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Results of a phase I trial of intravenous vinorelbine plus oral capecitabine as first-line chemotherapy of metastatic breast cancer
ARTICLE IN PRESS THE BREAST The Breast 17 (2008) 38–43 www.elsevier.com/locate/breast
Original article
Results of a phase I trial of intravenous vinorelbine plus oral capecitabine as first-line chemotherapy of metastatic breast cancer Laure Faviera, Nicolas Isamberta, Sylvie Zanettaa, Emmanuelle Ferranta, Franc- oise Mayera, Bruno Chaufferta, Pierre Fumoleaua, Je´rome Garnierb, Fabienne Bivillec, Bruno Couderta, Department of Medical Oncology, Centre Georges-Franc- ois Leclerc, 1 rue du Professeur Marion, 21000 Dijon, France b Laboratoires Roche, 52 boulevard du Parc, 92200 Neuilly-sur-Seine, France c Laboratoires Pierre Fabre Oncologie,45 place Abel Gance, 92100 Boulogne-Billancourt, France
a
Received 1 February 2006; received in revised form 5 February 2007; accepted 14 June 2007
Abstract The management of metastatic breast cancer becomes increasingly intricate, requiring new drugs and combinations. We present here the results of a phase I study evaluating the maximal tolerated dose of vinorelbine combined with capecitabine as first-line chemotherapy. Vinorelbine was administered intravenously on days 1 and 15, and capecitabine was given orally twice daily from day 1 to 14 (three cycles every 21 days). Three out of six patients receiving vinorelbine at 25 mg/m2/day and capecitabine at 2000 mg/m2/day presented with a dose-limiting toxicity, consisting of protracted grade 3 neutropenia, hand–foot syndrome and/or liver test disturbances. Despite of a dose reduction in vinorelbine (20 mg/m2/day), one patient among four developed a dose-limiting febrile neutropenia. This regimen cannot be recommended as first-line treatment of metastatic breast cancer. These findings are not in agreement with previous publications of this schedule, or with promising results using both drugs orally. r 2007 Elsevier Ltd. All rights reserved. Keywords: Metastatic breast cancer; Chemotherapy; Vinorelbine; Capecitabine; Phase I trial
Introduction Metastatic breast cancer remains an incurable disease even if new hormonal agents, cytotoxic drugs and targeted therapies currently improve its outcome. Therapeutic strategies are based on a palliative behavior and aim at decreasing symptoms, improving quality of life and prolonging survival. The lack of consensus leads us to use chemotherapy, combined or not with hormonal treatment.1 Various regimens of chemotherapy are at our disposal using either single agent or polychemotherapy, mainly based on anthracyclines, taxanes, gemcitabine, Abbreviations: V vinorelbine; C capecitabine; MTD maximal tolerated dose; WHO World Health Organization; GGT gamma-glutamyl transferase; ULN upper limit of normal; DPD dihydro-pyrimidine deshydrogenase; G-CSF granulocyte colony-stimulating factor; DLT dose-limiting toxicity; NCI-CTC National Cancer Institute Common Toxicity Criteria Corresponding author. Tel.: +33 (0)3 80 73 77 20; fax: +33 (0)3 80 73 77 12. E-mail address: [email protected] (B. Coudert). 0960-9776/$ - see front matter r 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.breast.2007.06.003
capecitabine, and vinorelbine.1–3 An increasing number of patients receive an anthracycline–taxane combination as adjuvant therapy, requiring the development of new drugs and combination for the treatment of metastatic disease. The association of vinorelbine to fluorouracil remains a frequently used chemotherapy for the treatment of metastatic breast cancer. In first-line therapy, an objective response was achieved in 62% of the patients, with a median duration of response ranging from 10 to 12.3 months, and a median survival time of 23 months.4,5 The main toxicity was grade 3 and 4 neutropenia, occurring in 77–90% of the patients, and febrile neutropenia in 3.6–8.8% of them.4,5 The other frequent reported events were thrombocytopenia (19%, of which 5% were grade 3–4), stomatitis (71%, of which 38% were grade 3–4), infection (12.7%), and constipation (9.5%).4,5 In secondline treatment, this combination showed a good efficacy, response rates ranging from 45% to 61%.6–10 Vinorelbine combined with a protracted, continuous infusion of fluorouracil improved the safety of such regimen, with a
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decrease in the incidence of neutropenia (0–14% of grade 3–4), and stomatitis (1.2–9.2% of grade 3).6–10 One of these studies evaluated a novel regimen consisting of vinorelbine 30 mg/m2 administered on days 1 and 15 every 28 days, and fluorouracil 200 mg/m2/day given continuously over a 24-h period between vinorelbine infusions.6 Among the 83 treated patients, only seven cases of grade 3 toxicity and one grade 4 were reported. This good safety profile was associated with a satisfying efficacy as a complete response was achieved in 7.2% of patients, a partial response in 54.2%, and stabilization in 25.3%. Capecitabine (Xeloda, Hoffmann–La Roche) is an oral fluoropyrimidine precursor, converted in fluorouracil preferentially in tumor tissue, allowing treatment at home, and thereby potentially improving the quality of life. Used as single agent in heavily pretreated patients with anthracyclines and/or taxanes, response rates were from 15% to 28%, with a median duration of response ranging from 5 to 8.9 months, and a survival time of 7.7–18.1 months.11–14 The most common non-hematological effects were gastrointestinal side effects and hand–foot syndrome. Several phase I and II trials explored the vinorelbine– capecitabine (VC) combination in the treatment of metastatic breast cancer, mainly after anthracyclines and/or taxanes failure.15–21 The reported response rates were from 39% to 68%. However, the dosing schedules were heterogeneous, capecitabine ranging from 800 to 2250 mg/m2/day from day 1 to 14, and vinorelbine from 20 until 30 mg/m2/day on days 1 and 8. Thus, the optimal regimen as well the maximal tolerated dose (MTD) of intravenous vinorelbine plus oral capecitabine is not currently determined. The purpose of our study was to better define the dose of this combination as first-line treatment in metastatic breast cancer patients, according to the well-tolerated schedule previously described by Berruti et al, consisting of vinorelbine administered before and after a continuous infusion of fluorouracil.6 Patients and methods Patients Non-pregnant women between 18 and 65 years of age, with documented metastatic breast cancer and who have not previously received chemotherapy for metastatic disease, were enrolled in the study. The main eligibility criteria were World Health Organization (WHO) performance statuso3; satisfactory hematological (neutrophils count 4 1.5 109/L, platelets count 4 120 109/L), hepatic (transaminases, alkaline phosphatases, and gamma-glutamyl transferase [GGT]o2.5 upper limit of normal [ULN]), and renal (serum creatinineo1.5 ULN, and creatinine clearance X 60 mL/min) tests; adjuvant chemotherapy and/or radiotherapy stopped for at least 4 weeks; radiotherapy involving less than 30% of medullary area; and ability to be followed every week. Patients were
39
excluded from the study if they had a NCI grade X 1 peripheral neuropathy; a severe constipation or subocclusive disease; a treatment with phenytoin, itraconazole, sorivudine or analogs; a known hypersensitivity to capecitabine or fluorouracil; a previous history of severe reactions to treatments formulated with fluoropyrimidines; a dihydro-pyrimidine deshydrogenase (DPD) deficiency; symptomatic or progressive brain metastases; or severe concomitant diseases (liver, renal, cardiac, or lung failure, angina, or disabling psychiatric disease). Written informed consent was obtained from each patient before inclusion. The protocol was reviewed and approved by the Ethics Committee/Institutional Review Board and the study was conducted according to the Declaration of Helsinki and European Good Clinical Practice requirements.
Treatment According to previous reports of VC combinations in which capecitabine was used from 800 to 2250 mg/m2/day (day 1–14) and vinorelbine from 20 to 30 mg/m2/day (days 1 and 8),15–18,20–22 chosen starting doses per cycle were 2000 mg/m2/day (day 1–14) (28,000 mg/m2/cycle) for capecitabine and 25 mg/m2/day (days 1 and 15) (50 mg/m2/ cycle) for vinorelbine. Vinorelbine doses were escalated from 20 to 30 mg/m2/day (i.e. 40–60 mg/m2/cycle), and capecitabine doses from 1750 to 2500 mg/m2/day (i.e. 24,500–35,000 mg/m2/cycle) (Table 1). Vinorelbine was administered intravenously as a 20minute infusion on days 1 and 15, every 21 days for three cycles. Capecitabine was given orally twice daily (equal doses morning and evening) from day 1 to day 14, every 21 days for three cycles. Capecitabine tablets must be swallowed within 30 minutes after meals. Antiemetic treatment was prescribed routinely before each cycle. Preventive use of granulocyte colony-stimulating factor (G-CSF) and antibiotics was prohibited. G-CSF (lenograstim) was recommended in case of febrile neutropenia and/ or grade 4 neutropenia lasting more than 7 days. No pharmacokinetics data were collected. Table 1 Dose escalation procedures of vinorelbine and capecitabine Level
2 1 0 1 2 3 4 5
Vinorelbine (mg/m2)
Capecitabine (mg/m2)
Per day (days 1 and 15)
Per cycle
Per day (day 1–14)
Per cycle
20 20 25 30 25 30 25 30
40 40 50 60 50 60 50 60
1750 2000 2000 2000 2250 2250 2500 2500
24,500 28,000 28,000 28,000 31,500 31,500 35,000 35,000
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L. Favier et al. / The Breast 17 (2008) 38–43
Dose-Limiting Toxicity Dose-limiting toxicity (DLT) was evaluated for three cycles in succession, and was defined as follows: febrile neutropenia, grade 4 neutropenia lasting more than 7 days, grade 3-4 anemia and/or thrombocytopenia, grade 4 vomiting, grade X 3 non-hematological toxicities (except alopecia and vomiting), grade X 2 hematological and/or non-hematological toxicities lasting more than 7 days after day 21; and non-recovery of biological tests lasting more than 21 days after day 21. The study protocol was started at level 0 (vinorelbine 25 mg/m2, capecitabine 2000 mg/m2). Three to six patients were treated at each dose level. If one of three patients at a given dose level developed DLT, three additional patients were entered at the same dose level. The MTD was defined as the dose at which at least two of the first three patients or at least three of six patients developed DLT. The recommended dose was defined as the dose level just below the MTD. Safety assessment Hematological tolerability was evaluated based on absolute blood cells counts performed weekly and before each cycle. In the event of febrile neutropenia, capecitabine was stopped and absolute blood cells count was performed daily until recovery. Non-hematological toxicities were evaluated during the period between each cycle, according to National Cancer Institute Common Toxicity Criteria (NCI-CTC). A laboratory assessment (blood sodium, potassium, calcium, urea, creatinine, AST, ALT, total bilirubin, fasting glucose, total protein, albumin, alkaline phosphatases, LDH, GGT) was performed before each treatment cycle. Serious adverse events were defined according to ICH guidelines. Discontinuation of treatment was required in patients who presented with a DLT, or a disease progression. In any case, the treatment could be discontinued according to the patient’s or investigator’s decision. At the end of the phase I study, an efficacy assessment was left to the discretion of each investigator to define subsequent chemotherapy regimens. Results Patient and treatment characteristics Between November 2002 and February 2004, 10 patients, aged between 46 and 67 years, were enrolled in the study from one center located in France. In each case, adjuvant treatment of early breast cancer was considered optimal. Initial surgery consisted of mastectomy in seven patients and tumorectomy in three all with axillary node sampling or clearance. All patients received adjuvant and/ or neoadjuvant chemotherapy: it was an anthracycline– based regimen in eight patients, a taxane-based regimen in
Table 2 Patient and treatment characteristics at baseline Characteristics
Patients (n ¼ 10) N
Metastatic localization Bone Liver Lung/pleura Nodes
6 5 5 1
Number of involved sites 1 2 3
3 5 2
one, and an anthracycline-taxane combination in one. The nine hormone-receptor positive patients had received tamoxifen. Radiotherapy was delivered in seven patients. The median time between initial diagnosis and the present relapse was 24 months (range, 11–243 months). Baseline characteristics are summarized in Table 2. Six patients were treated at level 0 (V 25 mg/m2, C 2000 mg/m2). Among them, three patients received the full schedule, one received two cycles, and two received one cycle. Due to unexpected toxicity, the initial doses had to be reduced rather than escalated. Four patients were included at a lower dose level (V 20 mg/m2, C 2000 mg/m2), of which three received three cycles and one patient received one cycle. The actual doses delivered are described in Table 3.
Safety and DLT Among the six patients treated at the first dose level, three of them developed a DLT (Table 4). After the first cycle, one patient developed a grade 3 neutropenia lasting more than 7 days after day 21, and one patient developed a grade 3 increase in GGT lasting more than 21 days. After the second cycle, a third patient, free of liver metastases, presented with a grade 2 increase in GGT lasting more than 21 days. Additionally, at this dose level, a fourth patient presented with a grade 2 protracted hand-foot syndrome lasting more than 7 days after day 21, requiring a delay in the onset of the third cycle. In spite of dose reduction, one patient among the following four patients developed a DLT consisting of a febrile neutropenia (cycle 1). At this dose level, another patient presented with a grade 1, protracted hand–foot syndrome lasting more than 7 days after day 21. Main hematological, laboratory and nonhematological toxicities reported are summarized in Tables 4 and 5. Among the 10 patients enrolled in the study, six of them were able to receive the three scheduled courses. Subsequently, three of them received the classical vinorelbine–fluorouracil combination as second-line therapy.
ARTICLE IN PRESS L. Favier et al. / The Breast 17 (2008) 38–43 Table 3 Actual dose received per patient and cycle Patient
Dose level
1
0
2
0
3
0
4
0
5
0
6
0
7
1
8
1
9
1
10
1
Cycle
1 2 3 1 1 2 3 1 1 2 1 2 3 1 2 3 1 2 3 1 2 3 1
Table 5 Incidence of laboratory and non-hematological adverse events per dose level and cycles
Theoretical dose mg/m2
Actual/Theoretical dose%
V
C
V
C
25
2000
25
2000
25
2000
25
2000
50 100 100 99 100 97 101 100
97 97 97 101 102 96 103 93
25
2000
25
2000
20
2000
101 101 87 87 87 101 101 101 99 100 99 99 99 99 97
98 97 87 87 87 101 101 93 97 97 96 93 94 94 96
20
2000
20
2000
20
2000
V, vinorelbine; C, capecitabine. Table 4 Incidence of hematological adverse events per dose level and cycles Toxicity
V/C (mg/m2)
Total
25/2000
20/2000
13
10
23
2 (15.4) 4 (30.8) 1 (7.7)
1 (10.0) 3 (30.0) 3 (30.0)
3 (13.0) 7 (30.4) 4 (17.4)
Neutropenia Grade 1 Grade 2 Grade 3 Grade 4 4 7 days Febrile neutropenia
1 3 3 0 1 0
1 1 2 3 0 1
2 4 5 3 1 1
Anemia Grade 1 Grade 2 Grade 3
6 (46.1) 1 (7.7) 0
Number of cycles Leucopenia Grade 1 Grade 2 Grade 3
(7.7) (23.1) (23.1) (7.7)
41
(10.0) (10.0) (20.0) (30.0) (10.0)
3 (30.0) 2 (20.0) 1 (10.0)
(8.7) (17.4) (21.7) (13.0) (4.3) (4.3)
9 (39.1) 3 (13.0) 1 (4.3)
V, vinorelbine ; C, capecitabine. dose-limiting toxicity.
Discussion The current combination of intravenous vinorelbine (days 1 and 15) plus oral capecitabine (day 1–14) provided
Toxicity
V/C (mg/m2) 25/2000
20/2000
Total
Number of cycles Biological tests Cytolysis Grade 1 Grade 2 4 7 days
13
10
23
7 (53.8) 3 (23.1) 1 (7.7)
5 (50.0) 0 0
12 (52.1) 3 (13.0) 1 (4.3)
Cholestasis Grade 1 Grade 2 Grade 3 4 7 days
8 2 1 1
7 (70.0) 0 0 0
15 (65.2) 2 (8.7) 1 (4.3) 1 (4.3)
Bilirubin Grade 1
1 (7.7)
0
1 (4.3)
Non-hematological toxicities Nausea Grade 1
2 (15.4)
0
2 (8.7)
0
1 (10.0)
1 (4.3)
1 (7.7) 1 (7.7)
1 (10.0) 0
2 (8.7) 1 (4.3)
0
1 (10.0)
1 (4.3)
0
1 (10.0)
1 (4.3)
0 0 0
3 (30.0) 0 1 (10.0)
3 (13.0) 0 1 (4.3)
0 0
1 (10.0) 1 (10.0)
1 (4.3) 1 (4.3)
0
1 (10.0)
1 (4.3)
Diarrhea Grade 1 Hand-foot syndrome Grade 1 Grade 2 Peripheral neuropathy Grade 1 Constipation Grade 1 Infection Grade 1 Grade 2 Grade 3 Alopecia Grade 1 Grade 2 Asthenia Grade 1
(61.5) (15.4) (7.7) (7.7)
V, vinorelbine ; C, capecitabine. dose-limiting toxicity.
a level of toxicity which is not consistent with its use in first-line therapy of metastatic breast cancer. Reported toxicities led investigators to prematurely stop the study without testing lower doses. These results stand in contrast with those of the phase I–II trials using capecitabine twice daily (day 1–14) plus IV vinorelbine (days 1 and 8).16–18,20,22 In the study published by Welt et al., capecitabine dose was fixed at 1000 mg/m2 from days 1 to 14. At a dose of vinorelbine of 30 mg/m2 (days 1 and 8), four patients among seven experienced a DLT with nausea/ vomiting, febrile neutropenia, grade 4 neutropenia, infection and diarrhea. At a dose of vinorelbine of 25 mg/m2 (days 1 and 8), 2 patients among 24 experienced a DLT with hospitalization due to febrile neutropenia and prolonged neutropenia. In the study published by Hess et al. the vinorelbine recommended dose was 20 mg/m2/day on days 1 and 8 and the capecitabine recommended dose differed if patients had bone involvement (1000 mg/m2 days
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L. Favier et al. / The Breast 17 (2008) 38–43
1–14) or not (1250 mg/m2 days 1–14). DLT was neutropenia. In the study published by Lorusso et al., DLT (grade 4 neutropenia plus grade 3 diarrhea and grade 3 oral mucositis) was reached at 2250 mg/m2 of capecitabine with vinorelbine administered on days 1 and 8 at a fixed dose of 25 mg/m2. MTD was defined at 2000 mg/m2 capecitabine. In all of the studies, authors concluded that the intravenous vinorelbine plus oral capecitabine combination was feasible and active. In another study, 49 patients with pre-treated advanced-stage breast cancer were treated with escalating doses of oral capecitabine from 500 to 1375 mg/m2 twice daily on days 1–14 and escalating doses of vinorelbine from 12.5 to 25 mg/m2 intravenously (I.V.) on days 1 and 3 every 3 weeks.22 The most frequent clinical adverse events were mild to moderate and corresponded to nausea (78%), asthenia (59%), constipation (51%), mucositis (47%), and hand–foot syndrome (41%). Maximum tolerated dose was defined as capecitabine 1250 mg/m2 twice daily on days 1–14 and vinorelbine 22.5 mg/m2 I.V. on days 1 and 3 and was retained for future phase II studies.22 Therefore these timings of administration of vinorelbine (D1 and D8 or D1 and D3) seem more advisable than the day 1 and 15 presently evaluated. Pharmacologic and pharmacokinetic interactions of the evaluated association were not initially scheduled and should be explored in order to explain the difference in those findings. Conclusions The current combination of intravenous vinorelbine (days 1 and 15) plus oral capecitabine (day 1–14) is not feasible in this setting. The available data regarding vinorelbine–capecitabine combination in metastatic breast cancer led us to carry on further clinical trials. Other vinorelbine-capecitabine schedules have to be investigated, especially those which combine both drugs orally.23–25 Acknowledgments This study was supported by grants from Laboratoires Roche (France), and Laboratoires Pierre Fabre Oncologie (France). Isabelle Chapelle-Marcillac provided editorial assistance in the preparation of the manuscript. References 1. Carlson RW, Edge SB, Theriault RL. NCCN: Breast cancer. Cancer Control 2001;8:54–61. 2. Blum JL, Jones SE, Buzdar AU, et al. Multicenter phase II study of capecitabine in paclitaxel-refractory metastatic breast cancer. J Clin Oncol 1999;17:485–93. 3. Fumoleau P, Delgado FM, Delozier T, et al. Phase II trial of weekly intravenous vinorelbine in first-line advanced breast cancer chemotherapy. J Clin Oncol 1993;11:1245–52. 4. Dieras V, Extra JM, Bellissant E, et al. Efficacy and tolerance of vinorelbine and fluorouracile combination as first line chemotherapy of advanced breast cancer: results of a phase II study using a sequential group method. J Clin Oncol 1996;14:3097–104.
5. 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;8:865–70. 6. Berruti A, Sperone P, Bottini A, et al. Phase II Study of vinorelbine with protracted fluorouracil infusion as a second- or third-line approach for advanced breast cancer patients previously treated with anthracyclines. J Clin Oncol 2000;18:3370–7. 7. Hochster HS, Vogel CL, Burman SL, et al. Activity and safety of vinorelbine combined with doxorubicin or fluorouracil as first-line therapy in advanced breast cancer: a stratified phase II study. Oncologist 2001;6:269–77. 8. Pienkowski T, Jagiello-Gruszfeld A. Five-day infusion of fluorouracil and vinorelbine for advanced breast cancer patients treated previously with anthracyclines. Int J Clin Pharmacol Res 2001;21: 111–7. 9. Zambelli A, Robustelli della Cuna FS, Ponchio L, et al. Four-day infusion of fluorouracil plus vinorelbine as salvage treatment of heavily pretreated metastatic breast cancer. Breast Cancer Res Treat 2000;61:241–7. 10. Zambetti M, Mariani G, Demicheli R, et al. Five-day infusion fluorouracil plus vinorelbine in women with breast cancer previously treated with anthracyclines and paclitaxel. Breast Cancer Res Treat 2000;62:135–9. 11. Fumoleau P, Largillier R, Clippe C, et al. Multicentre, phase II study evaluating capecitabine monotherapy in patients with anthracyclineand taxane-pretreated metastatic breast cancer. Eur J Cancer 2004;40:536–42. 12. Jones L, Hawkins N, Westwood M., et al. Systematic review of the clinical effectiveness and cost-effectiveness of capecitabine (Xeloda) for locally advanced and/or metastatic breast cancer. Health Technol Assess 2004; 8: iii, xiii–143. 13. Lee SH, Lee J, Park J, et al. Capecitabine monotherapy in patients with anthracycline- and taxane-pretreated metastatic breast cancer. Med Oncol 2004;21:223–31. 14. Leonard RC, Twelves C, Breddy J, et al. Capecitabine named-patient programme for patients with advanced breast cancer. the UK experience. Eur J Cancer 2002;38:2020–4. 15. Estevez LG, Batista N, Sanchez-Rovira P, et al. Phase II study with the combination of capecitabine (C) and vinorelbine (V) in metastatic breast cancer (MBC) previously treated with anthracyclines and taxanes. In: Proceedings of the annual meeting of the american society of clinical oncology, vol. 23. p. 63, ASCO 40th meeting, June 5–8, 2004 New Orleans, LA, USA, June 5, 2004. 16. Ghosn M, Kattan J, Farhat F, et al. Phase II trial of capecitabine and vinorelbine as first-line chemotherapy for metastatic breast cancer patients. Anticancer Res 2006;26:2451–6. 17. Hess D, Thurlimann B, Pagani O, et al. Capecitabine and vinorelbine in elderly patients (4 ¼ 65 years) with metastatic breast cancer: a phase I trial (SAKK 25/29). Ann Oncol 2004;15:1760–5. 18. Lorusso V, Crucitta E, Silvestris N, et al. A phase I study of capecitabine in combination with vinorelbine in advanced breast cancer. Clin Breast Cancer 2003;4:138–41. 19. Stuart N, Bishop JL, Johnson SRD, et al. Vinorelbine and capecitabine (VX) for advanced breast cancer-a phase II study showing good activity and potential for further development. In: Proceedings of the annual meeting of the American society of clinical oncology vol. 22. p. 46, ASCO 39th meeting, May 31–June 3, 2003 Chicago, Il, USA, May 31, 2005. 20. Welt A, von Minckwitz G, Oberhoff C, et al. Phase I/II study of capecitabine and vinorelbine in pretreated patients with metastatic breast cancer. Ann Oncol 2005;16:64–9. 21. Xu B, Tian L, Wu Q, et al. Capecitabine (X) combined with vinorelbine (V) in Chinese patients (pts) with metastatic breast cancer (MBC). In: Proceedings of the annual meeting of the American society of clinical oncology vol. 23: 61, ASCO 40th meeting, June 5–8, 2004 New Orleans, LA, USA, June 5, 2005.
ARTICLE IN PRESS L. Favier et al. / The Breast 17 (2008) 38–43 22. Nole F, Catania C, Munzone E, et al. Capecitabine/vinorelbine: an effective and well-tolerated regimen for women with pretreated advanced-stage breast cancer. Clin Breast Cancer 2006;6:518–24. 23. Delcambre C, Bourgois H, Veyret C, et al. A phase I/II study of capecitabine (X) combined with oral vinorelbine (V) as first or secondline chemotherapy in patients (pts) with locally advanced or metastatic breast cancer (MBC). Breast Cancer Res Treat 2004; 88: S68 [SABCS 2004, San Antonio, USA].
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24. Nole F, Catania C, Sanna G, et al. Dose-finding and pharmacokinetic study of an all-oral combination regimen of oral vinorelbine and capecitabine for patients with metastatic breast cancer. Ann Oncol 2006;17:322–9. 25. Lorusso V, Spada M, Giampaglia M, et al. Oral vinorelbine plus capecitabine (oral vincap) combination in patients with advanced breast cancer (ABC). A phase II study of the GOIM (Gruppo Oncologico dell’Italia Meridionale). Ann Oncol 2006;17:vii15–7.
Original article
Results of a phase I trial of intravenous vinorelbine plus oral capecitabine as first-line chemotherapy of metastatic breast cancer Laure Faviera, Nicolas Isamberta, Sylvie Zanettaa, Emmanuelle Ferranta, Franc- oise Mayera, Bruno Chaufferta, Pierre Fumoleaua, Je´rome Garnierb, Fabienne Bivillec, Bruno Couderta, Department of Medical Oncology, Centre Georges-Franc- ois Leclerc, 1 rue du Professeur Marion, 21000 Dijon, France b Laboratoires Roche, 52 boulevard du Parc, 92200 Neuilly-sur-Seine, France c Laboratoires Pierre Fabre Oncologie,45 place Abel Gance, 92100 Boulogne-Billancourt, France
a
Received 1 February 2006; received in revised form 5 February 2007; accepted 14 June 2007
Abstract The management of metastatic breast cancer becomes increasingly intricate, requiring new drugs and combinations. We present here the results of a phase I study evaluating the maximal tolerated dose of vinorelbine combined with capecitabine as first-line chemotherapy. Vinorelbine was administered intravenously on days 1 and 15, and capecitabine was given orally twice daily from day 1 to 14 (three cycles every 21 days). Three out of six patients receiving vinorelbine at 25 mg/m2/day and capecitabine at 2000 mg/m2/day presented with a dose-limiting toxicity, consisting of protracted grade 3 neutropenia, hand–foot syndrome and/or liver test disturbances. Despite of a dose reduction in vinorelbine (20 mg/m2/day), one patient among four developed a dose-limiting febrile neutropenia. This regimen cannot be recommended as first-line treatment of metastatic breast cancer. These findings are not in agreement with previous publications of this schedule, or with promising results using both drugs orally. r 2007 Elsevier Ltd. All rights reserved. Keywords: Metastatic breast cancer; Chemotherapy; Vinorelbine; Capecitabine; Phase I trial
Introduction Metastatic breast cancer remains an incurable disease even if new hormonal agents, cytotoxic drugs and targeted therapies currently improve its outcome. Therapeutic strategies are based on a palliative behavior and aim at decreasing symptoms, improving quality of life and prolonging survival. The lack of consensus leads us to use chemotherapy, combined or not with hormonal treatment.1 Various regimens of chemotherapy are at our disposal using either single agent or polychemotherapy, mainly based on anthracyclines, taxanes, gemcitabine, Abbreviations: V vinorelbine; C capecitabine; MTD maximal tolerated dose; WHO World Health Organization; GGT gamma-glutamyl transferase; ULN upper limit of normal; DPD dihydro-pyrimidine deshydrogenase; G-CSF granulocyte colony-stimulating factor; DLT dose-limiting toxicity; NCI-CTC National Cancer Institute Common Toxicity Criteria Corresponding author. Tel.: +33 (0)3 80 73 77 20; fax: +33 (0)3 80 73 77 12. E-mail address: [email protected] (B. Coudert). 0960-9776/$ - see front matter r 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.breast.2007.06.003
capecitabine, and vinorelbine.1–3 An increasing number of patients receive an anthracycline–taxane combination as adjuvant therapy, requiring the development of new drugs and combination for the treatment of metastatic disease. The association of vinorelbine to fluorouracil remains a frequently used chemotherapy for the treatment of metastatic breast cancer. In first-line therapy, an objective response was achieved in 62% of the patients, with a median duration of response ranging from 10 to 12.3 months, and a median survival time of 23 months.4,5 The main toxicity was grade 3 and 4 neutropenia, occurring in 77–90% of the patients, and febrile neutropenia in 3.6–8.8% of them.4,5 The other frequent reported events were thrombocytopenia (19%, of which 5% were grade 3–4), stomatitis (71%, of which 38% were grade 3–4), infection (12.7%), and constipation (9.5%).4,5 In secondline treatment, this combination showed a good efficacy, response rates ranging from 45% to 61%.6–10 Vinorelbine combined with a protracted, continuous infusion of fluorouracil improved the safety of such regimen, with a
ARTICLE IN PRESS L. Favier et al. / The Breast 17 (2008) 38–43
decrease in the incidence of neutropenia (0–14% of grade 3–4), and stomatitis (1.2–9.2% of grade 3).6–10 One of these studies evaluated a novel regimen consisting of vinorelbine 30 mg/m2 administered on days 1 and 15 every 28 days, and fluorouracil 200 mg/m2/day given continuously over a 24-h period between vinorelbine infusions.6 Among the 83 treated patients, only seven cases of grade 3 toxicity and one grade 4 were reported. This good safety profile was associated with a satisfying efficacy as a complete response was achieved in 7.2% of patients, a partial response in 54.2%, and stabilization in 25.3%. Capecitabine (Xeloda, Hoffmann–La Roche) is an oral fluoropyrimidine precursor, converted in fluorouracil preferentially in tumor tissue, allowing treatment at home, and thereby potentially improving the quality of life. Used as single agent in heavily pretreated patients with anthracyclines and/or taxanes, response rates were from 15% to 28%, with a median duration of response ranging from 5 to 8.9 months, and a survival time of 7.7–18.1 months.11–14 The most common non-hematological effects were gastrointestinal side effects and hand–foot syndrome. Several phase I and II trials explored the vinorelbine– capecitabine (VC) combination in the treatment of metastatic breast cancer, mainly after anthracyclines and/or taxanes failure.15–21 The reported response rates were from 39% to 68%. However, the dosing schedules were heterogeneous, capecitabine ranging from 800 to 2250 mg/m2/day from day 1 to 14, and vinorelbine from 20 until 30 mg/m2/day on days 1 and 8. Thus, the optimal regimen as well the maximal tolerated dose (MTD) of intravenous vinorelbine plus oral capecitabine is not currently determined. The purpose of our study was to better define the dose of this combination as first-line treatment in metastatic breast cancer patients, according to the well-tolerated schedule previously described by Berruti et al, consisting of vinorelbine administered before and after a continuous infusion of fluorouracil.6 Patients and methods Patients Non-pregnant women between 18 and 65 years of age, with documented metastatic breast cancer and who have not previously received chemotherapy for metastatic disease, were enrolled in the study. The main eligibility criteria were World Health Organization (WHO) performance statuso3; satisfactory hematological (neutrophils count 4 1.5 109/L, platelets count 4 120 109/L), hepatic (transaminases, alkaline phosphatases, and gamma-glutamyl transferase [GGT]o2.5 upper limit of normal [ULN]), and renal (serum creatinineo1.5 ULN, and creatinine clearance X 60 mL/min) tests; adjuvant chemotherapy and/or radiotherapy stopped for at least 4 weeks; radiotherapy involving less than 30% of medullary area; and ability to be followed every week. Patients were
39
excluded from the study if they had a NCI grade X 1 peripheral neuropathy; a severe constipation or subocclusive disease; a treatment with phenytoin, itraconazole, sorivudine or analogs; a known hypersensitivity to capecitabine or fluorouracil; a previous history of severe reactions to treatments formulated with fluoropyrimidines; a dihydro-pyrimidine deshydrogenase (DPD) deficiency; symptomatic or progressive brain metastases; or severe concomitant diseases (liver, renal, cardiac, or lung failure, angina, or disabling psychiatric disease). Written informed consent was obtained from each patient before inclusion. The protocol was reviewed and approved by the Ethics Committee/Institutional Review Board and the study was conducted according to the Declaration of Helsinki and European Good Clinical Practice requirements.
Treatment According to previous reports of VC combinations in which capecitabine was used from 800 to 2250 mg/m2/day (day 1–14) and vinorelbine from 20 to 30 mg/m2/day (days 1 and 8),15–18,20–22 chosen starting doses per cycle were 2000 mg/m2/day (day 1–14) (28,000 mg/m2/cycle) for capecitabine and 25 mg/m2/day (days 1 and 15) (50 mg/m2/ cycle) for vinorelbine. Vinorelbine doses were escalated from 20 to 30 mg/m2/day (i.e. 40–60 mg/m2/cycle), and capecitabine doses from 1750 to 2500 mg/m2/day (i.e. 24,500–35,000 mg/m2/cycle) (Table 1). Vinorelbine was administered intravenously as a 20minute infusion on days 1 and 15, every 21 days for three cycles. Capecitabine was given orally twice daily (equal doses morning and evening) from day 1 to day 14, every 21 days for three cycles. Capecitabine tablets must be swallowed within 30 minutes after meals. Antiemetic treatment was prescribed routinely before each cycle. Preventive use of granulocyte colony-stimulating factor (G-CSF) and antibiotics was prohibited. G-CSF (lenograstim) was recommended in case of febrile neutropenia and/ or grade 4 neutropenia lasting more than 7 days. No pharmacokinetics data were collected. Table 1 Dose escalation procedures of vinorelbine and capecitabine Level
2 1 0 1 2 3 4 5
Vinorelbine (mg/m2)
Capecitabine (mg/m2)
Per day (days 1 and 15)
Per cycle
Per day (day 1–14)
Per cycle
20 20 25 30 25 30 25 30
40 40 50 60 50 60 50 60
1750 2000 2000 2000 2250 2250 2500 2500
24,500 28,000 28,000 28,000 31,500 31,500 35,000 35,000
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L. Favier et al. / The Breast 17 (2008) 38–43
Dose-Limiting Toxicity Dose-limiting toxicity (DLT) was evaluated for three cycles in succession, and was defined as follows: febrile neutropenia, grade 4 neutropenia lasting more than 7 days, grade 3-4 anemia and/or thrombocytopenia, grade 4 vomiting, grade X 3 non-hematological toxicities (except alopecia and vomiting), grade X 2 hematological and/or non-hematological toxicities lasting more than 7 days after day 21; and non-recovery of biological tests lasting more than 21 days after day 21. The study protocol was started at level 0 (vinorelbine 25 mg/m2, capecitabine 2000 mg/m2). Three to six patients were treated at each dose level. If one of three patients at a given dose level developed DLT, three additional patients were entered at the same dose level. The MTD was defined as the dose at which at least two of the first three patients or at least three of six patients developed DLT. The recommended dose was defined as the dose level just below the MTD. Safety assessment Hematological tolerability was evaluated based on absolute blood cells counts performed weekly and before each cycle. In the event of febrile neutropenia, capecitabine was stopped and absolute blood cells count was performed daily until recovery. Non-hematological toxicities were evaluated during the period between each cycle, according to National Cancer Institute Common Toxicity Criteria (NCI-CTC). A laboratory assessment (blood sodium, potassium, calcium, urea, creatinine, AST, ALT, total bilirubin, fasting glucose, total protein, albumin, alkaline phosphatases, LDH, GGT) was performed before each treatment cycle. Serious adverse events were defined according to ICH guidelines. Discontinuation of treatment was required in patients who presented with a DLT, or a disease progression. In any case, the treatment could be discontinued according to the patient’s or investigator’s decision. At the end of the phase I study, an efficacy assessment was left to the discretion of each investigator to define subsequent chemotherapy regimens. Results Patient and treatment characteristics Between November 2002 and February 2004, 10 patients, aged between 46 and 67 years, were enrolled in the study from one center located in France. In each case, adjuvant treatment of early breast cancer was considered optimal. Initial surgery consisted of mastectomy in seven patients and tumorectomy in three all with axillary node sampling or clearance. All patients received adjuvant and/ or neoadjuvant chemotherapy: it was an anthracycline– based regimen in eight patients, a taxane-based regimen in
Table 2 Patient and treatment characteristics at baseline Characteristics
Patients (n ¼ 10) N
Metastatic localization Bone Liver Lung/pleura Nodes
6 5 5 1
Number of involved sites 1 2 3
3 5 2
one, and an anthracycline-taxane combination in one. The nine hormone-receptor positive patients had received tamoxifen. Radiotherapy was delivered in seven patients. The median time between initial diagnosis and the present relapse was 24 months (range, 11–243 months). Baseline characteristics are summarized in Table 2. Six patients were treated at level 0 (V 25 mg/m2, C 2000 mg/m2). Among them, three patients received the full schedule, one received two cycles, and two received one cycle. Due to unexpected toxicity, the initial doses had to be reduced rather than escalated. Four patients were included at a lower dose level (V 20 mg/m2, C 2000 mg/m2), of which three received three cycles and one patient received one cycle. The actual doses delivered are described in Table 3.
Safety and DLT Among the six patients treated at the first dose level, three of them developed a DLT (Table 4). After the first cycle, one patient developed a grade 3 neutropenia lasting more than 7 days after day 21, and one patient developed a grade 3 increase in GGT lasting more than 21 days. After the second cycle, a third patient, free of liver metastases, presented with a grade 2 increase in GGT lasting more than 21 days. Additionally, at this dose level, a fourth patient presented with a grade 2 protracted hand-foot syndrome lasting more than 7 days after day 21, requiring a delay in the onset of the third cycle. In spite of dose reduction, one patient among the following four patients developed a DLT consisting of a febrile neutropenia (cycle 1). At this dose level, another patient presented with a grade 1, protracted hand–foot syndrome lasting more than 7 days after day 21. Main hematological, laboratory and nonhematological toxicities reported are summarized in Tables 4 and 5. Among the 10 patients enrolled in the study, six of them were able to receive the three scheduled courses. Subsequently, three of them received the classical vinorelbine–fluorouracil combination as second-line therapy.
ARTICLE IN PRESS L. Favier et al. / The Breast 17 (2008) 38–43 Table 3 Actual dose received per patient and cycle Patient
Dose level
1
0
2
0
3
0
4
0
5
0
6
0
7
1
8
1
9
1
10
1
Cycle
1 2 3 1 1 2 3 1 1 2 1 2 3 1 2 3 1 2 3 1 2 3 1
Table 5 Incidence of laboratory and non-hematological adverse events per dose level and cycles
Theoretical dose mg/m2
Actual/Theoretical dose%
V
C
V
C
25
2000
25
2000
25
2000
25
2000
50 100 100 99 100 97 101 100
97 97 97 101 102 96 103 93
25
2000
25
2000
20
2000
101 101 87 87 87 101 101 101 99 100 99 99 99 99 97
98 97 87 87 87 101 101 93 97 97 96 93 94 94 96
20
2000
20
2000
20
2000
V, vinorelbine; C, capecitabine. Table 4 Incidence of hematological adverse events per dose level and cycles Toxicity
V/C (mg/m2)
Total
25/2000
20/2000
13
10
23
2 (15.4) 4 (30.8) 1 (7.7)
1 (10.0) 3 (30.0) 3 (30.0)
3 (13.0) 7 (30.4) 4 (17.4)
Neutropenia Grade 1 Grade 2 Grade 3 Grade 4 4 7 days Febrile neutropenia
1 3 3 0 1 0
1 1 2 3 0 1
2 4 5 3 1 1
Anemia Grade 1 Grade 2 Grade 3
6 (46.1) 1 (7.7) 0
Number of cycles Leucopenia Grade 1 Grade 2 Grade 3
(7.7) (23.1) (23.1) (7.7)
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(10.0) (10.0) (20.0) (30.0) (10.0)
3 (30.0) 2 (20.0) 1 (10.0)
(8.7) (17.4) (21.7) (13.0) (4.3) (4.3)
9 (39.1) 3 (13.0) 1 (4.3)
V, vinorelbine ; C, capecitabine. dose-limiting toxicity.
Discussion The current combination of intravenous vinorelbine (days 1 and 15) plus oral capecitabine (day 1–14) provided
Toxicity
V/C (mg/m2) 25/2000
20/2000
Total
Number of cycles Biological tests Cytolysis Grade 1 Grade 2 4 7 days
13
10
23
7 (53.8) 3 (23.1) 1 (7.7)
5 (50.0) 0 0
12 (52.1) 3 (13.0) 1 (4.3)
Cholestasis Grade 1 Grade 2 Grade 3 4 7 days
8 2 1 1
7 (70.0) 0 0 0
15 (65.2) 2 (8.7) 1 (4.3) 1 (4.3)
Bilirubin Grade 1
1 (7.7)
0
1 (4.3)
Non-hematological toxicities Nausea Grade 1
2 (15.4)
0
2 (8.7)
0
1 (10.0)
1 (4.3)
1 (7.7) 1 (7.7)
1 (10.0) 0
2 (8.7) 1 (4.3)
0
1 (10.0)
1 (4.3)
0
1 (10.0)
1 (4.3)
0 0 0
3 (30.0) 0 1 (10.0)
3 (13.0) 0 1 (4.3)
0 0
1 (10.0) 1 (10.0)
1 (4.3) 1 (4.3)
0
1 (10.0)
1 (4.3)
Diarrhea Grade 1 Hand-foot syndrome Grade 1 Grade 2 Peripheral neuropathy Grade 1 Constipation Grade 1 Infection Grade 1 Grade 2 Grade 3 Alopecia Grade 1 Grade 2 Asthenia Grade 1
(61.5) (15.4) (7.7) (7.7)
V, vinorelbine ; C, capecitabine. dose-limiting toxicity.
a level of toxicity which is not consistent with its use in first-line therapy of metastatic breast cancer. Reported toxicities led investigators to prematurely stop the study without testing lower doses. These results stand in contrast with those of the phase I–II trials using capecitabine twice daily (day 1–14) plus IV vinorelbine (days 1 and 8).16–18,20,22 In the study published by Welt et al., capecitabine dose was fixed at 1000 mg/m2 from days 1 to 14. At a dose of vinorelbine of 30 mg/m2 (days 1 and 8), four patients among seven experienced a DLT with nausea/ vomiting, febrile neutropenia, grade 4 neutropenia, infection and diarrhea. At a dose of vinorelbine of 25 mg/m2 (days 1 and 8), 2 patients among 24 experienced a DLT with hospitalization due to febrile neutropenia and prolonged neutropenia. In the study published by Hess et al. the vinorelbine recommended dose was 20 mg/m2/day on days 1 and 8 and the capecitabine recommended dose differed if patients had bone involvement (1000 mg/m2 days
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L. Favier et al. / The Breast 17 (2008) 38–43
1–14) or not (1250 mg/m2 days 1–14). DLT was neutropenia. In the study published by Lorusso et al., DLT (grade 4 neutropenia plus grade 3 diarrhea and grade 3 oral mucositis) was reached at 2250 mg/m2 of capecitabine with vinorelbine administered on days 1 and 8 at a fixed dose of 25 mg/m2. MTD was defined at 2000 mg/m2 capecitabine. In all of the studies, authors concluded that the intravenous vinorelbine plus oral capecitabine combination was feasible and active. In another study, 49 patients with pre-treated advanced-stage breast cancer were treated with escalating doses of oral capecitabine from 500 to 1375 mg/m2 twice daily on days 1–14 and escalating doses of vinorelbine from 12.5 to 25 mg/m2 intravenously (I.V.) on days 1 and 3 every 3 weeks.22 The most frequent clinical adverse events were mild to moderate and corresponded to nausea (78%), asthenia (59%), constipation (51%), mucositis (47%), and hand–foot syndrome (41%). Maximum tolerated dose was defined as capecitabine 1250 mg/m2 twice daily on days 1–14 and vinorelbine 22.5 mg/m2 I.V. on days 1 and 3 and was retained for future phase II studies.22 Therefore these timings of administration of vinorelbine (D1 and D8 or D1 and D3) seem more advisable than the day 1 and 15 presently evaluated. Pharmacologic and pharmacokinetic interactions of the evaluated association were not initially scheduled and should be explored in order to explain the difference in those findings. Conclusions The current combination of intravenous vinorelbine (days 1 and 15) plus oral capecitabine (day 1–14) is not feasible in this setting. The available data regarding vinorelbine–capecitabine combination in metastatic breast cancer led us to carry on further clinical trials. Other vinorelbine-capecitabine schedules have to be investigated, especially those which combine both drugs orally.23–25 Acknowledgments This study was supported by grants from Laboratoires Roche (France), and Laboratoires Pierre Fabre Oncologie (France). Isabelle Chapelle-Marcillac provided editorial assistance in the preparation of the manuscript. References 1. Carlson RW, Edge SB, Theriault RL. NCCN: Breast cancer. Cancer Control 2001;8:54–61. 2. Blum JL, Jones SE, Buzdar AU, et al. Multicenter phase II study of capecitabine in paclitaxel-refractory metastatic breast cancer. J Clin Oncol 1999;17:485–93. 3. Fumoleau P, Delgado FM, Delozier T, et al. Phase II trial of weekly intravenous vinorelbine in first-line advanced breast cancer chemotherapy. J Clin Oncol 1993;11:1245–52. 4. Dieras V, Extra JM, Bellissant E, et al. Efficacy and tolerance of vinorelbine and fluorouracile combination as first line chemotherapy of advanced breast cancer: results of a phase II study using a sequential group method. J Clin Oncol 1996;14:3097–104.
5. 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;8:865–70. 6. Berruti A, Sperone P, Bottini A, et al. Phase II Study of vinorelbine with protracted fluorouracil infusion as a second- or third-line approach for advanced breast cancer patients previously treated with anthracyclines. J Clin Oncol 2000;18:3370–7. 7. Hochster HS, Vogel CL, Burman SL, et al. Activity and safety of vinorelbine combined with doxorubicin or fluorouracil as first-line therapy in advanced breast cancer: a stratified phase II study. Oncologist 2001;6:269–77. 8. Pienkowski T, Jagiello-Gruszfeld A. Five-day infusion of fluorouracil and vinorelbine for advanced breast cancer patients treated previously with anthracyclines. Int J Clin Pharmacol Res 2001;21: 111–7. 9. Zambelli A, Robustelli della Cuna FS, Ponchio L, et al. Four-day infusion of fluorouracil plus vinorelbine as salvage treatment of heavily pretreated metastatic breast cancer. Breast Cancer Res Treat 2000;61:241–7. 10. Zambetti M, Mariani G, Demicheli R, et al. Five-day infusion fluorouracil plus vinorelbine in women with breast cancer previously treated with anthracyclines and paclitaxel. Breast Cancer Res Treat 2000;62:135–9. 11. Fumoleau P, Largillier R, Clippe C, et al. Multicentre, phase II study evaluating capecitabine monotherapy in patients with anthracyclineand taxane-pretreated metastatic breast cancer. Eur J Cancer 2004;40:536–42. 12. Jones L, Hawkins N, Westwood M., et al. Systematic review of the clinical effectiveness and cost-effectiveness of capecitabine (Xeloda) for locally advanced and/or metastatic breast cancer. Health Technol Assess 2004; 8: iii, xiii–143. 13. Lee SH, Lee J, Park J, et al. Capecitabine monotherapy in patients with anthracycline- and taxane-pretreated metastatic breast cancer. Med Oncol 2004;21:223–31. 14. Leonard RC, Twelves C, Breddy J, et al. Capecitabine named-patient programme for patients with advanced breast cancer. the UK experience. Eur J Cancer 2002;38:2020–4. 15. Estevez LG, Batista N, Sanchez-Rovira P, et al. Phase II study with the combination of capecitabine (C) and vinorelbine (V) in metastatic breast cancer (MBC) previously treated with anthracyclines and taxanes. In: Proceedings of the annual meeting of the american society of clinical oncology, vol. 23. p. 63, ASCO 40th meeting, June 5–8, 2004 New Orleans, LA, USA, June 5, 2004. 16. Ghosn M, Kattan J, Farhat F, et al. Phase II trial of capecitabine and vinorelbine as first-line chemotherapy for metastatic breast cancer patients. Anticancer Res 2006;26:2451–6. 17. Hess D, Thurlimann B, Pagani O, et al. Capecitabine and vinorelbine in elderly patients (4 ¼ 65 years) with metastatic breast cancer: a phase I trial (SAKK 25/29). Ann Oncol 2004;15:1760–5. 18. Lorusso V, Crucitta E, Silvestris N, et al. A phase I study of capecitabine in combination with vinorelbine in advanced breast cancer. Clin Breast Cancer 2003;4:138–41. 19. Stuart N, Bishop JL, Johnson SRD, et al. Vinorelbine and capecitabine (VX) for advanced breast cancer-a phase II study showing good activity and potential for further development. In: Proceedings of the annual meeting of the American society of clinical oncology vol. 22. p. 46, ASCO 39th meeting, May 31–June 3, 2003 Chicago, Il, USA, May 31, 2005. 20. Welt A, von Minckwitz G, Oberhoff C, et al. Phase I/II study of capecitabine and vinorelbine in pretreated patients with metastatic breast cancer. Ann Oncol 2005;16:64–9. 21. Xu B, Tian L, Wu Q, et al. Capecitabine (X) combined with vinorelbine (V) in Chinese patients (pts) with metastatic breast cancer (MBC). In: Proceedings of the annual meeting of the American society of clinical oncology vol. 23: 61, ASCO 40th meeting, June 5–8, 2004 New Orleans, LA, USA, June 5, 2005.
ARTICLE IN PRESS L. Favier et al. / The Breast 17 (2008) 38–43 22. Nole F, Catania C, Munzone E, et al. Capecitabine/vinorelbine: an effective and well-tolerated regimen for women with pretreated advanced-stage breast cancer. Clin Breast Cancer 2006;6:518–24. 23. Delcambre C, Bourgois H, Veyret C, et al. A phase I/II study of capecitabine (X) combined with oral vinorelbine (V) as first or secondline chemotherapy in patients (pts) with locally advanced or metastatic breast cancer (MBC). Breast Cancer Res Treat 2004; 88: S68 [SABCS 2004, San Antonio, USA].
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24. Nole F, Catania C, Sanna G, et al. Dose-finding and pharmacokinetic study of an all-oral combination regimen of oral vinorelbine and capecitabine for patients with metastatic breast cancer. Ann Oncol 2006;17:322–9. 25. Lorusso V, Spada M, Giampaglia M, et al. Oral vinorelbine plus capecitabine (oral vincap) combination in patients with advanced breast cancer (ABC). A phase II study of the GOIM (Gruppo Oncologico dell’Italia Meridionale). Ann Oncol 2006;17:vii15–7.