Uson Junior PLS, Kadakia KC, Araujo RLC. Neoadjuvant treatment in resectable pancreatic cancer: Why is upfront surgery so hard to be beaten? World J Clin Oncol 2025; 16(9): 108955 [PMID: 41024839 DOI: 10.5306/wjco.v16.i9.108955]
Corresponding Author of This Article
Raphael L C Araujo, FACS, MD, PhD, Adjunct Professor, Department of Surgery, Universidade Federal de São Paulo, R. Napoleão de Barros, 715, São Paulo 04024-002, Brazil. raphael.l.c.araujo@gmail.com
Research Domain of This Article
Oncology
Article-Type of This Article
Minireviews
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Pedro Luiz Serrano Uson Junior, Center for Personalized Medicine, Hospital Israelita Albert Einstein, São Paulo 05651901, Brazil
Kunal C Kadakia, Department of Oncology, Levine Cancer Institute, Atrium Health, Charlotte, NC 28204, United States
Raphael L C Araujo, Department of Surgery, Universidade Federal de São Paulo, São Paulo 04024-002, Brazil
Raphael L C Araujo, Department of Surgery, Hepato-pancreato-biliary Service, Carolinas Medical Center, Atrium Health, Charlotte, NC 28204, United States
Author contributions: Uson Junior PLS, Kadakia KC, and Araujo RLC contributed to the study conception, data preparation, data interpretation, and critical writing.
Conflict-of-interest statement: All authors declare that they have no conflict of interest to disclose.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Raphael L C Araujo, FACS, MD, PhD, Adjunct Professor, Department of Surgery, Universidade Federal de São Paulo, R. Napoleão de Barros, 715, São Paulo 04024-002, Brazil. raphael.l.c.araujo@gmail.com
Received: April 27, 2025 Revised: May 23, 2025 Accepted: August 12, 2025 Published online: September 24, 2025 Processing time: 149 Days and 20.9 Hours
Abstract
Neoadjuvant treatment is being extensively evaluated in pancreatic ductal adenocarcinoma (PDAC). This interest is appropriate given the dismal long-term prognosis for most patients who undergo upfront surgery. Despite prospective, retrospective and randomized trials supporting the role of neoadjuvant therapy in general for PDAC, the long-term benefit specifically for patients with resectable PDAC remains unclear. The phase III PREOPANC trial showed an improvement in overall survival in borderline resectable PDAC with neoadjuvant gemcitabine-based chemoradiation compared to upfront surgery alone, however, no such benefit was observed in the resectable cohort. Notably, three randomized trials (PANACHE01-PRODIGE 48, NORPACT-1, and PREOPANC-2) failed to show a clear improvement in overall survival with a neoadjuvant approach. The ongoing NeoFOL-R, PREOPANC-3, and the Alliance A021806 will help clarify the role of neoadjuvant therapy in resectable PDAC. In this minireview article we summarize the data surrounding neoadjuvant therapy in resectable pancreatic cancer and discuss future considerations of trials in this subgroup.
Core Tip: Upfront surgery remains essential for patients with truly resectable tumors since surgery followed by adjuvant therapy is evidence-based and should not be abandoned. Moreover, current neoadjuvant treatment for resectable lesions with FOLFIRINOX is insufficient due to poor survival outcomes. Better systemic approaches are needed, and germline testing and precision medicine hold promise but are actionable in only a minority of cases, molecular subtyping should be incorporated into future trial designs.
Citation: Uson Junior PLS, Kadakia KC, Araujo RLC. Neoadjuvant treatment in resectable pancreatic cancer: Why is upfront surgery so hard to be beaten? World J Clin Oncol 2025; 16(9): 108955
Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease[1]. In 2022, it was estimated to be around 510566 new cases over the world[2]. Although not in the top ten most common cancer, corresponding to 2.6% of all sites of cancer, it is the sixth leading cause of cancer related death, behind lung, colorectal, liver, breast and gastric cancer[2]. Further, the mortality is increasing, slight particularly in men[3]. The five-year expected survival rate is low, about 5%-10%[4]. This is largely because most patients are diagnosed with unresectable or metastatic disease[1]. Surgery is the only possibility of cure, however, only about 30% of the patients are eligible to surgery[5]. Chemotherapy has been used in the perioperative setting, and improvements have been made[6,7].
Adjuvant chemotherapy or neoadjuvant chemotherapy for patients with resectable PDAC are choices that are being evaluated in randomized trials for resected pancreatic cancer, but negative recent trials impose challenges for neoadjuvant treatment in these settings[8]. For the National Comprehensive Cancer Network (NCCN) and most trials, resectable lesions were generally defined as lesions without arterial contact and with less than 180° of interface between tumor and portal or superior mesenteric veins[9]. In this mini-review article, we will discuss neoadjuvant chemotherapy considering adjuvant data, the landmarks trials in the field of neoadjuvant chemotherapy in resectable pancreatic cancer, and future advances in the field. All studies were included after a search on PubMed/MEDLINE, in March 2025, with the MESH terms pancreatic cancer AND/OR chemotherapy AND neoadjuvant OR adjuvant.
ADJUVANT TREATMENT
Although surgery is still the only curative pathway for most patients with PDAC eligible for surgery, the rate of long-term survivors is only 8%-12% in 5 years, in the absence of adjuvant therapy[10,11]. These outcomes were initially demonstrated in the landmark trial CONKO-001, patients that underwent surgery were randomized to gemcitabine or observation alone[10]. It is important to note that the recruitment of this study started in July 1998, at that time, no adjuvant protocol was standard of care. With a median follow-up of 136 months, the disease-free survival (DFS) was significantly improved with gemcitabine, 13.4 months vs 6.7 months in the observation [hazard ratio (HR), 0.55 (95%CI: 0.44-0.69); P < 0.001]. Adjuvant gemcitabine improved overall survival (OS) [HR, 0.76 (95%CI: 0.61-0.95); P = 0.01], 5-year OS of 20.7% vs 10.4%, and 10-year OS of 12.2% vs 7.7%[10]. Based on this trial, gemcitabine became the standard of care for adjuvant therapy, as listed in Table 1.
Table 1 Studies based on Gemcitabine for adjuvant treatment of resectable pancreatic adenocarcinoma.
After CONKO-001, multiple adjuvant trials were completed (Table 1). The fluoropyrimidines were evaluated in the same setting, in the ESPAC trials[11,12]. In the ESPAC-1 trial, a two-by-two factorial design with resected PDAC, randomly assigned 73 patients to adjuvant chemoradiotherapy alone (20 Gy plus fluorouracil), 75 patients to fluorouracil and 72 patients to both chemoradiotherapy and chemotherapy. A group of 69 patients were included only for observation. Chemotherapy improved OS when compared to chemoradiotherapy and observation, five-year OS was 21% vs 8% in patients who did not receive chemotherapy (P = 0.009)[11].
Further investigations addressed whether fluoropyrimidines would have better results if associated with gemcitabine[12]. The ESPAC-4 study randomized 722 patients to adjuvant treatment with gemcitabine vs gemcitabine combined with capecitabine for 6 cycles. Interestingly, around in both arms 60% of the individuals had positive margins (≤ 1 mm) and accounting for both arms, 80% had positive lymph nodes[12]. Better OS was observed with the combination strategy vs gemcitabine alone group (28 months vs 25.5 months; HR = 0.8, 95%CI: 0.68-0.98; P = 0.03). The estimated five-year OS was 28.8 vs 16.3% in favor of the combination arm. As expected, higher rates of diarrhea, hand-foot syndrome, and neutropenia occurred with the combination. After the trial, this treatment became an important option for the patients[12].
The French phase III study PRODIGE 24 randomized 493 resected patients (R0 or R1) to receive adjuvant gemcitabine or mFOLFIRINOX (fluorouracil, irinotecan and oxaliplatin) for 6 months[6]. DFS, the primary endpoint, was higher in the mFOLFIRINOX group (21.6 months vs 12.8 months; HR = 0.58; 95%CI: 0.46-0.73; P < 0.0001). An update of the study with 69.7 months of follow-up[13] showed a gain in OS (53.5 months vs 35.5 months; HR = 0.64; 95%CI: 0.48-0.86; P = 0.003) and 5-year survival rates of 43.2% (95%CI: 36.5-49.7) and 31.4% (95%CI: 25.5-37.5) in favor of the FOLFIRINOX arm. Histological grade, tumor stage, and patient age were independent prognostic factors for GS. Completion of all 12 treatment cycles (regardless of dose duration and intensity) was also associated with more prolonged OS (HR = 0.64; 95%CI: 0.49-0.84; P < 0.002). Grade 3-4 adverse events were more common in the mFOLFIRINOX arm, reported in 51.1% vs 75.5%, including 12% grade 4 in each arm, with one death per toxicity in the gemcitabine arm. Thus, mFOLFIRINOX should be considered the standard after resection in individuals with pancreatic adenocarcinoma with a good performance status[13].
The phase III APACT study randomized 866 patients submitted to pancreatic cancer for PDAC, to 6 cycles of adjuvant QT with gemcitabine plus nanoparticulate paclitaxel vs gemcitabine[14]. The combination did not result in a significant gain in progression-free survival (PFS) by central review, the primary objective of the study (19.4 months vs 18.8 months; HR = 0.88; P = 0.18). However, there was a significant gain in PFS in the researchers' analysis (16.6 months vs 13.7 months; HR = 0.82; 95%CI: 0.69-0.96; P = 0.02). A recent publication, with 5 years of follow-up, showed a significant gain in OS (41.8 months vs 37.7 months; HR = 0.80; 95%CI: 0.67-0.94; P = 0.009) with adjuvant therapy with gemcitabine plus nanoparticulate paclitaxel. Despite the gain in OS, this is a conceptually negative study, as it did not achieve its primary objective[14].
Finally, another important study, the phase III study JASPAC 01, carried out with an exclusively Asian population, demonstrated superiority of adjuvant S-1 over gemcitabine (HR = 0.57; P < 0.0001 for superiority)[15].
NEOADJUVANT TREATMENT FOR RESECTABLE DISEASE
Neoadjuvant chemotherapy is considered by multiple guidelines for patients with resectable tumors who have high-risk features for systemic disease, including elevated preoperative carbohydrate antigen 19-9 (CA19-9), large primary tumors, enlarged peripancreatic lymph nodes, significant weight loss, or severe pain[16]. These recommendations are largely based on retrospective studies demonstrating poor outcomes in patients with such features, highlighting the importance of distinguishing between radiographic resectability and true biologic resectability. Recommended neoadjuvant regimens include modified FOLFIRINOX or gemcitabine plus nanoparticulate paclitaxel, with or without radiation therapy[8]. However, despite these recommendations, randomized trials have not shown an overall survival benefit for neoadjuvant therapy in resectable PDAC[8].
The phase III PREOPANC-1 study randomized 246 patients with resectable or borderline disease to either surgery or neoadjuvant chemotherapy plus radiotherapy, that consisted of 15 fractions of 2.4 Gy combined with gemcitabine, preceded and followed by a cycle of gemcitabine alone[7]. Both arms received adjuvant chemotherapy with gemcitabine, with 6 cycles in the surgery arm and 4 additional cycles of gemcitabine in the preoperative treatment arm. In the study update, OS was better in patients that received neoadjuvant treatment (HR = 0.73; 95%CI: 0.56-0.96; P = 0.02). Although the absolute difference in OS was only 1.4 months (15.7 months vs 14.3 months). The 5-year OS was 20.5% (95%CI: 14.2-29.8) for the neoadjuvant arm and only 6.5% for the upfront surgery arm (95%CI: 3.1-13.7). However, in the subgroup analysis, neoadjuvant treatment did not improve OS in resectable PDAC (HR = 0.79; IC de 95%: 0.54-1.16; P = 0.23), the positive results were mainly due borderline PDAC[17,18], as demonstrated in Table 2.
Table 2 Randomized Clinical trials of neoadjuvant treatment for resectable pancreatic adenocarcinoma.
The randomized phase II SWOG S1505 study evaluated 147 patients with resectable pancreatic cancer. The primary goal was to compare two neoadjuvant regimens — modified FOLFIRINOX and gemcitabine plus nanoparticulate paclitaxel — rather than to establish superiority. Both arms demonstrated similar outcomes, with a median OS of 22.4 and 23.6 months, respectively, and an R0 resection rate of 85%. Additionally, 25% of patients in the mFOLFIRINOX arm and 42% in the gemcitabine/nab-paclitaxel arm achieved a significant or complete pathologic response. Relapse-free survival was modest, at 14.2 months vs 10.9 months, respectively[17].
The S1505 results provide important context when comparing outcomes between neoadjuvant and adjuvant strategies. In PRODIGE 24, patients had already undergone surgery and recovered sufficiently to receive adjuvant therapy, introducing a degree of immortal time bias. In contrast, S1505 enrolled patients at diagnosis, capturing a broader and potentially less selected population. Another important observation was that contrary to expectations based on metastatic disease outcomes, mFOLFIRINOX did not demonstrate clear superiority over gemcitabine/nab-paclitaxel in the neoadjuvant setting.
Separately, the German AIO-NEONAX study randomized 127 patients with resectable disease to either perioperative treatment (two cycles preoperatively and four postoperatively) or adjuvant treatment alone with six cycles of gemcitabine plus nanoparticulate paclitaxel. The primary endpoint — 55% PFS at 18 months — was not met in either arm. However, perioperative treatment was associated with higher R0 resection rates (87.8% vs 67.4%), longer OS (25.5 months vs 16.7 months), and improved DFS (11.5 months vs 5.9 months)[18].
In the phase II study PANACHE01-PRODIGE 48, 153 patients with resectable tumor were randomized (2:2:1) to 4 cycles of neoadjuvant FOLFIRINOX or FOLFOX (discontinued due to lower efficacy) or surgery followed by adjuvant treatment[21]. The trial did not achieve the main objective, which was expected to be improved survival at 1 year for the neoadjuvant arms. However, the rates of PFS at 1 year (51.4, 43.1, and 41.7%, respectively) and median PFS (12.4, 11, and 9.2 months, respectively) numerically favored FOLFIRINOX[19].
The findings from the NORPACT-1 trial and PREOPANC -2 trials are particularly notable in addressing the role of neoadjuvant therapy for resectable PDAC. In the randomized phase II NORPACT-1, 140 patients with resectable tumors (by NCCN criteria) were randomized to perioperative FOLFIRINOX or upfront surgery followed by adjuvant FOLFIRINOX, with the primary objective of demonstrating superiority. Although perioperative chemotherapy resulted in higher rates of R0 resection (56% vs 39%) and N0 nodal status (29% vs 14%), there was no benefit in OS — in fact, median OS was numerically lower in the perioperative arm (25.1 months) compared to upfront surgery (38.5 months) (HR = 1.52; P = 0.09)[20]. It is important to note that the longer survival observed in the upfront surgery arm may reflect patient selection bias or the impact of surgical clearance before systemic therapy exposure, though further analyses are needed.
Similarly, the PREOPANC-2 trial evaluated neoadjuvant chemoradiotherapy with either gemcitabine- or FOLFIRINOX-based regimens in patients with resectable or borderline tumors. The majority (60%-70%) of enrolled patients had resectable tumors. Despite high compliance rates, the median survival in both arms was approximately 21 months — relatively lower than observed in other contemporary studies — and thus the data do not support FOLFIRINOX as a standard neoadjuvant approach for resectable PDAC[21].
Additional studies evaluating neoadjuvant strategies for resectable PDAC are summarized in Table 2[22-26]. A recent meta-analysis by our group, including these trials, found that while neoadjuvant therapy improved R0 resection rates by approximately 20%, it did not result in improved OS or DFS in the overall population[8].
CONCLUSION
The rationale for neoadjuvant therapy in potentially resectable pancreatic cancer follows the principles applied in other high-risk malignancies and is summarized in Table 3. However, after multiple negative randomized trials evaluating neoadjuvant therapy in resectable PDAC, several critical questions arise regarding optimal management.
Table 3 Rational regarding putative pros cons of neoadjuvant treatment for both resectable and borderline pancreatic adenocarcinoma.
Advantages
Disadvantages
Delivery of systemic therapy
Complications of pre-treatment procedures (biopsy, stents, etc.)
Increased efficacy of radiation
Occasional limiting toxicity due the treatment delaying surgical treatment
Removal of irradiated tissues
Occasional drop out due to either limiting toxicity or tumor progression
Increasing in R0 rates
No proven benefit for resectable lesions in randomized clinical trials
In the rare subset of patients with truly radiographically resectable disease — like those included in the PRODIGE cohort — upfront surgery followed by adjuvant therapy remains a valid and evidence-based approach. Long-term survival rates after neoadjuvant FOLFIRINOX remain unacceptably low and do not justify excluding surgery-first pathways. Thus, the current “standard of care” should not be viewed as sufficient; better strategies are urgently needed to improve outcomes.
Given the limitations of existing systemic therapies, several groups have explored precision medicine strategies. However, actionability in PDAC remains rare, largely derived from the identification of homologous recombination deficiency[27]. It is estimated that 10%-15% of patients with PDAC harbor pathogenic germline mutations, with only about 5%-8% demonstrating BRCAness[27]. While platinum-based chemotherapy can yield dramatic and durable responses in BRCA-mutated PDAC, as demonstrated in multiple studies, the role of BRCA status in early-stage disease remains less clear[28-30]. Nevertheless, consistent with NCCN guidelines, all patients with newly diagnosed PDAC should undergo germline testing, as these patients represent a biologically distinct subgroup across all stages of disease.
New molecular subtyping models have also emerged, notably those described in the COMPASS trial, which performed whole genomic sequencing and transcriptomic analysis to identify two dominant subtypes: Classical and basal-like PDAC[31]. Classical tumors, characterized by GATA6 expression, appear more sensitive to FOLFIRINOX, while basal-like tumors, lacking GATA6 expression, may respond better to gemcitabine plus nab-paclitaxel. These findings suggest that the absence of biological selection may explain negative results seen in both the neoadjuvant and metastatic settings and underscore the need for molecularly informed trial designs moving forward.
The PASS-1 trial further explored this concept by prospectively conducting upfront multi-omics profiling in patients with advanced PDAC before randomization to FOLFIRINOX or gemcitabine/nab-paclitaxel[32]. Approximately 20% of patients were classified as basal-like — a group unlikely to benefit from FOLFIRINOX — while about 50% had classical tumors. Importantly, differences in chemotherapy response correlated with these molecular subtypes. Although a proof-of-concept study, PASS-1 demonstrated the feasibility of upfront molecular profiling and suggested a path forward for more personalized systemic treatment strategies, including in the neoadjuvant setting.
Despite these advances, several ongoing trials, including NCT05529940, PREOPANC-3 (NCT04927780), and Alliance A021806 (NCT04340141), are evaluating neoadjuvant FOLFIRINOX without incorporating molecular selection and may yield similar negative outcomes. However, small studies are beginning to integrate PDAC molecular signatures into neoadjuvant decision-making (e.g., NCT03977233), signaling a potential paradigm shift. In the future, precision medicine approaches — alone or combined with chemotherapy and radiation — may guide multidisciplinary treatment strategies for both resectable and borderline lesions, as depicted in Figure 1.
Importantly, improving outcomes in resectable PDAC will not solely depend on new drugs but on better biological selection and smarter trial design. Additional strategies must also include: (1) Identifying patients at risk of early relapse through biomarkers such as circulating tumor cells and CA19-9; (2) Refining neoadjuvant regimens beyond current standards; (3) Profiling patients who achieve exceptional long-term survival; and (4) Preserving functional status through supportive care interventions during therapy. Ethical considerations must remain central — systemic therapy should not be reflexively administered to all patients with radiographically resectable disease, especially those lacking high-risk features. Our responsibility as clinicians is to balance toxicity, survival benefit, and quality of life with a patient-centered, evidence-driven approach.
Nowadays, accordingly to guidelines including NCCN[9], American Society of Clinical Oncology[33] and European Society of Medical Oncology[34], neoadjuvant treatment including chemotherapy and/or radiotherapy for resectable pancreatic cancer could be performed, particularly in patients with high-risk features i.e. equivocal or indeterminate imaging findings, elevated CA19-9, large primary tumors or regional lymph nodes, excessive weight loss or extreme pain.
Footnotes
Provenance and peer review: Invited article; Externally peer reviewed.
Peer-review model: Single blind
Corresponding Author's Membership in Professional Societies: American Hepato-Pancreato-Biliary Association; International Hepato-Pancreato-Biliary Association; Society for Surgery of the Alimentary Tract; and American College of Surgeons.
Specialty type: Oncology
Country of origin: Brazil
Peer-review report’s classification
Scientific Quality: Grade B, Grade B
Novelty: Grade B, Grade B
Creativity or Innovation: Grade B, Grade B
Scientific Significance: Grade A, Grade A
P-Reviewer: Yang WY, Assistant Professor, MD, PhD, China S-Editor: Liu JH L-Editor: A P-Editor: Wang WB
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