Summary
Purpose To assess safety and efficacy of folinic acid, 5-fluorouracil, gemcitabine (FFG) and folinic acid, fluorouracil, oxaliplatin (FOLFOX4) regimens with added bevacizumab as first-line treatment in patients with advanced colorectal cancer (CRC). Patients and Methods Patients with Stage III unresectable or Stage IV adenocarcinoma of the colon or rectum were randomly assigned to either FFG weekly for 6 weeks of an 8-week cycle or FOLFOX4 every 2 weeks. After FDA approval, bevacizumab 5 mg/kg was added every 2 weeks. Treatment continued until disease progression. Planned enrollment was 190 patients. Primary endpoint was overall response rate (ORR); secondary endpoints included evaluation of adverse events, time to progression (TTP), and overall survival (OS). Disease Control Rate (DCR; % of patients with complete or partial responses or stable disease) was a post hoc analysis. Results The trial was stopped prematurely due to low enrollment. Of 84 enrolled patients (42 to each arm), 36 patients (18 in each arm) received bevacizumab. ORR was greater (P = .002) for FOLFOX4 (17/42; 40.5%) than for FFG (4/42; 9.5%); however, TTP, OS, and DCR results were not statistically different comparing FOLFOX4 and FFG. Peripheral neuropathy was more frequent (P = <.001) with FOLFOX4 (18/42; 42.9%) than with FFG (1/42; 2.4%). Conclusions FFG and FOLFOX4 were generally well tolerated. Based on ORR, FOLFOX4 was superior to FFG. However, differences in TTP and OS comparing regimens were inconclusive. General use of gemcitabine as a biomodulator of 5-fluorouracil in CRC cannot be recommended at this time and the regimen remains investigational.
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References
Jemal A, Siegel R, Ward E et al (2008) Cancer statistics 2008. CA Cancer J Clin 58:71–96. doi:10.3322/CA.2007.0010
Kelly C, Cassidy J (2007) Chemotherapy in metastatic colorectal cancer. Surg Oncol 16:65–70. doi:10.1016/j.suronc.2007.04.006
Sabharwal A, Kerr D (2007) Chemotherapy for colorectal cancer in the metastatic and adjuvant setting: past, present and future. Expert Rev Anticancer Ther 7:477–487. doi:10.1586/14737140.7.4.477
Scheithauer W, Rosen H, Kornek GV et al (1993) Randomised comparison of combination chemotherapy plus supportive care with supportive care alone in patients with metastatic colorectal cancer. BMJ 306:752–755
Saltz LB, Cox JV, Blanke C et al (2000) Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. N Engl J Med 343:905–914. doi:10.1056/NEJM200009283431302
Goldberg RM, Sargent DJ, Morton RF et al (2004) A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol 22:23–30. doi:10.1200/JCO.2004.09.046
Díaz-Rubio E, Sastre J, Zaniboni A et al (1998) Oxaliplatin as single agent in previously untreated colorectal carcinoma patients: a phase II multicentric study. Ann Oncol 9:105–108. doi:10.1023/A:1008200825886
de Gramont A, Figer A, Seymour M et al (2000) Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 18:2938–2947
Merriman RL, Hertel LW, Schultz RM et al (1996) Comparison of the antitumor activity of gemcitabine and ara-C in a panel of human breast, colon, lung and pancreatic xenograft models. Invest New Drugs 14:243–247. doi:10.1007/BF00194526
Moore DF Jr, Pazdur R, Daugherty K et al (1992) Phase II study of gemcitabine in advanced colorectal adenocarcinoma. Invest New Drugs 10:323–325. doi:10.1007/BF00944189
Abbruzzese J, Pazdur R, Ajani J et al (1991) A phase II trial of gemcitabine in patients with advanced colorectal cancer. Proc Am Soc Clin Oncol 10: (abstr 456)
Poplin E, Roberts J, Tombs M et al (1999) Leucovorin, 5-fluorouracil, and gemcitabine: a phase I study. Invest New Drugs 17:57–62. doi:10.1023/A:1006239200772
Tampellini M, Tucci M, Saini A et al (2003) Weekly gemcitabine plus protracted continuous infusion of 5 fluorouracil as third line chemotherapy in advanced colorectal cancer patients. Proc Am Soc Clin Oncol 22: (abstr 1466).
Pachon V, Garcia-Alfonso P, Iglesias L et al (2005) Gemcitabine plus continuous infusion of 5-FU for heavily pretreated advanced colorectal cancer patients; phase I/II study. Proc Am Soc Clin Oncol 23: (abstr 3735)
Madajewicz S, Hentschel P, Burns P et al (2000) Phase I chemotherapy study of biochemical modulation of folinic acid and fluorouracil by gemcitabine in patients with solid tumor malignancies. J Clin Oncol 18:3553–3557
Giachetti S, Perpoint B, Zidani R et al (2000) Phase III multicenter randomized trial of oxaliplatin added to chronomodulated fluorouracil-leucovorin as first-line treatment of metastatic colorectal cancer. J Clin Oncol 18:136–147
Ferrara N (1999) Molecular and biological properties of vascular endothelial growth factor. J Mol Med 77:527–543. doi:10.1007/s001099900019
Hurwitz H, Fehrenbacher L, Novotny W et al (2004) Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350:2335–2342. doi:10.1056/NEJMoa032691
Hedrick EE, Hurwitz H, Sarkar S et al (2004) Post-progression therapy (PPT) effect on survival in AVF2107, a phase III trial of bevacizumab in first-line treatment of metastatic colorectal cancer (mCRC). J Clin Oncol 22:249s, suppl; abstr 3517
Kabbinavar FF, Hambleton J, Mass RD et al (2005) Combined analysis of efficacy: the addition of bevacizumab to fluorouracil/leucovorin improves survival for patients with metastatic colorectal cancer. J Clin Oncol 16:3706–3712. doi:10.1200/JCO.2005.00.232
National Cancer Institute: FDA approval for bevacizumab. http://www.cancer.gov/cancertopics/druginfo/fda-bevacizumab#Anchor-Approva-23287. Accessed 18 October 2009
Therasse P, Arbuck SG, Eisenhauer EA et al (2000) 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 92:205–216. doi:10.1093/jnci/92.3.205
National Cancer Institute: National Cancer Institute Common Toxicity Criteria Version 2.0. http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcv20_4-30-992.pdf. Accessed 18 October 2009
Kaplan E, Meier P (1958) Nonparametric estimation of incomplete observations. J Am Stat Assoc 53:457–81. doi:10.2307/2281868
Bland JM, Altman DG (2004) The logrank test. BMJ 328:1073
André T, Boni C, Mounedji-Boudiaf L et al (2004) Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med 350:2343–2351. doi:10.1056/NEJMoa032709
Grothey A, Hendrick EE, Mass RD et al (2008) Response-independed survival benefit in metastatic colorectal cancer: a comparative analysis of N9741 and AVF2107. J Clin Onc 26:183–189
Acknowledgements
This trial was supported by Lilly USA, LLC; Indianapolis, IN.
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Drs. Gill, Nicol, and Zhao are employees of Lilly USA, LLC and own stock in Eli Lilly and Company. All other authors state that they have no conflicts of interest.
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This study was sponsored by Lilly USA, LLC; Indianapolis, IN.
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Madajewicz, S., Waterhouse, D.M., Ritch, P.S. et al. Multicenter, randomized phase II trial of bevacizumab plus folinic acid, fluorouracil, gemcitabine (FFG) versus bevacizumab plus folinic acid, fluorouracil, oxaliplatin (FOLFOX4) as first-line therapy for patients with advanced colorectal cancer. Invest New Drugs 30, 772–778 (2012). https://doi.org/10.1007/s10637-010-9598-9
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DOI: https://doi.org/10.1007/s10637-010-9598-9