Vinorelbine, methotrexate and fluorouracil (VMF) as first-line therapy in metastatic breast cancer: a randomized phase II trial

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1 Original article Annals of Oncology 14: , 2003 DOI: /annonc/mdg199 Vinorelbine, methotrexate and fluorouracil (VMF) as first-line therapy in metastatic breast cancer: a randomized phase II trial I. Elomaa 1 *, H. Joensuu 1 & C. Blomqvist 2 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 Introduction Background: 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/m 2 was given as follows: 20 mg/m 2 on days 1 and 8 (group 1); 30 mg/m 2 on day 1 and 10 mg/m 2 on day 8 (group 2); or 40 mg/m 2 on day 1 (not exeeding 60 mg/m 2 ) (group 3). The methotrexate dose was 40 mg/m 2 on day 1 and the fluorouracil dose 600 mg/m 2 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/m 2 ) is divided ( mg/m 2 and mg/m 2 ) 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 *Correspondence to: Professor I. Elomaa, Cancer Center, University Hospital of Helsinki, PO Box 180, Huch, Finland. Tel: ; Fax: ; inkeri.elomaa@hus.fi Survival of metastatic breast cancer treated with chemotherapy has remained largely unchanged. Older established regimens consisting of combinations of cyclophosphamide and fluorouracil with methotrexate (CMF) or with anthracycline (CAF) have given a median survival of 14 months for non-anthracycline regimens and 18 months for anthracycline regimens [1]. Vinorelbine is one of the new agents which has shown a level of single-agent activity equivalent to that of many standard agents, including doxorubicin, epirubicin and mitoxantrone, with a response rate as first-line treatment of 40 60% [2, 3]. Since vinorelbine is in general a well-tolerated agent also in the elderly, and rarely causes total alopecia and severe nausea, we tested three different dose delivery regimens to find the optimal way to give vinorelbine. We combined vinorelbine with methotrexate and fluorouracil which also are well-tolerated (VMF). Vinorelbine 40 mg/m 2 was given intravenously on day 1 or divided ( mg/m 2 and mg/m 2 ) between days 1 and 8 of a 3-week cycle. The main aim was to develop a low toxic but more efficacious regimen than CMF for adjuvant and neoadjuvant use. Patients and methods A phase II study was conducted between April 1997 and February 2000 at the Cancer Center, University of Helsinki, Finland. Patients eligible for treatment were ambulant, displayed Eastern Cooperative Oncology Group (ECOG) status of 0 2 and were 75 years old, with histologically confirmed, measurable or evaluable metastatic breast cancer. Patients pretreated with adjuvant chemotherapy were included, as well as those treated with hormonal therapy, but patients with prior chemotherapy for metastatic disease were excluded. The characteristics of patients, previous treatments and the sites of metastatic disease in each group are given in Table 1. The VMF regimens consisted of three different doses of vinorelbine: 20 mg/m 2 on days 1 and 8 (group 1); 30 mg/m 2 on day 1 and 10 mg/m 2 on day 8 (group 2); or 40 mg/m 2 on day 1 (not exeeding 60 mg/m 2 ) (group 3). In each group methotrexate 40 mg/m 2 was given on day 1 and fluorouracil 600 mg/m 2 on days 1 and 8. Thirty patients were randomly allocated to three groups (first step). The study was further expanded to 60 patients, including the regimens 2003 European Society for Medical Oncology

2 700 Table 1. Patient characteristics and metastatic organs involved (MOI) Characteristics Group 1 Group 2 Group 3 Age, years a Area a Postmenopausal, % ER positive, % PR positive, % Previous treatment, % Adjuvant CMF FEC None Metastatic hormone Number of MOI, % Organs involved, % Bone Lung Liver Viscera Soft tissue a Median (range). CMF, cyclophosphamide and fluorouracil with methotrexate; ER, estrogen receptor; FEC, 5-fluorouracil, epirubicin and cyclophosphamide; PR, progestogen receptor. best tolerated (second step). Thus, group 1 had 26 patients, group 2 had 24 patients and group 3 had 10 patients. Hematological and nonhematological toxicities were investigated on the days of treatment and nadir values on days 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 Kruskal Wallis 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. Results Tolerability and toxicity The medium dose intensity (mg/m 2 ) per course and time was comparable between the groups, except for vinorelbine in group 3 Table 2. Dose intensity (median) as mg/m 2 per course and per time, total number of cycles in each group and range of cycles per patient and causes of interruptions of vinorelbine, methotrexate and fluorouracil therapy Group 1 Group 2 Group 3 Vinorelbine Course a Time Methotrexate Course Time b Fluorouracil Course Time No. of cycles Cycles per patient Interruptions Causes PD 1 NT 1 NT and NPS 1 2 a Chi-square test: P = b Kruskal Wallis test: P = NPS, neutropenic sepsis; NT, neurotoxicity; PD, progressive disease. Table 3. Hematological nadir values, median and range Group 1 Group 2 Group 3 Hemoglobin 105 (70 130) 110 (83 128) 110 (90 128) Leukocytes 2.1 ( ) 1.9 ( ) 1.6 ( ) Neutrophiles 0.6 ( ) 0.7 ( ) 0.5 ( ) Platelets 161 (81 251) 134 (9 322) 141 (31 327) where the maximum absolute dose was set at 60 mg (Table 2). Total number of cycles, range of cycles per patient and causes of interruption of therapy are given in Table 2. Table 3 shows hematological nadir and median values. Groups 1 and 2. No grade 3 4 nonhematological adverse effects were seen in the first 10 patients in groups 1 and 2 and the recruitment of patients continued in these groups. Dose-limiting grade 3 4 leukopenia was seen in 46% of patients in group 1 and 51% of patients in group 2. Only one patient in group 1 had grade 3 anemia and one patient in group 2 had grade 4 thrombocytopenia (Table 4). Grade 3 infection occurred in six patients and grade 4 infection in one patient. Total alopecia was not seen and nausea, stomatitis, diarrhea or local irritation were mainly mild (Table 4). Grade 1 2 constipation occurred in half of the patients and many of them complained of simultaneous abdominal colics and myalgia. In one patient in group 2 VMF therapy was interrupted

3 701 Table 4. Hematological and nonhematological toxicity (%) WHO grade Group 1 Group 2 Group Hematological Hemoglobin Leukopenia Neutropenia Platelets Hematology Nonhematological Alopecia Constipation Diarrhea Infection Local irritation Nausea Neurotoxicity Pain Stomatitis Neurotoxicity includes paresthesia; pain includes epigastric pain and myalgia; WHO, World Health Organization. Table 5. Maximal response (%), median overall survival (OS) and time to progression (TTP) in months Response Group 1 (%) Group 2 (%) Group 3 (%) CR 1 (4) 1 (4) 2 (22) PR 12 (46) 11 (50) 2 (22) NR 10 (39) 5 (23) 4 (45) PD 3 (11) 5 (23) 1 (11) OS (CI) 26 (12 40) 23 (13 34) 16 (4 49) TTP (CI) 7 (5 10) 10 (8 10) 8 (5 11) CI, 95% confidence interval; CR, complete response; NR, no response; PD, progressive disease; PR, partial response. after one cycle, according to her wishes, because of neurotoxic symptoms and neutropenic sepsis. Brain metastases which led to interruption of VMF therapy were detected after two cycles in one patient in group 1. Group 3. The tolerability of the VMF schedule was not acceptable in group 3: seven patients had grade 3 4 neutropenia, two had sepsis, four had milder infections and the majority had nausea and neurotoxicity which required treatment for constipation and myalgia (Table 4). One patient had serious convulsions after vinorelbine administration requiring anticonvulsant infusion for 24 h. She also had amnesia and developed grade 4 neutropenic sepsis; all symptoms were reversible within a week. VMF therapy was not continued in this patient, and two other patients discontinued the therapy because of repeated constipation, abdominal pain and infection. Thus, no more than 10 patients were included into group 3. Groups 1 3. 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). Discussion The tolerability was favorable in groups 1 and 2 where vinorelbine was divided into two doses. In contrast, one dose of 40 mg/m 2 in a 3-week cycle was too toxic. The main toxicity in group 3 was simultaneous grade 3 4 neurological and hematological adverse effects, which led to interruption of VMF therapy in three out of 10 patients and recruitment of patients into group 3 was discontinued. 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 1 2 has been reported in up to 30% of patients receiving vino-

4 702 Figure 1. Time to progression (TTP) between groups 1, 2 and 3 of vinorelbine, methotrexate and fluorouracil (VMF) therapy. Stippled line, group 1; thin line, group 2; thick line, group 3. Figure 2. Median overall survival between groups 1, 2 and 3 of vinorelbine, methotrexate and fluorouracil (VMF) therapy. Stippled line, group 1; thin line, group 2; thick line, group 3. relbine, but severe grade 3 4 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/m 2 given as a single infusion. One-half of all patients complained of grade 1 2 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 [2 5]. 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/m 2 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 cost benefit analysis of single agents in anthracyclineresistant 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/m 2 ) is divided ( mg/m 2 and mg/m 2 ) 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. References 1. Norris B, Pritchard KI, James K et al. 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 MA8. J Clin Oncol 2000; 18: Gregory RK, Smith IE. Vinorelbine a clinical review. Br J Cancer 2000; 82:

5 Spielmann M, Zelek L. Vinorelbine. In Nabholtz J-M, Tonkin K, Aapro MS, Buzdar AU (eds): Breast Cancer Management. BCIRG, Martin Dunitz Ltd 2000; Blomqvist C, Hietanen P, Teerenhovi L, Riussanen P. Vinorelbine and epirubicin in metastatic breast cancer. A dose finding study. Eur J Cancer 1995; 31: Nole F, de Braud F, Aapro M et al. Phase I II study of vinorelbine in combination with 5-fluorouracil and folinic acid as first-line chemotherapy in metastatic breast cancer: A regimen with a low subjective toxic burden. Ann Oncol 1997; 8: Blajman C, Balbiani L, Block J et al. A prospective, randomized phase III trial comparing combination chemotherapy with cyclophosphamide, doxorubicin, and 5-fluorouracil with vinorelbine plus doxorubicin in the treatment of advanced breast carcinoma. Cancer 1999; 85: Ejlertsen B, Mouridsen HT, Langkjer ST et al. Epirubicin and vinorelbine versus single agent epirubicin as first line chemotherapy in metastatic breast cancer. Eur J Cancer 2002; 38 (Suppl 3): Namer M, Soler-Michel P, Turpin F et al. Prospective randomized study comparing mitoxantrone (M) and vinorelbine (V) with fluorouracil (F), epirubicin (E) or adriamycin (A) and cyclophosphamide (C) in patients with metastatic breast cancer. Eur J Cancer 2001; 37: Bonneterre J, Roche H, Monnier A et al. Taxotere (TXT) versus 5-fluorouracil + navelbine (FUN) as second-line chemotherapy (CT) in patients (pts) with metastatic breast cancer (MBC) (preliminary results). Proc Am Soc Clin Oncol 1997; 16: 162a (Abstr 564). 10. Leung PP, Tannock IF, Oza AM et al. Cost utility analysis of chemotherapy using paclitaxel, docetaxel, or vinorelbine for patients with anthracycline-resistant breast cancer. J Clin Oncol 1999; 17: 3082.

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