This is the long-awaited final analysis of the EORTC 26053 (CATNON) Phase III trial, which utilized a 2x2 factorial design to parse the contributions of concurrent vs. adjuvant temozolomide (TMZ)...

RTOG 0424 was a single-arm phase II study of LGG patients with > 3 risk factors (age > 40, astrocytoma, bi-hemispheric tumor, size > 6 cm or preoperative neurologic function status >1) treated with RT (54 Gy/30 fractions) with concurrent TMZ and up to 12 cycles of adjuvant TMZ. The primary endpoint was overall survival with secondary endpoints of PFS and impact of MGMT methylation status on outcomes. The initial results published in 2015 showed a three-year overall survival of 73.1 %, significantly improved over the historical control OS rate of 54% (P <.001). Three-year progression-free survival was 59.2% and median survival was not reported. 

The OS results were confirmed in the recent nine-year update which showed a three, five, and ten year OS of 73.5%, 60.9&, and 34.6%, respectively, at a median follow up of 6.8 years (9.0 years for all living patients). The median survival was 8.2 years  The three, five, and ten year PFS was 59.2%, 46.8% and 25.5% respectively, with a median PFS of 4.5 years. 

Importantly, this study found MGMT methylation status and female gender to be the only statistically significant variables to remain after stepwise selection for OS, indicating increased efficacy of TMZ in MGMT methylated patients with LGG as had been previously reported in HGG studies (Stupp et al. Lancet Oncology 2009). 

In conclusion, RT with concurrent and adjuvant TMZ for high risk LGG patients offers a statistically significant OS and PFS benefit when compared to historical controls. The benefit is greatest in patients with a methylated MGMT status.  

Reference (PubMed Link): Fisher BJ, Pugh SL, Macdonald DR, et al. Phase 2 study of a temozolomide-based chemoradiation therapy regimen for high-risk, low-grade gliomas: Long-term results of radiation therapy oncology group 0424. Int J Radiat Oncol Biol Phys 2020;107:720-725.

Key Institution: Multi-Institutional
Keywords: Low grade glioma, temozolomide, MGMT, High risk

WBRT is still commonly used in the management of patients in brain metastases. This analysis aimed to evaluate the efficacy and cognitive effects of two different WBRT dose regimens.

The authors conducted a post hoc analysis of the results of NCCTG N107C [Alliance]/CEC.3, which randomized 194 patients with brain metastases to either adjuvant SBRT or WBRT. 92 patients received WBRT, 49 of whom (53%) received 30 Gy in 10 fractions and 43 of whom (47%) who received 37.5 Gy in 15 fractions.

The two groups were well balanced, with the exception that more patients in the group that received 37.5 Gy had a primary lung tumor (72% vs 45%, p<0.01). Most patients completed WBRT (93%).  

Patients who received 37.5 Gy did not have a longer time to cognitive failure (HR 0.9, CI 0.6 – 1.39, p=0.66), local control (HR 0.52, CI 0.22 – 1.25, p=0.14), intracranial control (HR 0.56, CI 0.28 – 1.12, p=0.09), or overall survival (HR 0.72, CI 0.45 – 1.16, p=0.18), There was a higher risk of grade 3 or greater toxicity in patients who received 37.5 Gy than 30 Gy, however (54% vs 31%, p=0.03). There were no reports of radionecrosis.

In sum, patients who received 37.5 Gy did not have a lower risk of cognitive deficits, improved local control (in the surgical bed), or overall survival. They did, however, have a higher risk of grade 3 or higher toxicity. 

Reference (PubMed Link): Trifiletti DM, Ballman KV, Brown PD, et al. Optimizing whole brain radiation therapy dose and fractionation: Results from a prospective phase 3 trial (ncctg n107c [alliance]/cec.3). Int J Radiat Oncol Biol Phys 2020;106:255-260.

Key Institution: Multi-Institutional
Keywords: Whole Brain Radiotherapy , Brain Metastasis 

Up to 30% of cancer patients will develop brain metastases during the course of their disease. Although stereotactic radiosurgery is increasingly being used for the treatment of brain metastases, Whole-brain radiotherapy (WBRT) continues to be an important treatment option. However, WBRT is associated with deterioration of cognitive function which is believed to be due to low dose radiation to the hippocampus. Furthermore, a previously reported Phase III trial demonstrated that the prophylactic use of memantine (NMDA receptor antagonist) resulted in better preservation of cognitive function thus establishing the addition of memantime to WBRT in patients with better prognosis. This phase III trial evaluated the risk of cognitive failure in patients with brain metastases treated with hippocampal avoidance WBRT (30 Gy in 10 fx) (HA-WBRT) plus memantine compared to WBRT (30 Gy in 10 fx) plus memantine. Secondary endpoints included the overall survival (OS), the intracranial progression free survival (PFS), toxicity and patient-reported symptoms. Cognitive tests assess learning and memory (Hopkins Verbal Test-Revised), verbal fluency (Control Oral Word Association), processing speed (Trail Making Test) and executive function (TMT Part B), whereas QOL and patient-related symptom burden was evaluated using the EQ-5D-5L and the MD Anderson Symptom Inventory-Brain Tumor module. After a median follow-up of 7.9 months, HA-WBRT plus memantine resulted in a lower risk of cognitive failure compared to WBRT plus memantine. In the HA-WBRT plus memantine arm, at 4 months, deterioration of executive function was 23.3% compared to 40.4% in the WBRT plus memantine arm. Furthermore, at 6 months, deterioration of learning and memory was 11.5% (HA-WBRT) vs 24.7% (WBRT) and 16.3% (HA-WBRT) vs 33.3% (WBRT) respectively. No difference was noted in the OS, intracranial PFS or toxicity between the 2 arms. Patients in the HA-WBRT plus memantine arm also reported less fatigue, less difficulty remembering things, less difficulty speaking and fewer cognitive symptoms. Based on the findings from this phase III trial, patients with brain metastatses and good performance status needing to undergo whole brain radiation therapy should be treated with HA-WBRT plus memantine.

Reference (PubMed Link): Brown PD, Gondi V, Pugh S, et al. Hippocampal avoidance during whole-brain radiotherapy plus memantine for patients with brain metastases: Phase iii trial nrg oncology cc001. J Clin Oncol 2020;38:1019-1029.

Key Institution: Multi-Institutional
Keywords: Whole brain radiation, memantine, hippocampal avoidance, cognitive function.