Whole Brain Radiation Treatment Research Articles

Hippocampus sparing in whole-brain radiotherapy

Radiation treatment techniques for whole-brain radiation therapy (WBRT) have not changed significantly since development of the procedure. However, the recent development of novel techniques such as intensity-modulated radiation therapy (IMRT), volumetric-modulated arc therapy (VMAT) and helical tomotherapy, as well as an increasing body of evidence concerning neural stem cells (NSCs) have altered the conventional WBRT treatment paradigm. In this regard, hippocampus-sparing WBRT is a novel technique that aims to spare critical hippocampus regions without compromising tumour control. Published data on this new technique are limited to planning and feasibility studies; data on patient outcome are still lacking. However, several prospective trials to analyse the feasibility of this technique and to document clinical outcome in terms of reduced neurotoxicity are ongoing.

Dose Reduction to the Scalp with Hippocampal Sparing Is Achievable with Intensity Modulated Radiotherapy.

We evaluated the feasibility of combined hippocampal- and scalp-sparing intensity-modulated radiotherapy (IMRT) plans. This study included 7 patients who received conventional palliative whole brain radiation treatment (WBRT) for brain metastasis. The brain, hippocampus, and scalp were contoured and replanned with intensity modulated radiation therapy. The prescription dose was 30 Gray (Gy) in 10 fractions with hippocampus and normal structure constraints per the Radiation Therapy Oncology Group (RTOG) 0933 protocol. Further planning was done to minimize the scalp dose while maintaining the dose constraints for the hippocampus. Dose volume histograms were obtained from conventional opposed lateral fields, IMRT and compared. Planning target volume (PTV) coverage for all plans fell within the RTOG 0933 critical structure acceptable variation category. When compared to traditional opposed lateral fields, the IMRT plan with combined hippocampal- and scalp-sparing constraints was able to significantly reduce the max and mean scalp dose as well as the percentage of scalp receiving 10 and 20 Gy by 46% and 35%, respectively, while maintaining acceptable RTOG 0933 hippocampal dose variations. We conclude that acceptable PTV coverage and sparing of the scalp and hippocampus can be accomplished using a 9-field non-coplanar IMRT plan. Prospective study is warranted to understand the impact on radiation induced alopecia.

Management of brain metastases from non-small cell lung cancer.

The purpose of the following study is to evaluate the treatment modalities, clinical status and prognostic factors affecting survival rates in patients with newly diagnosed brain metastasis from non-small cell lung cancer (NSCLC). NSCLC patients with a new diagnosis of one to four brain metastasis evaluated retrospectively for the effects of treatment regimens on local failure-relapse-free survival (LRFS) and overall survival (OS). The relationship between age, gender, performance status, recursive partitioning analysis (RPA) classification, the primary tumor under control, number of metastatic tumors in the brain and total volume of brain metastasis and prognosis is analyzed. Out of a total of 138 (121 male and 17 female) patients, nearly 44.2% received only gamma-knife (GK); 24.6% were received both GK and whole brain radiotherapy (WBRT), 2.9% had GK and surgery, 3.6% received GK, surgery and WBRT, 10.9% had surgery and WBRT and 12.3% received only WBRT for treatment. Median LRFS of surgery plus WBRT group was significantly higher when compared with WBRT group (P<0.0001). The OS was significantly longer for surgery plus WBRT group than the other treatment groups (P=0.037). When median survival of WBRT-only group compared with surgery plus WBRT, it was significantly higher (29.6 months vs. 16.7 months, P=0.006). Median OS of surgery plus WBRT group was significantly higher than GK plus WBRT group (29.6 months vs. 9.3 months, P=0.007). WBRT is still the most effective treatment method following surgery in selected patients according to their age, performance status and spread of the primary disease with NSCLC had limited number brain metastasis. Adding WBRT treatment after surgery significantly improved OS and LRFS.

Abstract P6-11-03: Follow up of breast cancer patients who underwent gamma knife radiosurgery for a diagnosis of brain metastases: A single institutional experience

Abstract Background: Breast cancer (BC) is the second most common cause of brain metastases in the United States. We performed a retrospective analysis of BC patients (pts) in the Yale Gamma Knife Radiosurgery (GKRS) database treated for brain metastases (mets) to report overall survival (OS) from time of GKRS, and to identify factors that predict improved survival outcomes. Methods: We performed retrospective review of the Yale database of BC pts treated with standard GKRS technique for brain mets from 2000 to May 2013. Treatment doses typically ranged from 16 to 24 Gy prescribed to the 40-85% isodose surfaces. Overall survival (OS) for each patient was calculated from the date of first GKRS treatment of brain metastases. Variables included age, Karnofsky Performance Status (KPS), pre/post whole-brain radiation treatment (WBRT) and/or surgical resection, and # of brain mets treated (1-4 vs ≥5). Results: A total of 80 BC pts were identified, with a mean age of 56.2 yrs; KPS 40-60 in 8pts (10%), 70-80 in 13 (16%), 90-100 in 41 (51%), unknown in 18 (23%); ER+ in 38 (48%), ER- in 38 (48%), unknown in 4 (5%); HER2 + in 38 (48%), HER2- in 33 (41%), indeterminate in 3 (4%) and unknown in 6 (8%). BC subtypes are Luminal A (ER+/HER2-) in 16 (20%), Luminal B (ER+/HER2+) in 19 (24%), HER-2(ER-/HER2+) in 17 (21%), Basal (ER-/HER2-) in 17 (21%), unknown in 11 (14%). Number of brain mets at time of first GKRS ≥5 in 32 (40%); prior WBRT in 30 (38%); WBRT post GKRS in 9 (11%); surgical resection for brain mets in 13 (16%) prior to GKRS and post GKRS in 9 (11%); 16% had ≥3 GKRS. Median time from primary BC dx to brain mets is 62.8 months (m) (range 46.2-81.6); with no significant difference among subtypes. Median OS from GKRS is 13.1 m (7.6-21.9); median OS from brain mets is 18.8 m (11.7-23.9). On univariate analysis, factors associated with significant improved OS from time of GKRS included HER-2 subtype (p = 0.005), KPS 90-100 (p = 0.008), good control of systemic disease (p = 0.017), pre (p = 0.041) and post GKRS surgical resection (p = 0.02). Age, pre or post WBRT, # of brain mets (1-4 vs. 5) were not significant predictors of OS from time of GKRS. In a multivariate Cox analysis (46 cases), HER-2 subtype remained a significant predictor of improved OS from time of GKRS; (HR) 0.26, 95%CI 0.08 to 0.8, p-value = 0.02. There was a trend in favor of surgical resection of brain mets pre GKRS (HR 0.14, 95% CI 0.02 to 1.15, p-value = 0.067 Conclusion: GKRS offers good local control for BC pts with brain mets, and is a reasonable option for pts with ≥5 brain mets. Our results show no associated survival benefit for administration of WBRT pre/post GKRS. HER-2 subtype is a significant predictor of improved survival in BC pts undergoing GKRS for brain mets. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-11-03.

Survival and Intracranial Control of Patients With 5 or More Brain Metastases Treated With Gamma Knife Stereotactic Radiosurgery

Limited data are available to help inform decisions about stereotactic radiosurgery for patients with ≥5 brain metastases. We therefore performed a retrospective analysis of patients treated for >5 brain metastases. Patients who underwent treatment for ≥5 brain metastases from October 2000 to September 2010 were identified. Overall survival (OS) for each patient was calculated from the date of first treatment of ≥5 metastases. Intracranial recurrence-free survival was defined when posttreatment magnetic resonance imaginag showed evidence for disease progression. Cox proportional hazards regression was performed for OS and intracranial recurrence free survival. Variables included sex, age, Karnofsky Performance Status (KPS), histology, prior whole-brain radiation treatment or Gamma Knife treatment, and number of metastases treated. A total of 103 patients were identified. Median OS was 8.3 months. Median OS was 7.6 months and 8.3 months, for patients with 5 to 9 and ≥10 metastases, respectively. KPS was the only significant variable affecting OS (P <0.01). Forty-six patients had post-Gamma Knife surveillance imaging recorded. There was a trend towards a higher hazard for intracranial failure for patients with 10+ versus 5 to 9 metastases, however, the association did not reach statistical significance (univariate P=0.09, multivariate P=0.21). OS for carefully selected patients with 5 or more brain metastases treated with stereotactic radiosurgery alone is reasonable and compares well with historical controls. KPS is the most important factor predicting OS.

Can hippocampus be spared in patients with small cell lung carcinoma (SCLC) during cranial radiation therapy (CRT)?

7596 Background: Although CRT is a standard therapy for prevention and treatment of brain metastases (BM) in patients with SCLC, neurocognitive impairment (NI) following therapeutic whole brain radiation treatment (WBRT) or prophylactic cranial irradiation (PCI) is a major problem and can cause impairment in quality of life. A RTOG study is assessing various outcomes by avoiding the hippocampus (AH) during WBRT in different malignancies. The estimated risk of hippocampal avoidance region metastases (HM) in patients with SCLC before &amp; after WBRT/PCI is not known. AH during CRT may delay the onset of NI in such patients. Our study aims to determine risk of HM in patients with SCLC and to assess clinical factors correlate with it. Methods: A patients cohort of SCLC diagnosed and treated at the Saskatoon Cancer Center between 2005 and 2012 were followed. All MRI and/or CT scans were independently reviewed by a neuroradiologist. HM was defined as BM within 5 mm of hippocampus. Binary Logistic regression analysis was done to assess correlation between various clinical variables and HM using SPSS. Results: 162 patients with SCLC were identified, 60 (37%) have developed BM. The preliminary data of 39/60 patients is presented here. All 39 patients received CRT and 17 patients received upfront chemotherapy. Their median age was 63 yrs (range: 41-82) &amp; M:F was 22:17. 30 (77%) had extensive stage SCLC and 30 (77%) had de novo BM before CRT. A total 198 (range: 1-33) BM were identified among these patients with a mean BM of 6.6 per patient. 4 (13.3%) of 30 patients had HM involvement with mean BM of 1.3 per patient. Median follow up was 13.5 months (range: 1-69). Post-CRT 13 (33%) of 39 patients (4 PCI, 9 WBRT) developed central nervous system (CNS) progression. None of 13 patients with CNS failure following CRT developed HM. Overall 4 (10.2%) of 39 patients developed HM. No clinical factors significantly correlated with HM. Conclusions: The preliminary result revealed that overall incidence of HM before and after WBRT/PCI is low. AH in such patients may consider during CRT to avoid NI. The study is ongoing and final analysis will be presented.

Vorinostat as a radiosensitizer for CNS malignancies: Preclinical results and phase I trial in brain metastasis.

2100 Background: To evaluate the effect of vorinostat as radiosensitizer in human Glioblastoma cell lines in preclinical study, as well as a phase I study to evaluate the safety, and tolerability of vorinostat, an HDAC inhibitor, when combined with whole brain radiation treatment (WBRT) for patients with brain metastasis. Methods: Preclinical studies evaluated the effect of vorinostat on DNA repair enzyme expression, repair of radiation induced DNA damage, and cell survival to radiation treatment as a proof of concept. Further phase I clinical trial included patients with histological diagnosis of malignancy and radiographic evidence of brain metastasis. WBRT was 37.5 Gy in 2.5 Gy fractions delivered over 3 weeks. Vorinostat was administrated by mouth, once daily, Monday through Friday, concurrently with radiation treatment. The vorinostat dose was escalated from 200 mg to 400 mg daily using a 3+3 trial design. Results: Preclinical studies showed with increasing doses of vorinostat more profoundly decrease expression of key genes involved in DNA repair, inhibiting the repair of DNA damage induced by ionizing radiation and leading to decreased clonogenic survival. It enhanced the radiation effect in vitro. In the phase I trial, 17 patients were enrolled, 4 patients were excluded from the analysis due to either incorrect radiation dose (n=1), or early treatment termination due to disease progression (n = 3). There were no treatment related grade 3 or higher toxicities in the 200 mg and 300 mg dose levels. In the 400mg cohort there was a grade 3 pulmonary embolus and one death within 30 days of treatment. Although both events were most likely related to disease progression rather than treatment. However, to be more conservative, we defined the death as a dose limiting toxicity. Conclusions: Preclinical studies demonostrated that vorinostat profoundly decrease expression of key genes involved in DNA repair, inhibiting the repair of DNA damage induced by ionizing radiation and leading to decreased clonogenic survival. Vorinostat administered orally once daily with concurrent whole brain radiation treatment is well tolerated to the dose of 300 mg. This is the recommended dose for phase II study. Clinical trial information: NCT00838929.

Gamma Knife surgery for metastatic brain tumors from primary breast cancer: treatment indication based on number of tumors and breast cancer phenotype

The goal of this study was to analyze prognostic factors for local tumor control and survival and indications for initial treatment with the Gamma Knife in patients with up to 10 metastatic brain tumors from primary breast cancer. Outcomes were retrospectively reviewed in 101 women with a total of 600 tumors, who underwent Gamma Knife surgery (GKS) for metastatic brain tumors between April 1992 and December 2008 at 1 institution. The inclusion criteria were up to 10 brain metastases, maximum diameter of tumor < 3 cm, and total tumor volume < 15 cm(3). The exclusion criteria were poor systemic condition, presence of carcinomatous meningitis, and previous whole brain radiation treatment and/or craniotomy. The mean tumor volume at GKS was 3.7 cm(3) (range 0.016-14.3 cm(3)). The mean margin dose was 19 Gy (range 8-30 Gy). Neuroimaging showed that the local tumor growth control rate was 97%, and the tumor response rate was 82.3%. Larger tumor volume (p = 0.001) and lower margin dose (p = 0.001) were significant adverse prognostic factors for local tumor growth control according to a multivariate analysis. The number of brain metastatic lesions was 4 or fewer in 76 patients and 5 or more in 25 patients. The median overall survival time was 13 months. Multivariate analysis revealed that the presence of extracranial metastases (p = 0.041) and lesions that were not the human epidermal growth factor receptor-2 (HER2)-positive type (p = 0.001) were significant adverse prognostic factors for overall survival. The number of brain metastases was not statistically significant, except for a single metastasis. The median new lesion-free survival time after initial GKS was 9 months. Five or more lesions at initial GKS (p = 0.007) and younger patient age (p = 0.008) reduced survival significantly. The prevention of neurological death after GKS was 93.9% at 1 year, and a lower Karnofsky Performance Scale score (p = 0.009) was the only unfavorable factor. Median overall survival associated with the HER2-positive phenotype was significantly longer than survival associated with the other phenotypes (luminal and triple-negative). There were no statistically significant differences between the 3 breast cancer phenotypes for the incidence of new brain metastases after initial GKS. Initial GKS resulted in excellent local tumor control rates, which were associated with prolonged survival and a low risk of neurological death for patients with up to 10 metastatic brain tumors from primary breast cancer. The authors recommend periodic clinical and neuroradiological follow-up examinations after GKS in patients with 5 or more lesions at initial GKS, because they carry a high risk of development of new brain metastases, and in patients with the HER2-positive phenotype, because they tend to have a favorable prognosis in overall survival. Last, the authors recommend additional GKS or whole-brain radiation treatment for salvage treatment if new brain metastases occur.

ORIGINAL ARTICLE: Sparing of the hippocampus and limbic circuit during whole brain radiation therapy: A dosimetric study using helical tomotherapy

AbstractIntroduction: The study aims to assess the feasibility of dosimetrically sparing the limbic circuit during whole brain radiation therapy (WBRT) and prophylactic cranial irradiation (PCI).Methods and Materials: We contoured the brain/brainstem on fused MRI and CT as the target volume (PTV) in 11 patients, excluding the hippocampus and the rest of the limbic circuit, which were considered organs at risk (OARs). PCI and WBRT helical tomotherapy plans were prepared for each patient with a 1.0‐cm field width, pitch = 0.285, initial modulation factor = 2.5. We attempted to spare the hippocampus and the rest of the limbic circuit while treating the rest of the brain to 30 Gy in 15 fractions (PCI) or 35 Gy in 14 fractions (WBRT) with V100 ≥ 95%. The quality of the plans was assessed by calculating mean dose and equivalent uniform dose (EUD) for OARs and the % volume of the PTV receiving the prescribed dose, V100.Results: In the PCI plans, mean doses/EUD were: hippocampus 12.5 Gy/14.23 Gy, rest of limbic circuit 17.0 Gy/19.02 Gy. In the WBRT plans, mean doses/EUD were: hippocampus 14.3 Gy/16.07 Gy, rest of limbic circuit 17.9 Gy/20.74 Gy. The mean V100 for the rest of the brain (PTV) were 94.7% (PCI) and 95.1% (WBRT). Mean PCI and WBRT treatment times were essentially identical (mean 15.23 min, range 14.27–17.5).Conclusions: It is dosimetrically feasible to spare the hippocampus and the rest of the limbic circuit using helical tomotherapy while treating the rest of the brain to full dose.

Sparing of the Neural Stem Cell Compartment During Whole-Brain Radiation Therapy: A Dosimetric Study Using Helical Tomotherapy

To assess the feasibility of dosimetrically sparing the hippocampus and neural stem cell (NSC) compartment during whole-brain radiotherapy (WBRT) and prophylactic cranial irradiation (PCI). We contoured the brain/brainstem on fused magnetic resonance /computed tomography images as the planning target volume (PTV) in 10 patients, excluding the hippocampus and NSC compartment as organs at risk. PCI and WBRT helical tomotherapy plans were prepared for each patient, with 1.0-cm field width, a pitch of 0.285, and a modulation factor of 2.5. We attempted to maximally spare the hippocampus and NSC compartment while treating the rest of the brain to 30 Gy in 15 fractions (PCI) or 35 Gy in 14 fractions (WBRT) with a V(100) of ≥95%. Plan quality was assessed by calculating mean dose, equivalent uniform dose (EUD), and biologically equivalent dose (BED) for organs at risk and the percent volume of the PTV receiving the prescribed dose of V(100). In the PCI plans, mean doses/EUD/BED for the hippocampus and NSC compartment were 11.5 Gy/13.1 Gy/15.7 Gy(2) (BED assuming alpha/beta ratio of 2Gy) and 11.5 Gy/13.1 Gy/12.3 Gy(10) (BED assuming alpha/beta ratio of 10Gy), respectively. In the WBRT plans, mean doses/EUD/BED for the hippocampus and NSC compartment were 11.8 Gy/14.8 Gy/16.8 Gy(2) and 11.8 Gy/14.8 Gy/12.8 Gy(10), respectively. The mean V(95) for the rest of the brain (PTV) was 96.9% for both the PCI and WBRT plans. Mean PCI and WBRT treatment times were 15.93 min (range, 14.28 min-17.50 min) and 20.18 min (range, 18.43 min-22.32 min), respectively. It is dosimetrically feasible to spare the hippocampus and NSC compartment using helical tomotherapy during the administration of whole-brain irradiation.

Treatment options for central nervous system lymphomas in immunocompetent patients

Despite recent advances in diagnosis and treatment, the prognosis of primary CNS lymphoma (PCNSL) and CNS relapse of systemic non-Hodgkin lymphoma remains poor, and the optimal treatment is yet to be defined. This review presents an overview of the current status of CNS lymphoma treatment. Treatment options include radiotherapy alone, intravenous conventional chemotherapy alone, intrathecal chemotherapy, high-dose chemotherapy with autologous stem cell transplantation, combined modality treatment (i.e., chemotherapy plus radiotherapy), immunotherapy, radioimmunotherapy and ocular radiation and/or chemotherapy for intraocular lymphoma. High-dose methotrexate remains an essential part of most first-line treatments for PCNSL and CNS relapse of systemic non-Hodgkin lymphoma. Treatment standardization is hampered by the rarity of the disease and the difficulty of conducting trials with a higher number of patients. However, a recently closed Phase III/IV trial will most likely define the role of adjuvant whole-brain radiation treatment in PCNSL. Future directions in the management of PCNSL and CNS relapse of systemic lymphoma may include treatment stratification according to patient age and clinical and biological prognostic factors.

Neurosurgical Rescue of Bradycardia Induced by Intracerebral Hypertension: A Case Report and Review of the Literature

Brain metastases usually occur secondary to lung, breast, unknown primary, melanoma, and colon cancers. A growing tumor in the brain is commonly associated with edema and increased intracranial pressure (ICP). Common signs and symptoms due to increased ICP or brain edema include headache, nausea, and vomiting. One of the main treatment modalities in the management of brain metastases is whole-brain radiation. However, increased ICP may lead to acute deterioration of the neurologic status due to development of radiation-induced edema. Therefore, alternative management options should be considered for these patients to avoid complications from whole-brain radiation treatment. We discuss the case of a brain metastases patient who presented with bradycardia induced by brain edema.

Outcomes and cost-effectiveness of gamma knife radiosurgery and whole brain radiotherapy for multiple metastatic brain tumors

We aimed to analyze the outcomes and cost-effectiveness of gamma knife radiosurgery (GKRS) and whole brain radiotherapy (WBRT) for multiple metastatic brain tumors. Over a period of 5 years, 156 patients with multiple metastatic brain tumors were enrolled and freely assigned by the referring doctors to either gamma knife radiosurgery (GKRS, Group A, n = 56), or to whole brain radiotherapy (WBRT, Group B, n = 100). The follow-up time was set at 1200 days (3.3 years) post-treatment. The number of tumors, patient age, extent of systemic disease and Karnofsky performance scale (KPS) score, were recorded and recursive partitioning analysis used. The outcomes analyzed were: mortality, survival time, neurological complications, post-treatment KPS score, quality-adjusted life years (QALY), and cost-effectiveness. A paired t-test was used for statistical analysis. Mortality rates for patients receiving GKRS and WBRT were 81.1% and 93.0%, respectively ( p = 0.05). The mortality rate was lower for GKRS (74.4%) than for WBRT (97.1%) in patients with initial KPS ⩾ 70 ( p = 0.02). The mortality rate was also significantly lower for GKRS (78.9%) than WBRT (95.5%) in patients with 2–5 tumors ( p < 0.05). Post-treatment KPS score (mean ± standard deviation [s.d.] was higher for patients receiving GKRS (73.8 ± 13.2) than for those receiving WBRT (45.5 ± 26.0), p < 0.01. The median survival time for GKRS and WBRT was 9.5 months and 8.3 months, respectively, p = 0.72. The mean (± s.d.) QALY was 0.76 ± 0.23 for GKRS and 0.59 ± 0.18 for WBRT, respectively ( p < 0.05). The cost-effectiveness per unit of QALY was better for the GKRS treatment (US$10,381/QALY) than in the WBRT treatment (US$17,622/QALY), p < 0.05. The cost-effectiveness per KPS score was also higher for the GKRS treatment (US$139/KPS score) than for WBRT (US$229/KPS score), p < 0.01. Thus, the mortality rate for multiple metastatic brain tumors treated by GKRS is significantly better with a good initial KPS score and when the tumor number is 2–5. GKRS results in a better post-treatment KPS score, QALY, and higher cost-effectiveness than WBRT for treating multiple metastatic brain tumors.

Incidence of radiation-induced leukoencephalopathy after whole brain radiotherapy in patients with brain metastases

Whole brain radiation therapy (WBRT) remains a recommended treatment for patients with brain metastases in terms of symptom palliation, especially when extracranial systemic disease is present. The aim of the study was to determine the clinical correlation between pre-existing leukoaraiosis and posterior leukoencephalopathy secondary to WBRT. We retrospectively reviewed the results of WBRT treatment in 44 patients with melanoma brain metastases. The neuroimaging abnormalities of the white matter (T2-weighted MRI) were graded over time. From the 37 evaluable patients the mean age was 53 years old, 23 male and 14 female. Vascular risk factors were present in 22 patients (59.5%). The WBRT total dose was 20 Gy/5fr (n=21) and 30 Gy/10fr (n=16). Leukoaraiosis pre-WBRT was observed in 9/37 patients (24.3%) and leukoencephalopathy post-WBRT in 2/37 (5.4%). Univariate analysis of prognostic factors (sex, age and vascular risk factors) for leukoaraiosis was conducted observing statistically significant differences for patients with age>or=65 years old (p=0.003). Nineteen patients survived more than 3 months. Twelve patients (63.2%) suffered from vascular risk factors. Univariate analysis demonstrated previous leukoaraiosis as a prognostic factor for developing further leukoencephalopathy after WBRT (p=0.015). Radiation-induced leukoencephalopathy is greater in patients with pre-existing leukoaraiosis. Because of the potential of long-term survival in a small subset of patients with brain metastases and the risk of radiation-induced dementia, neurotoxicity reduction in patients with leukoaraiosis is an important goal of treatment.

Seizure Recurrence and Risk Factors after Antiepilepsy Drug Withdrawal in Children with Brain Tumors

To study seizure outcome after antiepilepsy drug (AED) withdrawal in brain tumor patients and to analyze risk factors for seizure recurrence. Brain tumor patients with seizures and at least one attempt at AED discontinuation were identified from the hospital database and neurology clinic records. After defining study variables, patient charts were abstracted for clinical and demographic data. Statistical analyses used log-rank tests and multivariable Cox proportional hazards models. Sixty-two patients discontinued AEDs at a median time of 5.6 years from the first seizure (range, 1.2-19.6 years). Median time since AED withdrawal was 2.3 years (range, 0.4-15.1 years). Seizures recurred in 17 (27%) patients within a median time of 0.8 years (range, 0.06-7.7 years). Median seizure-free period before AED withdrawal was 1.3 years (range, 0.1-11 years). More than one tumor resection and whole-brain radiation treatment (WBRT) were associated with seizure recurrence, whereas posterior fossa tumor location was correlated with reduced seizure recurrence risk. At seizure recurrence, control was easily reestablished in 10 patients with AED reinstitution and after dose adjustment in five; two patients with poor drug compliance continue to have seizures. In 48 patients who had an EEG before AED withdrawal, spikes or slow waves did not correlate with seizure recurrence. AED withdrawal can be successfully achieved in majority of carefully selected patients. WBRT and multiple tumor resections seem to be associated with an increased hazard for seizure recurrence.

Down-regulation of caveolin-1 in glioma vasculature: modulation by radiotherapy.

Primary brain tumors, particularly glioblastomas (GB), remain a challenge for oncology. An element of the malignant brain tumors' aggressive behavior is the fact that GB are among the most densely vascularized tumors. To determine some of the molecular regulations occuring at the brain tumor endothelium level during tumoral progression would be an asset in understanding brain tumor biology. Caveolin-1 is an essential structural constituent of caveolae that has been implicated in mitogenic signaling, oncogenesis, and angiogenesis. In this work we investigated regulation of caveolin-1 expression in brain endothelial cells (ECs) under angiogenic conditions. In vitro, brain EC caveolin-1 is down-regulated by angiogenic factors treament and by hypoxia. Coculture of brain ECs with tumoral cells induced a similar down-regulation. In addition, activation of the p42/44 MAP kinase is demonstrated. By using an in vivo brain tumor model, we purified ECs from gliomas as well as from normal brain to investigate possible regulation of caveolin-1 expression in tumoral brain vasculature. We show that caveolin-1 expression is strikingly down-regulated in glioma ECs, whereas an increase of phosphorylated caveolin-1 is observed. Whole-brain radiation treatment, a classical way in which GB is currently being treated, resulted in increased caveolin-1 expression in tumor isolated ECs. The level of tumor cells spreading around newly formed blood vessels was also elevated. The regulation of caveolin-1 expression in tumoral ECs may reflect the tumoral vasculature state and correlates with angiogenesis kinetics.

A phase II evaluation of pentoxifylline combined with radiation in the treatment of brain metastases.

Pentoxifylline (PTX) has pharmacological properties that suggest potential utility as a radiation sensitizer, and preclinical animal studies have been promising. In a non-randomized phase II trial, we used PTX plus standard-dose external-beam whole-brain radiation treatment (WBRT) in patients with brain metastases. Seventeen patients were entered; 14 received both WBRT and PTX and were considered evaluable. Nine of the 14 completed treatment. Analyzing data on all 14 evaluable patients according to intent to treat, median survival time was 33 days, comparable to published data from historical controls. PTX toxicity was not a common cause of patient dropout, supporting higher PTX doses in future trials.