Modulation of 5-fluorouracil with methotrexate and low-dose N-(phosphonacetyl)-L-aspartate in patients with advanced colorectal cancer. Results of a phase II study.

Abstract

Methotrexate (MTX) and N-phosphonacetyl-L-aspartate acid (PALA) have been shown to modulate the cytotoxic effects of 5-fluorouracil (5-FU). A phase II study was initiated to evaluate the feasibility, toxicity and efficacy of PALA/MTX and 5-FU in patients with metastatic colorectal cancer. 26 patients received PALA 250 mg/m2 as an intravenous 15-min infusion plus MTX 200 mg/m2 as a 30-min intravenous (i.v.) infusion on day 1 and 5-FU 600 mg/m2 as i.v. push on day 2. Cycles were repeated every 14 days and the 5-FU dose was escalated in the individual patient in steps of 100 mg/m2 for the third, fifth and seventh cycle in the absence of toxicity. 7 patients had received prior 5-FU-based chemotherapy while 19 patients were chemotherapy naive. Objective responses occurred in 23% of patients (1 CR, 5 PR of which 2 were pretreated), no change in 13 patients (50%) and tumour progression (6 patients) or toxic death (one patient) in 27%. Responses lasted for a median of 7 months (range 6-9), the median time to progression was 4 months and median survival 13 months. Toxicity was mainly gastrointestinal with diarrhoea and mucositis, and severe or life threatening in only 3 patients. In 3 patients an increase in serum glucose levels occurred while being treated with PALA/MTX and 5-FU. 2 patients with insulin-dependent diabetes had a 33% increase in insulin requirement and 1 patient with dietary-controlled diabetes died due to a ketoacidotic coma. PALA/MTX/5-FU in this dose and schedule is active in patients with colorectal cancer. Hyperglycaemia may be a potential side-effect of PALA-containing regimens especially in patients with diabetes. Careful monitoring of serum glucose levels in these patients is indicated.

• Authors: C H Köhne, A Harstrick, W Hiddemann, P Schöffski, H Wilke, C Bokemeyer, B Dörken, H J Schmoll
• Journal: European journal of cancer (Oxford, England : 1990) (Eur J Cancer) Vol. 33 Issue 11 Pg. 1896-9 (Oct 1997) ISSN: 0959-8049 [Print] England
• PMID: 9470854 (Publication Type: Clinical Trial, Clinical Trial, Phase II, Journal Article)

Chemical References

• Aspartic Acid
• sparfosic acid
• Phosphonoacetic Acid
• Fluorouracil
• Methotrexate

Topics

• Adult
• Aged
• Antineoplastic Combined Chemotherapy Protocols (adverse effects, therapeutic use)
• Aspartic Acid (administration & dosage, adverse effects, analogs & derivatives)
• Colorectal Neoplasms (drug therapy)
• Female
• Fluorouracil (administration & dosage, adverse effects)
• Humans
• Male
• Methotrexate (administration & dosage, adverse effects)
• Middle Aged
• Phosphonoacetic Acid (administration & dosage, adverse effects, analogs & derivatives)
• Survival Analysis
• Treatment Outcome