Phase I Study of Oxaliplatin in Combination with Gemcitabine, Irinotecan, and 5-Fluorouracil/Leucovorin (G-FLIE) in Patients with Metastatic Solid Tumors Including Adenocarcinoma of the Pancreas

Purpose

The aims of this study were to establish the maximum tolerated dose (MTD) of oxaliplatin in combination with fixed doses of gemcitabine, irinotecan, and 5-fluorouracil/leucovorin (G-FLIE) in solid tumors, including advanced pancreatic cancer, and to evaluate the toxicity of the regimen.

Methods

Patients with metastatic solid tumors were treated with a regimen consisting of gemcitabine (500 mg/m² by fixed-dose-rate infusion), irinotecan (120 mg/m²), leucovorin 300 mg, bolus/infusion 5-fluorouracil (400 and 1,500 mg/m2, respectively), and oxaliplatin at doses from 50 to 85 mg/m² according to the escalation schema. Treatment was repeated every 14 days.

Results

The study enrolled 25 patients with a median age of 64 years and median Karnofsky performance score of 80. Patients had metastatic adenocarcinomas of pancreas (n?=?9), as well as gastroesointestinal, hepatobiliary, or unknown primary tumors. With only one dose limiting toxicity (neutropenia and constipation), the MTD of oxaliplatin was not reached up to the pre-specified maximum level of 85 mg/m². Other toxicities predictably included cytopenias, fatigue, sensory neuropathy, nausea/vomiting, diarrhea, and constipation. Four partial responses and ten disease stabilizations were observed. The overall median time to disease progression was 17 weeks (2–110 weeks) with median overall survival of 31.5 weeks (7–139 weeks).

Conclusions

G-FLIE is a tolerable multi-agent chemotherapy regimen with the oxaliplatin dose up to 85 mg/m². The combination of full-dose oxaliplatin with gemcitabine, irinotecan, and 5-fluorouracil is feasible with attenuated doses of the drugs, but further optimization is necessary before assessment of efficacy.     

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.     

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 II trial of the ribonucleotide reductase inhibitor 3-aminopyridine-2-carboxaldehydethiosemicarbazone plus gemcitabine in patients with advanced biliary tract cancer

Background

3-Aminopyridine-2-carboxaldehydethiosemicarbazone (3-AP) is a novel small molecule ribonucleotide reductase (RR) inhibitor which is more potent than hydroxyurea, the prototype of RR inhibitors. 3-AP enhances the cellular uptake and DNA incorporation of gemcitabine in tumor cell lines. We evaluated the combination of 3-AP plus gemcitabine in advanced biliary tract adenocarcinoma.

Methods

Thirty-three patients with advanced adenocarcinoma of the gall bladder or biliary tract received gemcitabine (1,000?mg/m² on days 1, 8, and 15 every 28?days) 1?h after completing a 4-h infusion of 3-AP given at a dose of 105?mg/m² in patients with normal liver function (stratum A) or 80?mg/m² if abnormal liver function (stratum B). The trial was designed to determine whether the response rate was at least 30% in stratum A and 20% in stratum B.

Results

Objective response occurred in 3 of 23 patients (13%, 95% confidence intervals [CI] 3, 34%) with normal liver function, and in 0 of 10 patients with abnormal liver function. The most common grade 3?C4 adverse events in all patients included neutropenia (42%), infection (33%), thrombocytopenia (27%), anemia (18%), and fatigue (15%). Fine needle aspiration of tumor samples obtained before and 24?h after 3-AP therapy showed increased R2 mRNA expression by in situ RT?CPCR, suggesting RR inhibition.

Conclusions

Despite evidence for RR inhibition in vivo, the 3-AP plus gemcitabine combination is not likely to be associated with a response rate exceeding 30% in patients with adenocarcinoma of the biliary tract.     

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.     

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.     

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.     

A phase I study of the biomodulation of capecitabine by docetaxel and gemcitabine (mGTX) in previously untreated patients with metastatic adenocarcinoma of the pancreas

Background

Pancreas cancer remains a formidable challenge. We report the first prospective analysis of the 3-drug combination of gemcitabine (G), docetaxel (T) and capecitabine (X) (mGTX) with schedule modification to maximize biomodulation of X.

Methods

We conducted a dose escalation study of mGTX in first-line treatment of metastatic pancreas cancer using three dose levels (DL 1-3). Patients received docetaxel on days 1 and 8, gemcitabine on days 8 and 15, and capecitabine on days 8 through 21. Gemcitabine dose was fixed at 750?mg/m² over 75?min, capecitabine was given twice daily and escalated from 500 to 650?mg/m² at DL2 and docetaxel increased from 30 to 36?mg/m² at DL3.

Results

Twenty-one patients (18 evaluable) were enrolled in the study. MTD was reached at DL3 and one DLT was observed at DL2 (prolonged neutropenia). The most common grade 3/4 toxicities were leukopenia (29%) and neutropenia (29%) and fatigue (25%). Tumor growth control rate was 80% (11% PR; 69% SD lasting at least 3?months). Median progression-free-survival was 5.8?months (95% CI 2.7, 10.6) and median overall survival was 7.4?months (95% CI 3.8 16.8). CA 19-9 decreased by at least 50% from baseline in half the patients.

Conclusion

mGTX demonstrates acceptable tolerability with interesting activity in patients with pancreatic cancer. The recommended doses for phase II studies are docetaxel 36?mg/m² days 1 and 8, gemcitabine 750?mg/m² over 75?min days 8 and 15, and capecitabine 625?mg/m² twice daily days 8 through 21.     

Hematologic toxicity of gemcitabine: a comparison between fixed-dose rate infusion and thirty-minute infusion in the treatment of malignancy

Objective

The aim of the study was to compare the hematologic toxicity of gemcitabine between fixed-dose rate (FDR) infusion and 30-minute standard infusion in the treatment of malignancy.

Methods

The 25 malignancy patients confirmed by histopathology or cytology received single-agent gemcitabine or gemcitabine in combination with other chemotherapeutic agents. These patients were randomly divided into gemcitabine 1000 mg/m² on d1, d8 at a rate of 10 mg/m²/min arm (FDR arm) or 30 min arm (standard arm), every 21 days one cycle. Hematologic toxicity was evaluated at the end of each cycle.

Results

The 13 of 25 patients received gemcitabine FDR therapy, a total of 28 cycles was completed, and 32 cycles in the others (12 of 25 patients) with the standard arm. All patients were evaluable for hematologic toxicity. The result showed that the grades 3–4 leucopenia was significantly different between the two arms (14.3% vs 0, P < 0.05), and no significant differences of neutropenia, thrombocytopenia and hemoglobin suppression of grades 3–4 (14.3% vs 3.1%, 10.7% vs 3.1%, 3.6% vs 9.4%, P > 0.05, respectively) were observed between the two arms, no grade 4 of hemoglobin suppression was observed.

Conclusion

Hematologic toxicity of gemcitabine therapy at a fixed-dose rate for malignancy is tolerable.     

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.     

Phase I/II study of irinotecan, UFT and leucovorin with hepatic arterial infusion using 5-FU in colorectal cancer patients with unresectable liver metastases

Purpose

To evaluate the efficacy and tolerability of systemic chemotherapy with irinotecan (CPT-11), UFT and leucovorin (LV) combined with hepatic arterial infusion (HAI) consisting of 5-fluorouracil (5-FU) in colorectal cancer patients with unresectable liver metastases.

Methods

Patients were treated concurrently with escalating doses of intravenous CPT-11 (100, 120, and 140?mg/m²) on day 1 of each 14-day treatment cycle, with oral UFT (300?mg/m² per day) and LV (75?mg/body per day) on days 1?C7 of each cycle, and with HAI 5-FU (2,000?mg/week) on days 8?C14 of each cycle.

Results

Twelve patients were enrolled in the phase I study. The maximum-tolerated dose was not reached. Consequently, the recommended dose of CPT-11 for the phase II study was determined to be 140?mg/m². Twenty-two patients were evaluated in the phase II study. Five patients experienced grade 3 neutropenia, two experienced grade 3 anorexia, two experienced nausea, and two experienced vomiting. An overall response was observed in 19 out of 22 patients (86.4%). The median progression-free survival period was 11.2?months, and the 3-year survival rate was 50.6%. Fourteen patients (63.6%) were ultimately able to undergo a complete liver resection.

Conclusions

Chemotherapy with CPT-11 and UFT/LV combined with HAI yielded a high response rate and enabled a significant proportion of patients with initially unresectable liver metastases to undergo surgical resection. Further trials are warranted.     

Pharmacokinetic study of gemcitabine, given as prolonged infusion at fixed dose rate, in combination with cisplatin in patients with advanced non-small-cell lung cancer

Introduction

Although some studies have suggested that gemcitabine delivered as a fixed dose rate (FDR) infusion of 10 mg/m²/min could be more effective than when administered as the standard 30-min infusion, the available pharmacokinetic data are still too limited to draw definitive conclusions. This study is aimed to investigate the plasmatic and intracellular pharmacokinetics of gemcitabine given as FDR at doses of 600 and 1,200 mg/m² in combination with 75 mg/m² of cisplatin in advanced non-small-cell lung cancer (NSCLC) patients.

Patients and method

The patients were divided into two groups receiving different initial doses of the drug: 4 patients received 600 mg/m² gemcitabine 60-min i.v. infusion and 4 patients 1,200 mg/m² gemcitabine 120-min i.v. infusion both as a FDR of 10 mg/m²/min on days 1 and 8 of a 21-day cycle (at first cycle). At the second cycle, all patients were treated with gemcitabine at 1,200 mg/m² 120-min i.v. infusion (FDR of 10 mg/m²/min) on days 1 and 8 of a 21-day cycle. At each cycle, gemcitabine was administered alone on day one, and in combination with 75 mg/m² of cisplatin on day 8. Plasmatic and intracellular pharmacokinetic analyses were performed on blood samples collected at defined time points before, during and after gemcitabine infusion.

Results

The plasmatic pharmacokinetic parameters were clearly different when the patients received a higher gemcitabine dose in the second cycle compared to the lower dose of the first course; in the same time, the intracellular drug levels were not modified. Comparing the pharmacokinetic parameters of different patients treated at different dose levels, the results appeared to be quite similar.

Conclusions

A substantially higher accumulation of metabolites in peripheral blood mononuclear cells was observed when the longer infusion time was employed, suggesting a pharmacological advantage for this treatment schedule.     

Oxaliplatin Plus 5-Fluorouracil and Folinic Acid (OFF) in Gemcitabine-Pretreated Advanced Pancreatic Cancer: A Phase II Study

Background

Despite median survival of less than 6 months, there is a significant proportion of advanced pancreatic cancer patients who progress on gemcitabine that remains fit, and these patients are candidates for second-line treatment.

Objective

The objective of this study is to evaluate the efficacy and safety of oxaliplatin plus 5-fluorouracil and folinic acid in patients with gemcitabine-pretreated advanced pancreatic cancer.

Patients and Methods

Thirty patients with advanced pancreatic cancer who were pretreated with gemcitabine received oxaliplatin (85 mg/m²) on days 1 and 15 followed by leucovorin (20 mg/m²) and 5-fluorouracil (500 mg/m²) on days 1, 8, and 15. The cycle was repeated every 3 weeks.

Results

The majority of patients (80 %) had locally advanced disease. Median age was 63 years, and 60 % were males. The liver was the most common site of metastasis. Partial response was observed in 2 patients (6.7 %) and stable disease in 6 patients (20 %), while 12 patients progressed (40 %). Improved performance status was reported in 10 patients (33.3 %). The median duration of response was 13 weeks, and median overall survival was 22 weeks. There was no grade 4 toxicity apart from grade 4 neutropenia in 6.6 % of patients. Neutropenia (46.5 %) and neuropathy (43.2 %) were the most common toxicities, while hand–foot syndrome was the least frequent one (20 %). There were no treatment-related deaths. The 6-month survival rate was 30 %.

Conclusion

This regimen is feasible and active with an acceptable toxicity; however, further investigation in phase III trial is needed.     

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 II study of FOLFIRI regimen in patients with advanced colorectal cancer refractory to fluoropyrimidine and oxaliplatin

Purpose

To evaluate the efficacy and safety of FOLFIRI regimen in patients with advanced colorectal cancer refractory to fluoropyrimidine and oxaliplatin.

Methods

The FOLFIRI regimen consisted of intravenous infusion of irinotecan 180?mg/m² on day 1 plus leucovorin (LV) 400?mg/m² on day 1 plus 5-fluorouracil (5-FU) 400?mg/m² bolus on day 1 plus 46-hour intravenous infusion of 5-FU 2,400?mg/m², every 2?weeks as one cycle. The main selection criterion for this study was the advanced colorectal cancer refractory to fluoropyrimidine and oxaliplatin.

Results

Of the 57 evaluable patients for efficacy, 4 (7.5%) had a partial response, 36 (67.9%) had stable disease, and 13 (24.5%) had progressive disease. Median progression-free survival was 4.8?months (95% CI 3.9?C5.7?months), and median overall survival was 7.8?months (95% CI 13.1?C16.5?months). Safety analysis was based on the data of 57 evaluable patients. The most frequently observed grade 3 or 4 toxicities were neutropenia 16 (27.8%), nausea/vomiting 7 (12.3%), and diarrhea 1 (1.8%).

Conclusion

FOLFIRI regimen is effective and well tolerated in patients with advanced colorectal cancer refractory to fluoropyrimidine and oxaliplatin in Chinese population.     

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).     

A phase II trial of gemcitabine and weekly high-dose 5-fluorouracil in a 48-hour continuous-infusion schedule in patients with advanced pancreatic carcinoma. A study of the Spanish Cooperative Group for Gastrointestinal Tumour Therapy (TTD)

Aim

A multi-centred, open-labelled, phase II study containing 46 patients was conducted to evaluate the clinical benefit of gemcitabine (1,400 mg/m²) combined with 5-FU (3 g/m²) in a 48 h continuous infusion (CI).

Methods

Both drugs were administered on days 1,8 and 15 of every 4 week cycle in chemotherapy-naïve patients with locally advanced un-resectable metastatic pancreatic carcinoma. The minimum follow-up was 6 months.

Results

Clinical benefit response was the primary endopint and this was achieved by 24.4% of the patients. Quality of life (QoL) improved in 16.6% of patients. Objective response was observed in 7% of the patients. The median progression-free survival (PFS) was 14.4 weeks and the median overall survival (OS) time was 22.7 weeks. One-year survival was 25%. The most frequent grade 3–4 toxicities were neutropenia (4.5%), mucositis (7.5%) and hyperbilirubinaemia (10.5%).

Conclusions

This schedule was not superior in terms of clinical benefit, response rate, PFS and OS than standard gemcitabine treatment.     

Feasibility study of gemcitabine plus docetaxel in advanced or recurrent uterine leiomyosarcoma and undifferentiated endometrial sarcoma in Japan

Background

Uterine leiomyosarcoma (LMS) and undifferentiated endometrial sarcoma (UES) are rare, aggressive malignancies. Both are treated similarly; however, few chemotherapy agents are effective. Recently, the combination of gemcitabine (900 mg/m², days 1 and 8) plus docetaxel (100 mg/m², day 8) with granulocyte colony-stimulating factor (G-CSF, 150 μg/m², days 9–15) has been shown to have activity in LMS. In Japan, neither prophylactic G-CSF at a dose of 150 μg/m² nor docetaxel at a dose of 100 mg/m² are approved for use. For this reason, we evaluated the combination of 900 mg/m² gemcitabine plus 70 mg/m² docetaxel regimen without prophylactic G-CSF support in advanced or recurrent LMS and UES in Japanese patients.

Methods

Eligible women with advanced or recurrent LMS and UES were treated with 900 mg/m² gemcitabine on days 1 and 8, plus 70 mg/m² docetaxel on day 8, every 3 weeks. The primary endpoint was overall response rate, defined as a complete or partial response.

Results

Of the eleven women enrolled, 10 were evaluated for a response. One complete response and 2 partial responses were observed (30 %) with an additional 4 (40 %) having stable disease. Mean progression-free survival was 5.4 months (range 1.3–24.8 months), and overall survival was 14 months (range 5.3–38.4 months). Grade 4 neutropenia was the major toxicity (50 %). The median number of cycles was 5 (range 2–18). Twenty-two cycles (44 %) employed G-CSF.

Conclusion

The gemcitabine plus docetaxel regimen without prophylactic G-CSF support was tolerable and highly efficacious in Japanese patients with advanced or recurrent LMS and UES.     

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 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.