Combination Of Stereotactic Radiosurgery Research Articles

CTIM-31. PRELIMINARY RESULTS OF A PHASE II STUDY OF STEREOTACTIC RADIOSURGERY IN CONJUNCTION WITH THE PD-1 INHIBITOR PEMBROLIZUMAB FOR THE TREATMENT OF RECURRENT HIGH-GRADE MENINGIOMA

Abstract Recurrence of higher-grade meningioma after initial resection and radiotherapy is frequent and associated with high rates of morbidity and mortality. Salvage therapies have limited efficacy and average survival after recurrence is approximately 5-10 years. We report here preliminary data from a phase 2 study combining immunotherapy with checkpoint inhibition with stereotactic radiosurgery for treatment of recurrent high-grade meningioma (NCT04659811). Adult patients with either grade 2 or 3 meningioma who have recurred despite treatment with surgery and radiation and who meet eligibility criteria received stereotactic radiosurgery, in 1 to 5 fractions, in conjunction with pembrolizumab 200mg on the first day of radiation and then every 3 weeks until progression, unacceptable toxicity or for 2 years. Primary objective is PFS12, and secondary objectives include safety of the combined treatment in recurrent meningioma, mOS, mPFS, and neurocognitive function and QOL metrics. To date we have enrolled 18 of planned 37 patients, 33% female, 39% grade 2 and 61% grade 3. Safety lead in was completed without any dose limiting toxicity. There have been 4 SAEs, only one of which was related to study treatment (cerebral edema). 29% of patients had at least one AE, the most common were GI disorders (23%), skin disorders (23%) and headache (17%). Preliminary data from 12 patients shows PFS12 to be 50%, which suggests that the combination of stereotactic radiosurgery may be more beneficial than treatment of Pembrolizumab alone (mPFS 7.6 months). One patient was found to have a homozygous focal deletion of the MLH1 gene and had a dramatic reduction in size of her meningioma with a durable response for over one year. These preliminary data suggest that the combination of stereotactic radiosurgery and pembrolizumab is safe, well tolerated and may be beneficial to patients with recurrent higher-grade meningioma.

Association of the combined stereotactic radiosurgery and embolization strategy and long-term outcomes in brain arteriovenous malformations with a volume >10 ml: A nationwide multicenter observational prospective cohort study

BackgroundTo assess the long-term outcome of large brain arteriovenous malformations (AVMs) (volume > 10 ml) underwent combined embolization and stereotactic radiosurgery (E+SRS) versus SRS alone. MethodsPatients were recruited from a nationwide multicenter prospective collaboration registry (MATCH study, August 2011–August 2021) and categorized into E+SRS and SRS alone cohorts. Propensity score-matched survival analysis was employed to control for potential confounding variables. The primary outcome was a composite event of non-fatal hemorrhagic stroke or death. Secondary outcomes were favorable patient outcomes, AVM obliteration, favorable neurological outcomes, seizure, worsened mRS score, radiation-induced changes (RIC), and embolization complications. Furthermore, the efficacy of distinct embolization strategies was evaluated. Hazard ratios (HRs) were computed utilizing Cox proportional hazard models. ResultsAmong 1063 AVMs who underwent SRS with or without prior embolization, 176 patients met the enrollment criteria. Following propensity score matching, the final analysis encompassed 98 patients (49 pairs). Median (interquartile range) follow-up duration for primary outcomes spanned 5.4 (2.7–8.4) years. Overall, the E+SRS strategy demonstrated a trend toward reduced incidence of primary outcomes compared to the SRS alone strategy (1.44 vs 2.37 per 100 patient-years; HR, 0.58 [95 % CI, 0.17–1.93]). Regardless of embolization degree or strategy, stratified analyses further consistently revealed a similar trend, albeit without achieving statistical significance. Secondary outcomes generally exhibited equivalence, but the combined approach showed potential superiority in most measures. ConclusionsThis study suggests a trend toward lower long-term non-fatal hemorrhagic stroke or death risks with the E+SRS strategy when compared to SRS alone in large AVMs (volume > 10 ml).

Stereotactic radiosurgery versus combined stereotactic radiosurgery and bevacizumab for recurrent glioblastoma; a systematic review and meta-analysis of survival.

Recurrent glioblastoma (rGBM) is a brain tumor that is resistant to standard treatments. Although stereotactic radiosurgery (SRS) is a non-invasive radiation technique, it cannot fully prevent tumor recurrence and progression. Bevacizumab blocks tumor blood supply and has been approved for rGBM. However, the best way to combine SRS and bevacizumab is still unclear. We did a systematic review and meta-analysis of studies comparing SRS alone and SRS plus bevacizumab for rGBM. We searched three databases for articles published until June 2023. All statistical analysis was performed by STATA v.17. Our meta-analysis included 20 studies with 926 patients. We found that the combination therapy had a significantly lower rate of overall survival (OS) than SRS alone at 6-month 0.77[95%CI:0.74-0.85] for SRS alone and (100%) for SRS plus bevacizumab. At 1-year OS, 0.39 [95%CI: 0.32-0.47] for SRS alone and 0.61 [95%CI:0.44-0.77] for SRS plus bevacizumab (P-value:0.02). However, this advantage was not seen in the long term (18 months and two years). Additionally, the combination therapy had lower chances of progression-free survival (PFS) than SRS alone at the 6-month and 1-year time points, but the differences were insignificant. Our study indicates that incorporating bevacizumab with SRS may lead to a short-term increase in OS for rGBM patients but not long-term. Additionally, the PFS rate did not show significant improvement in the group receiving combination therapy. Further clinical trials are necessary to validate the enhanced overall survival with combination therapy for rGBM.

Association of the combined stereotactic radiosurgery and embolization strategy and long-term outcomes in brain arteriovenous malformations with a volume ≤10 mL: a nationwide multicenter observational prospective cohort study

BackgroundTo compare the long-term outcomes of stereotactic radiosurgery (SRS) with or without prior embolization in brain arteriovenous malformations (AVMs) (volume ≤10 mL) for which SRS is indicated.MethodsPatients were recruited from...

Clinical outcomes of melanoma brain metastases treated with nivolumab and ipilimumab alone versus nivolumab and ipilimumab with stereotactic radiosurgery.

Upfront dual checkpoint blockade with immune checkpoint inhibitors (ICI) has demonstrated efficacy for treating melanoma brain metastases (MBM) in asymptomatic patients. Whether the combination of stereotactic radiosurgery (SRS) with dual checkpoint blockade improves outcomes over dual-checkpoint blockade alone is unknown. We evaluated clinical outcomes of patients with MBM receiving ICI with nivolumab and ipilimumab, with and without SRS. 49 patients with 158 MBM receiving nivolumab and ipilimumab for untreated MBM between 2015 and 2022 were identified at our institution. Patient and tumor characteristics including age, Karnofsky Performance Status (KPS), presence of symptoms, cancer history, MBM burden, and therapy course were recorded. Outcomes measured from initiation of MBM-directed therapy included overall survival (OS), local control (LC), and distant intracranial control (DIC). Time-to-event analysis was conducted with the Kaplan-Meier method. 25 patients with 74 MBM received ICI alone, and 24 patients with 84 MBM received concurrent SRS. Median follow-up was 24months. No differences in age (p = 0.96), KPS (p = 0.85), presence of symptoms (p = 0.79), prior MBM (p = 0.68), prior MBM-directed surgery (p = 0.96) or SRS (p = 0.68), MBM size (p = 0.67), or MBM number (p = 0.94) were seen. There was a higher rate of nivolumab and ipilimumab course completion in the SRS group (54% vs. 24%; p = 0.029). The SRS group received prior immunotherapy more often than the ICI alone group (54% vs. 8.0%; p < 0.001). There was no significant difference in 1-year OS (72% vs. 71%, p = 0.20) and DIC (63% v 51%, p = 0.26) between groups. The SRS group had higher 1-year LC (92% vs. 64%; p = 0.002). On multivariate analysis, LC was improved with combination therapy (AHR 0.38, p = 0.01). In our analysis, patients who received SRS with nivolumab and ipilimumab had superior LC without increased risk of toxicity or compromised immunotherapy treatment completion despite the SRS cohort having higher rates of prior immunotherapy. Further prospective study of combination nivolumab and ipilimumab with SRS is warranted.

Tucatinib and stereotactic radiosurgery in the management of HER2 positive breast cancer brain metastases.

HER2-positive breast cancer has a high risk of brain metastasis. Stereotactic radiosurgery (SRS) is standard of care for limited brain metastases. Tucatinib, a HER2-targeted tyrosine kinase inhibitor, has demonstrated intracranial efficacy in the HER2-CLIMB Trial. However, it is unknown whether tucatinib with SRS is safe or effective. A retrospective analysis of HER2-positive breast cancer treated with SRS and tucatinib for brain metastases management was performed. All patients received tucatinib and SRS for the management of active brain metastases. The primary endpoint was local and distant brain tumor control. Secondary endpoints were intracranial progression free survival (CNS-PFS), systemic PFS, overall survival (OS), and neurotoxicity. A total of 135 lesions treated with SRS over 39 treatment sessions in 22 patients were identified. Median follow-up from tucatinib initiation was 20.8months. Local brain control was 94% at 12-months and 81% at 24-months. Distant brain control was 39% at 12-months and 26% at 24-months. Median survival was 21.2months, with 12- and 24-month OS rates of 84% and 50%, respectively. Median CNS-PFS was 11.3months, with 12- and 24-month CNS-PFS rates of 44.9% at both time points. Median systemic PFS was not reached, with 12- and 24-month systemic PFS rates of 86% and 57%, respectively. Symptomatic radiation necrosis occurred in 6 (4%) lesions. No additional unexpected toxicities were noted. SRS in combination with tucatinib, capecitabine, and trastuzumab appears to be a safe and feasible treatment for HER2 + brain metastases. Further prospective evaluation of potential synergistic effects is warranted.

Melanoma Brain Metastases: A Systematic Review of Opportunities for Earlier Detection, Diagnosis, and Treatment

Introduction: Melanoma continues to represent the most serious skin cancer worldwide. However, few attempts have been made to connect the body of research on advanced melanoma. In the present review, we report on strides made in the diagnosis and treatment of intracranial metastatic melanoma. Methods: Relevant Cochrane reviews and randomized-controlled trials published by November 2022 were systematically retrieved from the Cochrane Library, EMBASE, and PubMed databases (N = 27). Search and screening methods adhered to the 2020 revision of the Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines. Results: Although the research surrounding the earlier detection of melanoma brain metastasis is scarce, several studies have highlighted specific markers associated with MBM. Such factors include elevated BRAFV600 mutant ctDNA, high LDH concentration, and high IGF-1R. The approach to treating MBM is moving away from surgery and toward nonsurgical management, namely, a combination of stereotactic radiosurgery (SRS) and immunotherapeutic agents. There is an abundance of emerging research seeking to identify and improve both novel and established treatment options and diagnostic approaches for MBM, however, more research is still needed to maximize the clinical efficacy, especially for new immunotherapeutics. Conclusions: Early detection is optimal for the efficacy of treatment and MBM prognosis. Current treatment utilizes chemotherapies and targeted therapies. Emerging approaches emphasize biomarkers and joint treatments. Further exploration toward preliminary identification, the timing of therapies, and methods to ameliorate adverse treatment effects are needed to advance MBM patient care.

Combined stereotactic radiosurgery and tyrosine kinase inhibitor therapy versus tyrosine kinase inhibitor therapy alone for the treatment of non-small cell lung cancer patients with brain metastases.

Whether combined radiation and tyrosine kinase inhibitor (TKI) therapy in non-small cell lung cancer (NSCLC) patients with brain metastases (BMs) and epidermal growth factor receptor (EGFR) mutations confers additional benefits over TKI therapy alone remains a matter of debate. The goal of this study was to compare outcomes between combined TKI therapy with stereotactic radiosurgery (SRS) versus TKI therapy alone in NSCLC patients with BMs and EGFR mutations. Consecutive cases of NSCLC patients with EGFR mutations and BMs treated with TKIs were selected for inclusion in this study. Patients were categorized into two groups based on SRS: TKI therapy alone (group I) and combined SRS and TKI therapy (group II). Patients who had SRS or TKI as salvage therapy and those with prior radiation treatment for BMs were excluded. Tumor control (< 10% increase in tumor volume) and overall survival (OS) rates were compared using Kaplan-Meier analyses. Independent predictors of tumor control and OS were identified using multivariable Cox regression analyses. The study cohort comprised 280 patients (n = 90 in group I and n = 190 in group II). Cumulative tumor control rates were higher in group II than in group I (79.8% vs 31.2% at 36 months, p < 0.0001). Cumulative OS rates were comparable between groups I and II (43.8% vs 59.4% at 36 months, p = 0.3203). Independent predictors of tumor control were older age (p < 0.01, HR 1.03), fewer BMs (p < 0.01, HR 1.09), lack of extracranial metastasis (p < 0.02, HR 0.70), and combined SRS and TKI therapy (p < 0.01, HR 0.25). Independent predictors of OS were fewer BMs (p < 0.01, HR 1.04) and a higher Karnofsky Performance Status score (p < 0.01, HR 0.97). Although the OS rate did not differ between TKI therapy with and without SRS, the addition of SRS to TKI therapy resulted in improvement of intracranial tumor control. The lack of effect on survival rate with the addition of SRS may be attributable to extracranial disease progression. The addition of SRS to TKI therapy is recommended for intracranial disease control in NSCLC patients with BMs and EGFR mutations. Potential benefits may include prevention of neurological deficits and seizures. Future prospective studies may help clarify the clinical outcome benefits of SRS in these patients.

Leptomeningeal disease and brain control after postoperative stereotactic radiosurgery with or without immunotherapy for resected brain metastases

PurposeImmunotherapy has shown activity in patients with brain metastases (BM) and leptomeningeal disease (LMD). We have evaluated LMD and intraparenchymal control rates for patients with resected BM receiving postoperative stereotactic...

Nonsurgical Management of Melanoma Brain Metastasis: Current Therapeutics, Challenges, and Strategies for Progress.

This review aims to provide an overview of nonsurgical treatment strategies for central nervous system metastases in melanoma as well as discuss treatment challenges and future directions. Recent strategies for melanoma brain metastases have involved proving the intracranial activity of approved therapies as well as identifying novel drug targets. BRAF/MEK combination therapy has intracranial activity in those with BRAF V600 mutations, though disease control is shorter for intracranial than extracranial metastases. Immunotherapy and combination immunotherapies have emerged as providing durable responses in melanoma, and newer studies combining immunotherapy with targeted therapies are emerging. Continued challenges include penetration through the blood-brain barrier and development of resistance mechanisms. Novel therapeutic targets and methods to improve central nervous system penetrance are being identified through the application of deep DNA- and RNA-sequencing analyses. Radiation therapy approaches, especially stereotactic radiosurgery in combination or in sequence with systemic therapies, are also being investigated. Both targeted therapies and immunotherapies have revolutionized the field of melanoma treatment. Multimodality approaches with multidisciplinary teams will pave the way for the future of central nervous system disease treatment in melanoma.

Radionecrosis (RN) in patients with brain metastases treated with stereotactic radiosurgery (SRS) and immunotherapy

Objectives Limited data exist regarding radionecrosis (RN) rates when patients receive immunotherapy (IT) and SRS for brain metastases. This study assesses the influence of such treatments on the rate of RN. Methods We retrospectively reviewed 352 lesions from 105 patients with metastatic melanoma or NSCLC treated with SRS and IT from 2012 to 2018. Lesions were excluded from analysis if patients had received WBRT or prior GK to the same lesion, if RN occurred before IT, or if IT had been discontinued >6 months pre-SRS or initiated >1 year post-SRS. IT was delivered concurrently (±30 days of SRS) or sequentially. Overall survival and RN rates were assessed with Kaplan-Meier analysis. Univariate analysis and multivariate analysis were performed to identify characteristics predicting RN. Results Of 195 lesions from 63 patients included in analysis, the median prescription dose, IDL, lesion volume, and maximum tumor dimension (MTD) were 19 Gy, 50%, 0.15 cc and 0.8 cm, respectively. RN rates at 1, 2, and 3 years were 7.3%, 10.4% and 10.4%. On UVA, RN risk increased with, isodose volume (IDV), MTD, and tumor volume (TV) whereas conformity index was associated with a trend toward decreased RN risk. Two-year RN rates increased with TV ≥ 0.3 cc (16% vs 1.1% p = 0.001), MTD ≥ 1.3 cm (19.1% vs 1.8% p < 0.003), and IDV ≥ 1.5 cc (19.6% vs 1.7% p = 0.001). Concurrent vs sequential timing of IT did not predict for RN. Conclusions Patients who received IT and SRS had acceptably low rates of RN. Timing of IT did not predict for RN. Further investigation is warranted to define RN risk with combined SRS and IT.

CTNI-46. A PHASE II TRIAL OF TUMOR TREATING FIELDS (TTFIELDS) CONCOMITANT WITH RADIOSURGERY FOR THE TREATMENT OF RECURRENT, BEVACIZUMAB-NAÏVE GLIOBLASTOMA

Abstract BACKGROUND Almost all GBM patients experience recurrent disease, and median survival after recurrence is 6 months. A phase III trial conducted to test safety and efficacy of TTFields alone versus chemotherapy (including bevacizumab) in recurrent GBM showed improved PFS at six months and one-year survival was 20% in both treatment arms. Stereotactic radiosurgery (SRS), another treatment option recommended at recurrence, has limitations due to the invasive nature of glioblastoma. TTFields may decrease the tumor aggressiveness outside the target area potentially by multiple pathways, including immunogenic cell death and DNA repair inhibition sensitizing to radiation. We hypothesize that combined SRS and TTFields will be complementary, improving outcomes with minimal toxicity. METHODS In this open-label, phase II trial 40 participants with recurrence will be treated with SRS and TTFields, starting in 2020. Recurrence will be defined on FET-PET or MRI using RANO criteria. At least 6 months between the end of the first course of radiotherapy and SRS is mandatory with recurrent tumor visible on FET-PET and/or MRI, with the maximum diameter &amp;lt; 5 cm by either technique. SRS must be delivered within 7 days of TTFields start. A 5-day SRS regimen is allowed. TTFields should be interrupted only during SRS. The sample size of the study was calculated for the comparison of survival against a historical control. With 40 patients followed until death, there is at least an 80% ability to detect a 19% difference in one-year survival rate and 17% difference in ORR (p=0.05) compared to the EF-11 clinical trial. The one-year survival and ORR rate were seen in 20% and 14% of TTFields patients in the historical control. Overall survival will be stratified by volume, PET-based treatment, SVZ invasion, MGMT methylation status, time to first progression, and TTFields compliance. Estimated study primary completion date is July 2023.

Stereotactic Radiosurgery With Concurrent Immunotherapy in Melanoma Brain Metastases Is Feasible and Effective.

Objective: Stereotactic radiosurgery (SRS) is an established treatment for brain metastases in the management of metastasized melanoma. The increasing use of checkpoint inhibitors in melanoma therapy leads to combined treatment schemes consisting of immunotherapy and SRS that need to be evaluated regarding safety and feasibility.Methods: We retrospectively analyzed 36 patients suffering from cerebral metastasized melanoma. Between November 2011 and May 2016, altogether 66 brain metastases were treated with single-fraction SRS (18–20 Gy prescribed to the 80% isodose) in combination with a checkpoint inhibitor (ipilimumab: 82%, pembrolizumab: 14% or nivolumab: 4%), administered within 3 months before or after SRS. Toxicity was evaluated with focus on the incidence of central nervous system (CNS) radiation necrosis (CRN). Overall survival (OS), freedom from local progression (FFLP), freedom from central nervous system radiation necrosis (FFCRN), and freedom from distant intracranial progression (FFDIP) were analyzed using the Kaplan-Meier method.Results: The median follow-up was 25 months (range: 2–115 months). Two patients (6%) presented with cerebral edema CTCAE °III and another two patients (6%) presented with one-sided muscle weakness CTCAE °III after SRS. One of these four symptomatic cases correlated with an observed CRN, the other three symptomatic cases were related to local tumor progression (n = 2) or related to the performance of additional whole brain radiotherapy (WBRT). No further CTCAE °III or °IV toxicity was seen. During follow-up, seven of the growing contrast-enhanced lesions were resected, revealing two cases of CRN and five cases of local tumor progression. Altogether, the observed CRN rate of the irradiated metastases was 6–17% at the time of analysis, ranging due to the radiologically challenging differentiation between CRN and local tumor progression. The observed ranges of the 1- and 2-years FFLP rates were 82–85% and 73–80%, respectively. The median FFDIP was 6.1 months, the median OS was 22.2 months.Conclusion: In the presented cohort, the combination of SRS and checkpoint inhibitors in the management of cerebral metastasized melanoma was safe and effective. Compared to historic data on SRS only, the observed CRN rate was acceptable. To gain resilient data on the incidence of CRN after combined treatment schemes, prospective trials are needed.

Stereotactic radiosurgery combined with targeted/ immunotherapy in patients with melanoma brain metastasis

BackgroundThere is limited data on the use of targeted or immunotherapy (TT/IT) in combination with single fraction stereotactic radiosurgery (SRS) in patients with melanoma brain metastasis (MBM). Therefore, we analyzed the outcome and toxicity of SRS alone compared to SRS in combination with TT/IT.MethodsPatients with MBM treated with single session SRS at our department between 2014 and 2017 with a minimum follow-up of 3 months after first SRS were included. The primary endpoint of this study was local control (LC). Secondary endpoints were distant intracranial control, radiation necrosis-free survival (RNFS), and overall survival (OS). The local/ distant intracranial control rates, RNFS and OS were analyzed using the Kaplan-Meier method. The log-rank test was used to test differences between groups. Cox proportional hazard model was performed for univariate continuous variables and multivariate analyses.ResultsTwenty-eight patients (17 male and 11 female) with 52 SRS-lesions were included. The median follow-up was 19 months (range 14–24 months) after first SRS. Thirty-six lesions (69.2%) were treated with TT/IT simultaneously (4 weeks before and 4 weeks after SRS), while 16 lesions (30.8%) were treated with SRS alone or with sequential TT/IT. The 1-year local control rate was 100 and 83.3% for SRS with TT/IT and SRS alone (p = 0.023), respectively. The estimated 1-year RNFS was 90.0 and 82.1% for SRS in combination with TT/IT and SRS alone (p = 0.935). The distant intracranial control rate after 1 year was 47.7 and 50% for SRS in combination with TT/IT and SRS alone (p = 0.933). On univariate analysis, the diagnosis-specific Graded Prognostic Assessment including the BRAF status (Melanoma-molGPA) was associated with a significantly improved LC. Neither gender nor SRS-PTV margin had a prognostic impact on LC. V10 and V12 were significantly associated with RNFS (p < 0.001 and p = 0.004).ConclusionSRS with simultaneous TT/IT significantly improved LC with no significant difference in radiation necrosis rate. The therapy combination appears to be effective and safe. However, prospective studies on SRS with simultaneous TT/IT are necessary and ongoing.Trial registrationThe institutional review board approved this analysis on 10th of February 2015 and all patients signed informed consent (UE nr. 128–14).

The combination of stereotactic radiosurgery with immune checkpoint inhibition or targeted therapy in melanoma patients with brain metastases: a retrospective study.

Evidence pointing to a synergistic effect of stereotactic radiosurgery (SRS) with concurrent immunotherapy or targeted therapy in patients with melanoma brain metastases (BM) is increasing. We aimed to analyze the effect on overall survival (OS) of immune checkpoint inhibitors (ICI) or BRAF/MEK inhibitors initiated during the 9weeks before or after SRS. We also evaluated the prognostic value of patients' and disease characteristics as predictors of OS in patients treated with SRS. We identified patients with BM from cutaneous or unknown primary origin melanoma treated with SRS between 2011 and 2018. We included 84 patients. The median OS was 12months (95% CI 9-20months). The median follow-up was 30months (95% CI 28-49). Twenty-eight patients with newly diagnosed BM initiated anti-PD-1 +/-CTLA-4 therapy (n = 18), ipilimumab monotherapy (n = 10) or BRAF+/- MEK inhibitors (n = 11), during the 9weeks before or after SRS. Patients who received anti-PD-1 +/-CTLA-4 mAb showed an improved survival in comparison to ipilimumab monotherapy (OS 24 vs. 7.5months; HR 0.32, 95% 0.12-0.83, p = 0.02) and BRAF +/-MEK inhibitors (OS 24 vs. 7months, respectively; HR 0.11, 95% 0.04-0.34, p = 0.0001). This benefit remained significant when compared to the subgroup of patients treated with dual BRAF/MEK inhibition (BMi) (n = 5). In a multivariate Cox regression analysis an age > 65, synchronous BM, > 2 metastatic sites, > 4 BM, and an ECOG > 1 were correlated with poorer prognosis. A treatment with anti-PD-1+/-CTLA-4 mAbs within 9weeks of SRS was associated with better outcomes. The presence of serum lactate dehydrogenase (LDH) levels ≥ 2xULN at BM diagnosis was associated with lower OS (HR 1.60, 95% CI 1.03-2.50; p = 0.04). The concurrent administration of anti-PD-1+/-CTLA-4 mAbs with SRS was associated with improved survival in melanoma patients with newly diagnosed BM. In addition to CNS tumor burden, the extension of systemic disease retains its prognostic value in patients treated with SRS. Elevated serum LDH levels are predictors of poor outcome in these patients.

Stereotactic radiosurgery with and without checkpoint inhibition for patients with metastatic non-small cell lung cancer to the brain: a matched cohort study.

Immune checkpoint inhibitors (ICIs) improve survival in patients with advanced non-small cell lung cancer (NSCLC). Clinical trials examining the efficacy of ICIs in patients with NSCLC excluded patients with untreated brain metastases (BMs). As stereotactic radiosurgery (SRS) is commonly employed for NSCLC-BMs, the authors sought to define the safety and radiological and clinical outcomes for patients with NSCLC-BMs treated with concurrent ICI and SRS. A retrospective matched cohort study was performed on patients who had undergone SRS for one or more NSCLC-derived BMs. Two matched cohorts were identified: one that received ICI before or after SRS within a 3-month period (concurrent ICI) and one that did not (ICI naive). Locoregional tumor control, peritumoral edema, and central nervous system (CNS) adverse events were compared between the two cohorts. Seventeen patients (45 BMs) and 34 patients (92 BMs) composed the concurrent-ICI and ICI-naive cohorts, respectively. There was no statistically significant difference in overall survival (HR 0.99, 95% CI 0.39-2.52, p = 0.99) or CNS progression-free survival (HR 2.18, 95% CI 0.72-6.62, p = 0.11) between the two groups. Similarly, the 12-month local tumor control rate was 84.9% for tumors in the concurrent-ICI cohort versus 76.3% for tumors in the ICI-naive cohort (p = 0.94). Further analysis did reveal that patients receiving concurrent ICI had increased rates of CNS complete response for BMs treated with SRS (8/16 [50%] vs 5/32 [15.6%], p = 0.012) per the Response Assessment in Neuro-Oncology (RANO) criteria. There was also a shorter median time to BM regression in the concurrent-ICI cohort (2.5 vs 3.1 months, p < 0.0001). There was no increased rate of radiation necrosis or intratumoral hemorrhage in the patients receiving concurrent ICI (5.9% vs 2.9% in ICI-naive cohort, p = 0.99). There was no significant difference in the rate of peritumoral edema progression between the two groups (concurrent ICI: 11.1%, ICI naive: 21.7%, p = 0.162). The concurrent use of ICI and SRS to treat NSCLC-BM was well tolerated while providing more rapid BM regression. Concurrent ICI did not increase peritumoral edema or rates of radiation necrosis. Further studies are needed to evaluate whether combined ICI and SRS improves progression-free survival and overall survival for patients with metastatic NSCLC.

Local tumor response and survival outcomes after combined stereotactic radiosurgery and immunotherapy in non-small cell lung cancer with brain metastases.

Concurrent use of anti-PD-1 therapies with stereotactic radiosurgery (SRS) have been shown to be beneficial for survival and local lesional control in melanoma patients with brain metastases. It is not known, however, if immunotherapy (IT) confers the same outcome advantage in lung cancer patients with brain metastases treated with SRS. The authors retrospectively reviewed 85 non-small cell lung cancer (NSCLC) patients with brain metastases who were treated with SRS between January 2006 and December 2016. Thirty-nine PD-L1 antibody-positive patients received anti-PD-1 therapy with SRS (IT group) and 46 patients received chemotherapy (CT) with SRS (CT group). Results were obtained using chi-square, Kaplan-Meier, and Mann-Whitney U tests and Cox regression analyses. Median survival following first radiosurgical treatment in the whole study group was 11.6 months (95% CI 8-15.5 months). Median survival times in the IT group and CT group were 10 months (95% CI 8.3-13.2 months) and 11.6 months (95% CI 7.7-15.6 months), respectively (p = 0.23). A Karnofsky Performance Status (KPS) score < 80 (p = 0.001) and lung-specific molecular marker Graded Prognostic Assessment (lungmol GPA) score < 1.5 (p = 0.02) were found to be predictive of worse survival.Maximal percent lesional shrinkage and time to maximal shrinkage were not significantly different between the CT and IT groups. Of the lesions for which a complete response occurred, 94.8% had pre-SRS volumes < 500 mm3. The amount of lesion shrinkage and time to maximal shrinkage were not different between the IT and CT groups for lesions with volumes < 500 mm3. However, in lesions with volume > 500 mm3, 90% of lesions shrank after radiosurgery in the IT group compared with 47.8% in the CT group (p = 0.001). Median times to initial response and times to maximal shrinkage were faster in the IT group than in the CT group: initial response 49 days (95% CI 33.7-64.3 days) versus 84 days (95% CI 28.1-140 days), p = 0.001; maximal response 105 days (95% CI 59-150 days) versus 182 days (95% CI 119.6-244 days), p = 0.12. Unlike patients with melanoma, patients with NSCLC with brain metastases undergoing SRS showed no significant benefit-either in terms of survival or total amount of lesional response-when anti-PD-1 therapies were used. However, in lesions with volume > 500 mm3, combining SRS with IT may result in a faster and better volumetric response which may be particularly beneficial in lesions causing mass effect or located in neurologically critical locations.

Stereotactic radiosurgery combined with nivolumab or Ipilimumab for patients with melanoma brain metastases: evaluation of brain control and toxicity

PurposeTo investigate the efficacy and safety of concurrent stereotactic radiosurgery (SRS) and ipilimumab or nivolumab in patients with untreated melanoma brain metastases.Patients and MethodsEighty consecutive patients with 326 melanoma brain metastases receiving SRS in combination with ipilimumab or nivolumab were identified from an institutional database and retrospectively evaluated. Patients started systemic treatment with intravenous nivolumab or ipilimumab within one week of receiving SRS. Nivolumab was given at doses of 3 mg/kg every two weeks. Ipilimumab was administered up to four doses of 10 mg/kg, one every 3 weeks, then patients had a maintenance dose of 10 mg/kg every 12 weeks, until disease progression or inacceptable toxicity. Primary endpoint of the study was intracranial progression-free survival (PFS). Secondary endpoints were extracranial PFS, overall survival (OS), and neurological toxicity.ResultsEighty patients were analyzed. Forty-five patients received SRS and ipilimumab, and 35 patients received SRS and nivolumab. With a median follow-up of 15 months, the 6-month and 12-month intracranial PFS rates were 69% (95%CI,54–87%) and 42% (95%CI,24–65%) for patients receiving SRS and nivolumab and 48% (95%CI,34–64%) and 17% (95%CI,5–31%) for those treated with SRS and ipilimumab (p = 0.02), respectively. Extracranial PFS and OS were 37 and 78% in SRS and nivolumab group, respectively, and 17 and 68% in SRS and ipilimumab group, respectively, at 12 months. Sub-group analysis showed significantly better intracranial PFS for patients receiving multi-fraction SRS (3 × 9 Gy) compared to single-fraction SRS (70% versus 46% at 6 months, p = 0.01), especially in combination with nivolumab. Grade 3 treatment-related adverse events occurred in 11 (24%) patients treated with SRS and ipilimumab and 6 (17%) patients who received SRS and nivolumab. Radiation-induced brain necrosis (RN) occurred in 15% of patients.ConclusionsConcurrent SRS and ipilimumab or nivolumab show meaningful intracranial activity in patients with either asymptomatic and symptomatic melanoma brain metastases, although a subset of patients may develop symptomatic RN. The combination of nivolumab with SRS is associated with better intracranial control.

Gamma Knife Stereotactic Radiosurgery in Combination with Bevacizumab for Recurrent Glioblastoma

Prior retrospective and prospective studies suggest improved survival with the use of stereotactic radiosurgery (SRS) and bevacizumab in the treatment of limited-volume glioblastoma (GBM) recurrences. We retrospectively reviewed our experience with gamma knife SRS in combination with bevacizumab for the treatment of focal GBM recurrence during 2009-2015. Outcomes include overall survival, progression free survival (PFS), and radiation-related adverse events. Kaplan-Meier methods and multivariable Cox proportional hazards models were performed for survival analysis. Within a median of 13.7 months after diagnosis, a total of 45 patients with GBM underwent gamma knife SRS and bevacizumab treatment. Median age was 57 years (range: 20-78 years) and 63.3% were women. The median Karnofsky Performance Score (KPS) at recurrence was 80 (range: 40-100). Sixty-four percent of patients had single radiosurgery target (range: 1-4) and median target volume and margin dose were 2.2 cm3 (range: 0.1-25.2 cm3) and 17.0 gray (Gy) (range: 13-24 Gy), respectively. Median PFS and overall survival were 9.3, 31.0 months following diagnosis, and 5.2, 13.3 months after SRS, respectively. Factors associated with poor outcomes were KPS ≤70, SRS dose <18 Gy, and use of <2 chemotherapy agents prior to SRS. No radiation-related adverse events occurred. SRS in combination with bevacizumab can be safely used to treat focal GBM recurrence. KPS, radiation dose, and multi-agent chemotherapy usage prior to SRS demonstrated significant impact on PFS. Bevacizumab may provide clinically relevant radioprotection.

Stereotactic radiosurgery combined with immune checkpoint inhibitors or kinase inhibitors for patients with multiple brain metastases of malignant melanoma.

The aim was to evaluate toxicity and oncological outcome of combined stereotactic radiosurgery (SRS) and immunotherapy or targeted therapy in patients with multiple brain metastases originating from malignant melanoma. Despite the fact that both SRS and kinase inhibitors or immune checkpoint inhibitors are considered standard treatment options for this indication, the optimal combination and sequence of these modalities remains largely unknown, especially for patients with a high number of brain metastases. For this retrospective analysis, conducted in two large SRS dedicated centers, we identified patients with brain metastases from malignant melanoma and simultaneous application of immunotherapy or targeted therapy within 30 days of SRS. Forty-eight patients with a total of 250 lesions (median: 3) were treated in 65 single fraction SRS sessions from 2012 to 2018. After a median follow-up of 8.3 months (range: 1.2-43.6 months), the 6-month and 1-year overall survival rates were 75.3 and 50.8%, respectively. The local control rate at one year was 89.5%. Immunotherapy and the application of systemic treatment directly before or concomitant to SRS were both associated with improved overall survival (P=0.037 and 0.045, respectively). We observed four grade III toxicities, of which only two can be clearly attributed to the combined treatment. Various combinations of SRS and kinase inhibitors or immune checkpoint inhibitors appear feasible and provide promising oncological results and safety profiles for treating few (n=1-4) and also multiple (n≥5) melanoma brain metastases.