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Commentary: Neoadjuvant treatment of resectable pancreatic cancer: Lack of level III evidence

2020; Elsevier BV; Volume: 168; Issue: 6 Linguagem: Inglês

10.1016/j.surg.2020.07.033

1532-7361

Martin Schneider, John P. Neoptolemos, Markus W. Büchler,

Colorectal and Anal Carcinomas

State-of-the-art management of malignant disease should rely on solid supporting evidence. The oncosurgical management of pancreatic cancer has, in this context, dramatically changed since the first major randomized trial published in 2001 by the European Study Group for Pancreatic Cancer (ESPAC) stimulated further improvements in adjuvant therapy for resectable cancer. 1 Neoptolemos J.P. Dunn J.A. Stocken D.D. et al. and the European Study Group for Pancreatic CancerAdjuvant chemoradiotherapy and chemotherapy in resectable pancreatic cancer: a randomised controlled trial. Lancet. 2001; 358: 1576-1585 Abstract Full Text Full Text PDF PubMed Scopus (836) Google Scholar , 2 Neoptolemos J.P. Stocken D.D. Friess H. et al. and the European Study Group for Pancreatic CancerA randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Eng J Med. 2004; 350: 1200-1210 Crossref PubMed Scopus (2008) Google Scholar , 3 Neoptolemos J.P. Stocken D.D. Tudur Smith C. et al. Adjuvant 5-fluorouracil and folinic acid vs observation for pancreatic cancer: composite data from the ESPAC-1 and -3(v1) trials. Br J Cancer. 2009; 100: 246-250 Crossref PubMed Scopus (152) Google Scholar , 4 Neoptolemos J.P. Stocken D.D. Bassi C. et al. and the European Study Group for Pancreatic CancerAdjuvant chemotherapy with fluorouracil plus folinic acid vs gemcitabine following pancreatic cancer resection: a randomized controlled trial. JAMA. 2010; 304: 1073-1081 Crossref PubMed Scopus (940) Google Scholar , 5 Liao W.C. Chien K.L. Lin Y.L. et al. Adjuvant treatments for resected pancreatic adenocarcinoma: a systematic review and network meta-analysis. Lancet Oncol. 2013; 14: 1095-1103 Abstract Full Text Full Text PDF PubMed Scopus (159) Google Scholar , 6 Valle J.W. Palmer D. Jackson R. et al. Optimal duration and timing of adjuvant chemotherapy after definitive surgery for ductal adenocarcinoma of the pancreas: ongoing lessons from the ESPAC-3 study. J Clin Oncol. 2014; 32: 504-512 Crossref PubMed Scopus (216) Google Scholar , 7 Neoptolemos J.P. Palmer D.H. Ghaneh P. et al. and the European Study Group for Pancreatic CancerComparison 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 Abstract Full Text Full Text PDF PubMed Scopus (816) Google Scholar , 8 Conroy T. Hammel P. Hebbar M. et al. and the Canadian Cancer Trials Group and the Unicancer-GI-PRODIGE GroupFOLFIRINOX or gemcitabine as adjuvant therapy for pancreatic cancer. N Engl J Med. 2018; 379: 2395-2406 Crossref PubMed Scopus (689) Google Scholar The ESPAC-1 trial was the first large, randomized trial to show a statistically significant survival benefit for the use of adjuvant chemotherapy with 5-fluorouracil (5FU) and folinic acid after pancreatic cancer resection while also demonstrating that adjuvant chemoradiotherapy did not prolong survival. 1 Neoptolemos J.P. Dunn J.A. Stocken D.D. et al. and the European Study Group for Pancreatic CancerAdjuvant chemoradiotherapy and chemotherapy in resectable pancreatic cancer: a randomised controlled trial. Lancet. 2001; 358: 1576-1585 Abstract Full Text Full Text PDF PubMed Scopus (836) Google Scholar , 2 Neoptolemos J.P. Stocken D.D. Friess H. et al. and the European Study Group for Pancreatic CancerA randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Eng J Med. 2004; 350: 1200-1210 Crossref PubMed Scopus (2008) Google Scholar , 3 Neoptolemos J.P. Stocken D.D. Tudur Smith C. et al. Adjuvant 5-fluorouracil and folinic acid vs observation for pancreatic cancer: composite data from the ESPAC-1 and -3(v1) trials. Br J Cancer. 2009; 100: 246-250 Crossref PubMed Scopus (152) Google Scholar The ESPAC-3 trial in 2010 showed that adjuvant monotherapy with gemcitabine was not superior to 5FU and folinic acid with regard to survival but was less toxic. 4 Neoptolemos J.P. Stocken D.D. Bassi C. et al. and the European Study Group for Pancreatic CancerAdjuvant chemotherapy with fluorouracil plus folinic acid vs gemcitabine following pancreatic cancer resection: a randomized controlled trial. JAMA. 2010; 304: 1073-1081 Crossref PubMed Scopus (940) Google Scholar Further analysis from ESPAC-3 demonstrated that delaying the start of adjuvant chemotherapy did not influence survival while completing all 6 cycles (6 months of adjuvant chemotherapy) improved survival dramatically compared with completing fewer cycles. 6 Valle J.W. Palmer D. Jackson R. et al. Optimal duration and timing of adjuvant chemotherapy after definitive surgery for ductal adenocarcinoma of the pancreas: ongoing lessons from the ESPAC-3 study. J Clin Oncol. 2014; 32: 504-512 Crossref PubMed Scopus (216) Google Scholar In 2013, network meta-analysis of adjuvant treatments for resected pancreatic adenocarcinoma concluded that chemotherapy with 5FU or gemcitabine was the optimum adjuvant treatment for pancreatic cancer and decreased mortality after resection by about a third, while chemoradiation plus chemotherapy was less effective in prolonging survival and was more toxic than chemotherapy alone. 5 Liao W.C. Chien K.L. Lin Y.L. et al. Adjuvant treatments for resected pancreatic adenocarcinoma: a systematic review and network meta-analysis. Lancet Oncol. 2013; 14: 1095-1103 Abstract Full Text Full Text PDF PubMed Scopus (159) Google Scholar In 2017, the ESPAC-4 trial demonstrated that adjuvant chemotherapy with a combination of gemcitabine with capecitabine was even more effective than either gemcitabine or 5FU with folinic acid, increasing 5-year survival rates from 8% with resection alone to nearly 30% with gemcitabine with capecitabine. 7 Neoptolemos J.P. Palmer D.H. Ghaneh P. et al. and the European Study Group for Pancreatic CancerComparison 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 Abstract Full Text Full Text PDF PubMed Scopus (816) Google Scholar The PRODIGE 24–ACCORD 24/0610-CCTG PA-6 trial showed that in selected patients able to tolerate the modified FOLFIRINOX treatment (folinic acid, 5FU, irinotecan, and oxaliplatin), the 5-year survival could be pushed up to approaching 50%. 8 Conroy T. Hammel P. Hebbar M. et al. and the Canadian Cancer Trials Group and the Unicancer-GI-PRODIGE GroupFOLFIRINOX or gemcitabine as adjuvant therapy for pancreatic cancer. N Engl J Med. 2018; 379: 2395-2406 Crossref PubMed Scopus (689) Google Scholar