Efficacy and safety of high-dose vs low-dose leucovorin in patients with colorectal cancer: systematic review and meta-analysis

Aim: The clinical benefits of a combination of leucovorin and fluorouracil have been established in the treatment of colorectal cancer. Due to a leucovorin shortage in 2008, many institutions revised their protocols to reduce the dose of leucovorin. After the shortage was resolved, some hospitals still maintained their modified protocols. Thus, we conducted a systematic review to evaluate the efficacy and safety of low- vs high-dose leucovorin in the treatment of colorectal cancer. Method: The PubMed, Embase and Cochrane databases were searched for studies published before May 2019. The meta-analysis was performed to estimate the pooled effect sizes by using a random effect model. The primary outcomes were median survival time and tumour response rate. Secondary outcomes were haematological and nonhaematological toxicities. Results: Eight randomized controlled trials and four retrospective studies were reviewed. The pooled median survival time was similar between the two dose levels (standard mean difference −0.06, 95% CI −0.19 to 0.08). The pooled tumour response rate was comparatively higher in the high-dose leucovorin regimen (OR 0.81; 95% CI 0.55–1.18). No statistically significant difference was found between the haematological and nonhaematological toxicities of the two groups. However, there were fewer diarrhoea events in the low-dose leucovorin regimen. Conclusion: Low-dose leucovorin regimens seemed feasible approaches for colorectal cancer treatment when the shortage happened, because both regimens manifested comparable outcomes in survival time and tumour response rate.