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

Lehrer, Eric J.; Kowalchuk, Roman O.; Gurewitz, Jason; Bernstein, Kenneth; Kondziolka, Douglas; Niranjan, Ajay; Wei, Zhishuo; Lunsford, L. Dade; Fakhoury, Kareem; Rusthoven, Chad G.; Mathieu, David; Trudel, Claire; Malouff, Timothy D.; Ruiz‐Garcia, Henry; Bonney, Phillip A.; Hwang, Larn; Yu, Cheng; Zada, Gabriel; Patel, Samir; Deibert, Christopher P.; Picozzi, Piero; Franzini, Andrea; Attuati, Luca; Prasad, Rahul N.; Raval, Raju R.; Palmer, Joshua D.; Lee, Cheng-chia; Yang, Huai‐Che; Harmsen, William S.; Jones, Brianna M.; Sharma, Sonam; Ahluwalia, Manmeet; Sheehan, Jason P.; Trifiletti, Daniel M.

doi:10.1016/j.ijrobp.2023.01.017

Cited by 21 publications

(19 citation statements)

References 45 publications

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“…Even if one-session SRS was delivered to the majority of patients in the largest published series [23 ▪▪ ], many recent studies favored a fractionated delivery (versus a single session) for brain metastasis sizes of more than 20 mm axis, particularly in the context of ICI combination, confirming the independent association of symptomatic radionecrosis with the brain metastasis volume [12 ▪▪ ].…”

Section: Radionecrosis After Immune Checkpoint Inhibitor and Stereota...mentioning

confidence: 97%

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Combination of radiosurgery and immunotherapy in brain metastases: balance between efficacy and toxicities

Botticella,

Dhermain

2023

Current Opinion in Neurology

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Purpose of review The incidence of brain metastasis is high and still increasing. Among local therapies, stereotactic radiosurgery (SRS) is an effective treatment option, optimally sparing normal brain, even for multiple brain metastases. Immune checkpoint inhibitors (ICIs) become the new standard of care in an increasing number of cancers, and the combination SRS and ICI is often proposed to patients, but few data have been published on the efficacy and the toxicity of this association. Recent findings Explaining this lack of consensus: retrospective studies with different primary cancers, various treatment lines and unknown levels of steroid exposure. Concerning the toxicity, the independent association of radionecrosis with brain-PTV volume was confirmed, and a decreased dose of SRS is now tested in a randomized study. Finally, a ‘concurrent’ delivery of SRS and ICI (within a 4 weeks’ interval) seems the optimal schedule; fractionated radiosurgery for large brain metastasis should be favored. Radio-sensitizing nanoparticles and devices aiming to increase the permeability of the blood brain barrier should be considered in future combinations. Summary The efficacy/toxicity balance of SRS-ICI combination should be regularly re-evaluated, anticipating continued progress in ICI and SRS delivery, with more long-survivors potentially exposed to long-term toxicities. Patients should be included in clinical trials and clearly informed to participate more closely in the final choice.

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Section: Radionecrosis After Immune Checkpoint Inhibitor and Stereota...mentioning

confidence: 97%

“…To be noted, only several phase 1 and 2 trials assessing the safety and efficacy of SRS and ICI in the treatment of brain metastasis are ongoing [23 ▪▪ ,27 ▪▪ ,28 ▪ ].…”

Section: Future Perspectivesmentioning

confidence: 99%

Combination of radiosurgery and immunotherapy in brain metastases: balance between efficacy and toxicities

Botticella,

Dhermain

2023

Current Opinion in Neurology

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“…However, a recent retrospective, multi-institutional series of 657 SRS patients observed comparable rates of necrosis with concurrent and delayed ICI. Importantly, the study lacked a control group treated with SRS alone, excluded patients treated with fSRS, and included only a small proportion of patients treated with dual ICI (15.8%) [119]. In contrast, a single institution series of 206 NSCLC and melanoma patients found that concurrent ICI and SRS within 4 weeks were associated with increased necrosis risk compared to SRS alone (HR: 6.47; 95%CI: 3.60-11.62) [79].…”

Section: Immunotherapymentioning

confidence: 99%

Novel Mechanisms and Future Opportunities for the Management of Radiation Necrosis in Patients Treated for Brain Metastases in the Era of Immunotherapy

Vaios

Winter

Shih

et al. 2023

Cancers

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Radiation necrosis, also known as treatment-induced necrosis, has emerged as an important adverse effect following stereotactic radiotherapy (SRS) for brain metastases. The improved survival of patients with brain metastases and increased use of combined systemic therapy and SRS have contributed to a growing incidence of necrosis. The cyclic GMP-AMP (cGAMP) synthase (cGAS) and stimulator of interferon genes (STING) pathway (cGAS-STING) represents a key biological mechanism linking radiation-induced DNA damage to pro-inflammatory effects and innate immunity. By recognizing cytosolic double-stranded DNA, cGAS induces a signaling cascade that results in the upregulation of type 1 interferons and dendritic cell activation. This pathway could play a key role in the pathogenesis of necrosis and provides attractive targets for therapeutic development. Immunotherapy and other novel systemic agents may potentiate activation of cGAS-STING signaling following radiotherapy and increase necrosis risk. Advancements in dosimetric strategies, novel imaging modalities, artificial intelligence, and circulating biomarkers could improve the management of necrosis. This review provides new insights into the pathophysiology of necrosis and synthesizes our current understanding regarding the diagnosis, risk factors, and management options of necrosis while highlighting novel avenues for discovery.

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“…MDT typically includes interventional radiology techniques, surgical resection, and radiotherapy, often using stereotactic planning techniques involving a sharp dose fall-off to a focal target (2). Clinical trials are ongoing to optimize patient selection for MDT to maximize cost-effectiveness, quality of life, and survival while minimizing side effects of treatment (3)(4)(5)(6). The SABR-COMET trial randomized 99 patients with one to five metastatic sites to standard of care with or without stereotactic body radiation therapy (SBRT) to each of the metastatic lesions, demonstrating an improvement in overall survival (OS) with SBRT (2,(7)(8)(9).…”

Section: Introductionmentioning

confidence: 99%

Development and validation of a unifying pre-treatment decision tool for intracranial and extracranial metastasis-directed radiotherapy

et al. 2023

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BackgroundThough metastasis-directed therapy (MDT) has the potential to improve overall survival (OS), appropriate patient selection remains challenging. We aimed to develop a model predictive of OS to refine patient selection for clinical trials and MDT.Patients and methodsWe assembled a multi-institutional cohort of patients treated with MDT (stereotactic body radiation therapy, radiosurgery, and whole brain radiation therapy). Candidate variables for recursive partitioning analysis were selected per prior studies: ECOG performance status, time from primary diagnosis, number of additional non-target organ systems involved (NOS), and intracranial metastases.ResultsA database of 1,362 patients was assembled with 424 intracranial, 352 lung, and 607 spinal treatments (n=1,383). Treatments were split into training (TC) (70%, n=968) and internal validation (IVC) (30%, n=415) cohorts. The TC had median ECOG of 0 (interquartile range [IQR]: 0-1), NOS of 1 (IQR: 0-1), and OS of 18 months (IQR: 7-35). The resulting model components and weights were: ECOG = 0, 1, and > 1 (0, 1, and 2); 0, 1, and > 1 NOS (0, 1, and 2); and intracranial target (2), with lower scores indicating more favorable OS. The model demonstrated high concordance in the TC (0.72) and IVC (0.72). The score also demonstrated high concordance for each target site (spine, brain, and lung).ConclusionThis pre-treatment decision tool represents a unifying model for both intracranial and extracranial disease and identifies patients with the longest survival after MDT who may benefit most from aggressive local therapy. Carefully selected patients may benefit from MDT even in the presence of intracranial disease, and this model may help guide patient selection for MDT.

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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

Cited by 21 publications

References 45 publications

Combination of radiosurgery and immunotherapy in brain metastases: balance between efficacy and toxicities

Combination of radiosurgery and immunotherapy in brain metastases: balance between efficacy and toxicities

Novel Mechanisms and Future Opportunities for the Management of Radiation Necrosis in Patients Treated for Brain Metastases in the Era of Immunotherapy

Development and validation of a unifying pre-treatment decision tool for intracranial and extracranial metastasis-directed radiotherapy

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