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.

Surgery and SRS are highly effective local treatments for brain metastases, including in patients with metastatic melanoma. However, they are at high risk of local recurrence after treatment. This trial aimed to evaluate the efficacy of adjuvant whole-brain radiotherapy in this patient population.

The authors conducted a phase III trial in which patients with melanoma and 1-3 brain metastases who received SRS or surgery were randomized to receive whole brain radiotherapy (WBRT) or observation. The trial was conducted at 24 centers in Australia and Europe. 215 patients were enrolled between April 2009 and September 2017. The minimum dose for WBRT was 30 Gy.

The primary end point was distant intracranial failure within 12 months. Secondary endpoints included time to intracranial failure, survival, and time to deterioration in performance status.

Median follow-up was 48.1 months. 42% of patients in the WBRT and 50.5% in the observation groups developed distant intracranial failure (p=0.22). Over the entire follow-up period, 52% of patients in the WBRT and 57% in the observation group developed intracranial failure (p=0.39). Local failure rates were improved after WBRT – 20% in the WBRT arm and 33.6% in the observation arm (p=0.03). 12-month overall survival was equivalent, 41.5% in the WBRT and 51.4% in the observation arms (p=0.28). Median time to deterioration in performance status was 3.8 months vs 4.4 months (p=0.32) in the WBRT and observation arms, respectively. WBRT was associated with more grade 1 or 2 acute toxicity. 

In sum, in patients with metastatic melanoma with 1-3 brain metastases who received surgery for SRS, adjuvant WBRT improved local control, but did not improve distant intracranial failure, overall survival, or preservation of performance status.

Reference (PubMed Link): Hong AM, Fogarty GB, Dolven-Jacobsen K, et al. Adjuvant whole-brain radiation therapy compared with observation after local treatment of melanoma brain metastases: A multicenter, randomized phase iii trial. J Clin Oncol 2019;37:3132-3141.

Key Institution: Multi-Institutional (Europe & Australia)
Keywords: Melanoma metastases, Whole-brain Radiotherapy, Resection, Radiosurgery

This study aims to evaluate whether SRS is an effective treatment approach for patient with 5-15 brain mets. This retrospective review 2083 patients who underwent Gamma Knife SRS as the initial treatment modality for intracranial metastases at 8 academic institutions between 1991 and 2013.

Compared with the 2 to 4 BM group, 5 to 15 BM was not associated with an increased hazard of death.

Predictors of Distant Brain Failure on multivariable analyses included age 65 years or greater, other histology, margin dose, 1 versus 2 to 4 BM and 5 to 15 versus 2 to 4 BM.

Several clinical outcomes differed between the 2 to 4 and 5 to 15 BM groups, such as cumulative incidence of Distant Brain Failure and Brain Metastasis Velocity, both of which were higher in patients with 5 to 15 BM. However, these differences did not translate into more patients with 5 to 15 BM requiring salvage therapy.

Bottom line: The present study confirms, in a North American population, findings from the Japanese multi-institutional study that patients with 2 to 4 BM do not have a significantly worse survival than patients with 5 or greater.  

The number of BM probably should not be used alone to determine the choice of initial SRS versus WBRT in the management of BM.

Prospective trials are needed to validate this finding.

Reference (PubMed Link): Hughes RT, Masters AH, McTyre ER, et al. Initial srs for patients with 5 to 15 brain metastases: Results of a multi-institutional experience. Int J Radiat Oncol Biol Phys 2019;104:1091-1098.

Key Institution: Multi-Institutional (Wake Forest School of Medicine)
Keywords: SRS, Brain Metastasis