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Journal of Clinical Oncology, Vol 22, No 11 (June 1), 2004: pp. 2061-2068 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.08.048 Failure of Higher-Dose Paclitaxel to Improve Outcome in Patients With Metastatic Breast Cancer: Cancer and Leukemia Group B Trial 9342From Dana-Farber/Partners Cancer Care, Boston, MA; State University of New York Upstate Medical University, Syracuse; Mount Sinai School of Medicine; Weill Medical College of Cornell University; Memorial Sloan-Kettering Cancer Center, New York, NY; University of Chicago Medical Center, Chicago, IL; University of Missouri/Ellis Fischel Cancer Center, Columbia, MO; Cancer and Leukemia Group B Statistical Center; Duke University Medical Center, Durham; University of North Carolina at Chapel Hill, Chapel Hill; Wake Forest University School of Medicine, Winston-Salem, NC; University of California San Francisco Cancer Center, San Francisco, CA; and Vermont Cancer Center, Burlington, VT. Address reprint requests to Eric Winer, MD, Dana-Farber Cancer Institute, 44 Binney St, D1210, Boston, MA 02115; e-mail: ewiner{at}partners.org
PURPOSE: Cancer and Leukemia Group B Protocol 9342 was initiated to determine the optimal dose of paclitaxel administered as a 3-hour infusion every 3 weeks to women with metastatic breast cancer. PATIENTS AND METHODS: Four hundred seventy-four women with metastatic breast cancer who had received one or no prior chemotherapy regimens were randomly assigned to one of three paclitaxel dosing regimens—175 mg/m2, 210 mg/m2, or 250 mg/m2—each administered as a 3-hour infusion every 3 weeks. Women completed self-administered quality of life and symptom assessment questionnaires at baseline and after three cycles of treatment. RESULTS: No evidence of a significant dose-response relationship was demonstrated over the dose range assessed. Response rates were 23%, 26%, and 21% for the three regimens, respectively. A marginally significant association (P = .04) was seen between dose and time to progression; however, in a multivariate analysis, the difference was even less apparent. No statistically significant difference was seen in survival. Neurotoxicity and hematologic toxicity were more severe on the higher dose arms. There was no significant difference in quality of life on the three arms. CONCLUSION: Higher doses of paclitaxel administered as a 3-hour infusion to women with metastatic breast cancer did not improve response rate, survival, or quality of life. There was a slight improvement in time to progression with higher dose therapy, which was offset by greater toxicity. When a 3-hour infusion of paclitaxel is administered every 3 weeks, 175 mg/m2 should be considered the optimal dose.
The taxanes—paclitaxel and docetaxel—are among the most active and widely used cytotoxic agents in the treatment of breast cancer. The US Food and Drug Administration's initial approval of paclitaxel for patients with metastatic breast cancer was based on promising activity in phase II studies.1,2 In the initial trials, paclitaxel was administered as a 24-hour infusion every 3 weeks at doses of 200 to 250 mg/m2. Subsequent phase II studies confirmed the safety and activity of paclitaxel when administered as a 3-hour infusion. A number of studies have compared different doses and schedules of paclitaxel. Among these studies, the National Surgical Adjuvant Breast and Bowel Project, comparing a 24-hour infusion of paclitaxel at 250 mg/m2 every 3 weeks to a 3-hour infusion of the same dose,3 showed a higher response rate on the 24-hour infusion arm but no significant difference in time to progression or survival between the two arms. Infusions even longer than 24 hours have been evaluated but have failed to improve overall results.4 Another area of interest has been the weekly administration of paclitaxel.5-7 Studies have shown that the weekly administration of paclitaxel is also active, with less hematologic toxicity. A multicenter, randomized trial demonstrated that a dose of 175 mg/m2 of paclitaxel administered over 3 hours every 3 weeks resulted in a longer time to progression than did 135 mg/m2 using the same infusion duration and treatment interval.8 Based on the results of this trial, the 175 mg/m2 dose administered every 3 weeks became the standard of care in the United States in the mid-1990s. The present study was designed to determine if doses in excess of the standard 175 mg/m2 dose would provide an advantage for women with metastatic breast cancer. In addition to comparing the standard 175 mg/m2 with the highest feasible dose (250 mg/m2), an intermediate dose of 210 mg/m2 was added to allow for assessment of a dose response across the range.
Patient Selection and Eligibility Women with histologically documented stage IV or inoperable breast cancer who had measurable disease, an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2, and a life expectancy of at least 12 weeks were eligible. When the study opened in January 1994, patients were required to have received prior chemotherapy in the metastatic setting or to have developed disease progression within 12 months of adjuvant chemotherapy. In August 1996, the study was amended to allow enrollment of patients who did not have progression within 12 months of adjuvant therapy and who had not received prior chemotherapy in the metastatic setting (first-line). Patients were required to be age 18 years or older, not pregnant, and at least 4 weeks out from the last dose of chemotherapy. Women could not have a previous malignancy (except for cervical carcinoma-in-situ) or a serious medical or psychiatric illness. Patients with CNS metastases were excluded unless previously treated and asymptomatic from a neurologic standpoint. Patients were not allowed to receive concurrent hormonal therapy. Additional eligibility criteria included adequate hematologic function as defined by granulocyte count > 1,500 cells/µL, platelet count > 100K cells/µL, normal renal function, AST less than two times normal, and normal bilirubin. All patients signed an informed consent approved by the institutional review board.
Drug and Dose Schedule
Patient Evaluation
Quality of Life Assessment
Statistical Analysis Survival was calculated as the time from study entry to date last known alive or to date of death. Time to progression was measured from study entry to first date of progression or to date of death. Patients who were alive and without progression were censored at the date they were last known to be progression-free. Univariate and multivariate Cox proportional hazards regression was used to compare dose and other covariates to survival and time to progression. Survival curves for response duration, overall survival, and time to progression were calculated using the Kaplan-Meier method.
Treatment-related toxicities were tabulated by type and grade according to the National Cancer Institute Common Toxicity Criteria. Toxicities of uncertain cause were assumed to be treatment-related. Mantel Haenszel The FLIC total score was computed by adding the 22 individual scores from the FLIC questionnaire. FLIC total scores were pro-rated for those who answered between 18 and 21 questions and set to missing for those who answered fewer than 18 questions. The SDS total score was computed by adding the 13 individual scores from the SDS questionnaire. Scores were pro-rated for those who answered between 10 and 12 questions. All patients who completed a baseline questionnaire were included in analyses of baseline data. Change in scores is defined as the change from baseline to follow-up and was calculated only for those who completed both questionnaires. Analysis of Variance was used to compare mean baseline, follow-up, and change in scores among the three treatment arms. Quality of life scores were analyzed as a continuous variable and were not categorized. Multivariate Cox proportional hazards regression was used to determine if the FLIC or SDS scores were correlated with survival or time to progression above and beyond the factors found significant in the primary survival analyses.
Patient Characteristics Four hundred seventy-four women were enrolled onto the protocol. One hundred sixteen patients had not previously received prior treatment in the metastatic setting, and 358 had received one prior regimen in the metastatic setting or had developed recurrent disease within 12 months of completing adjuvant therapy (second-line). Five patients never received treatment as part of the study and have been excluded from the analysis. Median follow-up for the entire study population is 5.2 years. One hundred fifty-eight patients were randomly assigned to 175 mg/m2; 156 patients were assigned 210 mg/m2, and 155 to 250 mg/m2. Randomization was similarly balanced for first- and second-line patients. Baseline demographic characteristics were well balanced across the three treatment arms (Table 1). Visceral disease was present in 66%, 76%, and 70% in the 175 mg/m2, 210 mg/m2, and 250 mg/m2 treatment arms, respectively. Time elapsed from original diagnosis to study entry was similar across the three arms and ranged from 34.6 to 40.8 months across the three arms (P = .37).
Response Rates There was no statistically significant difference in response rates across the three arms (Table 2), nor was the dose-response statistically significant. The response rate was 23% (95% CI, 15% to 31%) on the 175 mg/m2 arm, 26% (95% CI, 18% to 34%) on the 210 mg/m2 arm, and 21% (95% CI, 14% to 29%) on the 250 mg/m2 arm. Similarly, there was no difference across the treatment arms in the proportion of patients who achieved a complete response. A multivariate logistic regression analysis which included hormone receptor status, line of treatment, number of metastatic sites, prior adjuvant therapy, prior radiation, performance status, and treatment arm did not identify any factors that were significantly associated with clinical response. The estimated slope of response due to unit change in dose (in the logic scale) is –0.004, and its standard error is 0.004. Therefore, the estimate is nearly constant in dose and not statistically significantly different from 0. Response rates for patients with hormone receptor negative tumors (n = 153) by increasing dose were 21% (95% CI, 9% to 32%), 30% (95% CI, 18% to 42%), and 24% (95% CI, 12% to 37%). These rates are similar to response rates for all treated patients on the study.
Time to Progression In a univariate analysis, there was a marginally significant association between dosage and time to progression. Median time to progression was 3.9 months on 175 mg/m2, 4.1 months on 210 mg/m2, and 4.9 months on 250 mg/m2 (P = .045; Fig 1). In a multivariate analysis including dosage and covariates including estrogen-receptor (ER) status, line of therapy, number of metastatic sites, performance status, and prior treatment, a comparison across the three arms was no longer significantly associated with time to progression (P = .12).
Survival At the time of analysis, fewer than 10% of patients enrolled in the trial were still alive. Median survival was 11, 12, and 14 months on the 175 mg/m2, 210 mg/m2, and 250 mg/m2 arms, respectively (Fig 2). In a multivariate analysis, ER positivity (P = .0001), fewer metastatic sites (P = .023), and performance status of 0 versus 1 (P = .0001) were associated with longer survival. Dose did not have a significant (P = .30) impact on overall survival.
Toxicity From Treatment The study showed greater toxicity with increasing doses of paclitaxel. Table 3 details the worst toxicity across all treatment cycles seen for each patient. As noted in Table 3, the most common toxicities included neutropenia, neuropathy, and alopecia. Grade 4 neutropenia was seen in 34%, 44%, and 53% of patients on the three arms and increased in frequency stepwise with increasing doses of paclitaxel. The linear relationship between grade of neutropenia and treatment arm was highly significant (P = .0058). Of note, a total of 29 patients received G-CSF—10 patients on the 175 mg/m2 arm, six on the 210 mg/m2 arm, and 13 patients on the 250 mg/m2 arm. The higher incidence of neutropenia did not appear to result in a higher incidence of severe infection. Approximately one third of the patients on the highest-dose arm experienced grade 3 sensory neuropathy during their treatment course, in comparison to 19% and 7% on the 210 mg/m2 and 175 mg/m2 arms, respectively (P = .0001). There were two treatment-related deaths of patients on study, both of which were attributed to infection. One death occurred on the 175 mg/m2 arm; the other occurred on the 250 mg/m2 arm.
Quality of Life A total of 451 patients completed the baseline quality of life assessment. Follow-up data at 3 months were available on 302 patients (67%). As seen in Table 4, there were no baseline differences across the three arms in the FLIC total score, the FLIC subscales, or the SDS total score. Over time, total FLIC scores remained stable. There were no significant differences between the three arms in terms of change from baseline score to follow-up on the total score, emotional subscore, social subscore, or family subscore. In contrast, the physical functioning subscore remained stable from baseline to follow-up on the 175 mg/m2 arm, but fell (indicating a decline in physical function) on the other two arms (P = .04). Scores on the SDS were similar across the three arms at both baseline and follow-up.
Quality of Life As Predictor of Response and Survival Baseline and follow-up quality of life scores were not predictive of clinical response. However, a multivariate model that controlled for number of metastatic sites, performance status, and ER status, demonstrated a highly significant relationship between both baseline (Fig 3) and follow-up FLIC scores and survival (Fig 3). Scores on the SDS at baseline (Fig 4) and at follow-up were also significantly associated with survival.
This study failed to demonstrate a significant dose effect in the response to paclitaxel in the treatment of women with metastatic breast cancer across the 175 mg/m2 to 250 mg/m2 dose range. Although there was a marginally significant improvement in time to progression as dose increased, the significance was not maintained on multivariate analysis and the differences across the three doses in terms of response rate and survival were not significant. In addition, the higher doses caused significantly more clinically severe myelosuppression and neuropathy. One might hypothesize that women randomized to the higher dose arms were more likely to have a dose reduction and that this accounted for the similar outcome across all three arms. Since dose reductions were relatively infrequent across all three treatment arms, this would not appear to be the case. It is conceivable that increasing doses of paclitaxel could be beneficial in certain biologic subsets, such as HER-2/neu-positive tumors. There are conflicting reports of both higher and lower response rates to paclitaxel in tumors that overexpress HER-2/neu.9,10 An ongoing study is retrospectively evaluating HER-2 status and other molecular parameters. Recent breast cancer trials with other agents have failed to demonstrate that dose escalation beyond the standard range leads to improvements in outcome. In the adjuvant setting, increasing the dose of either cyclophosphamide or doxorubicin has failed to result in improvements in disease-free or overall survival.11-13 There is also little evidence that even more extreme increases in dose-intensity, such as administered as part of autologous transplant regimens, lead to meaningful improvements in disease control.14,15 On the other hand, there is evidence that substantial decreases in dose-intensity16,17 may compromise outcomes. The available evidence suggests that there is a threshold dose effect: administering doses below the threshold will lead to insufficient antitumor activity, but increasing doses of many of the most active breast cancer agents beyond this threshold level does not appear to result in any further improvement. Preclinical evidence suggests that the duration of exposure to paclitaxel may have a greater effect on tumor-cell kill than drug concentration.18 The results of this study are consistent with this preclinical work, though it remains unproven whether longer exposure will lead to improvements in clinical outcomes. Although increasing infusion duration has been associated with only marginal improvements,3,19 there is currently great interest in other paclitaxel schedules, such as weekly administration. It is possible that increasing the exposure to paclitaxel by administering the agent on a weekly schedule will lead to improvements in disease control in both the metastatic and adjuvant settings. Ongoing and recently completed studies will decide this issue for both paclitaxel and docetaxel. Until such studies are available, the 175 mg/m2 dose of paclitaxel remains a reasonable standard. Moreover, this dose of paclitaxel has been incorporated in multiple adjuvant regimens. Both the FLIC and SDS scores at baseline and follow-up were highly predictive of survival, independent of other prognostic factors in this patient population. Other investigators have reported similar findings in women with breast cancer20-22 and in patients with other malignancies.23,25 Our findings suggest that baseline quality of life status could be used as a stratification variable. Finally, low quality of life scores could potentially be used to identify women who might benefit from psychosocial and/or symptom-directed interventions.26,27 In summary, our study establishes 175 mg/m2 as the optimal dose of paclitaxel when administered on an every-3-week schedule in patients with metastatic breast cancer. Although there may be an improvement in disease control with dose escalation beyond 175 mg/m2, any improvement seems to be minimal and higher doses result in substantially greater toxicity.
The following also participated in this study: Stephen George, CALGB Statistical Office (CA33601); Jeffrey Crawford, Duke University Medical Center, Durham (CA47577); Thomas C. Shea, University of North Carolina at Chapel Hill, Chapel Hill (CA47559); David D. Hurd, Wake Forest University School of Medicine, Winston-Salem, NC (CA03927); George P. Canellos, Dana-Farber Cancer Institute (CA32291); Michael L. Grossbard, Massachusetts General Hospital, Boston (CA12449); Mary Ellen Taplin, University of Massachusetts Medical Center, Worcester, MA (CA37135); Marc S. Ernstoff, Dartmouth Medical School, Norris Cotton Cancer Center, Lebanon, NH (CA04326); Edward Gelmann, Georgetown University Medical Center, Washington, DC (CA77597); Daniel R. Budman, North Shore-Long Island Jewish Medical Center, Manhasset (CA35279); Ellis Levine, Roswell Park Cancer Institute, Buffalo (CA02599); Stephen L. Graziano, SUNY Upstate Medical University, Syracuse (CA21060); Lewis R. Silverman, Mount Sinai School of Medicine (CA04457); Michael Schuster, Weill Medical College of Cornell University, New York, NY (CA07968); Louis A. Leone, Rhode Island Hospital, Providence, RI (CA08025); Clara D. Bloomfield, The Ohio State University Medical Center, Columbus, OH (CA77658); Robert Diasio, University of Alabama Birmingham, Birmingham, AL (CA47545); David Gustin, University of Illinois at Chicago, Chicago, IL (CA74811); Gerald Clamon, University of Iowa, Iowa City, IA (CA47642); David Van Echo, University of Maryland Cancer Center, Baltimore, MD (CA31983); Bruce A. Peterson, University of Minnesota, Minneapolis, MN (CA16450); Anne Kessinger, University of Nebraska Medical Center, Omaha, NE (CA77298); Harvey B. Niell, University of Tennessee Memphis, Memphis, TN (CA47555); John C. Byrd, Walter Reed Army Medical Center, Washington, DC (CA26806); and Nancy Bartlett, Washington University, St. Louis, MO (CA77440).
The following authors 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: Gini Fleming, Bristol-Myers Squibb. Received more than $2,000 a year from a company for either of the last 2 years: Gini Fleming, Bristol-Myers Squibb.
Supported in part by National Cancer Institute Grants CA32291 (E.W. and A.K.), CA33601 (D.A.B.), CA21060 (S.W. and J.A.K.), CA47577 (L.N.H.), CA04457 (R.A.M.), CA41287 (G.F.F.), CA12046 (M.C.P.), CA47559 (M.L.G.), CA03927 (S.A.S.), CA07968 (R.K.), CA60138 (I.C.H.), CA77651 (C.H. and L.N.), and CA77406 (H.M.). The contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute. Authors' disclosures of potential conflicts of interest are found at the end of this article.
1. Holmes FA, Walters RS, Theriault RL, et al: Phase II trial of taxol, an active drug in the treatment of metastatic breast cancer. J Natl Cancer Inst 83:1797-1805, 1991
2. Reichman BS, Seidman AD, Crown JP, et al: Paclitaxel and recombinant human granulocyte colony-stimulating factor as initial chemotherapy for metastatic breast cancer. J Clin Oncol 11:1943-1951, 1993
3. Smith RE, Brown AM, Mamounas EP, et al: Randomized trial of 3-hour versus 24-hour infusion of high-dose paclitaxel in patients with metastatic or locally advanced breast cancer: National Surgical Adjuvant Breast and Bowel Project Protocol B-26. J Clin Oncol 17:3403-3411, 1999 4. Hortobagyi GN, Holmes FA: Single-agent paclitaxel for the treatment of breast cancer: An overview. Semin Oncol 23:4-9, 1996[Medline] 5. Seidman AD, Hudis CA, Albanel J, et al: Dose-dense therapy with weekly 1-hour paclitaxel infusions in the treatment of metastatic breast cancer. J Clin Oncol 16:3353-3361, 1998[Abstract] 6. Akerley W, Sikov WM, Cummings F, et al: Weekly high-dose paclitaxel in metastatic and locally advanced breast cancer: A preliminary report. Semin Oncol 24:87-90, 1997 (5 suppl 17)
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8. Nabholtz JM, Gelmon K, Bontenbal M, et al: Multicenter, randomized comparative study of two doses of paclitaxel in patients with metastatic breast cancer. J Clin Oncol 14:1858-1867, 1996
9. Van Poznak C, Tan L, Panageas KS, et al: Assessment of molecular markers of clinical sensitivity to single-agent taxane therapy for metastatic breast cancer. J Clin Oncol 20:2319-2326, 2002 10. Baselga J, Seidman AD, Rosen PP, et al: HER2 overexpression and paclitaxel sensitivity in breast cancer: Therapeutic implications. Oncology (Huntingt) 11:43-48, 1997
11. Fisher B, Anderson S, DeCillis A, et al: Further evaluation of intensified and increased total dose of cyclophosphamide for the treatment of primary breast cancer: Findings from National Surgical Adjuvant Breast and Bowel Project B-25. J Clin Oncol 17:3374-3388, 1999
12. Fisher B, Anderson S, Wickerham DL, et al: Increased intensification and total dose of cyclophosphamide in a doxorubicin-cyclophosphamide regimen for the treatment of primary breast cancer: Findings from National Surgical Adjuvant Breast and Bowel Project B-22. J Clin Oncol 15:1858-1869, 1997 13. Henderson IC, Berry D, Demetri G, 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. Proc Am Soc Clin Oncol 17:101a, 1998 (abstr 390a)
14. Stadtmauer EA, O'Neill A, 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 15. 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)
16. Wood WC, Budman DR, Korzun AH, et al: Dose and dose intensity of adjuvant chemotherapy for stage II, node-positive breast carcinoma. N Engl J Med 330:1253-1259, 1994 17. Bonneterre J, Roche H, Bremond A, et al: Results of a randomized trial of adjuvant chemotherapy with FEC 50 vs FEC 100 in high risk node-positive breast cancer patients. Proc Am Soc Clin Oncol 17:124a, 1998 (abstr 473) 18. Lopes NM, Adams EG, Pitts TW, et al: Cell kill kinetics and cell cycle effects of taxol on human and hamster ovarian cell lines. Cancer Chemother Pharmacol 32:235-242, 1993[CrossRef][Medline] 19. Holmes FA, Valero V, Buzdar AU, et al: Final results: Randomized phase III trial of paclitaxel by 3-hr versus 96-hr infusion in patients with metastatic breast cancer—The long and short of it. Proc Am Soc Clin Oncol 17:110a, 1998 (abstr 426)
20. Coates AS, Hurny C, Peterson HF, et al: Quality-of-life scores predict outcome in metastatic but not early breast cancer: International Breast Cancer Study Group. J Clin Oncol 18:3768-3774, 2000 21. Coates A, Gebski V, Signorini D, et al: Prognostic value of quality-of-life scores during chemotherapy for advanced breast cancer: Australian New Zealand Breast Cancer Trials Group. J Clin Oncol 10:1833-1838, 1992[Abstract] 22. Weeks J: Quality-of-life assessment: Performance status upstaged? J Clin Oncol 10:1827-1829, 1992[Medline] 23. Cella D, Fairclough DL, Bonomi PB, et al: Quality of life in advanced non-small cell lung cancer: Results from Eastern Cooperative Oncology Group study E5592. Proc Am Soc Clin Oncol 16:2a, 1997 (abstr 4) 24. Llobera J, Esteva M, Rifa J, et al: Terminal cancer: Duration and prediction of survival time. Eur J Cancer 36:2036-2043, 2000[CrossRef][Medline] 25. Herndon JE 2nd, Fleishman S, Kornblith AB, et al: Is quality of life predictive of the survival of patients with advanced non-small cell lung carcinoma? Cancer 85:333-340, 1999[CrossRef][Medline] 26. Chang VT, Thaler HT, Polyak TA, et al: Quality of life and survival: The role of multidimensional symptom assessment. Cancer 83:173-179, 1998[CrossRef][Medline]
27. Goodwin PJ, Leszcz M, Ennis M, et al: The effect of group psychosocial support on survival in metastatic breast cancer. N Engl J Med 345:1719-1726, 2001 Submitted August 7, 2003; accepted March 15, 2004.
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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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ABSTRACT
INTRODUCTION
7 days) received granulocyte colony-stimulating factor (G-CSF) in standard doses with subsequent cycles in an effort to avoid dose reductions. If prolonged neutropenia or febrile neutropenia developed despite treatment with G-CSF, the dose of paclitaxel was reduced by 15%. Patients randomly assigned to 210 mg/m2 did not receive G-CSF after an initial episode of febrile neutropenia or prolonged neutropenia. Instead, these patients were dose reduced by 15%, and G-CSF was added if a second episode of febrile or prolonged neutropenia developed despite the initial dose reduction. This approach was based on a view that the 210 mg/m2 dose would only be of interest if it could be administered without routine growth factor support. 
2 tests were used to compare toxicities across treatment arms. 
