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© 2001 American Society for Clinical Oncology Clinical Activity of Trastuzumab and Vinorelbine in Women With HER2-Overexpressing Metastatic Breast CancerFrom the Division of Adult Oncology and Department of Biostatistical Science, Dana-Farber Cancer Institute; Department of Medicine, Brigham & Women’s Hospital; Division of Hematology-Oncology, Massachusetts General Hospital; and Harvard Medical School, Boston, MA. Address reprint requests to Eric P. Winer, MD, Dana-Farber Cancer Institute, 44 Binney St, Boston, MA 02115; email: ewiner{at}partners.org
PURPOSE: To determine the response rate and toxicity profile of trastuzumab administered concurrently with weekly vinorelbine in women with HER2-overexpressing advanced breast cancer. PATIENTS AND METHODS: Forty women with HER2-positive (+3 by immunohistochemistry, n = 30; +2 or positive, n = 10) breast cancer were enrolled onto a study of trastuzumab (4 mg/kg x 1, 2 mg/kg weekly thereafter) and vinorelbine (25 mg/m2 weekly, with dose adjusted each week for neutrophil count). Eighty-two percent of women had received prior chemotherapy as part of adjuvant (30%), metastatic (25%), or both (28%) treatment, including substantial portions of patients who had previously received either anthracyclines (20%), taxanes (15%), or both types (38%) of chemotherapy. RESULTS: Responses were observed in 30 of 40 patients (overall response rate, 75%, conditional corrected 95% confidence interval, 57% to 89%). The response rate was 84% in patients treated with trastuzumab and vinorelbine as first-line therapy for metastatic disease, and 80% among HER2 +3 positive patients. High response rates were also seen in women treated with second- or third-line therapy, and among patients previously treated with anthracyclines and/or taxanes. Combination therapy was feasible; patients received concurrent trastuzumab and vinorelbine in 93% of treatment weeks. Neutropenia was the only grade 4 toxicity. No patients had symptomatic heart failure. Grade 2 cardiac toxicity was observed in three patients. Prior cumulative doxorubicin dose in excess of 240 mg/m2 and borderline pre-existing cardiac function were associated with grade 2 cardiac toxicity. CONCLUSION: Trastuzumab in combination with vinorelbine is highly active in women with HER2-overexpressing advanced breast cancer and is well tolerated.
THE HER2 PROTEIN is a 185-kd transmembrane tyrosine kinase with homology to the epidermal growth factor receptor.1 Tumor overexpression of HER2 arises through genetic amplification of the c-erbB-2/neu oncogene, which encodes HER2. HER2 overexpression is an adverse prognostic factor in early stage breast cancer and tends to be associated with other adverse prognostic factors such as higher tumor grade, increased tumor proliferation, tumor aneuploidy, and lack of hormone receptor expression. HER2 overexpression occurs in 25% to 30% of cases of metastatic breast cancer. Among women with metastatic breast cancer, tumor amplification of the HER2 gene confers relative resistance to treatment response with either anthracycline/alkylator- or taxane-based chemotherapy.2 Trastuzumab (Herceptin; Genentech, Inc, South San Francisco, CA) is a humanized monoclonal antibody with specificity for the HER2 protein. The original trials of trastuzumab selected patients whose tumors overexpressed HER2 as measured by immunohistochemistry (IHC). Trastuzumab given to such patients had therapeutic activity. As single-agent first-line therapy, trastuzumab achieved response rates of 20% to 25%.3 Among patients previously treated with chemotherapy for metastatic breast cancer, trastuzumab yielded response rates of 10% to 15%.4,5 In retrospective analyses of these trials, higher response rates to trastuzumab (31% as first-line, 18% as second- and third-line) were seen among patients whose tumors had more pronounced overexpression of HER2 (+3 by IHC). The side effects of trastuzumab are mild, particularly in comparison to standard chemotherapy. There are few gastrointestinal side effects, and no significant hematologic toxicity or alopecia. The most common treatment-related adverse effect is an infusion syndrome characterized by rigors, chills, or fever that may accompany the initial infusion of trastuzumab in approximately one-third of patients. A rare though life-threatening pulmonary hypersensitivity reaction has been reported, affecting fewer than one in 1,000 patients (see package insert). Preclinical models suggest that trastuzumab may potentiate the effects of chemotherapy when administered concurrently with chemotherapy.6 Clinical support for this observation comes from a randomized trial, in which women with HER2-positive metastatic breast cancer (IHC +2 or +3) received either chemotherapy or chemotherapy administered concurrently with trastuzumab.7 Combination therapy was associated with higher response rates and longer time to progression (TTP), as well as statistically significant improvement in survival.8 The use of trastuzumab in combination with anthracycline-based chemotherapy was associated with an unacceptably high incidence of cardiac dysfunction.9 This finding has precluded the concurrent use of trastuzumab and doxorubicin. Neither the optimal combination of trastuzumab with chemotherapy nor the optimal timing and sequencing of trastuzumab and chemotherapy have been determined. Preclinical studies have examined a variety of chemotherapeutic agents in association with trastuzumab to determine which combinations were synergistic when inhibiting the growth of HER2-positive tumor cell lines. Reproducible synergism in these preclinical models has been observed with trastuzumab paired with vinorelbine, platinum salts, taxanes, combinations of taxanes and platinum salts, etoposide, or alkylators.10-12 Vinorelbine (Navelbine; Glaxo Smithkline, Research Triangle Park, NC) is a vinca alkaloid with considerable activity against breast cancer. As first-line therapy, vinorelbine is typically associated with response rates of 35% to 50%, and retains response rates of 16% to 30% as second-line treatment.13-24 In most phase II and III studies of vinorelbine for advanced breast cancer, treatment dose-intensity averages between 19 and 21 mg/m2/wk. The principle side effects of vinorelbine are neutropenia, peripheral neuropathy, constipation, and phlebitis. Vinorelbine is not usually associated with cardiac toxicity, alopecia, or significant nausea or vomiting. We conducted a phase II study to examine the clinical efficacy and side effect profile of trastuzumab and vinorelbine in the treatment of women with HER2-positive metastatic breast cancer. The rationale for this particular combination stemmed from the preclinical data suggesting a favorable interaction between these two agents. In addition, the weekly schedule of administration, lack of cardiac toxicity, and minimal alopecia all made the addition of vinorelbine to trastuzumab a theoretically attractive combination.
Eligibility Patients were required to be at least 18 years of age, provide written informed consent, and have +2 or +3 HER2-overexpressing metastatic breast cancer. The study originally required that patients have received at least one and not more than two prior chemotherapy regimens for metastatic breast cancer. Based on the initial activity and toxicity experience, eligibility was expanded to include women who had not previously received chemotherapy for metastatic breast cancer. Patients could have received prior adjuvant chemotherapy, high-dose chemotherapy with stem-cell support, and hormonal therapy. Patients could not have received prior vinorelbine or trastuzumab.
Patients were required to have bidimensionally measurable disease that may have included lytic bone lesions. Adequate general health status (Eastern Cooperative Oncology Group performance status 0 to 2) and absence of active comorbid illness such as uncontrolled infections or diabetes or severe cardiovascular or pulmonary disease was required. Patients were required to have life expectancy Patients could not receive other concurrent antineoplastic therapy. Patients were initially required to have concluded any radiotherapy, chemotherapy, and/or hormonal therapy at least 2 weeks before protocol treatment. On September 22, 1999, the protocol was amended to require conclusion of hormonal therapy at least 1 week before protocol treatment. Patients were required to have recovered from all chemotherapy or radiation therapy toxicities in excess of grade 1 before initiating protocol treatment. Patients on study were excluded from taking ketoconazole, macrolide antibiotics, or zidovudine while on protocol because of possible drug interactions. Patients could receive concomitant bisphosphonate treatment. HER2 overexpression was determined by IHC. Patients with tumors scored as +2 or +3 positive for HER2 were eligible. IHC was performed using a modification of the DAKO HercepTest kit (Copenhagen, Denmark), which may be more specific than the manufacturers’ instructions.25 Outside reports of HER2 expression were accepted for study enrollment. This study was conducted in accordance with guidelines established by the United States Department of Health and Human Services. The Scientific Review and Human Protection Committees of Dana-Farber/Partners Cancer Care approved the study. Patients were enrolled between December 1998 and November 1999.
Treatment Plan Vinorelbine was given weekly on the same day as and after trastuzumab administration. The dose of vinorelbine was 25 mg/m2, administered through a free-flowing IV line as a 6- to 10-minute IV infusion, followed by 125 mL of saline. Patients were assessed with complete blood cell count with differential every week and liver function tests every 4 weeks. The protocol called for vinorelbine dose to be adjusted each week on the day of therapy based on hematologic toxicity, as listed in Table 1. If vinorelbine was delayed on account of low neutrophil count and then restarted, it was restarted at the dose appropriate for that treatment day. The protocol permitted granulocyte-macrophage colony-stimulating factor (G-CSF) use for treatment delay of more than 2 weeks on account of neutropenia, or for febrile neutropenia. Vinorelbine dose was to be reduced to 12.5 mg/m2 for bilirubin between 2 and 3 mg/dL, and held for bilirubin more than 3 mg/dL. Patients who developed grade 2 neurologic toxicity were to receive vinorelbine at 15 mg/m2 until toxicity resolved to grade 1 or less.
Patients had left ventricular EF measured every 8 weeks. Patients with asymptomatic decrease in EF of more than 15% from baseline or to less than the lower limit of normal, or with symptomatic congestive heart failure, were taken off protocol. Other grade 3 nonhematologic toxicity was managed with vinorelbine delay until resolution to grade 1 or less. If toxicity persisted more than 2 weeks, patients were taken off protocol, as were patients with grade 4 nonhematologic toxicity.
Study Analysis The primary study end point of this single-center phase II trial was overall response rate (complete response [CR] plus partial response [PR]). Disease responses (CR, disappearance of all measurable and nonmeasurable disease; PR, 50% decrease in the sum of bidimensionally measurable disease; PD, 25% increase in sum of bidimensionally measurable disease or appearance of new lesions; stable disease, neither CR, PR, or PD criteria met) were classified along the lines of World Health Organization criteria.27 Patients were accrued in a two-stage study design. The original accrual goal called for a total of 30 patients (n = 16, first stage; n = 14, second stage) with patients required to have at least one prior chemotherapy regimen for metastatic breast cancer. When the eligibility criteria were modified to permit women with no prior chemotherapy treatment in the metastatic setting to enter the study, the second-stage accrual goal was increased to 24 (for a total of 40 patients). A total of 16 responders among 40 patients were considered adequate to justify further study of the regimen. With this study design, the trial had a 90% chance of positive findings if the true response rate was 50% and an 11% chance of positive findings if the true response rate was 30%. Log-rank test, Fisher’s exact test, and calculation of confidence intervals were performed according to standard methods as indicated in the text. P values less than .05 were considered statistically significant. Exceptions to study eligibility criteria were granted to 10 women. One patient had inflammatory breast cancer refractory to two prior chemotherapy regimens but did not have overt metastatic disease. Six patients, all of whom had PD on their prior treatment, started protocol-based therapy without waiting at least 1 week (hormonal therapy, n = 4) or 2 weeks (chemotherapy or radiation therapy, n = 2) after concluding that therapy. Two patients had AST more than 2 x ULN but less than 3 x ULN, and were accrued before approval of the protocol revision requiring AST to be less than 3 x ULN. One patient was enrolled with a baseline glucose of more than 200 mg/dL, as the patient had no history of diabetes or insulin resistance, and the glucose level was elevated due to glucocorticoid therapy before the blood test. All these patients were included in the study analysis, as these exceptions were not believed to affect study end points. Data are reported on an intent-to-treat basis for all patients consenting to the study.
Patient and Treatment Characteristics A total of 40 women were enrolled onto the study. Table 2 lists the clinical characteristics of these women. Median age was 50 years; most women had good (Eastern Cooperative Oncology Group, 0 or 1) performance status. HER2 overexpression was determined by IHC. Thirty of the patients on study (75%) were +3 overexpressors, nine had tumors with +2 overexpression, and one patient had a tumor considered positive on IHC without quantification or other specification. The majority of women (78%) had visceral (either hepatic or pulmonary) disease. Patients had a median of three metastatic organ sites of disease. Most (83%) of the women had received prior chemotherapy in either the metastatic or adjuvant setting, with a variety of regimens as indicated in Table 2. Patients had previously been treated with either anthracycline-based (20%), taxane-based (15%), or both anthracycline- and taxane-based (38%) regimens, though patients were not necessarily refractory to such therapies. Four women (10%) had undergone high-dose chemotherapy with autologous stem-cell support. Nineteen patients (48%) received concomitant bisphosphonate therapy.
At the time of primary study analysis, a total of 1,044 weekly treatments had been given (see Table 3). Eighty percent of the weekly vinorelbine doses were administered at full dose. The only cause for vinorelbine dose adjustment was neutropenia; no patients developed hepatic or neurologic toxicity requiring dose adjustment of vinorelbine. In 13% of weekly treatments, vinorelbine dose was reduced by 40% to 15 mg/m2, and in 7% of weekly treatments, vinorelbine was omitted. Some of these omissions reflected patient preference (eg, social engagements, travel). None of the patients had vinorelbine dose delayed more than 2 weeks on account of neutropenia. No patient received G-CSF. The median dose-intensity for vinorelbine was 21.3 mg/m2/wk. There were no dose adjustments for trastuzumab therapy.
Efficacy The principal end point for the study was the overall response rate on an intent-to-treat basis. Of 40 patients on study, responses were observed in 30, for an overall response rate of 75% (Table 4). 28 Three complete and 27 partial responses were observed. An additional two patients had stable disease in excess of 6 months. Response rates among subgroups of patients defined by clinical characteristics and tumor features are listed in Table 5. As first-line therapy for metastatic breast cancer, trastuzumab and vinorelbine had an 84% response rate. Response rates in excess of 60% were also observed among patients receiving this regimen as second- or third-line therapy, though there were fewer numbers of patients in these subsets. Similar response rates were also observed among patients with prior chemotherapy treatment in either the adjuvant setting, metastatic setting, or both. Most patients on study had previously received either an anthracycline-based or taxane-based regimen, or both. Substantial response rates were observed in patients previously treated with those chemotherapeutic agents. Among the 15 patients previously treated with both anthracycline- and taxane-based chemotherapy, the response rate was 73%. Three of the four patients previously treated with high-dose chemotherapy and stem-cell support responded to treatment.
Response rates were analyzed as a function of the level of HER2 overexpression (Table 5). For those patients with +3 overexpression, the response rate was 80% (24 of 30) whereas among those patients with +2 overexpression or with overexpression simply scored as positive, the response rate was 60% (six of 10). Tumors were not analyzed for HER2 gene amplification by fluorescence in situ hybridization. The TTP and overall survival for patients on study are shown in Figs 1 and 2, respectively. Patients receiving trastuzumab and vinorelbine as first-line therapy had longer TTP and overall survival than did patients receiving this treatment as second- or third-line therapy (median TTP, 34 weeks v 16 weeks, log-rank P = .06; median overall survival, not yet reached v 77.5 weeks, log-rank P = .005). The median time on study was 27 weeks for the entire 40-patient cohort. For patients receiving first-line chemotherapy, time on study was a median of 33 weeks (7.6 months); among patients receiving treatment as second- or third-line therapy, time on study was 16 weeks (log-rank P = .005). Among those patients with objective response to therapy, the duration of response was a median of 22 weeks (range, 4 to 94+ weeks).
Patients were removed from study for several reasons, including PD (n = 27), withdrawal of consent or treatment break (n = 4), or changes in left ventricular EF (n = 4; discussed later in this article). Of those patients with PD, four (15%) were discovered to have new CNS metastases as their site of disease progression.
Toxicity
Nonhematologic toxicity related to study treatment is also listed in Table 6. Peripheral neuropathy affected 48% of patients; none exceeded grade 2, and no vinorelbine dose adjustment was required as a result of neuropathy. Many of the women with neuropathy had pre-existing symptoms from prior taxane-based treatments. Gastrointestinal side effects such as nausea/vomiting or stomatitis were mild. Phlebitis was rarely observed, even though most patients were treated through peripheral veins. One patient developed an upper extremity deep venous thrombosis related to a permanent indwelling central venous access device. One patient developed pancreatitis while on study that resolved with supportive measures and cessation of alcohol consumption, and the patient continued on study without further complication. Trastuzumab-related infusion reactions were observed in 38% of patients; none required hospitalization; and none precluded protocol-based therapy.
Cardiac function was monitored every 8 weeks with radioventriculogram or echocardiogram. Patients were taken off study for decrease in their left ventricular EF of more than 15% or to an absolute value of less than 50%. No patient developed symptomatic congestive heart failure on study. Three patients developed grade 2 cardiac toxicity (decline in EF of > 20% or to below 50%), and were removed from study (Table 6). A fourth patient experienced decline in EF of between 15% and 20% (grade 1) and was taken off study according to protocol criteria. The incidence of grade 2 cardiac toxicity was analyzed by assigning patients to four clinical groups based on prior cumulative doxorubicin exposure ( The clinical experience of the three patients with grade 2 cardiac toxicity is listed in Table 7. In subsequent follow-up, off of trastuzumab treatment, two of the three patients recovered their EF to baseline levels. None of these patients were subsequently retreated with trastuzumab. An additional seven patients had grade 1 cardiac toxicity (EF decline, 10% to 20%). Figure 3 shows mean EF over time for the first 40 weeks of therapy. In the aggregate, there did not seem to be progressive decline in EF with sustained therapy. No significant late declines in EF were subsequently observed among the patients treated for 16 weeks who did not experience initial changes in EF.
The results of this single-center phase II study suggest that treatment with trastuzumab and vinorelbine is highly active and well tolerated among women with HER2-overexpressing metastatic breast cancer who have not previously received either therapy. The overall response rate was 75%, with a suggestion of higher response rates observed in subgroups of patients with HER2 +3 positive tumors, and among patients receiving the combination regimen as first-line chemotherapy for metastatic breast cancer. Response rates in excess of 60% were observed for patients receiving the regimen as second- or third-line therapy for metastatic cancer, and among patients who had previously received anthracycline- and taxane-based chemotherapy. Acute toxicities were quite mild and manageable. Neutropenia was the most common severe toxicity, and was managed with vinorelbine dose modification without other sequelae. Gastrointestinal side effects and alopecia were modest. Sustained therapy with vinorelbine and trastuzumab was feasible without encountering cumulative side effects. A small percentage of patients were taken off study for asymptomatic declines in left ventricular EF. A confirmatory multicenter phase II trial of this regimen is currently underway. The optimal combination of trastuzumab with chemotherapy is not known. Previous clinical trials have examined trastuzumab in combination with either cisplatin,29 doxorubicin/cyclophosphamide,7,8 paclitaxel (both every 3 weeks7,8 and weekly schedules30), or in combination with platinum salts and docetaxel.31 Direct comparison between these various phase II/III studies and the current phase II study of trastuzumab and vinorelbine is difficult because of different patient selection criteria, especially differences in prior therapy and determination of HER2 overexpression. The response rate observed with trastuzumab and vinorelbine is at least comparable with that reported to date for any combination of trastuzumab with chemotherapy. One multicenter trial of first-line chemotherapy for HER2-positive (+2 or +3) metastatic breast cancer randomized women to either chemotherapy alone (doxorubicin/cyclophosphamide or paclitaxel) or chemotherapy with trastuzumab.7,8 In that study, the median TTP for treatment with trastuzumab and chemotherapy was 7.4 months overall, and 7.8 months among the HER2 +3 subset of patients. Among the similar though smaller cohort of patients treated with trastuzumab and vinorelbine in the current study, the median TTP for first-line patients (+2 and +3, n = 19) was 7.6 months. As seen in other trials of trastuzumab, there was a trend toward higher response rates among patients with greater overexpression of HER2. However, only 23% of the study population had tumors that were HER2 +2 positive, and the difference in response rates between +2 and +3 positive patients was not statistically significant. Further, it is not known what fraction of patients whose tumors overexpressed HER2 as measured by IHC also had genetic amplification of the HER2 gene. The inclusion of patients whose tumors lacked either +3 overexpression or genetic amplification of HER2 may underestimate the benefit of trastuzumab therapy.2 The toxicity observed when using trastuzumab in combination with vinorelbine did not differ appreciably from that expected from historical experience when using either agent alone. Cardiac toxicity is a particular concern when trastuzumab is administered in combination with chemotherapy. Grade 2 cardiac toxicity (EF decline, 10% to 20% or to < normal), occurred in three patients in this phase II study. Low-normal EF (range, 50% to 59%) together with prior cumulative doxorubicin exposure in excess of 240 mg/m2 were important predictors of the onset of grade 2 cardiac impairment. Based on this experience, formal measurement of left ventricular EF is warranted before initiating trastuzumab and vinorelbine therapy. Those patients with borderline cardiac function, prior doxorubicin exposure, or pre-existing heart disease warrant reevaluation of cardiac function during therapy. There is little data as yet on the clinical course of trastuzumab-related cardiac dysfunction. In the current trial, two of the three patients who developed grade 2 cardiac toxicity were found to have recovered cardiac function to baseline with cessation of trastuzumab therapy. This suggests that trastuzumab may, in some patients, cause a reversible cardiomyopathy. It is not known whether such patients could be safely retreated with trastuzumab. Preclinical studies suggested that vinorelbine might have favorable interactions with trastuzumab.10-12 The biochemical basis for such an interaction is not known. It is possible that intracellular signaling mediated through the HER2 receptor by trastuzumab might potentiate tumor cell sensitivity to vinorelbine, or that vinorelbine exposure may alter the expression of HER2 in a manner that renders the cell more susceptible to trastuzumab therapy. The response rates observed in this clinical study are higher than might have been expected with either trastuzumab or vinorelbine as single-agent therapy, based on response rates reported in phase II and III trials. This in and of itself does not prove that clinical synergy exists between these two agents. However, it is a provocative finding, and justifies further exploration of this regimen. Vinorelbine administered in this treatment protocol proved well tolerated. The weekly dose of 25 mg/m2 was delivered 80% of the time, and the reduced dose of 15 mg/m2 was given on 13% of weeks. Thus, on more than 90% of treatment dates, concurrent chemotherapy and trastuzumab could be administered. The observed dose-intensity (21 mg/m2/wk) is entirely consistent with other trials of single-agent vinorelbine for advanced breast cancer. There were no side effects that emerged with prolonged therapy, and no need for concurrent corticosteroid administration. Weekly vinorelbine administered on this schedule may be a useful foundation for combination treatment with other biologic agents, where long-term, sustained chemotherapy exposure is desired. The optimal use of trastuzumab in the treatment of HER2-positive advanced breast cancer is under active investigation. It is not known when trastuzumab should, ideally, be initiated, nor when it should be discontinued. The high rate of clinical activity and low incidence of severe toxicity seen among patients given trastuzumab and vinorelbine suggest that this regimen can be used in randomized trials to address fundamental clinical questions about the timing and duration of trastuzumab therapy.
Supported in part by a grant-in-aid from Genentech, South San Francisco, CA.
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Jacobs TW, Gown AM, Yaziji H, et al: Specificity of HerceptTest in determining HER-2/neu status of breast cancers using the United States Food and Drug Administration–approved scoring system. J Clin Oncol 17: 1983-1987, 1999 26. Hyrniuk WM, Goodyear M: The calculation of received dose intensity. J Clin Oncol 8: 1935-1937, 1990[Medline] 27. Miller AB, Hogestraeten B, Staquet M, et al: Reporting results of cancer treatment. Cancer 47: 207-214, 1981[Medline] 28. Burstein HJ, Kuter I, Richardson PG, et al: Herceptin and vinorelbine for HER2-positive metastatic breast cancer: A phase II study. Proc Am Soc Clin Oncol 19: 102a, 2000 (abstr 392) 29. Pegram MD, Lipton A, Hayes DF, et al: Phase II study of receptor-enhanced chemosensitivity using recombinant humanized anti-p185HER2/neu monoclonal antibody plus cisplatin in patients with HER2/neu-overexpressing metastatic breast cancer refractory to chemotherapy treatment. J Clin Oncol 16: 2659-2671, 1998[Abstract] 30. Seidman AD, Fornier M, Esteva F, et al: Final report: Weekly (W) Herceptin (H) and Taxol (T) for metastatic breast cancer (MBC): Analysis of efficacy by HER2 immunophenotype [immunohistochemistry (IHC)] and gene amplification [fluorescent in situ hybridization (FISH)]. Proc Am Soc Clin Oncol 19: 83a, 2000 (abstr 319) 31. Nabholtz JM, Crown J, Yonemoto L, et al: Results of two open-label multicentre pilot phase II trials with Herceptin in combination with docetaxel and platinum salts (cis- or carboplatin) (TCH) as therapy for advanced breast cancer in women overexpressing HER2. Breast Cancer Res Treat 64: 82, 2000 (abstr 327) Submitted September 26, 2000; accepted February 14, 2001.
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Copyright © 2001 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
3 months, to be neither pregnant nor nursing, and to have no other prior malignancy besides breast cancer unless that cancer was treated with curative intent. Patients were required to have a left ventricular ejection fraction (EF) of 50% or greater. Patients with neuropathy exceeding grade 1 according to the National Cancer Institute Common Toxicity Criteria were excluded. Patients were required to have absolute neutrophil count more than 1,500/uL, platelet count more than 100,000/uL, bilirubin less than 2 mg/dL, AST less than 2 x upper limit of normal (ULN), and glucose less than 200 mg/dL. On September 22, 1999, eligibility was extended to patients with AST less than 3 x ULN. 
240 mg/m2, > 240 mg/m2) and baseline EF (EF 50% to 59%, EF 
