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Doxorubicin and Paclitaxel Versus Doxorubicin and Cyclophosphamide as First-Line Chemotherapy in Metastatic Breast Cancer: The European Organization for Research and Treatment of Cancer 10961 Multicenter Phase III Trial

From the Investigational Drug Branch for Breast Cancer, European Organization for the Research and Treatment of Cancer Data Center, and Jules Bordet Institute, Brussels, Belgium; Institute of Oncology, Ljubljana, Slovenia; Antoni van Leeuwenhoek Ziekenhuis, Amsterdam, the Netherlands; Weston Park Hospital National Health Service Trust, Sheffield; Newcastle General Hospital, Newcastle-Upon-Tyne; and University of Glasgow, Glasgow, United Kingdom; Regina Elena Institute, Rome, Italy; Centre Georges-François Leclerc, Dijon, France; and Rambam Medical Centre, Haifa, Israel.

Address reprint requests to Martine Piccart, Jules Bordet Institute, Bd de Waterloo 125, 000 Brussels, Belgium; email: martine.piccart{at}bordet.be

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: To compare the efficacy and tolerability of the combination of doxorubicin and paclitaxel (AT) with a standard doxorubicin and cyclophosphamide (AC) regimen as first-line chemotherapy for metastatic breast cancer.

PATIENTS AND METHODS: Eligible patients were anthracycline-naive and had bidimensionally measurable metastatic breast cancer. Two hundred seventy-five patients were randomly assigned to be treated with AT (doxorubicin 60 mg/m² as an intravenous bolus plus paclitaxel 175 mg/m² as a 3-hour infusion) or AC (doxorubicin 60 mg/m² plus cyclophosphamide 600 mg/m²) every 3 weeks for a maximum of six cycles. A paclitaxel (200 mg/m²) and cyclophosphamide (750 mg/m²) dose escalation was planned at cycle 2 if no grade 3 neutropenia occurred in cycle 1. The primary efficacy end point was progression-free survival (PFS). Secondary end points were response rate (RR), safety, overall survival (OS), and quality of life.

RESULTS: A median number of six cycles were delivered in the two treatment arms. The relative dose-intensity and delivered cumulative dose of doxorubicin were lower in the AT arm. Dose escalation was only possible in 17% and 20% of the AT and AC patients, respectively. Median PFS was 6 months in the two treatments arms. RR was 58% versus 54%, and median OS was 20.6 versus 20.5 months in the AT and AC arms, respectively. The AT regimen was characterized by a higher incidence of febrile neutropenia, 32% versus 9% in the AC arm.

CONCLUSION: No differences in the efficacy study end points were observed between the two treatment arms. Treatment-related toxicity compromised doxorubicin-delivered dose-intensity in the paclitaxel-based regimen

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
BREAST CANCER is by far the most common malignancy in women in the Western world.¹ Metastatic breast carcinoma is largely incurable. The median survival of women with metastatic breast cancer is in the range of 2 years. Therefore, the development of drugs and strategies that improve overall survival is a high priority. Anthracyclines and taxanes are among the most active chemotherapeutic drugs for the treatment of breast cancer. A response rate of 40% has been consistently demonstrated using doxorubicin at doses of 60 to 75 mg/m² given every 3 weeks.²

The combination of anthracycline and cyclophosphamide (AC) is commonly used as first-line chemotherapy in metastatic breast cancer, with or without fluorouracil. Recent data from phase III trials show response rates of 37% to 57% and median time to progression ranging from 6 to 9 months for fluorouracil + AC–type regimens.^3-9 The taxanes, paclitaxel and docetaxel, have both shown significant activity in first- and second-line therapy of metastatic disease.^10-14 The association of these two classes of drugs was therefore investigated with the aim of improving on the results achieved with each single agent and standard chemotherapy regimens. In particular, the combination of doxorubicin and paclitaxel has been investigated in several phase I/II studies.¹⁵ Among the different doses and schedules evaluated, bolus doxorubicin followed after a short interval (15 to 30 minutes) by a 3-hour paclitaxel infusion (AT), had impressively high overall (83% to 94%) and complete (24% to 41%) response rates as first-line treatment in women with metastatic breast cancer.^16,17 The unacceptably high incidence of congestive heart failure (CHF; 21%) associated with this regimen could be overcome by limiting the cumulative total dose of doxorubicin to 360 mg/m².¹⁸

For these reasons, the European Organization for the Research and Treatment of Cancer (EORTC) Breast Group in collaboration with the Early Clinical Study Group decided to launch a randomized phase III study to compare the activity of AT with a standard AC combination as first-line chemotherapy for metastatic breast cancer patients. Both were to be given for a maximum of six cycles and doxorubicin was not to exceed a cumulative dose of 360 mg/m².

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Eligibility Criteria
Eligible for the study were women aged 18 to 70 years with histologically or cytologically proven breast cancer who had metastatic disease and uni-or bidimensionally measurable lesions, were anthracycline- and taxane-naïve, and had not been pretreated with chemotherapy for metastatic disease. Prior adjuvant chemotherapy with cyclophosphamide, methotrexate, and fluorouracil or comparable regimens was allowed if the interval between the end of chemotherapy and disease relapse was 6 months. Prior hormonal therapy, immunotherapy, and localized radiotherapy were permitted in the adjuvant and metastatic settings. Other requirements for eligibility were Eastern Cooperative Oncology Group performance status of 0 to 2, a life expectancy of at least 12 weeks, and the provision of written informed consent to participate in the trial.

Patients were required to have adequate hematologic (absolute neutrophil count 1.5 x 10⁹, platelet count 100 x 10⁹), renal (creatinine 1.25 times the upper normal limit), hepatic (total bilirubin 1.25 times the upper normal limit, AST and/or ALT 2.5 times the upper normal limit), and cardiac (left ventricular ejection fraction [LVEF] measured by echocardiography or multiple gated acquisition scan within normal institution limits) function. Baseline evaluation, performed within 2 weeks of therapy initiation, included medical history, physical examination, performance status, routine hematology and biochemistry parameters, electrocardiography, and tumor assessment.

Exclusion criteria included symptomatic brain metastases, bone metastases as the only site of disease, a past or current history of neoplasm other than breast carcinoma (except for nonmelanoma skin cancer or curatively treated carcinoma-in-situ of the cervix), a history of atrial or ventricular arrhythmias which were clinically significant or which required treatment or CHF, documented myocardial infarction, and pre-existing motor or sensory neuropathy greater than grade 1. The protocol was approved by the EORTC Protocol Review Committee and the ethics committees of the local participating institutions.

Treatment
In this multicenter trial, patients were centrally randomized at the EORTC Data Center in Brussels. After stratification for center, prior chemotherapy (none v adjuvant), performance status (Eastern Cooperative Oncology Group 0 v 1 to 2), and presence of bone metastases (yes v no), patients were randomized to receive either AT (doxorubicin 60 mg/m² as an intravenous [IV] bolus plus paclitaxel 175 mg/m² given as a 3-hour infusion starting 30 minutes after the end of doxorubicin) or AC (doxorubicin 60 mg/m² plus cyclophosphamide 600 mg/m²). Patients assigned to AT received premedication with dexamethasone 20 mg given orally 12 and 6 hours before therapy, diphenhydramine 50 mg, and cimetidine 300 mg or ranitidine 50 mg IV 30 minutes before paclitaxel. Both treatments were given every 3 weeks for a maximum of six cycles.

The starting dose level was defined as level 0. A dose escalation (level +1) was planned at cycle 2 for both regimens if no grade 3 or 4 neutropenia occurred in cycle 1. Level +1 doses of paclitaxel were 200 mg/m² and of cyclophosphamide, 750 mg/m².

Dose modifications were based on weekly monitoring of hematology and assessment of other toxicities every 3 weeks. Two dose-reduction levels (level -1/-2: doxorubicin 45 mg/m², paclitaxel 150/135 mg/m², cyclophosphamide 500/400 mg/m²) could be applied. After a dose reduction, all subsequent cycles had to be administered at the reduced dosage and no subsequent dose escalations were allowed. Dose reductions were required in case of grade 4 neutropenia and/or thrombocytopenia lasting 7 days, febrile neutropenia, grade 3 mucositis, or grade 3 neuropathy.

Treatment delay or discontinuation was instituted as follows. If on day 21 neutrophils were less than 1.5 x 10⁹/L and or the platelet count was less than 100 x 10⁹/L, the treatment was delayed for a maximum of 3 weeks. Patients who did not achieve hematologic recovery by day 42 were taken off treatment. In case of mucositis grade 2 or higher, the treatment was delayed for a maximum of 2 weeks. If on day 35 mucositis recovered to at least grade 2, the treatment was reduced by one dose level. If mucositis greater than grade 2 persisted, the patient was taken off treatment.

Doxorubicin was to be stopped in patients who developed CHF, an absolute LVEF drop of 5% below the normal limit, or a relative drop of 10% from baseline and to below the normal limit. The treatment was stopped if major organ toxicity of greater than grade 2 occurred, with the exception of the above-mentioned toxicities, alopecia, grade 3 vomiting, and myalgia. No secondary prophylaxis with hematologic growth factors was allowed. Secondary prophylaxis with antibiotics was permitted but not recommended.

Efficacy Analysis
Tumor measurements were performed every 6 weeks until disease progression. Patients who received at least two cycles of therapy were evaluated for tumor response. Tumor response was assessed according to the World Health Organization criteria.¹⁹ Duration of response was defined as the time between the date of first response (either complete response [CR] or partial response) and the date of progression or death.

Progression-free survival was calculated as the time interval from the date of randomization to the first indication of disease progression or death, whichever occurred first. Patients who received second-line therapy before progression was documented were considered as having progressed on the day second-line therapy was started. Survival was measured from the date of randomization to the time of death, and living patients were censored at the last follow-up date. Response rates, progression-free survival, and survival were analyzed according to the intent-to-treat principle.

Safety Analysis
All the patients who received at least one cycle of chemotherapy were included in the safety analysis. Physical examination and serum chemistry were repeated before each cycle, and hematologic monitoring was performed weekly while the patients were receiving therapy. A multiple gated acquisition scan or an echocardiography for the evaluation of the LVEF was mandatory at study entry, before cycles 3, 5, and 6, and 3 months after the last chemotherapy cycle (first follow-up). Toxicity was assessed according to the National Cancer Institute of Canada common toxicity criteria after each cycle of chemotherapy.

Quality of Life
Quality of life was assessed by the EORTC Quality of Life Questionnaire C30 and the Breast Cancer module BR-23 at baseline, before cycles 2, 4, and 6, and at the first follow-up.

Statistical Analysis
The planned sample size for this study was 260 patients. The study had 80% power to detect a 50% relative increase in progression-free survival (from 8 to 12 months in favor of the paclitaxel arm) based on a two-sided log-rank test with alpha equal to 0.05.

The primary end point of the study was progression-free survival; secondary end points were response rate, safety, survival, and quality of life. (Quality of life data will not be reported in this publication.) Progression-free survival and survival were estimated using the Kaplan-Meier method, and the two treatment groups were compared using a two-sided log-rank test. Response rates and febrile neutropenia rates were compared by the ² test.

	RESULTS

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Patient Population
Between November 1996 and February 1999, 275 patient from 24 institutions were randomized to receive AT (138 patients) or AC (137 patients) (Table 1). Patient characteristics were well balanced between the two treatment arms (Table 2). Of note, more than 80% of the patients had visceral disease and at least two cases involved sites of disease. The median disease-free interval was longer in the AC arm but the difference was not statistically significant (P = .0893).

View larger version (11K): [in this window] [in a new window]   Fig 1. Modification of doxorubicin mean relative dose-intensity during treatment.

Efficacy Results
All randomized patients were evaluated for response rate, progression-free survival, and overall survival according to the intent-to-treat principle. Progression-free survival curves are presented in Fig 2. At a median follow-up of 29.2 months, only 10 patients had not experienced progression or death. The median progression-free survival was 6 months in both the treatment arms (P = .65) (95% confidence interval [CI] for both arms, 5.1 to 6.8 months). The hazard ratio (HR) for AC versus AT was 1.06 (95% CI, 0.83 to 1.35).

View larger version (12K): [in this window] [in a new window]   Fig 2. Kaplan-Meier curve for progression-free survival.

View larger version (11K): [in this window] [in a new window]   Fig 3. Kaplan-Meier curve for overall survival.

Toxicity
All the treated patients were assessable for toxicity (Table 5). Both regimens were myelotoxic. The incidence of grade 4 neutropenia was similar in the two treatment arms, but neutropenic fever occurred more frequently in patients treated with AT (P > .001). Febrile neutropenia was first defined as the occurrence of grade 2 fever ( 38.1°C) associated with grade 4 neutropenia requiring hospitalization and IV anti-infective treatment. This definition was amended, while the study was ongoing, to grade 2 fever with grade 4 neutropenia requiring anti-infective treatment, because of the increasing practice of treating febrile neutropenic patients as outpatients with oral anti-infective agents. According to the latter definition, febrile neutropenia was reported in 32% and 9% of AT and AC patients, respectively. One toxic death caused by neutropenic sepsis occurred in the AC arm.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
This study showed no differences in terms of response rate, progression-free survival, or overall survival between the AT regimen and a standard anthracycline-based chemotherapy in the treatment of metastatic breast cancer patients. In order to identify the possible reasons leading to these results the data were critically reviewed.

The study population was particularly poor in terms of prognosis, given that more than 80% had visceral involvement and that more than three sites of disease were involved in 25% of the patients. However, these prognostic factors were evenly distributed among the two treatment groups. The median disease-free interval was longer in the AC arm, but this had no effect on the primary study end point in both a univariate (P = .3) and a multivariate analysis (HR = 1.6, P = .6). Therefore, the study results cannot be explained by an imbalance in major known prognostic factors between the two groups.

The ability to receive the initially prescribed treatment was substantially different between the two treatments arms, with a higher percentage of patients and cycles dose reduced in the AT arm. This resulted in a suboptimal dose-intensity of both doxorubicin and paclitaxel. A relative dose-intensity of doxorubicin and paclitaxel greater than 90% was delivered to only 54% and 60%, respectively, of the AT patients. The mean relative dose-intensity of doxorubicin progressively decreased from cycle 2 and dropped to below 80% at cycle 5. The cumulative delivered dose of doxorubicin was also significantly lower in the AT arm.

Several studies have evaluated either in a prospective or retrospective way the role of dose-intensity and cumulative dose in the treatment of breast cancer. The anthracyclines are among the most extensively studied drugs. Although the value of increased dose-intensity regimens has not yet been demonstrated, it is universally agreed, at least in treatment of early breast cancer, that the delivery of suboptimal doses of anthracyclines produces a worse outcome.²⁰ The low dose-intensity and cumulative delivered dose of doxorubicin might have compromised AT efficacy in this study.

Could dose-intensity have been maintained with granulocyte colony-stimulating factor (G-CSF)? Among the clinically relevant side effects reported in Table 5, the most frequent events to affect AT patients compared with the AC population were a fall in LVEF and febrile neutropenia. Despite the higher incidence of LVEF reductions in patients receiving AT, cardiotoxicity was the reason for first dose reduction in only 10 patients in each arm. Doxorubicin discontinuation because of cardiotoxicity was also similar between the two groups. In contrast, febrile neutropenia was the reason for first dose reduction in 50% of the AT patients compared with 17% of the AC patients. In view of the palliative nature of the treatment, it was decided not to allow secondary prophylaxis with G-CSF; dose reduction was considered a reasonable alternative to G-CSF.

In the Milan phase I/II trial (n = 34 patients) conducted in chemotherapy-naive metastatic breast cancer patients, the maximum-tolerated dose of paclitaxel in combination with doxorubicin (60 mg/m²) was 200 mg/m². Dose-limiting toxicities were febrile neutropenia, neutropenia lasting more than 7 days, and mucositis.¹⁸ The study was later amended by adding G-CSF in case of grade 4 neutropenia in order to improve adherence to schedule and tolerability. Among 49 patients assessable for toxicity, the use of G-CSF significantly decreased the duration of severe neutropenia but did not affect febrile neutropenia.¹⁸ The study failed to confirm the role of G-CSF as prophylaxis against febrile neutropenia. The small sample size and the relatively low incidence of febrile neutropenia, however, suggest that its role may not have been adequately tested. It can be concluded that the higher incidence of febrile neutropenia—and the required dose reductions that followed—was one of the major reasons for the lower dose-intensity in the AT arm. It is debatable whether G-CSF prophylaxis could have improved this, given the available data.

Was the study primary end point too ambitious? The answer is most likely "Yes!" The study was designed to have an 80% power to identify a 50% increase in progression-free survival for AT (12 months) compared with AC (8 months). The median progression-free survival observed was 6 months in both treatment arms. For the control arm, the outcome was worse than expected, probably because of the poor patient characteristics discussed previously. Unfortunately, progression-free survival of the taxane arm was far below our expectations, but none of the recently conducted phase III trials that have investigated the role of a taxane-based regimen as first-line chemotherapy for metastatic breast cancer showed a 12-month progression-free survival (Table 6). We therefore have to conclude that this target is not achievable with the currently available regimens.

Three randomized studies have evaluated the efficacy of an anthracycline-paclitaxel combination as first-line chemotherapy in the metastatic setting.^4,5,7 In two studies, from the Arbeitsgemeinschaft Gynäkologische Onkologie (AGO)⁴ and the United Kingdom Coordinating Committee on Cancer Research (UKCCCR),⁷ epirubicin was the selected anthracycline (epirubicin plus paclitaxel v epirubicin plus cyclophosphamide). Despite a larger sample size (AGO, 560 patients; UKCCCR, 750 patients), these studies also failed to show superiority of the paclitaxel-based regimen over the control treatment.

In the Central and Eastern Europe and Israel Paclitaxel Breast Cancer Study Group (CEEIPBCSG) trial,⁵ 267 patients were randomized to receive either doxorubicin 50 mg/m² followed 24 hours later by paclitaxel 220 mg/m² (AT) or fluorouracil 500 mg/m², doxorubicin 50 mg/m², and cyclophosphamide 500 mg/m² every 3 weeks for a maximum of eight cycles. Response rate, median time to progression, and median overall survival significantly favored the AT regimen. The statistical design of this study was identical to that of the study reported here. The major differences between the EORTC and the CEEIPBCSG trials were the interval between the delivery of doxorubicin and paclitaxel, the treatment duration, and the paclitaxel dose per cycle.

It is known that the time interval that separates the administration of doxorubicin and paclitaxel has an impact on doxorubicin pharmacokinetics.²¹ The area under the concentration-time curve, the elimination half-life, and the peak plasma drug concentration of doxorubicin and/or doxorubicinol were significantly higher in patients given doxorubicin by intravenous bolus 15 minutes before paclitaxel as compared with the administration of doxorubicin and paclitaxel 24 hours apart. These data could explain the lower incidence of AT-related hematologic (grade 4 neutropenia, 62% v 89%; febrile neutropenia, 32% v 8%) and cardiac toxicity reported by Jassem et al⁵ in comparison with those observed in the EORTC trial. As a consequence of the lower toxic profile, 88% of patients randomized to AT received greater than 90% of the relative dose-intensity in the former trial. In the EORTC study as well as in the AGO and UKCCCR studies, a maximum of six cycles of chemotherapy were allowed compared with a maximum of eight cycles in the CEEIPBCSG trial.

Are six cycles of a paclitaxel(-based) therapy an adequate treatment for metastatic breast cancer patients? Among 47 metastatic breast cancer patients treated with the doxorubicin and paclitaxel combination for six or eight cycles followed by single-agent paclitaxel, six treatment cycles were sufficient to achieve at least a partial response in all 44 responding patients.¹⁸ However, continuous treatment with single-agent paclitaxel after discontinuation of doxorubicin led to a marked increase in the final complete response rate. The possible antiangiogenic properties of paclitaxel suggest an advantage to prolonged treatment with paclitaxel.²² In the current trial, however, maintenance therapy with paclitaxel was not allowed because progression-free survival was the primary end point; also, the recommended maximum cumulative doxorubicin dose of 360 mg/m² precluded the delivery of more than six cycles of combination chemotherapy in the two arms of the present study. Thus, methodologic and safety reasons prevented the administration of more than six cycles of chemotherapy in the EORTC trial.

The paclitaxel dose per cycle was 175 mg/m² in the EORTC trial versus 220 mg/m² in the CEEIPBCSG study. Data from a randomized trial suggest 175 mg/m² to be the recommended dose of single-agent 3-hour infusion paclitaxel.²³ Whether higher doses of paclitaxel in combination regimens may increase efficacy has not been proven.

The doxorubicin-paclitaxel combination, as given in our trial, is no more effective than a standard doxorubicin-based combination as first-line chemotherapy in the treatment of breast cancer. Lower drug dose-intensities and doxorubicin cumulative doses in the AT arm, resulting from the higher hematologic toxicity of this regimen as well as the limitation to six cycles of therapy, are a possible explanation for these results.

Three randomized trials have evaluated the role of docetaxel-based regimens in comparison with standard anthracycline-based combinations as first-line treatment for metastatic breast cancer patients^3,8,9 (Table 6). All three show improved response rates with the docetaxel-based regimen, while only one so far reported an increase in time to progression (the others were either too early or a randomized phase II comparison).

Quality of life and survival are the main end points to consider when treating metastatic breast cancer patients. Only one of the experimental treatments reported in this article showed a benefit in terms of survival over the standard regimens, and all taxane-based regimens often resulted in more toxicity. On the basis of our trial and the available randomized trial literature, a standard anthracycline-based chemotherapy remains the treatment of choice as first-line chemotherapy for the treatment of metastatic breast cancer patients not previously treated with anthracyclines. It is the opinion of the authors that only a meta-analysis of all randomized clinical trials exploring anthracycline-taxane regimens will determine whether those regimens do have an impact on survival in women with metastatic breast cancer. Such a meta-analysis is being organized by the EORTC in close collaboration with the Breast Cancer International Research Group and the Center for Statistics of the Limburgs Universitair Centrum.

APPENDIX
The following investigators and their institutions also participated in the study: B. Rapoport, The Medical Oncology Center, Johannesburg, South Africa; M. Nooij, LUMC, Leiden, the Netherlands; P. Ellis, Guy’s Hospital, London, United Kingdom; A. Sulkes, Beilinson Medical Center, Petach Tikva, Israel; H. Curé, Centre Jean Perrin, Clermont Ferrand, France; C. Mendiola, Hospital Universitario 12 de Octubre, Madrid, Spain; D. Spaeth, Centre Alexis Vautrin, Vandoeuvre-les-Nancy, France; R. Morant, Kantonsspital, St Gallen, Switzerland; J.P. Guastalla, Centre Léon Bérard, Lyon, France; C. Dittrich, Kaiser Franz Josef-Spital, Vienna, Austria; L. Beex, Universitair Ziekenhuis Nijmegen, Nijmegen, the Netherlands; L. Mauriac, Fondation Bergonié, Bordeaux, France; K.J. Roozendaal, Onze Lieve Vrouw Gasthuis, Amsterdam, the Netherlands; T. Velu, Hôpital Erasme, Brussels, Belgium; and M. Aapro, European Institute of Oncology, Milan, Italy.

	ACKNOWLEDGMENTS

 
Supported by Bristol-Myers Squibb. C.L. was supported by a fellowship from Fonds Heuson.

We thank the women who agreed to participate in this trial. We also thank E. Donato Di Paola, MD, C. Yague, and I. Van Hoorenbeeck for their assistance and M. Delval for secretarial help.

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Submitted November 1, 2001; accepted April 2, 2002.

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