Phase I study of S-1 and biweekly docetaxel combination chemotherapy for advanced and recurrent gastric cancer

A phase I study of S-1 and biweekly docetaxel (DOC) combination therapy was conducted to determine the maximum tolerated dose (MTD) and pharmacokinetic parameters. Fourteen patients with advanced or recurrent gastric cancer were analyzed. The treatment consisted of S-1 [body surface area (BSA) <1.25 m2:80 mg/day, 1.25相似文献   

Combination chemotherapy study of biweekly paclitaxel and S-1 administration in patients with advanced gastric cancer

In the present article, we report the results of phase I/II combination chemotherapy study of biweekly paclitaxel and S-1 administration in patients with advanced gastric cancer. In the phase I study, we could determine the recommended dose for the phase II study with paclitaxel and S-1 to be 120 mg/m2 and 80 mg/m2, respectively. The side effect was not so severe. The overall response was 53%. In conclusion, biweekly paclitaxel and S-1 administration can be safely combined for the treatment of advanced gastric cancer. This combined therapy represents a novel and active treatment regimen with low toxicity and can be defined as safe and effective. Now we are analyzing the result of the phase II study.     

Effective salvage chemotherapy with S-1 alone in a patient with lung metastasis of breast cancer

A patient with lung metastasis of breast cancer was reported. The patient underwent surgery in December, 1999. Her breast cancer then recurred in December, 2000. After treatment failure with anthracycline and taxane antitumor drugs,she participated in a phase II study of S-1, a fluorinated pyrimidine anticancer drug, which was given orally at 80 mg/m2/day (2 doses). After completion of 4 courses of treatment,the target lesions of the lung metastasis markedly shrunk by 47.5% as compared with the pretreatment. Because salvage therapy with S-1 alone showed good antitumor efficacy and beneficial tolerability when the standard dosage was maintained, it was considered that this home therapy was effective for advanced/recurrent breast cancer that was resistant to anthracycline and taxane antitumor drugs.     

A case of advanced gastric cancer successfully treated by combination therapy of S-1 and docetaxel

A 70-year-old man with gastric cancer of Borrmann type 3, liver metastases and peritoneal dissemination was treated by combination therapy of S-1 and docetaxel (DOC). He received DOC intravenously at 40 mg/m(2) on day 1 and S-1 orally at 100 mg/body on day 1 to 14, repeated every 28 days. After 2 courses of treatment, a CT scan revealed improvement of the gastric wall thickness, the eminent decrease of the peritoneal fluid and the reduction of the liver metastasis. After 3 courses of treatment, the primary lesion was remarkably improved on endoscopic examination, and the tumor marker normalized after 4 courses of treatment. Toxicities included leukocytopenia (WHO grade 3), neutropenia ( grade 3), anorexia (grade 2), and nausea (grade 2). Outpatient chemotherapy was possible by reduction of dose (S-1 100--> 80 mg/body, DOC 40--> 32 mg/m2). The response was maintained on CT and endoscopic examination after 21 courses of treatment. A case of an advanced gastric cancer patient successfully treated by combination therapy of S-1 and DOC was reported.     

Irinotecan plus oral S-1 in patients with advanced colorectal cancer--biweekly IRIS regimen

We planned to conduct a phase II clinical study of combination therapy with CPT-11 and S-1. The antitumor effect was the primary endpoint, while the safety, progression-free survival time, and median survival time were the secondary endpoints. The subjects were untreated patients with inoperable advanced colorectal cancer aged 20-75 years. Based on the results of our previous phase I/II study in patients with gastric cancer, the dosage was established in consideration of safety for outpatient therapy. CPT-11 was administered at a dose of 100 mg/m2 (on days 1 and 15) as an intravenous infusion over 90 minutes, and oral S-1 (40 mg/m2) was administered after breakfast and dinner and then withdrawn for 2 weeks. No other serious adverse reactions occurred (either hematological or non-hematological), and all patients could receive therapy safely on an outpatient basis. Interim analysis suggested excellent results, with a response rate of 50%. Combination therapy with CPT-11 and S-1 achieved a high response rate and could be given safely. These findings suggest that the therapy has potential as first-line treatment for inoperable advanced recurrent colorectal cancer.     

Combination therapy with S-1 plus docetaxel (DOC) for previously treated patients with non-small cell lung cancer

The present paper presents a review of the second-line treatment of non-small cell lung cancer (NSCLC) and reports a phase I study of the combination chemotherapy of docetaxel (DOC) and S-1 as second-line chemotherapy. Current options for the second-line treatment of NSCLC include cytotoxic drugs, such as DOC, pemetrexed, and targeted therapies. However, single-agent chemotherapy has shown limited activities. A new treatment approach is needed for this patient population. We hypothesized that combination chemotherapy of DOC and S-1 would be effective through the additive and synergistic activities. We performed a phase I clinical trial of this combination chemotherapy. S-1 was administered orally at a dose of 80 mg/m2 for 14 days, followed by a drug-free interval of a week (one cycle). The starting dose level (level 1) of DOC was set to 40 mg/m2, until a dose of 60 mg/m2 was reached at level 3. Three patients were treated with level 2, in which the dose of DOC was increased up to 50 mg/m2. Two of 3 patients had grade 4 neutropenia, which was determined as dose-limiting toxicity. The dose level of DOC 40 mg/m2 on day 1 in combination with S-1 80 mg/m2 for 14 days of a three week cycle was recommended for a phase II study. Partial response was achieved in 4 of the 9 patients. This combined chemotherapy consisting of S-1 and DOC may prove effective for treating recurrent cases of NSCLC. A phase II study is ongoing.     

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)

Background  

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.     

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

The aims of this phase I/II study of docetaxel and S-1 were to determine the dose-limiting toxicity (DLT), maximum-tolerated dose (MTD), and recommended dose (RD) in the phase I part and to explore the tumour response, survival and safety in the phase II part. Patients with histologically- or cytologically confirmed unresectable or recurrent gastric cancer were eligible. Treatment consisted of intravenous docetaxel on day 1 (starting dose 50 mg m(-2)) and oral S-1 at a fixed dose of 40 mg m(-2) twice daily on days 1-14, every 4 weeks up to six cycles. Nine patients took part in the phase I portion of the study. The MTD of docetaxel was determined to be 50 mg m(-2), with the DLTs of grade 3 infection associated with grade 3 neutropenia and grade 4 neutropenia during S-1 administration. The RD of docetaxel was 40 mg m(-2) in combination with S-1 40 mg m(-2) b.i.d. The efficacy and safety of this regimen was therefore assessed in 46 patients with at least one measurable lesion. The overall response rate and estimated median overall survival were 46% (95% CI, 31-61%) and 14.0 months (8.3-17.3 months), respectively. The most common grade 3/4 toxicity was neutropenia (67% of patients), which was predictable and manageable. This regimen showed promising activity with moderate toxicities in advanced gastric cancer.     

Combination chemotherapy of S-1 and taxanes in Korea

Various combination treatments incorporating S-1 are undergoing clinical trials in Korea, especially combinations with taxane, oxaliplatin, or irinotecan. In a phase I study to estimate the maximum tolerated dose of docetaxel in combination with S-1 administered at a fixed dose of 40 mg/m² twice daily on days 1–14 of each 3-week cycle in patients with advanced gastric cancer, 60 mg/m² docetaxel was declared to be the maximum tolerated dose. A phase I/II study of the same schedule of combination chemotherapy with S-1 plus docetaxel reported doses of S-1/docetaxel of 40/75 mg/m² as the maximum tolerated dose. In a phase I study of S-1 plus weekly docetaxel, the patients received variable doses of docetaxel administered intravenously over 1 h on days 1 and 8 and S-1 administered on days 1–14 of each 3-week cycle. The maximum-tolerated doses of S-1 and docetaxel were determined to be 45 mg/m² and 35 mg/m² in this study. A phase I/II study of docetaxel plus S-1 combination chemotherapy from Korea reported a response rate of 43.3%. Also, a phase II study of paclitaxel plus S-1 as first-line therapy in patients with advanced or relapsed gastric cancer showed an overall response rate of 49%. The most frequent significant toxicities in combination chemotherapies with taxane plus S-1 were neutropenia and febrile neutropenia. However, nonhematological toxicities were mild to moderate. A taxane plus S-1 combination regimen could be a new standard regimen for advanced gastric cancer, given its significant activity and favorable toxicity pattern.     

Three cases of advanced gastric cancer successfully treated by combination therapy of biweekly S-1 and docetaxel

We report three cases of advanced gastric cancer successfully treated by combination therapy of S-1 and docetaxel (DOC). We administered S-1 orally at 80 mg/m2 on days 1 to 7 and days 15 to 21, and DOC intravenously at 40 mg/m2 on day 1 and 15, and evaluation was conducted every two courses. Case 1: A 73-year-old man with gastric cancer of cT4a, accompanied with bulky N2 lymph node metastasis, was treated with two courses of S-1 and DOC. Partial response was confirmed, followed by total gastrectomy, which revealed his histological grade to be 1b. Case 2: A 65-year-old man with gastric cancer of cT4a, accompanied with bulky lymph node metastasis, was treated with two courses of S-1 and DOC. Partial response was confirmed, followed by distal gastrectomy, which revealed his histological grade to be 1b. Case 3: A 76-year-old woman with gastric cancer of cT4b (panc), was treated with four courses of S-1 and DOC. After that, the main tumor was judged to be cT4a, followed by total gastrectomy, which revealed her histological grade to be 1b. Combined S-1 and DOC chemotherapy is an effective regimen for the treatment of unresectable gastric cancer.     

A phase I combination chemotherapy study of biweekly paclitaxel and S-1 administration in patients with advanced gastric cancer

The aim of the current study was to determine the maximum tolerated dose (MTD) and the dose limiting toxicity (DLT) of a combination of paclitaxel and S-1 in patients with advanced gastric cancer. Fifteen patients were enrolled. The dose for S-1 was set at 80 mg/m²/day (days 1–14), while the dose for paclitaxel increased by 10 mg/m² for every three patients, with a starting dose of 100 mg/m² and was given biweekly on day 1 and 15. There was no severe toxicity (grade 4) recorded in patients receiving up to 120 mg/m² of paclitaxel. Leukopenia/neutrophilia with grade 1 to 3 occurred in six patients up to level 3. At 130 mg/m² of paclitaxel, grade 4 leukocytopenia and neutropenia events and grade 3 diarrhea developed in one out of three patients. One patient in another group of three patients that were enrolled at level 3, developed grade 4 granulocytopenia with fever (a body temperature higher than 38°C) and grade 3 leukocytopenia. Eight patients, out of a total of 15, showed a partial response, resulting in an objective response rate of 53%. Five patients received gastrectomy. Median survival time was 428 days and the 1 year survival rate was 53%. Biweekly paclitaxel/S-1 combination chemotherapy could be safely used for the treatment of advanced gastric cancer. The recommended doses for a phase II study with paclitaxel and S-1 are 120 mg/m² and 80 mg/m², respectively.     

A randomized phase II trial to elucidate the efficacy of capecitabine plus cisplatin (XP) and S-1 plus cisplatin (SP) as a first-line treatment for advanced gastric cancer: XP ascertainment vs. SP randomized PII trial (XParTS II)

ABSTRACT: BACKGROUND: On the basis of international clinical trials, capecitabine plus cisplatin (XP) as a first-line treatment of advanced gastric cancer is considered a global standard regimen. However, the usefulness of XP as compared with S-1 plus cisplatin (SP), which is considered standard therapy in Japan, has not yet been assessed. METHODS: This is a multicenter randomized phase II trial to elucidate the efficacy of XP as compared with SP for first-line treatment of advanced gastric cancer. Patients with unresectable metastatic or recurrent gastric cancer, 20-74 years of age and human epidermal growth factor 2 (HER2)-negative status, will be assigned in a 1:1 ratio to receive either S-1 40mg/m2 bid for 21days plus cisplatin 60 mg/m2 (day 8) every 5-week cycle or capecitabine 1000mg/m2 bid for 14days plus cisplatin 80 mg/m2 (day 1) every 3-week cycle. Patients will be also asked to the analysis of tumor tissues for translational investigations. The Primary endpoint is progression-free survival and secondary endpoints are overall survival, time to treatment failure, tumor response rate and safety. These comparisons will also be evaluated in terms of biomarkers. Planned sample size is 100 (50 in each arm), which is appropriate for this trial. DISCUSSION: Fluoropyrimidine plus cisplatin combination is the standard regimen of the first line treatment for advanced gastric cancer. Both S-1 and capecitabine are the prodrug of 5-FU but differ from their process of metabolism. Result of this trial and translational research will provide the important clues to prepare the individualized therapy for advanced gastric cancer in the near future. Trial Registration: ClinicalTrials.gov Identifier NCT01406249.     

Salvage chemotherapy of biweekly irinotecan plus S-1 (biweekly IRIS) in previously treated patients with advanced gastric cancer

Purpose  

This phase II trial first describes the combination chemotherapy of biweekly irinotecan plus S-1 (biweekly IRIS) for pretreated advanced gastric cancer (AGC) patients.     

Three cases of gastric cancer treated by S-1 combined with docetaxel in place of cisplatin

Although combination of S-1 and cisplatin (CDDP) is a standard therapy for advance or recurrent gastric cancer patients, there are some cases where a CDDP administration is difficult for patients. We here report three such cases of gastric cancer treated by S-1 and docetaxel (DOC) combination therapy. Based on our three cases, we believe that S-1 and DOC combination therapy could be suitable for outpatients showing safety and efficacy.     

Phase I/II trial of combination therapy with S-1 and weekly paclitaxel in patients with unresectable or recurrent gastric cancer

Purpose  We aimed to examine the safety and antitumor effects of a combination of S-1 and paclitaxel in patients with unresectable or recurrent gastric cancer in a phase I/II setting. Patients and methods  The study was designed as a phase I/II clinical trial. In phase I portion, the dose of paclitaxel was escalated to estimate the maximum-tolerated dose (MTD) and recommended dose (RD) of paclitaxel with fixed dose of S-1. S-1 (daily dose, 80 mg/m²) was given orally on days 1–21 every 35-day cycle (rest on days 22–35). Paclitaxel was administered intravenously on days 1, 8 and 15, at an initial dose of 40 mg/m², stepping up to 70 mg/m² in 10-mg/m² increment. Dose-limiting toxicity (DLT) was defined as grade 4 hematological toxicity, grade 3 or higher nonhematological toxicity, and treatment discontinuation due to adverse reactions during the first course of treatment. In phase II portion, the efficacy and toxicity at the RD of paclitaxel with S-1 were assessed. Results  The MTD of paclitaxel was estimated to be 60 mg/m², because >33.3% of patients (2/3) developed DLTs. DLT included postponement of treatment due to grade 2 neutropenia, and grade 3 stomatitis, anorexia, and nausea. Therefore, the RD of paclitaxel was estimated to be 50 mg/m². In the phase II portion, 22 patients were evaluated with 50 mg/m² paclitaxel and 80 mg/m² S-1 in a 35-day cycle. The response rate was 54.5% (95% CI, 32.2–75.6%). The median survival time was 283 days (95% CI, 218–508 days). The median number of treatment courses was 4 (range 1–10), indicating that this regimen could be given repeatedly. Conclusions  This phase I/II trial of combination therapy with S-1 and paclitaxel in patients with unresectable or recurrent gastric cancer showed that this regimen has substantial antitumor activity and can be given safely.     

Clinical efficacy of biweekly paclitaxel and S-1 regimen for 14 gastric cancer patients with liver metastases

We evaluated efficacy of biweekly paclitaxel and S-1 for advanced gastric cancer patients with liver metastases. A total of 14 patients had multiple liver metastases. None of whom received chemotherapy before the current regimen. The patients were given 80 mg-130 mg/m(2) of paclitaxel every two weeks and 80 mg of S-1 during the first two weeks. Chemotherapeutic efficacy for liver metastases was 50%. The 3-year-survival rate of the 14 patients was 50%, which was significantly higher than that of historical control patients (p<0.01). Two patients received gastrectomy with curative intent. Histological exploration revealed disappearance of liver metastases. In conclusion, biweekly paclitaxel+S-1 regimen was one of the promising therapies for advanced gastric cancer patients with liver metastases.     

Effects of Intermittent 5-Fluorouracil and Low-dose Cisplatin Therapy on Advanced and Recurrent Gastric Cancer

BACKGROUND: Although combination therapy consisting of 5-fluorouracil (5-FU) and cisplatin for the treatment of gastric cancer has been reported, no consistent regimen has been established. Our aim was to determine the optimal treatment schedule of this therapy, for patients with advanced or recurrent gastric cancer. PATIENTS AND METHODS: We conducted a phase II study to evaluate the efficacy and safety of combination therapy consisting of intermittent 5-FU and low-dose cisplatin in 26 patients with advanced or recurrent gastric cancer. The treatment cycle consisted of intravenous cisplatin at 3.3 mg/m(2)/day for 5 consecutive days. 5-FU was administered as a continuous intravenous infusion at 300-500 mg/body every other day (days 1, 3, 5) for 4 weeks. RESULTS: The partial response rate was 34.6%. The median survival duration was 12.8 months and the one-year survival was 53.1%. There were a few adverse effects. CONCLUSION: Our results suggest that this mode of combination therapy led to a fairly favorable outcome for patients with advanced or recurrent gastric cancer.     

A case of advanced gastric cancer which has kept partial response with the fifth-line chemotherapy

We report a case of a 48-year-old male with advanced gastric cancer. A total gastrectomy was performed for cancer of remnant stomach. S-1 was administered for cytological cancer cells detected by abdominal cavity lavage as the first-line chemotherapy. After 2 cycles of S-1, cervical lymph nodes were enlarged, and the patient underwent paclitaxel monotherapy as the second-line chemotherapy. After 8 cycles, Virchow lymph nodes were enlarged. The regression of Virchow lymph nodes were observed with a S-1 /CPT-11 combination therapy as the third-line chemotherapy and DOC/CPT-11 as the fourth-line chemotherapy. We then used a combination chemotherapy of CPT-11 60 mg/m2 and CDDP 30 mg/m2 at day 1 and 15, every 4 weeks as the fifth-line chemotherapy. A partial response was achieved after 2 cycles, and has been continued for 7 months. The hematological toxicities and the non-hematological toxicities of grade 2 or higher were not observed. This regimen may be effective for patients with advanced gastric cancer resistant to prior chemotherapy with several agents.     

Latest progress on chemotherapy for advanced gastric cancer

Although recent phase II studies have demonstrated high antitumor activity in the treatment of advanced gastric cancer, no significant survival benefit has been clearly demonstrated yet, when compared with 5-FU alone. More recently, a number of new agents including irinotecan and S-1 have demonstrated significant activity against gastric cancer as single agent or in combination with other chemotherapeutic agents. A phase III trial of 5-FU alone versus irinotecan plus cisplatin versus S-1 alone in advanced gastric cancer patients will be initiated in Japan Clinical Oncology Group (JCOG) within a few months. These new regimens have a potential becoming a new standard chemotherapy for the treatment of gastric cancer. The patients with peritoneal dissemination has usually not yet evaluated and explored from clinical study because of risk of toxicity and having no measurable disease. A next randomized phase III trial comparing 5-FU alone with sequential methotrexate and 5-fluorouracil in patients with peritoneal metastasis will be initiated in JCOG next year. The development of molecular biology has demonstrated the molecular mechanisms of chemoresistance or chemosensitivity, as well as a number of molecular targets against cancer cells. To date, many molecular targeted agents are being evaluated in various stages of clinical testing. These advances may provide a possibility of tailor made treatment.     

Phase I/II study of S-1 combined with paclitaxel in patients with unresectable and/or recurrent advanced gastric cancer

Both paclitaxel and S-1 are effective against gastric cancer, but the optimal regimen for combined chemotherapy with these drugs remains unclear. This phase I/II study was designed to determine the maximum tolerated dose (MTD), recommended dose (RD), dose-limiting toxicity (DLT), and objective response rate of paclitaxel in combination with S-1. S-1 was administered orally at a fixed dose of 80 mg m-2 day-1 from days 1 to 14 of a 28-day cycle. Paclitaxel was given intravenously on days 1, 8, and 15, starting with a dose of 40 mg m-2 day-1. The dose was increased in a stepwise manner to 70 mg m-2. Treatment was repeated every 4 weeks unless disease progression was confirmed. In the phase I portion, 17 patients were enrolled. The MTD of paclitaxel was estimated to be 70 mg m-2 because 40% of the patients given this dose level (two of five) had DLT. The RD was determined to be 60 mg m-2. In the phase II portion, 24 patients, including five with assessable disease who received the RD in the phase I portion, were evaluated. The median number of treatment courses was six (range: 1-17). The incidence of the worst-grade toxicity in patients given the RD was 28 and 8%, respectively. All toxic effects were manageable. The response rate was 54.1%, and the median survival time was 15.5 months. Our phase I/II trial showed that S-1 combined with paclitaxel is effective and well tolerated in patients with advanced gastric cancer.