a Cancer Therapy Evaluation Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Bethesda, Maryland;
Radiat Res. 2014 Aug;182(2):252-7. doi: 10.1667/RR13707.1. Epub 2014 Jul 8.
As the immunotherapy of cancer comes of age, adding immunotherapeutic agents to radiation therapy has the potential to improve the outcomes for patients with a wide variety of malignancies. Despite the enormous potential of such combination therapy, laboratory data has been lacking and there is little guidance for pursuing novel treatment strategies. Animal models have significant limitation in combining radiation therapy with immunotherapy and some of the limitations of preclinical models are discussed in this article. In addition to the preclinical challenges, radiation therapy and immunotherapy combinations may have overlapping toxicities, and for both types of therapy, early and late manifestations of toxicity are possible. Given these risks, special attention should be given to the design of the specific Phase I clinical trial that is chosen. In this article, we describe several Phase I design possibilities that may be employed, including the 3 + 3 design (also known as the cohort of 3 design), the continual reassessment method (CRM), and the time-to-event continual reassessment method (TITE-CRM). Efficacy end points for further development of combination therapy must be based on multiple factors, including disease type, stage of disease, the setting of therapy and the goal of therapy. While the designs for future clinical trials will vary, it is clear that these two successful modalities of therapy can and should be combined for the benefit of cancer patients.
随着癌症免疫疗法的成熟，将免疫治疗药物与放射治疗相结合，有可能改善各种恶性肿瘤患者的治疗效果。尽管这种联合治疗具有巨大的潜力，但缺乏实验室数据，并且缺乏探索新治疗策略的指导。动物模型在将放射治疗与免疫治疗相结合方面存在显著的局限性，本文讨论了一些临床前模型的局限性。除了临床前的挑战，放射治疗和免疫治疗的组合可能具有重叠的毒性，对于这两种类型的治疗，都有可能出现早期和晚期的毒性表现。鉴于这些风险，应特别注意选择的具体 I 期临床试验的设计。在本文中，我们描述了几种可能采用的 I 期设计方案，包括 3+3 设计（也称为 3 队列设计）、连续评估法（CRM）和时间事件连续评估法（TITE-CRM）。联合治疗进一步发展的疗效终点必须基于多种因素，包括疾病类型、疾病阶段、治疗环境和治疗目标。虽然未来临床试验的设计会有所不同，但很明显，这两种成功的治疗模式可以而且应该结合起来，使癌症患者受益。
