A multi-centre randomised controlled trial comparing intensive treatment of pancreatic endocrine and exocrine dysfunction versus standard care in individuals with unresectable pancreatic cancer 

Background

Pancreatic cancer, of which pancreatic ductal adenocarcinoma (PDAC) is the main type, is a dismal cancer with an overall 5-year survival of 10-12%. For the majority of patients, unfortunately their disease is detected too late for surgery with curative intent and they are offered either palliative chemotherapy or best supportive palliative care. Ensuring patients have the best quality of life in this period is of paramount importance.

The pancreas has a dual role – endocrine and exocrine function. It produces hormones that control glucose regulation and enzymes that are required for the digestion of food. PDAC causes dysregulation of both of these functions. Pancreatic enzyme replacement therapy (PERT) had long been recognised as a treatment to control symptoms of pancreatic enzyme insufficiency (PEI) in PDAC. Indeed, it has been suggested that good PERT therapy can extend life as much as palliative chemotherapy. The importance of glucose dysregulation and diabetes mellitus in PDAC and the relationship between endocrine and exocrine dysfunction has recently been recognised.

Care during the last months of life must be patient centred and a balance between managing symptoms, alleviating suffering, but not be too burdensome on the patient and their caregivers. It is not clear how much management of endocrine and exocrine dysfunction in patients with unresectable PDAC improves quality of life for these individuals.

Aims

Primary Aim

To determine if a package of treatments for endocrine and exocrine dysfunction in unresectable PDAC vs normal care improves overall quality of life.

Secondary Aims

To determine

·   The incidence of PDAC-related diabetes mellitus and glucose dysregulation in patients with unresectable PDAC

·   If a package of treatments for endocrine and exocrine dysfunction in unresectable PDAC impacts overall survival

Translational Aims

·   To provide bioresources to further the study of the pathophysiology of pancreatic cancer-related diabetes mellitus in unresectable PDAC.

·   To provide bioresources to further the study of the pathophysiology of pancreatic enzyme insufficiency in unresectable PDAC.

Baseline and translational sample collection

The participant will be interviewed and notes reviewed at their baseline visit. In sites randomised to the treatment arm, HbA1c and random plasma glucose to determine diabetes status will be taken. If HbA1c is >48mmol/mol they will be referred urgently to a local diabetes service. Treatment will be as per local practice, but the study team recommend insulin as the first line therapy. They will also be started on a standard dose of PERT. If this is normal practice for the research site then this should also occur in the non-treatment arm, but sites should not start this if it was not usual for them prior to the study.

Assessments

Participants will be followed up every 3 months for 1 year (3, 6, 9, 12 months). They will have normal blood measurements taken, if this is standard practice, in both arms. In the treatment arm sites they will have HbA1c and random plasma glucose measured and treatment adjusted according to local practices by an expert in diabetes management (clinician or diabetes specialist nurse). PERT will be adjusted by a dietitian according to symptoms. Other aspects of care, such as nutrition, nausea, bowel and pain management should be as per the treating team’s discretion. Corticosteroids can be used thought the study if deemed appropriate by the treating team. They will be asked to complete the PEI-Q and IPOS questionnaires as well as the follow up CRF.

2-year outcomes

Follow up for participants will finish at 1 year. At this point, care should continue as the treating clinical team feels is suitable. At 2 years, we will ask sites to report if patients are dead or alive, to determine overall 2-year survival.

A translational multicentre observational cohort study to understanding the immunological and microbiome mechanisms of postoperative pancreatic fistula

Background

Pancreatic cancer is a deadly disease with a 5-year survival of 10-12%. Currently, the only chance of cure is through surgery with adjuvant chemotherapy. Surgery for pancreatic cancer is high risk. The two most common operations include distal pancreatectomy and partial pancreatoduodenectomy (Whipples procedure). During the Whipples procedure, the duodenum, head of pancreas, bile duct and first part of the small bowel are removed, and the remaining pancreas, bile duct and stomach are anastomosed. The most feared and serious complication of this surgery is an anastomotic leak from the pancreatojejunostomy (postoperative pancreatic fistula; POPF).  This occurs in up to 40% of individuals and can range from having minimal impact on the postoperative course (Type A) to sepsis (Type B), life threatening haemorrhage and death (Type C). Currently, our ability to mitigate and treat POPF is poor, with few evidence-based treatments available. Management consists of drainage of collections and treating complications if they occur. Fistula reduction treatments such as somatostatin analogues have limited evidence that these are effective. Thus, a greater understanding of the molecular pathophysiology is urgently needed to guide the development of novel strategies to reduce the incidence and severity of POPF.

Our current knowledge of POPF is based mainly on clinical observational data. Most research is focussed on risk prediction scores. We know that duct size (small, less than 3mm) and pancreatic texture (soft) increase the risk of POPF. There are also numerous risk prediction models based on pre- and intraoperative variables. However, none of these scores allow for different treatment strategies to be implemented. There are a number of surgical techniques to perform the pancreatojejunostomy anastomosis. The largest randomised clinical trial comparing two of these techniques (PANasta) showed that in a trial setting, neither techniques reduced the incidence of POPF. Recent work has moved to try and understand, therefore, the causes of POPF on a molecular level. Most of these studies include small sample sizes and focus on either circulating or drain levels of cytokines, suggesting a local inflammatory response may be important.

Colorectal cancer surgery also involves an anastomosis between the remaining sections of bowel. Anastomotic leak here is also a feared complication, although in colorectal surgery treatment can include stoma formation if a leak occurs. There is emerging evidence in colorectal surgery that the gut microbiome may play an important role in the development of anastomotic leak and that local bacteria may influence the healing process, particularly through the interaction between matrix metalloproteases (MMPs) and collagenase producing bacteria. The application of this to pancreatic surgery has never been studied. Understanding the immunological and microbiome influences may allow the development of future strategies to target this preoperatively through medication or nutrition to reduce the risk of POPF.

Aims

1.     Determine if POPF development if related to differences in background pancreatic microbiome

2. Determine if circulating or drain immunological markers can be used to predict development and severity of POPF.

Methods

Design

This would be a multi-centre observational cohort study of individuals undergoing Whipples procedures for all causes with translational sample collection. Operative technique and perioperative management would be as per the institutional preference, including use of somatostatin analogues.

         Data Collection

   Clinical Data

Standard demographic data, pathological outcomes, baseline comorbidity (especially diabetes state with preoperative HbA1c and smoking status) would be collected. Institutional perioperative care practice would be collected. Standardized 30-day outcomes would be collected according to ISGPS definitions.

   Biological Samples

Standard preoperative blood tests would be recorded, including a blood sample for research purposes to measure circulating immune markers. A sample of faeces to measure preoperative microbiome will also be taken and snap frozen. Research blood and drain samples will be taken on days 1-5 to observe changes in immune markers. Normal postoperative measurements including serum and drain amylase will be recorded from patient records. A slice of the pancreatic transection margin and a sample of jejunal fluid prior to anastomosis will be taken and snap frozen for microbiome analysis.

Outcomes

The primary outcome would be the development of a microbiome and immune signature that can determine increased risk of POPF development.

The secondary outcome would include the development of a postoperative biomarker to allow prediction of POPF development, utilising clinical and blood based biochemical and immune markers.