Thomas L. Ellis

Cavity-directed radiosurgery as adjuvant therapy after resection of a brain metastasis

OBJECT As a strategy to delay or avoid whole-brain radiotherapy (WBRT) after resection of a brain metastasis, the authors used high-resolution MR imaging and cavity-directed radiosurgery for the detection and treatment of further metastases. METHODS Between April 2001 and October 2009, 112 resection cavities in 106 patients with no prior WBRT were treated using radiosurgery directed to the tumor cavity and for any synchronous brain metastases detected on high-resolution MR imaging at the time of radiosurgical planning. A median dose of 17 Gy to the 50% isodose line was prescribed to the gross tumor volume, defined as the rim of enhancement around the resection cavity. Patients were followed up via serial imaging, and new brain metastases were generally treated using additional radiosurgery, with salvage WBRT typically reserved for local treatment failure at a resection cavity, numerous failures, or failures occurring at short time intervals. Local and distant treatment failures were determined based on imaging results. Kaplan-Meier curves were generated to estimate local and distant treatment failure rates, overall survival, neurological cause-specific survival, and time delay to salvage WBRT. RESULTS Radiosurgery was delivered to the resection cavity alone in 57.5% of patients, whereas 24.5% of patients also received treatment for 1 synchronous metastasis, 11.3% also received treatment for 2 synchronous metastases, and 6.6% also received treatment for 3-10 additional lesions. The median overall survival was 10.9 months. Overall survival at 1 year was 46.8%. The local tumor control rate at 1 year was 80.3%. The disease control rate in distant regions of the brain at 1 year was 35.4%, with a median time of 6.9 months to distant failure. Thirty-nine of 106 patients eventually received salvage WBRT, and the median time to salvage WBRT was 12.6 months. Kaplan-Meier estimates showed that the rate of requisite WBRT at 1 year was 45.9%. Neurological cause-specific survival at 1 year was 50.1%. Leptomeningeal failure occurred in 8 patients. One patient had treatment failure within the resection tract. Seven patients required reoperation: 2 for resection cavity recurrence, 3 for radiation necrosis, 1 for hydrocephalus, and 1 for a CSF cutaneous fistula. On multivariate analysis, a preoperative tumor diameter > 3 cm was predictive of local treatment failure. CONCLUSIONS Cavity-directed radiosurgery combined with high-resolution MR imaging detection and radiosurgical treatment of synchronous brain metastases is an effective strategy for delaying and even foregoing WBRT in most patients. This technique provides acceptable local disease control, although distant treatment failure remains significant.

Non-Thermal Irreversible Electroporation (N-TIRE) and Adjuvant Fractionated Radiotherapeutic Multimodal Therapy for Intracranial Malignant Glioma in a Canine Patient

Non-thermal irreversible electroporation (N-TIRE) has shown promise as an ablative therapy for a variety of soft-tissue neoplasms. Here we describe the therapeutic planning aspects and first clinical application of N-TIRE for the treatment of an inoperable, spontaneous malignant intracranial glioma in a canine patient. The N-TIRE ablation was performed safely, effectively reduced the tumor volume and associated intracranial hypertension, and provided sufficient improvement in neurological function of the patient to safely undergo adjunctive fractionated radiotherapy (RT) according to current standards of care. Complete remission was achieved based on serial magnetic resonance imaging examinations of the brain, although progressive radiation encephalopathy resulted in the death of the dog 149 days after N-TIRE therapy. The length of survival of this patient was comparable to dogs with intracranial tumors treated via standard excisional surgery and adjunctive fractionated external beam RT. Our results illustrate the potential benefits of N-TIRE for in vivo ablation of undesirable brain tissue, especially when traditional methods of cytoreductive surgery are not possible or ideal, and highlight the potential radiosensitizing effects of N-TIRE on the brain.

A Parametric Study Delineating Irreversible Electroporation from Thermal Damage Based on a Minimally Invasive Intracranial Procedure

BackgroundIrreversible electroporation (IRE) is a new minimally invasive technique to kill undesirable tissue in a non-thermal manner. In order to maximize the benefits from an IRE procedure, the pulse parameters and electrode configuration must be optimized to achieve complete coverage of the targeted tissue while preventing thermal damage due to excessive Joule heating.MethodsWe developed numerical simulations of typical protocols based on a previously published computed tomographic (CT) guided in vivo procedure. These models were adapted to assess the effects of temperature, electroporation, pulse duration, and repetition rate on the volumes of tissue undergoing IRE alone or in superposition with thermal damage.ResultsNine different combinations of voltage and pulse frequency were investigated, five of which resulted in IRE alone while four produced IRE in superposition with thermal damage.ConclusionsThe parametric study evaluated the influence of pulse frequency and applied voltage on treatment volumes, and refined a proposed method to delineate IRE from thermal damage. We confirm that determining an IRE treatment protocol requires incorporating all the physical effects of electroporation, and that these effects may have significant implications in treatment planning and outcome assessment. The goal of the manuscript is to provide the reader with the numerical methods to assess multiple-pulse electroporation treatment protocols in order to isolate IRE from thermal damage and capitalize on the benefits of a non-thermal mode of tissue ablation.

The effect of targeted agents on outcomes in patients with brain metastases from renal cell carcinoma treated with Gamma Knife surgery

OBJECT Gamma Knife surgery (GKS) has been reported as an effective modality for treating brain metastases from renal cell carcinoma (RCC). The authors aimed to determine if targeted agents such as tyrosine kinase inhibitors, mammalian target of rapamycin inhibitors, and bevacizumab affect the patterns of failure of RCC after GKS. METHODS Between 1999 and 2010, 61 patients with brain metastases from RCC were treated with GKS. A median dose of 20 Gy (range 13-24 Gy) was prescribed to the margin of each metastasis. Kaplan-Meier analysis was used to determine local control, distant failure, and overall survival rates. Cox proportional hazard regression was performed to determine the association between disease-related factors and survival. RESULTS Overall survival at 1, 2, and 3 years was 38%, 17%, and 9%, respectively. Freedom from local failure at 1, 2, and 3 years was 74%, 61%, and 40%, respectively. The distant failure rate at 1, 2, and 3 years was 51%, 79%, and 89%, respectively. Twenty-seven percent of patients died of neurological disease. The median survival for patients receiving targeted agents (n = 24) was 16.6 months compared with 7.2 months (n = 37) for those not receiving targeted therapy (p = 0.04). Freedom from local failure at 1 year was 93% versus 60% for patients receiving and those not receiving targeted agents, respectively (p = 0.01). Multivariate analysis showed that the use of targeted agents (hazard ratio 3.02, p = 0.003) was the only factor that predicted for improved survival. Two patients experienced post-GKS hemorrhage within the treated volume. CONCLUSIONS Targeted agents appear to improve local control and overall survival in patients treated with GKS for metastastic RCC.

Glossopharyngeal neuralgia treated with gamma knife surgery: treatment outcome and failure analysis

✓ Glossopharyngeal neuralgia (GPN) is a rare condition in which patients present with intractable deep throat pain. Similar to trigeminal neuralgia (TN), treatment with microvascular decompression (MVD) has been successful in both. Because gamma knife surgery (GKS) has also been shown to be effective in treating TN, it seemed reasonable to apply it to GPN. The authors present the first report of GKS-treated GPN in a patient who presented with severe, poorly controlled GPN and who refused MVD.

Predictive Variables for the Successful Treatment of Trigeminal Neuralgia With Gamma Knife Radiosurgery

BACKGROUND Gamma Knife radiosurgery (GKRS) has been reported to be an effective modality to treat trigeminal neuralgia. OBJECTIVE To determine predictive factors for the successful treatment of trigeminal neuralgia with GKRS. METHODS Between 1999 and 2008, 777 GKRS procedures for patients with trigeminal neuralgia were performed at our institution. Evaluable follow-up data were obtained for 448 patients. Median follow-up time was 20.9 months (range, 3-86 months). The mean maximum prescribed dose was 88 Gy (range, 80-97 Gy). Dosimetric variables recorded included dorsal root entry zone dose, pons maximum dose, dose to the petrous dural ridge, and cisternal nerve length. RESULTS By 3 months after GKRS, 86% of patients achieved Barrow Neurologic Institute I to III pain scores, with 43% of patients achieving a Barrow Neurologic Institute I pain score. Twenty-six percent of patients reported posttreatment facial numbness; 28% of patients reported a post-GKRS procedure for relapsed pain, and median time to next procedure was 4.4 years. Multivariate analysis revealed that the development of postsurgical numbness (odds ratio [OR], 2.76; P = .006) was the dominant factor predictive of efficacy. Longer cisternal nerve length (OR, 0.85; P = .005), prior radiofrequency ablation (OR, 0.35; P = .028), and diabetes mellitus (OR, 0.38; P = .013) predicted decreased efficacy. The mean dose delivered to the dorsal root entry zone dose in patients who developed facial numbness (57.6 Gy) was more than the mean dose (47.3 Gy) given to patients who did not develop numbness (P = .02). CONCLUSION The development of post-GKRS facial numbness is a dominant factor that predicts for efficacy of GKRS. History of diabetes mellitus or previous radiofrequency ablation may portend worsened outcome.

Repeat gamma knife radiosurgery for trigeminal neuralgia.

PURPOSE Repeat gamma knife stereotactic radiosurgery (GKRS) for recurrent or persistent trigeminal neuralgia induces an additional response but at the expense of an increased incidence of facial numbness. The present series summarized the results of a repeat treatment series at Wake Forest University Baptist Medical Center, including a multivariate analysis of the data to identify the prognostic factors for treatment success and toxicity. METHODS AND MATERIALS Between January 1999 and December 2007, 37 patients underwent a second GKRS application because of treatment failure after a first GKRS treatment. The mean initial dose in the series was 87.3 Gy (range, 80-90). The mean retreatment dose was 84.4 Gy (range, 60-90). The dosimetric variables recorded included the dorsal root entry zone dose, pons surface dose, and dose to the distal nerve. RESULTS Of the 37 patients, 81% achieved a >50% pain relief response to repeat GKRS, and 57% experienced some form of trigeminal dysfunction after repeat GKRS. Two patients (5%) experienced clinically significant toxicity: one with bothersome numbness and one with corneal dryness requiring tarsorraphy. A dorsal root entry zone dose at repeat treatment of >26.6 Gy predicted for treatment success (61% vs. 32%, p = .0716). A cumulative dorsal root entry zone dose of >84.3 Gy (72% vs. 44%, p = .091) and a cumulative pons surface dose of >108.5 Gy (78% vs. 44%, p = .018) predicted for post-GKRS numbness. The presence of any post-GKRS numbness predicted for a >50% decrease in pain intensity (100% vs. 60%, p = .0015). CONCLUSION Repeat GKRS is a viable treatment option for recurrent trigeminal neuralgia, although the patient assumes a greater risk of nerve dysfunction to achieve maximal pain relief.

Pilot study of irreversible electroporation for intracranial surgery

Irreversible electroporation (IRE) is a new minimally invasive technique to treat cancer using intense but short electric pulses. This technique is unique because of its non-thermal mechanism of tissue ablation. Furthermore it can be predicted with numerical models and can be confirmed with ultrasound and MRI. We present some preliminary results on the safety of using irreversible electroporation for canine brain surgery. We also present the electric field (460 V/cm – 560 V/cm) necessary for focal ablation of canine brain tissue and provide some guidelines for treatment planning and execution. This preliminary study is the first step towards using irreversible electroporation as a brain cancer treatment.

Clinical Experience With Radiation Therapy in the Management of Neurofibromatosis-Associated Central Nervous System Tumors

PURPOSE Patients with neurofibromatosis (NF) develop tumors of the central nervous system (CNS). Radiation therapy (RT) is used to treat these lesions. To better define the efficacy of RT in these patients, we reviewed our 20-year experience. METHODS AND MATERIALS Eighteen patients with NF with CNS tumors were treated from 1986 to 2007. Median follow-up was 48 months. Progression was defined as growth or recurrence of an irradiated tumor on serial imaging. Progression-free survival (PFS) was measured from the date of RT completion to the date of last follow-up imaging study. Actuarial rates of overall survival (OS) and PFS were calculated according to the Kaplan-Meier method. RESULTS Eighty-two tumors in 18 patients were irradiated, with an average of five tumors/patient. Median age at treatment was 25 years (range, 4.3-64 years). Tumor types included acoustic neuroma (16%), ependymoma (6%), low-grade glioma (11%), meningioma (60%), and schwanomma/neurofibroma (7%). The most common indication for treatment was growth on serial imaging. Most patients (67%) received stereotactic radiosurgery (median dose, 1,200 cGy; range, 1,000-2,400 cGy). The OS rate at 5 years was 94%. Five-year PFS rates were 75% (acoustic neuroma), 100% (ependymoma), 75% (low-grade glioma), 86% (meningioma), and 100% (schwanomma/neurofibroma). Thirteen acoustic neuromas had a local control rate of 94% with a 50% hearing preservation rate. CONCLUSIONS RT provided local control, OS, and PFS rates similar to or better than published data for tumors in non-NF patients. Radiation therapy should be considered in NF patients with imaging progression of CNS tumors.

Limited Margins Using Modern Radiotherapy Techniques Does Not Increase Marginal Failure Rate of Glioblastoma.

Objective:We investigate the patterns of failure in the treatment of glioblastoma (GBM) based on clinical target volume (CTV) margin size, dose delivered to the site of initial failure, and the use of temozolomide and intensity-modulated radiotherapy (IMRT). Methods:Between August 2000 and May 2010, 161 patients with GBM were treated with radiotherapy with or without concurrent temozolomide. Patients were treated with CTV expansions that ranged from 5 to 20 mm using a shrinking field technique. Patterns of failure and time to progression and overall survival were compared based on CTV margin, use of temozolomide, and use of IMRT. Kaplan Meier analysis was used to estimate survival times, and &khgr;2 test was used for comparison of cohorts. Results:For patients treated with 5-, 10-, and 15- to 20-mm CTV, 79%, 77%, and 86% experienced failures in the 60 Gy volume, respectively. Forty-eight percent, 55%, and 66% of patients with 5-, 10-, and 15- to 20-mm CTV experienced failures in the 46 Gy volume, respectively. There was no statistical difference between patients treated with 5-, 10-, 15- to 20-mm margins with regard to 60 Gy failure (P=0.76), 46 Gy failure (P=0.51), or marginal failure (P=0.73). Eighty percent of patients receiving temozolomide experienced failures in the 60 Gy volume. There was no increased likelihood of marginal failures in patients receiving IMRT (P=0.97). Conclusions:Modern treatment techniques including use of concurrent temozolmide, limited CTV margin size, and IMRT have not greatly changed the patterns of failure of GBM.