|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
Originally published as JCO Early Release 10.1200/JCO.2004.07.026 on April 26 2004 © 2004 American Society of Clinical Oncology. High-Dose Chemotherapy With Autologous Hematopoietic Stem-Cell Support Compared With Standard-Dose Chemotherapy in Breast Cancer Patients With 10 or More Positive Lymph Nodes: First Results of a Randomized TrialFrom the Transplant Center, University Hospital Hamburg-Eppendorf; Albertinen-Hospital, Hamburg; Centre for Clinical Studies, University Hospital, Freiburg; University Hospital, Ulm; City Hospital, Oldenburg; Humaine Hospital, Bad Saarow; University Hospital, Münster; University Hospital, Magdeburg; Benjamin Franklin Hospital; University Hospital Charité, Berlin; Medical Hospital, Nürnberg; Hospital of the Saarland, Homburg; Evangelische Diakonissenanstalt, Bremen; University Hospital, Kiel, Germany Address reprint requests to Axel R. Zander, MD, University Hospital Hamburg-Eppendorf, Transplant Center, Bone Marrow Transplantation, Martinistr 52, 20246 Hamburg, Germany; e-mail: zander{at}uke.uni-hamburg.de
PURPOSE: Investigation of high-dose chemotherapy (HD-CT) followed by autologous hematopoietic stem-cell support compared with standard-dose chemotherapy (SD-CT) as adjuvant treatment in patients with primary breast cancer and 10 or more positive axillary lymph nodes. PATIENTS AND METHODS: Between November 1993 and September 2000, 307 patients were randomized to receive (following four cycles of epirubicin 90 mg/m2 and cyclophosphamide 600 mg/m2, intravenously every 21 days) either HD-CT of cyclophosphamide 1,500 mg/m2, thiotepa 150 mg/m2, and mitoxantrone 10 mg/m2, intravenously for 4 consecutive days followed by stem-cell support; or SD-CT in three cycles of cyclophosphamide 500 mg/m2, methotrexate 40 mg/m2, and fluorouracil 600 mg/m2 intravenously on days 1 and 8, every 28 days. The primary end point was event-free survival. RESULTS: After a median follow-up of 3.8 years, 144 events with respect to event-free survival have been observed (HD-CT: 63 events; SD-CT: 81 events). The first event of failure (HD-CT v SD-CT) was an isolated locoregional recurrence (nine v 11), a distant failure (52 v 68), and death without recurrence (two v two). The estimated relative risk of HD-CT versus SD-CT was 0.75 (95% CI, 0.54 to 1.06; P = .095). Overall survival showed no difference (HD-CT: 40 deaths; SD-CT: 49 deaths). CONCLUSION: There was a trend in favor of HD-CT with respect to event-free survival, but without statistical significance. Further follow-up and a meta-analysis of all randomized studies will reveal the effect of HD-CT as compared with SD-CT as adjuvant treatment in high-risk primary breast cancer.
The role of high-dose chemotherapy (HD-CT) in breast cancer is still controversial. The scientific rationale for HD-CT followed by autologous hematopoietic stem-cell rescue for high-risk breast cancer has been discussed in several publications.1-5 Adjuvant chemotherapy has led to improvement in both event-free-survival (EFS) and overall survival (OS) in patients with 10 or more positive lymph nodes. But there is still a high recurrence rate at 5 years and an EFS of less than 50% in most studies.6-14 Several nonrandomized studies demonstrated improved outcomes in patients with primary breast cancer and 10 and more involved axillary lymph nodes after HD-CT.15-19 This led to the opinion that high-dose therapy might be the new standard of care for patients with high risk primary breast cancer. The publication of a small number of randomized studies, that did not show a benefit for the high-dose approach and the case of scientific misconduct, changed the public opinion.20-25 It seems that the initial uncritical believe in HD-CT and the more recent rejection of this modality are equally unreasonable. To obtain a reliable conclusion about the value of HD-CT in breast cancer, it is necessary to bring together the evidence of all randomized trials performed in this field. The optimal high-dose chemotherapy regimen for breast also remains to be defined. Carmustine-based high-dose regimens similar to that used by Peters et al20 are complicated by a high treatment-related mortality due to interstitial pneumonitis and hemolytic uremic syndrome. We had developed an effective alternative HD-CT regimen for breast cancer aiming to reduce the pulmonary toxicity. This regimen, a combination of high-dose cyclophosphamide, thiotepa, and mitoxantrone (CTM), was shown in a pilot study to produce excellent outcomes in stage II and III patients with 10 or more involved axillary lymph nodes.26 The purpose of the present study was the investigation of the therapeutic effect of this HD-CT (CTM) followed by autologous hematopoietic stem-cell support in a randomized trial, compared with standard-dose chemotherapy (SD-CT) as adjuvant treatment in patients with primary breast cancer and 10 and more positive axillary lymph nodes involved.
Study Design In 1993, a prospective randomized multicenter trial was begun in Germany for primary breast cancer patients with 10 or more positive axillary lymph nodes without distant metastases to investigate the effect of HD-CT followed by autologous hematopoietic stem-cell support, as compared with an SD-CT. The principal eligibility criteria were a histologically proven primary breast cancer of stage pT1-3 or pT4b, pN greater than 9, and M0. The primary local treatment was a mastectomy or breast-conserving surgery with axillary dissection, with at least 10 identifiable and involved lymph nodes in the specimen. Patients should not be older than 60 years, and should have a Karnofsky index of at least 70. Patients with heart disease or with reduced lung function had to be excluded. The following ranges for laboratory parameters were required: creatinine 2 mg/dL, bilirubin 2 mg/dL, hemoglobin 10 g/dL, platelets 100,000/L, and neutrophiles 1,800/L. Informed consent had to be obtained from each patient. The study was performed after approval by the local ethical committee. After four cycles of epirubicin 90 mg/m2 plus cyclophosphamide 600 mg/m2 (EC) intravenously (IV) every 21 days, patients received either an HD-CT regimen of CTM (cyclophosphamide 1,500 mg/m2 + thiotepa 150 mg/m2 + mitoxantrone 10 mg/m2, IV on 4 consecutive days) followed by autologous hematopoietic stem-cell support, or SD-CT of three cycles CMF (cyclophosphamide 500 mg/m2 + methotrexate 40 mg/m2 + fluorouracil 600 mg/m2, intravenously on days 1 and 8, every 28 days). Chemotherapy with EC should start within 42 days postsurgery. The application of radiotherapy was not specified in the study protocol before 1998. From 1998 on, it was recommended that radiotherapy be administered following mastectomy, as well as following breast-conserving surgery, and that it should start within 3 to 6 weeks after chemotherapy. In the SD-CT treatment arm, it was also permitted to give radiotherapy between EC and CMF. Recommended dose in the supraclavicular region was 50.4 Gy administered at 5 x 1.8 Gy weekly. Following breast-conserving surgery, an application of 50.4 Gy to the breast and a boost of 9 Gy with electrons to the tumor region was recommended. Following mastectomy, 50.4 Gy to the chest wall were recommended. In the initial study protocol, it was not planned to treat patients with tamoxifen. Because there was increasing evidence for a treatment with tamoxifen in receptor-positive patients, the protocol was amended and we prescribed a treatment with tamoxifen (20 mg daily) for 5 years for patients with positive hormone-receptor status (either estrogen-receptor [ER] or progesterone-receptor [PR]) simultaneously in both treatment arms. The randomization code was produced by the statistical center using a computerized random-number generator. The clinical center was used as a stratification criterion, and within each center block, randomization with varying block size was performed. The randomized treatment was communicated centrally by phone after registration of the patient, guaranteeing concealment of the randomized treatment. Random assignment could be performed at any time after surgery, but should take place before the fourth cycle of EC. Obviously, blinding was not possible, and the statistician was also aware of the treatment. It was planned to randomly assign 320 patients during a recruitment period of 4 years.
Determination of Prognostic Factors
Follow-Up Recurrence was defined as local (operation scar or chest wall), regional (axillary lymph nodes or supraclavicular region), or distant (metastases). Other events considered were second cancer (contralateral or at a distant site) and death without previous recurrence. The first event of failure was classified as isolated locoregional recurrence (appearance of local or regional recurrence at least 4 weeks before the diagnosis of distant failure), as distant failure (distant metastases or second cancer with or without a simultaneous locoregional recurrence), or as death without recurrence. EFS time was defined from primary surgery to the first event of failure or death without recurrence. OS time was defined as time from primary surgery, to patient's death of any cause. For patients who did not experience the event of interest with regard to EFS or OS during follow-up, the time from primary surgery to the last documented follow-up was used as censored observation.
Quality Control
Statistical Methods All data storage and analysis was performed using the Statistical Analysis System.27 All data analysis was carried out according to a prespecified analysis plan. EFS time was defined from primary surgery to the first event of failure (classified as isolated locoregional recurrence [ie, the appearance of local or regional recurrence at least 4 weeks before the diagnosis of distant failure] and as distant failure [ie, distant metastases or second cancer with or without a simultaneous locoregional recurrence]), or death without recurrence. OS time was defined as time from primary surgery to patient's death of any cause. For patients who did not experience the event of interest with regard to EFS or OS during follow-up, the time from primary surgery to the last documented follow-up was used as censored observation. The analysis was performed on an intention-to-treat basis. All analyses including prognostic factors were based on patients for whom all prognostic factors were completely documented. The EFS rates and the OS rates were calculated according to the Kaplan-Meier method, and comparison was made by the log-rank test.28,29 The relative risk between different groups defined by treatment or prognostic factors with corresponding 95% CI were determined by the Cox regression model.30 For a simultaneous assessment of the effects of treatment and prognostic factors, the classification of prognostic factors was predefined independently of study result. It was chosen as in previous studies.31 Interactions between treatment and the factors menopausal status, tumor grade, and ER status were investigated. This was done using a separate Cox regression model for each of these factors, including the three previously mentioned factors, and, additionally, for adjustment of those prognostic factors showing an effect in the multiple regression analysis at the 15% level. For the investigation of a possible interaction, the models included separate treatment effects for both values of the factor of interest, respectively. The interaction was tested by a Wald test of equality of the treatment effects in the resulting groups. Because of multiple testing, a significance level of 1% was used for these tests. Additionally, the corresponding multiplicative interactive effects were estimated with 99% CIs. For a quantification of treatment effects in the subgroups defined by each of the factors, the relative risks between the treatment groups were estimated with 99% CIs.
One interim analysis with regard to the primary outcome EFS had been performed after the observation of 43 events with significance level
Patient Recruitment Between November 1993 and September 2000, 307 patients were randomly assigned from 36 centers; 152 patients were randomly assigned to the HD-CT arm, and 155 patients were randomly assigned to the SD-CT arm; and 197 of these patients were randomly assigned from six larger centers randomly assigning more than 20 patients each. The remaining 110 patients were randomly assigned from 30 centers. Random assignment was stopped in September 2000 because of low recruitment. As shown in Figure 1, three centers with a total of five randomly assigned patients had to be excluded because of lack of cooperation of the patients after random assignment. Thus, all analyses are restricted to 302 randomized patients who had been entered from 33 institutions (SD-CT: 152 patients; HD-CT: 150 patients; Fig 1).
Entry criteria of the trial were violated as follows: metastases at randomization (one patient in treatment arm SD-CT and one patient in treatment arm HD-CT), history of cancer before breast cancer (one SD-CT), inflammatory breast cancer (one SD-CT), incomplete resection (two SD-CT, one HD-CT), laboratory parameters out of required range (one SD-CT), no EC (one SD-CT, two HD-CT), EC later than 42 days postsurgery (six SD-CT, one HD-CT), and randomization after fourth cycle EC (one SD-CT). At least one of the criteria were violated for 13 patients in treatment arm SD-CT, and for five patients in treatment arm HD-CT. None of these patients were excluded from the analyses.
Compliance
Study Population
Follow-Up and Observed Events Patients were followed up until April 2002, leading to a median follow-up time of approximately 3.8 years (SD-CT: 3.9 years; HD-CT: 3.8 years). Completeness of follow-up is displayed in Figure 1. One hundred forty-four events occurred with respect to the end point EFS. Table 2 presents the distribution of the patients to the different types of event of failure. Twenty patients experienced an isolated locoregional recurrence as first event of failure (HD-CT: nine patients v SD-CT: 11 patients), 120 patients had distant failure with or without simultaneous local failure as first event (52 v 68 patients), and four patients died without previous event (two v two); data are provided in Table 2.
Unadjusted Comparison of the Treatment Arms With Regard to EFS With respect to the end point EFS, 81 events occurred in treatment arm SD-CT, and 63 events occurred in treatment arm HD-CT. The relative risk of HD-CT versus SD-CT is estimated as 0.75 (CI, 0.54 to 1.06, calculated with level 95.32% due to adjustment for sequential test procedure with one interim analysis). This effect is not significant (P = .095). The corresponding EFS rates are displayed in Figure 2. There seems to be a slight superiority of HD-CT as compared with SD-CT emerging 2 years after primary surgery. Estimated EFS rate after 4 years is 42% (95% CI, 32% to 51%) in treatment arm SD-CT, and 52% (95% CI, 43% to 61%) in treatment arm HD-CT. As mentioned before, this difference is not significant (Fig 2).
Inclusion of Prognostic Factors In univariate analyses of the effects of prognostic factors on EFS the factors tumor size, tumor grade, and ER status showed an effect on EFS which was significant at the 5% level (results not shown in detail). Table 3 presents the results of the multivariate analysis of treatment and prognostic factors on EFS. In this analysis, the treatment effect is adjusted for the prognostic factors number of positive lymph nodes, degree of lymph node involvement, tumor grade, ER and PR status (prespecified because of results in31), and tumor size, because of its effect in the univariate analysis (Table 3).
In this adjusted analysis, we could demonstrate no significant effect of HD-CT (as compared with SD-CT) on EFS. The relative risk estimate is of similar magnitude as in the unadjusted analysis. The factors tumor size, tumor grade, and ER status show an effect on EFS also in the multivariate analysis, where the effects of the prognostic factors are analyzed simultaneously.
Analysis of Heterogeneous Treatment Effects in Prognostic Subgroups: Interactions
The trend to a superiority of HD-CT as compared with SD-CT with respect to EFS seems to be more pronounced in premenopausal patients as compared with postmenopausal patients, and in patients with grade 3 tumor as compared with patients with grade 1/2 tumor. As mentioned before, these differences are not significant.
OS
Toxicity and Adverse Events The analysis of toxicity after HD-CT is based on 124 patients who definitely received HD-CT (Fig 1). The median time from transplantation to engraftment of leukocytes with a value greater than 1.0/nL, was 10 days (range, 7 to 30 days; information missing for three patients). The median time to engraftment of platelets with a value greater than 20/nL, was 9 days (range, 5 to 48 days, information missing for seven patients). One hundred eight (87%) of the patients developed an episode of fever during the aplastic period following transplantation. In 27 patients (22%), an infection was diagnosed. Toxicity in different organ systems following HD-CT was recorded according to Bearman et al.32 The toxicity observed is displayed in Table 5. For 10 patients (8%), a toxicity of grade 3 or 4 was reported.
Serious adverse events probably related to treatment were reported for five patients following HD-CT. For three patients, they resulted in death. The events were respiratory insufficiency with hemorrhagic alveolitis 3 weeks after HD-CT (patient with reported grade 4 toxicity of the lung; Table 5), dilative cardiomyopathy 19 weeks after HD-CT, and possibly antracycline-induced AML 19 weeks after HD-CT. For one patient experiencing a respiratory insufficiency with pneumonia 2 weeks after HD-CT, the event was classified as life-threatening. For another patient, non–life-threatening thrombocytopenia and leukopenia were reported 16 weeks after HD-CT. In the treatment arm SD-CT, toxicity was not registered in a comprehensive manner. Investigators were asked for side effects of CMF being unexpected and of grade 3 or higher. For nine patients (7%), a total of 10 of those adverse effects were reported (leucopenia in two, thrombosis in two, influenzal symptoms in two, allergic reaction to fluorouracil in one, alopecia in one, vomiting/nausea in one, and mucositis in one).
This randomized study comparing high-dose mitoxantrone-containing chemotherapy with a standard chemotherapy showed a trend toward a better EFS in those patients who were treated with HD-CT. Reported toxicity in treatment arm HD-CT may not be compared directly with reported toxicity in treatment arm SD-CT, since toxicity was registered in a comprehensive manner only in the HD-CT arm. Despite the fact that there was some toxicity in the HD-CT arm, especially due to mucositis of the oral cavity and the gastrointestinal tract that required IV morphine and hyperalimentation in almost all patients, the treatment-related mortality is acceptable with only 2%. This low treatment-related mortality is in accordance with other trials in HD-CT of breast cancer,17,21-23,26,33 except for the large American Intergroup Cancer and Leukemia Group B 9082 trial, which reported an unacceptable treatment related mortality of 7% in the HD-CT arm.20 In this large study with 785 patients enrolled, the lower relapse rate of the HD-CT arm (32.2% v 42.7%), representing a 31% relative reduction in relapse was offset by the high transplant-related mortality. Compared with all published data, the result of the high-dose and of the intermediate dose are both strikingly better than all other published studies. It is conceivable that the intermediate dose cyclophosphamide, cisplatin, and carmustine has an effect superior to standard chemotherapy. In our study, after the relative short follow-up of 3.8 years, 81 events were observed in the SD-CT arm, and 63 in the HD-CT arm, that showed a relative risk reduction of 25% (95% CI, 6% to 46%). This difference did not lead to a statistically significant difference in EFS (P = .09). The observed slight imbalance between treatment arms with regard to the number of involved lymph nodes, tumor size, and tumor grade did not lead to a general tendency for treatment arm SD-CT to have more or less favorable prognosis than treatment arm HD-CT. It also had no influence on the observed treatment effect. This is reflected by the almost identical distribution of the NPI in both treatment groups, and by the fact that the treatment effects estimated in the univariate analysis, where the treatment effect is adjusted for these factors, are almost identical. Also with regard to the application of adjuvant radiotherapy and adjuvant hormonal treatment with tamoxifen, the randomized groups are well balanced and the study result is not compromised by possible effects of radiotherapy or tamoxifen on prognosis. In an Italian study including 382 patients with four or more involved lymph nodes, HD-CT resulted in a marginal difference of the 5-year EFS rate (65% v 62%). In this study, the median follow-up was only 52 months.34 The Anglo-Celtic trial randomized 605 patients with four or more positive lymph nodes, and found after a median follow-up of 4 years, no difference between the HD-CT arm and the control arms in terms of EFS (51% v 54%; P = .6).35 However, there were also prospective randomized studies, in favor of HD-CT. The French Pegase-01 study included 314 patients with more than seven involved lymph nodes. They reported a significant difference in the 3-year EFS for HD-CT compared with conventional therapy (71% v 55%; P = .02), but no difference with respect to OS could be observed.36 Furthermore, the planned subset analysis of the large national Dutch study, which includes the first 284 enrolled patients, was performed after a median follow-up of 4.5 years. They found a statistical significance for EFS in favor of HD-CT in both the "5-9" and the "more than 10" positive lymph nodes categories (77% v 62%; P = .09).33,37 After the first analysis of our study, we cannot exclude the fact that with longer follow-up of our study, a more pronounced difference in terms of event-free survival will emerge between HD-CT and SD-CT. The estimated relative risk reduction of 25% is in accordance with the 20% to 30% relative decrease in relapse reported by the Oxford meta-anaylsis for adjuvant systemic treatment in breast cancer.37 Therefore this reduction could be clinically important. The unrealistically high expectations of HD-CT in breast cancer may have led to a too small sample size calculation on the one hand, and to problems in patient recruitment otherwise. With 144 observed events, the power of our study is rather low, which is reflected by the large CI of 0.54 to 1.06 for the relative risk of HD-CT versus SD-CT with respect to EFS. The study was planned to be analyzed after observation of 183 events, ensuring a power of 80% for a relative risk of 0.66. The analysis had to be based on fewer events, because recruitment of the study was low. The absence of a statistically significant treatment effect in our study may therefore not be interpreted as the absence of a clinically significant treatment effect in reality. The Scandinavian Breast Cancer Study, which randomized 525 patients with high-risk breast cancer following induction treatment of three times fluorouracil + epiribicin + cyclophosphamide, to either six cycles of individually dose-escalated fluorouracil + epiribicin + cyclophosphamide, or simple HD-CT of the Solid Tumor Autologous Marrow Transplant Program V regimen, cannot be used as an argument against the HD-CT approach because the total therapy given in the HD-CT arm was significantly less than the total therapy of the control arm.38,39 The second important point before drawing conclusions about the value of HD-CT is the length of follow-up. The median follow-up of 3.8 years in our study is too short to draw definite conclusions from this randomized trial. For the randomized trial in high-grade non-Hodgkin's lymphomas, only a longer follow-up showed a statistical significant difference in disease-free survival.40 The same was true for the randomized trial of autologous transplantation in multiple myeloma in which the curves did not start to separate until 3 years of minimum follow-up.41 The importance of longer follow-up is once more emphasized by the subset analyses of the Dutch study in which a significant difference in disease-free survival was seen in the first 284 randomized patients with the longest follow-up. The complete study of 885 randomized patients revealed a 5-year relapse-free survival of 59% in the conventional dose group, and 65% in the HD-CT group. The HD-CT alkylating therapy seem to be more effective in stage II and III in breast cancer patients with 10 or more positive axillary lymph nodes.42 Another randomized study comparing adjuvant cyclophosphamide + adriamycin + fluorouracil chemotherapy with and without high-dose chemotherapy and autologous stem cell transplantation in high risk patients showed that the time to recurrence was longer for patients who underwent stem cell transplantation than for those who received cyclophosphamide + adriamycin + fluorouracil alone without significant difference in disease-free survival.43 This study was criticized for not optimizing the HD-CT arm.44 A third point which has to be taken into account when interpreting high-dose chemotherapy in breast cancer is the possibility, that the benefit is restricted to prognostic subgroups of patients, resulting in a small observed difference for the whole study group. In our study, there was a trend to an improved event-free survival for the premenopausal patients who underwent high-dose chemotherapy as compared to standard therapy, but this effect was not significant. The same trend of the younger patients to have a better event-free survival after high-dose chemotherapy was also observed in the Cancer and Leukemia Group B and the Italian study.20,41,43 Another group of patients, which might benefit more from high-dose chemotherapy, could be the patients with higher grade tumors, which showed a trend for a better event-free survival after high-dose chemotherapy in our study. Also biologic factors like the HER2/neu-expression on breast cancer cells might have an impact on the outcome of the HDCT. In conclusion, our data showed a trend to a better event-free survival in patients with primary breast cancer and more than nine involved lymph nodes treated with high-dose mitoxantrone-containing chemotherapy in comparison to standard chemotherapy. This effect was more pronounced in premenopausal patients and in patients with high-grade tumors. A longer follow-up is necessary to come to a reliable assessment of the value of high-dose chemotherapy. For an evaluation of subgroups of patients who might benefit most from high-dose chemotherapy a meta-analysis based on the individual patient data of all randomized studies is required.
Participating Centers: Universitätsklinikum Hamburg-Eppendorf, Hamburg; Universitätsklinikum, Ulm; Städtische Kliniken, Oldenburg; Klinikum Benjamin Franklin, Berlin; Humaine Klinikum, Bad Saarow; Klinikum der Charité, Berlin; Klinikum 5. Medizinische Klinik, Nürnberg; Universitätskliniken des Saarlandes, Homburg; Universitätsklinikum, Kiel; Evangelische Diakonissenanstalt, Bremen; Klinikum der Otto-von-Guericke-Universität, Magdeburg; Universitätsklinikum, Mainz; Universitätsklinikum, Münster; Medizinische Universität, Lübeck; Zentralkrankenhaus, Bremen; Klinikum der Universität, Rostock; Städtische Kliniken, Kassel; Krankenhaus; Kaiserslautern; Stiftung Deutsche Klinik für Diagnostik GmbH, Wiesbaden; Krankenhaus Neukoelln, Berlin; Franziskus Hospital, Bielefeldt; Klinikum rechts der Isar, München; Städtische Krankenanstalt, Idar-Oberstein; St. Josefs-Hospital, Cloppenburg; Onkologische Praxis Prof. Dr Kleeberg, Hamburg; Universitätsklinikum, Dresden; Klinikum Chemnitz gGmbH, Chemnitz; Klinikum der Philipps-Universität, Marburg; Dr Horst-Schmidt-Klinikum, Wiesbaden; Kantonspital, Basel; Klinikum Ernst von Bergmann, Potsdam; Campus Virchow-Klinikum, Berlin; Klinikum der Universität, Göttingen; Städtisches Krankenhaus Süd, Lübeck; Klinikum der J.W. von Goethe Universität, Frankfurt/Main.
The authors indicated no potential conflicts of interest.
We thank Dr Franke, Magdeburg; Dr Pflüger, Bremen, and Dr Hossfeld, Hamburg for their contribution of patients and their discussion of the data.
Supported by the Dr Mildred Scheel Stiftung der Deutschen Krebshilfe, by the Hamburger Krebsgesellschaft, and by the Erich and Gertrud Roggenbuck Foundation. Authors' disclosures of potential conflicts of interest are found at the end of this article.
1. Peters WP: The rationale for high-dose chemotherapy with autologous bone marrow support in treating breast cancer, in Dicke K, Spitzer G, Zander A (eds): Autologous Bone Marrow Transplantation. Proceedings on the First International Symposium. Houston, TX, AM Anderson Cancer Center Press, 1985, pp 189-196 2. Frei E III, Antman K, Teicher B, et al: Bone marrow autotransplantation for solid tumors: Prospects. J Clin Oncol 7:515-526, 1989[Abstract] 3. Antman K, Bearman SI, Davidson N, et al: Doise intensive strategy in breast cancer: Current status, in Champlin RE, Gale RP (eds): New Strategies in Bone Marrow Transplantation. New York, NY, Allen R. Liss, 1991, pp 423-436
4. Hryniuk W, Levine MN: Analysis of dose intensity for adjuvant chemotherapy trials in stage II breast cancer. J Clin Oncol 4:1162-1170, 1986 5. Hryniuk W, Bush H: The importance of dose intensity in chemotherapy of metastatic breast cancer. J Clin Oncol 2:1281-1288, 1986 6. Jones SE, Moon TE, Bonadonna G, et al: Comparison of different trials of adjuvant chemotherapy in stage II breast cancer using a natural history data base. Am J Clin Oncol 10:387-395, 1987[Medline] 7. Moon TE, Jones SE, Bonadonna G, et al: Development and use of a natural history data base of breast cancer studies. Am J Clin Oncol 10:396-403, 1987[Medline]
8. Abeloff MD, Beveridge RA, Donehower RC, et al: Sixteen-week dose-intense chemotherapy in the adjuvant treatment of breast cancer. J Natl Cancer Inst 82:570-574, 1990
9. Davidson NE, Abeloff MD: Adjuvant systemic therapy in women with early-stage breast cancer at high risk for relapse. J Natl Cancer Inst 84:301-305, 1992 10. Kaufmann M, Jonat W, Caffier H, et al: Adjuvant systemic risk adapted cytotoxic ± tamoxifen therapy in women with node positive breast cancer, in Salmon S (ed): Adjuvant Therapy of Cancer. Orlando, FL, V. Grune and Stratton, 1987, pp 337-346 11. Clark GM, McGuire WL: New biologic prognostic factors in breast cancer. Oncology 3:49-54, 1989 12. Buzzoni R, Bonadonna G, Valagussa P, et al: Adjuvant chemotherapy with doxorubicin plus cyclophosphamide, methotrexate and fluorouracil in the treatment of resectable breast cancer with more than three positive axillary nodes. J Clin Oncol 9:2134-2140, 1991[Abstract] 13. Bonadonna G, Zambetti M, Valagussa P: Sequential or alternating doxorubicin and CMF regimes in breast cancer with more than three positive nodes: Ten years results. JAMA 273:542-547, 1995[Abstract] 14. Buzdar AV, Kau S-W, Hortobagyi GN, et al: Clinical course of patients with breast cancer with ten or more positive nodes who were treated with doxorubicin-containing adjuvant therapy. Cancer 69:448-452, 1992[CrossRef][Medline]
15. Peters WP, Ross M, Vredenburgh JJ, et al: High-dose chemotherapy and autologous bone marrow support as consolidation after standard-dose adjuvant therapy for high-risk primary breast cancer. J Clin Oncol 11:1132-1143, 1993 16. Peters WP, Berry D, Vredenburgh JJ, et al: Five year follow-up of high-dose combination alkalyting agents with ABMT as consolidation after standard-dose CAF for primary breast cancer involving 10 axillary lymph nodes (Duke/CALGB 8782). Proc Am Soc Clin Oncol 14:317, 1995 (abstr 933)
17. Gianni AM, Siena S, Bregni M, et al: Efficiacy, toxicity and applicability of high-dose sequential chemotherapy as adjuvant treatment in operable breast cancer with 10 or more involved axillary lymph nodes: Five-year results. J Clin Oncol 15:2312-2321, 1997
18. Eddy D: High-dose chemotherapy with autologous bone marrow transplantation for the treatment of metastatic breast cancer. J Clin Oncol 10:657-670, 1992
19. Gradishar WJ, Tallman MS, Abrams JS: High-dose chemotherapy for breast cancer. Ann Intern Med 125:599-604, 1996 20. Peters WP, Rosner G, Vredenburgh J, et al: A prospective, randomized comparison of two doses of combination alkalyting agents (AA) as consolidation after CAF in high-risk primary breast cancer involving ten or more axillary lymph nodes (LN): Preliminary results of CALGB 9082/SWOG 9114/NCIC MA-13. Proc Am Soc Clin Oncol 18:1a, 1999 (abstr 3) 21. Rodenhuis S, Richel DJ, van der Wall E, et al: A randomized trial of high-dose chemotherapy and hematopoietic progenitor cell support in operable breast cancer with extensive axillary lymph node involvement. Lancet 352:515-521, 1998[CrossRef][Medline]
22. 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 23. The Scandinavian Breast Cancer Study 9401. Results from a randomized adjuvant breast cancer study with high dose chemotherapy with CTCb supported by autologous bone marrow stem cells versus dose escalated and tailored FEC therapy. Proc Am Soc Clin Oncol 18:2a, 1999 (abstr 6) 24. Bezwoda WR. Randomized, controlled trial of high-dose chemotherapy (HD-CNVp) vs. standard dose (CAF) chemotherapy for high risk, surgically treated, primary breast cancer. Proc Am Soc Clin Oncol 18:2a, 1999 (abstr 8) 25. Bezwoda WR, Seymour L, Dansey RD: High-dose chemotherapy with hematopoietic rescue as primary treatment for metastatic breast cancer: A randomized trial. J Clin Oncol 13:2483-2489, 1995[Abstract] 26. Damon LE, Wolf JL, Rugo HS, et al: High-dose chemotherapy (CTM) for breast cancer. Bone Marrow Transplant 26:257-268, 2000[CrossRef][Medline] 27. SAS Institute Inc: SAS Language, Version 6. Cary, NC, 1990 28. Kalbfleisch JD, Prentice RL: The Statistical Analysis of Failure Time Data. New York, NY Wiley, 1980 29. Kaplan EL, Meier P: Nonparametric estimation from incomplete observation. J Am Stat Assoc 53:457-481, 1958[CrossRef] 30. Cox DR: Regression models and life table (with discussion). J R Stat Soc B 34:187-220, 1972 31. Schmoor C, Sauerbrei W, Bastert G, et al: Long term prognosis of breast cancer patients with 10 or more positive lymph nodes treated with CMF. Eur J Cancer 37:1123-1131, 2001
32. Bearman SI, Appelbaum FR, Buckner CD, et al: Regimen-related toxicity in patients undergoing bone marrow transplantation. J Clin Oncol 6:1562-1568, 1988
33. Rodenhuis S: The status of high-dose chemotherapy in breast cancer. Oncologist 5:369-375, 2000 34. 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 lymph nodes. Proc Am Soc Clin Oncol 20:80, 2001 35. 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 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) 36. Roche H, Pouillard P, Meyer N, et al: Adjuvant high-dose improves early outcome for high-risk (N>7) breast cancer patients: The Pegase-01 trial. Proc Am Soc Clin Oncol 20:25a, 2000 (abstr 102) 37. Rodenhuis S, Bontenbal M, Beex L, 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. Proc Am Soc Clin Oncol 19:71a, 2002 (abstr 286) 38. Peto R, Boreham J, Clarke M, et al: UK and USA breast cancer deaths down 25% in year 2000 at ages 20-69 years. Lancet 355:18-22, 2000[CrossRef] 39. 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 Cancer Group 9401 study. Lancet 356:1384-1391, 2000[CrossRef][Medline]
40. Philip T, Guglielmi C, Hagenbeek A, et al: Autologous bone marrow transplantation as compared with salvage chemotherapy in relapses of chemotherapy-sensitive non-Hodgkin's lymphoma. N Engl J Med 333:1540-1545, 1995
41. Attal M, Harousseau JL, Stoppa AM, et al: A prospective, randomised trail of autologous bone marrow transplantation and chemotherapy in multiple myeloma. Intergroupe Francais du My élome. N Engl J Med335:91-97, 1996
42. Rodenhuis S, Bontenbal M, Beex LV, et al: High-dose chemotherapy with hematopoietic stem-cell rescue for high-risk breast cancer: Netherlands Working Party on Autologous Transplantation Solid Tumors. N Engl J Med 349:7-16, 2003
43. 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 44. Elfenbein GF: Stem-Cell Transplantation for high-risk breast cancer. N Engl J Med 3:80-82, 2000 Submitted July 7, 2003; accepted February 9, 2004. Related Editorial
This article has been cited by other articles:
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
TOP
ABSTRACT
INTRODUCTION
= 5%, which would require the observation of 183 events. Assuming a recruitment period of about 4 years and an additional follow-up period of about 2 years, 320 patients had to be randomized. 
