A less toxic regimen of 5-fluorouracil and high-dose folinic acid for advanced gastrointestinal adenocarcinomas

Abstract

Summary The combination of high-dose folinic acid with 5-fluorouracil has shown improved response rates in several trials in advanced colorectal carcinoma. This however is at the expense of increased toxicity: regimens using weekly bolus injections produce diarrhoea in most patients and occasional toxic deaths from this, whilst those using daily injections for one week in four report both diarrhoea and severe oral mucositis. Both types of regimen have significant rates of myelosuppression.A recent report described a different schedule of 5-fluorouracil and folinic acid, which appeared better tolerated but equally active (De Gramont et al., 1988 al., 1989). These reports also describe toxicity different from that produced by 5-fluorouracil alone: Regimens using weekly bolus injections are reported as frequently causing diarrhoea (in 22-80% of patients) with occasional toxic deaths from this (Petrelli et al., 1988;Petrelli et al., 1989), whilst those employing daily injections for one week in four report both diarrhoea and oral mucositis -the latter in 40-80% of patients (Machover et al., 1986;Erlichman et al., 1988;Poon et al., 1989

Bolus/infusional 5-fluorouracil and folinic acid. A report on two prospective, consecutive phase II studies with 5-fluorouracil dose escalation

“…In the initial phase II study of 37 patients, there was a response rate of 54% (CI 38-70%), and the regimen was well tolerated with no patients experiencing WHO grade 3 toxicity (De Gramont et al, 1988). A second phase II study in 43 patients confirmed this tolerability but showed a lower response rate of 24% (CI 11-37%) (Johnson et al, 1991). We reported previously a retrospective analysis of this combination using 300-500 mg m-2 of 5-FU and found a disappointing response rate of 11% (95% CI 4-18%) in 81 evaluable patients (Jodrell et al, 1994).…”

Phase I trial of oxaliplatin with fluorouracil, folinic acid and concurrent radiotherapy for oesophageal cancer

“…Folinic acid (FA) modulates the activity of 5FU and improves the outcome in both colorectal and gastric cancers (Machover et al, 1986;Johnson et al, 1991;Louvet et al, 1991;Rubin et al, 1996). It has been added to 5FU in several studies on oesophageal cancer with encouraging results (Highley et al, 1993;Stahl et al, 1994;Roca et al, 1996).…”

High-dose folinic acid with 5-fluorouracil bolus and continuous infusion in the treatment of advanced gastric and oesophageal adenocarcinoma

“…Early studies showed an increased response rate and survival benefit in colorectal adenocarcinoma (Erlichman et al, 1988), but more variable response rates of 12-48% in advanced gastric adenocarcinoma (Machover et al, 1986;Arbuck et al, 1987). Recently short infusions of high dose folinic acid and 5-FU have produced response rates of 40% and 43.5% (Johnson et al, 1991;Louvet et al, 1991).…”

“…Early studies showed an increased response rate and survival benefit in colorectal adenocarcinoma (Erlichman et al, 1988), but more variable response rates of 12-48% in advanced gastric adenocarcinoma (Machover et al, 1986;Arbuck et al, 1987). Recently short infusions of high dose folinic acid and 5-FU have produced response rates of 40% and 43.5% (Johnson et al, 1991;Louvet et al, 1991).We have treated 15 patients with advanced histologically confirmed gastric and oesophageal adenocarcinoma using the regimen described by De Gramont (De Gramont et al, 1988 The treatment regimen consisted of folinic acid 200mg m-2 in 500 ml of N-saline over 2 h followed by 5-FU 400 mg m2 IV bolus then 5-FU 400 mg m-2 in 1000 ml of N-saline over 22 h. This was repeated on day 2. Oral mucositis was limited by the prophylactic use of allopurinol mouthwash, initially hourly for 4 h after the folinic acid infusion, then four hourly.…”

“…Oral mucositis was limited by the prophylactic use of allopurinol mouthwash, initially hourly for 4 h after the folinic acid infusion, then four hourly. Laser (Johnson et al, 1991) achieved a response rate of 40% (95% CI 10-70%) in advanced gastric cancer. Similarly, Louvet (Louvet et al, 1991) …”