By Lynda Williams, medwireNews Reporter
medwireNews: A short course of hypofractionated proton beam therapy given alongside temozolomide may offer an improvement in overall survival (OS) for patients aged 65 years and older with a new diagnosis of glioblastoma, suggesting findings from a “hypothesis-generating” study.
After a median follow-up of 25.4 months, the median OS survival at 12 months was 56% for the 39 participants, and the median progression-free survival (PFS) at 12 months was 31%. The median durations of OS and PFS were 13.1 and 7.1 months, respectively, report Sujay Vora (Mayo Clinic, Phoenix, Arizona, USA) and co-workers.
“These [OS] results are superior to those of previous phase 3 studies of older patients receiving hypofractionated radiotherapy, which reported [OS] durations ranging from 5 months to 10 months”, they write in The Lancet Oncology.
The phase 2, single-arm study participants were aged a median of 70.2 years, 72% were men and 95% were White; all had a new diagnosis of WHO grade 4, malignant glioblastoma that was confirmed by resection or biopsy. All patients had IDH wildtype glioblastoma, and MGMT promotor status was methylated in 33%, unmethylated in 62% and unknown in 5%.
The patients were treated with a 1- or 2-week protocol of dose-escalated proton beam therapy, guided by 3,4-dihydroxy-6-[18F]fluoro-L-phenylalanine positron emission tomography, to a dose of 35–40 Gy.
Patients with a tumour volume of up to 65 cm3 were treated with 5 fractions over 1 week, while those with a larger tumour volume received 10 fractions over 2 weeks. Concurrent oral temozolomide 75 mg/m2 was given daily during proton beam therapy. Six cycles of temozolomide were then initiated 1 month later, at a dose of 150–200 mg/m2 on days 1–5 of each 28-day cycle.
Post-hoc analysis indicated that patients with MGMT promotor methylation had significantly longer median OS than those without (21.8 vs 10.7 months) but there was no correlation between the genetic marker and PFS (12.0 vs 6.0 months).
Vora et al say that “[a]ll patients were able to complete the prescribed radiotherapy course with concurrent temozolomide without any treatment breaks”, and that after considering baseline status, most of the probably or definitely treatment-related adverse events (TRAEs) were “relatively mild”, with no grade 4 or 5 AEs.
Grade 1, 2 and 3 TRAEs occurred in 77%, 44% and 13% of patients, respectively, with the most prevalent being central nervous system necrosis, occurring at corresponding rates of 36%, 33% and 10%, followed by grade 1 alopecia (62%) and fatigue (36%).
The researchers also monitored cognitive function and quality of life, with 97% of patients completing the Mini-Mental State Evaluation (MMSE) and 92% the EORTC QLC-C30 and QLQ-BN20 forms at baseline, and again a median of three and four times after treatment, respectively.
Overall, 66% of 38 patients maintained cognitive function, as demonstrated by a less than a 3-point decrease in their MMSE throughout the study and this included until progression in 85% of the 27 patients affected. Median time to either a 10-point or greater deterioration in QoL or increase in symptom burden was 7.6 months.
“Our hypofractionated treatment regimen efficiently delivered radiotherapy in only 1–2 weeks, and all patients who started radiotherapy completed the entire course”, the authors write.
“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”, they note.
Other advantages of proton beam therapy over conventional external beam radiotherapy include elimination of the radiation exit dose to reduce radiation exposure to healthy brain tissue, a higher relative biological effectiveness and less lymphopenia, Vora and co-workers summarise.
Acknowledging the study limitations of small patient numbers, use of a historical control group and the limited availability of proton beam therapy, the team concludes that their research is “hypothesis-generating” and that a larger phase 2, randomised study of proton and photon-based radiation is now underway in patients with glioblastoma of any age.
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Lancet Oncol 2024; doi:10.1016/S1470-2045(24)00585-0