Clinical outcomes of melanoma brain metastases treated with stereotactic radiosurgery and anti-PD-1 therapy, anti-CTLA-4 therapy, BRAF/MEK inhibitors, BRAF inhibitor, or conventional chemotherapy

Ahmed, Kamran A.; Abuodeh, Y.A.; Echevarria, M.; Arrington, John A.; Stallworth, D.G.; Hogue, Carol J.; Naghavi, A.O.; Kim, S.; Kim, Y.; Patel, Bindiya; Sarangkasiri, S.; Johnstone, Peter A.S.; Sahebjam, Solmaz; Khushalani, Nikhil I.; Forsyth, Peter; Harrison, Louis B.; Yu, Michael; Etame, Arnold B.; Caudell, Jimmy J.

doi:10.1093/annonc/mdw417

Cited by 125 publications

(110 citation statements)

References 26 publications

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“…Our findings indicate that these immune checkpoint inhibitors are effective for controlling not only the primary melanoma but also distant metastases to the brain. Several previous reports have shown a regional immunomodulatory effect and penetration of novel systemic agents into the brain [8,11,12,15,18,20,21,23]. The present results might indicate passage of these agents thorough the bloodbrain barrier in melanoma patients, thereby leading to suppression of new metastases to the brain.…”

Section: Discussionsupporting

confidence: 67%

Gamma Knife Radiosurgery for Metastatic Brain Tumors from Malignant Melanomas: A Japanese Multi-Institutional Cooperative and Retrospective Cohort Study (JLGK1501)

Matsunaga¹,

Shuto

Yamamoto

et al. 2018

Stereotact Funct Neurosurg

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Background: The incidences of metastatic brain tumors from malignant melanomas have increased and survival has been prolonged by novel molecular targeted agents and immunotherapy. However, malignant melanomas are uncommon in Asian populations. Objectives: We retrospectively analyzed treatment efficacy and identified prognostic factors impacting tumor control and survival in Japanese melanoma patients with brain metastases treated with gamma knife radiosurgery (GKRS). Methods: We retrospectively reviewed the medical records of 177 patients with 1,500 tumors who underwent GKRS for brain metastases from malignant melanomas. This study was conducted by the Japanese Leksell Gamma Knife Society (JLGK1501). Results: Six and 12 months after GKRS, the cumulative incidences of local tumor recurrence were 9.2 and 13.8%. Intratumoral hemorrhage (p < 0.0001) and larger tumor volume (p = 0.001) in GKRS were associated with significantly poorer local control outcomes. The use of immune checkpoint inhibitors before GKRS was significantly associated with symptomatic adverse events (p = 0.037). The median overall survival time after the initial GKRS was 7.3 months. Lower Karnofsky performance status scores (p = 0.016), uncontrolled primary cancer (p < 0.0001), and multiple brain metastases (p = 0.014) significantly influenced unfavorable overall survival outcomes. The cumulative incidences of neurological death 6 and 12 months after GKRS were 9.7 and 17.4%, those of neurological deterioration were 14.2 and 19.6%, and those of new tumor appearance were 34.5 and 40.5%. Conclusions: The results of the present multicenter study suggest that GKRS is a relatively effective and safe modality for control of tumor progression in Japanese patients with brain metastases from malignant melanomas.

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Section: Discussionsupporting

confidence: 67%

Gamma Knife Radiosurgery for Metastatic Brain Tumors from Malignant Melanomas: A Japanese Multi-Institutional Cooperative and Retrospective Cohort Study (JLGK1501)

Matsunaga¹,

Shuto

Yamamoto

et al. 2018

Stereotact Funct Neurosurg

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“…In addition, micrometastases elsewhere in the brain may contribute to an underlying endogenous immune response. The study on SRS plus nivolumab mentioned earlier showed an extended survival of 5/7 patients with resected metastases, whereas only 3/19 patients without resection were alive at 24 months (132). This strongly supports that irradiation of the resected cavity is indeed capable of eliciting an antitumor immune response and furthermore suggests that the tumor cell load may be an important factor in controlling residual disease.…”

Section: Potential Of Combining Iort With Immune Therapy For Bmmentioning

confidence: 92%

“…However, although one trial included four patients who underwent prior resection of metastases before SRS to the cavity plus IPI (131), none have a priori addressed therapy of a purely resected population. Combining SRS with an anti-PD-1 antibody (nivolumab) has only been described in a single study on 73 lesions in 26 patients with median 9.4 months follow-up (132), including patients with resected lesions. Overall, local control (82% at 12 months) was comparable to conventional treatments, while distant control (53%) was higher than for other treatments.…”

Section: Combining Srs With Immune Therapy For Bmmentioning

confidence: 99%

“…IORT as primary treatment after surgery would have the biological advantage of eliminating repopulation by remaining tumor cells during the delay between surgery and irradiation required for wound healing before SRS can be given. Based on the study on SRS plus nivolumab, in which neurotoxicity was mostly limited and could be relieved by treatment with steroids (132), combining IORT with anti-PD-1 is expected to be well tolerated. Immunogenicity after resection of the tumor : in contrast with most of the previous studies combining ICB with tumor irradiation, IORT is applied after the bulk of the tumor mass has been removed surgically. Therefore, only few tumor cells are expected to remain in the tumor bed after excision of the brain metastasis, raising the question whether the tumor load is sufficient to induce a tumor-directed immune response after irradiation.…”

Section: Potential Of Combining Iort With Immune Therapy For Bmmentioning

confidence: 99%

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Immunotherapy Combined with Large Fractions of Radiotherapy: Stereotactic Radiosurgery for Brain Metastases—Implications for Intraoperative Radiotherapy after Resection

2017

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Brain metastases (BM) affect approximately a third of all cancer patients with systemic disease. Treatment options include surgery, whole-brain radiotherapy, or stereotactic radiosurgery (SRS) while chemotherapy has only limited activity. In cases where patients undergo resection before irradiation, intraoperative radiotherapy (IORT) to the tumor bed may be an alternative modality, which would eliminate the repopulation of residual tumor cells between surgery and postoperative radiotherapy. Accumulating evidence has shown that high single doses of ionizing radiation can be highly efficient in eliciting a broad spectrum of local, regional, and systemic tumor-directed immune reactions. Furthermore, immune checkpoint blockade (ICB) has proven effective in treating antigenic BM and, thus, combining IORT with ICB might be a promising approach. However, it is not known if a low number of residual tumor cells in the tumor bed after resection is sufficient to act as an immunizing event opening the gate for ICB therapies in the brain. Because immunological data on tumor bed irradiation after resection are lacking, a rationale for combining IORT with ICB must be based on mechanistic insight from experimental models and clinical studies on unresected tumors. The purpose of the present review is to examine the mechanisms by which large radiation doses as applied in SRS and IORT enhance antitumor immune activity. Clinical studies on IORT for brain tumors, and on combined treatment of SRS and ICB for unresected BM, are used to assess the safety, efficacy, and immunogenicity of IORT plus ICB and to suggest an optimal treatment sequence.

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“…Median OS was 11.8 and 12.0 months, respectively, in patients receiving nivolumab for unresected disease. Median OS was not reached in patients treated in the resected setting [26].…”

Section: Nivolumabmentioning

confidence: 94%

Immuno-radiotherapy for brain metastases

Denaro¹,

Occelli²,

maria³

et al. 2017

Int Med Care

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Brain metastases (BM) are a lethal consequence of systemic dissemination of cancer. The most common malignancies that metastasize to the brain are lung, breast, and melanoma. Eighty percent of patients present with brain metastases within the cerebral hemispheres; 15% are within the cerebellar hemispheres and 5% are within the brainstem. The incidence of brain metastases is increasing because of better detection from improved imaging techniques (also for staging asymptomatic patients), and more effective systemic treatment regimens that can prolong life, permitting the cancer to disseminate to the brain, a sanctuary site.

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Clinical outcomes of melanoma brain metastases treated with stereotactic radiosurgery and anti-PD-1 therapy, anti-CTLA-4 therapy, BRAF/MEK inhibitors, BRAF inhibitor, or conventional chemotherapy

Abstract: In our institutional analysis of patients treated with SRS and various systemic immunologic and targeted melanoma agents, significant differences in distant MBM control and OS are noted. Prospective evaluation of the potential synergistic effect between these agents and SRS is warranted.

Cited by 125 publications

References 26 publications

Gamma Knife Radiosurgery for Metastatic Brain Tumors from Malignant Melanomas: A Japanese Multi-Institutional Cooperative and Retrospective Cohort Study (JLGK1501)

Gamma Knife Radiosurgery for Metastatic Brain Tumors from Malignant Melanomas: A Japanese Multi-Institutional Cooperative and Retrospective Cohort Study (JLGK1501)

Immunotherapy Combined with Large Fractions of Radiotherapy: Stereotactic Radiosurgery for Brain Metastases—Implications for Intraoperative Radiotherapy after Resection

Immuno-radiotherapy for brain metastases

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