title: Spine stereotactic radiosurgery with concurrent tyrosine kinase inhibitors for metastatic renal cell carcinoma.
abstract: OBJECT 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. 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. METHODS 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. RESULTS 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 < 0.01). 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 < 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. CONCLUSIONS 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.
authors.affiliation: Cleveland Clinic Lerner College of Medicine,.
authors.forename: Jacob A
authors.initials: JA
authors.lastname: Miller
authors.affiliation: Departments of 2 Radiation Oncology.
authors.forename: Ehsan H
authors.initials: EH
authors.lastname: Balagamwala
authors.affiliation: Neurosurgery and.|Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Lilyana
authors.initials: L
authors.lastname: Angelov
authors.affiliation: Departments of 2 Radiation Oncology.|Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center, Cleveland Clinic, Cleveland, Ohio.
authors.forename: John H
authors.initials: JH
authors.lastname: Suh
authors.affiliation: Medical Oncology, Taussig Cancer Institute; and.
authors.forename: Brian
authors.initials: B
authors.lastname: Rini
authors.affiliation: Medical Oncology, Taussig Cancer Institute; and.
authors.forename: Jorge A
authors.initials: JA
authors.lastname: Garcia
authors.affiliation: Medical Oncology, Taussig Cancer Institute; and.|Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Manmeet
authors.initials: M
authors.lastname: Ahluwalia
authors.affiliation: Departments of 2 Radiation Oncology.|Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Samuel T
authors.initials: ST
authors.lastname: Chao
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use* / Q000633:toxicity; D002292:Carcinoma, Renal Cell / Q000453:epidemiology / Q000473:pathology / Q000628:therapy*; D003131:Combined Modality Therapy / Q000009:adverse effects / Q000379:methods; D005260:Female; D006801:Humans; D007680:Kidney Neoplasms / Q000453:epidemiology / Q000473:pathology / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use* / Q000633:toxicity; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D016634:Radiosurgery / Q000009:adverse effects / Q000379:methods; D012189:Retrospective Studies; D013125:Spinal Neoplasms / Q000453:epidemiology / Q000556:secondary / Q000628:therapy*; D013131:Spine / Q000187:drug effects / Q000601:surgery; D017211:Treatment Failure
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases
keywords: SBRT = stereotactic body radiotherapy; SRS = stereotactic radiosurgery; TKI = tyrosine kinase inhibitor; mRCC = metastatic renal cell carcinoma; oncology; renal cell carcinoma; spine radiosurgery; tyrosine kinase inhibitors