A multicenter phase II study of biweekly capecitabine in combination with oxaliplatin as first-line chemotherapy in patients with locally advanced or metastatic gastric cancer

This is a multicenter study to investigate the safety and efficacy profiles of biweekly capecitabine (Xeloda^®) in combination with oxaliplatin (Eloxatin^®) as first-line therapy in patients with locally advanced or metastatic gastric cancer. The primary objective was to investigate the objective response rate of capecitabine plus oxaliplatin treatment in previously untreated locally advanced or metastatic gastric cancer patients. Secondary objectives included progression-free survival, duration of response, overall survival (OS), and safety profiles. The study protocol was approved by the medical ethics committees of all participating centers and was registered as ClinicalTrial.gov (NCT00436241). Signed informed consents were obtained from all patients.

Inclusion criteria for this study were as follows: histologically confirmed gastric adenocarcinoma with unresectable locally advanced or metastatic disease; at least one, non-irradiated, measurable lesion according to the Response Evaluation Criteria in Solid Tumors (RECIST) [27]; 18 years of age or older; calculated creatinine clearance ≥50 ml/min using the Cockroft–Gault formula; and Eastern Cooperative Oncology Group (ECOG) performance status ≤1.

Patients who fell under any of the following criteria were excluded from the study: previous cytotoxic chemotherapy (except given as adjuvant or neoadjuvant treatment completed at least 6 months prior to enrollment); organ allografts; clinically significant cardiac disease or myocardial infarction within the last 12 months; evidence of CNS metastases; history of another malignancy within the last five years except for cured basal cell carcinoma of the skin or cured carcinoma in situ of the uterine cervix; radiotherapy within 4 weeks of treatment start; major surgery within 4 weeks of the start of the treatment, without complete recovery; serious uncontrolled intercurrent infections; lack of physical integrity of the upper gastrointestinal tract or malabsorption syndrome; abnormal audiogram or auditory abnormality; significant or uncontrolled gastrointestinal bleeding; the following laboratory values: neutrophils ≤1.5 × 10⁹/L; platelet count <100 × 10⁹/L; serum bilirubin ≥1.5 × upper normal limit; alanine aminotransferase or aspartate aminotransferase >2.5 × upper normal limit or >5 × upper normal limit in the case of liver metastases; alkaline phosphatase >2.5 × upper normal limit or >5 × upper normal limit in the case of liver metastases or >10 × upper normal limit in the case of bone disease.

Capecitabine (1,000 mg/m² twice daily, days 1–10, followed by four days of rest period) plus oxaliplatin (85 mg/m² as a 2-h intravenous infusion on day 1) were administered in two-week cycles. Protocol treatment was discontinued for patients with clearly documented progressive disease (PD) at any time due to insufficient therapeutic response. Patients who tolerated treatment and showed either complete response (CR), partial response (PR), or stable disease (SD) continued to be treated and followed until disease progression.

The intensity of clinical adverse events was graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events v3.0 (CTCAE). Dose modifications were based on hematological and non-hematological toxicities.

For hematological toxicities, dose modifications were based on hematological parameters at the start of a treatment cycle. Administration of capecitabine was interrupted during a treatment cycle if a grade 3 or 4 hematological toxicity developed. The next treatment cycle could only start if hematological toxicity has recovered to grade ≤1. No dose reduction or interruption was required for anemia (non-hemolytic) as it could be satisfactorily managed by transfusions.

For non-hematological toxicities of capecitabine, if a grade 2 or 3 adverse event occurred, capecitabine was interrupted immediately; if a grade 4 non-hematological toxicity occurred, treatment was discontinued unless the investigator considered it to be in the best interest of the patient to continue at 50 % of the original dose, once toxicity has resolved to grade 0–1. The next treatment cycle could only start if non-hematological toxicity has recovered to grade ≤1. Capecitabine dose was reduced by 25 % for patients experiencing a second occurrence of a given grade 2 or any grade 3 event. The capecitabine dose was reduced by 50 % for patients who experienced a third occurrence of a given grade 2 or a second occurrence of a given grade 3 event. If the same toxicity occurred for a fourth time at grade 2 or a third time at grade 3, treatment was discontinued.

For grade <3 non-hematological toxicities of oxaliplatin, management was symptomatic, if possible. For grade ≥3 non-hematological adverse events, oxaliplatin was withheld for a maximum of 4 weeks until toxicities were resolved. After patients recovered from toxicity grade 3–2 or less, the dose of oxaliplatin was reduced to 65 mg/m² in subsequent cycles. In case of no resolution to grade 2 or less after a maximum of 4 weeks from the planned date of the next cycle, oxaliplatin treatment was discontinued. In case of grade 4 toxicity, patients were removed from oxaliplatin treatment and followed until the resolution of the adverse event.

Evaluations, including the patient’s medical history, physical examination, complete blood count, blood chemistry, abdominal–pelvic computed tomography (CT) scan, and chest X-ray, were performed before chemotherapy. After starting the protocol treatment, blood chemistry and complete blood count were assessed prior to the start of each cycle. Tumor measurements were carried out after every 3 cycles of treatment or when progression was suspected. Confirmation of overall response (complete or partial response), when applicable, was done at a minimum of 4 weeks after the first response had been recorded. Tumor response was evaluated according to the Response Evaluation Criteria in Solid Tumors (RECIST) [27]. Toxicities were recorded according to the National Cancer Institute Common Terminology Criteria grading system version 3, starting at the time of study entry and ending 28 days after the last dose of medication was administered.

Between March 2007 and November 2008, forty-six patients (ITT population) from ten medical centers in Taiwan were enrolled in this study. The clinical and pathologic characteristics of patients are listed in Table 1.

The tumor response rates are shown in Table 2. Five patients could not be evaluated for response due to failure to return for tumor measurements. Among the 41 evaluable patients, the best tumor response was partial response (PR) in 9 patients, whereas 25 patients showed stable disease and 7 patients progressive disease. The overall response rates of the evaluable and intent-to-treat (ITT) populations were 22 % (95 % CI 10–42 %) and 20 % (95 % CI 9–34 %), respectively, whereas the disease control rates in the corresponding populations were 83 % (95 % CI 68–93 %) and 74 % (95 % CI 59–86 %), respectively. Median time to tumor response was 1.4 months (range 1.2–2.8 months). The median duration of response was 5.1 months (95 % CI 2.8–9.7 months). Of the 46 patients, 26 received second-line and subsequent therapies, with a total of 47 additional regimens received. Among them, six patients received monotherapy (2 UFUR, 1 capecitabine, 1 everolimus, 1 irinotecan, and 1 paclitaxel), 9 patients received cisplatin plus fluoropyrimidine-based therapy, 4 patients received anthracycline-based therapy with various combinations of 5-FU, cisplatin, and cyclophosphamide, 4 patients received taxane-based therapy, 3 patients received oxaliplatin-based therapy, 4 patients received irinotecan-based therapy, and 2 patients received 5-FU plus cyclophosphamide or cetuximab. Three additional patients also received mainly fluoropyrimidine-based subsequent therapy.

Median follow-up time was 7.8 months (range 0.7–35.9 months). Median progression-free survival and overall survival were 5.6 months (95 % CI 4.1–6.3 months) and 8.0 months (95 % CI 6.3–10.1 months), respectively. The Kaplan–Meier estimated progression-free survival and overall survival curves are shown in Figs. 1 and 2, respectively. Overall survival at 1 year was 26.9 % and at 2 years was 13.4 %.

A total of 391 (median 7.5, range 1–29) cycles of chemotherapy were given. The median relative dose intensity was 88.5 % (range 51.4–103.2 %) for capecitabine and 99.3 % (range 43.6–103.9 %) for oxaliplatin. In total, 82.6 % of the patients received more than 80 % of the intended dose of capecitabine, and 95.7 % received more than 80 % of the intended dose of oxaliplatin.

All patients were evaluated for toxicities (Table 3). The most common hematological toxicity was thrombocytopenia (33 %), but without grade 3 or 4 events. Grade 3 leucopenia was observed in 2 % of the patients. Grade 3–4 anemia developed in five patients (11 %). The most common non-hematological toxicities were neuropathy (35 %), fatigue (31 %), diarrhea (26 %), vomiting (26 %), and hand-foot syndrome (22 %). Major grade 3 toxicities were diarrhea (9 %) and hand-foot syndrome (7 %). Treatment was delayed in 82 cycles (21 %), and dose modifications were implemented in 13 cycles (3 %). The most frequent cause of treatment delays was thrombocytopenia (31/82; 38 %), and the major reason for dose modification was hand-foot syndrome (6/13; 46 %). There were no treatment-related deaths.