Assessing clinical implications and immunomodulatory changes following liver resection using RF-based device in liver cancer

Liver cancer is an aggressive tumour and often presents late during the natural course of progression. In spite of advancements in the medical sciences, liver cancer has still remained recalcitrant to treatment. The exclusive treatment approach with curative intents is the resection of hepatic tumour if the disease gets diagnosed in an early stage. Nonetheless, better survival has also been observed following surgical resection in advanced stages, particularly for those who were not found to be apt for other treatment options by virtue of the extent of disease. The main purpose of surgical resections is to achieve complete oncological clearance; however, despite all endeavours, only 10-15% of newly diagnosed patients get a surgical resection. Additionally, in the case of hepatocellular carcinoma micro-metastasis beyond tumour margin and satellitosis are important attributes influencing the patient survival following resection. Five-year recurrence of up to 70% has been reported following curative resection with observed 5-year survival between 47% to 53% for early and small size tumours (<3 cm). Insofar, various kinds of hepatic resection devices have been evolved to facilitate hepatic tumour resection and are compared with the gold standard methodology of hepatic resection, the clamp-crush (CC) technique. The notable factors outlined in the literature that influence post-hepatic tumour resection outcomes are negatively influenced by the amount of bleeding, higher requirement for blood transfusions, bile leak and hepatic insufficiency. However, the questions as to the clinical benefits of one device over another in terms of minimal blood loss, reduction in transfusion requirement and postoperative complications and survival remain unanswered. The first paper in the index thesis includes a single-arm study assessing clinical outcomes following radiofrequency (RF) based liver resection and has been comparing it with the existing literature. The findings of the data analysis supports that RF-based device is a suitable and safe device for bloodless hepatic resection with acceptable perioperative morbidity and mortality when compared with contemporary literature. However, findings were limited from being a retrospective single centre study with no comparative group. Thus, a meta-analysis has been performed to evaluate RF-based liver resection device in comparison to the standard technique CC. The findings included lower blood loss with fewer patients requiring blood transfusion when hepatic resection was performed with RF-based devices with equivalent morbidity and mortality. The third study was to compare two contemporary liver resection devices. Here, retrospective data analysis was done to determine the survival benefits and other perioperative outcomes following liver resection through a direct comparison of RF-based device with Cavitron Ultrasonic Surgical Aspirator (CUSA). The study has demonstrated significant improvement in disease free survival and tumour recurrence have been reported with the RF-based device. Alongside, a significant reduction in all other parameters, including blood loss, blood transfusion and need for inflow occlusion during liver resection surgeries with the RF-based device as compared to CUSA. 13 The survival benefits observed following resection of hepatic tumour with RF-based device might be owing to the reinstatement of anti-tumour immune response following the application of RF energy. The assumption has been derived through the analysis of recent publications that demonstrated immunological changes following application of RF energy over hepatic tumour nodules. In order to prove this assumption, a fourth study was undertaken to understand changes in the serum inflammatory [neutrophil-lymphocyte-ration (NLR) and platelet-lymphocyte-ration (PLR)] and immunological parameters following radiofrequency ablation (RFA) or non RF-based liver resection. The study highlighted that a decrease in NLR, PLR and CD39+CD4+ T cells expression not only reciprocates with systemic inflammation and anti-tumour immune status but also act as an explicit marker for improved survival in liver cancer patients. The final study was performed to assess the changes in pre and post-liver resection levels of immunological parameters (cellular subtypes and cytokines) comparing the RF-based liver resection device with CUSA. Here significant changes in anti-tumour immune cells and cytokine levels were observed following liver resection with RF-based device and together with the analysis of contemporary literature revealed its favourable implications on survival and recurrences. Taken together, the above findings are suggestive of the need for modification in the current practice and incorporation of RF-based liver resection as the primary surgical technique for the management of very early and early HCC cancers. Moreover, the proof of concept suggests that positive immunomodulatory changes observed following RF-based liver resection can enhance the activity of checkpoint inhibitors. Hence, the synergism of RF-based liver resection along with checkpoint inhibitors does not only remove tumour tissue but also helps in re-establishing anti-tumour immunity which might further aid in improving survival and preventing recurrences. Future studies are required to better understand the applicability of RF-based liver resection with checkpoint inhibitors in liver cancers.