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© 2002 American Society for Clinical Oncology Phase II Multicenter Trial of a Weekly Paclitaxel and Carboplatin Regimen in Patients With Advanced Breast CancerByFrom U.S. Oncology, Inc, Houston, TX. Address reprint requests to David Loesch, MD, 1347 East County Line Rd South, Indianapolis, IN 46227; email: david.loesch{at}usoncology.com
PURPOSE: To determine the activity of weekly paclitaxel plus carboplatin as first-line therapy in patients with advanced breast cancer (ABC) by assessing response rate, survival, and safety.
PATIENTS AND METHODS: One hundred patients with ABC received paclitaxel 135 mg/m2 (group 1, n = 20) and carboplatin area under the concentration-time curve (AUC) of 2. Paclitaxel was subsequently reduced to 100 mg/m2 (group 2, n = 80) because of toxicity. The median age was 58.5 years, and most patients had an Eastern Cooperative Oncology Group performance status of RESULTS: The overall response rate (ORR) among 95 assessable patients was 62%, including 8% complete responses and 54% partial responses. The median time to response was 1.8 months, and the median duration of response was 13.3 months. The median time to progression was 4.8 months. The median survival was 16 months. Neutropenia and leukopenia were the most common grade 3 and 4 toxicities. In group 1, neutropenia (50%) and leukopenia (35%) necessitated dose reductions for 50% of patients during the first three cycles, prompting the reduction in paclitaxel dose to 100 mg/m2. Grade 3 and 4 nonhematologic toxicities for all patients included peripheral neuropathy (11%), infection (6%), anemia (5%), weakness (6%), and paresthesia (3%). CONCLUSION: The 62% ORR achieved with weekly paclitaxel plus carboplatin is among the highest achieved with chemotherapy for ABC. This high response rate and the lack of cardiotoxicity suggest that the regimen should be considered as a nonanthracycline regimen for future adjuvant therapy.
BREAST CANCER IS the most common type of cancer diagnosed in women, comprising 32% of female cancers.1 In the year 2001, an estimated 192,200 women were diagnosed with new invasive breast cancers, and there will be an estimated 40,200 deaths due to breast cancer, making it second only to lung cancer among the most common causes of death from cancer in women. Although the incidence of breast cancer continues to increase slightly each year, the mortality from the disease declined significantly between 1990 and 1997, suggesting that there is reason to be hopeful about the treatment of this disease. The development of the taxanes, paclitaxel and docetaxel, in the 1990s represented the biggest breakthrough in therapy for metastatic breast cancer since the development of the anthracyclines two decades earlier. With taxane therapy, tumor regression has been seen in more than 50% of patients with metastatic breast cancer who have had no prior chemotherapy and in 20% to 40% of those who have had prior cytotoxic therapy.2 Many studies have used paclitaxel as a single agent for the treatment of advanced breast cancer, with the recent focus on the use of a weekly regimen rather than the more conventional every-3-weeks schedule. Weekly paclitaxel regimens have been shown to provide greater dose-intensity when compared with the conventional schedules.3-5 Response rates ranging from 21.5% to 79% have been achieved in patients with locally advanced and metastatic breast cancers.3,6-10 In addition to its use as a single agent, paclitaxel has been used in combination with many agents, including the platinum compound carboplatin. Increased toxicity, especially myelosuppression, is always a concern with combination chemotherapy regimens. Interestingly, with the paclitaxel and carboplatin combination, paclitaxel seems to have a platelet-sparing effect, which actually lessens the thrombocytopenia seen with carboplatin. This effect was first observed in early studies in which there was a lower degree of thrombocytopenia than would be expected with carboplatin alone and was subsequently demonstrated in larger phase II studies.11-14 The mechanism behind the platelet-sparing effect remains unknown at this time. Although past studies have confirmed that it is not due to a pharmacokinetic interaction between paclitaxel and carboplatin,15-17 current research has focused on a pharmacodynamic basis for the phenomenon.18 The typical dose schedule for the paclitaxel and carboplatin combination has traditionally been paclitaxel 175 to 200 mg/m2 and carboplatin area under the concentration-time curve (AUC) of 5 to 7.5 given on day 1 of each 3-week cycle. However, with the incorporation of weekly paclitaxel into the combination regimen, a schedule of paclitaxel 80 to 100 mg/m2 and carboplatin AUC 2 given 3 out of every 4 weeks or 6 of every 8 weeks has also become common. The paclitaxel and carboplatin combination has become a standard of care for the treatment of non–small-cell lung cancer and ovarian cancer and is becoming a more common regimen in breast cancer therapy. Response rates from 43% to 62% have been obtained with the paclitaxel and carboplatin regimen on an every-3-weeks schedule to treat advanced breast cancer.19-21 The optimal regimen for the treatment of stage III and metastatic breast cancers is still being sought. However, new combinations and new treatment schedules bring research ever closer to the goal of more effective treatment regimens for stage III disease and effective therapies with less toxicity for metastatic breast cancer. This study was built on past research with weekly paclitaxel or the combination of paclitaxel and carboplatin on an every-3-weeks schedule to evaluate the combination on a weekly basis in patients with locally advanced or metastatic breast cancer. The optimal paclitaxel and carboplatin combination schedule would be that which offers the response rates seen with the combination used on an every-3-weeks schedule but has a toxicity profile that approximates that seen in studies with single-agent paclitaxel. This study was a first step toward optimizing the schedule for combination paclitaxel and carboplatin therapy in advanced breast cancer.
Eligibility Criteria Female patients older than 18 years of age with pathologically confirmed adenocarcinoma of the breast that was locally advanced (stage IIIB) or metastatic (stage IV) were eligible for this study. At least 4 weeks had to have passed since radiotherapy or 3 weeks had to have passed since major surgery, with full recovery. Measurable disease had to be completely outside the radiation portal; otherwise, there had to be pathologic proof of progressive disease. Eastern Cooperative Oncology Group (ECOG) performance status had to be 0, 1, or 2. Adequate bone marrow and organ function were required, as was a negative baseline pregnancy test for female patients. Patients were not allowed to have prior chemotherapy for advanced or metastatic disease. Prior neoadjuvant or adjuvant therapy was allowed, provided that the regimen did not contain a taxane and was completed at least 6 months before enrollment onto this study. Concurrent hormonal or immunotherapy was not allowed. The protocol for this study was approved by a central institutional review board with jurisdiction over the specific sites that registered patients onto the study. Each patient gave written informed consent, and the following pretreatment evaluations were performed: medical history, physical examination, vital signs, height and body weight, ECOG performance status, clinical (physical examination) and radiologic (chest x-ray, computed tomography scan) tumor assessment, complete blood count with differential and platelet count, hemoglobin, and chemistries (AST, ALT, bilirubin, and creatinine).
Treatment Plan Patients received premedication consisting of dexamethasone 20 mg orally administered approximately 12 and 6 hours before paclitaxel, diphenhydramine (or its equivalent) 50 mg intravenously 30 to 60 minutes before paclitaxel, and cimetidine 300 mg or ranitidine 50 mg intravenously 30 to 60 minutes before paclitaxel.
A maximum of two dose reductions were allowed per patient. A 25% reduction in both paclitaxel and carboplatin doses was made for an absolute neutrophil count between 500 and 1,500/µL or platelet count between 50,000 and 99,999/µL. For an absolute neutrophil count or platelet count of less than 500 or 50,000/µL, respectively, both drugs were withheld. If the blood counts did not recover within 7 days, both paclitaxel and carboplatin were reduced by 25% when therapy resumed. Patients who experienced Treatment continued until one or more of the following criteria were met: (1) the patient was withdrawn from the study after four cycles to undergo bone marrow or stem-cell transplantation; (2) an intercurrent illness developed which, in the judgment of the investigator, significantly affected assessments of clinical status or required drug discontinuation; (3) unacceptable toxicity developed; (4) disease progression occurred; (5) the patient asked to withdraw; (6) nonprotocol chemotherapy, immunotherapy, or antitumor hormonal therapy was administered or an indicator lesion was irradiated; (7) a third 25% dose reduction was required; (8) the patient became pregnant; or (9) the patient was noncompliant with the treatment regimen.
Assessment of Response and Toxicity The secondary efficacy end points included duration of tumor response, time to disease progression, and survival. Duration of response was the interval between the date of onset of a PR or CR and the date that progressive disease occurred. Time to disease progression was the interval between the date of the start of treatment and the date of occurrence of progressive disease or the date that other antitumor therapy was started. Survival was the interval between the date of the start of treatment and the date of death. If a patient was lost to follow-up, that patient was censored as of the date of last contact.
Statistical Methods
Patient Characteristics Between November 1998 and August 1999, 100 patients with advanced breast cancer were enrolled onto the study at 30 community sites. The initial paclitaxel dose was 135 mg/m2. On the basis of the toxicity profile seen with the first 20 patients enrolled (group 1), the paclitaxel dose was reduced to 100 mg/m2 for the remaining 80 patients enrolled (group 2). Patient characteristics are listed for the total population and each treatment group in Table 1.
The median age of the population overall was 58.5 years (range, 33 to 89 years). The majority of the patients had an ECOG performance status of 0 or 1, and estrogen and progesterone receptor status were evenly distributed between positive and negative in both treatment groups. Sixty-one patients (61%) received neoadjuvant or adjuvant chemotherapy before enrolling onto the study, 37 (61%) of whom received prior doxorubicin. Among the 47 patients who received prior hormonal therapy, 43 (91%) received tamoxifen. There were a total of 509 treatment cycles throughout the study, with a median number of five cycles per patient (range, one to 19 cycles). Sixty-four patients required a dose reduction, 15 (75%) in group 1 and 49 (61%) in group 2. Dose delay was seen in 50 patients, including 12 (60%) in group 1 and 38 (48%) in group 2. Of the total of 100 patients, three refused to start treatment, and 97 discontinued treatment. The reasons for discontinuation included bone marrow or stem-cell transplantation (4%); intercurrent illness (2%); unacceptable toxicity (55% of group 1 and 35% of group 2; overall incidence, 39%); disease progression (36%); patient refusal to continue therapy (4%); administration of nonprotocol chemotherapy, immunotherapy, or antitumor hormonal therapy or irradiation of an indicator lesion (7%); mastectomy (4%); and noncompliance with the treatment regimen (1%).
Efficacy Results
The response rate of each individual group was similar to that of the entire patient population (Table 2). For those patients in group 1 (paclitaxel 135 mg/m2), an overall response rate of 58% was obtained with 16% and 42% CR and PR rates, respectively. Likewise, for those patients in group 2 (paclitaxel 100 mg/m2), the overall response rate was 64%, with 7% CRs and 57% PRs. The median duration of response was 13.3 months (range, 1.5 to 25.0 months). The median time to progression was 4.8 months (range, < 1 to 26 months). The median survival was 16 months (range, < 1 to 27 months). Surviving patients were followed up for a median period of 17 months (range, 3 to 27 months). The estimated survival at 12 months and 18 months was 64% and 47%, respectively.
Toxicity
Response rates in single-agent paclitaxel studies in patients with advanced or metastatic breast cancer have ranged from 21.5% to 79%, with rates of more than 50% seen primarily in studies conducted in single-institution settings.3,6-10,23-26 In studies in which patients had received prior treatment including paclitaxel, response rates to single-agent paclitaxel therapy ranged from 53% to 67%.3,6-8 In a study of weekly paclitaxel as first-line therapy, patients with metastatic disease had an overall response rate of 78%, whereas those with locally advanced disease achieved a 79% overall response rate.9 In several randomized multicenter studies, response rates to single-agent paclitaxel (given every 3 weeks) ranged from 25% to 41% in patients receiving first-line therapy for metastatic breast cancer.23-26 Also in the setting of a larger multicenter metastatic breast cancer trial, Perez et al10 achieved an overall response rate of 25.5% to weekly paclitaxel for those patients who had received no prior chemotherapy for their metastatic disease. Together, these previous studies indicated single-agent paclitaxel to be a viable therapy for advanced breast cancer, capable even of inducing responses in patients who had relapsed after prior therapy. This study sought to increase efficacy with the addition of carboplatin to weekly paclitaxel. Carboplatin has been used, although not extensively, as a single agent in advanced breast cancer, with response rates ranging from 25% to 35%.27,28 However, the combination of carboplatin with paclitaxel has become an area of focus in breast cancer relatively recently. The earlier studies of the combination of paclitaxel and carboplatin for the treatment of advanced breast cancer were conducted by using an every-3-weeks schedule for treatment.19-21 In a study of previously treated patients with advanced breast cancer, Fountzilas et al19 achieved an overall response of 43% and a median survival time of 12 months. In studies using the regimen as first-line therapy for advanced and metastatic disease, Fountzilas et al20 and Perez et al21 achieved response rates of 54% and 62%, respectively. The median survival in the Fountzilas et al study was 20.4 months, and an estimated 12-month survival of 72% was obtained in the Perez et al study. The results of this study demonstrate that the addition of carboplatin to a weekly paclitaxel regimen resulted in a response rate (62%) comparable to the best response rates obtained with single-agent paclitaxel in single-institution settings. It represents nearly a doubling in response over rates obtained in randomized studies of single-agent paclitaxel on an every-3-weeks schedule23-26 and is more than double that obtained by Perez et al10 in their study of single-agent paclitaxel conducted in a multicenter community setting similar to that of this study. The data also clearly establish that paclitaxel and carboplatin, given on a weekly basis as first-line therapy for patients with advanced breast cancer, has comparable efficacy to that seen in studies of the combination using the traditional every-3-weeks schedule. In addition, the 62% response rate is comparable to rates obtained in multicenter studies combining a taxane and doxorubicin.29-31 Although the efficacy data alone offer a substantial argument for the use of weekly paclitaxel and carboplatin in advanced breast cancer, a full appreciation of the weekly paclitaxel and carboplatin schedule requires careful examination of toxicity profiles—specifically, those toxicity profiles seen with paclitaxel plus carboplatin given on an every-3-weeks schedule and of weekly single-agent paclitaxel in comparison to those seen with this study. The toxicity profile from this study (Table 3) falls between those seen with weekly single-agent paclitaxel and with the paclitaxel and carboplatin combination on an every-3-weeks schedule. The incidence of grade 3 and 4 neutropenia in this study was 35% for the total population, with an overall 17% incidence of leukopenia. The incidence of grade 3 or 4 neutropenia was 50% for group 1 and 31% for group 2, and for leukopenia it was 35% for group 1 and 13% for group 2, demonstrating that the dose reduction from 100 mg/m2 in group 1 to 80 mg/m2 in group 2 was successful in lessening hematologic toxicity. The incidence rate for grade 3 or 4 neuropathy was 11% overall. Other grade 3 and 4 toxicities included infection (6%), anemia (5%), weakness (6%), paresthesia (3%), and congestive heart failure (1%). The patient who experienced congestive heart failure had a history of cardiac disease, including congestive heart failure, and the exact cause of the event remains unknown. Table 4 compares the safety and efficacy results obtained in this study with those obtained by Perez et al10,21 in their single-agent weekly paclitaxel and paclitaxel/carboplatin studies in advanced breast cancer. They observed grade 3 and 4 neutropenia in 82% of their patients receiving paclitaxel and carboplatin combined, but there were no episodes of febrile neutropenia or sepsis. There was a 16% incidence rate of grade 3 neuropathy in the study. In contrast, grade 3 or 4 neutropenia was reported for only 15% of patients in the Perez et al single-agent weekly paclitaxel study, with the majority of those patients having received prior chemotherapy. Neuropathy was observed at only a 9% incidence rate in that study. With a 35% incidence of grade 3 or 4 neutropenia, the weekly regimen used in this study was clearly less myelosuppressive than the every-3-weeks regimen used by Perez et al (82% grade 3 or 4 neutropenia). The 11% neuropathy incidence approximates that seen by Perez et al in their single-agent weekly paclitaxel study. Also of interest in relation to the platelet-sparing effect of paclitaxel in combination with carboplatin, only one patient in the present study experienced thrombocytopenia (grade 3), in comparison to 18% grade 3 or 4 thrombocytopenia in the Perez et al study with the every-3-weeks schedule. Thus, use of the weekly schedule may take full advantage of the platelet-sparing phenomenon.
The safety and response data described for this study clearly demonstrate that the combination of weekly paclitaxel and carboplatin offers a more favorable toxicity profile than the every-3-weeks schedule while achieving similar efficacy. However, the time to progression was reduced in comparison to that obtained by Perez et al in their study of paclitaxel and carboplatin given on an every-3-weeks schedule (Table 4). The question then becomes what is the difference between the two regimens that accounts for similar response rates but a disparity in time to progression? Similar to doxorubicin, paclitaxel can be given on a weekly basis with a lessening in toxicity, in comparison to an every-3-weeks schedule, but without a loss of efficacy in terms of response rate. However, there may be a difference in a weekly versus an every-3-weeks schedule for carboplatin administration. With the advent of AUC dosing of carboplatin came corresponding improvements in the efficacy of the drug and the realization that there is a dose-dependence effect with carboplatin. Therefore, it may be that the difference in the methods of administration of carboplatin between this study, with a weekly regimen, and the Perez et al study, with an every-3-weeks regimen, is what accounts for the observed difference in time to progression. For use as a radiation sensitizer, a weekly carboplatin regimen is likely fine. However, for use as part of a combination cytotoxic regimen, carboplatin may best be given at higher doses on an every-3-weeks or every-4-weeks schedule. Burris et al32 recently reported on a study involving therapy with trastuzumab (Herceptin; Genentech, Inc, South San Francisco, CA) followed by combination therapy with trastuzumab, paclitaxel (70 mg/m2/wk), and carboplatin (AUC 2/wk) for patients with stable disease or paclitaxel and carboplatin alone for patients who progressed on single-agent trastuzumab. Paclitaxel and carboplatin were given on a 6 of every 8 weeks schedule. At the time that the data were presented, 16 patients had proceeded on to therapy with the trastuzumab, paclitaxel, and carboplatin combination. Among those 16 patients, there were three CRs and six PRs, giving a response rate of 56%. In addition, there were 12 patients who experienced disease progression with single-agent trastuzumab. When these patients went on to receive weekly paclitaxel plus carboplatin, a response rate of 58% was achieved (one CR and six PRs). The primary toxicity observed in the study was brief and reversible myelosuppression. Three patients experienced significant decreases in left ventricular ejection fraction values, but no symptomatic cardiotoxicity was observed in the study. Taken together, the results of our study and those reported by Burris et al have implications for the adjuvant regimens of the future. The necessity of using anthracycline-containing adjuvant therapy regimens for breast cancer is being questioned. Anthracyclines seem most active in HER-2–positive patients, but if the toxicity of the trastuzumab and anthracycline combination proves too great, which is more important, the trastuzumab or the anthracycline? The question also remains as to whether anthracyclines are needed for HER-2–negative patients. The weekly paclitaxel and carboplatin regimen introduced in this study has potential as a nonanthracycline regimen in the adjuvant therapy of HER-2–negative patients. In HER-2–positive patients, the regimen could ideally combine with weekly trastuzumab and avoid the potential cardiac toxicity of giving trastuzumab in proximity to an anthracycline. Therapy for first-line advanced and metastatic breast cancer is entering a new era with the use of combination regimens, including paclitaxel plus carboplatin. The 62% overall response rate obtained in this community-based, multicenter study introducing a new regimen of weekly paclitaxel and carboplatin is among the highest rates obtained in trials conducted in similar settings with current regimens for the treatment of advanced breast cancer. The toxicity profile of the combined paclitaxel and carboplatin regimen demonstrates that the schedule used in this study is less myelosuppressive than an every-3-weeks schedule and lacks the cardiotoxicity of doxorubicin regimens commonly used today. With comparable efficacy and a more favorable safety profile, the regimen may be ideal for elderly patients, those with physical debilitation who require less toxic therapy, or those with prior cardiac compromise who are not candidates for therapy with anthracyclines. The weekly paclitaxel plus carboplatin regimen used in this study brings us a step closer to that elusive optimal regimen for advanced breast cancer.
Supported in part by a grant from Bristol-Myers Squibb Oncology, Plainsboro, NJ.
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17. Belani CP, Kearns CM, Zuhowski EG, et al: Phase I trial, including pharmacokinetic and pharmacodynamic correlations, of combination paclitaxel and carboplatin in patients with metastatic non-small cell lung cancer. J Clin Oncol 17: 676-684, 1999
18. Pertussini E, Ratajczak J, Majka M, et al: Investigating the platelet-sparing mechanism of paclitaxel/carboplatin combination therapy. Blood 97: 638-644, 2001 19. Fountzilas G, Athanassiadis A, Kalogera-Fountzila A, et al: Paclitaxel by 3-h infusion and carboplatin in anthracycline resistant advanced breast cancer: A phase II study conducted by the Hellenic Cooperative Oncology Group. Eur J Cancer 33: 1893-1895, 1997[CrossRef][Medline]
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26. 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 B-26. J Clin Oncol 17: 3403-3411, 1999
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28. O’Brien ME, Talbot DC, Smith IE: Carboplatin in the treatment of advanced breast cancer: A phase II study using a pharmacokinetically guided dose schedule. J Clin Oncol 11: 2112-2117, 1993 29. Pluzanska A, Pienkowski T, Jelic S: Phase III multicenter trial comparing Taxol/doxorubicin (AT) vs. 5-fluorouracil/doxorubicin and cyclophosphamide (FAC) as first-line treatment for patients with metastatic breast cancer. Presented at the 22nd Annual San Antonio Breast Cancer Symposium 30, San Antonio, TX, December 8-11, 1999 (abstr 21) 30. Nabholtz JM, Falkson C, Campos D, et al: Doxorubicin and docetaxel (AT) is superior to standard doxorubicin and cyclophosphamide as first-line CT for MBC: Randomized phase III trial. Presented at the 22nd Annual San Antonio Breast Cancer Symposium 84, San Antonio, TX, 1999 (abstr 330) 31. Biganzoli L, Cufer T, Burning P, et al: Doxorubicin (a)/Taxol (T) versus doxorubicin/cyclophosphamide (C) as first-line chemotherapy in metastatic breast cancer (MBC): A phase III study. Proc Am Soc Clin Oncol 19: 73a, 2000 (abstr 282) 32. Burris HA, Hainsworth JD, Miranda FT, et al: Phase II trial of Herceptin induction followed by combination therapy with paclitaxel and carboplatin: A Minnie Pearl Research Network Trial. Presented at the 23rd Annual San Antonio Breast Cancer Symposium, San Antonio, TX, December 6-9, 2000 (abstr 24) Submitted August 21, 2001; accepted June 11, 2002.
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2. Estrogen and progesterone receptor status were evenly distributed among both groups. Sixty-one patients received prior chemotherapy, 37 (61%) of whom received prior doxorubicin. Among 47 patients who received prior hormonal therapy, 43 received tamoxifen. 
grade 3 peripheral neuropathy had their paclitaxel dose reduced by 25% in subsequent cycles. For other toxicities of 
