A Prospective Study to Establish a New-Onset Hyperglycemia and Diabetes Cohort (NOD)
Research Study | NOD
CPDPC16-01 | NOD
Protocol:
Protocol:
Background and Significance
Among the most compelling needs to impact the dismal mortality associated with PDAC cases today is a rational, evidence-based strategy to detect the cancer at an early stage when it is still resectable, thereby permitting therapeutic options that result in long-term survival. Greater than 90% of PDAC is sporadic (i.e. not arising in high-risk cohorts of patients with an underlying germline mutation), and 85% of such sporadic PDAC patients present at an advanced stage, rapidly progressing to death.1 Some of the principal challenges to developing an early detection program for sporadic PDAC are the lack of an ascertainable high-risk group for sporadic PDAC; limited availability of high-quality bio-specimens from pre-symptomatic cancer patients for study of biomarkers; a dearth of sensitive and specific biomarkers of early PDAC; and the inability of conventional imaging (and absence of novel imaging techniques) to identify early PDAC.1
A high-risk group for sporadic PDAC has been identified as subjects ≥50 years old who have newly developed diabetes mellitus (NOD).2 Chari and colleagues first described in a retrospective population-based study of 2122 NOD subjects, 18 (0.85%) were diagnosed with PDAC within 3 years of meeting criteria for NOD,3 resulting in a 6-8-fold higher risk for PDAC than general population.3, 4 Small prospective screening studies for PDAC in NOD have also shown a 3-10% prevalence of PDAC in NOD.5-7 Conversely, ~25% of PDAC patients develop NOD between 6 and 24 months prior to cancer diagnosis.8 A recent study showed hyperglycemia precedes PDAC diagnosis by ~36 months, providing a possible window of opportunity for the early detection of pancreatic cancer in new-onset diabetes patients.9 The National Cancer Institute (NCI) has acknowledged that studying the relationship between DM and PDAC is one of the highest research priorities in PDAC research.10 To respond to the challenges posed by early detection of sporadic PDAC, we developed the following research aims.
Specific Aims
We will prospectively develop a cohort of 10,000 subjects’ age ≥50 and ≤85 years with NOD to:
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Estimate the probability of PDAC in the NOD Cohort,
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Establish a biobank of clinically annotated bio-specimens including a reference set of bio-specimens from pre-symptomatic PDAC and controls new-onset type 2 DM,
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Conduct Phase 3 validation studies11 of promising biomarkers for identification of occult PDAC in NOD patients and,
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Provide a platform for the development of a future interventional screening protocol for early detection of PDAC in NOD patients that also incorporates imaging studies and clinical algorithms.
One key to accurately estimating the risk of harboring an occult PDAC in patients with NOD is to identify DM within a short time frame from first meeting biochemical criteria (defined as <90 days). In a pilot study at Mayo Clinic Rochester, investigators have been able to successfully identify incident DM subjects using surveillance of electronic databases and focused chart review (Examination of the Pancreas in New-onset Diabetes [EXPAND] trial; NCT0200133).
Rationale for NOD as a High-risk Group
The primary aim of NOD study is to estimate the incidence of PDAC in subjects with NOD. Based on previously published data, it is estimated that in the NOD cohort as defined, approximately 85 cases of incident PDAC will be diagnosed during the three years of study follow-up after meeting NOD study criteria, assuming the 1-year, 2-year, and 3-year cumulative incidence rate of PDAC is 0.63%, 0.73%, and 0.85%, respectively.12, 13 If diabetes in the study subjects is not due to a manifestation of occult PDAC, then the incidence rate of PDAC should be similar to the risk in the general population which is about 0.04% per patient year. Conservatively, we use 0.1%, 0.2%, and 0.3% for 1-year, 2-year, and 3-year cumulative risk, respectively, as null hypotheses. We will reject the null hypothesis of no association between NOD and PDAC if, one of the three observed proportions is significantly higher than the null hypothesis value, using an exact binomial test at a 2-sided nominal level 0.05/3. The power will be >90% to reject the null hypothesis if the true 1-year, 2-year, and 3-year cumulative incidence rate is at least 0.43%, 0.64%, and 0.85%, respectively, i.e. 50%, 75%, and 100% of underlying PDACs will be clinically diagnosed during 1-year, 2-year, and 3-year since baseline.
Objective:
Objective:
Anirban Maitra, MBBS, Ayush Sharma, MBBS, Randall E. Brand, MD, Stephen K. Van Den Eeden, PhD, William E. Fisher, MD, Phil A. Hart, MD, Steven J. Hughes, MD, Kieren J. Mather, MD, Stephen J. Pandol, MD, Walter G. Park, MD, Ziding Feng, PhD, Jose Serrano, MD PhD, Jo Ann Rinaudo, PhD, Sudhir Srivastava, PhD MPH, and Suresh T. Chari, MD, Consortium for the Study of Chronic Pancreatitis, Diabetes, and Pancreatic Cancer (CPDPC)
Authors:
Authors:
David P. Bradley. MD
Member Organization
Member Type/Role/Title
Members:
The National Cancer Institute and the National Institute for Diabetes and Digestive and Kidney Diseases initiated the Consortium for the study of Chronic Pancreatitis, Diabetes, and Pancreatic Cancer (CPDPC) in 2015 (the CPDPC’s origin, structure, governance and research objectives are described in another article in this journal). One of the key objectives of CPDPC is to assemble a cohort of 10,000 subjects ≥50 years with new-onset diabetes, called the NOD cohort. Using a DEF (Define, Enrich and Find) early detection approach, the aims of the NOD study are to: (a) estimate the 3-year probability of pancreatic ductal adenocarcinoma (PDAC) in NOD (Define); (b) establish a bio-bank of clinically annotated bio-specimens, from pre-symptomatic PDAC and control new-onset type 2 diabetes mellitus subjects; (c) conduct Phase 3 validation studies of promising biomarkers for identification of incident PDAC in NOD patients (Enrich); and (d) provide a platform for development of a future interventional screening protocol for early detection of PDAC in patients with NOD that incorporates imaging studies and/or clinical algorithms (Find). It is expected that 85-100 incidences of PDAC will be diagnosed during the study period in this cohort of 10,000 patients.
