1 Cancer Center, University Hospital of Helsinki, Finland; 2 Department of Oncology, University of Uppsala, Sweden
Received 27 June 2002; revised 5 December 2002; accepted 19 December 2002
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Abstract |
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The purpose of this study was to determine the best tolerated and efficacious dose of vinorelbine given once or twice in 3-week cycles in combination with methotrexate and fluorouracil (VMF).
Patients and methods:
Vinorelbine 40 mg/m2 was given as follows: 20 mg/m2 on days 1 and 8 (group 1); 30 mg/m2 on day 1 and 10 mg/m2 on day 8 (group 2); or 40 mg/m2 on day 1 (not exeeding 60 mg/m2) (group 3). The methotrexate dose was 40 mg/m2 on day 1 and the fluorouracil dose 600 mg/m2 on days 1 and 8. Thirty patients with evaluable metastases were randomly allocated to the groups (first step). The second step was to exclude the worst tolerated regimen and then to expand the study to 60 patients. Thus, group 1 had 26 patients, group 2 had 24 patients and group 3 had 10 patients.
Results:
World Health Organization (WHO) grade 3 hematological toxicity occurred in 23%, 36% and 50% of patients and grade 4 in 39%, 32% and 50% of patients in groups 1, 2 and 3, respectively; grade 3 infections were observed in 15%, 9% and 10% of patients in groups 1, 2 and 3, and grade 4 infections in 5% and 10% of patients in groups 2 and 3, respectively. Nonhematological toxicity included a mild to moderate neurotoxicity manifesting as constipation, abdominal colics and myalgia in the majority of patients. One patient in group 3 had serious convulsions after vinorelbine administration; she also developed neutropenic sepsis; all symptoms were reversible. No patient died from side-effects. The objective response rates were 50%, 55% and 44% for groups 1, 2 and 3, respectively. Median time to progression was 7, 10 and 8 months and median survival time was 26, 23 and 16 months in groups 1, 2 and 3, respectively.
Conclusion:
VMF regimens where the vinorelbine dose (40 mg/m2) is divided (20 + 20 mg/m2 and 30 + 10 mg/m2) between days 1 and 8 of a 3-week cycle are equally well tolerated and the efficacy is comparable to other modern first line regimens used in the treatment of metastatic breast cancer.
Key words: fluorouracil, metastatic breast cancer, methotrexate, vinorelbine
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Introduction |
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Patients and methods |
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Hematological and nonhematological toxicities were investigated on the days of treatment and nadir values on days 1115. If patients experienced dose-limiting toxicities, which were defined as WHO grade 3 granulocytopenia associated with grade >2 infection and/or grade >2 constipation, the vinorelbine dose was reduced by 20%. Similarly, grade >2 stomatitis, mucositis or diarrhea led to fluorouracil dose reduction of 20%. Response to treatment was assessed according to the UICC criteria. The regimens were given until progressive disease or serious side-effects occurred. The statistical significance of differences in toxicity and treatment response between the groups was tested with the chi-square test. Differences in the dose intensity per course and time were tested with the KruskalWallis test. The statistical significance of differences in time to progression (TTP) and survival between the three groups was tested with the log-rank test. The study was approved by the local ethics committee.
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Results |
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Groups 13. No patients died from side-effects.
Treatment response, TTP and survival
The overall response rates were 50% in group 1, 55% in group 2 and 44% in group 3 (Table 5). Median TTP was 7, 10 and 8 months and median survival time was 26, 23 and 16 months in groups 1, 2 and 3, respectively. There were no significant differences between the groups (Figures 1 and 2).
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Discussion |
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Vinorelbine is a semi-synthetic vinca-alkaloid targeting to microtubules. The capacity of vinorelbine to bind preferentially to mitotic rather than axonal microtubules has been demonstrated and might imply that neurotoxicity is less common than with the other vinca-alkaloids [2]. Mild peripheral neuropathy of grade 12 has been reported in up to 30% of patients receiving vinorelbine, but severe grade 34 toxicity has been observed in only 1% [2]. We saw life-threatening grade 4 neurotoxicity with convulsions and paralytic ileus in one patient with vinorelbine 40 mg/m2 given as a single infusion. One-half of all patients complained of grade 12 constipation, which was often accompanied by simultaneous nausea, epigastric pain and myalgia. Neurotoxicity led to treatment interruption in four patients (6%); three of them belonged to group 3 (33%). Neurotoxicity was commonly accompanied by hematological toxicity which is known to be the main dose-limiting toxicity of vinorelbine. Neutropenia has occurred in more than one-half of the patients in previous studies [25]. This was the case also in our patients. Neutropenia was rapidly reversible and caused curable grade 3 (11%) and grade 4 (3%) infections which required hospitalization.
Although we saw serious toxicity in some patients, none of them died from the side-effects. Most of the adverse effects were mild, always reversible and well tolerated. Local irritation at the injection site was infrequent, and total alopecia occurred in none of the patients. In general, VMF toxicity in groups 1 and 2 appeared seldom to exceed that of CMF and CAF regimens, and may be comparable with other phase II and III studies using vinorelbine [2, 3].
Response, TTP and median overall survival (OS) of VMF therapy are in accordance with other phase II trials which combine vinorelbine with fluorouracil, alkylating agents, mitomycin C, cisplatin and taxanes [3, 5]. The combination of an anthracycline with vinorelbine has had a better response rate than VMF, but the duration of response was similar, although the dose of vinorelbine was higher in these trials (25 mg/m2 twice) [3, 4]. Three randomized trials where vinorelbine and doxorubicin are compared to CAF [6] or doxorubicin alone [1, 7] demonstrated no significant differences between the arms regarding response rate, TTP and median OS. In contrast vinorelbine enhanced the toxicity. A further randomized trial where vinorelbine and mitoxantrone were compared to CAF did not show any difference in response rates [8]. When a combination of vinorelbine and fluorouracil was randomly compared to single-agent docetaxel, response rates were 44% and 54%, and response duration was 6 and 8 months, respectively [9]. The combination of oral vinorelbine and capecitabine is interesting.
Economic assessments of anticancer treatments are becoming increasingly important to allow for targeting of resources. A recent costbenefit analysis of single agents in anthracycline-resistant pre-treated patients with metastatic breast cancer compared vinorelbine-provided equivalent quality-adjusted disease-free survival with economic advantage over taxanes [10]. A similar analysis should be performed regarding oral vinorelbine and capecitabine.
We conclude that the VMF regimens where the vinorelbine dose (40 mg/m2) is divided (20 + 20 mg/m2 and 30 + 10 mg/m2) between days 1 and 8 of a 3-week cycle are equally well tolerated and efficacious. Response rate, TTP and median OS appear to be comparable to most other first-line regimens, including regimens containing anthracyclines. The VMF combination is suitable for patients who wish to avoid severe nausea and alopecia. It is a useful option also for elderly patients and those with heart failure. Before recommending VMF as adjuvant or neoadjuvant therapy in breast cancer, it is reasonable to compare its efficacy in randomized trials with anthracyclines and taxanes, either given as single agents or in combination. Oral vinorelbine with capecitabine is worthy of investigation.
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Footnotes |
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References |
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