Role of neoadjuvant therapy in resectable pancreatic carcinoma: a review article

Introduction

Pancreatic carcinoma is a common gastrointestinal malignancy that accounts for nearly 3% of all malignancies (1). The incidence of pancreatic carcinoma is rising and is currently the seventh leading cause of cancer-related death worldwide (2). It is more common in men than women (3). Around 90% of patients with pancreatic carcinoma are adenocarcinoma. Other subtypes include acinar carcinoma, pancreatic blastoma, or neuroendocrine tumor (4). Diagnosis and intervention in the early stages of pancreatic cancer are difficult due to non-specific symptoms such as nausea, bloating, fatigue, and loss of appetite (5). Endoscopy is performed to give pathological evidence and relieve obstruction in a jaundiced person by biliary stenting. A triple-phase computed tomography (CT) scan is required to evaluate pancreatic tumor resectability. National Comprehensive Cancer Network (NCCN) recognizes resectable pancreatic carcinoma (RPC) as tumors that do not show any contact with arteries (celiac axis, superior mesenteric artery, or common hepatic artery) or contact with ≤180° of the venous circumference (the superior mesenteric vein or portal vein) without any contour irregularity (6).

At diagnosis, around 10–20% are found to be RPC (7). It has been seen that 20–25% of RPC patients who had an exploratory laparotomy or laparoscopy cannot undergo the desired tumor resection (8,9). It could be due to inter-observer variation in determining resectability based on the CT scan. Around 50% of these RPC patients have a positive margin on resection, as seen in many randomized trials. It was also observed that the diffusion sequences in magnetic resonance image (MRI) of the abdomen in RPC helped find hidden liver metastases or omental deposits, sparing needless surgeries in 12% of cases (10). A positron emission tomography (PET) CT scan helps rule out metastasis in RPC patients with high-risk features such as high carbohydrate antigen 19.9 (CA 19.9), large tumor size, regional lymphadenopathy, excessive weight loss, and pain (11).

The prognosis of RPC can be dismal. This is due to radiographically occult infiltration of nearby vascular structures and premature metastasis in the early stages of the disease (12-14). Also, the effect of margin-positive RPC patients can worsen the prognosis. The addition of adjuvant chemotherapy has improved five-year survival in pancreatic cancer from 6% to 43% (15-20). The role of neoadjuvant therapy (NAT) in RPC is one of the recent topics in pancreatic cancer after trials have shown better pathological and survival outcomes in unresectable and borderline resectable pancreatic cancer (BRPC). Many randomized studies such as PRODIGE 24, ESPAC 4, and RTOG 9704 have shown worse prognosis in R1 resection RPC. The NCCN 2022 guidelines recommend NAT in high-risk RPC based on low-level evidence that shows a survival benefit. Well-structured and executed large studies are required to emphasize the advantage of NAT in RPC over upfront surgery.

Rationale for NAT

Pancreatic cancer is considered a systemic disease owing to its early metastatic potential (21). Like other systemic diseases, the outcome benefits might be seen with NAT in RPC due to a few theoretical advantages. These include:

• Eradication of occult micro-metastasis and reducing distant relapses.
• Selection of chemo-sensitive patients to increase chances of resection.
• Identification of highly aggressive tumors that might not benefit from surgery.
• Increase tolerance to chemotherapy by giving a chemotherapy-free interval during surgery.
• To mitigate high-risk factors for improved treatment outcomes.

Limitations of NAT

The main limitation is the potential risk of metastasis or progression in an RPC patient while on NAT (22). Such tumors might respond to different types of chemotherapy or targeted therapy. These aggressive tumors would likely not benefit from upfront surgery due to the high chance of occult micro-metastasis. The other limitation is the toxicity of NAT which might result in opting out or delaying surgery (22). In the SWOG s1505 study, 25–30% of neoadjuvant chemotherapy (NACT) patients could not undergo surgery due to disease progression and its toxicity (23). However, compared to NACT, only 66% of patients can undergo adjuvant chemotherapy after upfront surgery as per the literature (24). The possibility of overtreatment in the patients treated with NAT is less as few patients are cured after completion of treatment.

Meta-analysis of NAT in RPC

We performed an online search for meta-analyses comparing NAT and upfront surgery in RPC, including intention-to-treat and per-protocol analysis. We found seven meta-analyses (shown in Table 1) that analyzed the role of NAT in RPC and showed an increased pathological free (R0) resection rate, better treatment compliance, and fewer lymph nodes. All the studies compared the effectiveness of NAT in the form of chemotherapy and chemo-radiation. Two out of these studies showed improved survival of RPC in their per-protocol analysis, including the neoadjuvant chemo-radiation (NACT-RT) arm in the study by Pan et al. (25) and the NACT arm in the study by Lee et al. (26). Another study by Ye et al. showed a survival benefit in its sub-group analysis with the NACT arm (27) while Ghanem et al. showed a survival benefit with NACT and NACT-RT in the NAT arm (28).

The issues with all the meta-analyses were that most of them included retrospective studies and old chemotherapy regimens, few interpreted results on per-protocol analysis while others included both RPC and BRPC. One of the recent meta-analyses by Uson Junior et al. did not show any survival benefit of NAT in RPC, however, most of the studies included in it used gemcitabine-based chemotherapy when gemcitabine/nab-paclitaxel combination was the choice of chemotherapy in the adjuvant treatment of pancreatic cancer (31). Since 2019, the presence of specific molecular markers in pancreatic cancer has shown an excellent response to targeted therapy. The data on prognostic biomarkers or genetic mutations have been lacking in recent meta-analyses.

Due to heterogeneity in patient selection with outdated chemotherapy regimens, different radiation doses, and the retrospective nature of the studies, it is necessary to assess outcomes based on randomized controlled trials (RCTs) to rule out selection bias, with the current standard of treatment along with prognostic and predictive markers to select patients that could benefit from NAT.

RCTs of NACT in RPC

One of the earlier studies, the NEOPAC randomized phase III study, was done to compare NACT with upfront surgery but it was stopped prematurely due to low accrual of patients (32).

Five phase II/III RCTs (shown in Table 2) have shown the outcome of NACT compared to upfront surgery in RPC.

The NEPAFOX phase II study included NACT with FOLFIRINOX versus upfront surgery followed by adjuvant gemcitabine and it showed worse survival outcomes in the NACT arm. Due to low patient numbers, the analyses for primary and secondary endpoints were not robust and only descriptive. Another limitation was that the treatment arms were not balanced in the chemotherapy regimen and included BRPC patients as well (33).

Two trials, PACT-15 and NEONAX showed better numerical median survival in the NACT arm as compared to the upfront surgery arm. While the primary endpoint of the PACT-15 study was event-free survival analysis (34), the NEONAX showed that the gemcitabine/nab-paclitaxel combination was well tolerated in the neoadjuvant setting. In the NEONAX trial, there was a discrepancy of chemotherapy exposure in both the arms with 90% of patients in the neoadjuvant arm completing pre-operative chemotherapy and only 42% of patients starting chemotherapy in the adjuvant arm (35).

The largest of these studies, the Japanese PREP-02 phase III trial of neoadjuvant gemcitabine and oral fluoropyrimidine S-1 versus adjuvant chemotherapy S-1, randomized 362 RPC patients and showed a significant advantage of NACT over surgery followed by adjuvant chemotherapy [median overall survival (OS) of 36.7 versus 26.6 months; P=0.015] (36). It was seen that the patients in the neoadjuvant arm received two more cycles than the patients treated in the upfront surgery group. BRPC patients with portal vein involvement were also included in this study. The non-availability of S-1 in Europe and the United States limited its research and application in other parts of the world.

NORPACT-1 study presented in ASCO 2023 compared neoadjuvant FOLFIRINOX with upfront surgery in RPC and showed a numerical survival benefit of upfront surgery (37). The results were argumentative since 83% of the patients in the neoadjuvant arm started treatment, out of which 50% completed NACT. About 66% of patients in the upfront surgery arm received adjuvant chemotherapy. Though there was a favorable surgical outcome in the neoadjuvant arm, it did not result in improved survival, as seen in most of the previous trials.

Many studies were done to find the optimal choice of chemotherapy for pancreatic cancer. Gemcitabine/nab-paclitaxel and mFOLFIRINOX have shown better OS in both the metastatic first-line and adjuvant settings (38). SWOG s1505 study was done to compare the efficacy of these two chemotherapy regimens in neoadjuvant settings of RPC. The study showed that both regimens were safe, equally efficacious, and showed high resectability rates, without comparing it to upfront surgery (23). While the NEONAX study showed better survival outcomes in the NACT arm with gemcitabine/nab-paclitaxel, there are no trials showing benefit with neoadjuvant FOLFIRINOX compared to upfront surgery. Three randomized phase III trials ALLIANCE A021806, PRODIGE 48, and PREPOANC 3 are ongoing to evaluate the role of neoadjuvant versus adjuvant FOLFIRINOX in patients with RPC in terms of disease-free survival and OS (39-41).

RCTs of NACT-RT in RPC

Three phase III RCTs (shown in Table 3) have investigated the efficacy of NACT-RT over immediate surgery in RPC.

Two trials done by Casadei and Golcher intended to evaluate the use of preoperative CRT for patients with RPC. Both trials were closed early due to poor patient accrual with no significant differences observed in OS (42,43).

The PREOPANC was the first randomized phase III trial that reached full accrual in evaluating the efficacy of NACT-RT in RPC. NACT-RT was associated with better disease-free survival and locoregional failure-free period, with significantly lower rates of pathologic lymph nodes, perineural invasion, and venous invasion. In the final analysis, neoadjuvant treatment improved OS in the overall cohort; however, in the RPC group, the results were not statistically significant (P=0.23). The benefit of neoadjuvant treatment in the trial was mainly driven by borderline pancreatic cancer (P=0.045) (44). After the PRODIGE phase 3 study showed better OS with FOLFIRINOX than gemcitabine monotherapy in advanced pancreatic cancer, it was hypothesized that FOLFIRINOX might supersede the efficacy of gemcitabine-based chemoradiotherapy in the neoadjuvant setting. PREOPANC-2 study presented in ESMO 2023 compared neoadjuvant FOLFIRINOX versus neoadjuvant gemcitabine-based chemoradiotherapy in patients with early pancreatic cancer. However, the median OS was 21.9% in the FOLFIRINOX arm versus 21.3% in the gemcitabine-based NACT-RT arm [hazard ratio (HR) 0.87; 95% confidence interval (CI): 0.68–1.12; P=0.28]. Also, the resection rates (77% versus 75%, respectively; P=0.7) and serious adverse rates (49% versus 43%, respectively; P=0.26) were also similar between the treatment arms.

Potential role of bio-markers and molecular testing in RPC

Various biomarkers and genetic mutations (Table 4) are used to predict the treatment of pancreatic cancer. These markers can help select RPC patients with high chances of early metastasis and can benefit from NAT. A recent study performing next-generation sequencing (NGS) done on resected pancreatic cancer specimens found pathogenic variants in 94% of samples, 18% of which were potentially actionable (45).

The most common biomarker is CA 19.9 which has a sensitivity of 79% and specificity of 82% in symptomatic patients (46). CA 19.9 is not tumor-type specific and can be raised in other malignancies or benign diseases (47). Hence, other biomarkers such as CEA have been used in combination with CA 19.9 to increase the positive predictive value and know the prognosis of pancreatic cancer (48).

CA 19.9 has been used in pancreatic cancer to track the treatment response, predict resectability, and monitor the recurrence. Preoperative elevation of CA 19.9 in patients with RPC has been associated with decreased OS (49). A study by Humphris et al. analyzed RPC patients who underwent resection and found that a pre-operative CA 19.9 >120 U/mL had significantly longer disease-free survival than patients with a CA 19.9 ≤120 U/mL (36 versus 17 months, respectively). Post-operative CA 19.9 >37 U/mL was also associated with poor prognosis and shorter OS (50).

RPC with elevated CA 19.9 levels at diagnosis are biologically borderline resectable regardless of anatomic resectability, and neoadjuvant systemic therapy is advised (51). A recent prospective randomized study by Chiu et al. has shown CA 19.9 as a predictor of survival and distant failure in RPC based on response to adjuvant gemcitabine (52). Another study by Al Abbas et al. has shown serum CA 19.9 response as a useful marker after NAT and resection in predicting patient survival in pancreatic cancer. It has shown that serum CA 19.9 response ≥85% remained a strong independent predictor of survival (HR: 0.47; P=0.007) on multivariate analysis (53).

Some mutations have shown a correlation with treatment response in metastatic pancreatic cancer.

Tumors with deficient mismatch repair gene (dMMR) have been seen to benefit from programmed death-ligand 1 (PD-L1) inhibitors (54). Riazy et al. showed the addition of adjuvant chemotherapy in RPC patients significantly increased survival in those with proficient mismatch repair gene (pMMR) than dMMR patients. This data indicated the potential for dMMR as a useful predictive chemotherapy biomarker. NAT may be more appropriate in pMMR tumors than upfront surgery (55).

Patients with BRCA1/2 mutations have shown a higher response to platinum-based therapy (56) while tumors with low GATA6 expression show poor response to mFOLFIRINOX (57). In a retrospective review of 61 RPC and BRPC patients with known BRCA1/2 mutations, neoadjuvant FOLFIRINOX showed significantly higher rates of pathological complete response in the patients with a germline BRCA1/2 mutations (44%) compared to the BRCA wildtype (10%) (58). The application of BRCA1/2 testing is, however, currently limited to those with a positive family history or metastatic disease. GATA6 has been shown to inhibit metastasis by inhibiting de-differentiation of epithelial to mesenchymal transition (EMT). In the ESPAC 3 study, Martinelli et al. demonstrated that GATA6 expression strongly predicted survival in patients treated with adjuvant 5-FU, with a median survival of 27 months in patients with high expression against 14 months with low expression. This survival difference in GATA expression levels was not detected in patients treated with adjuvant gemcitabine (59).

KRAS inhibitors have shown promising results in early studies for patients with this mutation. A certain KRASG12C mutation seen in 1–2% of pancreatic adenocarcinoma patients has recently been identified as a druggable target. However, their application in assessing treatment response in RPC is still a long way off. A prospective phase II trial enrolling patients with resectable and BRPC and selecting NAT (fluoropyrimidine-based or gemcitabine-based) based on molecular profiling has reported high resection rates (60). Another phase II PIONEER-Panc study is investigating novel therapeutic strategies in early-stage pancreatic cancer.

In a retrospective study by Chen et al., the predictive role of CDKN2A in RPC patients receiving chemoradiation with gemcitabine showed that the presence of a CDKN2A mutation did not predict treatment response (61).

There is an emerging role of circulating tumor DNA (ctDNA) in early detection, treatment monitoring, and its prediction in pancreatic cancer. Genomic sequencing has shown the presence of mutations across four genes (KRAS, TP53, SMAD4, CDKN2A) in more than 90% of patients (62). Somatic variations are seen in around 5% of pancreatic cancer, reflecting extensive inter-tumoural genetic heterogeneity. Due to this, there is low concordance between plasma ctDNA detection rates in pancreatic cancer (63). It is around 10% in early pancreatic cancer which restricts its sensitivity for profiling. This suggests that the use of liquid biopsy testing requires greater sensitivity and specificity than targeting ctDNA alone. Molecules derived from tumors can be used to enhance their analytical validity and clinical utility. Such methods require rigorous testing in large-scale prospective studies to determine the use of liquid biopsy profiling in pancreatic cancer. Therefore, we need RCTs to incorporate these biomarkers to identify a subset of patients who can benefit from a specific NAT in RPC.

Conclusions

This review article aims to provide an update on the recent state of NAT in RPC. Studies have shown better surgical rates and compliance with NAT for RPC, however, very few have translated into better survival outcomes. Although NAT has shown better survival outcomes in BRPC, its limited benefit in RPC might be due to certain unknown confounding factors. Based on recent evidence, there is a need for the identification of biologically aggressive pancreatic cancer through reliable biomarkers, and personalization of therapy through molecular characterization and targeting. Molecular and genetic markers might help in identifying this subset of RPC patients who would benefit from NAT, compared to upfront surgery.

Acknowledgments

Funding: None.

Footnote

Peer Review File: Available at https://apc.amegroups.com/article/view/10.21037/apc-23-14/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://apc.amegroups.com/article/view/10.21037/apc-23-14/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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