Radiosurgery for melanoma brain metastases in the ipilimumab era and the possibility of longer survival Clinical article

Department of Radiation Medicine, Hofstra University North Shore-LIJ School of Medicine, Hofstra University, Manhasset, New York 11030, USA. .
Journal of Neurosurgery (Impact Factor: 3.74). 06/2012; 117(2):227-33. DOI: 10.3171/2012.5.JNS111929
Source: PubMed


A prospectively collected cohort of 77 patients who underwent definitive radiosurgery between 2002 and 2010 for melanoma brain metastases was retrospectively reviewed to assess the impact of ipilimumab use and other clinical variables on survival.
The authors conducted an institutional review board-approved chart review to assess patient age at the time of brain metastasis diagnosis, sex, primary disease location, initial radiosurgery date, number of metastases treated, performance status, systemic therapy and ipilimumab history, whole-brain radiation therapy (WBRT) use, follow-up duration, and survival at the last follow-up. The Diagnosis-Specific Graded Prognostic Assessment (DSGPA) score was calculated for each patient based on performance status and the number of brain metastases treated.
Thirty-five percent of the patients received ipilimumab. The median survival in this group was 21.3 months, as compared with 4.9 months in patients who did not receive ipilimumab. The 2-year survival rate was 47.2% in the ipilimumab group compared with 19.7% in the nonipilimumab group. The DS-GPA score was the most significant predictor of overall survival, and ipilimumab therapy was also independently associated with an improvement in the hazard for death (p = 0.03).
The survival of patients with melanoma brain metastases managed with ipilimumab and definitive radiosurgery can exceed the commonly anticipated 4-6 months. Using ipilimumab in a supportive treatment paradigm of radiosurgery for brain oligometastases was associated with an increased median survival from 4.9 to 21.3 months, with a 2-year survival rate of 19.7% versus 47.2%. This association between ipilimumab and prolonged survival remains significant even after adjustment for performance status without an increased need for salvage WBRT.

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    • "The combination of SRS and ipilimumab has recently been studied in a retrospective cohort of patients with melanoma brain metastases and showed improved survival as compared to SRS alone [8]. However, little has been reported about this treatment combination in patients with HIV. "
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    ABSTRACT: Cancers, such as melanoma, that are associated with immune deficiencies are a major cause of morbidity and mortality in HIV-infected patients. Once patients develop melanoma metastases to the brain, treatment is often limited to palliative surgery and/or radiation. Ipilimumab, a CTLA-4 antagonist, has been shown to improve the median survival of patients with metastatic melanoma. However, available data regarding the safety and efficacy of ipilimumab in HIV-infected patients who develop intracranial melanoma metastases is limited. Here we report our experience administering ipilimumab to a patient with HIV-AIDS who developed multiple intracranial melanoma metastases. Following treatment, our patient showed improvement in systemic tumor control without any apparent interference with antiretroviral treatment.
    Case Reports in Oncological Medicine 12/2013; 2013:946392. DOI:10.1155/2013/946392
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    • "As TMZ crosses the intact BBB, the drug can be used early in patient treatment. Large MW drugs such as ipilimumab (MW 148 kDa) have shown to improve patient survival when combined with SRS [65]. Our study clearly shows that 64 Cu-BSA leaks into tumor parenchyma late in tumor development, suggesting that large MW drugs should preferably be used on larger and well-established brain metastases. "
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    ABSTRACT: Our goal was to develop strategies to quantify the accumulation of model therapeutics in small brain metastases using multimodal imaging, in order to enhance the potential for successful treatment. Human melanoma cells were injected into the left cardiac ventricle of immunodeficient mice. Bioluminescent, MR and PET imaging were applied to evaluate the limits of detection and potential for contrast agent extravasation in small brain metastases. A pharmacokinetic model was applied to estimate vascular permeability. Bioluminescent imaging after injecting D-Luciferin (molecular weight (MW) 320D) suggested tumor cell extravasation had already occurred at week 1, which was confirmed by histology. 7T T1w MRI at week 4 was able to detect non-leaky 100 μm sized lesions and leaky tumors with diameters down to 200μm after contrast injection at week 5. PET imaging showed that (18)F-FLT (MW 244D) accumulated in the brain at week 4. Gadolinium-based MRI tracers (MW 559D and 2.066kD) extravasated after 5weeks (tumor diameter 600 μm), and the lower MW agent cleared more rapidly from the tumor (mean apparent permeabilities 2.27x10(-5)cm/s versus 1.12x10(-5)cm/s). PET imaging further demonstrated tumor permeability to (64)Cu-BSA (MW 65.55kD) at week 6 (tumor diameter 700 μm). In conclusion, high field T1w MRI without contrast may improve the detection limit of small brain metastases, allowing for earlier diagnosis of patients, although the smallest lesions detected with T1w MRI were permeable only to D-Luciferin and the amphipathic small molecule (18)F-FLT. Different-sized MR and PET contrast agents demonstrated the gradual increase in leakiness of the blood tumor barrier during metastatic progression, which could guide clinicians in choosing tailored treatment strategies.
    Journal of Controlled Release 10/2013; 172(3). DOI:10.1016/j.jconrel.2013.10.019 · 7.71 Impact Factor
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    • "Preliminary evidence suggests that this approach of combining radiation with immune checkpoint inhibitors may be translated effectively and safely to the clinic. Retrospective data of patients with intracranial melanoma metastases who received SRS with or without anti-CTLA-4, showed a significant improvement in overall survival (21.3 vs. 4.9 months) vs. SRS alone, with 47% of patients who received anti-CTLA-4 still living at 2 years [82]. "
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    ABSTRACT: Glioblastoma multiforme (GBM) is the most common primary brain cancer. Even with aggressive combination therapy, the median life expectancy for patients with GBM remains approximately 14 months. In order to improve the outcomes of patients with GBM, the development of newer treatments is critical. The concept of using the immune system as a therapeutic option has been suggested for several decades; by harnessing the body's adaptive immune mechanisms, immunotherapy could provide a durable and targeted treatment against cancer. However, many cancers, including GBM, have developed mechanisms that protect tumor cells from being recognized and eliminated by the immune system. For new immunotherapeutic regimens to be successful, overcoming immunosuppression via immune checkpoint signaling should be taken into consideration.
    04/2013; 1(1):2-8. DOI:10.14791/btrt.2013.1.1.2
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