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.     

Phase II study of Adriamycin with sequential methotrexate and 5-fluorouracil (AMF) in gastric carcinoma

Summary The purpose of this study was to evaluate the response rate, methotrexate plasma levels, and toxicity of a three-drug regimen in patients with gastric carcinoma. A total of 37 patients with advanced measurable adenocarcinoma of the stomach were treated with Adriamycin, methotrexate, and 5-fluorouracil (AMF). Adriamycin and methotrexate were given as i.v. infusions on day 1; 24 h following methotrexate administration, patients received an i.v. infusion of 5-fluorouracil concomitantly with oral leukovorin factor (given over 48 h). Methotrexate levels were monitored regularly in all patients, and courses were repeated every 3 weeks. The median dose levels per course were 50 mg/m² (range, 40–60 mg/m²) for Adriamycin, 1,000 mg/m² (range, 650–1,250 mg/m²) for 5-fluorouracil, and 500 mg/m² (range, 160–625 mg/m²) for methotrexate. Of 36 evaluable patients, 8 (22%) achieved an objective response, including 1 complete remission. Stable disease was noted in 11 patients and a minor tumor regression occurred in 1. The median survival duration of all patients was 6 months (range, 2–31 + months). AMF was well tolerated; toxicities were mild to moderate, most frequently involving nausea and vomiting, mucositis, and neutropenia with or without fever. There was no death directly attributable to chemotherapy. Although the AMF regimen used a well-documented preclinical concept of synergism between methotrexate and 5-fluorouracil, response and survival results suggest a modest activity of this combination in patients with gastric cancer. Better preclinical models are necessary for the development of effective combination chemotherapy.     

Neoadjuvant chemotherapy with sequential methotrexate and 5-fluorouracil scheduling,epirubicin and cisplatin for locally advanced bladder cancer

INTRODUCTION: Transitional cell carcinoma of the bladder is moderately sensitive to chemotherapy. Notably, the methotrexate, doxorubicin, vinblastine and cisplatin regimen was found to produce a high overall response rate and a modest survival advantage. However, toxicity was significant and the therapy rarely results in long-term disease-free survival. In several clinical series, sequentially delivered methotrexate and 5-fluorouracil followed by leucovorin rescue in expectation of a biochemical modulation has a higher response rate. METHODS: The combination chemotherapy using sequential methotrexate and 5-fluorouracil scheduling, epirubicin and cisplatin (MFAP regimen) for locally advanced bladder cancer was evaluated in a neoadjuvant setting. Thirty-seven patients (32 males and 5 females) were enrolled in this study. RESULTS: Six (16.2%) of the patients had complete responses and 26 (70.3%) had partial responses to the therapy amounting to a response rate of 86.5%. At follow-up, 10 of 13 patients (76.9%) who underwent bladder preservation had not developed muscle-invasive recurrence of the disease and kept their bladder. There is no statistical difference of the survival rate between the cystectomy group and the bladder preservation group (p = 0.86). Toxicity was relatively mild but with some severe myelotoxic effects. CONCLUSIONS: MFAP represents an active regimen in the treatment of locally advanced bladder cancer with a moderate toxicity profile.     

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.     

Phase II trial of 5-fluorouracil,adriamycin and cisplatin (FAP) in advanced gastric cancer

Summary Twenty patients (15 male, 5 female) with nonresectable gastric adenocarcinoma were treated with FAP (5-fluorouracil 300 mg/m² IV on days 1–5, adriamycin 50 mg/m² IV on day 1, cisplatin 20 mg/m² IV on day 1–5). Each course was repeated every 21 days. Eighteen patients were evaluable for response. The median age was 51 years, the range extending from 34 to 68. None had undergone chemotherapy. The median Karnofsky performance score was 80%. Nine (50%) partial responses (PR) and eight (44%) cases of stable disease (SD) were observed. One patients showed progression of the disease and died after 6 months. The median duration of response was 6+ months for PR and 6 months for SD. The median survival was 12 months. FAP toxicity was moderate, with the median WBC nadir 3.2×10⁹/l (range 0.7–4.2). One patient in PR died of septicemia. Nausea and vomiting were not dose-limiting. Neuropathy was mild in four and moderate in two patients. This FAP combination appears to be as effective with respect to response rate and duration as reported for 5-fluorouracil, adriamycin and mitomycin C (FAM).     

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.     

Phase II study of weekly paclitaxel,cisplatin, and 5-fluorouracil for advanced gastric cancer

Background  

Our previous phase I study provided evidence that weekly paclitaxel, cisplatin, and bolus 5-fluorouracil (weekly PCF) was effective and well tolerated in patients with advanced gastric cancer. This study was conducted to confirm the efficacy and toxicity of weekly PCF.     

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.     

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.     

High doses of 5-fluorouracil and epirubicin with or without cisplatin in advanced gastric cancer: a randomized study

BACKGROUND: A prospective randomized clinical study was performed in patients with locally advanced or metastatic gastric cancer. The purpose of the study was to determine the activity of high doses of 5-fluorouracil and epirubicin (FE) vs. the same combination + cisplatin (FEP), and particularly the value of cisplatin in the combination. PATIENTS AND METHODS: A total of 122 patients was included in the study; 110 of them were assessable. In the FE arm, the treatment involved 1000 mg/m2 in a 6-hr infusion of 5-fluorouracil on days 1, 2, 3, 4 and 5 and 120 mg/m2 of epirubicin i.v. on day 1. In the FEP arm, the same combination of cytostatics + cisplatin (30 mg/m2) was administered on days 2 and 4. The cycles were repeated after 4 weeks. Altogether, 468 cycles of chemotherapy were given (FE, 240; FEP, 228). RESULTS: In the FE arm, 56 patients were assessable, with 2 complete and 14 partial remissions (28.6%); in the FEP arm, 4 complete and 19 partial remissions (42.6%) were observed in 54 assessable patients. Median survival in the FE group was 7.1 months and in the FEP group 9.6 months. The survival difference was statistically significant (Cox's test, P<0.05). The most frequent side effects included grade 2 and 3 alopecia (FE, 93%; FEP, 94%) and grade 2 and 3 vomiting (FE, 20%; FEP, 35%). Grade 3 and 4 leukopenia was observed in 9% of patients in the FE group and in 13% of patients in the FEP group, with 6 cases of febrile neutropenia (FE, 4%; FEP, 7%). Stenocardia was registered in 1 patient in the FE group and in 2 patients in the FEP group. No treatment-related death was registered. CONCLUSIONS: The addition of cisplatin to high doses of 5-fluorouracil and epirubicin resulted in a statistically significant better survival of treated patients.     

A phase II study in advanced gastro-esophageal cancer using epirubicin and cisplatin in combination with continuous infusion 5-fluorouracil (ECF)

PURPOSE:: A phase II study was performed in patients with unresectableor metastatic gastric cancer evaluating the efficacy of a newchemotherapy schedule combining epirubicin and cisplatin witha continuous ambulatory infusion of 5-fluorouracil (ECF). PATIENTS AND METHODS:: One hundred thirty-nine consecutive, previously untreated patientswere given ECF. Of these, 128 had measurable disease. Epirubicin(50 mg/m² i.v.) and cisplatin (60 mg/m² i.v.) were administeredevery three weeks for 8 cycles during a 21 week continuous i.v.infusion of 5-fluorouracil (200 mg/m²/day). In total 773 cyclesof chemotherapy were given. RESULTS:: Objective tumour responses was seen in 91 (71%) of the 128 patientswith measurable disease, of which 15 (12%) had a complete response.Twenty patients with locally advanced disease responding toECF had attempted resection of the primary - 11 (55%) were completelyremoved, 4 of these had no residual tumour in the resected specimen.The overall median survival was 8.2 months with 1 and 2 yearsurvivals of 30% and 10% respectively. Grade 3 or 4 emesis occurredin 13%, stomatitis in 7%, diarrhoea in 4%, infection in 6%,leucopenia in 21% and thrombocytopenia in 8% of patients. Myelosuppressiondelayed treatment in 39 (5%) of the 773 cycles. Six of the 139patients (4.3%) had treatment related deaths. There was no measurablereduction in quality of life during chemotherapy, while 67%of the 66 patients with dysphagia had complete resolution ofthis symptom. CONCLUSIONS:: The ECF regimen displays high anti-tumour activity with moderatetoxicity in patients with gastric cancer and in some cases enabledresection of previously inoperable tumours. chemotherapy, gastro-oesophageal cancer     

Phase II study of sequential treatment of advanced non-small-cell lung cancer: three cycles of high-dose epirubicin plus cisplatin followed by weekly vinorelbine

Previous phase I, II, and III studies on high-dose epirubicin (HDEPI), alone or in combination with cisplatin (CP), indicate an interesting activity of this drug in the treatment of non-small-cell lung cancer (NSCLC). However, the toxicological profile of HDEPI limits its prolonged use. In our experience, vinorelbine (VNR) seems to be a suitable drug for long-term monotherapy for advanced NSCLC. On these grounds, advanced NSCLC patients were treated with the following strategy: 3 consecutive cycles of CP 60 mg/m2 and HDEPI 120 mg/m2 on day 1, every 3 weeks; then, irrespective of response, weekly VNR at a dose of 25 mg/m2 was administered at home. From December 1996 to March 1998, 25 patients entered the study. After receiving 3 cycles of CP/HDEPI, 8 patients (32%) had a partial response and 3 (12%) had a minor response. Nine patients had stable disease (36%) and 4 (16%) had progressive disease. Twenty-three patients received weekly VNR, and the median number of administrations was 10 (range, 1-38). After VNR treatment, we observed a partial response in 2 patients who previously had stable disease. Therefore, the overall response rate to sequential treatment was 40%; median time to progression was 7 months (range, 2-26 months). The major toxicities due to the CP/HDEPI regimen were neutropenia (72%) and alopecia (80%). During the VNR treatment, grade 3/4 neutropenia was seen in 36% of patients. The doses and the timing of VNR administrations were modified according to toxicity. Symptoms such as cough, dyspnea, and pain, present in 21 patients before the treatment, improved in 11 cases (52%). Median overall survival is 9 months (range, 3-40+ months); one patient is still alive after 40 months. One- and 2-year survival rates are, respectively, 44% and 16%. This study confirms the activity of CP/HDEPI in NSCLC and indicates that the sequential treatment of CP/HDEPI for 3 cycles followed by weekly VNR could be considered an effective strategy for locally advanced or metastatic NSCLC.     

Pharmaco-dynamic study of methotrexate (MTX) during intraperitoneal MTX/5-FU sequential therapy after gastric surgery

A pharmaco dynamic study of Methotrexate (MTX) during intraperitoneal MTX/5-FU sequential therapy was carried out after gastric surgery. A comparative study of the route of MTX administration and its dose was also done. 1) Comparative study of the serum concentration of MTX between i.p. and i.v. administration revealed a similar MTX concentration except immediately after administration. 2) A comparative study of the serum concentration of MTX administered i.p. between patients with and without malignant ascites was conducted. Immediate elevation of the serum concentration of MTX was observed in patients without malignant ascites. On the other hand, the MTX concentration was slowly elevated and washed out in patients with malignant ascites. 3) The MTX concentration in the intraperitoneal fluid was compared between patient with and without malignant ascites. In patients without malignant ascites, MTX disappeared quickly from the intraperitoneal fluid. However, the MTX concentration lasted long in the malignant ascites cases. These results were similar with a low-dose MTX (30 mg/body) or moderate dose (100 mg/body). MTX/5-FU sequential i.p. therapy can thus be an effective treatment for patients after gastric surgery, though clearance of MTX was slow in cases with malignant ascites.     

Neoadjuvant chemotherapy in advanced gastric cancer with non-curative factors: a Phase II study with 5-fluorouracil, leucovorin, and cisplatin

Background. Neoadjuvant chemotherapy (NAC) has recently received increasing attention in an attempt to increase the rate of complete tumor resections, reduce systemic metastases, and prolong survival in patients with advanced gastric cancer. Methods. Since 1993, 21 patients with unresectable or non-curative resectable gastric cancer received NAC, consisting of 5-fluorouracil, leucovorin, and cisplatin (FLP) with at least two cycles before surgery. Results. All except 2 patients underwent surgical treatment, and resection was performed in 18 (85.7%). There were no deaths and no major morbidity following operation. There was no complete response (CR), but 12 patients (57.1%) had a partial response (PR), the response rate was 47.6% for the primary region, 64.7% for abdominal para-aortic (No.16) lymph node metastasis, 40.0% for liver metastasis, and 11.1% for peritoneal dissemination. One-year survival of the 21 patients was 40.5%, and median survival time (MST) was 322 days. MST in the responders was 571 days, and that in non-responders was 199 days (P < 0.01). MST was 835 days in patients who underwent curative resection and 310 days in those who underwent non-curative surgery (P < 0.01). There was no grade 4 toxicity, but grade 3 leukopenia occurred in 4 patients (19.0%), grade 3 anemia occurred in 3 patients (14.3%), and grade 3 stomatitis in 2 patients (9.5%). There were no serious renal disorders and no treatment-related death. Conclusions. The combination of FLP for NAC was feasible and useful for tumor reduction, especially for No.16 lymph node metastasis. There was a survival benefit in patients whose tumor had PR or who had had curative resection. We should confirm the effect and survival benefit of FLP for NAC by a prospectively randomized clinical controlled study. Received for publication on Jan. 19, 1999; accepted on March 15, 1999     

Phase II intravenous study of epirubicin with 5-fluorouracil in patients with advanced hepatocellular carcinoma

Between August 1986 and September 1990, 22 previously untreated non-cirrhotic patients with measurable unresectable primary liver cancer were treated every 4 weeks with a combination of epirubicin and 5-fluorouracil. The dose of epirubicin was escalated; the starting dose was 40 mg/m², the second dose was 50 mg/m² and thereafter 60 mg/m² during subsequent cycles. The dose of 5-fluorouracil was always 800 mg/m². Objective response rate was 14%. Most of the patients experienced only mild haematological toxicity, and no other dose limiting toxicity was observed. Nonetheless, increasing the dose would probably not have increased the response rate.     

Phase II study of cisplatin, gemcitabine and 5-fluorouracil in advanced pancreatic cancer.

BACKGROUND: The aim of this study was to determine the activity of the combination of cisplatin, gemcitabine and 5-fluorouracil (5-FU) as therapy for metastatic or locally advanced inoperable pancreatic adenocarcinoma. PATIENTS AND METHODS: Patients with histologically proven advanced or metastatic pancreatic adenocarcinoma received first-line chemotherapy comprising cisplatin (20 mg/m2 on days 1, 8, 15, 22, 29 and 36), gemcitabine (1000 mg/m2 on days 1, 8, 29 and 36) and 5-FU (200 mg/m2 as continuous infusion on days 1-42) every 56 days. RESULTS: A total of 34 patients were studied. Eighty courses were administered (median two courses per patient). Among 32 patients evaluable for response, two patients had a complete response and four a partial response for an overall response rate of 19% (95% confidence interval 7% to 36%). Thirteen patients had stable disease (40%) and 13 progressed. Median progression-free survival was 4.7 months, median survival 9.0 months and 26% of patients achieved 1-year survival. Ten of 25 patients (40%) with pain at presentation had a sustained reduction of analgesic consumption. The principal grade 3/4 toxicities were neutropenia, thrombocytopenia, anaemia and mucositis, occurring in 24%, 21%, 9% and 3% of patients. CONCLUSION: This schedule seems well tolerated and active in pancreatic cancer and worthwhile of further evaluation.     

Cisplatinum plus epirubicin alternated with cyclophosphamide plus 5-fluorouracil in ovarian cancer

Fifty-two patients with ovarian cancer (post surgical residual tumor) were treated with the combination of platinum + epirubicin (PE) (P 50mg/m2, E 60 mg/m2) alternated with cyclophosphamide + 5-fluorouracil (CF) (C 800 mg/m2, F 600 mg/m2). The treatment was repeated every 28 days for a maximum of 10 cycles. Forty-three patients were evaluable for response. Complete remission (CR) was achieved in 13 (30%) patients (evaluated by second-look), while partial remission (PR) was achieved in 6 (14%) patients for a mean duration of 27 and 14 months, respectively. Eleven out of 13 patients with CR and 5 out of the nonevaluable patients are alive and do not show signs of disease after a mean follow-up of 29 + months (range 19-36). The main factors that conditioned complete remission were the tumor residue and performance status of the patient.     

Phase II study of cisplatin in advanced esophageal cancer and gastric cancer

Twenty-four patients with advanced gastric cancer and 4 patients with advanced esophageal cancer were treated with cisplatin at a dose of 80-100 mg/m2 for one day or 10-20 mg/m2 for 5 consecutive days every 3-4 weeks. As for gastric cancer, 21 of 24 were evaluable for this study according to the criteria of the Japan Society for Cancer Therapy. Four of 21 patients (19%) showed partial response (PR), 7 displayed no change (NC), and 10 evidenced progressive disease (PD). Among 4 PR cases, only one had effective primary lesion. As for esophageal cancer, all 4 patients were evaluable, while 2 showed no change (NC) and another 2 exhibited progressive disease (PD). Gastrointestinal toxicity occurred in 20 patients despite the use of anti-emetic drugs. Nephrotoxicity and hematological toxicity were observed in 14 patients and 22 patients, respectively. These did not impede the continuous treatment except one case of hematological toxicity. It was concluded that cisplatin is more effective for the metastatic lesion of gastric cancer than primary lesion.