{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T10:24:59Z","timestamp":1787653499434,"version":"build-2736575974"},"reference-count":116,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T00:00:00Z","timestamp":1787616000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies despite advances in surgical techniques and systemic therapy. Although surgical resection offers the only potential for cure, recurrence is common, underscoring the critical role of multimodal treatment. Over the past two decades, numerous clinical trials have cemented adjuvant chemotherapy as a cornerstone of multimodal management in resected PDAC, with progressive evolution from single-agent regimens to modern multiagent regimens. In contrast, the role of chemoradiation remains debated, with the body of evidence demonstrating conflicting results. Ongoing clinical trials are expected to elucidate optimal treatment modalities. Emerging targeted therapies, biomarker-directed treatment approaches, and immunotherapeutic strategies also hold promise for improving outcomes in select patient populations. This narrative review summarizes the landmark trials that have shaped adjuvant therapy, examines the evolution of adjuvant treatment over time, reviews current management guidelines, and highlights promising emerging therapeutic directions likely to influence the management of localized pancreatic cancer.<\/jats:p>","DOI":"10.3390\/cancers18172754","type":"journal-article","created":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T10:04:55Z","timestamp":1787652295000},"page":"2754","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Adjuvant Therapy in Pancreatic Ductal Adenocarcinoma\u2014Past, Present, and Future"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8370-9749","authenticated-orcid":false,"given":"Andy","family":"Tran","sequence":"first","affiliation":[{"name":"Department of Surgery, University of Iowa, 1509 Colloton Pavilion (JCP), 200 Hawkins Drive, Iowa City, IA 52242, USA"},{"name":"Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA 52242, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1886-685X","authenticated-orcid":false,"given":"Tejeshwar","family":"Jain","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of Alabama at Birmingham, Birmingham, AL 35294, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naomi","family":"Fei","sequence":"additional","affiliation":[{"name":"Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA 52242, USA"},{"name":"Division of Hematology, Oncology and Blood & Marrow Transplantation, University of Iowa, Iowa City, IA 52242, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vikas","family":"Dudeja","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of Iowa, 1509 Colloton Pavilion (JCP), 200 Hawkins Drive, Iowa City, IA 52242, USA"},{"name":"Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA 52242, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,25]]},"reference":[{"key":"ref_1","first-page":"e70043","article-title":"Cancer statistics, 2026","volume":"76","author":"Siegel","year":"2026","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1182","DOI":"10.1016\/S0140-6736(25)00261-2","article-title":"Pancreatic cancer","volume":"405","author":"Stoop","year":"2025","journal-title":"Lancet"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"16425","DOI":"10.1038\/s41598-020-73525-y","article-title":"The actual 5-year survivors of pancreatic ductal adenocarcinoma based on real-world data","volume":"10","author":"Bengtsson","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1200","DOI":"10.1056\/NEJMoa032295","article-title":"A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer","volume":"350","author":"Neoptolemos","year":"2004","journal-title":"N. Engl. J. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2403","DOI":"10.1200\/JCO.1997.15.6.2403","article-title":"Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: A randomized trial","volume":"15","author":"Burris","year":"1997","journal-title":"J. Clin. Oncol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1001\/jama.297.3.267","article-title":"Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer: A randomized controlled trial","volume":"297","author":"Oettle","year":"2007","journal-title":"JAMA"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1473","DOI":"10.1001\/jama.2013.279201","article-title":"Adjuvant chemotherapy with gemcitabine and long-term outcomes among patients with resected pancreatic cancer: The CONKO-001 randomized trial","volume":"310","author":"Oettle","year":"2013","journal-title":"JAMA"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"908","DOI":"10.1038\/sj.bjc.6605256","article-title":"A randomised phase III trial comparing gemcitabine with surgery-only in patients with resected pancreatic cancer: Japanese Study Group of Adjuvant Therapy for Pancreatic Cancer","volume":"101","author":"Ueno","year":"2009","journal-title":"Br. J. Cancer"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1019","DOI":"10.1001\/jama.299.9.1019","article-title":"Fluorouracil vs gemcitabine chemotherapy before and after fluorouracil-based chemoradiation following resection of pancreatic adenocarcinoma: A randomized controlled trial","volume":"299","author":"Regine","year":"2008","journal-title":"JAMA"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1319","DOI":"10.1245\/s10434-011-1630-6","article-title":"Fluorouracil-based chemoradiation with either gemcitabine or fluorouracil chemotherapy after resection of pancreatic adenocarcinoma: 5-year analysis of the U.S. Intergroup\/RTOG 9704 phase III trial","volume":"18","author":"Regine","year":"2011","journal-title":"Ann. Surg. Oncol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1073","DOI":"10.1001\/jama.2010.1275","article-title":"Adjuvant chemotherapy with fluorouracil plus folinic acid vs gemcitabine following pancreatic cancer resection: A randomized controlled trial","volume":"304","author":"Neoptolemos","year":"2010","journal-title":"JAMA"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1016\/S0140-6736(16)30583-9","article-title":"Adjuvant chemotherapy of S-1 versus gemcitabine for resected pancreatic cancer: A phase 3, open-label, randomised, non-inferiority trial (JASPAC 01)","volume":"388","author":"Uesaka","year":"2016","journal-title":"Lancet"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"e120","DOI":"10.1097\/MPA.0000000000002600","article-title":"Clinical Practice Guidelines for Pancreatic Cancer 2025 From the Japan Pancreas Society: A Synopsis","volume":"55","author":"Abe","year":"2026","journal-title":"Pancreas"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"478","DOI":"10.1111\/j.1349-7006.2010.01793.x","article-title":"Comparison of the pharmacokinetics and pharmacodynamics of S-1 between Caucasian and East Asian patients","volume":"102","author":"Chuah","year":"2011","journal-title":"Cancer Sci."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/S1470-2045(09)70160-3","article-title":"Population-based differences in treatment outcome following anticancer drug therapies","volume":"11","author":"Ma","year":"2010","journal-title":"Lancet Oncol."},{"key":"ref_16","first-page":"134","article-title":"Phase I study with pharmacokinetics of S-1 on an oral daily schedule for 28 days in patients with solid tumors","volume":"9","author":"Hoff","year":"2003","journal-title":"Clin. Cancer Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1960","DOI":"10.1200\/JCO.2006.07.9525","article-title":"Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: A phase III trial of the National Cancer Institute of Canada Clinical Trials Group","volume":"25","author":"Moore","year":"2007","journal-title":"J. Clin. Oncol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"3330","DOI":"10.1200\/JCO.2017.72.6463","article-title":"CONKO-005: Adjuvant Chemotherapy with Gemcitabine Plus Erlotinib Versus Gemcitabine Alone in Patients After R0 Resection of Pancreatic Cancer: A Multicenter Randomized Phase III Trial","volume":"35","author":"Sinn","year":"2017","journal-title":"J. Clin. Oncol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1691","DOI":"10.1056\/NEJMoa1304369","article-title":"Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine","volume":"369","author":"Ervin","year":"2013","journal-title":"N. Engl. J. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2007","DOI":"10.1200\/JCO.22.01134","article-title":"Adjuvant nab-Paclitaxel + Gemcitabine in Resected Pancreatic Ductal Adenocarcinoma: Results From a Randomized, Open-Label, Phase III Trial","volume":"41","author":"Tempero","year":"2023","journal-title":"J. Clin. Oncol."},{"key":"ref_21","unstructured":"NCCN (2026, March 06). NCCN Clinical Practice Guidelines in Oncology: Pancreatic Adenocarcinoma, Version 2.2025. Available online: https:\/\/www.nccn.org\/professionals\/physician_gls\/pdf\/pancreatic.pdf."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1011","DOI":"10.1016\/S0140-6736(16)32409-6","article-title":"Comparison of adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4): A multicentre, open-label, randomised, phase 3 trial","volume":"389","author":"Neoptolemos","year":"2017","journal-title":"Lancet"},{"key":"ref_23","first-page":"1240","article-title":"Pancreatic Adenocarcinoma: Long-Term Outcomes of Adjuvant Therapy in the ESPAC4 Phase III Trial","volume":"43","author":"Palmer","year":"2025","journal-title":"J. Clin. Oncol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2395","DOI":"10.1056\/NEJMoa1809775","article-title":"FOLFIRINOX or Gemcitabine as Adjuvant Therapy for Pancreatic Cancer","volume":"379","author":"Conroy","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1571","DOI":"10.1001\/jamaoncol.2022.3829","article-title":"Five-Year Outcomes of FOLFIRINOX vs Gemcitabine as Adjuvant Therapy for Pancreatic Cancer: A Randomized Clinical Trial","volume":"8","author":"Conroy","year":"2022","journal-title":"JAMA Oncol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1097\/SLA.0000000000006449","article-title":"Impact of Positive Resection Margins on Recurrence and Survival After Resection and Adjuvant Chemotherapy in Pancreatic Cancer: Results of the PRODIGE 24-CCTG PA-6 Randomized Controlled Trial","volume":"283","author":"Lambert","year":"2026","journal-title":"Ann. Surg."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1654","DOI":"10.1002\/ijc.33916","article-title":"Real-world evidence of adjuvant gemcitabine plus capecitabine vs gemcitabine monotherapy for pancreatic ductal adenocarcinoma","volume":"150","author":"Janssen","year":"2022","journal-title":"Int. J. Cancer"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"496","DOI":"10.1093\/jnci\/djae269","article-title":"Adjuvant modified FOLFIRINOX for resected pancreatic adenocarcinoma: Clinical insights and genomic features from a large contemporary cohort","volume":"117","author":"Keane","year":"2025","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Martin, R.C.G., Cantrell, R.A., and Gaskins, J.T. (2026). Chemotherapy Completion as a Quality Metric in Resected Pancreatic Ductal Adenocarcinoma. Cancers, 18.","DOI":"10.3390\/cancers18121912"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"e199126","DOI":"10.1001\/jamanetworkopen.2019.9126","article-title":"Association of Timing of Adjuvant Therapy with Survival in Patients with Resected Stage I to II Pancreatic Cancer","volume":"2","author":"Ma","year":"2019","journal-title":"JAMA Netw. Open"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"568","DOI":"10.1002\/jhbp.70117","article-title":"Timing of Adjuvant S-1 Chemotherapy and Survival After Pancreatectomy for Pancreatic Cancer: An Ancillary Analysis of the JASPAC 01 Trial","volume":"33","author":"Lee","year":"2026","journal-title":"J. Hepatobiliary Pancreat. Sci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"111165","DOI":"10.1016\/j.ejso.2025.111165","article-title":"Timing of adjuvant chemotherapy in patients with pancreatic ductal adenocarcinoma: A nationwide analysis","volume":"52","author":"Andel","year":"2026","journal-title":"Eur. J. Surg. Oncol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"866","DOI":"10.1097\/SLA.0000000000005710","article-title":"A Delay in Adjuvant Therapy Is Associated with Worse Prognosis Only in Patients with Transitional Circulating Tumor Cells After Resection of Pancreatic Ductal Adenocarcinoma","volume":"277","author":"Javed","year":"2023","journal-title":"Ann. Surg."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Witz, A., Conroy, T., Lambert, A., Salleron, J., Diallo, A., Husson, M., Nicolle, R., Hammel, P., Biagi, J., and Renouf, D.J. (2026). Impact of Tumor Genomic Profile on Adjuvant Chemotherapy Efficacy in Resected Pancreatic Adenocarcinoma: Results from the PRODIGE-24\/CCTG PA6 Study. J. Clin. Oncol., Epub ahead of printing.","DOI":"10.1200\/JCO-25-02508"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1038","DOI":"10.1001\/jamasurg.2019.3337","article-title":"Patterns of Recurrence After Resection of Pancreatic Ductal Adenocarcinoma: A Secondary Analysis of the ESPAC-4 Randomized Adjuvant Chemotherapy Trial","volume":"154","author":"Jones","year":"2019","journal-title":"JAMA Surg."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"106910","DOI":"10.1016\/j.ejso.2023.04.009","article-title":"Predicting post-recurrence survival for patients with pancreatic cancer recurrence after primary resection: A Bi-institutional validated risk classification","volume":"49","author":"Daamen","year":"2023","journal-title":"Eur. J. Surg. Oncol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"109114","DOI":"10.1016\/j.surg.2024.109114","article-title":"Impact of resection margin status on recurrence and survival in patients with resectable, borderline resectable, and locally advanced pancreatic cancer","volume":"180","author":"Rompen","year":"2025","journal-title":"Surgery"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"899","DOI":"10.1001\/archsurg.1985.01390320023003","article-title":"Pancreatic cancer. Adjuvant combined radiation and chemotherapy following curative resection","volume":"120","author":"Kalser","year":"1985","journal-title":"Arch. Surg."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"981","DOI":"10.1245\/s10434-009-0743-7","article-title":"Adjuvant chemoradiation for pancreatic adenocarcinoma: The Johns Hopkins Hospital-Mayo Clinic collaborative study","volume":"17","author":"Hsu","year":"2010","journal-title":"Ann. Surg. Oncol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1056\/NEJMoa1903387","article-title":"Maintenance Olaparib for Germline BRCA-Mutated Metastatic Pancreatic Cancer","volume":"381","author":"Golan","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"776","DOI":"10.1097\/00000658-199912000-00006","article-title":"Adjuvant radiotherapy and 5-fluorouracil after curative resection of cancer of the pancreas and periampullary region: Phase III trial of the EORTC gastrointestinal tract cancer cooperative group","volume":"230","author":"Klinkenbijl","year":"1999","journal-title":"Ann. Surg."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"734","DOI":"10.1097\/SLA.0b013e318156eef3","article-title":"Long-term survival and metastatic pattern of pancreatic and periampullary cancer after adjuvant chemoradiation or observation: Long-term results of EORTC trial 40891","volume":"246","author":"Smeenk","year":"2007","journal-title":"Ann. Surg."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1097\/01.sla.0000229980.81505.44","article-title":"On statistical reanalysis, the EORTC trial is a positive trial for adjuvant chemoradiation in pancreatic cancer","volume":"244","author":"Garofalo","year":"2006","journal-title":"Ann. Surg."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1372","DOI":"10.1038\/sj.bjc.6602513","article-title":"Meta-analysis of randomised adjuvant therapy trials for pancreatic cancer","volume":"92","author":"Stocken","year":"2005","journal-title":"Br. J. Cancer"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1016\/j.gassur.2005.11.006","article-title":"Is adjuvant 5-FU-based chemoradiotherapy for resectable pancreatic adenocarcinoma beneficial? A meta-analysis of an unanswered question","volume":"10","author":"Khanna","year":"2006","journal-title":"J. Gastrointest. Surg."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1095","DOI":"10.1016\/S1470-2045(13)70388-7","article-title":"Adjuvant treatments for resected pancreatic adenocarcinoma: A systematic review and network meta-analysis","volume":"14","author":"Liao","year":"2013","journal-title":"Lancet Oncol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"911","DOI":"10.1016\/j.ijrobp.2014.07.024","article-title":"Multi-institutional pooled analysis on adjuvant chemoradiation in pancreatic cancer","volume":"90","author":"Morganti","year":"2014","journal-title":"Int. J. Radiat. Oncol. Biol. Phys."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1097\/SLA.0000000000003242","article-title":"Association of Adjuvant Radiotherapy with Survival After Margin-negative Resection of Pancreatic Ductal Adenocarcinoma: A Propensity-matched National Cancer Database (NCDB) Analysis","volume":"273","author":"Kamarajah","year":"2021","journal-title":"Ann. Surg."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"4141","DOI":"10.1002\/cncr.29652","article-title":"Addition of radiotherapy to adjuvant chemotherapy is associated with improved overall survival in resected pancreatic adenocarcinoma: An analysis of the National Cancer Data Base","volume":"121","author":"Rutter","year":"2015","journal-title":"Cancer"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1058","DOI":"10.1097\/SLA.0000000000003770","article-title":"Optimal Adjuvant Treatment Approach After Upfront Resection of Pancreatic Cancer: Revisiting the Role of Radiation Based on Pathologic Features","volume":"274","author":"Moaven","year":"2021","journal-title":"Ann. Surg."},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Ren, B., Guo, Q., Ma, J., Zhu, W., Wang, Y., Feng, Z., Shen, Y., Zhu, Y., Xie, L., and Peng, Q. (BMC Cancer, 2026). Comparative efficacy of postoperative adjuvant chemoradiotherapy versus no chemoradiotherapy in the treatment of pancreatic adenocarcinoma, BMC Cancer, Epub ahead of printing.","DOI":"10.1186\/s12885-026-16408-1"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1844","DOI":"10.1001\/jama.2016.4324","article-title":"Effect of Chemoradiotherapy vs Chemotherapy on Survival in Patients with Locally Advanced Pancreatic Cancer Controlled After 4 Months of Gemcitabine With or Without Erlotinib: The LAP07 Randomized Clinical Trial","volume":"315","author":"Hammel","year":"2016","journal-title":"JAMA"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"2316","DOI":"10.1200\/JCO-25-02520","article-title":"Adjuvant Chemotherapy +\/\u2212 Chemoradiotherapy for Adenocarcinoma of The Pancreatic Head: Results of The Radiotherapy Randomization of NRG Oncology\/RTOG 0848","volume":"44","author":"Abrams","year":"2026","journal-title":"J. Clin. Oncol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1016\/j.jamcollsurg.2008.12.020","article-title":"Adjuvant chemoradiation therapy for pancreatic adenocarcinoma: Who really benefits?","volume":"208","author":"Merchant","year":"2009","journal-title":"J. Am. Coll. Surg."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1097\/00000658-200301000-00011","article-title":"Prognostic factors following curative resection for pancreatic adenocarcinoma: A population-based, linked database analysis of 396 patients","volume":"237","author":"Lim","year":"2003","journal-title":"Ann. Surg."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"2191","DOI":"10.1002\/cncr.23047","article-title":"Radiation therapy is associated with improved survival in patients with pancreatic adenocarcinoma: Results of a study from the Surveillance, Epidemiology, and End Results (SEER) registry data","volume":"110","author":"Hazard","year":"2007","journal-title":"Cancer"},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Lin, Z.B., Song, J.Y., Li, A.C., Chen, C., Huang, X.X., and Xu, B.H. (2020). The benefit of adjuvant radiotherapy on overall survival in resected stage I to II pancreatic cancer: A propensity-adjusted analysis. PLoS ONE, 15.","DOI":"10.1371\/journal.pone.0243170"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"982","DOI":"10.1016\/j.surg.2022.04.018","article-title":"In search of lost time: Delays in adjuvant therapy for pancreatic adenocarcinoma among under-resourced patient populations","volume":"172","author":"Hamad","year":"2022","journal-title":"Surgery"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1763","DOI":"10.1200\/JCO.19.02274","article-title":"Preoperative Chemoradiotherapy Versus Immediate Surgery for Resectable and Borderline Resectable Pancreatic Cancer: Results of the Dutch Randomized Phase III PREOPANC Trial","volume":"38","author":"Versteijne","year":"2020","journal-title":"J. Clin. Oncol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1220","DOI":"10.1200\/JCO.21.02233","article-title":"Neoadjuvant Chemoradiotherapy Versus Upfront Surgery for Resectable and Borderline Resectable Pancreatic Cancer: Long-Term Results of the Dutch Randomized PREOPANC Trial","volume":"40","author":"Versteijne","year":"2022","journal-title":"J. Clin. Oncol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1346","DOI":"10.1016\/S1470-2045(25)00363-8","article-title":"Neoadjuvant FOLFIRINOX versus neoadjuvant gemcitabine-based chemoradiotherapy in resectable and borderline resectable pancreatic cancer (PREOPANC-2): A multicentre, open-label, phase 3 randomised trial","volume":"26","author":"Janssen","year":"2025","journal-title":"Lancet Oncol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"502","DOI":"10.1002\/jso.26906","article-title":"Total neoadjuvant therapy is associated with improved overall survival and pathologic response in pancreatic adenocarcinoma","volume":"126","author":"Villano","year":"2022","journal-title":"J. Surg. Oncol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"946","DOI":"10.1002\/bjs.10870","article-title":"Meta-analysis comparing upfront surgery with neoadjuvant treatment in patients with resectable or borderline resectable pancreatic cancer","volume":"105","author":"Versteijne","year":"2018","journal-title":"Br. J. Surg."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1016\/S2468-1253(23)00405-3","article-title":"Neoadjuvant FOLFIRINOX versus upfront surgery for resectable pancreatic head cancer (NORPACT-1): A multicentre, randomised, phase 2 trial","volume":"9","author":"Labori","year":"2024","journal-title":"Lancet Gastroenterol. Hepatol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1016\/S2468-1253(22)00348-X","article-title":"Immediate surgery compared with short-course neoadjuvant gemcitabine plus capecitabine, FOLFIRINOX, or chemoradiotherapy in patients with borderline resectable pancreatic cancer (ESPAC5): A four-arm, multicentre, randomised, phase 2 trial","volume":"8","author":"Ghaneh","year":"2023","journal-title":"Lancet Gastroenterol. Hepatol."},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"van Dam, J.L., Verkolf, E.M.M., Dekker, E.N., Bonsing, B.A., Bratlie, S.O., Brosens, L.A.A., Busch, O.R., van Driel, L., van Eijck, C.H.J., and Feshtali, S. (2023). Perioperative or adjuvant mFOLFIRINOX for resectable pancreatic cancer (PREOPANC-3): Study protocol for a multicenter randomized controlled trial. BMC Cancer, 23.","DOI":"10.1016\/j.annonc.2023.09.2632"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"TPS4204","DOI":"10.1200\/JCO.2023.41.16_suppl.TPS4204","article-title":"Alliance A021806: A phase III trial evaluating perioperative versus adjuvant therapy for resectable pancreatic cancer","volume":"41","author":"Chawla","year":"2023","journal-title":"J. Clin. Oncol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"2945","DOI":"10.1016\/S0140-6736(25)01685-X","article-title":"Preoperative mFOLFIRINOX versus PAXG for stage I-III resectable and borderline resectable pancreatic ductal adenocarcinoma (PACT-21 CASSANDRA): Results of the first randomisation analysis of a randomised, open-label, 2 \u00d7 2 factorial phase 3 trial","volume":"406","author":"Reni","year":"2026","journal-title":"Lancet"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"TPS763","DOI":"10.1200\/JCO.2023.41.4_suppl.TPS763","article-title":"APOLLO: A randomized phase II double-blind study of olaparib versus placebo following curative intent therapy in patients with resected pancreatic cancer and a pathogenic BRCA1, BRCA2 or PALB2 mutation\u2014ECOG-ACRIN EA2192","volume":"41","author":"Reiss","year":"2023","journal-title":"J. Clin. Oncol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"e2453588","DOI":"10.1001\/jamanetworkopen.2024.53588","article-title":"KRAS Mutation Status and Treatment Outcomes in Patients With Metastatic Pancreatic Adenocarcinoma","volume":"8","author":"Norton","year":"2025","journal-title":"JAMA Netw. Open"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1056\/NEJMoa2208470","article-title":"Sotorasib in KRAS p.G12C-Mutated Advanced Pancreatic Cancer","volume":"388","author":"Strickler","year":"2023","journal-title":"N. Engl. J. Med."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"4097","DOI":"10.1200\/JCO.23.00434","article-title":"Adagrasib in Advanced Solid Tumors Harboring a KRAS(G12C) Mutation","volume":"41","author":"Yaeger","year":"2023","journal-title":"J. Clin. Oncol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"2382","DOI":"10.1056\/NEJMoa2105281","article-title":"Acquired Resistance to KRAS(G12C) Inhibition in Cancer","volume":"384","author":"Awad","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"e012886","DOI":"10.1136\/jitc-2025-012886","article-title":"Tumor immune microenvironment facilitates resistance to KRAS G12C inhibitor sotorasib by altered PD-L1 expression","volume":"14","author":"Liu","year":"2026","journal-title":"J. Immunother. Cancer"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"600","DOI":"10.1111\/cas.16441","article-title":"Mechanisms of Resistance to KRAS Inhibitors: Cancer Cells\u2019 Strategic Use of Normal Cellular Mechanisms to Adapt","volume":"116","author":"Tanaka","year":"2025","journal-title":"Cancer Sci."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1056\/NEJMoa2605555","article-title":"Daraxonrasib or Chemotherapy in Previously Treated Metastatic Pancreatic Cancer","volume":"395","author":"Wainberg","year":"2026","journal-title":"N. Engl. J. Med."},{"key":"ref_77","unstructured":"(2025, December 15). RASolute 304: A Phase 3 Multicenter, Open-Label, Randomized, 2-Arm Study of Adjuvant Daraxonrasib Versus Standard of Care Observation Following Completion of Neoadjuvant and\/or Adjuvant Chemotherapy in Patients with Resected Pancreatic Ductal Adenocarcinoma (PDAC), Available online: https:\/\/clinicaltrials.gov\/study\/NCT06625320."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"5727","DOI":"10.1038\/s44318-026-00854-5","article-title":"CDK8 remodels the tumor microenvironment and promotes resistance to KRAS(G12D) inhibitors and daraxonrasib in PDAC","volume":"45","author":"McAndrews","year":"2026","journal-title":"EMBO J."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1038\/s41589-025-01978-1","article-title":"ZBTB11 depletion targets metabolic vulnerabilities in KRAS inhibitor-resistant PDAC","volume":"22","author":"Tran","year":"2026","journal-title":"Nat. Chem. Biol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"3519","DOI":"10.1158\/0008-5472.CAN-24-1984","article-title":"KRAS Signaling Inhibition Induces a Targetable Metabolic Dependency on Lipophagy-Dependent Fatty Acid Oxidation in Pancreatic Cancer","volume":"86","author":"Thakur","year":"2026","journal-title":"Cancer Res."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"3267","DOI":"10.1016\/j.devcel.2025.07.014","article-title":"Dapk2 dysfunction leads to Mic60 lactylation and mitochondrial metabolic reprogramming, promoting lung cancer EGFR-TKI resistance and metastasis","volume":"60","author":"Zheng","year":"2025","journal-title":"Dev. Cell"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"e187024","DOI":"10.1172\/JCI187024","article-title":"Elevated protein lactylation promotes immunosuppressive microenvironment and therapeutic resistance in pancreatic ductal adenocarcinoma","volume":"135","author":"Sun","year":"2025","journal-title":"J. Clin. Investig."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1038\/s41392-025-02563-7","article-title":"Vertical RAS pathway inhibition in pancreatic cancer drives therapeutically exploitable mitochondrial alterations","volume":"11","author":"Hafner","year":"2026","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"851","DOI":"10.1038\/nm.4123","article-title":"Targeting focal adhesion kinase renders pancreatic cancers responsive to checkpoint immunotherapy","volume":"22","author":"Jiang","year":"2016","journal-title":"Nat. Med."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"eado2402","DOI":"10.1126\/scitranslmed.ado2402","article-title":"Stromal reprogramming overcomes resistance to RAS-MAPK inhibition to improve pancreas cancer responses to cytotoxic and immune therapy","volume":"16","author":"Liu","year":"2024","journal-title":"Sci. Transl. Med."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1111\/cas.70246","article-title":"A Combinatorial Effect of Immune Checkpoint Inhibitors and CD40 Agonistic Antibody in Murine Pancreatic Cancer Model","volume":"117","author":"Ichikawa","year":"2026","journal-title":"Cancer Sci."},{"key":"ref_87","doi-asserted-by":"crossref","unstructured":"Qi, X., Yang, H., Zhang, L., Yu, P., and Cheng, C. (2026). Advancing precision immunotherapy in advanced pancreatic cancer: A systematic review and meta-analysis of first-line ICI-based combinations. Front. Immunol., 17.","DOI":"10.3389\/fimmu.2026.1855859"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1038\/s41586-020-2229-5","article-title":"Autophagy promotes immune evasion of pancreatic cancer by degrading MHC-I","volume":"581","author":"Yamamoto","year":"2020","journal-title":"Nature"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1038\/s41586-022-04735-9","article-title":"Neoantigen quality predicts immunoediting in survivors of pancreatic cancer","volume":"606","author":"Luksza","year":"2022","journal-title":"Nature"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"102399","DOI":"10.1016\/j.xcrm.2025.102399","article-title":"In situ extended immune activation instantly after tumor resection by oncolytic virus controls postoperative tumor recurrence","volume":"6","author":"Guo","year":"2025","journal-title":"Cell Rep. Med."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"0247","DOI":"10.34133\/cbsystems.0247","article-title":"Hollow Mesoporous Carbon Nanospheres Derived from Metal-Organic Frameworks for Efficient Sono-immunotherapy against Pancreatic Cancer","volume":"6","author":"Chen","year":"2025","journal-title":"Cyborg Bionic Syst."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"109559","DOI":"10.1016\/j.mbs.2025.109559","article-title":"Analyzing the impact of threshold strategies on cancer treatment using non-smooth models","volume":"390","author":"Wu","year":"2025","journal-title":"Math. Biosci."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"600","DOI":"10.1016\/j.ejso.2008.12.006","article-title":"Patterns of recurrence after curative resection of pancreatic ductal adenocarcinoma","volume":"35","author":"Sergeant","year":"2009","journal-title":"Eur. J. Surg. Oncol."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"977","DOI":"10.1053\/j.gastro.2024.05.028","article-title":"Prognostic Factors for Early Recurrence After Resection of Pancreatic Cancer: A Systematic Review and Meta-Analysis","volume":"167","author":"Leonhardt","year":"2024","journal-title":"Gastroenterology"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"936","DOI":"10.1097\/SLA.0000000000002234","article-title":"Patterns, Timing, and Predictors of Recurrence Following Pancreatectomy for Pancreatic Ductal Adenocarcinoma","volume":"267","author":"Groot","year":"2018","journal-title":"Ann. Surg."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"109872","DOI":"10.1016\/j.surg.2025.109872","article-title":"Neoadjuvant therapy versus upfront surgery for resectable pancreatic cancer: Updated systematic review, individual-patient-data meta-analysis and trial sequential analysis of randomized controlled trials","volume":"193","author":"Tan","year":"2026","journal-title":"Surgery"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"e502","DOI":"10.1097\/SLA.0000000000004585","article-title":"Prospective Phase II Trials Validate the Effect of Neoadjuvant Chemotherapy on Pattern of Recurrence in Pancreatic Adenocarcinoma","volume":"276","author":"Chawla","year":"2022","journal-title":"Ann. Surg."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"4973","DOI":"10.1158\/1078-0432.CCR-19-0197","article-title":"Circulating Tumor DNA as a Clinical Test in Resected Pancreatic Cancer","volume":"25","author":"Groot","year":"2019","journal-title":"Clin. Cancer Res."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"997","DOI":"10.1097\/SLA.0000000000006209","article-title":"Prospective Evaluation of Circulating Tumor DNA Using Next-generation Sequencing as a Biomarker During Neoadjuvant Chemotherapy in Localized Pancreatic Cancer","volume":"281","author":"Shah","year":"2025","journal-title":"Ann. Surg."},{"key":"ref_100","doi-asserted-by":"crossref","unstructured":"Borges, F.C., Pinto, M.S., Borges, M.F., Joao, A.A., Francisco, E., Sousa, M., Aral, M., Oliveira, V., Cunha, J.F., and Mehrabi, A. (2026). The Role of Circulating Tumor DNA in Surgical Management of Pancreatic Cancer: Systematic Review and Meta-analysis. Ann. Surg., Epub ahead of print.","DOI":"10.1097\/SLA.0000000000007036"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"18020","DOI":"10.1002\/cam4.6407","article-title":"Heterogeneous tumor microenvironment in pancreatic ductal adenocarcinoma: An emerging role of single-cell analysis","volume":"12","author":"Byeon","year":"2023","journal-title":"Cancer Med."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"1322","DOI":"10.1002\/ijc.70519","article-title":"Transcriptome-Based Classification of Resected Pancreatic Ductal Adenocarcinoma Enhances Prognostic Modelling Accuracy of Overall Survival Following Adjuvant Treatment","volume":"159","author":"Lansbergen","year":"2026","journal-title":"Int. J. Cancer"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"e2500197","DOI":"10.1200\/PO-25-00197","article-title":"Real-World Validation of the Purity Independent Subtyping of Tumors Classifier for Informing Therapy Selection in Pancreatic Ductal Adenocarcinoma","volume":"9","author":"Wenric","year":"2025","journal-title":"JCO Precis. Oncol."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"3355","DOI":"10.1200\/JCO-25-00436","article-title":"PASS-01: Randomized Phase II Trial of Modified FOLFIRINOX Versus Gemcitabine\/Nab-Paclitaxel and Molecular Correlatives for Previously Untreated Metastatic Pancreatic Cancer","volume":"43","author":"Knox","year":"2025","journal-title":"J. Clin. Oncol."},{"key":"ref_105","doi-asserted-by":"crossref","unstructured":"Guenther, M., Surendran, S.A., Steinke, L.M., Liou, I., Palm, M.A., Heinemann, V., Haas, M., Boeck, S., and Ormanns, S. (2025). The Prognostic, Predictive and Clinicopathological Implications of KRT81\/HNF1A- and GATA6-Based Transcriptional Subtyping in Pancreatic Cancer. Biomolecules, 15.","DOI":"10.3390\/biom15030426"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"3239","DOI":"10.1158\/1078-0432.CCR-20-0418","article-title":"Genomic Methods Identify Homologous Recombination Deficiency in Pancreas Adenocarcinoma and Optimize Treatment Selection","volume":"26","author":"Park","year":"2020","journal-title":"Clin. Cancer Res."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1053\/j.gastro.2008.09.067","article-title":"Human equilibrative nucleoside transporter 1 levels predict response to gemcitabine in patients with pancreatic cancer","volume":"136","author":"Farrell","year":"2009","journal-title":"Gastroenterology"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"djt347","DOI":"10.1093\/jnci\/djt347","article-title":"Pancreatic cancer hENT1 expression and survival from gemcitabine in patients from the ESPAC-3 trial","volume":"106","author":"Greenhalf","year":"2014","journal-title":"J. Natl. Cancer Inst."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"5115","DOI":"10.1158\/1078-0432.CCR-22-2576","article-title":"hENT1 Expression Predicts Response to Gemcitabine and Nab-Paclitaxel in Advanced Pancreatic Ductal Adenocarcinoma","volume":"28","author":"Perera","year":"2022","journal-title":"Clin. Cancer Res."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"2913","DOI":"10.1158\/1078-0432.CCR-08-2080","article-title":"Human equilibrative nucleoside transporter 1 and human concentrative nucleoside transporter 3 predict survival after adjuvant gemcitabine therapy in resected pancreatic adenocarcinoma","volume":"15","author":"Marechal","year":"2009","journal-title":"Clin. Cancer Res."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1002\/bjs.10482","article-title":"Immunohistochemical hENT1 expression as a prognostic biomarker in patients with resected pancreatic ductal adenocarcinoma undergoing adjuvant gemcitabine-based chemotherapy","volume":"104","author":"Bird","year":"2017","journal-title":"Br. J. Surg."},{"key":"ref_112","doi-asserted-by":"crossref","unstructured":"Raffenne, J., Nicolle, R., Puleo, F., Le Corre, D., Boyez, C., Marechal, R., Emile, J.F., Demetter, P., Bardier, A., and Laurent-Puig, P. (2019). hENT1 Testing in Pancreatic Ductal Adenocarcinoma: Are We Ready? A Multimodal Evaluation of hENT1 Status. Cancers, 11.","DOI":"10.3390\/cancers11111808"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"851","DOI":"10.1016\/j.jmoldx.2024.05.015","article-title":"DPYD Genotyping Recommendations: A Joint Consensus Recommendation of the Association for Molecular Pathology, American College of Medical Genetics and Genomics, Clinical Pharmacogenetics Implementation Consortium, College of American Pathologists, Dutch Pharmacogenetics Working Group of the Royal Dutch Pharmacists Association, European Society for Pharmacogenomics and Personalized Therapy, Pharmacogenomics Knowledgebase, and Pharmacogene Variation Consortium","volume":"26","author":"Pratt","year":"2024","journal-title":"J. Mol. Diagn."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1080\/14622416.2024.2385289","article-title":"Meta-analysis revisiting the influence of UGT1A1*28 and UGT1A1*6 on irinotecan safety in colorectal cancer patients","volume":"25","author":"Nguyen","year":"2024","journal-title":"Pharmacogenomics"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"1459","DOI":"10.1016\/S1470-2045(18)30686-7","article-title":"DPYD genotype-guided dose individualisation of fluoropyrimidine therapy in patients with cancer: A prospective safety analysis","volume":"19","author":"Henricks","year":"2018","journal-title":"Lancet Oncol."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1016\/j.ejca.2021.12.009","article-title":"UGT1A1 genotype-guided dosing of irinotecan: A prospective safety and cost analysis in poor metaboliser patients","volume":"162","author":"Hulshof","year":"2022","journal-title":"Eur. J. Cancer"}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/17\/2754\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T10:08:31Z","timestamp":1787652511000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/17\/2754"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,25]]},"references-count":116,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["cancers18172754"],"URL":"https:\/\/doi.org\/10.3390\/cancers18172754","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,25]]}}}