Case Study 5fu Plus Leucovorin In Colon Cancer

As is clear, the history of clinical trials in GI cancer is long and has been very successful. As an example illustrating several facets of both the past history of GI clinical trials and issues that will likely be faced again in future studies, here we present a case study of the development, establishment and replacement of what was once the US standard of care for advanced colorectal cancer and, as of 2002, remains the standard for adjuvant stage 3 colon cancer, the 'Mayo Clinic' bolus regimen of 5-FU and leucovorin delivered for 5 consecutive days every 4 or 5 weeks.

The activity of fluorinated pyrimidines in the treatment of GI cancers has been reviewed extensively. 5-Fluorouracil (5-FU) is the most ubiquitous of the fluorinated pyrimidines, which at least in part exert their antineoplastic effect by inhibiting the activity of the enzyme thymidylate synthase (TS), which in turn interferes with DNA synthesis in dividing cells. Often agents designed to improve the efficacy of fluorinated pyrimidines are combined with these agents in an effort to preferentially sensitise tumour cells relative to host cells to the agent(s). Leucovorin is an agent commonly used in such a setting. The Mayo regimen of 5-FU and leucovorin is thus a combination of an active chemotherapy agent, 5-FU, with a 'biochemical modulator' leucovorin.

Prior to the early 1980s, 5-FU was primarily administered as a single agent. Administered in this fashion, it was associated with limited activity and moderate toxicity. Response rates for metastatic colorectal cancer were low, in the neighbourhood of 10%, and these responses were short-lived, lasting on average a few months.61

Based on pre-clinical laboratory studies,86-88 the addition of leucovorin to cell culture with one of the metabolites of 5-FU, fluorodeoxuridylate monophosphate (FdUMP), resulted in enhanced binding to and inhibition of TS as compared to the binding when FdUMP was used alone. This improved inhibition of thymidylate synthase resulted in inhibited DNA synthesis and resulted in enhanced tumour shrinkage. Depending on the model systems, optimal concentration of leucov-orin ranged from leucovorin 1-20 mmol/L.89-93 These studies supported the use of leucovorin doses ranging from 10 to 600 mg/m2 in clinical trials where leucovorin was added to 5-FU in an effort to improve on 5-FU's single agent activity. While such laboratory studies provided basic information on the modulation of 5-FU using leucovorin, the applicability of these results to humans with colorectal cancer was unclear. Based on clinical experience, individuals with colorectal cancer clearly exhibit significant heterogeneity in their response to treatment. The sequence of administration of 5-FU and leucov-orin, the optimal concentration of leucovorin, and the appropriate interval of 5-FU and leucovorin administration all were variables to be studied to explore the efficacy of 5-FU and leucovorin in inhibiting tumour growth.

Early investigators studying the biochemical modulation of 5-FU with leucovorin in the treatment of colorectal and gastric cancers included Machover and colleagues.9495 The Machover regimen consisted of administering high-dose leucovorin at 200 mg/m2/d prior to 5-FU at a dose of 370 mg/m2/d, with both drugs given consecutively for 5 days. With this dose of leucovorin, the blood level is approximately 10-20 ^mol/L.96 In large part to lower the cost of the regimen (leucovorin was very expensive at the time), the 'Mayo' regimen was devised to use the identical 5-FU schedule to the Machover regimen, but to use low-dose leucovorin at a dose of 20 mg/m2/d, which resulted in blood levels of 1-2 ^mol/L.

This regimen was first tested as part of a randomised Phase II study in advanced unresectable colorectal cancer.97 Three of the treatment arms are relevant for this discussion: (1) 5-FU as a single agent administered at a dose of 500 mg/m2/d by IV bolus for 5 consecutive days every 5 weeks; (2) the Machover regimen repeated at 4 weeks, 8 weeks and every 5 weeks thereafter; and (3) the Mayo regimen repeated at the same frequency as the Machover regimen. In this trial, provision was made in the protocol to escalate the 5-FU dose on any treatment arm if there was no observed myelosuppression or significant non-haematologic toxicity during the previous treatment course. When the toxicity was analysed after treatment of the first 100 patients, the starting dose of 5-FU for the Mayo regimen was increased to 425 mg/m2/d in order to produce definite but tolerable toxicity that was of similar magnitude between the six treatment arms.98 The original combination of low-dose leucovorin with 370 mg/m2/d of 5-FU for 5 consecutive days was empiric; no formal Phase I trial of this regimen had ever been performed. In the 208 eligible patients entered on the three study arms of interest, the overall response rates were 10% for 5-FU alone, 26% for the Machover regimen, and 43% for the Mayo regimen. Both leucovorin regimens demonstrated significant improvement in response rate and overall survival compared to 5-FU alone.

Concurrent to the previously mentioned study, investigators at the Roswell Park Memorial Cancer Institute (RPMI) began testing a regimen of leucovorin 500 mg/m2/d with 5-FU 600 mg/m2/d given for 6 consecutive weeks followed by a 2-week rest period.99 In a small study, the RPMI regimen was shown to significantly improve the tumour response rate compared to single agent 5-FU. Shortly thereafter, the RPMI and Mayo regimens were compared in a randomised trial of 366 patients.100 In this trial, the objective response rates and overall survival was similar between the two arms. The toxicity profile of the two regimens did differ, but no clear winner was identified. Based largely on cost considerations, investigators from the Mayo Clinic and the North Central Cancer Treatment group chose to pursue the Mayo regimen for future testing.

The activity seen with the combination of leucovorin and 5-FU in the advanced disease setting naturally led to the evaluation of several of these regimens in the adjuvant treatment of patients with stage 2 and 3 colon cancer. In a study that was suspended after accrual of 317 patients (based on the results of a large trial that demonstrated 5-FU plus levamisole was an effective treatment in this setting49), patients with resected stage 2 or 3 colon cancer were randomised to the Mayo 5-FU plus leucovorin regimen for 6 months or to a no treatment control arm.53 The 5-year survival for treated patients was 74%, compared to 63% in the control group (p = 0.02). This result established the efficacy of the Mayo 5-FU plus leucovorin regimen in the adjuvant setting.

Following this small study, a large trial was conducted to test four different combinations of 5-FU with leucovorin and/or levamisole in patients with stage 2 and 3 colon cancer.

The regimens included the Mayo 5-FU plus leucovorin regimen for 6 months, 5-FU plus levamisole for 12 months, 5-FU with high-dose leucovorin (the RPMI regimen) for 8 months, or 5-FU plus leucovorin plus levamisole for 12 months. In this study of 3759 patients, results were similar between the Mayo and RPMI 5-FU plus leucovorin programmes, and the 5-FU plus both leucovorin and levamisole regimen.55 Based on the essentially identical activity profiles of these regimens, the choice between the two 5-FU and leucovorin regimens (Mayo and RPMI) has been based on issues related to schedule (some patients preferred weekly therapy over five consecutive days of treatment), cost (at the time of these studies leucovorin was expensive), toxicity profile and clinician's preference.

From the late 1980s until the year 2000, the Mayo regimen of 5-FU and leucovorin was regarded as the standard of care for advanced colon cancer. As discussed previously, in the late 1990s and early 2000s, several randomised trials were conducted in both the US and Europe in which infusion-based 5-FU regimens or regimens that combine 5-FU with CPT-11 or oxaliplatin have demonstrated improved patient outcomes compared to those seen with the Mayo regimen. In addition, the oral agent capecitabine has been approved as an alternative to IV 5-FU in advanced disease. Thus it appears that in the advanced disease setting, the Mayo 5-FU + leucovorin regimen has been replaced as the standard of care, indeed a welcome advance. In the adjuvant setting, no randomised trial has been completed that demonstrates improved overall survival for a multiple drug combination, or equivalence for an oral regimen, although trials in both areas have completed accrual and are awaiting results. Increased toxicity has clearly been demonstrated for multiple drug combinations in the adjuvant setting,84 demonstrating the value of waiting for the results from these definitive trials before adopting a promising new therapy as a standard of care in the community.

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