The Major Dilemma in Pancreatic Cancer: Surgery First or Chemotherapy First?
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Pancreatic ductal adenocarcinoma represents one of oncology's toughest battles. Surgical resection remains the only potentially curative option — yet a substantial proportion of patients with resectable disease experience recurrence within five years. This reality has raised a critical question for years: Should treatment begin with surgery or systemic therapy? Strong evidence in favor of neoadjuvant therapy has accumulated in recent years, but some studies challenge this approach. Until two major phase III trials expected to provide definitive answers (PREOPANC-3 and Alliance A021806) are completed, clinicians will continue making decisions in a gray area. An up-to-date review published by Medscape offers a snapshot of this debate.
Why Is This Such a Critical Decision? The Nature of Pancreatic Cancer
The central tension in treating pancreatic ductal adenocarcinoma is this: surgical resection is theoretically curative — but many patients considered resectable (surgically removable) harbor micrometastatic disease that is not yet visible on imaging. Behind a tumor that appears “localized” on imaging, cancer cells may be circulating systemically. This reality underlies the rapid progression to metastatic disease in a substantial proportion of patients after surgery.
Starting postoperative adjuvant chemotherapy is not always achievable either: because of postoperative complications, nutritional problems, prolonged recovery, and early recurrence, approximately half of surgical patients never start or cannot complete adjuvant chemotherapy. This is the greatest practical weakness of the “surgery first” strategy.
Two Approaches, Two Philosophies
Rationale: Surgery is the only potentially curative option in pancreatic cancer. Removing the tumor as quickly as possible eliminates the risk of progression.
- ✅ Adjuvant mFOLFIRINOX supported by PRODIGE 24
- ✅ The most mature level 1 evidence
- ✅ The opportunity for resection is not missed
- ⚠ Selection bias — only those who recover receive chemotherapy
- ⚠ Approximately half of patients cannot receive adjuvant therapy
- ⚠ Surgical complications & early recurrence
Rationale: Micrometastatic disease is often already present. Starting systemic therapy first brings micrometastases under control and “tests” the tumor's biology.
- ✅ Treats micrometastases early
- ✅ A 3-fold long-term survival advantage in PREOPANC
- ✅ Screens out tumors with unfavorable biology early
- ✅ Prep-02/JSAP-05: 37 months vs 26.6 months
- ⚠ Risk of losing the opportunity for surgery
- ⚠ Overtreatment in cases with favorable biology
The Evidence Table: Anatomy of the Contradictions
The evidence in this field is not mutually supportive — on the contrary, some findings are clearly contradictory. A summary comparison of the key studies is presented below:
Results of neoadjuvant and surgery-first strategies across different studies — in months
CASSANDRA and the Search for New Regimens
The standard mFOLFIRINOX regimen causes substantial toxicity for many patients. The search for newer regimens therefore continues. Presented in 2025, the CASSANDRA studycompared the neoadjuvant PAXG regimen (cisplatin, nab-paclitaxel, capecitabine, and gemcitabine) with mFOLFIRINOX. The results are noteworthy: median event-free survival was 16.0 months in the PAXG arm versus 10.2 months in the mFOLFIRINOX group. In patients with resectable and borderline resectable disease, this difference suggests that PAXG could become an important alternative in the future.
Meanwhile, a phase III randomized trial conducted by Chinese researchers (Bai et al., Cancer Cell 2025) demonstrated that the sequential neoadjuvant combination of gemcitabine/nab-paclitaxel followed by mFOLFIRINOX significantly improved event-free survival compared with a surgery-first approach. This suggests that sequential multiagent neoadjuvant chemotherapy could become a new standard.
PREOPANC-3 and Alliance A021806: Awaited Answers
Definitively answering the current debate requires results from two major ongoing phase III trials. Both were designed to address a similar question: is perioperative mFOLFIRINOX (neoadjuvant + adjuvant) superior to surgery followed by adjuvant mFOLFIRINOX?
24 centers led by the Netherlands (Netherlands, Norway, Sweden)
- 378 patients with resectable PDAC
- Intervention: 8 cycles neoadjuvant + surgery + 4 cycles adjuvant mFOLFIRINOX
- Control: surgery + 12 cycles adjuvant mFOLFIRINOX
- Primary endpoint: overall survival (ITT)
- Expected hazard ratio: 0.70
- Coordinated by the Dutch Pancreatic Cancer Group
A large phase III trial involving the USA and Canada
- 352 patients with resectable PDAC
- Intervention: 8 cycles neoadjuvant + surgery + 4 cycles adjuvant mFOLFIRINOX
- Control: surgery + 12 cycles adjuvant mFOLFIRINOX
- Primary endpoint: overall survival
- Secondary endpoint: includes quality of life
- Coordinated by the Alliance for Clinical Trials in Oncology
How Should Decisions Be Made in Practice? A Risk-Adapted Framework
The critical point emphasized in Petrelli and Dottorini's perspective article is: Resectable disease is not a biologically uniform entity. A risk-adapted framework is therefore proposed in place of a “one-size-fits-all approach.” Matthew H.G. Katz, chair of Surgical Oncology at MD Anderson Cancer Center, shares this view, emphasizing the need to assess numerous factors: tumor anatomy and biology, the likelihood of occult metastatic disease, the genetic profiles of the tumor and patient, physiological and psychosocial status, and access to care.
🟢 PROFILE 1: Standard Risk + Fit Patient → SURGERY FIRST
A clearly resectable, anatomically suitable tumor, low CA 19-9, and good performance status. For these patients, surgery followed by adjuvant mFOLFIRINOX is a well-supported default option.
🔴 PROFILE 2: High-Risk Features → NEOADJUVANT THERAPY
Features such as high CA 19-9, large tumor size, and lymph node involvement indicate more advanced disease and strongly support a neoadjuvant approach.
🟠 PROFILE 3: Frail Patient / Unsuitable for Multiagent Therapy → ADAPTED STRATEGY
For older patients or those with comorbidities, individualized strategies are needed, such as surgery followed by reduced adjuvant therapy, or gemcitabine-based chemoradiotherapy + planned adjuvant gemcitabine.
🟣 ALL PROFILES: Multidisciplinary Assessment Is Essential
Treatment decisions should be made through shared decision-making at a multidisciplinary meeting (surgery, medical oncology, radiology, pathology, radiation therapy, and the patient). The Cedars-Sinai model reduces the usual 2 months to 4-5 hours through same-day multidisciplinary assessment.
A Real Physician's Real Story: The Reality of Surgery
Mark A. Lewis, director of gastrointestinal oncology at Intermountain Health Cancer Center in Utah, offers a different perspective on this debate: He has personally undergone this operation. In 2017, he underwent a Whipple procedure for a malignant tumor in the pancreatic head. He then experienced delayed gastric emptying lasting 5 weeks and required parenteral nutrition.
This experience calls into question the hidden assumption behind the “surgery first” approach: it is not always possible for a patient to recover sufficiently after surgery to proceed with adjuvant chemotherapy. Similarly, Mark O'Hara from the University of Pennsylvania says that some of his recent patients developed metastatic disease after surgery before they could start adjuvant chemotherapy. He describes this as “the worst feeling in the world” — because after a major operation, the patient ends up needing palliative care.
Same-Day Multidisciplinary Assessment: The Cedars-Sinai Example
Arsen Osipov, director of the pancreatic cancer program at Cedars-Sinai Cancer Center in Los Angeles, presents a model that dramatically shortens the interval between diagnosis and treatment initiation: A same-day multidisciplinary clinic. In this model, the patient undergoes imaging in a single day, the entire team gathers in one room, the patient meets each team member individually, and a treatment plan is produced that same day. If eligible, the patient also enrolls in a clinical trial on the same day.
According to Osipov: “We complete a process that normally takes about 2 months in approximately 4-5 hours.” Early results are encouraging: patients in the program were referred for somatic and germline testing at significantly higher rates, and the resectability classification changed in approximately 17% of patients — two-thirds of whom were upstaged. This finding shows that rapid, systematic assessment can influence not only time to treatment but also the correct treatment decision.
🎓 DROZDOGAN Academy — Commentary and Discussion
PANCREATIC CANCER · NEOADJUVANT · SURGERY · PRODIGE 24 · PREOPANC · CRITICAL APPRAISAL
The Significance of This Debate
Pancreatic cancer remains one of the deadliest solid tumors. Even in resectable disease, 5-year survival rates remain inadequate. In this context, the “surgery first or chemotherapy first” debate is not an academic nuance but a crucial clinical decision. Practices followed for years under the belief that “surgery is the only chance” are being reassessed in light of evidence from the past decade. In particular, the 3-fold difference in 5-year survival favoring the neoadjuvant group in long-term PREOPANC follow-up (20.5% vs 6.5%) strikingly demonstrates how critical treatment sequencing can be in this disease. However, another strong message is that this field does not offer a single answer and that biological heterogeneity requires individual assessment for each patient.
Strengths
This Medscape review is valuable for bringing together the perspectives of leading experts with differing opinions in a balanced way. Including clinicians from major centers such as USC, Minnesota, Penn, Cedars-Sinai, MD Anderson, and Intermountain reveals both agreement and disagreement in the field. Petrelli and Dottorini's risk-adapted framework provides a concrete roadmap for practical decision-making. Considering studies with contradictory findings, such as PREOPANC, Prep-02/JSAP-05, and NORPACT-1, together also reflects scientific civility in the field. Clearly stating expectations for the ongoing PREOPANC-3 and Alliance A021806 trials helps clinicians distinguish between “what we know for now” and “what we may know in the future.”
Limitations and Open Questions
The most serious limitation of the current evidence is that the studies report conflicting results. While long-term PREOPANC follow-up showed a substantial difference favoring neoadjuvant therapy, NORPACT-1 found surgery first significantly superior in the ITT analysis. This contradiction stems not only from differences in study design (number of neoadjuvant cycles: 4 in NORPACT, 8 in PREOPANC-3) but also from heterogeneous patient selection criteria. Another critical issue is that approximately 30-40% of patients receiving neoadjuvant therapy do not reach surgical resection — this rate of “lost opportunity for surgery” is too high to ignore. Moreover, most existing studies were conducted at major academic centers in developed countries; whether their results can be generalized to centers with moderate or low volumes is debatable. Finally, it is not yet clear how new tools such as ctDNA and circulating tumor biomarkers should be integrated into treatment decisions.
Implications for Clinical Practice
This review provides concrete messages for practice in Türkiye. First, reflexive decisions for “immediate surgery” in resectable pancreatic cancer should be avoided; every patient should undergo risk stratification based on CA 19-9, tumor size, lymph node status, and performance assessment. Second, in patients with high-risk features, neoadjuvant mFOLFIRINOX (8 cycles) + surgery + 4 cycles of adjuvant mFOLFIRINOX can be considered a reasonable standard. Third, new options such as the PAXG regimen in CASSANDRA and sequential neoadjuvant approaches are areas Turkish oncologists should follow in the literature. Fourth, major centers should implement clinical pathways that shorten time to treatment and accelerate multidisciplinary assessment — the Cedars-Sinai model should be studied as an example. Finally, completion rates for adjuvant therapy should be monitored systematically at centers in Türkiye, and treatment strategy should be discussed individually in light of these rates. We must remember how difficult it was even for a physician to complete a treatment he personally experienced (Mark Lewis's story) — for us as practitioners, this is an important lesson about the human dimension of the treatments we offer our patients.
Questions for the Future
We can group the critical questions for the coming period as follows: when the PREOPANC-3 and Alliance A021806 results are announced in 2027-2028, will perioperative mFOLFIRINOX prove superior to the adjuvant-only approach? Could CASSANDRA's PAXG regimen and sequential gemcitabine/nab-paclitaxel → mFOLFIRINOX become new standards? How can ctDNA-based minimal residual disease (MRD) monitoring be used to determine who needs neoadjuvant therapy — an approach already being considered in breast and colorectal cancer? How will immunotherapy and targeted treatments (KRAS G12 inhibitors, PARP inhibitors in patients with BRCA mutations) be integrated into perioperative treatment algorithms? And a particularly important question: could more sensitive imaging and molecular tools for resectability classification reduce the fear of “losing the opportunity for surgery,” allowing more patients to benefit from neoadjuvant therapy? All these questions point toward a dramatic evolution in pancreatic cancer treatment over the next decade.
Scientific References
- Medscape Medical News. Pancreatic Cancer: Should Surgery or Chemo Come First? Will Pass, 22 April 2026.
- Conroy T et al. (PRODIGE 24). FOLFIRINOX or Gemcitabine as Adjuvant Therapy for Pancreatic Cancer. N Engl J Med 2018;379:2395–2406.
- Versteijne E et al. (PREOPANC long-term follow-up). Neoadjuvant Chemoradiotherapy Versus Upfront Surgery for Resectable and Borderline Resectable Pancreatic Cancer: Long-Term Results of the Dutch Randomized PREOPANC Trial. J Clin Oncol 2022;40:1220–1230.
- Unno M et al. (Prep-02/JSAP-05). Randomized phase II/III trial of neoadjuvant chemotherapy with gemcitabine and S-1 versus upfront surgery for resectable pancreatic cancer. J Clin Oncol 2019;37(4_suppl):189.
- Labori KJ et al. (NORPACT-1). Neoadjuvant FOLFIRINOX versus upfront surgery for resectable pancreatic head cancer: a multicentre, randomised, phase 2 trial. Lancet Gastroenterol Hepatol 2024;9(3):205–217.
- Reni M et al. (CASSANDRA). Results of a randomized phase III trial of pre-operative chemotherapy with mFOLFIRINOX or PAXG regimen for stage I–III pancreatic ductal adenocarcinoma. J Clin Oncol 2025;43:LBA4004.
- Bai X et al. Neoadjuvant nab-paclitaxel plus gemcitabine followed by modified FOLFIRINOX for resectable pancreatic cancer: A randomized phase 3 trial. Cancer Cell 2025;43:2259–2267.
- van Dam JL et al. (PREOPANC-3 protocol). Perioperative or adjuvant mFOLFIRINOX for resectable pancreatic cancer (PREOPANC-3): study protocol for a multicenter randomized controlled trial. BMC Cancer 2023;23:728.
- Chawla A et al. (Alliance A021806). A Phase III Trial Evaluating Perioperative Versus Adjuvant Therapy for Resectable Pancreatic Cancer. J Clin Oncol 2023;41:TPS4204.
- Petrelli F, Dottorini L. Perspective on perioperative strategies in resectable pancreatic cancer. ASST Bergamo Ovest, Treviglio, Italy, 2026.
- NCCN Guidelines. Pancreatic Adenocarcinoma. National Comprehensive Cancer Network, Version 2.2026.
This article was created using various editorial tools, including artificial intelligence, as part of the process. It was reviewed by human editors before publication.
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