Chan Emily, Arlinghaus Lori R, Cardin Dana B, Goff Laura, Berlin Jordan D, Parikh Alexander, Abramson Richard G, Yankeelov Thomas E, Hiebert Scott, Merchant Nipun, Bhaskara Srividya, Chakravarthy Anuradha Bapsi
Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, United States.
Vanderbilt University Institute of Imaging Science, United States.
Radiother Oncol. 2016 May;119(2):312-8. doi: 10.1016/j.radonc.2016.04.013. Epub 2016 Apr 19.
This single institution phase I trial determined the maximum tolerated dose (MTD) of concurrent vorinostat and capecitabine with radiation in non-metastatic pancreatic cancer.
Twenty-one patients received escalating doses of vorinostat (100-400mg daily) during radiation. Capecitabine was given 1000mg q12 on the days of radiation. Radiation consisted of 30Gy in 10 fractions. Vorinostat dose escalation followed the standard 3+3 design. No dose escalation beyond 400mg vorinostat was planned. Diffusion-weighted (DW)-MRI pre- and post-treatment was used to evaluate in vivo tumor cellularity.
The MTD of vorinostat was 400mg. Dose limiting toxicities occurred in one patient each at dose levels 100mg, 300mg, and 400mg: 2 gastrointestinal toxicities and one thrombocytopenia. The most common adverse events were lymphopenia (76%) and nausea (14%). The apparent diffusion coefficient (ADC) increased in most tumors. Nineteen (90%) patients had stable disease, and two (10%) had progressive disease at time of surgery. Eleven patients underwent surgical exploration with four R0 resections and one R1 resection. Median overall survival was 1.1years (95% confidence interval 0.78-1.35).
The combination of vorinostat 400mg daily M-F and capecitabine 1000mg q12 M-F with radiation (30Gy in 10 fractions) was well tolerated with encouraging median overall survival.
本单中心I期试验确定了伏立诺他与卡培他滨同步放疗在非转移性胰腺癌中的最大耐受剂量（MTD）。
21例患者在放疗期间接受递增剂量的伏立诺他（每日100 - 400mg）。在放疗日给予卡培他滨1000mg，每12小时一次。放疗为10次分割，共30Gy。伏立诺他剂量递增遵循标准的3 + 3设计。未计划将伏立诺他剂量增至400mg以上。治疗前后采用扩散加权（DW）-MRI评估体内肿瘤细胞密度。
伏立诺他的MTD为400mg。在剂量水平100mg、300mg和400mg时，各有1例患者出现剂量限制性毒性：2例胃肠道毒性和1例血小板减少。最常见的不良事件是淋巴细胞减少（76%）和恶心（14%）。大多数肿瘤的表观扩散系数（ADC）升高。19例（90%）患者病情稳定，2例（10%）在手术时病情进展。11例患者接受了手术探查，4例R0切除，1例R1切除。中位总生存期为1.1年（95%置信区间0.78 - 1.35）。
每日400mg周一至周五的伏立诺他与每日1000mg周一至周五的卡培他滨联合放疗（10次分割，共30Gy）耐受性良好，中位总生存期令人鼓舞。
