Accelerated Hypofractionated Radiotherapy in the Era of Concurrent Temozolomide Chemotherapy in Elderly Patients with Glioblastoma Multiforme

Abstract

IntroductionPatients with glioblastoma multiforme (GBM) over age 65 represent nearly half of those diagnosed per annum. They have a different tumor markers profile, physiologic reserve, and a median survival as low as three to four months. An optimal treatment strategy in older GBM patients remains undefined, with many patients receiving radiation in 30 treatments over six weeks, a regimen based on trials originally excluding patients over age 70. Recent studies have suggested reducing the number of treatments to 10-15 over two to three weeks with similar efficacy. We present an elderly population of patients treated with six radiation treatments.MethodsAfter IRB approval, we reviewed the electronic medical records of 20 consecutive patients over the age 60 at diagnosis with GBM, treated with maximally safe neurosurgical resection, and adjuvant hypofractionated radiation (HFRT) and temozolomide (TMZ) between 2012 and 2015. HFRT was given every other weekday for two weeks, in a total of six fractions (6 × 6 Gy to contrast-enhancing tumor +5 mm and 6 × 4 Gy to fluid-attenuated inversion recovery (FLAIR) +2 cm) with concurrent TMZ (75 mg/m2 daily), followed by adjuvant TMZ (150-200 mg/m2 in 5/28 days). The response was assessed using the Macdonald and Revised Assessment in Neuro-Oncology (RANO) criteria, radiology reports, physician notes, and tumor board consensus notes. Descriptive statistics, overall survival (OS), progression-free survival (PFS), toxicity, and steroid use were calculated and compared to the historical controls of patients treated with a six-week radiation regimen of 60 Gy in 30 fractions with TMZ. ResultsThe median age at diagnosis was 70.5 years (range: 61 - 82 years). Median pre-radiation Karnofsky performance scale (KPS) was 60 (range: 40 - 90). The median preoperative maximum gross tumor diameter on MRI was 3.6 cm (range: 1.8 - 6 cm). Six patients (30%) had a gross total resection (GTR), eight (40%) had a subtotal resection (STR), and six (30%) had biopsy only. The median progression-free survival was five months (95% (confidence interval) CI: 2.8, 16.4) and median OS of 14 months (95% CI: 5.0, upper limit not estimable). Of the 19 patients tested for isocitrate dehydrogenase-1 (IDH), 100% were negative. Of the eight patients who had MGMT methylation status results, four (50%) were positive for O6-methylguanine-DNA methyltransferase (MGMT) methylation. In the 18 patients who completed radiation, the HFRT treatment was well tolerated without any Grade 3/4 acute toxicities.ConclusionsThe accelerated adjuvant course of HFRT with TMZ used for the elderly with GBM decreases radiation treatment days to six. It was well tolerated in patients over 60 years of age and provided similar OS, PFS, minimal toxicity, and decreased steroid usage compared to historical controls treated with six or even two to three weeks of radiotherapy.

Hypofractionated radiotherapy and concomitant temozolomide for high-grade glial tumors in elderly patients

“…In Uto et al's trial, only one patient had experienced grade 4 hematological adverse event, and no grade 3 or higher nonhematological adverse event was found (12). In Greer et al's study, hypofractionated RT was well tolerated, in which no RTOG grade 3/4 toxicities was reported (17). Similarly, in our study, any grade3/4toxicity was not noted.…”

PD-L1/PD-1 Axis in Glioblastoma Multiforme

“…However, not all studies agreed on this point. Research by Joseph et al indicates the existence of a negative relationship between VEGF-related genes and the activity of the PD-L1/PD1 axis [3]. A thorough understanding of the nature of this relationship requires further work.…”

“…The standard approach to glioma treatment consists in the most extensive as possible surgical resection and in adjuvant radiation strengthened by temozolomide (TMZ) administration [2]. The median overall survival (OS) oscillates between 14 and 17 months [3,4]. The survival rate of patients in a three-year follow up oscillates around 10% [5].…”

Glioma Stem Cells Upregulate CD39 Expression to Escape Immune Response through SOX2 Modulation

“…Despite extensive surgical resection and adjuvant radiotherapy with temozolomide (TMZ) management, tumor recurrence always occurs. In recurrent GBM, the median overall survival is estimated to be 24-44 weeks [2,3]. Increasing evidence showed that the low survival rate is closely related to GSCs [4].…”