Pancreatic Cancer Recurrence: A Multidisciplinary Perspective

Pancreatic ductal adenocarcinoma (PDAC) recurrence remains one of the major challenges in PDAC management. Recurrence rates remain high, and a lack of effective treatment options is making routine surveillance after PDAC resection redundant. This thesis explores advancements in the diagnosis, treatment, and survival of PDAC recurrence from a multidisciplinary perspective. First, alternative randomized trial designs are introduced and evaluated in the context of surgical research. Following, Part I focusses on the surgical perspective, investigating the application of surveillance strategies and use of routine diagnostics after resection of PDAC. Part II delves into the oncological perspective, discussing the prediction and management of PDAC recurrence. Finally, Part III examines the radiotherapeutic perspective, with a particular emphasis on treatment of isolated local recurrence with SBRT.

There were several main findings. Surgery and systemic chemotherapy remain the cornerstones of primary PDAC treatment. However, postoperative complications significantly impact long-term outcomes by reducing the likelihood of patients receiving adjuvant chemotherapy. Initiatives aimed at enhancing preoperative conditioning though prehabilitation programs and minimizing (the impact of) postoperative complications have the potential to improve recovery and increase the likelihood of completing systemic therapy. Furthermore, neoadjuvant therapy is emerging as a promising alternative to adjuvant chemotherapy, ensuring the administration of systemic therapy regardless of surgical outcomes. Postoperatively, routine diagnostics are increasingly utilized. Combining routine imaging with emerging biomarkers, such as dynamic CA 19-9 monitoring and liquid biopsies, might offer a
more comprehensive approach to detect recurrence. However, extensive diagnostic workups will entail significant healthcare costs, necessitating further research to identify patients most likely to benefit. Such strategies must align with value-based healthcare principles to ensure efficient use of resources. Additionally, routine diagnostics can only improve outcomes if followed by effective treatment for PDAC recurrence. Advances in systemic and localized therapies hold promise for improving survival outcomes. However, further investigation is required to determine optimal systemic treatment strategies and to evaluate the efficacy and potential synergistic effects of localized treatments, such as radiotherapy, in combination with other systemic therapies, including immunotherapy. Finally, with these many future research directions, the complexity of conducting traditional randomized controlled trials poses significant barriers to the rapid implementation of new interventions. Alternative trial designs may provide practical solutions, although it remains essential to carefully select the most appropriate design for each research question.