Advances in neoadjuvant therapy for pancreatic cancer: Current trends and future directions

Abstract

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most challenging malignancies, with poor survival rates due to late-stage diagnosis and limited treatment options. Neoadjuvant therapy (NAT), which involves chemotherapy or chemoradiation prior to surgical resection, has emerged as a promising approach to improve resectability and overall survival (OS). The integration of advanced imaging techniques and biomarkers for evaluating the response to NAT is crucial for optimizing therapeutic strategies and surgical outcomes. However, challenges related to the heterogeneity of treatment protocols and the need for predictive biomarkers remain, highlighting the necessity for further clinical trials. The aim is to evaluate the impact of NAT on surgical outcomes and predictive markers in pancreatic cancer. A comprehensive review of the literature was conducted to evaluate the impact of NAT on surgical resectability, survival outcomes, and the role of imaging and biomarkers in assessing therapeutic response. Studies examining the efficacy of NAT in patients with PDAC, the predictive value of serum biomarkers such as carbohydrate antigen 19-9 (CA 19-9), and the utility of advanced imaging modalities such as positron emission tomography/computed tomography with 18F-fluorodeoxyglucose (FDG-PET/CT) were included. NAT has demonstrated significant benefits in downstaging tumors, increasing margin-negative (R0) resection rates, and reducing micrometastatic disease. The use of serum CA 19-9 Levels as a biomarker for response evaluation and imaging modalities such as FDG-PET/CT and magnetic resonance imaging has proven valuable in predicting therapeutic efficacy and guiding surgical planning. Studies have shown that significant reductions in CA 19-9 Levels and favorable metabolic responses on imaging are associated with higher R0 resection rates and longer survival. Furthermore, the integration of multimodal imaging and biomarker assessment has enabled better stratification of patients and more personalized treatment strategies. NAT significantly improves surgical outcomes and survival in patients with resectable and borderline resectable PDAC. Advanced imaging techniques and biomarkers such as CA 19-9 play pivotal roles in evaluating the response to therapy and guiding surgical decision-making. Future research should focus on addressing variability in treatment strategies and developing more reliable predictive biomarkers.

Key Words: Neoadjuvant therapy; Pancreatic cancer; Surgical outcomes; Imaging techniques; Biomarkers

Core Tip: This review highlights the transformative role of neoadjuvant therapy in managing pancreatic ductal adenocarcinoma (PDAC), emphasizing its benefits in improving resectability, enhancing margin-negative resection (R0) rates, and addressing micrometastatic disease. The integration of advanced imaging modalities, such as positron emission tomography/computed tomography with 18F-fluorodeoxyglucose, and biomarkers like carbohydrate antigen 19-9 enables personalized treatment strategies and better surgical planning. By synthesizing recent evidence, the study underscores the critical importance of multimodal approaches, tailored regimens, and emerging therapies in optimizing outcomes for patients with resectable and borderline resectable PDAC.

INTRODUCTION

Pancreatic cancer, particularly pancreatic ductal adenocarcinoma (PDAC), is a formidable health challenge globally and is characterized by a dismal prognosis and increasing incidence rates. It ranks as the seventh most common cancer and the third leading cause of cancer-related deaths worldwide. The latest data show that the overall 5-year survival rate for patients with PDAC is 12%, which is largely due to late-stage diagnosis and aggressive tumor behavior[1,2]. Early detection and intervention are critical for improving survival rates, yet traditional diagnostic methods often fail to identify the disease until it has progressed to advanced stages[3]. This highlights the urgent need for effective biomarkers that can facilitate earlier diagnosis and better patient stratification[4]. Currently, carbohydrate antigen 19-9 (CA 19-9) remains the primary biomarker that is used in the clinic. However, emerging biomarkers, such as circulating tumor DNA (ctDNA) and exosomes, have potential for improving diagnostic accuracy and therapeutic monitoring; these emerging biomarkers are discussed in greater detail later in this review.

Neoadjuvant therapy (NAT) has emerged as a promising strategy for the management of resectable and borderline resectable PDAC. This approach involves the administration of chemotherapy or chemoradiotherapy before surgical intervention, with the aim of downstaging the tumor and increasing the likelihood of achieving margin-negative (R0) resection[5]. Recent studies have shown that NAT can improve surgical outcomes, increase overall survival (OS), and facilitate the evaluation of tumor biology prior to surgery[6]. The evolving landscape of neoadjuvant treatment options underscores the importance of identifying reliable biomarkers that can guide therapeutic decision-making and predict treatment response[7,8]. In this context, novel biomarkers such as ctDNA and exosomes may increase our ability to monitor therapeutic efficacy and develop individualized treatment strategies.

The integration of NAT into clinical practice raises several important questions regarding optimal treatment regimens, patient selection, and timing of surgical intervention[4]. While combinations of gemcitabine, fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX), and novel agents are under investigation, variability persists in treatment protocols and outcomes across institutions[3,5]. Improving standardization through predictive biomarkers and advanced imaging techniques remains an ongoing challenge and critical research focus.

Understanding the mechanisms by which NAT impacts tumor biology is crucial for optimizing treatment strategies. NAT not only aims to reduce tumor size but also addresses micrometastatic disease that may not be detectable at diagnosis[2]. The effects of chemotherapy on tumor microenvironment and cellular pathways can provide insights into tumor responsiveness and resistance[4]. Additionally, ongoing clinical trials are investigating the role of novel agents in conjunction with traditional therapies[9]. Further exploration of the predictive value of emerging biomarkers may help elucidate mechanisms underlying tumor resistance and response to treatment, ultimately improving the outcomes of patients with PDAC. In this review, we comprehensively summarize current trends and clinical evidence related to the use of NAT for treating PDAC, emphasize recent advances in imaging and biomarkers, and discuss future directions for clinical practice and research.

RATIONALE FOR NAT IN PANCREATIC CANCER

Assessments of resectability

The classification of PDAC resectability is predominantly based on the anatomical relationship between the tumor and the surrounding vasculature, according to the American Joint Committee on Cancer 8^th Edition and the tumor-node-metastasis system. This classification system categorizes PDAC into five types: Resectable pancreatic cancer (RPC), borderline RPC (BRPC), locally advanced pancreatic cancer (LAPC), oligometastatic pancreatic cancer, and metastatic pancreatic cancer[10]. For the purposes of surgical planning and the consideration of NAT, the three primary categories we will discuss are RPC, BRPC and LAPC. RPC is characterized by tumors without evidence of vascular involvement, allowing for straightforward surgical resection with a high likelihood of achieving R0 resection. In contrast, BRPC refers to tumors that present with limited vascular involvement, such as partial contact with the superior mesenteric vein/portal vein or superior mesenteric artery. These tumors are potentially resectable with the use of neoadjuvant treatment to downstage the disease. Finally, LAPC describes tumors with significant vascular encasement, making surgical resection technically challenging and often unfeasible with an elevated risk of positive margins or incomplete tumor removal. Understanding these classifications is crucial for tailoring treatment strategies and determining the feasibility of surgical intervention. Although the focus is typically on these three categories, PDAC can also present as oligometastatic or metastatic, characterized by the presence of limited or multiple distant metastases, respectively[11]. These subcategories highlight the spectrum of disease progression but require different therapeutic strategies beyond the scope of local resection. Figure 1 provides a schematic illustration of the three primary classifications-RPC, BRPC, and LAPC-highlighting their anatomical relationships and surgical considerations. While anatomical classification remains a cornerstone in determining resectability, it does not account for biological factors such as tumor markers (e.g., CA19-9) or patient performance status, which are increasingly recognized as critical determinants of prognosis and therapeutic response[11,12]. Future staging paradigms that integrate these clinical parameters may provide a more nuanced approach to guiding treatment strategies and improving patient outcomes.

Figure 1 Schematic representation of pancreatic cancer stages. A: Resectable pancreatic cancer (RPC). The primary tumor is separated from the superior mesenteric artery (SMA) by non-malignant pancreatic tissue or fat, indicating no direct contact. There may be a minimal interface between the tumor and the superior mesenteric vein (SMV), but the vein remains patent without occlusion; B: Borderline RPC. The primary tumor contacts less than 50% of the circumference of the SMA. While there may be occlusion of the superior mesenteric vein, the vessel must be amenable to reconstruction, whether through end-to-end anastomosis, patch placement, or short-segment grafting; C: Locally advanced pancreatic cancer. The primary tumor demonstrates encasement of the SMA and/or is associated with an SMV that cannot be reconstructed.

The challenge of achieving R0 resection

PDAC presents a significant challenge in achieving R0 resection because of its aggressive nature and late-stage presentation. Studies indicate that only 15%-20% of patients present with resectable disease at diagnosis, with the majority already exhibiting local invasion or metastatic spread[3]. The complex anatomy of the pancreas, alongside the proximity of the tumor to major vascular structures, complicates surgical resection, thereby increasing the likelihood of incomplete excision[13]. As a result, achieving R0 resection is crucial for long-term survival, and NAT plays a pivotal role in enhancing surgical outcomes.

NAT has been shown to downstage tumors, allowing for conversion from unresectable to resectable status. Research indicates that patients who receive NAT demonstrate higher rates of R0 resections than those who undergo upfront surgery do[2]. For example, a systematic review conducted by Dhir et al[3] revealed that NAT significantly increases the likelihood of R0 resection by reducing tumor size and vascular involvement. This evidence supports the integration of NAT into treatment protocols for PDAC to improve surgical outcomes and OS rates. Additionally, recent studies indicate that patients undergoing NAT tend to exhibit lower rates of early local and distant recurrence compared to patients treated with upfront surgery, suggesting improved control over micrometastatic disease. However, recurrence patterns remain heterogeneous and warrant further investigation.

Benefits of tumor downstaging and margin clearance

The principal benefit of NAT lies in its potential for effective tumor downstaging. As tumors respond to treatment, the likelihood of achieving clear margins during surgery significantly increases. Clinical evidence suggests that patients who undergo NAT often experience reductions in tumor size and local vascular invasion, which are critical for successful surgical outcomes[6]. Studies have demonstrated that neoadjuvant chemotherapy (NAC) regimens, such as FOLFIRINOX, not only decrease the tumor burden but also increase R0 resection rates[14].

Moreover, downstaging can facilitate less invasive surgical techniques, potentially resulting in fewer postoperative complications and faster recovery times. Successful downstaging is associated with improved OS rates, reinforcing the idea that achieving R0 resection following NAT is beneficial not only for immediate surgical success but also for long-term prognosis in PDAC patients[4]. For instance, a meta-analysis by Versteijne et al[2] revealed that patients who receive NAT have improved survival outcomes, emphasizing the necessity of this approach in clinical practice.

Role of NAT in managing micrometastatic disease

One of the critical challenges in treating PDAC is the presence of micrometastatic disease at diagnosis, which is often undetected by conventional imaging techniques[7]. NAT provides a systemic approach to address this hidden burden of disease. By administering chemotherapy prior to surgery, NAT aims to target these micrometastatic cells, thereby reducing the risk of recurrence after surgical resection[8]. This systematic control is crucial for managing microscopic foci that may not be amenable to surgical resection. Recent research suggests that NAT may also enhance the anti-tumor immune response by modulating the tumor microenvironment, increasing immune cell infiltration, and reducing immunosuppressive factors[7]. Additionally, NAT has been shown to decrease ctDNA, which could reflect reduced tumor burden and potentially lower metastatic potential.

Research indicates that patients who receive NAT exhibit lower rates of recurrence than those who undergo surgery alone do, highlighting the importance of addressing micrometastatic disease early in the treatment process[15].

Implications for treatment strategies

The integration of NAT into treatment strategies for PDAC not only improves surgical outcomes but also addresses the multifaceted nature of the disease. The heterogeneity of PDAC necessitates a tailored approach, and the use of NAT allows for the consideration of individual patient factors, including tumor biology and overall health status[3,16]. Additionally, ongoing research into the timing and sequencing of therapies can further refine treatment strategies, maximizing the benefits of neoadjuvant approaches[17].

Clinical trials are essential for validating the efficacy of various neoadjuvant regimens and optimizing their implementation in clinical practice. Studies such as those conducted by Versteijne et al[2] and Dhir et al[3] provide valuable insights into the outcomes of different treatment protocols, guiding clinical decision-making. As new agents and combinations are introduced, the landscape of NAT continues to evolve, offering hope for improved survival rates in patients with PDAC[2,3].

As our understanding of PDAC biology evolves, integrating NAT into treatment paradigms represents a significant advancement in the quest for improved patient survival and quality of life[14]. Continued research and clinical trials are essential to validate the efficacy of neoadjuvant approaches and refine strategies that will optimize outcomes for patients with PDAC.

IMPACT OF NAT ON RESECTABILITY

Analysis of resectability rates before and after neoadjuvant treatment

NAT has significantly transformed the treatment landscape for PDAC, particularly with respect to surgical resectability. Historically, resectability rates for PDAC have been dismally low, with only 15%-20% of patients being diagnosed with resectable disease[1]. However, the introduction of NAT, which encompasses chemotherapy and chemoradiation, has markedly improved these rates, enabling the conversion of initially unresectable tumors into resectable tumors.

As discussed, NAT has a significant effect on R0 resection rates and overall surgical outcomes in patients with RPC. Numerous studies have examined the effects of NAT on resection rates, margin clearance, and long-term survival, with varying treatment regimens showing promising results. Table 1 summarizes key studies evaluating NAT in RPC, highlighting the resection rates, R0 resection rates, median OS, and disease-free survival (DFS) across different treatment approaches. This provides a comprehensive view of the benefits and challenges associated with various neoadjuvant regimens in improving surgical outcomes.

Table 1 Neoadjuvant therapy in resectable pancreatic cancer.

Ref.	Type of study	Year	Treated with radiotherapy	Total (n)	Stage of disease	Treatment regimen	Resection rate (%)	R0 resection rate (%)	Median OS (months)	Other outcome measure	Median DFS (months)
Ahmad et al[64]	Clinical trial	2020	No	55	RPC	mFOLFIRINOX	87	85	22.4	2-year OS rate: 41.60%	10.9
			No	47	RPC	Gemcitabine/nab-paclitaxel	77	85	23.6	48.80%	14.2
Motoi et al[65]	Clinical trial	2019	No	182	RPC	Gemcitabine + S1	NR	NR	36.7	NR	NR
			No	180	RPC	Upfront surgery	NR	NR	26.6	NR	NR
Versteijne et al[66]	Clinical trial	2020	Yes	65	RPC	Gemcitabine + radiotherapy	68	66	14.6	NR	9.2
			No	68	RPC	Upfront surgery	79	59	15.6	NR	9.3
Golcher et al[67]	Clinical trial	2015	Yes	33	RPC	Gemcitabine + cisplatin + radiotherapy	58	89	17.4	NR	NR
			No	33	RPC	Upfront surgery	70	70	14.4	NR	NR
Cucchetti et al[68]	Clinical Trial	2022	Yes	182	RPC	Gemcitabine + S1	NR	NR	36.7	NR	NR
Heinrich et al[69]	Clinical Trial	2019	Yes	102	RPC, BRPC, LAPC	Gemcitabine + radiotherapy	79	70	26.8	Improved resectability and surgical outcomes	12.1
Fujii et al[70]	Observational study	2017	Yes	40	RPC	5-FU + oteracil + gimeracil + S-1 + radiotherapy	92	97	24.9	NR	NR
			No	233	RPC	Upfront surgery	88	70	23.5	NR	NR
			No	56	RPC	Upfront surgery	87.5	56.5	NR	NR	NR
Casadei et al[71]	Randomized controlled trial	2015	Yes	18	RPC	Gemcitabine + radiotherapy	61.1	38.9	22.4	NR	NR
			No	20	RPC	Upfront surgery	75	25	19.5	NR	NR
Tzeng et al[72]	Retrospective study	2014	Yes	115	RPC	Gemcitabine and cisplatin + radiotherapy	83	89.5	28	NR	NR
			No	52	RPC	Upfront surgery	92.3	81.3	25.3	NR	NR
Ielpo et al[73]	Retrospective study	2017	Yes	19	RPC	Gemcitabine and nab-paclitaxel + radiotherapy	78.9	NR	22.1	NR	21
			No	17	RPC	Upfront surgery	100	NR	24.8	NR	14
Hoffman[74]	Review article	2010	No	N/A	RPC	FOLFIRINOX, gemcitabine-based therapies	NR	NR	NR	Enhanced R0 resection and downstaging in advanced cases	NR
Gillen et al[18]	Systematic review	2010	No	720	RPC	Multiple regimens	68.5	73	25.3	Improved tumor response and resection rates	NR

Table 1 provides a detailed summary of clinical trials and studies evaluating the efficacy of various neoadjuvant therapy (NAT) regimens in patients with resectable pancreatic cancer (RPC). The table includes data on study type, references, treatment regimens, resection rates, margin-negative (R0) resection rates (indicating margin-negative resection), median overall survival, and disease-free survival, where available. This provides a comprehensive view of the benefits and challenges associated with various neoadjuvant regimens in improving surgical outcomes. These metrics highlight the outcomes of different approaches, including chemotherapy, chemoradiation, and combinations of targeted agents. By presenting these key parameters, Table 1 underscores the significant improvements in resectability and survival outcomes achieved through NAT, compared with upfront surgery. Notably, regimens such as modified fluorouracil, leucovorin, irinotecan, and oxaliplatin and gemcitabine-based therapies demonstrate the highest R0 resection rates, affirming the pivotal role of NAT in enhancing surgical outcomes. The table serves as a valuable resource for understanding the therapeutic potential and challenges associated with various NAT protocols in the management of RPC. RPC: Resectable pancreatic cancer; R0: Margin-negative resection; OS: Overall survival; DFS: Disease-free survival; mFOLFIRINOX: Modified fluorouracil, leucovorin, irinotecan, and oxaliplatin; 5-FU: 5-fluorouracil; N/A: Not applicable; NR: Not report; BRPC: Borderline resectable pancreatic cancer; LAPC: Locally advanced pancreatic cancer.

A meta-analysis by Dhir et al[3] provided compelling evidence that NAT increases R0 resection rates, emphasizing that patients who undergo neoadjuvant treatment have significantly better outcomes than those who receive upfront surgery. Specifically, the study indicated that neoadjuvant regimens, particularly FOLFIRINOX, lead to higher rates of complete surgical resection, ultimately improving patient survival. Similarly, a systematic review by Gillen et al[18] corroborated these findings, demonstrating that the implementation of NAT resulted in an average resectability rate increase of 60% for borderline resectable tumors.

Recent studies further highlight the efficacy of NAT. For example, Okada et al[19] reported that patients treated with nab-paclitaxel and gemcitabine had an R0 resection rate of 63.9%, emphasizing the potential of specific chemotherapy combinations to facilitate successful surgical outcomes. Furthermore, Gugenheim et al[20] noted that NAT has become a standard approach for managing BRPC and has improved OS and the quality of surgical margins. The increase in resectability rates following NAT is pivotal, as achieving R0 resection is critically associated with improved long-term survival in patients with PDAC.

Comparative studies on resectable vs borderline resectable tumors

The distinction between resectable and borderline resectable tumors is crucial for evaluating the effectiveness of NAT. Borderline resectable tumors, characterized by limited vascular involvement, provide a unique opportunity for effective intervention. Research by Hu et al[7] highlights that patients classified as borderline resectable who receive NAT demonstrate significantly higher rates of successful surgical resection than those who undergo upfront surgery. These findings suggest that neoadjuvant treatment not only increases surgical eligibility but also contributes to improved postoperative outcomes[7].

To provide a clearer understanding of the impact of NAT on BRPC, Table 2 provides a comprehensive summary of clinical trials and retrospective studies evaluating NAT in patients with borderline BRPC. This table highlights key metrics, including treatment regimens, whether radiotherapy was used, resection rates, R0 resection rates, median OS, and DFS. The data underscore the critical role of NAT in enhancing surgical outcomes for BRPC patients by increasing resection rates and achieving margin-negative (R0) resections, which are pivotal for long-term survival. Table 2 illustrates the efficacy of different NAT strategies in managing the unique challenges posed by BRPC, offering valuable insights for optimizing treatment protocols and advancing clinical management of this subset of pancreatic cancer.

Table 2 Neoadjuvant therapy in borderline resectable pancreatic cancer.

Ref.	Type of study	Year	Treated with radiotherapy	Total (n)	Stage of disease	Treatment regimen	Resection rate (%)	R0 resection rate (%)	Median OS (months)	Median DFS (months)
Tran et al[75]	Clinical trial	2020	Yes	25	BRPC	FOLFIRINOX + radiotherapy + gemcitabine	52	100	24.4	NR
Springett et al[76]	Clinical trial	2008	Yes	130	BRPC	Gemcitabine + chemoradiation	Improved resectability	NR	NR	NR
Okada et al[77]	Clinical trial	2016	No	10	BRPC	mFOLFIRINOX	70	71.4	NR	NR
Chaudhari et al[78]	Clinical trial	2022	Yes	70	BRPC	Gemcitabine + radiotherapy + surgery	62.5	80.2	28.4	NR
Katz et al[79]	Clinical trial	2016	Yes	22	BRPC	mFOLFIRINOX + capecitabine + radiotherapy	68.2	93.3	21.7	NR
Murphy et al[80]	Clinical trial	2018	Yes	48	BRPC	FOLFIRINOX + radiotherapy	66.7	96.9	37.3	NR
Peng et al[81]	Clinical trial	2019	No	85	BRPC	Pathologic tumor response to NAT correlated with node-negative disease	NR	NR	No significant OS benefit	NR
Masui et al[82]	Clinical trial	2016	No	18	BRPC	Gemcitabine + S1	83.3	80	21.7	NR
			No	19	BRPC	Upfront surgery	100	52.6	21.1	NR
Heinrich et al[83]	Clinical trial	2019	Yes	100	BRPC	Total neoadjuvant therapy	Improved pathologic response	NR	Improved OS in pCR patients	NR
Javed et al[84]	Retrospective study	2019	Yes	151	BRPC	Fluorouracil-based + radiotherapy	63.6	77.1	23.7	NR
Patel et al[85]	Retrospective study	2011	Yes	14	BRPC	Gemcitabine + docetaxel + capecitabine + 5-FU + radiotherapy	64.3	88.9	15.64	10.48
Kim et al[86]	Retrospective study	2017	Yes	40	BRPC	Gemcitabine-based + radiotherapy	85	76.5	20	NR
Barnes et al[87]	Retrospective study	2019	Yes	185	BRPC	FOLFIRINOX + radiotherapy	62.2	96.5	20	19
Ielpo et al[73]	Retrospective study	2017	Yes	26	BRPC	Gemcitabine and nab-paclitaxel + radiotherapy	61.5	NR	18.9	NR
			No	19	BRPC	Upfront surgery	100	NR	13.5	NR

To provide a clearer understanding of the impact of neoadjuvant therapy (NAT) on borderline resectable pancreatic cancer (BRPC), Table 2 provides a comprehensive summary of clinical trials and retrospective studies evaluating NAT in patients with borderline BRPC. This table highlights key metrics, including treatment regimens, whether radiotherapy was used, resection rates, margin-negative (R0) resection rates, median overall survival, and disease-free survival. The data underscore the critical role of NAT in enhancing surgical outcomes for BRPC patients by increasing resection rates and achieving R0 resections, which are pivotal for long-term survival. Table 2 illustrates the efficacy of different NAT strategies in managing the unique challenges posed by BRPC, offering valuable insights for optimizing treatment protocols and advancing clinical management of this subset of pancreatic cancer. RPC: Resectable pancreatic cancer; BRPC: Borderline resectable pancreatic cancer; NAT: Neoadjuvant therapy; R0: Margin-negative resection; OS: Overall survival; DFS: Disease-free survival; FOLFIRINOX: Fluorouracil, leucovorin, irinotecan, and oxaliplatin; NR: Not reported.

Furthermore, a comprehensive review by Oba et al[15] emphasized that the benefits of NAT are particularly pronounced for borderline resectable tumors. The study demonstrated that patients receiving NAT experienced improved surgical outcomes and OS rates, reinforcing the importance of tailored treatment strategies[15]. This is supported by Zhan et al[4], who reported that approximately one-third of initially nonresectable tumors became resectable following neoadjuvant treatment, highlighting the critical role of NAT in clinical practice for patients with challenging tumor presentations.

Additionally, the study conducted by Motoi et al[21] reinforces the need for neoadjuvant protocols. They reported that the R0 resection rate was significantly greater in patients with resectable tumors who received NAT than in those who underwent upfront surgery. These findings indicate that incorporating NAT into treatment regimens is essential for optimizing patient outcomes and potentially shifting the paradigm in managing borderline resectable tumors.

Discussion of surgical challenges after NAT

While the benefits of NAT are clear, several surgical challenges arise following neoadjuvant treatment. One primary concern is the alteration of anatomical relationships due to tumor shrinkage and fibrotic changes induced by therapy. Stoop et al[22] noted that these changes complicate surgical approaches, requiring surgeons to adapt their techniques to navigate altered vascular structures and anatomical configurations. For example, the presence of fibrosis can complicate the dissection of critical structures, necessitating careful planning and execution during surgery.

Moreover, the effects of NAT on the tumor microenvironment can significantly impact surgical outcomes. Oba et al[15] emphasized that while NAT often results in favorable tumor characteristics, it can also lead to increased fibrosis and inflammatory responses in surrounding tissues. These factors can create a more complex surgical field, highlighting the need for thorough preoperative imaging and assessment to adapt surgical strategies effectively[15].

Additionally, postoperative complications may differ between patients who receive NAT and those who undergo upfront surgery. Springfeld et al[23] reported that patients treated with NAT may experience a distinct risk profile for complications because of the effects of treatment on tissue integrity and healing. Enhanced postoperative care and monitoring strategies are essential to manage these potential complications effectively, ensuring optimal recovery and minimizing adverse events.

Furthermore, recent studies, such as those by Pu et al[24], suggest that systemic adjuvant chemotherapy following NAT could provide significant survival benefits, highlighting the complex interplay between neoadjuvant and adjuvant treatments. This interplay may require surgical teams to consider additional factors when planning surgeries and postoperative care[24].

As previously discussed, NAT substantially enhances surgical outcomes and resectability in PDAC patients across tumor subgroups, reinforcing the clinical importance of neoadjuvant approaches. Studies revealed that NAT not only improves rates of surgical resection but also contributes to better long-term survival outcomes[3,18]. However, the challenges associated with surgical management after NAT necessitate careful planning and adaptation of surgical strategies. Ongoing research and clinical trials are essential for refining neoadjuvant strategies and optimizing surgical approaches for patients with PDAC.

SURGICAL OUTCOMES FOLLOWING NAT

R0 resection rates: Pre- and post-treatment comparisons

Surgical resection is the only potentially curative treatment for PDAC, and achieving R0 resection-complete tumor removal without residual disease-is crucial for improving long-term survival. Historically, R0 resection rates for PDAC patients have been low, typically about 15%-20%[1]. However, the introduction of NAT has significantly increased these rates, particularly among patients initially deemed borderline resectable.

Cools et al[25] reported that among patients who underwent pancreaticoduodenectomy after receiving NAT, R0 resection rates improved, indicating that NAT effectively downstaged tumors and facilitated surgical intervention. Specifically, their study revealed that patients who received NAT had smaller tumors and fewer positive lymph nodes, which are positive prognostic indicators[25]. Similarly, Gillen conducted a systematic review that demonstrated a substantial increase in R0 resection rates in patients receiving NAT, with some studies reporting rates of up to 73% in those with borderline resectable tumors[18]. This highlights the significant role of NAT in improving surgical outcomes and achieving better prognostic results for patients facing challenging tumor presentations.

In addition, Zhang et al[26] discussed how the combination of NAT with extended surgical techniques can further enhance resectability. These findings support the notion that NAT not only reduces tumor size but also improves the feasibility of surgical resection in patients who might otherwise be deemed unresectable. This evidence underscores the critical importance of incorporating NAT into the treatment paradigm for PDAC.

Surgical complication rates

While NAT is beneficial for improving surgical resectability, it is essential to evaluate the associated complication rates and surgical morbidity. Studies indicate that patients receiving NAT may experience different patterns of postoperative complications than those undergoing upfront surgery. Mirkin et al[27] reported that patients who received NAT had increased complications related to operative time and postoperative recovery.

Cools et al[25] noted that while NAT led to more major vein resections, which can complicate the surgical process, the overall rates of postoperative complications were not significantly higher than those in patients who underwent upfront surgery. Interestingly, the study revealed a decreased likelihood of pancreatic fistulas in patients who received NAT, indicating that NAT may not increase overall surgical morbidity. These findings suggest that while NAT can complicate surgical procedures, it does not necessarily correlate with increased morbidity or mortality[25].

Moreover, Lyu et al[28] conducted a meta-analysis comparing metal and plastic stents for preoperative biliary drainage in patients undergoing NAT and reported that the use of metal stents was associated with lower rates of reintervention and complications during the perioperative period. These findings indicate that the choice of preoperative management strategy can significantly impact postoperative outcomes, highlighting the need for personalized approaches in treatment planning.

Postoperative recovery and long-term survival

The success of NAT is ultimately measured by its impact on postoperative recovery and long-term survival rates. Patients who successfully achieve R0 resection following NAT often have improved outcomes compared with those who do not undergo neoadjuvant treatment. Springfeld et al[23] reported that patients who underwent NAT had significantly longer median OS and progression-free survival (PFS) rates, emphasizing the importance of achieving R0 resection for better prognostic outcomes. Additionally, recent studies suggest that NAT impacts DFS differently from OS in various PDAC subgroups[1]. In borderline resectable and locally advanced PDAC, NAT often significantly prolongs DFS by reducing early recurrence rates, reflecting improved local and systemic disease control. However, improvements in OS, while notable, may be less pronounced and influenced by additional factors such as subsequent treatments and tumor biology, highlighting the complexity of NAT’s survival benefit in these patient subgroups.

Research by Reddy et al[29] indicated that somatic mutations in patients undergoing NAT can also influence postoperative recovery and long-term survival. Their study revealed that specific mutations, such as KRAS G12V, were associated with better tumor regression and survival outcomes following NAC and radiotherapy. This highlights the potential of molecular profiling to guide treatment strategies and improve long-term prognoses.

Furthermore, Takeda et al[30] emphasized the role of patient characteristics, such as body composition, in influencing recovery times and complication rates. Their study revealed that factors such as sarcopenia significantly impact postoperative outcomes, suggesting that comprehensive preoperative assessments are crucial for optimizing patient recovery[30]. To further illustrate the impact of NAT on LAPC, Table 3 summarizes key clinical trials and retrospective studies. The table provides detailed information on different treatment regimens, resection rates, and long-term survival outcomes, highlighting the effectiveness and limitations of various approaches in the management of LAPC.

Table 3 Neoadjuvant therapy in locally advanced pancreatic cancer.

Ref.	Type of Study	Year	Treated with radiotherapy	Total (n)	Stage of disease	Treatment regimen	Resection rate (%)	R0 resection rate (%)	Median OS (months)	Median DFS (months)
Murphy et al[88]	Clinical trial	2019	Yes	49	LAPC	FOLFIRINOX + losartan + radiotherapy	80.9	88.2	31.4	NR
Stein et al[89]	Clinical trial	2016	Yes	31	LAPC	mFOLFIRINOX + radiotherapy	41.9	100	26.6	17.8
Pross et al[90]	Clinical trial	2015	Yes	120	LAPC	Multiple regimens + radiotherapy	Improved R0 resection	NR	Improved survival	NR
Ou et al[91]	Clinical trial	2020	Yes	85	LAPC	Gemcitabine-based regimen + radiotherapy	77.1	84.5	30.1	12.2
Boone et al[92]	Retrospective study	2013	Yes	13	LAPC	FOLFIRINOX + radiotherapy	20	50	NR	NR
Sadot et al[93]	Retrospective study	2015	Yes	101	LAPC	FOLFIRINOX and gemcitabine + radiotherapy	30.7	51.6	25	NR
Wo et al[94]	Retrospective study	2018	Yes	74	LAPC	FOLFIRINOX and gemcitabine + radiotherapy	39.2	NR	18.1	14.9
Hackert et al[95]	Retrospective study	2016	Yes	575	LAPC	FOLFIRINOX + radiotherapy	60.8	NR	16	NR
			Yes	575	LAPC	Gemcitabine + radiotherapy	46.6	NR	16.5	NR
			Yes	575	LAPC	Other regimens	51.6	NR	14	NR
Marthey et al[96]	Observational study	2015	Yes	77	LAPC	FOLFIRINOX + radiotherapy	36.4	89.3	22	NR
Gillen et al[18]	Systematic review	2010	Yes	860	LAPC	Various chemoradiation regimens	Improved R0 resection	NR	Prolonged survival	NR
Hyung et al[97]	Narrative review	2022	Nr	N/A	LAPC, BRPC	Overview of neoadjuvant chemotherapy and chemoradiation approaches	NR	NR	NR	NR

To further illustrate the impact of neoadjuvant therapy (NAT) on locally advanced pancreatic cancer (LAPC), Table 3 provides a detailed overview of studies evaluating the efficacy of NAT in patients with LAPC. The table highlights a range of clinical trials, retrospective studies, observational studies, and reviews, focusing on treatment regimens, the use of radiotherapy, resection rates, margin-negative (R0) resection rates, median overall survival, and disease-free survival. The data underscore the transformative potential of NAT in LAPC, demonstrating its ability to convert unresectable tumors into resectable ones, improve R0 resection rates, and extend survival outcomes. Specific regimens, such as fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) combined with radiotherapy, are prominently featured for their superior performance in improving resectability and survival. The integration of innovative approaches, such as losartan with FOLFIRINOX, further highlights the emerging strategies to enhance tumor response. Table 3 serves as a critical reference for understanding the clinical impact of various NAT protocols and emphasizes the role of multimodal approaches in addressing the challenges of LAPC management. LAPC: Locally advanced pancreatic cancer; BRPC: Borderline resectable pancreatic cancer; NAT: Neoadjuvant therapy; R0: Margin-negative resection; OS: Overall survival; DFS: Disease-free survival; FOLFIRINOX: Fluorouracil, leucovorin, irinotecan, and oxaliplatin; mFOLFIRINOX: Modified fluorouracil, leucovorin, irinotecan, and oxaliplatin; NR: Not reported.

NEOADJUVANT TREATMENT PROTOCOLS AND THEIR SURGICAL IMPLICATIONS

Overview of common neoadjuvant regimens

NAT is integral to PDAC management, especially in borderline resectable and locally advanced cases. The most common regimens include FOLFIRINOX (leucovorin, fluorouracil, irinotecan, oxaliplatin) and gemcitabine combined with nab-paclitaxel (GNP). Clinical studies consistently demonstrate the efficacy of FOLFIRINOX in downstaging tumors, significantly improving R0 resection rates compared to gemcitabine monotherapy[18,31]. Similarly, the GNP regimen has gained attention due to its ability to convert initially unresectable tumors into resectable cases[32]. Comparative clinical trials suggest that FOLFIRINOX tends to achieve greater tumor reduction and improved surgical outcomes compared to GNP; however, treatment choice often depends on patient-specific factors such as performance status, age, and comorbidities[33,34].

Impact on surgical outcomes

The selected neoadjuvant regimen substantially influences surgical outcomes, including resection margins, postoperative complications, and survival. Studies indicate that patients receiving FOLFIRINOX frequently exhibit better pathological responses, smaller tumor sizes, and fewer positive lymph nodes, thereby optimizing surgical success[25]. However, these aggressive regimens may also increase immediate postoperative complications, underscoring the importance of careful patient selection and perioperative management strategies[27]. Additionally, preoperative interventions such as metal stent placement for biliary drainage have been shown to decrease complication rates during NAT, highlighting the multidisciplinary considerations essential to successful surgical outcomes[28].

Emerging therapies and future directions

In addition to conventional chemotherapy, emerging therapies such as targeted treatments and immunotherapy are promising options in the context of NAT for PDAC. Recent evidence highlights the potential benefits of combining gemcitabine with nimotuzumab (an anti-EGFR monoclonal antibody), especially for the treatment of KRAS wild-type tumors[35,36]. Targeted therapies like nimotuzumab may directly inhibit critical oncogenic pathways, potentially overcoming chemotherapy resistance and improving tumor sensitivity to cytotoxic agents. Additionally, studies on the integration of immunotherapies such as pembrolizumab with standard chemotherapy regimens (e.g., GNP) show promising early results, potentially redefining surgical approaches and long-term outcomes[37]. Immunotherapy shows promise because it enhances antitumor immune responses, overcomes the immunosuppressive microenvironment of pancreatic tumors, and potentially exerts synergistic effects with chemotherapy to achieve more durable tumor control. Innovations such as the incorporation of losartan to modulate the tumor microenvironment also highlight how emerging therapies could further improve surgical feasibility and postoperative recovery[38]. Such combinations might not only reduce tumor size but also increase immune cell infiltration, making tumors more amenable to surgical resection and subsequent therapies. Finally, novel therapeutic agents, including siRNA targeting KRAS or concurrent hypofractionated radiotherapy with oral fluoropyrimidines (S-1), demonstrate encouraging initial outcomes, warranting further investigation and validation through clinical trials[39,40].

COMPLEXITIES AND CONTROVERSIES IN NAT

Patient selection criteria and challenges

Patient selection is a critical factor in the success of NAT for PDAC. The complexities surrounding who should receive NAT are influenced by tumor characteristics, patient health, and the potential for surgical resection. The distinctions between resectable, borderline resectable, and locally advanced tumors necessitate careful evaluation of each patient's situation. Jung et al[41] reported that the OS rates for BRPC patients who underwent NAT were significantly greater than those of patients who underwent upfront surgery. This raises the question of how best to identify candidates who would benefit from NAT.

Challenges also arise in determining the appropriate timing and type of therapy for patients with BRPC. As Kang et al[42] noted, one of the main concerns is that while NAT can downstage tumors, it may also delay definitive surgical treatment. The fear of disease progression during the NAT period can lead to hesitancy in the recommendation of this approach. Therefore, establishing clear selection criteria on the basis of tumor biology and patient characteristics is essential for optimizing outcomes.

Furthermore, as Choi et al[43] noted, cost-effectiveness should also be considered when deciding on NAT. Their analysis revealed that, compared with a surgery-first approach, neoadjuvant chemoradiation not only improved survival but also reduced overall treatment costs. This suggests that thorough patient assessment, including the financial implications of different treatment strategies, is vital for informed decision-making.

Debates on neoadjuvant vs upfront surgery

The debate over whether NAT or upfront surgery is the superior approach for treating RPC remains contentious. Proponents of NAT argue that preoperative treatment allows for tumor downstaging and potentially increases the R0 resection rate, as highlighted by Lee et al[44]. Their systematic review revealed that while NAT may not show a significant survival advantage in intention-to-treat analyses, it did lead to improved outcomes among patients who completed both NAT and surgery. The analysis of clinical data from 3484 patients with PDAC from 38 studies revealed that the OS of patients receiving NAC was prolonged, increasing from 19.0 months in the upfront surgery group to 25.7 months, while also increasing the R0 resection rate[45].

Conversely, critics of NAT express concerns about delaying surgery and the potential for disease progression during the treatment window. For example, Xu et al[46] conducted a meta-analysis revealing that while NAT increased R0 resection rates and decreased the likelihood of positive lymph nodes, it did not significantly improve OS compared with upfront surgery. This underscores the need for rigorous studies to clarify the long-term benefits and drawbacks of each approach.

Impact of tumor biology on surgical outcomes

Tumor biology plays a pivotal role in determining the effectiveness of NAT and subsequent surgical outcomes. The presence of specific genetic mutations can influence both the response to NAT and the likelihood of successful surgical resection. Rajagopalan et al[47] noted that patients with certain KRAS mutations exhibited better pathologic responses to NAC, suggesting that tumor genomics should be considered when planning treatment.

Moreover, the findings of Wijetunga et al[48] indicated that the tumor response to NAT could be a predictor of long-term survival, further emphasizing the importance of understanding tumor biology. Their study revealed that patients who responded favorably to NAT were more likely to experience extended disease-free intervals postresection.

The significance of the histological response to NAT cannot be overstated. Leonhardt et al[49] suggested that the degree of histological response following neoadjuvant chemoradiotherapy serves as a strong prognostic indicator. A complete or near-complete pathological response is often associated with improved survival outcomes, making it crucial to assess tumor behavior in response to NAT. In Stoop et al's retrospective study[50] of 1758 patients, 4.8% of those with resected LAPC after preoperative chemotherapy (with or without radiotherapy) achieved pCR, which was linked to improved OS. The 5-year OS for these patients was 63%, which was twice that of those without pCR[50].

IMAGING AND BIOMARKERS FOR ASSESSING THE RESPONSE TO NAT

Role of imaging techniques in surgical planning

Advanced imaging modalities are essential for evaluating the response to NAT for PDAC and determining the feasibility of surgical resection. Traditional imaging techniques, such as computed tomography (CT) and magnetic resonance imaging (MRI), have been pivotal in identifying anatomical boundaries and resectability. However, these methods often fail to differentiate between viable tumors and fibrotic tissue posttherapy, leading to challenges in surgical planning[51].

Positron emission tomography (PET) combined with CT or MRI has shown promise in overcoming these limitations. The 18F-fluorodeoxyglucose (FDG)-PET combined with CT (PET/CT), which uses 18F-fluorodeoxyglucose, has been highlighted for its ability to assess metabolic activity, which correlates better with histological response and survival outcomes than size-based criteria alone do[52,53]. Studies by Evangelista et al[54] have underscored the utility of FDG-PET/CT in preoperative assessments, suggesting that metabolic response should be considered alongside anatomical findings when deciding on surgical intervention.

MRI, particularly diffusion-weighted imaging and MR angiography, offers superior soft tissue contrast and helps in evaluating the involvement of vascular structures, a crucial determinant of surgical resectability[55]. The combination of PET/MRI further enhances this approach, providing comprehensive information about tumor metabolism, vascularity, and tissue characteristics in a single examination[54]. This multimodal approach is increasingly being adopted to refine surgical strategies and optimize patient outcomes.

The complementary use of these advanced imaging modalities with serum biomarkers further refines the assessment of NAT response, enabling more precise patient stratification and therapeutic decision-making. Imaging provides essential spatial and metabolic context, whereas biomarkers such as CA19-9, ctDNA, and exosomes offer additional molecular-level insights, collectively improving predictive accuracy for surgical outcomes.

Predictive biomarkers for the success of NAT

Biomarkers such as CA19-9 are extensively used to monitor the response to NAT in patients with PDAC. Elevated baseline levels of CA19-9 are independently associated with poor prognosis and reduced OS, even in patients with anatomically resectable tumors[56]. The degree of reduction in CA19-9 following therapy has been shown to be correlated with histopathological response and survival. Boone et al[57] reported that a decrease of more than 50% in CA19-9 Levels after neoadjuvant treatment was a strong predictor of achieving R0 resection.

In addition to CA 19-9, other systemic inflammatory markers, such as the neutrophil-to-lymphocyte ratio (NLR) and the lymphocyte-to-monocyte ratio (LMR), have gained attention as potential prognostic indicators. Asari et al[58] and Qi et al[59] demonstrated that an increased posttherapy NLR is associated with a greater likelihood of disease recurrence and decreased OS, whereas a low LMR posttherapy predicts worse outcomes in patients with BRPC.

Perfusion CT, which measures tissue perfusion parameters such as blood flow and blood volume, has also emerged as a novel biomarker for assessing therapy response. Higher perfusion values before and during therapy are indicative of a favorable histological response, and changes in perfusion parameters can be used to predict treatment success[60]. These findings suggest that integrating biomarkers with imaging techniques can increase the precision of response evaluation and guide surgical decision-making more effectively.

Correlation between imaging response and surgical outcomes

The relationship between the imaging response and surgical outcome is crucial for evaluating the efficacy of NAT. Abdelrahman reported that patients with a significant reduction in FDG uptake on PET/CT had improved survival outcomes and were more likely to undergo successful resections than those with stable or increased uptake[52]. This metabolic response was a stronger predictor of survival than was the radiographic response alone.

Similarly, Barnes et al[61] examined the patterns of disease recurrence after NAT and surgery and reported that radiographic responses correlated well with local disease control and distant metastasis rates. Patients with a favorable imaging response had a reduced risk of local-only recurrence, which is a critical factor in determining the need for additional adjuvant therapy postsurgery.

Studies by Panda et al[53] further highlighted that combining PET/MRI with CT-based volumetric assessments can provide a more comprehensive evaluation of tumor burden and response. They reported that patients who showed a substantial decrease in standardized uptake value (SUVmax) after NAT had better PFS and OS, emphasizing the prognostic value of metabolic imaging metrics.

These findings underscore the importance of a multimodal imaging approach for predicting surgical outcomes and guiding treatment strategies. By correlating the imaging response with histopathological findings and long-term outcomes, clinicians can make more informed decisions regarding resection and subsequent adjuvant therapy.

DISCUSSION

Synthesis of evidence on the impact of NAT

NAT has emerged as a transformative approach in the management of PDAC, especially for borderline resectable and locally advanced tumors. Several studies have demonstrated that NAT not only enhances resectability rates but also improves OS by reducing the tumor burden and eliminating micrometastatic disease. Choi et al[43] illustrated the impact of NAT in downstaging tumors, which subsequently increases the likelihood of achieving R0 resection, which is considered a critical determinant of long-term survival. This evidence aligns with findings by Boone et al[57], who noted that a significant reduction in serum CA19-9 levels posttherapy was correlated with a higher rate of R0 resection and longer PFS.

The synthesis of evidence from recent studies highlights the role of imaging and biomarkers in predicting response and guiding treatment strategies. Abdelrahman et al[52] demonstrated that FDG-PET/CT is a valuable tool for assessing metabolic response, providing a more accurate prediction of therapeutic outcomes than conventional imaging modalities do. This evidence is supported by the work of Panda et al[53], who emphasized the role of FDG-PET/MRI in refining surgical planning and predicting survival outcomes[53]. Furthermore, the use of CA19-9 as a predictive biomarker remains an essential component in evaluating the success of NAT. Bergquist highlighted that elevated CA19-9 levels in anatomically resectable tumors are independently associated with poorer survival outcomes and serve as an indication for NAT, particularly in high-risk patients[56].

Overall, the collective evidence underscores the importance of an integrated approach combining imaging techniques and biomarker analysis in the optimization of NAT for PDAC. By incorporating advanced imaging modalities and biomarkers, clinicians can better stratify patients, personalize treatment regimens, and improve surgical outcomes. This approach not only ensures more precise assessment of tumor response but also enables better identification of patients who would benefit most from surgical resection after NAT, thus leading to improved long-term survival and reduced recurrence rates[61].

Clinical implications for surgical practice

The integration of NAT into the treatment paradigm for PDAC has redefined the role of surgery in this challenging disease. By downstaging tumors, improving R0 rates, and potentially eliminating micrometastatic disease, NAT has emerged as a cornerstone for enhancing surgical outcomes. Its impact on surgical practice extends to preoperative patient selection, intraoperative decision-making, and postoperative management strategies.

One of the critical benefits of NAT is its ability to increase the proportion of patients who are eligible for surgery. Historically, PDAC has been characterized by high rates of recurrence and limited survival, even in patients with resectable disease at diagnosis. However, the introduction of NAT has shifted the surgical criteria. Ferrone et al[51] reported that patients who initially presented with borderline resectable or locally advanced disease and received neoadjuvant FOLFIRINOX were more likely to achieve R0 resections, resulting in improved survival. These findings support the strategy of offering NAT to patients with borderline resectable PDAC to maximize surgical benefit.

NAT has also influenced the approach to vascular resection and reconstruction. With more patients experiencing significant tumor regression, the need for complex vascular resections has become more common. Evangelista et al[54] highlighted that postneoadjuvant imaging findings often necessitate modifications in surgical planning, including vascular resection or multivisceral resection. Consequently, surgical teams must be equipped with expertise in vascular and complex pancreatic resections to manage the potential complications associated with these procedures.

Additionally, the use of biomarkers such as CA19-9 and imaging modalities such as FDG-PET/CT has improved patient stratification for surgery following NAT. Abdelrahman demonstrated that patients with a significant reduction in CA19-9 levels post-therapy are more likely to have favorable surgical outcomes[52]. Similarly, Boone reported that a CA19-9 reduction greater than 50% is indicative of higher rates of R0 resection and prolonged survival[57]. These findings underscore the value of integrating biomarker response into preoperative decision-making to optimize surgical outcomes.

In summary, NAT has transformed the surgical management of PDAC, allowing more patients to undergo potentially curative resection. Its role in enhancing R0 resection rates, enabling complex resections, and guiding preoperative planning through biomarkers and imaging reinforces its value in contemporary PDAC surgery.

Areas for future research

While significant advancements have been made in the utilization of NAT for PDAC, several areas require further research to optimize patient outcomes. One key area for future investigations is the identification and validation of novel biomarkers that can better predict patient response to NAT. Current biomarkers, such as CA19-9, have shown predictive value; however, their specificity and sensitivity are not ideal, leading to the need for more accurate molecular and genetic biomarkers[56,57]. Future studies could focus on integrating multiomics approaches, including proteomics, genomics, and metabolomics, to develop comprehensive biomarker panels that can provide a more precise prognosis and guide personalized therapeutic strategies.

Another important research avenue is the role of advanced imaging techniques in enhancing treatment decision-making. Although FDG-PET/CT and MRI have shown potential in evaluating treatment response and guiding surgical resectability, more research is needed to determine their role in real-time monitoring of tumor response during NAT[52,53]. Additionally, exploring the utility of emerging imaging modalities such as radiomics and artificial intelligence-driven imaging analysis could significantly improve the accuracy of predicting treatment outcomes and facilitate earlier intervention when therapeutic responses are suboptimal.

Finally, interest in investigating the impact of combining NAT with immunotherapy or other targeted therapies is increasing. Preliminary studies suggest that combining these therapeutic modalities could enhance the immune response against tumors and improve long-term survival[36,37]. Future clinical trials should evaluate the safety and efficacy of these combination therapies, along with their role in reducing recurrence rates and extending OS. Furthermore, understanding the underlying mechanisms of resistance to NAT through molecular profiling could help identify novel therapeutic targets and optimize treatment sequencing, paving the way for more effective management of PDAC[62].

CONCLUSION

NAT has transformed the management of PDAC, particularly in borderline resectable and locally advanced cases, by improving resectability, enhancing margin-negative resection rates, and addressing micrometastatic disease. The integration of advanced imaging and biomarkers-such as CA19-9, ctDNA, and liquid biopsy-has enabled more personalized and adaptive treatment strategies. Multidisciplinary team collaboration remains essential, allowing clinicians to incorporate genomic profiling and therapeutic response markers into individualized regimens[63]. Emerging therapies, including immunotherapy and targeted agents, show promise in synergizing with chemotherapy to enhance immune responses and surgical outcomes. As precision medicine and multimodal treatment strategies evolve, NAT is poised to become the cornerstone of PDAC care, offering the potential for improved survival and quality of life.

ACKNOWLEDGEMENTS

The authors wish to express their gratitude to all individuals and institutions that contributed valuable insights and assistance to this work. We acknowledge the support of our colleagues and the constructive feedback from the reviewers, which greatly improved the quality of this manuscript.