A randomized phase II of gemcitabine and sorafenib versus sorafenib alone in patients with metastatic pancreatic cancer

被引:40
作者
El-Khoueiry, A. B. [1 ]
Ramanathan, R. K. [2 ]
Yang, D. Y. [3 ]
Zhang, W. [1 ]
Shibata, S. [4 ]
Wright, J. J. [5 ]
Gandara, D. [6 ]
Lenz, H. J. [1 ,3 ]
机构
[1] Univ So Calif, Norris Comprehens Canc Ctr, Keck Sch Med, Div Med Oncol, Los Angeles, CA 90033 USA
[2] Univ Pittsburgh, Inst Canc, Pittsburgh, PA USA
[3] Univ So Calif, Norris Comprehens Canc Ctr, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA
[4] City Hope Natl Med Ctr, Ctr Canc, Duarte, CA USA
[5] NCI, Invest Drug Branch, Canc Therapy Evaluat Program, Bethesda, MA USA
[6] UC Davis, Ctr Canc, Sacramento, CA USA
基金
美国国家卫生研究院;
关键词
Pancreatic cancer; Sorafenib; Gemcitabine; Ribonulceotide reductase; CELL LUNG-CANCER; RAF/MEK/ERK PATHWAY; CLINICAL-TRIALS; GENE; POLYMORPHISM; ASSOCIATION; POPULATION; EXPRESSION; CARCINOMA; SURVIVAL;
D O I
10.1007/s10637-011-9658-9
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Purpose Patients with metastatic pancreatic cancer have limited therapeutic options. The role of the Ras-Raf-MAPK pathway and of vascular endothelial growth factor in pancreatic carcinogenesis provided the rational to evaluate the efficacy of sorafenib with or without gemcitabine in a randomized phase II study. Methods Patients with metastatic pancreatic cancer were randomized to sorafenib alone (arm A) or sorafenib with gemcitabine (arm B). Results Arm A was closed to accrual at interim analysis due to the lack of objective response. Median PFS and OS were 2.3 and 4.3 months respectively. There was one partial response among the 37 patients in arm B. Median PFS and OS were 2.9 and 6.5 months respectively. There were more grade 3 and 4 toxicities in arm B with the most common being neutropenia (17%), thrombocytopenia (8%), alkaline phosphatase elevation (14%), venous thromboembolism (8%), diarrhea, hypokalemia and ALT elevation (5%) each. Several associations were noted between single nucleotide polymorphisms in ribonucleotide reductase, Cox-2, vascular endothelial growth factor and survival in patients treated with gemcitabine and sorafenib. Conclusions Neither sorafenib alone or sorafenib in combination with gemcitabine manifested promising activity in metastatic pancreatic cancer.
引用
收藏
页码:1175 / 1183
页数:9
相关论文
共 29 条
[1]  
[Anonymous], 2010, CANCER
[2]   Ribonucleotide reductase M1 gene promoter activity, polymorphisms, population frequencies, and clinical relevance [J].
Bepler, G ;
Zheng, Z ;
Gautam, A ;
Sharma, S ;
Cantor, A ;
Sharma, A ;
Cress, WD ;
Kim, YC ;
Rosell, R ;
McBride, C ;
Robinson, L ;
Sommers, E ;
Haura, E .
LUNG CANCER, 2005, 47 (02) :183-192
[3]   Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: A randomized trial [J].
Burris, HA ;
Moore, MJ ;
Andersen, J ;
Green, MR ;
Rothenberg, ML ;
Madiano, MR ;
Cripps, MC ;
Portenoy, RK ;
Storniolo, AM ;
Tarassoff, P ;
Nelson, R ;
Dorr, FA ;
Stephens, CD ;
VanHoff, DD .
JOURNAL OF CLINICAL ONCOLOGY, 1997, 15 (06) :2403-2413
[4]   Randomized Phase III Trial of Gemcitabine Plus Cisplatin Compared With Single-Agent Gemcitabine As First-Line Treatment of Patients With Advanced Pancreatic Cancer: The GIP-1 Study [J].
Colucci, Giuseppe ;
Labianca, Roberto ;
Di Costanzo, Francesco ;
Gebbia, Vittorio ;
Carteni, Giacomo ;
Massidda, Bruno ;
Dapretto, Elisa ;
Manzione, Luigi ;
Piazza, Elena ;
Sannicolo, Mirella ;
Ciaparrone, Marco ;
Cavanna, Luigi ;
Giuliani, Francesco ;
Maiello, Evaristo ;
Testa, Antonio ;
Pederzoli, Paolo ;
Falconi, Massimo ;
Gallo, Ciro ;
Di Maio, Massimo ;
Perrone, Francesco .
JOURNAL OF CLINICAL ONCOLOGY, 2010, 28 (10) :1645-1651
[5]  
Conroy T, 2010, P AM SOC CLIN ONCOLO
[6]   Phase III Randomized Comparison of Gemcitabine Versus Gemcitabine Plus Capecitabine in Patients With Advanced Pancreatic Cancer [J].
Cunningham, David ;
Chau, Ian ;
Stocken, Deborah D. ;
Valle, Juan W. ;
Smith, David ;
Steward, William ;
Harper, Peter G. ;
Dunn, Janet ;
Tudur-Smith, Catrin ;
West, Julia ;
Falk, Stephen ;
Crellin, Adrian ;
Adab, Fawzi ;
Thompson, Joyce ;
Leonard, Pauline ;
Ostrowski, Joe ;
Eatock, Martin ;
Scheithauer, Werner ;
Herrmann, Richard ;
Neoptolemos, John P. .
JOURNAL OF CLINICAL ONCOLOGY, 2009, 27 (33) :5513-5518
[7]   Biologic therapies for advanced pancreatic cancer [J].
He, Aiwu Ruth ;
Lindenberg, Andreas Peter ;
Marshall, John Lindsay .
EXPERT REVIEW OF ANTICANCER THERAPY, 2008, 8 (08) :1331-1338
[8]   A common polymorphism in the 3′UTR of cyclooxygenase 2/prostaglandin synthase 2 gene and risk of lung cancer in a Chinese population [J].
Hu, Z ;
Miao, X ;
Ma, H ;
Wang, X ;
Tan, W ;
Wei, Q ;
Lin, D ;
Shen, H .
LUNG CANCER, 2005, 48 (01) :11-17
[9]   Sorafenib Inhibits STAT3 Activation to Enhance TRAIL-Mediated Apoptosis in Human Pancreatic Cancer Cells [J].
Huang, Shengbing ;
Sinicrope, Frank A. .
MOLECULAR CANCER THERAPEUTICS, 2010, 9 (03) :742-750
[10]   Gemcitabine plus sorafenib in patients with advanced pancreatic cancer: a phase II trial of the University of Chicago Phase II Consortium [J].
Kindler, Hedy Lee ;
Wroblewski, Kristen ;
Wallace, James A. ;
Hall, Michael J. ;
Locker, Gershon ;
Nattam, Sreenivasa ;
Agamah, Edem ;
Stadler, Walter M. ;
Vokes, Everett E. .
INVESTIGATIONAL NEW DRUGS, 2012, 30 (01) :382-386