- Email: [email protected]
gemcitabine doublet versus capecitabine monotherapy in anthracycline- and taxane-pretreated women with metastatic breast cancer
original articles
Annals of Oncology
A multicenter randomized phase III trial of vinorelbine/ gemcitabine doublet versus capecitabine monotherapy in anthracycline- and taxane-pretreated women with metastatic breast cancer A. G. Pallis, I. Boukovinas, A. Ardavanis, I. Varthalitis, N. Malamos, V. Georgoulias & D. Mavroudis* Breast Cancer Study Group, Hellenic Oncology Research Group (HORG), Athens, Greece
Received 25 May 2011; revised 14 July 2011; accepted 18 July 2011
Background: The Breast Cancer Study Group of the Hellenic Oncology Research Group conducted a phase III trial of single-agent capecitabine versus the vinorelbine/gemcitabine doublet in patients with metastatic breast cancer (MBC) pretreated with anthracyclines and taxanes. The primary objective was to demonstrate superiority of combination treatment in terms of progression-free survival (PFS). Patients and methods: Women with MBC were randomly assigned to receive either capecitabine (Cap arm: 1250 mg/m2 twice daily, on days 1–14) or vinorelbine/gemcitabine doublet (VG arm: vinorelbine 25 mg/m2; gemcitabine 1000 mg/m2; both drugs on days 1 and 15). Results: Seventy-four women were treated on each arm and median PFS was 5.4 versus 5.2 months (P = 0.736), for VG and Cap, respectively. Median overall survival was 20.4 months for the VG arm and 22.4 months for the Cap arm (P = 0.319). Overall response rate was 28.4% in the VG arm and 24.3% in the Cap arm (P = 0.576). Both regimens were generally well tolerated. Neutropenia and fatigue were more common with VG arm and hand–foot syndrome with Cap arm. Conclusions: This trial failed to demonstrate superiority of vinorelbine/gemcitabine doublet over single-agent capecitabine in terms of PFS. Given the favorable toxicity and convenience of oral administration, single-agent capecitabine is recommended for compliant patients. Key words: capecitabine, gemcitabine, MBC, phase III, pretreated, vinorelbine
introduction Despite significant improvements in the treatment of metastatic breast cancer (MBC) during the last decade, MBC remains an incurable disease, responsible for 40 000 deaths annually and a median life expectancy of 2 to 3 years [1, 2]. For these *Correspondence to: Dr D. Mavroudis, Department of Medical Oncology, University General Hospital of Heraklion, 711 10 Heraklion, Crete, Greece. Tel: +30-2810-392783; Fax: +30-2810-392-857; E-mail: [email protected], [email protected]
patients, systemic chemotherapy offers survival prolongation and symptom palliation [3]. Among the chemotherapy agents used for first-line treatment of MBC, anthracyclines and taxanes are considered among the most active and represent widely used treatment options [4, 5]. It has been estimated that the risk of death is decreased by 4% with anthracyclinecontaining regimens compared with non-anthracycline therapy and by 10% with taxane-containing regimens [6, 7]. However, MBC often progresses because of primary or acquired
ª The Author 2011. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected]
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Annals of Oncology 23: 1164–1169, 2012 doi:10.1093/annonc/mdr405 Published online 21 September 2011
original articles
Annals of Oncology
patients and methods patients Women with histologically or cytologically confirmed MBC who had previously received treatment with anthracyclines and taxanes in the adjuvant and/or metastatic settings were eligible for the study. Patients with HER2positive tumors were eligible for the study, given that they had already received trastuzumab in the first-line setting. Additional inclusion criteria were age >18 years, at least one unidimensionally measurable lesion according to the RECIST [17], an Eastern Cooperative Oncology Group performance status (PS) of zero to two [18], a life expectancy of >3 months, adequate organ function [serum bilirubin £1.5 times the upper normal limit (UNL); aspartate aminotransferase and alanine aminitransferase £ 2.5 UNL in the absence of liver metastases or £5 UNL in the presence of liver metastases; serum creatinine £ 1.5 UNL; neutrophils ‡ 1.5 · 1029/l, and platelets ‡ 100 · 1029/l], central nervous system metastases were allowed provided that they had been irradiated and were clinically and radiologically stable, absence of active infection and of history of significant cardiac disease (unstable angina, congestive heart failure, myocardial infarction within the previous 6 months, ventricular arrhythmias) or malnutrition (loss of ‡20% of the original body weight). Previous radiotherapy was allowed provided that it was completed at least 2 weeks before enrollment and measurable lesions were outside the radiation fields. All patients gave written informed consent to participate in the study. The trial was approved by the Ethics and Scientific Committees of the participating centers and was conducted according to the Helsinki Declaration and Good Clinical Practice guidelines [19].
treatment plan Eligible patients were randomly assigned to receive treatment either with capecitabine (Cap arm: 1250 mg/m2 twice daily, on days 1 through 14) or
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with the vinorelbine/gemcitabine doublet (VG arm: vinorelbine 25 mg/m2 as a 30 min i.v. infusion followed by gemcitabine 1000 mg/m2 as a 30 min i.v. administration; both drugs were administered on days 1 and 15). Cycles were repeated every 21 days in the Cap arm and every 28 days in the VG arm. Treatment was continued until disease progression, appearance of unacceptable toxicity, patient’s withdrawal of consent or for a maximum of six cycles. Continuation of treatment beyond six cycles was allowed for 2responding patients. Further therapy after disease progression included best supportive care, palliative radiotherapy or chemotherapy and was based on physician’s discretion.
dose modifications For the treatment cycles to be administered according to the scheduled timetable, the absolute granulocyte count had to be >1.5 · 1029/l and the platelet count >100 · 1029/l while all other nonhematological toxic effects (except alopecia) had to be grade 1 or less [National Cancer Institute— Common Toxicity Criteria (NCI–CTC) v.3.0] [20]. In patients presenting with neutropenia grade 4, febrile neutropenia, thrombocytopenia grade 3–4 or nonhematological toxicity grade 3–4 (except nausea and vomiting), the doses of all drugs were reduced by 20% for all subsequent cycles. In the case of toxicity reoccurrence, a second dose reduction by 20% in the doses of all drugs was done. Patients requiring dose reductions >40% of the protocol dose were taken off study. The use of growth factors [granulocyte colony-stimulating factor and erythropoiesis-stimulating agents] was allowed at the discretion of the treating physician and according to international recommendations [21, 22].
baseline and follow-up assessments A complete medical history, evaluation of performance status, detailed physical examination and vital signs, 12-lead electrocardiogram, blood tests (complete blood cell count with differential and blood chemistry) and chest X-ray were carried out at baseline and before every cycle. Computed tomography (CT) scans of the chest, abdomen and brain and a whole-body radionuclide bone scan were also included in the baseline evaluation. Baseline evaluation had to be carried out within 2 weeks before therapy initiation. All measurable lesions were identified at baseline and were monitored throughout. Toxicity was also evaluated at every visit and was reported according to NCI–CTC, version 3 [20]. Tumor assessment for response or progression was carried out every 2 months. Objective tumor responses were evaluated according to RECIST criteria [17]. All CT scans were reviewed by an independent radiologist and all responses had to be confirmed after 4 weeks. Post-study assessments including PS, toxicity evaluation and tumor measurements were carried out after 30 days. Follow-up included physical examination and radiological tumor assessment and was carried out every 2 months until disease progression. Thereafter, patients were contacted every 4 months until death.
statistical analysis Randomization was done at the HORG headquarters by the use of a faxed form sent to all participating centers. Concealment of allocation sequence was carried out by use of a computer-generated random code. Patients were randomized to a 1 : 1 ratio, to receive either Cap or VG. The randomization to each arm was done by stratification according to PS (0–1 versus 2), age (£65 versus >65 years), menopausal status (pre- versus postmenopausal), and sensitivity or resistance to anthracycline/taxane treatment. Anthracycline and taxane resistance was defined as tumor progression during treatment or within three months of last dose of chemotherapy in case of metastatic disease or recurrence within 12 months in the adjuvant/neoadjuvant setting. All clinical data were centrally collected and analyzed. The primary end point was PFS; secondary endpoints included ORR, safety profile and OS associated with each regimen. The study was designed to have 80% power (a = 0.05, two-sided log-rank test) to detect an increase in median PFS from 3 months for the single-agent capecitabine arm [12, 13, 15] to 5 months for the VG arm [16] at the statistically significant level of 5%.
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resistance to anthracyclines and taxanes. Furthermore, chemotherapy regimens that contain anthracyclines and/or taxanes are now often considered as the ‘standard’ option for adjuvant treatment of early breast cancer [8, 9] especially in women at high risk, thus limiting their use in patients who subsequently develop disease relapse. Newer cytotoxic agents such as capecitabine, vinorelbine and gemcitabine are available for the treatment of patients with MBC who have been previously treated with anthracyclines and taxanes [10]. Capecitabine is approved as a single agent for patients with MBC who failed anthracycline and taxane treatment [11]. In this setting, capecitabine as single-agent is associated with an overall response rate (ORR) of 20%–26%, a median progression-free survival (PFS) of 3.0– 4.6 months and a median overall survival (OS) of 10.4–15.2 months [12–15]. In an attempt to improve treatment outcomes, combination regimens have been tested in the context of phase II trials. A phase II study published by Stathopoulos et al. [16] evaluated the combination of vinorelbine/gemcitabine administered every 2 weeks in anthracycline- and taxane-pretreated (in 50% of the patients) patients with MBC and observed encouraging results with an ORR of 54%, a median PFS of 6 months and a median OS of 11.5 months. Based on these results, the Breast Cancer Group of the Hellenic Oncology Research Group (HORG) initiated a phase III trial to compare single-agent capecitabine versus the vinorelbine/gemcitabine regimen in patients with MBC pretreated with anthracyclines and taxanes.
original articles
results patients From April 2002 to December 2008, a total of 172 patients were assessed for eligibility. Fourteen patients were excluded because they did not meet the eligibility criteria. Patients who were randomly assigned were 158 in number (80 patients to VG arm and 78 patients to Cap arm). The baseline patient- and diseaserelated characteristics were well balanced between the two treatment arms (Table 1). Four patients allocated to Cap and six in VG although randomized did not receive treatment (two patients in VG arm died before receiving any treatment and all other patients withdrew their consent). The CONSORT diagram of the study is presented in Figure 1. compliance with the treatment A total of 289 and 395 chemotherapy cycles were administered in the VG and Cap arms, respectively (P = 0.0001); the median number of cycles received per patient was 3.0 (range 1–11) in the VG arm and 6.0 (range 1–15) in the Cap arm. The median duration of cycle was 28 days for the VG arm (range 28–43 days) and 21 days for the Cap arm (range 21–32 days). Treatment administration was delayed in 49 (17.0%) VG and 47 (12.0%) Cap cycles (P = 0.060). The number of Cap cycles that were delayed due to toxicity were 13 (4.5%) and 10 (2.5%) (both hematological and nonhematological) (P = 0.159). All other cycles were delayed for reasons not related to treatment or toxicity (i.e. patient’s request for personal reasons, pending imaging studies for response assessment). Dose reductions were required in 2 (0.7%) VG and in 19 (4.8%) Cap cycles (P = 0.002). Dose reductions in both groups were mainly due to hematological and nonhematological toxic effects (mainly hand– foot syndrome in the case of Cap treatment). The median administered dose intensity for each drug were 11.4 mg/m2/week (range 4.0–12.5 mg/m2/week) for vinorelbine (91.2% of planned dose) and 469.0 mg/m2/week (range 155.6–500.0 mg/m2/week; 93.8% of the planned dose) for gemcitabine for the VG arm; the median administered dose intensity for capecitabine was 10 346.0 mg/m2/week (range 5490.0–11 667.0 mg/m2/week; 88.7% of planned dose). Thirty patients (40.5%) in the VG arm and 27 (36.5%) in the Cap arm discontinued treatment because of disease progression, while 4 (5.5%) (neutropenia n = 2, infection n = 1, allergic reaction n = 1) and 5 (6.8%) (neutropenia n = 2, allergic reaction n = 2, hand-foot syndrome n = 1) patients in ach arm, respectively, discontinued treatment due to toxicity.
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Table 1. Patient and disease characteristics per treatment arm Treatment arms VG (N = 74) Cap (N = 74) P-value n (%) n (%) Age Median (min–max) Menopausal status Premenopausal Postmenopausal Performance status 0 1 2 Histology Ductal Lobular Mixed Other Line of therapy 2nd line 3rd line >3rd line Taxane status Taxane sensitivea Taxane resistanta Anthracycline status Anthracycline sensitivea Anthracycline resistanta No. of organs involved 1 2 ‡3 Median Hormone receptors Positiveb Negative Unknown HER2 status Positive Negative Unknown
60 (32–82)
60 (34–82)
7 (9.5) 67 (90.5)
12 (16.2) 62 (83.8)
0.219
31 (41.9) 40 (54.1) 3 (4.1)
28 (37.8) 39 (52.7) 7 (9.5)
0.539 (0–1 versus 2)
63 5 2 4
59 7 2 6
(85.1) (6.8) (2.7) (5.4)
(79.7) (9.5) (2.8) (8.1)
41 (55.4) 22 (29.7) 11 (14.9)
41 (55.4) 23 (31.1) 10 (13.5)
0.966
23 (31.1) 51 (68.9)
29 (39.2) 45 (60.8)
0.302
30 (40.5) 44 (59.5)
33 (44.6) 41 (55.4)
0.618
38 25 11 1 (1–4)
37 26 11 1 (1–4)
38 (69.0) 17 (31.0) 19 (25.7)
44 (81.5) 10 (18.5) 20 (27.0)
0.134
11 (14.9) 39 (52.7) 24 (32.4)
9 (12.2) 43 (58.1) 22 (29.7)
0.416
Cap, capecitabine; HER2, human epidermal growth factor receptor 2; VG, vinorelbine/gemcitabine. a Sensitivity and resistance definition is provided in ‘Statistical Analysis’ section. b Either estrogen or progesterone.
The percentage of patients who received subsequent-line of treatment on disease progression was 56.8% in VG arm and 47.3% in Cap arm (P = 0.249).
efficacy Analysis was carried out on an intention-to-treat basis. After a median follow-up time of 32.8 months (range 1.85–55.0 months) for VG arm and 34.3 months (range 0.6–61.0 months) for Cap arm (P = 0.898), PFS was not significantly different between the two arms; median PFS was 5.4 months [95% confidence interval (CI) 2.6–8.1] for the VG arm versus 5.2 months (95% CI 4.3–6.2) for the Cap arm (P = 0.736). The Kaplan–Meier curve for PFS is presented in Figure 2. Similarly, no
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Assuming an enrollment period of 36 months, 72 patients should be enrolled in each arm to achieve the statistical requirements. Analysis was carried out on an intent-to-treat basis. The PFS was measured from study entry until the day of the first evidence of disease progression or death and OS from the date of study entry to death or last contact. The probability of survival was calculated by the method of Kaplan–Meier [23] and tested for differences by using the log-rank test. All tests were two-sided and were considered significant when the resulting P-value was £0.05. Comparison of response rates was conducted with Pearson’s v2 test. Duration of tumor response was measured from the date the first objective response [complete (CR) or partial response (PR)] was observed to the first date of tumor progression or death from any cause. This study is registered with ClinicalTrials.gov (number NCT00431106).
Annals of Oncology
original articles
Annals of Oncology
Figure 2. Kaplan–Meier survival curve for progression-free survival (PFS) per treatment arm.
significant difference was observed in terms of OS between the two arms. Median OS was 20.4 months (95% CI 14.3–26.4) for the VG arm and 22.4 months (95% CI 12.6–32.9) for the Cap arm (P = 0.319). Kaplan–Meier curve for OS is presented in Figure 3. Exploratory analyses of PFS and OS were also carried out across various subgroups (supplemental Figure S1A and B, available at Annals of Oncology online). The combination treatment did not offer any PFS or OS benefit in any of the subgroups tested. The only exception was patients with
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Figure 3. Kaplan–Meier survival curve for overall survival (OS) per treatment arm.
hormone receptor-negative tumor who had significantly longer PFS when treated with capecitabine compared with patients treated with VG (supplemental Figure S1A, available at Annals of Oncology online). ORR was also similar between the two arms (Table 2). In an intention-to-treat analysis, the ORR was 28.4% (1 patient (1.4%) with CR and 20 patients (27.0%) with PR; 95% CI 18.11% to 38.65%) in the VG arm and 24.3% [3 patients (4.1%) with CR and 15 patients (20.3%) with PR; 95% CI 15.55% to 34.10%] in the Cap arm (P = 0.576). The median
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Figure 1. CONSORT diagram of the trial. Cap, capecitabine; VG, vinorelbine/gemcitabine.
original articles
Annals of Oncology
duration of response was 7.3 months (range 2.6–24.6 months) and 10.8 months (range 1.7–27.8 months) in VG and Cap arms, respectively (P = 0.204).
discussion To our knowledge, this is the first phase III trial comparing the vinorelbine/gemcitabine doublet with single-agent capecitabine in patients with MBC previously treated with both an Table 2. Response rate by treatment arm
CR PR ORR 95% CI SD PD
Treatment arm VG (N = 74) n (%)
Cap (N = 74) n (%)
P-value
1 (1.4) 20 (27.0) 21 (28.4) 18.11–38.65 23 (31.1) 30 (40.5)
3 (4.1) 15 (20.3) 18 (24.3) 14.55–34.10 25 (33.8) 31 (41.9)
0.576
Cap, capecitabine; CR, complete response; CI, confidence interval; PD, progressive disease; PR, partial response; SD, stable disease; VG, vinorelbine/gemcitabine.
Table 3. Adverse events possibly or probably related to study treatment per patient
Neutropenia Anemia Thrombocytopenia Febrile neutropenia Nausea Vomiting Diarrhea Constipation Mucositis Neurotoxicity Allergy Fatigue Edema Hand-foot syndrome
Cap (N = 74) All grades n (%)
Cap (N = 74) Grade III n (%)
Cap (N = 74) Grade IV n (%)
VG (N = 74) All grades n (%)
VG (N = 74) Grade III n (%)
VG (N = 74) Grade IV n (%)
18 (25.6) 37 (50.0) 20 (27.0) — 8 (10.8) 3 (4.1) 8 (10.8) 3 (4.1) 1 (1.4) 8 (10.8) 3 (4.1) 21 (28.4) — 17 (23.0)
2 (2.7) 1 (1.4) — — — 1 (1.4) 1 (1.4) — — 1 (1.4) — 1 (1.4) — 4 (5.4)
1 (1.4) — — — — — — — — — 1 (1.4) — — —
39 45 20 1 19 13 7 9 5 10 7 26 3 5
13 (7.6) 1 (1.4) — — — — 1 (1.4) — — 1 (1.4) — 3 (4.1) — 1 (1.4)
4 (5.4) — — 1 (1.4) — — — — — — — — — —
(52.7) (60.8) (27.0) (1.4) (25.7) (17.6) (9.5) (12.2) (6.8) (13.5) (9.5) (35.1) (4.1) (6.8)
P-value 0.001 ns
ns ns
ns ns 0.034 0.001
P-value for neutropenia for grade III/IV. P-value for anemia, diarrhea, neurotoxicity, fatigue, vomiting, hand/foot syndrome for grade II/III. Cap, capecitabine; ns, nonsignificant; VG, vinorelbine/gemcitabine.
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toxicity Toxicity was assessed in all chemotherapy cycles and in all patients. Chemotherapy was in general well tolerated and grade III/IV toxic effects were relatively infrequent. No toxic deaths were observed. Table 3 summarizes all treatment-related toxic effects. The most frequent grade III/IV hematological toxicity was neutropenia, which occurred in 17 (23.0%) patients in the VG arm and in 3 (4.1%) in the Cap arm (P = 0.001). All resolved uneventfully. In terms of nonhematological toxicity, fatigue (P = 0.034) was more frequent in the VG arm, while hand–foot syndrome in the capecitabine arm (P = 0.001); however, in most patients, these toxic effects were of grade I or/and II.
anthracycline and a taxane. However, this trial failed to meet its primary end point of demonstrating a significant prolongation of PFS in favor of the combination arm. An overview of randomized phase III trials [24–26] comparing single-agent treatment versus combination chemotherapy regimens demonstrated that combination treatments were associated with a significant prolongation of PFS and significantly higher ORR compared with single-agent treatments. The reason for this difference between these studies and the current study is not quite clear. We cannot exclude that patients’ characteristics, genetic heterogeneity as well as prior treatments and disease sensitivity to chemotherapeutic agents could account for these observations. However, it should be noted that the above-mentioned studies demonstrated a relative increase in median PFS of 50%. If a difference of this magnitude in favor of the VG arm were to exist, this study would not have had the power to detect it. The sample size in this study was calculated assuming a median PFS of 3 months in the control arm (Cap arm), which was the median PFS reported by several phase II trials [12, 13, 15]. Similarly, PFS estimation for the experimental arm (VG arm) was done based on published results of a phase II trial demonstrating a median PFS of 6 months for the VG combination. Despite the small sample size of this study and its inherent limitations, our results showed a median PFS that is not significantly different between the two treatments. It is noteworthy that in our trial, capecitabine single-agent arm experienced a longer median PFS than expected. However, the results observed in the single-agent capecitabine arm of the current study are remarkably similar to those observed in recent phase III trials of capecitabine versus combination treatment in anthracycline- and taxane-pretreated patients with MBC [25–27]. Indeed, median PFS in these trials was 4.2 months and ORR 9.1%–28.8%, while the current study reported a median PFS of 5.2 months and an ORR of 24.3%. Similarly, the results in the VG arm were in the same range with previously reported phase III trials. The current study showed a median PFS of 5.4 months and an ORR of 28.4%, while a phase III trial of vinorelbine/
Annals of Oncology
disclosure The authors declare no conflicts of interest.
references 1. Jemal A, Siegel R, Xu J et al. Cancer statistics, 2010. CA Cancer J Clin 2010; 60: 277–300. 2. Hortobagyi GN, de la Garza SJ, Pritchard K et al. The global breast cancer burden: variations in epidemiology and survival. Clin Breast Cancer 2005; 6: 391–401. 3. Chia SK, Speers CH, D’yachkova Y et al. The impact of new chemotherapeutic and hormone agents on survival in a population-based cohort of women with metastatic breast cancer. Cancer 2007; 110: 973–979. 4. Amar S, Roy V, Perez EA. Treatment of metastatic breast cancer: looking towards the future. Breast Cancer Res Treat 2009; 114: 413–422. 5. Pronzato P, Rondini M. First line chemotherapy of metastatic breast cancer. Ann Oncol 2006; 17 (Suppl 5): v165–v168. 6. Fossati R, Confalonieri C, Torri V et al. Cytotoxic and hormonal treatment for metastatic breast cancer: a systematic review of published randomized trials involving 31,510 women. J Clin Oncol 1998; 16: 3439–3460.
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7. Ghersi D, Wilcken N, Simes J et al. Taxane containing regimens for metastatic breast cancer. Cochrane Database Syst Rev 2003; CD003366. 8. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 2005; 365: 1687–1717. 9. De Laurentiis M, Cancello G, D’Agostino D et al. Taxane-based combinations as adjuvant chemotherapy of early breast cancer: a meta-analysis of randomized trials. J Clin Oncol 2008; 26: 44–53. 10. Moreno-Aspitia A, Perez EA. Anthracycline- and/or taxane-resistant breast cancer: results of a literature review to determine the clinical challenges and current treatment trends. Clin Ther 2009; 31: 1619–1640. 11. Rivera E. Management of metastatic breast cancer: monotherapy options for patients resistant to anthracyclines and taxanes. Am J Clin Oncol 2010; 33: 176–185. 12. 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: 485–493. 13. Blum JL, Dieras V, Lo Russo PM et al. Multicenter, phase II study of capecitabine in taxane-pretreated metastatic breast carcinoma patients. Cancer 2001; 92: 1759–1768. 14. Fumoleau P, Largillier R, Clippe C et al. Multicentre, phase II study evaluating capecitabine monotherapy in patients with anthracycline- and taxane-pretreated metastatic breast cancer. Eur J Cancer 2004; 40: 536–542. 15. Reichardt P, Von MG, Thuss-Patience PC et al. Multicenter phase II study of oral capecitabine (Xeloda(‘‘)) in patients with metastatic breast cancer relapsing after treatment with a taxane-containing therapy. Ann Oncol 2003; 14: 1227–1233. 16. Stathopoulos GP, Rigatos SK, Pergantas N et al. Phase II trial of biweekly administration of vinorelbine and gemcitabine in pretreated advanced breast cancer. J Clin Oncol 2002; 20: 37–41. 17. Therasse P, Arbuck SG, Eisenhauer EA et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 2000; 92: 205–216. 18. Oken MM, Creech RH, Tormey DC et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982; 5: 649–655. 19. ICH Efficacy Guidelines. E6(R1). Good Clinical Practice: Consolidated Guideline. http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/ E6_R1/Step4/E6_R1__Guideline.pdf (10 April 2010, date last accessed). 20. Cancer Therapy Evaluation Program. Common Toxicity Criteria. Version 2.0. DCTD, NCI, NIH, DHHS 1998.; http://ctep.cancer.gov/protocolDevelopment/ electronic_applications/docs/ctcmanual_v4_10-4-99.pdf. 21. Smith TJ, Khatcheressian J, Lyman GH et al. 2006 update of recommendations for the use of white blood cell growth factors: an evidence-based clinical practice guideline. J Clin Oncol 2006; 24: 3187–3205. 22. Bokemeyer C, Aapro MS, Courdi A et al. EORTC guidelines for the use of erythropoietic proteins in anaemic patients with cancer: 2006 update. Eur J Cancer 2007; 43: 258–270. 23. Collet D. Modelling Survival Data in Medical Research, 3rd edition. Oxford, UK: Blackwell Scientific 1994. 24. Martin M, Ruiz A, Munoz M et al. Gemcitabine plus vinorelbine versus vinorelbine monotherapy in patients with metastatic breast cancer previously treated with anthracyclines and taxanes: final results of the phase III Spanish Breast Cancer Research Group (GEICAM) trial. Lancet Oncol 2007; 8: 219–225. 25. Sparano JA, Vrdoljak E, Rixe O et al. Randomized phase III trial of ixabepilone plus capecitabine versus capecitabine in patients with metastatic breast cancer previously treated with an anthracycline and a taxane. J Clin Oncol 2010; 28: 3256–3263. 26. Thomas ES, Gomez HL, Li RK et al. Ixabepilone plus capecitabine for metastatic breast cancer progressing after anthracycline and taxane treatment. J Clin Oncol 2007; 25: 5210–5217. 27. Miller KD, Chap LI, Holmes FA et al. Randomized phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer. J Clin Oncol 2005; 23: 792–799.
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gemcitabine doublet versus vinorelbine monotherapy by Martin et al. [24] reported a median PFS of 6.0 months and an ORR of 36% in a similarly pretreated patient population. Similarly, subgroup analyses failed to demonstrate any benefit in favor of the combination arm among all subgroups tested. Only patients with hormone receptor-negative primary tumors seemed to have significantly longer PFS with the Cap arm. However, it should be underlined that these analyses were exploratory and not preplanned by study design and therefore no valid conclusion can be drawn due to small sample size. Hematological toxicity was significantly higher in the combination arm as was fatigue. On the other hand, hand–foot syndrome was higher in the capecitabine arm as expected. However, our study reported lower rates of hand–foot syndrome compared with recent phase III trials [25–27]. In conclusion, this trial failed to demonstrate any significant benefit in terms of ORR, PFS and OS in favor of the combination treatment. Given the higher neutropenia and fatigue associated with doublet chemotherapy and the practical advantage of oral treatment in terms of ease of administration, the VG combination cannot be recommended as a preferable treatment option in this population except perhaps in patients where compliance with a daily oral regimen as well as gastrointestinal tolerance issues are significant. Despite the improvements observed in the treatment of MBC, there are still several unmet needs. Among them is to determine the best way to combine or sequence cytotoxic agents and targeted therapies in order to achieve the maximum clinical benefit and to develop reliable predictive factors which will allow the selection of patients who are most likely to benefit from a particular agent and save others from unnecessary toxicity of ineffective treatments. Many clinical trials are currently evaluating these questions and it is hoped that one or more of these approaches will prove successful and lead to further progress in the treatment of this devastating disease.
original articles
Annals of Oncology
A multicenter randomized phase III trial of vinorelbine/ gemcitabine doublet versus capecitabine monotherapy in anthracycline- and taxane-pretreated women with metastatic breast cancer A. G. Pallis, I. Boukovinas, A. Ardavanis, I. Varthalitis, N. Malamos, V. Georgoulias & D. Mavroudis* Breast Cancer Study Group, Hellenic Oncology Research Group (HORG), Athens, Greece
Received 25 May 2011; revised 14 July 2011; accepted 18 July 2011
Background: The Breast Cancer Study Group of the Hellenic Oncology Research Group conducted a phase III trial of single-agent capecitabine versus the vinorelbine/gemcitabine doublet in patients with metastatic breast cancer (MBC) pretreated with anthracyclines and taxanes. The primary objective was to demonstrate superiority of combination treatment in terms of progression-free survival (PFS). Patients and methods: Women with MBC were randomly assigned to receive either capecitabine (Cap arm: 1250 mg/m2 twice daily, on days 1–14) or vinorelbine/gemcitabine doublet (VG arm: vinorelbine 25 mg/m2; gemcitabine 1000 mg/m2; both drugs on days 1 and 15). Results: Seventy-four women were treated on each arm and median PFS was 5.4 versus 5.2 months (P = 0.736), for VG and Cap, respectively. Median overall survival was 20.4 months for the VG arm and 22.4 months for the Cap arm (P = 0.319). Overall response rate was 28.4% in the VG arm and 24.3% in the Cap arm (P = 0.576). Both regimens were generally well tolerated. Neutropenia and fatigue were more common with VG arm and hand–foot syndrome with Cap arm. Conclusions: This trial failed to demonstrate superiority of vinorelbine/gemcitabine doublet over single-agent capecitabine in terms of PFS. Given the favorable toxicity and convenience of oral administration, single-agent capecitabine is recommended for compliant patients. Key words: capecitabine, gemcitabine, MBC, phase III, pretreated, vinorelbine
introduction Despite significant improvements in the treatment of metastatic breast cancer (MBC) during the last decade, MBC remains an incurable disease, responsible for 40 000 deaths annually and a median life expectancy of 2 to 3 years [1, 2]. For these *Correspondence to: Dr D. Mavroudis, Department of Medical Oncology, University General Hospital of Heraklion, 711 10 Heraklion, Crete, Greece. Tel: +30-2810-392783; Fax: +30-2810-392-857; E-mail: [email protected], [email protected]
patients, systemic chemotherapy offers survival prolongation and symptom palliation [3]. Among the chemotherapy agents used for first-line treatment of MBC, anthracyclines and taxanes are considered among the most active and represent widely used treatment options [4, 5]. It has been estimated that the risk of death is decreased by 4% with anthracyclinecontaining regimens compared with non-anthracycline therapy and by 10% with taxane-containing regimens [6, 7]. However, MBC often progresses because of primary or acquired
ª The Author 2011. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected]
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Annals of Oncology 23: 1164–1169, 2012 doi:10.1093/annonc/mdr405 Published online 21 September 2011
original articles
Annals of Oncology
patients and methods patients Women with histologically or cytologically confirmed MBC who had previously received treatment with anthracyclines and taxanes in the adjuvant and/or metastatic settings were eligible for the study. Patients with HER2positive tumors were eligible for the study, given that they had already received trastuzumab in the first-line setting. Additional inclusion criteria were age >18 years, at least one unidimensionally measurable lesion according to the RECIST [17], an Eastern Cooperative Oncology Group performance status (PS) of zero to two [18], a life expectancy of >3 months, adequate organ function [serum bilirubin £1.5 times the upper normal limit (UNL); aspartate aminotransferase and alanine aminitransferase £ 2.5 UNL in the absence of liver metastases or £5 UNL in the presence of liver metastases; serum creatinine £ 1.5 UNL; neutrophils ‡ 1.5 · 1029/l, and platelets ‡ 100 · 1029/l], central nervous system metastases were allowed provided that they had been irradiated and were clinically and radiologically stable, absence of active infection and of history of significant cardiac disease (unstable angina, congestive heart failure, myocardial infarction within the previous 6 months, ventricular arrhythmias) or malnutrition (loss of ‡20% of the original body weight). Previous radiotherapy was allowed provided that it was completed at least 2 weeks before enrollment and measurable lesions were outside the radiation fields. All patients gave written informed consent to participate in the study. The trial was approved by the Ethics and Scientific Committees of the participating centers and was conducted according to the Helsinki Declaration and Good Clinical Practice guidelines [19].
treatment plan Eligible patients were randomly assigned to receive treatment either with capecitabine (Cap arm: 1250 mg/m2 twice daily, on days 1 through 14) or
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with the vinorelbine/gemcitabine doublet (VG arm: vinorelbine 25 mg/m2 as a 30 min i.v. infusion followed by gemcitabine 1000 mg/m2 as a 30 min i.v. administration; both drugs were administered on days 1 and 15). Cycles were repeated every 21 days in the Cap arm and every 28 days in the VG arm. Treatment was continued until disease progression, appearance of unacceptable toxicity, patient’s withdrawal of consent or for a maximum of six cycles. Continuation of treatment beyond six cycles was allowed for 2responding patients. Further therapy after disease progression included best supportive care, palliative radiotherapy or chemotherapy and was based on physician’s discretion.
dose modifications For the treatment cycles to be administered according to the scheduled timetable, the absolute granulocyte count had to be >1.5 · 1029/l and the platelet count >100 · 1029/l while all other nonhematological toxic effects (except alopecia) had to be grade 1 or less [National Cancer Institute— Common Toxicity Criteria (NCI–CTC) v.3.0] [20]. In patients presenting with neutropenia grade 4, febrile neutropenia, thrombocytopenia grade 3–4 or nonhematological toxicity grade 3–4 (except nausea and vomiting), the doses of all drugs were reduced by 20% for all subsequent cycles. In the case of toxicity reoccurrence, a second dose reduction by 20% in the doses of all drugs was done. Patients requiring dose reductions >40% of the protocol dose were taken off study. The use of growth factors [granulocyte colony-stimulating factor and erythropoiesis-stimulating agents] was allowed at the discretion of the treating physician and according to international recommendations [21, 22].
baseline and follow-up assessments A complete medical history, evaluation of performance status, detailed physical examination and vital signs, 12-lead electrocardiogram, blood tests (complete blood cell count with differential and blood chemistry) and chest X-ray were carried out at baseline and before every cycle. Computed tomography (CT) scans of the chest, abdomen and brain and a whole-body radionuclide bone scan were also included in the baseline evaluation. Baseline evaluation had to be carried out within 2 weeks before therapy initiation. All measurable lesions were identified at baseline and were monitored throughout. Toxicity was also evaluated at every visit and was reported according to NCI–CTC, version 3 [20]. Tumor assessment for response or progression was carried out every 2 months. Objective tumor responses were evaluated according to RECIST criteria [17]. All CT scans were reviewed by an independent radiologist and all responses had to be confirmed after 4 weeks. Post-study assessments including PS, toxicity evaluation and tumor measurements were carried out after 30 days. Follow-up included physical examination and radiological tumor assessment and was carried out every 2 months until disease progression. Thereafter, patients were contacted every 4 months until death.
statistical analysis Randomization was done at the HORG headquarters by the use of a faxed form sent to all participating centers. Concealment of allocation sequence was carried out by use of a computer-generated random code. Patients were randomized to a 1 : 1 ratio, to receive either Cap or VG. The randomization to each arm was done by stratification according to PS (0–1 versus 2), age (£65 versus >65 years), menopausal status (pre- versus postmenopausal), and sensitivity or resistance to anthracycline/taxane treatment. Anthracycline and taxane resistance was defined as tumor progression during treatment or within three months of last dose of chemotherapy in case of metastatic disease or recurrence within 12 months in the adjuvant/neoadjuvant setting. All clinical data were centrally collected and analyzed. The primary end point was PFS; secondary endpoints included ORR, safety profile and OS associated with each regimen. The study was designed to have 80% power (a = 0.05, two-sided log-rank test) to detect an increase in median PFS from 3 months for the single-agent capecitabine arm [12, 13, 15] to 5 months for the VG arm [16] at the statistically significant level of 5%.
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resistance to anthracyclines and taxanes. Furthermore, chemotherapy regimens that contain anthracyclines and/or taxanes are now often considered as the ‘standard’ option for adjuvant treatment of early breast cancer [8, 9] especially in women at high risk, thus limiting their use in patients who subsequently develop disease relapse. Newer cytotoxic agents such as capecitabine, vinorelbine and gemcitabine are available for the treatment of patients with MBC who have been previously treated with anthracyclines and taxanes [10]. Capecitabine is approved as a single agent for patients with MBC who failed anthracycline and taxane treatment [11]. In this setting, capecitabine as single-agent is associated with an overall response rate (ORR) of 20%–26%, a median progression-free survival (PFS) of 3.0– 4.6 months and a median overall survival (OS) of 10.4–15.2 months [12–15]. In an attempt to improve treatment outcomes, combination regimens have been tested in the context of phase II trials. A phase II study published by Stathopoulos et al. [16] evaluated the combination of vinorelbine/gemcitabine administered every 2 weeks in anthracycline- and taxane-pretreated (in 50% of the patients) patients with MBC and observed encouraging results with an ORR of 54%, a median PFS of 6 months and a median OS of 11.5 months. Based on these results, the Breast Cancer Group of the Hellenic Oncology Research Group (HORG) initiated a phase III trial to compare single-agent capecitabine versus the vinorelbine/gemcitabine regimen in patients with MBC pretreated with anthracyclines and taxanes.
original articles
results patients From April 2002 to December 2008, a total of 172 patients were assessed for eligibility. Fourteen patients were excluded because they did not meet the eligibility criteria. Patients who were randomly assigned were 158 in number (80 patients to VG arm and 78 patients to Cap arm). The baseline patient- and diseaserelated characteristics were well balanced between the two treatment arms (Table 1). Four patients allocated to Cap and six in VG although randomized did not receive treatment (two patients in VG arm died before receiving any treatment and all other patients withdrew their consent). The CONSORT diagram of the study is presented in Figure 1. compliance with the treatment A total of 289 and 395 chemotherapy cycles were administered in the VG and Cap arms, respectively (P = 0.0001); the median number of cycles received per patient was 3.0 (range 1–11) in the VG arm and 6.0 (range 1–15) in the Cap arm. The median duration of cycle was 28 days for the VG arm (range 28–43 days) and 21 days for the Cap arm (range 21–32 days). Treatment administration was delayed in 49 (17.0%) VG and 47 (12.0%) Cap cycles (P = 0.060). The number of Cap cycles that were delayed due to toxicity were 13 (4.5%) and 10 (2.5%) (both hematological and nonhematological) (P = 0.159). All other cycles were delayed for reasons not related to treatment or toxicity (i.e. patient’s request for personal reasons, pending imaging studies for response assessment). Dose reductions were required in 2 (0.7%) VG and in 19 (4.8%) Cap cycles (P = 0.002). Dose reductions in both groups were mainly due to hematological and nonhematological toxic effects (mainly hand– foot syndrome in the case of Cap treatment). The median administered dose intensity for each drug were 11.4 mg/m2/week (range 4.0–12.5 mg/m2/week) for vinorelbine (91.2% of planned dose) and 469.0 mg/m2/week (range 155.6–500.0 mg/m2/week; 93.8% of the planned dose) for gemcitabine for the VG arm; the median administered dose intensity for capecitabine was 10 346.0 mg/m2/week (range 5490.0–11 667.0 mg/m2/week; 88.7% of planned dose). Thirty patients (40.5%) in the VG arm and 27 (36.5%) in the Cap arm discontinued treatment because of disease progression, while 4 (5.5%) (neutropenia n = 2, infection n = 1, allergic reaction n = 1) and 5 (6.8%) (neutropenia n = 2, allergic reaction n = 2, hand-foot syndrome n = 1) patients in ach arm, respectively, discontinued treatment due to toxicity.
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Table 1. Patient and disease characteristics per treatment arm Treatment arms VG (N = 74) Cap (N = 74) P-value n (%) n (%) Age Median (min–max) Menopausal status Premenopausal Postmenopausal Performance status 0 1 2 Histology Ductal Lobular Mixed Other Line of therapy 2nd line 3rd line >3rd line Taxane status Taxane sensitivea Taxane resistanta Anthracycline status Anthracycline sensitivea Anthracycline resistanta No. of organs involved 1 2 ‡3 Median Hormone receptors Positiveb Negative Unknown HER2 status Positive Negative Unknown
60 (32–82)
60 (34–82)
7 (9.5) 67 (90.5)
12 (16.2) 62 (83.8)
0.219
31 (41.9) 40 (54.1) 3 (4.1)
28 (37.8) 39 (52.7) 7 (9.5)
0.539 (0–1 versus 2)
63 5 2 4
59 7 2 6
(85.1) (6.8) (2.7) (5.4)
(79.7) (9.5) (2.8) (8.1)
41 (55.4) 22 (29.7) 11 (14.9)
41 (55.4) 23 (31.1) 10 (13.5)
0.966
23 (31.1) 51 (68.9)
29 (39.2) 45 (60.8)
0.302
30 (40.5) 44 (59.5)
33 (44.6) 41 (55.4)
0.618
38 25 11 1 (1–4)
37 26 11 1 (1–4)
38 (69.0) 17 (31.0) 19 (25.7)
44 (81.5) 10 (18.5) 20 (27.0)
0.134
11 (14.9) 39 (52.7) 24 (32.4)
9 (12.2) 43 (58.1) 22 (29.7)
0.416
Cap, capecitabine; HER2, human epidermal growth factor receptor 2; VG, vinorelbine/gemcitabine. a Sensitivity and resistance definition is provided in ‘Statistical Analysis’ section. b Either estrogen or progesterone.
The percentage of patients who received subsequent-line of treatment on disease progression was 56.8% in VG arm and 47.3% in Cap arm (P = 0.249).
efficacy Analysis was carried out on an intention-to-treat basis. After a median follow-up time of 32.8 months (range 1.85–55.0 months) for VG arm and 34.3 months (range 0.6–61.0 months) for Cap arm (P = 0.898), PFS was not significantly different between the two arms; median PFS was 5.4 months [95% confidence interval (CI) 2.6–8.1] for the VG arm versus 5.2 months (95% CI 4.3–6.2) for the Cap arm (P = 0.736). The Kaplan–Meier curve for PFS is presented in Figure 2. Similarly, no
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Assuming an enrollment period of 36 months, 72 patients should be enrolled in each arm to achieve the statistical requirements. Analysis was carried out on an intent-to-treat basis. The PFS was measured from study entry until the day of the first evidence of disease progression or death and OS from the date of study entry to death or last contact. The probability of survival was calculated by the method of Kaplan–Meier [23] and tested for differences by using the log-rank test. All tests were two-sided and were considered significant when the resulting P-value was £0.05. Comparison of response rates was conducted with Pearson’s v2 test. Duration of tumor response was measured from the date the first objective response [complete (CR) or partial response (PR)] was observed to the first date of tumor progression or death from any cause. This study is registered with ClinicalTrials.gov (number NCT00431106).
Annals of Oncology
original articles
Annals of Oncology
Figure 2. Kaplan–Meier survival curve for progression-free survival (PFS) per treatment arm.
significant difference was observed in terms of OS between the two arms. Median OS was 20.4 months (95% CI 14.3–26.4) for the VG arm and 22.4 months (95% CI 12.6–32.9) for the Cap arm (P = 0.319). Kaplan–Meier curve for OS is presented in Figure 3. Exploratory analyses of PFS and OS were also carried out across various subgroups (supplemental Figure S1A and B, available at Annals of Oncology online). The combination treatment did not offer any PFS or OS benefit in any of the subgroups tested. The only exception was patients with
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Figure 3. Kaplan–Meier survival curve for overall survival (OS) per treatment arm.
hormone receptor-negative tumor who had significantly longer PFS when treated with capecitabine compared with patients treated with VG (supplemental Figure S1A, available at Annals of Oncology online). ORR was also similar between the two arms (Table 2). In an intention-to-treat analysis, the ORR was 28.4% (1 patient (1.4%) with CR and 20 patients (27.0%) with PR; 95% CI 18.11% to 38.65%) in the VG arm and 24.3% [3 patients (4.1%) with CR and 15 patients (20.3%) with PR; 95% CI 15.55% to 34.10%] in the Cap arm (P = 0.576). The median
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Figure 1. CONSORT diagram of the trial. Cap, capecitabine; VG, vinorelbine/gemcitabine.
original articles
Annals of Oncology
duration of response was 7.3 months (range 2.6–24.6 months) and 10.8 months (range 1.7–27.8 months) in VG and Cap arms, respectively (P = 0.204).
discussion To our knowledge, this is the first phase III trial comparing the vinorelbine/gemcitabine doublet with single-agent capecitabine in patients with MBC previously treated with both an Table 2. Response rate by treatment arm
CR PR ORR 95% CI SD PD
Treatment arm VG (N = 74) n (%)
Cap (N = 74) n (%)
P-value
1 (1.4) 20 (27.0) 21 (28.4) 18.11–38.65 23 (31.1) 30 (40.5)
3 (4.1) 15 (20.3) 18 (24.3) 14.55–34.10 25 (33.8) 31 (41.9)
0.576
Cap, capecitabine; CR, complete response; CI, confidence interval; PD, progressive disease; PR, partial response; SD, stable disease; VG, vinorelbine/gemcitabine.
Table 3. Adverse events possibly or probably related to study treatment per patient
Neutropenia Anemia Thrombocytopenia Febrile neutropenia Nausea Vomiting Diarrhea Constipation Mucositis Neurotoxicity Allergy Fatigue Edema Hand-foot syndrome
Cap (N = 74) All grades n (%)
Cap (N = 74) Grade III n (%)
Cap (N = 74) Grade IV n (%)
VG (N = 74) All grades n (%)
VG (N = 74) Grade III n (%)
VG (N = 74) Grade IV n (%)
18 (25.6) 37 (50.0) 20 (27.0) — 8 (10.8) 3 (4.1) 8 (10.8) 3 (4.1) 1 (1.4) 8 (10.8) 3 (4.1) 21 (28.4) — 17 (23.0)
2 (2.7) 1 (1.4) — — — 1 (1.4) 1 (1.4) — — 1 (1.4) — 1 (1.4) — 4 (5.4)
1 (1.4) — — — — — — — — — 1 (1.4) — — —
39 45 20 1 19 13 7 9 5 10 7 26 3 5
13 (7.6) 1 (1.4) — — — — 1 (1.4) — — 1 (1.4) — 3 (4.1) — 1 (1.4)
4 (5.4) — — 1 (1.4) — — — — — — — — — —
(52.7) (60.8) (27.0) (1.4) (25.7) (17.6) (9.5) (12.2) (6.8) (13.5) (9.5) (35.1) (4.1) (6.8)
P-value 0.001 ns
ns ns
ns ns 0.034 0.001
P-value for neutropenia for grade III/IV. P-value for anemia, diarrhea, neurotoxicity, fatigue, vomiting, hand/foot syndrome for grade II/III. Cap, capecitabine; ns, nonsignificant; VG, vinorelbine/gemcitabine.
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toxicity Toxicity was assessed in all chemotherapy cycles and in all patients. Chemotherapy was in general well tolerated and grade III/IV toxic effects were relatively infrequent. No toxic deaths were observed. Table 3 summarizes all treatment-related toxic effects. The most frequent grade III/IV hematological toxicity was neutropenia, which occurred in 17 (23.0%) patients in the VG arm and in 3 (4.1%) in the Cap arm (P = 0.001). All resolved uneventfully. In terms of nonhematological toxicity, fatigue (P = 0.034) was more frequent in the VG arm, while hand–foot syndrome in the capecitabine arm (P = 0.001); however, in most patients, these toxic effects were of grade I or/and II.
anthracycline and a taxane. However, this trial failed to meet its primary end point of demonstrating a significant prolongation of PFS in favor of the combination arm. An overview of randomized phase III trials [24–26] comparing single-agent treatment versus combination chemotherapy regimens demonstrated that combination treatments were associated with a significant prolongation of PFS and significantly higher ORR compared with single-agent treatments. The reason for this difference between these studies and the current study is not quite clear. We cannot exclude that patients’ characteristics, genetic heterogeneity as well as prior treatments and disease sensitivity to chemotherapeutic agents could account for these observations. However, it should be noted that the above-mentioned studies demonstrated a relative increase in median PFS of 50%. If a difference of this magnitude in favor of the VG arm were to exist, this study would not have had the power to detect it. The sample size in this study was calculated assuming a median PFS of 3 months in the control arm (Cap arm), which was the median PFS reported by several phase II trials [12, 13, 15]. Similarly, PFS estimation for the experimental arm (VG arm) was done based on published results of a phase II trial demonstrating a median PFS of 6 months for the VG combination. Despite the small sample size of this study and its inherent limitations, our results showed a median PFS that is not significantly different between the two treatments. It is noteworthy that in our trial, capecitabine single-agent arm experienced a longer median PFS than expected. However, the results observed in the single-agent capecitabine arm of the current study are remarkably similar to those observed in recent phase III trials of capecitabine versus combination treatment in anthracycline- and taxane-pretreated patients with MBC [25–27]. Indeed, median PFS in these trials was 4.2 months and ORR 9.1%–28.8%, while the current study reported a median PFS of 5.2 months and an ORR of 24.3%. Similarly, the results in the VG arm were in the same range with previously reported phase III trials. The current study showed a median PFS of 5.4 months and an ORR of 28.4%, while a phase III trial of vinorelbine/
Annals of Oncology
disclosure The authors declare no conflicts of interest.
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gemcitabine doublet versus vinorelbine monotherapy by Martin et al. [24] reported a median PFS of 6.0 months and an ORR of 36% in a similarly pretreated patient population. Similarly, subgroup analyses failed to demonstrate any benefit in favor of the combination arm among all subgroups tested. Only patients with hormone receptor-negative primary tumors seemed to have significantly longer PFS with the Cap arm. However, it should be underlined that these analyses were exploratory and not preplanned by study design and therefore no valid conclusion can be drawn due to small sample size. Hematological toxicity was significantly higher in the combination arm as was fatigue. On the other hand, hand–foot syndrome was higher in the capecitabine arm as expected. However, our study reported lower rates of hand–foot syndrome compared with recent phase III trials [25–27]. In conclusion, this trial failed to demonstrate any significant benefit in terms of ORR, PFS and OS in favor of the combination treatment. Given the higher neutropenia and fatigue associated with doublet chemotherapy and the practical advantage of oral treatment in terms of ease of administration, the VG combination cannot be recommended as a preferable treatment option in this population except perhaps in patients where compliance with a daily oral regimen as well as gastrointestinal tolerance issues are significant. Despite the improvements observed in the treatment of MBC, there are still several unmet needs. Among them is to determine the best way to combine or sequence cytotoxic agents and targeted therapies in order to achieve the maximum clinical benefit and to develop reliable predictive factors which will allow the selection of patients who are most likely to benefit from a particular agent and save others from unnecessary toxicity of ineffective treatments. Many clinical trials are currently evaluating these questions and it is hoped that one or more of these approaches will prove successful and lead to further progress in the treatment of this devastating disease.
original articles