Feasibility study of postoperative adjuvant chemotherapy with S-1 in patients with biliary tract cancer.

BACKGROUND: The role of adjuvant chemotherapy has not yet been established for patients with resected biliary tract cancer. S-1 has been shown to exert activity against advanced biliary tract cancer. Therefore, we evaluated the feasibility of adjuvant chemotherapy with S-1 in patients with resected biliary tract cancer. METHODS: Patients with complete macroscopic resection of intrahepatic/extrahepatic bile duct, gall bladder, or ampullary cancer were eligible. S-1 was administered orally twice daily for 4 weeks every 6 weeks, up to 4 cycles. The treatment was continued up to 24 weeks or until recurrence/appearance of unacceptable toxicity. The primary endpoint was the treatment completion rate, which was defined as the percentage of patients who received a relative dose intensity of ≥ 75%. This trial was registered as UMIN000004051. RESULTS: Thirty-three patients were enrolled between June 2010 and March 2011. The relative dose intensity was ≥ 75% in 27 patients representing a treatment completion rate of 81.8%. The most common grade 3/4 adverse event was neutropenia (18%). Grade 2 nausea or diarrhea was observed in 12%. The 3-year relapse-free survival rate was 39.4%. The 3-year survival rate was 54.5%. CONCLUSION: Adjuvant chemotherapy with S-1 is feasible treatment in patients with resected biliary tract cancer. It is necessary to conduct a phase III study to confirm the efficacy of adjuvant therapy of S-1 in patients with resected BTC.

SLCO1B1 Polymorphism Is a Drug Response Predictive Marker for Advanced Pancreatic Cancer Patients Treated With Gemcitabine, S-1, or Gemcitabine Plus S-1.

OBJECTIVES: The aim of this study was to evaluate the effects of single-nucleotide polymorphisms (SNPs) on advanced pancreatic cancer risk and overall survival (OS) in a candidate-gene approach. METHODS: Overall, 5438 SNPs in 219 candidate genes encoding several drug-metabolizing enzymes or transporters were analyzed. In the screening study, 3 SNPs were found associated with OS (P ≤ 0.0005). We validated these SNPs as part of the randomized phase 3 study (GEST study). The associations between OS and SNPs were investigated using log-rank test and Cox proportional hazards model. RESULTS: From the GEST study, the SNP rs4149086 in the 3' UTR of the solute carrier organic anion transporter family member 1B1 (SLCO1B1) gene showed significant interaction with treatment (P = 0.02). In the gemcitabine group, the SNP was associated with short OS (hazard ratio [HR], 3.75; 95% confidence interval [CI], 1.30-10.8; P = 0.008) even after multiple-comparisons adjustment. In contrast, the SNP was not associated with OS in S-1 (HR, 0.77; 95% CI, 0.33-1.81; P = 0.55) or gemcitabine plus S-1 groups (HR, 1.18; 95% CI, 0.46-3.00; P = 0.72). CONCLUSIONS: Patients with advanced pancreatic cancer with the rs4149086 AG or GG genotype may obtain good clinical results when treated with S-1-containing regimens.

Randomized phase III study of gemcitabine plus S-1, S-1 alone, or gemcitabine alone in patients with locally advanced and metastatic pancreatic cancer in Japan and Taiwan: GEST study.

PURPOSE: The present phase III study was designed to investigate the noninferiority of S-1 alone and superiority of gemcitabine plus S-1 compared with gemcitabine alone with respect to overall survival. PATIENTS AND METHODS: The participants were chemotherapy-naive patients with locally advanced or metastatic pancreatic cancer. Patients were randomly assigned to receive only gemcitabine (1,000 mg/m(2) on days 1, 8, and 15 of a 28-day cycle), only S-1 (80, 100, or 120 mg/d according to body-surface area on days 1 through 28 of a 42-day cycle), or gemcitabine plus S-1 (gemcitabine 1,000 mg/m(2) on days 1 and 8 plus S-1 60, 80, or 100 mg/d according to body-surface area on days 1 through 14 of a 21-day cycle). RESULTS: In the total of 834 enrolled patients, median overall survival was 8.8 months in the gemcitabine group, 9.7 months in the S-1 group, and 10.1 months in the gemcitabine plus S-1 group. The noninferiority of S-1 to gemcitabine was demonstrated (hazard ratio, 0.96; 97.5% CI, 0.78 to 1.18; P < .001 for noninferiority), whereas the superiority of gemcitabine plus S-1 was not (hazard ratio, 0.88; 97.5% CI, 0.71 to 1.08; P = .15). All treatments were generally well tolerated, although hematologic and GI toxicities were more severe in the gemcitabine plus S-1 group than in the gemcitabine group. CONCLUSION: Monotherapy with S-1 demonstrated noninferiority to gemcitabine in overall survival with good tolerability and presents a convenient oral alternative for locally advanced and metastatic pancreatic cancer.

Phase I results from a two-part Phase I/II study of cediranib in combination with mFOLFOX6 in Japanese patients with metastatic colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) is the second most common malignancy in Japan. Inhibition of vascular endothelial growth factor (VEGF) signaling is a clinically validated therapeutic strategy in patients with metastatic CRC. Cediranib is an oral, highly potent VEGF signaling inhibitor of all three VEGF receptors. METHODS: This Phase I study investigated the safety, tolerability and pharmacokinetics of cediranib (20 or 30 mg) in combination with mFOLFOX6 in Japanese patients with previously untreated metastatic CRC. If the safety of the 20 mg dose was confirmed, a second cohort of patients was to be recruited to receive cediranib 30 mg + mFOLFOX6. RESULTS: Six patients received cediranib 20 mg + mFOLFOX6 and seven received cediranib 30 mg + mFOLFOX6. One patient in the initial cediranib 20 mg cohort experienced a dose-limiting toxicity (DLT; grade 3 bilirubin increase); no DLTs were observed in the 30 mg cohort. The most commonly reported adverse events were diarrhea, decreased appetite, peripheral neuropathy, hypertension and fatigue. Two patients in the 20 mg cohort and three in the 30 mg cohort experienced serious adverse events during all treatment courses. Cediranib was generally well tolerated in this patient population with no evidence to suggest any significant pharmacokinetic interactions between cediranib and fluorouracil or oxaliplatin. A preliminary evaluation showed that five of nine evaluable patients achieved a best response of partial response. CONCLUSION: Cediranib (20 or 30 mg) in combination with mFOLFOX6 was considered tolerable according to the protocol-defined criteria, providing justification for the Phase II part of this study.

[Chemotherapy in advanced gastric cancer--to ensure timely and appropriate switch to subsequent treatment options].

Since irinotecan, S-1, docetaxel, and paclitaxel were approved, therapeutic options for chemotherapy in the treatment of gastric cancer have increased. It is suggested that the efficient use of the primary drugs prolongs life in the treatment of progressive colorectal cancer. Also, physicians have discussed ways to take full advantage of the drugs in the treatment of gastric cancer. In first-line treatment in other countries, combination therapy usually includes the administration of two drugs, while in Japan, where therapies based on S-1 have been developed, the most appropriate strategy must be determined after reporting the results of phase III trials in 2007. In the clinic, treatment must be selected on the basis of solid evidence in consideration of the organ dysfunction associated with progressive gastric cancer. The timing of any changes in the treatment should be considered because the cancer easily metastasizes to the peritoneum. Throughout the world, various regimens have been developed that replace cisplatin with oxaliplatin or mainly use oral fluoropyrimidine. Molecular target drugs, now being evaluated in phase II trials, will also be used in the treatment of gastric cancer in the near future. Novel therapies will be developed in Asia and Japan where the incidence of gastric cancer is high.

[Capecitabine].

Capecitabine, an oral fluoropyrimidine carbamate, is adopted worldwide. As the treatment for metastatic colorectal cancer, capecitabine showed at least comparable efficacy with a favorable safety profile to bolus 5-FU/LV. In a large phase III trial (Xeloda Adjuvant Chemotherapy Trial: X-ACT), as the adjuvant treatment of patients with resected stage III colon cancer, capecitabine showed at least comparable disease-free survival, overall survival, and relapse-free survival with a favorable safety profile to bolus 5-FU/LV. Additionally, capecitabine-based combination regimens with oxaliplatin or irinotecan are now under evaluation. In phase II studies, capecitabine has shown the promising results in combination therapy. In Japan, capecitabine has been evaluated since 1994. In a recent phase II study, which evaluated the global dose as first-line treatment for metastatic colorectal cancer, the response rate was 35% (95% CI 23.1-48.4). The median time to disease progression was 169 days and the median overall survival was 617 days. Hand-foot syndrome (HFS), a characteristic adverse event of capecitabine, was observed in 73.3% of the patients, but the grade 3/4 was observed in 13.3% of the patients and only one patient discontinued the treatment due to HFS. An immediate approval of capecitabine in Japan is expected.

Phase I-II study of biweekly paclitaxel administration with fixed-dose-rate cisplatin in advanced gastric cancer.

BACKGROUND: Both paclitaxel (TXL) and cisplatin (CDDP) show efficacy against gastric cancer. The aim of this phase I-II study was to determine the maximum tolerated dose (MTD) and to evaluate the toxicity and efficacy of combination chemotherapy with these two agents. METHODS: Nineteen patients entered the phase I part of the study, and 21 patients entered the phase II part. TXL infusions were administered on days 1 and 15, with a fixed 3mg/m2 dose of CDDP. RESULTS: In the phase I part of the study, we determined dose level 5, which represented a TXL dose of 18 mg/m2, with CDDP 3 mg/m2, to be the MTD. The recommended dose (RD) was level 4, with a TXL dose of 16 mg/m2 with CDDP, 3 mg/m2. In the phase II part of the study, the response rate was 25.0%; five patients had a partial response, seven had stable disease, 6 had progressive disease, and 2 were not evaluable. Grade 3 or 4 neutropenia was the most common adverse event and occurred in 65% of the patients. During treatment, 25% of the patients received granulocyte colony-stimulating factor, but febrile neutropenia was not shown in any of the patients. Major nonhematological toxicities were nausea/vomiting, anorexia, fatigue, alopecia, and sensory neuropathy. Adverse reactions of grade 3 or 4 were shown by two patients, one with anorexia (5%) and the other with sensory neuropathy (5%). CONCLUSION: The RD was determined to be TXL 14 mg/m2, with CDDP 3 mg/m2.