According to results of a retrospective study of patients diagnosed with stage III melanoma, the central nervous system (CNS) is not the first site of metastasis in most patients who develop distant disease. The findings were published in the Journal of Clinical Oncology.

Of the common solid tumors, melanoma is considered to have the highest risk of metastasis to the CNS. While population-based studies have shown that the risk of CNS metastasis is in the range of only 1% for patients diagnosed with cutaneous melanoma, this risk has been shown to be substantially higher for those with regionally metastatic (ie, stage III) disease.

However, many of these earlier studies included relatively small numbers of patients, and used American Joint Committee on Cancer (AJCC) staging criteria other than those from the latest edition to characterize stage III melanoma. This study was conducted to evaluate the incidence, timing, and risk factors associated with development of CNS metastasis in patients with stage III melanoma as defined by staging criteria in the 8th edition of the AJCC Staging Manual.

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In this study, clinicopathologic data for 1918 patients diagnosed with stage III melanoma between 1998 and 2014 who met AJCC 8th edition staging criteria were extracted from research databases from the University of Texas MD Anderson Cancer Center in Houston, and the Melanoma Institute Australia in Wollstonecraft. All patients were determined to be CNS-metastasis free within 4 months of diagnosis on the basis of computed tomography imaging.

At a median follow-up of 70.2 months, 16.7% of study patients had developed CNS metastasis, with 3.6%, 9.6%, 15.8%, of patients developing CNS metastasis by 1, 2, and 5 years following diagnosis, respectively. Of the 37.1% of patients who developed metastatic disease at a distant site, CNS metastasis was the first site of metastatic disease for only 3.9% of patients.

Analyses of multivariable models showed a high tumor mitotic rate (ie, greater than 9 per mm2 compared with 0-4 per mm2), male sex, stage IIIB and IIIC disease compared with stage IIIA melanoma, and melanomas present on the scalp compared with tumors occurring at all other primary sites, were predictive for development of CNS metastasis at 1 and 2 years following diagnosis. However, only high tumor mitotic rate remained significant at 5 years following diagnosis

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These findings “provide important data regarding the timing and risk of CNS metastasis that can be used to guide clinical surveillance strategies,” the study authors noted.

The authors further proposed that the data obtained through their research can provide a framework for evaluating the effect of recently approved adjuvant immune checkpoint inhibitor therapy (ie, ipilimumab, nivolumab, and pembrolizumab), as well as adjuvant combination targeted therapy (ie, dabrafenib plus trametinib), on the development of CNS metastasis in patients with stage III melanoma.  


Haydu LE, Lo SN, McQuade JL, et al. Cumulative incidence and predictors of CNS metastasis for patients with American Joint Committee on Cancer 8th edition stage III melanoma. J Clin Oncol. doi: 10.1200/JCO.19.01508