Biochemical modulation of fluorouracil: evidence of significant improvement of survival and quality of life in patients with advanced colorectal carcinoma.

Abstract

The purpose of this study was to evaluate the effectiveness of several new approaches designed to enhance the activity of fluorouracil (5-FU) in the management of advanced colorectal cancer. A total of 429 patients were randomized to one of the following regimens: single-agent 5-FU, given by standard 5-day, intensive-course intravenous bolus technique; 5-FU plus high-dose folinic acid (leucovorin) or 5-FU plus low-dose leucovorin; 5-FU plus high-dose methotrexate (MTX) with oral leucovorin rescue; 5-FU plus low-dose MTX; and 5-FU plus cisplatin (CDDP). The median survival for patients receiving 5-FU alone was 7.7 months. The high- and low-dose leucovorin plus 5-FU regimens had median survivals of 12.2 and 12.0 months, respectively, and offered a significant survival advantage over 5-FU alone with one-sided P values of .037 and .050, respectively (P = .051 for each treatment after correction for prognostic variables). The only other regimen possibly associated with improved survival was high-dose MTX plus 5-FU, with a median survival of 10.5 months (P = .21, P = .076 corrected). In addition, both high- and low-dose leucovorin plus 5-FU regimens were associated with significantly improved tumor response rates (P = .04 and .001) and significantly improved interval-to-tumor-progression rates (P = .015 and .007) when compared with 5-FU alone. Only the low-dose leucovorin plus 5-FU regimen was associated with significant (P less than .05) superiority in each of the following parameters of quality of life: performance status, weight gain, and symptomatic relief. The overall most therapeutically favorable regimen in this trial was 5-FU given with low-dose leucovorin; fortuitously, this regimen is associated with very low drug cost. Whereas this is the first study to demonstrate both improved palliation and survival for any regimen compared with 5-FU given by rapid intravenous (IV) injection for 5 consecutive days at a dose of 500 mg/m2/d in patients with advanced colorectal cancer, the magnitude of the gain is still relatively small. Our low-dose leucovorin plus 5-FU regimen is currently being studied in a national trial with the hope that this increased advanced disease activity may produce more substantive gains in the surgical adjuvant setting.

Mature results from three large controlled studies with raltitrexed ('Tomudex')

“…As shown in Figure 8, when all hospital components of treatment were accounted for (with the exclusion of pharmacy resources), the monthly cost of raltitrexed was considerably lower than that of the de Gramont regimen (5-FU 400 mg m-2 bolus + LV 200 mg m-2 2-h infusion, followed by 22-h infusion of 5-FU 400 mg m-2 for 2 days every 2 weeks) (de Gramont et al, 1995) and similar to those of the Mayo regimen (bolus 5-FU 425 mg m-2 + low-dose LV 20 mg m-2 for 5 days every 4-5 weeks) (Poon et al, 1989) and a continuous ambulatory infusional regimen (5-FU 300 mg m-2 per day). Total costs were as follows: Mayo regimen £954.03 (mean) and £659.68 (median); raltitrexed £1117.85 (mean) and £959.34 (median); continuous ambulatory 5-FU £1207.61 (mean) and £749.19 (median); and de Gramont £2028.52 (mean) and £1775.66 (median).…”

“…Although the optimal treatment regimen for these two drugs has not been unequivocally defined, the Mayo regimen of 5-FU and low-dose LV is widely regarded as an acceptable treatment and is the only regimen to have demonstrated a significant survival advantage over unmodulated 5-FU (Poon et al, 1989). However, other combination regimens, such as the Machover (5-FU with high-dose LV) regimen (Machover et al, 1986), or continuously infused 5-FU (Seifert et al, 1975;Lokich et al, 1989;de Gramont et al, 1995) are also used.…”

“…Despite their widespread acceptance, combinations of 5-FU and LV require complex and inconvenient dosing schedules and are associated with significant toxicity (Lokich et al, 1989;Poon et al, 1989;Buroker et al, 1994;Bleiberg, 1997). In view of the limitations of these therapies, there is a need for the development of new anti-cancer agents with greater or equivalent efficacy, improved tolerability and more acceptable administration schedules.…”

Treatment-induced mucositis: an old problem with new remedies

“…Mucositis may be the dose-limiting toxicity with a variety of regimens. As many as 80% of patients receiving 5-fluorouracil and folinic acid may develop mucositis and, in up to 26%, this may be severe (Poon et al, 1989). Ulceration of the oropharynx with consequent dysphagia reaches its peak 10 or so days after chemotherapy.…”

Clinical significance of prognostic and predictive markers in colorectal cancer

“…5FU/LV combination therapy has been demonstrated to improve survival and quality of life in CRC patients. 34 Pre-clinical studies have demonstrated that TS expression is a key determinant of 5FU sensitivity, 35 and multiple clinical investigations have demonstrated an improved response to 5FU-based therapy in patients with low TS expression in their tumours. 31,36 In addition, several studies have demonstrated that patients with high TS expression in their tumours have a significantly worse clinical outcome than those with low TS irrespective of response to treatment, therefore TS may also be a valuable prognostic marker.…”