Alfred Health Radiation Oncology, Alfred Hospital, Melbourne, Australia; Radiation Oncology Princess Alexandra Hospital Raymond Terrace, Brisbane, Australia; Monash University, Melbourne, Australia; Faculty of Medicine, University of Queensland, Brisbane, Australia.
Alfred Health Radiation Oncology, Alfred Hospital, Melbourne, Australia; Monash University, Melbourne, Australia.
Int J Radiat Oncol Biol Phys. 2020 Sep 1;108(1):150-156. doi: 10.1016/j.ijrobp.2020.05.022. Epub 2020 May 22.
To determine the maximum tolerated dose (MTD) of stereotactic ablative radiation therapy (SABR) in combination with immunotherapy for the treatment of patients with metastatic melanoma. The study also investigates the effects of timing and dosing of SABR on clinical efficacy.
Metastatic melanoma patients with at least 2 metastases received SABR to a single metastatic site. All patients had standard dose immunotherapy with anti-PD1 or anti-CTLA4 at the discretion of their treating clinician. Following a standard 3 + 3 design, patients were escalated through 3 SABR doses (10 Gy, 15 Gy, and 20 Gy) delivered at 3 different time points (with cycle 1, 2, or 3 of immunotherapy). Dose-limiting toxicities (DLT) were defined as grade 3 or higher toxicity within 3 months of first treatment and assessed by an independent data safety monitoring committee (IDSMC). Logistic or Cox regressions were used to assess the impact of SABR dose and timing on the progression free (PFS) and overall survival (OS) of this cohort.
Twenty-four patients were enrolled with a median clinical follow-up of 28 months. Four patients (16.7%) developed DLTs; 1 DLT occurred at a SABR-treated site, and all patients received 15 Gy. On this basis the IDSMC recommended stopping the trial and the MTD was defined at 10 Gy. The 2-year PFS was 21.9% (95% CI, 7.1%-41.8%) and 2-year OS was 49.6% (95% CI, 28.7%-67.6%). The median PFS for those receiving 10 Gy was numerically higher than for those receiving 15 Gy, 8.3 months versus 2.1 months (P = .38). The only treatment-related factor associated with both improved PFS (HR 0.08, P < .01) and OS (HR 0.008, P ≤ .01) was receiving SABR with cycle 3. SABR dose (PFS P = .17, OS P = .50) was not significant.
SABR at 10 Gy can be safely combined with immunotherapy. SABR timing appears to influence efficacy more than dose and warrants consideration in research attempting to optimize synergism.
确定立体定向消融放疗（SABR）联合免疫治疗治疗转移性黑色素瘤患者的最大耐受剂量（MTD）。本研究还探讨了 SABR 时间和剂量对临床疗效的影响。
至少有 2 个转移灶的转移性黑色素瘤患者接受单次转移灶的 SABR 治疗。所有患者均根据治疗医生的判断接受标准剂量的免疫治疗，包括抗 PD-1 或抗 CTLA-4。采用标准的 3+3 设计，患者通过 3 种 SABR 剂量（10Gy、15Gy 和 20Gy）进行递增，剂量递增时间分别为免疫治疗的第 1 周期、第 2 周期和第 3 周期。剂量限制性毒性（DLT）定义为首次治疗后 3 个月内出现 3 级或更高级别的毒性，并由独立数据安全监测委员会（IDSMC）评估。采用逻辑或 Cox 回归分析评估 SABR 剂量和时间对该队列无进展生存期（PFS）和总生存期（OS）的影响。
共纳入 24 例患者，中位临床随访时间为 28 个月。4 例患者（16.7%）发生 DLT；1 例 DLT 发生在 SABR 治疗部位，所有患者均接受了 15Gy 治疗。在此基础上，IDSMC 建议停止试验，MTD 定义为 10Gy。2 年 PFS 为 21.9%（95%CI，7.1%-41.8%），2 年 OS 为 49.6%（95%CI，28.7%-67.6%）。接受 10Gy 治疗的患者中位 PFS 高于接受 15Gy 治疗的患者，分别为 8.3 个月和 2.1 个月（P=0.38）。唯一与 PFS（HR 0.08，P<0.01）和 OS（HR 0.008，P≤0.01）均相关的治疗相关因素是在第 3 周期接受 SABR 治疗。SABR 剂量（PFS，P=0.17；OS，P=0.50）无显著意义。
10Gy 的 SABR 可与免疫治疗安全联合应用。SABR 时机似乎比剂量更能影响疗效，在试图优化协同作用的研究中值得考虑。
