A 'modified de Gramont' regimen of fluorouracil, alone and with oxaliplatin, for advanced colorectal cancer.

The standard de Gramont (dG) regimen of fortnightly leucovorin, bolus fluorouracil and 22-h infusion of fluorouracil, d1+2, and the same regimen plus oxaliplatin, are effective but also cumbersome. We therefore present simplified 'Modified de Gramont' (MdG) regimens. Forty-six advanced gastrointestinal cancer patients entered a dose-exploring study of MdG, including an expanded cohort of colorectal cancer patients at optimum dose. Treatment (fortnightly) comprised: 2-h i.v.i. leucovorin (350 mg d,l-LV or 175 mg l-LV, not adjusted for patient surface area); bolus fluorouracil (400 mg m(-2)), then ambulatory 46-h fluorouracil infusion (2000-3600 mg m(-2), cohort escalation). Subsequently, 62 colorectal patients (25 unpretreated; 37 fluorouracil-resistant) received MdG plus oxaliplatin (OxMdG) 85 mg m(-2). Fluorouracil pharmacokinetics during MdG were compared with dG. The optimum fluorouracil doses for MdG alone were determined as 400 mg m(-2) bolus + 2800 mg m(-2) 46-h infusion. A lower dose of 400 mg m(-2) bolus + 2400 mg m(-2) infusion which, like dG produces minimal toxicity, was chosen for the OxMdG combination. Fluorouracil exposure (AUC(0-48 h)) at this lower dose is equivalent to dG. With OxMdG, grade 3-4 toxicity was rare (neutropenia 2.8% cycles; vomiting or diarrhoea <1% cycles), but despite this there were two infection-associated deaths. Oxaliplatin was omitted for cumulative neurotoxicity in 17 out of 62 patients. Objective responses in colorectal cancer patients were: 1st-line MdG (22 assessable): PR=36%, NC=32%, PD=32%. 1st-line OxMdG (24 assessable): CR/PR=72%; NC=20%; PD=8%; 2nd line OxMdG (34 assessable): PR=12%; NC=38%; PD=50%. MdG and OxMdG are convenient and well-tolerated. OxMdG was particularly active as 1st-line treatment of advanced colorectal cancer. Both regimens are being further evaluated in the current UK MRC phase III trial.

Protracted infusional 5-fluorouracil (5-FU) with bolus mitomycin in 5-FU-resistant colorectal cancer.

BACKGROUND: MF (protracted infusion 5-fluorouracil (5-FU), 300 mg/m2/24 hours plus bolus mitomycin, 7 mg/m2 every 6 weeks, maximum 4 doses), was recently shown in a randomised trial to be superior to protracted 5-FU alone, as first-line chemotherapy for metastatic colorectal cancer (Ross et al. Ann Oncol 1997; 8: 995-1001 [5]). We have examined the same regimen in patients with 5-FU-resistant disease. PATIENTS AND METHODS: MF was given to 24 patients with metastatic colorectal cancer, median age 63 years. Two had progressed within four months of adjuvant 5-FU; the rest had already received palliative 5-FU, with progression during (11 patients), within four months (5 patients) or after four months of completion (6 patients). The prior 5-FU regimens were bolus 5-FU/FA (8 patients); 48 hour bolus + infusion 5-FU/FA (18 patients) or protracted 5-FU alone (3 patients). Five patients had received more than one prior 5-FU regimen. RESULTS: Three patients, 12.5%, achieved WHO partial response; seven others had minor response or stable disease (SD or better = 42%, 95% confidence interval (95% CI): 22%-64%). Median failure-free survival (FFS) was 15 weeks; median overall survival was 9.0 months. No grade 3 or 4 drug toxicity occurred, but dose reduction and/or interruption for persistent grade 2 toxicity was required in eight patients (33%). Three patients (12.5%) had venous line problems (2 thrombosis; 1 dislodged). There were no toxic deaths. 12 patients (50%) went on to receive third-line therapy after MF, including irinotecan or oxaliplatin. CONCLUSIONS: MF is a low-cost, well-tolerated regimen in second-line treatment of metastatic colorectal cancer. The response rate and FFS obtained in this small group are similar to those reported for single agent irinotecan. Half our patients obtained a useful period of control with MF before moving on to further treatment with new agents such as irinotecan and oxaliplatin.

Epirubicin, cisplatin and oral UFT with leucovorin ('ECU'): a phase I-II study in patients with advanced upper gastrointestinal tract cancer.

BACKGROUND: ECF (epirubicin, cisplatin, protracted venous fluorouracil) is superior to FAMTX in gastroesophageal cancer, but protracted fluorouracil adds to its morbidity and cost. In this dose-escalation pilot study, fluorouracil was replaced by oral UFT and leucovorin. PATIENTS AND METHODS: Thirty unpretreated patients with advanced upper gastrointestinal cancers received epirubicin 50 mg/m2 and cisplatin 60 mg/m2 i.v. on day 1, and leucovorin 45 mg p.o. on days 1, 8 and 15, of a 21-day cycle for up to 8 cycles. UFT was taken 12-hourly throughout, at escalating doses in four cohorts ranging from 150-325 mg/m2 per day. RESULTS: The maximum tolerable dose of UFT, recommended for further study, was 200 mg/m2 per day. At higher doses, more than two-thirds patients required dose reductions, although mostly for persistent mild (CTC grade 2) nausea, diarrhoea or fatigue, rather than for severe acute toxicity. Myelotoxicity was mild. Twenty patients, including 15 with gastroesophageal cancer, had assessable disease. Among these there were nine WHO objective responses, all in gastroesophageal patients, including two radiological complete responses. CONCLUSIONS: ECU is well tolerated at the defined dose, with activity comparable to ECF in gastroesophageal cancer. UFT and other oral 5FU dosing strategies make promising components of combination chemotherapy, deserving further, randomised evaluation.