DEHART: Dose-Escalated Hypofractionated Adaptive Radiation Therapy for Head and Neck Cancers

摘要 局部失败仍然是头颈部鳞状细胞癌的主要死亡方式 （HNSCC）用常规放化疗治疗超过7周。辐射剂量递增， 在许多其他恶性肿瘤中，如非小细胞肺癌，低分割已显示出无与伦比局部控制 癌症，但由于毒性问题，在HNSCC中受阻。MR引导放射治疗（MRgRT） 允许基于肿瘤反应的自适应辐射剂量递增，这可以改善治疗效果。 结果，同时限制毒性。 我们的建议，题为剂量递增的低分割自适应放射治疗（DEHART），评估了一种新的 在患者中使用MRgRT与并行PD-1/PD-L1靶向免疫疗法进行放射递送的框架 晚期HNSCC与传统放射治疗不同，DEHART通过以下方式使用MRgRT修改辐射剂量： 在治疗过程中每周调整放射计划，增加对残留肿瘤的放射剂量 同时降低对肿瘤消退区域的辐射剂量。我们假设DEHART会安全地 在3周内分15次提供消融性辐射剂量，同时限制毒性和肿瘤的影响， 通过耐药克隆原进行再增殖，从而提高治疗率。 我们的目标是通过I期临床试验来检验这一假设，具体目标如下：（1）确定 使用MRgRT递送的DEHART方案的最大耐受剂量（MTD）， 不适合或不适合接受明确放化疗的患者人群的免疫治疗 （2）评价DEHART方案的毒性和功能结局，包括 基线言语、吞咽和生活质量;（3）评估DEHART的疗效，并获得体积和 使用MRgRT作为未来试验的假设生成数据的功能成像与疗效相关 辐射剂量的适应。为了确定DEHART方案的MTD，我们提出了一项18例患者的研究 使用改良的事件发生时间持续再评估（TITE-CRM）I期设计， 用于消退疾病的剂量水平：50戈伊/15次，55戈伊/15次和60戈伊/15次 分数 如果DEHART在本研究中被发现是安全的并显示出有效性信号，我们将进行未来的II期研究。 一项将这种新的治疗策略与常规分次放化疗的标准治疗进行比较的试验， 局部晚期HNSCC患者。

Abstract Locoregional failure remains the principal mode of mortality in head and neck squamous cell carcinomas (HNSCCs) treated with conventional chemoradiation therapy over 7 weeks. Radiation dose escalation with hypofractionation has shown unparalleled local control in many other malignancies, such as non-small cell lung cancer, but has been stymied in HNSCCs due to toxicity concerns. MR-guided radiation therapy (MRgRT) allows for adaptive radiation dose escalation based on tumor response, which may improve therapeutic outcomes while limiting toxicities. Our proposal, titled Dose-Escalated Hypofractionated Adaptive Radiotherapy (DEHART), evaluates a novel framework for radiation delivery using MRgRT with concurrent PD-1/PD-L1 targeted immunotherapy in patients with advanced HNSCCs. Unlike conventional radiotherapy, DEHART modifies radiation dose using MRgRT by adapting the radiation plan weekly during the course of treatment, escalating radiation dose to residual tumor while deescalating radiation dose to areas of tumor regression. We hypothesize that DEHART will safely deliver ablative radiation doses in 15 fractions over 3 weeks while limiting both toxicity and the effect of tumor repopulation by resistant clonogens, thus resulting in an improved therapeutic ratio. We aim to test this hypothesis through a Phase I clinical trial with the following specific aims: (1) Determine the maximum tolerated dose (MTD) of the DEHART regimen delivered using MRgRT with concurrent immunotherapy in a population of patients who are not candidates or unsuitable for definitive chemoradiation therapy; (2) Evaluate the toxicity and functional outcomes of the DEHART regimen including changes in baseline speech, swallow and quality of life; and (3) Assess the efficacy of DEHART and obtain volumetric and functional imaging correlates of efficacy using MRgRT to serve as hypothesis-generating data for future trials of radiation dose adaptation. To determine the MTD of the DEHART regimen, we propose an 18 patient study using a modified Time-to Event Continual Reassessment (TITE-CRM) Phase I Design with three radiation dose levels delivered to regressing disease: 50 Gy in 15 fractions, 55 Gy in 15 fractions and 60 Gy in 15 fractions. If DEHART is found to be safe and shows a signal of efficacy in this study, we will conduct a future Phase II trial to compare this novel treatment strategy to standard-of care conventionally fractionated chemoradiation in patients with locally advanced HNSCCs.