Neoadjuvant treatment of pancreatic ductal adenocarcinoma: present and future

Abstract

Pancreatic ductal adenocarcinoma is a highly aggressive malignancy with a poor prognosis. Effective treatment with acceptable outcomes is yet to be found, with chemo- and radioresistance comprising major impediments towards this goal. Although upfront surgery is the established therapeutic approach for resectable and borderline resectable disease, neoadjuvant treatment has recently monopolized the interest in clinical trials. This also applies to locally advanced pancreatic adenocarcinomas that could potentially be rendered operable. Chemotherapy and chemoradiotherapy are the most utilized therapeutic modalities in the neoadjuvant setting, while immunotherapy and targeting agents have been gaining significant attention. This critical review focuses on the clinical experience gained from retrospective and phase II/III randomized trials, reporting on the outcomes of neoadjuvant chemotherapy and chemoradiotherapy for pancreatic adenocarcinoma. Moreover, the ongoing trials, including those that involve immunotherapy and targeting agents, are summarized.

Keywords

Pancreatic cancer / neoadjuvant treatment / chemotherapy / radiotherapy / surgery / immunotherapy

References

[1] Siegel RL,Fuchs HE.Cancer statistics, 2021.CA Cancer J Clin2021;71:7-33

[2] Maisonneuve P.Risk factors for pancreatic cancer: a summary review of meta-analytical studies.Int J Epidemiol2015;44:186-98

[3] Lee MS.Personalizing medicine with germline and somatic sequencing in advanced pancreatic cancer: current treatments and novel opportunities.Am Soc Clin Oncol Educ Book2021;41:1-13

[4] Buscail L,Cordelier P.Role of oncogenic KRAS in the diagnosis, prognosis and treatment of pancreatic cancer.Nat Rev Gastroenterol Hepatol2020;17:153-68

[5] Llach J,Moreira L.Familial pancreatic cancer: current perspectives.Cancer Manag Res2020;12:743-58 PMCID:PMC6999545

[6] National Comprehensive Cancer Network (NCCN). Pancreatic adenocarcinoma guidelines. Available from: https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1455 [Last accessed on 14 September 2022]

[7] Fathi A,George B.Neoadjuvant therapy for localized pancreatic cancer: guiding principles.J Gastrointest Oncol2015;6:418-29 PMCID:PMC4502155

[8] Oba A,Bao QR,Schulick RD.Neoadjuvant treatment in pancreatic cancer.Front Oncol2020;10:245 PMCID:PMC7058791

[9] Leal AD,Lieu CH.Neoadjuvant treatment of localized pancreatic adenocarcinoma.J Gastrointest Oncol2021;12:2461-74 PMCID:PMC8576215

[10] Yang K,Lian G.KRAS promotes tumor metastasis and chemoresistance by repressing RKIP via the MAPK-ERK pathway in pancreatic cancer.Int J Cancer2018;142:2323-34

[11] Fiorini C,Padroni C,Di Agostino S.Mutant p53 stimulates chemoresistance of pancreatic adenocarcinoma cells to gemcitabine.Biochim Biophys Acta2015;1853:89-100

[12] Swayden M,Soubeyran P.Pancreatic cancer chemo-resistance is driven by tumor phenotype rather than tumor genotype.Heliyon2018;4:e01055 PMCID:PMC6299038

[13] Grasso C,Giovannetti E.Drug resistance in pancreatic cancer: impact of altered energy metabolism.Crit Rev Oncol Hematol2017;114:139-52

[14] Ramachandran K,Gordian E,Singal R.Methylation-mediated silencing of TMS1 in pancreatic cancer and its potential contribution to chemosensitivity.Anticancer Res2010;30:3919-25

[15] Weniger M,Liss AS.The Extracellular matrix and pancreatic cancer: a complex relationship.Cancers (Basel)2018;10:316 PMCID:PMC6162452

[16] Amit M.Macrophages increase the resistance of pancreatic adenocarcinoma cells to gemcitabine by upregulating cytidine deaminase.Oncoimmunology2013;2:e27231 PMCID:PMC3912006

[17] Nakano Y,Koizumi K.Gemcitabine chemoresistance and molecular markers associated with gemcitabine transport and metabolism in human pancreatic cancer cells.Br J Cancer2007;96:457-63 PMCID:PMC2360025

[18] Komori S,Mori R.Contribution of thymidylate synthase to gemcitabine therapy for advanced pancreatic cancer.Pancreas2010;39:1284-92

[19] Capello M,Wang H.Carboxylesterase 2 as a Determinant of response to irinotecan and neoadjuvant FOLFIRINOX therapy in pancreatic ductal adenocarcinoma.J Natl Cancer Inst2015;107:djv132 PMCID:PMC4554193

[20] Tezuka S,Kobayashi S.Predictive value of ERCC1, ERCC2, ERCC4, and glutathione S-Transferase Pi expression for the efficacy and safety of FOLFIRINOX in patients with unresectable pancreatic cancer.Am J Cancer Res2018;8:2096-105 PMCID:PMC6220150

[21] Maloney SM,Morejon-Lasso LV.Mechanisms of taxane resistance.Cancers (Basel)2020;12:3323 PMCID:PMC7697134

[22] Shah VM,Sears RC.Hypoxia: friend or foe for drug delivery in pancreatic cancer.Cancer Lett2020;492:63-70 PMCID:PMC7879337

[23] Moir JA,White SA.The role of pancreatic stellate cells in pancreatic cancer.Surg Oncol2015;24:232-8

[24] Arnold CR,Skvortsova II.The role of cancer stem cells in radiation resistance.Front Oncol2020;10:164 PMCID:PMC7044409

[25] Burris HA 3rd,Andersen J.Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial.J Clin Oncol1997;15:2403-13

[26] Colucci G,Gebbia V.Gemcitabine alone or with cisplatin for the treatment of patients with locally advanced and/or metastatic pancreatic carcinoma: a prospective, randomized phase III study of the Gruppo Oncologia dell’Italia Meridionale.Cancer2002;94:902-10

[27] Colucci G,Di Costanzo F.Randomized phase III trial of gemcitabine plus cisplatin compared with single-agent gemcitabine as first-line treatment of patients with advanced pancreatic cancer: the GIP-1 study.J Clin Oncol2010;28:1645-51

[28] Golan T,Epelbaum R.Overall survival and clinical characteristics of pancreatic cancer in BRCA mutation carriers.Br J Cancer2014;111:1132-8 PMCID:PMC4453851

[29] Moore MJ,Hamm J.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.J Clin Oncol2007;25:1960-6

[30] Cunningham D,Stocken DD.Phase III randomized comparison of gemcitabine versus gemcitabine plus capecitabine in patients with advanced pancreatic cancer.J Clin Oncol2009;27:5513-8

[31] Li Q,Liu W,Yang Y.Efficacy and safety of gemcitabine-fluorouracil combination therapy in the management of advanced pancreatic cancer: a meta-analysis of randomized controlled trials.PLoS One2014;9:e104346 PMCID:PMC4122434

[32] Conroy T,François E.Irinotecan plus oxaliplatin and leucovorin-modulated fluorouracil in advanced pancreatic cancer--a Groupe Tumeurs Digestives of the Federation Nationale des Centres de Lutte Contre le Cancer study.J Clin Oncol2005;23:1228-36

[33] Conroy T,Ychou M.FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer.N Engl J Med2011;364:1817-25

[34] Suker M,Sadot E.FOLFIRINOX for locally advanced pancreatic cancer: a systematic review and patient-level meta-analysis.Lancet Oncol2016;17:801-10 PMCID:PMC5527756

[35] Hackert T,Hinz U.Locally advanced pancreatic cancer: neoadjuvant therapy with folfirinox results in resectability in 60% of the patients.Ann Surg2016;264:457-63

[36] Von Hoff DD,Borad MJ.Gemcitabine plus nab-paclitaxel is an active regimen in patients with advanced pancreatic cancer: a phase I/II trial.J Clin Oncol2011;29:4548-54 PMCID:PMC3565012

[37] Von Hoff DD,Arena FP.Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine.N Engl J Med2013;369:1691-703 PMCID:PMC4631139

[38] Macedo FI,Maithel SK.Survival outcomes associated with clinical and pathological response following neoadjuvant FOLFIRINOX or gemcitabine/nab-paclitaxel chemotherapy in resected pancreatic cancer.Ann Surg2019;270:400-13

[39] Arima S,Shimokawa M.Gemcitabine plus nab-paclitaxel versus FOLFIRINOX in locally advanced, unresectable pancreatic cancer: a multicenter observational study (NAPOLEON study).Pancreas2021;50:957-64

[40] Philip PA,Portales F.Nab-paclitaxel plus gemcitabine in patients with locally advanced pancreatic cancer (LAPACT): a multicentre, open-label phase 2 study.Lancet Gastroenterol Hepatol2020;5:285-94

[41] Kunzmann V,Algül H.Nab-paclitaxel plus gemcitabine versus nab-paclitaxel plus gemcitabine followed by FOLFIRINOX induction chemotherapy in locally advanced pancreatic cancer (NEOLAP-AIO-PAK-0113): a multicentre, randomised, phase 2 trial.Lancet Gastroenterol Hepatol2021;6:128-38

[42] Katz MH,Evans DB.Borderline resectable pancreatic cancer: the importance of this emerging stage of disease.J Am Coll Surg2008;206:833-46; discussion 846 PMCID:PMC5901743

[43] Chapman BC,Rigg D.Perioperative and survival outcomes following neoadjuvant FOLFIRINOX versus gemcitabine abraxane in patients with pancreatic adenocarcinoma.JOP2018;19:75-85 PMCID:PMC6018015

[44] Janssen QP,Suker M.Neoadjuvant FOLFIRINOX in patients with borderline resectable pancreatic cancer: a systematic review and patient-level meta-analysis.J Natl Cancer Inst2019;111:782-94 PMCID:PMC6695305

[45] Yoo C,Kim KP.Efficacy and safety of neoadjuvant FOLFIRINOX for borderline resectable pancreatic adenocarcinoma: improved efficacy compared with gemcitabine-based regimen.Oncotarget2017;8:46337-47 PMCID:PMC5542271

[46] Ghaneh P,Cicconi S.ESPAC-5F: four-arm, prospective, multicenter, international randomized phase II trial of immediate surgery compared with neoadjuvant gemcitabine plus capecitabine (GEMCAP) or FOLFIRINOX or chemoradiotherapy (CRT) in patients with borderline resectable pancreatic cancer.JCO2020;38:4505-4505

[47] Yamaguchi J,Fujii T.Results of a phase II study on the use of neoadjuvant chemotherapy (FOLFIRINOX or GEM/nab-PTX) for borderline-resectable pancreatic cancer (NUPAT-01).Ann Surg2022;275:1043-9

[48] Reni M,Balzano G.A randomised phase 2 trial of nab-paclitaxel plus gemcitabine with or without capecitabine and cisplatin in locally advanced or borderline resectable pancreatic adenocarcinoma.Eur J Cancer2018;102:95-102

[49] Lee JL,Kim JH.Prospective efficacy and safety study of neoadjuvant gemcitabine with capecitabine combination chemotherapy for borderline-resectable or unresectable locally advanced pancreatic adenocarcinoma.Surgery2012;152:851-62

[50] Saito K,Sakamoto Y.A phase II trial of gemcitabine, S-1 and LV combination (GSL) neoadjuvant chemotherapy for patients with borderline resectable and locally advanced pancreatic cancer.Med Oncol2018;35:100

[51] Tajima H,Kitagawa H.Pilot study of neoadjuvant chemotherapy with gemcitabine and oral S-1 for resectable pancreatic cancer.Exp Ther Med2012;3:787-92 PMCID:PMC3438612

[52] Heinrich S,Weber A.Neoadjuvant chemotherapy generates a significant tumor response in resectable pancreatic cancer without increasing morbidity: results of a prospective phase II trial.Ann Surg2008;248:1014-22

[53] OʼReilly EM,Jarnagin WR.A single-arm, nonrandomized phase II trial of neoadjuvant gemcitabine and oxaliplatin in patients with resectable pancreas adenocarcinoma.Ann Surg2014;260:142-8 PMCID:PMC4520299

[54] Motoi F,Fujishima F.Neoadjuvant chemotherapy with gemcitabine and S-1 for resectable and borderline pancreatic ductal adenocarcinoma: results from a prospective multi-institutional phase 2 trial.Ann Surg Oncol2013;20:3794-801

[55] Motoi F,Ueno H.Randomized phase II/III trial of neoadjuvant chemotherapy with gemcitabine and S-1 versus upfront surgery for resectable pancreatic cancer (Prep-02/JSAP05).Jpn J Clin Oncol2019;49:190-4

[56] Al-batran S,Bankstahl US.Randomized multicenter phase II/III study with adjuvant gemcitabine versus neoadjuvant/adjuvant FOLFIRINOX in resectable pancreatic cancer: the NEPAFOX trial.JCO2021;39:406-406

[57] Sohal D,Ahmad SA.SWOG S1505: results of perioperative chemotherapy (peri-op CTx) with mfolfirinox versus gemcitabine/nab-paclitaxel (Gem/nabP) for resectable pancreatic ductal adenocarcinoma (PDA).JCO2020;38:4504-4504

[58] Ahmad SA,Sohal DPS.Surgical outcome results from SWOG S1505: a randomized clinical trial of mFOLFIRINOX versus gemcitabine/nab-paclitaxel for perioperative treatment of resectable pancreatic ductal adenocarcinoma.Ann Surg2020;272:481-6 PMCID:PMC7856053

[59] Ettrich TJ,Kornmann M.Perioperative or adjuvant nab-paclitaxel plus gemcitabine for resectable pancreatic cancer: updated final results of the randomized phase II AIO-NEONAX trial.JCO2022;40:4133-4133 PMCID:PMC6311014

[60] Schwarz L,Meurisse A.Resectable pancreatic adenocarcinoma neo-adjuvant FOLF(IRIN)OX-based chemotherapy: a multicenter, non-comparative, randomized, phase II trial (PANACHE01-PRODIGE48 study).JCO2022;40:4134-4134

[61] Loehrer PJ Sr,Cardenes H.Gemcitabine alone versus gemcitabine plus radiotherapy in patients with locally advanced pancreatic cancer: an Eastern Cooperative Oncology Group trial.J Clin Oncol2011;29:4105-12 PMCID:PMC3525836

[62] Hammel P,van Laethem JL.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.JAMA2016;315:1844-53

[63] Seshacharyulu P,Souchek JJ.Biological determinants of radioresistance and their remediation in pancreatic cancer.Biochim Biophys Acta Rev Cancer2017;1868:69-92 PMCID:PMC5548591

[64] Zeng S,Lan B,Pilarsky C.Chemoresistance in pancreatic cancer.Int J Mol Sci2019;20:4504 PMCID:PMC6770382

[65] Krishnan S,Suh Y.Focal radiation therapy dose escalation improves overall survival in locally advanced pancreatic cancer patients receiving induction chemotherapy and consolidative chemoradiation.Int J Radiat Oncol Biol Phys2016;94:755-65 PMCID:PMC4792191

[66] Iacobuzio-Donahue CA,Yachida S.DPC4 gene status of the primary carcinoma correlates with patterns of failure in patients with pancreatic cancer.J Clin Oncol2009;27:1806-13 PMCID:PMC2668706

[67] Loeffler JS.Charged particle therapy-optimization, challenges and future directions.Nat Rev Clin Oncol2013;10:411-24

[68] Hiroshima Y,Saito T.Concurrent chemoradiotherapy using proton beams for unresectable locally advanced pancreatic cancer.Radiother Oncol2019;136:37-43

[69] Maemura K,Kurahara H.Comparison of proton beam radiotherapy and hyper-fractionated accelerated chemoradiotherapy for locally advanced pancreatic cancer.Pancreatology2017;17:833-8

[70] Shinoto M,Suefuji H.A single institutional experience of combined carbon-ion radiotherapy and chemotherapy for unresectable locally advanced pancreatic cancer.Radiother Oncol2018;129:333-9

[71] Ghaneh P,Halloran CM.The impact of positive resection margins on survival and recurrence following resection and adjuvant chemotherapy for pancreatic ductal adenocarcinoma.Ann Surg2019;269:520-9

[72] Oba A,Colborn KL.Comparing neoadjuvant chemotherapy with or without radiation therapy for pancreatic ductal adenocarcinoma: National Cancer Database cohort analysis.Br J Surg2022;109:450-4

[73] Kharofa J,Kelly T.Neoadjuvant chemoradiation with IMRT in resectable and borderline resectable pancreatic cancer.Radiother Oncol2014;113:41-6 PMCID:PMC4530020

[74] Katz MH,Bhosale P.Response of borderline resectable pancreatic cancer to neoadjuvant therapy is not reflected by radiographic indicators.Cancer2012;118:5749-56

[75] Hill CS,Hu C.Neoadjuvant stereotactic body radiotherapy after upfront chemotherapy improves pathologic outcomes compared with chemotherapy alone for patients with borderline resectable or locally advanced pancreatic adenocarcinoma without increasing perioperative toxicity.Ann Surg Oncol2022;29:2456-68 PMCID:PMC8933354

[76] Sherman WH,Chabot J.Neoadjuvant gemcitabine, docetaxel, and capecitabine followed by gemcitabine and capecitabine/radiation therapy and surgery in locally advanced, unresectable pancreatic adenocarcinoma.Cancer2015;121:673-80

[77] Eguchi H,Iwagami Y.Prolonged neoadjuvant therapy for locally advanced pancreatic cancer.Dig Surg2018;35:70-6

[78] Kim EJ,Herman JM.A multi-institutional phase 2 study of neoadjuvant gemcitabine and oxaliplatin with radiation therapy in patients with pancreatic cancer.Cancer2013;119:2692-700 PMCID:PMC4174603

[79] Chakraborty S,Bauer TW.Accelerated fraction radiotherapy with capecitabine as neoadjuvant therapy for borderline resectable pancreatic cancer.Gastrointest Cancer Res2014;7:15-22 PMCID:PMC3924761

[80] Katz MH,Ahmad SA.Preoperative modified FOLFIRINOX treatment followed by capecitabine-based chemoradiation for borderline resectable pancreatic cancer: alliance for clinical trials in oncology trial A021101.JAMA Surg2016;151:e161137 PMCID:PMC5210022

[81] Fiore M,Valeri S.Phase II study of induction chemotherapy followed by chemoradiotherapy in patients with borderline resectable and unresectable locally advanced pancreatic cancer.Sci Rep2017;7:45845 PMCID:PMC5381116

[82] Murphy JE,Ryan DP.Total neoadjuvant therapy with FOLFIRINOX followed by individualized chemoradiotherapy for borderline resectable pancreatic adenocarcinoma: a phase 2 clinical trial.JAMA Oncol2018;4:963-9 PMCID:PMC6145728

[83] Jang JY,Lee H.Oncological benefits of neoadjuvant chemoradiation with gemcitabine versus upfront surgery in patients with borderline resectable pancreatic cancer: a prospective, randomized, open-label, multicenter phase 2/3 trial.Ann Surg2018;268:215-22

[84] Katz MHG,Meyers JP.Alliance A021501: preoperative mFOLFIRINOX or mFOLFIRINOX plus hypofractionated radiation therapy (RT) for borderline resectable (BR) adenocarcinoma of the pancreas.JCO2021;39:377-377

[85] Okano K,Oshima M.A prospective phase II Trial of neoadjuvant S-1 with concurrent hypofractionated radiotherapy in patients with resectable and borderline resectable pancreatic ductal adenocarcinoma.Ann Surg Oncol2017;24:2777-84

[86] Versteijne E,Groothuis K.Preoperative chemoradiotherapy versus immediate surgery for resectable and borderline resectable pancreatic cancer: results of the dutch randomized phase III PREOPANC trial.J Clin Oncol2020;38:1763-73 PMCID:PMC8265386

[87] Versteijne E,Suker M.Neoadjuvant chemoradiotherapy versus upfront surgery for resectable and borderline resectable pancreatic cancer: long-term results of the dutch randomized PREOPANC trial.J Clin Oncol2022;40:1220-30

[88] Fietkau R,Grützmann R.Randomized phase III trial of induction chemotherapy followed by chemoradiotherapy or chemotherapy alone for nonresectable locally advanced pancreatic cancer: first results of the CONKO-007 trial.JCO2022;40:4008-4008

[89] Talamonti MS,Mulcahy MF.A multi-institutional phase II trial of preoperative full-dose gemcitabine and concurrent radiation for patients with potentially resectable pancreatic carcinoma.Ann Surg Oncol2006;13:150-8

[90] Evans DB,Crane CH.Preoperative gemcitabine-based chemoradiation for patients with resectable adenocarcinoma of the pancreatic head.J Clin Oncol2008;26:3496-502

[91] Turrini O,Moureau-Zabotto L.Neoadjuvant 5 fluorouracil-cisplatin chemoradiation effect on survival in patients with resectable pancreatic head adenocarcinoma: a ten-year single institution experience.Oncology2009;76:413-9

[92] Varadhachary GR,Crane CH.Preoperative gemcitabine and cisplatin followed by gemcitabine-based chemoradiation for resectable adenocarcinoma of the pancreatic head.J Clin Oncol2008;26:3487-95

[93] Golcher H,Witzigmann H.Neoadjuvant chemoradiation therapy with gemcitabine/cisplatin and surgery versus immediate surgery in resectable pancreatic cancer: results of the first prospective randomized phase II trial.Strahlenther Onkol2015;191:7-16 PMCID:PMC4289008

[94] Luo J.KRAS mutation in pancreatic cancer.Semin Oncol2021;48:10-8 PMCID:PMC8380752

[95] Troiani T,Capasso A.Targeting EGFR in pancreatic cancer treatment.Curr Drug Targets2012;13:802-10

[96] Mutgan AC,Wang S,Ceyhan GO.Insulin/IGF-driven cancer cell-stroma crosstalk as a novel therapeutic target in pancreatic cancer.Mol Cancer2018;17:66 PMCID:PMC5824531

[97] Annese T,Ruggieri S.Angiogenesis in pancreatic cancer: pre-clinical and clinical studies.Cancers (Basel)2019;11:381 PMCID:PMC6468440

[98] Hosein AN,Maitra A.Pancreatic cancer stroma: an update on therapeutic targeting strategies.Nat Rev Gastroenterol Hepatol2020;17:487-505 PMCID:PMC8284850

[99] Crowley F,O’Reilly EM.Targeting DNA damage repair pathways in pancreas cancer.Cancer Metastasis Rev2021;40:891-908 PMCID:PMC9391023

[100] Stephen AG,Bagni RK.Dragging ras back in the ring.Cancer Cell2014;25:272-81

[101] Infante JR,Park JO.A randomised, double-blind, placebo-controlled trial of trametinib, an oral MEK inhibitor, in combination with gemcitabine for patients with untreated metastatic adenocarcinoma of the pancreas.Eur J Cancer2014;50:2072-81

[102] Zhu X,Liu W.Stereotactic body radiotherapy plus pembrolizumab and trametinib versus stereotactic body radiotherapy plus gemcitabine for locally recurrent pancreatic cancer after surgical resection: an open-label, randomised, controlled, phase 2 trial.Lancet Oncol2022;23:e105-15

[103] Forster T,Springfeld C.Cetuximab in pancreatic cancer therapy: a systematic review and meta-analysis.Oncology2020;98:53-60

[104] Maurel J,Laquente B.Outcomes after neoadjuvant treatment with gemcitabine and erlotinib followed by gemcitabine-erlotinib and radiotherapy for resectable pancreatic cancer (GEMCAD 10-03 trial).Cancer Chemother Pharmacol2018;82:935-43

[105] Abdel-Wahab R,Bhosale PR.Randomized, phase I/II study of gemcitabine plus IGF-1R antagonist (MK-0646) versus gemcitabine plus erlotinib with and without MK-0646 for advanced pancreatic adenocarcinoma.J Hematol Oncol2018;11:71 PMCID:PMC5975422

[106] Sahai V,Kalyan A.A phase I/II open-label multicenter single-arm study of FABLOx (Metronomic 5-fluorouracil Plus.nab5:35-42 PMCID:PMC6761587

[107] Cascinu S,Sobrero A.Sorafenib does not improve efficacy of chemotherapy in advanced pancreatic cancer: a GISCAD randomized phase II study.Dig Liver Dis2014;46:182-6 PMCID:PMC4741511

[108] Reni M,Milella M.Maintenance sunitinib or observation in metastatic pancreatic adenocarcinoma: a phase II randomised trial.Eur J Cancer2013;49:3609-15

[109] Ioka T,Ohkawa S.Efficacy and safety of axitinib in combination with gemcitabine in advanced pancreatic cancer: subgroup analyses by region, including Japan, from the global randomized Phase III trial.Jpn J Clin Oncol2015;45:439-48 PMCID:PMC4412139

[110] Falcomatà C,Widholz SA.Selective multi-kinase inhibition sensitizes mesenchymal pancreatic cancer to immune checkpoint blockade by remodeling the tumor microenvironment.Nat Cancer2022;3:318-36 PMCID:PMC7612546

[111] Ko AH,Tempero MA.A phase I Study of FOLFIRINOX plus IPI-926, a hedgehog pathway inhibitor, for advanced pancreatic adenocarcinoma.Pancreas2016;45:370-5 PMCID:PMC5908466

[112] Van Cutsem E,Sigal D.Randomized phase III Trial of pegvorhyaluronidase Alfa with nab-paclitaxel plus gemcitabine for patients with hyaluronan-high metastatic pancreatic adenocarcinoma.J Clin Oncol2020;38:3185-94 PMCID:PMC7499614

[113] Ramanathan RK,Philip PA.Phase IB/II randomized study of FOLFIRINOX plus pegylated recombinant human hyaluronidase versus FOLFIRINOX Alone in patients with metastatic pancreatic adenocarcinoma: SWOG S1313.J Clin Oncol2019;37:1062-9 PMCID:PMC6494359

[114] Rubinson D,Warsofsky IS.Durable clinical benefit from PARP inhibition in a platinum-sensitive, BRCA2-mutated pancreatic cancer patient after earlier progression on placebo treatment on the POLO trial: a case report.J Gastrointest Oncol2021;12:3133-40 PMCID:PMC8748075

[115] Kindler HL,Reni M.Overall survival results from the POLO trial: a phase iii study of active maintenance olaparib versus placebo for germline BRCA-mutated metastatic pancreatic cancer.J Clin Oncol2022;JCO2101604

[116] Murphy JE,Ryan DP.Total neoadjuvant therapy with FOLFIRINOX in Combination with losartan followed by chemoradiotherapy for locally advanced pancreatic cancer: a phase 2 clinical trial.JAMA Oncol2019;5:1020-7 PMCID:PMC6547247

[117] Chen Z,Chu HY.Connective tissue growth factor: from molecular understandings to drug discovery.Front Cell Dev Biol2020;8:593269 PMCID:PMC7658337

[118] Carrieri FA,Siddiqui I,Tran PT.Tumor treating fields: at the crossroads between physics and biology for cancer treatment.Front Oncol2020;10:575992 PMCID:PMC7664989

[119] Henriksen A,Chen I.Checkpoint inhibitors in pancreatic cancer.Cancer Treat Rev2019;78:17-30

[120] Leinwand J.Regulation and modulation of antitumor immunity in pancreatic cancer.Nat Immunol2020;21:1152-9

[121] Angelini C,Muselli P.Preoperative interleukin-2 immunotherapy in pancreatic cancer: preliminary results.Hepatogastroenterology2006;53:141-4

[122] Caprotti R,Fumagalli L.Free-from-progression period and overall short preoperative immunotherapy with IL-2 increases the survival of pancreatic cancer patients treated with macroscopically radical surgery.Anticancer Res2008;28:1951-4

[123] Amin S,Meza J.The impact of neoadjuvant and adjuvant immunotherapy on the survival of pancreatic cancer patients: a retrospective analysis.BMC Cancer2020;20:538 PMCID:PMC7285784

[124] Byrne KT,Mick R.Neoadjuvant selicrelumab, an agonist CD40 antibody, induces changes in the tumor microenvironment in patients with resectable pancreatic cancer.Clin Cancer Res2021;27:4574-86 PMCID:PMC8667686

[125] Hilmi M,Turpin A.A randomized, non-comparative, phase II study of maintenance OSE2101 vaccine alone or in combination with nivolumab (nivo) or FOLFIRI after induction with FOLFIRINOX in patients (Pts) with advanced pancreatic ductal adenocarcinoma (aPDAC): first interim results of the TEDOPAM GERCOR D17-01 PRODIGE 63 STUDY.JCO2022;40:4148-4148