Adjuvant sequential methotrexate → 5-fluorouracil vs 5-fluorouracil plus leucovorin in radically resected stage III and high-risk stage II colon cancer

Abstract

The aim of the study was to determine whether modulation of 5-fluorouracil (FU) by methotrexate (MTX) improves survival compared to FU þ 6-s-leucovorin (LV) following potentially curative resection of stage II and III colon cancer. Within 8 weeks from surgery, 1945 patients with stage III (44%) or high-risk stage II (55%) colon cancer were randomly assigned to receive either 6 monthly cycles of FU 370 mg m À2 i.v. bolus preceded by LV 100 mg m À2 i.v. bolus on days 1 -5, or 6 monthly cycles of sequential MTX 200 mg m À2 i.v. days 1 and 15 and FU 600 mg m À2 i.v. on days 2 and 16 followed by LV rescue (15 mg given p.o. q 6 h  6 doses). Levamisole 50 mg p.o. t.i.d. on days 1 -3, every 14 days for 6 months, was planned to be given in both arms. After a median follow-up of 4.2 years, 568 patients have relapsed and 403 have died. Survival was similar with MTX-FU and FU þ LV (77 vs 77% at 5 years; P ¼ 0.90), as were 5-year disease-free survivals (67 vs 63%; P ¼ 0.44). Efficacy results were similar for both stage III and II patients. There were two toxic deaths, two in the MTX-FU arm (0.2%) and zero in the control arm. We conclude that biochemical modulation of FU with LV or with MTX produces similar results in the adjuvant setting of colon cancer. (Moertel et al, 1990) and of FU 6-s-leucovorin (LV) in 1993 (Wolmark et al, 1993), and the second was the proven equivalence of only 6 months of FU LV to the standard 12 months of FU levamisole, 5 years later (Haller et al, 1998). The third was the demonstration that the benefit of adjuvant chemotherapy extends to elderly patients as well (Sargent et al, 2001). And the last advancement regards the additional substantial benefit that the doublet FU þ oxaliplatin provides as compared to optimal FU chemotherapy (Andre et al, 2004). Other issues have been addressed and definitely answered by large-scale randomised trials in the last 5 years. Such is the case for the optimal dose of LV to potentiate FU: no need for high dose (Haller et al, 1998;Quasar, 2000); the best schedule of FU LV: equivalence between the weekly and the monthly schedule (Kerr, 2000), the lack of efficacy of levamisole (Haller et al, 1998;Quasar, 2000), the equivalence of the bolus and infusional FU regimens (Andre et al, 2003) and the inefficacy of short-term early postoperative intraportal FU infusions (Liver infusion meta-analysis group, 1997).INTACC is an Italian intergroup that has recently reported another large-scale randomised trial of adjuvant chemotherapy for colon cancer comparing FU levamisole vs FU LV levamisole (Di Costanzo et al, 2003). When the accrual of that first study was completed in February 1995, levamisole was still considered part of the standard adjuvant treatment. We postulated that our experimental arm in the first study was unlikely to be inferior to the standard arm and used that arm, FU LV levamisole, given for 6 months as control of the second study. The experimental arm was decided to be the sequential combination of methotrexate (MTX)-FU (Marsh et al, 1991) along with leva...

Methotrexate induces oxidative DNA damage and is selectively lethal to tumour cells with defects in the DNA mismatch repair gene MSH2

“…Methotrexate has been frequently used in the treatment of cancer and its low toxicity profile has led to efforts to derive further antifolates for cancer treatment (McGuire, 2003 ). In fact, methotrexate has already been trialed in colorectal cancer, in a sequential regimen with 5-FU (Sobrero et al, 2005 ). While this study determined that adjuvant sequential use of 5-FU and methotrexate results in similar outcome as the standard combination of 5-FU and leucovorin, the patient group studied was not stratified by MMR or MSH2 status and thus any selectivity of methotrexate for MSH2 deficient tumours would have gone unnoticed.…”

Real impact of oxaliplatin in adjuvant chemotherapy for patients with stage III colon cancer based on the Multi-Institutional Registry of Large Bowel Cancer in Japan

“…Postoperative adjuvant chemotherapy is given with the aim of killing any residual cancer cells to improve prognosis for cases in which R0 resection with curative intent was performed. Fluoropyrimidines and their biochemical modulation by leucovorin (LV) have been key drugs that are incorporated into treatment strategies for patients with advanced colorectal cancer at stage III and high-risk stage II (3)(4)(5). On the basis of results from the MOSAIC and XELOXA randomized trials, infused fluorouracil and LV with oxaliplatin (FOLFOX) and capecitabine with oxaliplatin (CapeOX) are widely used as standard postoperative adjuvant chemotherapies (6)(7)(8).…”