Stereotactic body radiotherapy for primary renal cell carcinoma: a systematic review and practice guideline from the International Society of Stereotactic Radiosurgery (ISRS).

Surgery is the standard of care for patients with primary renal cell carcinoma. Stereotactic body radiotherapy (SBRT) is a novel alternative for patients who are medically inoperable, technically high risk, or who decline surgery. Evidence for using SBRT in the primary renal cell carcinoma setting is growing, including several rigorously conducted prospective clinical trials. This systematic review was performed to assess the safety and efficacy of SBRT for primary renal cell carcinoma. Review results then formed the basis for the practice guidelines described, on behalf of the International Stereotactic Radiosurgery Society. 3972 publications were screened and 36 studies (822 patients) were included in the analysis. Median local control rate was 94·1% (range 70·0-100), 5-year progression-free survival was 80·5% (95% CI 72-92), and 5-year overall survival was 77·2% (95% CI 65-89). These practice guidelines addressed four key clinical questions. First, the optimal dose fractionation was 25-26 Gy in one fraction, or 42-48 Gy in three fractions for larger tumours. Second, routine post-treatment biopsy is not recommended as it is not predictive of patient outcome. Third, SBRT for primary renal cell carcinoma in a solitary kidney is safe and effective. Finally, guidelines for post-treatment follow-up are described, which include cross-axial imaging of the abdomen including both kidneys, adrenals, and surveillance of the chest initially every 6 months. This systematic review and practice guideline support the practice of SBRT for primary renal cell carcinoma as a safe and effective standard treatment option. Randomised trials with surgery and invasive ablative therapies are needed to further define best practice.

Utility of molecular markers in predicting local control specific to lung cancer spine metastases treated with stereotactic body radiotherapy.

BACKGROUND AND PURPOSE: We report outcomes following spine stereotactic body radiotherapy (SBRT) in metastatic non-small cell lung cancer (NSCLC) and the significance of programmed death-ligand 1 (PD-L1) status, epidermal growth factor receptor (EGFR) mutation and timing of immune check point inhibitors (ICI) on local failure (LF). MATERIALS AND METHODS: 165 patients and 389 spinal segments were retrospectively reviewed from 2009 to 2021. Baseline patient characteristics, treatment and outcomes were abstracted. Primary endpoint was LF and secondary, overall survival (OS) and vertebral compression fracture (VCF). Multivariable analysis (MVA) evaluated factors predictive of LF and VCF. RESULTS: The median follow-up and OS were: 13.0 months (range, 0.5-95.3 months) and 18.4 months (95% CI 11.4-24.6). 52.1% were male and 76.4% had adenocarcinoma. Of the 389 segments, 30.3% harboured an EGFR mutation and 17.0% were PD-L1 ≥ 50%. The 24 months LF rate in PD-L1 ≥ 50% vs PD-L1 < 50% was 10.7% vs. 38.0%, and in EGFR-positive vs. negative was 18.1% vs. 30.0%. On MVA, PD-L1 status of ≥ 50% (HR 0.32, 95% CI 0.15-0.69, p = 0.004) significantly predicted for lower LF compared to PD-L1 < 50%. Lower LF trend was seen with ICI administration peri and post SBRT (HR 0.41, 95% CI 0.16-1.05, p = 0.062). On MVA, polymetastatic disease (HR 3.28, 95% CI 1.84-5.85, p < 0.0001) and ECOG ≥ 2 (HR 1.87, 95% CI 1.16-3.02, p = 0.011) significantly predicted for worse OS and absence of baseline VCF predicted for lower VCF rate (HR 0.20, 95% CI 0.10-0.39, p < 0.0001). CONCLUSION: We report a significant association of PD-L1 ≥ 50% status on improved LC rates from spine SBRT in NSCLC patients.

Stereotactic body radiotherapy for distant metastases to the head and neck.

PURPOSE: To report clinical outcomes for patients with metastatic disease to the head and neck (HN) treated with stereotactic body radiation therapy (SBRT). METHODS: A retrospective review of patients treated with SBRT to HN sites from 2012 to 2020 was conducted. Treatment indications included the following: oligometastases, oligoprogression, and control a dominant area of progression (DAP). Kaplan-Meier method was used to estimate local control (LC), regional control (RC), overall survival (OS), and progression-free survival (PFS). Univariable (UVA) and multivariable analyses (MVA) were performed. Grade 3-4 acute and late toxicities were reported by the Common Terminology Criteria for Adverse Events v5.0. RESULTS: Fifty-six patients (58 lesions) were analysed with a median follow-up of 16 months. Primary sites included lung (25.0%), kidney (19.6%), breast (19.6%) and other (35.8%). SBRT indications were as follows: oligometastases (42.9%), oligoprogression (19.6%) and local control of a dominant area of progression (37.5%). Most patients received SBRT to a single neck node (n = 47, 81.0%). Median SBRT dose was 40 Gy (range 25-50 Gy) in five fractions, with a median biologically effective dose (BED10) of 72 Gy (range 37.5-100 Gy). One- and 2-year LC and RC rates were 97.6% and 72.7% as well as 100% and 86.7%, respectively. Median OS was 19.2 months (95% [CI] 14.8-69.4), and median PFS was 7.4 months (95% [CI] 5.2-11.9). The 1-year OS and PFS rates for oligometastases, oligoprogression and DAP were 95.8%, 63.6% and 38.1% (p = 0.0039) as well as 56.5%, 27.3% and 19.1% (p = 0.0004), respectively. On MVA, treatment indication and histology were predictive for OS, while indication and prior systemic therapy were predictive for PFS. Cumulative late grade 3 + toxicity rate was 11.3%, without grade 5 events. CONCLUSION: The use of SBRT for metastatic disease to the HN provided excellent LC rates with low rates of regional failure and an acceptable toxicity profile, highlighting its utility in these patients. Patients with oligometastatic disease had better OS and PFS than others.

Chemical Exchange Saturation Transfer MRI for Differentiating Radiation Necrosis From Tumor Progression in Brain Metastasis-Application in a Clinical Setting.

BACKGROUND: High radiation doses of stereotactic radiosurgery (SRS) for brain metastases (BM) can increase the likelihood of radiation necrosis (RN). Advanced MRI sequences can improve the differentiation between RN and tumor progression (TP). PURPOSE: To use saturation transfer MRI methods including chemical exchange saturation transfer (CEST) and magnetization transfer (MT) to distinguish RN from TP. STUDY TYPE: Prospective cohort study. SUBJECTS: Seventy patients (median age 60; 73% females) with BM (75 lesions) post-SRS. FIELD STRENGTH/SEQUENCE: 3-T, CEST imaging using low/high-power (saturation B1  = 0.52 and 2.0 µT), quantitative MT imaging using B1  = 1.5, 3.0, and 5.0 µT, WAter Saturation Shift Referencing (WASSR), WAter Shift And B1 (WASABI), T1 , and T2 mapping. All used gradient echoes except T2 mapping (gradient and spin echo). ASSESSMENT: Voxel-wise metrics included: magnetization transfer ratio (MTR); apparent exchange-dependent relaxation (AREX); MTR asymmetry; normalized MT exchange rate and pool size product; direct water saturation peak width; and the observed T1 and T2 . Regions of interests (ROIs) were manually contoured on the post-Gd T1 w. The mean (of median ROI values) was compared between groups. Clinical outcomes were determined by clinical and radiologic follow-up or histopathology. STATISTICAL TESTS: t-Test, univariable and multivariable logistic regression, receiver operating characteristic, and area under the curve (AUC) with sensitivity/specificity values with the optimal cut point using the Youden index, Akaike information criterion (AIC), Cohen's d. P < 0.05 with Bonferroni correction was considered significant. RESULTS: Seven metrics showed significant differences between RN and TP. The high-power MTR showed the highest AUC of 0.88, followed by low-power MTR (AUC = 0.87). The combination of low-power CEST scans improved the separation compared to individual parameters (with an AIC of 70.3 for low-power MTR/AREX). Cohen's d effect size showed that the MTR provided the largest effect sizes among all metrics. DATA CONCLUSION: Significant differences between RN and TP were observed based on saturation transfer MRI. EVIDENCE LEVEL: 3 Technical Efficacy: Stage 2.

Dose-dependent efficacy of bevacizumab in recurrent glioblastoma.

BACKGROUND: Bevacizumab (BEV), at a standard dose of 10 mg/kg every 2 weeks is associated with prolonged progression-free survival (PFS) but no improvement in overall survival (OS) in recurrent glioblastoma (rGBM). Few studies have examined the potential dose-dependent efficacy of BEV. In Ontario, reimbursement for the costs of BEV varies, and as a result, our practice began to routinely use lower dose regimens. The main aim of this study was to ensure that there was no harm to patients who received the low dose protocol. METHODS: A single-center retrospective study of patients given BEV for rGBM between 2015 and 2020 was performed. Clinical and treatment data including BEV dose regimen [SD (10 mg/kg every 2 weeks) vs. LD (5 mg/kg every 2-3 weeks or 10 mg/kg every 3 weeks)] received at the time of rGBM diagnosis were captured. Overall survival (OS) and progression-free survival (PFS) on BEV were compared using the Kaplan-Meier product-limit method. Log-rank test was used to compare potential predictive factors. Cox regression model was performed for multivariable analysis of OS and PFS. RESULTS: A total of 96 patients were included with a median follow-up duration of 6.84 months (range 1.12-50.63 months) from the date of the first infusion. The LD group consisted of 55 of the 96 patients. By virtue of funding mechanisms for BEV, the median age in the LD group was significantly higher (62 vs. 54 years p = 0.009). There was no difference in MGMT status between the two groups (p = 0.60). The LD group had prolonged median PFS (5.89 months versus 3.22 months; p = 0.0112) and OS (10.23 months versus 6.28 months; p = 0.0010). Multivariable analysis including the dose of BEV, the extent of resection, gender, and age revealed that standard dose of BEV, subtotal resection, and female sex were associated with worse overall survival. Nine patients in the SD group vs. 18 patients in the LD group reported an adverse event related to BEV. CONCLUSION: For patients with recurrent GBM, we found that a low dose regimen of BEV was associated with prolonged OS and PFS compared to the standard dose regimen. Lower dose schedules may be a better and more cost-effective option for patients with rGBM. Lower costs might provide more equitable access to this very important palliative drug.

Patterns of treatment and outcomes of patients with brain-only metastatic breast cancer.

BACKGROUND: We characterized the risk factors and survival of metastatic breast cancer (MBC) patients with brain metastases (BrM) as the first and only site of disease in a large, retrospective cohort. METHODS: MBC patients treated for BrM with radiation at a quaternary institution between 2005 and 2019 were identified. MBC patients with BrM but without concurrent extracranial metastases (ECM) or leptomeningeal disease (LMD) were classified as brain-only. Factors associated with brain-only MBC, brain-specific progression free survival (bsPFS) and overall survival (OS) were investigated. RESULTS: A total of 691 patients with MBC and BrM were analyzed. Among them, 67 patients (9.7%, n = 67/691) presented with brain-only MBC without concurrent ECM/LMD. Within this subgroup, 40 patients (5.8%, n = 40/691) remained free of any ECM or LMD, while 17 patients (2.5%) developed LMD, and 10 patients (1.4%%) developed ECM with a median follow-up of 8 months (IQR 2-35). Patients with brain-only MBC were more likely to have a single BrM [OR 3.41 (1.62-7.19), p = 0.001] and either HER2+ [OR 3.3 (1.13-9.65), p = 0.03] or TNBC [OR 4.09 (1.42-11.74), p = 0.009] subtypes. Patients who presented with brain-only MBC also had significantly longer OS [HR 0.45, (0.22-0.86), p = 0.008] and a trend toward longer bsPFS [HR 0.67 (0.44-1.03), p = 0.05] compared to those with concurrent ECM/LMD. CONCLUSION: Patients with brain-only MBC had a longer bsPFS and OS than those with ECM. Patients with HER2+ and TNBC were more likely to have brain-only disease compared to those with HR+/HER2- MBC.

Stereotactic body radiotherapy for spine metastases: a review of 24 Gy in 2 daily fractions.

PURPOSE: Stereotactic body radiotherapy (SBRT) has proven to be a highly effective treatment for selected patients with spinal metastases. Randomized evidence shows improvements in complete pain response rates and local control with lower retreatment rates favoring SBRT, compared to conventional external beam radiotherapy (cEBRT). While there are several reported dose-fractionation schemes for spine SBRT, 24 Gy in 2 fractions has emerged with Level 1 evidence providing an excellent balance between minimizing treatment toxicity while respecting patient convenience and financial strain. METHODS: We provide an overview of the 24 Gy in 2 SBRT fraction regimen for spine metastases, which was developed at the University of Toronto and tested in an international Phase 2/3 randomized controlled trial. RESULTS: The literature summarizing global experience with 24 Gy in 2 SBRT fractions suggests 1-year local control rates ranging from 83-93.9%, and 1-year rates of vertebral compression fracture ranging from 5.4-22%. Reirradiation of spine metastases that failed prior cEBRT is also feasible with 24 Gy in 2 fractions, and 1-year local control rates range from 72-86%. Post-operative spine SBRT data are limited but do support the use of 24 Gy in 2 fractions with reported 1-year local control rates ranging from 70-84%. Typically, the rates of plexopathy, radiculopathy and myositis are under 5% in those series reporting mature follow up, with no cases of radiation myelopathy (RM) reported in the de novo setting when the spinal cord avoidance structure is limited to 17 Gy in 2 fractions. However, re-irradiation RM has been observed following 2 fraction SBRT. More recently, 2-fraction dose escalation with 28 Gy, with a higher dose constraint to the critical neural tissues, has been reported suggesting improved rates of local control. This regimen may be important in those patients with radioresistant histologies, high grade epidural disease, and/or paraspinal disease. CONCLUSION: The dose-fractionation of 24 Gy in 2 fractions is well-supported by published literature and is an ideal starting point for centers looking to establish a spine SBRT program.

Re-irradiation for recurrent high-grade glioma: an analysis of prognostic factors for survival and predictors of radiation necrosis.

PURPOSE: Recurrent high-grade glioma (rHGG) is a heterogeneous population, and the ideal patient selection for re-irradiation (re-RT) has yet to be established. This study aims to identify prognostic factors for rHGG patients treated with re-RT. METHODS: We retrospectively reviewed consecutive adults with rHGG who underwent re-RT from 2009 to 2020 from our institutional database. The primary objective was overall survival (OS). Secondary endpoints included prognostic factors for early death (< 6 months after re-RT) and predictors of radiation necrosis (RN). RESULTS: For the 79 patients identified, the median OS after re-RT was 9.9 months (95% CI 8.3-11.6). On multivariate analyses, re-resection at progression (HR 0.56, p = 0.027), interval from primary treatment to first progression ≥ 16.3 months (HR 0.61, p = 0.034), interval from primary treatment to re-RT ≥ 23.9 months (HR 0.35, p < 0.001), and re-RT PTV volume < 112 cc (HR 0.27, p < 0.001) were prognostic for improved OS. Patients who had unmethylated-MGMT tumours (OR 12.4, p = 0.034), ≥ 3 prior systemic treatment lines (OR 29.1, p = 0.022), interval to re-RT < 23.9 months (OR 9.0, p = 0.039), and re-RT PTV volume ≥ 112 cc (OR 17.8, p = 0.003) were more likely to die within 6 months of re-RT. The cumulative incidence of RN was 11.4% (95% CI 4.3-18.5) at 12 months. Concurrent bevacizumab use (HR < 0.001, p < 0.001) and cumulative equivalent dose in 2 Gy fractions (EQD2, α/ß = 2) < 99 Gy2 (HR < 0.001, p < 0.001) were independent protective factors against RN. Re-RT allowed for less corticosteroid dependency. Sixty-six percent of failures after re-RT were in-field. CONCLUSION: We observe favorable OS rates following re-RT and identified prognostic factors, including methylation status, that can assist in patient selection and clinical trial design. Concurrent use of bevacizumab mitigated the risk of RN.

Hypofractionated stereotactic radiosurgery (HSRS) as a salvage treatment for brain metastases failing prior stereotactic radiosurgery (SRS).

INTRODUCTION: Various treatment options exist to salvage stereotactic radiosurgery (SRS) failures for brain metastases, including repeat SRS and hypofractionated SRS (HSRS). Our objective was to report outcomes specific to salvage HSRS for brain metastases that failed prior HSRS/SRS. METHODS: Patients treated with HSRS to salvage local failures (LF) following initial HSRS/SRS, between July 2010 and April 2020, were retrospectively reviewed. The primary outcomes were the rates of LF, radiation necrosis (RN), and symptomatic radiation necrosis (SRN). Univariable (UVA) and multivariable (MVA) analyses using competing risk regression were performed to identify predictive factors for each endpoint. RESULTS: 120 Metastases in 91 patients were identified. The median clinical follow up was 13.4 months (range 1.1-111.1), and the median interval between SRS courses was 13.1 months (range 3.0-56.5). 115 metastases were salvaged with 20-35 Gy in 5 fractions and the remaining five with a total dose ranging from 20 to 24 Gy in 3-fractions. 67 targets (56%) were postoperative cavities. The median re-treatment target volume and biological effective dose (BED10) was 9.5 cc and 37.5 Gy, respectively. The 6- and 12- month LF rates were 18.9% and 27.7%, for RN 13% and 15.6%, and for SRN were 6.1% and 7.0%, respectively. MVA identified larger re-irradiation volume (hazard ratio [HR] 1.02, p = 0.04) and shorter interval between radiosurgery courses (HR 0.93, p < 0.001) as predictors of LF. Treatment of an intact target was associated with a higher risk of RN (HR 2.29, p = 0.04). CONCLUSION: Salvage HSRS results in high local control rates and toxicity rates that compare favorably to those single fraction SRS re-irradiation experiences reported in the literature.

Single-fraction radiosurgery outcomes for large vestibular schwannomas in the upfront or post-surgical setting: a systematic review and International Stereotactic Radiosurgery Society (ISRS) Practice Guidelines.

PURPOSE: To perform a systematic review of literature specific to single-fraction stereotactic radiosurgery (SRS) for large vestibular schwannomas (VS), maximum diameter ≥ 2.5 cm and/or classified as Koos Grade IV, and to present consensus recommendations on behalf of the International Stereotactic Radiosurgery Society (ISRS). METHODS: The Medline and Embase databases were used to apply the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) approach. We considered eligible prospective and retrospective studies, written in the English language, reporting treatment outcomes for large VS; SRS for large post-operative tumors were analyzed in aggregate and separately. RESULTS: 19 of the 229 studies initially identified met the final inclusion criteria. Overall crude rate of tumor control was 89% (93.7% with no prior surgery vs 87.7% with prior surgery). Rates of salvage microsurgical resection, need for shunt, and additional SRS in all series versus those with no prior surgery were 9.6% vs 3.3%, 4.7% vs 6.4% and 1% vs 0.9%, respectively. Rates of facial palsy and hearing preservation in all series versus those with no prior surgery were 1.3% vs 3.4% and 34.2% vs 40.4%, respectively. CONCLUSIONS: Upfront SRS resulted in high rates of tumor control with acceptable rates of facial palsy and hearing preservation as compared to the results in those series including patients with prior surgery (level C evidence). Therefore, although large VS are considered classic indication for microsurgical resection, upfront SRS can be considered in selected patients and we recommend a prescribed marginal dose from 11 to 13 Gy (level C evidence).

Relationship between apparent diffusion coefficient and survival as a function of distance from gross tumor volume on radiation planning MRI in newly diagnosed glioblastoma.

PURPOSE: To investigate the changes in apparent diffusion coefficient (ADC) within incrementally-increased margins beyond the gross tumor volume (GTV) on post-operative radiation planning MRI and their prognostic utility in glioblastoma. METHODS: Radiation planning MRIs of adult patients with newly diagnosed glioblastoma from 2017 to 2020 were assessed. The ADC values were normalized to contralateral normal white matter (nADC). Using 1 mm isotropic incremental margin increases from the GTV, the nADC values were calculated at each increment. Age, ECOG performance status, extent of resection and MGMT promoter methylation status were obtained from medical records. Using univariate and multivariable Cox regression analysis, association of nADC to progression-free and overall survival (PFS, OS) was assessed at each increment. RESULTS: Seventy consecutive patients with mean age of 53.6 ± 10.3 years, were evaluated. The MGMT promoter was methylated in 31 (44.3%), unmethylated in 36 (51.6%) and unknown in 3 (4.3%) patients. 11 (16%) underwent biopsy, 41 (44%) subtotal resection and 18 (26%) gross total resection. For each 1 mm increase in distance from GTV, the nADC decreased by 0.16% (p < 0.0001). At 1-5 mm increment, the nADC was associated with OS (p < 0.01). From 6 to 11 mm increment the nADC was associated with OS with the p-value gradually increasing from 0.018 to 0.046. nADC was not associated with PFS. CONCLUSION: The nADC values at 1-11 mm increments from the GTV margin were associated with OS. Future prospective multicenter studies are needed to validate the findings and to pave the way for the utilization of ADC for margin reduction in radiation planning.

Quantifying uncertainties associated with reference dosimetry in an MR-Linac.

BACKGROUND: Magnetic resonance (MR)-guided radiation therapy provides capabilities to utilize high-resolution and real-time MR imaging before and during treatment, which is critical for adaptive radiotherapy. This emerging modality has been promptly adopted in the clinic settings in advance of adaptations to reference dosimetry formalism that are needed to account for the presence of strong magnetic fields. In particular, the influence of magnetic field on the uncertainty of parameters in the reference dosimetry equation needs to be determined in order to fully characterize the uncertainty budget for reference dosimetry in MR-guided radiation therapy systems. PURPOSE: To identify and quantify key sources of uncertainty in the reference dosimetry of external high energy radiotherapy beams in the presence of a strong magnetic field. METHODS: In the absence of a formalized Task Group report for reference dosimetry in MR-integrated linacs, the currently suggested formalism follows the TG-51 protocol with the addition of a quality conversion factor kBQ accounting for the effects of the magnetic field on ionization chamber response. In this work, we quantify various sources of uncertainty that impact each of the parameters in the formalism, and evaluate their overall contribution to the final dose. Measurements are done in a 1.5 T MR-Linac (Unity, Elekta AB, Stockholm, Sweden) which integrates a 1.5 T Philips MR scanner and a 7 MVFFF linac. The responses of several reference-class small volume ionization chambers (Exradin:A1SL, IBA:CC13, PTW:Semiflex-3D) and Farmer type ionization chambers (Exradin:A19, IBA:FC65-G) were evaluated throughout this process. Long-term reproducibility and stability of beam quality, TPR 10 20 ${\mathrm{TPR}}_{10}^{20}$ , was also measured with an in-house built phantom. RESULTS: Relative to the conventional external high energy linacs, the uncertainty on overall reference dose in MR-linac is more significantly affected by the chamber setup: A translational displacement along y-axis of ± 3 mm results in dose variation of < |0.20| ± 0.02% (k = 1), while rotation of ± 5° in horizontal and vertical parallel planes relative to relative to the direction of magnetic field, did not exceed variation of < |0.44| ± 0.02% for all 5 ionization chambers. We measured a larger dose variation for xy-plane (horizontal) rotations (< |0.44| ± 0.02% (k = 1)) than for yz-plane (vertical) rotations (< ||0.28| ± 0.02% (k = 1)), which we associate with the gradient of kB,Q as a function of chamber orientation with respect to direction of the B0 -field. Uncertainty in Pion (for two depths), Ppol (with various sub-studies including effects of cable length, cable looping in the MRgRT bore, connector type in magnetic environment), and Prp were determined. Combined conversion factor kQ × kB,Q was provided for two reference depths at four cardinal angle orientations. Over a two-year period, beam quality was quite stable with TPR 10 20 ${\mathrm{TPR}}_{10}^{20}$ being 0.669 ± 0.01%. The actual magnitude of TPR 10 20 ${\mathrm{TPR}}_{10}^{20}$ was measured using identical equipment and compared between two different Elekta Unity MR-Linacs with results agreeing to within 0.21%. CONCLUSION: In this work, the uncertainty of a number of parameters influencing reference dosimetry was quantified. The results of this work can be used to identify best practice guidelines for reference dosimetry in the presence of magnetic fields, and to evaluate an uncertainty budget for future reference dosimetry protocols for MR-linac.

Stereotactic radiosurgery versus whole brain radiotherapy in patients with intracranial metastatic disease and small-cell lung cancer: a systematic review and meta-analysis.

BACKGROUND: Patients with small-cell lung cancer (SCLC) are at high risk for intracranial metastatic disease (IMD). Although stereotactic radiosurgery (SRS) has supplanted whole brain radiotherapy (WBRT) as first-line treatment for IMD in most solid cancers, WBRT remains first-line treatment for IMD in patients with SCLC. We aimed to evaluate the efficacy of SRS in comparison with WBRT and assess treatment outcomes following SRS. METHODS: In this systematic review and meta-analysis, we searched MEDLINE, Embase, CENTRAL, and grey literature sources for controlled trials and cohort studies published in English reporting on SRS for IMD treatment in patients with SCLC from inception to March 23, 2022. Studies were excluded that did not report on SRS for IMD secondary to SCLC. Summary data were extracted. The primary outcome was overall survival, presented as pooled hazard ratios (HR) through random-effects meta-analysis for studies comparing SRS with WBRT with or without SRS boost, and as medians for single-arm SRS studies. This study is registered with the Open Science Framework, DOI 10.17605/OSF.IO/8M4HC, and PROSPERO, CRD42021258197. FINDINGS: Of 3823 identified records, 31 were eligible for inclusion; seven were included in the meta-analysis. Overall survival following SRS was longer than following WBRT with or without SRS boost (HR 0·85; 95% CI 0·75-0·97; n=7 studies; n=18 130 patients), or WBRT alone (0·77; 0·72-0·83; n=7 studies; n=16 961 patients), but not WBRT plus SRS boost (1·17, 0·78-1·75; n=4 studies; n=1167 patients). Using single-arm studies, pooled median overall survival from SRS was 8·99 months (95% CI 7·86-10·16; n=14 studies; n=1682 patients). Between-study heterogeneity was considerable when pooled among all comparative studies (I2=71·9%). INTERPRETATION: These results suggest survival outcomes are equitable following treatment with SRS compared with WBRT in patients with SCLC and IMD. Future prospective studies should focus on tumour burden and differences in local and distant intracranial progression between WBRT-treated and SRS-treated patients with SCLC. FUNDING: None.

Systemic considerations for the surgical treatment of spinal metastatic disease: a scoping literature review.

Systemic assessment is a pillar in the neurological, oncological, mechanical, and systemic (NOMS) decision-making framework for the treatment of patients with spinal metastatic disease. Despite this importance, emerging evidence relating systemic considerations to clinical outcomes following surgery for spinal metastatic disease has not been comprehensively summarised. We aimed to conduct a scoping literature review of this broad topic. We searched MEDLINE, Embase, Scopus, Cochrane Central Register of Controlled Trials, Web of Science, and CINAHL databases from Jan 1, 2000, to July 31, 2021. 61 articles were included, accounting for a total of 22 335 patients. Preoperative systemic variables negatively associated with postoperative clinical outcomes included demographics (eg, older age [>60 years], Black race, male sex, low or elevated body-mass index, and smoking status), medical comorbidities (eg, cardiac, pulmonary, hepatic, renal, endocrine, vascular, and rheumatological), biochemical abnormalities (eg, hypoalbuminaemia, atypical blood cell counts, and elevated C-reactive protein concentration), low muscle mass, generalised motor weakness (American Spinal Cord Injury Association Impairment Scale grade and Frankel grade) and poor ambulation, reduced performance status, and systemic disease burden. This is the first comprehensive scoping review to broadly summarise emerging evidence relevant to the systemic assessment component of the widely used NOMS framework for spinal metastatic disease decision making. Medical, surgical, and radiation oncologists can consider these findings when prognosticating spinal metastatic disease-related surgical outcomes on the basis of patients' systemic condition. These factors might inform a shared decision-making approach with patients and their families.

Trastuzumab emtansine increases the risk of stereotactic radiosurgery-induced radionecrosis in HER2 + breast cancer.

INTRODUCTION: In this study, we investigate factors associated with radionecrosis (RN) in HER2 + (human epidermal growth factor receptor 2) patients with brain metastases (BrM) treated with stereotactic radiosurgery (SRS). METHODS: Patients with HER2 + breast cancer BrM treated with SRS (2010-2020) were identified from an institutional database. The incidence of RN was determined per treated BrM according to serial imaging and/or histology. Factors associated with RN such as age, RT dose, BrM volume, and initiation of Trastuzumab Emtansine (T-DM1) were investigated with univariate and multivariable analyses (MVA). RESULTS: 67 HER2 + patients with 223 BrM were identified. 21 patients (31.3%) were treated with T-DM1 post-SRS, including 14 patients (20.9%) who received T-DM1 within 12 months of SRS. The median follow-up was 15.6 (interquartile range (IQR) 5.4-35.3) months. The overall probability of RN post-SRS was 21.6% (95% confidence interval (CI) 2.7-10.7), and the 1 and 2 year risk was 6.7% (95% CI 2.7-10.7) and 15.2% (95% CI 9.2-21.3). MVA identified T-DM1 treatment post-SRS (hazard ratio (HR) 2.5, 95% CI 1.2-5.3, p = 0.02) and equivalent dose in 2 Gy fractions (EQD2) > 90 Gy2 (HR 2.4, 95% CI 1.1-5.1, p = 0.02) as predictors of RN. Patients treated with T-DM1 and SRS had a 29.9% (95% CI 15.3-44.6%) probability of RN, with a 25.2% (95% CI 12.8-37.6%) risk at 1- and 2 years post-T-DM1. The majority of RN were symptomatic (71%), with a median time to RN of 4.8 months. CONCLUSION: T-DM1 exposure post-SRS was associated with a higher risk of RN among patients with HER2 + BrM.

Erythroblastic oncogene B-2 status and intracranial metastatic disease in patients with gastrointestinal cancer: a systematic review.

PURPOSE: The incidence of intracranial metastatic disease (IMD) in patients with gastrointestinal (GI) cancers is rising. Expression of the erythroblastic oncogene B-2 (ERBB2) is associated with an in increased risk of IMD in patients with breast cancer. The implications of ERBB2 expression for IMD risk in patients with GI cancers is less clear. The objective of this systematic review was to determine the incidence of IMD and OS in patients with ERBB2+ gastrointestinal cancers. METHODS: A literature search of MEDLINE, EMBASE, CENTRAL, and grey literature sources was conducted from date of database inception to July 2021. Included studies reported outcomes on patients with IMD secondary to ERBB2 GI cancers. RESULTS: Fourteen cohort studies met inclusion criteria, of which thirteen were retrospective. Eleven studies reported on gastric, esophageal, or gastroesophageal junction cancers. Three studies directly compared incidence of IMD based on ERBB2 status and among these, ERBB2+ patients had a higher incidence of IMD. One study indicated that ERBB2+ patients had significantly longer OS from the times of primary cancer (P = .015) and IMD diagnosis (P = .01), compared with patients with ERBB2- disease. CONCLUSIONS: In this systematic review, patients with ERBB2+ GI cancer were more likely to develop IMD. Future study is required on the prognostic and predictive value of ERBB2 status in patients with GI cancers.

Current state of therapeutic focused ultrasound applications in neuro-oncology.

INTRODUCTION: Despite manifold advances in oncology, cancers of the central nervous system remain among the most lethal. Unique features of the brain, including distinct cellular composition, immunological privilege, and physical barriers to therapeutic delivery, likely contribute to the poor prognosis of patients with neuro-oncological disease. Focused ultrasound is an emerging technology that allows transcranial delivery of ultrasound energy to focal brain targets with great precision. METHODS: A review of the clinical and preclinical focused ultrasound literature was performed to obtain data regarding the current state of the focused ultrasound in context of neuro-oncology. A narrative review was then constructed to provide an overview of current and future applications of this technology. RESULTS: Focused ultrasound can facilitate direct control of tumors by thermal or mechanical ablation, as well as enhance delivery of diverse therapeutics by disruption of the blood-brain barrier without local tissue damage. Indeed, ultrasound-sensitive drug formulations or sonosensitizers may be combined with ultrasound blood-brain barrier disruption to achieve high local drug concentration while limiting systemic exposure to therapeutics. Furthermore, focused ultrasound can induce radiosensitization, immunomodulation, and neuromodulation. Here we review applications of focused ultrasound with a focus on approaches currently under clinical investigation for the treatment of neuro-oncological disease, such as blood-brain barrier disruption for drug delivery and thermal ablation. We also discuss design of clinical trials, selection of patient cohorts, and emerging approaches to improve the efficacy of transcranial ultrasound, such as histotripsy, as well as combinatorial strategies to exploit synergistic biological effects of existing cancer therapies and ultrasound. CONCLUSIONS: Focused ultrasound is a promising and actively expanding therapeutic modality for diverse neuro-oncological diseases.

Radiation myelopathy following stereotactic body radiation therapy for spine metastases.

PURPOSE: Stereotactic body radiation therapy (SBRT) is now considered a standard of care treatment option in the management of spine metastases. One of the most feared complications of spine SBRT is radiation myelopathy (RM). METHODS: We provided a narrative review of RM following spine SBRT based on review of the published literature, including data on spinal cord dose constraints associated with the risk of RM, strategies to mitigate the risk, and management options for RM. RESULTS: There are limited published data of cases of RM following spine SBRT with detailed spinal cord dosimetry. The HyTEC report provided recommendations for the point maximal dose (Dmax) for the spinal cord that is associated with a < 5% risk of RM for 1-5 fractions spine SBRT. In the setting of spine SBRT reirradiation after previous conventional external beam radiation therapy (cEBRT), factors associated with RM are: SBRT spinal cord Dmax, cumulative spinal cord Dmax, and the time interval between previous RT and SBRT reirradiation. There are various strategies to mitigate the risk of RM, including accurate delineation of the spinal cord (or thecal sac), strict adherence to the recommended spinal cord dose constraints, and robust treatment immobilisation set-up and delivery. Limited effective treatment options are available for patients who develop RM, and these include corticosteroids, hyperbaric oxygen, and bevacizumab; however, none have been supported by high quality evidence. CONCLUSION: RM is a rare but devastating complication following SBRT for spine metastases. There are strategies to minimise the risk of RM to ensure safe delivery of spine SBRT.

Inter-fraction dynamics during post-operative 5 fraction cavity hypofractionated stereotactic radiotherapy with a MR LINAC: a prospective serial imaging study.

PURPOSE/OBJECTIVE(S): This study examined changes in the clinical target volume (CTV) and associated clinical implications on a magnetic resonance imaging linear accelerator (MR LINAC) during hypofractionated stereotactic radiotherapy (HSRT) to resected brain metastases. In addition, the suitability of using T2/FLAIR (T2f) sequence to define CTV was explored by assessing contouring variability between gadolinium-enhanced T1 (T1c) and T2f sequences. MATERIALS/METHODS: Fifteen patients treated to either 27.5 or 30 Gy with five fraction HSRT were imaged with T1c and T2f sequences during treatment; T1c was acquired at planning (FxSim), and fraction 3 (Fx3), and T2f was acquired at FxSim and all five fractions. The CTV were contoured on all acquired images. Inter-fraction cavity dynamics and CTV contouring variability were quantified using absolute volume, Dice similarity coefficient (DSC), and Hausdorff distance (HD) metrics. RESULTS: The median CTV on T1c and T2f sequences at FxSim were 12.0cm3 (range, 1.2-30.1) and 10.2cm3 (range, 2.9-27.9), respectively. At Fx3, the median CTV decreased in both sequences to 9.3cm3 (range, 3.7-25.9) and 8.6cm3 (range, 3.3-22.5), translating to a median % relative reduction of - 11.4% on T1c (p = 0.009) and - 8.4% on T2f (p = 0.032). We observed a median % relative reduction in CTV between T1c and T2f at FxSim of - 6.0% (p = 0.040). The mean DSC was 0.85 ± 0.10, and the mean HD was 5.3 ± 2.7 mm when comparing CTV on T1c and T2f at FxSim. CONCLUSION: Statistically significant reductions in cavity CTV was observed during HSRT, supporting the use of MR image guided radiation therapy and treatment adaptation to mitigate toxicity. Significant CTV contouring variability was seen between T1c and T2f sequences. Trial registration NCT04075305 - August 30, 2019.

Predicting survival in patients with glioblastoma using MRI radiomic features extracted from radiation planning volumes.

BACKGROUND: Quantitative image analysis using pre-operative magnetic resonance imaging (MRI) has been able to predict survival in patients with glioblastoma (GBM). The study explored the role of postoperative radiation (RT) planning MRI-based radiomics to predict the outcomes, with features extracted from the gross tumor volume (GTV) and clinical target volume (CTV). METHODS: Patients with IDH-wildtype GBM treated with adjuvant RT having MRI as a part of RT planning process were included in the study. 546 features were extracted from each GTV and CTV. A LASSO Cox model was applied, and internal validation was performed using leave-one-out cross-validation with overall survival as endpoint. Cross-validated time-dependent area under curve (AUC) was constructed to test the efficacy of the radiomics model, and clinical features were used to generate a combined model. Analysis was done for the entire group and in individual surgical groups-gross total excision (GTR), subtotal resection (STR), and biopsy. RESULTS: 235 patients were included in the study with 57, 118, and 60 in the GTR, STR, and biopsy subgroup, respectively. Using the radiomics model, binary risk groups were feasible in the entire cohort (p < 0.01) and biopsy group (p = 0.04), but not in the other two surgical groups individually. The integrated AUC (iAUC) was 0.613 for radiomics-based classification in the biopsy subgroup, which improved to 0.632 with the inclusion of clinical features. CONCLUSION: Imaging features extracted from the GTV and CTV regions can lead to risk-stratification of GBM undergoing biopsy, while the utility in other individual subgroups needs to be further explored.