Abstract
Background
Eight years have passed since the introduction of chemotherapy (chemo) and targeted therapy regimens for colorectal liver metastases (CRLM). This study aimed to clarify the effectiveness of chemo and targeted therapy in facilitating conversion hepatectomy and improving long-term survival in Japanese patients with CRLM.
Methods
A total of 199 patients with CRLM were treated between May 2005 and August 2012. Initial therapies for these patients included straightforward hepatic resection (n = 48; 24 %), induction chemotherapy (n = 148; 74 %), and radiofrequency ablation (n = 3; 2 %).
Results
In 56 of 137 patients (40.1 %) with initially unresectable CRLM, 7.5 courses of chemo and targeted therapy downsized and converted tumors to resectable tumors. The 5-year cumulative overall survival (OS) rate and the median survival time were significantly higher for the resectable CRLM than for the unresectable CRLM (54.6 vs. 5.3 % and 77.3 vs. 21.3 months, respectively; P < .0001). Multivariate analysis revealed that conversion hepatectomy (hazard ratio [HR] 0.19; P < .001) and responder to chemo and targeted therapy (HR 0.46; P < .01) were independent prognostic factors for OS. Multivariate analysis also revealed that left-sided colon or rectal cancer (odds ratio [OR] 8.4; P < .05), H1/H2 metastases (OR 7.3; P < .05), no extrahepatic metastases (OR 52.6; P < .001), and responder to chemo and targeted therapy (OR 6.1; P < .05) were significant predictors of conversion hepatectomy.
Conclusions
A chemo and targeted therapy can facilitate conversion hepatectomy and allow for an excellent prognosis in patients with initially unresectable CRLM.
Similar content being viewed by others
References
Scheele J, Stang R, Altendorf-Hofmann A, Paul M. Resection of colorectal liver metastases. World J Surg. 1995;19:59–71.
Bismuth H, Adam R, Levi F, Farabos C, Waechter F, Castaing D, et al. Resection of nonresectable liver metastases from colorectal cancer after neoadjuvant chemotherapy. Ann Surg. 1996;224:509–22.
Nordlinger B, van Cutsem E, Gruenberger T, Glimelius B, Poston G, Rougier P, et al. Combination of surgery and chemotherapy and the role of targeted agents in the treatment of patients with colorectal liver metastases: recommendations from an expert panel. Ann Oncol. 2009;20:985–92.
Poston GJ, Adam R, Alberts S, Curley S, Figueras J, Haller D, et al. OncoSurge: a strategy for improving resectability with curative intent in metastatic colorectal cancer. J Clin Oncol. 2005;23:7125–34.
Uehara K, Ishiguro S, Hiramatsu K, Nishio H, Takeuchi E, Takahari D, et al. Conversion chemotherapy using cetuximab plus FOLFIRI followed by bevacizumab plus mFOLFOX6 in patients with unresectable liver metastases from colorectal cancer. Jpn J Clin Oncol. 2011;41:1229–32.
Weiss L, Grundmann E, Torhorst J, Hartveit F, Moberg I, Eder M, et al. Haematogenous metastatic patterns in colonic carcinoma: an analysis of 1541 necropsies. J Pathol. 1986;150:195–203.
Kopetz S, Chang GJ, Overman MJ, Eng C, Sargent DJ, Larson DW, et al. Improved survival in metastatic colorectal cancer is associated with adoption of hepatic resection and improved chemotherapy. J Clin Oncol. 2009;27:3677–83.
Beppu T, Hayashi N, Masuda T, Komori H, Horino K, Hayashi H, et al. FOLFOX enables high resectability and excellent prognosis for initially unresectable colorectal liver metastases. Anticancer Res. 2010;30:1015–20.
Adam R, Delvart V, Pascal G, Valeanu A, Castaing D, Azoulay D, et al. Rescue surgery for unresectable colorectal liver metastases downstaged by chemotherapy: A model to predict long-term survival. Ann Surg. 2004;240:644–57.
Masi G, Loupakis F, Pollina L, Vasile E, Cupini S, Ricci S, et al. Long-term outcome of initially unresectable metastatic colorectal cancer patients treated with 5-fluorouracil/leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) followed by radical surgery of metastases. Ann Surg. 2009;249:420–5.
Adam R, Wicherts DA, de Haas RJ, Ciacio O, Lévi F, Paule B, et al. Patients with initially unresectable colorectal liver metastases: is there a possibility of cure? J Clin Oncol. 2009;27:1829–35.
Lam VW, Spiro C, Laurence JM, Johnston E, Hollands MJ, Pleass HC, Richardson AJ. A systematic review of clinical response and survival outcomes of downsizing systemic chemotherapy and rescue liver surgery in patients with initially unresectable colorectal liver metastases. Ann Surg Oncol. 2012;19:1292–301.
Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004;350:2335–42.
Tournigand C, Andre T, Achille E, Lledo G, Flesh M, Mery-Mignard D, et al. FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: randomized GERCOR study. J Clin Oncol. 2004;22:229–37.
Van Cutsem E, Kohne C-H, Hitre E, Zaluski J, Chang Chien CR, Makhson A, et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med. 2009;360:1408–17.
Watanabe T, Itabashi M, Shimada Y, Tanaka S, Ito Y, Ajioka Y, et al. Japanese Society for Cancer of the Colon and Rectum (JSCCR) guidelines 2010 for the treatment of colorectal cancer. Int J Clin Oncol. 2012;17:1–29.
Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst. 2000;92:205–16.
Sakamoto Y, Beppu T, Miyamoto Y, Okabe H, Ida S, Imai K, et al. Feasibility and short-term outcome of adjuvant FOLFOX after resection of colorectal liver metastases. J Hepatobiliary Pancreat Sci. 2013;20:307–12.
Mima K, Beppu T, Chikamoto A, Miyamoto Y, Nakagawa S, Kuroki H, et al. Hepatic resection combined with radiofrequency ablation for initially unresectable colorectal liver metastases after effective chemotherapy is a safe procedure with a low incidence of local recurrence. Int J Clin Oncol. 2013;18:847–55.
Beppu T, Ishiko T, Chikamoto A, Komori H, Masuda T, Hayashi H, et al. Liver hanging maneuver decrease blood loss and operative time in a right-side hepatectomy. Hepatogastroenterology. 2012;59:542–5.
Giacchetti S, Itzhaki M, Gruia G, Adam R, Zidani R, Kunstlinger F, et al. Long-term survival of patients with unresectable colorectal cancer liver metastases following infusional chemotherapy with 5-fluorouracil, leucovorin, oxaliplatin and surgery. Ann Oncol. 1999;10:663–9.
Capussotti L, Muratore A, Mulas MM, Massucco P, Aglietta M. Neoadjuvant chemotherapy and resection for initially irresectable colorectal liver metastases. Br J Surg. 2006;93:1001–6.
Jones RP, Vauthey JN, Adam R, Rees M, Berry D, Jackson R, et al. Effect of specialist decision-making on treatment strategies for colorectal liver metastases. Br J Surg. 2012;99:1263–9.
de Haas RJ, Wicherts DA, Flores E, Azoulay D, Castaing D, Adam R. R1 resection by necessity for colorectal liver metastases: is it still a contraindication to surgery? Ann Surg. 2008;248:626–37.
Nordlinger B, Sorbye H, Glimelius B, Poston GJ, Schlag PM, Rougier P, et al. Perioperative chemotherapy with FOLFOX4 and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC Intergroup trial 40983): a randomised controlled trial. Lancet. 2008;371:1007–16.
Samura H, Beppu T, Emi Y, Kakeji Y, Saeki H, Oki E, et al. Liver resectability following mFOLFOX6 with bevacizumab as the first-line treatment of unresectable liver limited metastases from colorectal cancer in Japanese patients. (KSCC 0802). ASCO-GI 2012. J Clin Oncol. 2012;30:abstract 666.
Folprecht G, Gruenberger T, Bechstein WO, Raab HR, Lordick F, Hartmann JT, et al. Tumour response and secondary resectability of colorectal liver metastases following neoadjuvant chemotherapy with cetuximab: the CELIM randomized phase 2 trial. Lancet Oncol. 2010;11:38–47.
Wang JY, Chiang JM, Jeng LB, Changchien CR, Chen JS, Hsu KC. Resection of liver metastases from colorectal cancer: are there any truly significant clinical prognosticators? Dis Colon Rectum. 1996;39:847–51.
Benedix F, Kube R, Meyer F, Schmidt U, Gastinger I, Lippert H. Comparison of 17,641 patients with right- and left-sided colon cancer: differences in epidemiology, perioperative course, histology, and survival. Dis Colon Rectum. 2010;53:57–64.
Yamaguchi T, Mori T, Takahashi K, Matsumoto H, Miyamoto H, Kato T. A new classification system for liver metastases from colorectal cancer in Japanese multicenter analysis. Hepatogastroenterology. 2008;55:173–8.
Beppu T, Sakamoto Y, Hasegawa K, Honda G, Tanaka K, Kotera Y, et al. A nomogram predicting disease-free survival in patients with colorectal liver metastases treated with hepatic resection: multicenter data collection as a Project Study for Hepatic Surgery of the Japanese Society of Hepato-Biliary-Pancreatic Surgery. J Hepatobiliary Pancreat Sci. 2012;19:72–84.
Folprecht G. Neoadjuvant treatment of unresectable colorectal liver metastases: correlation between tumour response and resection rates. Ann Oncol. 2005;16:1311–9.
Alberts SR, Horvath WL, Sternfeld WC, Goldberg RM, Mahoney MR, Dakhil SR, et al. Oxaliplatin, fluorouracil, and leucovorin for patients with unresectable liver-only metastases from colorectal cancer: A North Central Cancer Treatment Group phase II study. J Clin Oncol. 2005;23:9243–9.
Ychou M, Viret F, Kramar A, Desseigne F, Mitry E, Guimbaud R, et.al. Tritherapy with fluorouracil/leucovorin, irinotecan and oxaliplatin (FOLFIRINOX): a phase II study in colorectal cancer patients with non-resectable liver metastases. Cancer Chemother Pharmacol. 2008;62:195–201.
Goldberg RM, Sargent DJ, Morton RF, Fuchs CS, Ramanathan RK, Williamson SK, et al. A randomised controlled trial of Fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol. 2004;22:23–30.
Okines A, Puerto OD, Cunningham D, Chau I, Van Cutsem E, Saltz L, et al. Surgery with curative-intent in patients treated with first-line chemotherapy plus bevacizumab for metastatic colorectal cancer First BEAT and the randomised phase-III NO16966 trial. Br J Cancer. 2009;101:1033–8.
Garufi C, Torsello A, Tumolo S, Ettorre GM, Zeuli M, Campanella C, et al. Cetuximab plus chronomodulated irinotecan, 5-fluorouracil, leucovorin and oxaliplatin as neoadjuvant chemotherapy in colorectal liver metastases: POCHER trial. Br J Cancer. 2010;103:1542–7.
Petrelli F, Barni S. Anti-EGFR agents for liver metastases. Resectability and outcome with anti-EGFR agents in patients with KRAS wild-type colorectal liver-limited metastases: a meta-analysis. Int J Colorectal Dis. 2012;27:997–1004.
Graham JS, Cassidy J. Adjuvant therapy in colon cancer. Expert Rev Anticancer Ther. 2012;12:99–109.
Author information
Authors and Affiliations
Corresponding author
Additional information
Toru Beppu and Yuji Miyamoto are equal contributors.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Beppu, T., Miyamoto, Y., Sakamoto, Y. et al. Chemotherapy and Targeted Therapy for Patients with Initially Unresectable Colorectal Liver Metastases, Focusing on Conversion Hepatectomy and Long-Term Survival. Ann Surg Oncol 21 (Suppl 3), 405–413 (2014). https://doi.org/10.1245/s10434-014-3577-x
Received:
Published:
Issue Date:
DOI: https://doi.org/10.1245/s10434-014-3577-x