Adjuvant chemotherapy for unresectable locally advanced pancreatic cancer in light of its characteristics

The use of neoadjuvant chemotherapy for pancreatic cancer has been advocated for its potential ability to optimize patient selection for surgical resection and to downstage locally advanced tumors, especially for patients with Stage IV b (Japan criteria). We report our experience with a six-drug chemotherapeutic regimen that resulted in sufficient downstaging of the tumor in some patients to justify surgical resection. From Jan. 2001 through December 2003, 6 patients received 5-FU as a continuous infusion (200 mg/m2/day), calcium leucovorin weekly by intravenous bolus injection (30 mg/m2), mitomycin-C every 6 weeks (10 mg/m2 intravenously), and dipyridamole daily orally (75 mg), according to the UCLA regimen and gemcitabine weekly (600 mg/m2) and heparin as a continuous infusion (0-3,000 U/day) for locally advanced unresected pancreatic cancer. All of these patients were evaluable for response and survival. There were 5 partial responses (83% response rate) and 1 no response. Four of 5 responding patients had sufficient tumor regression to meet clinical criteria for resectability, three of whom underwent a curative resection. All patients who underwent downstage operation were still alive for the follow-up period (4-23 months).     

Phase II trial of cyclophosphamide, leucovorin, 5-fluorouracil 24-hour infusion and tamoxifen in pancreatic cancer

Leucovorin modulates the cytotoxic effects of 5-fluorouracil (5-FU) in the treatment of cancer. 24-hour infusion of 5-FU has been shown to enhance antitumor activity in colorectal cancer compared to bolus infusion. According to experimental data cyclophosphamide and tamoxifen may enhance the effectiveness of leucovorin and 5-FU. A phase II trial was initiated to evaluate the effect of a combination of low-dose cyclophosphamide (C), leucovorin (L), 5-FU (F) and tamoxifen (T) (CLFT) in advanced pancreatic cancer. Fifty patients were treated monthly with 300 mg/m2 cyclophosphamide and weekly with 500 mg/m2 leucovorin followed by a 24-hour infusion of 2000 mg/m2 5-FU and tamoxifen 20 mg bid. Three patients had a partial response (6%), two a minor response (4%) and 32 (64%) no change of disease. The median survival time was 8.5 months for all patients, the median time to progression of disease was 4.6 months and the 1-year survival rate was 28%. CLFT was fairly well tolerated. These data suggest that biochemical modulation of 24-hour infusional 5-FU with leucovorin together with cyclophosphamide and tamoxifen has some positive effects in the treatment of pancreatic cancer.     

Treatment of patients with advanced colorectal cancer with cisplatin, 5-fluorouracil, and leucovorin

Based on in vitro studies that have demonstrated synergy between 5-fluorouracil (5-FU), leucovorin (LV), and cisplatin (CDDP) against human colon cancer cell lines, a clinical trial was initiated to determine the effects of this combination in patients with advanced unresectable colorectal carcinoma. Fifty-nine patients were enrolled in the study and 12 of them had received prior conventional 5-FU chemotherapy. Treatment consisted of 4 weekly courses of high-dose LV (200 mg/m2) administered by intravenous (IV) bolus, followed by 5-FU (550 mg/m2) and CDDP (20 mg/m2) each administered as a 2-hour infusion on 4 consecutive days. After a median of 5.5 treatment cycles, objective tumor response was seen in 20 of 59 patients (34%) (this included 3 complete remissions). The response rate in the 47 previously untreated patients was 38% (95% confidence limits, 26% to 53%). Stable disease occurred in 16 (27%) patients, whereas the tumor progressed in 23 (39%) patients. The median survival time was 11.5 months, with 15% of the patients alive at 2 years. The regimen was well tolerated and the primary side effects were mild and reversible gastrointestinal symptoms and myelosuppression. There was no episode of life-threatening toxicity. Eastern Cooperative Oncology Group (ECOG) Grade III adverse reactions that required 25% dose reductions occurred in only 14% of the patients. The results of this trial suggest that 5-FU, LV, and CDDP is an active, safe, and well-tolerated combination regimen in patients with advanced colorectal cancer.     

Phase I study of 5-fluorouracil administered by protracted venous infusion, leucovorin, and pelvic radiation therapy.

BACKGROUND: This study was designed to assess the toxicity of pelvic radiation therapy, 5-fluorouracil (5-FU) administered by protracted venous infusion, and leucovorin. METHODS: Pelvic radiation therapy consisted of 50.4-54 gray (Gy) administered in 28-30 fractions. Systemic treatment consisted of leucovorin (10 mg daily) administered orally and protracted venous infusion of 5-FU. The initial daily 5-FU dose was 150 mg/m(2). Dose escalations were planned in increments of 25 mg/m(2). RESULTS: Forty eligible patients were registered, of whom 37 were evaluable for chemoradiotherapy-related toxicity. Grade 3 or 4 toxicity secondary to radiation therapy, protracted venous infusion of 5-FU, and leucovorin occurred in 2 of 17 patients at a daily 5-FU dose of 150 mg/m(2), in 5 of 10 patients at a daily 5-FU dose of 175 mg/m(2), and in 5 of 10 patients at a daily 5-FU dose of 200 mg/m(2). Diarrhea was dose-limiting in 7 of 8 patients with Grade 4 toxicity. Venous thrombosis, a treatment-related complication not directly related to chemotherapy or radiation therapy, occurred in 5 of the 40 patients entered into this study. Four thromboses occurred at the site of a central catheter. No thrombotic complications occurred in the last 7 patients, who were given warfarin orally (1 mg daily) during treatment. CONCLUSIONS: Toxicity due to radiation therapy, protracted venous infusion of 5-FU, and leucovorin when 5-FU is given daily at a dose of 150 mg/m(2) is similar to that observed in current chemoradiotherapy regimens for patients with rectal carcinoma. This regimen will be considered as a possible investigational treatment arm of a future trial of adjuvant therapy for rectal carcinoma patients.     

Fluorouracil modulation in colorectal cancer: lack of improvement with N -phosphonoacetyl- l -aspartic acid or oral leucovorin or interferon, but enhanced therapeutic index with weekly 24-hour infusion schedule--an Eastern Cooperative Oncology Group/Cancer and Leukemia Group B Study.

PURPOSE: To investigate mechanism-directed regimens in maximizing the efficacy of fluorouracil (5-FU) in advanced colorected cancer. PATIENTS AND METHODS: Based on promising phase II data, a randomized comparison of various methods for the biochemical modulation of 5-FU was undertaken in patients with advanced colorectal cancer. The control group received single-agent 5-FU as a 24-hour infusion weekly. Patients (N = 1,120) with no prior chemotherapy for metastatic disease were randomized to one of the following arms: arm A, 5-FU 2,600 mg/m2 by 24-hour infusion, weekly; arm B, N-phosphonoacetyl-l-aspartic acid 250 mg/m2 day l, 5-FU 2,600 mg/m2 by 24-hour infusion day 2, weekly; arm C, 5-FU 600 mg/m2 with oral leucovorin (LV) 125 mg/m2 hourly for the preceding 4 hours, weekly; arm D, 5-FU 600 mg/m2 with intravenous (IV) LV 600 mg/m2, weekly; arm E, 5-FU 750 mg/m2/d IV by continuous infusion for 5 days, then 750 mg/m2 weekly, and recombinant interferon alfa-2a 9 million units subcutaneously three times weekly. Median follow-up was 4.8 years. RESULTS: Of the 1,098 assessable patients, 57% had measurable disease. The toxicity of all the regimens was tolerable. Grade 4 or worse toxicity occurred in 11%, 11%, 30%, 24%, and 22% on each arm, respectively; diarrhea was the most common adverse effect. These toxicity patterns favored significantly (P <.001) the 24-hour infusion arms. Median survival (months) by arm was A, 14.8; B, 11.9; C, 13.5; D, 13.6; and E, 15.2. These survival durations did not differ significantly. CONCLUSION: We conclude that a weekly infusion regimen of 5-FU is significantly less toxic than and as effective as 5-FU bolus regimens modulated by either LV or interferon in patients with metastatic colorectal cancer.     

Weekly etoposide, epirubicin, cisplatin, 5-fluorouracil and leucovorin: an effective chemotherapy in advanced gastric cancer.

In order to optimize the therapeutic index of combining etoposide, epirubicin, cisplatin, 5-fluorouracil (5-FU), leucovorin (EEPFL) chemotherapy in the treatment of advanced gastric cancer, a trial of a novel schedule of weekly administration was conducted. Weekly EEPFL treatment consisted of a concomitant boost of etoposide 40 mg m(-2) i.v. over 30 min, epirubicin 10 mg m(-2) i.v. over 5 min to a backbone regimen, weekly PFL chemotherapy with cisplatin 25 mg m(-2), 5-FU 2200 mg m(-2), leucovorin 120 mg m(-2) given simultaneously by 24-h i.v. infusion. Response, survival and toxicity were evaluated. Forty-two patients were studied. Median age was 69 (range 31-84) years. Twenty-six per cent of patients showed complete response and 45% partial response. The overall response rate was 71% (95% confidence interval 58-84%). For a total of 507 weekly EEPFL cycles delivered, the incidence of grade 4 leucopenia was 1% of cycles. One patient died of neutropenia septicaemia. There was no other grade 4 toxicity. Grade 3 and 2 leucopenia occurred in 7% and 14% of cycles. The incidence of grade 3 and 2 mucositis was 1% and 3% of cycles. Grade 3 and 2 diarrhoea occurred in 0.4% and 1.6% of cycles. Overall median survival was 10 months (range 3-41+ months). Weekly EEPFL chemotherapy is an effective regimen with tolerable toxicities in the treatment of advanced gastric cancer. A randomized controlled clinical trial to formally assess the efficacy and benefit of EEPFL chemotherapy is under way.     

A phase I, II study of high-dose 5-fluorouracil and high-dose leucovorin with low-dose phosphonacetyl-L-aspartic acid in patients with advanced malignancies

Twenty-eight patients with refractory advanced malignancies were treated with a 24-hour infusion of 5-fluorouracil (5-FU), leucovorin (LV), and N-(phosphonacetyl)-L-aspartic acid (PALA) weekly. Twenty-seven patients were evaluable to assess toxicity and antitumor activity. The PALA was administered as an intravenous bolus over 15 minutes at a fixed dose (250 mg/m2) 24 hours before the start of the 5-FU and leucovorin infusions. Initially the dose of 5-FU was 750 mg/m2; this was increased incrementally to 2600 mg/m2. The LV was administered in a fixed dose of 500 mg/m2 concurrently with the 5-FU over a 24-hour period. This regimen was repeated weekly. Diarrhea, stomatitis, nausea, and vomiting were among the dose-limiting toxicities. Others were hand-foot syndrome, hair loss of the scalp and eyelashes, overall weakness, rhinitis, and chemical conjunctivitis. The maximum tolerated dose of 5-FU in this combination and schedule was 2600 mg/m2. Seven of 14 patients treated with 2600 mg/m2 were able to tolerate the chemotherapy on a weekly basis without interruption. The other seven patients required dose reductions, but most received 5-FU at a dose of 2100 mg/m2. Twenty-three of 27 patients were treated previously. Eight patients had a partial response; five of these were treated previously. A complete response was observed in one patient with pancreatic carcinoma, previously untreated. The overall response rate for patients treated with 2100 or 2600 mg/m2 of 5-FU was nine of 18 patients (50%). Three of four previously untreated patients with pancreatic cancer responded to this treatment (two responded partially, and one had a complete response). One of three heavily pretreated patients with non-small cell lung cancer had a partial response as did a patient with breast cancer. Four of ten patients with colorectal cancer responded to the treatment (four partial responses), of whom three had been treated previously.     

A phase I study of weekly docetaxel, 24-hour infusion of high-dose fluorouracil/leucovorin and cisplatin in patients with advanced gastric cancer

OBJECTIVES: To determine the maximum-tolerated dose (MTD) and dose-limiting toxicity (DLT) of both docetaxel and 5-fluorouracil (5-FU) when administered weekly in a regimen of docetaxel, 5-FU/leucovorin and cisplatin (DFLP) for 2 consecutive weeks every 3 weeks. PATIENTS AND METHODS: A total of 31 patients with chemo-naive, advanced adenocarcinoma of the stomach were enrolled in the study. Cisplatin and leucovorin dosages were fixed throughout the study at 30 and 300 mg/m2, respectively. 5-FU dosage was fixed at 1,600 mg/m2 while docetaxel was evaluated at weekly 1-hour infusion dosages of 30, 40 and 50 mg/m2 to determine the MTD. Cisplatin, 5-FU and leucovorin were administered together as a 24-hour continuous infusion following docetaxel. Weekly 5-FU dosages of 1,600, 2,000 and 2,400 mg/m2 were then evaluated after setting the docetaxel dosage at the MTD. RESULTS: A total of 95 chemotherapy cycles were administered, with a median of three cycles per patient. The MTD of docetaxel was defined at 40 mg/m2. At a docetaxel dosage of 50 mg/m2 per week, the dose-limiting events of grade 4 febrile neutropenia and grade 3 hypomagnesemia occurred. With fixation of docetaxel to 40 mg/m2, the DLT for 5-FU was found at 2,400 mg/m2 per week. This incurred grade 4 neutropenia such that the MTD of 5-FU was defined at 2,000 mg/m2. Grade 3/4 neutropenia occurred in 14 patients (45%), with 2 patients developing febrile neutropenia. Grade 2 and 3 hypomagnesemia and hypokalemia occurred in 9 (41%) and 4 (18%) patients, respectively, of the first 22 patients treated with a 24-hour infusion of cisplatin and 5-FU/leucovorin immediately following docetaxel. Following a change in the cisplatin administration schedule to a 3-hour infusion after 5-FU/leucovorin infusion, no such complications were observed in 9 subsequently treated patients. Grade 2 diarrhea was recorded in 11 patients (35%). Grade 2/3 asthenia occurred in 9 patients (30%), which resolved after correction of electrolyte disorders. Twenty-six patients were assessable for response analysis. There were 2 (7.8%) complete and 14 (53.8%) partial responses, with the overall response rate being 61.5% (95% confidence interval, 41.5-81.6%). Responses were observed at all dose levels. CONCLUSION: Two consecutive weeks of DFLP infusions every 3 weeks appear to be an active regimen with a tolerable toxicity profile in advanced gastric cancer. For further phase II studies, the recommended dose for this combination is 40 mg/m2 of docetaxel and 2,000 mg/m2 of 5-FU per week.     

A phase I study of sequential irinotecan and 5-fluorouracil/leucovorin.

BACKGROUND: Irinotecan (CPT-11) and 5-fluorouracil (5-FU)/leucovorin are active agents in colorectal cancer. A sequence-dependent synergism of SN-38 followed by 5-FU/leucovorin in vitro led us to conduct a phase I trial of CPT-11 followed by 5-FU/leucovorin to determine the maximum tolerated dose (MTD) and toxicities of this regimen and to obtain preliminary indications of its activity in patients with advanced solid tumors. PATIENTS AND METHODS: Fifty-six patients were enrolled in sequential cohorts to receive escalating doses of CPT-11 (90 min infusion) on day 1, followed by leucovorin 20 mg/m(2) (intravenous push) and 5-FU (90 min infusion) on days 2-5 of each 21-day cycle. RESULTS: A total of 347 treatment cycles (median 4, range 1-25) were administered. Dose-limiting toxicities were diarrhea, neutropenia and fatigue. Nine patients with colorectal cancer and one with gastric cancer had partial or minor responses. Eight of the 10 had prior chemotherapy. CONCLUSIONS: CPT-11 and 5-FU/leucovorin, as constituents of this novel mechanism-based schedule, have promising activity in patients who have received prior chemotherapy. The recommended phase II/III starting doses are CPT-11 275 mg/m(2) over 90 min on day 1, and 5-FU 400 mg/m(2) plus leucovorin 20 mg/m(2) on days 2-5 every 21 days. This combination can be administered safely to this schedule if there is strict adherence to the 90 min infusion time for both CPT-11 and 5-FU.     

Sequential 5-fluorouracil and leucovorin in patients with advanced symptomatic gastrointestinal cancer

50 patients with advanced symptomatic gastrointestinal cancer were treated with sequential 5-fluorouracil (5-FU)/leucovorin. Patients received an intravenous bolus injection of 5-FU (500 or 600 mg/m²) and leucovorin 30–40 min later, either 50 mg (41 patients) or 200 mg (9 patients). Treatment was given in repeated courses either once weekly or on 2 consecutive days every other week until progression. Toxicity was mild with the lower leucovorin dose, although grade 2 toxicity, particularly diarrhoea, occurred in 27 (66%) patients. All patients receiving the higher leucovorin dose had grade 2–4 toxicity. Toxicity was less with the lower 5-FU dose. Out of 40 patients with colorectal cancer, 34 received leucovorin 50 mg and 6 received 200 mg. Partial response occurred in 10 (29%) and 1 of these patients, respectively. This sequential 5-FU and intermediate-dose leucovorin regimen has acceptable toxicity and a definite anti-tumour activity.     

Treatment of advanced colorectal adenocarcinoma with weekly high-dose l-leucovorin and 5-fluorouracil.

We report the results of 5-fluorouracil (5-FU) combined with high-dose l-folinic acid (leucovorin) therapy for patients with advanced colorectal carcinoma. In each treatment course, the patients weekly received both 5-FU (600 mg/m2 by intravenous 15 min infusion) and l-folinic acid (250 mg/m2 by intravenous infusion over a period of 2 h). A total of six treatments were administered with a 14-day interval to the next course of six treatments. Forty-eight patients were evaluated for toxicity and 32 for response. The combined complete and partial response rate was 25% in 32 patients. Toxicity was within acceptable limits without grade 4 toxicity. Although the response rate was slightly lower than those reported in phase II trials in Japan, the result was satisfactory. This therapy can be the standard chemotherapy for colorectal cancer patients, even in Japan.     

Clinical evaluation of chemotherapy with irinotecan (CPT-11), l-leucovorin (l-LV), 5-fluorouracil (5-FU), and UFT for metastatic or recurrent colorectal cancer

A clinical study has been conducted since August 2001 to investigate whether chemotherapy with CPT-11/l-LV/ 5-FU/UFT could be an effective regimen for advanced or recurrent colorectal cancer. The chemotherapy consisted of CPT-11 30 mg/m2 iv, as a 120-minute infusion, followed by l-LV 30 mg/m2, as a 60-minute infusion, followed by 5-FU 300 mg/m2, as a 120-minute infusion. This treatment was administered weekly for 6 weeks followed by a 2-week rest period and repeated every 8 weeks. UFT (250 mg/m2/day) was orally administered daily. All patients were evaluable for efficacy, 2 CR, 5 PR, 3 SD and 7 PD. The overall response rate was 41.1% with a median time to progression of 7.1 months and a median survival time of 12.0 months. No grade 3/4 toxicities were observed. The present study suggests that combination chemotherapy with CPT-11, l-LV, 5-FU, and UFT is well tolerated and might be a promising regimen for advanced or recurrent colorectal cancer.     

A phase II study of modified deGramont 5-fluorouracil, leucovorin, and oxaliplatin in previously treated patients with metastatic colorectal cancer

Purpose: To evaluate the toxicity and efficacy of a modified deGramont regimen of 5-fluorouracil (5-FU), leucovorin, and oxaliplatin in patients with advanced colorectal cancer who have progressed on at least one but not more than two prior chemotherapy regimens. Patients and Methods: Patients with stage 4 colorectal cancer were treated with oxaliplatin 85 mg/m² by a 2-hour intravenous infusion, followed by leucovorin 500 mg/m² by a 2-hour intravenous infusion, followed by 5-FU 400 mg/m² by bolus injection, followed by 5-FU 2.4 g/m² administered by a 46-hour continuous infusion. Cycles were administered every 2 weeks. Results: Seventy patients were treated and 68 patients had previously received irinotecan. Eleven percent of patients had a partial response, 33% of CEA-evaluable patients had a ≥50% drop in their CEA level. The median time to progression was 6.2 months, and the median overall survival was 8.7 months. Toxicity was mild to moderate, as 14% of patients experienced grade 3 or 4 neutropenia and 3% of patients experienced grade 3 neuropathy. Conclusion: The modified deGramont regimen of 5-FU, leucovorin, and oxaliplatin is tolerable and is associated with a modest degree of antitumor activity in patients who have progressed on both 5-FU and irinotecan.     

Weekly high-dose 5-fluorouracil (5-FU), leucovorin (LV) and bimonthly cisplatin in patients with advanced gastric cancer

BACKGROUND: A phase II clinical trial was performed to evaluate the activity and toxicity of bimonthly cisplatin and weekly 24-h infusion of high-dose 5-fluorouracil and leucovorin in patients with advanced gastric cancer. PATIENTS AND METHODS: From September 1997 to March 1998, 23 chemo-naive patients of advanced gastric cancer were enrolled in this study. The regimen consisted of weekly 24-h infusion of 5-FU (2,600 mg/m2) and LV 150 mg and bimonthly cisplatin (25-50 mg/m2) bolus for 12 weeks followed by a 2-week break. RESULTS: There were 10 male and 13 female patients with a median age of 52 years. A total of 428 chemotherapy treatments were given with a mean of 11. Seventeen patients were evaluable for response. There were 41% (7/17) partial response, 18% (3/17) stable disease and 41% (7/17) progressive disease. The grade III or IV toxicity included anorexia 35% (8/23), fatigue 26% (6/23), vomiting 17% (4/23) and mucositis 9% (2/23). One patient developed perforated duodenal stump after chemotherapy. One patient died of hyperammonemia-related coma. The median times to disease progression and overall survival were 3.5 and 7 months, respectively. CONCLUSIONS: This regimen showed modest activity against gastric cancer. However, there was no survival advantage and there was greater toxicity than with weekly high-dose 5-FU-LV alone.     

Phase II study of oxaliplatin, 5-fluorouracil and leucovorin in previously platinum-treated patients with advanced gastric cancer.

BACKGROUND: Oxaliplatin shows preclinical activity in many cancer cell lines that are resistant to cisplatin, and also has synergism with 5-fluorouracil (5-FU). We undertook this study to evaluate the efficacy and toxicities of a combined oxaliplatin, 5-FU and leucovorin (LV) continuous infusion regimen in patients with advanced gastric cancer who progressed during or after treatment with 5-FU and platinum compounds. PATIENTS AND METHODS: Twenty-six patients with advanced gastric cancer, whose disease progressed while receiving, or after discontinuing, chemotherapy with a 5-FU and platinum regimen, were enrolled in this study. Treatment comprised oxaliplatin (85 mg/m2 on day 1) as a 2-h infusion followed by bolus 5-FU (400 mg/m2 on day 1), and 48-h infusion of 5-FU 2.4-3.0 g/m2 concurrently with LV 150 mg/m2. Cycles were repeated at 2-week intervals. RESULTS: Of the 23 evaluable patients, there were six partial responses (response rate 26%). All responding patients were among those who entered into this trial immediately after failure of previous chemotherapy with 5-FU and cisplatin. The median time to progression was 4.3 months and the median overall survival was 7.3 months. The most common hematologic toxicity was grade 1-2 anemia in 39 cycles (39%). No grade 4 leukopenia or thrombocytopenia were observed. The most common non-hematologic toxicity was nausea/vomiting (33%). Peripheral neuropathy of grade 1 or 2 was noted (27%), but there was no grade 3 or 4 neurotoxicity. CONCLUSIONS: This phase II study of oxaliplatin, 5-FU and LV continuous infusion showed activity in previously platinum-treated patients with advanced gastric cancer, with acceptable toxicities.     

Treatment of advanced-stage colorectal adenocarcinoma with fluorouracil and high-dose leucovorin calcium: a pilot study

Thirty-one evaluable patients with measurable advanced colorectal carcinoma were entered into a pilot study that used weekly fluorouracil (5-FU) at the dose of 600 mg/m2 by bolus infusion administered midway during a two-hour leucovorin calcium infusion of 500 mg/m2. This regimen was repeated weekly for six doses. Twenty-seven of these patients (87%) were considered to be refractory to prior 5-FU therapy and four (13%) were previously untreated. All 31 patients successfully completed at least one 6-week cycle of this regimen with acceptable toxicity. The combined complete (CR) and partial response (PR) rate was 45% with another 25% of patients remaining stable. The 95% confidence levels for the responding patients are 27.6% and 62.7%, respectively. The remaining 30% of the patients had all received prior 5-FU therapy and progressed. All of the responding patients and 80% of the patients with stable disease received two or more cycles of this regimen after a 3- to 4-week interval off therapy. The median time to disease progression was 16.1 months for responding patients and 6.7 months for those patients with stable disease. The median survival for the responders was 20.6 months and for those with stable disease 9.8 months. The median survival for the nonresponding patients was 3.9 months. Toxicity included diarrhea in 70% of patients, skin rash (erythema) in 10%, stomatitis in 15%, nausea and vomiting in 25%, and myelosuppression in 10%. This study confirms and extends previous observations that demonstrate the improved efficacy of 5-FU when used with high-dose leucovorin in advanced colorectal carcinoma.     

An overview of adjuvant systemic chemotherapy for colon cancer

This article summarizes the progress of adjuvant systemic chemotherapy of colon cancer. The study by Moertel et al that showed that the combination of 5-fluorouracil (5-FU) and levamisole in the adjuvant setting reduced mortality by 33% in stage III colon cancer; 5-FU/leucovorin (LV) became the standard of care in the adjuvant treatment of colon cancer after it showed superiority to 5-FU/levamisole. However, no standard schedule of 5-FU/LV has been established. The fortnightly regimen of bolus 5-FU/LV and continuous infusion 5-FU (LV5FU2) has the same efficacy as and is less toxic than the monthly regimen of bolus 5-FU/LV. Oxaliplatin combined with 5-FU and LV (FOLFOX4) is the first combination to demonstrate significant superiority in 3-year disease-free survival as compared with 5-FU/LV in the adjuvant treatment of colon cancer. Three-year disease-free survival is an excellent predictor of 5-year overall survival and, in future studies, can serve as a reliable endpoint that is associated with reproducible 5-year overall survival. Results of studies testing irinotecan combined with 5-FU and LV are not yet available. Adjuvant chemotherapy for patients with stage II colon cancer is a controversial subject. Because the available data suggest that stage II patients benefit from adjuvant chemotherapy, although to a lesser extent than patients with stage III disease, all patients with stage III and high-risk stage II disease should be offered adjuvant treatment with the new standard of care, FOLFOX4. Future studies in adjuvant therapy for colon cancer will explore oxaliplatin and 5-FU with or without antiangiogenesis or anti-epidermal growth factor agents.     

氟尿嘧啶/亚叶酸钙+紫杉醇联合化疗双周方案治疗晚期胃癌

背景与目的：近来有临床研究显示紫杉醇(paclitaxel,PTX)可用于治疗胃癌,与5．氟尿嘧啶(5-fluorouracil,5-FU)联合治疗晚期胃癌疗效显著,不良反应轻。本研究观察5-Fu／亚叶酸钙(1eueovorin,CF) PTX联合化疗双周方案治疗晚期胃癌的临床疗效和不良反应。方法：采用高剂量5-FU／CF PTX深静脉输注方案(CF 200mg／m^2,静滴2小时,第1天;5-FU 500mg／m^2,静脉推注,第1天;5-FU 1500mg／m^2,静滴46小时;PTX90mg／m^2,静脉输注3小时,第1天),化疗方案以每两周为1周期,重复4周期后评定疗效。结果：全组20例均可评价疗效,总有效率为65．0％(13／20),其中完全缓解(CR)率为10.0％(2／20),部分缓解率为55．0％(11／20)。无治疗相关死亡,主要不良反应为口腔炎、手足综合征和脱发。结论：5-FU／CF PTX联合化疗双周方案治疗晚期胃癌缓解率较高、不良反应可耐受,是治疗晚期胃癌安全有效的化疗方案。     

5-fluorouracil administered as a 48-hour semiintermittent infusion in combination with leucovorin, cisplatin and epirubicin: phase II study in advanced gastric cancer patients

The main objective of this study was to determine the feasibility and the antitumor activity of a chemotherapy regimen with a 48-hour infusion of 5-fluorouracil (5-FU), leucovorin (LV), cisplatin (CDDP), and epirubicin (EPIDX) administered every 3 weeks in patients with locally advanced or metastatic gastric cancer. Thirty-three patients received CDDP 60 mg/m2 over 30 minutes followed by 1-LV 250 mg/m2 over 2 hours followed by EPIDX 60 mg/m2 over 5 minutes (bolus) and followed by 5-FU 3,800 mg/m2 as a 48-hour semiintermittent continuous infusion, with 67% of total daily dose administered between 4 pm and midnight. Four patients had a locally advanced disease and 29 had metastatic disease. A total of 171 cycles were administered. Most relevant toxicities were stomatitis (grade III in 2% of cycles and 12% of patients) and neutropenia (grade III-IV in 8% of cycles and 28% of patients) with 3 (9%) patients experiencing 1 episode of febrile neutropenia. No toxic deaths occurred. Thirty-one patients were evaluable for response. In 3 patients (9.6%) a complete response and in 11 patients (35.4%) a partial response was observed, for an objective response rate of 45% (95% C.I. 27-64%). Median progression-free and overall survival were 5.9 and 9.8 months, respectively. In conclusion, this regimen is feasible in an outpatient setting with acceptable and manageable toxicities, and it is associated with promising antitumor activity, time to progression, and survival.     

5-Fluorouracil, leucovorin and interferon alpha 2b in advanced pancreatic cancer: A pilot study

Background: On the basis of data suggesting the possibilityof maximizing the efficacy of 5-FU by LV and IFN, a pilot clinicaltrial was initiated in advanced pancreatic cancer. Patients and methods: Twenty-four patients received weekly 5-FU600 mg/m² bolus 1 hour after the initiation of a 2-hour infusionof 500 mg/m² of leucovorin. Three MU of interferon alpha 2bwas administered subcutaneously three times a week. Results: Two of 22 evaluable patients obtained partial responses(8%, confidence interval 3%–33%). Toxicity was severe.Diarrhea and stomatitis were the most common side effects, occuringin 50% and 25% of patients, respectively. Conclusion: Because of the presence of severe toxicity we suggestthat further clinical trials in pancreatic cancer be attemptedonly after a better definition in preclinical studies of interactionsamong 5-FU, leucovorin and interferon. pancreatic cancer, 5-fluorouracil, modulation