Cohen Justin, Anvari Akbar, Samanta Santanu, Poirier Yannick, Soman Sandrine, Alexander Allen, Ranjbar Maida, Pavlovic Ramilda, Zodda Andrew, Jackson Isabel L, Mahmood Javed, Vujaskovic Zeljko, Sawant Amit
Department of Radiation Oncology, University of Maryland School of Medicine , Baltimore, MD , USA.
Br J Radiol. 2019 Mar;92(1095):20180759. doi: 10.1259/bjr.20180759. Epub 2019 Feb 12.
: Non-ablative or mild hyperthermia (HT) has been shown in preclinical (and clinical) studies as a localized radiosensitizer that enhances the tumoricidal effects of radiation. Most preclinical in vivo HT studies use subcutaneous tumor models which do not adequately represent clinical conditions (e.g. proximity of normal/critical organs) or replicate the tumor microenvironment-both of which are important factors for eventual clinical translation. The purpose of this work is to demonstrate proof-of-concept of locoregional radiosensitization with superficially applied, radiofrequency (RF)-induced HT in an orthotopic mouse model of prostate cancer.
: In a 4-arm study, 40 athymic male nude mice were inoculated in the prostate with luciferase-transfected human prostate cancer cells (PC3). Tumor volumes were allowed to reach 150-250 mm (as measured by ultrasound) following which, mice were randomized into (i) control (no intervention); (ii) HT alone; (iii) RT alone; and (iv) HT + RT. RF-induced HT was administered (Groups ii and iv) using the Oncotherm LAB EHY-100 device to achieve a target temperature of 41 °C in the prostate. RT was administered ~30 min following HT, using an image-guided small animal radiotherapy research platform. In each case, a dual arc plan was used to deliver 12 Gy to the target in a single fraction. One animal from each cohort was euthanized on Day 10 or 11 after treatment for caspase-9 and caspase-3 Western blot analysis.
: The inoculation success rate was 89%. Mean tumor size at randomization (~16 days post-inoculation) was ~189 mm . Following the administration of RT and HT, mean tumor doubling times in days were: control = 4.2; HT = 4.5; RT = 30.4; and HT + RT = 33.4. A significant difference (p = 0.036) was noted between normalized nadir volumes for the RT alone (0.76) and the HT + RT (0.40) groups. Increased caspase-3 expression was seen in the combination treatment group compared to the other treatment groups.
: These early results demonstrate the successful use of external mild HT as a localized radiosensitizer for deep-seated tumors.
: We successfully demonstrated the feasibility of administering external mild HT in an orthotopic tumor model and demonstrated preclinical proof-of-concept of HT-based localized radiosensitization in prostate cancer radiotherapy.
非消融性或轻度热疗（HT）在临床前（和临床）研究中已被证明是一种局部放射增敏剂，可增强放射的杀肿瘤效果。大多数临床前体内热疗研究使用皮下肿瘤模型，这些模型不能充分代表临床情况（如正常/关键器官的 proximity）或复制肿瘤微环境——这两个因素对于最终的临床转化都很重要。这项工作的目的是在前列腺癌原位小鼠模型中，通过表面应用射频（RF）诱导的热疗来证明局部放射增敏的概念验证。
在一项四组研究中，40只无胸腺雄性裸鼠在前列腺中接种了荧光素酶转染的人前列腺癌细胞（PC3）。待肿瘤体积达到150 - 250立方毫米（通过超声测量）后，将小鼠随机分为：（i）对照组（无干预）；（ii）单纯热疗组；（iii）单纯放疗组；（iv）热疗 + 放疗组。使用Oncotherm LAB EHY - 100设备对单纯热疗组和热疗 + 放疗组进行RF诱导的热疗，以使前列腺达到41°C的目标温度。热疗后约30分钟，使用图像引导的小动物放射治疗研究平台进行放疗。在每种情况下，采用双弧计划单次分割向靶区给予12 Gy剂量。治疗后第10天或第11天，对每个队列中的一只动物实施安乐死，进行caspase - 9和caspase - 3的蛋白质免疫印迹分析。
接种成功率为89%。随机分组时（接种后约16天）的平均肿瘤大小约为189立方毫米。放疗和热疗后，肿瘤平均倍增时间（以天计）分别为：对照组 = 4.2；热疗组 = 4.5；放疗组 = 30.4；热疗 + 放疗组 = 33.4。单纯放疗组（0.76）和热疗 + 放疗组（0.40）的标准化最低点体积之间存在显著差异（p = 0.036）。与其他治疗组相比，联合治疗组中caspase - 3表达增加。
这些早期结果证明了成功将外部轻度热疗用作深部肿瘤的局部放射增敏剂。
我们成功证明了在原位肿瘤模型中实施外部轻度热疗的可行性，并证明了在前列腺癌放疗中基于热疗的局部放射增敏的临床前概念验证。
