Clinical Trial of Oral Nelfinavir before and during Radiation Therapy for Advanced Rectal Cancer
Clinical Trial of Oral Nelfinavir before and during Radiation Therapy for Advanced Rectal Cancer
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DOI：
10.1158/1078-0432.ccr-15-1489
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发表时间：
2016-04-15
影响因子：
11.5
通讯作者：
Sharma, Ricky A.
中科院分区：
文献类型：
--
作者：
Hill, Esme J.;Roberts, Corran;Sharma, Ricky A.
目的：奈非那韦是一种PI 3 K通路抑制剂，是一种放射增敏剂，在临床前模型中增加肿瘤血流量。我们进行了一项早期研究，以证明奈非那韦联合低分割放射治疗（RT）的安全性，并开发肿瘤灌注和放射增敏的生物标志物，用于这种组合approach.Experimental Design：10例T3-4 N 0 -2 M1直肠癌患者接受7天的口服奈非那韦（1，250 mg b.i.d.）在盆腔RT期间再用奈非那韦7天（25戈伊/5次/7天）。灌注CT（p-CT）和DCE-MRI扫描进行了治疗前，后7天的奈非那韦和RT的最后一部分之前。活检采取治疗前和RT的最后一部分后7天进行了分析肿瘤细胞密度（TCD）。在DCE-MRI上，与奈非那韦联合治疗期间，中位Ktranss平均增加42%，p-CT上的平均血流量相应增加30%。中位TCD从基线时的24.3%降至RT后7天活检的9.2%（P = 0.01）。总体而言，5的9个可评估的患者表现出良好的肿瘤消退MRI评估肿瘤消退等级（mrTRG）。结论：这是第一项研究，以评估奈非那韦与RT相结合，没有同时化疗。研究表明，奈非那韦-RT耐受性良好，并且与直肠肿瘤血流量增加有关。奈非那韦-RT与单独RT相比的疗效值得临床评价，包括测量肿瘤血流量。(C)2016年AACR。
Purpose: Nelfinavir, a PI3K pathway inhibitor, is a radiosensitizer that increases tumor blood flow in preclinical models. We conducted an early-phase study to demonstrate the safety of nelfinavir combined with hypofractionated radiotherapy (RT) and to develop biomarkers of tumor perfusion and radiosensitization for this combinatorial approach.Experimental Design: Ten patients with T3-4 N0-2 M1 rectal cancer received 7 days of oral nelfinavir (1,250 mg b.i.d.) and a further 7 days of nelfinavir during pelvic RT (25 Gy/5 fractions/7 days). Perfusion CT (p-CT) and DCE-MRI scans were performed pretreatment, after 7 days of nelfinavir and prior to the last fraction of RT. Biopsies taken pretreatment and 7 days after the last fraction of RT were analyzed for tumor cell density (TCD).Results: There were 3 drug-related grade 3 adverse events: diarrhea, rash, and lymphopenia. On DCE-MRI, there was a mean 42% increase in median Ktrans, and a corresponding median 30% increase in mean blood flow on p-CT during RT in combination with nelfinavir. Median TCD decreased from 24.3% at baseline to 9.2% in biopsies taken 7 days after RT (P = 0.01). Overall, 5 of 9 evaluable patients exhibited good tumor regression on MRI assessed by tumor regression grade (mrTRG).Conclusions: This is the first study to evaluate nelfinavir in combination with RT without concurrent chemotherapy. It has shown that nelfinavir-RT is well tolerated and is associated with increased blood flow to rectal tumors. The efficacy of nelfinavir-RT versus RT alone merits clinical evaluation, including measurement of tumor blood flow. (C) 2016 AACR.