Cancer Chemother Pharmacol DOI 10.1007/s00280-015-2738-3

ORIGINAL ARTICLE

Randomized study of orally administered fluorinated pyrimidines (capecitabine versus S‑1) in women with metastatic or recurrent breast cancer: Japan Breast Cancer Research Network 05 Trial D. Yamamoto1,5 · S. Iwase2 · Y. Tsubota1 · K. Ariyoshi2 · T. Kawaguchi3 · T. Miyaji4 · N. Sueoka1 · C. Yamamoto5 · S. Teramoto6 · H. Odagiri7 · K. Kitamura8 · Y. Nagumo9 · T. Yamaguchi4,10 

Received: 29 October 2014 / Accepted: 24 March 2015 © Springer-Verlag Berlin Heidelberg 2015

Abstract  Purpose  Capecitabine and S-1 are orally administered fluorinated pyrimidines with high-level activity against metastatic breast cancer (MBC). This randomized, multicenter, phase II study compared the activities and safeties of the oral fluoropyrimidines, capecitabine and S-1, in breast cancer patients. Methods  Patients with MBC were randomly assigned to receive capecitabine 825 g/m2 twice daily on days 1–21 every 4 weeks or S-1 40–60 mg twice daily, according to

* T. Miyaji [email protected]‑tokyo.ac.jp 1

Department of Surgery, Kansai Medical University, Takii, Osaka, Japan

2

Department of Palliative Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan

3

Department of Practical Pharmacy, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan

4

Department of Clinical Trial Data Management, Graduate School of Medicine, The University of Tokyo, 7‑3‑1 Hongo, Bunkyo‑ku, Tokyo 113‑8655, Japan





body surface area, on days 1–28 every 6 weeks. The primary endpoint was progression-free survival (PFS). Results  A total of 142 patients were enrolled and randomized to either capecitabine (N  = 73) or S-1 (N  = 69). Median PFS (progression-free survival) was 1.2 years for capecitabine and 1.3 years for S-1, with a hazard ratio (S-1/ capecitabine) of 0.85 (95 % confidence interval [CI] 0.52– 1.38) (P  = 0.48 by log-rank). The confirmed objective response rates were 24.0 % for capecitabine and 23.1 % for S-1 (P  = 0.938). The most common treatment-related adverse events were grade 1–2 in intensity. Thrombocytopenia (S-1: 9.2 %, capecitabine: 1.4 %; P = 0.040) and nausea (S-1: 26.2 %, capecitabine: 14.1 %; P  = 0.079) were more frequent in the S-1 group, while hand-foot syndrome occurred more often in the capecitabine group (S-1: 10.8 %, capecitabine: 25.4 %; P = 0.029). Conclusions  The results of the current study demonstrate that both S-1 and capecitabine are effective and well-tolerated treatments in patients with MBC, while their adverse events were different. They are both convenient, orally administered drugs, making them attractive agents for use in outpatient treatment. Keywords  S-1 · Capecitabine · Metastatic breast cancer · Recurrent breast cancer · Clinical trial

5

Department of Internal Medicine, Seiko Hospital, Neyagawa, Osaka, Japan

6

Department of Breast Surgery, Kyushu Central Hospital, Fukuoka, Japan

Introduction

7

Department of Surgery, Hirosaki National Hospital, Hirosaki, Japan

8

Breast Unit, Nagumo Clinic, Fukuoka, Japan

9

Breast Unit, Nagumo Clinic, Tokyo, Japan

Breast carcinoma is the most frequent neoplasia in the USA, Europe, and Japan [1]. However, it is difficult to manage metastatic breast cancer (MBC) effectively with the currently available drug regimens. Approximately 20–30 % of all patients with breast cancer will develop metastasis, and the mean survival time from the diagnosis



10

Division of Biostatistics, Tohoku University Graduate School of Medicine, Sendai, Japan

13



of recurrence in these patients is 18–30 months [1–3]. Treatment for patients with MBC therefore aims to prolong survival, while relieving symptoms and maintaining a good quality of life (QOL) [1–3]. Capecitabine is an orally administered fluoropyrimidine that has been reported to be effective in patients with MBC [4]. Used as a single agent, capecitabine demonstrated an overall response rate (RR) of 29 % and a median time to disease progression of 4.6 months in large phase II trials involving taxane-pretreated MBC patients [5–7]. The convenient oral delivery of capecitabine causes mild gastrointestinal toxicity and myelosuppression, without hair loss, and its major adverse effect is hand-foot syndrome (HFS). The majority of cases are grade 1 or 2, but grade 3 HFS has also been reported in 10–24 % of patients receiving capecitabine at the registered dose, in phase II and III trials [8–11]. Because capecitabine can sustain QOL in MBC patients, it has been widely used as a third-line or subsequent chemotherapy regimen for heavily treated patients. S-1 is another orally administered fluorinated pyrimidine that has been reported to be well tolerated and active against solid cancers. S-1 showed a RR of 41.7 % and a median survival time of 872 days in a phase II study in taxane-pretreated patients with MBC. S-1 has therefore been approved for the treatment of MBC patients in Japan [6, 12]. Their oral formulations, promising efficacies, and favorable toxicity profiles suggest that capecitabine and S-1 may provide attractive treatment options for breast cancer patients. However, there are currently no clinical data comparing the efficacies and safeties of these agents in patients with MBC. This randomized multicenter exploratory trial was designed to evaluate the safety and time to progression-free survival (PFS) associated with first-line treatment with the oral fluoropyrimidines, capecitabine and S-1, in patients with MBC.

Cancer Chemother Pharmacol

Study design and randomization This study was an open-label, multicenter, randomized phase II trial with two treatment arms. Dynamic allocation was performed at the central registration center. Patients were allocated to one of the two treatment arms at a ratio of 1:1. Stratification factors for randomization were institution and the presence of pulmonary metastasis. Treatment dose and schedule

Patients and methods

Patients were randomly assigned to receive either capecitabine or S-1. Capecitabine was administered at a dose of 825 mg/m2 twice daily on days 1–21 every 4 weeks. The dosage was adjusted or interrupted for treatment-related adverse events of grade 2 or higher, based on a previously defined algorithm [6, 13]. The capecitabine dose was determined according to the Japanese package insert. S-1 was administered orally twice daily for 28 days, followed by 14-day rest. Three dosage levels of S-1 were defined, according to body surface area (BSA), as described previously [14]: BSA  1.5 m2, 60 mg twice daily. S-1 was temporarily discontinued, and the same dose subsequently retried, if a patient experienced grade 2 non-hematologic toxicity, grade 3 thrombocytopenia, or uncomplicated grade 4 neutropenia. If the toxicity recurred or grade 3 non-hematologic toxicities, grade 4 thrombocytopenia, or febrile neutropenia occurred, S-1 was interrupted until the toxicity subsided to grade 1 or less. The BSA-adjusted S-1 dose was then reduced from 120 to 100 mg per day, from 100 to 80 mg per day, or from 80 to 50 mg per day. In the case of grade 2 or higher toxicity, the administration was interrupted and not resumed until the toxicity had resolved or improved to grade 1. Each treatment was continued until the occurrence of disease progression, unacceptable toxicities, or patient refusal.

Eligibility

Evaluation of efficacy and safety

Eligible patients were women with breast cancer metastasized to sites other than the central nervous system. All patients were aged 20–75 years, with an Eastern Cooperative Oncology Group (ECOG) performance status

Randomized study of orally administered fluorinated pyrimidines (capecitabine versus S-1) in women with metastatic or recurrent breast cancer: Japan Breast Cancer Research Network 05 Trial.

Capecitabine and S-1 are orally administered fluorinated pyrimidines with high-level activity against metastatic breast cancer (MBC). This randomized,...
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