Systematic Review and Meta-Analysis of Current and Novel Approaches in the Management of Borderline Resectable and...

Background: Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related mortality with poor survival outcomes. Resection is the sole definitive management; however, most PDACs are diagnosed with unresectable disease including metastatic, locally advanced (LAPC) or borderline resectable (BRPC). Recently, neoadjuvant therapy has demonstrated potential in downstaging these tumours for resection. This literature review explores current and novel approaches in the management of BRPC and LAPC. Methods: A systematic search of Medline, Embase, Cochrane Central and Emcare databases was conducted on 7 April 2025. Inclusion criteria were primary articles that explored current and novel therapies that led to downstaging of BRPC and LAPC to resection, as well as resection outcomes and oncological outcomes associated with this. Articles that explored other pancreatic cancer subtypes or either resectable or metastatic disease were excluded. All meta-analyses were performed using a random-effects model based on the inverse variance method. Results: A total of 88 studies involving 8585 patients were included in the review, predominately from retrospective studies (57%, n = 50). Neoadjuvant regimens incorporating chemotherapy or radiotherapy, whether sequential or concurrent, demonstrated the highest proportions of R0 resections with N0 status. Overall, most modalities showed evidence of survival benefit following resection compared to non-operative management, with pooled differences demonstrated for chemotherapy alone (HR 0.33, 95% CI 0.25-0.44) and sequential chemotherapy and radiotherapy (HR 0.49, 95% CI 0.25-0.95). However, no significant differences between these modalities were demonstrated. Other modality-specific conclusions regarding survival benefit could not be elucidated. Conclusions: The rising incidence and global mortality from PDAC underscore the significance of identifying approaches to optimise the management of BRPC and LAPC. This review emphasises the importance of neoadjuvant therapy, both current and novel with surgical resection, which may warrant further investigation in future clinical trials. However, it is important to acknowledge the clinical heterogeneity of current data, which may introduce bias. Nevertheless, these findings can help to inform guidelines on the management of BRPC and LAPC.