Spine stereotactic radiosurgery with concurrent tyrosine kinase inhibitors for metastatic renal cell carcinoma

Abstract

<jats:sec> <jats:title>OBJECT</jats:title> <jats:p>Systemic control of metastatic renal cell carcinoma (mRCC) has substantially improved with the development of VEGF, mTOR, and checkpoint inhibitors. The current first-line standard of care is a VEGF tyrosine kinase inhibitor (TKI). In preclinical models, TKIs potentiate the response to radiotherapy. Such improved efficacy may prolong the time to salvage therapies, including whole-brain radiotherapy or second-line systemic therapy.</jats:p> <jats:p>As the prevalence of mRCC has increased, the utilization of spine stereotactic radiosurgery (SRS) has also increased. However, clinical outcomes following concurrent treatment with SRS and TKIs remain largely undefined. The purpose of this investigation was to determine the safety and efficacy of TKIs when delivered concurrently with SRS. The authors hypothesized that first-line TKIs delivered concurrently with SRS significantly increase local control compared with SRS alone or TKIs alone, without increased toxicity.</jats:p></jats:sec> <jats:sec> <jats:title>METHODS</jats:title> <jats:p>A retrospective cohort study of patients undergoing spine SRS for mRCC was conducted. Patients undergoing SRS were divided into 4 cohorts: those receiving concurrent first-line TKI therapy (A), systemic therapy–naïve patients (B), and patients who were undergoing SRS with (C) or without (D) concurrent TKI treatment after failure of first-line therapy. A negative control cohort (E) was also included, consisting of patients with spinal metastases managed with TKIs alone. The primary outcome was 12-month local failure, defined as any in-field radiographic progression. Multivariate competing risks regression was used to determine the independent effect of concurrent first-line TKI therapy upon local failure.</jats:p></jats:sec> <jats:sec> <jats:title>RESULTS</jats:title> <jats:p>One hundred patients who underwent 151 spine SRS treatments (232 vertebral levels) were included. At the time of SRS, 46% were receiving concurrent TKI therapy. In each SRS cohort, the median prescription dose was 16 Gy in 1 fraction. Patients in Cohort A had the highest burden of epidural disease (96%, p &lt; 0.01).</jats:p> <jats:p>At 12 months, the cumulative incidence of local failure was 4% in Cohort A, compared with 19%–27% in Cohorts B–D and 57% in Cohort E (p &lt; 0.01). Multivariate competing risks regression demonstrated that concurrent first-line TKI treatment (Cohort A) was independently associated with a local control benefit (HR 0.21, p = 0.04). In contrast, patients treated with TKIs alone (Cohort E) experienced an increased rate of local failure (HR 2.43, p = 0.03). No toxicities of Grade 3 or greater occurred following SRS with concurrent TKI treatment, and the incidence of post-SRS vertebral fracture (overall 21%) and pain flare (overall 17%) were similar across cohorts.</jats:p></jats:sec> <jats:sec> <jats:title>CONCLUSIONS</jats:title> <jats:p>The prognosis for patients with mRCC has significantly improved with TKIs. The present investigation suggests a local control benefit with the addition of concurrent first-line TKI therapy to spine SRS. These results have implications in the oligometastatic setting and support a body of preclinical radiobiological research.</jats:p></jats:sec>

The Efficacy of Conventionally Fractionated Radiation in the Management of Osseous Metastases from Metastatic Renal Cell Carcinoma

“…We did not find an association between use of TKI and improved pain response or local control in patients treated with conventional fractionated radiation. This contrasts with a recent study by Miller et al who registered improved local control in patients receiving SRS for spinal metastasis in systemic-therapy naïve patients [ 23 ]. These disparities may be accounted for by the known radiobiological differences between conventional and stereotactic radiation.…”

Overall survival and the response to radiotherapy among molecular subtypes of breast cancer brain metastases treated with targeted therapies

“…Among select patients with targetable metastatic disease, prior investigations have reported superior local control with the addition of concurrent TKIs to SRS. 28 We also observed that the addition of concurrent HER2/ EGFR TKIs to SRS significantly decreased the 12-month cumulative incidence of local failure from 15.1% to 5.7% (P < .001) (Fig. 2C), whereas the use of HER2 antibodies decreased the 12-month cumulative incidence from 18.4% to 10.2% (P 5 .003) (Fig.…”

The risk of radiation necrosis following stereotactic radiosurgery with concurrent systemic therapies

“…In a recentlypublished series of nearly 2000 patients undergoing SRS, renal histology, lung adenocarcinoma histology, HER2 amplification, and ALK/BRAF mutational status were associated with RN [4]. The mechanism for this effect may relate to the increased efficacy of radiation therapy when delivered with VEGFR and EGFR TKIs [20]. VEGFR TKIs alter both tumor angiogenesis and cell proliferation, simultaneously reducing vascularization of metastases while inducing cell apoptosis.…”