen also has been shown to decrease a woman’s risk of developing a contralateral breast cancer.1 The benefits of tamoxifen must be considered in light of the side effects and risks of treatment. The most common side effects include hot flashes and vaginal discharge. Tamoxifen is associated with an increased risk of thromboembolic events, endometrial cancer,2 and probably cerebrovascular disease, particularly in women over age 50.7,8 Some of the undesired effects from tamoxifen, such as the increased risk of endometrial cancer, were not apparent until tamoxifen had been in clinical use for many years. In general, the side effects associated with tamoxifen are limited and are far outweighed by the benefits. The National Institutes of Health Consensus Statement issued in late 2000 recommended that adjuvant tamoxifen be considered for all women with hormone receptor–positive breast cancer.9 The other established adjuvant hormonal therapy for premenopausal women with hormone receptor–positive tumors is ovarian ablation or suppression. A meta-analysis and selected individual studies suggest that the benefit from ovarian ablation or suppression is similar to that seen with chemotherapy.10-16 There is, however, less extensive experience with ovarian ablation or suppression than with chemotherapy. At this time, it remains unclear how ovarian ablation or suppression should be incorporated into the management strategies and treatment for premenopausal women with operable breast cancer.9,11
A number of hormonal therapies are available to women with hormone receptor–positive, advanced breast cancer, including selective estrogen receptor modulators, pure antiestrogens, progestins, estrogens, androgens, and aromatase inhibitors. Among these, aromatase inhibitors have played a role in the management of metastatic breast cancer for over two decades. For many years only aminoglutethimide, an agent with considerable toxicity, was available. Development of the third-generation aromatase inhibitors represented a significant advance in the treatment of metastatic breast cancer. Aromatase is an enzyme complex required for estrogen synthesis through conversion of androgens (androstenedione and testosterone) to estrone and estradiol, respectively. After menopause, conversion of androgens in muscle, skin, fat, and breast by aromatase results in relatively low, but generally stable, circulating estrogen levels.17 Each of the third-generation aromatase inhibitors leads to nearly total blockade of peripheral aromatization and a marked decline in circulating estrogen levels.18 With administration of the third-generation aromatase inhibitors, circulating estrogen levels are suppressed to approximately 1% to 10% of pretreatment levels.19 The selectivity of the third-generation aromatase inhibitors allows for marked decrease in estrogen levels without the concomitant side effects seen with earlier generation agents. In premenopausal women, first- and second-generation aromatase inhibitors were not able to suppress estrogen levels because of high levels of androstenedione as well as reflex increases in gonadotropins leading to higher levels of ovarian aromatase.17 The third-generation aromatase inhibitors have not been adequately tested in this setting. In the United States, the third-generation antiaromatase agents that are commercially available include two nonsteroidal preparations, anastrozole and letrozole, and a steroid agent, exemestane. Anastrozole and letrozole are often referred to as aromatase inhibitors, whereas exemestane is called an aromatase inactivator; all three will be collectively referred to as aromatase inhibitors in this document because the clinical significance of the difference between the steroidal and nonsteroidal structures and their mechanisms of action has not been elucidated. All three agents have been shown to be superior to megestrol acetate as second-line hormonal therapy, with better disease control and/or decreased toxicity.19-24 More recently, large randomized trials have compared anastrozole and letrozole, respectively, to tamoxifen.25-27 In patients with metastatic breast cancer, both anastrozole and letrozole demonstrated equivalent or improved efficacy when compared with tamoxifen, with similar or decreased toxicity. These studies have led to the approval of both anastrozole and letrozole as first-line hormonal therapy for postmenopausal patients with metastatic breast cancer. A smaller, randomized, phase II trial comparing exemestane with tamoxifen in women with metastatic disease also suggested superiority for the aromatase inhibitor;28 a larger phase III extension of that trial comparing exemestane and tamoxifen is underway. As a result of the trials detailed above, the third-generation aromatase inhibitors are established as either first- or second-line therapy for postmenopausal women with hormone receptor–positive, metastatic breast cancer. Most trials of the third-generation aromatase inhibitors have been conducted in women with metastatic breast cancer, and the median duration of therapy in these trials is consistently less than 12 months.19-28 There is no published experience describing the side effect profile associated with prolonged administration of the third-generation aromatase inhibitors. In particular, there are no data available concerning the tolerability of a 5-year course of these agents.
Given the importance of hormonal therapy in the management of patients with early-stage breast cancer and the promising activity of the third-generation aromatase inhibitors in the advanced disease setting, a series of clinical trials was initiated evaluating these agents in the adjuvant setting (Appendix 1). Two small studies had previously used aminoglutethimide in the adjuvant setting, demonstrating the feasibility of aromatase inhibition in the adjuvant setting.29-31 The current generation of adjuvant hormonal trials with aromatase inhibitors uses the following three distinct study designs in postmenopausal women: (1) randomized comparisons of tamoxifen versus a third-generation aromatase inhibitor; (2) randomized comparisons of a third-generation aromatase inhibitor versus placebo after the completion of 5 years of tamoxifen; and (3) randomized comparisons of sequential therapy (tamoxifen followed by a third-generation aromatase inhibitor or a third-generation aromatase inhibitor followed by tamoxifen) administered for a total of 5 years versus single-agent therapy for 5 years. An additional question addressed in the ATAC trial is the efficacy of the concurrent use of a combination of tamoxifen and an aromatase inhibitor (anastrozole). The preliminary results from the first of these trials were reported at the 2001 San Antonio Breast Conference.
The ATAC trial is a large, multinational, double-blind, placebo-controlled, randomized trial comparing standard adjuvant therapy of 5 years of tamoxifen versus 5 years of anastrozole versus 5 years of both agents given in combination in postmenopausal patients (Fig 1).32
Accrual of 9,366 postmenopausal women with hormone receptor–positive or unknown tumors to the trial began in July 1996 and ended in March 2000. A total of 381 centers participated in the study in 21 different countries. The primary study end points were disease-free survival (defined as locoregional recurrence, distant recurrence, new primary breast cancer, or death from any cause) and safety/tolerability. Secondary end points included the incidence of second non–breast cancer primaries, time to distant recurrence, and overall survival. Of note, the end points of distant recurrence and overall survival are incorporated into the aggregated primary end point and, as such, have an impact on the statistical considerations and should be considered secondary analyses. A subset analysis of patients with known hormone receptor–positive tumors was part of the initial planned analytic strategy. The predefined analyses were designed to assess if anastrozole was equivalent or superior to tamoxifen and to determine whether the combination of tamoxifen plus anastrozole was superior to tamoxifen. The first analysis was scheduled to occur when there had been a total of 1,056 events for the disease-free survival end point. Events were defined as locoregional or distant recurrence, contralateral invasive or noninvasive breast cancers, or death from any cause. As expected in a large randomized trial, patient characteristics were well balanced across the three treatment arms. Mean age was 64 years, tumor size was 2 cm or less in approximately 63% of patients, and about one third of patients on each of the arms had positive lymph nodes. Approximately 23% of patients had tumors that were characterized as poorly differentiated; the remaining patients had well-differentiated, moderately differentiated, or unclassified tumors. Approximately 48% of patients had undergone a mastectomy, and 95% had an axillary lymph node dissection. Radiotherapy was administered to approximately 62% of patients, whereas adjuvant chemotherapy was administered to approximately 21%. At the time of study analysis before the 2001 San Antonio Breast Conference, there were 1,079 events. Of these events, 766 occurred in the known hormone receptor–positive population. The median duration of therapy was 30.7 months, and the median follow-up was 33.3 months. There were 317 events on the anastrozole arm, 379 on the tamoxifen arm, and 383 on the combination arm (Table 1). A statistically significant improvement was detected in disease-free survival favoring anastrozole compared with tamoxifen (hazard ratio, 0.83; 95% confidence interval, 0.71 to 0.96; P = .013). There was no difference in disease-free survival between tamoxifen and the combination (hazard ratio, 1.02; 95% confidence interval, 0.88 to 1.18; P = .77). A formal survival analysis has yet to be performed and will be triggered by a predefined number of deaths in the study population (J. Purvis, personal communication, April 2002).
Adverse events associated with tamoxifen and anastrozole are listed in Table 2. Hot flashes, weight gain of  10% at 2 years, vaginal bleeding, vaginal discharge, endometrial cancer, ischemic cerebrovascular events, and venous thromboembolic events were all significantly more common with tamoxifen than with anastrozole. Musculoskeletal disorders, fractures (all sites), and fractures in spine, hip, and wrist were all more common in women on anastrozole compared with tamoxifen. No data were provided concerning toxicity on the combination arm. As can be seen in Table 2, the absolute incidence of most life-threatening complications (ie, cancer, thromboembolic events) is quite low, and the absolute differences between the two arms are generally small.
We define technology assessment as a process for determining whether a procedure is appropriate for broad-based conventional use in clinical practice. The process used in this technology assessment followed defined ASCO policies and procedures; these policies and procedures are similar to those published elsewhere.33,34 Pertinent information from the published literature was retrieved and reviewed for the creation of this assessment. Computerized literature searches of MEDLINE (National Library of Medicine, Bethesda, MD) were performed through January 2002. Abstracts presented at ASCO annual meetings were also included. Key words/phrases included in the literature search were: breast neoplasms, breast cancer, mammary neoplasms, randomized trials, phase, meta-analysis, aromatase, exemestane, anastrozole, letrozole, megestrol acetate, antiaromatase, Arimidex, triazole, Femara, and Aromasin. Limits included English language and human studies. In addition, the ASCO Health Services Research Department staff contacted representatives of American, Canadian, and European cooperative groups concerning ongoing adjuvant trials with aromatase inhibitors. Each of the three pharmaceutical companies that manufactures one of the commercially available aromatase inhibitors was also contacted and given an opportunity to provide the expert panel with unpublished data and the design of ongoing or planned trials.
Panel Composition
Disclosure of Conflict of Interest
The panel addressed the following questions to provide guidance to physicians and patients on the use of third-generation aromatase inhibitors in the adjuvant setting (see Appendix 3 for complete questions and answers):
1. What are the overall clinical implications of the findings from the ATAC trial for the adjuvant treatment of postmenopausal women with operable breast cancer? • Tamoxifen is known to be effective in improving recurrence-free and overall survival when used as adjuvant hormonal therapy in patients with early-stage breast cancer and remains the standard therapy. Although tamoxifen is not devoid of side effects, there is extensive, long-term follow-up data on patients treated with tamoxifen and a clearer understanding of the risks associated with tamoxifen therapy. • Except for musculoskeletal disorders and fractures, the short-term side effects with anastrozole seen in the ATAC trial seemed to be comparable with or fewer than those seen with tamoxifen; however, there are no data available concerning the toxicity of any of the aromatase inhibitors administered for extended periods (ie, 5 years or more). There are no data concerning the late effects (after discontinuation of therapy) of a prolonged course of an aromatase inhibitor. The long-term effects of profound estrogen deprivation as seen with the third-generation aromatase inhibitors are unknown. In particular, concern has been raised that the adverse bone effects seen in the ATAC trial could become more common and/or severe with further follow-up. • Although the difference in disease-free survival between anastrozole and tamoxifen is statistically significant, the absolute difference in the percentage of patients who were disease-free at follow-up is 2.02% (89.86% v 87.84%). The absolute difference in distant and locoregional recurrence rates between the two arms is 1.33% (7.14% v 8.47%). The absolute difference in distant recurrence is 0.80% (5.00% v 5.80%). • A 5-year course of treatment is required to see the full benefits of tamoxifen therapy.1 With a median follow-up of only 33 months in the ATAC trial, the full benefits of treatment with tamoxifen have yet to be realized. Despite the encouraging preliminary results, it is conceivable that 5 years of anastrozole could be inferior to 5 years of tamoxifen. Although this argument can be used in interpreting the preliminary results of any trial, the valid concern is particularly important when the known benefits of one of the treatments require prolonged therapy (ie, 5 years). Given the compelling survival advantage of a 5-year course of tamoxifen when compared with no adjuvant hormonal therapy, there is a genuine need for more mature data. • There are no reported differences in survival between the two arms. • The study continues to follow and to provide treatment to patients who are on the tamoxifen + placebo and anastrozole + placebo arms in a blinded fashion. • The ATAC study design does not address the question of how long anastrozole should be continued for optimal therapeutic benefit. • The ATAC trial does not study the sequence of tamoxifen for 2, 3, or 5 years followed by an aromatase inhibitor. This strategy is under active investigation in other trials. • The data from the ATAC trial have not yet been subjected to rigorous peer review.
Panel consensus.
2. Are all aromatase inhibitors equivalent? In the metastatic setting, all three aromatase agents are effective in the treatment of postmenopausal women with hormone receptor–positive metastatic breast cancer. Both anastrozole and letrozole are approved for first- and second-line treatment of hormone receptor–positive breast cancer based on the results of large randomized studies. Exemestane is approved for second-line treatment, and a phase III trial comparing exemestane with tamoxifen is actively accruing patients. In addition, there are several studies ongoing that compare the aromatase inhibitors with one another and with other agents. Preliminary data are available from a trial comparing letrozole to anastrozole in 713 postmenopausal women with locally advanced or metastatic breast cancer, all of whom had received prior antiestrogen therapy. This study demonstrated no difference in clinical benefit, time to progression, time to treatment failure, or duration of response, though there was an improvement in overall response rate for letrozole in comparison with anastrozole (19.1% v 12.3%, P = .014).36 In the adjuvant setting, the only reported treatment data are with anastrozole. Adjuvant trials are underway with both letrozole and exemestane, as well as additional studies with anastrozole.
Panel consensus.
3. What is the role of aromatase inhibitors in women who have already started taking tamoxifen in the adjuvant setting?
Panel consensus.
4. Is there a role for an aromatase inhibitor in women who have completed a 5-year course of tamoxifen and are disease-free?
Panel consensus.
5. If an aromatase inhibitor is used in the adjuvant setting, for how long should it be administered?
Panel consensus.
6. What is the role of aromatase inhibitors in women who are premenopausal at the time of initiation of adjuvant hormonal therapy?
Panel consensus.
7. What is the role of aromatase inhibitors in women who are premenopausal at diagnosis and who experience interruption of ovarian function from chemotherapy?
Panel consensus.
8. What is the role of aromatase inhibitors in patients with ductal carcinoma-in-situ (DCIS)?
Panel consensus.
9. What is the role of aromatase inhibitors in women wishing to lower their risk of developing breast cancer?
Panel consensus.
10. What is the role of aromatase inhibitors in women whose tumors have negative hormone receptors?
Panel consensus.
11. What is the role of aromatase inhibitors in patients with certain biologic features, such as HER-2/neu positivity? A recent randomized trial compared preoperative tamoxifen with preoperative letrozole in postmenopausal women who were ineligible for breast conservation at diagnosis.51 Among 39 women with HER-2–positive tumors, the response rate to letrozole was 69%, compared with 17% with tamoxifen. In 36 women whose tumors were confirmed to be estrogen receptor–positive as well as HER-1- and/or HER-2–positive, the response rate to letrozole was 88%, compared with 21% with tamoxifen. Although these findings are of great interest, they are derived from a small patient cohort and with only 4 months of preoperative treatment. Ongoing studies are attempting to replicate these results.
Panel consensus.
12. What is the role of aromatase inhibitors in patients with a relative or absolute contraindication to the initiation of adjuvant tamoxifen?
Panel consensus.
13. What is the role of aromatase inhibitors in patients who have developed hormone receptor–positive invasive breast cancer while taking either tamoxifen or raloxifene?
Panel consensus.
This technology assessment seeks to guide patients and physicians on the use of aromatase inhibitors in the adjuvant setting. Individual health care providers and their patients will need to come to their own conclusions, with careful consideration of all of the available data. The panel recognizes that there is an inherent tension between the desire to provide patients with the most up-to-date treatment approaches while at the same time exerting appropriate caution that such new treatments are adequately evaluated. The panel was influenced by the compelling, extensive, and long-term data available on tamoxifen. Overall, the panel considers the results of the ATAC trial and the extensive supporting data to be very promising but insufficient to change the standard practice at this time (May 2002). The panel recommends that physicians discuss the available information with patients, and, in making a decision, acknowledge that treatment approaches can change over time. Additional data will be available in the coming years concerning the role of aromatase inhibitors in the adjuvant setting. In particular, it will be important to see longer follow-up data, survival analyses, and the results from confirmatory studies, as well as those studies testing sequential use of aromatase inhibitors after tamoxifen. It is hoped that there will continue to be improvements in adjuvant hormonal therapy, leading to benefits for women with breast cancer in both overall survival and quality of life.
The appendices listing selected adjuvant breast cancer trials, the ASCO aromatase inhibitors expert panel, and the summary of the panels deliberations are available online at www.jco.org.
The panel wishes to express its gratitude to the following for their thoughtful review of earlier drafts: Drs Alan S. Coates, Judy E. Garber, Michael Goldstein, Deborah Schrag, and Ian Tannock and the ASCO Health Services Research Committee. The panel would also like to express its appreciation to Dr Melissa Brouwers and Manya Charet of Cancer Care Ontario Practice Guidelines Initiative for their guidance in the development of appropriate literature search strategies. Unpublished, clinical evidence was submitted for review to the panel by Dr Michael Baum of University College, London, United Kingdom, and the ATAC Steering Committee and Trials’ Group, Dr Joseph Purvis of AstraZeneca Pharmaceuticals, by Dr Paul Goss of the Princess Margaret Hospital and the National Cancer Institute of Canada Clinical Trials Group, by Dr Raimund Jakesz Leiter der klinischen Abteilung für Wien, Vienna, Austria, and by Dr Colin Lowery of Pharmacia Pharmaceuticals. The panel is grateful to the following for their assistance throughout the process of the document’s development: Joyce Light, of the Dana-Farber Cancer Institute, Jennifer J. Padberg, Sarah L. Revere, and Dr Mark R. Somerfield of the ASCO Health Services Research Department.
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ABSTRACT
INTRODUCTION
