Phase II study of biweekly docetaxel and S-1 combination chemotherapy as first-line treatment for advanced gastric cancer

Purpose

We evaluated the efficacy and toxicity of biweekly S-1 and docetaxel combination therapy in patients with advanced gastric cancer.

Methods

Patients with histologically proven, unresectable advanced or recurrent gastric cancer, a performance status (PS) of 0?C2 and no prior chemotherapy history were eligible for inclusion (n?=?45). Patients received a total of 215 treatment courses (median, 4; range, 2?C12) of S-1 oral administration twice daily for 1?week followed by a drug-free interval of 1?week. Docetaxel (40?mg/m²) was administered intravenously on days 1 and 15.

Results

We observed 25 partial responses (55.6%) and one complete response (2.2%), resulting in an overall response rate of 57.8%. Twenty-four patients (53.3%) received second-line chemotherapy. Five patients (11.1%) underwent R0 gastrectomy during the course of the study. The median overall survival time was 15.3?months, the median time to progression was 6.9?months, and the median duration of response in 26 patients was 8.0?months. Neutropenia was the most frequently observed (40.4%) haematological toxicity at grades 3 and 4 and leucopenia was the second most common (29.8%). There were no treatment-related deaths.

Conclusions

S-1 plus docetaxel combination therapy in an outpatient setting provided promising activity with acceptable adverse toxicities.     

A multicenter phase II study of combined chemotherapy with docetaxel, cisplatin, and S-1 in patients with unresectable or recurrent gastric cancer (KDOG 0601)

Purpose

We conducted a phase II study to evaluate the efficacy and safety of a triplet regimen of docetaxel, cisplatin, and S-1 in patients with unresectable or recurrent gastric cancer.

Methods

Docetaxel (40?mg/m²) and cisplatin (70 or 60?mg/m²) were given on day 1 of a 28-day cycle. S-1 (40?mg/m²) was given twice daily on days 1?C14. Treatment with this regimen was continued for a maximum of 6 cycles. Subsequently, patients with no disease progression received a combination of docetaxel and S-1.

Results

Fifty-nine patients were enrolled. The median number of administered cycles was 8 (range, 1?C25). Because some patients had serious myelosuppression and renal dysfunction with 70?mg/m² of cisplatin, dose of cisplatin was reduced to 60?mg/m² after 19 patients had been treated. Common severe toxic effects of grade 3 or 4 were leukocytopenia (44%), neutropenia (72%), anemia (15%), and febrile neutropenia (14%). The overall response rate of this group was 81% (95% confidence interval (CI), 71?C91%). The median overall survival and progression-free survival were 18.5 (95% CI, 15.6?C21.5) and 8.7 (95% CI, 6.7?C10.7) months, respectively.

Conclusions

Triplet of docetaxel, cisplatin, and S-1 is a well-tolerated and highly active regimen for advanced or recurrent gastric cancer. A 60?mg/m² of cisplatin is as effective as 70?mg/m² of cisplatin.     

Phase II study of S-1 and docetaxel for previously treated patients with locally advanced or metastatic non-small cell lung cancer

Purpose

The purpose of the present phase II study was to evaluate both the efficacy and toxicity of the combination of S-1 and docetaxel in previously treated patients with locally advanced or metastatic non-small cell lung cancer.

Methods

Thirty-eight previously treated patients with non-small cell lung cancer were treated with S-1 (80 mg/m², days 1–14, oral) and docetaxel (40 mg/m², day 1, intravenous) every 3 weeks.

Results

No complete response was observed, and seven patients had a partial response, yielding an overall response rate of 18.4% (95% CI, 7.7–34.3%). The median overall survival time and 1-year overall survival rate were 16.1 months and 60%, respectively. The median progression-free survival time was 4.4 months. Myelosuppression was the main toxicity with grade 3 or 4 neutropenia and leukopenia in 50 and 21%, respectively. There was no irreversible toxicity in this study.

Conclusions

The combination of S-1 and docetaxel is well tolerable and has substantial activity for patients with locally advanced or metastatic non-small cell lung cancer. A phase III trial comparing docetaxel with or without S-1 would warrant further investigation.     

Paclitaxel in combination with carboplatin as salvage treatment in patients with castration-resistant prostate cancer: a Hellenic oncology research group multicenter phase II study

Introduction

To evaluate the efficacy and tolerance of biweekly paclitaxel and carboplatin combination in patients with castration-resistant prostate cancer.

Patients and methods

Patients were treated with paclitaxel at the dose of 135?mg/m² followed by carboplatin AUC 3 on day 1 every 2?weeks in cycles of 28?days.

Results

Thirty-eight patients with castration-resistant prostate cancer were enrolled, and all of them had received frontline chemotherapy with docetaxel and prednisone, while 24 (63.2?%) had received 2 or more prior chemotherapy regimens. In an intention-to-treatment analysis, a clinical and/or biochemical response (>50?% decline) was observed in 10 patients (26.3?%; 95?% CI, 12.3?C40.3?%), stable disease in 13 (34.2?%) and progressive disease in 15 (39.5?%). The median duration of response was 6.1?months (range, 1.0?C9.8), the median time to tumor progression (TTP) 3.6?months (95?% CI, 2.1?C5.2) and the median overall survival 9.9?months (95?% CI, 6.2?C13.6). The probability for 1-year survival was 43?%. Grade 3 and 4 neutropenia was observed in three (7.9?%) and nine (23.7?%) patients, respectively.

Conclusion

The biweekly administration of paclitaxel/carboplatin regimen in patients with castration-resistant prostate cancer is an active and well-tolerated regimen which merits to be further evaluated in the context of salvage treatment.     

Phase II study of S-1 monotherapy in patients with previously treated, advanced non-small-cell lung cancer

Background

In this phase II clinical trial, we evaluated the efficacy and safety of S-1 monotherapy in patients with previously treated advanced non-small-cell lung cancer (NSCLC). We also measured plasma concentrations of 5-fluorouracil (5-FU) and 5-chloro-2,4-dihydroxypyridine components of S-1 and examined correlation with effectiveness and toxicity.

Methods

S-1 was given orally at a dose of 80?mg/m²/day for 14 consecutive days, followed by a 7-day rest period. This treatment course was repeated until disease progression or intolerable toxicity.

Results

We enrolled 30 patients. The response rate was 26.7% (8/30), and the disease control rate was 70% (21/30). Median progression-free survival (PFS) was 3.1?months, and median overall survival (OS) was 11.2?months. Mutations in the epidermal growth factor receptor (EGFR) gene were analyzed in 27 patients. The response rate was higher in patients with mutant EGFR (50.0%) than in those with wild-type EGFR (11.8%, P?=?0.0288). Median PFS was 4.8 and 2.5?months (P?=?0.038), and median OS was 22.4 and 8.4?months (P?=?0.071). There was no grade 4 toxicity in this study. Five patients had grade 3 non-hematologic toxicity, and there was a trend toward higher plasma concentrations of 5-FU in those patients than in another patients.

Conclusions

S-1 monotherapy is effective and well-tolerated treatment for previously treated advanced NSCLC.     

Evaluation of S-1 as third- or further-line chemotherapy in advanced non-small-cell lung cancer

Background

No investigation of S-1 monotherapy in previously treated advanced non-small-cell lung cancer (NSCLC) patients has yet been reported. We conducted a retrospective study to evaluate the efficacy and tolerability of S-1 in patients with failure of second- or further-line chemotherapy.

Patients and methods

The records of NSCLC patients who had received S-1 monotherapy between January 2005 and November 2006 with the following eligibility criteria were reviewed: previously treated with at least two regimens including platinum and docetaxel in the case of nonadenocarcinoma patients, and including platinum, docetaxel and epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) in the case of adenocarcinoma patients. S-1 was administered for 28 consecutive days, followed by a 14-day drug-free period (42 days in one course). The drug was administered in two divided doses daily at 80 mg/day for patients with a body surface area <1.25 m², 100 mg/day for those with a body surface area of 1.25–1.5 m², and 120 mg/day for those with a body surface area ≥1.5 m².

Results

Thirty-five patients were registered. The median number of courses administered per patient was 2 (range 1–9). The toxicity profile was mild, and grade 3 or more severe toxicity was rare. The overall response and disease control rates were 5.7% and 40%, respectively. The median survival time was 208 days.

Conclusion

S-1 exhibits modest activity and acceptable toxicity when used as a third or subsequent line of chemotherapy in patients with advanced NSCLC.     

Multicenter phase II trial of S-1, paclitaxel and cisplatin triplet combination chemotherapy in patients with advanced gastric cancer

Objective

The present study was conducted to evaluate the efficacy and safety of a combination regimen of S-1, paclitaxel plus cisplatin in patients with advanced gastric cancer.

Methods

Patients with previously untreated metastatic or recurrent, measurable gastric cancer received intravenous paclitaxel 80?mg/m² plus cisplatin 30?mg/m² on days 1, 8 and S-1 35?mg/m² orally twice daily on days 1?C14 based on a 3-week cycle.

Results

Forty-four patients were enrolled in the current study, among whom 38 were assessable for efficacy and all assessable for toxicity. Two complete response and 24 partial responses were confirmed, giving an overall response rate of 59.1%. At a median follow-up of 11.4?months, the median time to progression and median overall survival was 9.4 (95% CI 6.8?C12.1) months and 11.2 (95% CI 7.6?C14.8) months, respectively. Grade 3/4 neutropenia occurred in 45 events (20.9%) and febrile neutropenia was observed in five events (2.3%). The common non-hematologic toxicity was nausea (grade 1/2, 27.2%) and diarrhea (grade 1/2, 9.0%).

Conclusion

The combination of S-1, paclitaxel and cisplatin was found to be well tolerated and effective in patients with advanced gastric cancer.     

Phase I/II study of S-1 combined with biweekly irinotecan chemotherapy in previously treated advanced non-small cell lung cancer

Purpose

This phase I/II study was designed to evaluate a combination of irinotecan and S-1 a new regimen for salvage chemotherapy in patients with advanced or metastatic non-small cell lung cancer (NSCLC).

Methods

The study group comprised patients with advanced or metastatic NSCLC who had previously received at least one platinum-containing chemotherapy. Patients received irinotecan on days 1, 15 and oral S-1 (40?mg/m² twice daily as a fixed dose) on day 1 to 14 of a 28-day cycle.

Results

In the phase I part, irinotecan was given in escalating doses of 70 (Level 1), 80 (Level 2), and 90?mg/m² (Level 3). Three of the 5 patients given Level 3 had dose-limiting toxicity, and Level 2 (80?mg/m² of irinotecan) was designated as the recommended dose. In phase II, 38 patients received a median of 7.4 cycles of irinotecan at the recommended dose. The overall response rate was 15.8?% (90?% confidence interval (CI): 6.1–25.5?%), and the median progression-free and overall survival times were 4.5?months (95?% CI: 3.5–5.0) and 15.0?months (95?% CI: 9.5–20.6) months, respectively. Toxicity was generally mild. Grade 3 or higher toxicity included neutropenia in 17.9?% of the patients, thrombocytopenia in 5.1?% and nausea in 7.7?%.

Conclusion

Combination chemotherapy with S-1 and irinotecan was considered an effective salvage regimen in patients with advanced or metastatic NSCLC.     

Chemotherapy with gemcitabine, cisplatin, and docetaxel in the treatment for patients with muscle-invasive bladder cancer: a multicenter phase II study of the Hellenic Oncology Research Group (HORG)

Purpose

To assess the antitumor activity and toxicity of gemcitabine, cisplatin, and docetaxel (GCD) regimen in patients with locally advanced or metastatic urothelial cancer.

Patient and methods

Chemotherapy-na?ve patients, aged ??70?years with measurable or evaluable disease and a performance status (PS) of 0?C2 were treated with sequential cisplatin 80?mg/m² (d1), gemcitabine 1,100?mg/m² (d1 and d14), and docetaxel 80?mg/m² (d14) every 28?days.

Results

Sixty patients with an ECOG PS of 0?C2 were enroled. Most (71.7%) patients had stage IV disease. A median number of 4 chemotherapy cycles per patient (range, 1?C9) was administered. Eight (13.3%) patients achieved a CR and 16 (26.7%) a partial response (PR) (intention-to-treat: ORR 40%; 95% CI 27.6?C52.4%). Thirteen (21.7%) and 23 (38.3%) patients experienced stable and progressive disease, respectively. The median time to progression (TTP) was 7.7?months (range, 0.7?C43.4), and the median overall survival 21.4?months (range, 0.7?C68.6). Grade 3 and 4 neutropenia occurred in 27 (45%) patients and grade 3 and 4 thrombocytopenia in five (8.3%). Three (5%) patients developed febrile neutropenia. There were no treatment-related deaths. Severe non-haematological toxicity was infrequent.

Conclusions

The GCD combination is an active and well-tolerated regimen in patients with chemotherapy-naive locally advanced or metastatic TCC and merits to be further investigated.     

Second-line chemotherapy with Capecitabine (Xeloda) and Docetaxel (Taxotere) in previously treated, unresectable adenocarcinoma of pancreas: the final results of a phase II trial

Purpose

To investigate the efficacy and toxicity of the docetaxel and capecitabine combination in patients with previously treated, unresectable adenocarcinoma of the pancreas.

Patients and Methods

Patients with pancreatic adenocarcinoma, pre-treated with gemcitabine-based chemotherapy, were treated with capecitabine (800?mg/m² orally, twice a day for 14?days) and docetaxel (75?mg/m² i.v, on day1), every 3?weeks. The primary end-point was overall response rate (RR).

Results

Thirty-one patients were enrolled in the study; 93.6% of them had a performance status (PS) of 0?C1 and 96.8% had stage IV disease. Patients received a median of 4 cycles/patient, and the main reason for treatment discontinuation was disease progression. Partial response was observed in three (9.7%) patients, stable disease in seven (22.6%) (disease control rate: 32.3%, 95% CI: 15.80?C48.71%) and disease progression in 21 (67.6%). The median progression-free survival (PFS) was 2.4?months (95% CI: 1.6?C3.13) and the median overall survival (OS) was 6.3?months (95% CI: 3.38?C9.23); the estimated 1-year survival rate was 14.7%. Grade III/IV neutropenia occurred in 10 (32.2%) patients and febrile neutropenia in one patient. Other severe non-hematologic toxicities were mild and manageable. After 2 chemotherapy cycles, pain control occurred in 20% of patients and stabilization of body weight in 40%.

Conclusion

The combination of docetaxel/capecitabine may confer good disease control associated with improvement of quality of life as second-line chemotherapy in patients with metastatic pancreatic cancer.     

A lower dose of docetaxel at 60?mg/m2 could be continued longer for controlling peripheral edema in patients with metastatic breast cancer

Background

Docetaxel is a key drug for metastatic breast cancer (MBC). In patients with MBC, the treatment objective is durable response with minimum toxicity. In Japan, the approved dose of docetaxel is 60?C70?mg/m² every 3?weeks, whereas 75?C100?mg/m² docetaxel is common in the West.

Methods

We retrospectively examined the prevalence of edema in patients with MBC who were treated with docetaxel. Seventy-seven patients received docetaxel at a dose of 60?mg/m² every 3?weeks with prophylactic premedication of dexamethasone, 8?mg daily for 3?days.

Results

Median follow-up time was 28?months (range 4.3?C98). Overall response was 25% (95% CI 15?C34). Median time to progression and median survival time from the beginning of any systemic therapy for metastatic disease were 10 and 66?months, respectively. Neutropenia was the most common toxicity, with grade 3?C4 observed in 66%. Fifty-one percent of the patients experienced peripheral edema that could be controlled with oral diuretics. Grade 3 edema was observed in 4 patients only, and discontinuation because of edema was 9%. Other grade 3 or 4 toxicity was <5%. Median cumulative dose of docetaxel to onset of peripheral edema was 480?mg/m² (range 60?C780), and median cumulative given dose was 600?mg/m² (range 84?C2,928).

Conclusions

These results suggest that treatment with docetaxel at 60?mg/m² could be continued longer than the higher dose with manageable peripheral edema in patients with MBC. Further investigation is required to determine the superiority of low-dose docetaxel.     

A randomised phase II trial of two sequential schedules of docetaxel and cisplatin followed by gemcitabine in patients with advanced non-small-cell lung cancer

Purpose

The aim of this study was to determine the activity and toxicity of two sequential chemotherapy regimens in the first-line treatment of advanced non-small-cell lung cancer (NSCLC).

Methods

Eighty-eight chemonaive patients with stage IIIB/IV NSCLC were randomised to receive either three cycles of 75?mg/m² cisplatin plus 75?mg/m² docetaxel, both administered on day 1 every 21?days, followed by three cycles of 1,200?mg/m² gemcitabine on days 1 and 8 every 3?weeks (arm A), or three cycles of 25?mg/m² cisplatin plus 25?mg/m² docetaxel on days 1, 8 and 15 every 28?days, followed by three cycles of 1,200?mg/m² gemcitabine on days 1 and 8 every 3?weeks (arm B).

Results

Of the evaluable patients, 61% in arm A (n?=?41) and 36% (n?=?44) in arm B completed treatment as per the protocol. The best tumour response rates were as follows (arm A and arm B): complete response: 2.4 and 2.3%; partial response: 39 and 20.4%; stable disease: 26.8 and 13.6%; and progressive disease: 31.8 and 45.4%. The median progression-free and overall survival were 3.9 and 12.3?months in arm A, respectively, 3.1 and 7.7?months in arm B. Grade 3?C4 adverse events were more common in arm A. Grade 3?C4 neutropenia was the main toxicity observed (56.1% in arm A and 11.4% in arm B).

Conclusions

Our data demonstrate the feasibility of a sequential approach of cisplatin plus docetaxel followed by single-agent gemcitabine. Weekly administration of platinum-docetaxel is associated with an improved safety profile but lower efficacy than the conventional three-weekly schedule (registration ID 2004-001044-72).     

Phase II study of S-1 in patients with gemcitabine-resistant advanced pancreatic cancer

Purpose

The primary objective of this study was to assess the efficacy and safety of S-1 in patients with gemcitabine-resistant advanced pancreatic cancer.

Methods

Patients with histologically or cytologically proven, advanced pancreatic cancer who had received first-line chemotherapy with gemcitabine were eligible for this study. S-1 was administered orally at a dose of 40?mg/m² twice daily for 28?days, followed by 14?days?? rest. Treatment was repeated every 6?weeks until disease progression.

Results

Twenty-one patients were enrolled in this study. Grade 3 and 4 toxicities included anorexia in 14% of the patients, abdominal pain in 4.8% and infection without neutropenia in 4.8%. S-1 was discontinued in two patients because of toxicity. Of the 21 eligible patients, 2 (9.5%) achieved a partial response and 9 (43%) had stable disease. A marked decrease (??50%) in tumor marker (CA19-9) was observed in 5 (28%) of the 18 evaluable patients. The median progression-free survival and the median survival time from the first day of S-1 therapy were 4.1?months (95% CI, 1.3?C6.9?months) and 6.3?months (95% CI, 3.6?C8.9?months), respectively.

Conclusions

Second-line chemotherapy with S-1 was tolerated with acceptable toxicity and resulted in a relatively high disease control rate in patients with gemcitabine-resistant advanced pancreatic cancer. As an oral agent, S-1 may be a feasible treatment option for this patient population.     

Prospective assessment of XRCC3, XPD and Aurora kinase A single-nucleotide polymorphisms in advanced lung cancer

Purpose

New therapeutic approaches are being developed based on findings that several genetic abnormalities underlying non-small-cell lung cancer (NSCLC) can influence chemosensitivity. The identification of molecular markers, useful for therapeutic decisions in lung cancer, is thus crucial for disease management. The present study evaluated single-nucleotide polymorphisms (SNPs) in XRCC3, XPD and Aurora kinase A in NSCLC patients in order to assess whether these biomarkers were able to predict the outcomes of the patients.

Methods

The Spanish Lung Cancer Group prospectively assessed this clinical study. Eligible patients had histologically confirmed stage IV or IIIB (with malignant pleural effusion) NSCLC, which had not previously been treated with chemotherapy, and a World Health Organization performance status (PS) of 0?C1. Patients received intravenous doses of vinorelbine 25?mg/m² on days 1 and 8, and cisplatin 75?mg/m² on day 1, every 21?days for a maximum of 6 cycles. Venous blood was collected from each, and genomic DNA was isolated. SNPs in XRCC3 T241M, XPD K751Q, XPD D312N, AURORA 91, AURORA 169 were assessed.

Results

The study included 180 patients. Median age was 62?years; 87?% were male; 34?% had PS 0; and 83?% had stage IV disease. The median number of cycles was 4. Time to progression was 5.1?months (95?% CI, 4.2?C5.9). Overall median survival was 8.6?months (95?% CI, 7.1?C10.1). There was no significant association between SNPs in XRCC3 T241M, XPD K751Q, XPD D312N, AURORA 91, AURORA 169 in outcome or toxicity.

Conclusions

Our findings indicate that SNPs in XRCC3, XPD or Aurora kinase A cannot predict outcomes in advanced NSCLC patients treated with platinum-based chemotherapy.     

A multicenter phase II trial of docetaxel and capecitabine as salvage treatment in anthracycline- and taxane-pretreated patients with metastatic breast cancer

Objective

To evaluate the efficacy and safety of docetaxel plus capecitabine (DC) combination as salvage treatment in anthracycline- and taxane-pretreated patients with metastatic breast cancer (MBC).

Patients and treatment

Patients with MBC who had disease progression after initial chemotherapy with anthracyclines (n?=?29; 100?%) and taxanes (n?=?11; 37.9?%) were treated with oral capecitabine 950?mg/m² twice daily on days 1?C14 and docetaxel 75?mg/m² on day 1 every 3?weeks. Nineteen (65.5?%) patients received this regimen as second line and 10 (34.5?%) as???3rd line of therapy. All patients were evaluable for response and toxicity.

Results

Complete response occurred in two (6.9?%) patients and partial response in eleven (37.9?%) for an overall response rate of 44.8?% (95?% CI 26.7?C62.9?%). Eleven women (37.9?%) had stable disease and five (17.2?%) progressive disease. Of the eleven patients previously treated with anthracyclines and taxanes, five (45.5?%) responded to DC combination. The median duration of response was 5.7?months (range 3.4?C64.2), the median time to disease progression 9.3?months (range 1.2?C58), and the median overall survival 25.5?months. No toxic death occurred. Neutropenia grade 4 occurred in 58.6?% of patients and three of them (10.3?%) developed neutropenic fever. Non-hematological toxicities were manageable with grade 3 hand-foot syndrome occurring in 6.9?% of the patients, fatigue in 3.4?%, and neurotoxicity in 3.4?%.

Conclusion

The DC combination is a valuable regimen as salvage treatment in anthracycline- or anthracycline and taxane-pretreated patients with MBC.     

Combination therapy consisting of gemcitabine, carboplatin, and docetaxel as an active treatment for advanced urothelial carcinoma

Background

To evaluate the efficacy and toxicity of a combination chemotherapy consisting of gemcitabine, carboplatin, and docetaxel (GCD) in patients with advanced urothelial carcinoma (UC) as a phase II trial.

Materials and methods

Patients with metastatic or locally advanced unresectable UC were eligible for this trial. All enrolled patients were considered to be “unfit??for cisplatin-based chemotherapy, or to have methotrexate, vinblastine, doxorubicin, cisplatin (MVAC)-refractory UC. The chemotherapy regimen consisted of gemcitabine 1000?mg/m² on days 1 and 8, and carboplatin (with a target area under the curve of 5) and docetaxel 70?mg/m² on day 1; this was repeated every 21?days.

Results

Thirty-five patients were enrolled, with a median age of 68?years. A total of 89 cycles were administered (median, 2 cycles). Major toxicities were Grade 3/4 neutropenia in 28 (80.0%) patients and Grade 3/4 thrombocytopenia in 18 (51.5%). An objective response rate (ORR) was 11 of 21 patients (52.4%), including a complete response in 1 (4.8%). The median overall survival (OS) was 13.1?months (1-year survival rate, 60%) and the median progression-free survival (PFS) was 5.0?months. Among 16 patients who had previously received MVAC, the ORR, the median PFS, the median OS and 1-year survival rate was 56.3%, 5.0?months, 12.6?months and 54%, respectively.

Conclusions

GCD chemotherapy is active and well tolerated as a first- or second-line therapy for patients with advanced UC. Response rate, duration and survival did not differ between those with and without a history of MVAC treatment.     

Outcome, clinical prognostic factors and genetic predictors of adverse reactions of intermittent combination chemotherapy with docetaxel, estramustine phosphate and carboplatin for castration-resistant prostate cancer

Objectives

Docetaxel-based chemotherapy is effective in patients with castration-resistant prostate cancer (CRPC). This phase II study assessed the outcome and predictive factors for prognosis and toxicity following intermittent chemotherapy with docetaxel, estramustine phosphate, and carboplatin (DEC) in patients with CRPC.

Methods

Thirty-five patients were treated with a DEC regimen that consisted of a 28-day cycle of drugs as follows: docetaxel (60?mg/m² on day 1), carboplatin (AUC 5 on day 1) and estramustine phosphate (560?mg daily). Treatment was continued intermittently. The end point was to test the effect of DEC on the response rate and overall survival (OS). Statistical correlations between the outcomes and predictive factors, including clinical parameters and 8 single-nucleotide polymorphisms (SNPs) related to drug metabolism, were assessed.

Results

Prostate-specific antigen levels decreased by more than 30% in 65.7% of the patients. The median OS following DEC was 17.8?months, and the median total time of chemotherapy holiday was 7.7?months (range 1.7?C35.8). On multivariate analysis, serum lactate dehydrogenase (LDH) was an independent prognostic factor for OS (p?=?0.007). On SNP analysis, patients carrying the TT genotype of the ABCB1 C3435T polymorphism showed a significantly more severe leukocytopenia during the first cycle of DEC therapy compared to patients with the CC?+?CT genotype (p?=?0.036).

Conclusion

Combination chemotherapy with DEC has a potential effect on CRPC with acceptable toxicity. Serum LDH may be a promising predictor of prognosis, and the ABCB1 C3435T polymorphism may be a genetic predictor of the severity of leukocytopenia in patients with CRPC treated with DEC.     

Phase I/II trial of a biweekly combination of S-1 plus docetaxel in patients with previously treated non-small cell lung cancer (KRSG-0601)

Background:

Combination of S-1, an oral fluorouracil derivative, plus docetaxel against non-small cell lung cancer (NSCLC) showed promising efficacy but clinically problematic emesis. A phase I/II study utilising a new schedule for this combination was conducted.

Methods:

A biweekly regimen of docetaxel on day 1 with oral S-1 on days 1–7 was administered to previously treated NSCLC patients. Doses of docetaxel/S-1 were escalated to 30/80, 35/80, and 40/80 mg m⁻², respectively, and its efficacy was investigated at the recommended dose below maximum tolerated dose (MTD).

Results:

In phase I study employing 13 patients, dose-limiting toxicities were febrile neutropenia and treatment delay, with the respective MTDs for docetaxel 40 mg m⁻²/S-1 80 mg m⁻². In the phase II study, 34 patients were treated with docetaxel 35 mg m⁻²/S-1 80 mg m⁻² for a median cycle of 6. The response and disease control rates were 34.3% (95% confidence interval (CI), 18.6–50.0%) and 62.9% (95% CI, 46.8–72.9%), respectively. Median progression-free survival was 150.5 days. Haematologic grade 4 toxicities were observed in neutropenia (11.8%) and thrombocytopenia (2.9%). Regarding non-haematologic toxicities, including emesis, there were no grade 3/4 side effects.

Conclusion:

Combination of 1-week administration of S-1 with biweekly docetaxel is safe and active for NSCLC.     

Multicenter phase II study of S-1 and docetaxel combination chemotherapy for advanced or recurrent gastric cancer patients with peritoneal dissemination

Purpose

Peritoneal dissemination is the most frequent and life-threatening mode of metastasis and recurrence in patients with gastric cancer. A multicenter phase II study was designed to evaluate the efficacy and tolerability of S-1 and docetaxel combination chemotherapy regimen for the treatment of advanced or recurrent gastric cancer patients with peritoneal dissemination.

Methods

Nineteen patients with histologically confirmed unresectable or recurrent gastric cancer with peritoneal dissemination were enrolled. Oral S-1 at 80 mg/m²/day was administered twice daily for 2 weeks, followed by 1 drug-free week. Docetaxel infusion at 40 mg/m² was performed on day 1, simultaneous with S-1 administration. The primary endpoints were overall survival (OS) and time to progression (TTP). The secondary endpoints were the response rates and safety status.

Results

Patients received a median of 4 cycles of the S-1 and docetaxel regimen (range 1–43). The disease control rate was 73.7 % (14/19). Median overall survival was 459 days (15.3 months), while median time to progression was 212 days (7.1 months). Neutropenia was the most common type of toxicity (n = 7, 36.8 %).

Conclusions

Combination chemotherapy with S-1 and docetaxel is a tolerable and effective treatment for advanced or recurrent gastric cancer patients with peritoneal dissemination.     

Phase II study of biweekly S-1 and oxaliplatin combination chemotherapy in metastatic colorectal cancer and pharmacogenetic analysis

Purpose

To evaluate the efficacy and safety of S-1 in combination with oxaliplatin in a biweekly schedule as first-line treatment in metastatic colorectal cancer and the association between genetic polymorphisms and treatment outcomes.

Methods

Eligibility included age 18?C75?years, at least one measurable lesion, no prior chemotherapy except adjuvant chemotherapy, and Eastern Cooperative Oncology Group Performance Status (PS) 0?C2. S-1 40?mg/m² b.i.d. on days 1?C7 with 85?mg/m² of oxaliplatin on day 1 was repeated every 2?weeks. Genomic DNA from whole blood was analyzed for 15 single-nucleotide polymorphisms (SNPs) among 8 genes.

Results

Fifty-two patients (median age 63?years, range 37?C74) were enrolled: 37 men and 15 women; 44 with a PS of 0 and 8 with a PS of 1; and 41 with initially metastatic cancer and 11 with relapsed disease. Among 51 evaluable patients, objective response rate was 47.1% [95% confidence interval (CI) 32.9?C61.2]. Median follow-up duration was 17.1?months (range 3.9?C28.2?months). Median progression-free survival (PFS) was 6.4?months (95% CI 4.8?C8.1), and median overall survival had not been reached yet. Reported grade 3 toxicities were neutropenia (7.7%), thrombocytopenia (5.8%), sensory neuropathy (7.7%) and diarrhea (1.9%). There was no grade 4 toxicity or neutropenic fever. Patients with A/G or G/G genotype in GSTP1 Ile105Val SNP had longer PFS than patients with A/A (median 8.3 vs. 6.1?months, P?=?0.04).

Conclusions

Biweekly S-1 with oxaliplatin is effective and has improved tolerability and convenience compared to other fluoropyrimidine with oxaliplatin combinations. GSTP1 Ile105Val SNP is associated with treatment outcomes.