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Monograph Overview

Monograph Overview Beginning in 1977, the National Institutes of Health (NIH), the lead governmental agency for federally sponsored research in the United States, organized Consensus Development Conferences to review controversial areas of medical research (1). More than 120 such conferences have been held on a wide variety of diseases and medical disciplines. Adjuvant therapy of breast cancer has been one of the most popular topics for Consensus Development Conferences, with previous meetings held in 1980, 1985, and 1990 (2–4). As 10 years had elapsed since the last conference, the National Cancer Institute at NIH thought that it was time to once again cosponsor a Consensus Development Conference to review what progress had occurred in adjuvant breast cancer therapy. Consensus Development Conferences are structured to emphasize a balanced, critical review of the scientific evidence. A planning committee develops several key questions of paramount interest. It then selects experts in the field to present pertinent research results to an independent, nongovernmental panel consisting of academic and community-based physicians, biostatisticians, nurses, basic researchers, and other appropriate disciplines, along with lay patient advocates. The panelists are selected for their general expertise in their chosen field, but they cannot have published extensively or be considered “opinion leaders” on the topic selected for consensus development. Held November 1–3, 2000, the Consensus Conference on Adjuvant Therapy of Breast Cancer was open to the public, and admission was free. Discussion sections were interspersed throughout the formal presentations to provide both panelists and members of the audience an opportunity to query the speakers or to offer additional evidence. At the conclusion of the expert presentations, the panel met in a closed session and developed a draft Consensus Statement. The panel chairperson read the entire draft to all of the meeting participants, who offered comments and suggestions that were carefully considered by the panelists before they finalized the statement. At the close of the conference, the Consensus Statement was presented to the national press and made available on the NIH Web site (http://consensus.nih.gov) and has subsequently been published (5). The entire statement is reproduced in this monograph. The statement is intended to provide useful summary recommendations to professionals and the public that reflect the current state of the art. The planning committee believed that a broad review of adjuvant therapy was required to help clinicians deal with practical problems in selecting the appropriate adjuvant therapy. The following six questions were posed to the panel: 1) Which factors should be used to select systemic adjuvant therapy? 2) For which patients should adjuvant hormonal therapy be recommended? 3) For which patients should adjuvant chemotherapy be recommended, and which agents should be used and at what dose or schedule? 4) For which patients should postmastectomy radiotherapy be recommended? 5) How do side effects and quality-of-life issues factor into individual decision making about adjuvant therapy? 6) What are promising new research directions for adjuvant therapy? Before the conference, the panelists reviewed the existing medical evidence from the literature. Their review was then supplemented at the meeting by presentations from 33 expert speakers. This monograph presents the details of the evidence offered by the experts on which the consensus statement was largely based. Of the 33 presentations, all but nine speakers have contributed original articles to this monograph. In the overview of this monograph that follows, we mention the reviews by the contributing authors but focus our attention primarily on the presentations not included in the monograph, so the reader has a complete review of the basis for the consensus recommenda-tions. The full name of the presenter and his or her affiliation is provided for those who did not submit articles, while the reader can find this information for those who contributed in the original articles that follow. Question 1: Which Factors Should Be Used to Select Systemic Adjuvant Therapy? Progress in the development of new prognostic and predictive factors for adjuvant therapy has been difficult to realize. Traditional tumor-related factors, such as axillary lymph node status, tumor size, histologic type and grade, and hormone receptor status, were still the most useful indicators of prognosis, while receptor status was the most valuable predictor of response to endocrine therapy (6). These issues are reviewed thoroughly by Drs. Gary Clark, Stuart Schnitt, and Maria Grazia Daidone. Their presentations highlighted the fact that all too often, markers are touted before definitive studies are available to prove their value independent of established factors. In some cases, even when new markers have been shown to be independent predictors, the assays were either not reliable or were not generally available. Although poised technologically to make important advances in coming years, research in this area is dependent on the ability to amass large sample sizes with careful documentation of the patient, tumor, and treatment characteristics of the study population. Phase III cooperative group treatment trials in this country and abroad increasingly have such features and are potentially valuable sources of specimens. However, carefully performed clinical trials were thought to be only an initial step. New markers developed in the research laboratory must be transferable to general medical care before they can make an impact on clinical decision making. Drs. James Dignam, Aron Goldhirsch, and Hyman Muss examined patient-specific characteristics including racial/ethnic background, young age, and older age, respectively. Although breast cancer is a common disease in older women, relatively few older women participated in clinical trials, so their treatment was often extrapolated from younger populations. This problem was in need of remediation by the research community. For younger women, data now suggest that hormonal therapies are extremely important for hormone-sensitive tumors. As for race or ethnicity, a differential treatment effect was not detected according to these factors. Question 2: For Which Patients Should Adjuvant Hormonal Therapy Be Recommended? Multiple clinical trials supported the panel's recommendation that tamoxifen should be considered in all women with hormone receptor-positive breast cancer, irrespective of age, menopausal and lymph node status, tumor size, and treatment with chemotherapy (7). The only exception cited was for women with very small tumors, less than or equal to 1 cm, for whom the side effects might outweigh the advantages. Sir Richard Peto (Oxford University, England) presented the evidence supporting this recommendation by reviewing updated results from the September 2000 meta-analysis performed by the Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Comparing women treated with and without tamoxifen for 5 years, the results in 8000 women with estrogen receptor-positive tumors indicated that tamoxifen reduced death from breast cancer by 9% ± 1.4% at 15 years without increasing non-breast cancer deaths statistically significantly. The sole prognostic factor in the meta-analysis that correlated with survival was hormone receptor status. Only women with positive estrogen receptors benefited from tamoxifen. Dr. Kent Osborne (Baylor University, Houston, TX) discussed whether tamoxifen was indicated for hormone receptor-negative disease. Neither the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-23 trial (8) nor the Intergroup trial (9) demonstrated an improvement in overall survival or a reduction in contralateral breast cancer in hormone receptor-negative tumors. This was also the finding of the EBCTCG September 2000 meta-analysis. On the basis of these facts, the panelists recommended that tamoxifen not be used in women with hormone receptor-negative disease. Dr. Christina Davies (Oxford University, England) and Dr. Bryant debated the optimal duration of tamoxifen therapy. Dr. Davies presented the results of the September 2000 EBCTCG meta-analysis, which demonstrated that 5 years of tamoxifen compared with 1–2 years of tamoxifen produced an additional absolute survival increment of 3.2% ± 1% at 10 years while causing only a 0.1% increase in such serious side effects as pulmonary embolus or endometrial cancer. The panelists concluded that 5 years of therapy should be recommended routinely, since the advantages of the drug outweighed its toxicity for most women with invasive breast cancer. Studies comparing 5 years with longer durations of therapy (7–10 years) did not reveal a benefit for therapy beyond 5 years. Dr. Davies maintained that these results are premature, arguing that the survival benefit from 5 years of tamoxifen, rather than remaining constant, continues to increase during the next 5 years (“carryover effect”), despite the drug being stopped. An advantage for prolonged therapy, she reasoned, might be expected to emerge only after 10–15 years of follow-up. In support of this contention, more recurrences have occurred in the placebo (n = 16) than in the tamoxifen (n = 11) group in B-14 when only recurrences diagnosed more than 6 years after randomization were examined (10). However, Dr. Bryant contended in his article that the number of events during this time period is quite small, while the overall study results from B-14 continued to indicate no statistically significant survival advantage for the longer therapy, a finding similar to analyses from the Scottish (11) and Eastern Cooperative Oncology Group (12) trials of tamoxifen duration. Outside of clinical trials, the panelists recommended limiting tamoxifen treatment to 5 years. Dr. Nancy Davidson reviewed ovarian ablation, an alternative to tamoxifen. The evidence that she described convinced the panelists that ovarian ablation is an acceptable adjuvant therapy in women with premenopausal, hormone-responsive breast cancer. The panelists recommended that further clinical trials were needed to determine whether ablation was additive when combined with tamoxifen and chemotherapy. Question 3: For Which Patients Should Adjuvant Chemotherapy Be Recommended, and Which Agents Should Be Used and at What Dose or Schedule? Chemotherapy remained the systemic adjuvant therapy of choice for most patients with hormone receptor-negative breast cancer. Dr. Gabriel Hortobagyi presented a thorough review of progress in the field over the past decade. As demonstrated in earlier EBCTCG overviews (13) and at the most recent update in September 2000, all patient subsets, lymph node-negative/positive, pre/postmenopausal, and hormone receptor-negative/positive, derived a statistically significant survival advantage, in the range of 3%–12%, from chemotherapy compared with no chemotherapy. As anticipated, the absolute benefit was greatest for women at highest risk of relapse. Regarding specific regimens, the September 2000 overview also indicated that anthracycline-containing regimens yield a 3.5% absolute improvement in survival. For commonly used drugs such as doxorubicin and cyclophosphamide, clinical trials have demonstrated a threshold dose below which these drugs appear less effective, but dose escalation beyond the threshold level has not been demonstrated to lead to increased benefit. Dr. Larry Norton (Memorial Sloan-Kettering Cancer Institute, New York, NY) discussed several clinical trials that tested dose escalation without the need for stem cell support. He concluded that the optimal doses of cyclophosphamide and doxorubicin were 600 mg/m2 and 60 mg/m2, respectively, for adjuvant breast cancer treatment. A key unanswered question, he noted, was whether combination or sequential use of active agents is most beneficial. Dose escalation was also reviewed in the context of high-dose chemotherapy trials with autologous stem cell support. Dr. William Peters (Barbara Ann Karmanos Cancer Institute, Detroit, MI) presented an update of Cancer and Leukemia Group B (CALGB) 9082 (14). He found no difference in disease-free or overall survival with a median follow-up of 5.1 years between the high-dose arm with autologous stem cell support and an intermediate-dose arm using only granulocyte-colony stimulating factor support. Dr. Karen Antman reviewed results from five additional international randomized trials using high-dose therapy. Although a Dutch trial has encouraging preliminary results (15), the other trials did not indicate a survival advantage. Nine additional international trials were either ongoing or had completed accrual but are not yet analyzed. Until and unless additional clinical trials became available that demonstrate a benefit for high-dose therapy, the panelists concluded that this approach should not be used in routine practice. Dr. Norman Wolmark discussed neoadjuvant breast cancer therapy, noting that this approach had the potential to markedly shorten the time it takes to evaluate promising agents. Dr. Richard Gray (University of Birmingham, England) presented results from the September 2000 EBCTCG meta-analysis regarding comparisons of chemotherapy and hormonal therapy. He noted that, for women 50 years of age or more with hormone-sensitive tumors, tamoxifen yielded a greater survival benefit than did chemotherapy. However, the treatments generally appeared additive, with the combination producing superior survival results than either modality alone in most tumor subsets analyzed. The panel concluded that tamoxifen should be used whenever chemotherapy is considered for receptor-positive tumors. The most controversial issue faced by the panelists concerned the role of taxanes as part of adjuvant chemotherapy regimens. Dr. Craig Henderson (University of California, San Francisco) updated CALGB 9082, a U.S. Intergroup study (16). The study tested doxorubicin and cyclophosphamide (AC) for four cycles followed by paclitaxel for four cycles versus AC alone. With a median follow-up of 52 months, a statistically significant disease-free and overall survival advantage for the addition of paclitaxel persists. An unplanned subset analysis indicates that the advantage is limited to patients who did not receive tamoxifen. Dr. Eleftherios Mamounas (Aultman Cancer Center, Canton, OH) presented an interim analysis of NSABP B-28. This study was similar in design to the CALGB trial. With a median follow-up of 34 months, no disease-free or overall survival advantage was noted for the addition of paclitaxel to AC chemotherapy. A subset analysis has not indicated a statistically significant difference according to whether or not tamoxifen was administered. However, similar to the NSABP trial, a trend favoring paclitaxel was noted in patients who did not receive tamoxifen or who had hormone receptor-negative tumors. Dr. Martine Piccart discussed important differences between these two trials that might explain their results. Further follow-up of the NSABP trial and completion of other ongoing randomized trials examining the role of taxanes should clarify whether these agents will become a part of standard chemotherapy regimens. The panel concluded that definitive evidence was lacking regarding the role of taxanes but counseled against their usage in patients with lymph node-negative breast cancer outside clinical trials. To determine whether subsets of patients exist for whom the risk of recurrence does not justify the routine use of chemotherapy, Drs. Monica Morrow and Jonas Bergh analyzed population-based registry data from the United States and Europe, respectively. Their reviews suggested excellent outcomes without adjuvant therapy in selected subsets of lymph node-negative tumors with small tumors. In contrast to the registry data, Dr. Bernard Fisher compiled results across several NSABP lymph node-negative, randomized clinical trials that compared various systemic therapies. Selected subsets of women in these trials seemed to benefit from adjuvant hormonal therapy and/or chemotherapy. In view of the small yet statistically significant benefits for some patients with tumors considered to be at low risk, the challenge for physicians is to provide a balanced explanation of risks and benefits that will permit individuals to make an informed, personal decision. Question 4: For Which Patients Should Postmastectomy Radiotherapy Be Considered? Dr. Jack Cuzick (Imperial Cancer Research Fund, London, England) updated the recent EBCTCG meta-analysis (17) that demonstrated that adjuvant radiotherapy produces an absolute reduction of 20% in isolated local recurrences at 20 years, irrespective of the use of chemotherapy or tamoxifen. This large reduction in local recurrence was accompanied by a statistically significant absolute reduction in death by breast cancer of 5% at 15 years. However, a concomitant absolute increase of 4% in non-breast cancer deaths occurred in patients receiving radiotherapy. This increase did not begin to appear until about 5 years after treatment and seemed to increase at least out to 15 years after treatment. A stratified analysis, performed according to whether trials were initiated before or after 1975, indicated that the trials started before 1975 had a very statistically significant increase in non-breast cancer deaths, while those started after 1975 did not. This might be because of the use of improved radiotherapy techniques in the latter trials, but longer follow-up of the trials in this latter group was needed before this explanation could be fully accepted. It was also noteworthy that the majority of non-breast cancer deaths, although vascular in origin, were not cardiac related. To assess who should receive postmastectomy radiotherapy, Dr. Lori Pierce reviewed several risk factors potentially associated with local recurrence. On the basis of the information presented, the panelists agreed that postmastectomy radiotherapy was indicated for women with four or more positive axillary lymph nodes and for those with large primary tumors. The benefit was less clear for those with one to three positive lymph nodes, and participation of such patients in an ongoing Southwest Oncology Group clinical trial (S9927) testing this question was recommended. Question 5: How Do Side Effects and Quality-of-Life Issues Factor Into Individual Decision Making About Adjuvant Therapy? Ms. Amy Langer introduced the subject by explaining how patients view these issues and how they affect decision making. Drs. Patricia Ganz and Eric Winer described the side effects of tamoxifen and chemotherapy, respectively. The value of adjuvant therapy, a mix of benefits counterbalanced by risks, requires physicians to present detailed information to patients. Dr. Mark Levine reviewed research on how best to present information to patients. However, once the information is understood, the ultimate decision remains a personal one based on the individual's tolerance of risk and the value attributed to the benefits. Dr. Alan Coates described several studies that assessed the willingness of patients to receive adjuvant therapy based on scenarios that present differing degrees of survival gains. The panelists concluded that effective communication between physicians and patients is essential to the decision-making process regarding adjuvant therapy. Complex information must be conveyed regarding absolute risks and benefits, so patients can appreciate the trade-offs involved in their choices. This process can be facilitated through the use of decision aids and other well-designed patient information materials. Question 6: What Are Promising New Research Directions for Adjuvant Therapy? Integrating genomics and proteomics into the search for prognostic factors, testing the optimal duration and combinations of hormonal treatments and the value of chemotherapy in older patients, and including quality-of-life endpoints in adjuvant trials were all cited during the conference as important future research directions. The primary new therapeutic direction involved targeted therapies based on an improved understanding of molecular pathways. Herceptin and bisphosphonates were among the first of this new generation of targeted treatments to enter adjuvant clinical trials. Many other agents that target specific proliferative pathways are being studied in patients with advanced breast cancer. The challenge for the future is to integrate the most promising of these pathways into the current adjuvant therapy armamentarium. References 1 Guidelines for the planning and management of NIH Consensus Development Conferences. Bethesda (MD): National Institutes of Health, Office of the Director, Office of Medical Applications of Research; 1993. Google Scholar 2 Moxley JH, Allegra JC, Henney J, Muggia F. Treatment of primary breast cancer: summary of the National Institutes of Health Consensus Development Conference. JAMA  1980; 244: 797–803. Google Scholar 3 Consensus Conference. Adjuvant chemotherapy for breast cancer. JAMA  1985; 254: 3461–3. Google Scholar 4 NIH consensus conference. Treatment of early-stage breast cancer. JAMA  1991; 265: 391–5. Google Scholar 5 National Institutes of Health Consensus Panel. National Institutes of Health Consensus Development Conference statement: adjuvant therapy for breast cancer, November 1–3, 2000. J Natl Cancer Inst  2001; 93: 979–89. Google Scholar 6 Fitzgibbons PL, Page DL, Weaver D, Thor AD, Allred DC, Clark GM, et al. Prognostic factors in breast cancer: College of American Pathologists Consensus Statement 1999. Arch Pathol Lab Med  2000; 124: 966–78. Google Scholar 7 Early Breast Cancer Trialists' Collaborative Group. Tamoxifen for early breast cancer: an overview of the randomized trials. Lancet  1998; 351: 1451–67. Google Scholar 8 Fisher B, Anderson S, Tan-Chiu E, Wolmark N, Wickerham DL, Fisher ER, et al. Tamoxifen and chemotherapy for axillary node-negative, estrogen receptor-negative breast cancer: findings from National Adjuvant Breast and Bowel Project B-23. J Clin Oncol  2001; 19: 931–42. Google Scholar 9 Hutchins L, Green S, Ravdin P, Lew D, Martino S, Abeloff M, et al. CMF versus CAF with and without tamoxifen in high-risk node-negative breast cancer patients and a natural history follow-up study in low-risk node-negative patients: first results of intergroup trial INT 0102 [abstract]. Proc ASCO  1998; 17: 1a. Google Scholar 10 Fisher B, Dignam J, Bryant J, Wolmark N. Five versus more than five years of tamoxifen for lymph node-negative breast cancer: updated findings from the National Surgical Adjuvant Breast and Bowel Project B-14 randomized trial. J Natl Cancer Inst  2001; 93: 684–90. Google Scholar 11 Stewart HJ, Forrest AP, Everington D, McDonald CC, Dewar JA, Hawkins RA, et al. Randomised comparison of 5 years of adjuvant tamoxifen with continuous therapy for operable breast cancer. Br J Cancer  1996; 74: 297–9. Google Scholar 12 Tormey DC, Gray R, Falkson HC. Postchemotherapy adjuvant tamoxifen beyond five years in patients with lymph node-positive breast cancer. J Natl Cancer Inst  1996; 88: 1828–33. Google Scholar 13 Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Polychemotherapy for early breast cancer: an overview of the randomised trials. Lancet  1998; 352: 930–42. Google Scholar 14 Peters WP, Rosner G, Vredenburgh J, Shpall E, Crump M, Marks L, et al. Updated results of a prospective, randomized comparison of two doses of combination alkylating agents as consolidation after CAF in high-risk primary breast cancer involving ten or more axillary lymph nodes: CALGB 9082/SWOG 9114/NCIC MA-13 [abstract]. Proc ASCO  2001; 20: 81. Google Scholar 15 Rodenhuis S, Bontenbal M, Beex L, van der Wall E, Richel D, Nooij M, et al. Randomized phase III study of high-dose chemotherapy with cyclophosphamide, thiotepa, and carboplatin in operable breast cancer with 4 or more axillary lymph nodes [abstract]. Proc ASCO  2000; 19: 74. Google Scholar 16 Henderson IC, Berry D, Demetri G, Cirrincione C, Goldstein L, Martino S, et al. Improved disease-free and overall survival from the addition of sequential paclitaxel but not from the escalation of doxorubicin dose level in the adjuvant chemotherapy of patients with node-positive primary breast cancer [abstract]. Proc ASCO  1998; 17: 101a. Google Scholar 17 Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Favourable and unfavourable effects on long-term survival of radiotherapy for early breast cancer: an overview of the randomised trials. Lancet  2000; 355: 1757–70. Google Scholar © Oxford University Press http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png JNCI Monographs Oxford University Press

Monograph Overview

Abrams, Jeffrey S.; Eifel, Patricia
JNCI Monographs , Volume 2001 (30) – Dec 1, 2001
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Oxford University Press
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© Oxford University Press
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1052-6773
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1745-6614
DOI
10.1093/oxfordjournals.jncimonographs.a003444
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Abstract

Beginning in 1977, the National Institutes of Health (NIH), the lead governmental agency for federally sponsored research in the United States, organized Consensus Development Conferences to review controversial areas of medical research (1). More than 120 such conferences have been held on a wide variety of diseases and medical disciplines. Adjuvant therapy of breast cancer has been one of the most popular topics for Consensus Development Conferences, with previous meetings held in 1980, 1985, and 1990 (2–4). As 10 years had elapsed since the last conference, the National Cancer Institute at NIH thought that it was time to once again cosponsor a Consensus Development Conference to review what progress had occurred in adjuvant breast cancer therapy. Consensus Development Conferences are structured to emphasize a balanced, critical review of the scientific evidence. A planning committee develops several key questions of paramount interest. It then selects experts in the field to present pertinent research results to an independent, nongovernmental panel consisting of academic and community-based physicians, biostatisticians, nurses, basic researchers, and other appropriate disciplines, along with lay patient advocates. The panelists are selected for their general expertise in their chosen field, but they cannot have published extensively or be considered “opinion leaders” on the topic selected for consensus development. Held November 1–3, 2000, the Consensus Conference on Adjuvant Therapy of Breast Cancer was open to the public, and admission was free. Discussion sections were interspersed throughout the formal presentations to provide both panelists and members of the audience an opportunity to query the speakers or to offer additional evidence. At the conclusion of the expert presentations, the panel met in a closed session and developed a draft Consensus Statement. The panel chairperson read the entire draft to all of the meeting participants, who offered comments and suggestions that were carefully considered by the panelists before they finalized the statement. At the close of the conference, the Consensus Statement was presented to the national press and made available on the NIH Web site (http://consensus.nih.gov) and has subsequently been published (5). The entire statement is reproduced in this monograph. The statement is intended to provide useful summary recommendations to professionals and the public that reflect the current state of the art. The planning committee believed that a broad review of adjuvant therapy was required to help clinicians deal with practical problems in selecting the appropriate adjuvant therapy. The following six questions were posed to the panel: 1) Which factors should be used to select systemic adjuvant therapy? 2) For which patients should adjuvant hormonal therapy be recommended? 3) For which patients should adjuvant chemotherapy be recommended, and which agents should be used and at what dose or schedule? 4) For which patients should postmastectomy radiotherapy be recommended? 5) How do side effects and quality-of-life issues factor into individual decision making about adjuvant therapy? 6) What are promising new research directions for adjuvant therapy? Before the conference, the panelists reviewed the existing medical evidence from the literature. Their review was then supplemented at the meeting by presentations from 33 expert speakers. This monograph presents the details of the evidence offered by the experts on which the consensus statement was largely based. Of the 33 presentations, all but nine speakers have contributed original articles to this monograph. In the overview of this monograph that follows, we mention the reviews by the contributing authors but focus our attention primarily on the presentations not included in the monograph, so the reader has a complete review of the basis for the consensus recommenda-tions. The full name of the presenter and his or her affiliation is provided for those who did not submit articles, while the reader can find this information for those who contributed in the original articles that follow. Question 1: Which Factors Should Be Used to Select Systemic Adjuvant Therapy? Progress in the development of new prognostic and predictive factors for adjuvant therapy has been difficult to realize. Traditional tumor-related factors, such as axillary lymph node status, tumor size, histologic type and grade, and hormone receptor status, were still the most useful indicators of prognosis, while receptor status was the most valuable predictor of response to endocrine therapy (6). These issues are reviewed thoroughly by Drs. Gary Clark, Stuart Schnitt, and Maria Grazia Daidone. Their presentations highlighted the fact that all too often, markers are touted before definitive studies are available to prove their value independent of established factors. In some cases, even when new markers have been shown to be independent predictors, the assays were either not reliable or were not generally available. Although poised technologically to make important advances in coming years, research in this area is dependent on the ability to amass large sample sizes with careful documentation of the patient, tumor, and treatment characteristics of the study population. Phase III cooperative group treatment trials in this country and abroad increasingly have such features and are potentially valuable sources of specimens. However, carefully performed clinical trials were thought to be only an initial step. New markers developed in the research laboratory must be transferable to general medical care before they can make an impact on clinical decision making. Drs. James Dignam, Aron Goldhirsch, and Hyman Muss examined patient-specific characteristics including racial/ethnic background, young age, and older age, respectively. Although breast cancer is a common disease in older women, relatively few older women participated in clinical trials, so their treatment was often extrapolated from younger populations. This problem was in need of remediation by the research community. For younger women, data now suggest that hormonal therapies are extremely important for hormone-sensitive tumors. As for race or ethnicity, a differential treatment effect was not detected according to these factors. Question 2: For Which Patients Should Adjuvant Hormonal Therapy Be Recommended? Multiple clinical trials supported the panel's recommendation that tamoxifen should be considered in all women with hormone receptor-positive breast cancer, irrespective of age, menopausal and lymph node status, tumor size, and treatment with chemotherapy (7). The only exception cited was for women with very small tumors, less than or equal to 1 cm, for whom the side effects might outweigh the advantages. Sir Richard Peto (Oxford University, England) presented the evidence supporting this recommendation by reviewing updated results from the September 2000 meta-analysis performed by the Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Comparing women treated with and without tamoxifen for 5 years, the results in 8000 women with estrogen receptor-positive tumors indicated that tamoxifen reduced death from breast cancer by 9% ± 1.4% at 15 years without increasing non-breast cancer deaths statistically significantly. The sole prognostic factor in the meta-analysis that correlated with survival was hormone receptor status. Only women with positive estrogen receptors benefited from tamoxifen. Dr. Kent Osborne (Baylor University, Houston, TX) discussed whether tamoxifen was indicated for hormone receptor-negative disease. Neither the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-23 trial (8) nor the Intergroup trial (9) demonstrated an improvement in overall survival or a reduction in contralateral breast cancer in hormone receptor-negative tumors. This was also the finding of the EBCTCG September 2000 meta-analysis. On the basis of these facts, the panelists recommended that tamoxifen not be used in women with hormone receptor-negative disease. Dr. Christina Davies (Oxford University, England) and Dr. Bryant debated the optimal duration of tamoxifen therapy. Dr. Davies presented the results of the September 2000 EBCTCG meta-analysis, which demonstrated that 5 years of tamoxifen compared with 1–2 years of tamoxifen produced an additional absolute survival increment of 3.2% ± 1% at 10 years while causing only a 0.1% increase in such serious side effects as pulmonary embolus or endometrial cancer. The panelists concluded that 5 years of therapy should be recommended routinely, since the advantages of the drug outweighed its toxicity for most women with invasive breast cancer. Studies comparing 5 years with longer durations of therapy (7–10 years) did not reveal a benefit for therapy beyond 5 years. Dr. Davies maintained that these results are premature, arguing that the survival benefit from 5 years of tamoxifen, rather than remaining constant, continues to increase during the next 5 years (“carryover effect”), despite the drug being stopped. An advantage for prolonged therapy, she reasoned, might be expected to emerge only after 10–15 years of follow-up. In support of this contention, more recurrences have occurred in the placebo (n = 16) than in the tamoxifen (n = 11) group in B-14 when only recurrences diagnosed more than 6 years after randomization were examined (10). However, Dr. Bryant contended in his article that the number of events during this time period is quite small, while the overall study results from B-14 continued to indicate no statistically significant survival advantage for the longer therapy, a finding similar to analyses from the Scottish (11) and Eastern Cooperative Oncology Group (12) trials of tamoxifen duration. Outside of clinical trials, the panelists recommended limiting tamoxifen treatment to 5 years. Dr. Nancy Davidson reviewed ovarian ablation, an alternative to tamoxifen. The evidence that she described convinced the panelists that ovarian ablation is an acceptable adjuvant therapy in women with premenopausal, hormone-responsive breast cancer. The panelists recommended that further clinical trials were needed to determine whether ablation was additive when combined with tamoxifen and chemotherapy. Question 3: For Which Patients Should Adjuvant Chemotherapy Be Recommended, and Which Agents Should Be Used and at What Dose or Schedule? Chemotherapy remained the systemic adjuvant therapy of choice for most patients with hormone receptor-negative breast cancer. Dr. Gabriel Hortobagyi presented a thorough review of progress in the field over the past decade. As demonstrated in earlier EBCTCG overviews (13) and at the most recent update in September 2000, all patient subsets, lymph node-negative/positive, pre/postmenopausal, and hormone receptor-negative/positive, derived a statistically significant survival advantage, in the range of 3%–12%, from chemotherapy compared with no chemotherapy. As anticipated, the absolute benefit was greatest for women at highest risk of relapse. Regarding specific regimens, the September 2000 overview also indicated that anthracycline-containing regimens yield a 3.5% absolute improvement in survival. For commonly used drugs such as doxorubicin and cyclophosphamide, clinical trials have demonstrated a threshold dose below which these drugs appear less effective, but dose escalation beyond the threshold level has not been demonstrated to lead to increased benefit. Dr. Larry Norton (Memorial Sloan-Kettering Cancer Institute, New York, NY) discussed several clinical trials that tested dose escalation without the need for stem cell support. He concluded that the optimal doses of cyclophosphamide and doxorubicin were 600 mg/m2 and 60 mg/m2, respectively, for adjuvant breast cancer treatment. A key unanswered question, he noted, was whether combination or sequential use of active agents is most beneficial. Dose escalation was also reviewed in the context of high-dose chemotherapy trials with autologous stem cell support. Dr. William Peters (Barbara Ann Karmanos Cancer Institute, Detroit, MI) presented an update of Cancer and Leukemia Group B (CALGB) 9082 (14). He found no difference in disease-free or overall survival with a median follow-up of 5.1 years between the high-dose arm with autologous stem cell support and an intermediate-dose arm using only granulocyte-colony stimulating factor support. Dr. Karen Antman reviewed results from five additional international randomized trials using high-dose therapy. Although a Dutch trial has encouraging preliminary results (15), the other trials did not indicate a survival advantage. Nine additional international trials were either ongoing or had completed accrual but are not yet analyzed. Until and unless additional clinical trials became available that demonstrate a benefit for high-dose therapy, the panelists concluded that this approach should not be used in routine practice. Dr. Norman Wolmark discussed neoadjuvant breast cancer therapy, noting that this approach had the potential to markedly shorten the time it takes to evaluate promising agents. Dr. Richard Gray (University of Birmingham, England) presented results from the September 2000 EBCTCG meta-analysis regarding comparisons of chemotherapy and hormonal therapy. He noted that, for women 50 years of age or more with hormone-sensitive tumors, tamoxifen yielded a greater survival benefit than did chemotherapy. However, the treatments generally appeared additive, with the combination producing superior survival results than either modality alone in most tumor subsets analyzed. The panel concluded that tamoxifen should be used whenever chemotherapy is considered for receptor-positive tumors. The most controversial issue faced by the panelists concerned the role of taxanes as part of adjuvant chemotherapy regimens. Dr. Craig Henderson (University of California, San Francisco) updated CALGB 9082, a U.S. Intergroup study (16). The study tested doxorubicin and cyclophosphamide (AC) for four cycles followed by paclitaxel for four cycles versus AC alone. With a median follow-up of 52 months, a statistically significant disease-free and overall survival advantage for the addition of paclitaxel persists. An unplanned subset analysis indicates that the advantage is limited to patients who did not receive tamoxifen. Dr. Eleftherios Mamounas (Aultman Cancer Center, Canton, OH) presented an interim analysis of NSABP B-28. This study was similar in design to the CALGB trial. With a median follow-up of 34 months, no disease-free or overall survival advantage was noted for the addition of paclitaxel to AC chemotherapy. A subset analysis has not indicated a statistically significant difference according to whether or not tamoxifen was administered. However, similar to the NSABP trial, a trend favoring paclitaxel was noted in patients who did not receive tamoxifen or who had hormone receptor-negative tumors. Dr. Martine Piccart discussed important differences between these two trials that might explain their results. Further follow-up of the NSABP trial and completion of other ongoing randomized trials examining the role of taxanes should clarify whether these agents will become a part of standard chemotherapy regimens. The panel concluded that definitive evidence was lacking regarding the role of taxanes but counseled against their usage in patients with lymph node-negative breast cancer outside clinical trials. To determine whether subsets of patients exist for whom the risk of recurrence does not justify the routine use of chemotherapy, Drs. Monica Morrow and Jonas Bergh analyzed population-based registry data from the United States and Europe, respectively. Their reviews suggested excellent outcomes without adjuvant therapy in selected subsets of lymph node-negative tumors with small tumors. In contrast to the registry data, Dr. Bernard Fisher compiled results across several NSABP lymph node-negative, randomized clinical trials that compared various systemic therapies. Selected subsets of women in these trials seemed to benefit from adjuvant hormonal therapy and/or chemotherapy. In view of the small yet statistically significant benefits for some patients with tumors considered to be at low risk, the challenge for physicians is to provide a balanced explanation of risks and benefits that will permit individuals to make an informed, personal decision. Question 4: For Which Patients Should Postmastectomy Radiotherapy Be Considered? Dr. Jack Cuzick (Imperial Cancer Research Fund, London, England) updated the recent EBCTCG meta-analysis (17) that demonstrated that adjuvant radiotherapy produces an absolute reduction of 20% in isolated local recurrences at 20 years, irrespective of the use of chemotherapy or tamoxifen. This large reduction in local recurrence was accompanied by a statistically significant absolute reduction in death by breast cancer of 5% at 15 years. However, a concomitant absolute increase of 4% in non-breast cancer deaths occurred in patients receiving radiotherapy. This increase did not begin to appear until about 5 years after treatment and seemed to increase at least out to 15 years after treatment. A stratified analysis, performed according to whether trials were initiated before or after 1975, indicated that the trials started before 1975 had a very statistically significant increase in non-breast cancer deaths, while those started after 1975 did not. This might be because of the use of improved radiotherapy techniques in the latter trials, but longer follow-up of the trials in this latter group was needed before this explanation could be fully accepted. It was also noteworthy that the majority of non-breast cancer deaths, although vascular in origin, were not cardiac related. To assess who should receive postmastectomy radiotherapy, Dr. Lori Pierce reviewed several risk factors potentially associated with local recurrence. On the basis of the information presented, the panelists agreed that postmastectomy radiotherapy was indicated for women with four or more positive axillary lymph nodes and for those with large primary tumors. The benefit was less clear for those with one to three positive lymph nodes, and participation of such patients in an ongoing Southwest Oncology Group clinical trial (S9927) testing this question was recommended. Question 5: How Do Side Effects and Quality-of-Life Issues Factor Into Individual Decision Making About Adjuvant Therapy? Ms. Amy Langer introduced the subject by explaining how patients view these issues and how they affect decision making. Drs. Patricia Ganz and Eric Winer described the side effects of tamoxifen and chemotherapy, respectively. The value of adjuvant therapy, a mix of benefits counterbalanced by risks, requires physicians to present detailed information to patients. Dr. Mark Levine reviewed research on how best to present information to patients. However, once the information is understood, the ultimate decision remains a personal one based on the individual's tolerance of risk and the value attributed to the benefits. Dr. Alan Coates described several studies that assessed the willingness of patients to receive adjuvant therapy based on scenarios that present differing degrees of survival gains. The panelists concluded that effective communication between physicians and patients is essential to the decision-making process regarding adjuvant therapy. Complex information must be conveyed regarding absolute risks and benefits, so patients can appreciate the trade-offs involved in their choices. This process can be facilitated through the use of decision aids and other well-designed patient information materials. Question 6: What Are Promising New Research Directions for Adjuvant Therapy? Integrating genomics and proteomics into the search for prognostic factors, testing the optimal duration and combinations of hormonal treatments and the value of chemotherapy in older patients, and including quality-of-life endpoints in adjuvant trials were all cited during the conference as important future research directions. The primary new therapeutic direction involved targeted therapies based on an improved understanding of molecular pathways. Herceptin and bisphosphonates were among the first of this new generation of targeted treatments to enter adjuvant clinical trials. Many other agents that target specific proliferative pathways are being studied in patients with advanced breast cancer. The challenge for the future is to integrate the most promising of these pathways into the current adjuvant therapy armamentarium. References 1 Guidelines for the planning and management of NIH Consensus Development Conferences. Bethesda (MD): National Institutes of Health, Office of the Director, Office of Medical Applications of Research; 1993. Google Scholar 2 Moxley JH, Allegra JC, Henney J, Muggia F. Treatment of primary breast cancer: summary of the National Institutes of Health Consensus Development Conference. JAMA  1980; 244: 797–803. Google Scholar 3 Consensus Conference. Adjuvant chemotherapy for breast cancer. JAMA  1985; 254: 3461–3. Google Scholar 4 NIH consensus conference. Treatment of early-stage breast cancer. JAMA  1991; 265: 391–5. Google Scholar 5 National Institutes of Health Consensus Panel. National Institutes of Health Consensus Development Conference statement: adjuvant therapy for breast cancer, November 1–3, 2000. J Natl Cancer Inst  2001; 93: 979–89. Google Scholar 6 Fitzgibbons PL, Page DL, Weaver D, Thor AD, Allred DC, Clark GM, et al. Prognostic factors in breast cancer: College of American Pathologists Consensus Statement 1999. Arch Pathol Lab Med  2000; 124: 966–78. Google Scholar 7 Early Breast Cancer Trialists' Collaborative Group. Tamoxifen for early breast cancer: an overview of the randomized trials. Lancet  1998; 351: 1451–67. Google Scholar 8 Fisher B, Anderson S, Tan-Chiu E, Wolmark N, Wickerham DL, Fisher ER, et al. Tamoxifen and chemotherapy for axillary node-negative, estrogen receptor-negative breast cancer: findings from National Adjuvant Breast and Bowel Project B-23. J Clin Oncol  2001; 19: 931–42. Google Scholar 9 Hutchins L, Green S, Ravdin P, Lew D, Martino S, Abeloff M, et al. CMF versus CAF with and without tamoxifen in high-risk node-negative breast cancer patients and a natural history follow-up study in low-risk node-negative patients: first results of intergroup trial INT 0102 [abstract]. Proc ASCO  1998; 17: 1a. Google Scholar 10 Fisher B, Dignam J, Bryant J, Wolmark N. Five versus more than five years of tamoxifen for lymph node-negative breast cancer: updated findings from the National Surgical Adjuvant Breast and Bowel Project B-14 randomized trial. J Natl Cancer Inst  2001; 93: 684–90. Google Scholar 11 Stewart HJ, Forrest AP, Everington D, McDonald CC, Dewar JA, Hawkins RA, et al. Randomised comparison of 5 years of adjuvant tamoxifen with continuous therapy for operable breast cancer. Br J Cancer  1996; 74: 297–9. Google Scholar 12 Tormey DC, Gray R, Falkson HC. Postchemotherapy adjuvant tamoxifen beyond five years in patients with lymph node-positive breast cancer. J Natl Cancer Inst  1996; 88: 1828–33. Google Scholar 13 Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Polychemotherapy for early breast cancer: an overview of the randomised trials. Lancet  1998; 352: 930–42. Google Scholar 14 Peters WP, Rosner G, Vredenburgh J, Shpall E, Crump M, Marks L, et al. Updated results of a prospective, randomized comparison of two doses of combination alkylating agents as consolidation after CAF in high-risk primary breast cancer involving ten or more axillary lymph nodes: CALGB 9082/SWOG 9114/NCIC MA-13 [abstract]. Proc ASCO  2001; 20: 81. Google Scholar 15 Rodenhuis S, Bontenbal M, Beex L, van der Wall E, Richel D, Nooij M, et al. Randomized phase III study of high-dose chemotherapy with cyclophosphamide, thiotepa, and carboplatin in operable breast cancer with 4 or more axillary lymph nodes [abstract]. Proc ASCO  2000; 19: 74. Google Scholar 16 Henderson IC, Berry D, Demetri G, Cirrincione C, Goldstein L, Martino S, et al. Improved disease-free and overall survival from the addition of sequential paclitaxel but not from the escalation of doxorubicin dose level in the adjuvant chemotherapy of patients with node-positive primary breast cancer [abstract]. Proc ASCO  1998; 17: 101a. Google Scholar 17 Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Favourable and unfavourable effects on long-term survival of radiotherapy for early breast cancer: an overview of the randomised trials. Lancet  2000; 355: 1757–70. Google Scholar © Oxford University Press

Journal

JNCI Monographs – Oxford University Press

Published: Dec 1, 2001

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