The Trial

Patients identified to have what is considered high-risk IPMN are eligible for this study.  Each patient on the 3P-C trial will undergo a CT or CT angiogram in order to rule out any evidence of cancer before starting the sulindac or the placebo.

All trial participants will be closely monitored. They’ll receive alternating CT scans and endoscopic ultrasounds/fluid aspiration of their pancreas over the course of treatment. Participants will also have bloodwork done regularly, including complete blood count (CBC), comprehensive metabolic panel (CMP) and screening for tumor marker CA 19-9, which can signal the presence of pancreatic cancer.

During the study, Allen and the other investigators will utilize and evaluate a novel radiographic (radiomics) approach to detecting IPMN early and track progression, if at all, to malignancy.

They also plan to monitor and collect data on the effects of treatment on IPMN cyst-fluid biomarkers through a special biomarker panel they previously developed.

Allen’s group has already identified in their research, a variety of cyst-fluid biomarkers that are associated with the presence of advanced IPMN in the pancreas. A recently finished validation study further validated these markers, as well as radiographic features that predict the presence of high-grade IPMN.

This is important because whereas low-grade IPMNs don’t necessarily need to be removed, just monitored, identifying high-grade IPMNs for surgical removal before they progress to invasive carcinoma could be potentially curative. Allen can’t stress enough the importance of early diagnosis in pancreatic cancer and its impact on mortality.

“Less than 15% of patients are diagnosed prior to the development of identifiable metastatic disease. Only about 10% of all pancreatic cancer patients are alive five years after diagnosis,” he said. “That's why our studies of biomarkers that would place individuals in a very high-risk group for pancreatic adenocarcinoma, allowing for true early detection, are so meaningful.”

The 3P-C trial has just started enrolling patients at the study’s collaborating institutions. Investigators plan to accrue 200 patients (100 patients/arm) by 2023.

“We've already enrolled a few patients here at Duke,” said Allen. “We're excited about it. I think we're going to learn a great deal from this.”

The Earlier, the Better

The five-year survival rate for locally advanced pancreatic adenocarcinoma, before it spreads, is around 20%. Once it had spread, the rate drops significantly, with regionally advanced at 13% and a metastasis to other organs at 3%.

While patients will have the most meaningful outcome when a pre-cancerous lesion in the pancreas is detected and removed prior to it becoming a true cancer, the next best outcome, Allen explained, is in patients whose cancer is localized and can be safely surgically removed followed by chemotherapy, folfirinox in particular.

“These two treatments combined – surgery and chemotherapy — are really the best hope we currently have. In these early stages, we can effectively treat the cancer so that it does not recur or progress for years to come,” Allen said. “We are seeing more and more patients survive years and years after those treatments are delivered. Unfortunately, they're rarely curative, but we’re clearly headed in the right direction.”

Catching pancreas cancer early is especially difficult. People typically don’t have symptoms until the cancer becomes very large or has already spread to other organs. Because the pancreas is located deep in the body, patients can’t feel benign cysts or early cancerous tumors nor can health care providers detect them during routine physical exams.

Added to this, the symptoms of advanced pancreatic adenocarcinoma — weight loss and abdominal discomfort that may radiate to the back — are common to multiple other conditions, so people might not suspect they have pancreatic cancer.

In some cases, tumors can cause jaundice earlier on, which can lead to an earlier diagnosis. New-onset diabetes may also raise a red flag. (Recent studies have shown that 1% of adult patients diagnosed with new-onset diabetes after age 50 will also be diagnosed with pancreatic adenocarcinoma within three years of the date of their diabetes diagnosis). Typically, however it’s not until very late in the disease that patients experience the kind of severe abdominal pain, nausea, and vomiting that would set off any alarm bells.

All in the Family

At this point no major professional groups recommend screening for pancreatic adenocarcinoma in individuals of average risk who have no symptoms. Unfortunately, these individuals represent 90% of pancreatic adenocarcinoma diagnoses in the U.S.

“Because these cancers are relatively rare in the general population, and because of our limited ability to detect these cancers on imaging, routine screening is not recommended,” explained Allen.

Major risk factors for pancreatic adenocarcinoma include cigarette smoking (twice the risk of getting pancreatic cancer as never smokers) and use of smokeless tobacco. Other risk factors include long-standing diabetes, excess body weight, and a personal history of chronic pancreatitis. Heavy alcohol consumption may also increase risk. Many people, however, will get pancreatic adenocarcinoma with none of these risk factors. So, having one of these risk factors won’t trigger a referral for pancreatic cancer screening.

Screening in pancreatic adenocarcinoma is reserved for individuals with a strong family history of pancreas cancer and/or a known genetic syndrome (an inherited change in an individual’s DNA that would increase their lifetime risk for pancreatic cancer) — about 10% of pancreatic adenocarcinoma cases.

This includes:

• Peutz-Jeghers syndrome : a mutation in the STK11 gene that increases the risk of not only pancreas cancer, but other GI cancers, breast and ovarian cancer.
• Familial pancreatitis: inherited mutations in the PRSS1 gene.
• Lynch syndrome 
• An inherited mutation in the BRCA2 gene; a mutation that is also linked with breast, ovarian and prostate cancer.
• A family history of breast or ovarian cancer or colon cancer
• A strong family history of a hereditary stomach cancer

“We typically assess how much risk there is in the family; how many family members have had pancreatic cancer and at what age did it develop,” said Allen. “For example, if multiple members of one’s family developed pancreas cancer in their 50s or younger, there’s a pretty strong argument that they have significant risk. In this group of patients, we might consider annual imaging such as CT or an endoscopic ultrasound to evaluate for abnormalities in the pancreas.”

Top of the Game

A multidisciplinary team of pancreatic cancer specialists from DCI holds a weekly tumor board led by James Abbruzzese, MD, where they present patient cases and exchange ideas around how best to treat these patients.

“We have a very good program at DCI,” said Allen. “We are really strong in all areas of pancreas cancer therapy — medical oncology, radiation oncology, radiology, gastroenterology, pathology, and surgery — and I do think we have a lot to offer. We’re able to provide any type of intervention that's necessary. We're giving state-of-the-art treatment. We have a great, really solid group with a lot of research going on in this space right now, including looking at specific ways of timing chemotherapy around surgery. Our investigators are also researching ways to incite an immune system response in this cancer that’s not very immunogenic. It will be harder to put those therapies to the test, but we will.”

Celebrity deaths have raised the profile of pancreatic cancer — including game show host Alex Trebek, Supreme Court Justice Ruth Bader Ginsburg, actors John Hurt and Alan Rickman, singer Luciano Pavarotti, and jazz musician Dizzy Gillespie. Cancer of the pancreas was part of President Obama's Recalcitrant Cancer Act. It’s not enough, Allen said.

“We're still relatively underfunded, certainly when we compare federal pancreatic cancer funding to federal breast cancer funding, yet it's really becoming one of the leading killers of Americans. We need to raise the awareness and help to educate the public about what the real challenges are around it, and where the opportunities might be, and then design our research to try to make progress.”

The National Institutes of Health is the sole funder of the 3P-C trial: Preventing an Incurable Disease: The Prevention of Progression to Pancreatic Cancer Trial.