Pancreatic ductal adenocarcinoma (PDAC), often labeled the world's deadliest major cancer, continues to wreak havoc on U.S. adults. After years of consistent increases, PDAC is expected in 2020 to unseat colorectal cancer and become the second leading cause of cancer-related death in adults, according to the American Cancer Society. Meanwhile, more than 56,770 U.S. residents will be diagnosed with PDAC in 2019, and an estimated 45,750 people will die from it.
As scientists work to develop treatments that can prolong life after diagnosis (only 9% of patients achieve a 5-year survival rate), dedicated and passionate attention is simultaneously being paid to the need for early identification through screening. Richard Frank, MD, a medical oncologist/hematologist who is Director of Clinical Cancer Research for Western Connecticut Health Network, is one of a growing number of clinical researchers who are dedicating themselves to this formidable task. His focus is on the long-recognized link between new-onset diabetes (NOD) and the development of pancreatic cancer-a relationship he previously described in Oncology Times as a "complicated dance" (2017;39(19):1,8)
In this article, Frank announced the pancreatic cancer screening study that is seeking to identify a biomarker for PCAD. This trial began in November 2016 and has an estimated primary completion date of November 2021 (NCT03250078).
"We've been trying to get the word out about the study, and it has been challenging-especially among primary care physicians," Frank explained. "The main challenge for all large clinical trials is recruitment. We are looking for that tipping point effect. You keep at it and eventually you see wider recognition and a greater level of referrals."
Frank believes three primary reasons are influencing trial recruitment, a process that relies heavily on the providers who diagnose patients with diabetes-primary care physicians-to refer patients to the research opportunity.
"First, primary care physicians are extremely busy," he noted. "Second, when you tell someone they have diabetes, it requires further explanation at a subsequent time to tell them about their pancreatic cancer risk.
"The third factor is their understanding of the link between new-onset diabetes and pancreatic cancer," Frank continued. "I can tell you it's very strong. Models published by the Mayo Clinic show that people older than 50 with new-onset diabetes, especially if they have lost some weight, have a nearly 4 percent risk of being diagnosed with pancreatic cancer in the subsequent 3 years, but especially within the first 12 months."
A Long Observed Link
Although an association between diabetes and pancreatic cancer has been recognized for decades, the relationship between the two diseases isn't well understood. That is changing thanks to concentrated attention by multiple organizations and individual researchers. A key observation made thus far is that hyperglycemia appears to be a biomarker of early invasive PDAC-a conclusion that was foundational to development of the study at Western Connecticut Health Network as well as studies at Mayo Clinic (NCT02001337) and the University of Nebraska (NCT03568630). The trial at the University of Nebraska, titled "Blood Markers of Early Pancreas Cancer," is being performed in conjunction with the NCI as a collaborator.
The relationship between diabetes and PDAC was explored in depth at a 2017 workshop organized by the National Institute of Diabetes and Digestive and Kidney Diseases. It also examined links between PDAC and obesity and inflammation. A summary of this event was published in Pancreas (2018;47(5):516-525).
"Pancreatic cancer-related diabetes may provide the means to diagnose PDAC at a potentially curable point in its natural history," the authors wrote. In a section of the article focused on the pathophysiology of PDAC and diabetes, the authors noted "growing evidence that PDAC frequently causes diabetes mellitus." Nearly 85 percent of patients diagnosed with pancreatic cancer have diabetes or hyperglycemia that often was diagnosed in the 2-3 years preceding cancer diagnoses.
"In addition, patients with new-onset diabetes have a 5- to 8-fold increased risk of being diagnosed with PDAC within 1-3 years of developing diabetes," the authors stated.
Despite clear evidence of a relationship between diabetes and PDAC, universal screening of all patients with NOD is not appropriate because only 1 percent of them will develop PDAC within 2-3 years. Thus, researchers are exploring other ways to evaluate risk. Identifying a biomarker is a primary strategy-and a formidable one.
A Sole Focus
The study led by Frank is the only current trial focused on identifying a screening method through a specific protocol implemented at baseline and annually for 3 years (all covered by the study, not submitted to insurance). The study is enrolling patients aged 50 and older who have been diagnosed with NOD in the prior 12 months according to American Diabetes Association criteria. Participants undergo serum screening every 6 months and contrast-enhanced MRI/MRCP of the pancreas at entry and then annually for 3 years.
As of April 2019, the team at Western Connecticut Health Network has screened about 300 referrals, of which approximately one-third were determined eligible and then decided to participate. About 80 patients have enrolled in the study thus far. Less than 50 have a new diagnosis of diabetes; the others have a hereditary risk for pancreatic cancer. The enrollment goal of the study is 800. This research is currently funded by philanthropy, but Frank hopes to involve other hospital networks and win grant support.
"It's still too early to reach conclusions," Frank said of the study. "We have found a low incidence of incidental findings. We've had one endoscopy prompted by abnormal findings, but there was no cancer in this patient. We've been very vigilant about the MRI protocol utilizing thin slices through the pancreas, trying to avoid picking up incidental findings in other organs. ... We've made sure to be as definitive as possible in terms of appropriate follow-up of a benign finding, so that we don't burden the primary care providers."
The trial's slow enrollment rate may be a reflection of the seemingly unanswerable questions pancreatic cancer continues to present. "I think the field is challenged by the belief that there is no effective way to screen for pancreatic cancer," Frank stated. "But I think that skepticism can start to fall away."
Because it is difficult for primary care providers to keep abreast of the specialized literature reporting on the evolution of pancreatic cancer screening, Frank said he hopes the key findings will be reported in more of the journals and resources reaching primary care audiences.
"They need to start to buy in," he said. "What's more devastating than diagnosing a patient with diabetes and a year later they're diagnosed with pancreatic cancer-especially when there was a screening study in your region that the patient could have enrolled in?"
Frank described the necessary approach as casting a wider net in a field with no answers-yet. "This is a mission," he said. "This is what I have to do. I am determined to succeed."
For information on the pancreatic cancer screening study at Western Connecticut Health Network, visit https://bit.ly/2iT5eke.
Michelle Perron is a contributing writer.