Stein et al. BMC Cancer 2012, 12:356 http://www.biomedcentral.com/1471-2407/12/356 partial thromboplastin time; BfArM, Bundesinstitut für Arzneimittel und Medizinprodukte; BRAF, V-raf murine sarcoma viral oncogene homolog B1; CA 19–9, Carbohydrate antigen 19–9; CEA, Carcinoembryonic antigen; CLM, Colorectal liver metastases; CT, Computed tomography; DFS, Disease free survival; DNA, Deoxyribonucleic acid; ECOG-PS, Eastern cooperative oncology group – performance status; EGFR, Epidermal growth factor receptor; EORTC, European organisation for research and treatment of cancer; EudraCT, European Clinical Trials Database; FFS, Failure free survival; FFSR@18, Failure free survival rate at 18 months; FOLFIRI, 5-FU/LV and irinotecan; FOLFOX, 5-FU/LV and oxaliplatin; FOLFOXIRI, 5-FU/LV, oxaliplatin and irinotecan; G, Grade; G-CSF, Granulocyte colony-stimulating factor; HR, Hazard ratio; IFL, 5FU bolus and irinotecan regimen; INR, International Normalized Ratio; Iv, Intravenous; KRAS, Kirsten rat sarcoma viral oncogene homolog; LV, Leucovorin; mCRC, Metastatic colorectal cancer; min, Minutes; MRI, Magnetic resonance imaging; N, Number of patients; NCI- CTCAE, National Cancer Institute common terminology criteria for adverse events; ORR, Overall response rate; OS, Overall survival; P, P-value; PEI, Paul Ehrlich Institut; PFS, Progression free survival; PFSR@9, Progression free survival rate at 9 months; Po, Per os; RECIST, Response evaluation criteria in solid tumours; SAE, Severe adverse event; QoL, Quality of life; QLQ, Quality of life questionnaire; UICC, Union internationale contre le cancer; ULN, Upper Limit of Normal; V, Version; Vs, Versus; XELOX, Capecitabine and oxaliplatin. Competing interests Both trials are funded by Roche. AS has received honoraria from Roche and Merck KGaA. HJS has received research funding and honoraria from Roche. H-JS and DA have received honoraria and research funding from Roche and Merck KGaA and honoraria from Amgen. BH has received honoraria and research funding from Amgen, Roche and Merck KGaA. AW, AK, GG, MR and TE declare that there is no conflict of interest. Authors’ contributions AS and GG prepared the manuscript. HJS and H-JS are the coordinating investigators for the two trials and participated in the preparation of manuscript and study protocols. AS wrote both study protocols, GG participated in the PERIMAX protocol. DA coordinates the translational part of the CHARTA trial. AW performed the statistical analysis for both trials and participated in drafting of the manuscript. MR coordinates both trials as clinical research associate. TE, BH, SH, GI, AK participate in patient recruitment in both trials. All authors read and approved the final manuscript. Author details 1University Cancer Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. 2Department of Surgery, University Medical Center Regensburg, Regensburg, Germany. 3Department for Oncology/Hematology, Martin-Luther-University Halle, Ernst-Grube-Str. 40, 06120 Halle/Saale, Germany. 4MedCenter Nordsachsen, Schkeuditz, Germany. 5Charité Centrum für Tumormedizin, Campus Virchow-Klinikum, Berlin, Germany. 6Department for Gastroenterology, Academic Teaching Hospital, Celle, Germany. 7Department of Hematology/Oncology, Comprehensive Cancer Center University of Freiburg, Freiburg, Germany. 8Department of Surgery, University Hospital of Tübingen, Tübingen, Germany. 9Koordinierungszentrum Klinische Studien Halle, Martin-Luther-University, Halle, Germany. Received: 11 April 2012 Accepted: 17 July 2012 Published: 16 August 2012 References 1. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D: Global cancer statistics. CA Cancer J Clin 2011, 61:69–90. 2. Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM: Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer 2010, 127(12):2893–2917. 3. van der Pool AE, Damhuis RA, Ijzermans JN, de Wilt JH, Eggermont AM, Kranse R, Verhoef C: Trends in incidence, treatment and survival of patients with stage IV colorectal cancer: a population-based series. Colorectal Dis 2012, 14:56–61. 4. Mantke R, Schmidt U, Wolff S, Kube R, Lippert H: Incidence of synchronous liver metastases in patients with colorectal cancer in relationship to Page 8 of 10 clinico-pathologic characteristics. Results of a German prospective multicentre observational study. Eur J Surg Oncol 2012, 38:259–265. 5. Schmoll HJ, Sargent D: Single agent fluorouracil for first-line treatment of advanced colorectal cancer as standard? Lancet 2007, 370:105–107. 6. Van Cutsem E, Dicato M, Arber N, Berlin J, Cervantes A, Ciardiello F, De Gramont A, Diaz-Rubio E, Ducreux M, Geva R, et al: Molecular markers and biological targeted therapies in metastatic colorectal cancer: expert opinion and recommendations derived from the 11th ESMO/World Congress on Gastrointestinal Cancer, Barcelona, 2009. Ann Oncol 2010, 21(Suppl 6):vi1–10. 7. Schmiegel W, Pox C, Arnold D, Porschen R, Rodel C, Reinacher-Schick A: Colorectal carcinoma: the management of polyps, (neo)adjuvant therapy, and the treatment of metastases. Dtsch Arztebl Int 2009, 106:843–848. 8. Kopetz S, Chang GJ, Overman MJ, Eng C, Sargent DJ, Larson DW, Grothey A, Vauthey JN, Nagorney DM, McWilliams RR: Improved survival in metastatic colorectal cancer is associated with adoption of hepatic resection and improved chemotherapy. J Clin Oncol 2009, 27:3677–3683. 9. Morris EJ, Forman D, Thomas JD, Quirke P, Taylor EF, Fairley L, Cottier B, Poston G: Surgical management and outcomes of colorectal cancer liver metastases. Br J Surg 2010, 97:1110–1118. 10. Jonas S, Thelen A, Benckert C, Spinelli A, Sammain S, Neumann U, Rudolph B, Neuhaus P: Extended resections of liver metastases from colorectal cancer. World J Surg 2007, 31:511–521. 11. Wei AC, Greig PD, Grant D, Taylor B, Langer B, Gallinger S: Survival after hepatic resection for colorectal metastases: a 10-year experience. Ann Surg Oncol 2006, 13:668–676. 12. Tomlinson JS, Jarnagin WR, DeMatteo RP, Fong Y, Kornprat P, Gonen M, Kemeny N, Brennan MF, Blumgart LH, D’Angelica M: Actual 10-year survival after resection of colorectal liver metastases defines cure. J Clin Oncol 2007, 25:4575–4580. 13. Scheele J, Stang R, Altendorf-Hofmann A, Paul M: Resection of colorectal liver metastases. World J Surg 1995, 19:59–71. 14. Fong Y, Fortner J, Sun RL, Brennan MF, Blumgart LH: Clinical score for predicting recurrence after hepatic resection for metastatic colorectal cancer: analysis of 1001 consecutive cases. Ann Surg 1999, 230:309–318. discussion 318–321. 15. Adam R, Barroso E: Impact of the type and modalities of preoperative chemotherapy on the outcome of liver resection for colorectal metastases. J Clin Oncol 2011, 29:abstr 3519. 16. de Jong MC, Pulitano C, Ribero D, Strub J, Mentha G, Schulick RD, Choti MA, Aldrighetti L, Capussotti L, Pawlik TM: Rates and patterns of recurrence following curative intent surgery for colorectal liver metastasis: an international multi-institutional analysis of 1669 patients. Ann Surg 2009, 250:440–448. 17. Nagashima I, Takada T, Nagawa H, Muto T, Okinaga K: Proposal of a new and simple staging system of colorectal liver metastasis. World J Gastroenterol 2006, 12:6961–6965. 18. Poston GJ, Figueras J, Giuliante F, Nuzzo G, Sobrero AF, Gigot JF, Nordlinger B, Adam R, Gruenberger T, Choti MA, et al: Urgent need for a new staging system in advanced colorectal cancer. J Clin Oncol 2008, 26:4828–4833. 19. Van Cutsem E, Nordlinger B, Adam R, Kohne CH, Pozzo C, Poston G, Ychou M, Rougier P: Towards a pan-European consensus on the treatment of patients with colorectal liver metastases. Eur J Cancer 2006, 42:2212–2221. 20. 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, 55:173–178. 21. Nordlinger B, Van Cutsem E, Gruenberger T, Glimelius B, Poston G, Rougier P, Sobrero A, Ychou M: 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, 20:985–992. 22. Nordlinger B, Sorbye H, Glimelius B, Poston GJ, Schlag PM, Rougier P, Bechstein WO, Primrose JN, Walpole ET, Finch-Jones M, 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, 371:1007–1016. 23. 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