Phase II Study of Docetaxel and S-1 Combination Therapy for Advanced or Recurrent Gastric Cancer

Abstract

Purpose: To evaluate the efficacy and toxicity of docetaxel in combination with a novel oral 5-fluorouracil analogue S-1for patients with advanced or recurrent gastric cancer. Experimental Design: Patients with advanced or recurrent adenocarcinoma of the stomach and up to one previous chemotherapy regimen were treated with i.v. docetaxel 40 mg/m 2 on day 1and oral S-1 80 mg/m 2 /d on days 1to 14 every 3 weeks. Results: Forty-eight patients (median age, 65 years; range, 25-75 years) received a total of 272 treatment cycles (median, 4; range, 1-17). No complete responses and 27 partial responses were observed for an overall response rate of 56.3% [95% confidence interval (95% CI), 38-66%]. Eighteen patients (37.5%) had stable disease and three patients (6.3%) had progressive disease as best response. The tumor control rate (complete response + partial response + stable disease) was 93.8% (95% CI, 83-98%). Median overall survival was 14.3 months (95% CI, 10.7-20.3 months) and median time to tumor progression was 7.3 months (95% CI, 4.3-10.0 months). The most common grade 3 to 4 hematologic toxicities were neutropenia (58.3 %), leukopenia (41.7%), febrile neutropenia (8.3%), and anemia (8.3%). The most common grade 3 nonhematologic toxicities included anorexia (14.6%), stomatitis (8.3%), and nausea (6.3%). No grade 4 nonhematologic toxicities were reported and all treatment-related toxicities were resolved. Conclusion: Docetaxel/S-1combination is highly active and well tolerated in advanced or recurrent gastric cancer. Further investigation in randomized studies is warranted.The prognosis for patients with unresectable advanced or recurrent gastric cancer is extremely poor; indeed, gastric cancer is the second most frequent cause of cancer-related mortality worldwide, accounting for f700,000 deaths annually (1). Several novel chemotherapeutic agents, including the taxanes (paclitaxel and docetaxel), irinotecan, and, more recently, oxaliplatin, S-1, and capecitabine, have shown activity in gastric cancer and offer hope for improving patient outcomes in this setting (2, 3). Response rates of up to 65% were reported in phase II studies of regimens, including taxanes, irinotecan, or oxaliplatin, and, consequently, several combinations have been investigated in randomized phase II/III studies (3).Docetaxel has shown promising activity in gastric cancer, both as monotherapy (4, 5) and in combination with other agents (6 -8). In the phase III TAX 325 study, triple-agent therapy with docetaxel-cisplatin-5-fluorouracil (5-FU; TCF) was superior to cisplatin-5-FU in terms of response rate (37% versus 25%; m 2 , P = 0.0106), time to progression (TTP; 5.6 months versus 3.7 months; risk reduction 32%; log-rank P = 0.0004), and survival (risk reduction 23% after a median follow-up of 23 months; log-rank P = 0.0201) in patients with metastatic gastric cancer (7). However, grade 3 to 4 treatment-emergent adverse events (regardless of relationship to study medication) occurred in 81% and 75% of patients receiving TCF and cis...

Phase I/II study of docetaxel and S-1 in patients with advanced gastric cancer

“…These have explored docetaxel dosing intervals ranging from every week to every 4 weeks with relative dose intensities from 10 to 20 mg m À2 per week. However, because final reports of these studies are not yet available, the feasibility and efficacy of these alternative regimens remains unknown (Yoshida et al, 2004;Kim et al, 2006;Park et al, 2006;Rino et al, 2006;Satoh et al, 2006;Takahashi et al, 2006). In the phase II part of this study, we demonstrated that for patients with advanced GC, this regimen conferred an ORR of 46% and an estimated median survival of 14 months, with acceptable toxicity.…”

“…For example, the respective mean AUC and C max of 5-FU were 522.5 ng h ml À1 and 100.3 ng ml À1 with docetaxel 40 mg m À2 and 857.2 ng h ml À1 and 155.8 ng ml À1 , with docetaxel 50 mg m À2 (Yoshida et al, 2004). Synergy of this combination has been reported in vitro, suggesting that biochemical modulation of the two drugs occurs.…”

Phase I study of S-1, docetaxel and cisplatin combination chemotherapy in patients with unresectable metastatic gastric cancer

“…For combination chemotherapy regimens, which included S-1, either a 2-week administration with a 1-week interval protocol (Hyodo et al, 2003;Yoshida et al, 2006), or 3-week administration with a 1-to 2-week interval protocol have been reported (Koizumi et al, 2003;Ajani et al, 2005b). However, a recent post-marketing surveillance of S-1 disclosed that most toxicities increased during S-1/docetaxel/CDDP in metastatic gastric cancer T Takayama et al the third week of S-1 administration, often resulting in discontinuation of treatment (Nagashima et al, 2005).…”

“…The reason we administered docetaxel and CDDP on day 8 and not on day 1, as in previously reported S-1/CDDP combination studies (Ajani et al, 2005b), was that when we, in the pilot study, administered both drugs on day 1, we encountered severe neutropenia on days 10 -14. We used an S-1 dosage of 40 mg m À2 twice daily in this study according to the previous studies (Koizumi et al, 2000;Yoshida et al, 2006). Although this is a phase I study recruiting only 17 patients, the RR was quite high (88%) compared with those of phase II and phase III studies previously reported.…”

A multi-center phase II study of S-1 plus paclitaxel as first-line therapy for patients with advanced or recurrent unresectable gastric cancer

“…Many clinical trials of S-1 and other chemotherapeutic agents such as cisplatin and docetaxel have been carried out in patients with gastric cancer [2,15,25]. Some promising results have been reported with a response rate of 40-70% and a median survival of 11-14 months with these combination regimens.…”