Treatment for advanced colorectal carcinoma with 5-fluorouracil plus low-dose leucovorin]

From July 1992 to May 1996, 16 patients with non-curative postoperative or recurrent colorectal carcinomas were treated with 5-fluorouracil (5-FU) plus leucovorin (LV) systemic chemotherapy. LV was given at a dose of 20 mg/m2/d immediately followed by 5-FU at 370 mg/m2/d. LV was given by rapid intravenous (i.v.) injection and 5-FU by rapid or drip i.v. for 5 consecutive days. Courses were repeated once every 4 weeks for two months and then once every 5 weeks. All patients took 3 or more courses. The toxicity was tolerable, but one patient needed hospitalization because of severe gastro-intestinal toxicity. We observed 3 PR cases, no CR and an overall response rate of 19%. The response duration was 6 to 8 months, averaging 7.3 months, and median survival was 12 months. It was possible to perform this chemotherapy on an outpatient basis, so we think this chemotherapy is superior to in-hospital chemotherapy considering the issue of quality of life. However, the response rate was low and its duration was short. We must investigate chemotherapy further with new and more powerful chemical modulations to increase the response rate and to prolong the response duration.     

A phase II study with CPT-11 plus leucovorin and bolus IV 5-fluorouracil in patients with advanced colorectal carcinoma

Standard chemotherapy in advanced colorectal carcinoma (CRC) has not yet been established. The present study was conducted to assess the efficacy and toxicity profile of CPT-11, leucovorin (LV), and bolus 5-fluorouracil (5-FU) in a weekly schedule. Fifty-five patients were entered with no prior chemotherapy for advanced disease or adjuvant treatment ended at least 6 months preceding study entry, and 45 were assessable for response. Patients were treated with CPT-11 80 mg/m² (7 patients) or 70 mg/m² (48 patients). After completion of CPT-11 infusion, LV 200 mg/m² was administered over 2 hr followed immediately by 5-FU 450 mg/m², IV bolus, weekly for 6 weeks followed by a 2-week rest period. Treatment was continued for four cycles. Because of grade 3 and 4 diarrhea in four of the first seven patients, the study was amended to reduce the starting dose of CPT-11 from 80 to 70 mg/m² weekly. Four complete and 10 partial responses were observed (response rate: 25.5%), the median time to progression (TTP) was 7.7 months, 1-year survival rate was 62.3%, and the median overall survival was 15.0 months. Grade 3 and 4 diarrhea occurred in seven patients (12.7%), four of them treated with CPT-11 80 mg/m². Grade 3 myelotoxicity occurred in five patients (9.0%). Toxic death because of diarrhea, neutropenia, bacteremia, and sepsis occurred in a patient treated with CPT-11 80 mg/m². Our results confirm the efficacy of CPT-11, LV, and 5-FU in a weekly schedule in patients with advanced CRC. Further studies are needed to compare the present regimen with higher doses of CPT-11 with LV plus different schedules of 5-FU administration in the treatment of metastatic CRC.     

A phase III study of 5-fluorouracil versus 5-fluorouracil plus interferon alpha 2b versus 5-fluorouracil plus leucovorin in patients with advanced colorectal cancer: a Hellenic Cooperative Oncology Group (HeCOG) study

We conducted a phase III study in patients with advanced colorectal carcinoma (ACC). The total number of patients randomized from October 1993 until July 1998 was 192, whereas therapy was started on 179 and 158 (82.3%) have been evaluable. The treatment schedules consisted of weekly bolus administration for 6 weeks of 5-fluorouracil (5-FU), 600 mg/m2 (arm I) versus 5-FU (500 mg/m2) intravenous bolus and interferon-alpha, 5 MU subcutaneously, three times a week (arm II) versus leucovorin 200 mg/m2 in 2-hour infusion and 5-FU 500 mg/m2 intravenous bolus at the midtime of leucovorin infusion (arm III) followed by a 2-week rest period. Treatment was continued for six cycles or until progression. This study failed to show any superiority of the modulated 5-FU versus single administration of 5-FU. There were no significant differences between the three arms in the overall response rate (10.3% versus 11.3% versus 12.9%, p = 0.95), the time to tumor progression (median, 3.9 versus 3.8 versus 6.0 months, p = 0.59), or survival duration (median, 14.7 versus 12.4 versus 16.3 months, p = 0.71). The incidence of severe (grades III and IV) toxicity was significantly higher in patients in arm II and III (24.5% and 18.6%) versus arm I (6.0%) (p = 0.01). Because modulated 5-FU failed to show superiority versus 5-FU, new agents and new strategies are needed for the treatment of advanced colorectal carcinoma.     

Oral doxifluridine plus leucovorin in metastatic colorectal cancer: randomized phase II trial with intravenous 5-fluorouracil plus leucovorin

This phase II study was designed to evaluate the efficacy and toxicities of oral doxifluridine plus leucovorin as a randomized trial with those of intravenous 5-fluorouracil (5-FU) plus leucovorin in previously untreated metastatic colorectal cancer (CRC). Patients with metastatic CRC were randomized in either group A (oral doxifluridine 1,000 mg/m /d plus leucovorin 30 mg/d on days 1 to 7 and 15 to 21 of each cycle), or group B (intravenous 5-FU 400 mg/m /d plus leucovorin 20 mg/m /d on days 1-5 of each cycle), with the cycles repeated every 4 weeks. Between July 1998 and May 2000, 77 patients were enrolled (38 in group A and 39 in group B). Response rates were 23.7% (95% CI, 11-42%) in group A, and 15.4% (95% CI, 0-25%) in group B on an intent-to-treat analysis. The median response durations of the two groups were similar with 5.6 months in group A and 5.5 months in group B. Progression-free survival and overall survival were 5.4 months and 14.9 months in group A; 4.7 months and 19.5 months in group B. Toxicities in both groups were generally mild and reversible. This study shows that a combination of oral doxifluridine plus leucovorin can be active and safe as a first-line treatment for patients with metastatic CRC.     

The impact of adding low-dose leucovorin to monthly 5-fluorouracil in advanced colorectal carcinoma: Results of a phase III trial

Purpose: A wide variety of fluorouracil (FU)-plus-leucovorin (LV) doseschedules are in clinical use for the treatment of advanced colorectalcancer. Only the monthly low-dose LV- plus-FU regimen, as used by the NorthCentral Cancer Treatment Group, has demonstrated a lasting survival benefitas opposed to FU alone (J Clin Oncol 1989; 7: 1407–1417). The SwissCancer Group adopted this regimen for a confirmatory phase III trial butused the same dose-intensity of fluorouracil in both treatment arms.Patients and methods: Patients with inoperable or metastatic colorectalcancer were randomized to receive monthly FU 400 mg/m²/dayplus LV 20 mg/m²/day as intravenous push daily for five days,or FU alone.Results: Three hundred nine of the 310 patients randomized were eligibleand included in the analysis. The objective response rate for patients withmeasurable disease was 9% with FU alone and 22% withFU-plus-LV (P = 0.0001). The median progression-free survival was 3.9 versus6.2 months (P = 0.003) and the overall survival 10 versus 12.4 months (P =0.02). The major prognostic factors for survival were performance status,weight loss, and disease symptoms. WHO >2 toxicity, consisting ofstomatitis (P = 0.001), diarrhea (P = 0.001), and nausea (P = 0.001), wasmore pronounced for FU-plus-LV, without fatal events.Conclusions: This is the largest published randomized trial to compareFU-plus-LV to FU alone in advanced colorectal cancer. It confirms the survivalbenefit obtained from biomodulating monthly FU with low-dose LV. The toxiceffects of FU-plus-LV were acceptable to most patients, and they respondedwell to FU dose reductions. In the absence of an ideal dose-intense FUmonotherapy regimen, monthly FU with low-dose LV provides a simple andeconomical means by which to achieve adequate FU efficacy in the treatment ofadvanced colorectal cancer.     

A phase II trial of weekly high dose continuous infusion 5-fluorouracil plus oral leucovorin in patients with advanced colorectal cancer

Background. In a previous Phase II trial, the authors showed that a weekly continuous infusion of 5-fluorouracil (5-FU) at a dose of 3.5 g/m² for 48 hours is an active treatment for advanced colorectal cancer. The overall response rate was 38.5%, and the median survival was 12 months. These data were comparable to those achieved by biochemical modulation of 5-FU with leucovorin. To study the modulation of this weekly, high dose, continuous infusion 5-FU with oral leucovorin, a new Phase II trial was planned. Methods. From December 1991 to July 1992, 43 previously untreated patients with measurable advanced colorectal cancer were included in a multicenter study. They received on an outpatient basis 5-FU at a weekly dose of 3 g/m² by continuous infusion for 48 hours until progression or toxicity. Oral leucovorin (60 mg every 6 hours) also was given during the infusion of 5-FU. Results. Patients received a median dose intensity of 5-FU of 2.2 g/m²/week (range, 0.76-3 g/m²/week). One complete response and 11 partial responses were observed. The overall response rate was 29% (95% confidence interval [CI], 16–45%). Median time to progression was 7 months, and the median survival was 15 months. World Health Organization Grades 3 and 4 diarrhea were observed in 19 (45%) and 6 (14%) patients, respectively. Grade 3 mucositis also was observed in 10 (24%) patients, and Grade 4 mucositis was observed in 1. Grade 3 nausea and vomiting were reported in seven (17%) patients. Grade 3 hand–foot syndrome was detected in only two (2.5%) patients. No leukopenia or thrombocytopenia was observed. Conclusions. Oral leucovorin modulation of a weekly 48-hour infusion of 5-FU at a dose of 3 g/m² of leucovorin is a toxic regimen, always requiring dose reduction, with diarrhea and mucositis as the main limiting toxicities. Its antitumor activity does not seem superior to that observed with a weekly 48-hour infusion of 5-FU alone at a dose of 3.5 g/m². Cancer 1995; 76:559–63.     

Outpatient weekly high-dose continuous-infusion 5-fluorouracil plus oral leucovorin in advanced colorectal cancer. A phase II trial

BACKGROUND:: Background: In a previous phase I–II trial we showed thatmaximum tolerable dose (MTD) of 5-fluorouracil (5-FU) a weekly48-hour continuous infusion (CI) was 3.5 g/m². In a subsequentconfirmative phase II trial with 85 evaluable patients, a 38.5%response rate was obtained, and a median survival of 12 months.These data were comparable to those achieved by biochemicalmodulation of 5-FU with leucovorin. On this basis we attemptedto modulate high-dose 5-FU (3 g/m²) with oral leucovorin (LV)but the regimen too toxic and the dose had to be reduced. Anew phase II trial with 2 g/m²/week plus oral leucovorin wasplanned. PATIENTS AND METHODS:: From July 1992 to June 1994, 110 previously untreated patientswith advanced, measurable colorectal cancer were included ina multicenter study. The patients received, on an outpatientbasis, 5-FU 2 g/m² by continuous infusion for 48 hours oncea week until progression or the appearance of toxic effects.Oral leucovorin (60 mg every six hours) was also given duringthe 5-FU infusion. RESULTS:: Patients received a median dose intensity of 5-FU of 1.6 g/m²/week(range 0.9–2). Three complete responses and 36 partialresponses were observed. The overall response rate was 37.5%(95% CI, 28% to 46.8%), the median time to progression 7.4 monthsand median survival 14.5 months. W.H.O. grade 3 diarrhea occurredin 27 patients (24.5%); grade 3 mucositis was observed in 9(8.1%) patients and grade 4 in one. Grade 3 nausea and vomitingwas reported in 13 (11.7%) patients, while grade 3 hand-footsyndrome was detected in only 5 (4.5%). Grade 4 leukopenia occurredin one patient and grade 3–4 thrombocytopenia in two. CONCLUSION:: Oral leucovorin modulation of weekly 48-hour continuous infusionof 5-FU at 2 g/m² is an active regimen, with diarrhea and mucositisas the main limiting toxic effects. Its antitumor activity doesnot seem superior to that obtained with a weekly 48-hour continuousinfusion of 5-FU alone at a dose of 3.5 g/m². advanced colorectal cancer, biochemical modulation, continuous infusion, fluorouracil, phase II trial     

A double-blind placebo-controlled randomized phase III trial of 5-fluorouracil and leucovorin, plus or minus trimetrexate, in previously untreated patients with advanced colorectal cancer.

BACKGROUND: Trimetrexate (TMTX) biochemically modulates 5-fluorouracil (5-FU) and leucovorin (LCV). Two phase II trials demonstrated promising activity for TMTX/5-FU/LCV in patients with untreated advanced colorectal cancer (ACC). This trial was designed to demonstrate the safety and efficacy of TMTX/5-FU/LCV as first-line treatment in ACC. PATIENTS AND METHODS: Eligible patients with ACC were randomized in double-blind fashion to receive placebo or TMTX (110 mg/m2) intravenously (i.v.) followed 24 h later by i.v. LCV 200 mg/m2, and 5-FU 500 mg/m2 plus oral LCV rescue. Both schedules were given weekly for 6 weeks every 8 weeks. Patients were evaluated for progression-free survival (PFS), overall survival (OS), tumor response, quality of life (QoL) and toxicity. RESULTS: A total of 382 eligible patients were randomized. Significant toxicities were noted more frequently with TMTX/5-FU/LCV. Diarrhea was the most common grade 3 or 4 side-effect (41% and 28% on the TMTX and placebo arms, respectively). QoL scores and response rates did not differ between treatment arms. PFS was 5.3 months and 4.4 months in the TMTX and placebo arms, respectively (P = 0.77; Wilcoxon). OS was 15.8 months and 16.8 months, respectively (P = 0.73; Wilcoxon). CONCLUSIONS: The addition of TMTX to a weekly regimen of 5-FU/LCV worsened grade 3 or 4 diarrhea. The inclusion of TMTX did not yield any significant improvements in response rate, PFS or OS.     

羟基喜树碱联合5-FU/CF治疗晚期大肠癌临床观察

目的　观察应用羟基喜树碱联合治疗晚期大肠癌的近期疗效及毒副反应。方法　 72例晚期大肠癌随机分为两组 ,一组为治疗组 :10 羟基喜树碱 (Hydroxycamptothecin ,HCPT)联合 5 FU/CF ;另一组为对照组 :5 FU/CF。 结果　治疗组有效率5 2 .8% ,对照组有效率 30 .6 % ,差异有显著性 (P <0 .0 5 )。毒副反应主要是恶心、呕吐及白细胞减少 ,但大多限于Ⅰ～Ⅱ度 ,两组无显著性差异 (P >0 .0 5 )。结论　HCPT联合 5 FU/CF治疗晚期大肠癌有效而安全     

A prospective randomized trial of 5-fluorouracil versus 5-fluorouracil and high-dose leucovorin versus 5-fluorouracil and methotrexate in previously untreated patients with advanced colorectal carcinoma

Seventy-four previously untreated patients with metastatic colorectal adenocarcinoma were prospectively randomized into one of three treatment regimens: (1) 5-fluorouracil (5-FU) 450 mg/m2 as an intravenous (IV) bolus daily for five days or toxicity, then 200 mg/m2 IV bolus every other day for six doses; (2) methotrexate (MTX) 50 mg/m2 in normal saline by IV infusion over four hours followed by an IV bolus of 5-FU 600 mg/m2. This was administered weekly for 4 weeks and then every 2 weeks. (3) Leucovorin 500 mg/m2 in a two-hour IV infusion of normal saline with 5-FU 600 mg/m2 as an IV bolus one hour after the Leucovorin began every week for 6 weeks. The combined complete and partial response rates in the three regimens were 11%, 5%, and 48%, respectively (P = .0009). The median duration of response in the 5-FU and Leucovorin regimen was 10 months. There was no statistically significant difference between the treatment regimens with respect to survival time (P = .6). Toxicity in the 5-FU and Leucovorin regimen was predominantly diarrhea (13 of 30 patients, 40%). In this regimen, eight of 13 patients (52%) who developed diarrhea not only required a dose reduction of 5-FU, but also hospitalization for IV hydration. The predominant toxicity in the 5-FU alone regimen and the 5-FU and MTX regimen was leukopenia. One drug-related death occurred in each regimen.     

A prospective randomized study of irinotecan (CPT-11), leucovorin (LV) and 5-fluorouracil (5FU) versus leucovorin and 5-fluorouracil in patients with advanced colorectal carcinoma

The purpose of this study was to compare the activity and toxicity of an irinotecan (CPT-11), leucovorin (LV) and 5-fluorouracil (5FU) combination with a standard regimen of 5FU and LV, in patients with advanced colorectal carcinoma. One hundred and sixty patients were randomized; 80 patients (group A) received LV 20 mg/m(2) bolus i.v. and 5FU 425 mg/m(2) bolus i.v. on days 1-5, every 28 days; 80 patients (group B) received CPT-11 80 mg/m(2) (30-90 min i.v. infusion), followed by LV 20 mg/m(2) bolus i.v. and 5FU 425 mg/m(2) bolus i.v. on days 1, 8, 15, 22, 29, and 36, every 8 weeks. The overall response rate was 30% and 47.5% in groups A and B respectively. Progression-free survival was significantly higher in the triple-drug combination arm (median 7.5 vs. 4.5 months; p= 0. 0335). However, overall survival did not differ significantly between the two arms (15 months vs. 14 months for the groups B and A respectively; p=0.3531). The main grade 3 adverse events were diarrhea (19%, in group A vs. 35% in group B; p=0.032) and mucositis (2% vs. 14%; p=0.017). The regimen containing irinotecan showed activity in advanced colorectal cancer. The overall safety data confirm this combination as a well-tolerated treatment.     

Double modulation of 5-fluorouracil by trimetrexate and leucovorin in patients with advanced colorectal carcinoma

The purpose of this report is to evaluate the efficacy and toxicity (Tx) of a double modulation of 5-fluorouracil (5-FU) by trimetrexate (TMTX) and leucovorin (LV) in patients with advanced recurrent (inoperable) or metastatic colorectal cancer (ACC). Between December 1997 and August 2000, 36 patients were entered in this phase II study. Median age was 61 years, and 18 patients (50%) were female. Median performance status was 0 (range: 0-1), whereas primary tumor location was colon in 21 patients (58%) and rectum in 15 patients (42%). The number of metastatic sites was 1:29 patients (81%); 2:6 patients (17%) and 3:1 patient (3%). Hepatic involvement was observed in 33 patients (92%). Treatment consisted of TMTX 110 mg/m2 IV over 1 hour at hour (H) 0; LV 50 mg/m2 IV over 2 hours IV infusion starting at H 18; and 5-FU 900 mg/m2 IV bolus at H 20. LV (rescue) 15 mg/m2 orally was administered every 6 hours (total 6 doses) beginning at H 24. Cycles were repeated every 2 weeks until progressive disease (PD) or severe Tx. Thirty-four patients are assessable for response (R) (two patients refused further treatment after the first course of therapy), whereas all patients were assessable for Tx. Complete response: 1 patient (3%); partial response: 4 patients (12%), with an overall objective response rate of 15% (95% CI, 1%-25%); no change: 12 patients (35%); and progressive disease: 17 patients (50%). The median time to treatment failure was 4 months and median survival was 11 months. Tx was within acceptable limits. The dose-limiting side effect was mucositis. Eight episodes of grade II or III stomatitis were observed and were responsible for dosage modifications of TMTX and 5-FU. Leukopenia was observed in 16 patients (44%); neutropenia was registered in 19 patients (53%); anemia was seen in 18 patients (50%); emesis in 22 patients (61%); and dermatitis in 3 patients (8%). There were no therapy-related deaths. The double modulation of 5-FU by TMTX and LV showed modest antitumoral activity with mild to moderate Tx.     

A phase II trial of 5-fluorouracil and high-dose leucovorin in gastric carcinoma and a phase I trial of intraperitoneal 5-fluorouracil and leucovorin

Twenty-five patients with advanced measurable gastric carcinoma were treated with D,L-leucovorin (CF) (500 mg/m2) administered as a 2-hour infusion and FUra (600 mg/m2) iv push midinfusion. Patients were treated weekly for 6 weeks followed by a 2-week rest. Median age was 57 (range 32 to 82). Median Eastern Cooperative Oncology Group (ECOG) performance status was 2 (range 0 to 4). Thirteen patients had progressed on previous combination chemotherapy that included FUra. At the time of this report, 19 patients were evaluable for response: 3 patients had partial responses, 8 had stable disease, and 8 progressed (but 3 of these received only 3 or fewer treatments before early disease-related death). Two of the responders were previously treated with FUra. Four patients were too early to evaluate. Measurable responses of greater than 50% were seen in bone, liver, lung, and an abdominal mass. Diarrhea occurred in 9 patients and FUra dose reduction was necessary in 8 of them. Other toxicities included lacrimation, rash, nausea, and mucositis. One toxic death occurred. Nine patients with gastrointestinal tumors confined primarily to the intra-abdominal space were treated with ip FUra in escalating doses (2 mM to 4 mM) in combination with D,L-CF in a 2-liter volume, either by 8 consecutive 4-hour dwells (7 patients) or once daily for 5 days (2 patients). The D,L-CF dose was 20.8 microM except for the first day of the 5-day schedule when it was 104 microM. Toxicity included leukopenia, mucositis, nausea and vomiting, skin rash, and abdominal pain. Three episodes of peritonitis resolved with antibiotics.(ABSTRACT TRUNCATED AT 250 WORDS)     

Phase III trial of 5-fluorouracil and leucovorin plus either 3H1 anti-idiotype monoclonal antibody or placebo in patients with advanced colorectal cancer.

BACKGROUND: The monoclonal antibody 3H1 mimics the external structure of the carcinoembryonic antigen (CEA). It therefore has the potential, via the anti-idiotypic network, to stimulate immune responses to CEA that may benefit colorectal cancer patients. PATIENTS AND METHODS: A total of 630 patients with previously untreated metastatic colorectal cancer were randomised in a 2:1 fashion to receive bolus 5-fluorouracil (5-FU) and leucovorin (LV) plus either 3H1 (n = 422) or placebo (n = 208). RESULTS: The addition of 3H1 to 5-FU and LV did not result in increased toxicity. Survival for the full intent-to-treat population was 14.7 months for the 3H1 arm and 15.2 months for the placebo arm (P = 0.80). Anti-CEA antibody responses were observed in 70% of patients treated with 3H1. Patients with a negative CEA response had a median survival of 8.3 months (95% CI 7.5-11.0) compared with patients with a strong response: median survival not reached (P <0.001). CONCLUSION: 3H1 is safe and effectively induces immune responses to CEA. Addition of 3H1 to 5-FU and LV was not shown to improve overall patient outcomes. However, improved survival in patients developing anti-CEA responses to 3H1 are provocative and should be studied in further clinical trials.     

A phase II trial of gemcitabine, 5-fluorouracil and leucovorin in advanced esophageal carcinoma

BACKGROUND: The aim of this study was to evaluate the overall response rate, toxicity and overall survival in patients with locally advanced or metastatic esophageal cancer treated with gemcitabine, 5-fluorouracil (5-FU) and leucovorin. PATIENTS AND METHODS: Patients with either adenocarcinoma or squamous cell carcinoma of the esophagus could enroll; however, patients could not have received prior chemotherapy for metastatic disease. Treatment cycles consisted of infusions of all three agents at days 1, 8 and 15, repeated every 28 days. Patients received gemcitabine 1,000, leucovorin 25 and 5-FU 600 mg/m(2). Tumor assessment was performed every 2 cycles. Responses were assessed using the Eastern Cooperative Oncology Group solid tumor response criteria. RESULTS: Thirty-five patients with metastatic or locally advanced esophageal cancer enrolled. One complete response and ten partial responses were observed for an overall response rate of 31.4%. An additional 11 patients had stable disease as their best response. The median survival was 9.8 months with a 1-year survival rate of 37.1%. Toxicity was predominately hematologic, with 58% of patients experiencing grade 3 or 4 neutropenia. CONCLUSION: The combination of gemcitabine, 5-FU and leucovorin had activity in advanced esophageal cancer. Patients tolerated the regimen well, with myelosuppression occurring most commonly. The combination merits further investigation as a treatment for esophageal cancer.     

A Northern California Oncology Group randomized trial of leucovorin plus 5-fluorouracil versus sequential methotrexate, 5-fluorouracil, and leucovorin in patients with advanced colorectal cancer who failed treatment with 5-fluorouracil or 5-fluorodeoxyuridine alone

The current study was initiated to confirm preliminary reports that 20% or more of patients with colorectal cancer who fail treatment with 5-fluorouracil (FUra) will respond to treatment with either leucovorin plus FUra or with sequential methotrexate, FUra, leucovorin. One hundred two patients with advanced, measureable colorectal cancer who failed treatment with FUra and/or 5-fluorodeoxyuridine (FUdR) were randomized to treatment with either high-dose leucovorin plus FUra (Arm B) or sequential methotrexate, FUra, leucovorin (Arm C). In this interim report, 92 patients were evaluable for toxicity and 89 patients were evaluable for response. Grade 3 or 4 nonhematologic toxicity which was primarily gastrointestinal was experienced by 25% of patients on both treatment arms during at least 1 treatment cycle. Hematologic toxicity was minimal. Among 43 evaluable patients on Arm B, there were 2 complete responses (5%) and 1 minor response (3%). Among 46 evaluable patients on Arm C, there was 1 complete response (2%), 1 partial response (2%), and 6 minor responses (14%). The median time to treatment failure was 2.2 months on Arm B and 3.5 months on Arm C. The median survival was 8.3 months on Arm B and 8.7 months on Arm C. Colorectal cancers that are resistant to FUra are cross-resistant to both experimental combinations.     

Capecitabine plus oxaliplatin (xelox) versus protracted 5-fluorouracil venous infusion plus oxaliplatin (pvifox) as first-line treatment in advanced colorectal cancer: a GOAM phase II randomised study (FOCA trial)

This phase II randomised trial compares oxaliplatin plus protracted infusion of 5-fluorouracil (pviFOX) or oxaliplatin plus capecitabine (XELOX) in the first-line treatment of advanced colorectal cancer (ACRC). Methods: From December 2001 to March 2005, 118 patients were randomised to arm A ( pviFOX: pvi5-FU by a central venous catheter 250 mg/m2/daily d1-21 + oxaliplatin 130 mg/m2 d1 q3w) (56 pts) or arm B (XELOX: capecitabine 1000 mg/m2 po bid d1-14 + oxaliplatin at the same schedule) (62 pts). Results: Patient characteristics were well-balanced between the two arms. Median number of complete cycles was six. The objective responses were: CR 1 (1.7%) and 3 (4.8%), PR 26 (46.4 %) and 24 (38.7%), SD 13 (23.2%) and 20 (32.3%), P 13(23.2%) and 10 (16.1%), not evaluable 3 (5.4%) and 5 (8.1 %) in arms A and B, respectively; the CR + PR rate was 48.2% (95% confidence limits 34.6%–61.9%) versus 43.5 % (31.0%–56.7%). Median TTP was 7 versus 9 months, respectively. About 50% of the patients with symptoms or low performance status at baseline experienced improvement without major differences between the two arms. G3–4 diarrhoea was observed in 14.0% versus 8.2%, G3 stomatitis in 3.7% versus 0, and G3 neurotoxicity in 18.5% versus 24.6% in arms A and B, respectively. Eight patients in arm A (14.8%) had venous line problems that obliged the temporary suspension (six cases) or stopping (two cases) of the 5-FU infusion. Conclusion: Both pviFOX and XELOX are effective and safe first-line treatments for patients with ACRC. By avoiding intravenous (i.v.) administration by a central catheter, XELOX is favoured in clinical practice.     

Tegafur and uracil plus leucovorin in advanced colorectal cancer: a phase II trial

The objective of this study was to evaluate the activity and toxicity of tegafur and uracil (UFT; 1:4 molar ratio) plus leucovorin (LV) in patients with advanced colorectal cancer. One hundred forty-one patients were entered into the study. The treatment schedule consisted of UFT 300 mg/m2/day (in three divided doses) plus oral LV 150 mg/day (50 mg t.i.d.) over 28 days. The treatment cycle was repeated every 5 weeks until progression or unacceptable toxicity was observed. The treatment was interrupted if grade 3/4 toxicity appeared and was resumed at the same dosage on recovery. One hundred thirty-six patients were evaluable for response and 141 were evaluable for toxicity. The response rate was 19.9% (95% confidence interval: 12%-28%). The total number of patients without progression (objective response + stable disease) was 76 (55.9%). The median time to progression was 5.6 months, and the overall survival was 11.6 months. The toxicity profile was low, with 11% of patients experiencing grade 3/4 nausea and vomiting, while 17% had grade 3/4 diarrhea. Oral administration of UFT modulated with LV is a comfortable regimen of chemotherapy for patients with advanced colorectal cancer.