Dose escalating study of cetuximab and 5-FU/folinic acid (FA)/oxaliplatin/irinotecan (FOLFOXIRI) in first line therapy of patients with metastatic colorectal cancer

BMC Cancer

Gunnar Folprecht²  Susanne Hamann³  Katharina Schütte⁴  Tanja Trarbach⁵  Jan Stoehlmacher-Williams¹  Gerhard Ehninger² 

[1] Onkologische Praxis, Bonn, Germany

[2] Medical Department I, University Hospital Carl Gustav Carus, University Cancer Center, Fetscherstr 74, 01307 Dresden, Germany

[3] Medical Department IV, Klinikum Chemnitz, Chemnitz, Germany

[4] Onkologische Gemeinschaftspraxis, Arnoldstr. 18, Dresden, Germany

[5] ioMedico, Freiburg, Germany

关键词: Chemotherapy;    5-FU;    Oxaliplatin;    Irinotecan;    Metastatic colorectal cancer;    Phase I;    Cetuximab;   

Others  :  1125328
DOI  :  10.1186/1471-2407-14-521

 received in 2013-05-13, accepted in 2014-07-16,  发布年份 2014

【 摘 要 】

Background

The FOLFOXIRI regimen (irinotecan, oxaliplatin, fluorouracil [5-FU] and folinic acid [FA]) increased the response rate and overall survival compared to FOLFIRI in patients with metastatic colorectal cancer (mCRC). Adding cetuximab to FOLFOX or FOLFIRI increased efficacy in patients with k-ras wild type mCRC. We explored the dose limiting toxicity and feasibility of the combination cetuximab, irinotecan, oxaliplatin, 5-FU and FA in mCRC patients.

Methods

In a dose-escalation study patients with previously untreated mCRC and a WHO performance status 0–1 received cetuximab (500 mg/m², 2 h), followed by irinotecan (95, 125, and 165 mg/m² in the dose levels [DL] 1, 2, and 3 respectively), followed by oxaliplatin (85 mg/m², 2 h) which was given parallel to FA (400 mg/m², 2 h) and followed by 5-FU (3200 mg/m², 46 h) in an outpatient setting every two weeks. The primary endpoints were the maximum tolerable dose and the safety. The trial was approved by the local ethics committee.

Results

From 2007 to 2008, twenty patients were treated in this trial. In the first dose level (irinotecan 95 mg/m²) one patient developed neutropenia grade 4. One patient experienced diarrhoea grade 3 as DLT in dose level 2 (irinotecan 125 mg/m²). In dose level 3 (irinotecan 165 mg/m²), three patients experienced a DLT (diarrhoea grade 3 and two patients with neutropenia grade 4). Thus, the recommended dose for a phase II trial is 125 mg/m² irinotecan in combination with oxaliplatin, 5-FU/FA and cetuximab. Most common grade ≥3 toxicities were neutropenia (40%), diarrhoea (25%) and acne-like rash (15%). No therapy associated death occurred.

The confirmed overall response rate in all cohorts was 75% (95%-CI 51-91%). The best response was reached after a median of 3.0 (95%-CI 2.2 to 3.7) months. Median progression free survival (PFS) is 16 (95%-CI 12.6-19.4) months, overall survival (OS) 33 (95%-CI 26.2-39.8) months.

Conclusions

The combination of cetuximab and FOLFOXIRIis feasible and has an acceptable toxicity profile in patients with a good performance status. The observed clinical activity with a confirmed response rate of 75% is promising and further evaluated in the ongoing CELIM2.

Trial registration

http://www.clinicaltrials.gov webcite: NCT00422773.

【 授权许可】

   
2014 Folprecht et al.; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Adam R, Wicherts DA, de Haas RJ, Ciacio O, Levi F, Paule B, Ducreux M, Azoulay D, Bismuth H, Castaing D: Patients with initially unresectable colorectal liver metastases: is there a possibility of cure? J Clin Oncol 2009, 27:1829-1835.
• [2]Folprecht G, Grothey A, Alberts S, Raab HR, Köhne CH: Neoadjuvant treatment of unresectable colorectal liver metastases: correlation between tumour response and resection rates. Ann Oncol 2005, 16:1311-1319.
• [3]Saltz LB, Cox JV, Blanke C, Rosen LS, Fehrenbacher L, Moore MJ, Maroun JA, Ackland SP, Locker PK, Pirotta N, Elfring GL, Miller LL: Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. Irinotecan Study Group. N Engl J Med 2000, 343:905-914.
• [4]de Gramont A, Figer A, Seymour M, Homerin M, Hmissi A, Cassidy J, Boni C, Cortes-Funes H, Cervantes A, Freyer G, Papamichael D, Le Bail N, Louvet C, Hendler D, de Braud F, Wilson C, Morvan F, Bonetti A: Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 2000, 18:2938-2947.
• [5]Ychou M, Viret F, Kramar A, Desseigne F, Mitry E, Guimbaud R, Delpero JR, Rivoire M, Quenet F, Portier G, Nordlinger B: 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.
• [6]Falcone A, Ricci S, Brunetti I, Pfanner E, Allegrini G, Barbara C, Crino L, Benedetti G, Evangelista W, Fanchini L, Cortesi E, Picone V, Vitello S, Chiara S, Granetto C, Porcile G, Fioretto L, Orlandini C, Andreuccetti M, Masi G: Phase III trial of infusional fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) compared with infusional fluorouracil, leucovorin, and irinotecan (FOLFIRI) as first-line treatment for metastatic colorectal cancer: the Gruppo Oncologico Nord Ovest. J Clin Oncol 2007, 25:1670-1676.
• [7]Bokemeyer C, Bondarenko I, Hartmann JT, de BF, Schuch G, Zubel A, Celik I, Schlichting M, Koralewski P: Efficacy according to biomarker status of cetuximab plus FOLFOX-4 as first-line treatment for metastatic colorectal cancer: the OPUS study. Ann Oncol 2011, 22:1535-1546.
• [8]Van Cutsem E, Köhne CH, Lang I, Folprecht G, Nowacki MP, Cascinu S, Shchepotin I, Maurel J, Cunningham D, Tejpar S, Schlichting M, Zubel A, Celik I, Rougier P, Ciardiello F: Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status. J Clin Oncol 2011, 29:2011-2019.
• [9]Karapetis CS, Khambata-Ford S, Jonker DJ, O’Callaghan CJ, Tu D, Tebbutt NC, Simes RJ, Chalchal H, Shapiro JD, Robitaille S, Price TJ, Shepherd L, Au HJ, Langer C, Moore MJ, Zalcberg JR: K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med 2008, 359:1757-1765.
• [10]Pirker R, Pereira JR, Szczesna A, Von PJ, Krzakowski M, Ramlau R, Vynnychenko I, Park K, Yu CT, Ganul V, Roh JK, Bajetta E, O’Byrne K, de MF, Eberhardt W, Goddemeier T, Emig M, Gatzemeier U: Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): an open-label randomised phase III trial. Lancet 2009, 373:1525-1531.
• [11]Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, van Glabbeke M, Van Oosterom AT, Christian MC, Gwyther SG: 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, 92:205-216.
• [12]Garufi C, Torsello A, Tumolo S, Ettorre GM, Zeuli M, Campanella C, Vennarecci G, Mottolese M, Sperduti I, Cognetti F: Cetuximab plus chronomodulated irinotecan, 5-fluorouracil, leucovorin and oxaliplatin as neoadjuvant chemotherapy in colorectal liver metastases: POCHER trial. Br J Cancer 2010, 103:1542-1547.
• [13]Assenat E, Desseigne F, Thezenas S, Viret F, Mineur L, Kramar A, Samalin E, Portales F, Bibeau F, Crapez-Lopez E, Bleuse JP, Ychou M: Cetuximab plus FOLFIRINOX (ERBIRINOX) as first-line treatment for unresectable metastatic colorectal cancer: a phase II trial. Oncologist 2011, 16:1557-1564.
• [14]Karoui M, Penna C, Amin-Hashem M, Mitry E, Benoist S, Franc B, Rougier P, Nordlinger B: Influence of preoperative chemotherapy on the risk of major hepatectomy for colorectal liver metastases. Ann Surg 2006, 243:1-7.
• [15]Schmoll HJ, Van CE, Stein A, Valentini V, Glimelius B, Haustermans K, Nordlinger B, van de Velde CJ, Balmana J, Regula J, Nagtegaal ID, Beets-Tan RG, Arnold D, Ciardiello F, Hoff P, Kerr D, Kohne CH, Labianca R, Price T, Scheithauer W, Sobrero A, Tabernero J, Aderka D, Barroso S, Bodoky G, Douillard JY, El GH, Gallardo J, Garin A, Glynne-Jones R: ESMO Consensus Guidelines for management of patients with colon and rectal cancer. A personalized approach to clinical decision making. Ann Oncol 2012, 23:2479-2516.