International Journal of Radiation Oncology*Biology*Physics
Clinical InvestigationStereotactic Radiosurgery for Melanoma Brain Metastases in Patients Receiving Ipilimumab: Safety Profile and Efficacy of Combined Treatment
Introduction
Ipilimumab (Ipi), a human monoclonal antibody that blocks cytotoxic T-lymphocyte antigen-4 (CTLA-4), allows for T cell activation and proliferation, thereby enhancing immune response to cancer. In patients with metastatic melanoma, Ipi has been shown to improve overall survival (OS) in 2 phase 3 trials, 1 trial in comparison with the cancer vaccine gp100 and the other in combination with dacarbazine 1, 2. These trials led to the approval of Ipi by the U.S. Food and Drug Administration in 2011.
As many as 60% of patients with metastatic melanoma will experience brain metastases (BMs), and those with relatively good prognosis and few BMs often undergo treatment with stereotactic radiosurgery (SRS) 3, 4, 5, 6, 7. The rationale for combining Ipi and SRS is based on potential activity of Ipi in the brain, as demonstrated by Margolin et al (8) in a phase 2 trial, and on the possible abscopal effects of SRS that may enhance the systemic response to Ipi 8, 9, 10, 11, 12, 13, 14. Several series have reported promising preliminary results with the combination of SRS and Ipi, including a study by Knisely et al (5) showing median OS of 21.3 months in 27 patients 15, 16, 17, 18. Given our large institutional experience with Ipi and SRS, we conducted a retrospective study to investigate the safety and efficacy of this combination for treatment of melanoma BMs.
Section snippets
Methods and Materials
From an institutional melanoma database, 46 patients were identified who received Ipi and underwent single-fraction SRS for melanoma BMs between 2005 and 2011. Most of these patients (85%) received Ipi as part of a research protocol. Ipi was delivered intravenously every 3 weeks for 4 doses during the induction phase. After induction, 13 patients (28%) received maintenance therapy every 3 months.
Gadolinium-enhanced T1-weighted magnetic resonance imaging (MRI) with 3-mm slices was performed
Patient and tumor characteristics
This study included 46 patients with metastatic melanoma who received Ipi and SRS for BMs between 2005 and 2011. The patient, tumor, and treatment characteristics are shown in Table 1. The median age was 57 years (range, 24-76 years), and the male:female ratio was 1.4:1. The median mGPA was 3 out of 4, because most patients had KPS 90% and 1 to 2 BMs (4). Only 37% of patients had elevated lactate dehydrogenase. Almost all patients had other non-brain metastasea and underwent prior systemic
Discussion
This retrospective, single-institution study is the largest series to date investigating the combination of brain SRS and Ipi immunotherapy for patients with melanoma BMs (n=46 patients). Our results suggest several important hypotheses. First, delivery of SRS during or before Ipi may yield comparatively favorable survival and regional control compared with delivery of SRS after Ipi. These effects clearly need to be investigated further. Second, SRS during or before Ipi may cause a temporary
Conclusion
This largest-to-date single-institution retrospective study investigated the safety and efficacy of SRS in 46 patients with melanoma BMs who also received Ipi immunotherapy. We found that delivery of SRS during or before Ipi was associated with comparatively favorable survival and regional control compared with delivery of SRS after Ipi. However, SRS during or before Ipi may also be associated with a temporary increase in size or hemorrhage of the irradiated lesion. Overall, the combination of
References (29)
Stereotactic radiosurgery for brain oligometastases: Good for some, better for all?
Ann Oncol
(2005)- et al.
Ipilimumab in patients with melanoma and brain metastases: An open-label, phase 2 trial
Lancet Oncol
(2012) - et al.
Ionizing radiation inhibition of distant untreated tumors (abscopal effect) is immune mediated
Int J Radiat Oncol Biol Phys
(2004) - et al.
The abscopal effect associated with a systemic anti-melanoma immune response
Int J Radiat Oncol Biol Phys
(2013) - et al.
Melanoma brain metastases treated with brain-directed radiation followed by ipilimumab
Int J Rad Oncol Biol Phys
(2012) - et al.
Radiation Therapy Oncology Group: Radiosurgery quality assurance guidelines
Int J Radiat Oncol Biol Phys
(1993) - et al.
Transient enlargement of contrast uptake on MRI after linear accelerator (linac) stereotactic radiosurgery for brain metastases
Int J Radiat Oncol Biol Phys
(2001) - et al.
Improved survival with ipilimumab in patients with metastatic melanoma
N Engl J Med
(2010) - et al.
Ipilimumab plus dacarbazine for previously untreated metastatic melanoma
N Engl J Med
(2011) - et al.
Summary report on the graded prognostic assessment: An accurate and facile diagnosis-specific tool to estimate survival for patients with brain metastases
J Clin Oncol
(2012)
Radiosurgery for melanoma brain metastases in the ipilimumab era and the possibility of longer survival
J Neurosurg
Outcome predictors of Gamma Knife surgery for melanoma brain metastases. Clinical article
J Neurosurg
Multimodality treatment of melanoma brain metastases incorporating stereotactic radiosurgery (SRS)
Cancer
Fractionated but not single-dose radiotherapy induces an immune-mediated abscopal effect when combined with anti-CTLA-4 antibody
Clin Cancer Res
Cited by (308)
Concurrent Administration of Immune Checkpoint Inhibitors and Single Fraction Stereotactic Radiosurgery in Patients With Non-Small Cell Lung Cancer, Melanoma, and Renal Cell Carcinoma Brain Metastases
2023, International Journal of Radiation Oncology Biology PhysicsImmune microenvironment remodeling after radiation of a progressing brain metastasis
2023, Cell Reports MedicineFive-year overall survival with ipilimumab and stereotactic ablative radiotherapy for metastatic disease
2023, Radiotherapy and Oncology
Conflict of interest: none.