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© 2000 American Society for Clinical Oncology Phase III Comparative Study of Vinorelbine Combined With Doxorubicin Versus Doxorubicin Alone in Disseminated Metastatic/Recurrent Breast Cancer: National Cancer Institute of Canada Clinical Trials Group Study MA8From the Fraser Valley Cancer Centre, British Columbia Cancer Agency, Surrey; Vancouver Cancer Centre, British Columbia Cancer Agency, Vancouver, British Columbia. Toronto-Sunnybrook Regional Cancer Centre; University of Toronto; Toronto Hospital; Humber Memorial Hospital; Women’s College Hospital, Toronto; National Cancer Institute of Canada Clinical Trials Group; Kingston Regional Cancer Centre, Kingston; Hotel-Dieu Hospital, St. Catherine’s; London Regional Cancer Centre; University of Western Ontario, London; Glaxo-Wellcome Inc, Mississauga, Ontario; Nova Scotia Cancer Centre; Dalhousie University, Halifax, Nova Scotia; and Hotel-Dieu Hospital, Montreal, Quebec, Canada. Address reprint requests to Brian Norris, MD, Fraser Valley Cancer Centre, British Columbia Cancer Agency, 13750 96th Ave, Surrey, British Columbia, Canada V3V 1Z2.
PURPOSE: This phase III study was performed to determine the superiority of doxorubicin (DOX) and vinorelbine (VNB) (arm 1) versus DOX alone (arm 2) in metastatic breast cancer (MBC) for overall survival (OS), time to treatment failure (TTF), toxicity, and quality of life (QOL). PATIENTS AND METHODS: Three hundred three patients were randomized to DOX 50 mg/m2 intravenously (IV) on day 1 and VNB 25 mg/m2 IV on days 1 and 8 (arm 1) or DOX 70 mg/m2 IV on day 1 (arm 2). Both regimens were given every 3 weeks until a cumulative DOX dose of 450 mg/m2. After 16 of the first 65 randomized patients experienced febrile neutropenia (FN), the doses were reduced to DOX 40 mg/m2 on day 1 and VNB 20 mg/m2 on days 1 and 8 versus DOX 60 mg/m2 on day 1. Eligible patients were vinca alkaloid and anthracycline naive. Chemotherapy was first-line or second-line for MBC. RESULTS: Three patients were ineligible. Thus, 300 patients were assessable for toxicity and to determine time to disease progression (TTP), TTF, and OS. Two hundred eighty-nine patients were assessable for response, and 99 responders were assessable for response duration (RD). The response rates, QOL, and median RD, TTP, and TTF were not significantly different between the arms. Median OS was 13.8 months for arm 1 versus 14.4 months for arm 2 (P = .4). Grade 3 or 4 granulocytopenia was equivalent in both arms but more grade 3/4 neurotoxicity, mild venous toxicity, and FN were seen on arm 1. CONCLUSION: The survival with DOX and VNB is not superior to DOX alone in MBC.
OVER THE PAST 20 years, survival of metastatic breast cancer (MBC) treated with either single-agent or combination chemotherapy has remained largely unchanged. At the time this study was designed, doxorubicin (DOX) was considered the most active agent and was chosen as the comparator arm. Vinorelbine (VNB) was one of several new agents. Chemotherapy regimens of newer active agents like VNB were developed and required testing in randomized clinical trials. In phase II studies of previously untreated patients,1-3 the response rate (RR) of DOX is approximately 50%, and the median survival is 8 to 20 months. In patients pretreated with chemotherapy, mainly cyclophosphamide, fluorouracil, and methotrexate (CMF), the RR of DOX is approximately 30%, with a median survival of 6 to 9 months.4-6 DOX alone has been recommended7 as second-line treatment after CMF for MBC. As first-line treatment, DOX alone has been advocated8 without evidence of compromising survival.9 Older established regimens consisted of combinations of cyclophosphamide and fluorouracil with methotrexate (CMF) or DOX (CAF), with a median survival of 18 months for DOX regimens and 14 months for non-DOX regimens.10 Two phase III studies of CAF reported median survivals of approximately 13 and 15 months.11,12 More recently, paclitaxel and DOX have been studied in randomized clinical trials. As first-line chemotherapy, DOX has been compared with paclitaxel or both agents combined in a three-arm cross-over study.13 Median overall survival (OS) was approximately 22 months without a significant difference between the arms. In a two-arm cross-over study,14 paclitaxel has been compared with DOX as first-line chemotherapy. Median OS was approximately 17 months but not significantly different between the arms. In patients previously treated with alkylating chemotherapy, DOX has been compared with docetaxel.15 Median OS was similar at approximately 15 months. VNB (Navelbine; Glaxo-Wellcome, Mississauga, Ontario, Canada) is a semi-synthetic vinca alkaloid with a modification of the catharanthine moiety of vinblastine resulting in less neurotoxicity and major antitumor activity. In a phase II study, VNB as first-line chemotherapy in MBC has been reported to achieve an RR of 41%, with a median survival of 18 months.16 In vinca alkaloid– and anthracycline-naive patients treated with one prior regimen for their MBC, VNB has been reported to achieve an RR of 32%, with a median survival of 15.5 months.17 The RR of VNB in patients previously treated with anthracycline for their MBC has been reported to be 33%.18 In anthracycline-refractory patients19 randomized to VNB or melphalan, VNB has shown a significantly longer time to disease progression (TTP) and survival. A phase II study of DOX and VNB as first-line chemotherapy reported an RR of 74%, with a complete response rate of 21% and a median OS of 27.5 months.20 Given that VNB has major activity comparable with DOX in phase II studies, both as first-line or as second-line treatment after CMF, and given the encouraging results of the combination of DOX and VNB, a randomized phase III study was initiated to compare DOX and VNB versus DOX alone for efficacy and safety in patients previously untreated or with only one prior cytotoxic regimen for their MBC. Because of VNB’s substantial activity comparable with DOX and the possible non–cross-resistance of the two agents, it was hypothesized that the combination might prove superior.
The study accrued patients between January 15, 1992, and July 17, 1995. Women with histologically proven assessable and/or measurable MBC, an Eastern Cooperative Oncology Group performance status of 0 to 2, age 18 to 75 years, and an estimated life expectancy greater than 16 weeks were eligible for this study. They must not have previously received a vinca alkaloid, an anthracycline, or mitoxantrone. Prior adjuvant chemotherapy was allowed but only one prior cytotoxic regimen for their metastatic disease was permitted. At least 3 weeks must have elapsed after the last dose of previous chemotherapy or radiotherapy before study entry. Previous radiation should not have encompassed their sole site of measurable or assessable disease and could not have involved more than an estimated 40% of the active bone marrow. Patients must have had granulocyte counts  1.5 x 109/L, a platelet count 100 x 109/L, and a bilirubin level within normal limits. A pretreatment radionuclide cardiac scan (multigated angiogram [MUGA]) or cardiac ultrasound (echocardiogram [ECHO]) must have revealed a left ventricular ejection fraction (LVEF) of 50%. Patients with significant heart disease, such as uncontrolled arterial hypertension, documented myocardial infarction within 1 year, congestive heart failure, unstable angina, or ventricular/atrial arrhythmia, were excluded. Patients with clinically significant neuropathy, infection, or brain metastases were excluded. No second primary cancer was allowed except for treated in situ cervix cancer, nonmelanomatous skin cancer, and nonmetastatic treated colon, invasive cervix, or uterine cancer without recurrence more than 5 years before the diagnosis of breast cancer. Informed consent was according to local institutional and National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) guidelines. All patients must have been capable of completing the quality-of-life (QOL) questionnaires and accessible for treatment and follow-up at the participating center.
Evaluation Procedures and Treatment
Cycle doses were adjusted around the new standard (Table 1). Day-1 doses of the current cycle of both arms were adjusted based on day-1 granulocyte and platelet counts of the current cycle and the day-15 granulocyte and platelet counts of the previous cycle. The same VNB dose (arm 1) as day 1 of the current cycle was given on day 8 if the day-8 granulocytes were 0.5 x 109/L and platelets were 70 x 109/L. The day-8 dose was omitted from the current cycle if day-8 granulocytes were less than 0.5 x 109/L or platelets were less than 70 x 109/L or if febrile neutropenia or spontaneous bleeding was present.
After the first cycle, dose escalation to the +1 dose level was allowed if the day-8 (arm 1) and the day-15 granulocyte counts were If initially positive, imaging studies were repeated before the fourth cycle of treatment. If a complete or partial response was found, imaging studies were repeated again after a further two cycles, sooner, if necessary, to document any progression, or 6 weeks later if protocol treatment had ceased. After the completion of protocol treatment, imaging studies to assess response status were repeated every 6 weeks up to 37 weeks. Subsequently, planned evaluation included clinical and radiographic assessments as well as a CBC, biochemistry, and QOL assessment every 3 months. QOL was to be assessed just before every third cycle of study treatment with the European Organization for Research and Treatment of Cancer (EORTC) core quality-of-life questionnaire21 (EORTC QLQ-C30) consisting of nine domains and six single items, a 13-item breast cancer–specific questionnaire, and five questions evaluating interval change. Acute toxicity was graded by the NCIC CTG expanded common toxicity criteria22 and reported as the worst grade ever experienced by patient by treatment arm. A toxic death was attributed to protocol treatment if it occurred up to 30 days after the completion of protocol therapy. All patients who received at least one cycle of chemotherapy were considered assessable for toxicity, and those completing at least two cycles were considered assessable for response. Standard World Health Organization criteria of response were used.23 The diameters of any skin lymph node or chest x-ray lesion must have been at least 1 cm x 1 cm to be considered bidimensionally measurable (1 cm for unidimensionally measurable disease). The diameters of any lesion detected by CT scan, ultrasound, or liver lesion must have been at least 2 cm x 2 cm to be considered bidimensionally measurable (2 cm for unidimensionally measurable disease). Duration of response was measured from the first date that a response was recorded until relapse. Survival, time to treatment failure (TTF), and TTP were recorded from the date of randomization. All case reports of responding patients and the supporting documentation were reviewed by the principal investigator (B.N.) and the physician study coordinator (K.J.). Particular attention was paid to meeting response criteria for assessable disease. In responding patients with both assessable and measurable disease, the response status reported is the lesser response demonstrated in either disease category. At participating centers, protocol/study compliance was assessed by on-site study monitor visits. During the conduct of the study, toxicity was monitored closely and reported yearly by treatment arm to participating investigators.
Statistical Analysis
A total of 303 patients were randomized from 30 participating NCIC CTG centers. Three patients were ineligible because of a significant pre-existing arrhythmia (n = 1), the absence of assessable disease (n = 1), and a previous malignancy (n = 1). Median follow-up was 29 months. No patient was lost to follow-up. Two hundred eighty-nine patients were assessable for response, and 300 were assessable for toxicity. One patient randomized to arm 1 received DOX alone. Four patients received radiation not allowed by protocol. One hundred thirty-four relapses and 106 deaths have occurred on arm 1. One hundred thirty-six relapses and 105 deaths have occurred on arm 2.
Patient and Tumor Characteristics
Toxicity The major dose-limiting toxicity was granulocytopenia (Table 3), with 88% of patients on arm 1 and 86% of patients on arm 2 experiencing grade 3 or grade 4 toxicity. Overall, the median nadir granulocyte counts were 0.330 x 109/L (range, 0 to 5.6 x 109/L) for arm 1 and 0.305 x 109/L (range, 0 to 4.9 x 109/L) for arm 2. Clinically significant thrombocytopenia was rarely seen in either arm. Only 2% of patients experienced grade 3 thrombocytopenia (platelets, 25 to 49.9 x 109/L) or grade 4 thrombocytopenia (platelets, < 25 x 109/L) on arm 1, whereas 3% of patients experienced grade 4 thrombocytopenia on arm 2. Only 7% of patients on arm 1 experienced grade 3 anemia (hemoglobin, 65 to 79 g/L). On arm 2, 8% of patients experienced grade 3 or grade 4 anemia (hemoglobin, < 65 g/L).
Table 4 lists the major acute nonhematologic toxicity experienced by patients on both arms. On arm 1, 6% of patients (nine of 151) experienced grade 3 or 4 acute neurotoxicity compared with 1% of patients (two of 149) on arm 2 (P = .03). Forty-seven percent of patients (71 of 151) on arm 1 experienced constipation compared with 20% (29 of 149) in arm 2. On arm 1, 35% of patients (53 of 151) experienced mild grade 1 or grade 2 sensory neuropathy.
The tables show only acute toxicity on treatment. However, persistent neurotoxicity after protocol treatment was seen on arm 1, with one case of severe constipation, three cases of motor weakness resulting in functional impairment, and two cases of sensory neuropathy with functional impairment. More grade 2 or 3 venous reactions were seen on arm 1 (22%; 33 of 151 patients) compared with arm 2 (2%; three of 149 patients) (P < .0001). Acute gastrointestinal and cardiovascular toxicities between the arms were similar. Delayed cardiac toxicity was seen in both arms after protocol treatment. On arm 1, there was one case of symptomatic arrhythmia requiring treatment and one case of severe congestive heart failure, whereas one patient on arm 2 developed cardiomyopathy at 380 mg/m2 of DOX and died of congestive heart failure associated with a malignant pleural effusion. Initially, 16 out of the first 65 randomized patients experienced FN, 27% on arm 1 and 22% on arm 2. Subsequently, doses were amended (Table 1) around a new standard. Fifteen patients on arm 1 and 17 patients on arm 2 were escalated to the +1 dose level after the first cycle. After the dose modification of protocol doses, the FN rate was 12% on arm 1 and 7% on arm 2. The overall FN rate was 15% for arm 1 and 10% for arm 2 (P = .2) (Table 3). There were two deaths, one in each arm, from FN on protocol treatment. A total of 11% of patients on arm 1 went off protocol treatment because of toxicity compared with 4% on arm 2. More patients refused further protocol treatment on arm 1 (8%) compared with arm 2 (2%).
Response and Time-to-Event Outcomes
Time-to-event outcomes for each arm are listed in Table 6. The median duration of response was 7.2 months for arm 1 and 6.8 months for arm 2. Median TTP, median TTF, and median OS were 6.2 months, 6.0 months, 13.8 months, respectively, for arm 1 and 6.1 months, 5.5 months, and 14.4 months, respectively, for arm 2.
Patients were stratified for one versus no prior cytotoxic regimen for their metastatic disease. Overall, the median survival of patients as stratified for patients with no prior chemotherapy regimen was 16.4 months compared with 10.3 months for those with one prior chemotherapy regimen. For the subgroup with no prior chemotherapy for their MBC, the median TTP, median TTF, and median OS were 6.6 months, 6.6 months, and 16.8 months, respectively, for arm 1 and 6.5 months, 5.8 months, and 16.2 months, respectively, for arm 2. For the subgroup with one prior chemotherapy regimen for their MBC, the median TTP, median TTF, and median OS were 4.3 months, 3.5 months, and 9.4 months, respectively, for arm 1 and 5.3 months, 5.3 months, and 11.3 months, respectively, for arm 2. The study had inadequate power to detect subgroup differences between treatments for either RR or time-to-event outcomes. Thus, no definitive statement can be made about the treatment effects within any subgroup. A total of 27 patients (10 on arm 1 and 17 on arm 2) received nonprotocol treatment before disease progression. Eleven patients received hormone therapy, and eleven received chemotherapy. One patient received only DOX, although she was randomized to the DOX and VNB arm. Four patients received radiation therapy not allowed by protocol. All those receiving nonprotocol treatment before progression were included in the intent-to-treat analysis. Another analysis for TTF and TTP censoring those who received nonprotocol therapy was not different from the intent-to-treat analysis. There was no significant difference in TTF between arms (stratified log-rank, P = .7). Controlling for factors identified in a multivariate analysis did not change the result (P = .8). The Kaplan-Meier survival curves by arm are shown in Fig 1. A comparison of the survival curves showed no significant difference (stratified log-rank, P = .4). There was also no significant difference in survival after adjusting for prognostic factors identified in a multivariate model (P = .3). Cox proportional hazards analyses of time-to-event outcomes demonstrated the following five favorable prognostic factors associated with longer survival, TTP, and TTF: estrogen receptor positivity, longer interval between initial diagnosis of cancer and first relapse, no prior chemotherapy for metastatic cancer, normal AST, and lower WBC count.
QOL Two hundred ninety-nine out of 303 randomized patients completed a QOL questionnaire at baseline or on or before day 1 of the first cycle of chemotherapy. Two hundred thirty patients who completed at least three cycles of treatment filled out from two to four questionnaires. One hundred ninety-one patients who completed at least six cycles of treatment filled out from two to five questionnaires. Table 7 lists the means and SDs of the QOL scores for the nine domains of the EORTC QLQ-C30 for only those patients who completed six cycles of treatment. There was no significant difference between the arms or the profiles of the mean global QOL scores or mean scores for any of the eight additional domains (cognitive, emotional, physical, role, social, fatigue, nausea/vomiting, and pain) over the first six cycles. QOL scores showed a significant improvement over time in the global, emotion, social, pain, and nausea/vomiting domains for patients receiving six cycles.
Treatment Delivery Table 8 lists the parameters of chemotherapy delivery. There was no statistically significant difference in received dose-intensity of DOX by arm (P = .13), where dose-intensity is defined as the ratio of dose delivered over the time it was actually given to the expected dose over the same time.27 However, there was a statistically significant difference in the total mean cumulative dose of DOX in favor of arm 2. The mean cumulative dose of DOX was 328 mg/m2 for arm 2 compared with 260 mg/m2 for arm 1 (P = .0001). The median number of cycles was seven for arm 1 and six cycles for arm 2. The protocol plan was for responding patients to be treated until a cumulative DOX dose of 450 mg/m2. Therefore, patients on arm 1 would expect to receive more cycles of chemotherapy because of the lower cycle dose of DOX.
The hypothesis that the combination of DOX and VNB might prove superior to DOX alone was not confirmed by this study. An overview10 of randomized chemotherapy trials in advanced breast cancer revealed that DOX combinations had a median survival of 18 months compared with 14 months for non-DOX combinations. This represents approximately a 25% relative increase in median survival in favor of the DOX combinations. If a difference of this magnitude in favor of the DOX and VNB combination were to exist, this study would not have had the power to detect it. Although 25% of patients in this study had received one prior chemotherapy regimen for their metastatic disease, the OS of approximately 14 months seen in this study compares favorably with two randomized phase III studies11,12 of similar size in chemotherapy-naive patients treated with CAF, which demonstrated median survivals of 12.6 months11 and 14.8 months.12 A randomized study14 with a cross-over design has compared DOX with paclitaxel as first-line chemotherapy for MBC. In a similar first-line chemotherapy study,13 the Eastern Cooperative Oncology Group compared DOX with paclitaxel and to both drugs combined. For the single-agent arms, there was a cross-over to the alternate drug at progression. No treatment in these two studies showed a statistically significant survival advantage, with OS of 17 months14 and 22 months.13 Another study28 relevant to the issue of single-agent versus combination chemotherapy randomized MBC patients to low-dose epirubicin, a DOX analogue, or to cyclophosphamide, epirubicin, and fluorouracil as first-line treatment followed by mitomycin or mitomycin and vinblastine as second-line treatment. Median OS was 18 months. Combination chemotherapy, either as first-line or second-line treatment, offered no survival advantage. Patients treated with single-agent chemotherapy experienced less overall toxicity and better QOL. Based on these recent randomized study results and given the limitations of between-study comparisons, median survival for first-line chemotherapy in MBC with either an active-single agent or combination chemotherapy seems to be approximately 18 months. The median survival for first-line treatment patients treated on our study was 16.4 months, which is within close range of this estimate. The median survival of patients with one prior chemotherapy regimen was 10.3 months. The survival of this latter group compares favorably with the approximately 9-month median survival seen in patients treated with DOX after one prior nonanthracycline regimen.5 The achieved RRs did not differ and were 38% for arm 1 (95% CI, 30% to 46%) and 30% for arm 2 (95% CI, 23% to 38%). However, RR was not the primary end point. The responses are in keeping with the generally lower RRs seen in phase III studies, which reflect characteristics of an unselected patient population and a rigorous assessment and definition of response. The study population was drawn from 30 participating centers across Canada and included patients with poor prognostic features, including 53% of patients with three or more sites of disease and approximately 45% with liver disease. Sixty-six percent of patients on arm 1 and 55% of patients on arm 2 had bone disease. Despite defined response criteria, it was often difficult to categorize an assessable response in bone, thus accounting for the high percentage of stable disease. No significant differences were identified in global QOL or any of the assessed domains of the EORTC QLQ-C30, comparing baseline, after three cycles, and after six cycles of treatment, between the arms, but QOL improved in patients remaining on study treatment in both arms. It is possible that QOL differences were not captured because of nonrandom loss of patients filling out questionnaires or to inadequate power to detect small differences in the QOL domains between the arms. Global QOL and the emotion, social, nausea/vomiting, and pain domains improved over time with six cycles of chemotherapy. This difference may be a result of selection bias because only those patients who were stable or responding to chemotherapy received six cycles. In this study, higher baseline global QOL scores were independent predictors of chemotherapy response in a multivariate model. Physical QOL scores entered a multivariate model for survival but did not emerge as independently predictive of survival. Coates et al,29 using a different QOL instrument, found physical well-being in addition to other subscales at the start of treatment to be significant predictors of survival. Measures of QOL may predict for response and survival to chemotherapy in MBC. The QOL instrument used in this study, the EORTC QLQ-C30, did not demonstrate a difference in measured QOL between the two arms. This could reflect a lack of sensitivity30 of the instrument in this instance. The report31 of the Outcomes Working Group of the American Society of Clinical Oncology identified survival and QOL as priority treatment outcomes if QOL measures were sensitive to "clinically meaningful changes produced by treatment."31 The failure to show a survival difference in this study only underscores the continued relevance of a QOL evaluation in phase III chemotherapy MBC trials. Because of the importance of a QOL outcome, increased attention and study needs to be paid to the consistent performance of the EORTC QLQ C-30 and other QOL instruments in future trials. The major dose-limiting toxicity was granulocytopenia. Early on in the study, starting doses were reduced because of an unacceptable rate of FN. Overall, substantial and equivalent grade 3 and grade 4 granulocytopenia was seen in both arms. The hematologic and nonhematologic toxicity of the combination arm of our study exceeded or paralleled toxicity seen in the phase II studies testing the same schedule of DOX and VNB. Eighty-eight percent of patients on the DOX and VNB arm had grade 3 or grade 4 granulocytopenia, 15% had FN, and 35% developed a sensory neuropathy. Overall, more grade 3 and grade 4 neurotoxicity was seen on the combined arm. One third of the grade 3 or 4 neurotoxicity was either severe constipation or paralytic ileus. Spielmann et al20 and Hochster32 reported 41% and 95% grade 3/4 granulocytopenia, 16% and 8% FN, and 27% and 26% sensory neuropathy, respectively, for the combination of DOX and VNB. More, although usually mild, local venous toxicity was seen with the combination. However, patients on the combination arm were at increased risk of local venous toxicity caused by the day-8 injection. Two recommended methods of administration known to reduce venous reactions were specified in the protocol. However, routine initial placement of venous access devices was infrequently used in participating centers. The failure of the combination to prove superior does not seem to reflect any imbalance between the arms of the known prognostic factors. The similarity between the rates of FN, granulocytopenia, and other toxicity observed on arm 1 of this study and the phase II studies upon which this study is based indicate an adequate test of this schedule of DOX and VNB. Another phase III study33 has tested the same schedule of DOX and VNB against CAF as first-line therapy in advanced breast cancer. No significant difference in survival was reported. Median survival was 17.3 months for CAF and 17.8 months for DOX and VNB. Grade 3/4 (World Health Organization criteria) neutropenia was 7% for both regimens. Similar to our experience, more mild to moderate constipation, peripheral neurotoxicity, and phlebitis was seen with the VNB combination. Possible explanations for the results of our study are that VNB may not be as active a drug as DOX, that it lacks a significant degree of non–cross-resistance to DOX, or that overlapping toxicity, predominantly granulocytopenia, prevents the effective dose delivery of each drug when used in combination. This study was designed to compare DOX as an appropriate standard against a promising DOX/VNB regimen in doses as reported.20 The study was not designed to and cannot directly address the relative worth of equitoxic doses of VNB alone or combined with equitoxic doses of DOX to equitoxic doses of DOX. Only a three-arm study of VNB alone versus DOX alone compared with an alternate regimen of DOX and VNB, which would require the use of granulocyte colony-stimulating factor, could address these questions. Unfortunately, there was no third arm of VNB to make direct comparisons with DOX. The failure of the VNB combination in this study to achieve superior survival should not necessarily reflect on the activity of VNB because randomized studies13,28 of combinations of other active agents compared with single agents also do not show a survival advantage. VNB alone given as first-line or second-line treatment (without prior anthracycline or vinca alkaloid) achieves RRs of 35% and 32%, respectively, with median survivals of 17 months and 15 months, respectively.17 As a single agent, VNB would seem to have less nonhematologic toxicity and potentially comparable efficacy to DOX alone. Survival achieved with conventional-dose, active, single-agent or combination chemotherapy regimens for MBC has reached a plateau. The results of this study suggest that for a heterogeneous population with high tumor burdens, a combination of two active drugs given in conventional doses cannot achieve enough of an increase in tumor-cell kill with acceptable toxicity to provide an additional survival advantage. This has implications concerning the choice of which chemotherapy regimens to use in metastatic breast cancer. Monotherapy with a major active agent, such as DOX, given in maximally tolerated doses seems to achieve equivalent palliation in measured QOL outcomes without compromising survival.
Supported by the National Cancer Institute of Canada Clinical Trials Group and Glaxo-Wellcome, Inc. We thank Anita Gustavson for her secretarial assistance.
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ABSTRACT
INTRODUCTION
