Survival of patients with melanoma brain metastasis treated with stereotactic radiosurgery and active systemic drug therapies

Choong, Ee Siang; Lo, Serigne; Drummond, Martin; Fogarty, Gerald B; Menzies, Alexander M.; Guminski, Alexander; Shivalingam, Brindha; Clarke, Kathryn; Long, Georgina V.; Hong, Angela

doi:10.1016/j.ejca.2017.01.007

Cited by 98 publications

(92 citation statements)

References 34 publications

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“…Patients treated with surgery and/or stereotactic or whole-brain radiotherapy (WBRT) may have better outcomes with median OS rates ranging from 8.7 to 10.4 months (Fife et al , 2004) although this may be partially due to a selection bias. Melanoma has long been considered radio-resistant (Dossgg and Memula, 1982); despite this radiotherapy, particularly radiosurgery, remains an important contributor to the treatment of melanoma brain metastasis in the modern era (Choong et al , 2017). Targeted therapy using BRAF/MEK inhibitors and immunotherapy with checkpoint blockade have dramatically changed the therapeutic landscape and the prognosis for patients with metastatic melanoma (Menzies and Long, 2014); but the therapeutic benefit of immune checkpoint inhibitors in patients with brain metastases remains unclear.…”

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confidence: 99%

Efficacy of anti-PD-1 therapy in patients with melanoma brain metastases

et al. 2017

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Background:There is limited data on the efficacy of anti-programmed death 1 (PD-1) antibodies in patients (pts) with melanoma brain metastasis (BM), particularly those which are symptomatic.Method:We retrospectively assessed pts with melanoma BM treated with PD-1 antibodies, nivolumab and pembrolizumab. Clinicopathologic and treatment parameters were collected and outcomes determined for intracranial (IC) response rate (RR) using a modified RECIST criteria, with up to five IC target lesions used to determine IC response, disease control rate (DCR) and progression-free survival (PFS).Results:A total of 66 pts were identified with a median follow up of 7.0 months (range 0.8–24.5 months). A total of 68% were male and 45% BRAF V600 mutation positive. At PD-1 antibody commencement, 50% had an elevated LDH; 64% had local therapy to BM prior to commencing anti-PD1, of which 5% had surgical resection, 14% stereotactic radiosurgery (SRS), 18% whole-brain radiotherapy (WBRT), 27% had surgery and radiotherapy. Twenty-one per cent started anti-PD-1 as first line systemic therapy. No pt had prior anti-PD-1 treatment. The IC overall RR was 21 and DCR 56%. Responses occurred in 21% of pts with symptomatic BM. The median OS was 9.9 months (95% CI 6.93–17.74). Pts with symptomatic BM had shorter PFS than those without symptoms (2.7 vs 7.4 months, P=0.035) and numerically shorter OS (5.7 vs 13.0 months, P=0.068). Pts requiring corticosteroids also had a numerically shorter PFS (3.2 vs 7.4 months, P=0.081) and OS (4.8 vs 13.1 months, P=0.039).Conclusions:IC responses to anti-PD-1 antibodies occur in pts with BM, including those with symptomatic BM requiring corticosteroids. Prospective trials evaluating anti-PD-1 therapy in pts with BM are underway.

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Efficacy of anti-PD-1 therapy in patients with melanoma brain metastases

et al. 2017

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“…A retrospective analysis of patients treated for brain metastases of malignant melanoma revealed that inhibition of the PD-1 axis was more effective than inhibition of CTLA-4 in combination with external beam radiotherapy and that concurrent dosing (at least 4 weeks within the two treatments) was necessary to induce best responses [163]. Independent retrospective studies and one meta-analysis confirmed these results [145,[164][165][166][167][168][169][170][171] (Table 4), also showing the superiority of combining radiation with PD-1 inhibitors compared to combination with other agents such as v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) or dual specificity mitogen-activated protein kinase kinase (MEK) inhibitors [172,173] (Table 4). One retrospective study showed longer overall survival of patients irradiated more than 16 weeks after initiation of ipilimumab, compared to patients irradiated within 16 weeks of starting ipilimumab treatment [174].…”

Section: Current Clinical Insights On Irradiation and Immune Checkpoimentioning

confidence: 86%

Radiotherapy as a Backbone for Novel Concepts in Cancer Immunotherapy

Kabiljo

Harpain

Carotta

et al. 2019

Cancers

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Radiation-induced immunogenic cell death has been described to contribute to the efficacy of external beam radiotherapy in local treatment of solid tumors. It is well established that radiation therapy can induce immunogenic cell death in cancer cells under certain conditions. Initial clinical studies combining radiotherapy with immunotherapies suggest a synergistic potential of this approach. Improving our understanding of how radiation reconditions the tumor immune microenvironment should pave the way for designing rational and robust combinations with immunotherapeutic drugs that enhance both local and systemic anti-cancer immune effects. In this review, we summarize irradiation-induced types of immunogenic cell death and their effects on the tumor microenvironment. We discuss preclinical insights on mechanisms and benefits of combining radiotherapy with immunotherapy, focusing on immune checkpoint inhibitors. In addition, we elaborate how these observations were translated into clinical studies and which parameters may be optimized to achieve best results in future clinical trials.

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“…Recent data about anti-PD1 agents in concomitance with RT are more encouraging [20-22]. For example, Choong et al [23] reported a promising OS of 20.4 months with SBRT administered within 6 weeks from an anti-PD1. The result was more unsatisfactory with anti-CTLA4 (median OS 7.5 months).…”

Section: Discussionmentioning

confidence: 99%

Combination of Immunotherapy and Brain Radiotherapy in Metastatic Melanoma: A Retrospective Analysis

et al. 2019

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Background: Up to 40% of patients with metastatic melanoma (MM) develop brain metastases. Radiotherapy (RT) may potentiate the effects of immunotherapy (IO), even on distant sites (abscopal effect). Material and Methods: We retrospectively analyzed all our MM patients treated with IO within 6 months before/after brain RT between 2012 and 2016. Progression-free (PFS) and overall survival (OS) were estimated with the Kaplan-Meier method and compared with those of controls treated with IO during the same period. Results: Thirty-six cases and 25 controls were identified. Among cases, 23 patients received an anti-CTLA4 agent and 13 an anti-PD1 agent. Eighteen cases were treated with stereotactic RT and 18 with whole-brain RT. Median PFS from the beginning of RT was 4 months in first-line and 2 months in second-line treatment. A third of the cases progressed at first evaluation after RT. Median OS from the beginning of RT was 7 months in first-line and 4 months in second-line treatment. Median PFS and OS of each treatment line showed a trend towards inferiority compared with those of controls. Conclusion: Synergism between RT and IO was not observed in our case series. No cases of abscopal effect were seen, and most patients underwent early systemic progression after RT.

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Survival of patients with melanoma brain metastasis treated with stereotactic radiosurgery and active systemic drug therapies

Cited by 98 publications

References 34 publications

Efficacy of anti-PD-1 therapy in patients with melanoma brain metastases

Efficacy of anti-PD-1 therapy in patients with melanoma brain metastases

Radiotherapy as a Backbone for Novel Concepts in Cancer Immunotherapy

Combination of Immunotherapy and Brain Radiotherapy in Metastatic Melanoma: A Retrospective Analysis

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