Is radiation necrosis in radiated melanoma brain metastasis increasing because immunotherapy is contributing to this or are patients just living longer?

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e21518-e21518
Author(s):  
Elizabeth Iannotti Buchbinder ◽  
Diana D. Shi ◽  
Kathleen L. Pfaff ◽  
Michael P. Manos ◽  
Olivia Ouyang ◽  
...  
Keyword(s):  
Brain Metastasis ◽  
Brain Tissue ◽  
Radiation Necrosis ◽  
Checkpoint Inhibitors ◽  
Stereotactic Radiation ◽  
Immune Infiltrate ◽  
Melanoma Brain Metastasis ◽  
Pathologic Evaluation ◽  
History Of ◽  
Causative Effect

e21518 Background: The use of immune checkpoint inhibitors, particularly combination ipilimumab and nivolumab, has drastically changed the management of patients with melanoma brain metastasis. Select patients also benefit from brain-directed stereotactic radiation. Radiation necrosis is a risk associated with stereotactic radiation that oncologists have been observing more frequently in the era of immunotherapy. Methods: Patients were identified who had a history of metastatic melanoma treated with stereotactic brain radiation who subsequently developed radiation necrosis. Brain tissue from those patients with a subsequent resection of their radiation necrosis was obtained and examined for immune infiltrate and other factors. The tissue obtained was evaluated by blinded pathologists who graded % viable tissue, % necrosis, % tumor and % fibrosis. In addition, they graded inflammation on a scale of 1-3. Results: Seven patients were identified who had surgery for radiation necrosis following radiation to melanoma brain metastasis. Tissue was available for five patients. Two patients had received no prior immunotherapy, one patient had received ipilimumab and two patients received combination ipilimumab and nivolumab. The samples obtained consisted of almost entirely viable brain tissue or necrosis. There was minimal inflammation seen in all patients’ samples including those who had not received immunotherapy and those who had. Conclusions: Radiation necrosis in patients on immunotherapy who receive brain-directed stereotactic radiation is a rising problem. On pathologic evaluation increased immune infiltrate is not observed in patients on immunotherapy with radiation necrosis compared to those who never received immunotherapy. This suggests that the increased rates of radiation necrosis may be more likely associated with longer survival as opposed to a direct causative effect from the immunotherapy although with our limited sample size this will need further exploration.[Table: see text]

scholarly journals THER-02. IMPACT OF SYSTEMIC THERAPY IN MELANOMA BRAIN METASTASIS

2019 ◽  
Vol 1 (Supplement_1) ◽  
pp. i11-i11
Author(s):  
Soumya Sagar ◽  
Adam Lauko ◽  
Addison Barnett ◽  
Wei Wei ◽  
Samuel Chao ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Brain Metastasis ◽  
Brain Metastases ◽  
Systemic Therapy ◽  
Checkpoint Inhibitors ◽  
Care Center ◽  
Tertiary Care ◽  
P Value ◽  
Surgical Removal ◽  
Melanoma Brain Metastasis

Abstract BACKGROUND: Melanoma brain metastasis is associated with a median overall survival (OS) of approximately 9 months. In recent years, management of melanoma brain metastases (MBM) by surgery and radiation [stereotactic radiosurgery (SRS) and whole brain radiation therapy (WBRT)] has been bolstered by targeted therapy and immune checkpoint inhibitors (ICI). METHODS: 351 patients, who underwent treatment for MBM at our tertiary care center from 2000 to 2018, were grouped into those that received chemotherapy, ICI, or targeted therapy. Thirty-four percent of patients treated with ICI had received other systemic therapies as well as part of their management. OS was calculated from the date of diagnosis of the brain metastases. The Kaplan Meier analysis was utilized to determine median OS and difference in OS was determined by utilizing the Cox proportional hazard model. RESULTS: The median survival after the diagnosis of brain metastasis was 10.4, 11.96, and 7.06 months in patients who received ICI, chemotherapy and targeted therapy respectively. A multivariate model was developed including the type of systemic therapy, presence of extracranial metastases, age, KPS and number of intracranial lesions. 114 patients underwent SRS alone, 56 underwent SRS and WBRT, 43 underwent SRS and surgical removal, 28 had surgical removal, SRS and WBRT, and 78 had no intracranial therapy. Compared to patients who received chemotherapy, patients who received immunotherapy had a hazard ratio, HR = 0.628 (confidence interval = 0.396 – 0.994, p-value = 0.047). Presence of EC metastases (HR= 1.25, p-value < .001), lower KPS (HR = .97, p-value < .0001) and multiple brain lesions (HR = 1.117, p-value < .0001) were associated with significantly worse OS. CONCLUSIONS: Addition of ICI significantly improves the OS in MBM compared to chemotherapy. Lower performance status, multiple brain metastases, and EC metastases are associated with poor OS.

scholarly journals Stereotactic radiation therapy in melanoma brain metastasis: A European, multicentric cohort

2018 ◽  
Vol 29 ◽  
pp. viii455-viii456
Author(s):  
A. Paix ◽  
F. Thillays ◽  
F. Courtault-Deslandes ◽  
I. Popp ◽  
H. Herrscher ◽  
...  
Keyword(s):  
Radiation Therapy ◽  
Brain Metastasis ◽  
Stereotactic Radiation Therapy ◽  
Stereotactic Radiation ◽  
Melanoma Brain Metastasis

scholarly journals Verification of 5-Aminolevurinic Radiodynamic Therapy Using a Murine Melanoma Brain Metastasis Model

2019 ◽  
Vol 20 (20) ◽  
pp. 5155 ◽  
Author(s):  
Junko Takahashi ◽  
Shinsuke Nagasawa ◽  
Mitsushi J. Ikemoto ◽  
Chikara Sato ◽  
Mari Sato ◽  
...  
Keyword(s):  
Brain Metastasis ◽  
Brain Metastases ◽  
Therapeutic Efficacy ◽  
Checkpoint Inhibitors ◽  
Melanoma Metastasis ◽  
X Rays ◽  
Melanoma Brain Metastasis ◽  
Metastasis Model

Melanoma is a highly aggressive cancer with a propensity for brain metastases. These can be treated by radiotherapy, but the radiation-resistant nature of melanoma makes the prognosis for melanoma patients with brain metastases poor. Previously, we demonstrated that treatment of mice with subcutaneous melanoma with 5-aminolevurinic acid (5-ALA) and X-rays in combination, (“radiodynamic therapy (RDT)”), instead of with 5-ALA and laser beams (“photodynamic therapy”), improved tumor suppression in vivo. Here, using the B16-Luc melanoma brain metastasis model, we demonstrate that 5-ALA RDT effectively treats brain metastasis. We also studied how 5-ALA RDT damages cells in vitro using a B16 melanoma culture. Cell culture preincubated with 5-ALA alone increased intracellular photosensitizer protoporphyrin IX. On X-ray irradiation, the cells enhanced their ∙OH radical generation, which subsequently induced γH2AX, a marker of DNA double-strand breaks in their nuclei, but decreased mitochondrial membrane potential. After two days, the cell cycle was arrested. When 5-ALA RDT was applied to the brain melanoma metastasis model in vivo, suppression of tumor growth was indicated. Therapeutic efficacy in melanoma treatment has recently been improved by molecular targeted drugs and immune checkpoint inhibitors. Treatment with these drugs is now expected to be combined with 5-ALA RDT to further improve therapeutic efficacy.

scholarly journals TMOD-05. EXTRACRANIAL TUMORS INFLUENCE INTRACRANIAL RESPONSE TO IMMUNE CHECKPOINT INHIBITORS IN PRE-CLINICAL MODELS OF MELANOMA BRAIN METASTASIS

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii228-ii228
Author(s):  
Naema Nayyar ◽  
Mohini Singh ◽  
Jackson Stocking ◽  
Michael Brehm ◽  
Priscilla Brastianos
Keyword(s):  
Brain Metastasis ◽  
Brain Metastases ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Checkpoint Blockade ◽  
Intracranial Tumors ◽  
Clinical Model ◽  
Melanoma Brain Metastasis ◽  
Syngeneic Mouse Model

Abstract Melanomas frequently spread to the brain, with up to 75% of patients developing brain metastases. Treatment of metastatic melanoma has been revolutionized by the advent of immune checkpoint inhibitors (ICI) targeting PD-1 and CTLA-4. However, responses to ICI within the immune-specialized brain environment are not well understood owing to the lack of immunocompetent animal models for the investigation of intracranial responses to checkpoint blockade. We studied the effect of ICI in a syngeneic mouse model of melanoma brain metastasis with concurrent intracranial and subcutaneous tumors. Either D3UV3 cells, derived from a UVB irradiated clone of D4M.3A melanoma cell line, or vehicle were subcutaneously injected into the flank of C57BL/6 mice. 3 days later, D3UV3 cells tagged with firefly luciferase were implanted into the striatum using stereotactic injection. Mice were then treated with anti-PD-1 antibody, anti-CTLA-4 antibody, a combination of anti-PD-1 and anti-CTLA-4 antibodies, or isotype controls. We observed striking differences in survival between mice with concurrent intracranial and subcutaneous tumors compared to intracranial tumors alone. Mice with intracranial tumors alone experienced no benefit in survival following monotherapy with anti-PD-1 (p=1) or anti-CTLA-4 (p=0.1) compared to isotype-treated mice, and only a slight benefit with combination treatment (p=0.049). In contrast, mice with concurrent tumors experienced a significant increase in overall survival with anti-CTLA-4 monotherapy (p=0.01) and combination anti-CTLA-4 and anti-PD-1 treatment (p=0.01) compared to isotype-treated mice, although treatment with anti-PD-1 alone did not increase survival (p=0.28). These results indicate that the presence of extracranial disease can modulate intracranial immune responses following checkpoint blockade. We have therefore established a pre-clinical model with concurrent intracranial and extracranial tumors to better recapitulate the clinically observed context of brain metastases. We hope this model will lead to a better understanding of the setting in which ICI is effective for patients with melanoma brain metastases.

scholarly journals Acute motor axonal neuropathy after ipilimumab and nivolumab treatment in melanoma brain metastases: A case report and review of the literature

2021 ◽  
Vol 9 ◽  
pp. 2050313X2110422
Author(s):  
Yolanda Piña ◽  
Brittany R. Evernden ◽  
Nikhil Khushalani ◽  
Kim Margolin ◽  
Hussein Tawbi ◽  
...  
Keyword(s):  
Brain Metastasis ◽  
Adverse Events ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Axonal Neuropathy ◽  
Braf V600e ◽  
Acute Motor Axonal Neuropathy ◽  
Melanoma Brain Metastasis ◽  
First Case

The use of immune checkpoint inhibitors including ipilimumab and nivolumab has expanded for several tumors including melanoma brain metastasis. These have resulted in a growing spectrum of neurologic immune-related adverse events, including ones that are rare and difficult to diagnose and treat. Here, we present a patient with melanoma brain metastasis who was treated with immune checkpoint inhibitors and developed an Acute Motor Axonal Neuropathy. To our knowledge, this is the first case of Acute Motor Axonal Neuropathy as an immune-related adverse event associated with combination treatment of ipilimumab and nivolumab, who was successfully treated. A 28-year-old woman with metastatic BRAF V600E melanoma developed melanoma brain metastasis and was enrolled on Checkmate 204, a Phase 2 clinical trial using ipilimumab (3 mg/kg intravenous) and nivolumab (1 mg/kg intravenous) every 3 weeks for four cycles, followed by monotherapy with nivolumab (240 mg intravenous) every 2 weeks. A few days after Cycle 2 of ipilimumab and nivolumab, she developed a pure motor axonal neuropathy consistent with Acute Motor Axonal Neuropathy. She was treated with several immunosuppressive treatments including high dose methylprednisolone, immune globulin, and infliximab, and her motor neuropathy eventually improved several months after onset of symptoms. Unfortunately, she had progression of her systemic disease and died several months later. This is the first case reported of Acute Motor Axonal Neuropathy associated with ipilimumab and nivolumab, successfully treated with immune-suppressive therapy. As the field of immunotherapy expands with the increasing use of the immune checkpoint inhibitors, it is critical to increase our knowledge and understanding of the neurologic immune-related adverse events associated with immune checkpoint inhibitors. This includes the spectrum of rare neurologic immune-related adverse events, which can be quite difficult to recognize and treat. Early consultations with neurology may expedite a diagnosis and treatment plan in patients with unexplained weakness receiving immune checkpoint inhibitor therapy.

scholarly journals 62. PRESENCE OF EXTRACRANIAL TUMORS INFLUENCES RESPONSE TO IMMUNE CHECKPOINT INHIBITORS IN A PRE-CLINICAL MODEL OF MELANOMA BRAIN METASTASIS

2020 ◽  
Vol 2 (Supplement_2) ◽  
pp. ii13-ii13
Author(s):  
Naema Nayyar ◽  
Mohini Singh ◽  
Jackson Stocking ◽  
Michael Brehm ◽  
Priscilla Brastianos
Keyword(s):  
Brain Metastasis ◽  
Brain Metastases ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Intracranial Tumors ◽  
Clinical Model ◽  
Melanoma Brain Metastasis ◽  
Syngeneic Mouse Model ◽  
The Brain

Abstract Up to 75% of patients with melanoma develop brain metastases. While immune checkpoint inhibitors (ICI) targeting PD-1 and CTLA4 have revolutionized the treatment of metastatic melanoma, responses within the immune-specialized microenvironment of the brain are not well understood and there is a paucity of animal models to investigate the effect of ICI intracranially. We characterized responses to checkpoint inhibitors in a syngeneic mouse model of melanoma brain metastasis with concurrent intracranial and subcutaneous melanoma. D3UV3 cells (obtained from David Fisher’s laboratory) were derived using UVB irradiation from D4M.3A melanoma cell line and implanted into the striatum using stereotactic injection or subcutaneously injected into the flank of C57BL/6 mice. Mice were then treated with anti-PD-1 antibody, anti-CTLA4 antibody, a combination of anti-PD-1 and anti-CTLA4, or isotype controls. While mice with intracranial melanoma alone had no response to monotherapy with anti-PD-1 or anti-CTLA4 antibody (p=1 and 0.1, respectively), and only a slight response to combination therapy (p=0.049), mice with concurrent subcutaneous tumors had significantly improved responses to anti-PD-1, anti-CTLA4 and combination treatment (p=0.002, 0.01 and 0.01 respectively compared to mice with intracranial tumors alone with equivalent treatment). These results demonstrate that the presence of an extracranial tumor influences response to ICI in pre-clinical mouse models of melanoma brain metastasis. We have therefore established a pre-clinical model with concurrent intracranial and extracranial tumors to better recapitulate the clinically observed context of melanoma brain metastases and lead to a better understanding of the setting in which ICI are effective for patients with this devastating complication.

scholarly journals Survival and clinical outcomes of patients with melanoma brain metastasis in the era of checkpoint inhibitors and targeted therapies

BMC Cancer ◽  
2018 ◽  
Vol 18 (1) ◽  
Author(s):  
Elham Vosoughi ◽  
Jee Min Lee ◽  
James R. Miller ◽  
Mehdi Nosrati ◽  
David R. Minor ◽  
...  
Keyword(s):  
Brain Metastasis ◽  
Clinical Outcomes ◽  
Targeted Therapies ◽  
Checkpoint Inhibitors ◽  
Melanoma Brain Metastasis
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