Treatment of advanced digestive non-colon cancer with a weekly 24-h infusion of high-dose 5-fluorouracil modulated by folinic acid and cisplatin: an easy-to-use and well-tolerated combination.

The combination of 5-fluorouracil (5-FU) modulated by folinic acid (FA) and cisplatin is commonly used in advanced digestive non-colon cancers (ADNCC). In order to simplify treatment administration by avoiding cisplatin-related hydration, we investigated a weekly regimen of 5-FU/FA/cisplatin. Patients with ADNCC were treated with 5-FU 2.0 g/m2, FA 500 mg/m2 and cisplatin 25 mg/m2 day 1, for 6 weeks with a 2-week rest, and were assessed for toxicity, tumor response and disease-free survival. Forty-three patients with measurable ADNCC were treated with this weekly regimen. Primary tumor sites were mainly esophagus (n = 17), stomach (n = 12) and pancreas (n = 9). Results were as follows. Toxicity was mostly hematological, with 16% grade 3/4 neutropenia (seven of 43) and 4% febrile neutropenia (two of 43). Objective response (OR) was observed in 19 of 43 (44%) patients including four complete responses (9%) and 15 partial responses (35%). Another 18 patients (42%) experienced stable disease. Time to progression was 6.5 months. The median response and stable disease durations were 4.3 (range 3-34) and 5 (range 2-16) months, respectively. We conclude that weekly administration of 5-FU/FA/cisplatin is an active and well-tolerated regimen. Toxicity is manageable and allows chemotherapy on an outpatient basis without hydration program as required when cisplatin is used at the dose of 50 mg/m2.

High-dose 5-fluorouracil plus low dose methotrexate plus or minus low-dose PALA in advanced colorectal cancer: a randomised phase II-III trial of the EORTC Gastrointestinal Group.

The aim of this study was to investigate whether N-(phosphonacetyl)-L-aspartic acid (PALA) can enhance the activity of low-dose methotrexate (LD-MTX) modulated infusional 5-fluorouracil (5-FU) in patients with advanced colorectal cancer. 198 patients were randomised either to (i) 5-FU 60 mg/kg as a continuous infusion over 48 h, to be given weekly four times and thereafter every 2 weeks, with methotrexate 40 mg/m(2) administered just before 5-FU (control regimen) or to (ii) PALA 250 mg/m(2) as a 15 min infusion administered 24 h before 5-FU and methotrexate which was given as described in the control regimen. The response rate was 13% in the patients randomised to the control arm and 7% in the patients randomised to the experimental arm. If stabilisation of the disease was also considered as a positive response, these figures become 54 and 46%, respectively. All these differences did not reach statistical significance. The median durations of progression-free survival (PFS) in the two treatment groups were not significantly different. The median duration of survival was 13.1 months in the control arm and 11.9 months in the experimental arm (P=0.31). No benefit was obtained by adding PALA to LD-MTX+infusional FU. Taking into account data from US trials, the modulating effect of PALA, although 'promising' in phase II, could not be substantiated in randomised studies.

A weekly 24-h infusion of high-dose 5-fluorouracil (5-FU)+leucovorin and bi-weekly cisplatin (CDDP) was active and well tolerated in patients with non-colon digestive carcinomas.

In patients with non-colon digestive carcinomas, various schedules and doses of 5-fluorouracil (5-FU) and leucovorin combined with cisplatin (CDDP) have been used extensively. The present study explored the toxicity and activity of a weekly 24-h infusion of high dose 5-FU modulated by high dose leucovorin with bi-weekly CDDP. 59 patients with measurable disease were treated with a weekly infusion of high dose 5-FU (2 or 2.6 g/m2)+leucovorin 500 mg/m2 for 6 weeks and a bi-weekly dose of CDDP (50 mg/m2). All patients had metastatic or locoregionally advanced disease and had a performance status < or =3. All patients were evaluable for toxicity and 58 for response. Toxicity was different according to the schedule of 5-FU. Serious adverse events occurred most frequently when 5-FU was given at a dose of 2.6 g/m2 with a high incidence of grade 3/4 neutropenia (16%) and febrile neutropenia (13%), and led to dose reductions in both CDDP and 5-FU in 13 patients (34%). For patients who started 5-FU at a dose of 2 g/m2, no reduction in 5-FU was required, and only 4 patients required a dose reduction of CDDP (19%). Grade 3/4 neutropenia was seen in 10% of patients of this group and only 1 patient required hospitalisation for febrile neutropenia. Other grade 3/4 toxicities were rare in both groups. Renal toxicity was infrequent and mild and did not require dose adjustments. The overall response rate was 33%; 19 patients achieved a partial responses (PR). No patient had a complete response (CR). The median duration of response was 5.7 months (range 2-24 months) and the median survival was 7.9 months ( range: 1-30, 95% confidence interval (CI): 7-9). The combination of weekly 24-h infusion of high dose 5-FU with leucovorin and bi-weekly cisplatin seems a well-tolerated and active treatment in non-colon digestive carcinomas. A dose of 2 g/m2 of 5-FU seems to be recommended.

Final results of a randomized phase III trial of sequential high-dose methotrexate, fluorouracil, and doxorubicin versus etoposide, leucovorin, and fluorouracil versus infusional fluorouracil and cisplatin in advanced gastric cancer: A trial of the European Organization for Research and Treatment of Cancer Gastrointestinal Tract Cancer Cooperative Group.

PURPOSE: To compare the efficacy and tolerability of etoposide, leucovorin, and bolus fluorouracil (ELF) or infusional fluorouracil plus cisplatin (FUP) with that of the reference protocol of fluorouracil, doxorubicin, and methotrexate (FAMTX) in advanced gastric cancer. PATIENTS AND METHODS: A total of 399 patients with advanced adenocarcinoma of the stomach were randomized and analyzed for toxicity, tumor response, and progression-free and overall survival. Only reviewed and confirmed responses were considered. The analysis of remission was based on assessable patients with documented measurable lesions. The intent-to-treat principle, log-rank test, and Cox regression model were used for the statistical analysis of time-to-event end points. RESULTS: The overall response rate for 245 eligible patients with measurable disease was 9% with ELF, 20% with FUP, and 12% with FAMTX, with no significant differences. One hundred twelve patients were eligible for efficacy in assessable, nonmeasurable disease. No change was observed in 66% of patients treated with ELF, 56% with FUP, and 55% with FAMTX. Two patients achieved a complete tumor regression (one each for ELF and FAMTX). With a median follow-up time of 4.5 years, the median survival times were 7.2 months with ELF, 7.2 months with FUP, and 6.7 months with FAMTX, respectively, with no significant differences. Nonhematologic and hematologic toxicities of ELF, FUP, and FAMTX were acceptable, with neutropenia being the major toxicity for all three regimens. Seven treatment-related deaths occurred (two with FUP and five with FAMTX). CONCLUSION: All three investigated regimens demonstrate modest clinical efficacy and should not be regarded as standard treatment for advanced gastric cancer. New strategies should be considered to achieve a better clinical efficacy in the treatment of advanced gastric cancer.

[Colorectal cancer: a controllable disease]. / Le cancer colorectal: une maladie contrôlable.

Colorectal cancer is one of the most frequent cancers in western countries. Five years after curative surgery and adjuvant chemotherapy, about 10% more patients with Dukes C colon cancer are free of disease compared to the control group. Several regimens using 5-fluorouracil with folinic acid (5FU/FA) or levamisole are available. For patients with disseminated disease. 5FU/FA based treatments allows a doubling in survival as compared to best supportive care. Moreover, quality of life is significantly improved. New agents are upcoming. Tomudex seems to be equivalent to 5FU/FA but easier to administer. CPT-11 or oxaliplatin have been investigated in second line after failure of 5FU/FA. The available data suggest that median survival is prolonged by ten months, in addition to what was already obtained in first line with 5FU/FA. Colorectal cancer must be revisited. An active approach of our patients should allow to reduce the incidence of the disease, to increase the number of disease free patients 5 years after surgery, to prolong survival and improve the quality of life of those who will develop metastatic disease.

Modulation of high-dose infusional fluorouracil by low-dose methotrexate in patients with advanced or metastatic colorectal cancer: final results of a randomized European Organization for Research and Treatment of Cancer Study.

PURPOSE: Methotrexate (MTX) has been described to modulate the activity of fluorouracil (5-FU) in patients with metastatic colorectal cancer. The European Organization for Research and Treatment of Cancer (EORTC) Gastrointestinal Tract Cancer Cooperative Group (GITCCG) conducted a phase III trial to investigate the efficacy and tolarability of the addition of low-dose MTX (40 mg/m2) to high-dose infusional 5-FU (60 mg/kg over 48 hours) given weekly for 4 weeks and thereafter every 2 (for 4 weeks) and 3 weeks. PATIENTS AND METHODS: Three hundred ten patients were randomized between 1987 and 1992. Eligible patients had measurable advanced or metastatic colorectal cancer and had not been pretreated with antifolates or fluorodinated pyrimidines. All 297 eligible patients were evaluated for survival; toxicity was assessed in 292 patients who received at least one course of treatment. Patients with bidimensionally measurable disease (n = 230) were also evaluated for response according to standard criteria. RESULTS: The addition of low-dose MTX to high-dose infusional 5-FU led to a doubling of the response rate from 10% to 21% (P = .025). The median survival time also increased from 9.3 to 12.5 months, but this difference was not statistically significant (P = .12). High-dose infusional 5-FU with or without low-dose MTX was well tolerated, with grade 3 to 4 toxicity in greater than 10% of patients only occurring for stomatitis with the combination treatment. Performance status was the sole prognostic factor for survival in a multivariate analysis. CONCLUSION: Low-dose MTX effectively modulated high-dose infusional 5-FU in a large, randomized trial in which less than 5% of patients received leucovorin.

Colorectal cancer: the challenge.

Colorectal cancer is a common cancer and a common cause of death. The incidence varies widely and is highest in industrialised Western countries. Surgery remains the mainstay of treatment of localised tumours and, in addition, may also play a role in some patients with local recurrence and/or isolated liver or lung metastases. Chemotherapy is required to improve the results of surgery and to treat patients with disseminated disease. For more than 30 years, 5-fluorouracil (5-FU) has been the only active agent in advanced colorectal cancer with an overall response rate of less than 15%. Biomodulation of 5-FU with leucovorin has led to a substantial increase in the response rate, but only a modest benefit in survival. Improvement in palliative effects has also been observed. In adjuvant treatment after curative surgery, 5-FU with levamisole or leucovorin has shown approximately a 10% absolute increase in survival, compared with controls. Despite this progress, there is evidence that an important proportion of colorectal cancer patients remains untreated. New treatments, such as the direct and specific thymidylate synthase inhibitors (e.g. 'Tomudex'--raltitrexed, previously known as ZD1694) in first-line therapy, or CPT-11 or oxaliplatin, along with increased referral and a more consistent treatment approach could improve the outcome of patients with advanced colorectal cancer.

[Adjuvant chemotherapy in cancers of the colon and rectum]. / Chimiothérapie adjuvante des cancers du côlon et du rectum.

The high incidence of recurrence in patients with resected colorectal cancer at Dukes' stages B2, B3 and C indicates that these patients have micrometastases at the time of surgery and demonstrates the need for adjuvant therapy. Studies using 5-FU alone led to negative results. The combination of 5-FU and levamisole given every week during 1 year was shown to be an effective adjuvant treatment, significantly increasing survival at 5 years from 55% to 71% (p = 0.006). Other treatment modalities are under investigation. Leucovorin increases 5-FU activity in advanced cancers. A combination of the two could thus play an important role in adjuvant treatment. No results are available regarding the compared effects of 5-FU/folinic acid, 5-FU folinic acid/levamisole to 5-FU/levamisole. Portal vein chemotherapy with 5-FU administered during 7 days after surgery has been studies as well, and could also be effective. An association of a short postoperative course of intraportal chemotherapy with intravenous chemotherapy over several months may lead to a further improvement of survival in patients with colorectal cancer. Despite the substantial advances made in the adjuvant treatment of colorectal cancer, progress will be obtained only through continual research.

Sequential high-dose methotrexate and fluorouracil combined with doxorubicin--a step ahead in the treatment of advanced gastric cancer: a trial of the European Organization for Research and Treatment of Cancer Gastrointestinal Tract Cooperative Group.

In a prospective phase III multicenter trial, 213 patients with advanced measurable or nonmeasurable gastric cancer were randomized to receive methotrexate (MTX), fluorouracil (5-FU), and Adriamycin (doxorubicin; Farmitalia Carlo Erba, Milan, Italy) (FAMTX) or 5-FU, Adriamycin, and mitomycin (FAM). The results show a significantly superior response rate (41% v 9% [P less than .0001]), and survival (median, 42 weeks v 29 weeks [P = .004]) for FAMTX. There was a cumulative thrombocytopenia in FAM and not in FAMTX. The FAMTX protocol should be the reference treatment in future clinical trials that seek to improve the therapeutic outcome in advanced gastric cancer.

Adjuvant radiotherapy and chemotherapy in resectable gastric cancer. A randomized trial of the gastro-intestinal tract cancer cooperative group of the EORTC.

One hundred and fifteen patients with curative and palliative surgery for gastric cancer were randomized to receive radiotherapy alone (1) or in combination with short-term (ST) 5-FU (2), long-term (LT) 5-FU (3), ST and LT 5-FU (4). The ST 5-FU was given at a daily dose of 575 mg/m2, every 4-6 h during the first 4 days of treatment before starting irradiation. The LT 5-FU was given at a dosage of 750 mg/m2 every 2 weeks for 18 months or until progression. The median survival times for treatment 1 to 4 was respectively 12, 10, 15 and 18 months. There was a statistically significant overall difference between the four treatments (P = 0.041). However, when the comparisons were adjusted for the most significant prognostic factors, the difference in survival disappeared. Moreover, no difference was found between treatments in terms of time progression. Nevertheless, among 22 patients with residual tumour, the three who were still alive without disease progression (with survivals of 19+, 49+ and 90+ months at the time of this analysis) had been treated with radiotherapy combined with ST and LT 5-FU.

[Adjuvant treatment in cancer of the stomach]. / Les traitements adjuvants dans les cancers de l'estomac.

Surgical excision remains up to now the first potentially curative treatment for patients who are suffering from stomach cancer. The encouraging results recently obtained in the survival of these patients are to be attributed essentially to the screening for this disease. Unfortunately, in the countries of the Western World, 80 to 90% of patients with a stomach cancer still consult their physician at an advanced stage of the disease. This makes it necessary to look for new efficient adjuvant treatments to be implemented after surgery. Numerous chemotherapeutic combinations have been studied. The FAM association is the best known among all these; results of these treatments are reviewed. Other encouraging perspectives come from the association of chemotherapy and biochemical modulators, chemotherapy and radiation-therapy, IORT and other adjuvant treatments. These results are also reviewed.

An EORTC gastrointestinal (GI) group randomized evaluation of the toxicity of sequential high dose methotrexate and 5-fluorouracil combined with adriamycin (FAMTX) vs 5-fluorouracil, adriamycin and mitomycin (FAM) in advanced gastric cancer.

Until now advanced gastric cancer has been generally treated with the FAM chemotherapy protocol. Due to the relatively low response rates with this protocol we decided to start a randomized prospective phase II trial comparing the FAM with the FAMTX protocol. The primary aim of our trial was to compare the toxicity in both protocols. The FAMTX protocol has been demonstrated to be fully comparable with the toxicity of the FAM protocol. The trial has been extended to a phase III study. With respect to response rates and survival times it is too early for evaluation.

An EORTC Gastrointestinal Group evaluation of the combination of sequential methotrexate and 5-fluorouracil, combined with adriamycin in advanced measurable gastric cancer.

In a phase II multicenter trial, 71 patients with advanced measurable gastric cancer were registered to receive sequential high-dose methotrexate (MTX) and 5-fluorouracil (5-FU) combined with Adriamycin (A [Adria Laboratories, Columbus, OH]). The response rate was 33% (22 of 67), including all eligible patients. There were nine complete responders (CRs). The median survival for all patients was 6 months. There has been one toxic death; however, three other patients died from toxicity associated with major protocol violations. It is concluded that this protocol is active in gastric cancer. Toxicity, partly because of nonprotocol adherence, is considerable and is now under further investigation in a randomized trial comparing this schedule with a combination of 5-FU, Adriamycin, and mitomycin C (FAM).