Possible Interaction of Anti–PD-1 Therapy with the Effects of Radiosurgery on Brain Metastases

Abstract

Delayed radiation-induced vasculitic leukoencephalopathy related to stereotactic radiosurgery (SRS) of brain metastases has been reported to manifest clinically 9 to 18 months after treatment. Immune-modulating therapies have been introduced to treatment regimens for malignancies with metastatic predilection to the brain. The interaction of these systemic therapies with other modalities of treatment for brain metastases, namely, SRS, has not been fully characterized. We report two patients with metastatic malignancies to the brain who received SRS followed by immunotherapy with monoclonal antibodies (mAb) to programmed death 1 (PD-1). Both patients appeared to have early clinical and radiologic progression of their treated lesions, which was highly suspicious for tumor progression. Both patients underwent surgical resection of their lesions and the material was submitted for histopathologic examination. Pathologic examination in both cases showed predominantly radiation-induced changes characterized by reactive astrocytosis and vascular wall infiltration by T lymphocytes. The accelerated response to SRS in these two patients was temporally related to the initiation of immunotherapy. We propose a possible biologic interaction between SRS and the PD-1 mAbs. Additionally, awareness of this potential occurrence is critical for accurate interpretation and proper management of clinical and radiologic findings in these patients.

Toxicity of concurrent stereotactic radiotherapy and targeted therapy or immunotherapy: A systematic review

“…Our search did not find studies on concurrent pembrolizumab and SRT. For nivolumab, only 1 case report of SRT for NSCLC brain metastases and 1 retrospective study of SRT for melanoma brain metastases was identified [41,42]. The case report by Alomari et al observed a grade 4 cerebral oedema in one patient receiving concurrent therapy [41].…”

“…For nivolumab, only 1 case report of SRT for NSCLC brain metastases and 1 retrospective study of SRT for melanoma brain metastases was identified [41,42]. The case report by Alomari et al observed a grade 4 cerebral oedema in one patient receiving concurrent therapy [41]. Ahmed et al reported two events of grade 3 cerebral oedema in 20 patients treated with SRT and nivolumab for melanoma brain metastases (Table 2) [42].…”

Safety of Combined PD-1 Pathway Inhibition and Intracranial Radiation Therapy in Non–Small Cell Lung Cancer

“…However, retrospective evidence has been contradictory, with select studies demonstrating a significant increase in intracranial inflammation and related toxicity after combined cranial RT and ICI therapy that was not observed in other studies. [16][17][18] Furthermore, the sequence and timing of cranial RT and ICI therapy is a theoretical modifier of the extent of potential immune synergy and therefore may have implications for both efficacy and toxicity. 19 However, the optimal timing of combined therapy has not been established.…”

Immune checkpoint inhibitors in challenging populations

“…Other ongoing studies are prospectively evaluating interactions between brain radiation therapy and immunotherapy because early results have suggested that combining these modalities may augment efficacy and perhaps toxicity. [71][72][73] PREGNANCY Metastatic cancer in pregnancy is a devastating condition leading to difficult decisions involving the mother and the developing fetus. PD1/PD-L1 interactions appear to play a key role in maintaining fetal tolerance; indeed, the placenta is often used as a positive control for PD-L1 expression because of its strong and ubiquitous expression.…”