Table 1.
Results of the main trials on memantine combined with whole-brain radiotherapy and hippocampal-sparing whole-brain radiotherapy.
| Authors/Year [Ref] | Trial | Study Design | Study Characteristic | Main Findings |
|---|---|---|---|---|
| Brown PD et al., 2013 [129] | RTOG 0614 | Phase III, Random | Sample size and inclusion criteria: 508 adult patients with BM (only 149 evaluable at 24 weeks). Treatment: Patients were randomized to WBRT plus placebo versus WBRT plus memantine (20 mg/day for 24 weeks, starting within 3 days of WBRT start) |
Similar grade 3–4 toxicity and study compliance in the two arms. Lower rate of decline in delayed recall (at 24 weeks) in the memantine arm but without reaching statistical significance (p: 0.059). Memantine arm: significantly longer time to CD (53.8% versus 64.9% at 24 weeks; HR: 0.78; 95% CI: 0.62–0.99, p: 0.01). better executive function at 24 weeks (p: 0.008 at 8 weeks; p: 0.0041 at 16 weeks), processing speed (p: 0.0137), and delayed recognition (p: 0.0149). |
| Laack NN et al., 2019 [138] | RTOG 0614 (subanalysis) | Phase III, Random | Subanalysis of the RTOG 0614 trial evaluating the correlation between health-related quality of life and cognitive function using FACT-Br and MOS-C | 149 patients completed FACT-Br, MOS-C, and objective cognitive assessments at 24 weeks. Over time: worsening in all domains of objective cognitive function with no differences in FACT-Br and MOS-C between the 2 arms. improvement of emotional and functional well-being (FACT) with stability of the other FACT-Br domains. Conversely, declined MOS-C scores. |
| Tsai PF et al., 2015 [139] | RTOG 0933 | Prospective | Sample size and inclusion criteria: 40 patients participated in an NCF assessment, including memory, executive function and psychomotor speed, before and after (4 months) HS-WBRT (assessments available in 24 patients). Treatment: therapeutic or prophylactic HS-WBRT. DVHs were generated for the left hippocampus, right hippocampus and hippocampal composite structure by calculating EQD2 (α/β: 2 Gy). |
NCF scores are fairly stable before and after HS-WBRT in terms of hippocampus-dependent memory. EQD2 values < 12.60 Gy, <8.81 Gy, <7.45 Gy, and <5.83 Gy to 0%, 10%, 50%, and 80% volume of the hippocampal composite structure were significantly associated with preserved verbal memory. Specific dosimetric parameters of the left hippocampus impacted immediate recall of verbal memory (adjusted OR: 4.08; p: 0.042). |
| Brown PD et al., 2020 [145] | NRGCC001 | Phase III, Random | Sample size and inclusion criteria: 518 adult patients with BM Treatment: Patients underwent HS-WBRT plus memantine versus WBRT plus memantine. Primary endpoint: time to CD (defined as a decline in at least one of the cognitive tests). Secondary endpoints: OS, intracranial PFS, toxicity and patient-reported symptom burden. |
HS-WBRT arm: significantly lower CD risk (adjusted HR: 0.74; 95% CI: 0.58–0.95; p: 0.02), due to the lesser impairment of learning and memory at 6 months (11.5% versus 24.7% [p: 0.049] and 16.4% versus 33.3% [p: 0.02], respectively) and executive function at 4 months (23.3% versus 40.4%; p: 0.01). no differences in terms of OS, intracranial PFS and toxicity. at 6 months: less difficulty speaking (p: 0.049), less memory deficits (p: 0.01), and less fatigue (p: 0.04). |
Legend: BM: brain metastases; CD: cognitive decline; DVH: dose-volume histograms; EQD2: biologically equivalent doses in fractions of 2 Gy; FACT-Br: Functional Assessment of Cancer Therapy-Brain module; HS-WBRT: hippocampal-sparing whole-brain radiotherapy; MOS-C: Medical Outcomes Scale-Cognitive Functioning Scale; NCF: neurocognitive function; OS: overall survival; PFS: progression-free survival; VMAT: volumetric modulated arch therapy; WBRT: whole-brain radiotherapy.