Association of innovations in radiotherapy and systemic treatments with clinical outcomes in patients with melanoma brain metastasis from 2007 to 2016

Importance — Treatments for melanoma brain metastasis changed between 2007 and 2016 with the advent of new radiotherapy techniques, targeted therapeutic agents, and immunotherapy. Changes in clinical outcomes over time have not been systematically investigated in large population-based studies.

Objective — To investigate the association of innovations in radiotherapy techniques and systemic therapies with clinical outcomes among patients with melanoma brain metastasis.

Design, Setting and Participants — This population-based cohort study included all patients who received radiotherapy and/or surgery for the treatment of melanoma brain metastasis in Ontario, Canada, between January 1, 2007, and June 30, 2016. Brain treatment patterns and clinical outcomes were described by period (2007-2009, 2010-2012, and 2013-2016). Provincial administrative records were used to obtain data on surgery, radiotherapy, and drugs. Follow-up data were censored on August 31, 2016. A Kaplan-Meier analysis and multivariable Cox regression analyses were performed. Data were analyzed between November 8, 2017 and May 13, 2020.

Main Outcomes and Measures — Overall survival, whole-brain radiotherapy-free survival, and time to subsequent brain treatment.

Results — A total of 1096 patients (mean [SD] age, 61.7 [14.0] years; 751 men [68.5%]) with melanoma brain metastasis received treatment in Ontario between January 1, 2007, and June 30, 2016. Of those, 326 patients received treatment from 2007 to 2009 (period 1), 310 patients received treatment from 2010 to 2012 (period 2), and 460 patients received treatment from 2013 to 2016 (period 3). Patient age, other sociodemographic characteristics, and disease factors were similar between periods. Whole-brain radiotherapy was the first local brain-directed treatment used in 246 patients (75.5%; 95% CI, 70.8%-80.1%) in period 1, decreasing to 239 patients (52.0%; 95% CI, 47.4%-56.5%) in period 3. The use of partial-brain radiotherapy techniques as the first treatment increased from 11 patients (3.4%; 95% CI, 1.4%-5.3%) in period 1 to 98 patients (21.3%; 95% CI, 17.6%-25.0%) in period 3. After the first treatment for melanoma brain metastasis, the use of BRAF and MEK inhibitors and immunotherapy increased from less than 6 patients (<1.8%; 95% CI, <0.4% to <3.3%) in period 1 to 188 patients (40.9%; 95% CI, 36.4%-45.4%) in period 3. Overall survival was greater in period 3 (1-year survival, 21.8% [95% CI, 17.9%-25.9%] and 2-year survival, 13.8% [95% CI, 10.4%-17.8%]; Wilcoxon P = .001) compared with period 1 (1-year survival, 12.3% [95% CI, 9.0%-16.1%] and 2-year survival, 6.4% [95% CI, 4.1%-9.5%]), with an adjusted hazard ratio (aHR) of 0.65 (95% CI, 0.56-0.77). The findings were unchanged after accounting for the variation in imaging practice between periods. Between period 1 and period 3, the use of whole-brain radiotherapy decreased (aHR, 0.32; 95% CI, 0.22-0.46), and the use of multiple brain-directed treatments increased (aHR, 2.16; 95% CI, 1.48-3.14).

Conclusions and Relevance — These findings suggest that innovations in systemic therapy and radiotherapy are associated with improvements in clinical outcomes among patients with melanoma brain metastasis, even in population-wide routine practice. Overall survival improved over time, and the use of whole-brain radiotherapy decreased. However, many patients continued to receive whole-brain radiotherapy in the last period (2013-2016) examined.