Pancreatic cysts are common and usually benign—except those that turn deadly

An NCI trial compares surveillance regimens

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An argument can be made that only a government research agency like NCI has the capacity to answer questions about monitoring pancreatic cysts—and how some of them turn malignant.

Nobody knows exactly how prevalent pancreatic cysts are, just like no one knows exactly what to do once they appear on a scan.

The majority of these cysts are benign, but some signal the beginning of pancreatic cancer. There are two principal strategies for follow-up—one more intensive than the other.  But since these regimens have never been compared in a randomized trial, no one knows which one is better. 

And if you want to treat the disease surgically, options include pancreaticoduodenectomy, also known as the Whipple procedure. Alas, it’s unknown whether the surgery leads to a decrease in mortality. Nor is there a way to predict which patients would benefit from surgery.

To sort through some of these unknowns, NCI is conducting a prevention trial—EA2185—that seeks to enroll 4,600 patients with newly identified pancreatic cysts measuring 1 cm or greater.  

Stopping short of providing an answer on surgical intervention, the trial compares two commonly used regimens for monitoring pancreatic cysts, measuring impact on a composite of “unfavorable” outcomes, which include any pancreatic cancer without surgery and diagnosis of unresectable pancreatic cancer at surgery.

“I can tell you, because I do this for a living, the challenge is that the imaging studies are becoming so good that, inadvertently, we’re finding pancreatic cysts are incredibly common, and we’ve got to get our arms around figuring out how to manage these,” said Mitchell D. Schnall, a radiologist at the University of Pennsylvania and co-chair of ECOG-ACRIN Cancer Research Group. “Because every time somebody’s getting a workup because of hematuria, we’re looking at their kidneys. Every time somebody’s getting a workup because of GI distress or because their biliary tract is being worked up, right, we’re seeing the pancreas.

“And there’s almost an epidemic of pancreatic cystic lesions, and frankly, this is emblematic. There’s corollaries in other areas as well, where imaging is so good, there’s a proliferation; of small renal cell carcinomas, for example. And it’s not because there’s suddenly a proliferation, it’s because we’re seeing stuff that we’ve never seen before and trying to figure out how we should be caring for these patients is absolutely crucial,” Schnall said to The Cancer Letter

A conversation with Schnall and Peter J. O’Dwyer, an oncologist at Penn and co-chair of ECOG-ACRIN appears here.

The trial compares two guidelines for surveillance of these cysts. One set of guidelines in the trial is similar to the Fukuoka regimen and the lower-intensity guidelines similar to those promulgated by the American Gastroenterological Association. 

“Guidelines get promulgated in all sorts of settings, by all sorts of groups and they’re never compared, or they’re rarely compared,” David S. Weinberg, a gastroenterologist at Fox Chase Cancer Center and the principal investigator on the trial, said to The Cancer Letter

“We thought that this trial was important, because it allowed not only the opportunity to address an important question, it goes to the heart of one of NCI’s, and that should be anybody’s, concerns about over-diagnosis versus under-diagnosis. As we’ve discussed.

“The stakes of missing the cancer are high and the stakes of overreacting to a CAT scan or an MRI are also high,” Weinberg said. “So, getting a good answer makes sense. The ability to compare guidelines makes sense- and cost effectiveness is not a specific goal of this trial, but we would be foolish not to consider how much resources of all sorts are used here. 

“When you think about it, if there are roughly 50 million people in the United States over the age of 60, and even a fraction of that, 2, 3%, has a cyst that in theory requires some form of serial cross-sectional imaging,” Weinberg said. “The back of the envelope estimate is that we spend at least a billion dollars a year in the United States alone on radiology studies associated with pancreatic cysts. If I’m going to spend the billion dollars, I want to spend it well.

A conversation with Weinberg appears here

“The ECOG-ACRIN study is asking a critical question to help the field understand how to manage individuals with pancreatic cysts,” Lynn Matrisian, chief science officer at the Pancreatic Cancer Action Network, said to The Cancer Letter. “Because of the dismal survival rates of pancreatic cancer, detection at the earliest indication of progression to malignancy can greatly increase the patient’s likelihood of a good outcome.” 

Matrisian said that whenever people atdiagnosed with cysts call PanCAN’s Patient Services, case manager encourage them to get involved with this study.  Altogether, 85 individuals have been accrued to the study.

The trial complements an ongoing longitudinal cohort study supported by the NCI Early Detection Research Network, National Institute of Diabetes, Digestive and Kidney Diseases, and Pan Coast, designed to create a cohort of people who are newly diagnosed with diabetes in the hopes that this group, who are at increased risk of being diagnosed with pancreatic cancer, provide the clues in their blood and tissues for investigations in pancreatic cancer.

The timing of the launch of the ECOG-ACRIN trial was unfortunate, Weinberg said. 

“We started about a year ago. If you wanted to design the perfect study to be interrupted by COVID, this is it, because pancreatic cysts are not an emergency,” he said. “So, if patients are less likely to be going to their doctor because of COVID-related concerns, particularly a year ago—as we all know, there were many fewer visits to doctors, many fewer visits to emergency rooms, and many fewer incidental identifications of cysts.

“Further, if a family member called me and said, hey, I had a CAT scan, I did not have a kidney stone, but they told me I had a pancreatic cyst, do I have to deal with that right away, the answer, except under rare circumstances, is no, you can wait.

“So, in our trial, of course, we’ve got a protocol. And the protocol is that the cyst needs to be identified within the last six months. So, if a patient doesn’t get back to their doctor for six-and-a-half months after this CAT scan, because there’s nothing emergent on it, then unfortunately the patient can’t be a participant in our trial. COVID of course has also made it difficult to find research staff and keep research offices fully humming.

“That’s slowly coming back as well.”

Accruing patients to this study has been all the more difficult because institutions have to come up with ways to identify prospective patients and because physicians enrolling the patients aren’t oncologists, and many of them are unfamiliar with the mechanics of NCI trials. 

And it’s not because there’s suddenly a proliferation [of pancreatic cysts], it’s because we’re seeing stuff that we’ve never seen before and trying to figure out how we should be caring for these patients is absolutely crucial.

Mitchell Schnall

“The individuals who would put patients on this study are not medical oncologists, who are the drivers of most of the therapeutic studies, and they are often in specialties outside the traditional cancer research specialties, in this case, gastroenterology and surgical specialties, but also maybe less for this, but to a certain extent primary care,” O’Dwyer said to The Cancer Letter.

“Could we streamline [the process] in such a way as to have something like a ‘registration light’ for individuals who are not going to be treating patients, who don’t need to have their pharmacy information in there, for example, and other aspects that are required by our current registration procedures, so simplifying this, making it easier, ultimately for primary care,” O’Dwyer said.

“Our focus should be on primary care physicians, because if large screening trials are going to ever be implemented, we’re going to need the patients–they’re not even patients–the subjects to be screened at the level of their local doctor. So, that’s a big part of the way that we’re thinking about how to engage more people in this process.”

Physicians who put patients on these trials also have to figure out how their costs are reimbursed, essentially tapping into money coming from NCI.

Given the complexity of medical institutions, this is no simple task, Schnall said. 

“And to us, as a group, it means that we’ve got to put a ton of resources into that primary care doc to educate them on what it is to be in the NCTN, to walk them through a bunch of paperwork, most of which are irrelevant to the trial they’re going to go on that they’ve never seen before, heard before, and really are scared of, to work and try to create a relationship between them and the cancer center that would keep them whole for their costs and participating in the trial. It really creates challenges to getting these folks on these trials.

Recently, NCI Director Ned Sharpless asked an ad hoc group to review the institute’s portfolio of prevention trials, which were impacted by the COVID pandemic. (The Cancer LetterSept. 4Sept. 11, 2020).

The 13-member group focused primarily on the Tomosynthesis Mammographic Imaging Screening Trial. 

In a report earlier this spring, the group recommended that while TMIST needs to be streamlined, it should continue  (The Cancer Letter, March 19, 2021). 

Paul Goldberg
Editor & Publisher
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Paul Goldberg
Editor & Publisher