Randomized Phase 2 Study Comparing Pathological Responses of Resected Colorectal Cancer Metastases after Bevacizumab with mFOLFOX6 or FOLFIRI (BEV-ONCO Trial).
bevacizumab; chemotherapy; colorectal liver metastases; histological growth pattern; pathological response; tumoral homogeneity; Oncology; Cancer Research
Abstract :
[en] Retrospective studies reported that preoperative oxaliplatin-based chemotherapy increased pathological response (PR) in patients resected for colorectal liver metastases (CRLM). This multicenter prospective randomized (1/1) phase II trial evaluated PR on resected CRLM after preoperative mFOLFOX6 (arm A) or FOLFIRI (arm B) + bevacizumab. The primary endpoint was the major pathological response rate (MPRR), defined as the percentage of patients presenting CRLMs with mean tumor regression grade (TRG) < 3. Secondary endpoints included safety, progression-free survival (PFS) and overall survival (OS). Out of 65 patients, 57 patients (28 and 29 in arm A/B) were resected for CRLM (one patient with lung metastases). Clinical and treatment characteristics were similar in both arms. One-month postoperative complications were 39.3%/31.0% in arm A/B (p = 0.585). MPRR and complete PR were 32.1%/20.7% (p = 0.379) and 14.3%/0.0% (p = 0.052) in arm A/B, respectively. PFS and OS were not different. Patients with PR among all CRLMs (max TRG ≤ 3; 43.8% of patients) had a lower risk of relapse (PFS: HR = 0.41, 95%CI = 0.204−0.840, p = 0.015) and a tendency towards better survival (OS: HR = 0.34, 95%CI = 0.104−1.114, p = 0.075). The homogeneity of PR was associated with improved PFS/OS. This trial fails to demonstrate a significant increase in MPRR in patients treated with mFOLFOX6-bevacizumab but confirms PR as an important prognostic factor.
Disciplines :
Oncology
Author, co-author :
Baldin, Pamela; Pathology Department, Cliniques Universitaires Saint Luc (UCL)-Université Catholique de Louvain, 1200 Bruxelles, Belgium
Carrasco, Javier; Department of Medical Oncology, GHdC-Grad Hopital de Charleroi-Site Notre Dame, 6000 Charleroi, Belgium
Beniuga, Gabriela; Pathology Department, Institut de Pathologie et Génétique, 6041 Gosselies, Belgium
Jouret-Mourin, Anne; Pathology Department, Cliniques Universitaires Saint Luc (UCL)-Université Catholique de Louvain, 1200 Bruxelles, Belgium ; Pathology Department, Institut de Pathologie et Génétique, 6041 Gosselies, Belgium
Demolin, Gauthier ; Université de Liège - ULiège > Département des sciences cliniques
Delos, Monique; Pathology Department, CHU-UCL-Namur, Site Godinne, 5530 Yvoir, Belgium
Castella, Marie-Laure; Colorectal Clinical Research Unit, Institut Roi Albert II, Cliniques Universitaires Saint Luc (UCL)-Université Catholique de Louvain, 1200 Bruxelles, Belgium
van Maanen, Aline ; Support Statistique, Institut Roi Albert II, Cliniques Universitaires Saint Luc (UCL)-Université Catholique de Louvain, 1200 Bruxelles, Belgium
Van den Eynde, Marc ; Department of Medical Oncology and Gastroenterology, Cliniques Universitaires Saint Luc (UCL)-Université Catholique de Louvain, 1200 Bruxelles, Belgium
Randomized Phase 2 Study Comparing Pathological Responses of Resected Colorectal Cancer Metastases after Bevacizumab with mFOLFOX6 or FOLFIRI (BEV-ONCO Trial).
Funding: We received a restricted research grant from ROCHE (NV Roche SA, Rue Dantestraat 75, 1070 Brussels Belgium) to conduct this study (funding number Ro 4876646, ML28669, BEV-ONCO2012). The funder had no role in the study design; in the collection, analysis or interpretation of data; in the writing of the manuscript and the decision to submit this article for publication.
scite shows how a scientific paper has been cited by providing the context of the citation, a classification describing whether it supports, mentions, or contrasts the cited claim, and a label indicating in which section the citation was made.
Bibliography
Araghi, M.; Soerjomataram, I.; Bardot, A.; Ferlay, J.; Cabasag, C.J.; Morrison, D.S.; De, P.; Tervonen, H.; Walsh, P.M.; Bucher, O.; et al. Changes in colorectal cancer incidence in seven high-income countries: A population-based study. Lancet Gastroenterol. Hepatol. 2019, 4, 511–518. [CrossRef]
Viganò, L.; Russolillo, N.; Ferrero, A.; Langella, S.; Sperti, E.; Capussotti, L. Evolution of long-term outcome of liver resection for colorectal metastases: Analysis of actual 5-year survival rates over two decades. Ann. Surg. Oncol. 2012, 19, 2035–2044. [CrossRef] [PubMed]
Van Cutsem, E.; Cervantes, A.; Adam, R.; Sobrero, A.; Van Krieken, J.H.; Aderka, D.; Aguilar, E.A.; Bardelli, A.; Benson, A.; Bodoky, G.; et al. ESMO consensus guidelines for the management of patients with metastatic colorectal cancer. Ann. Oncol. 2016, 27, 1386–1422. [CrossRef] [PubMed]
Nordlinger, B.; Sorbye, H.; Glimelius, B.; Poston, G.J.; Schlag, P.M.; Rougier, P.; Bechstein, W.O.; Primrose, J.N.; Walpole, E.T.; Finch-Jones, M.; et al. Perioperative FOLFOX4 chemotherapy and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC 40983): Long-term results of a randomised, controlled, phase 3 trial. Lancet Oncol. 2013, 14, 1208–1215. [CrossRef]
Bridgewater, J.A.; Pugh, S.A.; Maishman, T.; Eminton, Z.; Mellor, J.; Whitehead, A.; Stanton, L.; Radford, M.; Corkhill, A.; Griffiths, G.O.; et al. Systemic chemotherapy with or without cetuximab in patients with resectable colorectal liver metastasis (New EPOC): Long-term results of a multicentre, randomised, controlled, phase 3 trial. Lancet Oncol. 2020, 21, 398–411. [CrossRef]
Folprecht, G.; Gruenberger, T.; Bechstein, W.; Raa, H.R.; Lordick, F.; Hartmann, J.T.; Lang, H.; Frilling, A.; Stoehlmacher, J.; Weitz, J.; et al. Tumour response and secondary resectability of colorectal liver metastases following neoadjuvant chemotherapy with cetuximab: The CELIM randomised phase 2 trial. Lancet Oncol. 2010, 11, 38–47. [CrossRef]
Gruenberger, B.; Tamandl, D.; Schueller, J.; Scheithauer, W.; Zielinski, C.; Herbst, F.; Gruenberger, T. Bevacizumab, capecitabine, and oxaliplatin as neoadjuvant therapy for patients with potentially curable metastatic colorectal cancer. J. Clin. Oncol. 2008, 26, 1830–1835. [CrossRef]
Wong, R.; Cunningham, D.; Barbachano, Y.; Saffery, C.; Valle, J.; Hickish, T.; Mudan, S.; Brown, G.; Khan, A.; Wotherspoon, A.; et al. A multicentre study of capecitabine, oxaliplatin plus bevacizumab as perioperative treatment of patients with poor-risk colorectal liver-only metastases not selected for upfront resection. Ann. Oncol. 2011, 22, 2042–2048. [CrossRef]
Gruenberger, T.; Bridgewater, J.; Chau, I.; Alfonso, P.G.; Rivoire, M.; Mudan, S.; Lasserre, S.; Hermann, F.; Waterkamp, D.; Adam, R. Bevacizumab plus mFOLFOX-6 or FOLFOXIRI in patients with initially unresectable liver metastases from colorectal cancer: The OLIVIA multinational randomised phase II trial. Ann. Oncol. 2015, 26, 702–708. [CrossRef]
Smith, M.D.; McCall, J.L. Systematic review of tumour number and outcome after radical treatment of colorectal liver metastases. Br. J. Surg. 2009, 96, 1101–1113. [CrossRef]
Andreou, A.; Aloia, T.A.; Brouquet, A.; Dickson, P.V.; Zimmitti, G.; Maru, D.M.; Kopetz, S.; Loyer, E.M.; Curtley, S.A.; Abdalla, E.K.; et al. Margin status remains an important determinant of survival after surgical resection of colo-rectal liver metastases in the era of modern chemotherapy. Ann. Surg. 2013, 257, 1079–1088. [CrossRef]
Rubbia-Brandt, L.; Giostra, E.; Brezault, C.; Roth, A.D.; Autard, V.; Santoretti, P.; Dousset, B.; Majno, P.E.; Soubrane, O.; Chaussade, S.; et al. Importance of histo-logical tumor response assessment in predicting the outcome in patients with colorectal liver metastases treated with neo-adjuvant chemotherapy followed by liver surgery. Ann. Oncol. 2007, 18, 299–304. [CrossRef]
Carrasco, J.; Gizzi, M.; Pairet, G.; Lannoy, V.; Lefesvre, P.; Gigot, J.-F.; Hubert, C.; Jouret-Mourin, A.; Humblet, Y.; Canon, J.; et al. Pathological responses after angiogenesis or EGFR inhibitors in metastatic colorectal cancer depend on the chemotherapy backbone. Br. J. Cancer 2015, 113, 1298–1304. [CrossRef]
Blazer, D.G.; Kishi, Y.; Maru, D.M.; Kopetz, S.; Chun, Y.S.; Overman, M.J.; Fogelman, D.; Eng, C.; Chang, D.Z.; Wang, H.; et al. Pathologic response to preoperative chemotherapy: A new outcome end point after resection of hepatic colorectal metastases. J. Clin. Oncol. 2008, 26, 5344–5351. [CrossRef]
Jácome, A.; Oliveira, F.; Lino, F.; Lima, J.P.S.N. Effect of adding bevacizumab to chemotherapy on pathologic response to preoperative systemic therapy for resectable colorectal liver metastases: A systematic review and meta-analysis. Clin. Colorectal. Cancer 2021, 20, 265–272. [CrossRef]
Eefsen, R.L.; Van den Eynden, G.G.; Høyer-Hansen, G.; Brodt, P.; Laerum, O.D.; Vermeulen, P.B.; Christensen, J.; Wettergren, A.; Federspiel, B.; Willemoe, G.L.; et al. Histopathological growth pattern, proteolysis and angiogenesis in chemonaive patients resected for multiple colorectal liver metastases. J. Oncol. 2012, 2012, 907971. [CrossRef]
van Dam, P.J.; van der Stok, E.P.; Teuwen, L.A.; Van den Eynden, G.G.; Illemann, M.; Frentzas, S.; Majeed, A.W.; Eefsen, R.L.; van den Braak, R.R.J.G.; Lazaris, A.; et al. International consensus guidelines for scoring the histopathological growth patterns of liver metastasis. Br. J. Cancer. 2017, 117, 1427. [CrossRef]
Tsilimigras, D.I.; Ntanasis-Stathopoulos, I.; Bagante, F.; Moris, D.; Cloyd, J.; Spartalis, E.; Pawlik, T.M. Clinica l significance and prognostic relevance of KRAS, BRAF, PI3K and TP53 genetic mutation analysis for resectable and unresectable colorectal liver metastases: A systematic review of the current evidence. Surg. Oncol. 2018, 27, 280–288. [CrossRef]
Viganò, L.; Capussotti, L.; De Rosa, G.; De Sassure, W.O.; Mentha, G.; Rubbia-Brandt, L. Liver resection for colorectal metastases after chemotherapy: Impact of chemotherapy-related liver injuries, pathological tumor response, and micro-metastases on long-term survival. Ann. Surg. 2013, 258, 731–740. [CrossRef]
Baldin, P.; Van den Eynde, M.; Mlecnik, B.; Bindea, G.; Beniuga, G.; Carrasco, J.; Haicheur, N.; Marliot, F.; Lafontaine, L.; Fredriksen, T.; et al. Prognostic assessment of resected colorectal liver metastases integrating pathological features, RAS mutation and Immunoscore. J. Pathol. Clin. Res. 2021, 7, 27–41. [CrossRef]
Van den Eynde, M.; Mlecnik, B.; Bindea, G.; Fredriksen, T.; Church, S.E.; Lafontaine, L.; Haicheur, N.; Marliot, F.; Angelova, M.; Vasaturo, A.; et al. The Link between the Multiverse of Immune Microenvironments in Metastases and the Survival of Colorectal Cancer Patients. Cancer Cell 2018, 34, 1012–1026.e3. [CrossRef] [PubMed]
Mlecnik, B.; Van den Eynde, M.; Bindea, G.; Church, S.E.; Vasaturo, A.; Fredriksen, T.; Lafontaine, L.; Haicheur, N.; Marliot, F.; Debetancourt, D.; et al. Comprehensive Intrametastatic Immune Quantification and Major Impact of Immunoscore on Survival. J. Natl. Cancer Inst. 2018, 110, 97–108. [CrossRef] [PubMed]
Nagtegaal, I.D.; Odze, R.D.; Klimstra, D.; Paradis, V.; Rugge, M.; Schirmacher, P.; Washington, K.M.; Carneiro, F.; Cree, I.A. WHO Classification of Tumors of the Digestive System, 5th ed.; International Agency for Research on Cancer (IARC): Lyon, France, 2019.
Eefsen, R.L.; Vermeulen, P.B.; Christensen, I.J.; Laerum, O.D.; Mogensen, M.B.; Rolff, H.C.; Van den Eynden, G.G.; Høyer-Hansen, G.; Osterlind, K.; Vainer, B.; et al. Growth pattern of colorectal liver metastasis as a marker of recurrence risk. Clin. Exp. Metastasis 2015, 32, 369–381. [CrossRef] [PubMed]
Rubbia-Brandt, L.; Audard, V.; Sartoretti, P.; Roth, A.D.; Brezault, C.; Le Charpentier, M.; Dousset, B.; Morel, P.; Soubrane, O.; Chaussade, S.; et al. Severe hepatic sinusoidal obstruction associated with oxaliplatin-based chemotherapy in patients with metastatic colorectal cancer. Ann. Oncol. 2004, 15, 460–466. [CrossRef]
Wanless, I.R. Micronodular transformation (nodular regenerative hyperplasia) of the liver: A report of 64 cases among 2500 autopsies and a new classification of benign hepatocellular nodules. Hepatology 1990, 11, 787–797. [CrossRef]
Chalasani, N.; Younossi, Z.; Lavine, J.E.; Charlton, M.; Cusi, K.; Rinella, M.; Harrison, S.A.; Brunt, E.M.; Sanyal, A.J. The diagnosis and management of nonalcoholic fatty liver disease: Practice guidance from the American Association for the Study of Liver Diseases. Hepatology 2018, 67, 328–357. [CrossRef]
Kesmodel, S.B.; Ellis, L.M.; Lin, E.; Chang, G.J.; Abdalla, E.K.; Kopetz, S.; Vauthey, J.N.; Rodriguez-Bigas, M.A.; Curley, S.A.; Feig, B.W. Preoperative bevacizumab does not significantly increase postoperative complication rates in patients undergoing hepatic surgery for colorectal cancer liver metastases. J. Clin. Oncol. 2008, 26, 5254–5260. [CrossRef]
Baldin, P.; Van den Eynde, M.; Hubert, C.; Jouret-Mourin, A.; Komuta, M. The role of the pathologist and clinical implications in colorectal liver metastasis. Acta Gastroenterol. Belg. 2018, 81, 419–426.
Linnekamp, J.F.; Wang, X.; Medema, J.P.; Vermeulen, L. Colorectal cancer heterogeneity and targeted therapy: A case for molecular disease subtypes. Cancer Res. 2015, 75, 245–249. [CrossRef]
Angelova, M.; Mlecnik, B.; Vasaturo, A.; Bindea, G.; Fredriksen, T.; Lafontaine, L.; Buttard, B.; Morgand, E.; Bruni, D.; Jouret-Mourin, A.; et al. Evolution of Metastases in Space and Time under Immune Selection. Cell 2018, 175, 751–765.e16. [CrossRef]
Bullman, S.; Pedamallu, C.S.; Sicinska, E.; Clancy, T.E.; Zhang, X.; Cai, D.; Nuberg, D.; Huang, K.; Guevara, F.; Nelson, T.; et al. Analysis of Fusobacterium persistence and antibiotic response in colorectal cancer. Science 2017, 358, 1443–1448. [CrossRef]
Marongiu, L.; Landry, J.J.M.; Rausch, T.; Abba, M.L.; Delecluse, S.; Delecluse, H.J.; Allgayer, H. Metagenomic analysis of primary colorectal carcinomas and their metastases identifies potential microbial risk factors. Mol. Oncol. 2021, 15, 3363–3384. [CrossRef]
Sabbagh, C.; Chatelain, D.; Attencourt, C.; Joly, J.P.; Chauffert, B.; Cosse, C.; Regibeau, J.M. Impact of homogeneous pathologic response to preoperative chemotherapy in patients with multiple colorectal liver metastases. World J. Gastroenterol. 2017, 23, 8027–8034. [CrossRef]
Pietrantonio, F.; Mazzaferro, V.; Miceli, R.; Cotsoglou, C.; Melotti, F.; Fanetti, G.; Perrone, F.; Biondani, P.; Muscarà, C.; Di Bartolomeo, M.; et al. Pathological response after neoadjuvant bevacizumab-or cetuximab-based chemotherapy in resected colorectal cancer liver metastases. Med. Oncol. 2015, 32, 182. [CrossRef]
Hubert, C.; Sempoux, C.; Humblet, Y.; van den Eynde, M.; Zech, F.; Leclercq, I.; Gigot, J.F. Sinusoidal obstruction syndrome (SOS) related to chemotherapy for colorectal liver metastases: Factors predictive of severe SOS lesions and protective effect of bevacizumab. HPB 2013, 15, 858–864. [CrossRef]
Klinger, M.; Eipeldauer, S.; Hacker, S.; Herberger, B.; Tamandl, D.; Dorfmeister, M.; Koelblinger, C.; Gruenberger, B.; Gruen-berger, T. Bevacizumab protects against sinusoidal obstruction syndrome and does not increase response rate in neoadjuvant XELOX/FOLFOX therapy of colorectal cancer liver metastases. Eur. J. Surg. Oncol. 2009, 35, 515–520. [CrossRef]
Khan, A.Z.; Morris-Stiff, G.; Makuuchi, M. Patterns of chemotherapy-induced hepatic injury and their implications for patients undergoing liver resection for colorectal liver metastases. J. Hepatobiliary Pancreat. Surg. 2009, 16, 137–144. [CrossRef]
Ryan, P.; Nanji, S.; Pollett, A.; Moore, M.; Moulton, C.A.; Gallinger, S.; Guindi, M. Chemotherapy-induced liver injury in metastatic colorectal cancer: Semiquantitative histologic analysis of 334 resected liver specimens shows that vascular injury but not steatohepatitis is associated with preoperative chemotherapy. Am. J. Surg. Pathol. 2010, 34, 784–789. [CrossRef]
Brouquet, A.; Benoist, S.; Julie, C.; Penna, C.; Beauchet, A.; Rougier, P.; Nordlinger, B. Risk factors for chemotherapy-associated liver injuries: A multivariate analysis of a group of 146 patients with colorectal metastases. Surgery 2009, 145, 362–371. [CrossRef]
Similar publications
Sorry the service is unavailable at the moment. Please try again later.
This website uses cookies to improve user experience. Read more
Save & Close
Accept all
Decline all
Show detailsHide details
Cookie declaration
About cookies
Strictly necessary
Performance
Strictly necessary cookies allow core website functionality such as user login and account management. The website cannot be used properly without strictly necessary cookies.
This cookie is used by Cookie-Script.com service to remember visitor cookie consent preferences. It is necessary for Cookie-Script.com cookie banner to work properly.
Performance cookies are used to see how visitors use the website, eg. analytics cookies. Those cookies cannot be used to directly identify a certain visitor.
Used to store the attribution information, the referrer initially used to visit the website
Cookies are small text files that are placed on your computer by websites that you visit. Websites use cookies to help users navigate efficiently and perform certain functions. Cookies that are required for the website to operate properly are allowed to be set without your permission. All other cookies need to be approved before they can be set in the browser.
You can change your consent to cookie usage at any time on our Privacy Policy page.
