The Role of Neoadjuvant Chemotherapy in Repeat Local Treatment of Recurrent Colorectal Liver Metastases: A Systematic Review and Meta-Analysis

SIMPLE SUMMARY: Up to 85% of patients with colorectal liver metastases develop distant intrahepatic recurrence after curative intent local treatment. (Inter)national guidelines and scientific societies consider repeat local treatment, comprising repeat thermal ablation and/or repeat resection, the standard of care to treat recurrent new colorectal liver metastases. This systematic review and meta-analysis assessed the potential additive value of neoadjuvant chemotherapy before repeat local treatment. The addition of neoadjuvant chemotherapy prior to repeat local treatment was suggested by merely all authors, though supporting evidence is lacking. The results do not substantiate the routine use of neoadjuvant chemotherapy. We are currently constructing a phase III randomized controlled trial directly comparing upfront repeat local treatment with neoadjuvant chemotherapy followed by repeat local treatment (COLLISION RELAPSE trial). ABSTRACT: The additive value of neoadjuvant chemotherapy (NAC) prior to repeat local treatment of patients with recurrent colorectal liver metastases (CRLM) is unclear. A systematic search was performed in PubMed, Embase, Web of Science, and an additional search in Google Scholar to find articles comparing repeat local treatment by partial hepatectomy and/or thermal ablation with versus without NAC. The search included randomized trials and comparative observational studies with univariate/multivariate analysis and/or matching as well as (inter)national guidelines assessed using the AGREE II instrument. The search identified 21,832 records; 172 were selected for full-text review; 20 were included: 20 comparative observational studies were evaluated. Literature to evaluate the additive value of NAC prior to repeat local treatment was limited. Outcomes of NAC were often reported as subgroup analyses and reporting of results was frequently unclear. Assessment of the seven studies that qualified for inclusion in the meta-analysis showed conflicting results. Only one study reported a significant difference in overall survival (OS) favoring NAC prior to repeat local treatment. However, further analysis revealed a high risk for residual bias, because only a selected group of chemo-responders qualified for repeat local treatment, disregarding the non-responders who did not qualify. All guidelines that specifically mention recurrent disease (3/3) recommend repeat local treatment; none provide recommendations about the role of NAC. The inconclusive findings of this meta-analysis do not support recommendations to routinely favor NAC prior to repeat local treatment. This emphasizes the need to investigate the additive value of NAC prior to repeat local treatment of patients with recurrent CRLM in a future phase 3 randomized controlled trial (RCT).