A Randomized Phase II Trial of Three Intensified Chemotherapy Regimens in First-Line Treatment of Colorectal Cancer Patients with Initially Unresectable or Not Optimally Resectable Liver Metastases. The METHEP Trial
Tóm tắt
This study was designed to evaluate neoadjuvant intensified chemotherapy in potentially resectable or unresectable liver metastases (LM) from colorectal cancer (CRC). Criteria for potentially resectable LM were complex hepatectomy and/or risky procedure, close contact with major vascular structures, and for unresectable LM, a future liver remnant predicted to be less than 25–30 % of total liver volume. Between October 2004 and August 2007, 125 patients were randomized to either standard (FOLFIRI/FOLFOX4) or intensified chemotherapy (FOLFIRI-HD/FOLFOX7/FOLFIRINOX). Primary endpoint was objective response rate (ORR) after 4 cycles of chemotherapy. Secondary endpoints included safety, R0 surgical resection, best ORR, progression-free survival (PFS), and overall survival (OS). A total of 122 patients were treated; 45 % of patients had less than 30 % of remaining liver tissue, 20 % had major vascular contact, and 35 % were potentially resectable. Grade 3/4 toxicities were neutropenia (24, 19, 10, 23 %) diarrhoea (0, 6, 3, 23 %), mucositis (0, 3, 0, 7 %), vomiting (7, 9, 0, 3 %), and neurotoxicity (0, 0, 10, 3 %) in arms (FOLFIRI + FOLFOX4)/FOLFIRI-HD/FOLFOX7/FOLFIRINOX, respectively. ORR was 33, 47, 43, and 57 % after the first 4 cycles in arms (FOLFIRI + FOLFOX4)/FOLFIRI-HD/FOLFOX7/FOLFIRINOX, respectively. FOLFIRINOX offered the best conversion rate to resectability (67 %). Disease-free status after chemotherapy and surgery (R0, R1, Rx) was achieved in 54 of 64 operated patients. Median PFS was 9.2 months in control arms versus 11.9 months in experimental arms (hazards ratio [HR] = 0.76, p = 0.115), and the median OS was 17.7 versus 33.4 months (HR = 0.73, p = 0.297), respectively. FOLFIRINOX showed promising activity in CRC patients with LM compared with standard or intensified bi-chemotherapy regimens.
Tài liệu tham khảo
Benoist S, Nordlinger B. The role of preoperative chemotherapy in patients with resectable colorectal liver metastases. Ann Surg Oncol. 2009;16:2385–90.
International registry of liver metastases of colorectal cancer. http://www.livermetsurvey.org/International.
Poston G, Adam R, Vauthey JN. Downstaging or downsizing: time for a new staging system in advanced colorectal cancer? J Clin Oncol. 2006;24:2702–6.
Folprecht G, Grothey A, Alberts S, et al. Neoadjuvant treatment of unresectable colorectal liver metastases: correlation between tumour response and resection rates. Ann Oncol. 2005;16:1311–9.
Adam R, Wicherts DA, de Haas RJ, et al. Patients with initially unresectable colorectal liver metastases: is there a possibility of cure? J Clin Oncol. 2009;27:1829–35.
Alberts SR. Evolving role of chemotherapy in resected liver metastases. J Clin Oncol. 2006;24:4952–3.
Pozzo C, Basso M, Cassano A, et al. Neoadjuvant treatment of unresectable liver disease with irinotecan and 5-fluorouracil plus folinic acid in colorectal cancer patients. Ann Oncol. 2004;15:933–9.
Ducreux M, Raoul JL, Marti P, et al. High-dose irinotecan plus LV5FU2 or simplified LV5FU (HD-FOLFIRI) for patients with untreated metastatic colorectal cancer: a new way to allow resection of liver metastases? Oncology. 2008;74:17–24.
Maindrault-Goebel F, de Gramont A, Louvet C, et al. High-dose intensity oxaliplatin added to the simplified bimonthly leucovorin and 5-fluorouracil regimen as second-line therapy for metastatic colorectal cancer (FOLFOX 7). Eur J Cancer. 2001;37:1000–5.
Taieb J, Artru P, Paye F, et al. Intensive systemic chemotherapy combined with surgery for metastatic colorectal cancer: results of a phase II study. J Clin Oncol. 2005;23:502–9.
Ychou M, Conroy T, Seitz JF, et al. An open phase I study assessing the feasibility of the triple combination: oxaliplatin plus irinotecan plus leucovorin/5-fluorouracil every 2 weeks in patients with advanced solid tumors. Ann Oncol. 2003;14:481–9.
Ychou M, Viret F, Kramar A 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.
Rivoire M, Thezenas S, Rebischung C, et al. Preliminary results of a randomized phase II trial comparing standard bi-therapy versus three intensified chemotherapy regimens as treatment for patients with non resectable liver metastases from colorectal cancer (LMCRC). (METHEP). J Clin Oncol. 2008;26(Suppl; abstr 4075).
Ismaili N. Treatment of colorectal liver metastases. World J Surg Oncol. 2011;9:154.
Van Cutsem E, Nordlinger B, Adam R, et al. Towards a pan-European consensus on the treatment of patients with colorectal liver metastases. Eur J Cancer. 2006;42:2212–21.
Nordlinger B, Sorbye H, Glimelius B, 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.
Vauthey JN, Pawlik TM, Ribero D, et al. Chemotherapy regimen predicts steatohepatitis and an increase in 90-day mortality after surgery for hepatic colorectal metastases. J Clin Oncol. 2006;24:2065–72.
Karoui M, Penna C, Amin-Hashem M, et al. Influence of preoperative chemotherapy on the risk of major hepatectomy for colorectal liver metastases. Ann Surg. 2006;243:1–7.
Brouquet A, Vauthey JN, Contreras CM, et al. Improved survival after resection of liver and lung colorectal metastases compared with liver-only metastases: a study of 112 patients with limited lung metastatic disease. J Am Coll Surg. 2011;213:62–9; discussion 69–71.
Folprecht G, Gruenberger T, Bechstein WO, 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.
Pawlik TM, Scoggins CR, Zorzi D, et al. Effect of surgical margin status on survival and site of recurrence after hepatic resection for colorectal metastases. Ann Surg. 2005;241:715–22, discussion 722–4.
de Haas RJ, Wicherts DA, Flores E, et al. R1 resection by necessity for colorectal liver metastases: is it still a contraindication to surgery? Ann Surg. 2008;248:626–37.
Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004;350:2335–42.
Van Cutsem E, Kohne CH, Hitre E, et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med. 2009;360:1408–17.
Bokemeyer C, Bondarenko I, Makhson A, et al. Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J Clin Oncol. 2009;27:663–71.
Masi G, Loupakis F, Salvatore L, et al. Bevacizumab with FOLFOXIRI (irinotecan, oxaliplatin, fluorouracil, and folinate) as first-line treatment for metastatic colorectal cancer: a phase 2 trial. Lancet Oncol. 2010;11:845–52.
Assenat E, Desseigne F, Thezenas S, et al. Cetuximab plus FOLFIRINOX (ERBIRINOX) as first-line treatment for unresectable metastatic colorectal cancer: a phase II trial. Oncologist. 2011;16:1557–64.