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.     

Sequential chemotherapy with cisplatin, leucovorin, and 5-fluorouracil followed by docetaxel in previously untreated patients with metastatic gastric cancer: a phase II study

Background

The combination of docetaxel, cisplatin, and 5-fluorouracil (5-FU) has demonstrated a survival advantage over cisplatin and 5-FU, but with substantial hematological toxicity. We aimed to evaluate the efficacy and toxicity of a sequential regimen with cisplatin, leucovorin, and 5-FU (PLF) followed by docetaxel in metastatic gastric cancer patients.

Methods

Treatment consisted of 4 cycles of biweekly PLF (cisplatin 50?mg/m² as a 30-min infusion on day 1, leucovorin 200?mg/m² in a 2-h infusion, and 5-FU 2,800?mg/m² in a 48-h continuous infusion starting on day 1) followed, in cases of response or stable disease, by 3 cycles of docetaxel (75?mg/m², every 3?weeks).

Results

Thirty-four patients were enrolled, with an average age of 64?years (range 34–69). The main cumulative grade 3–4 toxicities were: neutropenia (38.2%), febrile neutropenia (11.8%), and fatigue (14.7%). After the planned 7 cycles of treatment, the overall response rate was 38.2% (95% confidence interval [CI] 21.9–54.6), with 3 complete and 10 partial responses. Median progression-free survival and overall survival were 4.8 and 10.6?months, respectively.

Conclusions

For patients with metastatic gastric cancer, the sequential administration of cisplatin, leucovorin, 5-FU, and docetaxel may be an effective palliative option and offers a far more favorable toxicity profile than the simultaneous use of docetaxel, cisplatin, and 5-FU.     

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.     

Neoadjuvant chemoradiotherapy with docetaxel, cisplatin, and 5-fluorouracil for esophageal cancer

Purpose

We aimed to evaluate the safety, tolerability, and efficacy of combination preoperative chemoradiotherapy as first-line treatment in patients with advanced esophageal cancer.

Methods

We performed a phase I dose-escalation trial of docetaxel at 25–40?mg/m² in four planned dose levels in 3–6 patient cohorts on days 1, 15, 29, and 43 administered in combination with cisplatin (70?mg/m² on days 1 and 29) and 5-fluorouracil (70?mg/m²/day on days 1–4 and 29–32) and concurrent radiation therapy (40?Gy). The tumors were resected during weeks 10–13.

Results

This study included 7 patients with esophageal cancer. The dose-limiting toxicity was observed at a biweekly docetaxel dose of 30?mg/m² when patients developed grade 3 febrile neutropenia, grade 4 thrombocytopenia, and grade 4 pain/esophagus, resulting in a maximum tolerated dose of 25?mg/m². Grade 3/4 hematological toxicity was observed in 71% of the patients and grade 3/4 non-hematological toxicity in 57%. The overall tumor response rate was 86% (complete, 57% and partial, 29%). All patients underwent surgery, and there were no deaths as a result of postoperative complications.

Conclusions

This preoperative chemoradiotherapy regimen using triplets is feasible but results in moderate toxicity. It is noteworthy that this regimen was associated with a high rate of pathological complete remission.     

Efficacy and toxicity of concurrent chemoradiotherapy in patients with advanced oropharyngeal squamous cell carcinoma

Purpose

The aim of this study was to evaluate the feasibility and toxicity of concurrent chemoradiotherapy (CCRT) with docetaxel, cisplatin (CDDP) and 5-fluorouracil (5-FU) (TPF regimen) or with CDDP, 5-FU, methotrexate and leucovorin (PFML regimen) in previously untreated patients with advanced oropharyngeal squamous cell carcinoma (SCC).

Methods

Fifty-six eligible patients with stage III or IV oropharyngeal SCC were treated with CCRT. Forty-four patients were men and 12 were women, and the average age of the patients was 58.8?years (range, 37?C72?years). In the TPF group, patients received CCRT with the TPF regimen [docetaxel (50?mg/m², day 1), CDDP (60?mg/m², day 4) and a continuous 5-FU infusion (600?mg/m²/day, days 1?C5)]. In the PFML group, patients received CCRT with the PFML regimen [CDDP (60?mg/m², day 4), a continuous 5-FU infusion (600?mg/m²/day, days 1?C5), methotrexate (30?mg/m², day 1) and leucovorin (10?mg/m²/day, days 1?C5)]. The total radiation dose was between 66.6 and 70.2?Gy.

Results

The overall 5-year survival rate was 64.6% in all patients, 68.6% in the resectable group and 47.4% in the unresectable group. The 5-year disease-specific survival rate was 72.2% in all patients, 78.1% in the resectable group and 47.7% in the unresectable group. Regarding clinical stage, the 5-year disease-specific survival rates were 91% in stage III, 72% in stage IVa and 44% in stage IVb.

Conclusion

CCRT with TPF or PFML regimen for advanced oropharyngeal SCC is tolerable and effective, especially in patients with resectable disease.     

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).     

Biweekly docetaxel, cisplatin, and 5-fluorouracil (DCF) chemotherapy for advanced esophageal squamous cell carcinoma: a phase I dose-escalation study

Background and purpose

The optimal chemotherapeutic protocol for the treatment of esophageal cancer has not yet been established. A dose-escalation study of docetaxel combined with cisplatin and 5-fluorouracil (5-FU) was performed to determine the optimal dose in patients with advanced esophageal squamous cell carcinoma.

Patients and method

We studied a total of 18 patients who had previously untreated thoracic esophageal squamous cell carcinoma with T4 tumors and/or metastasis. The patients received an infusion of docetaxel at different dose levels (levels 1, 2, 3: 30, 35, 40 mg/m², respectively) and an infusion of cisplatin (40 mg/m²) on days 1 and 15 plus a continuous infusion of 5-FU (400 mg/m²/day) on days 1–5 and 15–19.

Results

Dose-limiting toxicities (DLT) included febrile neutropenia and leukopenia. DLT occurred in 2 of 6 patients at level 1, 2 and in 3 of 6 patients at level 3. The response rate was 88.9%, including a complete response rate of 33.3%.

Conclusions

To minimize toxicity and maximize dose intensity, we elected to investigate a biweekly regimen. The maximum tolerated dose was level 3, and the recommended dose was determined to be docetaxel 35 mg/m² with cisplatin 40 mg/m² plus 5-FU 400 mg/m², administered biweekly. This regimen was tolerable and highly active. A phase II study has been started.     

Phase I study of 3-weekly combination chemotherapy using epirubicin, oxaliplatin, and S-1 (EOS) in patients with previously untreated advanced gastric cancer

Purpose

This study was performed to determine the recommended dose (RD) and dose-limiting toxicity (DLT) associated with epirubicin, oxaliplatin, and S-1 (EOS) combination therapy in patients with previously untreated advanced gastric cancer (AGC).

Materials and methods

Previously untreated patients with histologically proven metastatic AGC, with an ECOG performance status of 0?C2, were enrolled in this study. A fixed dose of epirubicin (50?mg/m²) and oxaliplatin (130?mg/m²) was intravenously administered on day 1 of treatment, followed by oral S-1 administration twice daily on days 1?C14. The S-1 dose was escalated according to the following schedule: level I, 35?mg/m²; level II, 40?mg/m²; level III, 45?mg/m²; Level IV, 50?mg/m². Each cycle was repeated every 21?days. DLTs were evaluated during the first two cycles of treatment.

Results

Nineteen patients with a median age of 53?years (range, 40?C71?years) were enrolled in this study. One case of DLT (grade 4 neutropenia lasting more than 5?days) developed from among the six dose level II patients, while 2 DLTs (grade 3 diarrhea and nausea) were observed among the 4 dose level III patients. Based on these results, dose level II was determined as the RD. Of the 13 patients with measurable lesions, eight achieved partial response, three showed stable disease, and the objective response rate was 61.5?% (95?% confidence interval (CI), 13.3?C66.6?%). The median progression-free survival and overall survival of all patients was 6.8?months (95?% CI, 1.4?C9.5?months) and 13.3?months (95?% CI, 1.9?C24.6?months), respectively.

Conclusion

The RD of the EOS regimen in patients with previously untreated AGC was 50?mg/m² of epirubicin and 130?mg/m² of oxaliplatin on day 1, with administration of 40?mg/m² of S-1 twice a day on days 1?C14 for each 21-day cycle. The EOS regimen described produced promising results.     

Phase I dose-escalating study of 24-h continuous infusion of 5-fluorouracil in combination with weekly docetaxel and cisplatin in patients with advanced gastric cancer

Purpose

To determine the maximum-tolerated dose (MTD) of a 24-h continuous infusion of 5-fluorouracil (5-FU) when administered in combination with a fixed weekly dose of docetaxel and cisplatin in patients with advanced gastric cancer.

Methods

Patients with advanced gastric adenocarcinoma (n = 21) received a weekly regimen of docetaxel, cisplatin and 5-FU (DCF) for 3 consecutive weeks every 4 weeks. The doses of docetaxel and cisplatin were fixed at 33.3 and 30 mg/m², respectively. The dose of 5-FU was increased from a starting dose of 1,000 mg/m² to the MTD.

Results

A total of 53 cycles of chemotherapy were administered (median = 3 cycles/patient). The MTD of 5-FU was 1,750 mg/m². All 21 patients were assessed for toxicity and 19 patients (90%) were evaluated for response. Both grade 3–4 hematologic and non-hematologic toxicities occurred in less than 10% of patients and there were no treatment-related deaths. Among the 19 patients, we observed 1 complete and 4 partial responses for an overall response rate of 26% (95% CI: 6–46%). This rate increased to 39% (95% CI: 12–66%) in 13 chemotherapy-naïve patients.

Conclusions

A consecutive weekly DCF regimen at 4-week intervals appears feasible for advanced gastric cancer with a favorable toxicity profile. The recommended doses are 33.3 mg/m² of docetaxel, 30 mg/m² of cisplatin and 1,500 mg/m² of a 24-h continuous intravenous infusion of 5-FU. The response of this weekly regimen in our study was favorable and deserved further investigation in a phase II trial.     

Phase II study of S-1, a novel oral fluoropyrimidine, and biweekly administration of docetaxel for previously treated advanced non-small-cell lung cancer

Purpose

We examined the safety and efficacy of the combination of S-1 and biweekly docetaxel in patients with previously treated advanced non-small-cell lung cancer (NSCLC).

Methods

Patients with previously treated advanced NSCLC were eligible if they had a performance status of 2 or less, were 80?years or younger, and had adequate organ function. Forty-nine patients (38 men and 11 women; median age, 66?years; range 43?C79?years) were enrolled. Patients were treated with the combination of 80?mg/m² per day of S-1 for 14 consecutive days and 35?mg/m² of docetaxel on days 1 and 15 every 4?weeks.

Results

The overall response rate was 16.3% (95% confidence interval, 7.6?C30.5%). The disease-control rate was 49.0% (95% confidence interval, 34.4?C63.7%). The median survival time after this treatment was 9?months (range 1?C22?months). The median progression-free survival time was 3?months (range 1?C11?months). Response rates and survival times did not differ significantly according to the histological type. Grade 3?C5 toxicities included neutropenia in 51.0% of patients, thrombocytopenia in 2.0%, anemia in 20.4%, infection in 24.5%, anorexia in 12.2%, diarrhea in 14.3%, nausea in 6.1%, and dehydration in 4.2%. There was 1 treatment-related death due to severe anorexia, stomatitis, diarrhea, and, as consequence, dehydration.

Conclusions

The combination of S-1 and biweekly docetaxel is an acceptable therapeutic option in patients with previously treated advanced NSCLC regardless of the histological type.     

Sequential chemotherapy with dose-dense docetaxel, cisplatin, folinic acid and 5-fluorouracil (TCF-dd) followed by combination of oxaliplatin, folinic acid, 5-fluorouracil and irinotecan (COFFI) in metastatic gastric cancer: results of a phase II trial

Purpose

To evaluate a new strategy of two sequential, intensified chemotherapy regimens in metastatic gastric cancer.

Patients and methods

Chemo-na?ve patients with metastatic gastric cancer were enrolled to receive 4 cycles of TCF-dd (docetaxel initially 85?mg/m² and cisplatin initially 75?mg/m² on day 1 [later modified due to toxicity: 70 and 60?mg/m² respectively], l-folinic acid 100?mg/m² on days 1 and 2, 5-fluorouracil 400?mg/m² bolus and then 600?mg/m² as a 22?h continuous infusion on day 1 and 2, every 14?days). Subsequently, patients with CR, PR or SD received 4 cycles of COFFI (oxaliplatin 85?mg/m², irinotecan 140?mg/m², l-folinic acid 200?mg/m², 5-fluorouracil bolus 400?mg/m² on day 1 followed by 2,400?mg/m² as a 48?h continuous infusion, every 14?days). In both regimens pegfilgrastim 6?mg subcutaneously on day 3 was included.

Results

Forty consecutive patients were enrolled. TCF-dd regimen achieved an ORR of 55% (95% CI, 40?C70). Twenty-three patients proceeded to COFFI. After this regimen the ORR was then increased to 60% (95% CI, 45?C75). Among the 21 patients treated with TCF-dd after the protocol amendments, main grade 3?C4 toxicities were: neutropenia (29%), thrombocytopenia (19%), asthenia (24%) and diarrhea (14%). COFFI caused grade 3?C4 neutropenia (all not febrile) and diarrhea in 35% and 17% of patients respectively.

Conclusions

A sequential strategy with TCF-dd followed by COFFI is very active and may be of special interest in selected patients.     

Phase I study of 3-weekly docetaxel, capecitabine and oxaliplatin combination chemotherapy in patients with previously untreated advanced gastric cancer

Purpose

Adding docetaxel to cisplatin and 5-fluorouracil (5-FU) (DCF) significantly improved clinical efficacy in advanced gastric cancer (AGC). To further improve the efficacy and tolerability, we substituted oxaliplatin for cisplatin and capecitabine for 5-FU in the DCF regimen and performed a phase I study to determine the recommended dose (RD) and dose-limiting toxicity (DLT) of docetaxel, capecitabine and oxaliplatin (DXO) combination in patients with AGC.

Materials and methods

Previously untreated patients with histologically proven metastatic AGC and ECOG performance status 0–2 were enrolled. Docetaxel and oxaliplatin were administered i.v. on day 1. Capecitabine was administered orally bid on days 1–14. Each cycle was repeated every 3 weeks. DLTs were evaluated during the first two cycles of treatment.

Results

Twenty-one patients were enrolled: 15 patients in dose-escalation phase and 6 patients in the extension at the RD. Median age was 50 years (range 21–65 years). At dose level 3 (60 mg/m² docetaxel, 1,000 mg/m² capecitabine, 100 mg/m² oxaliplatin), 1 diarrhea (DLT) was found among 6 patients while at dose level 4 (60 mg/m² docetaxel, 800 mg/m² capecitabine, 130 mg/m² oxaliplatin), 2 DLTs (febrile neutropenia and diarrhea) were observed among 3 patients. Therefore, the dose level 3 was determined as RD. DLTs include grade 3 diarrhea and febrile neutropenia. Cumulative (all cycles) grade 3/4 toxicity included neutropenia (75%), leucopenia (50%), febrile neutropenia (25%), diarrhea (17%), and neuropathy (17%). Of 14 patients with measurable lesions, 11 achieved partial response and 3 showed stable disease.

Conclusion

The RD of the DXO regimen in patients with AGC is capecitabine 1,000 mg/m² twice daily on days 1–14, in combination with decetaxel 60 mg/m² (day 1) and oxaliplatin 100 mg/m² (day 1) repeated every 3 weeks. The DXO regimen seems to have promising activity and offers an easy alternative to DCF. The toxicities appear to be still substantial, but manageable.     

Randomized trial of weekly docetaxel and cisplatin combined with concurrent 3DCRT in patients with locally advanced esophageal cancer

Objective

This randomized controlled clinical study was to assess and compare the efficacy and safety of two chemoradiotherapy regimens [cisplatin + 5-fluorouracil + 3 dimensional conformal radiation therapy (3DCRT) and cisplatin + weekly docetaxel + 3DCRT] in patients with locally advanced esophageal squamous cell carcinoma.

Methods

A total of seventy-four patients with clinical stages IIB to IIIB esophageal squamous cell carcinoma were enrolled. Chemotherapy for PF group comprised 5-fluorouracil at days 1–5 (250 mg/m²/d) and cisplatin (20 mg/m²) at days 1–3 of every 28-day cycle; full treatment course included 2 cycles. Chemotherapy for DP group comprised docetaxel (20 mg/m²) and cisplatin (20 mg/m²) at days 1, 8, 15, 22, 29, and 36. Both groups treated with concurrent 60 Gy 3DCRT at 200 cGy/d.

Results

Seventy-four patients were enrolled and 71 completed the planned treatment, with a follow-up rate of 95.94%. Short-term curative effect was not statistically significant between the two groups (P = 0.471). The 2-year survival rates were 65.7% and 61.1%, respectively (P = 0.806), 5 years survival rates were 34.29% and 27.78%, respectively (P = 0.221), and there was no significant difference by Fisher test (P = 0.734). As common side effects, incidence rates of radioactive esophagitis and hematological toxicity were lower in DP group.

Conclusion

For locally advanced esophageal cancer patients, current chemoradiotherapy with chemotherapy regimen of weekly docetaxel plus cisplatin has equal curative effect with 5-fluorouracil plus cisplatin, but well-tolerated by reducing side effects such as radioactive esophagitis and bone marrow suppression.     

Phase I study of cediranib in combination with cisplatin plus fluoropyrimidine (S-1 or capecitabine) in Japanese patients with previously untreated advanced gastric cancer

Purpose

The primary objective of this Phase I study was to assess the safety and tolerability of the vascular endothelial growth factor signalling inhibitor cediranib in combination with cisplatin plus an oral fluoropyrimidine, in Japanese patients with previously untreated advanced gastric cancer.

Methods

Patients received continuous, once-daily oral doses of cediranib 20?mg in combination with either cisplatin (60?mg/m² iv day 1) plus S-1 (40?C60?mg bid, days 1?C21) every 5?weeks for a maximum of eight cycles [Arm A]; or cisplatin (80?mg/m² iv, day 1) plus capecitabine (1,000?mg/m² bid, days 1?C14) every 3?weeks for a maximum of six cycles [Arm B]. In both arms, the assessment period for dose-limiting toxicities (DLTs) was the first 21?days of cycle 1.

Results

Fourteen patients (Arm A, n?=?6; Arm B, n?=?8) were enrolled and received at least one dose of cediranib. One patient in each arm experienced a DLT (Arm A; decreased appetite, grade 3; Arm B, decreased appetite, fatigue and hyponatraemia, all grade 3). Overall, the most common adverse events were decreased appetite, fatigue and nausea (all n?=?13 [92.9%]). Preliminary efficacy evaluation showed one confirmed (Arm A) and three unconfirmed (Arm A, n?=?1; Arm B, n?=?2) partial responses that were ongoing at data cut-off.

Conclusions

Cediranib 20?mg/day in combination with cisplatin and S-1 or capecitabine was tolerable, with no new toxicities identified, and showed preliminary evidence of antitumour activity.     

Three-week combination chemotherapy with S-1 and cisplatin as first-line treatment in patients with advanced gastric cancer: a retrospective study with 159 patients

Background

Doses and schedules of the combination of S-1 and cisplatin for the treatment of advanced gastric cancer (AGC) have not been standardized. We therefore evaluated the efficacy and feasibility of a 3-week schedule of S-1 and cisplatin in patients with AGC, as well as assessing factors prognostic of patient outcomes.

Methods

A total of 159 patients with AGC were treated with S-1 (40?mg/m² bid on days?1–14) and cisplatin (60?mg/m² IV on day?1) between January 2004 and December 2008.

Results

Median follow-up duration was 20.0?months (range, 11.4–48.5?months), during which time 129 patients (81.1%) died. Patients received a median 6 cycles of chemotherapy (range, 1–19 cycles). Among the 59 patients with measurable disease, 1 achieved a complete response (1.7%) and 24 (40.7%) had partial responses, giving an overall response rate of 42.4% (95% CI, 23.0–61.8%). The median progression-free survival (PFS) was 5.8?months (95% CI, 4.8–6.9?months), and the median overall survival (OS) was 11.3?months (95% CI, 9.6–13.0?months). Multivariate analysis showed that initial metastasis, bone metastasis, and liver metastasis were independent prognostic factors for reduced PFS, whereas poor performance status, initial metastasis, and bone metastasis were prognostic for reduced OS. Application of a previous prognostic model showed that observed PFS and OS survival curves for patients in various risk groups differed significantly (P?Conclusions A 3-week regimen of S-1 plus cisplatin was active and well tolerated as first-line treatment in patients with AGC. Disease status and bone metastasis were the most important prognostic factors.     

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.     

A randomized phase II trial of two different 4-drug combinations in advanced pancreatic adenocarcinoma: cisplatin, capecitabine, gemcitabine plus either epirubicin or docetaxel (PEXG or PDXG regimen)

Purpose

PEFG regimen (P:cisplatin, E:epirubicin, F:5-fluorouracil, G:gemcitabine) significantly prolonged progression-free (PFS) and overall survival (OS) of patients with advanced pancreatic adenocarcinoma (PA) with respect to standard gemcitabine. The current trial was aimed at assessing whether the replacement of E with docetaxel (D) may improve 6?months PFS (PFS6).

Methods

Chemo-naive patients with stage III or metastatic PA received P (30?mg/m² day 1 and 15), G (800?mg/m² day 1 and 15), and capecitabine (1,250?mg/m²/day?days 1?C28, without a break) and were randomized to receive either D at 25?C30?mg/m² day 1 and 15 (arm A: PDXG regimen) or E at 30?mg/m² day 1 and 15 (arm B: PEXG regimen). Cycles were repeated every 28?days for a maximum of 6?months. The Fleming design was used to calculate the sample size on the probability of being PFS6. Assuming P0?=?40% and P1?=?60%, ???=?0.05 and ???=?0.10; the study was to enroll 52 patients per arm.

Results

Between July 2005 and September 2008, 105 patients were enrolled, stratified by stage and randomized. Patients?? characteristics were (A/B) the following: median age 61/59, PS?>70 92/88%, metastatic disease 66/65%. PFS6 was 58%, and median OS was 11?months in both arms. A partial response was observed in 60/37% of patients. Main per cycle G3-4 toxicity was the following: neutropenia 4/13%, thrombocytopenia 2/4%, anemia 4/4%, and fatigue 6/3%.

Conclusions

The inclusion of D instead of E yielded more objective response and less G3-4 neutropenia but did not improve PFS and OS. The present trial confirms the relevant impact on outcome of advanced PA of 4-drug regimens.     

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.     

Preoperative S-1 and docetaxel combination chemotherapy in patients with locally advanced gastric cancer

Purpose

The combination of docetaxel and S-1 (DS) therapy is effective in patients with unrespectable gastric cancer and is expected to be a regimen in neoadjuvant setting for advanced gastric cancer. This study was held to evaluate the efficacy and safety of DS followed by surgery.

Methods

Patients with resectable gastric cancer received 2 courses of docetaxel 40 mg/m² on days 1, 15 and S-1 40 mg/m² bid orally on days 1–7, 15–21 every 4 weeks, followed by standard radical gastrectomy. Primary end point was the pathological response rate: rate of tumors in which one-third or more parts were affected.

Results

Fourteen patients were enrolled. Thirteen (92.8 %) patients completed two courses of chemotherapy. Grade 3 adverse events were neutropenia in 3 (21.4 %) patients, anemia in 1 (6.2 %) patient and diarrhea in 1 (6.2 %) patient. There were no grade 4 adverse event and febrile neutropenia. All patients underwent R0 resection, and pathological response was found in 50.0 % of patients. There were no major surgical complications and no treatment-related mortality.

Conclusions

The neoadjuvant chemotherapy with DS was effective for patients with locally advanced gastric cancer with manageable toxicities. Further study to confirm the usefulness of this regimen is needed.     

A randomized phase-II trial comparing sequential and concurrent paclitaxel with oral or parenteral fluorinated pyrimidines for advanced or metastatic gastric cancer

Background

The purpose of this study was twofold: (1) to compare S-1 with infusional 5-fluorouracil (FU) to determine which would be a better partner of paclitaxel (PTX), and (2) to compare a concurrent strategy with a sequential one, the latter strategy being the one that is widely used in Japanese general practice.

Methods

The 161 eligible patients were randomized into four arms to receive the following regimens: A (sequential), intravenous 5-FU at 800?mg/m² for 5?days every 4?weeks followed by weekly PTX at 80?mg/m²; B (sequential), S-1 at 80?mg/m² for 4?weeks and 2-week rest followed by PTX; C (concurrent), intravenous 5-FU at 600?mg/m² for 5?days and weekly PTX at 80?mg/m² every 4?weeks; and D (concurrent), S-1 for 14?days and PTX at 50?mg/m² on days 1 and 8 every 3?weeks. The primary endpoint was the overall survival (OS) rate at 10?months.

Results

The ten-month OS rates in arms A, B, C, and D were 63, 65, 61, and 73%, respectively. The OS was best in the concurrent S-1/PTX arm, with a mean survival time of 15.4?months, but no significant difference was observed between the four arms. Response rates were higher in the concurrent arms than in the sequential arms.

Conclusion

Our study did not show sufficient prolongation of survival with the concurrent strategy to proceed to a phase-III trial; however, the sequential arms showed survival comparable to that in the concurrent arms, with less toxicity. In patients who are ineligible for cisplatin (CDDP), sequential treatment starting with S-1 and proceeding to PTX would be a good alternative strategy, considering quality of life (QOL) and the cost-benefits of an oral agent as first-line treatment.