Sequential therapy with methotrexate and 5-fluorouracil in the treatment of advanced colorectal carcinoma

Twenty-nine patients with advanced colorectal carcinoma were entered in this study to evaluate the efficacy and toxicity of a sequential chemotherapeutic schedule with methotrexate (MTX), 200 mg/m2 intravenously (IV) (push injection) and 5-fluorouracil (5-FU), 1,200 mg/m2 in continuous IV infusion, using a 20-hour time interval. All patients received calcium leucovorin (LV), 25 mg, intramuscularly (IM) every six hours for eight doses beginning 24 hours after methotrexate administration. Courses were administered every 15 days. Of the 24 patients evaluable for response, 11 (46%) had major objective regressions (one complete remission [CR] and ten partial remissions [PR]). The survival rate of patients who responded to treatment was 60% at 16 months, whereas patients with no change and those in whom the disease progressed had a median survival of 9 months and 3 months, respectively. The median duration of response has not yet been reached in patients who presented objective tumor regression, and was 7.5 months in those with no change. Significant differences were found between objective regression and no change (P less than .0005) and between no change and tumor progression (P less than .05). All patients were evaluable for toxicity. There were three toxic-related deaths (10%) because of severe myelosuppresion, sepsis, and hemorrhage. These promising results, despite important toxicity, reveal the synergism between the two chemotherapeutic agents and also indicate that the response rate achieved could be a consequence of the 20-hour interval and high dose of 5-FU. Further studies are necessary to determine the optimal time interval and the adequate 5-FU dose.     

Sequential chemotherapy with low-dose methotrexate and 5-fluorouracil in advanced gastric cancer

Sequential chemotherapy with low-dose methotrexate (30 mg/body) and 5-FU (750 mg/m2) was undertaken in 16 patients with advanced gastric cancer. Following the chemotherapy, leucovorin (30 mg/body) was injected intravenously. These treatment were repeated weekly for two to eight weeks. Out of 16 patients, two partial remissions and two minor responses were obtained. The overall response rate was 12.5%. There were no cases of renal or hematologic toxicity. The only adverse effect was nausea. We concluded therefore, that sequential chemotherapy with low-dose methotrexate and 5-FU is a useful method for advanced gastric cancer.     

Sequential methotrexate, 5-fluorouracil, and calcium leucovorin in colorectal carcinoma

Forty-four patients with locally recurrent or metastatic colorectal adenocarcinoma were treated with methotrexate (MTX) 100 mg/m2 i.v. followed 1 h later by 5-fluorouracil (5-FU) 600 mg/m2 i.v. Calcium leucovorin 10 mg/m2 p.o. q 6 h X four doses was given 24 h after MTX. The regimen was given on days 1 and 8 and repeated every 28 days. Six of 44 patients (14%) obtained either complete or partial response with a mean response duration of 6.8 months. Of 26 previously untreated patients there were one complete response (4%), four partial responses (15%), and 12 (46%) instances of stabilization of disease. Patients obtaining response or stabilization of disease experienced improved survival compared to those with progressive disease. Toxicity consisted of stomatitis and hematopoietic suppression requiring dose attenuation in six patients (14%); there were no treatment-related deaths. Sequenced MTX/5-FU is modestly active with acceptable toxicity in previously untreated patients with colorectal adenocarcinoma but offers no apparent advantage over single-agent 5-FU.     

Second-line chemotherapy of advanced colorectal cancer with sequential high-dose methotrexate and 5-fluorouracil

Twenty-five patients with pretreated advanced colorectal carcinoma were subjected to second-line chemotherapy with sequential high-dose methotrexate and 5-fluorouracil. In 20 evaluable patients 2 (10%) partial responses, 12 (60%) stable disease and 6 (30%) progressions were observed. Partial responses were maintained for 3 and 4 months respectively; stable disease had a median duration of 4 months. The overall median survival after progression was 7 months. From our results sequential high-dose methotrexate and 5-fluorouracil cannot be recommended as second-line chemotherapy in advanced colorectal cancer.     

Sequential methotrexate and 5-fluorouracil in the primary treatment of metastatic colorectal carcinoma

Thirty-three patients with metastatic colorectal carcinoma were treated with sequential conventional dose methotrexate (60 mg/m2) followed within 1 hour by 5-fluorouracil (1000 mg/m2) every 3 weeks. Thirty of 33 patients were assessable for response. One patient (3%) achieved a partial remission (3.5 months). Three patients demonstrated minor tumor regressions. In an additional 17 patients, tumor stabilization was observed. The treatments were tolerated without any significant morbidity. A disappointingly low response rate was observed in our study as opposed to previous reports. Further clinical studies are necessary to establish the optimum dose levels and scheduling of sequential methotrexate and 5-fluorouracil.     

A combination of 5-fluorouracil and thymidine in advanced colorectal carcinoma

Summary Concurrent administration of thymidine (TdR) has been shown to increase the antitumor activity of 5-fluorouracil (5-FU) in various experimental models. The clinical response rate, side-effects, and toxicity of 5-FU und TdR were evaluated in 27 patients with advanced colorectal carcinomas. Each 6-day treatment course consisted of an IV loading dose of TdR (405 mg/kg, over 30 min), followed by continuous IV infusions of 5-FU (7.5 mg/kg per day for 5 days), and TdR (216 mg/kg per day for 6 days); courses were repeated every 4 weeks. The overall partial response rate was 4.5%, or 16.7% in patients with no prior 5-FU chemotherapy. Short-lived stable disease was seen at an overall rate of 27.3%, half of these patients with prior 5-FU chemotherapy. Myelotoxicity occurred in 64% of the patients, but this was dose-limiting in only 20%. Gastrointestinal and neurological symptoms were mild and infrequent. There was one case of treatment-related death due to sepsis secondary to leukopenia. It is concluded that the concurrent IV administration of 5-FU and TdR does not improve the response rate over that obtained with 5-FU alone.     

Sequential moderate-dose methotrexate and 5-fluorouracil in advanced gastric adenocarcinoma

Summary A total of 23 patients with advanced gastric adenocarcinoma were treated with a combination of moderate-dose methotrexate (MDMTX), 250 mg/m² i.v., with folinic acid rescue and 5-fluorouracil (5-FU) 600 mg/m² i.v. Therapy was given every 7 days for 4 courses and then at 14-day intervals. All patients were evaluable for response. No complete responses occurred, but five patients (22%) had partial remissions (95% confidence limit, 5%–39%). The median duration of remission was 6 months, with a median survival of 11 months amongst responding patients. In all, six patients (26%) had stable disease for a median period of 5 months. The overall median survival was 6 months. Therapy was generally well tolerated, with principal toxicities consisting of neutropenia, nausea and vomiting, mucositis and diarrhoea. In terms of activity or survival in advanced gastric carcinoma, the combination of moderate-dose MTX and 5-FU does not appear to offer an advantage over single-agent therapy.     

Methyl-CCNU and methotrexate therapy in patients with advanced colorectal cancer after failure of 5-fluorouracil chemotherapy

Thirty-six patients with advanced colorectal cancer whose disease progressed during treatment with 5-fluorouracil (5-FU) chemotherapy were treated with methyl-CCNU and methotrexate. Five patients (14%) achieved a partial response (PR), three (8%) showed disease regression less than that required for a PR, and three (8%) showed evidence of stable disease. Twenty-five patients (69%) progressed on treatment. Tumor regression was seen only in patients with good performance status (ECOG 0.1). The median survival time of patients achieving a PR was 31 weeks. Those patients with stable disease or disease regression less than a PR had median survival times of 49 and 32 weeks, respectively. The comparable figure for those patients with disease progression was 17 weeks. Myelosuppression, principally in the form of leukopenia and thrombocytopenia, was common. Nausea and vomiting were universal with methyl-CCNU, and mucositis and diarrhea occurred commonly due to methotrexate. These results demonstrate the limited activity of chemotherapy in refractory colorectal cancer. They also reaffirm that poor pretreatment performance status should exclude patients from futile attempts at palliative therapy or phase II clinical trials, as these patients derive little or no benefit from them.     

Biweekly low-dose cisplatin and 5-fluorouracil combination chemotherapy for advanced gastrointestinal carcinoma

Biweekly intravenous infusions of low-dose cisplatin (CDDP) and 5-fluorouracil (5-FU) were evaluated in 80 patients with advanced or recurrent gastric, colorectal, pancreatic or gallbladder adenocarcinoma. CDDP was given biweekly at a dose of 15 mg/m2 infused for 30 minutes, and 5-FU 375 mg/m2 was infused for 2 hours as many times as possible. The response rate among patients with gastric cancer was 26%, colorectal cancer 10%, pancreatic cancer 7.7%, and gallbladder cancer 42.9%. The response rates were not so high, but the median survival time of patients with recurrent gastric cancer was 17.3 months, pancreatic cancer 6.7 months, and gallbladder cancer 10.7 months. A patient with unresected advanced pancreatic head cancer with liver and para-aortic lymph node metastases received this therapy 38 times, and lived for 54 months. No severe side effects occurred in any of these cases. Thus, this chemotherapy could well be effective for the outcome of cases of advanced gastrointestinal carcinoma.     

Modification of 5-fluorouracil activity by high-dose methotrexate or leucovorin in advanced colorectal carcinoma

21 patients with advanced colorectal carcinoma were entered into a phase II study to evaluate efficacy and toxicity of methotrexate (MTX), 1500 mg/m² rapid infusion on day 1, combined with continuous infusion of 5-fluorouracil (5-FU), 600 mg/m² per 24 h on days 1–4. 12 patients who had progressive disease during this regimen subsequently received high-dose leucovorin, 200 mg/m² bolus injection on days 1–4, combined with 4 days' continuous infusion of 5-FU. In the MTX/5-FU group 1 pathologically proven complete remission and 3 partial remissions were seen (response rate 20%). The median progression-free interval was 30 weeks. In 12 patients with progressive disease leucovorin/5-FU stabilized disease in 2 (17%). Toxicity in both regimens was tolerable, gastro-intestinal side-effects being most frequent. There were no treatment-related deaths. Median survival time was 10 months. Serum levels of carcinoembryonic antigen before treatment or doubling-time during progression did not correlate with survival.     

Sequential 5-fluorouracil and methotrexate. Negative experience in metastatic colorectal cancer

Forty-two patients with measurable advanced colorectal cancer were treated with sequential methotrexate (MTX) and 5-fluorouracil (5-FU), followed by folinic acid rescue. Twenty-one patients had received prior chemotherapy, mainly 5-FU (group 1) and remaining 21 patients had not been previously treated by cytotoxic agents (group 2). Two different treatment schedules were used. Regimen I (27 patients): MTX 250 mg/m2 was infused over 1 hour. Two hours from start 5-FU 600 mg/m2 was given as intravenous bolus. Folinic acid rescue started 24 hours after MTX infusion. Regimen II (15 patients): MTX 250 mg/m2 was given as 1-hour infusion. Three hours after the start of MTX a 46-hour 5-FU infusion (2000 mg/m2) was started. Folinic acid rescue as in regimen I. The chemotherapy courses were repeated every second week. After 3 cycles only one patient had partial response, 33 had no change and 8 progressive disease. The median time until progression was 2 1/2 months in group 1 and 4 months in group 2. The median survival was 7 months in group 1 and 10 1/2 months in group 2. Almost identical results were obtained by the two treatment schedules. The toxicity of both regimens was low.     

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.     

Comparison of 5-fluorouracil with 5-fluorouracil, cyclophosphamide, and methotrexate in metastatic colorectal carcinoma.

Thirty-eight patients with metastatic colorecal carcinoma were treated with 5-fluorouracil (5-FU), and 38 patients were treated with the combination of 5-FU, cyclophosphamide, and methotrexate. In terms of percent response, response duration, and survival there was no apparent difference between the two regimens. Combination chemotherapy was found to be effective in 6 of 16 patients refractory to treatment with 5-FU alone, but was associated with more morbidity.     

Sequential methotrexate and 5-fluorouracil: improved response rate in metastatic colorectal cancer

The efficacy of chemotherapy with sequential methotrexate (MTX) and 5-fluorouracil (5-FU) in metastatic colorectal cancer was studied in a multicenter phase II trial using a seven-hour time interval. Forty-two patients were evaluable for response and 16 achieved objective tumor regression (greater than 50%). Median survival of all patients was 12.5 months. The result of this study indicates that MTX and 5-FU are synergistic in human colorectal cancer if given sequentially with a seven-hour time interval. This is supported by a review of the literature that reveals a significantly higher response rate in patients treated with a four-hour or more MTX/5-FU interval as compared to a one-hour interval.     

国产奥沙利铂联合亚叶酸钙和5-氟脲嘧啶治疗晚期结直肠癌的临床观察

目的：评价奥沙利铂联合亚叶酸钙、5—氟脲嘧啶(OXA—CF—5—Fu)方案治疗晚期结直肠癌的疗效与安全性。方法：奥沙利铂(OXA)130mg／m^2，静脉滴注4h，d1；亚叶酸钙(CF)200mg静脉滴注2小时，5—氟脲嘧啶(5—Fu)0．25g于CF滴完后静脉推注，5-Fu0．5g持续静脉滴注6-8小时，d1-5，每3周重复。结果：全组26例患者，有效率(CR PR)为42．31％，不良反应为恶心、呕吐和骨髓抑制，但多为Ⅰ～Ⅱ度，一过性感觉异常。结论：奥沙利铂联合亚叶酸钙和5—氟脲嘧啶治疗晚期结直肠癌疗效较高，不良反应轻而且安全。     

Irinotecan,oxaliplatin, and 5-fluorouracil/leucovorin combination chemotherapy in advanced colorectal carcinoma: a phase II study

The purpose of this study was to evaluate the efficacy and tolerance of a combination of irinotecan, oxaliplatin, and 5-fluorouracil (5-FU)/leucovorin in advanced colorectal cancer (ACC). Twenty-six consecutive patients with ACC and an Eastern Cooperative Oncology Group performance status of 0-2 were treated with a combination of oxaliplatin (120 mg/m2 intravenously [i.v.] for 2 hours) on day 1, irinotecan (250 mg/m2 i.v. for 90 minutes) on day 1, and 5-FU (2600 mg/m2 plus leucovorin 500 mg/m2 i.v. in a 24-hour infusion) on day 1 and 15, every 4 weeks. Five of the patients (19.2%) had shown previous chemoresistance. One hundred sixty-two cycles were administered (median, 6; range, 3-13 cycles). All patients were evaluated for toxicity; 23 were evaluable for response. According to intention-to-treat, the overall response rate was 69.2% (18 patients; 95% CI: 48.2%-85.7%), including 3 complete remissions (11.5%). Four additional patients (15.3%) had stable disease, and only 1 (3.8%) progressed. Major toxicities were neutropenia and diarrhea. Grade 3 neutropenia occurred in 9 patients (34.6%), and grade 4 occurred in 1 patient (3.8%). Grade 3 diarrhea occurred in 8 patients (30.7%) and grade 4 in 1 patient (3.8%). Other toxicities were mild. After a median follow-up of 15.5 months, the median progression-free survival was 14 months. Seventeen patients (65.4%) are still alive, and the median overall survival has not been reached yet. This combination of irinotecan, oxaliplatin, and 5-FU/leucovorin is fairly well tolerated and shows promising activity in ACC. This treatment merits further comparison with other combination regimens.     

Sequential methotrexate and 5-fluorouracil with bleomycin and cisplatin in the chemotherapy of advanced squamous cancer of the head and neck

A bolus intravenous dose of 5-fluorouracil of 600 mg/M2 was added exactly 1 hour after methotrexate administration in an established combination program including bleomycin and cisplatin for advanced squamous cell cancer of the head and neck. Results were no better than those observed previously with the three drugs, and hematologic and mucosal toxicities were slightly worse. The overall response rate was 41% in 34 patients with recurrent or metastatic disease, with only 6% complete remissions. Median time to disease progression for responding patients was 14 weeks, compared with 10 weeks for nonresponders. Partial response had little impact on survival. Among 12 patients with far-advanced disease confined above the clavicles without prior radiotherapy, 9 (75%) achieved partial remission, but the median survival, even with later surgery or irradiation, was only 34 weeks.     

Four cases of advanced colorectal cancer successfully treated with irinotecan plus 5-fluorouracil and l-leucovorin combination chemotherapy

We successfully treated four advanced colorectal cancers with irinotecan (CPT-11) plus 5-fluorouracil (5-FU) and l-leucovorin (l-LV) combination chemotherapy. We diagnosed moderately-differentiated adenocarcinoma of the colon in two patients and of the rectum in two patients. We recognized lymph node metastases in one patient and liver metastases in three patients at the time of operation. After excision for a lesion of the colon or the rectum, all patients underwent a 2-week chemotherapy regimen (CPT-11 100 mg/m2/week + 5-FU 500 mg/m2/week + l-LV 10 mg/m2/week). The effect was PR in all patients. The progressive free survival time was 9.5 months and survival time ranged 5-18 months. Grade 3 diarrhea and leukopenia were seen in one patient. All other adverse reactions were mild (grade 1 or 2). CPT-11/5-FU/l-LV combination chemotherapy appears to be effective for advanced and metastatic colorectal cancer.     

Sequential high dose methotrexate, 5-fluorouracil and folinic acid does not improve response rates in advanced colorectal cancer

27 patients with advanced colorectal cancer were treated in a phase-II trial with high dose sequential methotrexate (MTX), 5-fluorouracil (5-FU), and folinic acid (FA). Following a 4 h infusion of 800 mg/m2 MTX and a 4 h interval, 1,500 mg/m2 5-FU and 200 mg/m2 FA were given as a 24 h infusion. Out of 23 evaluable patients we observed one partial remission and 9 disease stabilizations. Median survival time of all patients was 10.4 months. Overall toxicity was low. In comparison to a previous trial we did not observe better treatment results by adding high dose FA to a sequential MTX/5-FU schedule.     

High-dose methotrexate and 5-fluorouracil in patients with advanced colorectal carcinoma. A randomized study of two pretreatment intervals

Thirty-two patients with untreated advanced colorectal carcinoma received high-dose methotrexate pretreatment followed sequentially by 5-fluorouracil (5-FU). Patients were randomized to receive high-dose methotrexate pretreatment at one of two intervals (0 h or 3 h before 5-FU). There were 16 patients in each study arm. The median methotrexate dose was 1,000 mg/m2 (range, 600-1,200 mg/m2) and that of 5-FU was 1,000 mg/m2 (range, 800-1,200 mg/m2). Treatments were repeated every 21 days. Three patients achieved partial remission (1 in the 3-h interval arm and 2 in the 0-h interval arm). As the response rate using this regimen was noted to be 9% with a less than 5% chance of achieving a response rate higher than 20%, we terminated this study although the therapy resulted in mild-to-moderate but infrequent toxicity. We thus conclude that pretreatment with high-dose methotrexate given at short intervals followed by 5-FU has no significant activity against colorectal carcinoma.