Neoadjuvant Therapy for Resectable Pancreatic Cancer: A New Standard of Care. Pooled Data From 3 Randomized Controlled Trials.
Journal
Annals of surgery
ISSN: 1528-1140
Titre abrégé: Ann Surg
Pays: United States
ID NLM: 0372354
Informations de publication
Date de publication:
01 11 2021
01 11 2021
Historique:
pubmed:
3
8
2021
medline:
23
11
2021
entrez:
2
8
2021
Statut:
ppublish
Résumé
The aim of this study was to pool data from randomized controlled trials (RCT) limited to resectable pancreatic ductal adenocarcinoma (PDAC) to determine whether a neoadjuvant therapy impacts on disease-free survival (DFS) and surgical outcome. Few underpowered studies have suggested benefits from neoadjuvant chemo (± radiation) for strictly resectable PDAC without offering conclusive recommendations. Three RCTs were identified comparing neoadjuvant chemo (± radio) therapy vs. upfront surgery followed by adjuvant therapy in all cases. Data were pooled targeting DFS as primary endpoint, whereas overall survival (OS), postoperative morbidity, and mortality were investigated as secondary endpoints. Survival endpoints DFS and OS were compared using Cox proportional hazards regression with study-specific baseline hazards. A total of 130 patients were randomized (56 in the neoadjuvant and 74 in the control group). DFS was significantly longer in the neoadjuvant treatment group compared to surgery only [hazard ratio (HR) 0.6, 95% confidence interval (CI) 0.4-0.9] (P = 0.01). Furthermore, DFS for the subgroup of R0 resections was similarly longer in the neoadjuvant treated group (HR 0.6, 95% CI 0.35-0.9, P = 0.045). Although postoperative complications (Comprehensive Complication Index, CCI®) occurred less frequently (P = 0.008), patients after neoadjuvant therapy experienced a higher toxicity, but without negative impact on oncological or surgical outcome parameters. Neoadjuvant therapy can be offered as an acceptable standard of care for patients with purely resectable PDAC. Future research with the advances of precision oncology should now focus on the definition of the optimal regimen.
Sections du résumé
OBJECTIVE
The aim of this study was to pool data from randomized controlled trials (RCT) limited to resectable pancreatic ductal adenocarcinoma (PDAC) to determine whether a neoadjuvant therapy impacts on disease-free survival (DFS) and surgical outcome.
SUMMARY BACKGROUND DATA
Few underpowered studies have suggested benefits from neoadjuvant chemo (± radiation) for strictly resectable PDAC without offering conclusive recommendations.
METHODS
Three RCTs were identified comparing neoadjuvant chemo (± radio) therapy vs. upfront surgery followed by adjuvant therapy in all cases. Data were pooled targeting DFS as primary endpoint, whereas overall survival (OS), postoperative morbidity, and mortality were investigated as secondary endpoints. Survival endpoints DFS and OS were compared using Cox proportional hazards regression with study-specific baseline hazards.
RESULTS
A total of 130 patients were randomized (56 in the neoadjuvant and 74 in the control group). DFS was significantly longer in the neoadjuvant treatment group compared to surgery only [hazard ratio (HR) 0.6, 95% confidence interval (CI) 0.4-0.9] (P = 0.01). Furthermore, DFS for the subgroup of R0 resections was similarly longer in the neoadjuvant treated group (HR 0.6, 95% CI 0.35-0.9, P = 0.045). Although postoperative complications (Comprehensive Complication Index, CCI®) occurred less frequently (P = 0.008), patients after neoadjuvant therapy experienced a higher toxicity, but without negative impact on oncological or surgical outcome parameters.
CONCLUSION
Neoadjuvant therapy can be offered as an acceptable standard of care for patients with purely resectable PDAC. Future research with the advances of precision oncology should now focus on the definition of the optimal regimen.
Identifiants
pubmed: 34334656
doi: 10.1097/SLA.0000000000005126
pii: 00000658-202111000-00006
doi:
Types de publication
Journal Article
Review
Langues
eng
Sous-ensembles de citation
IM
Pagination
713-720Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.
Déclaration de conflit d'intérêts
The authors report no conflicts of interest.
Références
Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018; 68:394–424.
SEER (Surveillance, Epidemiology, and End Results Program) National Cancer Institute 2020. Available at: https://seer.cancer.gov/statfacts/html/pancreas.html . Accessed on February 1, 2021.
Jemal A, Murray T, Samuels A, et al. Cancer statistics, 2003. CA Cancer J Clin 2003; 53:5–26.
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin 2019; 69:7–34.
Neoptolemos JP, Stocken DD, Friess H, et al. A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med 2004; 350:1200–1210.
Regine WF, Winter KA, Abrams RA, et al. Fluorouracil vs gemcitabine chemotherapy before and after fluorouracil-based chemoradiation following resection of pancreatic adenocarcinoma: a randomized controlled trial. JAMA 2008; 299:1019–1026.
Neoptolemos JP, Stocken DD, Bassi C, et al. Adjuvant chemotherapy with fluorouracil plus folinic acid vs gemcitabine following pancreatic cancer resection: a randomized controlled trial. JAMA 2010; 304:1073–1081.
Conroy T, Hammel P, Hebbar M, et al. FOLFIRINOX or gemcitabine as adjuvant therapy for pancreatic cancer. N Engl J Med 2018; 379:2395–2406.
Neoptolemos JP, Palmer DH, Ghaneh P, et al. 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 2017; 389:1011–1024.
Oettle H, Neuhaus P, Hochhaus A, et al. Adjuvant chemotherapy with gemcitabine and long-term outcomes among patients with resected pancreatic cancer: the CONKO-001 randomized trial. JAMA 2013; 310:1473–1481.
Partelli S, Tamburrino D, Cherif R, et al. Risk and predictors of postoperative morbidity and mortality after pancreaticoduodenectomy for pancreatic neuroendocrine neoplasms: a comparative study with pancreatic ductal adenocarcinoma. Pancreas 2019; 48:504–509.
Krautz C, Nimptsch U, Weber GF, et al. Effect of hospital volume on in-hospital morbidity and mortality following pancreatic surgery in Germany. Ann Surg 2018; 267:411–417.
Balzano G, Zerbi A, Capretti G, et al. Effect of hospital volume on outcome of pancreaticoduodenectomy in Italy. Br J Surg 2008; 95:357–362.
Sánchez-Velázquez P, Muller X, Malleo G, et al. Benchmarks in pancreatic surgery: a novel tool for unbiased outcome comparisons. Ann Surg 2019; 270:211–218.
Shapiro J, van Lanschot JJB, Hulshof MCCM, et al. Neoadjuvant chemoradiotherapy plus surgery versus surgery alone for oesophageal or junctional cancer (CROSS): long-term results of a randomised controlled trial. Lancet Oncol 2015; 16:1090–1098.
Al-Batran S-E, Homann N, Pauligk C, et al. Perioperative chemotherapy with fluorouracil plus leucovorin, oxaliplatin, and docetaxel versus fluorouracil or capecitabine plus cisplatin and epirubicin for locally advanced, resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4): a randomised, phase 2/3 trial. Lancet 2019; 393:1948–1957.
Cunningham D, Allum WH, Stenning SP, et al. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J of Med 2006; 355:11–20.
Bahadoer RR, Dijkstra EA, van Etten B, et al. Short-course radiotherapy followed by chemotherapy before total mesorectal excision (TME) versus preoperative chemoradiotherapy, TME, and optional adjuvant chemotherapy in locally advanced rectal cancer (RAPIDO): a randomised, open-label, phase 3 trial. Lancet Oncol 2021; 22:29–42.
Conroy T, Lamfichekh N, Etienne P-L, et al. Total neoadjuvant therapy with mFOLFIRINOX versus preoperative chemoradiation in patients with locally advanced rectal cancer: Final results of PRODIGE 23 phase III trial, a UNICANCER GI trial. J Clin Oncol 2020; 38:4007–14007.
Katz MHG. Alliance A021501: Preoperative mFOLFIRINOX or mFOLFIRINOX plus hypofractionated radiation therapy (RT) for borderline resectable (BR) adenocarcinoma of the pancreas. J Clin Oncol 2021.
Ghaneh P, Palmer DH, Cicconi S, et al. 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. J Clin Oncol 2020; 38:4505–14505.
Fietkau R, Grützmann R, Wittel UA, et al. R0 resection following chemo (radio)therapy improves survival of primary inoperable pancreatic cancer patients. Interim results of the German randomized CONKO-007± trial. Strahlenther Onkol 2021; 197:8–18.
Gemenetzis G, Groot VP, Blair AB, et al. Survival in locally advanced pancreatic cancer after neoadjuvant therapy and surgical resection. Ann Surg 2019; 270:340–347.
Versteijne E, Vogel JA, Besselink MG, et al. Meta-analysis comparing upfront surgery with neoadjuvant treatment in patients with resectable or borderline resectable pancreatic cancer. Br J Surg 2018; 105:946–958.
Heinrich S, Schäfer M, Weber A, et al. Neoadjuvant chemotherapy generates a significant tumor response in resectable pancreatic cancer without increasing morbidity: results of a prospective phase II trial. Ann Surg 2008; 248:1014–1022.
Casadei R, Di Marco M, Ricci C, et al. Neoadjuvant chemoradiotherapy and surgery versus surgery alone in resectable pancreatic cancer: a single-center prospective, randomized, controlled trial which failed to achieve accrual targets. J Gastrointest Surg 2015; 19:1802–1812.
Golcher H, Brunner TB, Witzigmann H, et al. 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 2015; 191:7–16.
Palmer DH, Stocken DD, Hewitt H, et al. A randomized phase 2 trial of neoadjuvant chemotherapy in resectable pancreatic cancer: gemcitabine alone versus gemcitabine combined with cisplatin. Ann Surg Oncol 2007; 14:2088–2096.
Versteijne E, Suker M, Groothuis K, et al. 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; 38:1763–1773.
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/JSAP05). Jpn J Clin Oncol 2019; 49:190–194.
Barbier L, Turrini O, Grégoire E, et al. Pancreatic head resectable adenocarcinoma: preoperative chemoradiation improves local control but does not affect survival. HPB (Oxford) 2011; 13:64–69.
Moutardier V, Turrini O, Huiart L, et al. A reappraisal of preoperative chemoradiation for localized pancreatic head ductal adenocarcinoma in a 5-year single-institution experience. J Gastrointest Surg 2004; 8:502–510.
Heinrich S, Pestalozzi B, Lesurtel M, et al. Adjuvant gemcitabine versus NEOadjuvant gemcitabine/oxaliplatin plus adjuvant gemcitabine in resectable pancreatic cancer: a randomized multicenter phase III study (NEOPAC study). BMC Cancer 2011; 11:346.
Pancreatic Adenocarcinoma. Available at: https://www.nccn.org/professionals/physician_gls/pdf/pancreatic.pdf. Available at: https://www.nccn.org/professionals/physician_gls/pdf/pancreatic.pdf . Accessed February 8th, 2021.
Dindo D, Demartines N, Clavien PA. Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg 2004; 240:205–213.
Clavien PA, Barkun J, de Oliveira ML, et al. The Clavien-Dindo classification of surgical complications: five-year experience. Ann Surg 2009; 250:187–196.
Slankamenac K, Nederlof N, Pessaux P, et al. The comprehensive complication index: a novel and more sensitive endpoint for assessing outcome and reducing sample size in randomized controlled trials. Ann Surg 2014; 260:757–762. discussion 762-3.
Bassi C, Marchegiani G, Dervenis C, et al. The 2016 update of the International Study Group (ISGPS) definition and grading of postoperative pancreatic fistula: 11 years after. Surgery 2017; 161:584–591.
Hartwig W, Werner J, Büchler MW. Prognosis of resected pancreatic cancer: is the refined resection margin status dispensable? Langenbecks Arch Surg 2012; 397:859–860.
Brookmeyer R, Crowley J. A confidence interval for the median survival time. Biometrics 1982; 38:29–41.
de Jong VMT, Moons KGM, Riley RD, et al. Individual participant data meta-analysis of intervention studies with time-to-event outcomes: A review of the methodology and an applied example. Res Synth Methods 2020; 11:148–168.
Riley RD, Lambert PC, Abo-Zaid G. Meta-analysis of individual participant data: rationale, conduct, and reporting. BMJ 2010; 340:c221.
Cox DR. Regression models and life-tables. J Royal Stat Soc B 1972; 34:187–202.
(2020) RCT. A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. Available at: https://www.R-project.org/ .
2010; Viechtbauer W. Conducting Meta-Analyses in R with the metafor Package. 36:1–48.
World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. JAMA 2013; 310:2191–2194.
Pierre-Alain Clavien MGS, Yuman Fong, Masaru Miyazaki. Atlas of Upper Gastrointestinal and Hepato-Pancreato-Biliary: Springer, 20. October 2015.
Fokas E, Eccles C, Patel N, et al. A treatment planning comparison of four target volume contouring guidelines for locally advanced pancreatic cancer radiotherapy. Radiother Oncol 2013; 107:200–206.
Sivendran S, Latif A, McBride RB, et al. Adverse event reporting in cancer clinical trial publications. J Clin Oncol 2014; 32:83–89.
Staiger RD, Cimino M, Javed A, et al. The Comprehensive Complication Index (CCI) is a novel cost assessment tool for surgical procedures. Ann Surg 2018; 268:784–791.
Evans DB, Varadhachary GR, Crane CH, et al. Preoperative gemcitabine-based chemoradiation for patients with resectable adenocarcinoma of the pancreatic head. J Clin Oncol 2008; 26:3496–3502.
Reni M, Balzano G, Zanon S, et al. Safety and efficacy of preoperative or postoperative chemotherapy for resectable pancreatic adenocarcinoma (PACT-15): a randomised, open-label, phase 2-3 trial. Lancet Gastroenterol Hepatol 2018; 3:413–423.
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; 35:515–522.
Ahmad SA, Duong M, Sohal DPS, et al. 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 Surg 2020; 272:481–486.
Clavien PA, Puhan MA. Biased reporting in surgery. Br J Surg 2014; 101:591–592.
Djurisic S, Rath A, Gaber S, et al. Barriers to the conduct of randomised clinical trials within all disease areas. TRIALS 2017; 18:360.
Sequential Use of Nab-paclitaxel Plus Gemcitabine and mFOLFIRINOX as Neoadjuvant Chemotherapy for Resectable Pancreatic Cancer: A Randomized Control Study June 2021, 2018. Available at: https://clinicaltrials.gov/ct2/show/study/NCT03750669?term=neoadjuvant+FOLFIRINOX+pancreatic+cancer&recrs=abd&draw=3&rank=12 .
Ettrich TJ, Berger AW, Perkhofer L, et al. Neoadjuvant plus adjuvant or only adjuvant nab-paclitaxel plus gemcitabine for resectable pancreatic cancer—the NEONAX trial (AIO-PAK-0313), a prospective, randomized, controlled, phase II study of the AIO pancreatic cancer group. BMC Cancer 2018; 18:1298.
Labori KJ, Lassen K, Hoem D, et al. Neoadjuvant chemotherapy versus surgery first for resectable pancreatic cancer (Norwegian Pancreatic Cancer Trial - 1 (NorPACT-1)) - study protocol for a national multicentre randomized controlled trial. BMC Surg 2017; 17:94.
Schwarz L, Vernerey D, Bachet JB, et al. Resectable pancreatic adenocarcinoma neo-adjuvant FOLF(IRIN)OX-based chemotherapy - a multicenter, non-comparative, randomized, phase II trial (PANACHE01-PRODIGE48 study). BMC Cancer 2018; 18:762.
A Phase III Trial of Perioperative Versus Adjuvant Chemotherapy for Resectable Pancreatic Cancer June 2021, 2020. Available at: https://clinicaltrials.gov/ct2/show/study/NCT04340141 .
Neoptolemos JP, Dunn JA, Stocken DD, et al. Adjuvant chemoradiotherapy and chemotherapy in resectable pancreatic cancer: a randomised controlled trial. Lancet 2001; 358:1576–1585.
Janssen QP, van Dam JL, Bonsing BA, et al. Total neoadjuvant FOLFIRINOX versus neoadjuvant gemcitabine-based chemoradiotherapy and adjuvant gemcitabine for resectable and borderline resectable pancreatic cancer (PREOPANC-2 trial): study protocol for a nationwide multicenter randomized controlled trial. BMC Cancer 2021; 21:300.