Phase III Trial Results May Be Practice-Changing for Melanoma Brain Metastases

Whole-brain radiotherapy did not improve outcomes in patients with melanoma brain metastasis, according to the results of a phase III international trial (abstract 9500) presented at the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago.

“Patients with stage IV melanoma are at high risk of developing brain metastasis. The risk is up to 25% within the first year and up to 30% to 40% within the first 2 years,” said Angela Hong, PhD, of Melanoma Institute Australia, who presented the results.

While local surgery and stereotactic radiosurgery are highly effectively for individuals with single metastasis or few metastases, explained Hong, these patients have a high risk of subsequent brain metastases, as high as 50% within 1 year.

Previous trials with adjuvant whole-brain radiotherapy have enrolled patients with mixed cancer histologies. Therefore, the investigators sought to test the use of this therapy specifically in patients with metastatic melanoma. The trial compared the effects of whole-brain radiotherapy with observation in patients after local treatment of 1 to 3 melanoma brain metastases with stereotactic radiosurgery (SRS). The primary endpoint was distant intracranial failure within 12 months of randomization. The secondary endpoints included local failure and overall survival (OS).

Between 2009 and 2017, 207 eligible, consenting patients (mean age, 62 years; 67% male and 33% female) from 31 sites across Australia, the United Kingdom, and Norway were randomized to receive whole-brain radiotherapy (30 Gy in 10 fractions; n = 100) or observation after local treatment (n = 107). Overall, 61% of patients had a single melanoma brain metastasis (mean size, 2 cm) and 67% had extracranial disease. Any form of systemic therapy was permitted during the trial.

The median follow up was 48 months. The treatment completion rate for whole-brain radiotherapy was 97%. At 12 months, 50.5% of the observation group (54 of 107 patients) and 42% of the radiotherapy group (42 of 100 patients) had distant intracranial failure (hazard ratio [HR], 1.28; 95% CI, 0.89–1.84; P = .16). No differences were observed between the groups in terms of local failure (P = .100). Regarding OS, 54% of patients in the observation group compared with 58.4% of those in the radiotherapy group were alive at 12 months (log-rank P = .89).

Patients who received whole-brain radiotherapy experienced higher grade 1/2 fatigue (68.2% vs 28.1), nausea (33% vs 15.7%), alopecia (62.4% vs 4.4%), and dermatitis (11.8% vs 0%; all P < .001) than patients in the observation group.

“For patients with 1 to 3 melanoma brain metastases, after the local treatment, there was no benefit with the adjuvant whole-brain radiotherapy,” said Hong, “Therefore, we do not recommend adjuvant whole-brain radiotherapy in this setting.”

The investigators concluded that this practice-changing trial justifies the recent move in the field away from the use of whole-brain radiotherapy.

“Whole-brain radiation clearly doesn’t add much, but stereotactic radiosurgery with the higher doses is in fact very effective,” said Harriet Kluger, MD, of the Yale School of Medicine and Smilow Cancer Center at Yale New Haven Hospital and the discussant of the study. “However, SRS [stereotactic radiosurgery] is not without toxicities or consequences. Radiation necrosis is now being seen more frequently and earlier in patients who then get treated with immune therapy.”

Kluger suggests that the use of systemic immune therapies may allow the approximately 50% of melanoma patients who do respond to these new therapies to avoid surgery. She also highlighted the need for more randomized trials comparing immune therapy with stereotactic radiosurgery or regular surgery.