Increase of Survival Benefit in Advanced Resectable Colon Cancer by Extent of Adjuvant Treatment: Results of a Randomized Trial Comparing Modulation of 5-FU + Levamisole With Folinic Acid or With Interferon-α

With an estimated 600,000 new cases occurring each year, colorectal cancer represents the third common most solid cancer worldwide with approximately 54,000 of these patients being diagnosed in Germany.1 Despite continuous improvements in screening, prevention, and early detection in conjunction with refinement of surgical techniques, overall survival increased only slightly during the last decades.2 The prognosis primarily depends on the tumor stage3 and the quality of surgery,4 while postoperative follow-up and relapse surgery only insignificantly influence survival.2 The outcome of colorectal cancer patients with potentially curative resection (R0) of their primary tumor, however, a high risk to develop recurrence, can be improved by multimodal neo-adjuvant and adjuvant therapy.2 Because colon and rectal cancers show distinct patterns of recurrence and metastasizing, various neo-adjuvant and adjuvant treatment strategies have been recommended.5 The benefit of systemic adjuvant therapy in R0-resected lymph node positive colon cancer (UICC III) was established more than a decade ago. A large-scale trial demonstrated that a 12-month adjuvant treatment with 5-fluorouracil (5-FU) and levamisole (LEV) significantly improved survival, compared with LEV or surgery alone.6 5-FU + LEV was subsequently recommended as standard by NIH and European consensus conferences. While the potential antitumoral effects of the antiworm agent LEV remain still unclear, the mechanisms of cytotoxicity of 5-FU have been extensively studied.7 Thus, this pyrimidine antimetabolite is incorporated into DNA and RNA after metabolism to 5-fluoro-2′-deoxyuridine-5′-triphosphate and 5-fluoro-uridine-5′-triphosphate, respectively. However, the main mechanism of 5-FU cytotoxicity seems to be the inhibition of thymidylate synthase (TS). TS is the rate limiting enzyme of DNA synthesis catalyzing the methylation of deoxyuridine-5′-monophosphate (dUMP) to deoxythymidine-5′-monophosphate (dTMP) with 5,10-methylenetetrahydrofolate (CH2THF) as cofactor. 5-FU inhibits TS activity after conversion to 5-fluoro-2′-deoxyuridine-5′-monophosphate (FdUMP) by formation of a very stable ternary complex of TS, FdUMP, and CH2THF. Besides deceleration of the rate of DNA synthesis, TS inhibition results in depletion of dTMP pools and accumulation of dUMP pools with incorporation of uridine nucleotides into DNA followed by DNA strand breaks.7 At the time when 5-FU + LEV were recommended as standard,8 it seemed possible to improve adjuvant treatment by modulation of 5-FU with either folinic acid (FA) or interferon-α (IFN-α). The addition of FA increases the concentration of the cofactor CH2THF, thereby stabilizing the ternary complex formation of FdUMP with TS,7 while INF-α enhances 5-FU metabolism and, moreover, has immunomodulating and antiangiogenic effects.7,9,10 Indeed, in metastatic colorectal cancer, the combination of 5-FU with either FA or IFN-α enhanced the efficacy of 5-FU monotherapy.11 This clinical effect was paralleled by an increase of the number of DNA strand breaks in cultured colon cancer cells when either FA or IFN-α was combined with 5-FU.12 Although both combinations demonstrated similar in vitro and in vivo activity, the enhanced efficacy of the 5-FU + INF-α combination was associated with higher toxicity.11 Based on this basic and clinical knowledge, the Research Group Oncology of Gastrointestinal Tumors (FOGT) designed a prospective randomized trial called FOGT-1 to optimize adjuvant treatment of high-risk colon cancer. The aim of this study was to determine the efficacy of 5-FU + LEV alone compared with 5-FU + LEV modulated by either FA or IFN-α. In the largest German adjuvant colon cancer trial conducted so far, we now report that addition of FA significantly increased survival, whereas addition of IFN-α increased toxicity without markedly influencing the outcome of these patients.