Multi-institutional Analysis of Prognostic Factors and Outcomes After Hypofractionated Stereotactic Radiotherapy to the Resection Cavity in Patients With Brain Metastases

Abstract

IMPORTANCEFor brain metastases, the combination of neurosurgical resection and postoperative hypofractionated stereotactic radiotherapy (HSRT) is an emerging therapeutic approach preferred to the prior practice of postoperative whole-brain radiotherapy. However, mature large-scale outcome data are lacking.OBJECTIVE To evaluate outcomes and prognostic factors after HSRT to the resection cavity in patients with brain metastases.DESIGN, SETTING, AND PARTICIPANTS An international, multi-institutional cohort study was performed in 558 patients with resected brain metastases and postoperative HSRT treated between December 1, 2003, and October 31, 2019, in 1 of 6 participating centers. Exclusion criteria were prior cranial radiotherapy (including whole-brain radiotherapy) and early termination of treatment.EXPOSURES A median total dose of 30 Gy (range, 18-35 Gy) and a dose per fraction of 6 Gy (range, 5-10.7 Gy) were applied. MAIN OUTCOMES AND MEASURESThe primary end points were overall survival, local control (LC), and the analysis of prognostic factors associated with overall survival and LC. Secondary end points included distant intracranial failure, distant progression, and the incidence of neurologic toxicity.RESULTS A total of 558 patients (mean [SD] age, 61 [0.50] years; 301 [53.9%] female) with 581 resected cavities were analyzed. The median follow-up was 12.3 months (interquartile range, 5.0-25.3 months). Overall survival was 65% at 1 year, 46% at 2 years, and 33% at 3 years, whereas LC was 84% at 1 year, 75% at 2 years, and 71% at 3 years. Radiation necrosis was present in 48 patients (8.6%) and leptomeningeal disease in 73 patients (13.1%). Neurologic toxic events according to the Common Terminology Criteria for Adverse Events grade 3 or higher occurred in 16 patients (2.8%) less than 6 months and 24 patients (4.1%) greater than 6 months after treatment. Multivariate analysis identified a Karnofsky Performance Status score of 80% or greater (hazard ratio [HR], 0.61; 95% CI, 0.46-0.82; P < .001), 22 to 33 days between resection and radiotherapy (HR, 1.50; 95% CI, 1.07-2.10; P = .02), and a controlled primary tumor (HR, 0.69; 95% CI, 0.52-0.90; P = .007) as prognostic factors associated with overall survival. For LC, a single brain metastasis (HR, 0.57; 95% CI, 0.35-0.93; P = .03) and a controlled primary tumor (HR, 0.59; 95% CI, 0.39-0.92; P = .02) were significant in the multivariate analysis. CONCLUSIONS AND RELEVANCETo date, this cohort study includes one of the largest series of patients with brain metastases and postoperative HSRT and appears to confirm an excellent risk-benefit profile of local HSRT to the resection cavity. Additional studies will help determine radiation dose-volume parameters and provide a better understanding of synergistic effects with systemic and immunotherapies.

The Judicious Use of Stereotactic Radiosurgery and Hypofractionated Stereotactic Radiotherapy in the Management of Large Brain Metastases

“…These studies estimate the risk of LMD following SRS alone to be 5–6.2% [ 40 , 41 , 42 ]. Modern series examining rates of 1-year LMD with post-operative SRS estimate the rate to be 7.2–30% with the large heterogeneity potentially due to the variable definitions of LMD versus focal dural recurrence within the resection cavity [ 11 , 15 , 43 , 44 , 57 ]. LMD following resection is thought to be due to an increased risk of tumor spillage into the CSF at the time of surgery, which was not clinically relevant previously when post-operative WBRT was routinely used and potentially sterilized the intracranial CSF [ 46 ].…”

“…While the reduced dose regimen delivered pre-operatively is considered sub-therapeutic for definitive treatment, the current consensus recommendation is for surveillance and consideration of re-irradiation as a last resort for continued progression [ 37 ]. Nonetheless, cases of subtotal resection are difficult clinical scenarios with worse outcomes compared to GTR regardless of whether pre-operative or post-operative SRS is chosen [ 35 , 57 ].…”

“…Interest has increased for the utilization of HSRT, and multiple retrospective studies have been published examining the rates of local control and RN for HSRT [ 26 , 28 , 57 , 68 , 69 , 70 , 71 , 72 ]. The 1-year local control rate for HSRT following resection of a large brain metastasis ranges widely between 65% and 95% [ 26 , 57 , 68 , 69 , 70 , 71 , 72 ]. The rates of RN with HSRT range from 5% to 25% for the same cohort of patients with resected large brain metastases [ 26 , 57 , 72 ].…”

“…The 1-year local control rate for HSRT following resection of a large brain metastasis ranges widely between 65% and 95% [ 26 , 57 , 68 , 69 , 70 , 71 , 72 ]. The rates of RN with HSRT range from 5% to 25% for the same cohort of patients with resected large brain metastases [ 26 , 57 , 72 ]. Recently published guidelines updating the radiation dose-volume tolerances of brain tissue for novel 3-fraction HSRT regimens reported the volume of normal brain tissue receiving 18 Gy (V18 Gy) as less than 30 mL and the volume of normal brain tissue receiving 23 Gy (V23 Gy) as less than 7 mL kept RN risk below 10% on a pooled analysis of available studies [ 65 ].…”

“…Lastly, a multi-institutional retrospective analysis by Eitz et al examining outcomes and prognostic factors for patients receiving post-operative HSRT was recently published and provides additional insight to what was learned from the Lehrer et al meta-analysis. This large multi-institutional analysis of 558 patients with 581 resection cavities demonstrated 1-year local control of 84% for a median dose of 30 Gy over 5 fractions with a median resection cavity volume of 10.9 mL (max diameter >2.6 cm using spherical modeling) and median PTV volume of 23.9 mL [ 57 ]. The 1-year rate of RN was 8.6% and 1-year rate of LMD was 13.1% [ 57 ].…”