Future directions based on evaluation of long-term efficacy of total pancreatectomy and autologous islet transplantation

Chronic pancreatitis (CP) is a progressive inflammatory disease that results in irreversible destruction of pancreatic tissue, leading to impaired pancreatic exocrine and endocrine functions. As the disease progresses, pancreatic islets are affected by severe inflammation, and patients are at risk of developing diabetes. Furthermore, patients experience severe pain and seek therapeutic interventions; however, treatments such as pancreatic duct drainage or partial pancreatic resection may be ineffective or provide temporary improvement followed by exacerbation of symptoms (1). The quality of life (QOL) of these patients is significantly diminished compared to that of healthy individuals (2).

Total pancreatectomy (TP) remains the sole definitive method for long-term pain management; however, it invariably results in postoperative development of surgical insulin-dependent diabetes. This complication significantly affects the disease prognosis, with a minimum of approximately 20% of patients experiencing diabetic vascular complications (3). TP with islet autotransplantation (TP-IAT) is increasingly being recognized as an efficacious intervention for patients with CP who are refractory to conventional medical management (4). This combined approach offers a unique solution: eliminating the source of chronic pain through TP, while aiming to preserve some endogenous insulin production through the transplantation of the islet cells of the patient into the liver. The primary objectives of TP-IAT are to alleviate the incapacitating pain associated with CP and prevent the onset of brittle-type insulin-dependent diabetes through IAT. Initially performed in 1977 (5), TP-IAT was used to mitigate debilitating pain in patients afflicted with CP, yielding favorable outcomes in terms of reduced opioid requirements and enhanced QOL (6). Despite the necessity for advanced technical expertise in its implementation, TP-IAT has been increasingly adopted in North America, Europe, and Australia.

The assessment of TP-IAT indications presents significant challenges and necessitates comprehensive evaluation, considering the numerous surgery-associated risks, including hemorrhage, wound and intra-abdominal infections, anastomotic leaks, delayed gastric emptying, and portal vein thrombosis (7). Following TP-IAT, patients experience lifelong exocrine insufficiency, and the majority require permanent exogenous insulin supplementation even with IAT. There is a critical need for global recommendations to evaluate the efficacy of TP-IAT. Consequently, the TP-IAT Working Group, a component of the International Consensus Guidelines for Chronic Pancreatitis, has been established. Despite the limited available evidence, this working group has put forth several recommendations regarding TP-IAT indications and outcomes (8). Implementing TP-IAT can effectively decrease opioid use and severe pain, leading to significant improvements in QOL (9). TP-IAT is primarily recommended for debilitating pancreatitis-related pain, which diminishes QOL. However, it is contraindicated in patients with ongoing alcoholism, pancreatic cancer, end-stage systemic illness, and psychiatric or socioeconomic conditions that prevent safe surgical and postoperative care (8). Additionally, TP-IAT can provide superior glycemic control compared with TP alone (8). Transplanted islet mass is the most reliable predictor of islet graft function and insulin independence. The likelihood of achieving insulin independence post-TP-IAT is directly related to the transplanted islet yield (10). Factors that may negatively affect islet yield include prior pancreatic surgery, alcoholic pancreatitis, and advanced pancreatic disease with atrophy and calcification. The timing of TP-IAT is crucial because extended illness can adversely affect islet yield. While conditional agreement has been reached, the role of TP-IAT in all forms of CP remains unclear. Consequently, further research comparing TP-IAT with other treatment options, such as medical, endoscopic, or alternative surgical approaches, is necessary. Thus, TP-IAT may be considered an effective management strategy for carefully selected groups of patients with CP. Performing surgery early, before multiple endoscopic interventions and activation of neuropathic pain circuits, is likely to result in improved pain outcomes.

Longitudinal studies are essential to elucidate the long-term efficacy of these procedures in the years following surgery, thereby informing best practices and refining the criteria for patient selection. The recent publication by Pollard et al. in HepatoBiliary Surgery and Nutrition, “Assessment of long-term graft function following TP and autologous islet transplantation: The Leicester experience”, sheds important light on the long-term efficacy and viability of a complex but promising surgical approach for patients suffering from debilitating pancreatic disorders (11). This study provides critical insight into the outcomes of patients undergoing TP-IAT, a procedure with high potential to preserve glycemic function following complete removal of the pancreas.

Pollard et al. provided valuable data on the outcomes of TP-IAT based on a comprehensive cohort of patients treated at the Leicester Center, a leading institution for this procedure in the United Kingdom. In the “good response” group according to the modified Auto-Igls classification (12), all patients remained insulin-free for the initial 5 years and subsequently required minimal support (<10 units/day up to 10 years post-TP-IAT). Insulin requirements were <20 units/day in the “partial response” group and exceeded 20 units/day in the “poor response” group post-TP-IAT. Glycosylated hemoglobin (HbA1c) and oral glucose tolerance tests (OGTTs) were also evaluated, and superior outcomes were observed in the “good response” subgroup compared to the partial and “poor response” subgroups. These findings demonstrate that endogenous insulin production is preserved and can be observed for a minimum of 10 years following TP-IAT and are consistent with previous studies indicating that early metabolic status in TP-IAT is strongly correlated with subsequent diabetic outcomes (13).

Conversely, this study has limitations due to the substantial attrition of patients during follow-up, which introduces potential bias and compromises the reliability of the conclusions. Moreover, it omits an assessment of QOL, a critical endpoint for comprehending the broader impact of treatment on patients’ well-being. Furthermore, while the study reported 16 fatalities, it lacks sufficient detail regarding the causes or circumstances surrounding these deaths, thereby impeding a comprehensive interpretation of the implications for patient safety and treatment efficacy.

The findings from this study elucidate significant issues that remain to be addressed in TP-IAT. Despite numerous reports indicating that the success of autologous islet transplantation is contingent on the quality and quantity of harvested islet cells, this study did not demonstrate a clear correlation between islet yield and islet graft function. The limited number of patients available for long-term follow-up was a contributing factor impeding comprehensive evaluation; however, the findings suggest a high degree of inter-patient variability in graft function. Several factors including age, duration of pancreatitis, and preoperative metabolic state appear to influence graft function. This research suggests that accurately forecasting the long-term outcomes of TP-IAT is challenging, emphasizing the need for meticulous patient selection. TP-IAT is not suitable for all individuals suffering from CP, and determining which patients will benefit the most from this procedure remains a significant hurdle. Biomarkers of islet cell health, along with enhanced imaging techniques, could play a role in refining the patient selection criteria.

The primary consideration in patient selection was the feasibility of safely performing TP-IAT. Several health risks persist following TP-IAT, including diabetes, exocrine insufficiency, alterations in the gut anatomy and function, and asplenia. Mortality following TP-IAT has not been investigated extensively. Although some data on overall survival are available, the cause of death remains undetermined. Hooks et al. conducted a study to ascertain survival rates, causes of death after TP-IAT, and risk factors for mortality in the largest single-center population of TP-IAT patients. The overall survival rate was 93.1% at 5 years, 85.2% at 10 years, and 76.2% at 15 years after surgery, and 53 of 89 deaths were reported to be potentially related to TP-IAT. Causes include chronic gastrointestinal disease, malnutrition, diabetes, liver failure, and infection/sepsis. In the multivariate model, younger age, longer disease duration, and a more recent TP-IAT were associated with decreased mortality (14). In future research, it is imperative to consider long-term effects beyond the function of transplanted islets and to evaluate the indications for performing TP-IAT with optimal safety and efficacy.

As the long-term efficacy of TP-IAT becomes evident, expanding its indications beyond CP may be considered. Some centers suggest including patients undergoing pancreatectomy for reasons other than CP, such as pancreatic arteriovenous malformations and trauma. However, further investigation is necessary due to the limited number of cases studied. If these conditions require extensive pancreatic resection, IAT may be a viable treatment option. Expanding indications for neoplastic diseases must be approached cautiously, as neoplasms are generally contraindicated for IAT owing to potential malignant cell dissemination during islet infusion, which may contain some acinar and ductal cells even after purification. Pancreatic resection with IAT for neoplasms with low malignant potential, such as pancreatic neuroendocrine tumors, has been reported (15). Consequently, tumors with low malignant potential, such as intraductal papillary mucinous neoplasms, serous cystic neoplasms, pancreatic neuroendocrine tumors, metastatic tumors, and mucinous cystic neoplasms, may be considered for IAT in the future.

The investigation conducted by Pollard et al. constitutes a substantial advancement in elucidating the long-term effects of TP-IAT in individuals afflicted with severe pancreatic disease. Through delineation of both the efficacy and limitations of this therapeutic approach, as well as refinement of treatment indications, the global implementation of TP-IAT could be expanded. Their research establishes a foundation for subsequent investigations, potentially guiding clinicians towards an era in which individualized approaches to pancreatic surgery and transplantation may yield enhanced outcomes.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, HepatoBiliary Surgery and Nutrition. The article did not undergo external peer review.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-2024-648/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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