Phase I Clinical Trial of Everolimus Combined with Trimodality Therapy in Patients with Muscle-Invasive Bladder Cancer.
Phase I Clinical Trial of Everolimus Combined with Trimodality Therapy in Patients with Muscle-Invasive Bladder Cancer.
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DOI：
10.3233/blc-160090
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发表时间：
2017-04-27
期刊：
影响因子：
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通讯作者：
Kassouf W
中科院分区：
文献类型：
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作者：
Bachir BG;Souhami L;Mansure JJ;Cury F;Vanhuyse M;Brimo F;Aprikian AG;Tanguay S;Sturgeon J;Kassouf W
背景：肌层浸润性膀胱癌（MIBC）三联疗法（TMT）后的局部控制需要进一步优化。目的：评估 MIBC 患者中依维莫司联合 TMT 的生物学终点、可行性和毒性。方法：这是一项针对不适合手术或拒绝膀胱切除术的 MIBC 患者的 I 期试验。最大程度经尿道肿瘤切除术后，患者接受放射治疗（50Gy/20 次）、吉西他滨（100mg/m2/每周）和递增剂量的依维莫司（2.5-5.0mg/天）。放疗前、治疗期间和放疗后 1 个月，每天给予依维莫司 1 个月。毒性评估遵循放射治疗肿瘤学组急性放射发病率评分标准。使用免疫组织化学评估磷酸-S6 (pS6) 下调的生物学终点。治疗后通过影像学和膀胱活检评估局部反应。结果：共招募10名患者；男8人，女2人。中位年龄为 78 岁（范围：63-85 岁）。 4 名患者进入依维莫司 2.5mg 队列。其他 6 名患者进入依维莫司 5.0mg 队列。 2 名患者（I 级）、6 名患者（II 级）、9 名患者（III 级）和 1 名患者（IV 级）出现毒性，有些患者出现不止一种毒性。大多数 III 级和 IV 级毒性是在联合测试之前单独使用依维莫司时遇到的。由于毒性，试验提前终止。有趣的是，6/10 的患者 (60%) 获得完全缓解，治疗后活检呈阴性。治疗后 pS6 显着下降 (p = 0.03)。结论：尽管依维莫司与 TMT 联合治疗在大量 MIBC 和不良预后因素患者中实现了生物学终点和完全缓解，但它与不可接受的毒性增加相关。
Background: Local control following trimodality therapy (TMT) for muscle-invasive bladder cancer (MIBC) requires further optimization. Objective: Evaluating the biologic endpoint, feasibility, and toxicity of integrating everolimus to TMT in patients with MIBC. Methods: This was a phase I trial in patients with MIBC who were not surgical candidates or who refused cystectomy. Following maximal transurethral tumor resection, patients were treated by radiotherapy (50 Gy/20 fractions), gemcitabine (100 mg/m2/weekly) and escalating doses of everolimus (2.5–5.0 mg/day). Everolimus was given daily for one month prior to radiation, during treatment, and one month post-radiation. Toxicity assessment followed the Radiation Therapy Oncology Group Acute Radiation Morbidity Scoring Criteria. Biologic endpoint with downregulation of phospho-S6 (pS6) was assessed using immunohistochemistry. Local response was evaluated with imaging and bladder biopsy post-therapy. Results: 10 patients were recruited; 8 males, 2 females. Median age was 78 years (range: 63–85). Four patients entered everolimus 2.5 mg cohort. Six other patients entered everolimus 5.0 mg cohort. Toxicities were encountered in 2 patients (Grade I), 6 patients (Grade II), 9 patients (Grade III) and 1 patient (Grade IV), with some experiencing more than one toxicity. Most Grade III and IV toxicities were encountered from everolimus alone prior to combination testing. Trial was terminated early due to toxicity. Interestingly, 6/10 patients (60%) achieved a complete response with negative post-treatment biopsies. Significant decrease of pS6 was demonstrated post-therapy (p = 0.03). Conclusions: Although combining everolimus with TMT achieved a biological endpoint and complete response in a significant number of patients with MIBC and negative prognostic factors, it was associated with unacceptable increased toxicity.