R0 resection following chemo (radio)therapy improves survival of primary inoperable pancreatic cancer patients. Interim results of the German randomized CONKO-007± trial
Tóm tắt
Chemotherapy with or without radiotherapy is the standard in patients with initially nonmetastatic unresectable pancreatic cancer. Additional surgery is in discussion. The CONKO-007 multicenter randomized trial examines the value of radiotherapy. Our interim analysis showed a significant effect of surgery, which may be relevant to clinical practice. One hundred eighty patients received induction chemotherapy (gemcitabine or FOLFIRINOX). Patients without tumor progression were randomized to either chemotherapy alone or to concurrent chemoradiotherapy. At the end of therapy, a panel of five independent pancreatic surgeons judged the resectability of the tumor. Following induction chemotherapy, 126/180 patients (70.0%) were randomized to further treatment. Following study treatment, 36/126 patients (28.5%) underwent surgery; (R0: 25/126 [19.8%]; R1/R2/Rx [n = 11/126; 6.1%]). Disease-free survival (DFS) and overall survival (OS) were significantly better for patients with R0 resected tumors (median DFS and OS: 16.6 months and 26.5 months, respectively) than for nonoperated patients (median DFS and OS: 11.9 months and 16.5 months, respectively; p = 0.003). In the 25 patients with R0 resected tumors before treatment, only 6/113 (5.3%) of the recommendations of the panel surgeons recommended R0 resectability, compared with 17/48 (35.4%) after treatment (p < 0.001). Tumor resectability of pancreatic cancer staged as unresectable at primary diagnosis should be reassessed after neoadjuvant treatment. The patient should undergo surgery if a resectability is reached, as this significantly improves their prognosis.
Tài liệu tham khảo
Siegel RL, Miller KD, Jema A (2015) Cancer statistics, 2015. CA Cancer J Clin 65(1):5–29. https://doi.org/10.3322/caac.21254
Lutz MP, Zalcberg JR, Ducreux M, Aust D, Bruno MJ, Buchler MW, Delpero JR, Gloor B, Glynne-Jones R, Hartwig W et al (2017) 3rd St. Gallen EORTC Gastrointestinal Cancer Conference: Consensus recommendations on controversial issues in the primary treatment of pancreatic cancer. Eur J Cancer 79:41–49. https://doi.org/10.1016/j.ejca.2017.03.022
Tempero MA, Malafa MP, Al-Hawary M, Asbun H, Bain A, Behrman SW, Benson AB 3rd, Binder E, Cardin DB, Cha C et al (2017) Pancreatic adenocarcinoma, version 2.2017, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw 15(8):1028–1061. https://doi.org/10.6004/jnccn.2017.0131
Bhayani NH, Enomoto LM, James BC, Ortenzi G, Kaifi JT, Kimchi ET, Staveley-O’Carroll KF, Gusani NJ (2014) Multivisceral and extended resections during pancreatoduodenectomy increase morbidity and mortality. Surgery 155(3):567–574. https://doi.org/10.1016/j.surg.2013.12.020
Petrucciani N, Debs T, Nigri G, Giannini G, Sborlini E, Kassir R, Ben Amor I, Iannelli A, Valabrega S, D’Angelo F et al (2018) Pancreatectomy combined with multivisceral resection for pancreatic malignancies: is it justified? Results of a systematic review. HPB (Oxford) 20(1):3–10. https://doi.org/10.1016/j.hpb.2017.08.002
Bachmayer S, Fastner G, Vaszi A, Iglseder W, Kopp P, Holzinger J, Dinnewitzer A, Rinnerthaler G, Gampenrieder SP, Emmanuel K et al (2018) Nonmetastatic pancreatic cancer: improved survival with chemoradiotherapy >40 Gy after systemic treatment. Strahlenther Onkol 194(7):627–637. https://doi.org/10.1007/s00066-018-1281-7
Satoi S, Yamaue H, Kato K, Takahashi S, Hirono S, Takeda S, Eguchi H, Sho M, Wada K, Shinchi H et al (2013) Role of adjuvant surgery for patients with initially unresectable pancreatic cancer with a long-term favorable response to non-surgical anti-cancer treatments: results of a project study for pancreatic surgery by the Japanese Society of Hepato-Biliary-Pancreatic Surgery. J Hepatobiliary Pancreat Sci 20(6):590–600. https://doi.org/10.1007/s00534-013-0616-0
Dobiasch S, Goerig NL, Fietkau R, Combs SE (2018) Essential role of radiation therapy for the treatment of pancreatic cancer: novel study concepts and established treatment recommendations. Strahlenther Onkol 194(3):185–195. https://doi.org/10.1007/s00066-017-1227-5
Mazzola R, Fersino S, Aiello D, Gregucci F, Tebano U, Corradini S, Di Paola G, Cirillo M, Tondulli L, Ruffo G et al (2018) Linac-based stereotactic body radiation therapy for unresectable locally advanced pancreatic cancer: risk-adapted dose prescription and image-guided delivery. Strahlenther Onkol 194(9):835–842. https://doi.org/10.1007/s00066-018-1306-2
Matuschek C, Haussmann J, Bolke E, Tamaskovics B, Djiepmo Njanang FJ, Orth K, Peiper M, Gerber PA, Anooshar B, Kammers K et al (2019) Adjuvant radiochemotherapy vs. chemotherapy alone in gastric cancer: a meta-analysis. Strahlenther Onkol 195(8):695–706. https://doi.org/10.1007/s00066-019-01431-y
Vitz S, Gobel H, Leibl B, Aigner T, Grabenbauer GG (2018) Adenocarcinoma of the oesophagus: neoadjuvant chemoradiation and radical surgery: long-term results. Strahlenther Onkol 194(11):1007–1016. https://doi.org/10.1007/s00066-018-1320-4
Conroy T, Desseigne F, Ychou M, Bouche O, Guimbaud R, Becouarn Y, Adenis A, Raoul JL, Gourgou-Bourgade S, de la Fouchardiere C et al (2011) FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med 364(19):1817–1825. https://doi.org/10.1056/NEJMoa1011923
Team RC (2017) R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna
Katz MHG, Shi Q, Ahmad SA, Herman JM, Marsh RD, Collisson E, Schwartz L, Frankel W, Martin R, Conway W et al (2016) Preoperative modified FOLFIRINOX treatment followed by capecitabine-based chemoradiation for borderline resectable pancreatic cancer alliance for clinical trials in oncology trial A021101. JAMA Surg. https://doi.org/10.1001/jamasurg.2016.1137
Bouchart C, Navez J, Closset J, Hendlisz A, Van Gestel D, Moretti L, Van Laethem JL (2020) Novel strategies using modern radiotherapy to improve pancreatic cancer outcomes: toward a new standard? Ther Adv Med Oncol 12:1758835920936093. https://doi.org/10.1177/1758835920936093
Gemenetzis G, Groot VP, Blair AB, Laheru DA, Zheng L, Narang AK, Fishman EK, Hruban RH, Yu J, Burkhart RA et al (2019) Survival in locally advanced pancreatic cancer after neoadjuvant therapy and surgical resection. Ann Surg 270(2):340–347. https://doi.org/10.1097/SLA.0000000000002753
Hosein PJ, Macintyre J, Kawamura C, Maldonado JC, Ernani V, Loaiza-Bonilla A, Narayanan G, Ribeiro A, Portelance L, Merchan JR et al (2012) A retrospective study of neoadjuvant FOLFIRINOX in unresectable or borderline-resectable locally advanced pancreatic adenocarcinoma. BMC Cancer 12:199. https://doi.org/10.1186/1471-2407-12-199
Marthey L, Sa-Cunha A, Blanc JF, Gauthier M, Cueff A, Francois E, Trouilloud I, Malka D, Bachet JB, Coriat R et al (2015) FOLFIRINOX for locally advanced pancreatic adenocarcinoma: results of an AGEO multicenter prospective observational cohort. Ann Surg Oncol 22(1):295–301. https://doi.org/10.1245/s10434-014-3898-9
Nanda RH, El-Rayes B, Maithel SK, Landry J (2015) Neoadjuvant modified FOLFIRINOX and chemoradiation therapy for locally advanced pancreatic cancer improves resectability. J Surg Oncol 111(8):1028–1034. https://doi.org/10.1002/jso.23921
Nitsche U, Wenzel P, Siveke JT, Braren R, Holzapfel K, Schlitter AM, Stoss C, Kong B, Esposito I, Erkan M et al (2015) Resectability after first-line FOLFIRINOX in initially unresectable locally advanced pancreatic cancer: a single-center experience. Ann Surg Oncol 22:S1212–S1220. https://doi.org/10.1245/s10434-015-4851-2
Sadot E, Doussot A, O’Reilly EM, Lowery MA, Goodman KA, Do RKG, Tang LH, Gonen M, D’Angelica MI, DeMatteo RP et al (2015) FOLFIRINOX induction therapy for stage 3 pancreatic adenocarcinoma. Ann Surg Oncol 22(11):3512–3521. https://doi.org/10.1245/s10434-015-4647-4
Suker M, Beumer BR, Sadot E, Marthey L, Faris JE, Mellon EA, El-Rayes BF, Wang-Gillam A, Lacy J, Hosein PJ et al (2016) FOLFIRINOX for locally advanced pancreatic cancer: a systematic review and patient-level meta-analysis. Lancet Oncol 17(6):801–810. https://doi.org/10.1016/S1470-2045(16)00172-8
Neoptolemos JP, Palmer DH, Ghaneh P, Psarelli EE, Valle JW, Halloran CM, Faluyi O, O’Reilly DA, Cunningham D, Wadsley J et al (2017) 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. Lancet 389(10073):1011–1024. https://doi.org/10.1016/S0140-6736(16)32409-6
Sinn M, Bahra M, Liersch T, Gellert K, Messmann H, Bechstein W, Waldschmidt D, Jacobasch L, Wilhelm M, Rau BM et al (2017) 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. J Clin Oncol 35(29):3330. https://doi.org/10.1200/Jco.2017.72.6463
Michelakos T, Pergolini I, Fernandez-del Castillo C, Honselmann KC, Cai L, Deshpande V, Wo JY, Ryan DP, Allen JN, Blaszkowsky LS et al (2019) Predictors of resectability and survival in patients with borderline and locally advanced pancreatic cancer who underwent neoadjuvant treatment with FOLFIRINOX. Ann Surg 269(4):733–740. https://doi.org/10.1097/Sla.0000000000002600
Murphy JE, Wo JY, Ryan DP (2018) Total neoadjuvant therapy with FOLFIRINOX followed by individualized chemoradiotherapy for borderline resectable pancreatic adenocarcinoma: a phase 2 clinical trial. Oncology 4(10):1439–1439. https://doi.org/10.1001/jamaoncol.2018.4985
Yoo C, Kang J, Kim KP, Lee JL, Ryoo BY, Chang HM, Lee SS, Park DH, Song TJ, Seo DW et al (2017) Efficacy and safety of neoadjuvant FOLFIRINOX for borderline resectable pancreatic adenocarcinoma: improved efficacy compared with gemcitabine-based regimen. Oncotarget 8(28):46337–46347. https://doi.org/10.18632/oncotarget.17940
Ferrone CR, Marchegiani G, Hong TS, Ryan DP, Deshpande V, McDonnell EI, Sabbatino F, Santos DD, Allen JN, Blaszkowsky LS et al (2015) Radiological and surgical implications of neoadjuvant treatment with FOLFIRINOX for locally advanced and borderline resectable pancreatic cancer. Ann Surg 261(1):12–17. https://doi.org/10.1097/Sla.0000000000000867
Wagner M, Antunes C, Pietrasz D, Cassinotto C, Zappa M, Cunha AS, Lucidarme O, Bachet JB (2017) CT evaluation after neoadjuvant FOLFIRINOX chemotherapy for borderline and locally advanced pancreatic adenocarcinoma. Eur Radiol 27(7):3104–3116. https://doi.org/10.1007/s00330-016-4632-8
Krautz C, Nimptsch U, Weber GF, Mansky T, Grutzmann R (2018) Effect of hospital volume on in-hospital morbidity and mortality following pancreatic surgery in Germany. Ann Surg 267(3):411–417. https://doi.org/10.1097/Sla.0000000000002248
Nimptsch U, Krautz C, Weber GF, Mansky T, Grutzmann R (2016) Nationwide in-hospital mortality following pancreatic surgery in Germany is higher than anticipated. Ann Surg 264(6):1082–1090. https://doi.org/10.1097/SLA.0000000000001693
Zimmermann C, Distler M, Jentsch C, Blum S, Folprecht G, Zophel K, Polster H, Troost EGC, Abolmaali N, Weitz J et al (2020) Evaluation of response using FDG-PET/CT and diffusion weighted MRI after radiochemotherapy of pancreatic cancer: a non-randomized, monocentric phase II clinical trial-PaCa-DD-041 (Eudra-CT 2009-011968-11). Strahlenther Onkol. https://doi.org/10.1007/s00066-020-01654-4
Czosnyka NM, Borgert AJ, Smith TJ (2017) Pancreatic adenocarcinoma: effects of neoadjuvant therapy on post-pancreatectomy outcomes—an American College of Surgeons National Surgical Quality Improvement Program targeted variable review. HPB (oxford) 19(10):927–932. https://doi.org/10.1016/j.hpb.2017.07.001
Dindo D, Demartines N, Clavien PA (2004) Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg 240(2):205–213. https://doi.org/10.1097/01.sla.0000133083.54934.ae
Golcher H, Brunner TB, Witzigmann H, Marti L, Bechstein WO, Bruns C, Jungnickel H, Schreiber S, Grabenbauer GG, Meyer T et al (2015) 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 Onkol 191(1):7–16. https://doi.org/10.1007/s00066-014-0737-7