Abstract
Aim: The aim of this study was to evaluate efficacy and toxicity of low dose of docetaxel in combination with standard dose of S-1 for patients with recurrent or metastatic gastric cancer, and to investigate whether β-tubulin protein expression level is a predictive or prognostic factor. Methods: From March 2010 to December 2011, 90 patients from Medical Oncology Department of Shanghai Zhongshan Hospital, Fudan University, were enrolled in this study. Patients with recurrent or metastatic gastric adenocarcinoma were treated with docetaxel of 40 mg/m2 intravenously on day 1 and S-1 of 80 mg/m2 orally for 14 days with one-week intermission as first-line chemotherapy. The chemotherapeutic effects were evaluated every 3 cycles using the Response Evaluation Criteria In Solid Tumors (RECIST1.1). The tumor tissues and the serum of peripheral blood were obtained at the start of the study to analyze the protein expression level of β-tubulin, which were estimated using immunohistochemistry (IHC) and enzyme-linked immunosorbent assay (ELISA), respectively. Response and toxicity were analyzed. All the patients were followed-up until the time of progression, death, or the censored time, to calculate progression-free survival (PFS) and overall survival (OS) time. Results: In total, 90 patients (median age: 60.5 years [range: 28–76 years]) received a total of 491 treatment cycles (median: 6 [range: 2–9]) of docetaxel combined with S-1 chemotherapy, and 291 cycles of single S-1- maintenance treatment. Three complete response (CR) and thirty-eight partial responses (PR) were observed, with an overall response rate (ORR) of 45.1%. Median OS was 12.5 months, and median PFS was 7.0 months. PFS and OS in patients with peritoneal metastases were significantly longer compared to patients with other metastatic loci. β-tubulin protein expression levels in tumor tissue and in serum were significantly lower in responders than in nonresponders. Lower expression of β-tubulin protein in serum but not in tumor tissues was associated with more serious toxicities.There was significant correlation between tumor tissues and peripheral blood about the expression of β-tubulin. Peritoneal metastasis was an independent prognostic factor by COX regression. PFS and OS were not correlated with β-tubulin expressive level. Conclusion: This combination of standard dose of S-1 and low dose of docetaxel is effective and well tolerated in patients with recurrent or metastatic gastric cancer. Peritoneal metastasis is treated more effectively by this regimen than other forms of metastases. Baseline expression levels of β-tubulin could predict the response. β- tubulin is a predictive marker.
Highlights
Docetaxel is a taxane anti-mitotic agent that binds to free tubulin and leads to the assembly of stabilized microtubule bundles, inhibition of the cell cycle, and cell death due to apoptosis
(docetaxel-cisplatin plus fluorouracil) regimen in Chinese patients reported that 60 mg/m2 docetaxel got 7.2 months progression-free survival (PFS) and 10.15 months overall survival (OS) with 60.5% incidence of grade 3~4 neutropenia
Phase II studies on S-1 administered at a dose of 40 mg/m2 twice daily for two weeks in combination with docetaxel administered in doses ranging from 35 to 60 mg/m2 have indicated that the rates of grade 3 and 4 neutropenia were between 29.4% and 67%
Summary
Docetaxel is a taxane anti-mitotic agent that binds to free tubulin and leads to the assembly of stabilized microtubule bundles, inhibition of the cell cycle, and cell death due to apoptosis. Phase II trials have shown that single-agent docetaxel, which inhibits microtubule depolymerization and is widely used for the treatment of metastatic gastric cancer, has response rates of 16–24% [1,2,3]. Docetaxel in gastric cancer is considered effective in the pivotal study of V325. In the V325 study, the dose of docetaxel was 75 mg/m2 with TTP (time to progression) of 5.6 months and OS of 9.2 months, but the grade 3~4 hematologic toxicity was severe, especially the incidence of neutropenia was as high as 82% [4]. Whether low dose docetaxel is appropriate for Asian patients, with high effectiveness and less toxicity is a question needed to be answered. In 2014, Japanese START clinical trial published the final results that standard dose of S-1 (80 mg/m2) combined with low dosage of docetaxel (40 mg/m2) got the median OS of 12.5 months [5]
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