Current evidence for neoadjuvant therapy in resectable pancreatic cancer

By 2030, pancreatic cancer is projected to become the second-leading cause of cancer-related death in the United States (1). Among the reasons for its grim prognosis is that only about 15% of patients have resectable disease at diagnosis and there are high rates of recurrence after surgery: 60–80% will have a recurrence within 2 years and 5-year survival after surgery alone is 10% (2-5). Pancreatic cancer is thus considered a systemic disease even at an early stage, and research has shown that the metastases contain nearly the same mutational profile as the primary pancreatic tumor providing the molecular underpinning for this perception (6). Adjuvant therapy is the current standard of care based on overall survival (OS) benefit demonstrated in several trials (4,5,7-9). Neoadjuvant therapy is of interest given the potential advantages of earlier systemic therapy to treat micrometastatic disease, prevention of futile surgery in patients with rapidly progressive disease, downsizing the tumor, superior R0 resection rates, and increasing chemotherapy use as ~80% of patients who undergo surgical resection do not undergo adjuvant therapy (10-12). Below we discuss the phase II NORPACT-1 study and detail how it extends our knowledge on the use of neoadjuvant therapy in resectable pancreatic cancer in the context of similar trials, particularly NEONAX, PREOPANC, and Prep02-JSAP (Table 1) (13).

NORPACT-1 is a phase II study of 140 patients from 12 Nordic centers enrolled from 2017–2021. Patients were randomized to either neoadjuvant full-dose FOLFIRINOX for four cycles (2 months) followed by surgery and then adjuvant chemotherapy, or upfront surgery followed by adjuvant chemotherapy. Adjuvant chemotherapy initially was gemcitabine plus capecitabine but following a protocol amendment allowed adjuvant modified FOLFIRINOX. Central radiology review was not performed. Only patients with pancreatic head tumors were included, and resectability was defined as per National Comprehensive Cancer Network (NCCN) guidelines. Patients randomized to neoadjuvant therapy had to have a histologic diagnosis of pancreatic ductal adenocarcinoma. The primary endpoint was OS at 18 months. After a study amendment, only the neoadjuvant group required cytological or histological confirmation of pancreatic ductal adenocarcinoma and management of hyperbilirubinemia.

Superior surgical outcomes were achieved in the neoadjuvant chemotherapy group, with improved R0 and N0 resections. In the intention-to-treat population, 56% of the neoadjuvant chemotherapy group had R0 resection vs. 39% in the upfront surgery group. Twenty-nine percent of the neoadjuvant group had N0 disease vs. 14% in the upfront surgery group. This differs from the NEONAX trial, which compared neoadjuvant gemcitabine/nab-paclitaxel vs. upfront surgery in patients with resectable disease and found that the N0 resection rate was similar in both groups (33% in the neoadjuvant group vs. 29% in the upfront surgery group) (14). This difference could be accounted for by the difference in type of neoadjuvant therapy in each trial: NORPACT-1 prescribed four neoadjuvant cycles (2 months) of full-dose FOLFIRINOX whereas NEONAX prescribed two neoadjuvant cycles (2 months) of gemcitabine/nab-paclitaxel.

The improved surgical outcomes in NORPACT-1 did not translate to improved survival. Median OS was approximately 25 months in the neoadjuvant chemotherapy group vs. 39 months in the upfront surgery group. In comparison, other trials have shown a survival benefit, but importantly some enrolled patients with resectable or borderline resectable disease with the borderline resectable group appearing to benefit most. The PREOPANC trial, which compared neoadjuvant gemcitabine with radiation vs. upfront surgery, showed improved median and 5-year OS in the neoadjuvant chemotherapy group (16). However, the borderline resectable group benefited the most [hazard ratio (HR) =0.67, P=0.045], and the difference was not statistically significant in the resectable group (HR =0.79, P=0.23) (Table 1). The PREP-02/JSAP-05 study, which was conducted exclusively in Japan, compared neoadjuvant gemcitabine with S-1 vs. upfront surgery and enrolled patients with borderline resectable and resectable disease (15). A statistically significant 10-month improvement in median OS favoring the neoadjuvant group was found, but full results are not yet available to discern the comparative benefit for resectable and borderline resectable subgroups (Table 1). Finally, the NEONAX trial, which enrolled only patients with resectable disease, showed a 9-month improvement in median OS favoring the neoadjuvant group but this was a secondary endpoint and it did not meet its primary endpoint of improved disease-free survival. Moreover, the neoadjuvant group had twice the rate of grade 3 toxicity although this may have been due to higher rates of neoadjuvant completion (90%).

Possible reasons for the lower-than-expected survival in NORPACT-1 include:

• Low neoadjuvant completion rate—less than half of the patients assigned to the neoadjuvant arm completed therapy, and 21% did not complete even the first cycle. This limited exposure to the experimental treatment is expected to result in less differences being detected between the two groups. This also likely accounts for the low rate of histological response (56%) in the neoadjuvant arm.
• Differences in adjuvant therapy—after the results of the PRODIGE-24 study were made known in 2018 showing a 19.4-month improvement in median OS with adjuvant modified FOLFIRINOX compared to gemcitabine, the protocol was amended to change the adjuvant therapy from gemcitabine/capecitabine to modified FOLFIRINOX after 21 patients had already been enrolled. The upfront surgery group had more patients start and complete adjuvant mFOLFIRINOX compared to the neoadjuvant chemotherapy group, which predominantly received gemcitabine-based adjuvant therapy. In the intention-to-treat population, 48% (37 of 77) of the neoadjuvant chemotherapy group started gemcitabine-based adjuvant therapy vs. 38% (24 of 63) in the upfront chemotherapy group. Seventeen percent (13 of 77) of the neoadjuvant chemotherapy group started adjuvant mFOLFIRINOX vs. 30% (19 of 63) in the upfront surgery group. Thirteen percent (10 of 77) of the neoadjuvant chemotherapy group completed adjuvant mFOLFIRINOX vs. 19% (12 of 63) of the upfront surgery group.
• Use of granulocyte colony stimulating factor (G-CSF) & neutropenic complications—the use of G-CSF was not mandatory. The amount of G-CSF use in the neoadjuvant and upfront surgery group is not reported; however, during the adjuvant therapy phase the neoadjuvant chemotherapy group had more neutropenic complications: 14% (11 of 77) of the neoadjuvant chemotherapy group had neutropenia, neutropenic fever, infection, or neutropenic colitis compared to 11% (7 of 63). Tab. 3 in the manuscript notes that in four patients in the neoadjuvant chemotherapy group, infection was the reason for not completing all 4 cycles of neoadjuvant therapy.

In addition to the limitations identified by the authors, the decision to enroll only pancreatic head tumors limits the generalizability of the study. As the study was conducted only in Nordic centers, the geographic and racial diversity is also not representative of all countries. The prescribed chemotherapy in the neoadjuvant portion of the perioperative treatment was more intense than the adjuvant portion—the 5-fluorouracil (5-FU) bolus and full dose irinotecan (180 mg/m²) were given neoadjuvantly (i.e., full-dose FOLFIRINOX), whereas adjuvantly the 5-FU bolus was excluded and dose-reduced irinotecan (150 mg/m²) was given (i.e., mFOLFIRINOX). This is not representative of practice in which mFOLFIRINOX is preferred in the curative intent setting based on PRODIGE-24.

Overall, the trials that compare neoadjuvant therapy vs. upfront surgery are heterogeneous which limits the already precarious practice of cross trial comparisons and makes drawing general conclusions difficult. They differ in the number of neoadjuvant cycles given, type and dosage of neoadjuvant therapy (e.g., irinotecan 150 vs. 180 mg/m², inclusion/exclusion of the 5-FU bolus), use of concurrent radiation, tumor anatomy (head tumor only in NORPACT-1 vs. any location in the other studies), and resectability (resectable only vs. resectable and borderline resectable). The only trial thus far to show a statistically significant improvement in median OS is the Japanese Prep02/JSAP-05 study, which used neoadjuvant gemcitabine and S-1 (an oral fluoropyrimidine) which is not available in all countries and enrolled a mixed population of resectable and borderline resectable disease (15). Thus, practices vary regarding the use of neoadjuvant treatment in patients with resectable disease as there is insufficient evidence to recommend one particular approach. There are two ongoing phase 3 trials that may shed light on the optimal number of neoadjuvant cycles: PREOPANC-3 and ALLIANCE A021806 are both studying 8 cycles (4 months) of neoadjuvant mFOLFIRINOX vs. upfront surgery, which contrasts with the other trials to date which have studied only 2–4 cycles (1.5–2 months) of neoadjuvant therapy.

A predictive biomarker for response to chemotherapy may assist in personalizing the decision to pursue neoadjuvant chemotherapy or upfront surgery. For example, patients with tumors that demonstrate chemoresistant features may benefit most from upfront surgery. Through retrospective studies and select prospective trials, promising predictive biomarkers have been identified in early-stage pancreatic cancer such as BRCA1/2, microRNA21, and GATA6. A retrospective analysis of nine patients with borderline resectable pancreatic cancer and germline BRCA mutation who were treated with neoadjuvant FOLFIRINOX showed significantly higher rates of pathologic complete response compared to the 30 patients with wild-type BRCA (44% vs. 10%, P=0.009), superior median disease-free survival (not reached vs. 7 months, P=0.03), and numerically improved median OS (not reached vs. 32 months, P=0.2) (21). BRCA germline mutations confer sensitivity to platinum-based regimens due to their deficiency in homologous recombination. The NCCN guidelines recommend neoadjuvant FOLFIRINOX or gemcitabine/cisplatin for patients with germline BRCA1/2 or PALB2 mutations. A phase II trial of patients with resectable and borderline resectable pancreatic cancer assigned patients to neoadjuvant therapy (either fluoropyrimidine-based or gemcitabine-based) according to their composite molecular profile consisting of six biomarkers predictive of chemosensitivity [thymidylate synthase (low levels predict 5-FU response), excision repair cross-complementing protein (low levels predict cisplatin response), ribonucleotide reductase M1 (low levels predict gemcitabine response), SPARC protein (high levels predict nab-paclitaxel response), topoisomerase I (high levels predict irinotecan response), and hENT1, a transporter of gemcitabine (high levels predict gemcitabine response)] (22). High resection rates were reported: 92% among those with resectable pancreatic cancer and 74% among those with borderline resectable pancreatic cancer, which is superior to what has been reported in other neoadjuvant trials and suggests that molecular profiling is a promising strategy. MicroRNAs are small noncoding RNAs involved in regulating gene expression which may also serve as predictive biomarkers. A retrospective analysis of patients with resected pancreatic cancer demonstrated that a low microRNA21 expression level was associated with benefit from adjuvant chemotherapy (improved disease-free survival and OS) in a Korean and Italian cohort, and that in vitro transfection with anti-microRNA21 restored chemosensitivity (23). Also, the transcriptional subtype of pancreatic cancer may predict response to therapy. A study by The Cancer Genome Atlas confirmed the findings of prior studies which clustered pancreatic cancer into two main subtypes based on mRNA: a classical and basal-like subtype (24). The classical subtype is associated with high expression of GATA6, a transcription factor which has been associated with response to 5-FU but not gemcitabine (25). To analyze this in a prospective manner, NeoPancONE (NCT04472910) is a phase 2 trial being conducted in Canada assessing GATA6 (via RNA in situ hybridization) as a positive predictive biomarker of response to neoadjuvant mFOLFIRINOX in patients with resectable pancreatic cancer. A key challenge in a biomarker-guided approach will be the scant tissue available in early-stage disease, which may be overcome by plasma-based assays. Additionally, assays will need a rapid turnaround time to avoid delaying treatment initiation.

Other future directions include studying the use of total neoadjuvant chemotherapy in resectable pancreatic cancer, although the definition of total neoadjuvant chemotherapy for pancreatic cancer is not yet harmonized with studies varying in the number of cycles, choice of regimen, and sequencing of chemotherapy/radiation/chemoradiation (26). PREOPANC-2 included a neoadjuvant chemotherapy-only arm (eight cycles FOLFIRINOX followed by surgery), but it was compared against neoadjuvant chemoradiation with a different chemotherapy (three cycles of gemcitabine-radiation followed by surgery and four cycles of adjuvant gemcitabine) therefore conclusions about the benefit of total neoadjuvant therapy are difficult to make (18,19). Full results are not yet available, but resection rate and median OS did not differ significantly between the two groups (Table 1). The pancreatic cancer pipeline also includes new developments in screening, diagnostics, and therapeutics which make the issue of neoadjuvant therapy increasingly important as potentially more patients are identified with early-stage disease and better tools become available to predict early disease progression. The PRECEDE study is an international pancreatic cancer screening program for patients at high-risk (based on family history and germline testing) which recently published on the promising feasibility of this surveillance program with nearly 80% of patients adhering to the screening recommendations (27). Novel magnetic resonance imaging techniques are being developed that can differentiate the microcirculation properties of the pancreas and accurately distinguish chronic pancreatitis from pancreatic cancer, and in the future may be used to monitor response to neoadjuvant therapy (28). Circulating tumor DNA (which is derived from tumor cell apoptosis) and exosomal DNA (which is derived from viable cancer cells) are being studied as possible predictive biomarkers of treatment response to enhance the current trio of clinical exam, carbohydrate antigen 19-9 (CA 19-9), and computed tomography scans. Innovative therapies include a phase 1 trial of pre-operative fecal transplants (NCT04975217) based on data that long-term survivors of pancreatic cancer have a more diverse microbial composition of their tumor and animal studies suggesting a gut-tumor crosstalk (29). A phase 1 trial (NCT04161755) of the mRNA vaccine autogene cevumeran given in the adjuvant setting has shown durable responses in T-cells and delayed recurrence as presented orally at the 2024 American Association for Cancer Research (AACR) meeting (written results pending). At a median follow-up of 3.2 years, patients who had a T-cell response to the vaccine had a median recurrence-free survival that was not yet reached, compared to 13.4 months in those who did not have an immunologic response to the vaccine.

In summary, there remains significant equipoise in the question of the role of neoadjuvant and perioperative chemotherapy in the treatment of resectable pancreatic cancer. Only one study thus far, the Japanese Prep02/JSAP-05 study, has shown a statistically significant OS benefit but enrolled a mixed population of resectable and borderline resectable disease with full results forthcoming regarding the relative benefit in each subgroup (15). At this time, no standardized treatment exists for patients with resectable disease. Neoadjuvant chemotherapy can be considered after multidisciplinary discussion in patients with high-risk features (defined by the NCCN as high CA19-9, large primary tumors, large regional lymph nodes, excessive weight loss, or extreme pain) or as part of a clinical trial. The pending results of studies such as PREOPANC-3 and ALLIANCE A021806 may provide further insight, with results expected after 2029–2030.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-24-116/prf

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-24-116/coif). E.J.K. reports honorarium from Eisai, Seagen, and Relay, and has private stock options in RomTech. The other author has 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.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Rahib L, Wehner MR, Matrisian LM, et al. Estimated Projection of US Cancer Incidence and Death to 2040. JAMA Netw Open 2021;4:e214708. [Crossref] [PubMed]
2. Tzeng CW, Fleming JB, Lee JE, et al. Yield of clinical and radiographic surveillance in patients with resected pancreatic adenocarcinoma following multimodal therapy. HPB (Oxford) 2012;14:365-72. [Crossref] [PubMed]
3. Alfano MS, Garnier J, Palen A, et al. Peak Risk of Recurrence Occurs during the First Two Years after a Pancreatectomy in Patients Receiving Neoadjuvant FOLFIRINOX. Cancers (Basel) 2023;15:5151. [Crossref] [PubMed]
4. Oettle H, Neuhaus P, Hochhaus A, et al. Adjuvant chemotherapy with gemcitabine and long-term outcomes among patients with resected pancreatic cancer: the CONKO-001 randomized trial. JAMA 2013;310:1473-81. [Crossref] [PubMed]
5. Neoptolemos JP, Palmer DH, Ghaneh P, Valle JW, Cunningham D, Wadsley J, et al. ESPAC-4: A multicenter, international, open-label randomized controlled phase III trial of adjuvant combination chemotherapy of gemcitabine (GEM) and capecitabine (CAP) versus monotherapy gemcitabine in patients with resected pancreatic ductal adenocarcinoma: Five year follow-up. J Clin Oncol 2020;38:4516. [Crossref]
6. Yachida S, Jones S, Bozic I, et al. Distant metastasis occurs late during the genetic evolution of pancreatic cancer. Nature 2010;467:1114-7. [Crossref] [PubMed]
7. Conroy T, Castan F, Lopez A, et al. Five-Year Outcomes of FOLFIRINOX vs Gemcitabine as Adjuvant Therapy for Pancreatic Cancer: A Randomized Clinical Trial. JAMA Oncol 2022;8:1571-8. [Crossref] [PubMed]
8. Tempero MA, Pelzer U, O'Reilly EM, et al. Adjuvant nab-Paclitaxel + Gemcitabine in Resected Pancreatic Ductal Adenocarcinoma: Results From a Randomized, Open-Label, Phase III Trial. J Clin Oncol 2023;41:2007-19. [Crossref] [PubMed]
9. Neoptolemos JP, Stocken DD, Friess H, et al. A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med 2004;350:1200-10. [Crossref] [PubMed]
10. Li D, O'Reilly EM. Adjuvant and neoadjuvant systemic therapy for pancreas adenocarcinoma. Semin Oncol 2015;42:134-43. [Crossref] [PubMed]
11. Michelakos T, Pergolini I, Castillo CF, et al. Predictors of Resectability and Survival in Patients With Borderline and Locally Advanced Pancreatic Cancer who Underwent Neoadjuvant Treatment With FOLFIRINOX. Ann Surg 2019;269:733-40. [Crossref] [PubMed]
12. Gillen S, Schuster T, Meyer Zum Büschenfelde C, et al. Preoperative/neoadjuvant therapy in pancreatic cancer: a systematic review and meta-analysis of response and resection percentages. PLoS Med 2010;7:e1000267. [Crossref] [PubMed]
13. Labori KJ, Bratlie SO, Andersson B, et al. Neoadjuvant FOLFIRINOX versus upfront surgery for resectable pancreatic head cancer (NORPACT-1): a multicentre, randomised, phase 2 trial. Lancet Gastroenterol Hepatol 2024;9:205-17. [Crossref] [PubMed]
14. Seufferlein T, Uhl W, Kornmann M, et al. Perioperative or only adjuvant gemcitabine plus nab-paclitaxel for resectable pancreatic cancer (NEONAX)-a randomized phase II trial of the AIO pancreatic cancer group. Ann Oncol 2023;34:91-100. [Crossref] [PubMed]
15. Unno M, Motoi F, Matsuyama Y, Satoi S, Matsumoto I, Aosasa S, et al. Randomized phase II/III trial of neoadjuvant chemotherapy with gemcitabine and S-1 versus upfront surgery for resectable pancreatic cancer (Prep-02/JSAP-05). J Clin Oncol 2019;37:189. [Crossref]
16. Versteijne E, van Dam JL, Suker M, et al. Neoadjuvant Chemoradiotherapy Versus Upfront Surgery for Resectable and Borderline Resectable Pancreatic Cancer: Long-Term Results of the Dutch Randomized PREOPANC Trial. J Clin Oncol 2022;40:1220-30. [Crossref] [PubMed]
17. Schwarz L, Bachet JB, Meurisse A, et al. Resectable pancreatic adenocarcinoma neo-adjuvant FOLF(IRIN)OX-based chemotherapy: A multicenter, non-comparative, randomized, phase II trial (PANACHE01-PRODIGE48 study). J Clin Oncol 2022;40:4134. [Crossref]
18. Janssen Q, van Dam JL, Besselink MGH, et al. Total neoadjuvant FOLFIRINOX or gemcitabine-based chemoradiotherapy and adjuvant gemcitabine for resectable and borderline resectable pancreatic cancer (PREOPANC-2): A nationwide multicenter randomized controlled trial. J Clin Oncol 2021;39:TPS4171. [Crossref] [PubMed]
19. Groot Koerkamp B, Janssen QP, van Dam JL, Bonsing BA, Bos H, Bosscha KP, et al. LBA83 Neoadjuvant chemotherapy with FOLFIRINOX versus neoadjuvant gemcitabine-based chemoradiotherapy for borderline resectable and resectable pancreatic cancer (PREOPANC-2): A multicenter randomized controlled trial. Annals of Oncology 2023;34:S1323. [Crossref]
20. Sohal DPS, Duong M, Ahmad SA, et al. Efficacy of Perioperative Chemotherapy for Resectable Pancreatic Adenocarcinoma: A Phase 2 Randomized Clinical Trial. JAMA Oncol 2021;7:421-7. [Crossref] [PubMed]
21. Golan T, Barenboim A, Lahat G, et al. Increased Rate of Complete Pathologic Response After Neoadjuvant FOLFIRINOX for BRCA Mutation Carriers with Borderline Resectable Pancreatic Cancer. Ann Surg Oncol 2020;27:3963-70. [Crossref] [PubMed]
22. Tsai S, Christians KK, George B, et al. A Phase II Clinical Trial of Molecular Profiled Neoadjuvant Therapy for Localized Pancreatic Ductal Adenocarcinoma. Ann Surg 2018;268:610-9. [Crossref] [PubMed]
23. Hwang JH, Voortman J, Giovannetti E, et al. Identification of microRNA-21 as a biomarker for chemoresistance and clinical outcome following adjuvant therapy in resectable pancreatic cancer. PLoS One 2010;5:e10630. [Crossref] [PubMed]
24. Cancer Genome Atlas Research Network. Electronic address: andrew_aguirre@dfci.harvard; . Integrated Genomic Characterization of Pancreatic Ductal Adenocarcinoma. Cancer Cell 2017;32:185-203.e13. [Crossref]
25. Martinelli P, Carrillo-de Santa Pau E, Cox T, et al. GATA6 regulates EMT and tumour dissemination, and is a marker of response to adjuvant chemotherapy in pancreatic cancer. Gut 2017;66:1665-76. [Crossref] [PubMed]
26. Cannas S, Vollmer CM Jr. Total Neoadjuvant Therapy for Pancreatic Cancer-What Is Totality?. JAMA Surg 2024;159:828-9. [Crossref] [PubMed]
27. Zogopoulos G, Haimi I, Sanoba SA, et al. The Pancreatic Cancer Early Detection (PRECEDE) Study is a Global Effort to Drive Early Detection: Baseline Imaging Findings in High-Risk Individuals. J Natl Compr Canc Netw 2024;22:158-66. [Crossref] [PubMed]
28. Wang N, Gaddam S, Xie Y, et al. Multitasking dynamic contrast enhanced magnetic resonance imaging can accurately differentiate chronic pancreatitis from pancreatic ductal adenocarcinoma. Front Oncol 2022;12:1007134. [Crossref] [PubMed]
29. Riquelme E, Zhang Y, Zhang L, et al. Tumor Microbiome Diversity and Composition Influence Pancreatic Cancer Outcomes. Cell 2019;178:795-806.e12. [Crossref] [PubMed]