Masahiro Gotoh

Phase I/II study of S-1 combined with cisplatin in patients with advanced gastric cancer

A dose-escalation study of cisplatin (CDDP) combined with S-1, a new oral dihydropyrimidine dehydrogenase inhibitory fluoropyrimidine, was performed to determine the maximum-tolerated dose (MTD), recommended dose (RD), dose-limiting toxicities (DLTs), and objective response rate (RR) in advanced gastric cancer (AGC). S-1 was given orally at 40u2009mgu2009m−2 b.i.d. for 21 consecutive days following a 2-week rest. CDDP was planned to be given intravenously on day 8, at a dose of 60, 70, or 80u2009mgu2009m−2 depending on the DLT. Treatment was repeated every 5 weeks, unless disease progression was observed. In the phase I portion, the MTD of CDDP was presumed to be 70u2009mgu2009m−2, because 33.3% of patients (2/6) developed DLTs, mainly neutropenia. Therefore, the RD of CDDP was estimated as 60u2009mgu2009m−2. In the phase II portion, 19 patients including six patients of the RD phase I portion were evaluated. The median administered courses was four (range: 1–8). The incidences of severe (grades 3–4) haematological and nonhaematological toxicities were 15.8 and 26.3%, respectively, but all were manageable. The RR was 74% (14/19, 95% confidence interval: 54.9−90.6%), and the median survival day was 383. This regimen is considered to be active against AGC with acceptable toxicity.

Phase III study comparing oxaliplatin plus S-1 with cisplatin plus S-1 in chemotherapy-naïve patients with advanced gastric cancer

BACKGROUNDnWe evaluated the efficacy and safety of S-1 plus oxaliplatin (SOX) as an alternative to cisplatin plus S-1 (CS) in first-line chemotherapy for advanced gastric cancer (AGC).nnnPATIENTS AND METHODSnIn this randomized, open-label, multicenter phase III study, patients were randomly assigned to receive SOX (80-120mg/day S-1 for 2 weeks with 100mg/m2 oxaliplatin on day 1, every 3 weeks) or CS (S-1 for 3 weeks with 60mg/m2 cisplatin on day 8, every 5 weeks). The primary end points were noninferiority in progression-free survival (PFS) and relative efficacy in overall survival (OS) for SOX using adjusted hazard ratios (HRs) with stratification factors; performance status and unresectable or recurrent (+adjuvant chemotherapy) disease.nnnRESULTSnOverall, 685 patients were randomized from January 2010 to October 2011. In per-protocol population, SOX (n = 318) was noninferior to CS (n = 324) in PFS [median, 5.5 versus 5.4 months; HR 1.004, 95% confidence interval (CI) 0.840-1.199; predefined noninferiority margin 1.30]. The median OS for SOX and CS were 14.1 and 13.1 months, respectively (HR 0.958 with 95% CI 0.803-1.142). In the intention-to-treat population (SOX, n = 339; CS, n = 337), the HRs in PFS and OS were 0.979 (95% CI 0.821-1.167) and 0.934 (95% CI 0.786-1.108), respectively. The most common ≥grade 3 adverse events (SOX versus CS) were neutropenia (19.5% versus 41.8%), anemia (15.1% versus 32.5%), hyponatremia (4.4% versus 13.4%), febrile neutropenia (0.9% versus 6.9%), and sensory neuropathy (4.7% versus 0%).nnnCONCLUSIONnSOX is as effective as CS for AGC with favorable safety profile, therefore SOX can replace CS.nnnCLINICAL TRIAL NUMBERnJapicCTI-101021.BACKGROUNDnWe evaluated the efficacy and safety of S-1 plus oxaliplatin (SOX) as an alternative to cisplatin plus S-1 (CS) in first-line chemotherapy for advanced gastric cancer (AGC).nnnPATIENTS AND METHODSnIn this randomized, open-label, multicenter phase III study, patients were randomly assigned to receive SOX (80-120 mg/day S-1 for 2 weeks with 100 mg/m(2) oxaliplatin on day 1, every 3 weeks) or CS (S-1 for 3 weeks with 60 mg/m(2) cisplatin on day 8, every 5 weeks). The primary end points were noninferiority in progression-free survival (PFS) and relative efficacy in overall survival (OS) for SOX using adjusted hazard ratios (HRs) with stratification factors; performance status and unresectable or recurrent (+adjuvant chemotherapy) disease.nnnRESULTSnOverall, 685 patients were randomized from January 2010 to October 2011. In per-protocol population, SOX (n = 318) was noninferior to CS (n = 324) in PFS [median, 5.5 versus 5.4 months; HR 1.004, 95% confidence interval (CI) 0.840-1.199; predefined noninferiority margin 1.30]. The median OS for SOX and CS were 14.1 and 13.1 months, respectively (HR 0.958 with 95% CI 0.803-1.142). In the intention-to-treat population (SOX, n = 339; CS, n = 337), the HRs in PFS and OS were 0.979 (95% CI 0.821-1.167) and 0.934 (95% CI 0.786-1.108), respectively. The most common ≥grade 3 adverse events (SOX versus CS) were neutropenia (19.5% versus 41.8%), anemia (15.1% versus 32.5%), hyponatremia (4.4% versus 13.4%), febrile neutropenia (0.9% versus 6.9%), and sensory neuropathy (4.7% versus 0%).nnnCONCLUSIONnSOX is as effective as CS for AGC with favorable safety profile, therefore SOX can replace CS.nnnCLINICAL TRIAL NUMBERnJapicCTI-101021.

Subgroup analyses of the safety and efficacy of ramucirumab in Japanese and Western patients in RAINBOW: a randomized clinical trial in second-line treatment of gastric cancer

BackgroundWe evaluated the safety and efficacy of ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients previously treated for advanced gastric or gastroesophageal junction adenocarcinoma in Japanese and Western subgroups from the RAINBOW trial.MethodsPatients received ramucirumab at 8xa0mg/kg or placebo (days 1 and 15) plus paclitaxel at 80xa0mg/m2 (days 1, 8, and 15 of a 28-day cycle). End points were compared between treatment arms within Japanese (Nxa0=xa0140) and Western (Nxa0=xa0398) populations.ResultsThe incidence of adverse events of grade 3 or higher was higher for ramucirumab plus paclitaxel in both populations (Japanese population, 83.8xa0% vs 52.1xa0%; Western population, 79.1xa0% vs 61.9xa0%). Neutropenia was the commonest adverse event of grade 3 or higher, with a higher incidence for ramucirumab plus paclitaxel (Japanese population, 66.2xa0% vs 25.4xa0%; Western population, 32.1xa0% vs 14.7xa0%). The incidence of febrile neutropenia was low and was similar between treatment arms in both populations. The overall survival hazard ratio was 0.88 (95xa0% confidence interval, 0.60–1.28) in the Japanese population and 0.73 (95xa0% confidence interval, 0.58–0.91) in the Western population. The progression-free survival hazard ratio was 0.50 (95xa0% confidence interval, 0.35–0.73) in the Japanese population and 0.63 (95xa0% confidence interval, 0.51–0.79) in the Western population. The objective response rate was higher for ramucirumab plus paclitaxel in both populations (Japanese population, 41.2xa0% vs 19.4xa0%; Western population, 26.8xa0% vs 13.0xa0%), as was the 6-month survival rate (Japanese population, 94.1xa0% vs 71.4xa0%; Western population, 66.0xa0% vs 49.0xa0%).ConclusionsSafety profiles of the ramucirumab plus paclitaxel arm were similar between populations, though there was a higher incidence of neutropenia in Japanese patients. Progression-free survival and objective response rate improvements were observed for ramucirumab plus paclitaxel in both populations.ClinicalTrials.gov identifier:NCT01170663

Phase I and Pharmacokinetic Study of S-1 Combined with Weekly Paclitaxel in Patients with Advanced Gastric Cancer

Objective: A dose-escalation study of weekly paclitaxel combined with S-1, a novel oral fluoropyrimidine, was performed to determine the maximum tolerated dose (MTD), the recommended dose (RD) and the dose-limiting toxicities (DLTs) in advanced gastric cancer. Patients and Methods: Twelve patients were enrolled. S-1 was given orally at a fixed dosage of 40 mg/m2 b.i.d. for 14 consecutive days, followed by a 1-week rest. Paclitaxel was scheduled to be given intravenously on days 1 and 8 at a dose of 50, 60, 70 or 80 mg/m2, depending on the DLTs. Treatment was repeated every 3 weeks. A pharmacokinetic study was conducted in an additional 5 patients on days 7 and 8 during the first course given at the RD. Results: The MTD of paclitaxel was presumed to be 60 mg/m2, because 50.0% of patients (2/4) developed DLTs (mainly grade 3 anorexia). DLT was observed in 1 out of 8 patients at a dose of 50 mg/m2. Therefore, the RD of paclitaxel was estimated to be 50 mg/m2. The preliminary response rate was 62.5% (5/8) at the RD. There were no significant pharmacokinetic interactions between S-1 and paclitaxel. An adequate plasma paclitaxel concentration for an antineoplastic effect was achieved with weekly doses of 50 mg/m2. Conclusion: Weekly paclitaxel combined with S-1 was demonstrated to exhibit a tolerable toxicity profile with therapeutic plasma concentration at the dose of 50 mg/m2. This regimen could represent a novel and low toxic combination for advanced gastric cancer.

S-1 plus leucovorin versus S-1 plus leucovorin and oxaliplatin versus S-1 plus cisplatin in patients with advanced gastric cancer: a randomised, multicentre, open-label, phase 2 trial

BACKGROUNDnAlthough leucovorin enhances the efficacy of fluorouracil, the anti-tumour activity of S-1 and leucovorin and their combination with oxaliplatin for patients with advanced gastric cancer is unknown. We compared the activity and safety of S-1 plus leucovorin, S-1 plus leucovorin and oxaliplatin, and S-1 plus cisplatin as first-line chemotherapy for advanced gastric cancer.nnnMETHODSnIn this multicentre, randomised, open-label, phase 2 trial, we recruited chemotherapy-naive patients with unresectable or recurrent gastric cancer with measurable lesions aged 20 years or older from 25 general hospitals and specialist centres in Japan. Patients were randomly assigned (1:1:1) centrally to receive S-1 plus leucovorin (S-1 40-60 mg orally plus oral leucovorin 25 mg twice a day for 1 week, every 2 weeks), S-1 plus leucovorin and oxaliplatin (S-1 plus leucovorin and intravenous oxaliplatin 85 mg/m(2) on day 1, every 2 weeks), or S-1 plus cisplatin (S-1 40-60 mg orally twice a day for 3 weeks, plus intravenous cisplatin 60 mg/m(2) on day 8, every 5 weeks). Randomisation was done with the minimisation method using performance status (0 vs 1) and tumour stage (stage IV vs recurrent) as stratification factors. The primary endpoint was independently reviewed overall response in the full analysis set. This trial is registered with Japic CTI, number 111635.nnnFINDINGSnBetween Oct 20, 2011, and Dec 17, 2012, we enrolled and randomly assigned 145 patients: 49 patients were assigned to S-1 plus leucovorin, 47 to S-1 plus leucovorin and oxaliplatin, and 49 to S-1 plus cisplatin. An objective response assessed by the independent review committee was achieved in 20 (43% [95% CI 28·3-57·8]) of the 47 patients in the S-1 plus leucovorin group, 31 (66% [50·7-79·1]) of the 47 patients in the S-1 plus leucovorin and oxaliplatin group, and 22 (46% [31·4-60·8]) of the 48 patients in the S-1 plus cisplatin group (Fishers exact test, p=0·84 for S-1 plus leucovorin vs S-1 plus cisplatin, p=0·063 for S-1 plus leucovorin and oxaliplatin vs S-1 plus cisplatin, and p=0·038 for S-1 plus leucovorin and oxaliplatin vs S-1 plus leucovorin). The most common grade 3-4 adverse events were neutropenia (three [6%] of 48 patients in the S-1 plus leucovorin group vs 12 [26%] of 47 patients in the S-1 plus leucovorin and oxaliplatin group vs 17 [35%] of 49 patients in the S-1 plus cisplatin group), decreased appetite (six [13%] vs 14 [30%] vs 12 [24%]), anaemia (five [10%] vs seven [15%] vs 13 [27%]), and hyponatraemia (two [4%] vs two [4%] vs nine [18%]).nnnINTERPRETATIONnS-1 plus leucovorin and oxaliplatin was more active than S-1 plus leucovorin or S-1 plus cisplatin with acceptable toxic effects for patients with advanced gastric cancer. A phase 3 trial comparing S-1 plus leucovorin and oxaliplatin with S-1 plus cisplatin is underway.nnnFUNDINGnTaiho Pharmaceutical.

Randomised phase II study of S-1/cisplatin plus TSU-68 vs S-1/cisplatin in patients with advanced gastric cancer

BACKGROUNDnThis study aimed to determine whether combination S-1 plus cisplatin (CDDP) therapy, the most widely used therapy for Japanese patients with advanced gastric cancer, and the novel oral antiangiogenic agent TSU-68 could contribute to gastric cancer treatment.nnnMETHODSnNinety-three patients with chemotherapy-naïve unresectable or recurrent advanced gastric cancers were randomised into two groups: TSU-68 plus S-1/CDDP (group A) and S-1/CDDP (group B) groups. Both patient groups received identical S-1 and CDDP dosages. TSU-68 was orally administered for 35 consecutive days. Group B patients received S-1 orally twice daily for three consecutive weeks, followed by intravenous CDDP on day 8. The primary endpoint was progression-free survival (PFS).nnnRESULTSnMedian PFS periods were 208 and 213 days in groups A and B, respectively (P=0.427). Median survival periods for groups A and B were 497.0 and 463.5 days, respectively (P=0.219). No statistically significant differences were noted for PFS, survival or the adverse event (AE) incidence rate. All AEs were expected according to previous reports for TSU-68, TS-1, and CDDP.nnnCONCLUSIONnCombination therapy involving TSU-68, S-1, and CDDP was safe and well tolerated in patients with chemotherapy-naïve unresectable or recurrent advanced gastric cancers. However, factors related to therapeutic efficacy should be investigated further.Background:This study aimed to determine whether combination S-1 plus cisplatin (CDDP) therapy, the most widely used therapy for Japanese patients with advanced gastric cancer, and the novel oral antiangiogenic agent TSU-68 could contribute to gastric cancer treatment.Methods:Ninety-three patients with chemotherapy-naïve unresectable or recurrent advanced gastric cancers were randomised into two groups: TSU-68 plus S-1/CDDP (group A) and S-1/CDDP (group B) groups. Both patient groups received identical S-1 and CDDP dosages. TSU-68 was orally administered for 35 consecutive days. Group B patients received S-1 orally twice daily for three consecutive weeks, followed by intravenous CDDP on day 8. The primary endpoint was progression-free survival (PFS).Results:Median PFS periods were 208 and 213 days in groups A and B, respectively (P=0.427). Median survival periods for groups A and B were 497.0 and 463.5 days, respectively (P=0.219). No statistically significant differences were noted for PFS, survival or the adverse event (AE) incidence rate. All AEs were expected according to previous reports for TSU-68, TS-1, and CDDP.Conclusion:Combination therapy involving TSU-68, S-1, and CDDP was safe and well tolerated in patients with chemotherapy-naïve unresectable or recurrent advanced gastric cancers. However, factors related to therapeutic efficacy should be investigated further.

Adjuvant capecitabine plus oxaliplatin after D2 gastrectomy in Japanese patients with gastric cancer: a phase II study

BackgroundAdjuvant chemotherapy with XELOX (capecitabine plus oxaliplatin) has been shown to be beneficial following resection of gastric cancer in South Korean, Chinese, and Taiwanese patients. This phase II study (J-CLASSIC-PII) was undertaken to evaluate the feasibility of XELOX in Japanese patients with resected gastric cancer.MethodsPatients with stage II or III gastric cancer who underwent curative D2 gastrectomy received adjuvant XELOX (eight 3-week cycles of oral capecitabine, 1000xa0mg/m2 twice daily on days 1–14, plus intravenous oxaliplatin 130xa0mg/m2 on day 1). The primary endpoint was dose intensity. Secondary endpoints were safety, proportion of patients completing treatment, and 1-year disease-free survival (DFS) rate.ResultsOne hundred patients were enrolled, 76 of whom completed the study as planned. The mean dose intensity was 67.2xa0% (95xa0% CI, 61.9–72.5xa0%) for capecitabine and 73.4xa0% (95xa0% CI, 68.4–78.4xa0%) for oxaliplatin, which were higher than the predefined age-adjusted threshold values of 63.4xa0% and 69.4xa0%, respectively, and the study therefore met its primary endpoint. The 1-year DFS rate was 86xa0% (95xa0% CI, 77–91xa0%). No new safety signals were identified.ConclusionsThe feasibility of adjuvant XELOX in Japanese patients with resected gastric cancer is similar to that observed in South Korean, Chinese, and Taiwanese patients in the Capecitabine and Oxaliplatin Adjuvant Study in Stomach Cancer (CLASSIC) study. Based on findings from this study and the CLASSIC study, the XELOX regimen can be considered an adjuvant treatment option for Japanese gastric cancer patients who have undergone curative resection.

Randomized phase II study of second-line chemotherapy with the best available 5-fluorouracil regimen versus weekly administration of paclitaxel in far advanced gastric cancer with severe peritoneal metastases refractory to 5-fluorouracil-containing regimens (JCOG0407).

BackgroundThis randomized phase II study compared weekly administration of paclitaxel (wPTX) with the best available 5-fluorouracil (5-FU) regimen as second-line treatment for advanced gastric cancer patients with severe peritoneal metastasis refractory to fluoropyrimidine.MethodsIn the best available 5-FU arm, continuous infusion of 5-FU (800xa0mg/m2/day, daysxa01–5, every 4xa0weeks) was given to patients with prior chemotherapy including bolus 5-FU, and methotrexate and 5-FU sequential bolus injection (methotrexate at 100xa0mg/m2 followed by bolus 5-FU at 600xa0mg/m2 with leucovorin, weekly) was given to those who had previously received continuous infusion of 5-FU or oral administration of fluoropyrimidine. In the wPTX arm, paclitaxel (80xa0mg/m2) was administered on days 1, 8, and 15, every 4xa0weeks. This study adopted a screening design (one-sided αxa0=xa030xa0%) with the primary end point of overall survival.ResultsOne hundred patients were randomized to the 5-FU arm (nxa0=xa049) or the wPTX arm (nxa0=xa051). Although the median survival time was 7.7xa0months in both arms, the 2-year survival rates were 2.9xa0% in the 5-FU arm and 9.1xa0% in the wPTX arm [hazard ratioxa00.89 (95xa0% confidence interval 0.57–1.38), one-sided pxa0=xa00.298}. The median progression-free survival was longer with wPTX than with 5-FU [3.7xa0months vs 2.4xa0months; hazard ratio 0.58 (95xa0% confidence interval 0.38–0.88), one-sided pxa0=xa00.005]. The incidences of grade 4 neutropenia, grade 3/4 febrile neutropenia, diarrhea, and treatment-related death were 6xa0%, 4xa0%, 10xa0%, and 2xa0%, respectively, in the 5-FU arm and 2xa0%, 0xa0%, 0xa0%, and 0xa0%, respectively, in the wPTX arm.Conclusions As second-line chemotherapy, wPTX appears feasible and promising. This regimen can be included in a test arm in future phase III trials for treatment of advanced gastric cancer with severe peritoneal metastasis.

Efficacy and safety of S-1 and oxaliplatin combination therapy in elderly patients with advanced gastric cancer

BackgroundA randomized phase III study of Japanese patients with advanced gastric cancer, the G-SOX trial, revealed that S-1 and oxaliplatin (SOX) combination therapy was noninferior to S-1 and cisplatin (CS) combination therapy. However, it is unclear whether the efficacy and safety in elderly patients were different between the two regimens.MethodsA total of 685 patients registered in the G-SOX trial were classified as elderly (70xa0years or older) or not elderly (younger than 70xa0years), and 663 patients (SOX therapy, elderly 113 of 333 patients, 34xa0%; CS therapy, elderly 99 of 330 patients, 30xa0%) and 673 patients (SOX therapy, elderly 114 of 338 patients, 34xa0%; CS therapy, elderly 101 of 335 patients, 30xa0%) were analyzed for efficacy and safety, respectively. Treatment delivery of SOX was also compared between elderly and nonelderly groups.ResultsNo differences in efficacy were identified between the elderly and nonelderly groups for either regimen. In the elderly groups, SOX therapy showed better trends in progression-free survival (hazard ratio 0.805, 95xa0% confidence interval 0.588–1.102) and overall survival (hazard ratio 0.857, 95xa0% confidence interval 0.629–1.167) compared with CS therapy, although there were no significant differences. Grade 3 or worse adverse events were less frequent in the elderly group receiving SOX than in the elderly group receiving CS except for the low incidence of sensory neuropathy (5.3xa0% vs 0xa0%), neutropenia (25.4xa0% vs 42.6xa0%), anemia (21.1xa0% vs 42.6xa0%), febrile neutropenia (1.8xa0% vs 10.9xa0%), increased creatinine level (0.9xa0% vs 3.0xa0%), and hyponatremia (7.9xa0% vs 18.8xa0%).ConclusionsSOX is an effective and feasible therapy in both nonelderly and elderly patients with advanced gastric cancer. In elderly patients, SOX demonstrated favorable efficacy and safety compared with CS.

Comparison between neoadjuvant chemotherapy followed by surgery and definitive chemoradiotherapy for overall survival in patients with clinical Stage II/III esophageal squamous cell carcinoma (JCOG1406-A)

BackgroundnNeoadjuvant chemotherapy followed by surgery (NAC-S) represents the standard treatment for patients with Stage II/III esophageal squamous cell carcinoma (ESCC) in Japan. Chemoradiotherapy (CRT) is performed in patients who refuse or have contraindications to surgery. However, randomized clinical trials that compare NAC-S with CRT have not been conducted. The aim of this study was to explore subgroups of patients undergoing CRT to identify those with survival outcomes potentially equivalent to NAC-S.nnnMethodsnPooled data from two clinical trials in patients with Stage II/III ESCC, the JCOG9907 trial and the JCOG9906 trial were used. JCOG9907 demonstrated that NAC-S resulted in superior overall survival (OS) compared with surgery followed by adjuvant chemotherapy. JCOG9906 was a single-arm trial that explored the efficacy and safety of CRT. The eligibility criteria in the two trials were almost identical. Subgroup analyses of clinical data (serum albumin, cT, cN, cstage and tumor location) were conducted with Cox proportional hazards regression models for patients assigned to receive NAC-S in JCOG9907 and patients in JCOG9906.nnnResultsnThe analysis comprised 163 patients from JCOG9907 in NAC-S arm (NAC-S group) and 73 patients from JCOG9906 who received CRT (CRT group). Baseline characteristics were similar between the two groups. OS was better in the NAC-S group than the CRT group (adjusted hazard ratio 1.72; 95% confidence interval 1.19-2.50). All subgroups in the NAC-S group had longer OS compared with those in the CRT group.nnnConclusionsnOS was superior after NAC-S rather than CRT. None of the CRT subgroups had similar OS to the NAC-S groups.