Abstract
Background: As there are no reports of S-1 in combination with trastuzumab in clinical settings, we evaluated the safety and efficacy of S-1 in combination with trastuzumab for human epidermal-growth factor receptor (HER2)-positive metastatic breast cancer (MBC) and determined the recommended dose (RD). Patients and Methods: Patients with HER2-positive MBC received trastuzumab (a fixed initial dose of 4 mg/kg/day, then 2 mg/kg every week) plus S-1 (4 weeks followed by a 2-week rest) every 42 days. The dosage of S-1 was set of three levels (1: 80 mg/m2, 2: 65 mg/m2, 3: 50 mg/m2). The purposes of this study were the determination of the RD and safety. Dose-limiting toxicity (DLT) data were continually monitored to assess S-1 dose decreases. Results: Twelve patients were treated at level 1. Because no patients experienced DLT, the RD of S-1 plus trastuzumab therapy was 80 mg/m2 S-1 and 4 mg/kg followed by 2 mg/kg trastuzumab. The overall response rate and disease control rate were 33.3% and 83.3%, respectively. Conclusion: S-1 plus trastuzumab could be safely and effectively used for the treatment of HER2-positive MBC. The RD for a phase II study of this regimen was determined to be 80 mg/m2 S-1 and 2 mg/kg trastuzumab every week (loading dose, 4 mg/kg).
Approximately 20% of patients with metastatic breast cancer (MBC) show overexpression of human epidermal growth factor receptor 2 (HER2) (1, 2). The prognosis of such patients was usually poor until the introduction of the humanized monoclonal antibody trastuzumab, which specifically targets HER2 (3). The efficacy of trastuzumab in HER2-positive MBC has been demonstrated in several studies and the combination of trastuzumab with chemotherapeutic drugs such as anthracyclines and taxanes shows superiority to chemotherapy alone in terms of response rates, time to progression (TTP) and overall survival (4, 5). Although the conventional diagnostic algorithm proposed by Hortobagyi (6) did not take HER2 status into account, the MBC treatment algorithm proposed by Piccart in 2001 (7) did include HER2 status, which is now accepted as a trigger to introduce a therapeutic strategy that includes trastuzumab.
Preclinical data have shown that fluoropyrimidines counteract the antitumor activity of trastuzumab and that combination of trastuzumab and fluoropyrimidines may be ineffective (8). In clinical settings, however, capecitabine in combination with trastuzumab was reported to be effective in HER2-positive MBC (9-12). However, no studies have investigated the efficacy of trastuzumab in combination with other oral fluoropyrimidines in HER2-positive MBC. S-1 (TS-1®; Taiho Pharmaceutical Co. Ltd., Tokyo, Japan) is an oral fluoropyrimidine derivative that combines tegafur with two modulators of 5-fluorouracil (5-FU) metabolism, 5-chloro-2,4-dihydroxy pyridine (gimeracil) and potassium oxonate (oteracil), in a molar ratio of 1:0.4:1. Tegafur, an oral prodrug of 5-FU, is gradually converted to 5-FU and rapidly catabolized by dihydropyrimidine dehydrogenase (DPD) in the liver. Gimeracil inhibits the degradation of 5-FU by inhibition of DPD. Oteracil inhibits orotate phosphoribosyl transferase, which is preferentially localizes in the digestive tract. This component of S-1 reduces the phosphorylation of 5-FU in the gastrointestinal mucosa and thus reduces the incidence and severity of diarrhea (13). In a phase II study of S-1 monotherapy in patients with MBC, the overall response rate of S-1 was 41.7% (14). Meanwhile, in taxane-pretreated MBC, a phase II study of S-1 reported an overall response rate of approximately 20% (15).
An in vitro study of the efficacy of S-1 in combination with trastuzumab suggested that this combination might be appropriate for HER2-positive MBC. Therefore, we conducted a phase I study to evaluate the tolerability and clinical efficacy of S-1 plus trastuzumab for patients with HER2-positive MBC, and hence determine the effective dose for subsequent studies.
Patients and Methods
This was a prospective, multicenter, open-label, phase I study in patients with HER2-positive MBC to determine the feasible dose of oral S-1 in combination with trastuzumab and evaluate the safety of this regimen. The Bayesian posterior probability of the occurrence of dose-limiting toxicity (DLT) was calculated to provide the basis on which to reduce the dose of S-1. A dose level was considered acceptable if it was highly likely that the probability of developing DLT was <30%. For the Bayesian calculations, a beta distribution corresponding to the Bayes-Laplace uniform prior was used for the prior distribution, while a binomial distribution was used for the observed data (16, 17).
Eligibility criteria. Patients aged ≥20 years old with a histological or cytological diagnosis of HER2-positive (IHC 3+ or IHC 2+/FISH+) MBC were eligible. Eligibility required measurable cancer by RECIST criteria (18); baseline left ventricular ejection fraction (LVEF) >55%; an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-2; expected survival >6 months; adequate organ function defined as hemoglobin >9 g/dl, leukocyte count 3000-12,000/mm3, neutrophil count >1500 /mm3, platelet count >100,000/mm3, serum total bilirubin level less than the upper limit of normal in each institution ×1.5, and serum creatinine level less than the upper limit of normal. Treatment with one prior chemotherapeutic regimen was permitted for those with metastatic disease. Patients with any of the following were excluded: lung metastasis with dyspnea; brain metastasis with symptoms; a second primary cancer; serious concomitant illness; cardiac abnormalities; or cases with possible infection. The protocol was reviewed and approved by the Institutional Review Boards at all participating centers. Written informed consent was obtained from all patients.
Study treatment. Patients received S-1 in combination with trastuzumab. Trastuzumab was administered intravenously of an initial fixed dose of 4 mg/kg, and then of 2 mg/kg over 90 min every week. S-1 was administered orally, twice daily after meals for 4 weeks, followed by a 2-week rest. This cycle was repeated every 42 days until disease progression. S-1 was administered at one of three dose levels (level 1: 80 mg/m2; level −1: 65 mg/m2; level −2: 50 mg/m2). Study treatments continued until disease progression, unmanageable toxicity, or the patient requested to withdraw from the study. All patients were initially assigned to receive dose level 1. The safety at level 1 was evaluated based on DLT in three patients forming the group. If none of the three patients developed any DLT in the first cycle, additional patients were to be enrolled at the same dose level until there were 12 patients. If patients developed any DLT in the first cycle, decisions to reduce the dose were made by a data center according to the Bayesian calculations.
Evaluation of safety and efficacy. Adverse events (AEs) were graded according to the National Cancer Institute Common Toxicity Criteria (NCI-CTC) version 3.0 (19). Hematology and biochemistry assessments were performed before each cycle. LVEF was monitored by echocardiography or electrocardiography after every two cycles. DLT was defined as the occurrence of any of the following within the first treatment cycle: (i) grade 4 leukopenia and neutropenia; (ii) grade 3 or 4 neutropenia along with fever (febrile neutropenia) for ≥3 days; (iii) grade 3 or 4 thrombocytopenia; (iv) grade ≥3 nonhematologic toxicity, excluding alopecia and nausea/vomiting; (v) a decrease in LVEF compared with baseline of ≥20%; (vi) treatment period <14 days; or (vii) the second treatment cycle did not start within 4 weeks after treatment discontinuation.
RR was evaluated according to the RECIST criteria (Version 1.0) until disease progression and included all patients with complete response (CR) and partial response (PR). DCR was defined as the proportion of patients with CR, PR and stable disease (SD). CR and PR required confirmation at least 4 weeks after first being reported.
Results
Patient characteristics. A total of 12 patients were enrolled from five institutes (Sakai Municipal Hospital, Osaka City University Hospital, Osaka University, Rinku General Medical Center, and Osaka Police Hospital) between February 2007 and June 2009. All patients were treated with a fixed dose (initial dose: 4 mg/kg, treatment dose: 2 mg/kg) of trastuzumab plus 80 mg/m2 S-1. The baseline clinical characteristics are summarized in Table I. The median age was 66 years (range, 46-71 years). Two patients had distant metastatis when breast cancer was first diagnosed, and 10 patients had recurrent breast cancer and underwent surgery. Six patients (50%) had hormone receptor-positive tumors (ER+ and/or PR+); six patients (50%) had hormone-negative tumors. In total, 9 patients had received prior chemotherapy (8 patients in adjuvant setting, one in MBC). The sites of metastatic disease were the bone and/or soft tissue in 7 patients (58%) and visceral sites in 5 patients (42%). The majority of patients (n=11) received S-1 plus trastuzumab treatment as first-line therapy.
Toxicity. All the patients were assessed for toxicities during the first treatment cycle. No DLT was observed in this cohort. Based on the absence of DLT in the 12 patients, the 90% quantile of the Bayesian posterior distribution of DLT occurrence was 16.2%, indicating that level 1 dose of S-1 plus trastuzumab combination treatment was tolerated. Furthermore, few grade 3/4 toxicities were observed in patients treated at level 1. Grade 3 toxicities were observed in three patients and included leukopenia, neutropenia, and dizziness. Hematological toxicities, such as leukopenia and thrombocytopenia, were the most common adverse events. Although nine patients developed variable degrees of leukopenia and thrombocytopenia, these events were not severe. In terms of non-hematological toxicities, the most common was diarrhea (grade 1 or 2 in 6 patients). The hematological and non-hematological events in all 12 patients are reported in Table II.
Patient characteristics.
Efficacy. All the patients had measurable lesions and received level 1 dose of S-1 plus trastuzumab combination therapy. One patient achieved CR, three patients showed PR, and six patients showed SD, therefore the clinical RR was 33.3% (4/12) and the disease control rate (DCR) was 83.3% (10/12), as summarized in Table III. These data indicate that the combination therapy regimen was effective and supported proceeding to the phase II trial.
Discussion
The results of this phase I clinical study of S-1 plus trastuzumab revealed that the RD of S-1 was 80 mg/m2 in combination with initial infusion of 4 mg/kg trastuzumab followed by 2 mg/kg trastuzumab. These results may have important implications for future therapeutic strategies for HER2-positive breast cancer and for other types of carcinomas commonly treated with S-1.
Toxicities experienced using S-1 with trastuzumab for metastatic breast cancer (n=12).
Response rate of S-1 with trastuzumab therapy (n=12).
Patients with HER2-positive breast cancer and even those with node-negative cancer, usually have a poor prognosis. However, the introduction of trastuzumab, which was developed to specifically target HER2, has dramatically improved the prognosis of patients with this type of cancer (3). Trastuzumab is a recombinant humanized monoclonal antibody that targets the extracellular domain of the HER2 receptor. RR to trastuzumab in the treatment of HER2-positive MBC ranged from 26% to 32% when used as monotherapy (20) and was 50% when used in combination with chemotherapy (4). Some investigators have reported that trastuzumab in combination with chemotherapy improved disease progression and overall survival (4, 5), although trastuzumab as monotherapy was significantly inferior in usefulness to trastuzumab in combination with chemotherapy (21). These findings indicate that trastuzumab plus chemotherapy combination should be considered as the standard therapy for HER2-positive MBC.
Unlike adjuvant or neo-adjuvant therapy, therapeutic strategies for MBC need to provide maximal life-prolonging effects while keeping the patient's quality of life (QOL) at a satisfactory level. In this respect, the treatment algorithm proposed by Hortobagyi provides an important guideline because it takes into account both therapeutic efficacy and QOL (6). Furthermore, in the treatment of breast cancer, along with advances in basic research, a tailored treatment approach in which the regimen takes into account the expected responsiveness to a particular therapy on the basis of the biological characteristics of the carcinoma and the factors associated with the patient is becoming increasingly important.
The present study results may have significant implications for establishing a new therapeutic regimen that is associated with fewer serious adverse events and does not reduce the patient's QOL. Adverse effects, particularly those that affect QOL such as alopecia, nausea, vomiting and febrile neutropenia, are generally less common with treatment using oral fluoropyrimidines than those with anthracyclines and taxanes. In addition, patients can reduce the need for hospital visits when side-effects develop, if instructed about how to manage the adverse drug reaction compared with other treatment regimens. Accordingly, oral fluoropyrimidine combination therapy offers an advantage over other therapies in that the patient will continue to receive therapy for MBC while maintaining QOL at a satisfactory level. This approach seems to be beneficial for the patients such as the elderly, who have complications for which particularly serious adverse drug reactions are a specific concern. Under these circumstances, the present phase I clinical study of S-1 in combination with trastuzumab was planned with the aim of developing a regimen expected to provide therapeutic efficacy without compromising the patient's QOL.
S-1 was primarily developed for the treatment of carcinomas of the gastrointestinal tract and has been widely used as a key drug for the treatment of gastric cancer in Asia. The ACTS-GC trial demonstrated that S-1 monotherapy is effective as postoperative adjuvant treatment in patients with gastric cancer (22). In advanced settings, the JCOG9912 and SPIRITS trials revealed that S-1 monotherapy was non-inferior to 5-FU (23), while S-1 in combination with cisplatin was superior to S-1 alone (24). Therefore, the standard therapy in Japan for patients with unresectable advanced or recurrent gastric cancer is S-1 in combination with cisplatin for patients who can tolerate cisplatin, or S-1 alone for patients who cannot be treated with cisplatin. Several in vitro studies have demonstrated the efficacy of S-1 in combination with trastuzumab in several cancer cell types (25, 26). Meanwhile, trastuzumab has also attracted attention for other types of cancer, such as HER2-positive advanced gastric cancer, in addition to its efficacy in breast cancer (27). However, to date, no clinical studies have evaluated about the efficacy and safety of S-1 in combination with trastuzumab. Thus, our study has important implications for the development of therapeutic strategies based on S-1 plus trastuzumab in various types of carcinoma. Based on the findings of this phase I study, a phase II clinical study of S-1 in combination with trastuzumab for MBC is currently underway and its results are eagerly awaited.
Acknowledgements
This work was supported, in part, by a non-profit organization Epidemiological & Clinical Research Information Network (ECRIN). We would like to thank Ms Mai Hatta for her devoted logistical support for this clinical trial.
Footnotes
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Conflict of Interest
None.
- Received May 26, 2011.
- Revision received June 29, 2011.
- Accepted June 30, 2011.
- Copyright© 2011 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved
