Pancreatic Cancer Treatment Is Changing for the Better

For some time, surgical oncology has been in the midst of sweeping change. Pancreatic cancer may finally be reaping the benefits.

In addition to being one of the first specialties to embrace artificial intelligence, oncology has seen numerous advances in surgical techniques, adjuvant and neoadjuvant therapy, and immunotherapy in recent years. In part, these advancements present some challenges, as surgical oncologists now routinely debate which therapies should be given to specific kinds of patients and in which order; however, many cancer types have established important improvements to disease control, cure, and survival.

In some ways, pancreatic cancer has stood apart from this milieu of improvement. While mortality caused by many major cancers has declined by approximately 2% per year since 2000, the mortality rate of pancreatic ductal adenocarcinoma (PDAC) has risen in that timeframe.¹ Outcomes vary widely between high- and low-income countries for most cancer types, while pancreatic cancer has equally poor outcomes worldwide¹—suggesting that access to the most innovative, expensive treatments available may do little to ease the disease’s toll.

After pioneering surgeon Allen O. Whipple, MD, FACS (1881–1963), created his eponymous surgery for pancreatic disease in 1935, one of his first few patients lived for 24 months before dying of liver metastases. That survival time is nearly equal to the 25-month median survival time today² for patients with PDAC, which constitutes 90% of all pancreatic cancer cases.

In the face of this difficulty, surgeons and scientists persist in developing innovative pancreatic cancer treatments. In recent years, they have made strides forward in understanding the usefulness of the Whipple procedure (also known as pancreaticoduodenectomy), completing that operation robotically, and averting pancreatic cancer recurrence via cancer vaccines.

Examining Usefulness of PDAC Therapies

As with other cancer types, understanding the most effective treatment options for PDAC is an active area of research.

A Panel Session at ACS Clinical Congress 2025 on biological criteria for PDAC resectability featured hepatopancreatobiliary (HPB) surgeons from Italy, Germany, Japan, and the US detailing surgical and nonsurgical care options; most noted the absence of international consensus on the optimal approach.

“We do not know what we are doing at the moment—which patient for which therapy,” summarized Professor Thilo Hackert, MD, chairman of the Department of General, Visceral, and Thoracic Surgery at the University Medical Center Hamburg-Eppendorf in Germany, after presenting evidence from randomized clinical trials on radiation, chemotherapy, and combined regimens.

Dr. Hackert did, however, reinforce the common view on resection: “When no resection is achieved, that’s much worse. That’s not new.”

If not new, resection’s potential benefits are still occasionally surprising. For example, a November 2025 Journal of the American College of Surgeons article by Anteby and colleagues³ examined the survival times after surgery alone in patients with PDAC for whom no multimodal care was planned. Using data from the ACS National Cancer Database^®, they examined patients with stage I or II disease who either underwent or refused surgery. Among 471 well-balanced pairs, surgery was found to increase overall survival time to 14.09 months, compared with 6.34 months for those who had no operation. The study showed that resection alone, without further care, can have meaningful impact. However, the authors also found that patients with residual disease (non-R0 status) after resection experienced no survival benefit over those who refused surgery—establishing that patient selection is critical for effective outcomes.

Robotic Whipple

John L. Cameron, MD, FACS, who is the Alfred Blalock Distinguished Service Professor of Surgery at the Johns Hopkins School of Medicine in Baltimore, Maryland, and an ACS Past President (2008–2009), spent a lifetime refining the Whipple procedure. Over a long career, he completed more than 2,000 of these challenging operations and played a crucial role in lowering the procedure’s mortality rate. For this work, he was the 2025 recipient of the ACS Wangensteen Scientific Forum Award.

In a 2017 speech,⁴ Dr. Cameron, then 80 years old, made it clear exactly how tough the work is: “People frequently ask me, ‘How many Whipples do you have to do before you feel comfortable and know how to do the operation?’ My answer is always the same: ‘I’ll let you know when I get there.’”

Greg C. Wilson, MD, FACS, associate professor of clinical surgery at the University of Cincinnati College of Medicine in Ohio, is part of the next wave of improvement in the Whipple procedure—and he, too, is cautious about the operation’s steep learning curve. (Read more about Dr. Wilson in the September 2024 issue of the ACS Bulletin.)

Dr. Wilson’s career has tracked the rise of the robotic Whipple procedure. After a fellowship focused on the robotic Whipple procedure at the University of Pittsburgh Medical Center in Pennsylvania, he initiated robotic pancreatic surgery at the University of Cincinnati.

“Prior to my arrival, there was essentially no pancreatic surgery being done with a robotic approach, so I started the robotic program for pancreatic malignancies and benign conditions,” he said.

Dr. Wilson now performs 15 to 20 robotic Whipple procedures per year, which is 30% to 40% of all Whipple procedures done at his center. It is a rate far higher than the roughly 10% of all pancreatoduodenectomies completed robotically nationwide.⁵

In Dr. Wilson’s view, the robotic approach is a substantial step forward from the laparoscopic approach—equivalent to the quality of the still-dominant open procedure (which Dr. Cameron used for many of his Whipple surgeries).

“When I’m doing the robotic approach or an open approach, the surgery’s the exact same. There are no differences in how I do the dissection. There’s no difference in how I do the reconstruction; it’s almost identical,” Dr. Wilson explained. “I think the ability to do that is why the robotic approach has kind of become the main minimally invasive approach for this operation, and why it’s the one that is expanding in use.”

In contrast, the efficacy of the laparoscopic Whipple procedure can be somewhat inhibited by the instruments, which are mounted on straight sticks and limited to rotation and open-close movements.

“When you’re trying to do an intricate anastomosis using very fine suture, doing that is much more challenging,” Dr. Wilson said. “With the robotic approach, you have the ability to see and alter your angle and really throw the suture at any angle you’d like to take. It allows you to be much more precise, and it’s a much easier skill set to attain than trying to do it laparoscopically.”

However, the selection of patients for robotic Whipples remains essential, he said. His approach focuses primarily on anatomic characteristics, including vasculature, to accommodate one element that the robotic procedure cannot replicate from the open procedure: haptic feedback, including the ability of finding arteries by feeling for a pulse. Careful attention to imaging and clinical findings is essential.

Objective evidence from a December 2025 Annals of Surgery study comparing open, laparoscopic, and robotic pancreaticoduodenectomies via national data from Japan⁶ showed the value of the robotic procedure also includes better patient outcomes.

Although just 2.5% of the 46,166 total cases were performed robotically (1,337; compared with 20,898 performed via an open method and 1,378 performed laparoscopically), the robotic procedure was associated with lower odds of severe postoperative complications than open (odds ratio, 0.82 [95% CI, 0.68-0.98]) and laparoscopic (odds ratio, 0.78 [95% CI, 0.64-0.95]) surgery.⁶

Significant reductions also were found in postoperative pancreatic fistula, major blood loss, and length of stay. All benefits occurred despite the robotic procedures taking an average of 10 hours, far longer than the dominant open procedure (which averaged 7 hours).⁶

Dr. Wilson is working to better understand some of the same outcomes by investigating whether the open procedure, with larger incisions but a shorter OR time, or robotic surgery with minimized incision but longer OR time has better outcomes in elderly patients.

Additionally, Dr. Wilson cautioned against attempting to move toward the robotic Whipple too quickly. “There’s a lot of media coverage about the robotic Whipple, and it kind of becomes a marketing tool,” Dr. Wilson said. “I think it sometimes forces people to adopt that approach sooner than they may be ready for it. That’s the one thing I worry about.”

Preventing Recurrence via Cancer Vaccines

Of course, even the most adept pancreatoduodenectomy often does not ensure a cure. “The current treatments for pancreatic cancer, which include surgery, chemotherapy, and radiation, are largely ineffective, despite how much progress we have made with the Whipple procedure,” said Vinod P. Balachandran, MD, FACS, an HPB surgeon-scientist, and director of The Olayan Center for Cancer Vaccines at Memorial Sloan Kettering Cancer Center in New York, New York.

Typical survival rates for PDAC are only about 25% after 5 years, even in resected patients. These low rates are attributed in large part to the disease’s tendency to develop micro-metastases early, which seed disease recurrence and cannot be fully ameliorated by surgery. Patients who are imaging-negative for disease after surgery often nonetheless show residual disease via circulating tumor DNA. Despite the rise of neoadjuvant and adjuvant FOLFIRINOX (folinic acid, fluorouracil, irinotecan, and oxaliplatin in combination), gemcitabine-based regimens, and other options, complete response and long-term control remain rare.

Notably, most immunological approaches to pancreatic cancer treatment also have proven to be ineffective. This reality is thought to be attributable to pancreatic cancer biology, which includes a desmoplastic stroma that blocks immune cell infiltration to the tumor. This form of cancer also features few mutations and thus few neoantigens, which are the targets of immunotherapies. Furthermore, pancreatic cancer features a highly immunosuppressive microenvironment.

Despite these treatment limitations, meaningful improvement may be on the horizon.

“The most striking difference in these rare survivors of PDAC,” he said, referring to the 10% of patients who experience long-term survival after surgery, “is that their immune systems spontaneously are able to generate an immune response to their cancer. We found this immune response not only occurs in their primary tumor but persists in their blood for over a decade, which was really quite striking.”

These findings upended an assumption, Dr. Balachandran said, that “PDACs are essentially not seen by the immune system.”

After publishing analyses of long-term survivors’ immune responses,⁷ Dr. Balachandran began working to help the 90% of patients who do not experience spontaneous disease control.

“All of this evidence was indicating that if you can generate an immune response to PDAC, that maybe you could improve outcomes,” he explained. “So, could we induce it in other patients where it’s not happening naturally? The best way to target the immune system is with a vaccine, but we need to know what the immune system is recognizing in the tumor.”

Genetic analysis of long-term survivors led to the discovery that each person’s immune system responded to unique neoantigens, rather than ones common to the full cohort. With this in mind, Dr. Balachandran and collaborators launched a phase I trial in which patients undergoing surgery had their resected tissue subjected to genetic analysis for the creation of a bespoke mRNA vaccine containing up to 20 major histocompatibility class I and II restricted neoantigens. A company in Germany assisted researchers with genetic analysis and vaccine manufacture.

The resulting study, published in 2023, examined 16 patients who received the personalized vaccines, termed autogene cevumeran, alongside a regimen of the immune checkpoint inhibitor atezolizumab and mFOLFIRINOX.⁸ Eight patients had an immune response to the vaccine; by the 3-year follow-up, their median recurrence-free survival time had not yet been reached. In contrast, eight nonresponding patients had recurrence-free survival of 13.4 months.⁹ In responders, vaccines induce a strong, long-lasting, functional CD8+ T cell immune response that correlated with delayed recurrence.

While the benefits may be considerable, Dr. Balachandran admits the patient population to be limited, at least for now, to resected patients.

“One current understanding is that hosts are optimally fit in the post-resected state,” he said. “This does not mean that there could not be other ways to teach the immune system to recognize tumors in other clinical scenarios. There could be—and I believe ongoing research, including clinical trials of personalized and off-the-shelf approaches, will help reveal what it takes for a cancer vaccine to trigger a meaningful immune response.”

One alternative approach to producing a cancer vaccine may be found in additional efforts to generate a vaccine for PDAC. Roughly 90% of pancreatic cancers include mutations to KRAS, a proto-oncogene that becomes locked “on,” endlessly generating KRAS proteins in tumors. Although previously thought to be undruggable, some specific mutations are now considered susceptible to emerging chemotherapy options. A team at The University of Texas MD Anderson Cancer Center in Houston is investigating a KRAS-targeted cancer vaccine.

“It’s truly the Achilles’ heel of the tumor,” explained Shubham Pant, MD, MBBS, who is a gastrointestinal medical oncologist in the Division of Cancer Medicine at MD Anderson and a leader of this research.

The aim is not only to develop an off-the-shelf vaccine for pancreatic cancer, Dr. Pant said. It also is to learn from past efforts by shifting focus away from stage IV disease, when the tough stroma surrounding large metastases can make vaccines and other therapies ineffective, to the point when only micro-metastases exist.

“Our thought was that these cells, which do not have that protective desmoplastic stroma, might be more easily targetable with vaccines,” he said.

Dr. Pant and colleagues recently completed a phase I trial of 25 patients (20 with pancreatic cancer and five with colorectal cancer), who had at least one of two mutant alleles of KRAS, G12D and G12R, and were positive for circulating tumor DNA after undergoing resection and adjuvant therapy.¹⁰ In addition to establishing safety and tolerance, the trial found that the patients “tended to do better, even through long-term follow-up—and interestingly, in pancreatic cancer, the patients who had an increased, more robust immune response tended to do better than the patients who did not.”

Currently, Drs. Pant and Balachandran are both conducting phase II trials to test for possible survival benefits among vaccinated pancreatic cancer patients. Dr. Pant and colleagues are exploring a new version of the KRAS cancer vaccine, targeting seven mutant alleles rather than two. Dr. Balachandran and collaborators are completing a multicenter trial (including enrolling patients at Dr. Wilson’s hospital in Cincinnati) that will further test bespoke vaccines. Although neither is ready to share results, both are hopeful, with Dr. Pant predicting a vaccine may be available as soon as 2028.

Dr. Balachandran is remarkably enthusiastic about the potential for developing a cancer vaccine.

“You can generate a really strong immune response in the toughest cancer, where no immune therapy has worked, and where it was thought that nothing could work,” he said. “If you could do it in pancreas cancer, you should be able to do it in many of the other cancer types that are like pancreas cancer. Here, essentially, this encompasses all human cancer.”

M. Sophia Newman is the Medical Writer and Speechwriter in the ACS Division of Integrated Communications in Chicago, IL.

References

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