Effectiveness of and Adherence to Triage Algorithms During Prehospital Response to Mass Casualty Incidents.

Mass casualty incidents (MCIs) can rapidly exhaust available resources and demand the prioritization of medical response efforts and materials. Principles of triage (i.e., sorting) from the 18th century have evolved into a number of modern-day triage algorithms designed to systematically train responders managing these chaotic events. We reviewed reports and studies of MCIs to determine the use and efficacy of triage algorithms. Despite efforts to standardize MCI responses and improve the triage process, studies and recent experience demonstrate that these methods have limited accuracy and are infrequently used.

Massive MCA stroke requiring alteplase followed by thrombectomy in a 34-year-old female with alport syndrome.

34-year-old-female with a medical history significant for Alport's syndrome, chronic kidney disease on dialysis, and hypertension, was brought to the emergency department for sudden onset aphasia and facial droop that began 30 min prior to arrival. She denied a history of prior strokes, recent illness, or fever. The vital signs on arrival as follows: blood pressure 151/71 mmHg, temperature of 98.4F, pulse of 77 beats/min, and respirations of 16 breaths/min. Upon examination, she appeared in mild distress with a left sided facial droop, right sided hemiparesis, and expressive aphasia, only answering to yes/no. Neurological examination revealed: expressive aphasia, intact sensation throughout the face and bilateral extremities, no effort in the right arm against gravity, some effort against gravity of the right leg, left arm and left leg had muscle strength of 5/5. Patient had an NIH stroke scale of 8. The remainder of the exam was unremarkable. Radiographic imaging with CT revealed no intracranial hemorrhage (Fig. 1) and the patient was given alteplase (tPA) injection 5.6 mg within 1 h of her arrival to the Emergency Department. After administration of tPA a CT perfusion scan was performed (Fig. 2). Imaging demonstrated decreased cerebral blood flow and prolonged mean transit time within the majority of the left middle cerebral artery territory, sparing the basal ganglia. This indicated a left middle cerebral artery M1 occlusion. Neurosurgery was consulted and the patient underwent thrombectomy. Her hospital course was complicated by hemorrhagic transformation (HT) on hospital day 2. The patient underwent MRI that showed a large left MCA distribution acute infarction with focal reperfusion hemorrhage and parenchymal hematoma measuring approximately 3 cm in each dimension (Fig. 3). This finding prompted emergent decompression and hemicraniectomy on day 2 of hospitalization. The patient was discharged on hospital day 17 to a rehab center.

Cs-131 brachytherapy for patients with recurrent glioblastoma combined with bevacizumab avoids radiation necrosis while maintaining local control.

PURPOSE: Re-irradiation of recurrent glioblastoma (GBM) may delay further recurrence but re-irradiation increases the risk of radionecrosis (RN). Salvage therapy should focus on balancing local control (LC) and toxicity. We report the results of using intraoperative Cesium-131 (Cs-131) brachytherapy for recurrent GBM in a population of patients who also received bevacizumab. METHODS AND MATERIALS: Twenty patients with recurrent GBM underwent maximally safe neurosurgical resection with Cs-131 brachytherapy between 2010 and 2015. Eighty Gy was prescribed to 0.5 cm from the surface of the resection cavity. All patients previously received adjuvant radiotherapy and temozolomide, and received bevacizumab before or after salvage brachytherapy. Seven of 20 (35%) tumors were multiply recurrent and had been previously salvaged with external beam radiotherapy. Patients received MRI scans every 2 months monitored for recurrence, progression, and RN. RESULTS: Median tumor diameter was 4.65 cm (range, 1.2-6.3 cm). Median number of seeds pace was 41 (range, 20-74) with total seed activity 96.8U (range, 41.08-201.3U). At a median followup of 19 months, crude LC was 85% and median overall survival was 9 months (range, 5-26 months). There were two postoperative wound infections (10%), three seizures (15%), and 0% incidence of RN. CONCLUSIONS: Our study demonstrates that while LC and survival are similar to other studies of postoperative external beam radiotherapy, no RN occurred in any of these patients, including 7 multiply re-irradiated patients. Of interest, there were patients with multiple recurrences whose survival extended beyond 20 months. These findings suggest that the use of highly conformal Cs-131 brachytherapy is a promising treatment for patients with recurrent GBM with minimal risk of development of RN.

A matched-pair analysis of clinical outcomes after intracavitary cesium-131 brachytherapy versus stereotactic radiosurgery for resected brain metastases.

OBJECTIVE: Adjuvant radiation therapy (RT), such as cesium-131 (Cs-131) brachytherapy or stereotactic radiosurgery (SRS), reduces local recurrence (LR) of brain metastases (BM). However, SRS is less efficacious for large cavities, and the delay between surgery and SRS may permit tumor repopulation. Cs-131 has demonstrated improved local control, with reduced radiation necrosis (RN) compared to SRS. This study represents the first comparison of outcomes between Cs-131 brachytherapy and SRS for resected BM. METHODS: Patients with BM treated with Cs-131 and SRS following gross-total resection were retrospectively identified. Thirty patients who underwent Cs-131 brachytherapy were compared to 60 controls who received SRS. Controls were selected from a larger cohort to match the patients treated with Cs-131 in a 2:1 ratio according to tumor size, histology, performance status, and recursive partitioning analysis class. Overall survival (OS), LR, regional recurrence, distant recurrence (DR), and RN were compared. RESULTS: With a median follow-up of 17.5 months for Cs-131-treated and 13.0 months for SRS-treated patients, the LR rate was significantly lower with brachytherapy; 10% for the Cs-131 cohort compared to 28.3% for SRS patients (OR 0.281, 95% CI 0.082-0.949; p = 0.049). Rates of regional recurrence, DR, and OS did not differ significantly between the two cohorts. Kaplan-Meier analysis with log-rank testing showed a significantly higher likelihood of freedom from LR (p = 0.027) as well as DR (p = 0.018) after Cs-131 compared to SRS treatment (p = 0.027), but no difference in likelihood of OS (p = 0.093). Six (10.0%) patients who underwent SRS experienced RN compared to 1 (3.3%) patient who received Cs-131 (p = 0.417). CONCLUSIONS: Postresection patients with BM treated with Cs-131 brachytherapy were more likely to achieve local control compared to SRS-treated patients. This study provides preliminary evidence of the potential of Cs-131 to reduce LR following gross-total resection of single BM, with minimal toxicity, and suggests the need for a prospective study to address this question.

Placement of 131Cs permanent brachytherapy seeds in a large combined cavity of two resected brain metastases in one setting: case report and technical note.

Large brain metastases are presently treated with surgical resection and adjuvant radiotherapy. However, local control (LC) for large tumors decreases from over 90% to as low as 40% as the tumor/cavity increases. Intraoperative brachytherapy is one of the focal radiotherapy techniques, which offers a convenient option of starting radiation therapy immediately after resection of the tumor and shows at least an equivalent LC to external techniques. Our center has pioneered this treatment with a novel FDA-cleared cesium-131 (131Cs) radioisotope for the resected brain metastases, and published promising results of our prospective trial showing superior results from 131Cs application to the large tumors (90%). We report a 57-year-old male patient, with metastatic hypopharyngeal brain cancer. The patient presented with two metastases in the right frontal and right parietal lobes. Post-resection of these lesions resulted in a large total combined cavity diameter of 5.3 cm, which was implanted with 131Cs seeds. The patient tolerated the procedure well, with 100% local control and 0% radiation necrosis. This case is unique in demonstrating that the 131Cs isotope was not only a convenient option of treating two resected brain metastases in one setting, but also that this treatment option offered excellent long-term LC and minimal toxicity rates.

Radiation and Immunotherapy in High-grade Gliomas: Where Do We Stand?

High-grade glioma is the most common primary brain tumor, with glioblastoma multiforme (GBM) accounting for 52% of all brain tumors. The current standard of care (SOC) of GBM involves surgery followed by adjuvant fractionated radiotherapy and chemotherapy. However, little progress has been made in extending overall survival, progression-free survival, and quality of life. Attempts to characterize and customize treatment of GBM have led to mitigating the deleterious effects of radiotherapy using hypofractionated radiotherapy, as well as various immunotherapies as a promising strategy for the incurable disease. A combination of radiotherapy and immunotherapy may prove to be even more effective than either alone, and preclinical evidence suggests that hypofractionated radiotherapy can actually prime the immune system to make immunotherapy more effective. This review addresses the complications of the current radiotherapy regimen, various methods of immunotherapy, and preclinical and clinical data from combined radioimmunotherapy trials.

Accelerated Hypofractionated Radiotherapy in the Era of Concurrent Temozolomide Chemotherapy in Elderly Patients with Glioblastoma Multiforme.

Introduction Patients with glioblastoma multiforme (GBM) over age 65 represent nearly half of those diagnosed per annum. They have a different tumor markers profile, physiologic reserve, and a median survival as low as three to four months. An optimal treatment strategy in older GBM patients remains undefined, with many patients receiving radiation in 30 treatments over six weeks, a regimen based on trials originally excluding patients over age 70. Recent studies have suggested reducing the number of treatments to 10-15 over two to three weeks with similar efficacy. We present an elderly population of patients treated with six radiation treatments. Methods After IRB approval, we reviewed the electronic medical records of 20 consecutive patients over the age 60 at diagnosis with GBM, treated with maximally safe neurosurgical resection, and adjuvant hypofractionated radiation (HFRT) and temozolomide (TMZ) between 2012 and 2015. HFRT was given every other weekday for two weeks, in a total of six fractions (6 × 6 Gy to contrast-enhancing tumor +5 mm and 6 × 4 Gy to fluid-attenuated inversion recovery (FLAIR) +2 cm) with concurrent TMZ (75 mg/m2 daily), followed by adjuvant TMZ (150-200 mg/m2 in 5/28 days). The response was assessed using the Macdonald and Revised Assessment in Neuro-Oncology (RANO) criteria, radiology reports, physician notes, and tumor board consensus notes. Descriptive statistics, overall survival (OS), progression-free survival (PFS), toxicity, and steroid use were calculated and compared to the historical controls of patients treated with a six-week radiation regimen of 60 Gy in 30 fractions with TMZ.   Results The median age at diagnosis was 70.5 years (range: 61 - 82 years). Median pre-radiation Karnofsky performance scale (KPS) was 60 (range: 40 - 90). The median preoperative maximum gross tumor diameter on MRI was 3.6 cm (range: 1.8 - 6 cm). Six patients (30%) had a gross total resection (GTR), eight (40%) had a subtotal resection (STR), and six (30%) had biopsy only. The median progression-free survival was five months (95% (confidence interval) CI: 2.8, 16.4) and median OS of 14 months (95% CI: 5.0, upper limit not estimable). Of the 19 patients tested for isocitrate dehydrogenase-1 (IDH), 100% were negative. Of the eight patients who had MGMT methylation status results, four (50%) were positive for O6-methylguanine-DNA methyltransferase (MGMT) methylation. In the 18 patients who completed radiation, the HFRT treatment was well tolerated without any Grade 3/4 acute toxicities. Conclusions The accelerated adjuvant course of HFRT with TMZ used for the elderly with GBM decreases radiation treatment days to six. It was well tolerated in patients over 60 years of age and provided similar OS, PFS, minimal toxicity, and decreased steroid usage compared to historical controls treated with six or even two to three weeks of radiotherapy.

Clinical Outcomes of Large Brain Metastases Treated With Neurosurgical Resection and Intraoperative Cesium-131 Brachytherapy: Results of a Prospective Trial.

PURPOSE: Studies on adjuvant stereotactic radiosurgery to the cavity of resected brain metastases have suggested that larger tumors (>2.0 cm) have greater rates of recurrence and radionecrosis (RN). The present study assessed the effect of permanent low-dose 131Cs brachytherapy on local control and RN in patients treated for large brain metastases. METHODS AND MATERIALS: After institutional review board approval, 42 patients with 46 metastases ≥2.0 cm in preoperative diameter were accrued to a prospective trial from 2010 to 2015. Patients underwent surgical resection with intraoperative placement of stranded 131Cs seeds as permanent volume implants in the resection cavity. The primary endpoint was local freedom from progression (FFP). Secondary endpoints included regional and distant FFP, overall survival (OS), and RN rate. Failures 5 to 20 mm from the cavity and dural-based failures were considered regional. A separate analysis was performed for metastases >3.0 cm. RESULTS: Of the 46 metastases, 18 were >3.0 cm in diameter. The median follow-up period was 11.9 months (range 0.6-51.9). The metastases had a median preoperative diameter of 3.0 cm (range 2.0-6.8). The local FFP rate was 100% for all tumor sizes. Regional recurrence developed in 3 of 46 lesions (7%), for a 1-year regional FFP rate of 89% (for tumors >3.0 cm, the FFP rate was 80%, 95% confidence interval 54%-100%). Distant recurrences were found in 19 of 46 lesions (41%), for a 1-year distant FFP rate of 52%. The median OS was 15.1 months, with a 1-year OS rate of 58%. Lesion size was not significantly associated with any endpoint on univariate or multivariate analysis. Radioresistant histologic features resulted in worse survival (P=.036). No cases of RN developed. CONCLUSIONS: Intraoperative 131Cs brachytherapy is a promising and effective therapy for large brain metastases requiring neurosurgical intervention, which can offer improved local control and lower rates of RN compared with stereotactic radiosurgery to the resection cavity.

Cesium-131 brachytherapy for recurrent brain metastases: durable salvage treatment for previously irradiated metastatic disease.

OBJECTIVE Managing patients whose intraparenchymal brain metastases recur after radiotherapy remains a challenge. Intraoperative cesium-131 (Cs-131) brachytherapy performed at the time of neurosurgical resection may represent an excellent salvage treatment option. The authors evaluated the outcomes of this novel treatment with permanent intraoperative Cs-131 brachytherapy. METHODS Thirteen patients with 15 metastases to the brain that recurred after stereotactic radiosurgery and/or whole brain radiotherapy were treated between 2010 and 2015. Stranded Cs-131 seeds were placed as a permanent volume implant. Prescription dose was 80 Gy at 5-mm depth from the resection cavity surface. The primary end point was resection cavity freedom from progression (FFP). Resection cavity freedom from progression (FFP), regional FFP, distant FFP, median survival, overall survival (OS), and toxicity were assessed. RESULTS The median duration of follow-up after salvage treatment was 5 months (range 0.5-18 months). The patients' median age was 64 years (range 51-74 years). The median resected tumor diameter was 2.9 cm (range 1.0-5.6 cm). The median number of seeds implanted was 19 (range 10-40), with a median activity per seed of 2.25 U (range 1.98-3.01 U) and median total activity of 39.6 U (range 20.0-95.2 U). The 1-year actuarial local FFP was 83.3%. The median OS was 7 months, and 1-year OS was 24.7%. Complications included infection (3), pseudomeningocele (1), seizure (1), and asymptomatic radionecrosis (RN) (1). CONCLUSIONS After failure of prior irradiation of brain metastases, re-irradiation with intraoperative Cs-131 brachytherapy implants provides durable local control and limits the risk of RN. The authors' initial experience demonstrates that this treatment approach is well tolerated and safe for patients with previously irradiated tumors after failure of more than 1 radiotherapy regimen and that it results in excellent response rates and minimal toxicity.

Surgical Technique and Clinically Relevant Resection Cavity Dynamics Following Implantation of Cesium-131 (Cs-131) Brachytherapy in Patients With Brain Metastases.

BACKGROUND: Cesium-131 (Cs-131) brachytherapy is used to reduce local recurrence of resected brain metastases. In order to ensure dose homogeneity and reduce risk of radiation necrosis, inter-seed distance and cavity volume must remain stable during delivery. OBJECTIVE: To investigate the efficacy of the "seeds-on-a-string" technique with intracavitary fibrin glue in achieving cavity volume stability. METHODS: We placed intra-operative Cs-131 brachytherapy in 30 cavities post-resection of brain metastases. Seeds-on-a-string were placed like barrel staves within the cavity with fibrin glue. Serial MRI imaging occurred post-operatively. Pre-operative tumor volumes were compared with post-operative cavity volumes to evaluate volume stability. Thirty patients who underwent post-resective stereotactic radiosurgery (SRS) were used as a control group for volumetric comparison. RESULTS: Cs-131 and SRS patients exhibited consistent cavity shrinkage over the median 110-day follow-up (p<.001), with total median shrinkage of 56.5% (Cs-131) and 84.8% (SRS). During the first month when ~88% of Cs-131 dosage is delivered, however, there was non-significant volume decrease in the Cs-131 group (median 22.0%; p=.063), while SRS patients showed significantly more shrinkage (46.7%; p=.042). No events of radiation necrosis occurred in either group. CONCLUSION: Cs-131 patients exhibited significantly less cavity shrinkage than SRS patients during the first critical month with 88% Cs-131 dose delivery. This significant difference in shrinkage suggests that the intracavitary seeds-on-a-string technique facilitates increased cavity stability, promoting more homogenous dose delivery.

Innovative Hypofractionated Stereotactic Regimen Achieves Excellent Local Control with No Radiation Necrosis: Promising Results in the Management of Patients with Small Recurrent Inoperable GBM.

Management of recurrent glioblastoma multiforme (GBM) remains a challenge. Several institutions reported that a single fraction of ≥ 20 Gy for small tumor burden results in excellent local control; however, this is at the expense of a high incidence of radiation necrosis (RN). Therefore, we developed a hypofractionation pattern of 33 Gy/3 fractions, which is a radiobiological equivalent of 20 Gy, with the aim to lower the incidence of RN. We reviewed records of 21 patients with recurrent GBM treated with hypofractionated stereotactic radiation therapy (HFSRT) to their 22 respective lesions. Sixty Gy fractioned external beam radiotherapy was performed as first-line treatment. Median time from primary irradiation to HFSRT was 9.6 months (range: 3.1 - 68.1 months). In HFSRT, a median dose of 33 Gy in 11 Gy fractions was delivered to the 80% isodose line that encompassed the target volume. The median tumor volume was 1.07 cm3 (range: 0.11 - 16.64 cm3). The median follow-up time after HFSRT was 9.3 months (range: 1.7 - 33.6 months). Twenty-one of 23 lesions treated (91.3%) achieved local control while 2/23 (8.7%) progressed. Median time to progression outside of the treated site was 5.2 months (range: 2.2 - 9.6 months). Progression was treated with salvage chemotherapy. Five of 21 patients (23.8%) were alive at the end of this follow-up; two patients remain disease-free. The remaining 16/21 patients (76.2%) died of disease. Treatment was well tolerated by all patients with no acute CTC/RTOG > Grade 2. There was 0% incidence of RN. A prospective trial will be underway to validate these promising results.

Glioblastoma: Radiation treatment margins, how small is large enough?

Standard treatment for glioblastoma consists of surgical resection followed by radiation therapy with concurrent and adjuvant chemotherapy. Conventional radiation clinical treatment volumes include a 2- to 3-cm margin around magnetic resonance imaging or computed tomography enhancing abnormalities in the brain as well as a margin around the T2 or fluid-attenuated inversion recovery abnormality. However, there remains significant variability with respect to whether such extensive margins are necessary. Collectively, we as authors of this manuscript also use different margins, with A.G.W. employing European Organization for Research and Treatment of Cancer recommendations of a 2- to 3-cm margin on T1 enhancement for 60 Gy and M.P.M. using Radiation Therapy Oncology Group recommendations of 2 cm on T2 signal abnormality for the initial 46 Gy and 2.5-cm margin on T1 enhancement for a 14-Gy boost. Our experiences reflect the heterogeneity of margin definition and selection for this disease and underscore an important area of further research to minimize this variability. In this article, we review studies exploring recurrence patterns and outcomes in patients treated using both conventional and more limited margins. We conclude that treating to "smaller" margins does not alter recurrence patterns nor does it result in inferior survival, but whether this is because of the inherently limited benefit of radiation therapy in the first place, or whether it is truly because microscopic tumor control at larger distances is not an issue, remains unestablished.