Efficacy and Safety of Fixed-Dose-Rate Infusions of Gemcitabine Plus Erlotinib for Advanced Pancreatic Cancer
Keywords:Adenocarcinoma, efficacy, erlotinib, fixed-dose-rate infusion, gemcitabine, pancreas, safety
Purpose: To evaluate the efficacy and safety of fixed-dose-rate infusions of gemcitabine in combination with erlotinib for advanced pancreatic cancer. Methods/Patients: Patients with locally advanced (LAPC) or metastatic pancreatic cancer (MPC) without previous treatment for the advanced disease and Eastern Cooperative Oncology Group performance status received 1500 mg/m2 of gemcitabine in 150-minute infusions (10 mg/m2/minute) on days 1, 8 and 15 in 4-week cycles combined with 100 mg/day of oral erlotinib. The primary endpoint was overall survival (OS). Results: Sixty-two evaluable patients were enrolled (LAPC, n=16; MPC, n=46). Median OS was 10.0 (95% CI, 7.1-13.0) months. OS was longer in patients with LAPC (p=0.019), females (p=0.010) and patients not receiving opioids (p=0.027). A trend towards longer OS was shown in patients with grade rash (p=0.078). In multivariate analysis, only gender remained statistically significant (p=0.01). Median PFS was 4.9 (95% CI, 3.1-6.8) months, which was longer in patients with LAPC (p=0.004) and females (p=0.013). Overall response rate was 12.9% (95% CI, 4.7-21.3), with eight patients achieving partial response, and tumour growth control rate was 67.7% (95% CI, 79.3-56.1). The main grade 3/4 adverse events were neutropenia (40.3%), asthenia (22.6%), anaemia (19.4%), thrombocytopenia (17.7%) and infections (14.5%). Three patients died due to septic shock, cholangitis or pulmonary embolism. Conclusions: The combination of fixed-dose-rate infusions of gemcitabine and erlotinib represents a feasible and active regimen for advanced pancreatic cancer with a manageable safety profile.
Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin 2012; 62: 10-29. http://dx.doi.org/10.3322/caac.20138
Ferlay J, Parkin DM, Steliarova-Foucher E. Estimates of cancer incidence and mortality in Europe in 2008. Eur J Cancer 2010; 46: 765-81. http://dx.doi.org/10.1016/j.ejca.2009.12.014
Ying JE, Zhu LM, Liu BX. Developments in metastatic pancreatic cancer: is gemcitabine still the standard? World J Gastroenterol 2012; 18: 736-45. http://dx.doi.org/10.3748/wjg.v18.i8.736
Burris HA, III, Moore MJ, Andersen J, et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol 1997; 15: 2403-13.
Veltkamp SA, Beijnen JH, Schellens JH. Prolonged versus standard gemcitabine infusion: translation of molecular pharmacology to new treatment strategy. Oncologist 2008; 13: 261-76. http://dx.doi.org/10.1634/theoncologist.2007-0215
Poplin E, Feng Y, Berlin J, et al. Phase III, randomized study of gemcitabine and oxaliplatin versus gemcitabine (fixed-dose rate infusion) compared with gemcitabine (30-minute infusion) in patients with pancreatic carcinoma E6201: a trial of the Eastern Cooperative Oncology Group. J Clin Oncol 2009; 27: 3778-85. http://dx.doi.org/10.1200/JCO.2008.20.9007
Mane JM, Sancho A, Munoz A, et al. Fixed-dose-rate gemcitabine infusion in patients with advanced pancreatic or biliary tree adenocarcinoma. Tumori 2010; 96: 405-10.
Moore MJ, Goldstein D, Hamm J, et al. Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 2007; 25: 1960-6. http://dx.doi.org/10.1200/JCO.2006.07.9525
Feliu J, Borrega P, Leon A, et al. Phase II study of a fixed dose-rate infusion of gemcitabine associated with erlotinib in advanced pancreatic cancer. Cancer Chemother Pharmacol 2011; 67: 215-21. http://dx.doi.org/10.1007/s00280-010-1472-0
Tempero M, Plunkett W, Ruiz Van Haperen V, et al. Randomized phase II comparison of dose-intense gemcitabine: thirty-minute infusion and fixed dose rate infusion in patients with pancreatic adenocarcinoma. J Clin Oncol 2003; 21: 3402-8. http://dx.doi.org/10.1200/JCO.2003.09.140
Therasse P, Arbuck SG, Eisenhauer EA, 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. http://dx.doi.org/10.1093/jnci/92.3.205
National Cancer Institute. Common Terminology Criteria for Adverse Events (version 3). National Cancer Institute 2006;
Nedaeinia R, Avan A, Manian M, Salehi R, Ghayour-Mobarhan M. EGFR as a potential target for the treatment of pancreatic cancer: dilemma and controversies. Curr Drug Targets 2014 Epub ahead of print: DOI: CDT-EPUB-63563 (pii).
Boeck S, Jung A, Laubender RP, et al. EGFR pathway biomarkers in erlotinib-treated patients with advanced pancreatic cancer: translational results from the randomised, crossover phase 3 trial AIO-PK0104. Br J Cancer 2013; 108: 469-76. http://dx.doi.org/10.1038/bjc.2012.495
Tzeng CW, Frolov A, Frolova N, et al. Pancreatic cancer epidermal growth factor receptor (EGFR) intron 1 polymorphism influences postoperative patient survival and in vitro erlotinib response. Ann Surg Oncol 2007; 14: 2150-8. http://dx.doi.org/10.1245/s10434-007-9409-5
Aranda E, Manzano JL, Rivera F, et al. Phase II open-label study of erlotinib in combination with gemcitabine in unresectable and/or metastatic adenocarcinoma of the pancreas: relationship between skin rash and survival (Pantar study). Ann Oncol 2012; 23: 1919-25. http://dx.doi.org/10.1093/annonc/mdr560
Herrmann R, Bodoky G, Ruhstaller T, et al. Gemcitabine plus capecitabine compared with gemcitabine alone in advanced pancreatic cancer: a randomized, multicenter, phase III trial of the Swiss Group for Clinical Cancer Research and the Central European Cooperative Oncology Group. J Clin Oncol 2007; 25: 2212-7. http://dx.doi.org/10.1200/JCO.2006.09.0886
Cunningham D, Chau I, Stocken DD, et al. Phase III randomized comparison of gemcitabine versus gemcitabine plus capecitabine in patients with advanced pancreatic cancer. J Clin Oncol 2009; 27: 5513-8. http://dx.doi.org/10.1200/JCO.2009.24.2446
Kindler HL, Niedzwiecki D, Hollis D, et al. Gemcitabine plus bevacizumab compared with gemcitabine plus placebo in patients with advanced pancreatic cancer: phase III trial of the Cancer and Leukemia Group B (CALGB 80303). J Clin Oncol 2010; 28: 3617-22. http://dx.doi.org/10.1200/JCO.2010.28.1386
Philip PA, Benedetti J, Corless CL, et al. Phase III study comparing gemcitabine plus cetuximab versus gemcitabine in patients with advanced pancreatic adenocarcinoma: Southwest Oncology Group-Directed Intergroup trial S0205. J Clin Oncol 2010; 28: 3605-10. http://dx.doi.org/10.1200/JCO.2009.25.7550
Van Cutsem E, Vervenne WL, Bennouna J, et al. Phase III trial of bevacizumab in combination with gemcitabine and erlotinib in patients with metastatic pancreatic cancer. J Clin Oncol 2009; 27: 2231-7. http://dx.doi.org/10.1200/JCO.2008.20.0238