A randomized phase II clinical trial of tailored CPT-11 + S-1 vs S-1 in patients with advanced or recurrent gastric carcinoma as the first line chemotherapy

A randomized phase II clinical trial has been designed and started in the Japanese Foundation for Multidisciplinary Treatment of Cancer (JFMC) to select the better regimen between tailored CPT-11 + S-1 and the standard S-1 treatment for advanced or recurrent gastric cancer as the first line chemotherapy. Selection of the better treatment for general clinical practice in this clinical trial will lead to a more precise assignment of a promising regimen for a future phase III randomized trial, placing continuous 5-FU infusion as the reference arm. In this trial, subsidiary pharmacokinetic analysis for the tailored dose arm is also proposed. In order to continue chemotherapy for a long time and to obtain longer survival, our study design for the tailored therapy could be exploited, especially in the field of general clinical practice.     

A case of TS-1 resistant recurrent gastric cancer responding to TS-1 +CPT-11 combination therapy

A 71-year-old man underwent distal partial gastrectomy for gastric cancer. Four years after surgery, the tumor marker was elevated. Examinations by computed tomography (CT) revealed para-aortic lymphnode swelling and hydronephrosis. The patient treated oral administration of TS-1 (120 mg/day). After 3 courses of treatment of TS-1, progressive disease was observed. TS-1+CPT-11 (TS-1 120 mg/day day 1-14, CPT-11 100 mg/day day 1, 15) combination therapy was then chosen as second-line chemotherapy. After 5 courses of combination therapy, the tumor marker was decreased and para-aortic lymphnodes could not be detected by CT. Only grade 2 leukopenia was observed as an adverse event during the therapy. TS-1+CPT-11 combination therapy could be useful as the second-line chemotherapy for cases of TS-1 resistant recurrent gastric cancer.     

Second-line chemotherapy in gastric cancer following S-1 with CPT-11 chemotherapy performed as clinical trial

We previously conducted a phase I/II study of irinotecan (CPT-11) combined with S-1 as first-line chemotherapy for metastatic advanced gastric cancer. In the present study,second-line chemotherapy was given to 32 of 44 patients whose disease became refractory to this first-line treatment. Overall survival time of the patients given second-line chemotherapy was significantly longer than that of patients not given such therapy (444 days vs. 230 days, p = 0.013). The response rate to second-line chemotherapy was 13% (4/32). Survival time of patients who responded to second-line chemotherapy was significantly longer than that of non-responders. Second-line chemotherapy may produce a better clinical response in patients who have progressive disease during first-line chemotherapy. Overall survival time and time to progression after second-line chemotherapy did not significantly differ between patients who received second-line chemotherapy regimens including S-1 and those who received regimens not including S-1.     

Every-other-day TS-1 administration for recurrent or non-curative advanced gastric carcinoma

We report 3 cases in which palliation was achieved with every-other-day administration of TS-1 for recurrent or non-curative advanced gastric carcinoma that had resulted in obstructive jaundice. Two patients had received MTX-5-FU chemotherapy as first-line therapy and showed progressive disease, presenting with obstructive jaundice 6-24 months later. One of them experienced obstructive jaundice 2 months after surgery. After lowering serum bilirubin via per-cutaneous transhepatic biliary drainage (PTBD), TS-1 was given not in full dose but every other day based upon Shirasaka's theory, as well as for fear of further liver damage. Palliation in terms of long NC and/or decreased serum CEA level persisted for 4-14 months without severe liver dysfunction. Other side effects of the drug were negligible. Shirasaka's theory stresses the difference in proliferation cycles between cancer cells and normal tissue cells (GI tract, bone marrow, etc.); therefore, with every-other-day administration of chemotherapeutic agents, the cytotoxic effects against tumors would be augmented while the adverse reactions in normal cells could be reduced. The present experience seems to support the theoretical and clinical feasibility of every-other-day TS-1 administration for unresectable gastric cancer.     

A randomised multicentre phase II trial of capecitabine vs S-1 as first-line treatment in elderly patients with metastatic or recurrent unresectable gastric cancer

This randomised multicentre phase II study was conducted to investigate the activity and safety of two oral fluoropyrimidines, capecitabine or S-1, in elderly patients with advanced gastric cancer (AGC). Elderly (>or=65 years) chemo-naive patients with AGC were randomly assigned to receive capecitabine 1250 mg m(-2) two times daily on days 1-14 every 3 weeks or S-1 40-60 mg two times daily according to body surface area on days 1-28 every 6 weeks. Ninety-six patients were enrolled and 91 patients were randomised to capecitabine (N=46) or S-1 (N=45). Overall response rate, the primary end point, was 27.2% (95% CI, 14.1-40.4, 12 of 44 assessable patients) with capecitabine and 28.9% (95% CI, 15.6-42.1, 13 of 45) with S-1. Median times to progression and overall survival in the capecitabine arm (4.7 and 9.5 months, respectively) were similar to those in the S-1 arm (4.2 and 8.2 months, respectively). The incidence of grade 3-4 granulocytopenia was 6.8% with capecitabine and 4.8% with S-1. Grade 3-4 nonhaematologic toxicities were: asthenia (9.1% with capecitabine vs 7.1% with S-1), anorexia (6.8 vs 9.5%), diarrhoea (2.3 vs 0%), and hand-foot syndrome (6.8 vs 0%). Both capecitabine and S-1 monotherapies were active and tolerable as first-line treatment for elderly patients with AGC.     

Complete response of recurrent gastric cancer to chemotherapy with TS-1 and CPT-11--a case report

A 58-year-old man with gastric cancer who had undergone distal gastrectomy on February 8, 2001 was revealed to have anorexia, and was diagnosed with a local recurrence in anastomosis by upper GI examination in August 2003. In September 2003, he was given combination chemotherapy with TS-1 50 mg/m2 (days 1-14) and CPT-11 80 mg/m2 (days 1, 8) every 3 weeks. A complete response (CR) was confirmed by endoscopy in December 2003. At present, he has been receiving chemotherapy with only TS-1 50 mg/m2 as a maintenance therapy and continuing CR. However, a trial of combination therapy with TS-1 plus CPT-11 is ongoing, and this combination chemotherapy may well achieve a high response rate. Because the adverse events of this chemotherapy have been mild and tolerable in some of our cases, this regimen is considered very useful.     

Combination chemotherapy with S-1 plus CPT-11 for patients with advanced or recurrent colorectal cancer

Various kinds of combination chemotherapies with 5-FU as a base agent have been performed for patients with advanced or recurrent colorectal cancer. S-1 was a newly developed 5-FU derivative and was orally administered. One of the combination therapies with S-1 plus irinotecan (CPT-11) has also been expected to have a better therapeutic value. Recently this combination therapy has been undertaken by our department, and its clinical use and toxicities are described in this article.     

Clinical efficacy and safety of CPT-11+CDDP therapy as third-line chemotherapy for advanced and recurrent gastric cancer

The clinical efficacy and safety of CPT-11+CDDP therapy were studied retrospectively in 34 patients with advanced and recurrent gastric cancer. The overall response rate was 5. 9%; MST was 209 days. The adverse effects observed were grade 3 in 7 patients(20. 6%). CPT-11+CDDP therapy could be useful and safe as third-line chemotherapy.     

Gemcitabine plus vinorelbine as first-line chemotherapy in advanced nonsmall cell lung carcinoma a phase II trial

BACKGROUND: Response and survival in patients with advanced or metastatic nonsmall cell lung carcinoma (NSCLC) remain poor. As single agents, the nucleoside analog gemcitabine, and the semisynthetic vinca alkaloid vinorelbine, have been shown to be effective in NSCLC and to have a low toxicity profile. METHODS: Fifty-four chemotherapy-naive patients with NSCLC Stage IIIB (any TN3M0 or T4 any NM0) or IV (any T any NM1) were enrolled in this single-institution Phase II study. Gemcitabine 1250 mg/m(2) and vinorelbine 25 mg/m(2) were both administered on Days 1 and 8 every 3 weeks for up to 9 courses unless disease progression or severe toxicity required their discontinuation. RESULTS: Partial tumor regression was observed in 16 patients, for an overall response rate of 30% (95% confidence interval, 18.4-46.7%) on an intent-to-treat basis. The median time to progression was 5 months (range, 3-20). The median survival was 12 months (range, 5-42+); 1-year and 2-year survival rates were 49.1% and 17%, respectively. Hematologic toxicity was mild with only 11% of the patients developing Grade 3 neutropenia. None of the patients developed any Grade 4 toxicity. CONCLUSIONS: The combination of gemcitabine plus vinorelbine is feasible on an outpatient basis. The good activity and tolerability of the regimen make it a suitable candidate for further trials, using platinum-based regimens as comparators and possibly selecting elderly and less fit patients.     

A multi-center phase II study of S-1 plus paclitaxel as first-line therapy for patients with advanced or recurrent unresectable gastric cancer

Purpose  This study was conducted to evaluate the safety and efficacy of S-1 and paclitaxel combination therapy for patients with advanced gastric cancer. Methods  Eligible patients had previously untreated advanced or relapsed gastric cancer with measurable lesion(s) and an ECOG PS of 0-2. Treatment consisted of S-1 35 mg/m² p.o. b.i.d. on days 1–14 followed by a 7-day off plus paclitaxel 70 mg/m² i.v. on days 1 and 8 of a 21-day cycle. Results  Fifty-six patients (M/F = 37/19) were enrolled. The median age was 59 years. The median number of cycles administered was six (range 1–18). Out of the 53 patients evaluated, there was 1 (1.9%) CR, 20 (37.7%) confirmed PRs, 5 (9.4%) unconfirmed PRs, 21 (39.6%) SDs, and 6 (11.3%) PDs. The objective tumor response was 39.6%. The median time to progression was 29 weeks. The median survival was 51 weeks. All 56 patients were assessed for treatment safety. The treatment was well tolerated with grade 3/4 neutropenia in 20%/13%, grade 3 febrile neutropenia in 7%, grade 2/3 diarrhea in 9%/4%, vomiting in 11%/0%, stomatitis in 4%/4%, and neuropathy in 4%/0% of patients. Conclusions  S-1 and paclitaxel combination treatment is an effective regimen with a favorable toxicity profile in patients with advanced gastric cancer.     

Second-or third-line chemotherapy with CPT-11+TS-1 for 5 cases of metastatic and recurrent colorectal cancer

The 3-drug regimen of CPT-11+5-FU+l-LV is generally used for metastatic and/or recurrent colorectal cancer. We have applied this treatment as the first-line intervention in our hospital. However,when the efficacy is reduced we try chemotherapy using CPT-11+TS-1 for 5 outpatients as second- or third-line chemotherapy. Decreased CEA levels were subsequently observed in 4 of 5 cases. In addition, 2 cases exhibited grade 1 or 2 adverse effects, but no case developed neutropenia. We could expect such effects even for patients after only 5-FU, and this treatment may be performed safely on ambulatory patients.     

Combination of irinotecan (CPT-11) plus oxaliplatin (L-OHP) as first-line treatment in locally advanced or metastatic gastric cancer: a multicentre phase II trial.

BACKGROUND: The purpose of this study was to evaluate the efficacy and tolerance of irinotecan (CPT-11) in combination with oxaliplatin (L-OHP) as first-line treatment in patients with locally advanced or metastatic gastric cancer (AGC). PATIENTS AND METHODS: Thirty-two patients with AGC who had not received previous therapy for metastatic disease were enrolled. The median age was 62.5 years and the World Health Organization performance status was 0-1 in 29 patients; 13 (40.6%) patients had previous surgery and three (9.4%) had adjuvant chemotherapy. L-OHP (85 mg/m2 as a 2-h i.v. infusion) followed by CPT-11 (200 mg/m2 as a 30-min i.v. infusion) was given on day 1, in cycles of 21 days. RESULTS: All patients were evaluable for toxicity and 31 were evaluable for response. Complete response was achieved in one (3.1%) patient and a partial response was achieved in 15 (46.9%) [overall response rate = 50% (95% confidence interval 38.7-72.4%)]. Eight (25%) patients had stable disease, and eight (25%) had progressive disease. The median duration of response was 5 months and the median time to disease progression was 5.5 months. After a median follow-up period of 16 months, the median survival time was 8.5 months. Grade 3-4 neutropenia occurred in six (18.6%) patients, febrile neutropenia in two (6.2%) and grade 3 anaemia in one (3.1%). Grade 3 diarrhoea was observed in two (6.2%) patients, grade 1 neurotoxicity in five (15.6%) and grade 3 asthenia in two (6.2%). There was no treatment-related death. CONCLUSIONS: The combination of CPT-11/L-OHP is an active regimen as front-line treatment in AGC with a favourable toxicity profile and deserves further evaluation in randomised studies.     

CPT-11 plus cisplatin in patients with advanced, untreated gastric or gastroesophageal junction carcinoma: results of a phase II study

BACKGROUND: This Phase II study assessed the response rate and toxicity profile of the combination CPT-11 and cisplatin administered weekly to patients with untreated, advanced adenocarcinoma of the stomach or the gastroesophageal junction. METHODS: Patients with histologic proof of adenocarcinoma of the stomach or the gastroesophageal junction with adequate liver, kidney, and bone marrow functions were treated with 65 mg/m(2) CPT-11 plus 30 mg/m(2) cisplatin, both administered intravenously 1 day per week for 4 consecutive weeks, followed by a recovery period of 2 consecutive weeks. The response rate, time to disease progression, survival, and toxic effects were analyzed. RESULTS: Thirty-six of 38 registered patients (95%) were assessable. The median number of 6-week cycles per patient was 2.5 (range, 1-7 6-week cycles). Four patients (11%) achieved a complete response, and 17 patients (47%) had a partial response for an overall response rate of 58%. The median time to progression of carcinoma was 24 weeks, and the median survival was 9 months (range, 1-23+ months). There was one treatment-related death. Major toxic effects included diarrhea, neutropenia, and fatigue. Ninety percent of all planned doses were delivered on time; however, 53 of 79 canceled or delayed weekly doses (66%) occurred in the third or fourth week of the therapy cycle. CONCLUSIONS: The combination of CPT-11 and cisplatin is active against gastric or gastroesophageal adenocarcinoma and needs to be studied further. A modification in doses and schedules may be warranted to make the regimen more tolerable to patients. The addition of other active drugs or radiation therapy to this regimen would be of interest.     

Usefulness of TS-1 and lentinan combination immunochemotherapy in advanced or recurrent gastric cancer--pilot study aiming at a randomized trial

The quality of life (QOL) of patients with advanced or recurrent gastric cancer is poor and their immunocompetence is low, making it important to conduct chemotherapy while at the same time improving their QOL and maintaining their immunocompetence. To improve QOL and increase compliance by reducing the side effects but not the antitumor effect of TS-1, a 2-week regime with 2-week administration of TS-1, and a 1-week drug-free interval in combination with the immunotherapeutic agent lentinan (LNT) was started in 5 patients with advanced or recurrent gastric cancer. Toxicity, efficacy, QOL, and immunological parameters were investigated preliminarily to examine whether or not usefulness of lentinan could be evaluated. QOL scores for appetite, nausea/vomiting, and abdominal pain/diarrhea showed improvement, although not in statistically significant values. The Th2 (CD4-positive, IL4-positive T cells) response in peripheral blood decreased significantly. TS-1 and lentinan combination immunotherapy was carried out safely with advanced recurrent gastric cancer. In order to examine the usefulness of LNT combined use, it was thought that a randomised trial using toxicity with not only efficacy but QOL and immunological parameters as indicators would be beneficial.     

Phase II trial of cisplatin as first-line chemotherapy in patients with advanced or recurrent uterine sarcomas: a Gynecologic Oncology Group study

Ninety-six assessable patients with advanced or recurrent uterine sarcomas, who were no longer controllable with surgery and radiotherapy, and who had not received prior chemotherapy were treated with cisplatin 50 mg/m2 intravenously every 3 weeks. Of 63 cases with mixed mesodermal tumors, five complete responses (CRs; 8%) and seven partial responses (PRs; 11%) were observed (95% confidence interval [CI], 10.3% to 30.9%). Of 33 patients with leiomyosarcoma, one PR (3%) was observed (95% CI, .1% to 15.8%). Adverse effects included leukopenia (23%), nausea and vomiting (73%), and mild azotemia (42%). No patients experienced life-threatening toxicity. Cisplatin has definite activity when given at the dose and schedule that we tested for patients with mixed mesodermal sarcomas who have not received prior chemotherapy, but has little activity in patients with leiomyosarcoma.     

Multicenter phase II trial of combination chemotherapy with weekly paclitaxel and 5-fluorouracil for the treatment of advanced or recurrent gastric carcinoma

The aim of this study was to investigate the efficacy and safety of combination chemotherapy with weekly paclitaxel and 5-fluorouracil (5-FU) as first-line treatment in patients with advanced or recurrent gastric carcinoma. A total of 65 patients were treated with the following regimen, administered every 28 days; 5-FU 600 mg/m2 by 24-hour continuous infusion from days 1 through 5, and weekly paclitaxel 80 mg/m2 by 3-hour intravenous infusion on days 8, 14, and 21. A total of 272 cycles were conducted with a median of 4 (2-13) cycles per case. Out of 57 patients with measurable disease by RECIST criteria, there were 2 complete responses (3.5%), 20 partial responses (35.1%) and 25 cases with stable disease (43.9%). The overall response rate was 38.6% (95%CI: 26.0-51.2%). The median survival time and 1-year survival rates were 329 days and 47.4%, respectively. Both hematologic and non-hematologic toxicities were well tolerated.     

Phase II tailored S-1 regimen study of first-line chemotherapy in elderly patients with advanced and recurrent non-small cell lung cancer

Purpose

We investigated the efficacy and toxicity of a novel oral 5-fluorouracil (5-FU) formulation (S-1), administered according to a tailored dose regimen.

Methods

S-1 was administered orally for 28?days, followed by 14?days of no treatment, in 23 patients who received a tailored dose of S-1, adjusted on the basis of individual creatinine clearance and body surface area. In 8 of the patients, pharmacokinetic study was performed on the 6 points on 7th day after S-1 administration.

Results

Of the 23 patients enrolled in this study, 2 (8.7?%) had a partial response and 14 (60.9?%) had stable disease. The disease control rate was 69.6?% (16/23) (95?% confidence interval, 50.8?C88.4?%). Grade 3/4 hematologic and non-hematologic toxicities were minor. In the pharmacokinetic study group, the maximum plasma concentration (C _max) and the area under the plasma concentration curve of 5-FU at all 6 points after administration of the tailored S-1 dose regimen were similar to the values reported in a previous study describing cancer patients with normal renal function who received a standard dose of S-1 (80?mg/m²/day).

Conclusions

Our results suggest that tailored S-1 monotherapy is safe and therapeutically useful as first-line treatment for elderly patients with advanced and recurrent non-small cell lung cancer.     

Randomized phase II study comparing paclitaxel with S-1 vs. S-1 as first-line treatment in patients with advanced gastric cancer

Purpose

This randomized phase II study was conducted to compare the efficacy and safety of paclitaxel with S-1 (PS) vs. S-1 in patients with advanced gastric cancer (AGC).

Methods

Eighty-two (82) patients were 1:1 randomly assigned to oral S-1 (daily for 2 weeks, every 4 weeks’ cycle) or S-1 (daily for 2 weeks, every 4 weeks’ cycle) plus paclitaxel (on day 1, 8 and 15 of a 4 weeks’ cycle). S-1 was orally administered with a fixed quantity according to body surface area (BSA), while paclitaxel was given 60 mg/m² i.v. daily through an implanted catheter. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), overall responsible rates and safety.

Results

The median OS with PS versus S-1 monotherapy was 14.0 versus 11.0 months (P = 0.02), survival at 12 months was 61.0 % in the PS group and 46.3 % in the S-1 group. Median PFS was also significantly longer in the PS group (6.0 months) than in the S-1 group (4.0 months). The overall response rate was determined in 82 evaluable patients, and was significantly higher (P = 0.04) with PS (19 patients, 46.3 %) than with S-1 monotherapy (10 patients, 24.4 %). PS was well tolerated with no treatment-related deaths, all were grade 3–4 gastrointestinal toxicities, including anorexia, nausea, and diarrhea developed in less than 10 % of the patients.

Conclusions

Combination chemotherapy of paclitaxel with S-1 is well tolerated and active in AGC patients. Further investigation with comparative trials is needed for confirmation.