gms | German Medical Science

Objective: The incidence rate of brain metastases (BM) is difficult to estimate and no substantial data exist for melanoma. We sought to depict the incidence of melanoma BM before and after the era of immune checkpoint (anti-CTLA4 or anti-PD1) and BRAF/VEGFR-inhibitors.

Methods: A total of 1406 consecutive patients with newly diagnosed malignant melanoma were identified in our clinic between 01.01.2008-31.12.2013. All patients were followed for image-proven brain metastases. Recurrence-free survival times until BM (RFS-BM) were correlated to primary melanoma characteristics and therapy modalities applied before BM. Univariate associations were analyzed using Kaplan-Meier survival analysis and the multivariate Cox proportional hazards regression.

Results: 6.1% (n=86) of patients developed BM during a median follow-up time of 35.4 months. Median RFS-BM was 22.9 ± 20.3 months. The cumulative 4-year incidence of BM in all patients diagnosed from 2008 – 2013 was 8%, 4.8%, 4.9%, 6.6%, 4.1% and 4.0%, respectively. Although there were no differences in the 12-, 24- and 36-months recurrence-free survivals over the years, the BM-free RFS-times extended, especially after 2012. After multivariate analyses, clinical variables significantly predictive of BM included the histological subtype (p=0.0091) and the AJCC stadium (p<0.0001). Patients with primary AJCC 3 and 4 developed BM in 4% and 11% during follow-up. Surprisingly, even patients initially diagnosed with AJCC 1 and 2 developed BM in 1.5% and 5%. The use of newer agents applied for treatment of primary melanoma (before BM) had a significant influence on the incidence of BM. Patients of AJCC3 or 4 treated with immune checkpoint-inhibitors (anti-CTLA4 or anti-PD1) or in combination with immune checkpoint inhibitors revealed 100% BM-free survival times at 48 months. Patients treated with BRAF/MEK or VEGFR-inhibitors revealed BM-free survival proportions of only 80%, 72% and 42% at 12, 24, and 48 months.

Conclusion: The cumulative incidence of BM in melanoma is declining over the recent years. Highest risk for BM is in patients with amelanotic, mucosal and nodal melanoma. One should be aware that even patients diagnosed with initial AJCC 2 have a risk for BM in up to 5% during follow-up. But especially anti-CTLA4/anti-PD1-therapy seems to "prevent" BM. In contrast, BRAF/VEGFR/MEK-inhibitor-therapy does not have a positive influence on the development of BM. Newer generations of patients have to be reanalyzed.