Infusional 5-fluorouracil, cisplatin and mitomycin C in advanced gastric cancer: a low cost effective regimen

Recently, we reported a highly active regimen in advanced gastric cancer including a weekly administration of cisplatin, epidoxorubicin, leucovorin, 5-fluorouracil with the support of filgrastim. In order to simplify the administration and to decrease the toxicity of these drugs, mainly epidoxorubicin-induced alopecia, we designed a regimen including an infusional 5-fluorouracil schedule according to the de Gramont regimen, cisplatin and mitomycin C replacing epidoxorubicin. Forty-five patients with advanced or metastatic gastric cancer were treated with cisplatin 50 mg m(-2) i.v. on day 1, every 2 weeks, 6S-stereoisomer-leucovorin 100 mg m(-2) i.v. followed by 5-fluorouracil 400 mg m(-2) i.v. bolus and 600 mg m(-2) i.v. in a 22-h infusion, on days 1 and 2, every 2 weeks, and mitomycin C 7 mg m(-2) i.v. bolus on day 2, every 6 weeks. Grades 3-4 toxicities (National Cancer Institute-Common Toxicity Criteria) consisted mainly of neutropenia and thrombocytopenia. Five patients had a complete response and 16 had a partial response for an overall response rate of 46.7% (95% confidence interval, 32.1-61.2%). The median survival was 11 months. The combination of cisplatin, 5-fluorouracil and leucovorin according to de Gramont, and mitomycin C seems to be an active and safe regimen in the treatment of advanced gastric cancer. Because of its low cost it may be suggested for patients not enrolled into clinical trials.     

Treatment of advanced gastric cancer with 5-fluorouracil versus mitomycin C

Thirty-eight patients of advanced adenocarcinoma of the stomach were randomly administered intensive courses; of either 5-FU or mitomycin C by intravenous route, The 5-FU administration resulted in a slightly better response than mitomycin C, although the toxic effects of the two drugs were more or less the same. The selection of drug regime in the present study has been based on cost, availability, potential toxicity, and minimal alteration of the patients' life style.     

Early postoperative intraperitoneal chemotherapy with mitomycin C, 5-fluorouracil and cisplatin for advanced gastric cancer

OBJECTIVE: The long-term survival of patients who undergo surgery for stage IV gastric cancer is poor, due to metastatic spread of the tumor. Intraperitoneal chemotherapy (IPT) as a possible treatment for peritoneal dissemination has been investigated in a number of different tumors. The aim of this study was to investigate the toxicity and impact of early postoperative IPT on the survival of patients with advanced gastric cancer. METHODS: Between 1993 and 1997, a total of 91 patients with stage IV gastric cancer who underwent potentially curative or palliative resection received intraperitoneal mitomycin C before closure of the abdominal wound. 5-Fluorouracil and cisplatin were administered intraperitoneally on postoperative days 1-4, and this was repeated at 4-week intervals. RESULTS: All patients received a median of 3 IPT perfusions. There were 24 (26.4%) postoperative complications and 1 (1.1%) mortality. The most frequent hematologic toxicity (grade 3-4) was leukopenia. The major nonhematologic toxicities (grade 3-4) were emesis and nephrotoxicity. After a median follow-up period of 26 months, 14 patients remain alive without evidence of recurrence, whereas 75 patients died due to recurrence or progression of disease. The median survival period for all 91 patients was 15.4 months. When survival according to the residual tumor was analyzed, median survival was 36.0 months in the R0 (curative resection) group, 20.6 months in the R1 group (margins of resected specimens showing microscopic residual tumor or diameter of each residual tumor less than 3 mm) and 9.0 months in the R2 group (macroscopic residual tumor larger than 3 mm) (p < 0.001). CONCLUSIONS: IPT was found to be safe, and it appears to improve the prognosis in patients with minimal residual tumors. However, complete cytoreductive surgery is mandatory for achieving the beneficial effect of IPT.     

Cure of advanced gastric cancer by combined chemotherapy with cisplatinum, mitomycin C, and 5-fluorouracil

A 55-year-old female, in which an unresectable Borrmann II-type gastric cancer (moderately differentiated adenocarcinoma) extending from vicinity of the cardia to the lower portion of the corpus, with direct invasion into the pancreas and extensive lymph node metastases, confirmed by laparotomy, was treated postoperatively by 3 courses of chemotherapy with cisplatinum in combination with mitomycin C and 5-fluorouracil. A complete response was confirmed by roentgenography and endoscopy, and, at 4 months after the first operation, a total gastrectomy with radical lymphadenectomy was performed successfully. Cancer cells were not detectable histologically in the stomach specimen and in all the lymph nodes removed. One year and 5 months after the second operation she is well, showing no sign of recurrence.     

FILM (5-fluorouracil, ifosfamide, leucovorin and mitomycin C), an alternative chemotherapy regimen suitable for the treatment of advanced breast cancer in the `out-patient'' setting

FILM, a combination of 5-fluorouracil (5-FU) 750 mg/m², ifosfamide 1 g/m², leucovorin 200 mg/m² and mitomycin C 6 mg/m² (alternate cycles), was administered to 24 chemo-naive patients with inoperable disease, locally advanced or metastatic. Up to 6 2 3-weekly cycles of FILM were administered on an out-patient basis. Responses included 8 patients in complete remission (CR) and 12 showing a partial response (PR) (83%). Following analysis of these results, the FILM regimen was introduced as a standard out-patient protocol at the North Middlesex Hospital, United Kingdom. A further 66 patients have been treated in this setting. Retrospective analysis of these data confirm the trial results and allow conclusions regarding tolerability, toxicity, duration of response and survival to be drawn from a total cohort of 90 patients. A total of 524 cycles have been administered. Nineteen cycles (4%) were delayed owing to slow recovery of white blood cells (WBC), but no dose reductions were necessary. Five blood transfusions were required for anaemia. The most frequent non-haematological toxicities included nausea, vomiting and fatigue. Of 80 patients treated for inoperable or locally advanced disease, 56 (70%) remain in remission, and 69 (86%) remain alive after 5 years.     

A phase III randomized trial of 5-fluorouracil, doxorubicin, and mitomycin C versus 5-fluorouracil and mitomycin C versus 5-fluorouracil alone in curatively resected gastric cancer.

BACKGROUND: A phase III single-center randomized trial was performed in order to determine whether the addition of mitomycin C (MMC) and/or doxorubicin to 5-fluorouracil (5-FU) as adjuvant chemotherapy could influence survival in patients with curatively resected gastric cancer. PATIENTS AND METHODS: A total of 416 patients who had undergone curative resection for stage IB-IIIB gastric adenocarcinoma were stratified according to the stage and type of surgery, and then randomized to receive one of the three chemotherapy regimens, 5-FU alone (F) or 5-FU and MMC (FM) or 5-FU, doxorubicin and MMC (FAM) within 5 weeks after surgery. RESULTS: Of 416 patients registered, 395 (133 in F, 131 in FM and 131 in FAM) were assessable. Median follow-up duration was 91 months. Five-year overall survival rates were 67.2% for F, 67.0% for FM and 66.7% for FAM (P = 0.97). Five-year disease-free survival rates were 62.1% for F, 63.3% for FM and 62.5% for FAM (P = 0.83). Hematological toxicities were more frequent in the FM and FAM groups, whereas stomatitis was more common in the F group. CONCLUSIONS: Compared with adjuvant 5-FU alone, the addition of MMC and/or doxorubicin to 5-FU did not influence survival in patients with resected gastric cancer.     

Phase II trial of the combination of paclitaxel and 5-fluorouracil in the treatment of advanced gastric cancer: a novel, safe, and effective regimen

This prospective phase II clinical trial was performed to explore the activity and efficacy of the combination of paclitaxel and 5-fluorouracil in the treatment of advanced gastric adenocarcinoma. Thirty-one patients ages 18 to 70 years, with Karnofsky performance status (KPS) >50, adequate cardiac, renal, and hepatic functions, measurable metastatic or locally unresectable disease, life expectancy > or =3 months, signed written informed consent, and without any previous chemotherapy were assigned to receive on an outpatient basis: paclitaxel--175 mg/m2, in a 3-hour infusion on day 1 and 5-fluorouracil--1.5 g/m2, also in a 3-hour infusion on day 2 every 21 days, for a maximum of seven cycles. A system to assess clinical benefit based on KPS, analgesic consumption, and weight gain was also used in this trial. Median age was 61 years (range, 31-70 years). The 29 patients eligible for response and toxicity evaluation underwent 147 cycles of chemotherapy. There were 19 (65.5%) objective responses (95% confidence interval: 48%-83%), including 7 (24.1%) complete responses and 12 (41.4%) partial responses. Three patients had the complete response pathologically confirmed. In three of six patients who went to second-look laparotomy, a potentially curative esophagogastrectomy was possible. The toxicity of this combination was considered low, predictable, and manageable and was characterized mainly by reversible alopecia, peripheral neuropathy, myalgia, and mild neutropenia. Fifteen (51.7%) patients attained a clinical benefit response. The median overall survival was 12 months (range, 2-30+ months) and the 30-month overall survival was 20%. This novel regimen appears to be very effective in advanced gastric cancer. The projected 2-year survival of 20% is higher than that achieved with other first-line regimens. These encouraging results indicate the need for further studies to confirm the merit of this regimen.     

Weekly 24-hour infusion of high-dose 5-fluorouracil plus folinic acid in combination with mitomycin C for the treatment of advanced gastric cancer

PURPOSE: This study was performed to investigate the activity and safety of high dose 5-fluorouracil (5-FU) given as a weekly 24-hour infusion in combination with folinic acid plus mitomycin C in patients with advanced gastric cancer. PATIENTS AND METHODS: Chemonaive patients with locally advanced inoperable, recurrent or metastatic gastric cancer were treated with 15 mg/m(2) i.v. mitomycin C as bolus on day 1 of a 7-week cycle followed by a 2-hour infusion of folinic acid (500 mg/m(2)) and a 24-hour infusion of 5-FU (2,600 mg/m(2)) given on days 1, 8, 15, 22, 29, and 36 as outpatient treatment. RESULTS: Thirty evaluable patients (median age 58 years and median ECOG performance status 1) received 1-4 cycles (median 3). 53% of the patients had liver metastases. Treatment-related toxicity was low with 10% of patients experiencing diarrhea >/=grade 3, 3% mucositis grade 3 and 3% nausea grade 3 (CTC). Hematological toxicity was mild with 13% thrombopenia grade 3 and no leukopenia grade 4. Eleven patients achieved a partial remission (major response rate 37%; 95% confidence interval 22-53%). Median time to progression was 5 months and median overall survival time was 7 months. CONCLUSION: This regimen is a well-tolerated outpatient treatment for patients with advanced gastric cancer with efficacy being comparable to other chemotherapy protocols.     

Open phase II with 5-fluorouracil, 4-epi-doxorubicin and mitomycin C (FEM) in advanced gastric cancer

Forty-four patients with advanced gastric cancer were treated with a combination including 5-fluorouracil, 4-epi-doxorubicin and mitomycin C. 4-Epi-doxorubicin was substituted for adriamycin in MacDonald's original schedule. The combined treatment involved 600 mg/m2 i.v. of 5-fluorouracil on days 1, 8, 29 and 36; 80 mg/m2 i.v. of 4-epi-doxorubicin on days 1 and 29; and 10 g/m2 i.v. of mitomycin C on day 1. The cycle was repeated on day 57 after the start of treatment. Out of 44 patients, 39 were evaluable. Thirteen partial remissions (33%) were achieved. The average duration of remission was 7 months (range, 3-12 months). The average survival of the responders was 9 months, and that of nonresponders 3.5 months. Toxicity was moderate, well-tolerated and, as compared with the FAM schedule, less pronounced, particularly as regards myelotoxicity. Thus, the substitution of 4-epi-doxorubicin for adriamycin in the original schedule of MacDonald et al. (1980) did not improve treatment results, but the observed toxicity was less pronounced.     

A phase II study of combined 5-fluorouracil and mitomycin C in advanced breast cancer

In a Phase II study, 50 patients with advanced breast cancer were treated with a combination of 5-fluorouracil (1000 mg/m2 on days 1 and 2) and mitomycin C (6 mg/m2 on day 2) (FuMi regimen). The courses were repeated every third to sixth week. Although 35 patients had previously received combination chemotherapy and 40 patients had received endocrine treatment, objective responses were obtained in 29 patients (six complete, 23 partial). The survival was significantly correlated to the response (P less than 0.001, log rank test) complete versus partial response, partial response versus no change, no change versus progressive disease. The regimen was well tolerated (19 of 50 experienced nausea). Thirteen patients had hematopoietic toxicity at the day of starting a new course and in six cases, the FuMi regimen had to be discontinued because of longlasting thrombocytopenia. Otherwise, no side-effect of clinical importance was observed. The FuMi regimen is now compared with Adriamycin regimens and can be recommended for both first line chemotherapy and salvage chemotherapy.     

Combination of dacarbazine,mitomycin C, 5-fluorouracil and vincristine in advanced colorectal cancer

Summary Thirty patients with advanced measurable colorectal cancer received monthly courses of a combination of dacarbazine, mitomycin C, 5-fluorouracil, and vincristine (FIV Mit-Or). Four of the patients had received prior chemotherapy. Two patients were not evaluable for response. Objective response was obtained in four patients. Severe toxicity was encountered in 11 patients. It is concluded that unlike the fourdrug combination of 5-fluorouracil, DTIC, vincristine and BCNU (FIVB), the present regimen did not have significant antitumour activity in advanced colorectal cancer.     

High-dose 5-fluorouracil / folinic acid in combination with three-weekly mitomycin C in the treatment of advanced gastric cancer. A phase II study

BACKGROUND: The 24-hour continuous infusion of 5-fluorouracil (5-FU) and folinic acid (FA) as part of several new multidrug chemotherapy regimens in advanced gastric cancer (AGC) has shown to be effective, with low toxicity. In a previous phase II study with 3-weekly bolus 5-FU, FA and mitomycin C (MMC) we found a low toxicity rate and response rates comparable to those of regimens such as ELF, FAM or FAMTX, and a promising median overall survival. In order to improve this MMC-dependent schedule we initiated a phase II study with high-dose 5-FU/FA and 3-weekly bolus MMC. PATIENTS AND METHODS: From February, 1998 to September, 2000 we recruited 33 patients with AGC to receive weekly 24-hour 5-FU 2,600 mg/m(2) preceded by 2-hour FA 500 mg/m(2) for 6 weeks, followed by a 2-week rest period. Bolus MMC 10 mg/m(2) was added in 3-weekly intervals. Treatment given on an outpatient basis, using portable pump systems, was repeated on day 57. Patients' characteristics were: male/female ratio 20/13; median age 57 (27-75) years; median WHO status 1 (0-2). 18 patients had a primary AGC, and 15 showed a relapsed AGC. Median follow-up was 11.8 months (range of those surviving: 2.7-11.8 months). RESULTS: 32 patients were evaluable for response - complete remission 9.1% (n = 3), partial remission 45.5% (n = 15), no change 27.3% (n = 9), progressive disease 15.1% (n = 5). Median overall survival time was 10.2 months [95% confidence interval (CI): 8.7-11.6], and median progression-free survival time was 7.6 months (95% CI: 4.4-10.9). The worst toxicities (%) observed were (CTC-NCI 1/2/3): leukopenia 45.5/18.2/6.1, thrombocytopenia 33.3/9.1/6.1, vomitus 24.2/9.1/0, diarrhea 36.4/6.1/3.0, stomatitis 18.2/9.1/0, hand-foot syndrome 12.1/0/0. Two patients developed hemolytic-uremic syndrome (HUS). CONCLUSIONS: High-dose 5-FU/FA/MMC is an effective and well-tolerated outpatient regimen for AGC (objective response rate 54.6%). It may serve as an alternative to cisplatin-containing regimens; however, it has to be considered that possibly HUS may occur.     

Treatment of advanced gastric carcinoma with 5-fluorouracil adriamycin,and mitomycin C (FAM)

Summary Thirty-three evaluable patients with advanced gastric adenocarcinoma were treated with a combination of 5-fluorouracil, adriamycin, and mitomycin C (FAM). Two complete and five partial remissions (21% response rate) were observed. The overall median survival of all 33 patients was 5.9 months. Responding patients had significantly better survival than the non-responders (P<0.02). Analysis of the results according to sex, pretreatment performance status, and the histologic differentiation of the tumor failed to demonstrate that any of these factors influenced therapeutic results. The low response rate to FAM found in this study might be related to the fact that in the majority of the patients (85%) the primary gastric tumor had not been resected. The side-effects of this regimen were moderate. Taking into account the low response rate and the moderate myelotoxicity observed, a more intensive use of these three drugs in combination is suggested.     

Further studies on the treatment of advanced gastric cancer by 5-fluorouracil, Adriamycin (doxorubicin), and mitomycin C (modified FAM)

Twenty-two previously untreated patients with advanced gastric adenocarcinoma were treated with a modification of the original 5-fluorouracil, Adriamycin (doxorubicin), and mitomycin C (FAM) combination chemotherapy. The cycles were repeated every 6 weeks. There were four partial remissions and no complete response (overall response rate of 18%, with confidence interval of 0.02-0.34 for a confidence level of 95%). Duration of response ranged between 2.5 and 12 months. The overall median survival was 6.8 months. The median survival of responding patients (13.6 months) and the nonresponders (5.8 months) did not significantly differ. Sex and initial performance status did not influence the response to FAM. Toxicity was mild to moderate, and in only a few patients was it necessary to significantly reduce the drug doses or to prolong the intervals between treatments. Combining the current results with those obtained in a study recently reported the authors in which the original FAM was given to 33 evaluable patients, 11 responders have been seen among 55 consecutive patients with evaluable disease. These results are obviously inferior to those reported by other groups of investigators and led the authors to try another combination chemotherapy.     

The efficacy of 5-fluorouracil, mitomycin C, and methyl CCNU in advanced colorectal cancer

Sixty-six patients with advanced colorectal cancer were treated with 5-fluorouracil, Mitomycin C, and 1-(2-chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea. Fifty-seven patients were evaluable by completing 2 months of therapy. Nine patients (16.0%) achieved a complete remission (CR) with the above combination. A partial remission (PR) was seen in 9 patients. The response rate (CR + PR) was 32%. The average duration of response was 8.5 months. Mucositis, leukopenia, and thrombocytopenia were the significant toxicities experienced in this study.     

Capecitabine and mitomycin C may be an effective treatment option for third-line chemotherapy in advanced colorectal cancer

AIMS AND BACKGROUND: We evaluated the activity in terms of time to progression (TTP) of mitomycin C and capecitabine in patients with advanced colorectal cancer who progressed after 2 lines of chemotherapy. METHODS: Patients with advanced colorectal cancer undergoing third-line chemotherapy after failure of 5-FU with CPT-11 or oxaliplatin-based chemotherapy regimens were treated with capecitabine and mitomycin C. RESULTS: Sixty-one patients were enrolled in this study. The median age was 55 years (range, 26-78 years) and the male:female ratio 21:40. We observed partial remissions in 5 patients (8%), stable disease in 25 patients (40%) and progression of disease in 31 patients (52%). Median TTP was 3 months and median survival was 6 months. Global toxicity was mild and entirely acceptable. Grade 3-4 hematological toxicity occurred in 12 patients and grade 3-4 nonhematological toxicity in 5 patients. CONCLUSIONS: The combination of capecitabine and mitomycin C could represent an effective and manageable treatment option for colorectal cancer patients failing previous chemotherapy regimens.     

紫杉醇联合氟尿嘧啶和顺铂方案治疗晚期胃癌

目的：观察紫杉醇联合氟尿嘧啶及顺铂（PFC）方案治疗国人晚期胃癌的临床疗效和毒副反应.方法：晚期胃癌患者25例,给予紫杉醇（PTX）50mg/m^2,静滴3小时,第1、8、15天给药;氟尿嘧啶（5-FU）750mg/m^2,持续静脉输注24小时,第1～5天;顺铂（CDDP）20mg/m^2,静脉滴注,第1～5天,28天为1周期.分别化疗2～6周期后按WHO标准评价疗效和毒副反应.结果：全组25例均可评价疗效,获得CR 2例,PR 11例,SD 7例,PD 5例,近期客观有效率52.0%,中位TTP为6.5月.主要毒副反应为骨髓抑制、恶心呕吐和脱发.结论：PFC方案治疗国人晚期胃癌疗效较高,毒副反应轻,多数患者耐受良好,值得推广应用.     

Three cases of effective hepatic arterial infusion with OK-432, mitomycin C and 5-fluorouracil in liver metastasis from gastric cancer

A combined therapy with OK-432. mitomycin C (MMC) and 5-fluorouracil (5-FU) by administration through hepatic arterial infusion was performed in three patients with liver metastasis from gastric cancers. A catheter was introduced into hepatic artery by laparotomy. The dosage was 250 mg/day for 5-FU continuously, 10 mg/week for MMC and 5 KE/week for OK-432, respectively. Two cases with advanced gastric cancer and synchronous hepatic metastasis were treated by hepatic arterial infusion after surgical removal of primary lesion. Metastatic lesion in liver was completely eliminated. Another case with metastatic liver tumor from gastric cancer was also treated by the same protocol. The reduction rate of this case was 70% by CT scan. These results suggested that combined therapy with OK-432, MMC and 5-FU by hepatic arterial infusion is a good modality for liver metastases from gastric cancers.