Abstract: ackground: There is still debate regarding the principal role and ideal timing of perioperative chemotherapy (CTx) for patients with upfront resectable colorectal liver metastases (CRLM). This study assesses long-term oncological outcomes in patients receiving neoadjuvant CTx only versus those receiving neoadjuvant combined with adjuvant therapy (perioperative CTx). Methods: International multicentre retrospective analysis of patients with CRLM undergoing liver resection between 2010 and 2015. Characteristics and outcomes were compared before and after propensity score matching (PSM). Primary endpoints were long-term oncological outcomes, such as recurrence-free survival (RFS) and overall survival (OS). Furthermore, stratification by the tumour burden score (TBS) was applied. Results: Of 967 patients undergoing hepatectomy, 252 were analysed, with a median follow-up of 45 months. The unmatched comparison revealed a bias towards patients with neoadjuvant CTx presenting with more high-risk patients (p = 0.045) and experiencing increased postoperative complications ?Clavien-Dindo III (20.9% vs. 8%, p = 0.003). Multivariable analysis showed that perioperative CTx was associated with significantly improved RFS (hazard ratio [HR] 0.579, 95% confidence interval [CI] 0.420-0.800, p = 0.001) and OS (HR 0.579, 95% CI 0.403-0.834, p = 0.003). After PSM (n = 180 patients), the two groups were comparable regarding baseline characteristics. The perioperative CTx group presented with a significantly prolonged RFS (HR 0.53, 95% CI 0.37-0.76, p = 0.007) and OS (HR 0.58, 95% CI 0.38-0.87, p = 0.010) in both low and high TBS patients. Conclusions: When patients after resection of CRLM are able to tolerate additional postoperative CTx, a perioperative strategy demonstrates increased RFS and OS in comparison with neoadjuvant CTx only in both low and high-risk situations.

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