Short-course hypofractionated proton beam therapy, incorporating 18F-DOPA PET and contrast-enhanced MRI targeting, for patients aged 65 years and older with newly diagnosed glioblastoma: a single-arm

Prof Sujay Vora, MDa ∙ Deanna Pafundi, PhDd ∙ Molly Voss, BSe ∙ Matthew Buras, MSe ∙ Jonathan Ashman, MDa ∙ Prof Bernard R Bendok, MDb  Lancet Oncol 2024; 25: 1625–34 Published Online

November 18, 2024

https://doi.org/10.1016/

S1470-2045(24)00585-0 Summary

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.

요약 (Summary)

배경(Background)

·         65세 이상 고령의 교모세포종(Glioblastoma) 환자는 젊은 환자에 비해 예후가 나쁘고, 중앙 생존기간은 6–9개월임.

·         18F-DOPA PET은 대사적으로 활발한 교모세포종을 민감하고 특이적으로 찾아내어 표적치료에 유용함

·         양성자빔 치료(proton beam therapy)는 광선 방사선(photon radiotherapy)보다 정상 뇌조직을 덜 손상시켜, 환자의 삶의 질(QOL)을 향상시킬 수 있음

·         이 연구는 고령 환자에서 저분할 양성자빔 치료가 생존률과 삶의 질을 향상시킬 수 있는지를 확인하기 위해 진행됨.

방법(Methods)

·         단일군, 2상 임상시험

·         대상:

o    65세 이상,

o    ECOG 수행능력 점수 0–2,

o    새롭게 진단된 WHO grade 4 교모세포종 환자

o    장소: Mayo Clinic (미국 애리조나 피닉스, 미네소타 로체스터)

·         방사선 치료 표적 부위:

o    18F-DOPA PET 및 조영증강 MRI로 설정

·         치료 요법:

o    저분할 양성자빔 치료 : 5회 또는 10회에 걸쳐 35–40 Gy 상당의 방사선

o    경구 테모졸로마이드 병용 (75 mg/m²를 5회 요법: 7일간(1~7일간), 75 mg/m²를 10회 요법: 14일간 투약(1~14일간)

o    방사선 치료 종료 후 1개월 뒤부터 보조 테모졸로마이드 (150–200 mg/m², 5일간, 28일 간격으로 6주기)

·         주 평가 지표:

o    등록 후 12개월 생존률

o    분석군: 치료 시작한 모든 환자 (intention-to-treat)

·         ClinicalTrials.gov (NCT03778294)**에 등록되었으며 현재 완료된 상태

결과(Findings)

·         등록 환자 수: 43명 (2019.5.22 ~ 2021.5.25)→ 이 중 39명 치료 시작(진행, 사망, 보험 거절 등으로 4명 제외)

·         환자 특성:

o    중앙 연령: 70.2세

o    남성 72%, 여성 28%

o    대부분 백인(95%) (백인 37명(95%), 흑인 1명(3%), 비공개 1명)

·         중앙 추적 기간: 25.4개월 (2024.1.30 기준)

·         12개월 생존률: 56% (22명 생존)

·         중앙 전체 생존기간: 13.1개월 (기존보다 향상됨)

·         3등급 이상 이상반응:

o    중추신경계 괴사(CNS necrosis):  4명 (10%)

o    혈소판 감소증: 1명 (3%)

o    4등급 이상반응 및 치료 관련 사망 없음

해석(Interpretation)

·         기존 역사적 대조군 보다 생존률 향상이 관찰 되었으며, 부작용도 비교적 낮고 양호함.

·         이러한 결과를 바탕으로,새로 진단된 모든 연령대의 교모세포종 환자를 대상으로 본 치료법과 표준 치료를 비교하는 제2상 임상시험(NCT05781321)이 진행 중임.

연구 지원(Funding)

·         Mayo Clinic Marley Endowment Funds

Lawrence W 및 Marilyn W Matteson 암 연구 기금