Incidence Of Radionecrosis Research Articles

RADT-34. RE-IRRADIATION REGIMENS FOR RECURRENT GLIOMA: SURVIVAL AND TOXICITY

Abstract Re-irradiation is a common treatment option for recurrent high-grade glioma (HGG), though the optimal dose-fractionation regimen remains unclear. This report presents single-center data from an ongoing multicenter, retrospective study in the Netherlands. We included adult HGG patients treated with re-irradiation. Dose-fractionation regimens were categorized in 3 groups: conventionally fractionated radiotherapy (CFRT, <3Gy/fraction), hypofractionated radiotherapy (HFRT, 3-5 Gy/fraction) and stereotactic radiotherapy (SRT, ≥5Gy/fraction). We compared baseline characteristics, overall survival, and toxicity including incidence of radionecrosis between groups to identify the optimal dose-fractionation regimen. Of 112 patients, 33 underwent CFRT, 60 HFRT and 19 SRT. 21 patients had a good prognostic Niyazi score, 70 intermediate and 6 poor, with more poor scores in the SRT group. SRT patients had smaller median GTVs compared to HFRT and CFRT (1.9, 20.5, 32.8 respectively, p=0.003). Radiation groups also differed in primary histology (less grade 4 in CFRT, p=0.009), but not in age and KPS. Overall survival (OS) was worse for HFRT (median OS 9 months (95%-CI 6.5-11.5)) compared to CFRT (12 months (8.9-15.2, p=0.039)) and SRT (12 months (9.2-14.8, p = 0.012)), but did not differ between CFRT and SRT (p=0.437). In Cox regression, Karnofsky performance score <80 (hazard ratio (HR): 1.874, p=0.006) and large GTV (HR: 1.011, p=0.003) were independently associated with poor survival, while the fractionation schedule was not. Multivariable logistic regression on toxicity analysis indicated an increased risk of radionecrosis in the CFRT and HFRT groups compared to the SRT group (OR 5.861, p=0.011), even after adjusting for GTV and age. In conclusion, re-irradiation schemes in HGG are univariably, but not independently, associated with overall survival; this relationship seems to be confounded by differences in GTV and possibly by KPS. Radionecrosis was more common in HFRT and CFRT than in SRT. Extension and/or validation of findings will be performed in a multicenter cohort.

Adaptive stereotactic radiosurgery for cerebral metastases of non-small cell lung cancer: a retrospective study

INTRODUCTION: Non-small cell lung cancer (NSCLC) is a common cause of brain metastases (BM). Adaptive stereotactic radiosurgery (ASRS) may be a useful option in the treatment of patients with large unresectable brain metastases (BM), but to date there are only a limited number of studies evaluating the effectiveness of this method.OBJECTIVE: To analyze the effectiveness of ASRS in patients with large BM NSCLC not subject to surgical resection.MATERIAL AND METHODS: We retrospectively analyzed data from 37 patients suffering from NSCLC with 45 large (>2 cm in diameter, volume >4 cm3) unresectable BM treated with the Gamma Knife Perfexion model using two- and three-fraction ASRS. Of these, 14 foci (31.1%) were metastases of squamous cell lung cancer, 31 (68.9%) were metastases of adenocarcinoma. The median volume of lesions treated with ASRS was 9.8 (range 4.6–30.6 cm3). The dynamics of volume changes between fractions and the cumulative incidence of local relapses (CILR) were studied, and ROC analysis was performed for the tumor volume parameter. Intracranial progression-free survival (iPFS) and overall survival (OS) were assessed. Statistics: To establish statistical significance of differences for related variables, the Wilcoxon test for pairwise comparisons and the Friedman test for three or more groups were used. The Kaplan-Meier method was used to calculate local control, PFS, and OS rates. The log-rank test was used to compare survival data in two groups.RESULTS: The median follow-up period was 19.4 months. With two-fraction ASRS, the median volume of metastasis decreased by 28.6% by the second session, with three-fraction — by 40.0% by the third session. The 1-year and 2-year CILR rates were 8.6±6.1%, respectively; 26.1±12.3%. In ROC analysis, the area under the curve (AUC) for tumor volume was 0.80 (95% CI 0.6– 1.0) with an optimal cutoff of 18.5 cm3. The differences in CILR between the groups with metastasis volume <18.5 cm3 and ≥18.5 cm3 were statistically significant (p<0.001). Median iPFS was 8.3 (95% CI 5.9–10.7) months, 1-year iPFS was 33.5±8.1%;2-year — 7.8±5.2%. Median OS was 13.2 (95% CI 9.0–17.4) months; 1-year OS — 52.9±8.7%, 2-year — 22.4±8.8%.DISCUSSION: Using two- and three-fraction ASRS, we delivered doses to large BM sufficient for a high level of local control with an acceptable risk of neurotoxicity: 1-year local control was 91.4%; 2-year — 73.9%; the incidence of radionecrosis is 8.5%. A statistically significant effect of lesion volume ≥18.5 cm3 on the risk of local recurrence was found. The iPFS and OS indicators after ASRS can be considered satisfactory for this group of patients.CONCLUSION: ASRS is an effective and perhaps optimal strategy for the treatment of large unresectable BM in patients with NSCLC, but comparison with other modern radiotherapy modalities such as stereotactic hypofractionated radiotherapy and WBRT with simultaneous integrated boost is needed.

CEREBRAL RADIONECROSIS IN PATIENTS IRRADIATED FOR CAVUM CANCER: RETROSPECTIVE STUDY OF 15 CASES

Introduction: Cerebral radionecrosis is a rare but a serious complication induced by radiotherapy of the nasopharyngeal cancer. Since nasopharyngeal cancer is common to have skull base infiltration, radiation fields cover inevitably the temporal lobes despite the use of the more advanced intensity-modulated radiotherapy (IMRT). Even though the development of imaging means and the systematic practice of CT and MRI in post-therapeutic monitoring, the diagnosis and treatment of cerebral remain challenging. Materiel and Method:A retrospective study including fifteen cases of cerebral radionecrosis occurring after radiotherapy of cavum cancer, based on data from 382 irradiated for cavum cancer during the period from January 2017 to January 2022 and who were regularly followed in post-therapeutic monitoring. Results: The incidence of cerebral radionecrosis in our patients was 3,9%. The average age of patients was 47.5 years (range 28 - 62 years), with a female predominance (sex ratio: 4M/11F = 0.36). All our patients were followed for locally advanced UCNT of the cavum (73% stage IVA and 27 % stage III). 80% of cases have benefited from conformal radiotherapy technique by intensity modulation (VMAT archtherapy). And all cases have had concomitant chemotherapy. Cerebral radionecrosis occurred after an average delay of 31.6 months (11-77 months) from the end of irradiation. The location of the cerebral radionecrosis lesions was temporal in all our patients. Exploring dosimetric data of our patients, we noted that in 58% of cases the dose constraint at the level of the temporal lobe affected by radionecrosis was not respected. Cerebral radionecrosis was initially discovered on MRI of the cavum, a brain MRI was subsequently requested to show areas of cerebral radionecrosis. Spectroscopy was carried out in 33% of patients. Cerebral radionecrosis was treated with corticosteroid therapy in 53% of cases. After a mean follow-up of 19.8 months (2-63 months) the evolution of cerebral radionecrosis in patients irradiated fornasopharyngeal cancer, was marked by radiological stability without the appearance of clinical symptoms in 53% of cases. Conclusion: Cerebral radionecrosis of radiation-treated cavum patients could be a devastating complication. Furthermore, the differential diagnosis remains challenging and may require the use of advanced imaging modalities. The intricate relationship between dose parameters and radionecrosis incidence requires large-scale longitudinal studies. Despite the fact that there is no definitive treatment for cerebral radionecrosis, bevacizumab has proven to be an encouraging treatment option.

Long-Term Results of Stereotactic Radiotherapy in Patients with at Least 10 Brain Metastases at Diagnosis.

to evaluate an SRT approach in patients with at least 10 lesions at the time of BM initial diagnosis. This is a monocentric prospective cohort of patients treated by SRT, followed by a brain MRI every two months. Subsequent SRT could be delivered in cases of new BMs during follow-up. The main endpoints were local control rate (LCR), overall survival (OS), and strategy success rate (SSR). Acute and late toxicity were evaluated. Seventy patients were included from October 2014 to January 2019, and the most frequent primary diagnosis was non-small-cell lung cancer (N = 36, 51.4%). A total of 1174 BMs were treated at first treatment, corresponding to a median number of 14 BMs per patient. Most of the patients (N = 51, 72.6%) received a single fraction of 20-24 Gy. At 1 year, OS was 62.3%, with a median OS of 19.2 months, and SSR was 77.8%. A cumulative number of 1537 BM were treated over time, corresponding to a median cumulative number of 16 BM per patient. At 1-year, the LCR was 97.3%, with a cumulative incidence of radio-necrosis of 2.1% per lesion. Three patients (4.3%) presented Grade 2 toxicity, and there was no Grade ≥ 3 toxicity. The number of treated BMs and the treatment volume did not influence OS or SSR (p > 0.05). SRT was highly efficient in controlling the BM, with minimal side effects. In this setting, an SRT treatment should be proposed even in patients with ≥10 BMs at diagnosis.

Investigation of the risk factors in the development of radionecrosis in patients with brain metastases undergoing stereotactic radiotherapy.

To investigate the incidence, timing, and the factors predictors radionecrosis (RN) development in brain metastases (BMs) undergoing stereotactic radiotherapy (SRT). The study evaluated 245 BMs who exclusively received SRT between 2010 and 2020. RN was detected pathologically or radiologically. The median of follow-up was 22.6 months. RN was detected in 18.4% of the metastatic lesions, and 3.3% symptomatic, 15.1% asymptomatic. The median time of RN was 22.8 months (2.5-39.5), and the rates at 6, 12, and 24 months were 16.8%, 41.4%, and 66%, respectively. Univariate analysis revealed that Graded Prognostic Assessment (P = .005), Score Index of Radiosurgery (P = .015), Recursive Partitioning Analysis (P = .011), the presence of primary cancer (P = .004), and localization (P = .048) significantly increased the incidence of RN. No significant relationship between RN and brain-gross tumour volume doses, planning target volume, fractionation, dose (P > .05). Multivariate analysis identified SIR > 6 (OR: 1.30, P = .021), primary of breast tumour (OR: 2.33, P = .031) and supratentorial localization (OR: 3.64, P = .025) as risk factors. SRT is used effectively in BMs. The incidence of RN following SRT is undeniably frequent. It was observed that the incidence rate increased as the follow-up period increased. We showed that brain-GTV doses are not predictive of RN development, unlike other publications. In study, a high SIR score and supratentorial localization were identified as factors that increased the risk of RN. RN is still a common complication after SRT. Symptomatic RN is a significant cause of morbidity. The causes of RN are still not clearly identified. In many publications, brain dose and volumes have been found to be effective in RN. But, with this study, we found that brain dose volumes and fractionation did not increase the incidence of RN when brain doses were taken into account. The most important factor in the development of RN was found to be related to long survival after SRT.

P03.04.B EFFICACY OF NEOADJUVANT STEREOTACTIC RADIOSURGERY IN SOLID CANCER BRAIN METASTASES: A SYSTEMATIC REVIEW AND METANALYSIS

Abstract BACKGROUND Neoadjuvant stereotactic radiosurgery (NaSRS) is a novel strategy for brain metastasis (BMs) management, promising to achieve lower rates of toxicity, leptomeningeal progression, and high percentage of local control. MATERIAL AND METHODS An extensive systematic literature review and meta-analysis of proportions were performed. A total of 8 papers were eligible for final analysis after searching MEDLINE via PubMed, Web-of-science, Cochrane Wiley, and Embase databases. RESULTS A total of 551 patients undergoing NaSRS to treat 583 lesions were included. Median age was 57.7 [56.5-61.1] years, with a median tumor volume of 9.1 [8.3-14.4] cc. The most frequent histology was non-small cell lung cancer (40.7%), followed by breast (20.5%), and melanoma (15.6%). Most of the lesions had a supratentorial location (77.6%). Treatment parameters were homogenous across the studies and showed a median dose of 16 [14.9-20.5] Gy at 80% isodose.Surgery was performed after a median of 1 [1-2] day and achieved gross-total extent in 92.4% of cases. Median follow-up was 12.9 [9.9-18.9] months.Pooled proportion of patients showed an overall mortality rate of 50% (CI 37-63; I2=87%), local failure of 15% (CI 12-20%; I2=12.1%) and a rate of distant brain failure of 42% (CI 35-49%; I2=55.3%). The median local progression-free survival (PFS) was 10.4 months, while median survival without distant failure was 8 months.Rate of radionecrosis (RN) and leptomeningeal dissemination (LMD) were 4% respectively. Median overall survival (OS) was 14.4 months. CONCLUSION Existing data suggest that NaSRS achieves good local control on BMs with relatively lower dose than adjuvant treatment and low incidence of RN and other complications. These results need to be confirmed by larger studies with higher level of evidence to address formal comparisons with other regimens.

Effects of Ataxia-Telangiectasia Mutated Variants on Radionecrosis and Local Control After Stereotactic Radiation Surgery for Non-Small Cell Lung Cancer Brain Metastases

Genetic variants affecting the radiation response protein ataxia-telangiectasia mutated (ATM) have been associated with increased adverse effects of radiation but also with improved local control after conventional radiation therapy. However, it is unknown whether ATM variants affect rates of radionecrosis (RN) and local intracranial progression (LIP) after stereotactic radiosurgery (SRS) for brain metastases. Patients undergoing an initial course of SRS for non-small cell lung cancer (NSCLC) brain metastases at a single institution were retrospectively identified. Kaplan-Meier estimates were calculated and Cox proportional hazards testing was performed based on ATM variant status. A total of 541 patients completed SRS for brain metastasis secondary to NSCLC, of whom 260 completed molecular profiling. Variants of ATM were identified in 36 cases (13.8%). Among patients who completed molecular profiling, RN incidence was 4.9% (95% CI, 1.6%-8.2%) at 6 months and 9.9% (95% CI, 4.8%-15.0%) at 12 months. Incidence of RN was not significantly increased among patients with ATM variants, with an RN incidence of 5.3% (95% CI, 0.0%-15.3%) at both 6 and 12 months (P=.46). For all patients who completed genomic profiling, LIP was 5.4% (95% CI, 2.4%-8.4%) at 6 months and 9.8% (5.5%-14.1%) at 12 months. A significant improvement in LIP was not detected among patients with ATM variants, with an LIP incidence of 3.1% (0.0%-9.1%) at both 6 and 12 months (P=.26). Although differences according to ATM variant type (pathologic variant or variant of unknown significance) did not reach significance, no patients with ATM pathologic variants experienced LIP. We did not detect significant associations between ATM variant status and RN or LIP after SRS for NSCLC brain metastases. The current data set allows estimation of patient cohort sizes needed to power future investigations to identify genetic variants that associate with significant differences in outcomes after SRS.

Time interval from diagnosis to treatment of brain metastases with stereotactic radiosurgery is not associated with radionecrosis or local failure.

Brain metastases are the most common intracranial tumor diagnosed in adults. In patients treated with stereotactic radiosurgery, the incidence of post-treatment radionecrosis appears to be rising, which has been attributed to improved patient survival as well as novel systemic treatments. The impacts of concomitant immunotherapy and the interval between diagnosis and treatment on patient outcomes are unclear. This single institution, retrospective study consisted of patients who received single or multi-fraction stereotactic radiosurgery for intact brain metastases. Exclusion criteria included neurosurgical resection prior to treatment and treatment of non-malignant histologies or primary central nervous system malignancies. A univariate screen was implemented to determine which factors were associated with radionecrosis. The chi-square test or Fisher's exact test was used to compare the two groups for categorical variables, and the two-sample t-test or Mann-Whitney test was used for continuous data. Those factors that appeared to be associated with radionecrosis on univariate analyses were included in a multivariable model. Univariable and multivariable Cox proportional hazards models were used to assess potential predictors of time to local failure and time to regional failure. A total of 107 evaluable patients with a total of 256 individual brain metastases were identified. The majority of metastases were non-small cell lung cancer (58.98%), followed by breast cancer (16.02%). Multivariable analyses demonstrated increased risk of radionecrosis with increasing MRI maximum axial dimension (OR 1.10, p=0.0123) and a history of previous whole brain radiation therapy (OR 3.48, p=0.0243). Receipt of stereotactic radiosurgery with concurrent immunotherapy was associated with a decreased risk of local failure (HR 0.31, p=0.0159). Time interval between diagnostic MRI and first treatment, time interval between CT simulation and first treatment, and concurrent immunotherapy had no impact on incidence of radionecrosis or regional failure. An optimal time interval between diagnosis and treatment for intact brain metastases that minimizes radionecrosis and maximizes local and regional control could not be identified. Concurrent immunotherapy does not appear to increase the risk of radionecrosis and may improve local control. These data further support the safety and synergistic efficacy of stereotactic radiosurgery with concurrent immunotherapy.

Investigating the role of delayed contrast magnetic resonance imaging (MRI) to differentiate radiation necrosis from tumour recurrence in brain metastases after stereotactic radiosurgery.

The incidence of radionecrosis (RN) after stereotactic radiosurgery (SRS) to brain metastases is increasing. An overlap in the conventional MRI appearances of RN and tumour recurrence (TR) is diagnostically challenging. Delayed contrast MRI compares contrast enhancement over two time periods to create treatment response assessment maps (TRAMs). We aim to assess the utility of TRAMs in brain metastases patients. Delayed contrast MRI scans were performed on ten brain metastases patients, previously treated with SRS, who developed equivocal lesion(s) on routine MRI follow-up. T1-weighted images were obtained five minutes and 60-75 min after contrast injection, followed by Brain Lab software analysis to create TRAMs. TRAMs patterns were then compared with the patient's clinical status, subsequent imaging, and histology results. We identified three regions on TRAMs: central, peripheral, and surrounding. Each region could be described either as contrast accumulation (red colour and representing non-tumour tissue) or contrast clearance (blue colour and representing tumour tissue). Our analysis demonstrated similarities in the TRAMs pattern between TR and RN, though to varying degrees. In conclusion, the TRAMs appearances of RN and TR overlap. Our findings suggest that the previously-described correlation between contrast clearance and TR is at least partially attributable to more solid initial enhancement, rather than convincingly a difference in the underlying tissue properties, and the additional diagnostic value of TRAMs may be limited. Thus, further research on TRAMs is necessary prior to incorporating it into routine clinical management after SRS for brain metastases.

Mature Local Control and Radiation Necroses Outcomes Specific to Brain Metastases Treated with Salvage Stereotactic Radiosurgery for Radiosurgical Failures

<h3>Purpose/Objective(s)</h3> The management of locally recurrent brain metastases is a clinical challenge. A second course of radiosurgery may be delivered as the primary salvage treatment or as postoperative radiosurgery to the surgical cavity if the recurrence resected. We report our institutional experience of repeat radiosurgery for locally recurrent brain metastases, with a focus on local control and radionecrosis (RN) outcomes. <h3>Materials/Methods</h3> We report a single institution retrospective cohort study specific to patients with recurrent brain metastases treated with repeat radiosurgery. Clinical and dosimetric details were collected. Overall survival was estimated using the Kaplan Meier method. Local recurrence and RN rates were estimated using the Aalen-Johnson method, with death from any cause as the competing risk for both endpoints. Univariable competing risk regression using Fine and Gray's methods were performed, and subsequent multivariable (MVA) regression based on a priori variable selection generated final adjusted models. <h3>Results</h3> We identified 96 patients and 130 brain metastases re-treated with radiosurgery (either single fraction or hypofractionation between July 2010 to April 2020. The most common primary sites were lung (N = 44, 33.8%), breast, (N = 38, 29.2%), and melanoma (N = 26, 20%). More than half of the retreated lesions were postoperative cavities (N = 68, 52.3%). Re-treatment was most commonly delivered with 25 Gy in 5 fractions (N = 77, 59.2%) followed by 27.5 Gy in 5 fractions (N = 23, 17.7%). The mean BED₁₀ was 39.71 Gy (standard deviation [SD] 6.16) with a mean treatment volume of 14.94 cm³ (SD, 20.15). Nearly half (N = 64, 49.2%) of lesions were treated in the absence of systemic therapy, while 43.8% (N = 57) and 6.9% (N = 9) were treated while receiving targeted therapy/immunotherapy and chemotherapy, respectively. The median time between treatment courses was 13.7 months (IQR 10.88). With a median follow up of 34.9 months (interquartile range [IQR] 25-41.9), the 1 and 2-year overall survival rates were 59.8% (95% confidence interval [95% CI] 50.4-70.9) and 36.2% (95% CI, 27.2-48.2), respectively. The risk of local failure at 1 and 2 years was 26.2% (95%CI, 18.5-34) and 28% (95%CI, 20.1-35.9), respectively. MVA identified increasing target volume (hazard ratio [HR] 1.03; 95% CI, 1.02-1.04), and a shorter time-interval between radiosurgery courses (HR 0.29; 95% CI, 0.19-0.45) to be associated with worse local control. The crude incidence of RN was 18.5% (N = 24), of which 8 events (6.15%) were symptomatic. The 1 and 2-year rates of RN were 17.6% (95% CI, 10.9-34) and 19.3% (95%CI, 12.3-35.9), respectively. <h3>Conclusion</h3> Repeat radiosurgery for locally recurrent brain metastases results in good local control with a moderate risk of RN. Larger target volume and a shorter timeframe between radiosurgery treatments are associated with worse control.

Pre-operative stereotactic radiosurgery for cerebral metastatic disease: A retrospective dose-volume study

Background and purposeStereotactic radiosurgery (SRS) after maximal safe resection is an accepted treatment strategy for patients with cerebral metastatic disease. Despite its high conformality profile, the incidence of radionecrosis (RN) remains high. SRS delivered pre-operatively could be associated with a reduced incidence of RN. We sought to evaluate whether neoadjuvant SRS could reduce radiotherapy doses in a cohort of patients treated with post-operative SRS. MethodsA cohort of 47 brain metastases (BM) treated at 2 academic institutions was retrospectively analyzed. Subjects underwent surgical extirpation of BMs and subsequent SRS to surgical bed. Post-operative volumetric and dosimetric data was collected from records or recreations of delivered plans; pre-operative data were derived from hypothetical radiotherapy courses and compared using Wilcoxon signed-rank tests. ResultsHigher planned tumor volume post-operatively (median[IQR] 12.28 [6.54, 18.69]cc vs 10.20 [4.53, 21.70]cc respectively, p = 0.4150) was observed. The median prescribed radiotherapy dose (DRx) was 16 Gy pre-operatively and 24 Gy post-operatively (p < 0.0001). Further investigations revealed improved pre-operative conformity index (1.23[1.20, 1.29] vs 1.29[1.23, 1.39], p = 0.0098) and gradient index (2.72[2.59, 2.98] vs 2.94[2.69, 3.47], p = 0.0004). A significant difference was found in normal brain tissue exposed to 10 Gy (12.97[6.78, 25.54]cc vs 32.13[19.42, 48.40]cc, p < 0.0001), 12 Gy (9.31[4.56, 17.43]cc vs 23.80[14.74, 36.56]cc, p < 0.0001), and 14 Gy (5.62[3.23, 11.61]cc vs 17.47[9.00, 28.31]cc, p < 0.0001), favoring pre-operative SRS. ConclusionsNeoadjuvant SRS is associated reduced DRx, better conformality profile and decreased radiation to normal tissue. These findings could support the use of neoadjuvant SRS for the treatment of BMs.

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

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). 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). 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 12months 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 2year 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 2Gy 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 2years post-T-DM1. The majority of RN were symptomatic (71%), with a median time to RN of 4.8months. T-DM1 exposure post-SRS was associated with a higher risk of RN among patients with HER2 + BrM.

Local control and radionecrosis of brain metastases from non-small-cell lung cancer treated by hypofractionated stereotactic radiotherapy: Evaluation of predictive factors

BackgroundThe objective of our study was to report predictive factors of local control (LC) and radionecrosis (RN) of brain metastases (BM) of non-small cell lung carcinoma (NSCLC) treated by multifractionated stereotactic radiotherapy (MF-SRT) according to French recommendations. MethodFrom 2012 to 2020, 87 patients with 101 BM were retrospectively included. The median age was 63 years (37–85). GTV was defined using contrast-enhanced T1w MRI and was isotropically extended by 2 mm to form PTV. Mean maximum BM diameter was 24.5 mm (10–46). Patients were treated with dynamic arctherapy from May 2012 to February 2016 and then with VMAT. The totalprescribed dose was 23.1 Gy prescribed to the encompassing 70% isodose, in 3 fractions. ResultsLC rates at 6 months, 1 year and 2 years was 95.7%, 90.7% and 87.9% respectively. In multivariate analysis, high GTV Dmin (HR = 0.822, p = 0.012) was in favor of better LC whereas a large maximum diameter was predictive of poor LC (HR = 1.124, p = 0.02). GTV Dmin of 27.4 Gy was identified as a discriminant threshold of LC. In case of GTV Dmin ≥ 27.4 Gy, LC at 1 year was 95.3% versus 75.1% with GTV Dmin < 27.4 Gy. Cumulative incidence of RN at 6 months, 1 year and 2 years was 6.3%, 15.4% and 18.1%, respectively. In multivariate analysis, only dyslipidemia was predictive of RN (HR = 2.69, p = 0.03). No dosimetric predictive factor of RN was found in our study. ConclusionMF-SRT (3x7.7 Gy on 70% isodose line, with PTV = GTV + 2 mm; according to French recommendations) of BM from NSCLC gives high LC rates with acceptable RN rate. A GTV Dmin of at least 27.4 Gy could be proposed to optimize dosimetric objectives. No dosimetric predictive factors of RN were found in this study. However, dyslipidemia was identified as a potential predictive factor of RN.

Optimal Scheme in Hypofractionated Stereotactic Radiation Therapy for Brain Metastases

Stereotactic radiosurgery (SRS) is common technique used in the treatment of brain metastases. In lieu of single-fraction SRS, hypofractionated stereotactic radiation therapy (HF-SRT) is employed for large metastases and/or for those in sensitive areas of the brain in order minimize toxicity while maintaining effectual local control (LC) rates. There is currently no consensus on an optimal dose-fractionation, with most of the surrounding evidence being in the form of retrospective institutional studies resulting in a variety of utilized fractionation schemes. Some of these studies have suggested that BED10 may predict for improved LC. Our hypothesis is that HF-SRT delivered to BED10 ≥50 Gy would confer improved LC without a significant detriment in radionecrosis (RN) rates.A search of medical literature in PubMed/MEDLINE, Embase, and Cochrane databases was conducted using Preferred Reporting Items for Systematic Reviews and Meta-Analyses of Observational Studies in Epidemiology (PRISMA) guidelines. Search terms included 'brain metastases and 'radiosurgery' yielding studies which were individually reviewed for inclusion. To meet inclusion, studies must have 1) utilized hypofractionated stereotactic radiosurgery techniques defined as ≥2.5 Gy per fraction in the treatment of brain metastases, 2) described LC and RN rate data, and 3) administered radiosurgery as definitive or post-operative treatment. Linear regression of the logarithmically transformed 1-year LC rate weighted by the number of lesions in each study was performed. In addition, a non-parametric, exact Mann-Whitney U-test was used to test a potential difference in 1-year LC or RN rate according to whether studies achieved a median BED10 ≥50 Gy.A total of 27 studies spanning 2000 to 2019 comprising of 2399 lesions met our inclusion criteria and were analyzed. Median BED10 across all studies was 51.3 Gy (range 37.5 to 69.3), with 836 lesions receiving BED10 < 50 Gy and 1563 lesions BED10 ≥50 Gy. Median total dose and number of treatments were 30 Gy (range 23.1 to 40) and 5 fractions (range 3 to 10), respectively. There was no statistically significant difference in LC with BED10 ≥50 Gy versus BED10 < 50 Gy (2-tailed, P = 0.104), nor was there a difference in reported necrosis rate (P = 0.85). On multivariate analysis of 1-year LC, the only significant factor was volume of tumor treated, where increased tumor volume was associated with increased LC (P = 0.0011).This analysis showed there was no statistically significant difference between dose-fractionation regimens delivering BED10 ≥50 Gy versus BED10 < 50 Gy with regards to 1-year LC and the incidence of RN. Studies appeared heterogeneous and this may explain the unexpected association between increasing tumor volume and LC. Future randomized controlled trials should be conducted to identify the optimal dose-fractionation for patients with large brain metastases.O.M. Siddiqui: None. C. Haskins: None. S.M. Bentzen: Travel Expenses; University of Copenhagen. M.V. Mishra: Employee; Orthofix. Research Grant; ASTRO, Keep Punching. Advisory Board; Patient Centers Outcomes Research Institute (PCORI. Travel Expenses; Patient Centers Outcomes Research Institute (PCORI.

T-DM1 Increases the Risk of SRS-Induced Radiation Necrosis in Her2+ Breast Cancer

Stereotactic radiosurgery (SRS) is an important treatment modality in the management of breast cancer-related brain metastases (BrM). Recent research has found Trastuzumab emtansine (T-DM1) to be effective against Her2+ BrM. However, the risk of radionecrosis (RN) with T-DM1 in combination with SRS is unclear. The objective of this study was to investigate factors associated with RN post-SRS in patients with Her2+ BrM.Patients with Her2+ BrM treated with SRS at the Sunnybrook Odette Cancer Centre between 2010 and 2020 were retrospectively identified. The incidence of RN was determined on a lesion-by-lesion basis using serial brain imaging with or without histological confirmation. Clinical factors associated with RN, such as age, RT dose, lesion volume, intracranial location, total number of BrM, along with history of whole brain RT, and T-DM1 treatment were investigated with univariable and multivariable competing risks regression (MVR) using death from any cause as a competing risk factor. A P-value of < 0.05 in MVR following backward selection was considered statistically significant.67 patients with Her2+ BrM (223 lesions) treated with SRS were identified; among them, 21 (31.3%) were treated with T-DM1 post-SRS, including 14 (20.9%) who received T-DM1 within 12 months of SRS. The median follow-up was 15.6 (IQR 5.4-35.3) months. The 1-year, and 2-year risk of RN post-SRS was 6.7% (95% CI 2.7-10.7%), and 15.2% (95% CI 9.2-21.3%), respectively. MVR identified T-DM1 treatment post-SRS (HR 2.5, 95% CI 1.2-5.3, P = 0.02) and RT dose with a biologically effective dose (BED) > 50.4 Gy (HR 2.4, 95% CI 1.1-5.1, P = 0.02) as independent risk factors of RN. Patients treated with T-DM1 and SRS had a 25.2% (95% CI 12.8-37.6%) risk of RN at both 1- and 2-years post-T-DM1. The median time to RN after T-DM1 among the affected was 4.8 (95% CI: 3.8-25.6) months with 80% of all RN cases occurring within 12 months of T-DM1 treatment.This study demonstrates that T-DM1 exposure post-SRS was independently associated with a higher risk of RN in Her2+ BrM patients. The potential side effects of brain-penetrating agents post-SRS merit greater awareness.B. Id Said: None. H. Chen: None. K. Jerzak: Research Grant; Astra Zeneca, Eli Lilly. Consultant; Amgen, AstraZeneca, Apo Biologix, Eli Lilly, Esai, Genomic Health, Knight Therapeutics, Merck, Myriad Genetics Inc, Pfizer, Roche, Novartis, Purdue Pharma. S.D. Myrehaug: Advisory Board; Novartis AG.C. Tseng: Consultant; Sanofi. Travel Expenses; Elekta. Member; Elekta MR-LINAC.J. Detsky: None. Z.A. Husain: None. A. Sahgal: Research Grant; Elekta AB. Honoraria; Elekta AB, Varian, BrainLAB, Medtronic Kyphon. Consultant; Varian. Travel Expenses; Elekta AB, Varian. H. Soliman: None.

Impact of EGFR mutation on outcomes following SRS for brain metastases in non-small cell lung cancer

IntroductionPatients with EGFR-mutated (EGFRm) non-small cell lung cancer (NSCLC) are at particularly high risk of developing brain metastases (BrM). In addition to EGFR targeting tyrosine kinase inhibitors (TKI), radiosurgery (SRS) has an important role in the management of EGFRm BrM. However, data specific to the response and toxicity of EGFRm BrM to SRS are sparse. We evaluated the incidence of local failure (LF) and toxicity of EGFRm and EGFR-wild-type (EGFRwt) BrM treated with SRS. MethodsWe analyzed a prospective registry of BrM patients treated at our centre between 2008 and 2017 and identified EGFRm and EGFRwt NSCLC patients treated with SRS ± systemic therapy for BrM. Incidences of local failure (LF) and radionecrosis (RN) were determined, and Cox regression was performed for univariate and multivariate analyses (MVAs). ResultsWe analyzed data from 218 patients (615 lesions - 225 EGFRm and 390 EGFRwt). Median imaging follow-up per patient was 14.5 months (0.5–96.3). Prior to or concomitant with SRS, 62 % of EGFRm patients received TKI and 93 % received TKI post SRS. The 24-month incidence of LF was 6% and 16 % for EGFRm BrM and EGFRwt, respectively (0.43(0.19−0.95); p = 0.037). The 24-month incidence of RN was 4% and 6% for EGFRm and EGFRwt BrM, respectively (0.8(0.32−1.98) p = 0.63). On MVA, BrM size and prescription dose (PD) significantly correlated with a higher risk of LF and BrM size correlated with a higher risk of RN. ConclusionWe observed excellent rates of response and toxicity following SRS in EGFRm compared to EGFRwt NSCLC, suggesting that EGFRm BrM have a favourable risk benefit ratio compared to EGFRwt NSCLC.

The efficacy of hypofractionated radiotherapy (HFRT) with concurrent and adjuvant temozolomide in newly diagnosed glioblastoma: A meta-analysis

PurposeThe efficacy of hypofractionated radiotherapy (HFRT) in glioblastoma (GBM) without age restrictions remains unclear. The aim of this meta-analysis is to access the survival outcomes of HFRT in these patients. MethodsA comprehensive electronic literature search of PubMed, Web of Science and Cochrane Library was conducted up to June 1, 2020. The main evaluation data were the overall survival (OS) rate at 12 months and 24 months and the progression-free survival (PFS) rate at 6 and 12 months. The secondary evaluation data was the incidence of radionecrosis and adverse events. The study was performed using R “meta” package. ResultsEleven studies met the inclusion criteria, which totally contained 484 participants. The 12-month OS and 24-month OS rate of HFRT in GBM were 71.3% and 34.8%, while the 6-month PFS and 12-month rate were 74.0% and 40.8%. Compared to low-BED (biological equivalent dose) schedules (<78Gy), high-BED schedules may increase survival benefit both in PFS-6 (P=0.003) and PFS-12 (P=0.011), while the difference did not show on OS. Different dose per fraction had no significant effect on both OS and PFS. Incidence of radionecrosis was 14.2%. Although the overall incidence of adverse reactions cannot be quantified, the toxicity of HFRT was acceptable. ConclusionsCompared with survival data for standard treatment, HFRT seemed to improve overall survival and progression-free survival, while high BED schedules may future increase benefit on PFS. Meanwhile, the toxicity of HFRT was tolerable. Further randomised controlled clinical studies are needed to confirm these findings.

Rates Of Radionecrosis In Re-Irradiation Of Brain Metastases Using Hypofractionated Stereotactic Radiotherapy

Improved overall survival rates among brain metastases (BM) patients have led to higher rates of salvage re-irradiation in patients with local failure. Hypofractionated stereotactic regimens are an attractive option due to the possibility of lower rates of radionecrosis (RN). This study aims to determine the incidence and risk factors of RN following re-irradiation with hypofractionated stereotactic radiotherapy (hSRT) and compares the results to the incidence of RN following re-irradiation with single fraction SRS reported in literature. Retrospective chart review was conducted on patients from a single institution who received re-irradiation using hSRT to BMs that previously received stereotactic radiotherapy. Patients who received additional whole brain radiation (WBRT), prior to, or after stereotactic radiotherapy were included. Patient, tumor, treatment characteristics, and follow-up data were collected. MRI and pathology of any lesions resected post-radiotherapy were reviewed to assess for the development of RN and the response to treatment. RN was confirmed through MRI or by surgical resection. Associations between RN and target volume, as well as number of months between stereotactic treatments were examined using logistic regression. Association between RN and use of additional WBRT was examined using relative risk and chi-square tests. A total of 110 metastatic brain lesions in 90 patients received hSRT reirradiation between August 2010 and December 2019. 26.7% (n = 24) of patients also received additional WBRT. The most common histologies were breast (n = 31), NSCLC (n = 30), and melanoma (n = 29). The median volume of lesions was 12.25cc (IQR 4.97 – 25.07cc). The most common fractionation scheme was 25 Gy in 5 fractions (72 lesions). The incidence of local failure was 11.6% and 17.4% at 6 and 12 months, respectively. Incidence of symptomatic RN was 6.15% and 15% at 6 and 12 months, respectively. There was no statistically significant association between symptomatic RN at 12-months and radiation dose (p = 0.40), target volume (p = 0.96), use of additional WBRT (p = 0.74), or number of months between SRT (p = 0.99). The incidence of symptomatic RN following re-irradiation with hSRT is lower compared to re-irradiation with single fraction SRS as reported in literature. hSRT provides an alternative salvage option for treating local failure of BMs to reduce risk of RN while achieving local control.

Peri-SRS Administration Of Bevacizumab Offers Promising Efficacy For Large Brain Metastases With Tolerable Toxicity: A Prospective Case Series

Brain metastases (BM) are the most common brain tumors in adults. It is estimated that around 10-30% of cancer patients would develop brain metastases during the course of their illness. Stereotactic radiosurgery (SRS) is the treatment of choice to achieve intracranial control while sparing neurocognitive function. However, the risk of radionecrosis (RN) after single-fraction SRS could be as high as 38% at 12 months if treated brain metastases were larger than 1.5 cm. Therefore, radiation dose is often compromised to avoid excessive toxicities. Herein, we propose a new combined treatment strategy to evaluate the efficacy and safety of SRS with concurrent bevacizumab for large brain metastases. Patients with the diameter of the largest BM ≥ 2 cm were enrolled for combined therapy. Bevacizumab with 5 to 10 mg/kg was given one day before the first fraction of radiosurgery and 2 weeks after the first dose. SRS was given in 1 to 5 fractions depending on tumor size. Radiographic response was assessed by RANO criteria. Intracranial (IC) metastasis progression-free survival (PFS), and overall survival (OS) were calculated by Kaplan-Meier analysis. Forty-eight patients were enrolled in this prospective case series. Nine patients (19%) had prior brain radiotherapy. The median number of BM per patient was 3 (range 1–22). The largest tumor diameter ranged from 20 to 54 mm (median 27.4 mm; 46% were ≥ 3 cm) and the median prescribed biological equivalent dose was 51.3 Gy10 (18.3 Gy single fraction equivalent). With a median follow-up of 18 months, the estimated median OS was 22.6 months (95% CI, 6.9 to 38.3 months) and the median ICPFS was 13.9 months (95% CI, 9 to 18.9 months). Only 4 patients developed local failure (LF). Significant radiographic response (complete and partial response, CR+PR) was achieved in 40 patients (83.3%). No grade 4 or 5 toxicities were observed. Eight patients (16.7%) developed ≥ grade 2 RN, and two of them required surgical intervention. After adjusting death as a competing risk, the cumulative incidence of LF, IC progression and RN at 12 months were 2.5% (95% CI, 0.3% to 17.9%), 39.4% (95% CI, 27.2% to 57.1%), and 14.4% (95% CI, 6.8% to 30.4%), respectively. Four patients (8.3%) had grade 3 hypertension. One patient experienced tumor hemorrhage without significant neurological deficit or need for intervention. Stereotactic radiosurgery with peri-radiosurgical Bevacizumab for large brain metastases is highly effective with low incidence of radionecrosis and low risk of excessive treatment-related toxicities. The combination strategy warrants further evaluation.Abstract 3723; TableMaximum relative tumor reduction and response rate observed as best response by RANO criteria among different tumor sizesLargest tumor diameterNumber of patientsMaximum relative tumor reduction (median, range)Response rate (CR+PR)2-2.5 cm1451% (7-100%)85.7%2.5-3 cm1354% (16-100%)92.3%3-3.5 cm838% (24-55%)75%>3.5 cm1335% (2-63%)76.9% Open table in a new tab

Five-Fraction Stereotactic Radiosurgery (SRS) For Resected Brain Metastases

Randomized trials have demonstrated improved rates of local control (LC) in patients who undergo postoperative stereotactic radiosurgery (SRS) compared to observation following resection of brain metastases. However, for larger tumors, dose reduction is commonly required for single-fraction SRS in order to minimize toxicity, potentially compromising LC. Hypofractionated SRS (HF-SRS) may improve LC with minimal toxicity, in particular radionecrosis (RN). In this IRB-approved retrospective study, patients who received 5-fraction HF-SRS at Duke University Medical Center from 2008 to 2018 were identified. GTVs were contoured per consensus guidelines; PTV expansions were 2mm. Patients were treated with 5 or 5.5 Gy per fraction, the latter typically utilized for tumor histologies considered to be radioresistant. Treatment consisted of linear-accelerator-based image-guided SRS with HD-MLC. Data collected included demographics, primary disease characteristics and treatment details. For patients with sufficient radiographic follow up, rates of LC, distant brain failure (DBF), RN, overall survival (OS), and leptomeningeal disease (LMD) were calculated. 250 patients were identified. Lung was the most common primary site (43%), followed by breast (16%) and GI (13%). 69% had evidence of active systemic disease at time of treatment. Of 144 patients with recorded Karnofsky performance status (KPS), 90% had a KPS of 70 or greater. Median age at time of craniotomy was 63 years. Median time interval between craniotomy and start of SRS was 4 weeks (range 1-16). 86% of patients had at least 1 subsequent brain MRI post SRS. 3-year LC was 84% and median OS was 12.8 months (95% CI 10.9-15.5). 24-month incidence of DBF was 50% (95% CI 44%-56%). 24-month incidence of RN was 4% (95% CI 2% to 7%). 14% of patients developed LMD. On univariate analysis (UVA), a dose of 5.5 Gy/fraction was associated with improved LC, HR 0.25 (0.08, 0.82), as was no prior treatment, HR 0.40 (0.20, 0.82). Location, receipt of immunotherapy or small molecule inhibitor, dural contact, and cavity volume were not significant for LC on UVA. Compared to historical standards of single fraction SRS, post-operative, five-fraction HF-SRS results in low rates of LC and RN. The use of 5.5 Gy per fraction and the absence of prior treatment were associated with improved LC. Rates of LMD in this patient population are comparable to other studies in the postoperative setting.