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Journal of Clinical Oncology, Vol 24, No 24 (August 20), 2006: pp. 3919-3926 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.04.0352 Randomized Trial of Single Compared With Tandem High-Dose Chemotherapy Followed by Autologous Stem-Cell Transplantation in Patients With Chemotherapy-Sensitive Metastatic Breast Cancer
From the Bone Marrow Transplantation, University Hospital Hamburg-Eppendorf, Hamburg; Department of Transfusion Medicine, and Department of Gynecology and Obstetrics, Breast Centre, University Hospital Düsseldorf, Düsseldorf; Department of Oncology/Hematology, Klinikum Oldenburg, Oldenburg; Department of Gynecology and Obstetrics, University Hospital Münster, Münster; Department of Oncology/ Hematology, University Hospital Bonn, Bonn; Department of Hematology/ Oncology, Catholic Hospital, Hagen, University Witten-Herdecke, Witten; Department of Oncology/Hematology, Zentralkrankenhaus St Jürgensstraße, Bremen; Department of Oncology/ Hematology, Klinikum Lippe-Lemgo, Lemgo; Thüringer Institut für Blutzellanalyse und therapy (IBAT), Jena; Department of Oncology/Hematology, Klinikum Chemnitz, Chemnitz; Department of Hematology/Oncology, Klinikum Minden, Minden; Department of Hematology/Oncology, University Hospital Marburg, Marburg; Department of Oncology/ Hematology, University Hospital Dresden, Dresden; Department of Hematology/Oncology, University Hospital Halle, Halle; Department of Hematology/Oncology, University Hospital Mainz, Mainz; and WISP Research Institute, Langenfeld, Germany Address reprint requests to Nicolaus Kröger, MD, Bone Marrow Transplantation, University Hospital Hamburg-Eppendorf, Martinistrasse 52, D-20246 Hamburg, Germany; e-mail: nkroeger{at}uke.uni-hamburg.de
PURPOSE: To compare progression-free survival between single and tandem high-dose chemotherapy (HDT) followed by autologous stem-cell transplantation in chemotherapy-sensitive metastatic breast cancer patients. PATIENTS AND METHODS: Between February 1997 and June 2001, 187 patients with complete and partial remission were randomly assigned to receive either one or two cycles of HDT, consisting of thiotepa (125 mg/m2/d for 4 days), cyclophosphamide (1,500 mg/m2/d for 4 days), and carboplatin (200 mg/m2/d for 4 days), followed by autologous stem-cell transplantation. RESULTS: One hundred seventy one of 187 randomly assigned patients completed first HDT, but only 52 of 85 completed the second HDT cycle in the tandem HDT arm. The rate of complete remission on an intent-to-treat-basis was 33% in the single-dose HDT arm and 37% in the tandem HDT arm (P = .48). The median progression-free survival times in single and tandem HDT arms were 9.4 and 11.2 months, respectively (one-sided P = .06; two one-sided P = .12), whereas median overall survival time tended to be greater after single versus tandem HDT (29 v 23.5 months, respectively; P = .4). In a multivariate analysis for progression-free survival, tandem HDT (hazard ratio [HR] = 0.71; 95% CI, 0.52 to 0.98; P = .03) and achievement of complete remission after induction chemotherapy (HR = 0.59; 95% CI, 0.37 to 0.96; P = .03) were factors for a better progression-free survival, whereas the factor of three or more sites of metastases (HR = 1.66; 95% CI, 1.12 to 2.47; P = .01) was associated with a worse progression-free survival. CONCLUSION: Despite a trend of improved progression-free survival, tandem HDT cannot be recommended for patients with chemotherapy-sensitive metastatic breast cancer because of a trend for shorter overall survival and higher toxicity compared with single HDT.
Breast cancer is one of the leading causes of death in women in Western countries. Despite adjuvant therapy, 50% of patients will experience relapse or develop metastatic disease that will ultimately lead to death; and despite the responsiveness to various combinations of chemotherapy or hormonal therapy, the median survival of patients with metastatic disease is only 18 to 24 months.1 Patients with complete remission after chemotherapy or hormonal therapy have a better prognosis; however, only 10% of these patients will achieve a complete remission after conventional hormonal therapy or chemotherapy.2 Early phase II studies investigating high-dose chemotherapy (HDT) followed by autologous stem-cell transplantation in chemotherapy-sensitive metastatic breast cancer patients resulted in complete remission rates of approximately 50%, which led to a 30% to 40% disease-free survival rate after 2 to 3 years of follow-up.3-6 To eradicate all tumor cells, the feasibility and efficacy of a tandem HDT in breast cancer has been evaluated in several phase II studies, resulting in an 11% to 27% increase of complete remissions after a second HDT cycle without an increase in treatment-related mortality.7-9 The current prospective randomized study for chemotherapy-sensitive metastatic breast cancer was conducted to investigate whether tandem HDT would achieve a higher complete remission rate, which might result in longer progression-free and overall survival than a single HDT regimen.
Patients Eligible patients had metastatic breast cancer. Other inclusion criteria included age of 18 to 60 years, an Eastern Cooperative Oncology Group performance status of less than 2, and a partial or complete remission after no more than six cycles of induction chemotherapy; adequate hematologic, hepatic, and pulmonary function were also required (defined as absolute neutrophils count  1.5 x 109/L cells, platelet count 100 x 109/L cells, and serum creatinine and serum bilirubin  1.25x upper normal limit). Patients could be premenopausal or postmenopausal, and if they had positive estrogen or progesterone receptor assay, they must have experienced treatment failure with at least one prior hormonal treatment unless life-threatening visceral disease was present. Exclusion criteria included presence of CNS metastases, more than six cycles of induction chemotherapy, second-line chemotherapy, and isolated metastases that can be treated by local therapy alone. The protocol was approved by the local ethics committees of all participating centers and carried out in accordance with the Declaration of Helsinki. All patients gave written informed consent for the study.
Treatment Eligible patients were randomly assigned to receive either one or two cycles of HDT, consisting of thiotepa (125 mg/m2 on days –6 to –3), cyclophosphamide (1,500 mg/m2 on days –6 to –3), and carboplatin (200 mg/m2 on days –6 to –3), followed by autologous peripheral blood stem-cell transplantation. The peripheral blood progenitor cells were administered 48 hours after the last dose of chemotherapy and were followed by a daily treatment with filgrastim to enhance the engraftment. Patients were stratified according to presence or absence of visceral metastases and to remission status (complete or partial remission). The second HDT cycle was administered 28 days after the first HDT cycle at earliest or, at the latest, 70 days after the first HDT cycle. The supportive care after transplantation consisted of uroprotection with mesna, hydration, and nursing the patient in a single room during aplasia. Antibiotic treatment was initiated in case of fever according to the local policy. Adverse effects were graded according to the National Cancer Institute Common Toxicity Criteria, version 1.
Statistical Analysis
Characteristics and Enrollment of the Patients Between February 1997 and June 2001, 187 patients from 32 centers were enrolled and underwent random assignment. None of the patients was found to be ineligible. Patient characteristics are listed in Table 1.
Mobilization and Harvest of Peripheral Progenitor Cells A total of 144 patients received chemotherapy plus filgrastim to mobilize hematopoietic stem cells. Chemotherapy consisted mainly of anthracycline- and taxane-based combination therapies (65%) or other regimens (35%). Twenty-seven patients received only granulocyte colony-stimulating factor to mobilize stem cells from steady-state. The median harvest of CD34+ cells per kilogram body weight was 7 x 106 cells/kg (range, 2.2 to 49 x 106 cells/kg) in the single HDT arm and 8.8 x 106 cells/kg (range, 2.5 to 69 x 106 cells/kg) in the tandem HDT arm. The number of performed apheresis procedures was higher in the tandem HDT arm than in the single HDT arm (158 v 104 procedures, respectively). The median number of transplanted CD34+ cells was 3.0 x 106 per kilogram of body weight per high-dose cycle in both arms.
HDT
Engraftment After HDT and stem-cell transplantation, the leukocyte and platelet engraftment was similar between the first and second HDT cycles.
Response to HDT
Toxicities Major nonhematologic grade 3 to 4 toxicities in both arms were nausea, mucositis, vomiting, and diarrhea without significant difference between the two arms (Table 3). Only grade 3 to 4 dyspnea was significantly higher in the tandem HDT arm.
In the tandem HDT arm, it was possible to compare, in a single patient, the toxicity between the first and the second HDT cycle, and no significant increase in severe grade 3 or 4 nausea, vomiting, diarrhea, or mucositis was observed (Table 4). In both the single and tandem HDT arms, three patients (3%) died of therapy-related causes, which were cardiac failure (n = 2), multiorgan failure (n = 2), sepsis (n = 1), and encephalitis (n = 1).
Progression-Free and Overall Survival After a median follow-up time for surviving patients of 63 months (range, 8 to 88 months), the progression-free and overall survival rates at 5 years for the whole study group were 7% (95% CI, 4% to 12%) and 20% (95% CI, 15% to 27%), respectively. The median progression-free and overall survival times were 10.3 and 24.8 months, respectively. At 2 years, the progression-free survival rate was 10% (95% CI, 5% to 18%) for the single HDT arm and 19.6% (95% CI, 12% to 29%) for the tandem HDT arm. Comparing the treatment arms, the estimated progression-free and overall survival rates at 5 years were 6% (95% CI, 3% to 14%) and 20% (95% CI, 13% to 31%), respectively, for the single HDT arm and 8% (95% CI, 4% to 16%) and 20% (95% CI, 14% to 31%), respectively, for the tandem HDT arm (Figs 2 and 3). Regarding the primary study objective, the median progression-free survival time was 9.4 months for the single HDT arm and 11.2 months for the tandem HDT arm (log-rank test: one-sided P = .061 and two-sided P = .12). If only patients who completed their proposed HDT cycles were included, the median progression-free survival time was 9.8 months for the single HDT arm and 13.3 months for the tandem HDT arm (log-rank test, P = .053).
Results of univariate analysis are listed in Table 5. In 54% of the patients, the location of the progression or the relapse was identical with the primary metastatic location. In a landmark analysis including only patients without event in the first 3 months after autologous stem-cell transplantation, patients who achieved or remained in complete remission had a better median progression-free survival time than patients who were not in complete remission (13.6 v 9.4 months, respectively; P < .001).
In a multivariate analysis for progression-free survival, tandem HDT (hazard ratio [HR] = 0.71; P = .04) and achievement of complete remission after induction chemotherapy (HR = 0.59; P = .03) remained protective factors for progression-free survival, whereas the factor of three or more sites of metastases (HR = 1.66; P = .01) was an independent significant factor for worse progression-free survival after therapy. In a multivariate analysis for overall survival, the factor of three or more sites of metastases was associated with a worse overall survival (HR = 1.71; P = .007), whereas being in complete remission before HDT resulted in an improved overall survival (HR = 0.58; P = .048; Fig 4, Table 6).
The dose-intensity concepts12 and the availability of peripheral blood stem cells to circumvent dose-limiting hematologic toxicity prompted numerous prospective phase II trials of HDT in metastatic breast cancer with a high rate of complete remissions.3,4,13,14 However, only a few randomized trials of HDT in stage IV breast cancer were conducted, and those few were hampered by low recruitment as a result of an unjustified enthusiasm in HDT.15-21 After a median follow-up time of 5 years, our study could show only a trend for a longer time to progression for the tandem HDT arm compared with the single HDT arm. These results were based on an intent-to-treat analysis. However, the dropout rate in the tandem HDT arm was substantial at 44%, which reflects the difficulty and concerns in performing a second HDT cycle in those patients. The Philadelphia Bone Marrow Transplant Group,15 compared HDT with a conventional maintenance chemotherapy consisting of cyclophosphamide, methotrexate, and fluorouracil. In that trial, patients with partial or complete remission were included, and 199 patients were randomly assigned. With a median follow-up time of 67 months, an intent-to-treat analysis showed no difference between the transplantation arm and the control arm regarding progression-free survival rate (4% v 3%, respectively) and overall survival rate (14% v 13%, respectively) at 5 years.15 A study performed by the National Cancer Institute of Canada randomly assigned 224 patients with metastatic breast cancer who initially responded to conventional chemotherapy to additional chemotherapy or to one cycle of HDT.16 In this trial, a 20% dropout rate for the HDT arm was reported, and the transplantation-related mortality rate was high at 7.7%. In a first intent-to-treat-analysis with a relatively short follow-up time of a median of 19 months, there was a significant difference in favor of transplantation plus HDT compared with standard chemotherapy regarding disease-free survival rate (38% v 24%, respectively; P = .01), but there was no significant difference in the overall survival (P = .9). In the French High-Dose Chemotherapy for Breast Cancer Study Group (PEGASE) 03 trial,22 180 patients with chemotherapy-sensitive metastatic breast cancer were randomly assigned to receive either HDT consisting of thiotepa and cyclophosphamide (n = 89) or observation (n = 91). A relatively low dropout rate of only 10% and a low transplantation-related mortality rate of 1% were reported, and after a median follow-up time of 48 months, a significant difference in disease-free survival was observed in favor of HDT versus observation (27% v 10%, respectively; P = .002), with no difference in overall survival (38% v 30%, respectively; P = .7).22 Another French trial,17 which included 61 responding patients with metastatic breast cancer (PEGASE 04), randomly assigned patients to conventional chemotherapy or one cycle of HDT. Despite the differences between progression-free survival (20 v 45 months for conventional chemotherapy v HDT, respectively) and overall survival (20 v 43 months for conventional chemotherapy v HDT, respectively) at 5 years in favor of the HDT arm, because of the low number of patients, these differences did not reach statistical significance (P = .06 and P = .1, respectively). There have been two trials in patients with metastatic breast cancer conducted by the Duke University group but published so far in abstract form only. In the first trial,18 100 patients with hormone-refractory metastatic breast cancer who achieved complete remission after anthracycline-based induction chemotherapy were randomly assigned to an immediate transplantation according to the Solid Tumor Autologous Marrow Transplant Program I regimen or to observation. In the observation arm, patients were offered HDT at time of relapse. The disease-free survival favored the immediate transplantation (P = .06), whereas overall survival favored the delayed transplantation (P = .032).18 In the second trial from Duke University,23 69 patients with hormone-refractory breast cancer and bone disease only were treated with first-line chemotherapy and either immediate HDT and radiotherapy for all bone metastases or radiotherapy and observation and late transplantation. In this trial, the progression-free survival rate was in favor of immediate transplantation versus late transplantation (17% v 9%, respectively; P = .01), whereas for the overall survival rate, there was no significant difference between early and late transplantation (28% v 22%, respectively).23 In a German trial, two cycles of HDT without induction chemotherapy were compared with conventional treatment with doxorubicin and paclitaxel in 93 patients with untreated metastatic breast cancer.20 After a median follow-up of 22.5 months, there was no difference in the median time to progression between the HDT and conventional chemotherapy arms (11.1 v 10.6 months, respectively; P = .39) and no significant difference in the median overall survival time (26.9 v 23.4 months, respectively; P = .60). Another international randomized breast cancer dose-intensity study21 compared a tandem HDT regimen with eight cycles of anthracycline-based conventional chemotherapy in breast cancer patients who had not experienced progression after three cycles of induction chemotherapy with doxorubicin and docetaxel. The study failed to accrue 264 patients and had to be stopped after 110 patients were accrued, 56 of whom received tandem HDT and 54 of whom received conventional chemotherapy. After a median follow-up time of 42 months, the event-free survival rate was in favor of HDT compared with conventional chemotherapy (29% v 22%, respectively; P = .047), but the overall survival did not significantly differ. Taking together the available results of HDT in metastatic breast cancer, in the majority of the trials, an intensification of the chemotherapy was in favor of HDT with respect to disease-free survival, but none of the studies demonstrated that this benefit could be translated into a benefit in overall survival. The lack of a conventional chemotherapy arm or an observation arm in our study makes a direct comparison between the reported studies and the patients in our study inappropriate, but in line with an improved progression-free survival after one HDT cycle, it might be suggested that second intensification after a first cycle of HDT will result in a further benefit in time to progression. In a multivariate analysis including other risk factors, complete remission after induction chemotherapy was a significant protective factor for progression-free and overall survival. Several studies dealing with prognostic factors for metastatic breast cancer patients undergoing HDT showed that patients who were in complete remission or who had only oligometastatic disease at time of transplantation were likely to achieve long-term remission.24,25 In our study, patients with complete remission after induction chemotherapy had a disease-free survival rate at 5 years of 21% and an overall survival rate at 5 years of 48%. However, because there was no conventional treatment arm in our studies, no conclusion about the value of HDT in those small subgroups of patients can be drawn. We conclude that tandem HDT for patients with metastatic breast cancer who achieved at least partial remission after induction chemotherapy leads to a trend of prolonged time to progression compared with single HDT but also leads to a trend of a shorter overall survival. Therefore, tandem HDT (Solid Tumor Autologous Marrow Transplant Program regimen V) cannot be recommended for chemotherapy-sensitive metastatic breast cancer.
Although all authors completed the disclosure declaration, the following authors or their immediate family members 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. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Dollar Amount Codes (A) $10,000 (B) $10,000-99,999 (C) $100,000 (N/R) Not Required
We thank the staff of the Bone Marrow Transplantation Unit for providing excellent care of our patients and the referring physicians. We thank S. Rodenhuis, MD, PhD, for giving toxicity data of tandem cyclophosphamide, thiotepa, and carboplatin (CTC) and triple-tiny CTC.
Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Clark GM, Sledge GW Jr, Osborne CK, et al: Survival from first recurrence: Relative importance of prognostic factors in 1015 breast cancer patients. J Clin Oncol 5: 55-61, 1987[Abstract] 2. Hortobagyi GN, Frye D, Buzdar AU, et al: Complete remission in metastatic breast cancer: A thirteen year follow-up report. Proc Am Soc Clin Oncol 7: 143, 1988 (abstr) 3. Williams SF, Gilewski T, Mick R, et al: High-dose consolidation therapy with autologous stem-cell rescue in stage IV breast cancer: Follow-up report. J Clin Oncol 10: 1743-1747, 1992 4. Antman K, Ayash L, Elias A, et al: A phase II study of high-dose cyclophosphamide, thiotepa and carboplatin with autologous marrow support in women with measurable advanced breast cancer responding to standard dose therapy. J Clin Oncol 10: 102-110, 1992[Medline] 5. Peters WP: Five year follow-up of high-dose combination alkylating agents with ABMT as consolidation after standard-dose CAF for primary breast cancer involving >10 axillary lymph nodes (Duke/CALBGI 8782). Proc Am Soc Clin Oncol 14: 317, 1995 (abstr 933) 6. Dunphy FR, Spitzer G, Buzdar AU, et al: Treatment of estrogen receptor negative or hormonally refractory breast cancer with double dose chemotherapy intensification and bone marrow support. J Clin Oncol 8: 1207-1216, 1990[Abstract] 7. Broun ER, Sridhara R, Sledge W, et al: Tandem autotransplantation for the treatment of metastatic breast cancer. J Clin Oncol 13: 2050-2055, 1995 8. Bitran J, Samuels B, Klein L, et al: Tandem high-dose chemotherapy supported by hematopoietic progenitor cells yields prolonged survival in stage in stage IV breast cancer. Bone Marrow Transplant 17: 157-162, 1996[Medline] 9. Ayash LJ, Elias A, Schwartz G, et al: Double dose-intensive chemotherapy with autologous stem-cell support for metastatic breast cancer: No improvement in progression-free survival by the sequence of high-dose melphalan followed by cyclophosphamide, thiotepa, and carboplatin. J Clin Oncol 14: 2984-2992, 1996[Abstract] 10. Peto R, Peto J: Asymptotically efficient rank invariation test procedures (with discussion). J R Stat Soc A 135: 185-206, 1972 11. Cox DR: Regression models and life tables. J R Stat Soc B 34: 187-220, 1972 12. Hryniuk W, Levine MN: Analysis of dose intensity for adjuvant chemotherapy trials in stage II breast cancer. J Clin Oncol 4: 1162-1170, 1986 13. Peters WP, Shpall EJ, Jones RB, et al: High-dose combination alkylating agents with bone marrow support as initial treatment for metastatic breast cancer. J Clin Oncol 6: 1368-1376, 1988 14. Kennedy MJ, Beveridge RA, Rowley SD, et al: High-dose chemotherapy with reinfusion of purged autologous bone marrow following dose intense induction as initial therapy for metastatic breast cancer. J Natl Cancer Inst 83: 920-926, 1991 15. Stadtmauer EA, O'Neill L, Goldstein LJ, et al: Conventional-dose chemotherapy compared with high-dose chemotherapy plus autologous hematopoietic stem-cell transplantation for metastatic breast cancer: Philadelphia Bone Marrow Transplant Group. N Engl J Med 342: 1069-1076, 2000 16. Crump M, Gluck S, Stewart D, et al: A randomized trial of high-dose chemotherapy (HDC) with autologous peripheral blood stem cell support (AHPCT) compared to standard chemotherapy in women with metastatic breast cancer: A National Cancer Institute of Canada (NCIC) Clinical Trials Group study. Proc Am Soc Clin Oncol 20: 21a, 2001 (abstr 82) 17. Lotz JP, Curé H, Janvier M, et al: Intensive chemotherapy and autograft of hematopoietic stem cells in the treatment of metastatic cancer: Results of the national protocol PEGASE 04. Hematol Cell Ther 41: 71-74, 1999[CrossRef][Medline] 18. Peters WP, Jones RB, Vredenburgh J, et al: A large, prospective, randomized trial of high-dose combination alkylating agents (CPB) with autologous cellular support (ABMS) as consolidation for patients with metastatic breast cancer achieving complete remission after intensive doxorubicin-based induction therapy (ARM). Proc Am Soc Clin Oncol 15: 121, 1996 (abstr 149) 19. Berry DA, Broadwater G, Klein JP, et al: High-dose versus standard chemotherapy in metastatic breast cancer: Comparison of Cancer and Leukemia Group B trials with data from the Autologous Blood and Marrow Transplant Registry. J Clin Oncol 20: 743-750, 2002 20. Schmid P, Schippinger W, Nitsch T, et al: Up-front tandem high-dose chemotherapy compared with standard chemotherapy with doxorubicin and paclitaxel in metastatic breast cancer: Results of a randomized trial. J Clin Oncol 23: 432-440, 2005 21. Crown J, Perey L, Lind M, et al: Superiority of tandem high-dose chemotherapy (HDC) versus optimized conventionally-dosed chemotherapy (CDC) in patients (pts) with metastatic breast cancer (MBC): The International Randomized Breast Cancer Dose Intensity Study (IBDIS 1). Proc Am Soc Clin Oncol 22: 23, 2003 (abstr 88) 22. Biron P, Durand M, Roché H, et al: High dose thiotepa (TTP), cyclophosphamide (CPM) and stem cell transplantation after 4 FEC 100 compared with 4 FEC alone allowed a better disease free survival but the same overall survival in first line chemotherapy for metastatic breast cancer: Results of the PEGASE 03 French Protocol. Proc Am Soc Clin Oncol 21: 42a, 2002 (abstr 167) 23. Madan B, Broadwater G, Ruin P, et al: Improved survival with consolidation high-dose cyclophosphamide, cisplatin and carmustine (Hd-Cpb) compared with observation in women with metastatic breast cancer (Mbc) and only bone metastases treated with induction Adriamycin, 5-fluorouracil and methotrexate. Proc Am Soc Clin Oncol 19: 48a, 2000 (abstr 184) 24. Nieto Y, Nawaz S, Jones RB, et al: Prognostic model for relapse after high-dose chemotherapy with autologous stem-cell transplantation for stage IV oligometastatic breast cancer. J Clin Oncol 20: 707-718, 2002 25. Rowlings PA, Williams SF, Antman KH, et al: Factors correlated with progression-free survival after high-dose chemotherapy and hematopoietic stem cell transplantation for metastatic breast cancer. JAMA 282: 1335-1343, 1999 Submitted August 30, 2005; accepted June 13, 2006. This article has been cited by other articles:
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
