Stereotactic Radiosurgery Group Research Articles

Single-fraction versus hypofractionated stereotactic radiosurgery for medium-sized brain metastases of 2.5 to 3cm.

Given recently suggested utility of hypofractionated stereotactic radiosurgery (SRS) in treating large brain metastases (BMs) > 3cm, we sought to prospectively control tumor size variable to investigate the efficacy and safety of hypofractionated SRS for medium-sized BMs (2.5 to 3cm) compared with single-fraction SRS. Between 2011 and 2015, a total of 100 patients with newly diagnosed BMs (n = 105) of 2.5 to 3cm had been treated with either single-fraction (n = 67; median dose 20Gy) or hypofractionated SRS (n = 38; median cumulative dose 35Gy in 5 daily fractions). No patients received any prior or upfront whole brain radiotherapy. In each patient, treatment outcome was measured by local tumor control (LTC), overall and progression-free survival (OS and PFS), and the occurrence of radiation necrosis (RN). With a median follow-up of 14months, significant differences were observed between the single-fraction versus hypofractionated SRS groups in the incidence of RN (29.9% vs. 5.3%, P < 0.001) and LTC (1-year LTC rates 66.6% vs. 92.4%, P = 0.028). There were no differences in PFS (median 6months vs. 6months, P = 0.381) and OS (median 13months vs. 18months, P = 0.239). Treatment-related adverse events ( ≥ grade 2 toxicity by CTCAE ver. 4.0) occurred more frequently in single-fraction group, although the difference did not reach statistical significance (56.3% vs. 36.1%, P = 0.084). Our results suggest a better safety and efficacy profile of hypofractionated SRS for medium-sized BMs compared with single-fraction SRS. Further prospective studies are needed to confirm these results.

Assessment of costs in open surgery and stereotactic radiosurgery for vestibular schwannomas.

Microsurgical resection and radiosurgery remain the most widely used interventions in the treatment of vestibular schwannomas. There is a growing demand for cost-effectiveness analyses to evaluate these two treatment modalities and delineate the factors that drive their total costs. Here, the authors evaluated specific cost drivers for microsurgical and radiosurgical management of vestibular schwannoma by using the Value Driven Outcomes system available at the University of Utah. The authors retrospectively reviewed all cases involving microsurgical and radiosurgical treatment of vestibular schwannomas at their institution between November 2011 and September 2017. Patient and tumor characteristics, subcategory costs, and potential cost drivers were analyzed. The authors identified 163 vestibular schwannoma cases, including 116 managed microsurgically and 47 addressed with stereotactic radiosurgery (SRS). There were significant differences between the two groups in age, tumor size, and preoperative Koos grade (p < 0.05), suggesting that indications for treatment were markedly different. Length of stay (LOS) and length of follow-up were also significantly different. Facility costs were the most significant contributor to both microsurgical and SRS groups (58.3% and 99.4%, respectively); however, physician professional fees were not specifically analyzed. As expected, microsurgical treatment resulted in an average 4-fold greater overall cost of treatment than for SRS cases (p < 0.05), and there was a greater variation in costs for open cases as well. Costs remained stable over time for both open resection and SRS. Multivariable analysis showed that LOS (β = 0.7, p = 0.0001), discharge disposition (β = 0.2, p = 0.004), nonserviceable hearing (β = 0.1, p = 0.02), and complications (β = 0.2, p = 0.005) affected cost for open surgery, whereas no specifically examined factor could be identified as driving costs for SRS. This analysis identified the fact that facility utilization constitutes the majority of total costs for both microsurgery and SRS treatment modalities of vestibular schwannomas. LOS, discharge disposition, nonserviceable hearing, and complications contributed significantly to the total costs for the microsurgical group, whereas none of the factors could be identified as driving total costs for the SRS group. This information may be used to establish policies and protocols to reduce facility costs, with the goal of decreasing the total costs without jeopardizing patient care.

Cranial Irradiation for Patients with Epidermal Growth Factor Receptor (EGFR) Mutant Lung Cancer Who Have Brain Metastases in the Era of a New Generation of EGFR Inhibitors.

Immediate whole brain radiation (WBRT) has been the standard for patients with lung cancer with brain metastases. The study aims to evaluate the effect of immediate cranial irradiation in patients with epidermal growth factor receptor (EGFR) mutant lung cancer in the era of a new generation of EGFR inhibitors. Medical records of 198 patients with EGFR mutant non-small cell lung cancer and brain metastases at initial metastatic diagnosis were reviewed. Patients were categorized into four groups: immediate WBRT, immediate cranial stereotactic radiosurgery (SRS), delayed radiation upon progression of cranial lesions (DRT), and never cranial irradiation (NRT). Overall survival (OS) and progression-free survival related to EGFR inhibitors were analyzed. The SRS group had the fewest brain metastases and fewest extracranial lesions, and the DRT and NRT groups had the smallest brain metastases. Median survival were 18.5, 55.7, 21.1, and 18.2 months for the WBRT, SRS, DRT, and NRT groups, respectively. Patients who had received EGFR T790M inhibitors survived longer (41.1 vs. 19.8 months). In multivariate analysis, the OS of patients in the SRS group was longer than that in the NRT group (adjusted hazard ratio [aHR]: 0.315). Patients who had fewer extracranial lesions and who had received EGFR T790M inhibitor treatments also survived longer (aHR: 0.442 and 0.357, respectively). Immediate stereotactic radiosurgery but not whole brain radiation was associated with longer survival. Because of patient heterogeneity and the introduction of EGFR T790M inhibitors, the timing and modality of cranial irradiation should be determined individually, and cranial irradiation may be omitted for selected patients. Immediate whole brain radiation has been the standard for patients with lung cancer with brain metastases. In this study, it was observed that, for patients with epidermal growth factor receptor (EGFR) mutant advanced lung cancer who had brain metastases, there was no difference in survival between patients who never received cranial irradiation and those who received whole brain radiation immediately. Patients who received immediate stereotactic radiosurgery or who had ever received EGFR T790M inhibitors survived longer. Patients who received immediate stereotactic radiosurgery have fewer brain metastases. These findings suggest that the timing and modality of cranial irradiation should be determined individually, and cranial irradiation may be omitted in selected patients.

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.

Comparison between stereotactic radiosurgery and whole-brain radiotherapy for 10-20 brain metastases from non-small cell lung cancer.

The efficacy and safety of stereotactic radiosurgery (SRS) in comparison with whole brain radiotherapy (WBRT) for brain metastases (BMs) remains unclear. The present study retrospectively reviewed 44 patients who received SRS or WBRT as an initial treatment for 10-20 BMs from non-small cell lung cancer between 2009 and 2016. Of the patients, 24 (54.5%) were treated with SRS and 20 (45.5%) were treated with WBRT. Overall survival (OS), time to intracranial progression (TTIP), neurological survival (NS), and prognostic factors were examined. OS did not significantly differ between the two groups: 7.3 months in the SRS group vs. 7.2 months in the WBRT group (P=0.502). Median TTIP was significantly shorter in the SRS group than in the WBRT group (7.1 vs. 19.1 months, P=0.009). In contrast, there were no significant differences in NS between the two groups (14.5 months in the SRS group vs. 12.9 months in the WBRT group, P=0.346). Univariate and multivariate analysis revealed that the type of initial treatment for BMs (WBRT or SRS) was not a significant prognostic factor (hazard ratio=0.80, 95% confidence interval: 0.42-1.52, P=0.502). However, histology, performance status, subsequent molecular targeted drugs, subsequent chemotherapy and salvage treatment were independent prognostic factors. There were no significant differences in OS and NS between treatment with SRS and treatment with WBRT in patients with 10-20 BMs, although TTIP was improved with WBRT. As an upfront treatment for 10-20 BMs, SRS may delay WBRT and the adverse events associated with WBRT.

Empirical versus progression-guided stereotactic radiosurgery for non-functional pituitary macroadenomas after subtotal resection.

There is a lack of consensus regarding whether if residual non-functional macroadenomas (NFM) should undergo empirical stereotactic radiosurgery (SRS) or be monitored until tumor progression before SRS treatment. The aim of this study is to compare the risks and benefits of empirical versus progression-guided SRS for NFM after subtotal resection. This is a retrospective study of consecutive NFM patients who subtotal surgical resection followed by SRS between 1999 and 2014. Patients were dichotomized into two groups: empirical SRS (SRS without evidence of tumor progression) and progression-guided SRS (SRS after demonstration of tumor progression) groups. Tumor response was categorized into: (1) regression, ≥ 10% decrease in tumor volume; (2) stable, < 10% increase or decrease in tumor volume; and (3) progression, ≥ 10% increase in tumor volume. Tumor control comprised stable tumor response and tumor regression. Of the 112 patients who underwent SRS for NFM, 106 patients were treated for residual NFM after surgical resection, and included in the final analysis. The empirical SRS and progression-guided SRS groups comprised 46 and 60 patients, respectively. Overall tumor control rate was 88.7%. Higher rate of tumor control was achieved in the empirical SRS group compared to the progression-guided SRS group (95.65% vs. 83.33%, p = 0.047). Rates of new visual field deficit, cranial neuropathy and endocrinopathy were comparable between the two groups. Empirical SRS group had higher rates of progression-free survival compared to progression-guided SRS group (p = 0.015). Actuarial progression-free survival rates for the empirical SRS group were 93.2%, 93.2%, and 81.5% at 3, 5, and 10years after SRS. Actuarial progression-free survival rates for the progression-guided SRS were 86.4%, 82.1%, and 68.4% at 3, 5, and 10years after SRS. Empirical SRS offers higher rates of tumor control and progression-free survival compared to progression-guided SRS in patients with residual NFM after surgical resection. Rates of new hypopituitarism and cranial neuropathies were comparable between the two groups.

Impact of stereotactic radiosurgery on first recurrence of glioblastoma

Background and Aim: The benefit of stereotactic radiosurgery (SRS) in recurrent glioblastoma multiforme (GBM) remains unclear, partly due to disease heterogeneity. Subventricular zone (SVZ) invasion is a prognostic factor for primary GBM, but whether SVZ involvement is also prognostic in recurrent GBM treated with SRS is unknown. Here, we aimed to determine prognostic factors after first GBM recurrence. Materials and Methods: Thirty-nine consecutive patients with a first recurrence of glioblastoma treated at the Gamma Knife Center, Warsaw, Poland and the Franciszek Lukaszczyk Oncology Center, Bydgoszcz, Poland, between 2012 and 2016 were retrospectively reviewed. Magnetic resonance images were reviewed according to SVZ invasion by primary tumors and at the time of recurrence. Outcomes were evaluated using univariable and multivariable analyses. The study protocol was approved by the Ludwik Rydygier Collegium Medicum of Nicolas Copernicus University Institutional Review Board (approved No. KB 494/2018) on June 19, 2018. Results: SRS was the only prognostic factor for overall survival after recurrence in multivariable analysis. The median overall survival after the first recurrence was 18 months in the SRS group versus 6.5 months in the non-SRS group (P = 0.02). Survival after the first recurrence treated with SRS was shorter when recurrences were localized to the SVZ. Conclusion: SRS appears to be an effective salvage modality for small recurrent GBMs. Although SVZ-positive tumors have a worse prognosis, these tumors may benefit from SRS.

Acute neurologic toxicity of palliative radiotherapy for brain metastases in patients receiving immune checkpoint blockade.

The interaction between immune checkpoint blockade (ICB) and radiation (RT) for brain metastases has not been well understood. Given that acute neurotoxicity from this combination is not well characterized, we reviewed patients receiving ICB and RT for brain metastases. Patients treated with ICB and cranial RT from 2010 through 2017 were reviewed. ICB and RT must have been administered within 30 days of each other. Treatment parameters, performance status, symptoms prior to treatment, and toxicity were extracted from the electronic medical record. Survival was calculated from the end of RT to last follow-up or death. Seventy-eight patients were included. Median follow-up was 177 days (range, 12-1603). Median age was 64 years old (range, 29-98) and 47 (63%) were male. The main tumor types were melanoma (n = 47) and nonsmall-cell lung cancer (n = 19). Fifty-seven patients were treated with stereotactic radiosurgery (SRS) and 21 with whole-brain radiotherapy (WBRT). Most patients received single-agent ICB, though 4 patients received nivolumab and ipilimumab. Forty-one (53%) patients reported no neurologic toxicity. Grade 2 or greater neurologic toxicities were reported in 12 (21%) and 8 (38%) patients in the SRS and WBRT groups, respectively. WBRT was associated with a greater risk of any neurotoxicity, though there was no correlation between ICB agent and toxicity. Sequencing of ICB and RT (ie, <30 days vs <7) did not influence rates of toxicity. ICB during SRS or WBRT does not appear to worsen acute neurotoxicity compared to historical controls of RT alone.

Fractionated Radiotherapy Is Associated with Lower Rates of Treatment-Related Edema than Stereotactic Radiosurgery in Magnetic Resonance Imaging–Defined Meningiomas

Both stereotactic radiosurgery (SRS) and fractionated radiation therapy (FRT) techniques are used for treatment of intracranial meningiomas with excellent local control (LC) rates. Although SRS techniques are convenient, toxicity including treatment-related edema can significantly impact patient quality of life. The long-term clinical outcomes of patients with magnetic resonance imaging (MRI)-defined meningiomas treated with radiation therapy (RT) alone are reported. The charts of 211 patients with meningiomas diagnosed by contrast-enhanced MRI treated with either SRS or FRT between 1991 and 2012 at a single institution were reviewed. Actuarial rates for LC and development of treatment-related radiographic edema (TRE) were determined by the Kaplan-Meier method. There were 211 patients who received radiation therapy for 223 lesions. Median follow-up was 5.7 years. Eleven patients experienced a local failure; of these, 2 were ultimately found to have pathologically proven metastatic carcinoma. Two- and 5-year LC was 97.8% and 94.6%, respectively, with no significant difference based on modality of therapy. Actuarial rate for development of TRE at 1 and 2 years was 30.1% and 34.6% for the SRS group and 1.6% and 2.5% for the FRT group, respectively (P < 0.001). RT alone using a limited margin is an effective treatment option for MRI-defined meningiomas and should be considered even without biopsy if surgery will present significant morbidity. Although LC with SRS versus FRT was comparable, FRT was associated with a significantly decreased risk of TRE.

주요간문맥종양혈전을 동반한 간세포암에 대한 다기관 체부정위방사선치료계획 비교연구(KROG 16-17)

Background/Aims: To evaluate the technical feasibility of stereotactic body radiotherapy (SBRT) for hepatocellular carcinoma (HCC) with the major portal vein tumor thrombosis (PVTT). Methods: Ten institutions affiliated with the Korean Stereotactic Radiosurgery Group were provided the contours of four cases: the first case was the first branch PVTT with sufficient normal liver volume (NLV), the second was the first branch PVTT with insufficient NLV, the third was the main trunk PVTT at confluence level, and the fourth was the main trunk PVTT with entire length. The institutions were asked to make SBRT plans according to their current treatment protocols and to complete facility questionnaires. Results: Based on institutional protocols, SBRT was feasible in nine institutions for the first case (32-60 Gy in 3-5 fractions), in eight institutions for the second case (32-50 Gy in 3-5 fractions), in seven institutions for the third case (35-60 Gy in 3-5 fractions), and in four institutions for the fourth case (35-42 Gy in 4-5 fractions). The other institutions recommended hypo- or conventional fractionation due to insufficient NLV or gastrointestinal organ proximity. With analysis of the SBRT dose to the central hepatobiliary tract, the major PVTT could theoretically be associated with a high risk of hepatobiliary toxicity. Conclusions: Although SBRT is a technically feasible option for HCC with the major PVTT, there was a variability among the participating institutions. Therefore, further studies will be necessary to standardize the practice of SBRT for the major PVTT. (J Liver Cancer 2018;18:130-141)

Robotic Stereotactic Radiosurgery in Melanoma Patients with Brain Metastases under Simultaneous Anti-PD-1 Treatment.

Combination concepts of radiotherapy and immune checkpoint inhibition are currently of high interest. We examined imaging findings, acute toxicity, and local control in patients with melanoma brain metastases receiving programmed death 1 (PD-1) inhibitors and/or robotic stereotactic radiosurgery (SRS). Twenty-six patients treated with SRS alone (n = 13; 20 lesions) or in combination with anti-PD-1 therapy (n = 13; 28 lesions) were analyzed. Lesion size was evaluated three and six months after SRS using a volumetric assessment based on cranial magnetic resonance imaging (cMRI) and acute toxicity after 12 weeks according to the Common Terminology Criteria for Adverse Events (CTCAE). Local control after six months was comparable (86%, SRS + anti-PD-1, and 80%, SRS). All toxicities reported were less than or equal to grade 2. One metastasis (5%) in the SRS group and six (21%) in the SRS + anti-PD-1 group increased after three months, whereas four (14%) of the six regressed during further follow-ups. This was rated as pseudoprogression (PsP). Three patients (23%) in the SRS + anti-PD-1 group showed characteristics of PsP. Treatment with SRS and anti-PD-1 antibodies can be combined safely in melanoma patients with cerebral metastases. Early volumetric progression of lesions under simultaneous treatment may be related to PsP; thus, the evaluation of combined radioimmunotherapy remains challenging and requires experienced teams.

Abstract P1-17-05: Prognostic impact of initial treatment modality for brain metastasis in metastatic breast cancer

Abstract Background: The routine screening of brain metastasis (BM) is not recommended in patients with metastatic breast cancer (MBC) by guidelines. Due to survival improvement and increased use of magnetic resonance imaging (MRI) contribute the increasing of MBC BM incidence. The incidence of BM and survival from BM were various by molecular subtypes. The prognostic role of early detection of oligo BM and subsequent local treatment by subtypes is not clear. We aimed to compare BM free survival (BMFS) and BM overall survival (BMOS) by both treatment modalities and subtypes. Methods: In the Yonsei Breast Cancer MBC Database, we identified 1252 MBC patients who were diagnosed from 2006 to 2016. Data of 358 MBC patients (127 HR+/HER2-, 80 HR+/HER2+, 64 HR-/HER2+, 87 HR-/HER2-) with BM were available for the analysis. BMFS was defined as the time from the diagnosis of MBC to the diagnosis of BM. MBC patients with initial BM were excluded from analysis of BMFS. BMOS was defined as the time from the diagnosis of BM to any cause of death. Treatment modalities were analyzed as three categories; whole brain radiotherapy (WBRT), stereotactic radiosurgery (SRS), and neurosurgery. Results: Among the 1252 MBC patients, 47.7%, 14.7%, 13.1%, 17.6%, and 6.9% had HR+/HER2-, HR+/HER2+, HR-/HER2+, HR-/HER2-, and unknown subtypes, respectively. The incidence of initial BM were highest among patients with HR-/HER2- (14.5%) and were lowest with HR+/HER2- (5.2%) Incidence of initial metastasisInitial metastatic sitesHR+/HER2-, n(%)HR+/HER2+, n(%)HR-/HER2+, n(%)HR-/HER2-, n(%)Unknown, n(%)PBrain31 (5.2)16 (8.7)12 (7.3)32 (14.5)6 (6.9)&amp;lt;0.001Lung197 (33)72 (39.1)62 (37.8)99 (45)33 (37.9)0.036Liver137 (22.9)46 (25)52 (31.7)56 (25.5)16 (18.4)0.122Bone403 (67.5)109 (59.2)66 (40.2)90 (40.9)48 (55.2)&amp;lt;0.001Distant LN176 (29.5)74 (40.2)60 (36.6)93 (42.3)22 (25.3)0.011Pleura116 (19.4)19 (10.3)23 (14)40 (18.2)13 (14.9)0.045 . The median BMFS was 17.3 months (95% confidence interval (CI); 14.32-20.28) among the all patients with BM. The median BMFS was significantly shorter in the ER-/HER- subtypes (12 months, 95% CI; 20.73-31.67), and followed by ER-/HER2+ (14.8 months, 95% CI; 11.50-18.10), ER+/HER2+ (20.9 months, 95% CI; 16.88-24.92), and ER+/HER2- (26.2 months, 95% CI; 20.73-31.67). The median BMOS was significantly better in the SRS (16.8 months; 95% CI; 13.53-20.07) and surgery group (13.4 months, 95% CI; 7.19-19.61) compared with WBRT (6.9 months, 95% CI; 5.04-8.76) and no treatment (1.2 months, 95% CI; 0.32-2.08). Conclusions: Incidence of initial BM and BMFS were significantly different by subtypes. Patients who were treated with SRS or neurosurgery showed better survival compared to WBRT. This findings support to consideration of screening of BM in HER2+ or triple negative subtypes for the early detection of oligo BM. Citation Format: Kim GM, Cho YU, Kim SI, Park S, Park HS, Kim JY, Chun YJ, Sohn J. Prognostic impact of initial treatment modality for brain metastasis in metastatic breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-17-05.

Quality of Life in Vestibular Schwannoma Patients: A Longitudinal Study

Objective To examine differences in quality of life in patients with vestibular schwannoma following a single treatment modality: observation, stereotactic radiosurgery (SRS), or microsurgery. Study design Retrospective review. Setting Tertiary academic medical center. Patients Patients diagnosed with sporadic vestibular schwannoma who had completed at least 2 Penn Acoustic Neuroma Quality of Life (PANQOL) surveys. Interventions Treatment via SRS, microsurgery, or observation. Main outcome measures PANQOL total survey and subdomain scores. Results One hundred and thirty-four patients (94 observations, 24 SRS, 16 microsurgeries) were included. The mean number of PANQOL surveys completed was 2.8 (range 2-5). The total PANQOL scores were significantly lower in the SRS group, but not the microsurgery group, compared with observation at the time of diagnosis (observation 550.4 ± 58.4; SRS 471.4 ± 37.4; microsurgery 492.6 ± 40.7; p = 0.03). Over time, there were no significant differences in the change of PANQOL scores across the 3 groups (SRS PANQOL score worsened 6.8/year compared with observation, p = 0.3; microsurgery PANQOL score worsened 7.8/year compared with observation, p = 0.5). Anxiety was the only subdomain that significantly worsened over time in the microsurgery group (microsurgery PANQOL score worsened 3.8/year compared with observation; p = 0.009). Conclusion Despite differences in PANQOL scores at baseline, changes in total PANQOL score over time were not found to be statistically significant, regardless of the treatment group chosen. Overall, these results hold implications for patient counseling when considering treatment choice and quality of life predictions.

Efficacy and safety of stereotactic radiosurgery for pulmonary metastases from osteosarcoma: Experience in 73 patients

Osteosarcoma pulmonary metastases are typically treated with resection and/or chemotherapy. We hypothesize that stereotactic radiosurgery (SRS) can be an alternative to surgery that can achieve high rates of local control with limited toxicity. From January 2005 to December 2013, 73 patients who developed pulmonary metastasis during period of adjuvant chemotherapy or follow-up were analyzed. 33 patients were treated by stereotactic radiosurgery using the body gamma-knife system. A total dose of 50 Gy was delivered at 5 Gy/fraction to the 50% isodose line covering the planning target volume, whereas a total dose of 70 Gy was delivered at 7 Gy/fraction to the gross target volume. The other 40 patients were treated by surgical resection. Four-year progression-free survival rate, four-year survival rate, median time of PRPFS (post-relapse progress-free survival) and PROS (post-relapse overall survival) in SRS group were parallel to that in surgical group. Patients tolerated gamma knife radiosurgery well. Our study demonstrates that SRS is well-tolerated with excellent local control and less complications. SRS should be considered as a potential option in patients with pulmonary metastases from osteosarcoma, especially in those who are medically inoperable, refuse surgery.

Whole brain radiation therapy (WBRT) alone versus WBRT and radiosurgery for the treatment of brain metastases.

Historically, whole brain radiation therapy (WBRT) has been the main treatment for brain metastases. Stereotactic radiosurgery (SRS) delivers high-dose focused radiation and is being increasingly utilized to treat brain metastases. The benefit of adding SRS to WBRT is unclear. This is an updated version of the original Cochrane Review published in Issue 9, 2012. To assess the efficacy of WBRT plus SRS versus WBRT alone in the treatment of adults with brain metastases. For the original review, in 2009 we searched the following electronic databases: CENTRAL, MEDLINE, Embase, and CancerLit in order to identify trials for inclusion in this review. For the first update the searches were updated in May 2012.For this update, in May 2017 we searched CENTRAL, MEDLINE, and Embase in order to identify trials for inclusion in the review. We restricted the review to randomized controlled trials (RCTs) that compared use of WBRT plus SRS versus WBRT alone for upfront treatment of adults with newly diagnosed metastases (single or multiple) in the brain resulting from any primary, extracranial cancer. We used the generic inverse variance method, random-effects model in Review Manager 5 for the meta-analysis. We identified three studies and one abstract for inclusion but we could only include two studies, with a total of 358 participants in a meta-analysis. This found no difference in overall survival (OS) between the WBRT plus SRS and WBRT alone groups (hazard ratio (HR) 0.82, 95% confidence interval (CI) 0.65 to 1.02; 2 studies, 358 participants; moderate-quality evidence). For participants with one brain metastasis median survival was significantly longer in the WBRT plus SRS group (6.5 months) versus WBRT group (4.9 months; P = 0.04). Participants in the WBRT plus SRS group had decreased local failure compared to participants who received WBRT alone (HR 0.27, 95% CI 0.14 to 0.52; 2 studies, 129 participants; moderate-quality evidence). Furthermore, we observed an improvement in performance status scores and decrease in steroid use in the WBRT plus SRS group (risk ratio (RR) 0.64 CI 0.42 to 0.97; 1 study, 118 participants; low-quality evidence). Unchanged or improved Karnofsky Performance Scale (KPS) at six months was seen in 43% of participants in the combined therapy group versus only 28% in the WBRT-alone group (RR 0.78 CI 0.61 to 1.00; P value = 0.05; 1 study, 118 participants; low-quality evidence). Overall, risk of bias in the included studies was unclear. Since the last version of this review we have identified one new study that met the inclusion criteria. However, due to a lack of data from this study we were not able to include it in a meta-analysis. Given the unclear risk of bias in the included studies, the results of this analysis have to be interpreted with caution. In our analysis of all included participants, SRS plus WBRT did not show a survival benefit over WBRT alone. However, performance status and local control were significantly better in the SRS plus WBRT group. Furthermore, significantly longer OS was reported in the combined treatment group for recursive partitioning analysis (RPA) Class I patients as well as patients with single metastasis. Most of our outcomes of interest were graded as moderate-quality evidence according to the GRADE criteria and the risk of bias in the majority of included studies was mostly unclear.

Post-operative stereotactic radiosurgery versus observation for completely resected brain metastases: a single-centre, randomised, controlled, phase 3 trial

SUMMARYBackgroundAfter brain metastasis resection, whole-brain radiation therapy (WBRT) decreases local recurrence but may cause cognitive decline. We performed this study to determine if stereotactic radiosurgery (SRS) to the surgical cavity improved local tumor tumor-free recurrence rates compared to surgical resection alone as an alternative to the need for immediate WBRT.MethodsThe main entry criteria for the study included patients >3 years of age, with a Karnofsky Performance Score ≥ 70, who were able to undergo an MRI scan and who had a complete resection of 1–3 brain metastases (the maximum diameter of the resection cavity had to be ≤4cm). Patients were assigned randomly to either SRS treatment of the resection cavity (within 30 days of surgery) or observation (OBS). Patients were stratified by histology, tumor size, and number of metastases. Patients were recruited at a single tertiary cancer center. The primary endpoint was time to local recurrence in the resection cavity assessed by blinded central review of brain MRI scans in the intention-to-treat population. The trial was registered at clinicaltrials.gov (Trial NCT00950001, status: closed to new participants).FindingsBetween 8/13/2009 and 2/16/2016, 132 patients were randomized to OBS (N=68) or SRS (N=64), with 128 patients available for analysis. We stratified by metastasis size (maximum diameter of ≥3 cm vs. <3 cm), histology (melanoma vs. other), and number of metastases (one vs. two or three). The 12-month local tumor recurrence-free rate was 43% (OBS) (95% CI 31%–59%) and 72% (SRS) (95% CI 60%–87%) (hazard ratio [HR] 0.46, 95% confidence interval [CI] 0.24–0.88, p=0.015).InterpretationThis prospective randomized trial of patients undergoing surgical resection for 1–3 brain metastases indicates that SRS administered to the resection cavity significantly lowers local recurrence compared to observation alone. Thus, the use of SRS after brain metastasis resection is an alternative to WBRT.

Postoperative stereotactic radiosurgery compared with whole brain radiotherapy for resected metastatic brain disease (NCCTG N107C/CEC·3): a multicentre, randomised, controlled, phase 3 trial

Whole brain radiotherapy (WBRT) is the standard of care to improve intracranial control following resection of brain metastasis. However, stereotactic radiosurgery (SRS) to the surgical cavity is widely used in an attempt to reduce cognitive toxicity, despite the absence of high-level comparative data substantiating efficacy in the postoperative setting. We aimed to establish the effect of SRS on survival and cognitive outcomes compared with WBRT in patients with resected brain metastasis. In this randomised, controlled, phase 3 trial, adult patients (aged 18 years or older) from 48 institutions in the USA and Canada with one resected brain metastasis and a resection cavity less than 5·0 cm in maximal extent were randomly assigned (1:1) to either postoperative SRS (12-20 Gy single fraction with dose determined by surgical cavity volume) or WBRT (30 Gy in ten daily fractions or 37·5 Gy in 15 daily fractions of 2·5 Gy; fractionation schedule predetermined for all patients at treating centre). We randomised patients using a dynamic allocation strategy with stratification factors of age, duration of extracranial disease control, number of brain metastases, histology, maximal resection cavity diameter, and treatment centre. Patients and investigators were not masked to treatment allocation. The co-primary endpoints were cognitive-deterioration-free survival and overall survival, and analyses were done by intention to treat. We report the final analysis. This trial is registered with ClinicalTrials.gov, number NCT01372774. Between Nov 10, 2011, and Nov 16, 2015, 194 patients were enrolled and randomly assigned to SRS (98 patients) or WBRT (96 patients). Median follow-up was 11·1 months (IQR 5·1-18·0). Cognitive-deterioration-free survival was longer in patients assigned to SRS (median 3·7 months [95% CI 3·45-5·06], 93 events) than in patients assigned to WBRT (median 3·0 months [2·86-3·25], 93 events; hazard ratio [HR] 0·47 [95% CI 0·35-0·63]; p<0·0001), and cognitive deterioration at 6 months was less frequent in patients who received SRS than those who received WBRT (28 [52%] of 54 evaluable patients assigned to SRS vs 41 [85%] of 48 evaluable patients assigned to WBRT; difference -33·6% [95% CI -45·3 to -21·8], p<0·00031). Median overall survival was 12·2 months (95% CI 9·7-16·0, 69 deaths) for SRS and 11·6 months (9·9-18·0, 67 deaths) for WBRT (HR 1·07 [95% CI 0·76-1·50]; p=0·70). The most common grade 3 or 4 adverse events reported with a relative frequency greater than 4% were hearing impairment (three [3%] of 93 patients in the SRS group vs eight [9%] of 92 patients in the WBRT group) and cognitive disturbance (three [3%] vs five [5%]). There were no treatment-related deaths. Decline in cognitive function was more frequent with WBRT than with SRS and there was no difference in overall survival between the treatment groups. After resection of a brain metastasis, SRS radiosurgery should be considered one of the standards of care as a less toxic alternative to WBRT for this patient population. National Cancer Institute.

Comparison of WBRT alone, SRS alone, and their combination in the treatment of one or more brain metastases: Review and meta-analysis.

Whole brain radiotherapy has been a standard treatment of brain metastases. Stereotactic radiosurgery provides more focal and aggressive radiation and normal tissue sparing but worse local and distant control. This meta-analysis was performed to assess and compare the effectiveness of whole brain radiotherapy alone, stereotactic radiosurgery alone, and their combination in the treatment of brain metastases based on randomized controlled trial studies. Electronic databases (PubMed, MEDLINE, Embase, and Cochrane Library) were searched to identify randomized controlled trial studies that compared treatment outcome of whole brain radiotherapy and stereotactic radiosurgery. This meta-analysis was performed using the Review Manager (RevMan) software (version 5.2) that is provided by the Cochrane Collaboration. The data used were hazard ratios with 95% confidence intervals calculated for time-to-event data extracted from survival curves and local tumor control rate curves. Odds ratio with 95% confidence intervals were calculated for dichotomous data, while mean differences with 95% confidence intervals were calculated for continuous data. Fixed-effects or random-effects models were adopted according to heterogeneity. Five studies (n = 763) were included in this meta-analysis meeting the inclusion criteria. All the included studies were randomized controlled trials. The sample size ranged from 27 to 331. In total 202 (26%) patients with whole brain radiotherapy alone, 196 (26%) patients receiving stereotactic radiosurgery alone, and 365 (48%) patients were in whole brain radiotherapy plus stereotactic radiosurgery group. No significant survival benefit was observed for any treatment approach; hazard ratio was 1.19 (95% confidence interval: 0.96-1.43, p = 0.12) based on three randomized controlled trials for whole brain radiotherapy only compared to whole brain radiotherapy plus stereotactic radiosurgery and hazard ratio was 1.03 (95% confidence interval: 0.82-1.29, p = 0.81) for stereotactic radiosurgery only compared to combined approach. Local control was best achieved when whole brain radiotherapy was combined with stereotactic radiosurgery. Hazard ratio 2.05 (95% confidence interval: 1.36-3.09, p = 0.0006) and hazard ratio 1.84 (95% confidence interval: 1.26-2.70, p = 0.002) were obtained from comparing whole brain radiotherapy only and stereotactic radiosurgery only to whole brain radiotherapy + stereotactic radiosurgery, respectively. No difference in adverse events for treatment difference; odds ratio 1.16 (95% confidence interval: 0.77-1.76, p = 0.48) and odds ratio 0.92 (95% confidence interval: 0.59-1.42, p = 71) for whole brain radiotherapy + stereotactic radiosurgery versus whole brain radiotherapy only and whole brain radiotherapy + stereotactic radiosurgery versus stereotactic radiosurgery only, respectively. Adding stereotactic radiosurgery to whole brain radiotherapy provides better local control as compared to whole brain radiotherapy only and stereotactic radiosurgery only with no difference in radiation related toxicities.

A Nationwide Study of Stereotactic Radiosurgery in a Newly Diagnosed Spine Metastasis Population

Background: Stereotactic radiosurgery (SRS), a technique that is emerging as a new treatment option, has been reported to be an effective, noninvasive treatment for spine metastasis patients. Objective: This nationwide study aimed to understand the current state of SRS for spine metastasis. Methods: Patients in this study were first diagnosed with a metastatic spine tumor between 1 July and 31 December 2011. One group (the SRS group) received SRS at least once within 1 year of diagnosis and the other (the non-SRS group) did not receive SRS. We analyzed the characteristics, medication, and survival of each group. Results: In 628 new patients, there were no significant differences between groups regarding gender, age, type of health insurance, and comorbidities. There were significant differences with regard to the medical costs (USD 23,276 vs. 18,458; p = 0.001) and the duration of hospital stay (101.3 vs. 86.5 days; p = 0.023). Median survival was significantly longer in the SRS group (p = 0.003). Conclusions: There was no significant pretreatment baseline demographic difference between the SRS and the non-SRS group. There was a tendency for greater use of medication in the SRS group. Patients with a longer overall survival tended to be those who underwent SRS treatment.

Quality Assessment of Stereotactic Radiosurgery of a Melanoma Brain Metastases Model Using a Mouselike Phantom and the Small Animal Radiation Research Platform

To establish a novel preclinical model for stereotactic radiosurgery (SRS) with combined mouselike phantom quality assurance in the setting of brain metastases. C57B6 mice underwent intracranial injection of B16-F10 melanoma cells. T1-weighted postcontrast magnetic resonance imaging (MRI) was performed on day 11 after injection. The MRI images were fused with cone beam computed tomography (CBCT) images using the Small Animal Radiation Research Platform (SARRP). The gross tumor volume (GTV) was contoured using the MRI. A single sagittal arc using the 3×3mm2 collimator was used to deliver 18Gy prescribed to the isocenter. MRI was performed 7days after radiation treatment, and the dose delivered to the mice was confirmed using 2 mouselike anthropomorphic phantoms: 1 in the axial orientation and the other in the sagittal orientation. The SARRP output was measured using a PTWFarmer type ionization chamber as per the American Association of Physicists in Medicine Task Group report 61, and the H-D curve was generated up to a maximum dose of 30Gy. Irradiated films were analyzed based on optical density distribution and H-D curve. The tumor volume on day 11, before intervention, was 2.48±1.37mm3 in the no-SRS arm versus 3.75±1.19mm3 in the SRS arm (NS). In the SRS arm, GTV maximum dose (Dmax) and mean dose were 2048±207 and 1785±14cGy. Using the mouselike phantoms, the radiochromic film showed close precision in comparison with projected isodose lines, with a Dmax of 1903.4 and 1972.7cGy, the axial and sagittal phantoms, respectively. Tumor volume 7days after treatment was 7.34±8.24mm3 in the SRS arm and 60.20±40.4mm3 in the no-SRS arm (P=.009). No mice in the control group survived more than 22days after implantation, with a median overall survival (mOS) of 19days; mOS was not reached in the SRS group, with 1 death noted. Single-fraction SRS of 18Gy delivered in a single arc can be delivered accurately with MRI T1-weighted postcontrast-based treatment planning. The mouse like phantom allows for verification of dose delivery and accuracy.