Date of Award

January 2017

Document Type


Degree Name

Medical Doctor (MD)



First Advisor

Veronica L. Chiang


IMMUNE CHECKPOINT THERAPY AND STEREOTACTIC RADIOSURGERY FOR MELANOMA BRAIN METASTASES. Jack M. Qian, James B. Yu, Harriet M. Kluger, and Veronica L. Chiang. Departments of Therapeutic Radiology, Medicine, and Neurosurgery, Yale University, School of Medicine, New Haven, CT.

Growing evidence suggests that immunotherapy and radiation therapy can be synergistic in the treatment of cancer. We sought to determine the effect of the relative timing and type of immune checkpoint therapy on the response of melanoma brain metastases to treatment with stereotactic radiosurgery (SRS) by reviewing our institutional experience.

Patients with melanoma brain metastases were identified from an institutional database of patients treated with Gamma Knife SRS. SRS treatment plans, follow-up imaging, and details of immunotherapy treatment were reviewed. Immunotherapy and radiosurgery treatment to any single lesion was considered concurrent if SRS was administered within four weeks of immunotherapy. The primary outcome of interest was lesional response, as measured by changes in individual lesion volume during follow-up. The impact of timing and type of immunotherapy on lesional response was determined using the Wilcoxon rank sum test to compare median percent lesion volume change at 1.5 months, 3 months, and 6 months after SRS treatment, with significance determined by p=0.0167, per the Bonferroni correction for multiple comparisons. Secondary endpoints included lesional regrowth, distant brain recurrence, and overall survival.

75 melanoma patients with 566 brain metastases treated between 2007 and 2015 were included in this study. Concurrent use of immunotherapy and SRS resulted in significantly greater median percent reduction in lesion volume at 1.5 months (-63.1% vs -43.2%, p<0.0001), 3 months (-83.0% vs -52.8%, p<0.0001), and 6 months (-94.9% vs -66.2%, p<0.0001) compared to non-concurrent therapy. Median percent reduction in lesion volume was also significantly greater for anti-PD-1 than for anti-CTLA-4 at 1.5 months (-71.1% vs -48.2%, p<0.0001), 3 months (-89.3% vs -66.2%, p<0.0001), and 6 months (-95.1% vs -75.9%, p=0.0004). The median overall survival for the entire cohort was 18.5 months.

Our study shows that administration of immunotherapy within four weeks of SRS results in improved lesional response of melanoma brain metastases compared to treatment separated by greater than four weeks. Anti-PD-1 therapy also results in greater lesional response than anti-CTLA-4 after SRS.


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