CANCER THERAPY WITH RETINOIDS, INTERFERON, AND RADIATION

这个项目的目标是结合生物反应 修饰药物13-顺式维甲酸和干扰素α-2a， 超分割放射治疗，以努力改善 头颈部局部进展期患者的治疗结果 癌症。 据估计，将有29,600人罹患头颈癌 1994年在美国。大约7925人(27%)将死亡 从疾病中脱身。放射治疗是主要的治疗方法。 治疗头颈癌的临床研究 不能在没有不适当的并发症的情况下通过手术切除。潜力 手术并发症包括毁容和失声或 可听懂的语言取决于肿瘤发生的部位。 由于这些肿瘤中的许多都是大的和局部晚期的， 治疗结果往往很差。不到30%的这类患者 是用常规放射治疗治愈的，使用 超分割放射治疗(每日多次放射治疗) 改善了晚期头颈癌的局部控制 而不会增加正常组织损伤。在这些 患者，存活率有改善的趋势，但 这并不重要。 最近，13-顺式维甲酸和干扰素α-2a已经被 放射治疗联合治疗大肠癌的临床研究 宫颈有较高的反应率。α干扰素和 维甲酸增强放射细胞毒性。我们已经获得了 初步数据表明，维甲酸的结合 和干扰素α增强辐射对小鼠的细胞毒性 组织培养中的细胞系。 在这个拟议项目的初始阶段，第一阶段试验 将确定13-顺式维甲酸的最大耐受量 和干扰素α，可以与超分割 局部晚期和颈部肿瘤患者的放射治疗 癌症。如果这些代理能够在阶段中成功组合 I期试验，超分割放射治疗的II期试验 最大耐受量的药物将在相同的 病人群体。如果有足够的证据证明 该方案的活性，这是一项随机的III期试验 将启动与超分割放射治疗相比较的方案 通过合作组机制。 伴随临床试验的将是支持性的基础 侧重于辐射敏感性变化的实验室项目 干扰素-α和顺式维甲酸诱导。 随着头颈部癌症的分子生物学变化 在一项平行研究中，将尝试将 临床试验中对治疗的反应(S) 肿瘤中可识别的基因变化。

The objective of this project is to combine the biologic response modifying drugs, 13-cis-retinoic acid an interferon alfa-2a, with hyperfractionated radiotherapy in an effort to improve the treatment outcome of patients with locally advanced head and neck cancer. An estimated 29,600 individuals will develop head and neck cancer in the United States in 1994. Approximately 7,925 (27%) will die from the disease. Radiation therapy is used as the primary treatment for patients with cancers of the head and neck that cannot be surgically removed without undue morbidity. Potential surgical morbidity would include disfigurement and loss of voice or intelligible speech depending on the site in which the tumor arose. Because many of these tumors are large and locally advanced, the treatment outcome is often poor. Fewer than 30% of such patients are cured with conventional radiation treatment The use of hyperfractionated radiation (multiple daily radiation treatments) has improved the local control of advanced head and neck cancer without any concomitant increase in normal tissue injury. In these patients, there was a trend towards improvement in survival but this was not significant. Recently, 13-cis-retinoic acid and interferon alfa-2a have been combined with radiation therapy in patients with large cancers of the uterine cervix with high response rates. Alpha interferon and retinoic acid enhance radiation cytotoxicity. We have obtained preliminary data to suggest that the combination of retinoic acid and interferon alpha enhance the cytotoxicity of radiation against cell lines in tissue culture. In the initial phase of this proposed project, a phase I trial would determine the maximum tolerated doses of 13-cis-retinoic acid and interferon alpha that could be combined with hyperfractionated radiation therapy in patients with locally advanced and neck cancer. If these agents can be successfully combined in the Phase I trial, a phase ll trial of hyperfractionated radiation with these agents at the maximum tolerated dose would be conducted in the same patient population. If there is sufficient evidence of promising activity of this regimen, a randomized, phase III trial of the regimen compared to hyperfractionated radiation would be initiated through the cooperative group mechanism. Accompanying the clinical trial would be supportive basic laboratory projects focused on changes in radiation sensitivity induced by interferon-alfa and cis-retinoic acid. As molecular biologic changes in head and neck cancers are being studied in a parallel study, an attempt will be made to correlate responses to treatment in the clinical trial(s) with any identifiable genetic changes in the tumors.