Background

Older patients (aged ≥65 years) with glioblastoma have a worse prognosis than younger patients and a median overall survival of 6–9 months. 3,4-Dihydroxy-6-[¹⁸F]fluoro-L-phenylalanine (¹⁸F-DOPA) PET sensitively and specifically identifies metabolically active glioblastoma for preferential targeting. Proton beam therapy potentially improves quality of life (QOL) by sparing more healthy brain tissue than photon radiotherapy. With improved targeting and the dosimetric advantages of proton beam therapy, we aimed to test whether hypofractionated proton beam therapy could improve survival and QOL in older patients with glioblastoma.

Methods

In this single-arm phase 2 trial, we enrolled patients aged 65 years and older with an Eastern Cooperative Oncology Group performance status score of 0–2 and newly diagnosed WHO grade 4, malignant glioblastoma from two Mayo Clinic campuses (Phoenix, AZ, and Rochester, MN, USA). Radiotherapy target volumes were defined by ¹⁸F-DOPA PET and MRI regions of contrast enhancement. Patients were given dose-escalated hypofractionated proton beam therapy (35–40 Gy equivalents in five or ten treatments) plus oral concurrent temozolomide (75 mg/m² daily on days 1–7 for the five-treatment regimen or on days 1–14 for the ten-treatment regimen), and 1 month after completing radiotherapy patients were given adjuvant temozolomide (150–200 mg/m² on days 1–5 for six 28-day cycles). The primary endpoint was overall survival at 12 months after enrolment. The primary endpoint and safety were assessed in the intention-to-treat population (defined as all eligible patients who started radiotherapy). This study is registered with ClinicalTrials.gov, NCT03778294, and is now complete.

Findings

Between May 22, 2019, and May 25, 2021, 43 patients were enrolled, of whom four did not receive treatment because of progression (n=2), death (n=1), or insurance denial (n=1), such that 39 patients received treatment (median age 70·2 years [IQR 67·4–74·3]; 11 [28%] of 39 patients were female, 28 [72%] were male, 37 [95%] were White, one [3%] was Black or African American, and one chose not to disclose their race). As of data cutoff (Jan 30, 2024), median follow-up was 25·4 months (IQR 22·1–29·7). 22 (56% [95% CI 39–72]) of 39 patients were alive at 12 months. Median overall survival was 13·1 months (95% CI 11·1–19·1). Grade 3 baseline-adjusted, treatment-associated adverse events were CNS necrosis (four [10%] of 39) and thrombocytopenia (one [3%]). No baseline-adjusted, treatment-associated grade 4 adverse events or deaths occurred.

Interpretation

We observed improved overall survival compared with historical controls and a promising adverse event profile by using ¹⁸F-DOPA PET−guided, dose-escalated, hypofractionated proton beam therapy. These findings have resulted in the opening of a phase 2 study (NCT05781321) investigating this regimen versus standard-of-care treatment in adults of any age with newly diagnosed glioblastoma.

Funding

Mayo Clinic Marley Endowment Funds and the Lawrence W and Marilyn W Matteson Fund in Cancer Research.

中文翻译：

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针对 65 岁及以上新诊断的胶质母细胞瘤患者的短程大分割质子束治疗，结合 18F-DOPA PET 和对比增强 MRI 靶向：一项单臂 2 期试验

 背景

患有胶质母细胞瘤的老年患者 （≥65 岁） 的预后比年轻患者更差，中位总生存期为 6-9 个月。3,4-二羟基-6-[¹⁸F]氟-L-苯丙氨酸 （¹⁸F-DOPA） PET 可灵敏且特异性地识别代谢活跃的胶质母细胞瘤，以优先靶向。质子束治疗比光子放射治疗保留更多健康的脑组织，从而可能改善生活质量 （QOL）。随着质子束治疗的靶向性和剂量学优势的提高，我们旨在测试大分割质子束治疗是否可以提高老年胶质母细胞瘤患者的生存率和 QOL。

 方法

在这项单臂 2 期试验中，我们招募了来自梅奥诊所两个院区（亚利桑那州凤凰城和美国明尼苏达州罗切斯特）的 65 岁及以上、东部肿瘤合作组体能状态评分为 0-2 分且新诊断为 WHO 4 级恶性胶质母细胞瘤的患者。放疗靶区体积由 ¹⁸个 F-DOPA PET 和 MRI 对比增强区域定义。患者接受剂量递增的大分割质子束治疗（5 次或 10 次治疗中 35-40 Gy 当量）加口服同步替莫唑胺（5 次治疗方案第 1-7 天每天 75 mg/m² 或第 10 次治疗方案第 1-14 天每天一次），放疗完成后 1 个月，患者给予替莫唑胺辅助治疗 （150-200 mg/m²第 1-5 天，共 6 个 28 天周期）。主要终点是入组后 12 个月的总生存期。在意向治疗人群 （定义为所有开始放疗的符合条件的患者） 中评估主要终点和安全性。这项研究已在 ClinicalTrials.gov NCT03778294 注册，现已完成。

 发现

在 2019 年 5 月 22 日至 2021 年 5 月 25 日期间，共纳入 43 名患者，其中 4 名因进展 （n=2）、死亡 （n=1） 或保险否认 （n=1） 而未接受治疗，因此 39 名患者接受了治疗（中位年龄 70·2 岁 [IQR 67·4–74·3];39 名患者中有 11 名 [28%] 为女性，28 名 [72%] 为男性， 37 名 [95%] 是白人，一名 [3%] 是黑人或非裔美国人，一名选择不透露他们的种族）。截至数据截止日（2024 年 1 月 30 日），中位随访时间为 25·4 个月 （IQR 22·1–29·7）。39 例患者中有 22 例 （56% [95% CI 39-72]） 在 12 个月时存活。中位总生存期为 13·1 个月 （95% CI 11·1–19·1）。3 级基线调整的治疗相关不良事件是 CNS 坏死（39 例中的 4 例 [10%]）和血小板减少症（1 例 [3%]）。未发生基线调整的、与治疗相关的 4 级不良事件或死亡。

 解释

与历史对照相比，我们观察到使用 ¹⁸F-DOPA PET 引导、剂量递增、大分割质子束治疗提高了总生存期和有希望的不良事件概况。这些发现导致了一项 2 期研究 （NCT05781321） 的开始，该研究调查了该方案与标准护理治疗在任何年龄的新诊断胶质母细胞瘤成人中的疗效。

 资金

妙佑医疗国际 Marley 捐赠基金以及癌症研究领域的 Lawrence W 和 Marilyn W Matteson 基金。