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.     

A retrospective study of docetaxel or paclitaxel in patients with advanced or recurrent esophageal squamous cell carcinoma who previously received fluoropyrimidine- and platinum-based chemotherapy

Introduction

Fluoropyrimidine plus platinum (FP)-based chemotherapy has been widely used as a first-line regimen for advanced or recurrent esophageal cancer, and taxanes have shown efficacy after FP-based chemotherapy, but there is no standard regimen for second-line chemotherapy (SLC). We retrospectively investigated the clinical features of taxane therapy in SLC for esophageal squamous cell carcinoma (ESCC).

Methods

The selection criteria were pathologically proven ESCC; advanced or recurrent disease previously treated with FP at our hospital; performance status (PS) 0–2; and adequate organ function. Docetaxel (DTX) was administered 3-weekly at 70 mg/m². Paclitaxel (PTX) was administered at 100 mg/m² weekly for 6 weeks, with 1 week’s rest.

Results

The analysis covered 163 patients from August 2006 to June 2012. Median age was 64 years (range 37–83: DTX group 132 patients and PTX group 31). Progression-free survival and median overall survival (OS) were 2.3 and 6.1 months, respectively, with PTX and 2.3 and 5.3 months with DTX. Response rates were 20.7 % for PTX and 5.9 % for DTX. The rate of grades 3–4 neutropenia was higher with DTX (32.6 %) than with PTX (16.1 %). Grade 3 febrile neutropenia was seen in 6.1 % of DTX recipients but in no PTX group. According to multivariate analyses of OS, PS 2, number of metastatic sites ≧2, and CRP ≧1 mg/dL were independent predictors of poor prognosis.

Conclusions

PTX and DTX were both effective in SLC for ESCC, but their toxicity profiles differed. In terms of febrile neutropenia, PTX seems more appropriate.     

First-line paclitaxel and cisplatin used sequentially or in combination in metastatic breast cancer: A phase II randomized study

Introduction

Breast cancer (BC) is the commonest cancer among females worldwide. Some patients present initially at advanced stages and more than 50% of them will develop metastasis (MBC) at some point. Compared to single agents, combination chemotherapy produces higher response rates (RR), longer progression-free survival (PFS) than single agents. This is associated with remarkably higher toxicities. At the same time, overall survival (OS) is comparable. This study aimed to compare safety and efficacy of combination and sequential chemotherapy.

A phase I study of combination therapy with S-1 and irinotecan in patients with previously untreated metastatic or recurrent colorectal cancer

Background

To investigate the combination of S-1 and irinotecan (CPT-11) as an alternative to infusional 5-fluorouracil/leucovorin plus CPT-11, we performed a phase I trial to determine the maximum tolerated dose, recommended dose (RD), and dose-limiting toxicities (DLTs) in patients with metastatic or recurrent colorectal cancer.

Patients and methods

S-1 and CPT-11 doses were escalated using a standard 3?+?3 design. S-1 was administered orally at 70?mg/m² (levels 1?C3) or 80?mg/m² (levels 4 and 5) for 14 consecutive days followed by 1-week rest. CPT-11 was administered intravenously on day 1, at 175?mg/m² (level 1), 200?mg/m² (level 2), 225?mg/m² (levels 3 and 4), or 250?mg/m² (level 5). Treatment was repeated every 3?weeks, unless disease progression or severe toxicities were observed.

Results

Twenty-three patients were treated. One patient at each of levels 2 and 4 developed a DLT, grade 3 ileus, and grade 3 diarrhea, respectively. At both levels, an additional three patients did not experience DLTs. At level 5, two of five patients experienced DLTs, including grade 3 enteritis and grade 4 neutropenia for more than 5?days. The RD was determined at level 4 (80?mg/m² S-1 and 225?mg/m² CPT-11). An objective response was observed in 7 of 17 patients with measurable disease: 2 of 5 at level 2; 3 of 4 at level 4; and 2 of 4 at level 5.

Conclusions

The RDs of CPT-11 and S-1 were determined as 225 and 80?mg/m², respectively, and further phase II trials are warranted.     

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.     

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.     

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.     

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.     

Prospective multicenter study to investigate the introduction rate of second-line S-1 in gemcitabine-refractory unresectable pancreatic cancer

Purpose

S-1 is one of the second-line candidate agents for gemcitabine-refractory unresectable pancreatic cancer. Two phase II studies have been reported for second-line chemotherapy with S-1, but these studies did not investigate introduction rate and suitable dose of second-line S-1. Therefore, we conducted a prospective multicenter study in which chemo-na?ve patients were enrolled and had two levels of S-1 dose.

Methods

Chemo-na?ve patients with unresectable pancreatic cancer were enrolled. This study started with 80?mg/m²/day dose of S-1 as second-line chemotherapy and tolerability was checked. When tolerability was not confirmed in initial patients, the dose of S-1 was shifted to 60?mg/m²/day. When tolerability was confirmed at 80 or 60?mg/m²/day, the study continued, and up to 20 patients were accumulated with the dose. In addition, the introduction rate of second-line S-1 was examined.

Results

Six of the initial 7 patients with 80?mg/m²/day dose of S-1 completed one course of second-line chemotherapy. Twenty patients were accumulated with an 80?mg/m²/day dose of S-1. With the exception of one patient continued gemcitabine chemotherapy, two of the remaining 19 patients withdrew from this study because of toxicity during the period of gemcitabine chemotherapy. Fifteen of the remaining 17 gemcitabine-refractory patients could complete one course of S-1 as second-line chemotherapy with acceptable toxicity.

Conclusions

This prospective multicenter study showed that 15 (78.9%) out of 19 chemo-na?ve unresectable pancreatic cancer patients could complete one course of 80?mg/m²/day dose of S-1 as second-line chemotherapy after first-line gemcitabine chemotherapy failure with tolerable toxicity.     

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.     

Two phase I studies of concurrent radiation therapy with continuous-infusion 5-fluorouracil plus epirubicin, and either cisplatin or irinotecan for locally advanced upper gastrointestinal adenocarcinomas

Purpose

Multimodality therapy with chemotherapy and radiation treatment may improve disease control and overall outcome of locally advanced upper gastrointestinal (UGI) malignancies including esophageal, gastric, pancreatic, and biliary tract carcinomas. However, more effective and less toxic chemotherapy regimens with concomitant radiotherapy are needed beyond concurrent continuous-infusion fluorouracil (CIFU) with radiation that is commonly applied in general practice. Epirubicin, cisplatin, and irinotecan are active cytotoxic chemotherapy agents in UGI cancers.

Methods

Two parallel phase I studies were designed to test the tolerability (dose-limited toxicity [DLT] and maximum tolerable dose [MTD]) of the combination of radiotherapy concurrently with CIFU, epirubicin, and cisplatin (ECF/radiation) or CIFU, epirubicin, and irinotecan (EIF/radiation) in the treatment of locally advanced upper GI malignancies. CIFU was administered through a portable infusion pump for 5 1/2?weeks during radiation treatment (50.4?Gy?Ca dose of 45?Gy in 25 fractions of 1.8?Gy, with additional comedown of 5.4?Gy). Epirubicin, cisplatin, or irinotecan were administered intravenously each week for 5?weeks (days 1, 8, 15, 22, and 29).

Results

The MTDs recommended for further studies are: 5-fluorouracil 200?mg/m²/day CI, weekly cisplatin 20?mg/m² and epirubicin 10?mg/m² for ECF/radiation combination; 5-fluorouracil 200?mg/m²/day CI, weekly irinotecan 30?mg/m² and epirubicin 10?mg/m² for EIF/radiation regimen. The DLTs are neutropenia, diarrhea/dehydration, and mucositis as expected.

Conclusions

Both regimens are safe with expected toxicities, and the efficacy of both regimens was encouraging. Further larger scale studies should be considered.     

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.     

Induction gemcitabine in standard dose or prolonged low-dose with cisplatin followed by concurrent radiochemotherapy in locally advanced non-small cell lung cancer: a randomized phase II clinical trial

Background

The optimal combination of chemotherapy with radiation therapy for treatment locally advanced non-small cell lung cancer (NSCLC) remains an open issue. This randomized phase II study compared gemcitabine in two different schedules and cisplatin - as induction chemotherapy, followed by radiation therapy concurrent with cisplatin and etoposid.

Patients and methods.

Eligible patients had microscopically confirmed inoperable non-metastatic non-small cell lung cancer; fulfilled the standard criteria for platin-based chemotherapy; and signed informed consent. Patients were treated with 3 cycles of induction chemotherapy with gemcitabine and cisplatin. Two different aplications of gemcitabine were compared: patients in arm A received gemcitabine at 1250 mg/m² in a standard half hour i.v. infusion on days 1 and 8; patients in arm B received gemcitabine at 250 mg/m² in prolonged 6-hours i.v. infusion on days 1 and 8. In both arms, cisplatin 75 mg/m² on day 2 was administered. All patients continued treatment with radiation therapy with 60–66 Gy concurrent with cisplatin 50 mg/m² on days 1, 8, 29 and 36 and etoposid 50 mg/m² on days 1–5 and 29–33. The primary endpoint was response rate (RR) after induction chemotherapy; secondary endpoints were toxicity, progression-free survival (PFS) and overall survival (OS).

Results

From September 2005 to November 2010, 106 patients were recruited to this study. No statistically signifficant differences were found in RR after induction chemotherapy between the two arms (48.1% and 57.4%, p = 0.34). Toxicity profile was comparable and mild with grade 3/4 neutropenia as primary toxicity in both arms. One patient in arm B suffered from acute peripheral ischemia grade 4 and an amputation of lower limb was needed. With a median follow-up of 69.3 months, progression-free survival and median survival in arm A were 15.7 and 24.8 months compared to 18.9 and 28.6 months in arm B. The figures for 1- and 3-year overall survival were 73.1% and 30.8% in arm A, and 81.5 % and 44.4% in arm B, respectively.

Conclusions

Among the two cisplatin-based doublets of induction chemotherapy for inoperable NSCLC, both schedules of gemcitabine have a comparable toxicity profile. Figures for RR, PFS and OS are among the best reported in current literature. While there is a trend towards better efficacy of the treament with prolonged infusion of gemcitabine, the difference between the two arms did not reach statistical significance.     

A retrospective study of S-1 and oxaliplatin combination chemotherapy in patients with refractory pancreatic cancer

Purpose

The aim of this study was to evaluate S-1 and oxaliplatin combination chemotherapy (SOX) in patients with refractory pancreatic cancer (PC).

Methods

Consecutive patients with advanced PC refractory to gemcitabine who were treated with oral S-1 (80 mg/m²) on days 1–14 and intravenous oxaliplatin (100 mg/m²) on day 1 every 3 weeks were studied retrospectively. The primary end point was the objective response rate (ORR). The secondary end points were progression-free survival (PFS), overall survival (OS), the disease control rate (DCR), and safety.

Results

Between March 2009 and October 2011, 30 patients were treated with SOX, with a median of two courses (range 1–8). The ORR and DCR were 10.0 and 50.0 %, respectively. Median PFS and OS were 3.4 months (95 % confidence interval [CI] 1.3–5.3) and 5.0 months (95 % CI 3.4–7.4), respectively. The median PFS and OS were 5.6 and 9.1 months in patients receiving S-1 and oxaliplatin as a second-line treatment. Major grade 3 or 4 adverse events included neutropenia (10.0 %), anemia (3.3 %), and diarrhea (6.7 %).

Conclusions

SOX was well tolerated and moderately effective in patients with refractory PC.     

A phase I trial of gemcitabine,S-1 and LV combination (GSL) therapy in advanced pancreatic cancer

Purpose

In our previous randomized controlled trial, the addition of S-1 to gemcitabine for advanced pancreatic cancer did not prolong overall survival (OS) significantly, despite its higher response rate and longer progression-free survival (PFS). Leucovorin is known to enhance efficacy of S-1, and we conducted this phase I trial of combination therapy of gemcitabine, S-1 and leucovorin (GSL).

Methods

Patients with advanced pancreatic cancer who had received no prior chemotherapy were eligible for this study. Gemcitabine was administered at an escalating dose of 600, 800 and 1,000 mg/m² over 30 min on day 1, and oral S-1 at a dose of 40 mg/m² twice daily and oral leucovorin at a dose of 25 mg twice daily on days 1–7, every 2 weeks. A standard “3 + 3” phase I dose escalation design was utilized.

Results

Fifteen patients were enrolled across three dose levels. Three patients developed DLTs: two patients in level 1 (grade 3 anorexia in 1 and grade 3 anorexia, stomatitis and diarrhea in 1) and one patient in level 2 (grade 3 deep vein thrombosis). No DLT was observed in level 3. Response rate and the disease control rate were 33 and 93 %, respectively. The median PFS and OS were 5.4 and 16.6 months. Ten of 12 patients (83 %) with elevated CA19-9 at baseline had a ≥50 % decline.

Conclusions

RD of gemcitabine in GSL was determined as 1,000 mg/m². GSL was well tolerable and showed promising results in advanced pancreatic cancer.     

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 I study of adjuvant gemcitabine or S-1 in patients with biliary tract cancers undergoing major hepatectomy: KHBO1003 study

Background

Standardized adjuvant therapy is not performed after major hepatectomy for biliary tract cancer (BTC) because of frequent adverse events, which may be caused by insufficient liver function. Therefore, the aim of this multicenter study (KHBO1003) was to determine the safety protocol for adjuvant chemotherapy after major hepatectomy.

Methods

Within 12 weeks of R0 or R1 major hepatectomy (hemihepatectomy or trisectionectomy) for BTC, the following adjuvant chemotherapy was performed for 6 months: 800–1,000 mg/m² gemcitabine on days 1, 8, and 15 and then every 3–4 weeks or 40–80 mg/m²/day S-1 on days 1–28 and every 3–6 weeks. Major dose-limited toxicity (DLT) was defined as grade 4 hematotoxicity, grade 3/4 febrile neutropenia, grade 3/4 non-hematotoxicity, skipped gemcitabine on days 8 and 15, or halting the course at or after 14 days. Dose-escalation and de-escalation decisions were based on the continual reassessment method. Every three patients were alternately assigned to each arm.

Results

Thirty-three patients (14 intrahepatic bile duct, 1 gall bladder, 18 extrahepatic bile duct) were enrolled in this study from February 2011 to July 2012 (n = 18 gemcitabine, n = 15 S-1). At 10 % of DLT, the recommended dose was 1,000 mg/m² gemcitabine biweekly and 80 mg/m²/day S-1 on days 1–28 and every 6 weeks. Major DLT and adverse drug reactions were neutropenia. No grade 3 or 4 non-hematological adverse events were noted.

Conclusion

We determined RDs for gemcitabine and S-1 adjuvant chemotherapy after major hepatectomy with a DLT that does not exceed 10 %.     

Phase I/II study of intraperitoneal docetaxel plus S-1 for the gastric cancer patients with peritoneal carcinomatosis

Purpose

We designed a phase I/II trial of intraperitoneal (IP) docetaxel plus S-1 to determine the maximum tolerated dose (MTD) and recommended dose (RD) and to evaluate its efficacy and safety in gastric cancer patients with peritoneal carcinomatosis (PC).

Methods

Patients with PC confirmed by laparoscopy or laparotomy received IP docetaxel on days 1 and 15 and S-1 (80 mg/m²) on days 1–14 every 4 weeks.

Results

In the phase I part (n = 12), each cohort received escalating doses of docetaxel (35–50 mg/m²); the MTD was determined to be 50 mg/m² and the RD was determined to be 45 mg/m². Dose-limiting toxicities included grade 3 febrile neutropenia and grade 3 diarrhea. In the phase II part (n = 27), the median number of courses was 4 (range 2–11). The 1-year overall survival (OS) rate was 70 % (95 % confidence interval 53–87 %). The overall response rate was 22 % and peritoneal cytology turned negative in 18 of 22 (81 %) patients. The most frequent grade 3/4 toxicities included anorexia (19 %), neutropenia (7 %), and leukopenia (7 %).

Conclusion

IP docetaxel plus S-1 is active and safety in gastric cancer patients with PC.     

Phase I/II study of gemcitabine as a fixed dose rate infusion and S-1 combination therapy (FGS) in gemcitabine-refractory pancreatic cancer patients

Purpose

There is no standard regimen for gemcitabine (Gem)-refractory pancreatic cancer (PC) patients. In a previous phase II trial, S-1 was found to exhibit marginal efficacy. Gem administration by fixed dose rate infusion of 10?mg/m²/min (FDR-Gem) should maximize the rate of intracellular accumulation of gemcitabine triphosphate and might improve clinical efficacy. We conducted the phase I/II of FDR-Gem and S-1 (FGS) in patients with Gem-refractory PC.

Methods

The patients received FDR-Gem on day 1 and S-1 orally twice daily on days 1–7. Cycles were repeated every 14?days. Patients were scheduled to receive Gem (mg/m²/week) and S-1 (mg/m²/day) at four dose levels in the phase I: 800/80 (level 1), 1,000/80 (level 2), 1,200/80 (level 3) and 1,200/100 (level 4). Forty patients were enrolled in the phase II study at recommended dose.

Results

The recommended dose was the level 3. In the phase II, a partial response has been confirmed in seven patients (18%). The median overall survival time and median progression-free survival time are 7.0 and 2.8?months, respectively. The common adverse reactions were anorexia, leukocytopenia and neutropenia.

Conclusion

This combination regimen of FGS is active and well tolerated in patients with Gem-refractory PC.     

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.