Consortium for the Study of Chronic Pancreatitis, Diabetes, and Pancreatic Cancer (CPDPC): Achievements and Future directions.

Abstract

Purpose of Review:

To answer several important clinical questions, the CPDPC research consortium has established several ongoing clinical cohort studies focused on pancreatitis in adults and children, pancreatic cancer, and diabetes associated with pancreatic disease. These will provide a unique resource for clinical and basic science research into these hard to treat disease.

Recent Findings:

The etiology, natural history and prognosis of acute relapsing and chronic pancreatitis in adults and children is being delineated. The mechanisms of diabetes associated with chronic pancreatitis, acute pancreatitis, and pancreatic cancer is being defined. The ability to predict the presence of early stage pancreatic cancer, thought the presence of new onset diabetes, is being explored as a strategy to improve survival. The CPDPC is now also turning to developing clinically useful biomarkers, and initiating clinical trials in these difficult to treat pancreatic diseases.

Summary:

These large prospective patient cohorts, established and followed up by the CPDPC, provide a unique resource to improve the care of patients of all ages with pancreatitis, and to allow earlier diagnosis of pancreatic cancer.

Introduction:

The Consortium for the study of Chronic Pancreatitis, Diabetes, and Pancreatic Cancer (CPDPC) was conceptualized and established by two of the institutes of the National Institutes of Health, the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and the National Cancer Institute (NCI). CPDPC was launched in September 2015. The CPDPC was formed because there was an appreciation at NIDDK and NCI that pancreatic diseases, and risk factors for pancreatic cancer, needed to be examined within the domain of clinical studies (1,2). Also, because of the lack of progress in pancreatic cancer, grass roots efforts to improve outcomes in pancreatic cancer patients led to the Recalcitrant Cancer Act passed by the US Congress in 2012, and signed by President Obama in 2013. There was general agreement that only large-scale human studies could delineate the complex relationships between inflammatory pancreatitis, diabetes and pancreatic cancer, and that mechanistic studies were needed considering that diabetes acts both as a risk factor, a consequence, and an early clinical marker of pancreatic cancer. The lack of progress, both in pancreatitis and pancreatic cancer, and their bidirectional relationship to diabetes indicated that new strategies utilizing clinical consortia were needed to make progress in these diseases.

The overriding objective of the CPDPC is to provide a platform for clinical and translational studies to understand the complex relationships between pancreatitis, diabetes, and pancreatic cancer. The first cycle of CPDPC funding was focused on the establishment and follow-up of large cohorts of well characterized patients with, or at risk of, these pancreatic diseases, supplemented by a broad range of carefully annotated biospecimens. These cohorts, once fully recruited and followed, can support studies on basic mechanisms, natural history, early detection and diagnosis, prognosis, prevention, and more effective treatment. These cohorts will provide a unique and powerful tool to answer many of these important clinical questions. Some of the ongoing work of the CPDPC is described in this issue of Current Opinion in Gastroenterology. We would like to highlight some noteworthy current accomplishments, and to describe the ongoing and future plans of the CPDPC.

Achievements of the CPDPC

One of the major goals of the CPDPC was to design studies to improve our knowledge of the mechanisms and natural history of acute relapsing and chronic pancreatitis in adults and children. Our current understanding of these conditions is quite limited; and our therapeutic options are sparse. We do not have accurate tools to predict the natural history of these conditions; effective treatments to delay or prevent progression; or effective treatment for the often intractable symptoms.

Our Adult Chronic Pancreatitis Working Group and Pediatric Chronic Pancreatitis Working Group have established two major longitudinal major studies to address this lack of effective options. The Prospective Evaluation of Chronic Pancreatitis for Epidemiologic and Translational Studies (PROCEED) cohort has already recruited approximately 80% of an 1800-person prospective cohort, including adult patients with acute pancreatitis, acute recurrent pancreatitis, indeterminate chronic pancreatitis, established chronic pancreatitis, and controls (3).

The International Study Group of Pediatric Pancreatitis: In Search of a Cure (INSPPIRE and INSPPIRE-2) cohort has also recruited approximately 80% of a planned 860-person prospective cohort, including children with acute relapsing and chronic pancreatitis (4). Both cohorts can provide a longitudinal assessment of natural history and prognosis, determine the risk factors for progression, develop diagnostic, prognostic, and therapeutic biomarkers, and finally provide a platform for mechanistic and therapeutic clinical studies. It cannot be overstated how important these unique cohort studies will be in developing preventative therapies, slowing progression and complications, and identifying effective therapies.

The PROCEED study, and the investigators of the Adult Chronic Pancreatitis Working Group which oversee it, developed a set of highly-detailed standard operating procedures for the collection and preservation of biologic specimens for future analysis (5). No such reference existed, and this work is essential for progress in the field, and is already being used as a model for other research consortia. Identification of any biomarker will require this standardized and reproducible specimen processing and storage. The Working Group also developed new standards for reporting of imaging studies in chronic pancreatitis, setting the stage for imaging features to be harmonized and developed into a reproducible method for staging, monitoring of progression, and early diagnosis (6). Additionally, the Working Group reviewed the entire medical literature on biomarkers studies in chronic pancreatitis, work which will inform the next steps as the biosamples we have collected are analyzed (7).

The INSPPIRE study, and the investigators of the Pediatric Chronic Pancreatitis Working Group have developed a highly-functional international consortium to study pediatric pancreatitis (4). Numerous important clinical observations have already come forward through this work, including an understanding of the oversized role of genetics in causing pediatric pancreatitis (8), large variations in clinical management of these patients (9), the burden of pancreatitis in children (8), the development of non-opioid approaches to treat chronic pancreatitis pain (10), and the best approach to transition these patients as they become adults.

Another primary goal of the CPDPC is to understand the complex relationships between diabetes and benign and malignant pancreatic diseases. Diabetes is a risk factor for acute and chronic pancreatitis (11), and a risk factor for pancreatic cancer (11, 12). Acute and chronic pancreatitis can cause diabetes (11), a variant termed pancreatogenic or Type 3c diabetes. Pancreatic cancer may also cause diabetes through an apparent para-neoplastic process and may do so at a point where the cancer is otherwise asymptomatic and at a potentially curable stage (12). The complexities of these relationships are outlined in other articles in this issue. It is worth pointing out here that a cross-sectional cohort of patients with chronic pancreatitis and pancreatic cancer who have coexistent diabetes is being studied within the CPDPC, with the detailed metabolic profiling of a mixed meal test, to identify biomarkers that differentiate typical forms of diabetes (Type 2) from pancreatogenic diabetes due to pancreatitis, or pancreatic cancer. The Evaluation of a Mixed Meal Test for Diagnosis and Characterization of Pancreatogenic Diabetes Mellitus Secondary to Pancreatic Cancer and Chronic Pancreatitis (DETECT) cohort, initiated and managed by the Type 3c Diabetes Working Group, will allow these biomarkers to be developed. This could allow clinicians to identify diabetes as a consequence rather that a cause of pancreatic disease, with significant clinical benefit as this information can guide therapy and potentially allow earlier detection of pancreatic cancer.

This ability to differentiate these types of diabetes is an essential underpinning of a major effort of the CPDPC, to leverage the fact that early stage, otherwise asymptomatic, and potentially curable pancreatic cancer may cause diabetes. This new onset diabetes is the focus of the New Onset Diabetes cohort (NOD) developed by the Diabetes and Pancreatic Ductal Adenocarcinoma (DM-PDAC) Working Group. The NOD cohort study is an ambitious undertaking, recognizing that 1–2% of individuals developing diabetes after age 50 have underlying PDAC (12, 13). This cohort is utilizing the resources of not only the CPDPC but several other institutions, practices, consortia, and patient advocacy groups. The goal of the NOD study is to recruit up to 10,000 individuals above the age of 50 with new onset of laboratory evidence of diabetes, to obtain biospecimens, and to follow them for the subsequent diagnosis of pancreatic malignancy, and 1000 subjects have already been recruited. Within this cohort, 100–200 individuals will be diagnosed with pancreatic cancer, and the biospecimens will provide an unmatched resource in which to identify early markers of potentially curable pancreatic cancer. A cohort of this size will take the resources of this entire team. The potential benefits are profound, developing strategies for early detection of a highly lethal and increasingly common malignancy.

The Combined Power of Patients and Investigators in the CPDPC Consortium can Improve Outcomes in Pancreatic Diseases.

The large number of clinically deeply phenotyped patients in the longitudinal cohorts of CPDPC now provides an extraordinary opportunity to conduct biomarker discovery and validation, and interventional trials, to markedly enhance treatments and improve outcomes. Some key examples are listed here. Of note, these studies are carried out as ancillary studies to the cohorts of patients described above.

1. Prevent recurrent episodes of acute pancreatitis and progression to chronic pancreatitis, with complications of exocrine and endocrine insufficiency, as well as increased risk for pancreatic cancer in both children and adults.

2. Identify more effective therapy for the often-intractable pain of chronic pancreatitis and for its complications of exocrine pancreatic insufficiency and diabetes.

3. Identify individuals with a high risk for pancreatic cancer for monitoring with the development of biomarker tests and high-resolution imaging for early diagnosis to result in improved outcomes; and develop interventions to prevent and intercept early lesions to prevent development into advanced cancer.

The power of CPDPC’s ability to improve outcomes lies in the large number of patients in the longitudinal cohort studies recruited across several centers and cities in the United States and the multidisciplinary expert members of CPDPC. Some key observations have demonstrated why this combination is necessary to make progress in addressing key unmet needs as listed above. As an example, not all patients with recurrent acute and chronic pancreatitis have the same underlying causes and pathophysiology of pancreatitis. Recent studies show that a majority of children with recurrent acute or chronic pancreatitis have underlying genetic findings that likely underlie the disease mechanisms (14, 15). In contrast, genetic causes are less common in adults where alcohol, smoking, dyslipidemia are commonly associated (16,17). Moreover, recent studies show fibro-inflammatory process differences in patient groups and etiologies (18). For example, lymphocytes predominate the fibro-inflammatory milieu of the pancreas of patients with hereditary pancreatitis while macrophages predominate the fibro-inflammatory response of the pancreas in patients with idiopathic pancreatitis (18). These observations, and many similar insights, can be clinically validated through the patients and biospecimens within the CPDPC cohorts, utilizing the variable and broad-based expertise of the CPDPC investigators and their colleagues. Not only do we have to consider phenotypic and genotypic subsets of patients, we have to appreciate different stages of the disease that occur over time in an individual. For example, it is unlikely that therapies developed for recurrent acute and early chronic pancreatitis will be effective in late chronic pancreatitis with extensive fibrosis with exocrine and endocrine deficiency. These variables in the disease states are applicable across several therapies whether they are endoscopic and surgical interventions; cognitive behavioral therapies to improve pain and quality of life; or medications for fibro-inflammatory process, pain, or endocrine/exocrine insufficiency. The ability of the Consortium to recruit high-risk patients for pancreatic cancer into longitudinal cohorts, for developing methods of early diagnosis or for interventions to improve outcomes, also depends on the large number of recruited subjects and the strength of investigators and their multidisciplinary makeup.

This discussion emphasizes the importance of the need for talented investigators across a number of scientific disciplines to make progress in these complex diseases. These include experts in clinical trials and their design, epidemiology, biomarker discovery and validation, imaging methodology, genetics, immunology, and gut microbiome. Furthermore, study coordination, data management and data analysis including advanced methodologies in artificial intelligence will be needed to support these efforts.

The CPDPC is evolving to allow a robust platform to advance its ability to address key objectives in pancreatic diseases. Figure 1 represents our interventional trials platform. In addition to our current structure of Working Groups and Committees, we are establishing a Clinical Trials Unit and supporting Analytical Cores to help define outcomes and measures for clinical trials. These Analytical Cores, including genetics, biomarker validation, radiomics, and immunology will support standardized measures and outcomes for clinical interventional trials in these pancreatic diseases. A new era is truly dawning in the effective treatment and slowing of progression of pancreatitis, and of the potential early detection of treatable pancreatic cancer. The CPDPC, and similar consortia, represent an important step forward for our current and future patients.

• The clinical cohorts being recruited by the CPDPC research consortium will proved a unique platform to define the etiology, mechanisms, natural history, and prognosis of adult and pediatric patients with acute relapsing and chronic pancreatitis.

• The interactions of diabetes, pancreatitis, and pancreatic cancer being investigated by the CPDPC will help identify diagnostic and prognostic biomarkers, focused on early stage diagnosis of pancreatic malignancy at a treatable stage and improved management of pancreatitis.

• The CPDPC investigators and structure will facilitate the development of interventional therapeutic trials in acute relapsing and chronic pancreatitis, and in pancreatic adenocarcinoma.

Figure 1. Platform for Interventional Trials in CPDPC.

The focus of the platform is the design and performance of interventional trials. The trials are conceived by the Working Groups. Important in trial design will be phenotypic and genotypic profiling of subjects both for the purposes of inclusion in a trial and measuring outcomes associated with the profiling. The CPDPC Coordinating and Data Management Center (CDMC) assists in data management, biospecimen tracking and data integration/analysis as well as assisting in trial design. Finally, Analytic Cores with expertise in measurement methodology are used for phenotypic, genotypic and outcome measures. This figure was constructed by Philip Hart, MD.