Clinical Colorectal Cancer August 2002 • 111 Contribution Original Introduction 5-fluorouracil (5-FU) has long been the mainstay of adju- vant and advanced colon cancer treatment. In the presence of the reduced-folate cofactor 5,10-methylenetetrahydrofolate (CH 2 THF), a major mechanism of action of 5-FU involves the inhibition of thymidylate synthase (TS) by the formation of a stable ternary complex of the 5-FU metabolite 2'-deoxy- 5'-fluorouridine-5'-monophosphate, TS, and CH 2 THF. 1 The production of 2'-deoxythymydine-5'-monophosphate is im- paired, and cell death occurs as a consequence of inhibition of DNA synthesis. A second mechanism involves the incorpora- tion of 5-fluorodeoxyuridine-5' triphosphate (FdUTP) into DNA. Repair mechanisms recognize the incorporation of this 5-FU metabolite and excise the FdUTP causing strand break- age, which then results in activation of p53-dependent and p53-independent pathways and the triggering of apoptosis. A third mechanism involves the incorporation of 5'fluorouri- dine-5'triphosphate into RNA, which then results in alter- ations in RNA processing and impaired messenger RNA trans- lation. The relative contribution of each of these pathways to the ultimate cytotoxic effects of 5-FU remains unclear. How- ever, the rapidly-proliferating cells with higher rates of metab- olism appear to be more sensitive to 5-FU treatment. Treatment of advanced colorectal cancer with bolus 5-FU alone produces a 15%-20% objective response rate with sig- nificant toxicity and the absence of a consistent survival bene- fit. 2 Various biochemical modulators have been investigated in order to improve the therapeutic index of 5-FU. 2,3 In sev- eral trials, folinic acid (FA) was found to be a superior mod- ulator in terms of tumor response and survival, presumably because it stabilizes the formation of the ternary complex with maximal inhibition of TS enzyme activity. 4,5 Therefore, several trials involving different dosing regimens of 5-FU/FA were conducted. 6-8 In North America, the version known as the Mayo Clinic regimen became the widely accepted treat- ment and, until 2 years ago, was the gold standard compara- Toxicity Analysis of the 5-Day Bolus 5-Fluorouracil/ Folinic Acid Regimen for the Treatment of Colorectal Carcinoma from 2 Randomized Controlled Trials: A Concern About Dose Abstract The goal of this study was to ascertain the first cycle intolerability rate of the standard Mayo Clinic regimen, 5-fluo- rouracil (5-FU) 425 mg/m 2 with low-dose folinic acid (FA) 20 mg/m 2 , as a rapid bolus intravenous injection (5-FU/FA) for 5 days every 4-5 weeks for advanced colorectal cancer chemotherapy.The 5-FU/FA arms of 2 large, randomized, controlled trials of 5-FU/FA versus raltitrexed, performed in Europe and North America, were analyzed for intoler- ability.Two hundred and twelve European patients and 200 North American patients with locally advanced or distant metastatic colorectal cancer were assigned to the Mayo Clinic regimen. During cycle 1, intolerability of the therapy was assessed. Intolerability was recognized as a protocol-driven, toxicity-mandated dose reduction in cycle 2, the in- ability to complete 5 days of cycle 1 due to toxicity, or failure to receive cycle 2 at all because of toxicity. After the first cycle of chemotherapy, the intolerability rate for the European trial was 41.0% (95% confidence interval [CI], 34.3-47.6) and 49.0% (95% CI, 42.0-56.0) for the North American trial. For the combined 5-FU/FA populations, the intolerability rate was 44.8% (95% CI, 40.0-49.7). The predominant toxicities were stomatitis, diarrhea, and leukope- nia.The standard Mayo Clinic regimen was associated with a higher level of dose-limiting toxicities than the accept- ed maximum of up to 33% for standard chemotherapy. Clinical Colorectal Cancer, Vol. 2, No. 2, 111-118, 2002 Key words: Thymidylate synthase, Mayo regimen, Toxicity profile, Intolerability rate analysis, 5-FU Submitted: May 15, 2002; Revised: Jul 22, 2002; Accepted: Jul 26, 2002 Address for correspondence: Mark Vincent, MD, London Regional Cancer Centre, 790 Commissioners Rd E., London, Ontario, N6A 4L6 Canada Fax: 1-519-685-8624; e-mail: mark.vincent@lrcc.on.ca London Regional Cancer Centre, London, ON, Canada Mark Vincent, Cheryl Ho, Anna Tomiak, Eric Winquist, Frances Whiston, Larry Stitt