Randomized phase III study comparing the efficacy and safety of irinotecan plus S-1 with S-1 alone as first-line treatment for advanced gastric cancer (study GC0301/TOP-002)

Division of Clinical Oncology, Hiroshima University Graduate School of Biomedical Sciences, Hiroshima, 734-8551, Japan.
Gastric Cancer (Impact Factor: 3.72). 02/2011; 14(1):72-80. DOI: 10.1007/s10120-011-0009-5
Source: PubMed


Irinotecan hydrochloride and S-1, an oral fluoropyrimidine, have shown antitumor activity against advanced gastric cancer as single agents in phase I/II studies. The combination of irinotecan and S-1 (IRI-S) is also active against advanced gastric cancer. This study was conducted to compare the efficacy and safety of IRI-S versus S-1 monotherapy in patients with advanced or recurrent gastric cancer.
Patients were randomly assigned to oral S-1 (80 mg/m² daily for 28 days every 6 weeks) or oral S-1 (80 mg/m² daily for 21 days every 5 weeks) plus irinotecan (80 mg/m² by intravenous infusion on days 1 and 15 every 5 weeks) (IRI-S). The primary endpoint was overall survival. Secondary endpoints included the time to treatment failure, 1- and 2-year survival rates, response rate, and safety.
The median survival time with IRI-S versus S-1 monotherapy was 12.8 versus 10.5 months (P = 0.233), time to treatment failure was 4.5 versus 3.6 months (P = 0.157), and the 1-year survival rate was 52.0 versus 44.9%, respectively. The response rate was significantly higher for IRI-S than for S-1 monotherapy (41.5 vs. 26.9%, P = 0.035). Neutropenia and diarrhea occurred more frequently with IRI-S, but were manageable. Patients treated with IRI-S received more courses of therapy at a relative dose intensity similar to that of S-1 monotherapy.
Although IRI-S achieved longer median survival than S-1 monotherapy and was well tolerated, it did not show significant superiority in this study.

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Available from: Akira Tsuburaya, Dec 24, 2013
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    • "However, S-1 as a monotherapy was merely noninferior to the conventional infusional 5-FU in the treatment of advanced gastric cancer. Meanwhile, phase III studies comparing single agent (S-1 alone) and its combination with newly approved drugs (TXT plus S-1 or CPT-11 plus S-1) eventually showed no difference in survival rates [19, 20]. In the present study, the 1-year survival rate in both combination chemotherapy regimens was higher in the sensitive group in terms of CD-DST than in the resistant group. "
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    ABSTRACT: We conducted a multicenter phase II trial to assess the suitability of three types of chemotherapy (docetaxel plus S-1, irinotecan plus S-1, or S-1 alone) for patients with advanced gastric cancer by means of the collagen gel droplet embedded culture-drug sensitivity test (CD-DST). To our knowledge, this is the first multicenter clinical trial that has employed CD-DST to choose anticancer agents for the treatment of advanced gastric cancer. Subjects (n = 64) were patients with advanced or recurrent gastric cancer. Patients were allocated to one of the treatment regimens on the basis of CD-DST results. Outcome of the patients was compared between the groups deemed chemosensitive or chemoresistant by the CD-DST. Thirty-three patients showed high sensitivity (T/C ratio <60 %) to at least one type of anticancer agent (sensitive group), and 31 showed low sensitivity (T/C ratio ≥60 %) to all agents (resistant group). Specifically, the 1-year survival rate was significantly higher in the sensitive group (78.5 %; 95 % CI, 67.2-94.7 %) than in the resistant group (54.7 %; 95 % CI, 38.7-74.3 %; P = 0.019), whereas time to progression (TTP) was significantly longer in the sensitive group (59.8 %; 95 % CI, 48.2-81.7 %) than in the resistant group (30.0 %; 95 % CI 13.6-46.4 %; P = 0.023). Median survival time was also significantly longer in the sensitive group (15.5 months; 95 % CI, 12.8-18.2) than in the resistant group (12.5 months; 95 % CI, 10.2-14.9; P = 0.038). CD-DST predicts the outcome of patients undergoing chemotherapy for advanced gastric cancer, presumably through evaluating chemosensitivity.
    Gastric Cancer 12/2013; 17(4). DOI:10.1007/s10120-013-0320-4 · 3.72 Impact Factor
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    • "In Western countries, a phase III study comparing docetaxel plus cisplatin/5-fluorouracil with cisplatin plus 5-fluorouracil was ongoing in patients with advanced gastric cancer (V325 study). In Japan, S-1 had become the most widely used drug for the treatment for advanced gastric cancer, and phase III studies of S-1 plus cisplatin versus S-1 alone (SPIRITS trial: Koizumi et al. 2008) and S-1 plus irinotecan versus S-1 alone (TOP-002 trial: Narahara et al. 2011) were ongoing. "
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    ABSTRACT: PURPOSE: Cisplatin plus 5-fluorouracil has been globally accepted as a standard regimen for the treatment for advanced gastric cancer. However, cisplatin has several disadvantages, including renal toxicity and the need for admission. S-1 plus cisplatin has become a standard treatment for advanced gastric cancer in East Asia. This phase III study was designed to evaluate the potential benefits of adding docetaxel to S-1 without a platinum compound in patients with advanced gastric cancer. METHODS: Patients were randomly assigned to receive docetaxel plus S-1 or S-1 alone. The docetaxel plus S-1 group received docetaxel on day 1 and oral S-1 on days 1-14 of a 21-day cycle. The S-1 alone group received oral S-1 on days 1-28 of a 42-day cycle. The primary end point was overall survival. RESULTS: Of the 639 patients enrolled, 635 were eligible for analysis. The median overall survival was 12.5 months in the docetaxel plus S-1 group and 10.8 months in the S-1 alone group (p = 0.032). The median progression-free survival was 5.3 months in the docetaxel plus S-1 group and 4.2 months in the S-1 alone group (p = 0.001). As for adverse events, neutropenia was more frequent in the docetaxel plus S-1 group, but remained manageable. CONCLUSION: As first-line treatment for advanced gastric cancer, docetaxel plus S-1 significantly improves median overall and progression-free survival as compared with S-1 alone. (ClinicalTrials.gov number: NCT00287768).
    Journal of Cancer Research and Clinical Oncology 12/2013; DOI:10.1007/s00432-013-1563-5 · 3.08 Impact Factor
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    • "The response rate of standard cancer therapies is still generally around 30% to 40% [1-3]. To determine standard therapies based on tumors of origin through epigenetic studies, large-scale clinical trials are important. "
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    ABSTRACT: Background The use of standard chemotherapy regimens has changed the application of chemosensitivity tests from all chemotherapy-eligible patients to those who have failed standard chemotherapy, which includes patients with highly advanced, relapsed, or chemoresistant tumors. Methods We evaluated a total of 43 advanced primary and relapsed gastric cancers for chemosensitivity based on drug dose response curves to improve the objectivity and quality of quantitative measurements. The dose response curves were classified based on seven expected patterns. Instead of a binary chemosensitivity evaluation, we ranked drug sensitivity according to curve shapes and comparison with the peak plasma concentration (ppc) of each drug. Results A total of 193 dose response curves were obtained. The overall informative rate was 67.4%, and 85.3% for cases that had a sufficient number of cells. Paclitaxel (PXL)and docetaxel tended to show a higher rank, while cisplatin (CIS) and 5-fluorouracil (5-FU) tended to show resistance, particularly among the 20 cases (46.5%) that had recurrent disease after receiving chemotherapy with CIS and S-1 (5-FU). As such, we speculate that the resistant pattern of the chemosensitivity test suggests that cells with acquired drug resistance were selected by chemotherapy. Indeed, we observed a change in the chemosensitivity pattern of a sample before and after chemotherapy in terms of PXL sensitivity, which was used after primary chemotherapy. Conclusions These results suggest that: (i) the dose–response pattern provides objective information for predicting chemosensitivity; and (ii) chemotherapy may select resistant cancer cell populations as a result of the therapy.
    World Journal of Surgical Oncology 01/2013; 11(1):11. DOI:10.1186/1477-7819-11-11 · 1.41 Impact Factor
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