Penas-Prado Marta, Hess Kenneth R, Fisch Michael J, Lagrone Lore W, Groves Morris D, Levin Victor A, De Groot John F, Puduvalli Vinay K, Colman Howard, Volas-Redd Gena, Giglio Pierre, Conrad Charles A, Salacz Michael E, Floyd Justin D, Loghin Monica E, Hsu Sigmund H, Gonzalez Javier, Chang Eric L, Woo Shiao Y, Mahajan Anita, Aldape Kenneth D, Yung W K Alfred, Gilbert Mark R
Department of Neuro-Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas (M.P.-P., M.D.G., V.A.L., J.F.D.G., C.A.C., M.E.L., W.K.A.Y., M.R.G.); Biostatistics, University of Texas MD Anderson Cancer Center, Houston, Texas (K.R.H.); General Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas (M.J.F., L.W.L.); Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas (A.M.); Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas (K.D.A); Department of Neurosurgery, Kaiser Permanente Redwood City Medical Center, Redwood City, California (V.A.L.); Department of Neurological Surgery, Ohio State University Comprehensive Cancer Center, Columbus, Ohio (V.K.P.); Department of Neurosurgery, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah (H.C.); Atlanta Regional Community Clinical Oncology Program, Georgia Cancer Specialists, Canton, Georgia (G.V.-.R.); Department of Neurosciences, Medical University of South Carolina Brain & Spine Tumor Program, Charleston, South Carolina (P.G.); Department of Hematology and Oncology, The University of Kansas Cancer Center, Overland Park, Kansas (M.E.S.); Department of Hematology and Oncology, Saint Francis Medical Center, Cape Girardeau, Missouri (J.D.F.); Department of Neurosurgery, University of Texas Health Science Center, Houston, Texas (S.H.H.); Department of Neurology, West Virginia University, Morgantown, West Virginia (J.G.); Department of Radiation Oncology, Keck School of Medicine, University of Southern California, U.S.C Norris Cancer Hospital, Los Angeles, California (E.L.C.); Department of Radiation Oncology, University of Louisville, James Graham Brown Cancer Center, Louisville, Kentucky (S.Y.W.).
Neuro Oncol. 2015 Feb;17(2):266-73. doi: 10.1093/neuonc/nou155. Epub 2014 Sep 19.
Chemoradiation, followed by adjuvant temozolomide, is the standard treatment for newly diagnosed glioblastoma. Adding other active agents may enhance treatment efficacy.
The primary objective of this factorial phase II study was to determine if one of 3 potential chemotherapy agents added to dose-dense temozolomide (ddTMZ) improves progression-free survival (PFS) for patients with newly diagnosed glioblastoma. A prior phase I trial established the safety of combining ddTMZ with isotretinoin, celecoxib, and/or thalidomide. Adults with good performance status and no evidence of progression post chemoradiation were randomized into 8 arms: ddTMZ alone (7 days on/7 days off) or doublet, triplet, and quadruplet combinations with isotretinoin, celecoxib, and thalidomide.
The study enrolled 155 participants with a median age of 53 years (range, 18-84 y). None of the agents demonstrated improved PFS when compared with arms not containing that specific agent. There was no difference in PFS for triplet compared with doublet regimens, although a trend for improved overall survival (OS) was seen (20.1 vs 17.0 months, P = .15). Compared with ddTMZ, the ddTMZ + isotretinoin doublet had worse PFS (10.5 vs 6.5 months, P = .043) and OS (21.2 vs 11.7 months, P = .037). Trends were also seen for worse outcomes with isotretinoin-containing regimens, but there was no impact with celecoxib or thalidomide combinations. Treatment was well tolerated with expected high rates of lymphopenia.
The results do not establish a benefit for these combinations but indicate that adding isotretinoin to ddTMZ may be detrimental. This study demonstrated the feasibility and utility of the factorial design in efficiently testing drug combinations in newly diagnosed glioblastoma.
NCT00112502.
同步放化疗后给予辅助替莫唑胺是新诊断胶质母细胞瘤的标准治疗方法。添加其他活性药物可能会提高治疗效果。
这项析因II期研究的主要目的是确定添加到剂量密集型替莫唑胺（ddTMZ）中的3种潜在化疗药物之一是否能改善新诊断胶质母细胞瘤患者的无进展生存期（PFS）。先前的I期试验确定了ddTMZ与异维A酸、塞来昔布和/或沙利度胺联合使用的安全性。性能状态良好且放化疗后无进展证据的成年人被随机分为8组：单独使用ddTMZ（7天用药/7天停药）或与异维A酸、塞来昔布和沙利度胺的双联、三联和四联组合。
该研究招募了155名参与者，中位年龄为53岁（范围18 - 84岁）。与不含该特定药物的组相比，没有一种药物显示出PFS改善。三联方案与双联方案的PFS没有差异，尽管观察到总生存期（OS）有改善趋势（20.1对17.0个月，P = 0.15）。与ddTMZ相比，ddTMZ +异维A酸双联方案的PFS更差（10.5对6.5个月，P = 0.043），OS也更差（21.2对11.7个月，P = 0.037）。含异维A酸方案的预后也有变差趋势，但塞来昔布或沙利度胺组合没有影响。治疗耐受性良好，淋巴细胞减少发生率较高。
结果未证实这些组合有益，但表明在ddTMZ中添加异维A酸可能有害。本研究证明了析因设计在有效测试新诊断胶质母细胞瘤药物组合方面的可行性和实用性。
NCT00112502。
