Search

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 χ 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.

Gamma Knife Radiosurgery (GKRS) has been reported in the treatment of brainstem metastases while dose volume toxicity thresholds remain mostly undefined. A retrospective review of 52 brainstem metastases in 44 patients treated with GKRS was completed. A median dose of 18 Gy (range 10–22 Gy) was prescribed to the tumor margin (median 50 % isodose). 25 patients had undergone previous whole brain radiation therapy. Toxicity was graded by the LENT-SOMA scale. Mean and median follow-up was 10 and 6 months. Only 3 of the 44 patients are living. Multiple brain metastases were treated in 75 % of patients. Median size of lesions was 0.134 cc, (range 0.013–6.600 cc). Overall survival rate at 1 year was 32 % (95 % CI 51.0–20.1 %) with a median survival time of 6 months (95 % CI 5.0–16.5). Local control rate at 6 months and 1 year was 88 % (95 % CI 70–95 %) and 74 % (95 % CI 52–87 %). Cause of death was neurologic in 17 patients, non-neurologic in 20 patients, and unknown in four. Four patients experienced treatment related toxicities. Univariate analysis of tumor volume revealed that volume greater than 1.0 cc predicted for toxicity. A strategy of using lower marginal doses with GKRS to brain stem metastases appears to lead to a lower local control rate than seen with lesions treated within the standard dose range in other locations. Tumor size greater than 1.0 cc predicted for treatment-related toxicity.

Novel therapeutic options for patients with recurrent primary central nervous system lymphoma (RPCNSL) are needed. Bendamustine, a bifunctional purine analog/alkylating agent, is approved for use in patients with progressive systemic indolent non-Hodgkin's B-cell lymphomas. Limited data suggests that bendamustine may partition into the brain in the setting of a disrupted blood-brain barrier. This report describes the first known experience of patients with RPCNSL treated with bendamustine. Therapy was well-tolerated and best response was noted as stable disease after eight cycles of bendamustine followed by a subsequent local systemic recurrence found at five months follow-up. CNS involvement in this patient remained stable 20 + months post-bendamustine treatment. Based on our observations, further neuropharmacokinetic and efficacy studies with bendamustine may be warranted in this patient population.

Purpose: To assess toxicity in patients with either a collagen vascular disease (CVD) or multiple sclerosis (MS) treated with intracranial radiosurgery. Methods and Materials: Between January 2004 and April 2009, 6 patients with MS and 14 patients with a CVD were treated with Gamma Knife radiosurgery (GKRS) for intracranial tumors. Treated lesions included 15 total brain metastases in 7 patients, 11 benign brain tumors, 1 low grade glioma, and 1 cavernous malformation. Toxicities were graded by the Radiation Therapy Oncology Group Acute/Late Radiation Morbidity Scoring Criteria. 'Rare toxicities' were characterized as those reported in the scientific literature at an incidence of

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.

Influenza is a common RNA virus that causes yearly epidemics with an illness typically presenting with fever, myalgias, constitutional symptoms, and upper and/or lower respiratory tract symptoms. Patients with malignancies receiving chemotherapy are at increased risk for influenza-related illness1,2 and have been shown to have higher complication and mortality rates.3–5 The Centers for Disease Control (CDC) recommends annual influenza vaccination for all persons older than 6 months.6 The CDC endorses the practice of influenza vaccination for patients with malignancies, although little concrete evidence exists to suggest that patients with malignancies and/or those undergoing active chemotherapy mount a sufficient immunologic response to achieve clinical protection. In the general population, influenza vaccination results in prevention of infection in ∼70%–90% of healthy young adults.7,8 Serologic response is high, with seroconversion rates of 75%–80% and seroprotection rates of around 95% based on hemagglutinin inhibition (HI) titer assessment.9,10 Studies have demonstrated reduced immunogenicity in elderly populations, with seroconversion rates of 23%–51% and seroprotection rates of 68%–97%,11 as well as other groups including patients with end-stage renal disease,12 renal transplants,13,14 liver transplants,15 and lung transplants,16 HIV populations,17 and others. Investigation of influenza vaccine efficacy in patients with malignancies has been limited. Cancer patients are vaccinated at rates well below 50%. Lack of awareness of the current recommendations, fear of side effects, and concerns about vaccine efficacy have been cited as the primary reasons for not offering vaccination.18 Studies have demonstrated seroconversion and seroprotection rates similar to healthy adults following vaccination of patients with lung cancer19 as well as those with a variety of solid tumors.20 In patients with hematologic malignancies, seroconversion rates have been reported to be lower (21%).21 Some studies have evaluated the efficacy of single vaccination, while others have suggested additional efficacy using a multidose regimen.22 The efficacy of influenza vaccination has not been evaluated in patients with central nervous system (CNS) malignancies. Nevertheless, this is a potentially robust population for study given the immunosuppressive effects of gliomas and its associated treatment,23 variable degrees of therapy-induced lymphopenia and neutropenia, and the inclusion of glucocorticoids into pharmocotherapeutic regimens. The current study pilots an investigation into influenza vaccine immunogenicity in a group of patients with CNS malignancy.

Purpose: To report initial clinical experience with a novel high-precision stereotactic radiotherapy system. Methods and Materials: Sixty patients ranging in age from 2 to 82 years received a total of 1426 treatments with the University of Florida frameless stereotactic radiotherapy system. Of the total, 39 (65%) were treated with stereotactic radiotherapy (SRT) alone, and 21 (35%) received SRT as a component of radiotherapy. Pathologic diagnoses included meningiomas (15 patients), low-grade astrocytomas (11 patients), germinomas (9 patients), and craniopharyngiomas (5 patients). The technique was used as means of dose escalation in 11 patients (18%) with aggressive tumors. Treatment reproducibility was measured by comparing bite plate positioning registered by infrared light-emitting diodes (IRLEDs) with the stereotactic radiosurgery reference system, and with measurements from each treatment arc for the 1426 daily treatments (5808 positions). We chose 0.3 mm vector translation error and 0.3° rotation about each axis as the maximum tolerated misalignment before treating each arc. Results: With a mean follow-up of 11 months, 3 patients had recurrence of malignant disease. Acute side effects were minimal. Of 11 patients with low grade astrocytomas, 4 (36%) had cerebral edema and increased enhancement on MR scans in the first year, and 2 required steroids. All had resolution and marked tumor involution on follow-up imaging. Bite plate reproducibility was as follows. Translational errors: anterior-posterior, 0.01 ± 0.10; lateral, 0.02 ± 0.07; axial, 0.01 ± 0.10. Rotational errors (degrees): anterior-posterior, 0.00 ± 0.03; lateral, 0.00 ± 0.06; axial, 0.01 ± 0.04. No patient treatment was delivered beyond the maximum tolerated misalignment. Daily treatment was delivered in approximately 15 min per patient. Conclusion: Our initial experience with stereotactic radiotherapy using the infrared camera guidance system was good. Patient selection and treatment strategies are evolving rapidly. Treatment accuracy was the best reported, and the treatment approach was practical.

We investigate the variance in patterns of failure after Gamma Knife™ radiosurgery (GKRS) for patients with brain metastases based on the subtype of the primary breast cancer. Between 2000 and 2010, 154 breast cancer patients were treated with GKRS for brain metastases. Tumor subtypes were approximated based on hormone receptor (HR) and HER2 status of the primary cancer: Luminal A/B (HR+/HER2(-)); HER2 (HER2+/HR(-)); Luminal HER2 (HR+/HER2+), Basal (HR(-)/HER2(-)), and then based on HER2 status alone. The median follow-up period was 54 months. Kaplan-Meier method was used to estimate survival times. Multivariable analysis was performed using Cox regression models. Median number of lesions treated was two (range 1-15) with a median dose of 20 Gy (range 9-24 Gy). Median overall survival (OS) was 7, 9, 11 and 22 months for Basal, Luminal A/B, HER2, and Luminal HER2, respectively (p = 0.001), and was 17 and 8 months for HER2+ and HER(-) patients, respectively (p < 0.001). Breast cancer subtype did not predict time to local failure (p = 0.554), but did predict distant brain failure rate (76, 47, 47, 36 % at 1 year for Basal, Luminal A/B, HER2, and Luminal HER2 respectively, p < 0.001). An increased proportion of HER2+ patients experienced neurologic death (46 vs 31 %, p = 0.066). Multivariate analysis revealed that HER2+ patients (p = 0.007) independently predicted for improved survival. Women with basal subtype have high rates of distant brain failure and worsened survival. Our data suggest that differences in biologic behavior of brain metastasis occur across breast cancer subtypes.

Atypical meningiomas have poor local control with emerging literature indicating the use of radiosurgery in treatment. The purpose of this study was to evaluate clinical outcomes including local control and failure pattern after Gamma Knife radiosurgery (GKRS) and factors that may affect these outcomes. Between 1999 and 2008, 24 patients were treated with GKRS as either primary or salvage treatment for pathologically proven atypical meningiomas. Treatment failures were determined by serial magnetic resonance imaging. A median marginal dose of 14 Gy was used (range 10.5–18 Gy). Overall local control rates at 1, 2, and 5 years were 75, 51, and 44%, respectively. With median follow-up time of 42.5 months, 14 of 24 patients experienced a treatment failure at time of last follow-up. Eight recurrences were in-field, four were marginal failures, and two were distant failures. Wilcoxon analysis revealed that the conformality index (CI) was a significant predictor of local recurrence (P = 0.04). CI did not predict for distant recurrences (P = 0.16). On multivariate analysis evaluating factors predicting progression free survival, dose >14 Gy was found to be statistically significant (P = 0.01). There appears to be a dose response using GKRS beyond 14 Gy but given the suboptimal local control rates in this study, higher doses may still be needed to obtain better local control.

Purpose Radiosurgery has been successfully used in selected cases to avoid repeat whole-brain irradiation (WBI) in patients with multiple brain metastases of most solid tumor histological findings. Few data are available for the use of radiosurgery for small-cell lung cancer (SCLC). Methods and Materials Between November 1999 and June 2009, 51 patients with SCLC and previous WBI and new brain metastases were treated with GammaKnife stereotactic radiosurgery (GKSRS). A median dose of 18 Gy (range, 10–24 Gy) was prescribed to the margin of each metastasis. Patients were followed with serial imaging. Patient electronic records were reviewed to determine disease-related factors and clinical outcomes after GKSRS. Local and distant brain failure rates, overall survival, and likelihood of neurologic death were determined based on imaging results. The Kaplan-Meier method was used to determine survival and local and distant brain control. Cox proportional hazard regression was performed to determine strength of association between disease-related factors and survival. Results Median survival time for the entire cohort was 5.9 months. Local control rates at 1 and 2 years were 57% and 34%, respectively. Distant brain failure rates at 1 and 2 years were 58% and 75%, respectively. Fifty-three percent of patients ultimately died of neurologic death. On multivariate analysis, patients with stable (hazard ratio [HR] = 2.89) or progressive (HR = 6.98) extracranial disease (ECD) had worse overall survival than patients without evidence of ECD ( p = 0.00002). Concurrent chemotherapy improved local control (HR = 89; p = 0.006). Conclusions GKSRS represents a feasible salvage option in patients with SCLC and brain metastases for whom previous WBI has failed. The status of patients' ECD is a dominant factor predictive of overall survival. Local control may be inferior to that seen with other cancer histological results, although the use of concurrent chemotherapy may help to improve this.

Thalidomide and procarbazine have demonstrated single agent activity against malignant gliomas (MG). We evaluated the combination of thalidomide and procarbazine with a single arm phase II trial in adults with recurrent or progressive MG. Procarbazine was given at a dose of 250 mg/m(2)/d × 5day q 28 days. Thalidomide was administered at a dose of 200 mg/day continuously. Intrapatient dose escalation of thalidomide was attempted (increase by 100 mg/day weekly as tolerated) to a maximum of 800 mg/day. The primary outcome was tumor response, assessed by MRI and CT. Secondary outcomes were progression free survival (PFS), overall survival (OS) and toxicity. In addition, quality of life questionnaires were performed at baseline and prior to each odd cycle in all treated patients. Eighteen patients (median age of 50) were accrued and received a total of 36 cycles (median 2) of therapy. The median maximum thalidomide dose achieved was 400 mg (range 0-800). No complete or partial responses were seen. One patient (6%) experienced stable disease, fourteen (78%) progressed as best response and three (17%) were not evaluable for response. Median time to progression was 2.1 months (95% CI, 1.5-2.5). Seventeen patients have died (one patient lost to follow-up after progression); median survival from enrollment was 7.6 months (95% CI, 3.5-9.4). Grade 3/4 drug related toxicity was minimal. Quality of life diminished over time. The combination of thalidomide and procarbazine demonstrated no efficacy in this trial.

Objectives To describe the results of a Phase I dose escalation trial for newly diagnosed glioblastoma multiforme (GBM) using a hypofractionated concurrent intensity-modulated radiotherapy (IMRT) boost. Methods Twenty-one patients were enrolled between April 1999 and August 2003. Radiotherapy consisted of daily fractions of 1.8 Gy with a concurrent boost of 0.7 Gy (total 2.5 Gy daily) to a total dose of 70, 75, or 80 Gy. Concurrent chemotherapy was not permitted. Seven patients were enrolled at each dose and dose limiting toxicities were defined as irreversible Grade 3 or any Grade 4–5 acute neurotoxicity attributable to radiotherapy. Results All patients experienced Grade 1 or 2 acute toxicities. Acutely, 8 patients experienced Grade 3 and 1 patient experienced Grade 3 and 4 toxicities. Of these, only two reversible cases of otitis media were attributable to radiotherapy. No dose-limiting toxicities were encountered. Only 2 patients experienced Grade 3 delayed toxicity and there was no delayed Grade 4 toxicity. Eleven patients requiring repeat resection or biopsy were found to have viable tumor and radiation changes with no cases of radionecrosis alone. Median overall and progression-free survival for this cohort were 13.6 and 6.5 months, respectively. One- and 2-year survival rates were 57% and 19%. At recurrence, 15 patients received chemotherapy, 9 underwent resection, and 5 received radiotherapy. Conclusions Using a hypofractionated concurrent IMRT boost, we were able to safely treat patients to 80 Gy without any dose-limiting toxicity. Given that local failure still remains the predominant pattern for GBM patients, a trial of dose escalation with IMRT and temozolomide is warranted.

Purpose To investigate the efficacy of 3.0-T magnetic resonance imaging (MRI) for detecting brain metastases for stereotactic radiosurgery (SRS) planning. Methods and Materials All adult patients scheduled for SRS treatment for brain metastases at our institution between October 2005 and January 2008 were eligible for analysis. All patients underwent radiosurgery treatment planning 3.0-T MRI on the day of scheduled radiosurgery and a diagnostic 1.5-T MRI in the days or weeks prior to radiosurgery for comparison. Both scans were interpreted by neuroradiologists who reported their findings in the radiology reports. We performed a retrospective review of the radiology reports to determine the number of brain metastases identified using each MRI system. Results Of 254 patients scheduled for treatment from October 2005 to January 2008, 138 patients had radiology reports that explicitly described the number of metastases identified on both scans. With a median interval of 17 days (range, 1–82) between scans, the number of metastases detected using 1.5-T MRI system ranged from 1 to 5 and from 1 to 8 using the 3.0 T-MRI system. Twenty-two percent of patients were found to have a greater number of metastases with the 3.0 T-MRI system. The difference in number of metastases detected between the two scans for the entire cohort ranged from 0 to 6. Neither histology (p = 0.52 by chi-sq test) nor time between scans (p = 0.62 by linear regression) were significantly associated with the difference in number of metastases between scans. Conclusions The 3.0-T MRI system appears to be superior to a 1.5-T MRI system for detecting brain metastases, which may have significant implications in determining the appropriate treatment modality. Our findings suggest the need for a prospectively designed study to further evaluate the use of a 3.0 T-MRI system for stereotactic radiosurgery planning in the treatment of brain metastases.

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.

2067 Background: Thal and Pro are among the few agents with demonstrated activity against MG. A two-stage, phase II trial was initiated within the WFURB to establish the response rate of combination Thal-Pro in patients (pts) with recurrent or progressive MG. Methods: Eligibility included pt age = 18 with measurable tumor on contrast enhanced brain scans; KPS = 60; normal liver, kidney and hematologic function; and treatment with = 2 prior regimens. Pts were required to participate in the S.T.E.P.S. Program and mandated to comply with agreed upon measures to avoid conception. Protocol therapy included Pro 250mg/m2/d x 5d q 28days and Thal 200mg/day continuously. Intrapatient dose escalation of Thal was attempted (increase by 100mg/day weekly as tolerated) to a maximum of 800mg/day. All pts received daily pyridoxine(100mg), warfarin(1mg) and stool softeners/laxatives. MRI/CT scans were performed prior to each odd cycle (every 8 weeks) to assess response based upon changes in the products of the largest bidimensional tumor diameters. Quality of life questionnaires including the FACT-Br were performed at baseline and prior to each odd cycle in all treated pts. Results: 18 pts (11 male) were enrolled (median age 50, range 27–63). One pt refused any therapy and is excluded from the analysis. The 17 treated pts received 36 cycles (median 2) of therapy. The median maximum Thal dose achieved was 400mg (range 200–800). No complete or partial responses were seen; 1 pt (6%) experienced stable disease, 14 (82%) progressed as best response and 2 (12%) were not evaluable for response. Median time to progression was 2.1 months (95% CI, 1.5–2.5). 14 pts have died; median survival was 7.6 months (95% CI, 3.5–9.4). Grade 3/4 drug related toxicity was minimal. Conclusions: Despite modest individual response rates in multiple prior phase II and III trials, the combination of Pro and Thal demonstrated no efficacy in this trial and this combination is unworthy of further investigation in pts with MG. Supported by NCI 1 U10 CA81851 and Celgene. No significant financial relationships to disclose.