Neoadjuvant Therapy for Resectable and Borderline Resectable Pancreatic Cancer

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers, with poor survival even after surgical resection. Clinical stages include resectable (R-PDAC), borderline resectable (BR-PDAC), locally advanced, and metastatic disease. Neoadjuvant therapy (NAT)—chemotherapy or chemoradiotherapy before surgery—has emerged as a promising strategy to improve outcomes by increasing margin-negative resection rates and enhancing overall survival. For R-PDAC, surgery followed by adjuvant chemotherapy remains the standard, but NAT may be considered in high-risk patients, such as those with severe pain, elevated CA 19-9, or large tumors. For BR-PDAC, NAT is the primary approach, significantly increasing R0 resection rates and prolonging survival. Common regimens include mFOLFIRINOX and gemcitabine-based combinations. NAT also carries risks, including disease progression during therapy, loss of resectability, and uncertainty in evaluating response. Current tools, such as imaging and CA 19-9, offer limited predictive value. The role of NAT in R-PDAC remains under debate, while its benefits in BR-PDAC are more established. This review summarizes current evidence and guidelines on NAT in PDAC, with a focus on treatment strategies, patient selection, and emerging approaches.

1. Introduction

Pancreatic cancer remains one of the greatest challenges in modern oncology. It is currently the fourth leading cancer-related cause of death among men and the third in the female population in the United States [1]. By 2030, it is projected to become the second leading cancer-related cause of death in this country [2]. The most common histological type of pancreatic cancer is pancreatic ductal adenocarcinoma (PDAC), which accounts for approximately 90% of diagnoses [3]. The five-year survival rate for this cancer is only around 13%, largely due to the advanced stage of the disease at the time of diagnosis and limited treatment options available [1].

In clinical practice, PDAC is classified based on anatomical resectability, which directly influences treatment planning. According to current guidelines, including those of the National Comprehensive Cancer Network (NCCN) and European Society for Medical Oncology (ESMO), the disease is divided into the following categories [4,5]:

• Resectable PDAC (R-PDAC)—These tumors that do not involve major peripancreatic vessels (such as the superior mesenteric artery (SMA), celiac axis, or portal vein) and can be removed surgically with a high likelihood of achieving R0 resection (no microscopic residual tumor). There are no distant metastases.
• Borderline resectable PDAC (BR-PDAC)—These tumors demonstrate limited contact with surrounding vessels, such as ≤180° involvement of the SMA or celiac axis, or short segment occlusion of the portal or superior mesenteric vein, where vascular reconstruction is feasible. These tumors are technically resectable but carry a higher risk of incomplete resection (R1).
• Locally advanced PDAC—These tumors involve extensive vascular encasement or occlusion without possibility of reconstruction, precluding curative surgery.
• Metastatic PDAC—These are characterized by the presence of distant metastases, such as to the liver, peritoneum, or lungs, which excludes the possibility of curative surgical intervention.

All PDAC cases can be classified into one of these categories based on anatomical criteria, which are detailed in the following chapter.

Only about 13.8% of PDAC cases are diagnosed at a resectable stage, where surgical intervention offers the chance for longer survival [1]. One promising approach is neoadjuvant therapy (NAT), which involves administering systemic chemotherapy or chemoradiotherapy (CRT) before surgery. This method can potentially improve outcomes by increasing the rate of complete tumor resection (R0 resection), reducing recurrence rates through the elimination of micro-metastases, and facilitating surgical intervention with tumor shrinking.

On the other hand, this approach is associated with a delay in surgery, and during this time, some patients may experience disease progression, making the tumor unresectable [6,7]. In recent years, this approach has been the focus of numerous studies, yielding different results.

2. Tumor Resectability Criteria

Before surgery, it should be carefully assessed whether the pancreatic tumor is resectable [8]. Such criteria have been formulated by organizations including the NCCN [4], MD Anderson Cancer Center (MDACC) [9], Japan Pancreas Society (JPS) [10], Americas Hepato-Pancreato-Biliary Association, the Society of Surgical Oncology and the Society for Surgery of the Alimentary Tract (AHPBA/SSO/SSAT) [11]. Each of these scales may be applied to tumors of the different pancreatic sections [7]. Criteria of different scientific societies differ slightly from each other and are based on the anatomy of the primary tumor and its relationships to the key vessels, including the superior mesenteric vein, portal vein, SMA, common hepatic artery and its first-order branches, and the coeliac trunk [7]. The detailed criteria developed by the various societies are shown in Table 1. Different resectability criteria based on computer tomography (CT) or magnetic resonance imaging (MRI) were proposed by different medical societies. However, it is worth noting that those criteria have particularly high positive predictive value (90–100%) only when the tumor is unresectable. When it is resectable, the positive predictive value is unsatisfactory (45–75%), which means that in a significant proportion of patients, intraoperatively, it turns out that the tumor is finally unresectable [12]. Surgical resection remains the only treatment offering a chance of cure and the most effective way of prolonging survival. As a result, surgery is often performed even when resectability is uncertain and the tumor may ultimately turn out to be inoperable. The risk is taken in the hope that the patient will benefit; however, in a significant number of cases, this results in non-therapeutic laparotomies that do not improve prognosis. These procedures expose patients with limited life expectancy to postoperative morbidity and a significant, albeit temporary, reduction in quality of life [13].

The first radiological criteria describing BR-PDAC were published in 2005 [14]. In 2016, the International Association of Pancreatology (IAP) expanded this definition by introducing biological and conditional factors, in addition to anatomical characteristics. According to these findings, if a tumor meets the anatomical conditions for resectability but additional biological or conditional factors are present, the tumor should be classified as borderline resectable. Biological factors mean those associated with suspected distant metastases that are not clearly demonstrated. These include CA 19-9 level of more than 500 units/mL or regional lymph nodes metastasis diagnosed by biopsy or positron emission tomography (PET-CT). Conditional factors are derived from an assessment of the patient’s general condition, with an Eastern Cooperative Oncology Group Performance Status (ECOG) score of more than 2 [15]. Work is also underway to introduce more factors that can help assess the resectability. At the 2021 Japanese Society of Hepato-Biliary-Pancreatic Surgery (JSHBPS), among other things, the use of genetic markers such as microsatellite instability or BRCA1 or BRCA2 was considered, which could enable the prediction of treatment response and personalized therapy [16]. For example, BRCA mutation has been shown to be associated with a favorable prognosis in case of patients with BR-PDAC after neoadjuvant FOLFIRINOX before surgery, which is likely related to the increased sensitivity of BRCA-mutated tumors to platinum-based chemotherapy [17].

Table 1. Anatomical criteria of resectability according to different Guidelines [4,9,11,15].

	Anatomical Structure	NCCN	MDACC	AHPBA/SSO/SSAT	IAP
Resectable	SMA	No tumor contact	No extension; normal fat plane between the tumor and the artery	Clear fat planes around the SMA	No tumor contact
	CA and CHA	No tumor contact	No extension	Clear fat planes around the CA and PHA	No tumor contact
	SMV and PV	No tumor contact, with or ≤180° contact without vein contour irregularity.	Patent	No radiographic evidence abutment, distortion, tumor thrombus, or venous encasement.	No tumor contact, or unilateral narrowing
Borderline resectable	SMA	Solid tumor contact, with the SMA of ≤180°.	Tumor abutment ≤ 180°	Tumor abutment of the SMA not to exceed 180°	tumor contact of less than 180° without showing deformity/stenosis.
	CA and CHA	Solid tumor contact, with CHA without extension to CA or PHA bifurcation allowing for safe and complete resection and reconstruction Solid tumor contact, with variant arterial anatomy	Short-segment encasement/abutment of the CHA (typically at the gastroduodenal origin); the surgeon should be prepared for vascular resection/interposition grafting	Gastroduodenal artery encasement up to the PHA with either short segment encasement or direct abutment of the PHA without extension to the CA	CA: tumor contact of less than 180° without showing deformity/stenosis. CHA: tumor contact without showing tumor contact of the PHA and/or CA.
	SMV and PV	Solid tumor contact, of >180° or contact of ≤180° with contour irregularity or thrombosis but allowing for safe and complete resection and vein reconstruction or Solid tumor contact, with the IVC	Short-segment occlusion with suitable vessel above and below; segmental venous occlusion alone without SMA involvement is rare and should be apparent on CT images	Tumor abutment, narrowing of the lumen, encasement of the SMV/PV but without encasement of the nearby arteries, or short segment venous occlusion with suitable vessel proximal and distal to the area of vessel involvement, allowing for safe resection and reconstruction	tumor contact 180 or greater or bilateral narrowing/occlusion, not exceeding the inferior border of the duodenum.
Locally advanced	SMA	Solid tumor contact > 180°	Encased (>180°)	Encasement	Tumor contact/invasion of 180 or more degree.
	CA and CHA	Solid tumor contact > 180° Solid tumor contact, with the CA and aortic involvement	Encased and no technical option for reconstruction usually because of extension to the CA/splenic/left gastric junction or the celiac origin	Unreconstructable	CA: tumor contact/invasion of ≥180° CHA: tumor contact/invasion showing tumor contact/invasion of the PHA and/or CA. Tumor contact or invasion of Aorta
	SMV and PV	Not currently amenable to resection and primary reconstruction due to complete occlusion of SMV/PV	Occluded and no technical option for reconstruction	Unreconstructable	Bilateral narrowing/occlusion, exceeding the inferior border of the duodenum

SMA—Superior Mesenteric Artery, CA—Celiac Axis, CHA—Common Hepatic Artery, SMV—Superior Mesenteric Vein, PV—Portal Vein, IVC—Inferior Vena Cava, and PHA—Proper Hepatic Artery.

Table 1. Anatomical criteria of resectability according to different Guidelines [4,9,11,15].

	Anatomical Structure	NCCN	MDACC	AHPBA/SSO/SSAT	IAP
Resectable	SMA	No tumor contact	No extension; normal fat plane between the tumor and the artery	Clear fat planes around the SMA	No tumor contact
	CA and CHA	No tumor contact	No extension	Clear fat planes around the CA and PHA	No tumor contact
	SMV and PV	No tumor contact, with or ≤180° contact without vein contour irregularity.	Patent	No radiographic evidence abutment, distortion, tumor thrombus, or venous encasement.	No tumor contact, or unilateral narrowing
Borderline resectable	SMA	Solid tumor contact, with the SMA of ≤180°.	Tumor abutment ≤ 180°	Tumor abutment of the SMA not to exceed 180°	tumor contact of less than 180° without showing deformity/stenosis.
	CA and CHA	Solid tumor contact, with CHA without extension to CA or PHA bifurcation allowing for safe and complete resection and reconstruction Solid tumor contact, with variant arterial anatomy	Short-segment encasement/abutment of the CHA (typically at the gastroduodenal origin); the surgeon should be prepared for vascular resection/interposition grafting	Gastroduodenal artery encasement up to the PHA with either short segment encasement or direct abutment of the PHA without extension to the CA	CA: tumor contact of less than 180° without showing deformity/stenosis. CHA: tumor contact without showing tumor contact of the PHA and/or CA.
	SMV and PV	Solid tumor contact, of >180° or contact of ≤180° with contour irregularity or thrombosis but allowing for safe and complete resection and vein reconstruction or Solid tumor contact, with the IVC	Short-segment occlusion with suitable vessel above and below; segmental venous occlusion alone without SMA involvement is rare and should be apparent on CT images	Tumor abutment, narrowing of the lumen, encasement of the SMV/PV but without encasement of the nearby arteries, or short segment venous occlusion with suitable vessel proximal and distal to the area of vessel involvement, allowing for safe resection and reconstruction	tumor contact 180 or greater or bilateral narrowing/occlusion, not exceeding the inferior border of the duodenum.
Locally advanced	SMA	Solid tumor contact > 180°	Encased (>180°)	Encasement	Tumor contact/invasion of 180 or more degree.
	CA and CHA	Solid tumor contact > 180° Solid tumor contact, with the CA and aortic involvement	Encased and no technical option for reconstruction usually because of extension to the CA/splenic/left gastric junction or the celiac origin	Unreconstructable	CA: tumor contact/invasion of ≥180° CHA: tumor contact/invasion showing tumor contact/invasion of the PHA and/or CA. Tumor contact or invasion of Aorta
	SMV and PV	Not currently amenable to resection and primary reconstruction due to complete occlusion of SMV/PV	Occluded and no technical option for reconstruction	Unreconstructable	Bilateral narrowing/occlusion, exceeding the inferior border of the duodenum

SMA—Superior Mesenteric Artery, CA—Celiac Axis, CHA—Common Hepatic Artery, SMV—Superior Mesenteric Vein, PV—Portal Vein, IVC—Inferior Vena Cava, and PHA—Proper Hepatic Artery.

3. PDAC Management Options

Patients with potentially R-PDAC, no signs of metastatic spread, adequate performance status and comorbidity profile should be considered for primary surgical resection of the tumor and regional lymph nodes [18]. However, despite complete (R0) resection, the prognosis remains poor, with 5-year overall survival (OS) rates rarely exceeding 20% [4,19]. Median OS after surgery ranges from 15 to 24 months, depending on tumor stage, lymph node involvement, and the use of adjuvant therapies [20].

This poor prognosis, despite radical surgery, reflects the biological aggressiveness of PDAC and the high likelihood of occult micrometastatic disease at the time of diagnosis [19]. PDAC is a biologically invasive cancer, leading to the occurrence of perineural and lymphovascular invasion even in relatively small tumors [21]. Rhim et al. [22] conducted a study in genetically engineered mice (KPC model, carrying pancreas-specific mutations in Kras and p53) where they traced pancreatic epithelial cells. The authors showed that pancreatic epithelial cells acquire mesenchymal characteristics, stem-like features and the ability to colonize liver, before cancerous cells in the pancreas were detectable in histological analysis. The process was exacerbated by pancreatic inflammation, and induction of pancreatitis increased the number of circulating cells. These findings challenge the traditional view of metastasis as a late event in tumor progression [23].

Over the past three decades, the role of chemotherapy in PDAC has evolved substantially [24], driven by a series of pivotal clinical trials. One of the most significant early milestones in this evolution was the ESPAC-1 trial, which provided the first high-level evidence supporting the use of adjuvant chemotherapy following curative-intent resection [25].

The adjuvant chemotherapy is recommended for all patients who did not receive neoadjuvant therapy (administered prior to surgery) and have an adequate performance status following resection [18]. According to the NCCN guidelines, for patients with good performance status ECOG 0–1, the preferred regimen is mFOLFIRINOX (consisting of oxiplatin, irinotecan, leucovorin and 5-fluorouracil (5-FU), administered in modified doses to improve tolerability compared to the standard FOLFIRINOX regimen). In patients who are not candidates for aggressive combination therapy due to poor performance status or comorbidities, gemcitabine or 5-FU-based monotherapy is considered a reasonable alternative. In selected cases, gemcitabine plus capecitabine may also be used. Adjuvant treatment should be introduced once the patient has sufficiently recovered from surgery, ideally within 12 weeks postoperatively. Treatment selection should be guided by the patient’s performance status, comorbidities, surgical recovery, and potential toxicity profiles of each regimen. The duration of adjuvant chemotherapy is typically six months [4].

The same combination regimens are recommended by ESMO, American Society of Clinical Oncology (ASCO), and the Polish Society of Gastroenterology [5,18,26]. The ESMO guidelines emphasize that mFOLFIRINOX should be used in all patients who are fit for intensive chemotherapy, generally under the age of 75; however, age alone should not be a strict exclusion criterion. Treatment decisions should be based on a comprehensive assessment of fitness rather than chronological age alone [5].

The role of adjuvant CRT in R-PDAC remains a subject of ongoing debate. According to the Polish Society of Gastroenterology, routine use of adjuvant CRT is not recommended [18]. However, according to the ASCO guidelines, it may be considered in selected cases, particularly in patients with positive surgical margins (R1 resection), occurrence of metastases to lymph nodes, and after administering 4–6-month adjuvant chemotherapy [26]. According to the ESMO guidelines, postoperative chemoradiation is not recommended outside the context of clinical trials [5].

4. NAT in R-PDAC

For clearly resectable tumors without high-risk features, current guidelines from major societies—including NCCN, ESMO, ASCO, and the Polish Society of Gastroenterology—still support upfront surgery (US) followed by adjuvant chemotherapy as the standard of care [4,5,18,26]. However, for R-PDAC, NAT may be considered for selected patients, especially those with comorbidities or reversible conditions delaying surgery, large tumors, markedly elevated CA 19-9 levels, or severe pain [4,5]. NAT may enable early control of systemic disease, increase R0 resection rates, and help select surgical candidates. However, risks include tumor progression during therapy and delays to surgery [27,28]. Randomized clinical trials assessing the efficacy of NAT in this group are summarized below and in Table 2.

To date, there have been few studies evaluating the use of NAT in patients with R-PDAC. In the NORPACT-1 study, 140 patients were randomly assigned to either the neoadjuvant FOLFIRINOX group or the US group, followed by adjuvant chemotherapy. The NAT involved four cycles of FOLFIRINOX, after which patients underwent surgery and further received adjuvant chemotherapy. In the other group, patients underwent surgery first and then received adjuvant chemotherapy. Adjuvant therapy, including gemcitabine and capecitabine, was administered in four cycles for the neoadjuvant FOLFIRINOX group and in six cycles for the US group. In this analysis, median OS in the neoadjuvant group was 25.1 months, compared to 38.5 months in the US group (p = 0.050), showing no significant survival benefit with NAT. One factor that may have impacted these results is that only 61% of patients in the neoadjuvant FOLFIRINOX group completed all four cycles due to toxicity, declines in performance status, or early deaths. Moreover, some patients received a suboptimal dose of chemotherapy. The secondary analysis included only those who received all the assigned treatment. In this group, median OS was 23.0 months for the NAT group versus 34.4 months for the US group (p = 0.058), with no survival gain with NAT as well [29].

Similarly, the NEONAX study failed to meet its primary endpoint, which was to achieve disease-free survival (DFS) of 18 months in 55% of patients. It included 166 patients and compared the perioperative use of gemcitabine plus nab-paclitaxel with the same drugs used only as adjuvant treatment. DFS rates at 18 months were 30.8% in the NAT group and 19.3% in the adjuvant therapy group, but the difference did not reach statistical significance. The secondary endpoint was OS, for which the median OS was 25.5 months in the perioperative arm and 16.7 months in the US arm, in the intention-to-treat population (ITT). While numerically higher in the perioperative group, the difference did not reach statistical significance [30]. Lack of statistically significant differences between groups was met with criticism, particularly regarding the interpretation of the study’s clinical relevance. Also, a major point of criticism was the low proportion of patients who completed the full intended treatment regimen in both study arms. About 90% of patients in the perioperative chemotherapy arm completed neoadjuvant treatment, only approximately 63% proceeded to surgery, and of those, around 65% completed adjuvant chemotherapy. As a result, only about 40% of patients in the perioperative group received the full planned treatment regimen. In the adjuvant-only arm, only about 42% of patients initiated adjuvant chemotherapy after surgery [31]. In the response, the NEONAX investigators pointed out that the low rate of postoperative chemotherapy initiation reflects a broader challenge in the treatment of pancreatic cancer—many patients are not fit to undergo adjuvant therapy after surgery because of toxicity, progression, or performance decline [32].

In contrast to these negative or inconclusive findings, the Italian PACT-15 trial reported more promising results. This study compared three treatment strategies: adjuvant treatment with gemcitabine monotherapy, adjuvant treatment with PEXG (consisting of cisplatin, epirubicin, gemcitabine, and capecitabine), and perioperative PEXG (three cycles before and three cycles after surgery). In the group where PEXG was used perioperatively, R0 resections were achieved in 17 of 27 patients (63%). This was notably higher compared to 6 of 22 (27%) in the gemcitabine group and 10 of 27 (37%) in the adjuvant PEXG group. Furthermore, significant differences were observed in median OS, with adjuvant gemcitabine at 20.4 months, adjuvant PEXG at 26.4 months, and neoadjuvant PEXG at 38.2 months. A similar pattern emerged for the 5-year survival rate, ranging from 13% to 24% and 49%, respectively. Taken together, these findings suggest a potential survival advantage for intensified perioperative chemotherapy with PEXG in patients with R-PDAC. However, the trial’s small sample size limits statistical power. Consistent with NEONAX and NORPACT-1 study, PACT-15 also demonstrated that up to half of patients in the adjuvant arms were unable to complete planned postoperative therapy due to surgical complications or early disease progression, underlining one of the advantages of the perioperative approach [33].

While randomized evidence remains inconclusive, retrospective analyses such as the work of Mokdad et al. [34] have suggested a potential survival advantage for NAT. In their study using National Cancer Database data from 2006 to 2012, the authors identified more than 2000 patients who underwent NAT followed by resection and compared them with over 12,000 patients treated with US. Median OS was significantly longer in the NAT group (26 vs. 21 months), and this benefit was consistent across 1-, 3-, and 5-year survival rates (83%, 35%, and 21% for the NAT group, and 71%, 29%, and 18% for the US group, respectively). These results support the feasibility and potential benefit of preoperative systemic treatment in R-PDAC. Importantly survival benefit was achieved without an increase in postoperative risk, supporting the feasibility of preoperative systemic treatment in R-PDAC.

Beyond database analyses, smaller retrospective studies have also evaluated the impact of NAT. Shin et al. [35] analyzed 202 patients with resectable PDAC, of whom 35 received NAT (mainly FOLFIRINOX or gemcitabine-based regimens) followed by surgery. After propensity score matching, both PFS (29.6 vs. 13.2 months) and OS (72.7 vs. 28.3 months) were significantly longer in the NAT group compared with US. NAT was also associated with higher R0 resection rates (74.3% vs. 49.5), and less lymphatic invasion (20.0% vs. 52.4%), supporting a potential survival advantage in this setting.

Recently, the results of a large international multicenter retrospective study involving patients who underwent left-sided pancreatectomy for histologically confirmed R-PDAC were published. The study included 2282 patients; 290 of them (13%) received NAT—most commonly (m)FOLFIRINOX (38%) and gemcitabine-nab-paclitaxel (22%). Patients treated with NAT showed significantly longer median OS (53 vs. 37 months; Δ +16 months) and improved 5-year survival rates (47% vs. 35%; Δ +11%) than those who underwent US. Moreover, the survival benefit of NAT was particularly pronounced among patients with large tumors (≥30 mm) and elevated CA19-9 levels, suggesting its high efficacy in biologically aggressive disease. However, no additional benefit was observed in patients with more locally advanced disease features, such as involvement of the splenic artery, splenic vein, retroperitoneal tissues, or in cases requiring multivisceral resection [36].

Shimane G. et al. [37] recently published a retrospective single-center study in which they evaluated the efficacy of NAT in patients with R-PDAC and sought to identify its negative prognostic factors. The study included 359 patients who underwent surgical resection between 2003 and 2022, among whom 51 patients received NAT. Based on their analysis, five preoperative factors were identified as independent predictors of poor OS: tumor size ≥ 35 mm, serum albumin level ≤ 3.5 g/dL, neutrophil-to-lymphocyte ratio ≥ 3.5, carbohydrate antigen 19-9 level ≥ 250 U/mL, and Duke pancreatic monoclonal antigen type 2 level ≥ 750 U/mL. A cumulative prognostic score was calculated based on these variables. The presence of two or more prognostic factors was associated with markedly reduced survival, with median OS decreasing from 59.0 months to 22.9 months (p < 0.001). When stratified by risk score, NAT was associated with a significant improvement in ITT OS in patients with a prognostic score of ≥ 2 (n = 96) (37.7 vs. 19.7 months; p = 0.006) than the US group. On the other hand, there was no significant survival difference in low-risk patients (score 0–1; n = 263) (55.1 vs. 51.7 months; p = 0.850). However, the R0 resection rate was significantly higher in the neoadjuvant therapy group (70.6%) than in the US group (64.0%), regardless of the risk factors. This study demonstrated that the long-term benefits of NAT in R-PDAC depend on the presence of additional risk factors. It may improve survival among patients with high-risk profiles, as determined by clinical and biochemical parameters. The authors suggest that those risk factors need to be considered in the R-PDAC management decisions [38].

In summary, randomized trials to date have not demonstrated a consistent survival benefit for NAT in R-PDAC, although perioperative strategies such as PACT-15 have yielded encouraging results. Retrospective studies and database analyses suggest a potential advantage, particularly in biologically high-risk subgroups. Overall, NAT in clearly resectable disease should not be considered routine, but rather an individualized option guided by clinical and biochemical risk factors.

Table 2. Randomized clinical trials on neoadjuvant therapy in R-PDAC.

Author	Year	Primary Outcome	Treatment by Group	Number of Patients	Resection Rate (R0 Resection Rate)	Median Overall Survival
Palmer et al. [39]	2007	Resection Rate	Neoadjuvant GEM + Cisplatin	26	70% (46%)	15.6 mth
			Neoadjuvant GEM	24	38% (25%)	9.9 mth
Golcher et al. [40]	2015	OS	Neoadjuvant GEM + Cisplatin + RT (55.8 Gy)	33	57.6% (51.5%)	17.4 mth
			US	33	69.7% (48.5%)	14.4 mth
Casadei et al. [41]	2015	R0 resection rate	Neoadjuvant GEM + RT (45 Gy)	18	61% (38.9%)	22.4 mth
			US	20	75% (25%)	19.5 mth
Reni et al. (PACT-15) [33]	2018	1-year event free	Surgery followed by adjuvant gemcitabine	26	84.6% (23.1%)	20.4 mth
			Surgery followed by adjuvant PEXG	30	90% (33%)	26.4 mth
			Three cycles of PEXG before and three after surgery	32	84.4% (53.1%)	38.2 mth
Unno et al. (Prep-02/JSAP-05) [42]	2019	OS	Neoadjuvant GEM + S1	180	No data available	36.7 mth
			US	182		26.6 mth
Sohal et al. (SWOG S1505) [43]	2021	2-year OS	Neoadjuvant FOLFIRINOX	55	73% (61.2%)	23.2 mth
			Neoadjuvant GEM/nab-PTX	47	70% (59.6%)	23.6 mth
Seufferlein et al. (NEONAX) [30]	2022	DFS at 18 mth	Neoadjuvant GEM/nab-PTX	59	69.5% (87.8%)	25.5 mth
			Upfront surgery and adjuvant GEM/nab-PTX	59	78% (67.4%)	16.7 mth
Sugiura et al. (JASPAC-04) [44]	2023	2-year progression-free survival rate	Neoadjuvant S1 + RT (50.4 Gy)	52	80.3% (78.4%)	37.7 mth 2-year survival rate: 66.7%
			Neoadjuvant Gem + S1	51	88.2% (76.5%)	not reached 2-year survival rate: 72.4%
Labori KJ et al. (NORPACT-1) [29]	2024	OS	Neoadjuvant FOLFIRINOX	77	82% (56%)	25.1 mth
			US	63	89% (39%)	38.5 mth

GEM—gemcitabine, RT—radiotherapy, US—upfront surgery, nab-PTX—nab-paclitaxel, OS—overall survival, and DFS—disease-free survival.

Table 2. Randomized clinical trials on neoadjuvant therapy in R-PDAC.

Author	Year	Primary Outcome	Treatment by Group	Number of Patients	Resection Rate (R0 Resection Rate)	Median Overall Survival
Palmer et al. [39]	2007	Resection Rate	Neoadjuvant GEM + Cisplatin	26	70% (46%)	15.6 mth
			Neoadjuvant GEM	24	38% (25%)	9.9 mth
Golcher et al. [40]	2015	OS	Neoadjuvant GEM + Cisplatin + RT (55.8 Gy)	33	57.6% (51.5%)	17.4 mth
			US	33	69.7% (48.5%)	14.4 mth
Casadei et al. [41]	2015	R0 resection rate	Neoadjuvant GEM + RT (45 Gy)	18	61% (38.9%)	22.4 mth
			US	20	75% (25%)	19.5 mth
Reni et al. (PACT-15) [33]	2018	1-year event free	Surgery followed by adjuvant gemcitabine	26	84.6% (23.1%)	20.4 mth
			Surgery followed by adjuvant PEXG	30	90% (33%)	26.4 mth
			Three cycles of PEXG before and three after surgery	32	84.4% (53.1%)	38.2 mth
Unno et al. (Prep-02/JSAP-05) [42]	2019	OS	Neoadjuvant GEM + S1	180	No data available	36.7 mth
			US	182		26.6 mth
Sohal et al. (SWOG S1505) [43]	2021	2-year OS	Neoadjuvant FOLFIRINOX	55	73% (61.2%)	23.2 mth
			Neoadjuvant GEM/nab-PTX	47	70% (59.6%)	23.6 mth
Seufferlein et al. (NEONAX) [30]	2022	DFS at 18 mth	Neoadjuvant GEM/nab-PTX	59	69.5% (87.8%)	25.5 mth
			Upfront surgery and adjuvant GEM/nab-PTX	59	78% (67.4%)	16.7 mth
Sugiura et al. (JASPAC-04) [44]	2023	2-year progression-free survival rate	Neoadjuvant S1 + RT (50.4 Gy)	52	80.3% (78.4%)	37.7 mth 2-year survival rate: 66.7%
			Neoadjuvant Gem + S1	51	88.2% (76.5%)	not reached 2-year survival rate: 72.4%
Labori KJ et al. (NORPACT-1) [29]	2024	OS	Neoadjuvant FOLFIRINOX	77	82% (56%)	25.1 mth
			US	63	89% (39%)	38.5 mth

GEM—gemcitabine, RT—radiotherapy, US—upfront surgery, nab-PTX—nab-paclitaxel, OS—overall survival, and DFS—disease-free survival.

5. NAT in BR-PDAC

Major guidelines (NCCN, ESMO, ASCO) recommend NAT for BR-PDAC. All endorse mFOLFIRINOX and gemcitabine-based regimens (e.g., with nab-paclitaxel) as acceptable options, depending on performance status, but none of them point out to a single preferred regimen due to insufficient comparative evidence [4,5,26]. The use of neoadjuvant CRT is more selective and may be considered in cases where tumor shrinkage is necessary to achieve resectability [18].

A significant study in the context of BR-PDAC is the meta-analysis conducted by Yang et al. [45]. This study included 117,254 patients with both resectable and BR-PDAC. The paper included 50 studies, including randomized clinical trials, retrospective and prospective cohort studies, and database analyses. NAT was associated with improved OS (HR 0.74), higher R0 resection rates in BR-PDAC (OR 2.36), and lower rates of nodal involvement. Although the proportion of patients ultimately undergoing surgery was lower in the NAT group—likely reflecting progression during therapy—long-term outcomes, including OS and recurrence-free survival, remained superior. Importantly, NAT did not increase postoperative morbidity, supporting its feasibility in BR-PDAC. Other studies that explore this subject are presented below and in Table 3 and Table 4.

NAT in BR-PDAC was evaluated in the ESPAC-5 trial. This randomized phase 2 clinical trial compared four treatments: immediate surgery, neoadjuvant gemcitabine plus capecitabine (GemCap), neoadjuvant FOLFIRINOX, and neoadjuvant CRT (radiotherapy at a total dose of 50.4 Gy and capecitabine). 90 patients were assigned to four groups: immediate surgery (n = 33), GemCap (n = 20), FOLFIRINOX (n = 20), and CRT (n = 17). R0 resection was achieved in 3 of 21 (14%) patients after immediate surgery and in 7 of 30 (23%) who received any NAT before resection (p = 0.49). One-year survival rates were 39% for immediate surgery and 76% for the combined NAT groups (p = 0.0052). Among the NAT groups, one-year survival rates were 84% for FOLFIRINOX, 78% for GemCap, and 60% for CRT. No serious side effects that would disable further treatment were observed in any NAT group. Perioperative complications occurred in 29 of 68 (43%) patients who underwent surgery: 14 of 28 (50%) in the immediate surgery group and 15 of 40 (38%) in all NAT groups combined (p = 0.54). The study did not report which complications were most frequent. No deaths occurred within 30 days of surgery. FOLFIRINOX caused more adverse events than GemCap, but both regimens were better tolerated as neoadjuvant therapy than after resection. Surgical complication rates appeared similar in all study arms. This was the first randomized clinical trial to confirm the favorable effect of NAT on survival in BR-PDAC compared to immediate surgery. It also confirmed that NAT was safe and tolerable for patients. Adding radiotherapy to neoadjuvant chemotherapy did not improve outcomes. The study was published in 2023, but patient recruitment was from 2014 to 2018. Therefore, immediate surgery was also performed in BR-PDAC as the gold standard at that time, although it is not currently recommended [46].

Jang et al. [47] conducted a randomized clinical trial involving patients with BR-PDAC, comparing neoadjuvant CRT (27 patients) with immediate surgery (23 patients), and demonstrated significant differences in favor of the NAT group. In pathological specimens after surgery, the NAT group showed a significantly smaller tumor size, 2.9 cm ± 1.4 cm vs. 3.9 cm ± 0.9 cm (p = 0.014), and a significantly higher R0 resection rate, 82.4% vs. 33% (p = 0.01). The percentage of 1- and 2-year survival and median survival were also higher in the NAT group: 74.1%, 40.7%, and 21 months, compared to 47.8%, 26.1%, and 12 months, respectively, after US. In this study, however, a very similar rate of recurrence at follow-up was observed: 88.2% in the NAT group and 88.9% in the operated group. In addition, metastases were less frequent in the NAT group compared to the surgery-only group, 70.6% vs. 88.9%, but the difference was not statistically significant. On the other hand, a higher rate of loco-regional recurrence was observed in the NAT group (35.3%) compared to the upfront surgery group (27.8%). The study was discontinued after recruiting 50% of the participants due to the clear advantage of NAT, which was already observed at this stage, and the high mortality rate in the second group.

A recent secondary analysis applied a cure model to patients with BR-PDAC treated with NAT followed by radical resection. The estimated statistical cure fraction was approximately 8%, compared with 15% in R-PDAC undergoing US. While the exact time to cure could not be determined for BR-PDAC due to limited follow-up, this modeling approach indicates that a small subset of patients may achieve long-term, recurrence-free survival resembling true cure [48].

In summary, NAT is now considered the standard of care for BR-PDAC, endorsed by all major guidelines. Randomized trials such as ESPAC-5 [46] and Jang et al. [47] have demonstrated improvements in R0 resection rates and survival compared with US, while meta-analyses confirm consistent benefits across large patient populations. Importantly, NAT has proven feasible and safe, with no excess in perioperative morbidity. Nevertheless, key questions remain regarding the optimal chemotherapy backbone and the role of radiotherapy.

Table 3. Randomized clinical trials on neoadjuvant therapy in borderline resectable pancreatic adenocarcinoma.

Author	Year	Primary Outcome	Groups	Number of Patients	Resection Rate (R0 Resection Rate)	Median Overall Survival
Jang et al. [47]	2018	2-year survival rate	Neoadjuvant GEM + RT (45 Gy)	27	63% (51.8%)	22.0 mth
			US	23	78.3% (26.1%)	19.5 mth
Yamaguchi et al. (NUPAT-01) [49]	2022	R0 resection rate	Neoadjuvant FOLFIRINOX	26	88.5% (73.1%)	No data available 3-year overall survival rate: 62.6%
			Neoadjuvant GEM/nab-PTX	25	80% (56%)	No data available 3-year overall survival rate: 55.1%
Katz et al. (ALLIANCE A021501) [50]	2022	18-month overall survival rate	Neoadjuvant mFOLFIRINOX	65	49% (43%)	29.8 mth
			Neoadjuvant FOLFIRINOX + RT (33–40 Gy)	55	35% (25.5%)	17.1 mth
Ghaneh et al. (ESPAC-5) [46]	2023	Resection rate	US	31	68% (9.7%)	No data available 1-year overall survival rate: 39%
			Neoadjuvant FOLFIRINOX	20	55% (10%)	No data available. 1-year overall survival rate: 84%
			Neoadjuvant GemCap	19	57.9% (10.5%)	No data available. 1-year overall survival rate: 78%
			Neoadjuvant Cap + RT (50.4 Gy)	16	50% (18.5%)	No data available 1-year overall survival rate: 60%

GEM—gemcitabine, RT—radiotherapy, US—upfront surgery, nab-PTX—nab-paclitaxel, Cap—capecitabine, and OS—overall survival.

Table 3. Randomized clinical trials on neoadjuvant therapy in borderline resectable pancreatic adenocarcinoma.

Author	Year	Primary Outcome	Groups	Number of Patients	Resection Rate (R0 Resection Rate)	Median Overall Survival
Jang et al. [47]	2018	2-year survival rate	Neoadjuvant GEM + RT (45 Gy)	27	63% (51.8%)	22.0 mth
			US	23	78.3% (26.1%)	19.5 mth
Yamaguchi et al. (NUPAT-01) [49]	2022	R0 resection rate	Neoadjuvant FOLFIRINOX	26	88.5% (73.1%)	No data available 3-year overall survival rate: 62.6%
			Neoadjuvant GEM/nab-PTX	25	80% (56%)	No data available 3-year overall survival rate: 55.1%
Katz et al. (ALLIANCE A021501) [50]	2022	18-month overall survival rate	Neoadjuvant mFOLFIRINOX	65	49% (43%)	29.8 mth
			Neoadjuvant FOLFIRINOX + RT (33–40 Gy)	55	35% (25.5%)	17.1 mth
Ghaneh et al. (ESPAC-5) [46]	2023	Resection rate	US	31	68% (9.7%)	No data available 1-year overall survival rate: 39%
			Neoadjuvant FOLFIRINOX	20	55% (10%)	No data available. 1-year overall survival rate: 84%
			Neoadjuvant GemCap	19	57.9% (10.5%)	No data available. 1-year overall survival rate: 78%
			Neoadjuvant Cap + RT (50.4 Gy)	16	50% (18.5%)	No data available 1-year overall survival rate: 60%

GEM—gemcitabine, RT—radiotherapy, US—upfront surgery, nab-PTX—nab-paclitaxel, Cap—capecitabine, and OS—overall survival.

Table 4. Randomized clinical trials on neoadjuvant therapy in resectable and borderline resectable pancreatic adenocarcinoma.

Author	Year	Primary Outcome	Groups	Number of Patients	Resection Rate (R0 Resection Rate)	Median Overall Survival
Versteijne et al. (PREOPANC-1) [28]	2021	OS	Neoadjuvant GEM + RT (36 Gy)	119	61% (41%)	15.7 mth
			US	127	72% (28%)	14.3 mth
Koerkamp et al. (PREOPANC-2) [51]	2023	OS	Neoadjuvant FOLFIRINOX	188	77% (No data available about R0 resection rate)	21.9 mth
			Neoadjuvant GEM + RT (36 Gy)	187	75% (No data available about R0 resection rate)	21.7 mth
Yamada et al. (CSGO-HBP-015) [52]	2024	2-year progression-free survival	Neoadjuvant GEM/nab-PTX	48	84% (79.2%)	42 mth
			Neoadjuvant GEM + S1	46	72% (65.2%)	22 mth

GEM—gemcitabine, RT—radiotherapy, US—upfront surgery, nab-PTX—nab-paclitaxel, and OS—overall survival.

Table 4. Randomized clinical trials on neoadjuvant therapy in resectable and borderline resectable pancreatic adenocarcinoma.

Author	Year	Primary Outcome	Groups	Number of Patients	Resection Rate (R0 Resection Rate)	Median Overall Survival
Versteijne et al. (PREOPANC-1) [28]	2021	OS	Neoadjuvant GEM + RT (36 Gy)	119	61% (41%)	15.7 mth
			US	127	72% (28%)	14.3 mth
Koerkamp et al. (PREOPANC-2) [51]	2023	OS	Neoadjuvant FOLFIRINOX	188	77% (No data available about R0 resection rate)	21.9 mth
			Neoadjuvant GEM + RT (36 Gy)	187	75% (No data available about R0 resection rate)	21.7 mth
Yamada et al. (CSGO-HBP-015) [52]	2024	2-year progression-free survival	Neoadjuvant GEM/nab-PTX	48	84% (79.2%)	42 mth
			Neoadjuvant GEM + S1	46	72% (65.2%)	22 mth

GEM—gemcitabine, RT—radiotherapy, US—upfront surgery, nab-PTX—nab-paclitaxel, and OS—overall survival.

6. Neoadjuvant Chemotherapy Strategies in PDAC

The development of effective neoadjuvant chemotherapy strategies has become a key area of focus in the management of PDAC. As it was mentioned before, current clinical guidelines—NCCN, ESMO, ASCO—acknowledge NAT as a preferred strategy for patients with BR-PDAC, and as a reasonable option in selected cases, particularly in patients with biologically aggressive disease characterized by elevated CA 19-9 levels, large tumors, low serum albumin, or severe pain. However, none of these guidelines specify a single recommended regimen, reflecting ongoing debate and variability in clinical practice [4,5,26].

The recently published PANACHE01-PRODIGE48 trial was a multicenter, randomized, non-comparative phase II study investigating the feasibility, safety, and preliminary efficacy of two neoadjuvant chemotherapy regimens—mFOLFIRINOX and FOLFOX (containing leucovorin, fluorouracil, and oxaliplatin)—in patients with R-PDAC. Both arms involved four cycles of preoperative chemotherapy followed by surgery and adjuvant treatment. Patients were allocated as follows: 72 to mFOLFIRINOX, 50 to FOLFOX, and 28 to immediate surgery (control arm). The 12-month OS was higher in the mFOLFIRINOX group than in the FOLFOX and US groups (84.3% vs. 71.4% vs. 70.8%, respectively). The full therapeutic sequence (at least two cycles of chemotherapy followed by surgery) was achieved by 70.8% in the mFOLFIRINOX group and 68% in the FOLFOX group. Grade 3–4 toxicity occurred in 47% of patients receiving mFOLFIRINOX and 38% receiving FOLFOX. The FOLFOX arm was discontinued early based on an interim analysis of futility. Based on these findings, the authors concluded that neoadjuvant mFOLFIRINOX is a feasible and effective treatment option for patients with R-PDAC, demonstrating favorable oncologic outcomes and acceptable toxicity. This study also highlighted the potential superiority of mFOLFIRINOX over FOLFOX [53].

The NUPAT-01 trial compared the efficacy of two neoadjuvant therapies recommended by the NCCN for BR-PDAC: FOLFIRINOX and GEM/nab-PTX. A total of 51 patients were included in the study, with 26 assigned to the FOLFIRINOX group and 25 to the GEM/nab-PTX group. Surgical resection was performed in 23 patients (88.5%) in the FOLFIRINOX group and in 20 patients (80.0%) in the GEM/nab-PTX group. The R0 resection rate in the ITT population was 73.1% in the FOLFIRINOX group and 56.0% in the GEM/nab-PTX group. Among patients who underwent surgical resection, the 3-year OS rate was 62.6% in the FOLFIRINOX group and 55.1% in the GEM/nab-PTX group, which was not statistically different. Adverse events of grade 3 or higher occurred in 30.4% of patients treated with FOLFIRINOX (n = 7) and in 70.0% of patients treated with GEM/nab-PTX (n = 14), with this difference reaching statistical significance. Neutropenia was reported in 37.5% of all patients, being more prevalent in the GEM/nab-PTX group (14 patients) compared to the FOLFIRINOX group (4 patients). Other notable grade 3 or higher toxicities included thrombocytopenia in 4 patients (8.3%), nausea in 4 patients (8.3%), and diarrhea in 2 patients (4.2%). No significant differences were observed between the two groups in terms of radiological response rates, CA19-9 reduction, or changes in SUVmax on PET imaging. According to the authors, the NUPAT-01 trial demonstrated that neoadjuvant chemotherapy with either FOLFIRINOX or GEM/nab-PTX is feasible, well-tolerated, and associated with a high rate of R0 resections, providing favorable survival outcomes in BR-PDAC [49].

Yamada et al. [52] studied the combination of gemcitabine and nab-paclitaxel (GEM/nab-PTX) versus gemcitabine and S-1, which is an oral fluoropyrimidine derivative consisting of tegafur—a prodrug of 5-FU—combined with gimeracil and oteracil to enhance efficacy and reduce gastrointestinal toxicity (GEM/S-1) in patients with R-PDAC and BR-PDAC. This study showed superiority of the GEM/nab-PTX regimen in terms of PFS (median 14 months vs. 9 months) and OS: median 42 months vs. 22 months, but statistical significance was not achieved in this regard. Both groups also experienced a similar number of adverse events; adverse effects of any grade occurred in 94% of patients in the GEM/nab-PTX group and 91% of patients in the GEM/S-1 group, and severe adverse effects occurred in 73% and 78%, respectively. According to the authors, the trial indicates that both regimens are feasible and tolerable as neoadjuvant options in R-PDAC and BR-PDAC, with GEM/nab-PTX showing a favorable trend in PFS and OS.

A promising approach with liposomal irinotecan has been introduced. Its unique nanoliposomal formulation allows for higher and more sustained intratumoral concentrations of the active metabolite SN-38, compared to standard irinotecan [54]. Building on these features, the phase II nITRO trial evaluated the perioperative use (3 cycles before and 3 cycles after resection) of the NALIRIFOX regimen (liposomal irinotecan, 5-fluorouracil, leucovorin, and oxaliplatin) in patients with R-PDAC. In this trial, patients who achieved stable disease or a radiological response proceeded to surgical resection, which was performed 4–8 weeks after completing the initial treatment. Following pancreatectomy, and within 4–8 weeks, eligible patients without signs of progression and with adequate clinical status received an additional three cycles of the same regimen in the adjuvant setting. Out of 107 enrolled patients, 87 underwent surgical exploration and 75 proceeded to resection, resulting in an R0 resection rate of 65.3%. Notably, the median OS in the study group was 32.3 months, and the median DFS after surgery was 19.3 months. Diarrhea and neutropenia were the most frequent grade ≥ 3 adverse events [55]. To place these outcomes in context, the authors compared them with results from contemporary perioperative trials, including SWOG S1505, which reported a median OS of approximately 22–23 months, and NORPACT-1, which showed a median OS of 25.1 months with an R0 resection rate of 59% [29,43].

7. The Role of Neoadjuvant Chemoradiotherapy

The addition of radiotherapy to neoadjuvant treatment regimens was also considered. The NCCN guidelines include radiation therapy as an optional component of NAT [4]. Data on this issue are controversial; however, some indicate that RT may lead to a higher likelihood of R0 surgery and better control of the local disease.

Several studies have explored CRT as an alternative to immediate surgery. Golcher et al. [40] randomized 66 patients to CRT (gemcitabine, cisplatin, RT) followed by surgery versus upfront surgery (US). Resection was possible in 58% CRT vs. 70% US, with similar R0 rates (52% vs. 48%) and median OS (17.4 vs. 14.4 months). CRT was safe and feasible but did not significantly improve outcomes.

Casadei et al. [41] studied the results of treatment involving neoadjuvant CRT with gemcitabine, followed by surgery, in comparison to US. After surgery, both groups received adjuvant treatment according to the protocol of the CONKO-001 trial (gemcitabine 1000 mg/m² on days 1, 8, and 15 every 4 weeks for 6 cycles) [56]. In this study, the primary surgery group included 20 patients, among whom resections were successful in 15 (75%). The NAT group included 18 patients, and 11 (61.1%) of them underwent successful resections. R0 resections were more frequently achieved in patients in the NAT group, with rates of 38.9% compared to 25% in the primary surgery group. The median OS was slightly better for the NAT group—22.4 months compared to 19.5 months in the US group. The researchers pointed out the difficulties in recruiting patients who probably opted for the prompt tumor removal. However, they showed that neoadjuvant CRT was effective, with acceptable toxicity.

On the other hand, a meta-analysis of 5 randomized clinical trials involving 437 patients with R-PDAC and BR-PDAC compared CRT to US. The analysis showed significant benefits that patients can derive from this type of NAT. The study observed a higher resection rate in the US group. However, resections after NAT CRT were significantly more likely to achieve negative margins (OR, 3.38; p < 0.01). In addition, the authors observed significantly less frequent lymph node involvement (OR 0.18, p < 0.01) and a higher 2-year survival rate (OR 1.6, p = 0.04) in the chemoradiotherapy group. Interestingly, despite the expected toxicities of neoadjuvant CRT, the overall incidence of severe adverse events reported across the treatment was lower in the NAT-CRT group compared to the US group (OR 0.56, p = 0.02) [57].

While earlier studies compared CRT with US, more recent randomized trials have focused on whether adding radiotherapy to modern multi-agent chemotherapy provides additional benefit. In the study ALLIANCE (A021501), the authors compared the efficacy of NAT consisting of 8 cycles of mFOLFIRINOX with 7 cycles of the same treatment but supplemented with radiotherapy. In both groups, NAT was followed by surgery and postoperative chemotherapy with the FOLFOX6 regimen consisting of oxaliplatin, leucovorin, bolus fluorouracil, and fluorouracil. This study showed that the use of mFOLFIRINOX alone represented better treatment outcomes than the same chemotherapy with radiotherapy. The median OS in the group treated with neoadjuvant chemotherapy alone was 29.8 months, while in the group that received neoadjuvant mFOLFIRINOX with radiotherapy, the median OS was 17.1 months [50].

The authors of the PREOPANC-2, the multicenter, randomized phase III study, aimed to evaluate the impact of neoadjuvant FOLFIRINOX chemotherapy versus neoadjuvant gemcitabine-based CRT on OS in patients with R-PDAC and BR-PDAC. A total of 375 patients were enrolled and randomly assigned to receive either neoadjuvant FOLFIRINOX (n = 188) or gemcitabine-based CRT (n = 187). The FOLFIRINOX arm received FOLFIRINOX every 14 days for 8 cycles, followed by surgery, while the CRT arm received 3 cycles of neoadjuvant gemcitabine with hypofractionated radiotherapy (36 Gy in 15 fractions) during the second cycle, followed by surgery and 4 cycles of adjuvant gemcitabine. After a median follow-up of 42.3 months, the median OS was 21.9 months in the FOLFIRINOX arm and 21.3 months in the CRT arm, indicating no statistically significant difference between the two treatment arms. Resection rates were 77% for the FOLFIRINOX arm and 75% for the CRT arm (p = 0.69). The rate of serious adverse events was comparable, at 49% in the FOLFIRINOX group and 43% in the CRT group (p = 0.26). Notably, patients receiving FOLFIRINOX experienced a higher rate of multiple grade ≥ 3 adverse events (46% vs. 34%, p = 0.02). Although neoadjuvant FOLFIRINOX did not demonstrate a survival advantage over gemcitabine-based CRT, the latter remains a valid and effective alternative, particularly for patients with suboptimal performance status who may not tolerate intensive multi-agent chemotherapy [58].

In the JASPAC 04 randomized phase II clinical trial, the efficacy and safety of two neoadjuvant chemoradiotherapy regimens were compared in 103 patients with R-PDAC. Patients were randomized into two groups: one receiving gemcitabine, S-1, and radiotherapy (NAT-GS), and the other receiving S-1 and radiotherapy alone (NAT-RT), with 51 patients in each group. Surgery was performed in 47 patients in the NAT-GS group and in 46 patients in the NAT-RT group. The study indicated a slightly higher efficacy for NAT-GS, achieving a 2-year progression-free survival rate of 54.9% compared to 45% for NAT-RT (p = 0.35), as well as a 2-year overall survival rate of 72.7% versus 66.7% (p = 0.3). However, the NAT-GS group experienced significantly more hematologic complications, including grade ≥ 3 neutropenia in 72.0% and leukopenia in 39.0% of patients, compared with 13.0% and 9.0%, respectively, in the NAT-RT group. Despite similar surgical outcomes and non-significant differences in survival, the safety profile favored the NAT-RT approach [44].

Hill et al. [59] evaluated 64 patients with BR-PDAC who received neoadjuvant chemotherapy supplemented with radiation therapy. The R0 resection rate among the operated patients was as high as 96%. However, 33% of the studied patients experienced local recurrence, and the median OS did not exceed 18.7 months. When compared to other studies—in which median OS after NAT often reaches 22–30 months [28,46]—these findings suggest that, although radiation therapy may improve resection rates, it does not appear to provide a proportionate benefit in long-term survival or local disease control.

The addition of radiotherapy may also be considered if the tumor infiltrates arterial vessels. Although direct evidence is limited, radiotherapy has been shown to achieve local tumor control and effective hemostasis in bleeding malignancies, which may help reduce the risk of vascular complications during systemic therapy [60]. A phase II study conducted by Nagakawa et al. [61] analyzed the efficacy and safety of neoadjuvant CRT in patients with BR-PDAC and arterial involvement. They used Intensity-Modulated Radiotherapy (IMRT) at a dose of 50.4 Gy in 28 fractions supplemented with gemcitabine and S-1. IMRT is an advanced form of radiation therapy that precisely targets tumors by modulating the intensity of radiation beams to spare surrounding healthy tissue. The study included 27 patients; 25 (92.6%) completed NAT, and 19 (70.3%) underwent successful resection. Of this group, 18 (94.7%) achieved R0 resection. Postoperative complications occurred in 3 patients (15.8%). The authors emphasized that this treatment strategy was feasible and well-tolerated, with a very low rate of severe gastrointestinal toxicity. Notably, they highlighted the high rate of R0 resections as a major strength of the protocol. The median OS was 22.4 months, with a one-year survival rate of 81.3%, which they considered encouraging. Importantly, the pattern of recurrence was dominated by distant metastases (68.4%), while local recurrence was rare. This suggests that the regimen provides excellent local control but remains limited in preventing systemic disease progression.

Additionally, it has been observed that radiotherapy may reduce pain, which is a serious problem in PDAC patients. The PAINPANC trial evaluated the effect of palliative radiotherapy on pain in patients with inoperable pancreatic cancer. Patients with moderate to severe pain (rated 5–10 on a scale of 0–10) were recruited for the study. After 7 weeks of treatment, 80% of patients experienced a clinically meaningful reduction in pain, defined as a decrease of at least 2 points on the aforementioned scale. On average, a decrease in pain severity of 3.15 points was achieved (p = 0.045). A significant reduction in opioid doses was also observed, from a median morphine equivalent dose of 129.5 mg/day before radiotherapy to 75 mg/day post-treatment. These findings highlight the potential role of neoadjuvant radiotherapy in not only disease control but also improving patient quality of life. Patients with severe pain in whom NAT could increase the likelihood of successful surgery could particularly benefit from such therapy [62].

An important aspect of incorporating radiotherapy into NAT protocols is its potential impact on surgical morbidity. For instance, Snyder et al. [63] reported on the incidence of major complications observed in the previously mentioned Alliance A021501 study, which compared neoadjuvant mFOLFIRINOX alone with the same regimen supplemented by radiotherapy. Notably, no statistically significant differences were observed between the two groups in the rate of severe complications (50% vs. 67%, p = 0.37). The most reported complications included delayed gastric emptying, postoperative pancreatic fistula, hemorrhage, and infections. Importantly, complication rates were comparable to those reported in patients undergoing pancreaticoduodenectomy without any neoadjuvant therapy, suggesting that adding radiotherapy does not substantially increase perioperative risk. These findings align with a systematic review including over 25,000 patients, which found that preoperative CRT was associated with a lower rate of clinically relevant postoperative fistulas compared to immediate surgery. However, it is important to note that this effect was not observed with preoperative chemotherapy alone [64]. Overall, therefore, it appears that neoadjuvant treatment does not significantly impact postoperative complications [65].

The decision to include radiotherapy in NAT regimens should be individualized based on anatomical, clinical, and functional factors. While the addition of radiotherapy to neoadjuvant chemotherapy does not consistently improve OS [40,59], it may offer benefits in selected patients. Radiotherapy should be considered particularly in cases of arterial involvement [61], severe pain [62], and borderline performance status [50], where intensive chemotherapy may not be tolerated but effective local treatment is needed. Radiotherapy can also improve R0 resection and nodal clearance rates, though its impact on long-term survival remains uncertain [41,57].

8. Challenges and Risks Associated with NAT

The use of NAT introduces a potential drawback—a delay in surgical treatment. During this time, despite treatment, the disease may progress [7]. Moreover, large registry-based studies, such as the recent analysis by Fromer et al. [66], based on over 10,000 patients, indicate that only one-third of patients with anatomically R-PDAC who start neoadjuvant chemotherapy ultimately proceed to surgery. Factors such as treatment at community hospitals, lower socioeconomic status, and minority race were independently associated with reduced likelihood of resection. Importantly, patients who did not undergo surgery had markedly worse survival, with a median OS of 10.6 months compared to 26.6 months for those who were resected. The most frequent single reason for not proceeding to surgery was intraoperative discovery of unresectability, accounting for nearly 40% cases.

However, not all studies have shown increased perioperative risk associated with delayed surgery following NAT. In the previously mentioned study conducted by Mokdad AA et al. [34], the extended time to surgery of R-PDAC in the NAT group (128 days vs. 25 days) did not result in increased rates of complications or mortality at 30 and 90 days postoperatively. Importantly, some reports even suggest a protective effect: the incidence of postoperative complications was lower in the neoadjuvant group in R-PDAC. The authors reported fewer cases of pancreatic fistula and postpancreatectomy hemorrhage among patients who received NAT, which they attributed to treatment-induced pancreatic and peripancreatic fibrosis, reducing the risk of pancreatic anastomotic leakage [41].

Adverse events represent another key challenge. A meta-analysis of 5520 patients with PDAC at various stages who received NAT found grade ≥ 3 toxicities in 36% of cases, with about 20% requiring hospitalization. Despite this, more than 90% of patients were able to complete the entire planned neoadjuvant treatment regimen. Hematologic toxicities such as leukopenia (25%) and neutropenia (23%) were most common, but non-hematologic events like vomiting, cholangitis, diarrhea, and GI bleeding were also observed.

Another challenge is the effectiveness of adjuvant chemotherapy in patients who have undergone NAT, which remains a topic of debate. Direct comparison between outcomes from neoadjuvant and adjuvant clinical trials presents significant methodological challenges. These difficulties arise from fundamental differences in patient selection criteria for each type of study. Adjuvant trials typically include only those patients who have successfully undergone surgical resection, have good postoperative performance status, and show no signs of disease progression after surgery. As a result, these cohorts represent a highly selected group with relatively favorable prognoses. In contrast, neoadjuvant trials evaluate all patients with a radiologically defined resectable or BR-PDAC diagnosis before any treatment. This includes individuals who may experience disease progression or other adverse events during NAT, which can ultimately preclude surgical resection. Consequently, survival outcomes in neoadjuvant trials reflect a broader and more heterogeneous patient population. Adjuvant trial results represent only the subset of patients who successfully reached and recovered from surgery. These differences introduce substantial selection bias, making direct comparisons between the two trial types difficult and often misleading [67,68].

Another important challenge is the assessment of treatment response. The methods most commonly used are CT imaging and CA 19-9 monitoring. Both have limited accuracy and do not reliably predict survival. CT may not distinguish tumor invasion from inflammation and fibrosis caused by chemotherapy. Hence, NCCN guidelines for PDAC discourage the use of radiologic response as a relevant treatment endpoint. Radiologic response does not reliably predict survival [4]. Similarly, the utility of CA 19-9 as a marker in this context is limited. Some studies showed that a decrease in its level is associated with improved survival [69,70]. However, nearly 10% of patients do not produce CA 19-9. Approximately one-third exhibit normal baseline levels, thereby reducing their overall diagnostic sensitivity [71]. Moreover, some nonmalignant conditions, such as chronic pancreatitis or cholangitis, may elevate the level of this biomarker. According to Truty et al. [72], evaluating response to NAT in patients with BR-PDAC and locally advanced PDAC is more accurate when multiple factors are considered together. These include radiologic imaging, postoperative histopathologic assessment of tumor regression, and CA 19-9 levels. Relying on CA 19-9 as a sole indicator is not recommended. Beyond CA 19-9, composite serum panels such as CA 19-9 combined with CA-125 have recently been reported to outperform CA 19-9 alone in predicting treatment response and survival in PDAC [73].

New approaches, such as fluorodeoxyglucose positron emission tomography (FDG-PET) or circulating tumor DNA (ctDNA) analysis, are being investigated. Their role in clinical practice has not yet been established [74,75]. Increasing evidence suggests that the metabolic response, as assessed by FDG-PET/CT, particularly reductions in SUVmax, correlates more strongly with R0 resection rates and OS than conventional radiologic criteria. However, this modality is not yet recommended as a routine clinical tool [74,76]. Recently, Botta et al. [77] demonstrated in a large multicenter cohort of R-PDAC that postoperative positivity of tumor-informed ctDNA strongly predicted early recurrence and markedly shorter DFS, compared with ctDNA-negative patients, clearly outperforming conventional clinicopathological factors and CA 19-9. Moreover, exploratory analyses suggested that KRAS genotype further modulated prognosis, with KRAS wild-type tumors showing the most favorable DFS and KRAS^G12V, and to a lesser extent KRAS^G12D, being associated with particularly poor outcomes.

Gene-expression-based subtyping has further refined our understanding of biological heterogeneity in PDAC. The “classical” subtype is generally more chemosensitive, whereas the “basal-like” subtype is associated with primary resistance and poor survival. GATA6 expression has emerged as a practical immunohistochemical surrogate for these subtypes: loss of GATA6 expression identifies basal-like tumors and consistently correlates with inferior outcomes [78]. Recent studies have demonstrated that GATA6, alone or in combination with cytokeratin 5 (CK5), stratifies prognosis in patients undergoing neoadjuvant chemotherapy and surgery, suggesting that molecular subtyping could help tailor NAT regimens and inform post-operative management. In a cohort of patients with PDAC resected after neoadjuvant chemotherapy, Kokumai et al. [79] showed that a simple four-group classification based on GATA6 and CK5 expression clearly stratified survival, with GATA6-high/CK5-low “classical” tumors having the best outcomes and GATA6-low/CK5-low “null” tumors the worst. Nevertheless, these molecular classifiers remain largely confined to research settings.

A further challenge is the complex and highly immunosuppressive tumor microenvironment, which strongly influences response to NAT. PDAC is characterized by a dense desmoplastic stroma, abundant cancer-associated fibroblasts and an immunosuppressive infiltrate enriched in myeloid cells and regulatory T cells, all of which contribute to chemoresistance [80,81]. Translational studies in patients treated with neoadjuvant FOLFIRINOX or chemoradiotherapy have shown that effective NAT is associated with a reduction in protumorigenic myeloid and regulatory T cells and with an increase in CD8+ T-cell infiltration in the resected tumor [82,83,84]. In addition, the presence and density of intratumoral tertiary lymphoid structures after neoadjuvant chemoradiotherapy have been associated with more favorable survival [85,86]. Pre-treatment “inflamed” immune signatures, including lower neutrophil-to-lymphocyte ratio and higher densities of tumor-infiltrating lymphocytes, have been linked to better pathological response and survival, suggesting that the immunologic state of the tumor microenvironment may serve as a predictive biomarker and a potential therapeutic target in combination strategies [87,88,89]. However, these immune-based biomarkers remain exploratory, and their integration into routine NAT decision-making requires prospective validation.

The potential role of immunotherapy in the neoadjuvant setting also deserves attention. While immune checkpoint inhibitors and other immunomodulatory agents have transformed treatment in several malignancies like melanoma or renal cell carcinoma [90,91], their efficacy in PDAC remains limited due to the tumor’s low immunogenicity and immunosuppressive microenvironment [92]. Early-phase studies combining immunotherapy with chemotherapy or chemoradiotherapy have shown acceptable safety and some promising activity [93], but randomized trials to date have not demonstrated a clear survival benefit [94]. Thus, immunotherapy remains investigational, and its integration into NAT regimens requires further evidence [95,96,97].

9. Conclusions

NAT is a promising treatment strategy in both R-PDAC and BR-PDAC. The principal benefit of NAT lies in its ability to achieve tumor downstaging—clinical evidence consistently shows that NAT reduces tumor size and vascular involvement, thereby increasing the likelihood of R0 resections and improving surgical outcomes. NAT may also provide early systemic treatment for micrometastatic disease, which is present in the majority of patients at the time of diagnosis. Since many patients do not complete adjuvant chemotherapy, administering systemic treatment preoperatively ensures that more patients receive effective therapy. In BR-PDAC, current evidence strongly supports its routine use due to improved OS.

In resectable tumors, NAT may be beneficial in selected high-risk patients. Some studies in resectable cohorts have shown less favorable outcomes with NAT, mainly due to toxicity, disease progression during therapy, and lower resection rates compared with US. These limitations underscore the importance of careful patient selection. Importantly, therapy should be tailored based on clinical and biological risk factors, such as CA 19-9 levels ≥ 250 U/mL, tumor size ≥ 30–35 mm, serum albumin ≤ 3.5 g/dL, neutrophil-to-lymphocyte ratio ≥ 3.5, Duke pancreatic monoclonal antigen type 2 level ≥ 750 U/mL, and performance status.

A variety of chemotherapy regimens have been investigated, with mFOLFIRINOX and gemcitabine-based combinations remaining the most widely used. Recent trials exploring intensified or novel strategies, such as perioperative PEXG or NALIRIFOX, suggest promising survival benefits and highlight the need for further comparative studies. The role of radiotherapy in NAT remains debated: while some studies demonstrate higher R0 resection rates and excellent local control, its impact on long-term survival is inconsistent, and treatment-related toxicity must be considered.

Key challenges associated with NAT include treatment-related toxicity and the risk of disease progression during therapy, and the fact that a substantial proportion of patients may never proceed to surgery. Assessing treatment response is another major limitation, as conventional tools such as CT imaging and CA 19-9 remain imperfect. Future directions should focus on validating biomarkers that can better guide patient selection and response monitoring, improving diagnostic tools to assess the effectiveness of therapy, and comparing treatment regimens in large-scale clinical trials.