Phase II clinical trial of advanced and metastatic gastric cancer based on continuous infusion of 5-fluorouracil combined with epirubicin and oxaliplatin

PURPOSE: To evaluate the efficacy and tolerability of systematic treatment of unresectable advanced or metastatic gastric cancer (A/MGC) based on EOF5 regimen (the combination of epirubicin, oxaliplatin and 5-day continuous infusion of 5-fluorouracil). PATIENTS AND METHODS: Twenty-six patients (18 males, 8 females; age range, 35-72 years) with histologically confirmed metastatic (n = 23) or unresectable advanced (n = 3) gastric adenocarcinoma with (n = 6) or without previous chemotherapy (n = 20) were consented to receive EOF5 (epirubicin 50 mg/m(2) and oxaliplatin 130 mg/m(2) on day 1, followed by continuous infusion of 5-fluorouracil 375-425 mg/m(2) day(-1) on day 1-5), and the treatment cycle was repeated every 3 weeks. Responses to treatment and toxicity were evaluated every 2 cycles. RESULTS: In the first-line treatment group of 20 patients, complete (CR) and partial (PR) remission were observed in two (10%) and six (30%) patients, respectively with an overall response rate of 40%). Eleven (55%) patients showed stable (SD) and one (5%) progressive disease (PD). One-year survival rate, time to progression (TTP) and median overall survival (OS) were 45%, 9.7 and 12.5 months, respectively. In the second-line treatment group of six patients, the numbers of CR, PR, SD and PD were 0, 1, 4 and 1, respectively. Symptomatic response rates were 88.2, 76.9, 89.5, and 88.9% for abdominal pain, distention, anorexia and weight loss. The mean Karnofsky performance status score was increased (P < 0.001) and maintained after two and four cycles treatment. The major adverse events were nausea/vomiting, oral mucositis, peripheral neuropathy, phlebitis, constipation and myelosuppression. CTC grade 3 or 4 hematologic toxicities included leucopenia (7.7%), neutropenia (15.4%), thrombocytopenia (19.2%), and anemia (3.8%). No treatment-related deaths were recorded. CONCLUSIONS: EOF5 regimen shows good efficacy and an acceptable safety profile in A/MGC patients, and would be a suitable alternative regimen for this indication.     

Epirubicin,cisplatin, and protracted infusion of 5-FU (ECF) in advanced intrahepatic cholangiocarcinoma

Purpose Intrahepatic cholangiocarcinoma usually presents late in the clinical course and has a poor prognosis. No effective systemic therapy is currently available. This study aimed to determine the efficacy and toxicity of the ECF regimen (epirubicin, cisplatin. and 24-h continuous infusion of 5-FU) in advanced intrahepatic cholangiocarcinoma.Patients and method On day 1, epirubicin 50 mg/m² and cisplatin 60 mg/m² were administered i.v., repeated every 21 days. 5-FU (200 mg/m²/day was given continuous i.v. via an ambulatory infusion pump throughout the treatment course. A total of 24 patients (15 men and nine women) with advanced intrahepatic cholangiocarcinoma between August 1996 and April 2002 were enrolled in this study.Results Of the 20 evaluable patients, two had partial response (10%) and nine had stable disease (45%), including two minor response. Grade 3/4 neutropenia was observed in six patients, while grade 3/4 thrombocytopenia was seen in five patients. There was no neutropenic infection or thrombocytopenic bleeding during any of the cycles of chemotherapy.Conclusion ECF regimen is well-tolerated but is not an effective treatment for advanced intrahepatic cholangiocarcinoma. Newer clinical trials with combination drugs should be developed.     

5-fluorouracil continuous infusion combined with cisplatin for advanced pancreatic cancer: a Japanese Cooperative Study

BACKGROUND/AIMS: The prognosis of patients with advanced pancreatic cancer is extremely poor. To improve their prognosis, providing effective chemotherapy is necessary. The aim of this study was to evaluate the anti-tumor activity and toxicity of combined chemotherapy (FP therapy) using 5-fluorouracil and cisplatin in Japanese chemo-naive patients with advanced pancreatic cancer. METHODOLOGY: Thirty-seven previously untreated patients with histologically proven pancreatic adenocarcinoma were treated with FP therapy. 5-fluorouracil was administered at 500 mg/m2/day by continuous intravenous infusion for 5 days and cisplatin was administered at 80 mg/m2 intravenously on the 1st day. Therapy was repeated every 4 weeks until there was evidence of disease progression or unacceptable toxicity. RESULTS: Three patients achieved partial responses, whereas none exhibited a complete response. The overall response rate was 8% (95% confidence interval, 2-22%) and the response durations were 6, 9 and 12 months, respectively. The median survival time of patients was 5 months. Toxicities were generally mild and acceptable, although nausea/vomiting was the most commonly observed toxicity. CONCLUSIONS: FP therapy on this schedule had limited anti-tumor activity for pancreatic cancer, indicating that, practically, it should not be performed in Japanese patients with advanced pancreatic cancer.     

Efficacy of hepatic arterial infusion therapy for advanced hepatocellular carcinoma using 5-fluorouracil, epirubicin and mitomycin-C]

BACKGROUND/AIM: Prognosis of advanced hepatocellular carcinoma (HCC) treated by conventional therapies has been considered to be poor. The aim of this study was to evaluate the efficacy of hepatic arterial infusion therapy (HAIT) using FEM (5-fluorouracil, epirubicin, mitomycin-C) regimen for advanced HCC. METHODS: Eighteen patients received repeated HAIT using an implanted drug delivery system. Of the 18 patients, 8 patients had HCC with portal vein tumor thrombosis, 9 patients had recurrent HCC after transarterial chemoembolization (TACE) and 1 patient after surgical resection. The patients received 5-fluorouracil (330 mg/m(2), every week), epirubicin (30 mg/m(2), every 4 weeks) and mitomycin-C (2.7 mg/m(2), every 2 weeks). RESULTS: Mean age was 51 years. The response rate (complete response+partial response) by tumor size on abdominal CT was 38.9%. Survival ranged from 2 to 24 months and the median survival time was 8 months. The cumulative survival rate of responders group was significantly higher than non-responders group (p=0.0385). The mean levels of serum alpha-FP and PIVKA-II in responders group decreased after HAIT (3,179 ng/mL and 2,850 ng/mL) than before (11,218 ng/mL and 4,396 ng/mL), but not significantly. Chemotherapy-related side effects were nausea, vomiting and alopecia. Three patients had catheter-related complications. One patient developed gastric ulcer. CONCLUSIONS: HAIT using FEM regimen is a useful therapeutic option for patients with advanced HCC with portal vein tumor thrombosis or ineffective response to other therapies.     

Phase II clinical trial of 5-fluorouracil, trimetrexate, and leucovorin (NFL) in patients with advanced pancreatic cancer

Background. Advanced pancreatic cancer has limited treatment options. 5-fluorouracil (5-FU) is frequently used in the treatment of pancreatic cancer. Preclinical studies suggest synergism between trimetrexate (TMTX), 5-FU, and leucovorin (NFL). Aim. We conducted a phase II trial to evaluate the activity and safety of NFL in pancreatic cancer. Method. Eligible patients (n=21) with untreated advanced pancreatic cancer were treated with 110 mg/m² intravenous (IV) THTX on day 1 and 200 mg/m² IV leucovorin prior to 500 mg/m² IV 5-FU on day 2. Oral leucovorin (15 mg every 6 h for seven doses) started intravenous 24 h later. Results. Treatment was administered for 6 wk followed by a 2-wk rest period. Response was evaluated every 8 wk. All patients were evaluable for response and toxicity. Most patients (80%) had distant metastases. Forty-five cycles of chemotherapy were administered. The most common serious toxicities were Grade 3 diarrhea (23.8%) and nausea and vomiting (14.2%). The response rate was 4.1% (95% CI, 0–23%), median survival was 6.8 mo, and 1-yr survival was 19%. Conclusion. Treatment with NFL is well-tolerated in patients with advanced pancreatic cancer. The median survival and 1-yr survival in these patients with poor prognosis compares favorably with other treatment options.     

Continuous 5-fluorouracil (5FU) infusion in carcinoma of the pancreas: a phase II study

Sixteen patients with metastatic carcinoma of the pancreas were treated with continuous ambulatory 5-Fluorouracil (5FU) infusion (200-300 mg/m2/day) through a chronic indwelling central venous catheter. Twelve of sixteen patients (75%) had two or more sites of disease, and eleven of sixteen (69%) had liver metastases. Five patients had previous chemotherapy. Results: partial remission, 3/16 (19%); stable disease, 8/16 (50%); and progressive disease, 5/16 (31%). Improvement in ECOG performance status was observed in 2/3 responding and 6/8 stable disease patients, respectively. Toxicities included hand-foot syndrome, mucositis, diarrhea, and cerebellar ataxia, which required treatment interruption in 9/16 patients (56%). No myelosuppression or catheter related problems were seen. The authors conclude that continuous infusion 5FU is a potentially efficacious palliative therapy in the management of carcinoma of the pancreas.     

Phase II study of cisplatin, 5-FU, and allopurinol in advanced esophageal cancer

Forty patients with advanced squamous cell carcinoma of the esophagus were treated with a combination of cisplatin, 5-FU (by continuous 5-day infusion), and allopurinol; 37 are evaluable for response. Thirteen remissions (35%) were obtained, including three complete and ten partial, with a median duration of 9 months. After chemotherapy, seven responding patients underwent a surgical procedure, which was radical in four. The most frequent side effects were nausea and vomiting. This regimen is effective and can be included in a multimodality approach.     

Twenty-four hour intra-arterial infusion of 5-fluorouracil, cisplatin, and leucovorin is more effective than 6-hour infusion for advanced hepatocellular carcinoma

AIM To evaluate the time dependence of intra-arterial 5-fluorouracil (5-FU) therapy for advanced hepatocellular carcinoma (aHCC).METHODS Thirty-seven adult Japanese patients who had aHCC and liver cirrhosis were treated with combined intra-arterial 5-FU, cisplatin (CDDP), and leucovorin (LV). The Japan Integrated Staging score (JIS score) of each patient was 3 or more. The patients were divided into two groups, after which the 15 patients in group S were treated with 6-h infusion chemotherapy (LV at 12 mg/h, CDDP at 10 mg/h, and 5-FU at 250 mg/m2 per 4 h) and the 22 patients in group L were treated with 24-h infusion chemotherapy (LV at 12 mg/h, CDDP at 10 mg/h, and 5-FU at 250 mg/m2 per 22 h). Continuous infusion chemotherapy was performed via the proper hepatic artery every 5 d for 4 wk using an implanted drug reservoir.RESULTS The percentages of patients with a partial response after 4 wk of chemotherapy were 6.7% in group S and 31.8% in group L. The survival of group L was significantly better than that of group S, with the median survival time being 496 d in group L and 226 d in group S (P ＜ 0.05).CONCLUSION Continuous 24-h intra-arterial infusion is more effective for aHCC and can markedly prolong survival time as compared to 6-h infusion.     

Long-term clinical outcomes of hepatic arterial infusion chemotherapy with cisplatin with or without 5-fluorouracil in locally advanced hepatocellular carcinoma

Purpose  

Hepatic arterial infusion chemotherapy (HAIC) has often been used as a therapeutic option for patients with advanced hepatocellular carcinoma (HCC). This study aimed to evaluate the efficacy and safety of HAIC using cisplatin with or without 5-fluorouracil in patients with advanced HCC.     

Phase II study of hepatic arterial infusion of a fine-powder formulation of cisplatin for advanced hepatocellular carcinoma.

Aim: Intra-arterial cisplatin appears to have high therapeutic efficacy, but this has not been studied in detail. Accordingly, we developed a fine-powder cisplatin formulation and tested it in advanced hepatocellular carcinoma (HCC) patients in an open-label, uncontrolled study in which 27 institutions participated. Methods: The patients in this study had inoperable advanced HCC without extrahepatic metastases. All received two infusions of high-concentration cisplatin (1.43 mg/mL) via the hepatic artery at a dose of 65 mg/m(2), with an intervening 4-6 week interval. Results: Cisplatin efficacy and safety were assessed in 80 patients. We found partial responses in 27 cases, no change in 37, and progressive disease in 11 (five were not evaluated). The overall response rate was 33.8%. The 1-year survival rate was 67.5% and the 2-year survival rate was 50.8%. Severe adverse effects (>/=grade 3) included anorexia in 22.5%, vomiting in 6.3%, abdominal pain in 1.3%, thrombocytopenia in 25%, neutropenia in 13%, leukopenia in 1.3%, hypochromia in 1.3%, elevated serum aspartate aminotransferase in 32.5%, elevated serum alanine aminotransferase in 11.3%, elevated serum bilirubin in 3.8%, decreased serum albumin in 1.3%, elevated serum alkaline phosphatase in 1.3%, elevated gamma-glutamyltranspeptidase in 3.8%, and elevated serum creatinine in 2.5%. Death from myocardial infarction occurred as an incidental event in one case, and no other life-threatening, adverse events were observed. Conclusion: Although intra-arterial cisplatin has substantial local and systemic toxicity, high therapeutic efficacy suggests the potential usefulness of this agent in the treatment of advanced HCC.     

Efficacy of chemoradiotherapy with low-dose cisplatin and continuous infusion of 5-fluorouracil for unresectable squamous cell carcinoma of the esophagus

We retrospectively investigated the efficacy of a chemoradiotherapy regimen using daily low-dose cisplatin and continuous 5-fluorouracil infusion in 71 registered patients with unresectable esophageal cancer. The overall response rate (complete response plus partial response) was 59%. The major toxicities observed were leukopenia and anorexia. The 1- and 3-year overall survival rates were 54.6% and 18.4%, respectively. A low preoperative C-reactive protein level was found to be associated with a good response. The pretreatment performance status and response results were both shown to be prognostic factors for overall survival. These findings confirmed that the chemoradiotherapy regimen had curative potential for unresectable esophageal cancer.     

A phase II study of combination chemotherapy with gemcitabine, 5-fluorouracil, and cisplatin for advanced pancreatic cancer]

BACKGROUND/AIMS: Gemcitabine has been the standard regimen for advanced pancreatic cancer, but the effect on the response rate and survival is still disappointing, leading to many trials of combination chemotherapy. 5-FU and cisplatin were combined with gemcitabine in this trial, as they are synergistic with gemcitabine and each other as well. This study was aimed to assess the effectiveness and safety of combination chemotherapy with gemcitabine, 5-FU, and cisplatin for advanced pancreatic cancer. METHODS: Patients with advanced pancreatic cancer were entered into this study. Gemcitabine at a dose of 800 mg/m2 on day 1 and 8, 5-FU 1,000 mg/m2/day from day 1 to 3 for 72 hours, and cisplatin 60 mg/m2 on day 2, 24 hours after the start of gemcitabine were administered every 3 weeks. RESULTS: From December 2001 to January 2004, twenty patients were enrolled in this study. Among 17 of these patients assessable, 3 patients had a partial remission with the response rate of 23.6% (95% confidence interval, 6.2-41.0%). The median time to disease progression was 230 days and median duration of survival was 322 days. Among total of 91 cycles, leukopenia, neutropenia, and thrombocytopenia of grade 3 or 4 occurred in 12 cycles (13.2%), 12 cycles (13.2%), and 23 cycles (24.4%), respectively. Grade 3 or 4 mucositis developed at 2 cycles (2.2%), and nausea and vomiting were encountered in 3 cycles (3.3%). CONCLUSIONS: Combination chemotherapy with gemcitabine, 5-FU, and cisplatin for advanced pancreatic cancer is active and well-tolerated, warranting a phase III study.     

Phase II study of leucovorin, 5-fluorouracil and gemcitabine for locally advanced and metastatic pancreatic cancer (FOLFUGEM 2)

AIM: FOLFUGEM 1 (leucovorin 400 mg/m2 combined with 5-flurorouracil (FU) bolus 400 mg/m2 then 5-FU 2-3 g/m2/46 hours and gemcitabine 1000 mg/m2 in 30 min) in patients with locally-advanced and metastatic pancreatic adenocarcinoma appeared to be toxic (neutropenia and alopecia). The aims of this phase II multicentric study were to evaluate the response rate, clinical benefit and tolerance of a new scheme of combined leucovorin, 5-FU and gemcitabine (FOLFUGEM 2). PATIENTS AND METHODS: FOLFUGEM 2 associated leucovorin 400 mg/m2 in 2 hours followed by 5-FU 1000 mg/m2 in 22 hours, then gemcitabine 800 mg/m2 (10 mg/m2/min) with cycles every 14 days. Gemcitabine dose could be increased (1000 then 1250 mg/m2) when NCI/CTC toxicity was < or = grade 2. RESULTS: Fifty-eight patients were included (locally-advanced tumor: N = 13 and metastatic: N = 45). Among the 39 patients with measurable disease, 11 had partial response (28.2%, 95% confidence interval: 14-42%) and 11 had stable disease (28.2%). On an intent-to-treat analysis, the objective response rate was 19% (95% confidence interval: 9-29%). Clinical benefit rate was 46%. Median progression-free survival and median overall survival were 3.1 and 7.2 months, respectively. There were 13% grade 3-4 neutropenia and 36% complete alopecia. CONCLUSION: FOLFUGEM 2 schema has an antitumoral effect in advanced pancreatic cancer and has an acceptable toxicity which appears to be less than that of FOLFUGEM 1.     

Phase II study of high dose epirubicin in combination with cyclophosphamide in patients with advanced breast cancer

Abstract Background: Combination chemotherapy for metastatic breast cancer will palliate symptoms in the majority of patients but only a small percentage will have prolonged survival. Higher doses of doxorubicin lead to increased response rates in breast cancer and early studies have shown that epirubicin could be tolerated in higher doses with less relative toxicity than doxorubicin. Aims: This study was initiated to assess the dose of epirubicin that could be tolerated by escalating its dose while maintaining a fixed dose of cyclophosphamide. Simultaneously tumour response rate, spectrum of toxicities, duration of response and overall survival in patients with metastatic breast cancer were assessed. Methods: Patients with metastatic breast cancer commenced chemotherapy with a starting dose of epirubicin of 120 milligram per metre squared (mg/m²) and cyclophosphamide 600 mg/m². The dose of epirubicin was to be escalated or reduced depending on toxicity. Results: Forty female patients were entered into this study and three patients withdrew because of toxicity. Overall tumour response rate was 75% with 27.5% of patients obtaining a complete response. Median time to progressive disease was 35 weeks and median overall survival was 48 weeks, with median survival for complete responders being 103 weeks. Thirty-one (77%) patients completed five or more courses of treatment. Haematological toxicity was the main side effect and 70% of patients required a dose reduction. No patients were eligible for a dose escalation. One patient died as a consequence of neutropenic sepsis. Four (10%) patients had treatment ceased because of decrease in left ventricular ejection fraction and one patient died as a consequence of heart failure. Four patients remain alive. Conclusions: High dose epirubicin combined with cyclophosphamide is an effective treatment regimen for metastatic breast cancer obtaining higher overall response rates with increased percentage complete responses compared to conventional dose chemotherapy. Although toxicity was increased, high dose chemotherapy was well tolerated and mortality associated with treatment was not increased. No dose escalations of epirubicin were possible and a dose of 90mg/m² of epirubicin would be the maximum dose when used in combination with cyclophosphamide. Further trials are required to determine the influence of this high dose therapy on survival duration and whether comparable benefits can be achieved with shorter durations of therapy. (Aust NZ J Med 1995; 25: 474–478.)     

Phase II trial evaluating continuous infusion of etoposide, cisplatin, and hexamethylmelamine in extensive-disease small cell carcinoma of the lung

A total of 27 untreated and 24 previously treated patients with extensive-disease small cell lung cancer (SCLC) were treated with a combination chemotherapeutic regimen of continuous-infusion etoposide for 5 days, cisplatin, and hexamethylmelamine. of 25 evaluable patients with untreated SCLC, three (12%) achieved a complete response and 16 (64%) achieved a partial response. Among 23 evaluable patients with relapsed SCLC there were no complete responses and nine (39%) achieved a partial response. Median survival times were 252 and 109 days for the above groups, respectively. Myelotoxicity, especially thrombocytopenia, was moderately severe. Other toxic effects, including renal and neurologic, were minimal. These results compare favorably with other regimens including etoposide and cisplatin. Our results further confirm the activity of etoposide and cisplatin as both initial therapy and as a salvage regimen in the management of patients with extensive-stage SCLC.