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© 2001 American Society for Clinical Oncology Doxorubicin and Paclitaxel Versus Fluorouracil, Doxorubicin, and Cyclophosphamide as First-Line Therapy for Women With Metastatic Breast Cancer: Final Results of a Randomized Phase III Multicenter Trial kowski uzaska
From the Medical University, Gda
Address reprint requests to Jacek Jassem, MD, PhD, Department of Oncology and Radiotherapy, Medical University of Gda
PURPOSE: This phase III trial compared the efficacy and safety of doxorubicin and paclitaxel (AT) to 5-fluorouracil, doxorubicin, and cyclophosphamide (FAC) as first-line therapy for women with metastatic breast cancer. PATIENTS AND METHODS: A total of 267 women with metastatic breast cancer were randomized to receive either AT (doxorubicin 50 mg/m2 followed 24 hours later by paclitaxel 220 mg/m2) or FAC (5-fluorouracil 500 mg/m2, doxorubicin 50 mg/m2, cyclophosphamide 500 mg/m2), each administered every 3 weeks for up to eight cycles. Patients had to have measurable disease and an Eastern Cooperative Oncology Group performance status of 0 to 2. Only one prior non–anthracycline, nontaxane-containing adjuvant chemotherapy regimen was allowed. RESULTS: Overall response rates for patients randomized to AT and FAC were 68% and 55%, respectively (P = .032). Median time to progression and overall survival were significantly longer for AT compared with FAC (time to progression 8.3 months v 6.2 months [P = .034]; overall survival 23.3 months v 18.3 months [P = .013]). Therapy was generally well-tolerated (median of eight cycles delivered in each arm). Grade 3 or 4 neutropenia was more common with AT than with FAC (89% v 65%; P < .001); however, the incidence of fever and infection was low. Grade 3 or 4 arthralgia and myalgia, peripheral neuropathy, and diarrhea were more common with AT, whereas nausea and vomiting were more common with FAC. The incidence of cardiotoxicity was low in both arms. CONCLUSION: AT conferred a significant advantage in response rate, time to progression, and overall survival compared with FAC. Treatment was well-tolerated with no unexpected toxicities.
IT IS CLEAR that chemotherapy provides clinical benefit to many women with metastatic breast cancer.1-3 However, metastatic breast cancer remains essentially incurable and almost all women so diagnosed will eventually die from their disease. Therefore, important goals of current therapy are to palliate symptoms and prolong patient survival. The anthracycline doxorubicin has long been considered one of the most active agents in the treatment of breast cancer.1 Anthracycline-containing regimens such as 5-fluorouracil, doxorubicin, and cyclophosphamide (FAC) are associated with overall response rates of 60% to 80% in women with advanced breast cancer.3 Recent data indicate that use of an anthracycline-based chemotherapy regimen, results in higher overall response rates compared with non–anthracycline-containing regimens.4,5 Improvements in time to disease progression and overall survival have also been suggested.4 The taxanes, paclitaxel and docetaxel, are also highly active agents in advanced breast cancer.6-16 Data from a recent phase III randomized study, comparing paclitaxel to a regimen of cyclophosphamide, methotrexate, 5-fluorouracil, and prednisone, indicated that therapy with paclitaxel results in an improved survival outcome compared with the combination regimen.6 In a phase III trial docetaxel was demonstrated to produce higher response rates than doxorubicin.12 In another phase III trial in patients with disease progression after anthracycline-based therapy, docetaxel therapy resulted in an improved response rate, time to progression, and overall survival compared with a regimen of mitoxantrone and vinblastine.13 Given the high individual activities of the anthracyclines and the taxanes, and their incomplete clinical cross-resistance, the combination of these two types of agents seemed to be potentially attractive. In a phase II trial, an overall response rate of 57% was reported in women receiving docetaxel 60 mg/m2 and doxorubicin 60 mg/m2 with granulocyte colony-stimulating factor support as first-line therapy for metastatic breast cancer.17 Preliminary reports from a phase III trial comparing a combination of docetaxel 50 mg/m2 with doxorubicin 75 mg/m2 versus doxorubicin 60 mg/m2 with cyclophosphamide 600 mg/m2 have indicated a higher overall response rate for the docetaxel-based regimen (60% v 47%, respectively) with an improved time to progression.18,19 In several phase II trials of short infusions of paclitaxel with doxorubicin, encouraging overall response rates ranging from 52% to as high as 94% were demonstrated.20-24 However, a higher than expected incidence of congestive heart failure (CHF) noted in two of the early trials using this combination was cause for concern.21,22 Further investigation revealed that the risk for increased cardiac toxicity was generally associated with cumulative doxorubicin doses greater than 360 mg/m2 when combined with short infusions of paclitaxel.25 It is now appreciated that a pharmacokinetic interaction between doxorubicin and paclitaxel was the likely cause for the increase in cardiac toxicity.26 When short infusions of paclitaxel are given in close temporal relationship to bolus doses of doxorubicin, the elimination of doxorubicin and its major metabolite doxorubicinol can be decreased by as much as 30%. However, evaluation of clinical data from more than 900 patients revealed that if the cumulative doxorubicin dose was limited to 360 mg/m2, no increased risk of cardiac toxicity was observed.25 Another possibility is to increase the duration of time between paclitaxel and doxorubicin administration. Amadori et al evaluated the safety and efficacy of a regimen of doxorubicin 50 mg/m2 followed 16 hours later by a 3-hour infusion of escalating doses of paclitaxel up to 250 mg/m2 administered every 3 weeks for eight courses.20 An overall response rate of 78%, with a complete response rate of 31%, was observed among 32 patients enrolled. No patient developed CHF. Given the encouraging response rates observed with the combination of doxorubicin and paclitaxel (AT), we initiated a randomized phase III trial comparing this regimen to the commonly used FAC regimen as first-line treatment for women with metastatic breast cancer. To reduce the potential cardiotoxicity of AT combination, we used a modified version of the Amadori regimen in which the time interval between administration of doxorubicin and paclitaxel was increased to 24 hours. The trial was conducted from November 1996 to April 1998 and enrolled patients from 29 institutions in Central and Eastern Europe and Israel. The primary study end point was time to progression, with response rate, overall survival, and quality of life evaluated as secondary endpoints.
Patient Eligibility Patients with histologically confirmed metastatic breast cancer who had not received prior chemotherapy for metastatic disease were eligible for study. Patients were required to be between 18 and 75 years of age, have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2, have a life expectancy of more than 12 weeks, and provide written informed consent in accordance with institutional review board guidelines. A negative pregnancy test before study entry was required for women of childbearing potential. Patients may have received one non–anthracycline-containing adjuvant chemotherapy regimen provided treatment was completed at least 6 months before study entry. Prior taxane therapy was not allowed. Prior hormonal therapy, immunotherapy, and localized radiotherapy for metastatic disease were permitted. Concurrent palliative radiotherapy was allowed provided indicator lesions were outside of the radiation field.
All patients had to have clinically or radiographically uni- or bidimensionally measurable disease. Patients with asymptomatic brain metastases or nonmeasurable bone metastases were eligible provided they had other measurable sites of disease. At study entry, all patients were required to have adequate renal, hepatic, bone marrow, and cardiac functions defined as follows: serum creatinine Patients were ineligible if they had a history of neoplasm of other than breast carcinoma (excepting nonmelanomatous skin cancer or curatively treated cervical carcinoma in situ), a history of ventricular arrhythmias or congestive heart failure, pre-existing motor or sensory neuropathy more than grade 1, or any other underlying medical condition that would hinder study participation.
Treatment Dose reductions for both regimens were defined by protocol and allowed in the event of serious granulocytopenia, thrombocytopenia, stomatitis, febrile neutropenia, documented infection, or hemorrhage. Paclitaxel alone was dose reduced in the event of World Health Organization (WHO) grade 3 paresthesia. All therapy was discontinued if a patient developed symptomatic arrhythmia or heart block (other than first degree), a decrease in LVEF by more than 10%, a decline in LVEF below 50% with or without clinical symptoms of CHF, any other major organ toxicity, or a significant hypersensitivity reaction.
Response and Toxicity Assessment Physical examination and serum chemistries were repeated before each cycle and a CBC count and platelet count were obtained weekly while on therapy. Assessment of LVEF was performed before cycles five and seven and at the end of the study. Toxicity was assessed according to WHO criteria after each cycle of chemotherapy. All patients who received at least one course of therapy were assessable for toxicity.
Statistical Methods
The primary hypothesis test for time to progression was based on comparison between the two treatment arms using a logrank test stratified by prior adjuvant chemotherapy and presence of bone metastases. The associated hazard ratio (FAC/AT) and its 95% confidence interval (CI) were calculated. In addition to the stratification factors, several prognostic factors were prospectively identified: age at initial diagnosis (< 50 v Time to progression and survival were displayed using the Kaplan-Meier method.27 A 95% CI for the median of each variable was computed using the method of Brookmeyer and Crowley.28 For response, the treatment arms were compared using a Cochran-Mantel-Haenszel test stratified for prior adjuvant chemotherapy and presence of bone metastases. Fisher’s exact test for r*c tables was used to compare the treatment arms for the nominal and bivariate categorical variables.
Quality-of-Life Assessment
A total of 267 patients were enrolled at 29 participating institutions, with 134 patients randomized to receive AT therapy and 133 to receive FAC therapy. Patient characteristics were well-balanced between two treatment arms ( Table 1). The majority of patients, 93% in each arm, had an ECOG performance status of 0 or 1. All patients had disseminated disease, with 66% having visceral involvement and only 24% having disease confined to soft tissue and/or lymph nodes. Overall, 36% of patients had bone metastases, 33% had liver metastases, and 40% had lung metastases. Of the 267 patients, 94 (35%) had three or more involved metastatic sites. The extent of prior therapy was comparable in both arms. Overall, 45% of patients had received prior adjuvant chemotherapy. The number of patients who had not received any prior therapy was similar for each arm, 28% and 26% for patients randomized to AT and FAC, respectively.
Overall, 264 patients received treatment and 259 were assessable for response (one patient did not have measurable disease and four patients did not have adequate serial tumor measurements). A total of 871 courses of AT and 852 courses of FAC were administered. Most patients received the full planned therapy, as the median number of courses administered was eight (range, one to eight) in both arms. Planned dose-intensity was maintained in the majority of patients, with 88% of patients randomized to AT and 80% of patients randomized to FAC receiving greater than 90% of the intended dose. The dose-intensity of doxorubicin was equivalent between the two arms at 16 mg/m2 per week.
Response and Survival
All enrolled patients were evaluated for time to progression and overall survival in the intent-to-treat analyses. At the time of this analysis, tumor progression was documented in 196 (68% in the AT arm and 79% in the FAC arm) of 267 patients. For patients who received AT, the estimated median time to progression was 8.3 months (95% CI, 7.2 to 9.0), significantly longer (P = .034) than the estimated median of 6.2 months (95% CI, 5.8 to 7.6) for patients who received FAC ( Fig 1).
Overall survival was analyzed at a median follow-up time of 29 months, with 54 patients still alive in the AT arm compared with 38 in the FAC arm. The median overall survival estimate for patients treated with AT was 23.3 months (95% CI, 21.2 to 30.7), significantly longer (P = .013) than the median of 18.3 months (95% CI, 16.2 to 21.3) for patients receiving FAC ( Fig 2).
A total of 209 patients, 110 (82%) in the AT arm and 99 (74%) in the FAC arm received second-line therapy in the form of surgery, radiotherapy, chemotherapy, or hormonal therapy. There were 59 patients (44%) on the AT arm and 64 patients (48%) on the FAC arm who received second-line chemotherapy. The predominant agents used as second-line therapy included fluorouracil, cyclophosphamide, and methotrexate. Paclitaxel was used in the second-line setting in 1% of patients treated with AT and in 10% of patients treated with FAC, whereas docetaxel was used as second-line therapy in 1% and 14% of patients treated with AT or FAC, respectively. Aside from the taxanes, other second-line agents were used in comparable frequency for patients treated on each of the study arms. Multivariate analyses using a Cox regression model evaluated the impact of the potential prognostic factors on time to progression and survival. Analyzed factors included age at diagnosis, ECOG performance status, prior hormonal therapy, dominant site of disease, and time from initial diagnosis ( Table 3). These analyses confirmed a statistically significant treatment effect of AT versus FAC for both time to progression (adjusted P = .020) and overall survival (adjusted P = .019). Factors associated with a shorter time to relapse were ECOG performance status of 2, presence of visceral dominant disease, and a time of less than 24 months from an initial diagnosis of breast cancer. Visceral dominant disease and a shorter time from initial diagnosis were also associated with poorer overall survival.
Toxicity All 264 patients who received therapy were assessable for toxicity. Overall, therapy was well tolerated, with only 17 patients (6%) discontinuing therapy for treatment-related adverse events (11 patients in the AT arm and six patients in the FAC arm). Hospitalizations were recorded for 14% of patients but for only 3% of courses. Most hospitalizations were related to toxicities, particularly neutropenia, although tumor progression and other reasons were also reported. Neutropenia was the most frequently encountered toxicity, with grade 3 or 4 observed in 89% of patients receiving AT and in 65% of patients receiving FAC (P < .001) ( Table 4). There was no difference in the incidence of febrile neutropenia between the AT and FAC arms, (8% and 5% of patients, respectively; P = .339). Serious thrombocytopenia and anemia were infrequent.
Nonhematologic toxicities were generally reflective of the expected toxicity profiles of each of the regimens. Arthralgia/myalgia and peripheral neuropathy were more frequent in the AT arm but were usually of mild or moderate severity. Of the 16 patients (12%) who experienced severe peripheral neuropathy, only four discontinued treatment due to this toxicity. Peripheral neuropathy was generally reversible on cessation of therapy. Nausea and vomiting, including severe toxicity, were more common with FAC, whereas diarrhea was encountered more frequently in the AT arm. There were no differences in the incidence of severe diarrhea events or in the incidence of stomatitis between the two study arms. Serial evaluations of LVEF while on study were available for 124 patients in the AT arm and 123 patients in the FAC arm. A decline in LVEF to below 50% occurred in eight patients on each of the two study arms. At a cumulative doxorubicin dose of 400 mg/m2, the median LVEF value was 61% in patients treated with AT and 62% in patients treated with FAC. One patient in the FAC arm developed WHO grade 4 CHF after receiving a cumulative doxorubicin dose of 100 mg/m2.
Following therapy, LVEF values were available for 168 patients who did not receive second-line anthracycline-containing therapy (89 patients in the AT arm and 79 patients in the FAC arm). A relative decrease in LVEF of
There were two treatment-related deaths on study. One patient who had received AT had a myocardial infarction, developed septic shock, and died 8 days after the start of the first treatment cycle. The second patient treated with FAC developed acute cardiac, liver, and renal failure and died from toxicity after five courses of therapy.
Quality of Life
In this randomized phase III trial, the overall response rate, time to progression, and overall survival significantly favored the AT regimen compared with FAC therapy. This is the first phase III trial to demonstrate these benefits for a paclitaxel and anthracycline-containing regimen compared with a standard anthracycline-based multidrug regimen. Median time to progression, the primary study end point, was 2 months longer for patients receiving AT compared with those who received FAC, and median overall survival was 5 months longer for AT compared with FAC. The treatment benefit for AT therapy compared with FAC therapy on time to progression and overall survival was confirmed by multivariate analysis. Features associated with a shorter progression-free period and overall survival included visceral dominant disease and less than 24 months from initial diagnosis, whereas an ECOG performance status of 2 was associated with a shorter time to progression alone. We compared the results we achieved with the AT and FAC regimens to those reported in other phase III trials enrolling similar groups of patients. The median time to progression of 8.3 months that we observed with AT therapy is comparable to 8.0 months observed by Sledge et al for AT combination therapy in a phase III Intergroup trial.30 We observed an overall survival of 23.3 months, similar to the 22.4 months reported by Sledge et al We compared the overall survival we obtained with FAC to the results reported in four other randomized phase III trials enrolling comparable patients.31-34 In these studies, the median overall survival for FAC ranged from 12.8 to 20.3 months, suggesting that overall survival rate we observed in our control arm was representative and valid for comparison. The 5-month improvement in overall survival we observed with AT therapy seems to represent a considerable improvement in therapy for women with metastatic breast cancer. Several recent preliminary reports of randomized phase III studies have indicated that the combination of a taxane and anthracycline may potentially improve outcomes in women with metastatic breast cancer. In a phase III study of docetaxel and doxorubicin versus doxorubicin and cyclophosphamide, both overall response rate and time to progression favored patients receiving the docetaxel-based therapy.18,19 Preliminary results from a phase III study comparing epirubicin and paclitaxel to epirubicin and cyclophosphamide also indicated an advantage in time to progression for the paclitaxel/anthracycline combination.35 Response and survival data from a phase III trial of doxorubicin/paclitaxel versus doxorubicin/cyclophosphamide in women with metastatic breast cancer are awaited.36 Although results of these studies are preliminary at this time, they suggest that the combination of a taxane with an anthracycline may improve response and survival outcomes in women with metastatic breast cancer and are supportive of the findings in our trial. In the present study the ability to deliver the planned doses was comparable between study arms. The majority of patients in both treatment arms completed all eight cycles of therapy, and the delivered doxorubicin dose-intensity was equivalent between study arms. The potential impact of second-line therapy must always be considered when evaluating overall survival. The percent of patients who received second-line chemotherapy on disease progression was similar in both groups, except for taxane use, which was more common in patients who received FAC. Other agents used as second-line therapy were similar in both study arms. The percent of patients who received other forms of salvage therapy was also similar between study arms. Thus, it is unlikely that second-line therapy introduced bias with respect to survival. Therapy was generally well-tolerated on both arms of the trial, reflected by the fact that most patients received all planned therapy and more than 90% of intended dose-intensity was maintained in 88% of patients receiving AT and in 80% of patients receiving FAC. Grade 3 or 4 neutropenia was more common with AT therapy compared with FAC therapy; however, neutropenia was generally uncomplicated and the incidence of fever and infection was equivalent between the two arms. As could be expected, arthralgia, myalgia, and peripheral neuropathy were more common with AT therapy. Although 16 patients experienced serious neuropathy, only one patient had grade 4 toxicity, and only four patients discontinued therapy secondary to neuropathy. Neuropathy generally resolved after therapy was discontinued. Diarrhea was more common with AT therapy, whereas nausea and vomiting occurred more frequently in patients receiving FAC. The planned cumulative dose of doxorubicin was 400 mg/m2 on both arms of the study. There was no increased incidence of CHF on either study arm. Median LVEF was the same for patients on both arms, and declines in LVEF below 50% occurred with equal frequency (eight patients in each arm). These data confirm that the cardiac safety profile of doxorubicin and paclitaxel, given in the doses and schedules we used, is equivalent to what would be expected with doxorubicin alone. The time interval between doses of doxorubicin and paclitaxel presumably mitigated the pharmacokinetic interaction between drugs, resulting in no increase in cardiac effects. From a practical point of view, this regimen with a 24-hour interval between doxorubicin and paclitaxel should be amenable to outpatient administration. With respect to quality of life, there were no differences in eight of 10 functional scales and in eight of 13 symptom scales between the two study arms. Physical and sexual functioning, as well as pain, fatigue, insomnia, and diarrhea favored the FAC arm, whereas nausea and vomiting favored the AT arm. In principle, these measures reflect the higher incidence of several treatment toxicities in the AT arm, along with the increased incidence of nausea and vomiting in the FAC arm. We conclude that as first-line therapy for women with metastatic breast cancer, AT has a significant advantage over FAC in response rate, median time to progression, and most notably in overall survival. If our findings are confirmed in additional clinical studies, the use of the AT regimen should seriously be considered in current clinical practice.
APPENDIX
Supported by an unrestricted grant from Bristol-Myers Squibb Company, Waterloo, Belgium.
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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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, Poland; Institute of Oncology and Radiology, Belgrade, Yugoslavia; Oncology Research Center, Moscow, Russia; University Hospital for Tumors, Zagreb, Croatia; Latvian Cancer Center, Riga, Latvia; Uzsoki Hospital, Budapest, Hungary; Ichilov Hospital, Tel Aviv, Israel; and Bristol-Myers Squibb Company, Waterloo, Belgium.
binki St, 80-211, Gda
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ABSTRACT
INTRODUCTION
1.25 x laboratory upper normal limit; total bilirubin 
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