IMPORTANCE: The benefit of adjuvant chemotherapy after resection of pancreatic cancer following neoadjuvant combination treatment with folinic acid, fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX) is unclear. OBJECTIVE: To assess the association of adjuvant chemotherapy with overall survival (OS) in patients after pancreatic cancer resection and neoadjuvant FOLFIRINOX treatment. DESIGN, SETTING, AND PARTICIPANTS: This international, multicenter, retrospective cohort study was conducted from January 1, 2012, to December 31, 2018. An existing cohort of patients undergoing resection of pancreatic cancer after FOLFIRINOX was updated and expanded for the purpose of this study. All consecutive patients who underwent pancreatic surgery after at least 2 cycles of neoadjuvant FOLFIRINOX chemotherapy for nonmetastatic pancreatic cancer were retrospectively identified from institutional databases. Patients with resectable pancreatic cancer, borderline resectable pancreatic cancer, and locally advanced pancreatic cancer were eligible for this study. Patients with in-hospital mortality or who died within 3 months after surgery were excluded. EXPOSURES: The association of adjuvant chemotherapy with OS was evaluated in different subgroups including interaction terms for clinicopathological parameters with adjuvant treatment in a multivariable Cox model. Overall survival was defined as the time starting from surgery plus 3 months (moment eligible for adjuvant therapy), unless mentioned otherwise. RESULTS: We included 520 patients (median [interquartile range] age, 61 [53-66] years; 279 [53.7%] men) from 31 centers in 19 countries. The median number of neoadjuvant cycles of FOLFIRINOX was 6 (interquartile range, 5-8). Overall, 343 patients (66.0%) received adjuvant chemotherapy, of whom 68 (19.8%) received FOLFIRINOX, 201 (58.6%) received gemcitabine-based chemotherapy, 14 (4.1%) received capecitabine, 45 (13.1%) received a combination or other agents, and 15 (4.4%) received an unknown type of adjuvant chemotherapy. Median OS was 38 months (95% CI, 36-46 months) after diagnosis and 31 months (95% CI, 29-37 months) after surgery. No survival difference was found for patients who received adjuvant chemotherapy vs those who did not (median OS, 29 vs 29 months, univariable hazard ratio [HR], 0.99; 95% CI, 0.77-1.28; P = .93). In multivariable analysis, only the interaction term for lymph node stage with adjuvant therapy was statistically significant: In patients with pathology-proven node-positive disease, adjuvant chemotherapy was associated with improved survival (median OS, 26 vs 13 months; multivariable HR, 0.41 [95% CI, 0.22-0.75]; P = .004). In patients with node-negative disease, adjuvant chemotherapy was not associated with improved survival (median OS, 38 vs 54 months; multivariable HR, 0.85; 95% CI, 0.35-2.10; P = .73). CONCLUSIONS AND RELEVANCE: These results suggest that adjuvant chemotherapy after neoadjuvant FOLFIRINOX and resection of pancreatic cancer was associated with improved survival only in patients with pathology-proven node-positive disease. Future randomized studies should be conducted to confirm this finding.

Department of Clinical Epidemiology Amsterdam University Medical Center University of Amsterdam the Netherlands

Department of Digestive and Hepatobiliary Surgery Liver Transplantation University Hospital of Clermont Ferrand Clermont Ferrand France

Department of Digestive Surgery and Liver Transplantation Croix Rousse University Hospital Hospices Civils de Lyon University of Lyon Lyon France

Department of Gastroenterological Surgery Helsinki University Hospital Helsinki Finland

Department of General and Hepatobiliary Surgery Gent University Hospital Gent Belgium

Department of General and Pancreatic Surgery The Pancreas Institute University of Verona Hospital Trust Verona Italy

Department of General Surgery Hospital Universitario Marques de Valdecilla Santander Spain

Department of General Surgery Istituto Ospedaliero Fondazione Poliambulanza Brescia Italy

Department of General Visceral and Transplantation Surgery Universitätsklinikum Heidelberg Heidelberg Germany

Department of Hepato Biliary Pancreatic Surgery Liver Transplant Center Paul Brousse Hospital Université Paris Sud Université Paris Saclay Villejuif France

Department of Hepato Pancreato Biliary Surgery Oslo University Hospital Oslo Norway

Department of Medical Oncology Cancer Center Amsterdam Amsterdam University Medical Center University of Amsterdam the Netherlands

Department of Medical Oncology Odense University Hospital Odense Denmark

Department of Radiology St Antonius Hospital Nieuwegein the Netherlands

Department of Surgery Cancer Center Amsterdam Amsterdam University Medical Center University of Amsterdam the Netherlands

Department of Surgery Charles University and Central Military Hospital Prague Czech Republic

Department of Surgery Clermont Auvergne University Clermont Ferrand France

Department of Surgery Erasmus University Medical Center Rotterdam the Netherlands

Department of Surgery Karolinska Institutet Stockholm Sweden

Department of Surgery Odense Pancreas Center Odense University Hospital Odense Denmark

Department of Surgery Pederzoli Hospital Peschiera Italy

Department of Surgery Trinity College Dublin Trinity Centre for Health Sciences Dublin Ireland

Department of Surgery Universitaet zu Luebeck Luebeck Germany

Department of Surgery University Hospital Birmingham Birmingham United Kingdom

Department of Surgery University Hospital Southampton National Health Service Southampton Hampshire United Kingdom

Department of Surgery University of California at San Francisco San Francisco

Department of Surgery University of Colorado Hospital Aurora

Department of Surgery Virginia Mason Medical Center Seattle Washington

Department of Visceral Vascular and Endocrine Surgery Martin Luther University Halle Wittenberg Halle Germany

General Surgery Department Azienda Ospedaliera Ospedali Riuniti Villa Sofia Cervello Palermo Italy

Hepatobiliary Surgery and Liver Transplantation Unit Royal Free Hospital London United Kingdom

Pancreatic Surgery Pancreas Translational and Clinical Research Center San Raffaele Hospital Milan Italy

Zobrazit více v PubMed

Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019;69(1):7-34. doi:10.3322/caac.21551 PubMed DOI

Groot VP, Rezaee N, Wu W, et al. . Patterns, timing, and predictors of recurrence following pancreatectomy for pancreatic ductal adenocarcinoma. Ann Surg. 2018;267(5):936-945. doi:10.1097/SLA.0000000000002234 PubMed DOI

Neoptolemos JP, Stocken DD, Friess H, et al. ; European Study Group for Pancreatic Cancer . A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med. 2004;350(12):1200-1210. doi:10.1056/NEJMoa032295 PubMed DOI

Conroy T, Hammel P, Hebbar M, et al. ; Canadian Cancer Trials Group and the Unicancer-GI–PRODIGE Group . FOLFIRINOX or gemcitabine as adjuvant therapy for pancreatic cancer. N Engl J Med. 2018;379(25):2395-2406. doi:10.1056/NEJMoa1809775 PubMed DOI

Versteijne E, Vogel JA, Besselink MG, et al. ; Dutch Pancreatic Cancer Group . Meta-analysis comparing upfront surgery with neoadjuvant treatment in patients with resectable or borderline resectable pancreatic cancer. Br J Surg. 2018;105(8):946-958. doi:10.1002/bjs.10870 PubMed DOI PMC

Jang JY, Han Y, Lee H, et al. . 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 Surg. 2018;268(2):215-222. doi:10.1097/SLA.0000000000002705 PubMed DOI

Motoi F, Kosuge T, Ueno H, 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). Jpn J Clin Oncol . 2019;49(2):190-194. doi:10.1093/jjco/hyy190 PubMed DOI

Versteijne E, Suker M, Groothuis K, et al. ; Dutch Pancreatic Cancer Group . Preoperative chemoradiotherapy versus immediate surgery for resectable and borderline resectable pancreatic cancer: results of the Dutch randomized phase III PREOPANC trial. J Clin Oncol. 2020;38(16):1763-1773. doi:10.1200/JCO.19.02274 PubMed DOI PMC

Janssen QP, Buettner S, Suker M, et al. . Neoadjuvant FOLFIRINOX in patients with borderline resectable pancreatic cancer: a systematic review and patient-level meta-analysis. J Natl Cancer Inst. 2019;111(8):782-794. doi:10.1093/jnci/djz073 PubMed DOI PMC

Suker M, Beumer BR, Sadot E, et al. . FOLFIRINOX for locally advanced pancreatic cancer: a systematic review and patient-level meta-analysis. Lancet Oncol. 2016;17(6):801-810. doi:10.1016/S1470-2045(16)00172-8 PubMed DOI PMC

Truty MJ, Kendrick ML, Nagorney DM, et al. . Factors predicting response, perioperative outcomes, and survival following total neoadjuvant therapy for borderline/locally advanced pancreatic cancer. Ann Surg . Published online April 5, 2019. doi:10.1097/SLA.0000000000003284 PubMed DOI

Mokdad AA, Minter RM, Zhu H, et al. . Neoadjuvant therapy followed by resection versus upfront resection for resectable pancreatic cancer: a propensity score matched analysis. J Clin Oncol. 2017;35(5):515-522. doi:10.1200/JCO.2016.68.5081 PubMed DOI

EAHPBA et al. EAHPBA study protocol outcomes of resection of pancreatic cancer after FOLFIRINOX chemotherapy. Published 2018. Accessed December 2019. http://eahpba.org/eahpba-study-protocol-outcomes-of-resection-of-pancreatic-cancer-after-folfirinox-chemotherapy/

Giobbie-Hurder A, Gelber RD, Regan MM. Challenges of guarantee-time bias. J Clin Oncol. 2013;31(23):2963-2969. doi:10.1200/JCO.2013.49.5283 PubMed DOI PMC

Castor EDC. Castor electronic data capture. Published 2019. Accessed August 2019. https://castoredc.com

Marthey L, Sa-Cunha A, Blanc JF, et al. . FOLFIRINOX for locally advanced pancreatic adenocarcinoma: results of an AGEO multicenter prospective observational cohort. Ann Surg Oncol. 2015;22(1):295-301. doi:10.1245/s10434-014-3898-9 PubMed DOI

Tempero MA, Malafa MP, Al-Hawary M, et al. . Pancreatic adenocarcinoma, version 2.2017, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw. 2017;15(8):1028-1061. doi:10.6004/jnccn.2017.0131 PubMed DOI

Campbell F, Cairns A, Duthie F, Feakins R Dataset for the histopathological reporting of carcinomas of the pancreas, ampulla of Vater and common bile duct. Published 2017. Accessed February 1, 2020. https://www.rcpath.org/uploads/assets/34910231-c106-4629-a2de9e9ae6f87ac1/G091-Dataset-for-histopathological-reporting-of-carcinomas-of-the-pancreas-ampulla-of-Vater-and-common-bile-duct.pdf

Kakar S, Pawlik TM, Allen PJ. AJCC Cancer Staging Manual. 8th ed. Springer-Verlag; 2016.

Altman DG, Bland JM. Interaction revisited: the difference between two estimates. BMJ. 2003;326(7382):219. doi:10.1136/bmj.326.7382.219 PubMed DOI PMC

Conroy T, Desseigne F, Ychou M, et al. ; Groupe Tumeurs Digestives of Unicancer; PRODIGE Intergroup . FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011;364(19):1817-1825. doi:10.1056/NEJMoa1011923 PubMed DOI

Skau Rasmussen L, Vittrup B, Ladekarl M, et al. . The effect of postoperative gemcitabine on overall survival in patients with resected pancreatic cancer: a nationwide population-based Danish register study. Acta Oncol. 2019;58(6):864-871. doi:10.1080/0284186X.2019.1581374 PubMed DOI

Perri G, Prakash L, Qiao W, et al. . Postoperative chemotherapy benefits patients who received preoperative therapy and pancreatectomy for pancreatic adenocarcinoma. Ann Surg. 2020;271(6)996-1002. doi:10.1097/SLA.0000000000003763 PubMed DOI

Pietrasz D, Marthey L, Wagner M, et al. . Pathologic major response after FOLFIRINOX is prognostic for patients secondary resected for borderline or locally advanced pancreatic adenocarcinoma: an AGEO-FRENCH, prospective, multicentric cohort. Ann Surg Oncol. 2015;22(suppl 3):S1196-S1205. doi:10.1245/s10434-015-4783-x PubMed DOI

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(4):733-740. doi:10.1097/SLA.0000000000002600 PubMed DOI

Pietrasz D, Turrini O, Vendrely V, et al. . How does chemoradiotherapy following induction FOLFIRINOX improve the results in resected borderline or locally advanced pancreatic adenocarcinoma? an AGEO-FRENCH multicentric cohort. Ann Surg Oncol. 2019;26(1):109-117. doi:10.1245/s10434-018-6931-6 PubMed DOI

Validation of the PANAMA Score for Survival and Benefit of Adjuvant Therapy in Patients With Resected Pancreatic Cancer after Neoadjuvant FOLFIRINOX

Surgical and Oncological Outcomes After Preoperative FOLFIRINOX Chemotherapy in Resected Pancreatic Cancer: An International Multicenter Cohort Study