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Originally published as JCO Early Release 10.1200/JCO.2004.02.927 on April 26 2004 © 2004 American Society of Clinical Oncology.
What Is the Role of High-Dose Chemotherapy in the Era of Targeted Therapies?The University of Texas M.D. Anderson Cancer Center, Houston, TX The development of high-dose chemotherapy treatment for breast cancer provides ample opportunity to reflect on the integration of science into medicine. It also exemplifies the ongoing tension in a clinical investigator between being a physician and a scientist. As physicians, we want to provide our patients with the most effective therapy and want to do so as soon as such therapy becomes available. For a scientist, the primary objective is the successful testing of hypotheses and the generation of proof that would lead one to either accept or reject such hypotheses. Clinical trials with high-dose chemotherapy were developed almost at the same time as the introduction of combination chemotherapy in the management of breast cancer. Although myelosuppression was identified as the dose-limiting toxicity for most cytotoxic drugs available 30 years ago, the initial steps in bone marrow transplantation were taken in the early 1970s, during the same time as the first trials of adjuvant chemotherapy.1-4 Reports about decreased survival associated with reduced doses of chemotherapy provided additional stimulus for the concept of dose-intensification.5,6 Hryniuk and others were instrumental in crystallizing this concept, providing a scientific platform for the development of multiple approaches to dose enhancement.7,8 From these initial steps emerged substantial enthusiasm for testing high-dose chemotherapy with autologous bone marrow transplantation as a potentially curative therapeutic intervention for both solid tumors and hematologic malignancies. Early results provided information about tolerance and toxicity, as well as the criteria for optimal selection of patients likely to tolerate treatment without life-threatening toxicity. The development of the technique to harvest, manipulate, and reinfuse peripheral hematopoietic stem cells facilitated the development of the field, improved the safety of the procedure, and resulted in the widespread application of the technology, well before the assessment of both benefits and risks had been definitely established. Throughout the 1980s, enthusiasm overtook discipline, and well-tested clinical trials methodology was shoved aside by the perception that randomized trials in patients with very poor prognosis were ethically unjustified. High-dose chemotherapy with autologous stem-cell support became established in clinical practice, to the extent that access to this unproven treatment strategy was legislated in several states, insurance companies were forced to provide coverage, and centers not offering this treatment were considered outdated. However, doubts ultimately emerged. High-dose chemotherapy was clearly not an option for all patients, as it was restricted to a highly selected population.9 Extensive pretreatment evaluation excluded patients with microscopic metastatic disease, resulting in stage migration, resulting in turn in a stage-by-stage improvement in outcome independent of the treatment administered.10 Eventually, randomized trials were initiated; some were completed despite substantial difficulties in accrual. Many randomized trials were closed before completing accrual, thus precluding the development of high-quality evidence. We now have the results of 10 randomized trials that tested the contribution of high-dose chemotherapy to the systemic adjuvant treatment of patients with high-risk breast cancer.11-20 In these trials, high-risk patients were usually defined as having 10 or more positive axillary lymph nodes, though some of the trials included patients with four or more nodes, while others required only biopsy confirmation of an apical axillary lymph node. The regimens were heterogeneous, the trial designs varied, and most trials were hopelessly underpowered to detect anything less than major clinical differences in outcome. In this issue of the Journal of Clinical Oncology, Zander et al21 provide additional information on adjuvant high-dose chemotherapy for breast cancer. Patients initially received four cycles of epirubicin and cyclophosphamide, and were then randomized to a single cycle of high-dose combination chemotherapy, or to three additional cycles of intravenous cyclophosphamide, methotrexate, and fluorouracil (CMF). Subsequently, the protocol was amended to include radiotherapy to the chest wall, and tamoxifen for women with receptor-positive breast cancer. The trial was closed prematurely, due to poor accrual. The results, based on 307 patients, provide no evidence supporting a survival benefit from high-dose chemotherapy, and no significant reduction in risk of recurrence, though there was a nonsignificant trend in event-free survival. Retrospective subgroup analyses suggest that premenopausal women and those with grade 3 tumors benefited from high-dose chemotherapy, though these differences did not reach statistical significance. Of the 10 high-dose chemotherapy randomized adjuvant trials reported to date, none has shown a significant survival difference. Only one, the French Pegase 01 trial, showed a significant improvement in the 3-year disease-free survival rate.22 Longer follow-up of this trial is not available. Several others were reported to show a numerical decrease in recurrences in the group treated with high-dose chemotherapy,13,17 including Zander et al, in this issue. Some trials have reported a significant delay in time to recurrence, without affecting the recurrence rate.20 Furthermore, retrospective subset analyses have suggested that trends emerge favoring high-dose chemotherapy in younger patients groups, with either estrogen receptor–negative tumors or high-grade tumors. These randomized trials comparing high-dose chemotherapy with standard-dose regimens represent a major collaborative effort involving multiple investigators. Because of the rather dramatic differences in treatment, these trials are difficult to conduct. It is perhaps for this reason that all these trials, without exception, are underpowered to detect anything less than very substantial differences in outcome. The largest trial included 885 patients; the second largest, 875; and all other trials were considerably smaller. These trials were also designed with relatively small sample sizes because of the high cost of conducting such trials and because of the expectations, based on phase II studies, that major differences in outcome would favor high-dose chemotherapy. It was also assumed that smaller trials in high-risk patients could show a difference with smaller numbers, because event rates are higher. Other randomized trials comparing different standard-dose adjuvant systemic treatment regimens conducted in the same era were designed to recruit anywhere from 2,000 to 9,300 patients. Based on such large trials, statistically significant and clinically relevant therapeutic effects were observed for paclitaxel, docetaxel, anastrozole, and the dose-dense administration of chemotherapy.23-26 These interventions were associated with relative reductions in annual odds of recurrence and death in the range of 20% to 30%. Such clinically important therapeutic benefit could not be detected by any of the individual high-dose chemotherapy randomized trials. The 10 randomized trials include 4,521 patients with high-risk primary breast cancer—a sample size large enough to detect even modest differences in outcome. Therefore, a meta-analysis of updated information on these 10 trials would contribute substantially to our assessment of the value of high-dose adjuvant chemotherapy regimens. If no significant therapeutic benefit can be demonstrated, then high-dose chemotherapy is unlikely to be a fruitful area of future clinical investigation, and the effort of many skilled clinical investigators could be channeled into more productive directions of therapeutic research. On the other hand, if significant treatment benefit from high-dose chemotherapy can be discerned from the meta-analysis, then efforts to identify the patient subgroups most likely to benefit from such an intervention would be helpful, so that additional refinements of this treatment strategy could be implemented, while sparing many patients from the increased levels of toxicity if they are unlikely to benefit from high-dose chemotherapy. If we know that currently available regimens of high-dose chemotherapy will not produce dramatic reductions in mortality, the issues related to morbidity and mortality become even more important. Technological advances in stem-cell support, the development of hematopoietic growth factors, better antibiotics, and other forms of supportive care have clearly contributed to transforming a formidable in-patient procedure with a mortality rate of up to 25% in the early days, to an outpatient treatment modality with mortality rates in the 1% to 2% range in most expert hands. Treatment-related mortality rates in the reported studies ranged from 1% to 7%, with reports indicating that mortality in small-volume centers might reach 11%.13 The use of peripheral stem-cell support and treatment in a high-volume, expert center, reduces mortality rates to within 1% to 2%. Acute leukemia and myelodysplastic syndrome were reported in as many as 7% of patients in one study, and 4% in a second; mortality from treatment-related leukemias is very high.15,20 The morbidity rate of high-dose chemotherapy continues to be high and exceeds that observed with standard-dose adjuvant chemotherapy regimens. Zander et al report neutropenic fever in 87% of patients, definite infections in 22%, nonhematologic grade 3 and 4 toxicity in 8% (excluding neutropenic fever and infections), and treatment-related deaths in 2%. The Oxford meta-analysis of first-generation adjuvant chemotherapy trials demonstrated that these regimens (mostly CMF or CMF-like combination chemotherapy) produced relative reductions in odds of recurrence (23.5%) and death (17%); the use of anthracycline-containing regimen improved results by another 11% and 12% for odds of recurrence and death, respectively.27 More recent trials, employing optimal anthracycline-containing regimens, have indicated that the incremental benefit of these regimens over CMF was in the range of 30% for reduction in risk of recurrence and death.28,29 Finally, the introduction of taxanes in adjuvant therapy results in reductions in odds of recurrence in the range of 17% to 30%, and in odds of death, from 18% to 31%. It can be estimated that the use of an anthracycline-taxane–containing regimen would result in a relative reduction in odds of recurrence compared with no adjuvant systemic therapy, of 40% to 60%, depending on age and hormone receptor status. This is without considering the major contribution of endocrine therapy, especially the selective aromatase inhibitors and antiestrogens, to the adjuvant therapy of hormone receptor–positive breast cancer, or the introduction of dose-dense schedules of administration for chemotherapy. Therefore, the target has moved, and even if a meta-analysis of high-dose chemotherapy regimens suggested significant activity, the next generation of clinical trials would have to demonstrate that high-dose chemotherapy is better than the current best standard regimens, and that the incremental benefit exceeds the probability of lethal and life-threatening toxicity. Based on the results presented by Zander and collaborators, and the weight of the information from the other nine adjuvant high-dose chemotherapy randomized trials, there is no role today for high-dose chemotherapy in the standard management of primary breast cancer, even in subgroups at high risk. Positive results from a meta-analysis of all completed trials of high-dose chemotherapy would provide justification to initiate additional trials and the enthusiasm in the oncology community to complete such trials. However, the major lesson of the development of high-dose chemotherapy in breast cancer is that good ideas and good hypotheses are insufficient justification for routinely adopting a therapeutic strategy, and that evidence in support of new therapies must come from well-designed, well-conducted clinical trials before they can be adopted into standard practice. Author's Disclosures of Potential Conflicts of Interest The following author or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Acted as a consultant within the last 2 years: Gabriel N. Hortobagyi, Pfizer. Received more than $2,000 a year from a company for either of the last 2 years: Gabriel N. Hortobagyi, AstraZeneca, Aventis, Pfizer. REFERENCES 1. Ariel IM: Treatment of disseminated cancer by intravenous hydroxyurea and autogenous bone-marrow transplants: Experience with 35 patients. J Surg Oncol 7:331-335, 1975[Medline] 2. Spitzer G, Dicke KA, Verma DS, et al: High dose chemotherapy with autologous bone marrow transfusion. Exp Hematol 7:38-53, 1979 (suppl 5) 3. Spitzer G, Dicke KA, Litam J, et al: High-dose combination chemotherapy with autologous bone marrow transplantation in adult solid tumors. Cancer 45:3075-3085, 1980[CrossRef][Medline] 4. Stewart PS: Autologous bone marrow transplantation in metastatic breast cancer. Breast Cancer Res Treat 2:85-92, 1982[CrossRef][Medline] 5. Bonadonna G, Valagussa P: Dose-response effect of adjuvant chemotherapy in breast cancer. N Engl J Med 304:10-15, 1981[Abstract] 6. Buzdar AU, Smith TL, Marcus CE, et al: Significance of drug dose, timing and radiotherapy in adjuvant therapy of breast cancer, in Recent Results in Cancer Research (vol 96), Berlin, Germany, 1984, pp 141-147
7. Hryniuk W, Levine MN: Analysis of dose intensity for adjuvant chemotherapy trials in stage II breast cancer. J Clin Oncol 4:1162-1170, 1986 8. Hryniuk WM, Bush H: The importance of dose intensity in chemotherapy of metastatic breast cancer. J Clin Oncol 2:1281-1288, 1984[Medline] 9. Rahman Z, Frye DK, Buzdar AU, et al: Impact of selection process on response rate and long-term survival of potential high-dose chemotherapy candidates treated with standard-dose doxorubicin-containing chemotherapy in patients with metastatic breast cancer. J Clin Oncol 15:3171-3177, 1997[Abstract] 10. Crump M, Goss PE, Prince M, et al: Outcome of extensive evaluation before adjuvant therapy in women with breast cancer and 10 or more positive axillary lymph nodes. J Clin Oncol 14:66-69, 1996[Abstract]
11. Hortobagyi GN, Buzdar AU, Theriault RL, et al: Randomized trial of high-dose chemotherapy and blood cell autografts for high-risk primary breast carcinoma. J Natl Cancer Inst 92:225-233, 2000 12. Rodenhuis S, Richel DJ, van der Wall E, et al: Randomised trial of high-dose chemotherapy and haemopoietic progenitor-cell support in operable breast cancer with extensive axillary lymph-node involvement. Lancet 352:515-521, 1998[CrossRef][Medline] 13. Peters W, Rosner G, Vredenburgh J, et al: 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: Preliminary results of CALGB 9082/SWOG 9114/NCIC MA-13. Proc Am Soc Clin Oncol 18:1a, 1999 (abstr 2) 14. Peters WP, Rosner G, Vredenburgh J, 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. Proc Am Soc Clin Oncol 20:21a, 2001 (abstr 81) 15. Bergh J, Wiklund T, Erikstein B, et al: Tailored fluorouracil, epirubicin, and cyclophosphamide compared with marrow-supported high-dose chemotherapy as adjuvant treatment for high-risk breast cancer: A randomised trial—Scandinavian Breast Group 9401 study. Lancet 356:1384-1391, 2000[CrossRef][Medline] 16. Crown JP, Lind M, Gould A, et al: High-dose chemotherapy (HDC) with autograft (PBP) support is not superior to cyclophosphamide (CPA), methotrexate and 5-FU (CMF) following doxorubicin (D) induction in patients (pts) with breast cancer (BC) and 4 or more involved axillary lymph nodes (4+ LN): The Anglo-Celtic I study. Proc Am Soc Clin Oncol 21:42a, 2002 (abstr 166) 17. Gianni A, Bonadonna G: Five-year results of the randomized clinical trial comparing standard versus high-dose myeloablative chemotherapy in the adjuvant treatment of breast cancer with > 3 positive nodes. Proc Am Soc Clin Oncol 20:21a, 2001 (abstr 80) 18. Roche HH, Pouillard P, Meyer N, et al: Adjuvant high dose chemotherapy (HDC) improves early outcome for high risk (N>7) breast cancer patients: The Pegase 01 Trial. Proc Am Soc Clin Oncol 20:26a, 2001 (abstr 102)
19. Rodenhuis S, Bontenbal M, Beex LV, et al: High-dose chemotherapy with hematopoietic stem-cell rescue for high-risk breast cancer. N Engl J Med 349:7-16, 2003
20. Tallman MS, Gray R, Robert NJ, et al: Conventional adjuvant chemotherapy with or without high-dose chemotherapy and autologous stem-cell transplantation in high-risk breast cancer. N Engl J Med 349:17-26, 2003
21. Zander AR, Kroger N, Schmoor C, et al: High-dose chemotherapy with autologous hematopoietic stem-cell support versus standard-dose chemotherapy in breast cancer patients with 10 or more positive lymph nodes: First results of a randomized trial. J Clin Oncol 22:2273-2283, 2004 22. Roche H, Viens P, Biron P, et al: High-dose chemotherapy for breast cancer: The French PEGASE experience. Cancer Control 10:42-47, 2003[Medline]
23. Henderson IC, Berry DA, Demetri GD, et al: Improved outcomes from adding sequential paclitaxel but not from escalating doxorubicin dose in an adjuvant chemotherapy regimen for patients with node-positive primary breast cancer. J Clin Oncol 21:976-983, 2003 24. Nabholtz J-M, Pienkowski T, Mackey J, et al: Phase III trial comparing TAC (docetaxel, doxorubicin, cyclophosphamide) with FAC (5-fluorouracil, doxorubicin, cyclophosphamide) in the adjuvant treatment of node positive breast cancer patients: Interim analysis of the BCIRG 001 study. Proc Am Soc Clin Oncol 21:36a, 2002 25. The ATAC Trialists' Group. Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: First results of the ATAC randomised trial. Lancet 359:2131-2139, 2002[CrossRef][Medline]
26. Citron ML, Berry DA, Cirrincione C, et al: Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: First report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741. J Clin Oncol 21:1431-1439, 2003 27. Early Breast Cancer Trialists' Collaborative Group: Polychemotherapy for early breast cancer: An overview of the randomised trials. Lancet 352:930-942, 1998[CrossRef][Medline] 28. Levine MN, Bramwell VH, Pritchard KI, et al: Randomized trial of intensive cyclophosphamide, epirubicin, and fluorouracil chemotherapy compared with cyclophosphamide, methotrexate, and fluorouracil in premenopausal women with node-positive breast cancer: National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 16:2651-2658, 1998[Abstract] 29. Poole CJ, Earl HM, Dunn JA, et al: NEAT (National Epirubicin Adjuvant Trial) and SCTBG BR9601 (Scottish Cancer Trials Breast Group) phase III adjuvant breast trials show a significant relapse-free and overall survival advantage for sequential ECMF. Proc Am Soc Clin Oncol 22:4, 2003 (abstr 13)
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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