Neurocognitive outcomes in a phase-3 randomised trial comparing adjuvant whole brain radiotherapy with observation after local treatment of brain metastases in patients with melanoma

Aim: Concerns regarding neurocognitive function (NCF) after whole brain radiotherapy (WBRT) exist. This trial compared WBRT versus observation (OBS) following local treatment in patients with one to three melanoma brain metastases. Here, we present the NCF results. Methods: Objective NCF was evaluated in English speakers at baseline, then two‐monthly. Primary outcome was change in delayed recall at 4 months on the Hopkins Verbal Learning Test‐Revised (HVLT‐R). Other NCF tests were also performed. A mixed linear model calculated the effect of intervention on relative raw scores, adjusted for baseline score and time. Cognitive failure was determined by Reliable Change Index; global cognitive impairment was defined as Global Deficit Score >0.5. Analysis was by intention‐to‐treat, with nominal two‐sided significance level 5%. Results: A total of 207 patients were randomised (100 WBRT and 107 OBS) from 31 sites in three countries. NCF testing was completed by 73 WBRT and 70 OBS patients at baseline. Patients had similar characteristics. OBS group had greater relative improvement in HVLT‐R from baseline at every time point. At 4 months, delayed recall declined 2.7% from baseline in WBRT but improved by 20.9% in OBS; overall adjusted average intervention effect 23.6% (95% CI, 9.0‐38.2%; P = .0018). Significant effects were seen between groups at 4 months in HVLT‐total recall and delayed recognition; the overall adjusted average intervention effects were 8.3% (95% CI, 0.4‐16.1%; P = .0397) and 25.0% (95% CI, 14.3‐35.7%; P < .0001), respectively. There were no significant differences in time to cognitive failure (log‐rank P = .44) or proportions with global cognitive impairment at 4 months (OBS 32% vs WBRT 53%; P = .11). Cognitive decline in T‐scores, baseline to 4 months, of 1 SD in at least one NCF test occurred in 24 of 38 (63%) WBRT versus 11 of 25 (44%) OBS (P = .13). Conclusion: Cognitive impairment was common in both groups but greater memory decline occurred in patients receiving WBRT.