Biliary and pancreatic excretion of methotrexate (MTX) and 5-FU on the MTX/5-FU sequential therapy

On the postoperative adjuvant MTX/5-FU sequential therapy, biliary and pancreatic excretion of both drugs was studied through the hepatic and pancreatic drainages in pancreatoduodenectomized patients. MTX: 100 mg/m2 of bolus injection and 5-FU: 800 mg/m2 of sequential one hour drip infusion were used in this series. Biliary excretion of MTX was reached peak concentration at 90 min, its mean value being 5 fold of serum concentration. During the observation period of 4.5 hours, the recovery of MTX in bile was calculated as 3-12% which presumed to be more because of still continuing biliary excretion on the terminal observation. Pancreatic excretion of MTX was minimal and not so as to have further clinical meaning. Though the serum concentration of 5-FU was raised up with its infusion, biliary and pancreatic outputs of 5-FU were small, each value showing one third compared with at a single shot of the same doses. From the obtained mode and time lag of concentration curves of both drugs, the rationale of per oral and earlier administration of Leucovorin was discussed as a possible way of removal of MTX from intestine.     

An effective weekly paclitaxel administration for gastric cancer with malignant ascites--a case report

A 71 year-old woman underwent total gastrectomy for advanced gastric cancer of p stage IV (pathological findings: por1 type 3 pT3, pN3 (12p: 1/1, 16b1 int: 3/3, 16b1 lat: 2/2), P1, CY1, H0) in March 2002. She was treated with the double modulation therapy of MTX/CDDP/5-FU intraperitoneally after the surgery. After leaving the hospital, she was carrying out the chemotherapy with MTX/5-FU continually. In August 2002, she became hospitalized once again because an appetite decrease and diarrhea appeared. CT of abdomen showed that malignant ascites had obviously accumulated, and she was admitted. Because it was conceivable in all cases of an inflammation by the chemical stimulation that originated in an anticancer drug, we suspended the intraperitoneal chemotherapy. Paclitaxel 90 mg/body administration was started intravenously on a weekly basis from the end of the same month. Those symptoms improved and she was discharged from the hospital, and was continued the paclitaxel administration. In CT of the abdomen that was taken in November in 2002, malignant ascites had obviously been decreasing and disappeared completely after that.     

Therapeutic effect of sequential doses of methotrexate (MTX) and 5-fluorouracil (5-FU) in advanced gastric cancer: comparison of intermediate-dose MTX with high-dose MTX

Twenty-one patients were treated with sequential doses of MTX and 5-FU so as to be classified by MTX dosage into an intermediate MTX-dose group and a high MTX-dose group. In the intermediate-dose MTX group, the drug was given at a dosage of 100 mg/m2 intravenously (i.v.) and followed 1 hour later by 5-FU at 800 mg/m2 i.v. (dripping for 1 hour); the drugs were recycled every 1 week. In the high-dose MTX group, the drug was administered at a dose of 1.5 g/m2 i.v. (dripping for 2 hours) and followed 1 hour later by 5-FU at 1.5 g/m2 i.v. (dripping for 2 hours); the drugs were recycled every 2-3 weeks. Average MTX concentrations in serum at the start of 5-FU administration were 1.69 X 10(-5) and 1.33 X 10(-4) mol/l/h in the intermediate and high-dose MTX groups, respectively. Six (50%) of 12 patients adequately treated with intermediate-dose MTX had a partial response (PR), and one (14.3%) of 7 evaluable patients treated with high-dose MTX had a PR. Major toxicity included diarrhea (33.3%) in the intermediate-dose MTX group and hair loss (71.4%) in the high-dose MTX group. Hematological toxicity was mild in MTX group: six (50%) of 12 patients had a granulocyte count nadir less than 1,000/microliters and one (8.3%) of 12 patients had a platelet count nadir less than 10(5)/microliters in the intermediate-dose MTX group. Five (71.4%) of 7 patients had a granulocyte nadir less than 1,000/microliters and two (28.6%) of 7 patients had a platelet count nadir less than 10(5)/microliters in the high-dose MTX group.     

MTX/CDDP/5-FU double modulation intra-peritoneal chemotherapy for advanced and metastatic gastric cancer--comparison with intra-aortic route and intra-venous route

We studied the efficacy of MTX/CDDP/5-FU intra-peritoneal chemotherapy for advanced and metastatic gastric cancer (n=24), and compared the results with intra-aortic (n=26) and intra-venous (n=21) routes of MTX-CDDP-5-FU double modulation therapy. I.p. administration was more efficient for reduction of malignant acites (p=0.049). However, median survival duration of malignant acites cases showed no difference between the i.p. group and i.a., i.v. groups (p=0.103). Survival rate of the i.p. group was no different with those of i.a. and i.v. groups (p=0.36). Frequency of side effects is much lower in the i.p. group.     

Sequential methotrexate and 5-fluorouracil therapy for gastric cancer patients with bone metastasis

Background. Patients with bone metastasis of gastric cancer occasionally experience disseminated intravascular coagulation (DIC), with a very poor prognosis. Methods. We treated 18 gastric cancer patients with bone metastasis with sequential methotrexate and 5-fluorouracil (sequential MTX/5-FU therapy). The treatment schedule comprised weekly administration of methotrexate (MTX; 100 mg/m², i.v. bolus) followed by 5-fluorouracil (5-FU; 600 mg/m², i.v. bolus) after an interval of 3 h. Calcium leucovorin (10 mg/m², p.o. or i.v.) was administered six times, every 6 h starting 24 h after the administration of MTX. Results. In 11 patients with measurable metastatic lesions, the response rate was 64% (7/11). Nine patients (50%) had DIC before the initiation of chemotherapy, and 8 of them (89%) recovered from it. Two of these 9 patients (22%) survived for more than 1 year. The median survival times for all patients and for the 9 with DIC were 186 and 113 days, respectively. Grade 4 leukopenia was observed in 3 patients (17%). No treatment-related deaths occurred. Conclusion. Sequential MTX/5-FU therapy may have palliative potential and may be a feasible treatment for gastric cancer patients with bone metastasis with or without DIC. Received: December 10, 1999 / Accepted: January 28, 2000     

Phase II study of sequential methotrexate and 5-fluorouracil chemotherapy against peritoneally disseminated gastric cancer with malignant ascites: a report from the Gastrointestinal Oncology Study Group of the Japan Clinical Oncology Group, JCOG 9603 Trial

BACKGROUND: The efficacy of systemic chemotherapy against peritoneal dissemination from advanced gastric cancer (AGC) remains unclear, because the peritoneal dissemination was not defined as a measurable lesion in conventional phase II studies. In this study, we evaluated the efficacy and toxicity of sequential MTX and 5FU therapy (MF) in chemotherapy-naive patients with AGC accompanied by malignant ascites in a phase II setting. METHODS: The treatment schedule comprised weekly administration of MTX (100 mg/m2, i.v. bolus) followed by 5FU (600 mg/m2, i.v. bolus) with a 3 h interval. Leucovorin rescue (10 mg/m2 every 6 h, for a total of six times) was commenced 24 h after MTX administration. RESULTS: Thirty-seven chemotherapy-naive patients with AGC presenting with malignant ascites were enrolled in this trial. The median age was 60 years (range, 25-74 years) and most patients (86%) had a performance status of 0-1. In total, 355 administrations of the sequential MTX/5FU therapy were performed. Major toxicity consisted of myelosuppression and gastrointestinal toxicity. Grade 4 neutropenia occurred in 10.8% of the patients. The overall objective response rate was 5.7% (two partial responses in 35 patients; 95% confidence interval: 0.7-19.2%). However, the response rate of ascites was 35.1% (complete disappearance in three patients and apparent decrease in 10 patients; 95% confidence interval: 20.2-52.5%). CONCLUSIONS: Sequential MTX/5FU therapy is effective against AGC with malignant ascites with acceptable toxicity and warrants further investigations in a phase III setting.     

Long-term results with FAMTX (5-fluorouracil, adriamycin, methotrexate) in advanced gastric cancer

In a phase II trial we tried to evaluate the efficacy of a sequential combination of high-dose (HD) MTX and 5-FU combined with Adriamycin (ADM). In a pilot study we found HDMTX effective as a single agent in gastric cancer. MTX and 5-FU were combined sequentially because Cadman and Bertino had shown synergism for this combination. The treatment protocol consisted of HDMTX, 1.5 g/m2 of body surface, and HD5-FU, 1.5 g/m2. MTX was administered 1 hour prior to 5-FU. Both drugs were given as a bolus. 24 hours after MTX administration, citrovorum factor rescue was started, 15 mg/m2, q6h x 12, orally. 48 hours after MTX administration, the serum concentration of the drug was measured by HPLC. 14 days after MTX was given, ADM, 30 mg/m2, was injected as a bolus. This protocol was repeated every 28 days. Patients eligible for this treatment were required to have a creatinine clearance of greater than 60 ml/min. 116 patients with metastasized gastric cancer and a performance status between 40 and 70% were treated. The response rate was 58% (67/116 patients). 14/116 patients (12%) had complete remission. The median survival probability for all patients was 9 months, for responders 15 months, while for patients with complete response it has not been reached. The median survival for nonresponders was only 4 months. Around 10% of all patients lived longer than 6 years. The median follow-up-time was 4 years. Cytostatic treatment was relatively well tolerated. The deaths of 3 patients were drug-related. A quarter of all patients could be treated on an outpatient basis.     

Evaluation of MTX/5-FU sequential chemotherapy utilized MTT assay for gastrointestinal cancer

Fresh human gastrointestinal cancer cells are more resistant to anticancer drugs compared to other cancer cells, and the selection of anticancer drugs for cancer chemotherapy is important. In the present study, it is demonstrated that MTX enhanced the chemosensitivity of 5-FU, especially, in the tumor cells with less than 70% inhibition ratio by the MTT assay. It has been reported that MTX/5-FU sequential chemotherapy was one of the effective chemotherapies against gastric cancer and colon cancer, and it is possible to anticipate the efficacy of MTX/5-FU sequential chemotherapy by the MTT assays.     

Prolonged treatment schedules with intraperitoneal 5-fluorouracil diminish the local-regional nature of drug distribution

The levels of 5-fluorouracil (5-FU) in plasma and peritoneal fluid were determined after the bolus administration of drug in 2 L of dialysis fluid through a Tenckhoff catheter into the peritoneal cavity of colon cancer patients. An increasing dose of intraperitoneal (i.p.) 5-FU resulted in an increased level of 5-FU in the blood. In 18 treatment cycles studied in four patients, the clearance of 5-FU from peritoneal fluid and the level of drug in the plasma were increased by day 5 of i.p. treatment. In one of these patients, the peritoneal clearance of 5-FU did not further increase between days 8 and 12. If ascites fluid was not removed prior to subsequent 5-FU administration, drug absorption from the peritoneal cavity was markedly decreased. These studies show that a dose of 5-FU given within a body compartment may profoundly affect the pharmacokinetics of subsequent doses of the same chemotherapy.     

Treatment of peritoneal dissemination of gastric cancer with sequential methotrexate and 5-fluorouracil

Background. Pretreatment with methotrexate (MTX) followed by 5-fluorouracil (5-FU) (sequential MTX and 5-FU), exerts biochemical modulation in which the antitumor effect of 5-FU is enhanced by the preceding MTX. Since the early 1980s, the sequential MTX/5-FU regimen has been employed clinically for gastric cancer in Japan, with high response rates for undifferentiated type gastric carcinoma. Methods. Peritoneal dissemination is more frequent in undifferentiated type carcinoma, we therefore employed sequential MTX and 5-FU for the treatment of 39 gastric cancer patients with peritoneal dissemination. We also investigated MTX levels in blood and ascitic fluid during the treatment. Results. Partial response (PR) was achieved in 6 of 26 patients (23%) who had evaluable lesions. PR lesions included abdominal wall tumors, primary gastric foci, inguinal lymph node, and rectal stenosis. Ascites was eliminated in 50% of the patients, and pleural effusion disappeared in 2 patients. Conclusions. In our study, sequential MTX and 5-FU had low toxicity and was beneficial for advanced gastric cancer patients with peritoneal dissemination. Further investigation of this treatment as induction and postoperative adjuvant chemotherapy for Borrmann type 4 gastric cancer seems warranted. Received for publication on Feb. 8, 1999; published on March 15, 1999     

Sequential methotrexate-5-fluorouracil (MTX-5-FU) treatment of patients with advanced gastric and colorectal cancer. Sequential Methotrexate-5-FU Study Group

A multicenter cooperative study was conducted from July 1984 to March 1986 to evaluate the clinical efficacy of sequential MTX-5-FU treatment in 96 cases of advanced gastric cancer and 39 cases of colorectal cancer. 5-FU 600 mg/m2 i.v. was given and MTX 30 mg/m2 (A), 100 mg/m2 (B) and 300 mg/m2 (C) i.v. were given, and the administration interval between MTX and 5-FU was 1 to 3 h for the gastric cancer group, and 7 h for the colorectal cancer group. Leucovorin rescue of 10 mg/m2 p.o. was given 24 h after MTX administration. In the gastric cancer group, the response rate for Regimen A was 23.2% (CR 1 and PR 12) out of 56 evaluable cases, and for Regimen B, 40.5% (CR 1 and PR 14) out of 37 evaluable cases. In the colorectal cancer group, the response rate for Regimen A was 28.6% (PR 6) out of 21 evaluable cases and for Regimen B, 20.0% (PR 3) out of 15 cases. Median survival time for the gastric cancer group was 5.5 months with Regimen A and 7.6 months with Regimen B, and for the colorectal cancer group 10.9 months with Regimen A and 7.9 months with Regimen B. Main adverse effects were marrow impairment and gastrointestinal symptoms such as nausea, diarrhea, and stomatitis. In this study Regimen B showed relatively good results. In order to evaluate the biochemical modulation occurring with sequential MTX-5-FU treatment, a further phase III study in gastric cancer patients should be conducted.     

Safety of intraperitoneal chemotherapy with paclitaxel in gastric cancer patients with peritoneal dissemination

We evaluated the safety of paclitaxel (TXL) via intraperitoneal (i.p.) administration in 6 patients with peritoneal dissemination of gastric cancer. Four patients were treated with TXL via i.p. administration at a dosage of 80-90 mg/m2 every 1 to 2 weeks. Grade 4 leukopenia was observed in 1 patient, accompanied with massive ascites. Two other patients, who also had malignant peritoneal effusion, were treated with TXL via i.p. administration at a dosage of 60 mg/m2 every 1 to 2 weeks. All toxicities were mild in those two patients. TXL via i.p. administration at a dosage of less than 90 mg/m2 has never been reported to cause a grade 4 leukopenia. These results suggest that a phase I/II study of TXL via i.p. administration should be tried in gastric cancer patients with malignant peritoneal effusion.     

Prospective randomized trial of one-hour sequential versus simultaneous methotrexate plus 5-fluorouracil in advanced and recurrent squamous cell head and neck cancer

Results from experimental systems suggest that the combination of methotrexate (MTX) and 5-fluorouracil (5-FU) produces synergistic cytotoxic effects that are dependent on the sequence of drug administration. Biochemical studies have demonstrated plausible mechanisms of a synergistic effect when MTX precedes 5-FU. A variety of phase I and phase II studies have employed this sequential combination with promising but inconclusive results. In this study, 79 evaluable patients with squamous cell head and neck cancer were randomized to receive MTX (200 mg/m2 IV) and 5-FU (600 mg/m2 IV) either simultaneously or sequentially with MTX preceding 5-FU by one hour. All patients were ambulatory and patients were stratified as to whether they presented with primary disease or with recurrence after prior radiation and/or surgical therapy. The overall response rate was superior for simultaneous therapy (62%) compared with sequential therapy (38%) (p less than 0.06). Among patients with primary head and neck cancer, the stage of the disease influenced the response rate. Eight of nine stage III patients who received simultaneous therapy responded while none of the four patients who received sequential therapy responded (p less than 0.01). This study demonstrates that one-hour sequential MTX plus 5-FU is not superior to simultaneous treatment in patients with squamous cell head and neck cancer.     

ACNU, MTX And 5-FU Penetration of Rat Brain Tissue and Tumors

The distribution of radio-labeled ACNU, MTX and 5-FU in brain and tumor tissue was studied in female Wistar rats by macroautoradiography after intrathecal administration. In normal rats, ACNU and 5-FU, administered intracisternally, distributed rapidly in the subarachnoid space, ventricular system and cerebrospinal fluid (CSF). 5-FU and MTX penetrated the brain deeply; the diffusional transport of ACNU was limited to a depth of 1 or 2mm from the CSF surface of the brain. MTX and 5-FU clearance into the blood circulation was rather slow while ACNU cleared relatively quickly. The half time of ACNU, 5-FU and MTX radioactivity at the ventricular surface was 10, 21, and 110min, respectively, at their maximal concentration after intracisternal administration. In rats with leptomeningeal tumor induced by intracisternal inoculation of Walker 256 cells, the distribution patterns of ACNU, 5-FU, and MTX were essentially the same as in normal rats despite 10–20 cell layers of tumor growing in the subarachnoid space. 5-FU and MTX were able to penetrate tumor masses in the subarachnoid space; MTX penetration was slower than that of 5-FU and ACNU failed to penetrate to more than a depth of 1 or 2mm from the tumor surface.     

Pharmacologic study of intraperitoneal docetaxel in gastric cancer patients with peritoneal dissemination

This study was designed to evaluate the pharmacokinetics and toxicity of docetaxel administered via an intraperitoneal (i.p.) route for patients with gastric cancer. Eleven patients with peritoneal dissemination were entered into this trial. Patients were treated with 45 mg/m2 of i.p. docetaxel administration in 1 l of saline. Peak peritoneal concentration was 40.0 +/- 14.5 micrograms/ml and peritoneal concentration at 24 hours after drug administration was 4.3 +/- 3.9 micrograms/ml. The median pharmacokinetic advantage (AUC peritoneal/AUC plasma) was 515 (range 22-1, 770). Grade 2 and 3 toxicities included 5 episodes of diarrhea; 3 of abdominal pain; 3 of ascites; 2 of alopecia; and 1 of neutropenia. We conclude that intraperitoneal docetaxel administration is well tolerated and provides a peritoneal pharmacokinetic advantage for the treatment of peritoneal dissemination.     

5-fu dose-dependency in mtx/s-fu sequential therapy assessed by in-vitro assay using gastric-cancer cell-lines

The sequential administration of methotrexate (MTX) and 5-fluorouracil (5-FU) (MTX/5-FU therapy) on gastric cancers has shown higher response rates than standard chemotherapy. The response rate of these cancers, however, still showed from 18 to 48%. The purpose of this study was to determine the appropriate interval time and doses of MTX/5-FU therapy using a panel of 4 cell lines originated from the poorly-differentiated gastric cancers. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was used as the chemosensitivity test. The sequential administration of MTX and 5-FU inhibited the growth of 2 cell lines more than 5-FU alone. In one cell line (GCIY), it inhibited the growth 6 times, and the longest interval time (6 h) was the most effective. In the other cell line (KATOIII), it inhibited growth 3 times, and the shortest interval time (O h) was the most effective. The growth inhibition in these cases did not depend on the dose of MTX (0.01 mu g/ml to 100 mu g/ml), but on the dose of 5-FU. In conclusion, 2 out of 4 cell lines showed a synergic effect between MTX and 5-FU. While the appropriate interval time between the two drugs varied between two cell lines, 5-FU dose was more critical than that of MTX. If 5-FU dose were to be increased in future trials with MTX, its efficacy might be higher. This model should also be good to screen other anti cancer drugs combined with MTX/5-FU therapy.     

Efficacy of sequential methotrexate and 5-fluorouracil (MTX/5FU) in improving oral intake in patients with advanced gastric cancer with severe peritoneal dissemination

Background

Although peritoneal dissemination of gastric cancer is common and often causes deterioration of the patient’s condition and quality of life (QOL), these patients are usually excluded from clinical trials. We retrospectively investigated the clinical benefit and toxicity of sequential methotrexate and 5-fluorouracil (MTX/5FU) therapy for patients with peritoneal dissemination.

Methods

The subjects were 31 patients with severe peritoneal dissemination of gastric cancer who were treated with MTX/5FU. The treatment schedule comprised weekly administration of MTX (100 mg/m²) followed by 5FU (600 mg/m²). Leucovorin (10 mg/m²) was administered six times, every 6 h, starting 24 h after MTX administration.

Results

The median survival time was 255 days, and the median progression-free survival was 127 days. Of the 21 patients with measurable lesions, 4 (19%) patients achieved a partial response. Ascites volume decreased markedly in 14 (54%) of the 26 patients with ascites. Seventeen patients had adequate oral intake, but the other 14 patients had required nutritional support before treatment. The median dripinfusion free survival was 100 days in the former 17 patients, and oral intake improved in 3 (21%) of the latter 14 patients. Grade 3 or 4 neutropenia was observed in 26% of the patients and anemia was observed in 45%. The grade 3 nonhematological toxicities were vomiting (6%) and fatigue (10%). Early death, within 30 days of the last administration of MTX/5FU, occurred due to disease progression in 2 patients, but there were no treatment-related deaths.

Conclusion

MTX/5FU chemotherapy may be effective in treating peritoneal dissemination of gastric cancer and might improve the patient’s condition in terms of reducing ascites and improving oral intake.     

Intraperitoneal 5-fluorouracil in the management of colorectal liver cancer.

Twenty-five patients with colorectal liver metastases had a subcutaneous portal connection with a peritoneal catheter implanted for the intraperitoneal (i.p.) administration of 5-fluorouracil (5-FU). In five patients, the malignant disease rapidly progressed and the implanted catheter system was never used. Among the remaining 20 patients, seven patients had i.p. 5-FU as adjuvant treatment following liver resection and 13 patients received palliative chemotherapy (5-FU) owing to unresectable liver metastases. 5-FU was administered on a regular basis every 4 to 6 weeks by continuous infusion of 1000 mg/day (approximately 15 mg/kg/day) for 5 days. In seven patients, i.p. chemotherapy was managed on an outpatient basis. In general, i.p. 5-FU treatment was well tolerated with only minor abdominal complaints during the initial treatments. No definite effect on survival has been noted. All patients (n = 13) receiving palliative i.p. 5-FU died after a median of 4 (range 1.5-18) months. Two patients receiving adjuvant chemotherapy died owing to recurrence after 20 and 23 months, while five patients are alive, two with recurrent disease and three without, after 14-35 months.     

Intra-aortic infusion therapy with sequential methotrexate (MTX) and 5-FU in advanced gastric carcinoma

Fifteen patients with advanced gastric carcinoma were treated by intraaortic infusion therapy with sequential MTX and 5-FU. Intraaortic bolus injection with 50-100 mg/body MTX was followed 3 hours later with 500-750 mg/body 5-FU and 24 hours later with 30 mg/body leucovorin. Treatment was repeated weekly. Of these 15 patients who were evaluated, 4 had PR and 3 had MR. Response rate was 27%. Two patients had WBC nadir of less than 3,000 cells/mm and other two had a platelet count nadir of less than 10/mm. Gastrointestinal symptoms such as nausea and vomiting were mild. Three patients had diarrhea and 3 had mucositis. No other toxicity was seen. This regimen has been well tolerated for long periods.     

Combination therapy with methotrexate and 5-fluorouracil: a prospective randomized clinical trial of order of administration

Because of biochemical and tissue culture evidence casting doubt on the physiologic relevance of reported synergy afforded by sequential administration of methotrexate (MTX) followed by 5-fluorouracil (5-FU), a randomized controlled clinical trial was conducted in 108 patients with advanced cancer, including 70 with squamous cell carcinoma (SCC) of the head and neck, nine with SCC of other primary sites, 24 with colorectal, and five with gastric adenocarcinomas. Patients were randomized to receive weekly therapy consisting of MTX followed one hour later by 5-FU, or 5-FU followed one hour later by MTX. There was a trend to higher tumor response rates in patients treated with MTX before 5-FU (45% v 33% overall; 65% v 39% in patients with previously untreated head and neck cancer), but these differences were not significant, either by chi-square test or by multivariate stepwise logistic regression. The trend in survival favoring the reverse sequence of 5-FU before MTX was not significant in univariate analyses. Stepwise multivariate Cox model analysis showed that Eastern Cooperative Oncology Group performance status at study entry was the major prognostic factor for survival (P less than 0.001), but among the 70 patients with head and neck cancer, the sequence of drug administration was the only other significant prognostic factor for survival, and favored the sequence of 5-FU followed by MTX (P less than 0.025).