The Relationship Between Enzyme Supplementation and Clinical Outcomes Among Patients with Pancreatic Ductal Adenocarcinoma Undergoing Pancreatectomy Arany Uthayakumar, Vishaan Nursey, Manuel Beltran Del Rio PhD, Renee Cercone, Joel Stern PhD, and Horacio Rilo, MD Donald and Barbara Zucker School of Medicine at Hofstra/Northwell
Background Pancreatic ductal adenocarcinoma is the 12th most common cancer worldwide, and seventh leading cause of mortality due to cancer in both men and women. PDAC leads to 330,000 deaths every year. Pancreatic cancer’s toll is not just emotional, or physical–it also has a significant economic burden, particularly in a patient population that is predominantly older and under the coverage of Medicare (in the United States). Pancreatectomy, a surgery to remove all or part of the pancreas, is one procedure in the arsenal of treatments for Pancreatic Ductal Adenocarcinoma. It is a procedure that is also utilized to treat conditions such pancreatitis, or other forms of cancer, including pancreatic neuroendocrine tumors or metastasis of renal cell cancers. Normally, the pancreas’ exocrine function includes the secretion of critical digestive enzymes such as lipase, amylase, elastase, trypsin, and chemotrypsin into the duodenum. The release of these enzymes can be drastically decreased due to the adenocarcinoma itself, or the lack of pancreatic parenchyma following pancreatectomy, resulting in maldigestion and malabsorption that severely impact a patient’s quality of life. Pancreatic Enzyme replacement Therapy (PERT) is an established method of addressing exocrine insufficiency to restore digestive function and quality of life. Typically, these enzymes are administered via an enteric coated or non-enteric coated formulations; entericcoating serves to prevents the gastric-acid mediated denaturation of enzymes. The enzyme products used for PERT are derived from extracts of porcine pancreas, in formulations that vary fractions of amylase, protease, and lipase. Patients typically ingest these enzyme products at the same time as meals and snacks, so these medications can mimic endogenous pancreatic enzymatic function. Because the response of treatment varies widely from patient to patient based on factors such as size/fat content of meals, and degree of function and anatomy of any remaining pancreatic tissue, dosing is accordingly tailored. Side effects of PERT include irritation of the mouth locally, if the pancreatic extract capsules or crushed, chewed, or held in the oral cavity for too long. The efficacy of PERT is usually monitored by the alleviation of exocrine insufficiency symptoms, including improvements in the consistency of bowel movements, weight gain, and the loss of oily content in stool. The figures below are schematic diagrams illustrating what portions of the pancreas are removed in partial vs. total pancreatectomies (left: distal pancreatectomy, middle: Whipple procedure, right: total pancreatectomy)
Hypothesis
Conclusions Conclusions
Results 174 patients met study inclusion criteria; PERT data was available for 132 patients. 22 patients were treated with PERT, 110 were not. In patients deceased at the time of analysis, average years survival post-surgery was significantly higher among the PERT group (Fig 1, PERT: 2.52 years, non-PERT: 1.76 years; P value< 0.005). Overall survival rates were approximately 1.7 times higher in the PERT group (Fig 2, 9.1% vs. 5.45%). Long-term survival rates (5+ years) were nearly three times greater in PERT (13.6%) vs. non-PERT (5.45%) patients (Fig 3). PERT was prescribed almost identically between patients who presented with clinical malabsorption features (20.3%) and those who did not (16.7%; P-value> 0.95 ). Figure 1
Our results indicate that patients administered PERT enjoyed higher overall survival rates, and long term (5+ year) survival rates than those not given PERT. The data also found that pre-operative symptoms of malabsorption were not associated with higher rates of postoperative PERT administration. Despite the encouraging findings of our preliminary results, we acknowledge that there are definite limitations in our study. The most notable limitation is a lack of laboratory testing that assessed pancreatic exocrine function, including secretincaerulin testing, fecal elastase testing, fecal chymotrypsin testing, fecal fat quantification, 13C triglyceride breath testing, or secretin-stimulated MRI. This prevented us from being able to analyze the frequency of pancreatic exocrine insufficiency in the PDAC population, or the differences in how PERT was utilized between PDAC patients who experienced clinical malabsorption and those who did not. This lack of testing can be potentially be reasoned by the confusion that exists surrounding best diagnostic approaches to pancreatic exocrine insufficiency, as well as the diversity of guidelines regarding PERT dosing. This again underscores the need for not only widespread education, but also consensus on the overall diagnosis and treatment of exocrine insufficiency. The lack of exocrine function testing is not a unique challenge to our study; current literature has highlighted the disproportionate lack of testing in patients who are susceptible to exocrine insufficiency. Lack of testing is an issue that merits further attention because of the subsequent ways it shapes, or fails to shape patient care. There are several different etiologies to pancreatic exocrine insufficiency, and testing adds precision to the diagnostic workup, which in turn translates to a more targeted approach to a patient’s care. The benefits to patients in treatment and care should incentivize the medical field’s efforts to improve testing rates. Work to improve these testing rates might include a combination of education on the relevance and incidence of pancreatic exocrine insufficiency, consensus on diagnostic methods, as well as studies examining the cost-effectiveness of treatment.
Figure 2
Future Directions Figure 3
There is mixed data on the effects of PERT on increased survival, but PERT has remained an important part of patient care for its improvement of life quality. The goal of this current study was to shed more light on the impacts of PERT on patient survival after PDAC and to determine if certain pre-operative clinical features or symptomology were associated with higher post-operative PERT administration rates. We predicted that to this end, a retrospective chart analysis conducted on a sizeable patient population who underwent pancreatectomy as a treatment for PDAC would reveal positive trends associated with PERT administration and quality of life, and a negative trend between PERT administration and mortality.
It would be beneficial for future research to expand upon the low rates of PERT administration currently seen in this patient population, despite findings that have demonstrated a definite benefit in terms of quality of life and other factors. Additionally, it would be worth exploring how other indicators of malabsorption correlate with PERT administration, which we were not able to investigate further in this particular study.
Methods
Resources
The study was a retrospective chart review, collecting electronic health record data on PDAC patients 18+ years undergoing pancreatectomy between 2004-2016 at Northwell LIJ or NSUH. Data was deidentified and stored in REDcap. Mortality rates, and clinical malabsorption symptoms were used as primary endpoints to assess significant differences regarding clinical outcomes between the PERT and non-PERT cohorts. Microsoft excel was used for statistical analysis; P-value < 0.05 was considered statistically significant.
Preliminary results show PERT administration leads to improved overall and long-term survival rates (5+ year) in PDAC patients undergoing pancreatectomy. Based on these findings, we advocate for educating healthcare professionals on the importance of testing for pancreatic exocrine insufficiency, Figure Independent CRISPRa knockout of medical CDK4 or CDK6 as7:well as collecting thorough history that may also be indicative of pancreatic insufficiency. does not cause dropout in most breast cancer cell lines Exocrine insufficiency significantly impacts quality of life, and we encourage increased measures to studied. bring this aspect of patient care to the forefront of conversation surrounding PDAC and pancreatectomy, and how patients with these conditions can benefit from PERT. We also recommend educating healthcare professionals on correct PERT dosing to address confusion that prevails regarding dosing and administration. It is our strong belief that through the widespread dissemination of information surrounding PERT, the improvement of patient trajectories with PDAC can be maximized, and quality of lives greatly improved.
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