Should patients with operable pancreatic cancer go straight to surgery or receive systemic therapy first?

While surgical resection remains the only potentially curative option for pancreatic ductal adenocarcinoma, many patients with resectable disease relapse within 5 years. Patients who relapse may have micrometastases left behind after surgery or biologic features that place them at a higher risk for recurrence.

A growing body of evidence suggests that neoadjuvant therapy can reduce the risk for recurrence in patients at high risk for relapse, but it’s unclear whether this approach definitively improves overall survival for these patients. And if applied too generally, neoadjuvant therapy may lead to overtreatment in patients with more favorable-risk disease and some patients may lose the option for surgery altogether.

“This tension — curative-intent surgery versus early systemic control — underpins the ongoing debate about the optimal perioperative sequence and regimen, particularly for patients who are technically resectable but at high risk of rapid systemic failure,” explained Fausto Petrelli, MD, and Lorenzo Dottorini, MD, of ASST Bergamo Ovest, Treviglio, Italy, in a recent perspective.

At stake is a fundamental trade-off: preserving the opportunity for potentially curative surgery vs addressing occult metastatic disease and the risk for early systemic failure.

National Comprehensive Cancer Network guidelines highlight both strategies as options for patients with resectable disease — surgery for those without high-risk features and neoadjuvant therapy, particularly for those with high-risk features — leaving clinicians to navigate a gray zone.

Experts address the case and caveats for each strategy and how to make decisions amid the uncertainty.

Surgery vs Chemo First: the Evidence

Surgery followed by adjuvant chemotherapy remains standard of care for fit patients with clearly resectable disease and without high-risk features.

This approach is supported by “the most mature level 1 evidence,” according to Sandra Algaze, MD, an assistant professor of medicine at the Keck Medicine of University of Southern California, Los Angeles.

The PRODIGE 24 trial established adjuvant modified FOLFIRINOX as the standard for fit patients after resection compared with gemcitabine, with a median overall survival of 53.5 months with mFOLFIRINOX vs 35.5 months with gemcitabine.

However, the surgery-first approach comes with limitations.

“This evidence is inherently selection biased,” Algaze said, because only patients who recover adequately from surgery receive therapy. “In practice, a meaningful proportion of patients never initiate or complete adjuvant treatment due to postoperative complications or early recurrence.”

Although surgical resection is ultimately required to cure pancreatic adenocarcinoma, a growing body of evidence suggests that receiving systemic therapy before surgery can reduce the risk for recurrence observed in patients who undergo surgery first.

“As we often see in practice, radiographic resectability does not necessarily reflect tumor biology, and that is one of the key reasons neoadjuvant therapy is increasingly being incorporated,” Algaze said.

Emil Lou, MD, PhD, a medical oncologist at the University of Minnesota, Minneapolis, said that his institution has offered neoadjuvant therapy “for almost all cases of anatomically resectable pancreatic cancer for over a decade.” A systemic treatment-first approach can help treat micrometastatic disease before it leads to metastatic disease, Lou explained.

Mark O’Hara, MD, associate professor of medicine at the Abramson Cancer Center at the University of Pennsylvania, Philadelphia, echoed this take, noting how fast metastatic disease can develop.

“I’ve had a handful of patients recently that have had surgery, and then, unfortunately, right before I started adjuvant chemotherapy, they already had metastatic disease,” O’Hara told Medscape Medical News.

“That’s the worst feeling in the world because they’ve gone through a huge surgery, and now, all of a sudden, they’re palliative — I won’t be able to cure them,” he said.

Although O’Hara noted that it’s unclear whether neoadjuvant therapy would have improved outcomes for these patients, recent trials suggest neoadjuvant therapy may have an edge over upfront surgery in both resectable and borderline resectable cases. 

The PREOPANC trial showed, for instance, that neoadjuvant gemcitabine-based chemoradiotherapy improved overall survival compared with upfront surgery in patients with resectable or borderline resectable pancreatic ductal adenocarcinoma in long-term follow-up, with 5-year overall survival rates of 20.5% in the neoadjuvant group vs 6.5% in the upfront surgery group. The Japanese Prep-02/JSAP-05 trial also found neoadjuvant gemcitabine plus S-1 was associated with improved overall survival — 37.0 months vs 26.6 months for upfront surgery — in patients with resectable disease.

Recent data point to emerging neoadjuvant strategies. The CASSANDRA trial, for instance, found that neoadjuvant PAXG (cisplatin, nab-paclitaxel, capecitabine, and gemcitabine) was associated with longer median event-free survival compared with mFOLFIRINOX — 16.0 months vs 10.2 months — in patients with resectable or borderline resectable pancreatic ductal adenocarcinoma.

Despite the potential benefits of neoadjuvant therapy, the approach carries important caveats, Petrelli and Dottorini noted. “The trade-off is the risk of overtreatment or loss of resection opportunity in some patients with favorable biology, particularly when neoadjuvant therapy is applied broadly in anatomically resectable disease.”

Some patients with very aggressive disease will recur early with surgery or chemotherapy. “At least if you start with chemo, you’re going to know this and not have that person go through a massive surgery,” Arsen Osipov, MD, medical director of the pancreatic cancer and Multidisciplinary Cancer Programs and Integration at Cedars-Sinai, Los Angeles.

Mark A. Lewis, MD, director of gastrointestinal oncology at Intermountain Health Cancer Center in Murray, Utah, described the harsh reality of surgery firsthand: he underwent a Whipple procedure in 2017 for a malignant tumor in the head of his pancreas, after which he suffered 5 weeks of delayed gastric emptying and required parenteral nutrition.

“Not every patient recovers from surgery quickly enough for timely initiation of adjuvant therapy,” said Lewis.

What’s more, not all randomized data have supported the neoadjuvant approach, including the NORPACT-1 trial, which found a median overall survival benefit with upfront surgery in the intention-to-treat analysis: 38.5 months vs 25.1 in the neoadjuvant FOLFIRINOX group.

Resectable disease “is not a biologically uniform entity,” Petrelli and Dottorini wrote, and “the net value of neoadjuvant therapy likely depends on patient selection, regimen, and center experience.”

How to Decide

To provide greater clarity on the neodjuvant therapy vs surgery first debate, two trials — Alliance A021806 and PREOPANC-3— are underway to compare perioperative mFOLFIRINOX to upfront resection followed by adjuvant mFOLFIRINOX.

Until findings from those studies become available, several experts advocated for personalized treatment planning in operable pancreatic cancer.

“I take an individualized approach rather than a one-size-fits all approach to each patient with anatomically resectable pancreatic cancer,” said Matthew H.G. Katz, MD, professor and chair in the Department of Surgical Oncology at The University of Texas MD Anderson Cancer Center, Houston.

Katz noted that he evaluates numerous factors, including tumor anatomy and biology, occult metastatic disease likelihood, genetic profiles of the tumor and patient, physiologic and psychosocial status, and access to care.

Petrelli and Dottorini agreed that clinicians should follow a risk-adapted framework based on patient and disease characteristics.

For fit patients with clearly standard-risk resectable disease, they suggest upfront surgery followed by adjuvant mFOLFIRINOX remains a well-supported default option.

For patients presenting with higher-risk clinical features, however, the decision shifts toward systemic therapy first. Features such as a high cancer antigen 19-9, larger tumors, and nodal involvement point to more advanced disease and strongly favor neoadjuvant therapy.

For frail patients or those unsuited for multiagent chemotherapy, tailored strategies become even more essential, such as surgery first with de-escalated adjuvant therapy or gemcitabine-based chemoradiotherapy with planned adjuvant gemcitabine.

Any treatment plan, however, depends on timely and accurate characterization of the case, which is why Cedars-Sinai in Los Angeles has implemented a same-day multidisciplinary clinic to accelerate evaluation of patients with pancreatic cancer.

Osipov, who oversees this program, explained how it works.

“The patient comes in on a single day, they get a scan, then they get a full evaluation,” Osipov said. The entire team “sit in a room and we interrogate the person’s case.”

The patient then meets with each member of the care team, resulting in a same-day treatment plan, and, if eligible, enrollment in a clinical trial.

“Normally, what takes probably 2 months…we do in about 4-5 hours,” Osipov said.

Early results in patients with resectable to metastatic disease have been promising. Patients in the program were significantly more likely to undergo somatic and germline testing. Additionally, tumor resectability classification changed in about 17% of patients, two thirds of whom were upstaged.

Osipov noted that overall Cedars-Sinai recommends neoadjuvant chemotherapy more often than upfront surgery for resectable patients. Yet even with this growing institutional preference for neoadjuvant therapy, careful patient selection — rather than a rigid adherence to one sequence — remains best practice.

“Treatment decisions must ultimately be individualized through multidisciplinary evaluation and shared decision-making with the patient, particularly in the resectable setting where both upfront surgery and neoadjuvant therapy remain reasonable options,” Algaze concluded.

Algaze disclosed having relationships with Bristol Myers Squibb, Caris Life Sciences, Elevar Therapeutics, and others. Petrelli, Dottorini, Katz, Lewis, O’Hara, Lou, and Osipov reported having no competing interests.