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Phase III Study of Intravenous Vinorelbine in Combination With Epirubicin Versus Epirubicin Alone in Patients With Advanced Breast Cancer: A Scandinavian Breast Group Trial (SBG9403)

From the Departments of Oncology, Rigshospitalet, Copenhagen University Hospital, Copenhagen; Vejle County Hospital, Vejle; Aarhus University Hospital; Aalborg County Hospital, Aarhus, Denmark; and Helsinki University Hospital, Helsinki, Finland

Address reprint requests to Bent Ejlertsen, MD, PhD, Department of Oncology, Bldg. 5012 Rigshospitalet, 9 Blegdamsvej, DK-2100 Copenhagen, Denmark; e-mail: ejlertsen{at}rh.dk

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
PURPOSE: To determine whether the addition of intravenous (IV) vinorelbine to epirubicin increased the progression-free survival in first-line treatment of metastatic breast cancer.

PATIENTS AND METHODS: A total of 387 patients were randomly assigned to receive IV epirubicin 90 mg/m² on day 1 and vinorelbine 25 mg/m² on days 1 and 8, or epirubicin 90 mg/m² IV on day 1. Both regimens were given every 3 weeks for a maximum of 1 year but discontinued prematurely in the event of progressive disease or severe toxicity. In addition, epirubicin was discontinued at a cumulative dose of 1,000 mg/m² (950 mg/m² from June 1999). Prior anthracycline-based adjuvant chemotherapy and prior chemotherapy for metastatic breast cancer was not allowed. Reported results were all based on intent-to-treat analyses.

RESULTS: Overall response rates to vinorelbine and epirubicin, and epirubicin alone, were 50% and 42%, respectively (P = .15). The complete response rate was significantly superior in the combination arm (17% v 10%; P = .048) as was median duration of progression-free survival (10.1 months v 8.2 months; P = .019). Median survival was similar in the two arms (19.1 months v 18.0 months; P = .50). Leukopenia related complications, stomatitis, and peripheral neuropathy were more common in the combination arm. The incidences of cardiotoxicity and constipation were similar in both arms.

CONCLUSION: Addition of vinorelbine to epirubicin conferred a significant advantage in terms of complete response rate and progression-free survival, but not in terms of survival.

	INTRODUCTION

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Indirect evidence from a population-based study suggests that systemic therapy may prolong median survival 6 to 9 months in advanced breast cancer.¹ Anthracyclines are among the most active drugs in metastatic breast cancer with response rates (RRs) of approximately 30% to 40%.^2,3 Reviews in the early 1990s concluded from comparative studies that the efficacy of epirubicin was identical to doxorubicin, but with less toxicity.^4,5 Fossati et al⁶ reported in a more recent overview a significant survival benefit in favor of doxorubicin over epirubicin, based on six randomized trials, including 1,097 patients in direct comparisons of doxorubicin and epirubicin. In another overview, Findlay et al⁷ divided the same trials in those using equal doses and those using higher doses of epirubicin than doxorubicin. When comparing four of the trials, together with a trial⁸ not included in Fossati et al,⁶ this analysis indicated that doxorubicin and epirubicin are equally efficacious even at equal doses. Both overviews reported that epirubicin generated less toxicity than doxorubicin, including leukopenia and cardiac toxicity. Used in a 3-week schedule, epirubicin doses of 90 to 100 mg/m² have been more efficacious compared to lower doses, both as single agent^9,10 and in combinations.^11-13 Escalation beyond 100 mg/m² does not seem to convert into a further increase in efficacy when compared to 60^14,15 or 90 mg/m².¹⁰

Vinorelbine is a semisynthetic vinca-alkaloid, which is significantly less neurotoxic than other vinca-alkaloids. Its main dose-limiting toxicities are leukopenia, neutropenia, and constipation. Response rates of 35% to 50% have consistently been demonstrated for first-line single-agent vinorelbine.^16-23 In noncomparative studies, the antitumor activity of vinorelbine appeared to be enhanced when combined with other cytotoxic agents commonly used in the treatment of advanced breast cancer. Few randomized studies, however, have tested a vinorelbine-containing regimen as first-line chemotherapy. Vinorelbine plus doxorubicin had essentially similar efficacy as standard fluorouracil, adriamycin, and cyclophosphamide.²⁴ Response rate and survival achieved with vinorelbine plus mitoxantrone or standard fluorouracil, adriamycin, and cyclophosphamide/fluorouracil, epirubicin, and cyclophosphamide were also similar.²⁵ Vinorelbine 20 mg/m² on days 1 and 8 plus doxorubicin 40 mg/m² on day 1 compared with doxorubicin 60 mg/m² on day 1, with both regimens being given every 3 weeks, failed to prove a survival advantage.²⁶ However, the unusual low-dose intensity of vinorelbine (11 mg/m²/wk) and the statistically inferior mean cumulative dose of doxorubicin in the combination arm versus the single-agent arm did not allow a definitive conclusion.

Vinorelbine has been safely and effectively combined with epirubicin in several noncomparative studies.^27-30 The tolerability and efficacy of increasing doses of epirubicin and vinorelbine as first-line chemotherapy of advanced breast cancer was also investigated by the Danish Breast Cancer Cooperative Group (DBCG) in a phase I-II trial. Acute toxicity was manageable at all dose levels for combinations of epirubicin 60 to 90 mg/m² on day 1 and vinorelbine 15 to 25 mg/m² on days 1 and 8.³¹ Given the promising results of vinorelbine in combination with epirubicin in phase II studies, a multicenter, randomized phase III study was conducted to challenge the position of epirubicin versus the combination.

	PATIENTS AND METHODS

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Between February 1995 and January 1999, 387 patients entered this trial from 15 departments of oncology in Denmark, Finland, Iceland, and Sweden. This study was approved by the respective national health authorities and the ethical committees of the participating institutions.

Eligibility
Women with histologically verified metastatic breast cancer were considered for the trial provided they were 18 to 75 years of age, had progressive disease with measurable, assessable, and/or bone lesions according to the WHO criteria,³² and the following further inclusion criteria were met: WHO performance status 2; leukocyte count 3.0 x 10⁹/L; platelet count 100 x 10⁹/L; total bilirubin < 35 µmol/L/L; transaminases (AST and ALT) < 120 U/L; serum creatinine 0.140 mg/L; left ventricular ejection fraction (LVEF) 0.50. Exclusion criteria were prior or concomitant malignant disease, except appropriately treated basal cell carcinoma of the skin or carcinoma-in-situ of the cervix, congestive heart failure, clinical symptoms suggesting peripheral neuropathy or brain metastases, prior irradiation of 25% or more of the red bone marrow, and prior anthracycline, or prior cytotoxic treatment for locally recurrent or metastatic disease. Informed consent had to be signed by the patient before study enrollment.

Treatment
Patients were randomly assigned to receive either vinorelbine plus epirubicin or epirubicin alone. Randomization was performed centrally at the DBCG office and was stratified by center. The combination arm included vinorelbine 25 mg/m² IV on days 1 and 8 plus epirubicin 90 mg/m² IV on day 1, and the single-agent arm epirubicin 90 mg/m² IV on day 1, both given every 3 weeks. Treatment was continued until disease progression, severe toxicity, patient refusal, or for a maximum of 1 year. However, epirubicin was to be ceased at a cumulative dose of 1,000 mg/m² until June 1999 and thereafter, when the total cumulative dose was in excess of 900 mg/m² but still less than 950 mg/m² following the publication by Ryberg et al.³³ Severe toxicity requiring treatment discontinuation included: congestive heart failure or cardiomegaly or arrhythmia requiring treatment or decline of LVEF 0.20 from baseline, or decline of LVEF 0.10 from baseline to a final value 0.50; increase of bilirubin > 3 x upper limit of normal (ULN) or increase of transaminases 4 x ULN; or any severe or life-threatening adverse event.

Day 1 doses in both arms were to be reduced by 20% in the event of febrile neutropenia reported during the previous cycle. In the combination arm, hematologic assessment was only done on day 8 on specific clinical indication. The day 8 dose of vinorelbine had to be reduced by 50% if leukocyte count was less than 2.0 x 10⁹/L and cancelled if leukocyte count was less than 1.0 x 10⁹/L.

Pretreatment and Follow-Up Investigations
Pretreatment investigations performed within 2 weeks of therapy initiation included full history and physical examination, CBC, serum chemistry, chest x-ray, multigated equilibrium imaging (MUGA) or echocardiography, bone scan or bone x-rays, and site-specific imaging as appropriate.

Tumor measurements were assessed at baseline and then every three cycles. Assessment of response was performed according to the WHO criteria.³² Duration of response, progression-free survival (PFS), and overall survival were defined according to the European Organization for Research and Treatment of Cancer guidelines.³⁴ PFS was measured from the date of randomization until the date of progression or death from any cause. Survival was measured from the date of randomization until death or the last follow-up date. For all patients, tumor assessments and dates of progression were reviewed by an Independent Review Committee (IRC).

CBC counts were obtained on day 1 of each cycle in both arms and only, if clinically indicated, on day 8 in the combination arm. Serum chemistry was performed every three cycles. MUGA or echocardiography had to be assessed every two cycles when the cumulative dose of epirubicin was 500 mg/m². Following a decline in the LVEF 0.10 but less than 0.20 to a value still above 0.50, MUGA or echocardiography had to be repeated every cycle. Toxicity was assessed according to WHO criteria. Febrile neutropenia was defined as an absolute neutrophil count less than 500/m³ or leukocyte count less than 1,000/m³ concomitant with fever, defined by three increases of oral temperature above 38°C measured every 8 hours in a 24-hour period, or a single oral temperature above 38.5°C.

Statistical Methods
The primary end point of the study was PFS, while response rate, survival, and toxicity were secondary end points. A triangular test³⁵ was originally planned to compare PFS at every 50 events in both arms. Boundaries of triangle were calculated using PEST (RockWare Inc, Colden, CO) software enabling 90% chances to detect a 50% increase of median PFS. This design was quit after the third inspection—the three plots of z versus v values given by the log-rank test falling within the boundaries. It was decided after the third inspection to continue accrual until a fixed number of approximately 380 patients.

PFS and overall survival were analyzed by using a log-rank test stratified by center. Final P value corrected for the three previous inspections was provided by PEST software which implemented an algorithm for calculation, making use of a continuous approximation to the sample path up to the third inspection. PFS was also analyzed by using a Cox model adjusted for the most important prognostic factors, previously found to be significantly associated with survival in the DBCG study of epirubicin at four different dose levels.¹⁰

	RESULTS

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A total of 387 patients were enrolled, with 193 patients randomly assigned to receive vinorelbine plus epirubicin, and 194 to receive epirubicin alone. Median follow-up was 42.8 months and 41.6 months, respectively. Three patients were ineligible because of a previous malignancy (n = 1), performance status of 4 (n = 1), and presence of brain metastases (n = 1). These three patients were included in the intent-to-treat analyses.

Patient and Tumor Characteristics
Patient and tumor baseline characteristics were balanced in the treatment arms (Table 1). About one third of patients had received prior adjuvant chemotherapy, which consisted exclusively of cyclophosphamide, methotrexate, and fluorouracil (CMF). For approximately 30% of those patients who had received prior CMF, relapse occurred less than 12 months after the end of adjuvant chemotherapy.

View larger version (15K): [in this window] [in a new window]   Fig 1. Kaplan-Meier estimate of progression-free survival (PFS): for vinorelbine (VNR) plus epirubicin (EPI), the median PFS was 10.1 months; for single-agent epirubicin, the median PFS was 8.2 months.

View larger version (16K): [in this window] [in a new window]   Fig 2. Kaplan-Meier estimate of overall survival (OS): For vinorelbine (VNR) plus epirubicin (EPI), the median OS was 19.1 months; for single-agent epirubicin, the median OS was 18.0 months.

Toxicity
Of the 387 patients enrolled in the study, seven patients were never treated and were not assessable for toxicity. The proportion of patients who went off study treatment because of toxicity was similar in both arms, 12% in the epirubicin group and 9% in the combination group. More patients refused further study treatment in the combination arm (19%) compared with the single-agent arm (7%).

Leukopenia was the main dose-limiting toxicity. Grade 3 and 4 leukopenia was significantly more frequent in the combination arm, with 50% of patients experiencing grade 3 or 4 toxicity compared with 12% in the single-agent arm. Febrile neutropenia and neutropenic infection were more frequently seen in the combination arm than in the single-agent arm; 20% of patients versus 2%, and 11% of patients versus 5%, respectively. Three patients treated with epirubicin and seven treated with vinorelbine plus epirubicin died from febrile neutropenia or sepsis. Among those, one patient, ineligible because of performance status 4, died from febrile neutropenia after having received one cycle of the combination regimen. As shown in Table 5, thrombocytopenia and anemia were also significantly more frequently reported in the combination arm but were associated with no clinical complications.

Five patients randomly assigned to single-agent epirubicin developed symptomatic cardiotoxicity: four cases of congestive heart failure and one case of cardiomyopathy. On the vinorelbine plus epirubicin arm, seven patients experienced symptomatic cardiotoxicity: five cases of congestive heart failure, one case of cardiomyopathy, and one transient episode of atrial fibrillation. Among the five patients having experienced congestive heart failure on treatment with vinorelbine plus epirubicin, one received four additional cycles following the documentation of a significant decline of LVEF (> 10% to a value of 0.45). This patient developed untreatable cardiac insufficiency and died. Serial evaluations of LVEF were performed for 133 patients in the epirubicin alone arm and 135 patients in the vinorelbine plus epirubicin arm when the total cumulative dose of epirubicin was 500 mg/m². The proportion of patients who experienced a significant decline of LVEF according to the study protocol was comparable (eg, 24% in the single-agent arm and 32% in the combination arm). Local venous irritation, usually mild, was reported in a relatively similar proportion of patients for both arms.

	DISCUSSION

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Anthracyclines and the taxanes are the most active cytotoxic drugs in the treatment of metastatic breast cancer, and epirubicin was selected for this trial owing to a more favorable toxicity profile and a better defined dose-response relationship compared with doxorubicin.⁷ The combination with vinorelbine was supported by the established activity of vinorelbine as a single agent and the absence of cross-resistance between the two drugs.^16-23

PFS, the primary end point in this trial, was 2 months longer for patients receiving the combination regimen compared with those receiving epirubicin alone. This resulted in a 27% reduction in the risk of progression for patients treated with vinorelbine plus epirubicin. A gain of 1 month in overall survival was obtained and did not reach the level of statistical significance. Combination therapy resulted in a higher response rate in patients with visceral metastases, and visceral metastases had a significant impact on PFS in the multivariate analysis. How this should be interpreted remains problematic in the absence of a survival benefit. The major dose-limiting toxicity was leukopenia, which together with febrile neutropenia and neutropenic infection, was significantly more frequent in patients receiving the combination. Stomatitis and peripheral neuropathy were also significantly more frequently encountered in the combination arm, while cardiotoxicity, nausea/vomiting, constipation, and local venous irritation did not differ between the two study groups. The relative lack of major overlapping toxicities allowed us to use what might be considered an optimal dose of epirubicin and still administer a cumulative dose and relative dose-intensity of epirubicin that was similar in both study arms.

The SBG9403 trial is the only randomized trial comparing single-agent epirubicin with the combination of epirubicin and vinorelbine in first-line chemotherapy of advanced breast cancer. Another randomized trial conducted by the National Cancer Institute of Canada (NCIC) compared single-agent doxorubicin with the combination vinorelbine plus doxorubicin and failed to show any superiority for the combination.²⁶ The NCIC trial aimed for equitoxicity between the two regimens resulting in a low-dose-intensity of vinorelbine (11 mg/m²/wk), and the median cumulative dose of doxorubicin was 260 mg/m² in the combination arm versus 328 mg/m² in the single-agent arm. In contrast to the present SBG9403 trial, a high number of patients with poor prognostic features and patients with a history of previous chemotherapy for advanced disease were included in the NCIC trial.

Randomized trials published in the 1980s and early 1990s reported higher response rates on combination compared with single-agent chemotherapy in metastatic breast cancer, and this converted in a meta-analysis to a 0.87 mortality hazard ratio (95% CI, 0.78 to 0.97) for anthracycline-containing combinations.⁶ Two newer trials not included in the meta-analysis reported, in accordance with the present study, a significant prolongation in PFS but without a significant improvement in overall survival with the addition of cisplatin to epirubicin and the addition of doxorubicin to paclitaxel.^36,37 Another three recent trials failed to show any superiority combining epirubicin with cyclophosphamide and fluorouracil, epirubicin with cisplatin, and doxorubicin with vinorelbine.^26,38,39 In contrast, O'Shaughnessy et al⁴⁰ reported superior outcomes in tumor response, PFS (as well as in the secondary end point), and overall survival using the combination of docetaxel and capecitabine compared with docetaxel alone. The rational basis for the design of the O'Shaughnessy trial was preclinical evidence of synergy, while in the present trial and the recently published Intergroup trial E1193,³⁷ it was lack of cross-resistance. In E1193 739, patients with metastatic breast cancer were randomly assigned to single-agent doxorubicin 60 mg/m² versus single-agent paclitaxel 175 mg/m² versus the combination of doxorubicin 50 mg/m² and paclitaxel 150 mg/m² plus granulocyte colony-stimulating factor. The combination resulted in a significant increase in response rate and PFS, but did not result in a survival benefit and led to substantial toxicity. Paclitaxel and doxorubicin was reduced 14% to 17% in the combination arm of the E1193 trial, and a full dose of epirubicin was given in both arms of SBG9403. In the O'Shaughnessy trial, on the contrary, docetaxel was reduced by 25% in the combination arm, and a large randomized dose-response trial has clearly demonstrated that 75 mg/m² of docetaxel, as used in the combination, is suboptimal compared to the 100 mg/m² used in the single-agent arm.⁴¹

Ideally, combination chemotherapy should be compared with a preassigned sequence of monochemotherapy. In advanced breast cancer, however, the general condition of a proportion of the patients will have deteriorated and prohibit further chemotherapy at the time of progression on first-line chemotherapy, invalidating any formal comparison of the whole sequences. Examples are the Joensuu et al trial,³⁸ where half of the patients received the second part of the assigned sequence, and E1193 were 57% of the patients adhered to the preassigned sequence of second-line chemotherapy following single-agent doxorubicin or paclitaxel.³⁷ In the present SBG9403 study, 55% of the patients received second-line therapy following progression on single-agent epirubicin, only 22% with single-agent vinorelbine.

In the absence of factors that efficiently predict which patients have a high probability to benefit from the individual cytotoxic therapies, we are still left with a trial-and-error-resembling approach. Moreover, we are unable to give specific recommendations as to the use of sequential monotherapy or combination therapy, according to limitations in existing data of toxicities and effect on early (response rate, PFS) and late (survival) end points. However, when balancing harms and benefits, it seems reasonable to recommend a combination with proven superiority in early end points to patients with extensive and rapidly progressing disease, unlikely to be eligible for a second-line therapy following failure to first line. Epirubicin plus vinorelbine represents such a combination. However, in patients with more indolent disease, the sequential approach might be applied.

Appendix
Principal investigators (in addition to listed authors) were as follows: Dr Erik Andersen, Viborg Hospital, Viborg; Dr Carl Gadebjerg, Vejle Hospital, Vejle; Dr Ebbe Lindegaard Madsen, Sonderborg Hospital, Sonderborg; Dr Knud Aage Moller, Herning Hospital, Herning; Dr Preben Philip, Naestved Hospital, Naestved; Dr Carsten Rose, Odense University Hospital, Odense, and Dr Erik Sandberg,Esbjerg Hospital, Esbjerg, Denmark; Dr Carl Blomqvist, Helsinki University Hospital, Helsinki; and Dr Guillermo Blanco, Oulu University Hospital, Oulu, Finland; Dr Helgi Sigurdsson, Reykjavik University Hospital, Reykjavik, Iceland; and Dr Niels Bengtsson, Umeaa Hospital, Umeaa, and Dr Per Malmstrom, Lund University Hospital, Lund, Sweden.

	Authors' Disclosures of Potential Conflicts of Interest

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The authors indicated no potential conflicts of interest.

	NOTES

 
Supported in part by Institut de Recherche Pierre Fabre, Boulogne, France; and Medical Affairs Oncology, Pharmacia, Milan, Italy.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

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TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
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Submitted November 1, 2003; accepted March 19, 2004.

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