Impact of Tyrosine Kinase Inhibitors (TKIs) Combined With Radiation Therapy for the Management of Brain Metastases From Renal Cell Carcinoma

Abstract

Background: Targeted therapy has transformed the outcome for patients with metastatic renal cell carcinoma. Their efficacy and safety have also been demonstrated in brain metastatic RCC. Preclinical evidence suggests synergism of radiation and tyrosine kinase inhibitors. Consequently, several studies have compared their efficacy in the treatment of RCC brain metastases to the era of brain management with surgery/radiation only. Objectives: We seek to systematically review and meta-analyze the results of those studies that involved comparative intervention groups of brain management; TKIs, and never used TKIs. Methods and Materials: Online databases (PubMed, EMBASE, Cochrane library, and ClinicalTrials.gov) were searched for comparative studies. Overall survival as the primary outcome of interest, and local brain control, distant control, and adverse events as secondary outcomes of interest were recorded for meta-analysis. Hazard ratios were pooled together using Review Manager 5.3. Fixed effects or random effects model were adopted according to the level of heterogeneity. Subgroup analysis included studies that involved SRS as the local treatment of management. Results: Overall 7 studies (n = 897) were included for meta-analysis. TKI use was associated with better survival (HR 0.60 [0.52, 0.69], p < 0.00001) and local brain control (HR 0.34 [0.11, 0.98], p = 0.05). SRS subgroup also revealed significantly better survival (HR 0.61 [0.44, 0.83], p = 0.002) and local brain control (HR 0.19 [0.08, 0.45], p = 0.0002). Distant brain control (HR 0.95 [0.67, 1.35], p = 0.79) and brain progression free survival were unaffected (HR 0.94 [0.56, 1.56], p = 0.80). Only one study (n = 376) reported significantly greater 12-months cumulative incidence of radiation necrosis with TKI use within 30 days of SRS (10.9 vs. 6.4%, p = 0.04). Khan et al. TKIs for RCC BM Conclusions: TKIs use in combination with SRS is safe and effective for treating RCC brain metastases. Larger randomized controlled trials are warranted to validate the results.

Bevacizumab for radiation necrosis following radiotherapy of brain metastatic disease: a systematic review & meta-analysis

“…The most common primary tumor metastasizing to the brain is lung cancer (up to 50%), followed by breast cancer (up to 25%), melanoma (up to 20%), and to a lesser extent, renal cell carcinoma, colorectal cancer, and others [1][2][3][4]. Nonetheless, the incidence and frequency of BM is growing as newer systemic and immunotherapeutic agents are entering the treatment paradigm of these primary cancers [5][6][7][8][9]. Patients are living longer and are more prone to experience BM in their lifetime.…”

“…Depending on various prognostic factors, management of BM may involve surgical resection and/or radiation therapy in the form of stereotactic radiosurgery (SRS), whole brain radiotherapy, or a combination of two [1,[10][11][12][13]. A surge has been witnessed in the use of radiosurgery in BM patients with the approval of various targeted and immunotherapeutic agents for the management of primary sites of systemic cancers [6][7][8][9]14]. Targeted agents after SRS for the brain have also been continued and have prolonged survival outcomes for patients with BM [6,7,9,15,16].…”

“…A surge has been witnessed in the use of radiosurgery in BM patients with the approval of various targeted and immunotherapeutic agents for the management of primary sites of systemic cancers [6][7][8][9]14]. Targeted agents after SRS for the brain have also been continued and have prolonged survival outcomes for patients with BM [6,7,9,15,16]. Radiation therapy has long been associated with the development of radiation necrosis (RN) in patients with intracranial disease [17][18][19][20][21].…”

“…An increased incidence of RN has also been reported with a combination of SRS and systemic agents [22,23]. In fact, the benefits of synergism from a combination of radiation and targeted agents are weighed against RN toxicity [7,22,23]. Hence, the management of RN takes a center stage in patients with intracranial disease.…”

Bevacizumab Treatment of Radiation-Induced Brain Necrosis: A Systematic Review

“…Radiation-induced brain necrosis (RBN) is one of the main limiting toxicities, generally occurring 6 months to several years after treatment ( 7 ). Furthermore, combining radiation with targeted/immunotherapeutic agents to treat metastatic brain disease confers an increased risk of RBN that must be weighed against the synergistic effects of the treatment ( 8 , 9 ). Therefore, the diagnosis and treatment of RBN are a crucial element in the management of patients with brain diseases.…”