Short-Course Radiation Aids Survival in Older Patients With Glioblastoma

Treatment with Dihydroxy-6-(¹⁸F)fluoro-L-phenylalanine (¹⁸F-DOPA) PET−guided, dose-escalated, hypofractionated proton beam therapy was associated with an improved overall survival (OS) compared with historical controls in patients aged 65 years and older with newly diagnosed glioblastoma, as well as an acceptable adverse effect (AE, side effects) profile, according to data from a single-arm phase 2 trial published in Lancet Oncology.

“Our hypofractionated treatment regimen efficiently delivered radiotherapy in only one to two weeks, and all patients who started radiotherapy completed the entire course,” study authors explained in a discussion of the trial data. “These regimens, which were shorter than those typically used in practice, help reduce the social and financial burdens for patients and their caregivers, particularly those who live far from treatment centers.”

Between May 22, 2019 and May 25, 2021, a total of 39 patients received treatment short-course hypofractionated proton beam therapy, incorporating ¹⁸F-DOPA PET and contrast-enhanced MRI targeting. At a data cut of Jan 30, 2024, the median follow-up was 25.4 months and 22 of the 39 patients were alive at 12 months; the median OS was 13.1 months in this patient population. Regarding safety, no baseline-adjusted, treatment-associated grade 4 (life-threatening) AEs or deaths were recorded, though four patients experienced grade 3 (severe) central nervous system (CNS) necrosis and one patient experienced grade 3 thrombocytopenia.

“In the current study, the median OS of patients with MGMT promoter methylation was significantly longer than that of patients without MGMT methylation and was similar to outcomes in the EORTC/NCIC trial, despite our study having an older patient population, more patients undergoing biopsy only and including only patients with IDH wildtype glioblastoma,” study authors emphasized

Understanding the Outcomes of the Phase 2 Trial

Accounting for 49% of malignant CNS cases among adults in the U.S., glioblastoma is the most common primary malignant intracranial tumor among individuals, and its incidence increases with age. Specifically, patients older than 65 have considerably worse five-year survival rates than younger patients with the disease do. Because older patients with glioblastoma have worse survival, short-course radiotherapy schedules were developed in order to reduce treatment burden on patients and phase 3 trials have shown similar survival rates for patients receiving this hypofractionated radiotherapy versus longer course therapy.

Despite these similar survival rates, investigators go on to note that appropriate target delineation remains a challenge in glioblastoma and treatment approaches used to address these challenges have concerning deficiencies because tumors can extend beyond the contrast-enhanced regions. Therefore, improved targeting is believed to potentially be able to reduce treatment margins while facilitating dose escalation of metabolically active areas. ¹⁸F-DOPA PET is a sensitive and specific approach that may be able to identify metabolically active glioblastoma, specifically when combined with proton beam therapy, an advanced form of external beam radiotherapy.

“We hypothesized that to effectively and safely treat patients with shorter radiation courses and higher doses per treatment, we needed to combine improved targeting [like, use of ¹⁸F-DOPA PET] with the dosimetric advantages of proton beam therapy,” investigators explained.

To investigate the hypothesis, investigators enrolled eligible patients at two campuses of Mayo Clinic: one in Phoenix, Arizona, and the other in Rochester, Minnesota. Eligible participants consisted of patients aged 65 years or older with newly diagnosed, histologically confirmed, WHO grade 4, malignant glioblastoma following surgical resection or biopsy with an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 to 2.

The primary end point of the study was 12-month OS rate which was defined from date of enrolment until date of death or last follow-up, while secondary end points were 12-month progression-free survival (PFS) and AEs, which was defined as time to first progression or death due to any cause.

Enrolled patients had a median age of 70.2 years and a majority of them were male. Participants were treated with a median of five cycles and salvage therapy at progression included chemotherapy, surgery, repeat radiotherapy and tumor treating fields (TTFields).

Moreover, at 12 months, PFS was 31% and 69% of patients had progression. Investigators noted that 10 patients had PFS events and 17 died. At the data cutoff, the median PFS was 7.1 months.

All patients were able to complete the radiotherapy and prescribed treatment courses without any breaks and the median time observed to quality-of-life deterioration was 7.6 months.

“We observed improved OS compared with historical controls and a promising AE 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 investigating this regimen versus standard-of-care treatment in adults of any age with newly diagnosed glioblastoma,” the study authors concluded.

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