s-1-(combination) and Kidney-Neoplasms

5-FU is a major anti-tumor agent, and many clinical trials have been conducted to determine the efficacy of 5-FU and fluoropyrimidine derivatives for the treatment of urological cancers. S-1 is an oral fluoropyrimidine derivative that should be tested to demonstrate clinical efficacy for the treatment of urological cancers. Two phase II trials are being conducted to evaluate the efficacy and safety of S-1 as a single agent therapy for patients with hormone-refractory prostate cancer (HRPC) and renal cell carcinoma (RCC).

Topics: Antimetabolites, Antineoplastic; Carcinoma, Renal Cell; Clinical Trials, Phase II as Topic; Drug Administration Schedule; Drug Combinations; Female; Humans; Kidney Neoplasms; Male; Oxonic Acid; Prostatic Neoplasms; Tegafur; Urologic Neoplasms

The potential of S-1 for the treatment of metastatic renal cell carcinoma (mRCC) has been shown in two phase II studies. We aimed to assess the safety, tolerance, pharmacokinetics and clinical activity of S-1 combined with sorafenib in patients with mRCC.. In this multicenter, single-arm, open-label, phase I/II study of S-1 plus sorafenib, we recruited patients with clear-cell or papillary renal cell carcinoma who had received a maximum of one prior cytokine-based regimen. The phase I primary end points were the maximum tolerated dose (MTD) and recommended dose (RD). S-1 was administered orally at 60, 80, 100 or 120 mg/day on days 1-28 of a 42-day cycle in combination with sorafenib (400 or 800 mg/day), given daily with dose adjustment. In phase II, the primary end point was to assess the overall response rate (ORR) at the RD.. Nine patients were enrolled into phase I and 21 (including 6 patients who received the RD in the phase I portion) were enrolled into phase II. In the phase I portion, the MTD could not be determined, and the RD was defined as S-1 80 mg/m(2)/day on days 1-28 + sorafenib 800 mg/day on days 1-42. In the phase II portion, 21 patients were fully assessable for efficacy and safety. The confirmed ORR was 52% [95% confidence interval (CI) 29.8-74.3], including one complete response (5%) and 10 partial responses (48%). The median progression-free survival was 9.9 (95% CI 6.5-17.1) months. The most frequently reported treatment-related adverse event for all grades was hand-foot skin reaction (100%). The major reasons for dose reduction were hand-foot skin reaction (38%) and rash (14%).. Combination therapy with S-1 plus sorafenib is effective and tolerable for patients with mRCC. However, skin events management is important in S-1 plus sorafenib combination therapy.

Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Renal Cell; Disease-Free Survival; Drug Combinations; Female; Humans; Kidney Neoplasms; Male; Maximum Tolerated Dose; Middle Aged; Niacinamide; Oxonic Acid; Phenylurea Compounds; Sorafenib; Tegafur; Treatment Outcome

A planned primary analysis of a Phase II study of S-1 demonstrated that the drug was active and tolerable in Japanese patients with cytokine-refractory metastatic renal cell carcinoma. Furthermore, pharmacogenomic analysis suggested that low expression of thymidylate synthase mRNA may have been associated with clinical outcome in terms of overall response rate and progression-free survival. Here, we report the results of the final analysis assessing the efficacy and safety of S-1 including overall survival.. Patients with renal cell carcinoma were eligible if they had had at least one regimen of cytokine for metastatic disease. S-1 was orally administered on Days 1-28 of a 42-day cycle until disease progression. The primary endpoint was the overall response rate, and the secondary endpoint included progression-free survival, overall survival and safety.. A total of 45 patients were treated with S-1 and were fully assessable for efficacy and safety. At the final analysis, a response was seen in 11 patients (overall response rate, 24.4%; 95% confidence interval: 12.9-39.5%), including two patients who achieved a complete response. The final median progression-free and overall survival were 9.2 and 42.8 months, respectively. The safety profile of S-1 was favorable. It was suggested that there was no relation between overall survival and the expression level of thymidylate synthase.. This final analysis confirms that S-1 treatment is effective and safe in patients with cytokine-refractory renal cell carcinoma.

Topics: Adult; Aged; Antimetabolites, Antineoplastic; Carcinoma, Renal Cell; Cytokines; Disease-Free Survival; Drug Administration Schedule; Drug Combinations; Drug Resistance, Neoplasm; Female; Humans; Kaplan-Meier Estimate; Kidney Neoplasms; Male; Middle Aged; Oxonic Acid; Tegafur; Treatment Outcome

S-1, an oral anticancer agent, contains tegafur (FT), 5-chloro-2,4-dihydroxypyridine (CDHP), and potassium oxonate (Oxo) at a molar ratio of FT:CDHP:Oxo = 1:0.4:1. The aim of this trial was to investigate the efficacy and safety of S-1 in Japanese patients with cytokine-refractory metastatic renal cell carcinoma (RCC).. We conducted a non-randomized, open-label trial in Japanese patients with metastatic RCC who had received nephrectomy and had failed cytokine-based immunotherapy. The primary endpoint was response rate. S-1 40-60 mg based on the body surface area was administered twice daily (80-120 mg/day) for 4 consecutive weeks, followed by a 2-week rest period; cycles were repeated every 6 weeks. Patients continued treatment until disease progression, unacceptable toxicity, or withdrawal of consent.. A total of 20 eligible patients were enrolled. Among these, 3 patients had partial response, yielding objective response rate of 15%; 13 patients had no change; 4 patients had progressive disease. The median time-to-progression and median overall survival were 12.0 and 25.7 months, respectively. The initial adverse event was generally mild to moderate in severity. The most common grade 3/4 drug-related hematological and non-hematological adverse events were neutropenia (20.0%) and anorexia (20.0%), respectively.. S-1 is active and well tolerated for the treatment of cytokine-refractory metastatic RCC.

Topics: Adult; Aged; Antimetabolites, Antineoplastic; Carcinoma, Renal Cell; Cytokines; Disease Progression; Drug Combinations; Drug Resistance, Neoplasm; Female; Humans; Interferons; Interleukin-2; Japan; Kaplan-Meier Estimate; Kidney Neoplasms; Male; Middle Aged; Oxonic Acid; Tegafur; Time Factors; Treatment Outcome

This phase II multicenter trial was conducted to evaluate the activity and safety of S-1 in Japanese patients with metastatic renal cell carcinoma (mRCC). We also examined the relation between response and mRNA expression levels of enzymes involved in the metabolism of fluorouracil (FU).. Patients with mRCC who had received nephrectomy in whom cytokine-based immunotherapy was ineffective or contraindicated were studied. S-1 was administered orally at 80-, 100-, or 120-mg daily, assigned according to body surface area, on days 1 to 28 of a 42-day cycle. The primary end point was the objective response rate. The mRNA expression levels of FU-related enzymes were measured by reverse-transcriptase polymerase chain reaction in formalin-fixed, paraffin-embedded specimens of tumors obtained at nephrectomy.. A total of 45 eligible patients were enrolled. Eleven (24.4%) of 45 patients had partial responses to S-1, and 28 (62.2%) had stable disease. Median progression-free survival was 9.2 months. The severity of most adverse events was mild to moderate. The most common grade 3/4 drug-related adverse events were neutropenia (8.9%) and anorexia (8.9%). The expression level of thymidylate synthase (TS) mRNA was significantly lower in patients who responded to treatment (t-test, P = .048), and progression-free survival was significantly longer in patients whose TS mRNA expression levels were below the median value, as compared with those with higher levels (log-rank test, P = .006).. S-1 is active against cytokine-refractory mRCC. Quantification of TS mRNA levels in tumors before treatment may facilitate prediction of the response of mRCC to S-1.

Topics: Aged; Antimetabolites, Antineoplastic; Carcinoma, Renal Cell; Dihydrouracil Dehydrogenase (NADP); Disease-Free Survival; Drug Combinations; Female; Gene Expression; Humans; Kidney Neoplasms; Male; Middle Aged; Neoplasm Recurrence, Local; Orotate Phosphoribosyltransferase; Oxonic Acid; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Salvage Therapy; Tegafur; Thymidine Kinase; Thymidine Phosphorylase; Thymidylate Synthase; Treatment Outcome

We present the first case report of the use of sorafenib and S-1 for the treatment of renal cell carcinoma (RCC) producing granulocyte colony-stimulating factor (G-CSF). This entity is clinically rare and has a poor outcome. A 78-year-old Japanese man presented with macrohematuria, left flank pain, and a palpable mass. Laboratory data showed marked leukocytosis with increased serum and urinary G-CSF. The histopathological diagnosis was unclassified RCC. New combination therapy with sorafenib and S-1 exerted a therapeutic effect and apparently decreased serum and urinary G-CSF levels, although the patient died of gastrointestinal perforation. The use of combined sorafenib and S-1 may be worthy of consideration in the treatment of RCC producing G-CSF.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Benzenesulfonates; Carcinoma, Renal Cell; Drug Combinations; Granulocyte Colony-Stimulating Factor; Humans; Kidney Neoplasms; Leukocytosis; Male; Medical Futility; Niacinamide; Oxonic Acid; Phenylurea Compounds; Pyridines; Sorafenib; Tegafur

Sorafenib, a multikinase and tyrosine-kinase inhibitor, has anti-tumor activity in patients with advanced renal cell carcinoma (RCC). Recently, we reported that S-1 was active and well tolerated for the treatment of cytokine-refractory metastatic RCC. Therefore, we hypothesized that S-1 might be a good candidate for combination therapy with molecular targeting agents. In this study, we examined the mechanisms underlying for the synergism between S-1 and Sorafenib for RCC treatment in vitro and in tumor-bearing murine models.. Human RCC cell lines were used for the in vitro cell proliferation assay. ACHN and 786-O tumors were subcutaneously transplanted into NCr-nu/nu-mice. Mice were treated with S-1 and/or Sorafenib, and tumor growth and side effects were monitored.. Synergistic anti-proliferative effects of Sorafenib and S-1 were clearly demonstrated in ACHN and 786-O cell lines in vitro due to the suppression of TS and E2F-1 expression. In the NCr-nu/nu model, the synergistic anti-tumor effects of S-1 and Sorafenib were again clearly seen, indicating direct synergistic effects of each drug on tumor growth.. Our results demonstrate the synergistic activity of S-1 and Sorafenib and provided the rationale for combination therapy with S-1 and Sorafenib for the treatment of patients with advanced RCC.

Topics: Animals; Antineoplastic Agents; Benzenesulfonates; Carcinoma, Renal Cell; Cell Line, Tumor; Drug Combinations; Drug Synergism; E2F1 Transcription Factor; Female; Fluorouracil; Humans; Kidney Neoplasms; Mice; Mice, Inbred BALB C; Niacinamide; Oxonic Acid; Phenylurea Compounds; Pyridines; RNA, Messenger; Sorafenib; Tegafur; Thymidylate Synthase

Topics: Antineoplastic Agents; Carcinoma, Renal Cell; Clinical Trials as Topic; Drug Combinations; Humans; Kidney Neoplasms; Oxonic Acid; Tegafur

We report herein a case with stage IV gastric cancer previously treated with TS-1 completely responding to second-line chemotherapy with weekly paclitaxel therapy. A 65-year-old female was diagnosed as having type 3 gastric cancer with para-aortic lymph node metastases. She underwent total gastrectomy with extended lymph node dissection on March 2003. Histopathological examination revealed that the tumor was poorly-differentiated adenocarcinoma with para-aortic lymph nodes metastases and completely resected. After the operation,she was treated by adjuvant chemotherapy with TS-1. In March of 2004, she suffered from hematuria, and a CT scan revealed para-aortic lymph nodes metastases and left kidney metastasis. Then, she was treated by a weekly infusion of paclitaxel as second-line chemotherapy. After 3 courses, the tumor disappeared and efficacy was judged as CR. Moreover, CR was maintained after 7 courses. At this writing in January of 2005, she is well and has been treated with paclitaxel without any severe adverse events. Therefore, weekly paclitaxel therapy was considered to be one of the promising second-line chemotherapies for advanced or recurrent gastric cancer previously treated by TS-1.

Topics: Adenocarcinoma; Aged; Antimetabolites, Antineoplastic; Antineoplastic Agents, Phytogenic; Chemotherapy, Adjuvant; Drug Administration Schedule; Drug Combinations; Female; Gastrectomy; Humans; Kidney Neoplasms; Lymph Nodes; Lymphatic Metastasis; Neoplasm Staging; Oxonic Acid; Paclitaxel; Pyridines; Remission Induction; Stomach Neoplasms; Tegafur