Brain Tumor Research: 2002-2006
     
Cancer. 2006 Nov 1;107(9):2291-7.
Phase II study of oxaliplatin in children with recurrent or refractory medulloblastoma, supratentorial primitive neuroectodermal tumors, and atypical teratoid rhabdoid tumors: a pediatric brain tumor consortium study.
Fouladi M, Blaney SM, Poussaint TY, Freeman BB 3rd, McLendon R, Fuller C, Adesina AM, Hancock ML, Danks MK, Stewart C, Boyett JM, Gajjar A.
St. Jude Children's Research Hospital, Memphis, Tennessee.

BACKGROUND.: An open-label Phase II study of oxaliplatin was conducted to evaluate its safety and efficacy in children with recurrent or refractory medulloblastoma (MB), supratentorial primitive neuroectodermal tumors (SPNET), and atypical teratoid rhabdoid tumor (ATRT). METHODS.: Patients were stratified as follows: stratum IA, first recurrence MB with measurable disease; IB, recurrent MB with only cerebral spinal fluid (CSF) positivity or linear leptomeningeal disease (LLD); IC, MB >/=second recurrence; stratum II, recurrent SPNET; stratum III, recurrent ATRT. Patients received oxaliplatin, 130 mg/m(2) intravenously over 2 hours every 3 weeks. The primary objective was to estimate the sustained response rate in stratum 1A. Plasma ultrafiltrate platinum pharmacokinetics were evaluated. RESULTS.: A total of 43 patients with a median age of 8.5 years (range, 0.6-18.9 years) were enrolled. In stratum 1A, 2 of 15 had partial responses (PRs, 1 sustained PR). No responses were observed in other strata. The most frequent Grade 3 and 4 toxicities included thrombocytopenia (25.6%), neutropenia (16.3%), leukopenia (12%), increase in serum alanine transaminase (ALT) (7%), vomiting (4.7%), and sensory neuropathy (4.7%). No severe ototoxicity or nephrotoxicity was reported. Plasma ultrafiltrate platinum pharmacokinetic parameters were similar to adults, with a median clearance of 12.2 L/hr (range, 4.4-30 L/hr) and median area under the curve (AUC(0-infinity)) of 9.4 mug/mL/hr (range, 6.2-13.9 mug/mL/hr). CONCLUSIONS.: Oxaliplatin was well tolerated in children but has limited activity in children with recurrent CNS embryonal tumors previously treated with platinum compounds. Cancer 2006. (c) 2006 American Cancer Society.

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Anticancer Drugs. 2006 Oct;17(9):1003-16.
New approaches to primary brain tumor treatment.
Sathornsumetee S, Rich JN.
Departments of aMedicine bSurgery cNeurobiology, The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, North Carolina, USA.

Primary brain tumors represent over 100 different tumor types with widely divergent biologies and clinical outcomes, but these neoplasms frequently pose similar challenges to neuro-oncologists. Malignant gliomas are the most common type of primary intrinsic brain tumor in adults and remain extremely lethal. Current standard-of-care therapies for these cancers include surgery, radiation and palliative cytotoxics, which have significant side-effects and limited efficacy. Advances in our understanding of the molecular underpinnings of cancer have led to targeted molecular therapies that may permit improvement in therapeutic efficacy and reduced toxicity; these therapies, however, still face many challenges. Signal transduction pathways that are inappropriately regulated in brain cancers include growth factors and their receptors (e.g. epidermal growth factor receptor, vascular endothelial growth factor receptor and platelet-derived growth factor receptor), which regulate cellular interactions with the microenvironment and intracellular oncogenic pathways. Low-molecular-weight inhibitors have been developed to target many kinases and may have advantages in terms of delivery. Monoclonal antibodies may have greater specificity, but face delivery restrictions. Preferential tumor delivery of chemotherapies, conjugated toxins and radioisotopes has been achieved through convection-enhanced delivery, intratumoral implants and intra-arterial infusion. Despite these advances, few molecularly targeted therapies have demonstrated significant antineoplastic activity for a broad range of patients, possibly due to tumor and patient heterogeneity. Improved functional neuropathology and imaging may permit identification of patient subgroups for which clinical responses may be enriched. It is probable, however, that targeted therapies will be most effective in combination either with one another or with cytotoxic therapies. In this study, we review the current state of new therapies for malignant gliomas.

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Expert Rev Neurother. 2006 Oct;6(10):1481-94.
Immunotherapy for patients with malignant glioma: from theoretical principles to clinical applications.
Yang MY, Zetler PM, Prins RM, Khan-Farooqi H, Liau LM.
Division of Neurosurgery, David Geffen School of Medicine at UCLA, University of California, Los Angeles, CA 90095-6901, USA. yangmy04@yahoo.com.tw

Malignant gliomas are the most common type of primary brain tumor and are in great need of novel therapeutic approaches. Advances in treatment have been very modest, significant improvement in survival has been lacking for many decades and prognosis remains dismal. Despite 'gross total' surgical resections and currently available radio-chemotherapy, malignant gliomas inevitably recur due to reservoirs of notoriously invasive tumor cells that infiltrate adjacent and nonadjacent areas of normal brain parenchyma. In principle, the immune system is uniquely qualified to recognize and target these infiltrative pockets of tumor cells, which have generally eluded conventional treatment approaches. In the span of the last 10 years, our understanding of the cancer-immune system relationship has increased exponentially, and yet, we are only beginning to tease apart the intricacies of the CNS and immune cell interactions. This article reviews the complex associations of the immune system with brain tumors. We provide an overview of currently available treatment options for malignant gliomas, existing gaps in our knowledge of brain tumor immunology, and molecular techniques and targets that might be exploited for improved patient stratification and design of 'custom immunotherapeutics'. We will also examine major new immunotherapy approaches that are being actively investigated to treat patients with malignant glioma, and identify some current and future research priorities in this area.

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Radiother Oncol. 2006 Oct;81(1):33-38. Epub 2006 Sep 14.
Outcome of secondary high-grade glioma in children previously treated for a malignant condition: A study of the Canadian Pediatric Brain Tumour Consortium.
Carret AS, Tabori U, Crooks B, Hukin J, Odame I, Johnston DL, Keene DL, Freeman C, Bouffet E; On behalf of the Canadian Pediatric Brain Tumour Consortium (CPBTC).
Pediatric Hematology/Oncology, The Montreal Children's Hospital/McGill University Health Center, Que., Canada.

BACKGROUND AND PURPOSE: Reports of secondary high-grade glioma (HGG) in survivors of childhood cancer are scarce. The aim of this study was to review the pattern of diagnosis, the treatment, and outcome of secondary pediatric HGG. PATIENTS AND METHODS: We performed a multi-center retrospective study among the 17 paediatric institutions participating in the Canadian Pediatric Brain Tumour Consortium (CPBTC). RESULTS: We report on 18 patients (14 males, 4 females) treated in childhood for a primary cancer, who subsequently developed a HGG as a second malignancy. All patients had previously received radiation therapy +/- chemotherapy for either acute lymphoblastic leukaemia (n=9) or solid tumour (n=9). All HGG occurred within the previous radiation fields. At the last follow-up, 17 patients have died and the median survival time is 9.75 months. CONCLUSION: Although aggressive treatment seems to provide sustained remissions in some patients, the optimal management is still to be defined. Further documentation of such cases is necessary in order to better understand the pathogenesis, the natural history and the prevention of these tumours.

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J Neurooncol. 2006 Sep 22; [Epub ahead of print]
A North American brain tumor consortium (NABTC 99-04) phase II trial of temozolomide plus thalidomide for recurrent glioblastoma multiforme.
Groves MD, Puduvalli VK, Chang SM, Conrad CA, Gilbert MR, Tremont-Lukats IW, Liu TJ, Peterson P, Schiff D, Cloughesy TF, Wen PY, Greenberg H, Abrey LE, Deangelis LM, Hess KR, Lamborn KR, Prados MD, Yung WK.
Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, 1400 Holcombe, 431, Houston, TX, 77030, USA, mgroves@mdanderson.org.

BACKGROUND: Laboratory and clinical data suggest that the anti-angiogenic agent, thalidomide, if combined with cytotoxic agents, may be effective against recurrent glioblastoma multiforme (GBM). OBJECTIVES: To determine 6-month progression-free survival (6PFS) and toxicity of temozolomide plus thalidomide in adults with recurrent GBM. PATIENTS AND METHODS: Eligible patients had recurrent GBM after surgery, radiotherapy, and/or adjuvant chemotherapy. Temozolomide was given at 150-200 mg/m(2)/day on days 1-5 of each 28-day cycle. Thalidomide was given orally at 400 mg at bedtime (days 1-28) and increased to 1,200 mg as tolerated. Patients were evaluated with magnetic resonance imaging scans every 56 days. The study was designed to detect an increase of the historical 6PFS for GBM from 10 to 30%. RESULTS: Forty-four patients were enrolled, 43 were evaluable for efficacy and safety. The study population included 15 women, 29 men; median age was 53 years (range 32-84); median Karnofsky performance status was 80% (range 60-100%). Thirty-six (82%) patients were chemotherapy-naive. There were 57 reports of toxicity of grade 3 or greater. Non-fatal grade 3-4 granulocytopenia occurred in 15 patients (34%). The objective response rate was 7%. The estimated probability of being progression-free at 6 months with this therapy is 24% [95% confidence interval (C.I.) 12-38%]. The median time to progression is 15 weeks (95% C.I. 10-20 weeks). There was no observed correlation between serum levels of vascular endothelial growth factor, basic fibroblast growth factor, and IL-8 and the 6PFS outcome. CONCLUSION: This drug combination was reasonably safe, but with little indication of improvement compared to temozolomide alone.

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J Clin Oncol. 2006 Sep 20;24(27):4412-7.
Phase II trial of lomustine plus temozolomide chemotherapy in addition to radiotherapy in newly diagnosed glioblastoma: UKT-03.
Herrlinger U, Rieger J, Koch D, Loeser S, Blaschke B, Kortmann RD, Steinbach JP, Hundsberger T, Wick W, Meyermann R, Tan TC, Sommer C, Bamberg M, Reifenberger G, Weller M.
Department of General Neurology, Hertie Institute for Clinical Brain Research, University of Tubingen, Tubingen, Germany. Ulrich.Herrlinger@ukb.uni-bonn.de

PURPOSE: To evaluate toxicity and efficacy of the combination of lomustine, temozolomide (TMZ) and involved-field radiotherapy in patients with newly diagnosed glioblastoma (GBM). PATIENTS AND METHODS: Thirty-one adult patients (median Karnofsky performance score 90; median age, 51 years) accrued in two centers received involved-field radiotherapy (60 Gy in 2-Gy fractions) and chemotherapy with lomustine 100 mg/m2 (day 1) and TMZ 100 mg/m2/d (days 2 to 6) with individual dose adjustments according to hematologic toxicity. RESULTS: A median of five courses (range, one to six courses) were delivered. WHO grade 4 hematotoxicity was observed in five patients (16%) and one of these patients died as a result of septicemia. Nonhematologic toxicity included one patient with WHO grade 4 drug-induced hepatitis (leading to discontinuation of lomustine and TMZ) and one patient with WHO grade 2 lung fibrosis (leading to discontinuation of lomustine). The progression-free survival (PFS) rate at 6 months was 61.3%. The median PFS was 9 months (95% CI, 5.3 to 11.7 months), the median overall survival time (MST) was 22.6 months (95% CI, 12.5 to not assessable), the 2-year survival rate was 44.7%. O6-methylguanine-DNA methyltransferase (MGMT) gene-promoter methylation in the tumor tissue was associated with longer PFS (P = .014, log-rank test) and MST (P = .037). CONCLUSION: The combination of lomustine, TMZ, and radiotherapy had acceptable toxicity and yielded promising survival data in patients with newly diagnosed GBM. MGMT gene-promoter methylation was a strong predictor of survival.

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Tumori. 2006 Jul-Aug;92(4):299-305.
Temozolomide and radiotherapy as first-line treatment of high-grade gliomas.
Corsa P, Parisi S, Raguso A, Troiano M, Perrone A, Cossa S, Munafo T, Piombino M, Spagnoletti G, Borgia F.
Department of Radiation Therapy of IRCCS, Casa Sollievo della Sofferenza, San Giovanni Rotondo, FG, Italy. pierocorsa@virgilio.it

AIMS AND BACKGROUND: Temozolomide, a novel alkylating agent, has shown promising results in the treatment of patients with high-grade gliomas, when used as single agent as well as in combination with radiation therapy. MATERIALS AND METHODS: In this report we retrospectively reviewed the clinical outcome of 128 consecutive patients with a diagnosis of high-grade gliomas referred to our Institutions from April 1994 to November 2001. The first 64 patients were treated with radiotherapy alone and the other 64 with a combination of radiotherapy and temozolomide (31 with radiotherapy and adjuvant temozolomide and 33 with radiotherapy and concomitant temozolomide followed by adjuvant temozolomide). RESULTS: Grade 3 hematological toxicity was scored in 9% of 64 patients treated with radiotherapy and temozolomide. No grade 4 hematological toxicity was reported, and the other acute side effects observed were mild or easily controlled with medications. Age, histology and administration of temozolomide were statistically significant prognostic factors associated with better 2-year overall survival. In contrast, we did not observe a significant difference in overall survival between adjuvant and concomitant/adjuvant temozolomide administration. CONCLUSIONS: We report the favorable results of a schedule combining radiotherapy and temozolomide in the treatment of patients with high-grade gliomas. The literature data and above all the findings of the phase III EORTC-NCIC 26981 trial suggest that actually the schedule can be used routinely in clinical practice. Further clinical studies, using temozolomide in combination with other agents, are required.

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J Clin Oncol. 2006 Aug 1;24(22):3651-6.
Phase II trial of tipifarnib in patients with recurrent malignant glioma either receiving or not receiving enzyme-inducing antiepileptic drugs: a North American Brain Tumor Consortium Study.
Cloughesy TF, Wen PY, Robins HI, Chang SM, Groves MD, Fink KL, Junck L, Schiff D, Abrey L, Gilbert MR, Lieberman F, Kuhn J, DeAngelis LM, Mehta M, Raizer JJ, Yung WK, Aldape K, Wright J, Lamborn KR, Prados MD.
UCLA Neuro-Oncology Program, David Geffen School of Medicine at UCLA, University of California, Los Angeles, Los Angeles, CA 90095, USA. tcloughe@ucla.edu

PURPOSE: A phase II study was undertaken in patients with recurrent malignant glioma to determine the efficacy and safety of tipifarnib, a farnesyltransferase inhibitor, dosed at the respective maximum-tolerated dose (MTD) for patients receiving and not receiving enzyme-inducing antiepileptic drugs (EIAEDs). Because tipifarnib undergoes extensive hepatic metabolism, MTD is doubled in patients on EIAEDs. The population included 67 patients with glioblastoma multiforme (GBM) and an exploratory group of 22 patients with anaplastic glioma (AG). PATIENTS AND METHODS: Patients received tipifarnib (300 and 600 mg bid for 21 days every 4 weeks in non-EIAED and EIAED patients, respectively). All patients were assessable for efficacy and safety. RESULTS: Two AG patients (9.1%) and eight GBM patients (11.9%) had progression-free survival (PFS) more than 6 months. Among the latter eight GBM patients, six of 36 patients (16.7%; 95% CI, 7% to 32%) were not receiving EIAEDs and two of 31 patients (6.5%; 95% CI, 1% to 20%) were receiving EIAEDs. Four patients had partial responses in group A GBM and one patient had a partial response group B GBM. An exploratory comparison of PFS between GBM groups A and B was statistically significant (P = .01). Patients not receiving EIAEDs had a higher incidence and increased severity of hematologic events. However, the incidence and severity of rash (the previously determined dose-limiting toxicity in patients receiving EIAEDs) seemed similar in EIAED and non-EIAED subgroups. CONCLUSION: Tipifarnib (300 mg bid for 21 days every 4 weeks) shows modest evidence of activity in patients with recurrent GBM who are not receiving EIAEDs and is generally well tolerated in this population.

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Cochrane Database Syst Rev. 2006 Jul 19;3:CD003869.
Whole brain radiotherapy for the treatment of multiple brain metastases.
Tsao M, Lloyd N, Wong R, Chow E, Rakovitch E, Laperriere N.

BACKGROUND: Brain radiotherapy is used to treat cancer patients who have brain metastases resulting from various primary malignancies. OBJECTIVES: To assess the effectiveness and adverse effects of whole brain radiotherapy (WBRT) in adult patients with multiple metastases to the brain. SEARCH STRATEGY: CENTRAL (The Cochrane Library), MEDLINE, EMBASE, CANCERLIT, and CINAHL were searched. SELECTION CRITERIA: Randomized controlled trials (RCTs) in which adult patients with multiple metastases to the brain from any primary cancer and treated with WBRT were included. Trials of prophylactic WBRT were excluded as well as trials that dealt with surgery or WBRT, or both, for the treatment of a single brain metastasis. DATA COLLECTION AND ANALYSIS: Two review authors independently abstracted information for each predetermined outcome: overall survival at six months, intracranial progression-free duration, local brain response, local brain control, quality of life, symptom control, neurological function, and the proportion of patients able to reduce the daily dexamethasone dose. Adverse effects were also collected. MAIN RESULTS: Eight published reports (nine trials) showed no benefit of altered dose-fractionation schedules as compared to control fractionation (3000 cGy in 10 fractions) of WBRT on the probability of survival at six months. These studies also showed no difference in symptom control nor neurologic improvement among the different dose-fractionation schemes. The addition of radiosensitizers, in five RCTs, did not confer additional benefit to WBRT in either overall median survival times or brain tumor response rates. The addition of the radiosensitizer motexafin gadolinium did not improve quality of life nor time to neurologic progression overall. For the radiosensitizer misonidazole, there was no improvement in Karnofsky performance score outcomes. Three RCTs found no benefit in overall survival with the use of WBRT and a radiosurgery boost as compared to WBRT alone for selected patients with multiple brain metastases (up to four brain metastases). Overall, however, there was a statistically significant improvement in local brain control favoring the whole brain radiotherapy and radiosurgery boost arm. Only one trial of radiosurgery boost with WBRT reported an improved Karnofsky performance score outcome and improved ability to reduce dexamethasone dose. One RCT examined the use of WBRT and prednisone versus prednisone alone and produced inconclusive results. AUTHORS' CONCLUSIONS: None of the RCTs with altered dose-fractionation schemes as compared to standard delivery (3000 cGy in ten fractions) found a benefit in terms of overall survival, neurologic function, or symptom control. The use of radiosensitizers or chemotherapy in conjunction with WBRT remains experimental. A radiosurgery boost with WBRT may improve local disease control in selected patients, although survival remains unchanged. The benefit of WBRT as compared to supportive care alone has not been studied in RCTs. It may be that supportive care alone, without WBRT, may be appropriate for some patients, particularly those with advanced disease and poor performance status.

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Nippon Rinsho. 2006 Jul;64(7):1327-32.
[Glioma]
[Article in Japanese]
Wakabayashi T, Natsume A, Yoshida J.
Center for Genetic and Regenerative Medicine, Nagoya University Hospital.

This chapter outlines the current clinical application of interferon for treatment of brain tumor, especially glioma. Since approved as a therapeutic drug for brain tumor originally produced in Japan, interferon-beta has been reported to be effective when it was used alone, in combination with chemo-radiotherapy (ACNU/MCNU as a nitrosourea derivative chemodrug, and radiation for 60 Gy totally). Recently, the regimen of combination with interferon-beta have been improved to obtain a higher efficacy rate. For example, as a fundamental study, temozolomide is an enthusiastic chemodrug to enhance the anti-tumor effect of interferon-beta when it is combined, pre-clinical and clinical trial will be scheduled. As for interferon-beta gene therapy by means of liposome as ad drug delivery system, already clinical trial has been performed and clinical safety and effectiveness have been proved, and it is expected that newly development in the field of gene therapy will be established and improvement of therapeutic results for malignant brain tumor will be achieved.

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Expert Rev Anticancer Ther. 2006 Jul;6(7):1087-104.
New treatment strategies for malignant gliomas.
Sathornsumetee S, Rich JN.
The Preston Robert Tisch Brain Tumor Center Division of Neurosurgery/Neuro-Oncology, Duke University Medical Center, DUMC 3624, Durham, NC 27710, USA. satho001@mc.duke.edu

Malignant gliomas are the most prevalent type of primary brain tumor in adults. Despite progress in brain tumor therapy, the prognosis of malignant glioma patients remains dismal. The median survival of patients with glioblastoma multiforme, the most common grade of malignant glioma, is 10-12 months. Conventional therapy of surgery, radiation and chemotherapy is largely palliative. Essentially, tumor recurrence is inevitable. Salvage treatments upon recurrence are palliative at best and rarely provide significant survival benefit. Therapies targeting the underlying molecular pathogenesis of brain tumors are urgently required. Common genetic abnormalities in malignant glioma specimens are associated with aberrant activation or suppression of cellular signal transduction pathways and resistance to radiation and chemotherapy. Several low molecular weight signal transduction inhibitors have been examined in preclinical and clinical malignant glioma trials. The efficacy of these agents as monotherapies has been modest, at best; however, small subsets of patients who harbor specific genetic changes in their tumors may display favorable clinical responses to defined small molecule inhibitors. Multitargeted kinase inhibitors or combinations of agents targeting different mitogenic pathways may overcome the resistance of tumors to single-agent targeted therapies. Well designed studies of small molecule kinase inhibitors will include assessment of safety, drug delivery, target inhibition and correlative biomarkers to define mechanisms of response or resistance to these agents. Predictive biomarkers will enrich for patients most likely to respond in future clinical trials. Additional clinical studies will combine novel targeted therapies with radiation, chemotherapies and immunotherapies.

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Expert Rev Anticancer Ther. 2006 Jul;6(7):1053-64.
Gene therapeutics: the future of brain tumor therapy?
Cutter JL, Kurozumi K, Chiocca EA, Kaur B.
Dardinger Laboratory for Neuro-Oncology and Neurosciences, Department of Neurological Surgery and Comprehensive Cancer Center, The Ohio State University Medical Center, 410 West 12th Avenue, Columbus, OH 43210, USA. jennifer.cutter@osumc.edu

Primary glioblastoma multiforme is an aggressive brain tumor that has no cure. Current treatments include gross resection of the tumor, radiation and chemotherapy. Despite valiant efforts, prognosis remains dismal. A promising new technique involves the use of oncolytic viruses that can specifically replicate and lyse in cancers, without spreading to normal tissues. Currently, these are being tested in relevant preclinical models and clinical trials as a therapeutic modality for many types of cancer. Results from recent clinical trials with oncolytic viruses have revealed the safety of this approach, although evidence for efficacy remains elusive. Oncolytic viral strategies are summarized in this review, with a focus on therapies used in brain tumors.

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J Neurooncol. 2006 Jun 29; [Epub ahead of print]
Medical management of patients with brain tumors.
Wen PY, Schiff D, Kesari S, Drappatz J, Gigas DC, Doherty L.
Division of Neuro-Oncology, Department of Neurology, Brigham and Women's Hospital and Center for Neuro-Oncology, Dana-Farber Brigham and Women's Cancer Center, SW430D, 44 Binney Street, Boston, MA, 02115, USA, pwen@partners.org.

The most common medical problems in brain tumor patients include the management of seizures, peritumoral edema, medication side effects, venous thromboembolism (VTE), fatigue and cognitive dysfunction. Despite their importance, there are relatively few studies specifically addressing these issues. There is increasing evidence that brain tumor patients who have not had a seizure do not benefit from prophylactic antiepileptic medications. Patients on corticosteroids are at greater risk of Pneumocystis jerovecii pneumonia and may benefit from prophylactic therapy. There is also growing evidence suggesting that anticoagulation may be more effective than inferior vena cava IVC) filtration devices for treating VTE in brain tumor patients and the risk of hemorrhage with anticoagulation is relatively small. Low-molecular weight heparin may be more effective than coumadin. Medications such as modafinil and methylphenidate have assumed an increasing role in the treatment of fatigue, while donepezil and memantine may be helpful with memory loss.

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J Neurosurg. 2006 Jun;104(6 Suppl):377-82.
Seizures in children with low-grade tumors: outcome after tumor resection and risk factors for uncontrolled seizures.
Khan RB, Boop FA, Onar A, Sanford RA.
Departments of Radiological Sciences, Biostatistics, and Neuro-surgical Service, St. Jude Children's Research Hospital, Memphis, Tennessee 38105-2794, USA. raja.khan@stjude.org

OBJECT: The goals of this study were to define the incidence of seizures in children with low-grade tumors, study seizure outcome after lesionectomy in these children, and identify risk factors for poor seizure outcome. METHODS: The authors performed a retrospective chart review of children who harbored low-grade brain tumors, experienced seizures, and were treated in a single institution. Statistical analyses included step-wise as well as single-variable binary logistic regression analyses. Fifty-five children (20%) with seizures were identified in a cohort of 280 children with low-grade tumors. Of these 55 children, 35 harbored cortical cerebral tumors and 20 had noncortical lesions, including six whose tumors were in the posterior fossa. Seizures were defined as controlled if there was no seizure in the 12 months preceding the last clinic visit. All cortical tumors were treated by lesionectomy as an initial procedure. Of the 27 children with cortical tumors whose seizures began before tumor diagnosis, 23 had complete resection and 52% of these 23 experienced no further seizures after surgery. Seizures are presently controlled in 84% of the total 55 patients at a median follow-up time of 4.5 years after the first seizure (range 1-17.4 years). Only two variables, a pericavity hyperintense signal on T2-weighted magnetic resonance (MR) images and at least 10 seizures prior to therapy for seizures, were associated with uncontrolled seizures. CONCLUSIONS: Lesionectomy may be appropriate in children with low-grade brain tumors. A large number of seizures before therapy and a hyperintense area around the tumor cavity on postresection MR images are associated with uncontrolled seizures. Medical therapy and tumor resection will control seizures in the majority of children with low-grade tumors.

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Anticancer Res. 2006 May-Jun;26(3B):2429-35.
High-grade gliomas: results in patients treated with adjuvant radiotherapy alone and with adjuvant radio-chemotherapy.
Valeriani M, Ferretti A, Franzese P, Tombolini V.
Operative Unit of Radiation Oncology, S. Salvatore Hospital, L'Aquila, Italy. mauval1@libero.it

BACKGROUND: Despite advances in the surgical, radiotherapeutic and chemotherapeutic fields, the outcome for patients with high-grade gliomas remains poor. Our experience of patients treated with and without chemotherapy is reported. MATERIALS AND METHODS: From April 1999 to July 2003, 30 patients with high-grade gliomas were treated: 13 received adjuvant radiotherapy (RT) alone whereas 17 received temozolomide 75 mg/m2/d during the irradiation time and 200 mg/m2 daily per 5 consecutive days, every 28 days for three to six cycles, starting 4 weeks after the end of radiotherapy. RESULTS: The median follow-up was 12.5 months. The median overall survival (OS) was 15 months. In patients treated with RT plus chemotherapy, no statistical difference was observed between those who had undergone partial surgical resection and those with total resection (p=0.5128). In patients with glioblastoma multiforme (GBM) treated with combined radiochemotherapy, the median OS was 18 months, while it was 7 months (p=0.0204) in those treated without chemotherapy. Multivariate analysis (Cox model) evidenced statistical differences for performance status (p =0.002) and for the type of adjuvant therapy (p=0.006). CONCLUSION: Radio-chemotherapy plus adjuvant temozolomide seemed to offer the best results in patients not submitted to debulking surgery. The performance status remained the most important prognostic factor. Tolerance to the combined regimen was very good.

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NeuroRx. 2006 Apr;3(2):276-91.
Advances in treatment of pediatric brain tumors.
Robertson PL.

The long-term survival of children with brain tumor has improved considerably in the last three decades, owing to advances in neuroimaging, neurosurgical, and radiation therapy modalities, coupled with the application of conventional chemotherapy. MRI, MR spectroscopy and diffusion-weighted MRI have contributed to more accurate diagnosis, prognostication and better treatment planning. Neurosurgical treatment has been advanced by the use of functional MRI, and intraoperative image-guided stereotactic techniques and electrophysiologic monitoring. The use of 3-D conformal and intensity-modulated radiation therapy, stereotactic radiosurgery, and radiosensitizing agents has made radiation therapy safer and more effective. Conventional chemotherapy, administered either alone or combined with radiation therapy has improved survival and quality of life of children with brain tumors. These improved outcomes have also occurred, due, in part, to their treatment on collaborative national and international studies. Recent promising diagnostic and therapeutic strategies have resulted from advances in understanding molecular brain tumor biology. Important new approaches include the refinement of drug-delivery strategies, the evaluation of biologic markers to stratify patients for optimal treatment and to exploit these molecular differences using "targeted" therapeutic strategies. These approaches include blocking tumor cell drug resistance mechanisms, immunotherapy, inhibition of molecular signal transduction pathways important in tumorigenesis, anti-angiogenic therapy, and gene therapy. The thrust of such approaches for children with brain tumors is especially directed at reducing the toxicity of therapy and improving quality-of-life, as well as increasing disease-free survival.

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J Clin Oncol. 2006 Mar 20;24(9):1415-20.
Phase II study of donepezil in irradiated brain tumor patients: effect on cognitive function, mood, and quality of life.
Shaw EG, Rosdhal R, D'Agostino RB Jr, Lovato J, Naughton MJ, Robbins ME, Rapp SR.
Department of Radiation Oncology, Wake Forest University School of Medicine, Brain Tumor Center of Excellence of WFU, Winston-Salem, NC 27157-1030, USA. eshaw@wfubmc.edu

PURPOSE: A prospective, open-label phase II study was conducted to determine whether donepezil, a US Food and Drug Administration-approved reversible acetylcholinesterase inhibitor used to treat mild to moderate Alzheimer's type dementia, improved cognitive functioning, mood, and quality of life (QOL) in irradiated brain tumor patients. PATIENTS AND METHODS: Thirty-four patients received donepezil 5 mg/d for 6 weeks, then 10 mg/d for 18 weeks, followed by a washout period of 6 weeks off drug. Outcomes were assessed at baseline, 12, 24 (end of treatment), and 30 weeks (end of wash-out). All tests were administered by a trained research nurse. RESULTS: Of 35 patients who initiated the study, 24 patients (mean age, 45 years) remained on study for 24 weeks and completed all outcome assessments. All 24 patients had a primary brain tumor, mostly low-grade glioma. Scores significantly improved between baseline (pretreatment) and week 24 on measures of attention/concentration, verbal memory, and figural memory and a trend for verbal fluency (all P < .05). Confused mood also improved from baseline to 24 weeks (P = .004), with a trend for fatigue and anger (all P < .05). Health-related QOL improved significantly from baseline to 24 weeks, particularly, for brain specific concerns with a trend for improvement in emotional and social functioning (all P < .05). CONCLUSION: Cognitive functioning, mood, and health-related QOL were significantly improved following a 24-week course of the acetylcholinesterase inhibitor donepezil. Toxicities were minimal. We are planning a double blinded, placebo-controlled, phase III trial of donepezil to confirm these favorable results.

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J Neurooncol. 2006 Mar 16; [Epub ahead of print]
Retrospective analysis of the efficacy and tolerability of levetiracetam in brain tumor patients.
Newton HB, Goldlust SA, Pearl D.
Dardinger Neuro-Oncology Center and Division of Neuro-Oncology, Department of Neurology, Ohio State University Medical Center, Columbus, Ohio, USA.

Seizures are a common complication of primary (PBT) and metastatic (MBT) brain tumors, affecting approximately 50% of all patients during the course of their illness. Anti-convulsant therapy of these tumor-induced seizures is often inadequate with conventional anti-epileptic drugs (AEDs), due to a variety of factors, including activation of glutaminergic NMDA receptors, immune-mediated neuronal damage, and anatomic alterations of neuronal input pathways. Levetiracetam (LEV) is a new AED with a novel mechanism of action, which includes reducing the Ca(++) current through neuron-specific, high voltage activated Ca(++) channels (n-type). Because of this unique mechanism, it has been postulated that LEV may be effective in controlling tumor-induced seizures. A retrospective chart review was performed of all patients who had received LEV for seizure control. Forty-one patients were reviewed (22 female, 19 male), with a median age of 47.5 years (range 25-81). There were 34 patients with PBT and 7 with MBT. LEV was used as an add-on AED in 33 patients and as monotherapy in eight patients, with a median dose of 1500 mg/day (range 500-3500). The baseline median seizure frequency for the cohort was 1 per week. After the addition of LEV and follow-up for a minimum of 4 weeks, the median seizure frequency was reduced to 0 per week (59% of patients noted complete seizure control). Overall, the seizure frequency was reduced in 90% of patients (P<0.0001; Sign test). The most common toxicity was somnolence, noted in 37% of patients. LEV was very effective and well tolerated in brain tumor patients with seizures, and should be considered for add-on therapy to current AEDs, or as a substitute anti-convulsant for monotherapy.

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Neuro-oncol. 2006 Mar 13; [Epub ahead of print]
A phase 2 trial of irinotecan (CPT-11) in patients with recurrent malignant glioma: A North American Brain Tumor Consortium study.
Prados M, Lamborn K, Yung WK, Jaeckle K, Robins HI, Mehta M, Fine HA, Wen PY, Cloughesy T, Chang S, Nicholas MK, Schiff D, Greenberg H, Junck L, Fink K, Hess K, Kuhn J.
University of California.

The purpose of this study was to determine the response of CPT-11 administered every three weeks to adults with progressive malignant glioma, treated with or without enzyme-inducing antiepileptic drug (EIAED) therapy, at the recommended phase 2 dose determined from a previous phase 1 study. Adult patients age 18 or older with a KPS of 60 or higher who had measurable recurrent grade III anaplastic glioma (AG) or grade IV glioblastoma multiforme (GBM) were eligible. No more than one prior chemotherapy was allowed, either as adjuvant therapy or for recurrent disease. The CPT-11 dose was 350 mg/m(2) i.v. every three weeks in patients not on EIAED and 750 mg/m(2) in patients on EIAED therapy. Patients with stable or responding disease could be treated until tumor progression or a total of 12 months of therapy. The primary end point of the study was to determine whether CPT-11 could significantly delay tumor progression, using the rate of six-month progression-free survival (PFS-6). The trial was sized to be able to discriminate between a 15% and 35% rate for the GBM group alone and between a 20% and 40% rate for the entire cohort. There were 51 eligible patients, including 38 GBM and 13 AG patients, enrolled. The median age was 52 and 42 years, respectively. PFS-6 for the entire cohort was 17.6%. PFS-6 was 15.7% (95% confidence interval [CI], 0.07-0.31) for the GBM patients and 23% (95% CI, 0.07-0.52) for AG patients. Toxicity for the group included diarrhea and myelosuppression. We conclude that the recommended phase 2 dose of CPT-11 for patients with or without EIAED was ineffective on this schedule, in this patient population.

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Clin Cancer Res. 2006 Mar 1;12(5):1540-6.
Phase I trial of intrathecal spartaject busulfan in children with neoplastic meningitis: a Pediatric Brain Tumor Consortium Study (PBTC-004).
Gururangan S, Petros WP, Poussaint TY, Hancock ML, Phillips PC, Friedman HS, Bomgaars L, Blaney SM, Kun LE, Boyett JM.
The Preston Robert Tisch Brain Tumor Center at Duke, Duke University Medical Center, Durham, North Carolina 27710, USA. gurur002@mc.duke.edu

PURPOSE: A phase I trial of intrathecal Spartaject Busulfan (SuperGen, Inc., San Ramon, CA) was conducted in children with neoplastic meningitis following recurrent primary brain tumors to describe toxicities, estimate the maximum tolerated dose (MTD), and document evidence of responses to this agent. EXPERIMENTAL DESIGN: The continuous reassessment method was used to assign cohorts of patients to doses of intrathecal Spartaject Busulfan via an Ommaya reservoir and/or lumbar puncture twice weekly for 2 weeks followed by an assessment of toxicity and response. Patients with stable disease or an objective response continued to receive intrathecal Spartaject Busulfan plus systemic chemotherapy at regular intervals. Cerebrospinal fluid and blood were obtained for pharmacokinetic studies in patients with Ommaya reservoirs after the first dose of intrathecal Spartaject Busulfan. Seven evaluable patients were assigned to the starting dose of 5 mg, two patients to 7.5 mg, three patients to 10 mg, seven patients to 13 mg, and four patients to 17 mg. RESULTS: Between September 2000 and May 2003, 28 patients were enrolled in this study. Twenty-three patients (median age, 8.8 years; range, 2.5-19.5 years) were evaluable for estimating the MTD, and dose-limiting toxicities were observed in three and included grade 3 vomiting (n = 1 at 5 mg), grade 3 headache (n = 1 at 17 mg), and grade 3 arachnoiditis (n = 1 at 17 mg). Pharmacokinetic data showed that post-infusion concentrations of busulfan ranged from 50 to 150 microg/mL and declined to <1 microg/mL within 5 hours. CONCLUSIONS: Intrathecal Spartaject Busulfan was well tolerated in children with neoplastic meningitis from brain tumors, and the recommended dose for future phase II studies is 13 mg.

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J Clin Oncol. 2006 Mar 10;24(8):1289-94.
Resectable brain metastases.
Vogelbaum MA, Suh JH.
Brain Tumor Institute/ND40, Cleveland Clinic Foundation, Cleveland, OH, USA. vogelbm@neus.ccf.org

Brain metastases are the most common brain tumors seen in clinical practice, comprising well over half of all brain tumors. For many years, surgical resection of brain metastases was considered a form of palliative therapy only, but more recently it has been shown to have a more important role in extending survival in appropriately selected patients. Newer surgical techniques have helped to reduce the morbidity associated with tumor resection. Although randomized studies have demonstrated the need for postoperative whole-brain radiotherapy, there remains interest in the use of other surgical adjuncts to delay or eliminate the need for fractionated radiotherapy. The use of various treatment modalities, particularly image-guided surgery and stereotactic radiosurgery, allows clinicians who are focused on the treatment of brain metastases to achieve superior levels of tumor control within the brain. As a result, overall survival is much more dependent on the status of the patient's systemic disease.

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J Clin Oncol. 2006 Mar 10;24(8):1273-80.
Diagnosis and treatment of recurrent high-grade astrocytoma.
Butowski NA, Sneed PK, Chang SM.
Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA 94143-0350, USA.

High-grade gliomas represent a significant source of cancer-related death, and usually recur despite treatment. In this analysis of current brain tumor medicine, we review diagnosis, standard treatment, and emerging therapies for recurrent astrocytomas. Difficulties in interpreting radiographic evidence, especially with regard to differentiating between tumor and necrosis, present a formidable challenge. The most accurate diagnoses come from tissue confirmation of recurrent tumor, but a combination of imaging techniques, such as magnetic resonance spectroscopy imaging, may also be relevant for diagnosis. Repeat resection can prolong life, but repeat irradiation of the brain poses serious risks and results in necrosis of healthy brain tissue; therefore, reirradiation is usually not offered to patients with recurrent tumors. We describe the use of conventional radiotherapy, intensity-modulated radiotherapy, brachytherapy, radiosurgery, and photodynamic therapy for recurrent high-grade glioma. The use of chemotherapy is limited by drug distribution and toxicity, but the development of new drug-delivery techniques such as convection-enhanced delivery, which delivers therapeutic molecules at an effective concentration directly to the brain, may provide a way to reduce systemic exposure to cytotoxic agents. We also discuss targeted therapies designed to inhibit aberrant cell-signaling pathways, as well as new experimental therapies such as immunotherapy. The treatment of this devastating disease has so far been met with limited success, but emerging knowledge of neuroscience and the development of novel therapeutic agents will likely give patients new options and require the neuro-oncology community to redefine clinical trial design and strategy continually.

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Epilepsy Behav. 2006 Feb 20; [Epub ahead of print]
A step-by-step resection guided by electrocorticography for nonmalignant brain tumors associated with long-term intractable epilepsy.
Mikuni N, Ikeda A, Takahashi JA, Nozaki K, Miyamoto S, Taki W, Hashimoto N.
Department of Neurosurgery, Kyoto University Graduate School of Medicine, Kyoto, Japan.

To delineate a surgical strategy for long-term intractable epilepsy associated with nonmalignant brain tumor, we developed a protocol for 25 patients whereby removal of tumor alone and additional irritative peritumoral tissue between sulci (gyrectomy), as well as further resectioning, was performed based on intraoperative electrocorticogram results. In five patients, no irritative zones were observed that required resectioning following complete removal of tumors. Additional gyrectomy was indicated in 18 patients who demonstrated gliosis or cortical dysplasia in the peritumoral residual irritative zone. Remote irritative zone observed in two patients was correlated with long-term and frequent seizures. During a follow-up period of at least 5 years, seizure outcome was Engel category I in 92%, and all patients have remained tumor-free. Peritumoral gyrectomy as a means of removing likely epileptic tissue following tumor resection appears to be a useful method for treating long-term intractable tumoral epilepsy. Further resectioning of remote tissue should be considered in patients with severely intractable seizures.

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J Endocrinol Invest. 2005 Dec;28(11):978-83.
Efficacy and safety of 48 weeks of treatment with octreotide LAR in newly diagnosed acromegalic patients with macroadenomas: an open-label, multicenter, non-comparative study.
Grottoli S, Celleno R, Gasco V, Pivonello R, Caramella D, Barreca A, Ragazzoni F, Pigliaru F, Alberti D, Ferrara R, Angeletti G.
Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Turin, Turin, Italy.

The aim of the present multicentric, open-label, non-comparative study was to evaluate the role of octreotide long-acting repeatable (LAR) as primary therapy for the treatment of GH-secreting pituitary macroadenomas. The patients received octreotide LAR 20 mg every 4 weeks for 12 weeks; afterwards the dose was confirmed or adjusted at 30 mg every 4 weeks, for the remaining 12 weeks, for responder or non-responder patients, respectively. Responder patients continued the study until 48 weeks. Twenty-one naive active acromegalic patients were enrolled. In all patients, GH profile, IGF-I levels and magnetic resonance imaging (MRI) were evaluated at baseline and during treatment. The ability of octreotide LAR to decrease mean GH < 2.5 microg/I and/or normalize IGF-I levels, adjusted for age and gender, was defined respectively as total or partial success. Total success was achieved in 5/21 (23.8%), 6/20 (30%) and 4/14 (28.6%) patients after 12, 24 and 48 weeks; partial success in 7/21 (33.3%), 9/20 (45%) and 9/14 (64%) patients at 12, 24 and 48 weeks according to GH levels, while according to IGF-I levels in 7/21 (33.3%), 7/20 (35%) and 5/14 (35.7%) patients at 12, 24 and 48 week. Tumor size was notably decreased after treatment with octreotide LAR: in 16 macroadenoma patients completing the study, the tumor sizes were 1609 +/- 1288, 818 +/- 616 (49.1 +/- 23.7%) and 688 +/- 567 mm3 (54.6 +/- 24.4%) at baseline, 24 and 48 weeks. This study shows that octreotide LAR is effective in suppressing GH/IGF-I secretion and inducing tumor shrinkage in GH-secreting macroadenomas in a 48-week treatment. Octreotide LAR could be used as primary therapy in patients harbouring large pituitary tumors, who are less likely to be cured by neurosurgery.

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Bull Cancer. 2006 Jan 1;93(1):73-81.
[Update on cerebral tumors]
[Article in French]
Benouaich-Amiel A, Delattre JY.
Service de neurologie Mazarin, CHU Pitie-Salpetriere, 47-84 bd de l'Hopital, 75013 Paris. alexbenouaich@hotmail.com

This review aims to discuss the main advances in gliomas, primary cerebral lymphomas and cerebral metastasis. The recent development of molecular biology and cerebral imaging allows a better understanding and management of gliomas and phase III studies have concluded to the benefit of adjuvant temozolomide administered during and after radiotherapy for glioblastomas: this strategy is yet to become a standard. Optimal treatment for primary central nervous system lymphoma remains to be defined, and several studies aims to precise the value of radiotherapy as consolidation treatment. Several trials reviewing the current treatment options for brain metastasis (whole brain radiation therapy, surgical resection stereotactic radiosurgery and chemotherapy) are highlighted.

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Neuro-oncol. 2006 Jan;8(1):67-78.
Phase 1 study of erlotinib HCl alone and combined with temozolomide in patients with stable or recurrent malignant glioma.
Prados MD, Lamborn KR, Chang S, Burton E, Butowski N, Malec M, Kapadia A, Rabbitt J, Page MS, Fedoroff A, Xie D, Kelley SK.
Department of Neurosurgery, University of California, San Francisco, CA 94143-0372, USA. pradosm@neurosurg.ucsf.edu

The purpose of this study was to define the maximum tolerated dose of erlotinib and characterize its pharmaco-kinetics and safety profile, alone and with temozolomide, with and without enzyme-inducing antiepileptic drugs (EIAEDs), in patients with malignant gliomas. Patients with stable or progressive malignant primary glioma received erlotinib alone or combined with temozolomide in this dose-escalation study. In each treatment group, patients were stratified by coadministration of EIAEDs. Erlotinib was started at 100 mg orally once daily as a 28-day treatment cycle, with dose escalation by 50 mg/day up to 500 mg/day. Temozolomide was administered at 150 mg/m2 for five consecutive days every 28 days, with dose escalation up to 200 mg/m2 at the second cycle. Eightythree patients were evaluated. Rash, fatigue, and diarrhea were the most common adverse events and were generally mild to moderate. The recommended phase 2 dose of erlotinib is 200 mg/day for patients with glioblastoma multiforme who are not receiving an EIAED, 450 mg/day for those receiving temozolomide plus erlotinib with an EIAED, and at least 500 mg/day for those receiving erlotinib alone with an EIAED. Of the 57 patients evaluable for response, eight had a partial response (PR). Six of the 57 patients had a progression-free survival of longer than six months, including four patients with a PR. Coadministration of EIAEDs reduced exposure to erlotinib as compared with administration of erlotinib alone (33%-71% reduction). There was a modest pharmacokinetic interaction between erlotinib and temozolomide. The favorable tolerability profile and evidence of antitumor activity indicate that further investigation of erlotinib is warranted.

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Curr Treat Options Neurol. 2006 Jan;8(1):21-32.
Headache related to brain tumors.
Loghin M, Levin VA.
Neuro-Oncology Unit 431, UT MD Anderson Cancer Center, PO Box 301402, Houston, TX 77230, USA. vlevin@mdanderson.org.

Headache is one of the most common somatic complaints of patients seeking medical care. Most headaches are not of serious cause and can be diagnosed easily with a good history and physical examination. The challenges to the physician are to determine when underlying intracranial pathology may be causing the symptoms and signs, and to identify the few patients in whom a tumor is the cause of the headache. The subject of headache in patients with brain tumors has been reviewed in neurologic textbooks and in several investigations before, as well as after, modern imaging diagnostic techniques became available. Headache can also manifest as an acute or chronic complication of radiation treatment and/or chemotherapy in patients with intracranial neoplasm, but there are few data in the literature specifically addressing this subject. This article provides an overview of headache in patients with primary and secondary brain tumor, including headache characteristics, the putative mechanism for these headaches, the role of diagnostic testing, and the general principles of management.

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Lancet Oncol. 2005 Dec;6(12):953-60.
High-dose conformal radiotherapy for supratentorial malignant glioma: a historical comparison.
Tanaka M, Ino Y, Nakagawa K, Tago M, Todo T.
Department of Neurosurgery, University of Tokyo, Tokyo, Japan.

BACKGROUND: Although radiotherapy remains the main postoperative treatment for patients with malignant glioma, modifications to regimens have not improved the poor outlook of patients with this disease. We aimed to investigate whether high-dose conformal radiotherapy improves the survival of patients with supratentorial malignant glioma compared with conventional radiotherapy. METHODS: 29 patients with anaplastic astrocytoma and 61 patients with glioblastoma who received high-dose conformal radiotherapy during 1990-2002 were compared with 34 patients with anaplastic astrocytoma and 60 patients with glioblastoma who received conventional 60 Gy radiotherapy during 1979-89. 77 of the 90 patients receiving high-dose radiotherapy were given 80 Gy; the remaining 13 patients, all with glioblastoma, received 90 Gy. Radiotherapy was planned on the basis of images taken before surgery, and doses were delivered in 2 Gy per fraction per day for 5 days a week. Hazard ratios for death were calculated with a Cox model, and were adjusted for age, Karnofsky performance scale, tumour size, and extent of resection. FINDINGS: Patients who received high-dose radiotherapy had significantly longer overall survival compared with those who received conventional radiotherapy (adjusted hazard ratio 0.30 [95% CI 0.12-0.76], p=0.011 for anaplastic astrocytoma and 0.49 [0.28-0.87], p=0.014 for glioblastoma). Patients with anaplastic astrocytoma in the high-dose group have not yet reached median survival; median survival in the conventional radiotherapy group was 22.3 months (95% CI 20.6-24.0). 5-year survival was 51.3% (29.2-73.4) for the high-dose group and 14.7% (0.0-30.0) for the conventional group. Median survival in patients with glioblastoma was 16.2 months (12.8-19.6) for the high-dose group and 12.4 months (10.0-14.8) for the conventional group. 2-year survival was 38.4% (23.5-53.3) for the high-dose group and 11.4% (0.0-25.3) for the conventional group. Survival did not differ between those that received 80 Gy radiotherapy and those that received 90 Gy (hazard ratio 0.94 [95% CI 0.42-2.12]). The higher frequency of radiation-induced white matter abnormality in the high-dose group compared with the conventional radiotherapy group did not lead to increased disability. INTERPRETATION: High-dose, standard-fractionated radiotherapy shows potential as the main postoperative treatment for patients with supratentorial malignant glioma.

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Nat Clin Pract Oncol. 2004 Dec;1(2):97-103; quiz 1 p following 111.
Technology insight: Proton beam radiotherapy for treatment in pediatric brain tumors.
Yock TI, Tarbell NJ.
Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA 02114, USA. tyock@partners.org

Tumors of the central nervous system are the most common solid tumor in childhood. Treatment options for childhood brain tumors include radiation therapy, surgery and chemotherapy, often given in combination. Radiation therapy regularly has a pivotal role in treatment, and technological advancements during the past quarter of a century have dramatically improved the ability to deliver radiation in a more focused manner. Improvements in imaging and computing ability led to better targeting of tumor tissue using conventional X-ray therapy. These advances have been harnessed for proton radiation therapy. Proton radiotherapy has special physical characteristics that allow normal tissues to be spared better than even the most conformal photon radiation, and it will reduce the complications from treatment. This review discusses the characteristics of proton radiation, and describes examples of pediatric brain tumor patients who would benefit most from this form of treatment.

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Radiother Oncol. 2005 Dec;77(3):278-85. Epub 2005 Nov 21.
Role of radiotherapy in anaplastic ependymoma in children under age of 3 years: Results of the prospective German brain tumor trials HIT-SKK 87 and 92.
Timmermann B, Kortmann RD, Kuhl J, Rutkowski S, Dieckmann K, Meisner C, Bamberg M.
Department of Radiooncology, University of Tubingen, Tubingen, Germany; Division of Radiation Medicine, Paul Scherrer Institute, Villigen, Switzerland.

BACKGROUND AND PURPOSE: To evaluate the outcome of very young children with anaplastic ependymoma after delayed or omitted radiotherapy (RT). MATERIALS AND METHODS: Children under age of 3 years with anaplastic ependymoma were enrolled in the HIT-SKK 87 trial from 1987. After surgery, low-risk patients (R0, M0) received maintenance chemotherapy until elective RT at age of three. In high-risk patients (R+, M+) intensive induction chemotherapy was followed by maintenance chemotherapy and subsequently delayed RT. If there was, progression radiotherapy started immediately. In the HIT-SKK 92, trial MTX-based chemotherapy was applied. RT was administered in non-responders only. RESULTS: Thirty-four children with anaplastic ependymoma were eligible (age 1.0-33.0 months). All children received chemotherapy. In 13 children, no RT was administered. Preventive RT after chemotherapy was given in nine, and salvage RT in 12 children. OS and PFS rates after 3-year were 55.9 and 27.3%, respectively. Twenty-five children relapsed. Positive impact on survival was observed in children with higher age, M0-stage, complete resection, and treatment with radiotherapy. Without RT only 3/13, children survived. CONCLUSION: Delaying RT jeopardizes survival even after intensive chemotherapy. Predominant site of failure is the primary tumor site. RT of the neuraxis should be omitted in localized disease.

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Cancer. 2005 Dec 15;104(12):2784-91.
Long-term survivors after gamma knife radiosurgery for brain metastases.
Kondziolka D, Martin JJ, Flickinger JC, Friedland DM, Brufsky AM, Baar J, Agarwala S, Kirkwood JM, Lunsford LD.
Department of Neurological Surgery, University of Pittsburgh School of Medicine, University of Pittsburgh Medical Center, PA 15213, USA. kondziolkads@upmc.edu

BACKGROUND: Stereotactic radiosurgery, with or without whole-brain radiation therapy, has become a valued management choice for patients with brain metastases, although their median survival remains limited. In patients who receive successful extracranial cancer care, patients who have controlled intracranial disease are living longer. The authors evaluated all brain metastasis in patients who lived for > or = 4 years after radiosurgery to determine clinical and treatment patterns potentially responsible for their outcome. METHODS: Six hundred seventy-seven patients with brain metastases underwent 781 radiosurgery procedures between 1988 and 2000. Data from the entire series were reviewed; and, if patients had > or = 4 years of survival, then they were evaluated for information on brain and extracranial treatment, symptoms, imaging responses, need for further care, and management morbidity. These long-term survivors were compared with a cohort who lived for < 3 months after radiosurgery (n = 100 patients). RESULTS: Forty-four patients (6.5%) survived for > 4 years after radiosurgery (mean, 69 mos with 16 patients still alive). The mean age at radiosurgery was 53 years (maximum age, 72 yrs), and the median Karnofsky performance score (KPS) was 90. The lung (n = 15 patients), breast (n = 9 patients), kidney (n = 7 patients), and skin (melanoma; n = 6 patients) were the most frequent primary sites. Two or more organ sites outside the brain were involved in 18 patients (41%), the primary tumor plus lymph nodes were involved in 10 patients (23%), only the primary tumor was involved in 9 patients (20%), and only brain disease was involved in 7 patients (16%), indicating that extended survival was possible even in patients with multiorgan disease. Serial imaging of 133 tumors showed that 99 tumors were smaller (74%), 22 tumors were unchanged (17%), and 12 tumors were larger (9%). Four patients had a permanent neurologic deficit after brain tumor management, and six patients underwent a resection after radiosurgery. Compared with the patients who had limited survival (< 3 mos), long-term survivors had a higher initial KPS (P = 0.01), fewer brain metastases (P = 0.04), and less extracranial disease (P < 0.00005). CONCLUSIONS: Although the expected survival of patients with brain metastases may be limited, selected patients with effective intracranial and extracranial care for malignant disease can have prolonged, good-quality survival. The extent of extracranial disease at the time of radiosurgery was predictive of outcome, but this does not necessarily mean that patients cannot live for years if treatment is effective. Copyright 2005 American Cancer Society.

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Anticancer Res. 2005 Nov-Dec;25(6A):3715-23.
Efficacy and feasibility of procarbazine, ranimustine and vincristine chemotherapy, and the role of surgical resection in anaplastic oligodendroglioma.
Yamamoto M, Iwaasa M, Nonaka M, Tsugu H, Nabeshima K, Fukushima T.
Department of Neurosurgery, Fukuoka University School of Medicine, Fukuoka 814-0180, Japan. masaaki@fukuoka-u.ac.jp

The safety, tolerance and preliminary efficacy of a chemotherapy regimen consisting of procarbazine (PCB), ranimustine (MCNU) and vincristine (VCR) were assessed for patients with newly diagnosed supratentorial anaplastic oligodendroglioma. MATERIALS AND METHODS: Between October 1999 and September 2003, 5 patients were enrolled. The initial regimens were prescribed as adjuvant therapy in conjunction with radiotherapy following standard surgical treatment. All patients received a chemotherapy comprising ranimustine (100 mg/m2) intravenously on Day 1, procarbazine (60 mg/m2) on Days 8 to 21, and vincristine (1.4 mg/m2, maximum total 2 mg) on Days 8 and 29. The cycles were repeated every 8 weeks until tumor progression was evident, or for a total of 6 cycles over a 1-year period. The primary end-points were safety and tolerability, while the secondary end-point was overall survival. RESULTS: Five consecutive eligible patients were treated. Of the 4 evaluable patients, 3 partially responded to the treatment (PR), while 1 had a complete response (CR): all patients are still alive. However, 3 of the 5 patients showed relapse, with a time to tumor progression (TTP) of 50, 143 and 241 weeks, respectively. Two of these patients received combined treatment with carboplatin, etoposide and recombinant human mutant tumor necrosis factor-alpha at the first relapse. This regimen appeared to be safe and neither neurological toxicity, severe or life-threatening hematological toxicity, nor fatal toxicity (WHO Grade 4) were experienced. CONCLUSION: These results suggest that a chemotherapy regimen consisting of PCB, MCNU and VCR in this patient population seems to be safe and tolerable, and the response rate was high. Thus, wide resection with a risk of major neurological morbidity due to nearby functionally critical areas can be avoided. However, since the relapse rate was high, a second-line chemotherapy should be developed for anaplastic oligodendroglioma to improve the long-term control of the disease.

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Expert Rev Neurother. 2005 Nov;5(6 Suppl):S71-6.
Managing symptoms and side effects during brain tumor illness.
Stewart-Amidei C.
Section of Neurosurgery, University of Chicago, 5841 S. Maryland Avenue, MC 3026, Chicago, IL, USA. camidei@surgery.bsd.uchicago.edu

Malignant brain tumors and the therapies used to treat them can present challenging problems. Headache is the most common symptom during brain tumor illness. Etiology determines the exact management approach, but pharmacologic and non pharmacologic measures may be used. Seizures also commonly occur and are best managed with anti epileptic drug therapy. Infection and deep venous thrombosis are concerns and are best approached by preventive measures and early aggressive intervention if those measures fail. Depression, fatigue, memory and personality changes may complicate care and are approached on an individual basis. Early discussion about end-of-life issues is necessary because the disease itself can impair decision-making ability.

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J Neurosurg. 2005 Oct;103(4 Suppl):312-8.
Preoperative chemotherapy in children with high-risk medulloblastomas: a feasibility study.
Grill J, Lellouch-Tubiana A, Elouahdani S, Pierre-Kahn A, Zerah M, Renier D, Valteau-Couanet D, Hartmann O, Kalifa C, Sainte-Rose C.
Department de Cancerologie de l'Enfant et de l'Adolescent, Institut Gustave Roussy, Villejuif, France. grill@igr.fr

OBJECT: The authors set out to evaluate the feasibility and effectiveness of preoperative chemotherapy in treating high-risk medulloblastomas. METHODS: Between 1997 and 2000, 21 children with high-risk medulloblastomas (M > or = 2 and/or T3b/T4 according to the Chang classification) were treated consecutively in a pilot study. The protocol began with treatment of the hydrocephalus and confirmation of the diagnosis. Tumor surgery was performed either after conventional chemotherapy (eight patients) or after subsequent high-dose chemotherapy (HDCT; 11 patients). Two children with early leptomeningeal progression died before surgery. Craniospinal irradiation was applied to children older than 5 years of age, whereas younger children received local irradiation only. Hydrocephalus was present in 17 children and was treated with ventriculocisternostomy in 13 and shunt insertion in four. A biopsy procedure was performed with a stereotactic frame in 10 children, an open surgery was performed in four, an endoscope was used during the ventriculocisternostomy in three, and the diagnosis was made based on cerebrospinal fluid cytological analysis in two. The response rate to the first two courses of chemotherapy was 71% for the tumor and 59% for the metastases. The pathological analysis of the residue after chemotherapy showed true medulloblastomas in seven cases, complete neuroglial maturation in three cases, and a mixture of both in nine cases. Three-year progression-free survival was 37% and was significantly better in children older than 5 years of age. There was one death related to the HDCT. CONCLUSIONS: Preoperative chemotherapy is feasible and safe in children with high-risk medulloblastomas provided that the hydrocephalus can be treated at diagnosis. A larger study is warranted to ensure that the high response rate to adjuvant chemotherapy can lead to better surgical results and survival advantage.

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J Neurosurg. 2005 Oct;103(4):630-5.
Stereotactic interstitial radiosurgery for cerebral metastases.
Curry WT Jr, Cosgrove GR, Hochberg FH, Loeffler J, Zervas NT.
Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA. wcurry@partners.org

OBJECT: The Photon Radiosurgery System (PRS) is a miniature x-ray generator that can stereotactically irradiate intracranial tumors by using low-energy photons. Treatment with the PRS typically occurs in conjunction with stereotactic biopsy, thereby providing diagnosis and treatment in one procedure. The authors review the treatment of patients with brain metastases with the aid of the PRS and discuss the indications, advantages, and limitations of this technique. METHODS: Clinical characteristics, treatment parameters, neuroimaging-confirmed outcome, and survival were reviewed in all patients with histologically verified brain metastases who were treated with the PRS at the Massachusetts General Hospital between December 1992 and November 2000. Local control of lesions was defined as either stabilization or diminution in the size of the treated tumor as confirmed by Gd-enhanced magnetic resonance imaging. Between December 1992 and November 2000, 72 intracranial metastatic lesions in 60 patients were treated with the PRS. Primary tumors included lung (33 patients), melanoma (15 patients), renal cell (five patients), breast (two patients), esophageal (two patients), colon (one patient), and Merkle cell (one patient) cancers, and malignant fibrous histiocytoma (one patient). Supratentorial metastases were distributed throughout the cerebrum, with only one cerebellar metastasis. The lesions ranged in diameter from 6 to 40 mm and were treated with a minimal peripheral dose of 16 Gy (range 10-20 Gy). At the last follow-up examination (median 6 months), local disease control had been achieved in 48 (81%) of 59 tumors. An actuarial analysis demonstrated that the survival rates at 6 and 12 months were 63 and 34%, respectively. Patients with a single brain metastasis survived a mean of 11 months. Complications included four patients with postoperative seizures, three with symptomatic cerebral edema, two with hemorrhagic events, and three with symptomatic radiation necrosis requiring surgery. CONCLUSIONS: Stereotactic interstitial radiosurgery performed using the PRS can obtain local control of cerebral metastases at rates that are comparable to those achieved through open resection and external stereotactic radiosurgery. The major advantage of using the PRS is that effective treatment can be accomplished at the time of stereotactic biopsy.

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Mol Ther. 2005 Oct;12(4):585-98.
Gene therapy for malignant glioma: current clinical status.
Pulkkanen KJ, Yla-Herttuala S.
Department of Molecular Medicine, A. I. Virtanen Institute, University of Kuopio, P.O. Box 1627, FIN-70211 Kuopio, Finland; Department of Oncology, Kuopio University Hospital, Kuopio, Finland.

Glioblastoma is an aggressive brain tumor with a dismal prognosis. Gene therapy may offer a new option for the treatment of these patients. Several gene therapy approaches have shown anti-tumor efficiency in experimental studies, and the first clinical trials for the treatment of malignant glioma were conducted in the 1990s. HSV-tk gene therapy has been the pioneering and most commonly used approach, but oncolytic conditionally replicating adenoviruses and herpes simplex virus mutant vectors, p53, interleukins, interferons, and antisense oligonucleotides have also been used. During the past few years, adenoviruses have become the most popular gene transfer vectors, and some recent randomized, controlled trials have shown significant anti-tumor efficacy in clinical use. However, efficient gene delivery into the brain still presents a major problem, and there is a lack of definitive phase III trials, which would avoid potential problems associated with a small number of patients, inadvertent patient selection, and overinterpretation of results based on a few long-time survivors. For clinical efficacy, median survival is one of the most rigorous endpoints. It is used here to evaluate the usefulness of various treatment approaches and current clinical status of gene therapy for malignant glioma.

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Lancet. 2005 Sep 17;366(9490):985-90.
Long-term efficacy of early versus delayed radiotherapy for low-grade astrocytoma and oligodendroglioma in adults: the EORTC 22845 randomised trial.
van den Bent MJ, Afra D, de Witte O, Ben Hassel M, Schraub S, Hoang-Xuan K, Malmstrom PO, Collette L, Pierart M, Mirimanoff R, Karim AB; EORTC Radiotherapy and Brain Tumor Groups and the UK Medical Research Council.
Erasmus Medical Centrum Daniel den Hoed Oncology Center, Rotterdam. m.vandenbent@erasmusmc.nl

BACKGROUND: Postoperative policies of "wait-and-see" and radiotherapy for low-grade glioma are poorly defined. A trial in the mid 1980s established the radiation dose. In 1986 the EORTC Radiotherapy and Brain Tumor Groups initiated a prospective trial to compare early radiotherapy with delayed radiotherapy. An interim analysis has been reported. We now present the long-term results. METHODS: After surgery, patients from 24 centres across Europe were randomly assigned to either early radiotherapy of 54 Gy in fractions of 1.8 Gy or deferred radiotherapy until the time of progression (control group). Patients with low-grade astrocytoma, oligodendroglioma, mixed oligoastrocytoma, and incompletely resected pilocytic astrocytoma, with a WHO performance status 0-2 were eligible. Analysis was by intention to treat, and primary endpoints were overall and progression-free survival. FINDINGS: 157 patients were assigned early radiotherapy, and 157 control. Median progression-free survival was 5.3 years in the early radiotherapy group and 3.4 years in the control group (hazard ratio 0.59, 95% CI 0.45-0.77; p<0.0001). However, overall survival was similar between groups: median survival in the radiotherapy group was 7.4 years compared with 7.2 years in the control group (hazard ratio 0.97, 95% CI 0.71-1.34; p=0.872). In the control group, 65% of patients received radiotherapy at progression. At 1 year, seizures were better controlled in the early radiotherapy group. INTERPRETATION: Early radiotherapy after surgery lengthens the period without progression but does not affect overall survival. Because quality of life was not studied, it is not known whether time to progression reflects clinical deterioration. Radiotherapy could be deferred for patients with low-grade glioma who are in a good condition, provided they are carefully monitored.

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Cancer Gene Ther. 2005 Sep 2; [Epub ahead of print]
Genetic strategies for brain tumor therapy.
Lawler SE, Peruzzi PP, Chiocca EA.
1Department of Neurological Surgery, The Dardinger Family Laboratory for Neuro-oncology and Neurosciences, The Ohio State University Medical Center, Columbus, OH, USA.

Gene therapy is a potentially useful approach in the treatment of human brain tumors, which are notoriously refractory to conventional approaches. Most human clinical trials to date have been unsuccessful in terms of improving patient outcome. Recent improvements in viral vectors, the development of stem cell technology, and increased understanding of the mechanism of action of therapeutic transgenes provide hope that the next generation of gene therapeutics may show increased efficacy in treatment of this devastating disease.Cancer Gene Therapy advance online publication, 2 September 2005; doi:10.1038/sj.cgt.7700886.

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J Clin Oncol. 2005 Sep 1;23(25):6207-19.
Current management of brain metastases, with a focus on systemic options.
Langer CJ, Mehta MP.
Division of Thoracic Oncology, Fox Chase Cancer Center, 333 Cottman Ave, Philadelphia, PA 19111, USA. CJ_Langer@fccc.edu

Brain metastases are an important sequelae of many types of cancer, most commonly lung cancer. Current treatment options include whole-brain radiation therapy (WBRT), surgical resection, stereotactic radiosurgery, and chemotherapy. Corticosteroids and antiepileptic medications are commonly used for palliation of mass effect and seizures, respectively. The overall median survival is only 4 months after WBRT. Combined-modality strategies of WBRT with either chemotherapy or novel anticancer agents are under clinical investigation. Promising results have been obtained with several experimental agents and confirmatory phase III trials are underway. Although improvement in overall survival has not been seen universally, reduction in death due to progression of brain metastases and prolongation of the time to neurologic and neurocognitive progression have been reported in selected series. On the basis of these findings, it might be possible to identify new agents that may enhance the efficacy of WBRT.

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Cancer Causes Control. 2005 Sep;16(7):877-891.
Maternal Diet During Pregnancy and its Association with Medulloblastoma in Children: A Children's Oncology Group Study (United States).
R Bunin G, Kushi LH, Gallagher PR, Rorke-Adams LB, McBride ML, Cnaan A.
Oncology, Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA, bunin@email.chop.edu.

Fruit, vegetables, vitamin C, and folate during pregnancy have been suggested as protective factors for medulloblastoma/primitive neuroectodermal tumor (PNET), a common brain tumor in children. The authors sought to replicate these findings and investigate other aspects of diet. Mothers of 315 cases under age six at diagnosis and 315 controls were interviewed about their pregnancy diet. The authors observed modest, inverse associations for fruits/juices (odds ratio (OR) for highest compared to lowest category = 0.6, 95% confidence interval (CI): 0.3, 1.1) and vitamin C (OR = 0.6, 95% CI: 0.4, 1.1). In contrast to the previous study, folate and vegetables showed no association. As hypothesized, cured meats were not associated with medulloblastoma/PNET, in contrast to other childhood brain tumors. An inverse association with nonfresh peaches and similar fruits (OR = 0.5, 95% CI: 0.3, 0.8) and a positive association with nonchocolate candy (OR = 1.7, 95% CI: 1.0, 3.0) replicated previous findings. French fries (OR = 2.4, 95% CI: 1.2, 4.9) and chili peppers (OR = 1.8, 95% CI: 1.0, 3.0) were associated with medulloblastoma/PNET. The results suggest that some aspects of diet are worthy of further research.

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Int J Radiat Oncol Biol Phys. 2005 Sep 1;63(1):47-55.
The American Society for Therapeutic Radiology and Oncology (ASTRO) evidence-based review of the role of radiosurgery for malignant glioma.
Tsao MN, Mehta MP, Whelan TJ, Morris DE, Hayman JA, Flickinger JC, Mills M, Rogers CL, Souhami L.
The American Society for Therapeutic Radiology and Oncology, Fairfax, VA.

Purpose: To systematically review the evidence for the use of stereotactic radiosurgery or stereotactic fractionated radiation therapy in adult patients with malignant glioma. Methods: Key clinical questions to be addressed in this evidence-based review were identified. Outcomes considered were overall survival, quality of life or symptom control, brain tumor control or response and toxicity. MEDLINE (1990-2004 June Week 2), CANCERLIT (1990-2003), CINAHL (1990-2004 June Week 2), EMBASE (1990-2004 Week 25), and the Cochrane library (2004 issue 2) databases were searched using OVID. In addition, the Physician Data Query clinical trials database, the proceedings of the American Society of Clinical Oncology (1997-2004), ASTRO (1997-2004), and the European Society of Therapeutic Radiology and Oncology (ESTRO) (1997-2003) were searched. Data from the literature search were reviewed and tabulated. This process included an assessment of the level of evidence. Results: For patients with newly diagnosed malignant glioma, radiosurgery as boost therapy with conventional external beam radiation was examined in one randomized trial, five prospective cohort studies, and seven retrospective series. There is Level I evidence that the use of radiosurgery boost followed by external beam radiotherapy and carmustine (BCNU) does not confer benefit with respect to overall survival, quality of life, or patterns of failure as compared with external beam radiotherapy and BCNU. There is Level I-III evidence of toxicity associated with radiosurgery boost as compared with external beam radiotherapy alone. The results of the prospective and retrospective studies may be influenced by selection bias. Radiosurgery used as salvage for recurrent or progressive malignant glioma after conventional external beam radiotherapy failure was reported in zero randomized trials, three prospective cohort studies, and five retrospective series. The available data are sparse and insufficient to make absolute recommendations. Stereotactic fractionated radiation therapy has been reported as boost therapy with external beam radiotherapy for patients with newly diagnosed malignant glioma in only three prospective studies. As primary therapy alone without conventional external beam radiotherapy for newly diagnosed malignant glioma patients, stereotactic fractionated radiation therapy has been reported in only one prospective study. There were only three prospective series and two retrospective studies reported for patients with recurrent or progressive malignant glioma. Conclusions: For patients with malignant glioma, there is Level I-III evidence that the use of radiosurgery boost followed by external beam radiotherapy and BCNU does not confer benefit in terms of overall survival, local brain control, or quality of life as compared with external beam radiotherapy and BCNU. The use of radiosurgery boost is associated with increased toxicity. For patients with malignant glioma, there is insufficient evidence regarding the benefits/harms of using radiosurgery at the time progression or recurrence. There is also insufficient evidence regarding the benefits/harms in the use of stereotactic fractionated radiation therapy for patients with newly diagnosed or progressive/recurrent malignant glioma.

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Int J Radiat Oncol Biol Phys. 2005 Sep 1;63(1):37-46.
The American Society for Therapeutic Radiology and Oncology (ASTRO) evidence-based review of the role of radiosurgery for brain metastases.
Mehta MP, Tsao MN, Whelan TJ, Morris DE, Hayman JA, Flickinger JC, Mills M, Rogers CL, Souhami L.
The American Society for Therapeutic Radiology and Oncology, Fairfax, VA.

Purpose: To systematically review the evidence for the use of stereotactic radiosurgery in adult patients with brain metastases. Methods: Key clinical questions to be addressed in this evidence-based review were identified. Outcomes considered were overall survival, quality of life or symptom control, brain tumor control or response and toxicity. MEDLINE (1990-2004 June Week 2), CANCERLIT (1990-2003), CINAHL (1990-2004 June Week 2), EMBASE (1990-2004 Week 25), and the Cochrane library (2004 issue 2) databases were searched using OVID. In addition, the Physician Data Query clinical trials database, the proceedings of the American Society of Clinical Oncology (ASCO) (1997-2004), ASTRO (1997-2004), and the European Society of Therapeutic Radiology and Oncology (ESTRO) (1997-2003) were searched. Data from the literature search were reviewed and tabulated. This process included an assessment of the level of evidence. Results: For patients with newly diagnosed brain metastases, managed with whole-brain radiotherapy alone vs. whole-brain radiotherapy and radiosurgery boost, there were three randomized controlled trials, zero prospective studies, and seven retrospective series (which satisfied inclusion criteria). For patients with up to three (<4 cm) newly diagnosed brain metastases (and in one study up to four brain metastases), radiosurgery boost with whole-brain radiotherapy significantly improves local brain control rates as compared with whole-brain radiotherapy alone (Level I-III evidence). In one large randomized trial, survival benefit with whole-brain radiotherapy was observed in patients with single brain metastasis. In this trial, an overall increased ability to taper down on steroid dose and an improvement in Karnofsky performance status was seen in patients who were treated with radiosurgery boost as compared with patients treated with whole-brain radiotherapy alone. However, Level I evidence regarding overall quality of life outcomes using a validated instrument has not been reported. All randomized trials showed improved local control with the addition of radiosurgery to whole-brain radiotherapy. For patients with multiple brain metastases, there is no overall survival benefit with the use of radiosurgery boost to whole-brain radiotherapy (Level I-III evidence). Radiosurgery boost is associated with a small risk of early or late toxicity. In patients treated with radiosurgery alone (withholding whole-brain radiotherapy) as initial treatment, there were 2 randomized trials, 2 prospective cohort studies, and 16 retrospective series. There is Level I to Level III evidence that the use of radiosurgery alone does not alter survival as compared to the use of whole-brain radiotherapy. However, there is Level I to Level III evidence that omission of whole-brain radiotherapy results in poorer intracranial disease control, both local and distant (defined as remaining brain, outside the radiosurgery field). Quality of life outcomes have not been adequately reported. Radiosurgery is associated with a small risk of early or late toxicity. Radiosurgery as salvage for patients with brain metastases was reported in zero randomized trials, one prospective study, and seven retrospective series. Conclusions: Based on Level I-III evidence, for selected patients with small (up to 4 cm) brain metastases (up to three in number and four in one randomized trial), the addition of radiosurgery boost to whole-brain radiotherapy improves brain control as compared with whole-brain radiotherapy alone. In patients with a single brain metastasis, radiosurgery boost with whole-brain radiotherapy improves survival. There is a small risk of toxicity associated with radiosurgery boost as compared with whole-brain radiotherapy alone. In selected patients treated with radiosurgery alone for newly diagnosed brain metastases, overall survival is not altered. However, local and distant brain control is significantly poorer with omission of upfront whole-brain radiotherapy (Level I-III evidence). Whether neurocognition or quality of life outcomes are different between initial radiosurgery alone vs. whole-brain radiotherapy (with or without radiosurgery boost) is unknown, because this has not been adequately tested. There was no statistically significant difference in overall toxicity between those treated with radiosurgery alone vs. whole-brain radiotherapy and radiosurgery boost based on an interim report from one randomized study. There is insufficient evidence as to the clinical benefit/risks radiosurgery used in the setting of recurrent or progressive brain metastases, although radiographic responses are well-documented.

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Onkologie. 2005 Aug;28(8-9):391-6. Epub 2005 Aug 29.
Pharmacotherapy of epileptic seizures in glioma patients: who, when, why and how long?
Wick W, Menn O, Meisner C, Steinbach J, Hermisson M, Tatagiba M, Weller M.
Abteilung fur Allgemeine Neurologie, Hertie-Institut fur Klinische Hirnforschung, Zentrum fur Neurologie, Universitatsklinikum Tubingen, Germany. wolfgang.wick@uni-tuebingen.de

BACKGROUND: The risk for patients with primary brain tumors of experiencing an epileptic seizure at least once in the course of disease probably exceeds 50%, depending on tumor location and tumor type. Several aspects regarding the role of anticonvulsants in the treatment of brain tumor patients have remained controversial. PATIENTS AND METHODS: We reviewed the seizure history in 107 patients undergoing a surgical procedure for glioma at our institution. RESULTS: The overall seizure incidence was 68%. Pre-operative seizures did not predict the occurrence of post-operative seizures. After surgery, postoperative chemo- or radiotherapy and anticonvulsive therapy one third of patients was seizure-free whereas one third showed frequent seizures despite this treatment. Seizure frequency increased regardless of anticonvulsive treatment with progressive or recurrent tumor growth. CONCLUSIONS: Based on a literature review and our institutional experience, we delineate some recommendations for the management of seizures in patients with brain tumors.

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J Neurosurg. 2005 Jul;103(1):31-7.
Long-term outcome in patients harboring intracranial ependymoma.
Kawabata Y, Takahashi JA, Arakawa Y, Hashimoto N.
Department of Neurosurgery, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan. ykawabata-kyt@umin.ac.jp

OBJECT: The prognostic significance of tumor grade and resection and the efficacy of prophylactic radiation remain controversial in the management of intracranial ependymoma. The outcomes in patients with intracranial ependymoma treated at the Kyoto University Hospital were reviewed retrospectively, and prognostic significance was analyzed. METHODS: Between 1972 and 2002, 29 patients were seen at the authors' institution. Eighteen cases involved a Grade II lesion according to the World Health Organization classification of ependymoma and 11 involved a Grade III lesion. Postoperative radiation was applied in 24 cases and chemotherapy was administered in nine. Overall survival and progression-free survival rates were significantly higher in patients with Grade II ependymoma (p = 0.006 and 0.004, respectively) and in patients who had undergone gross-total resection of the tumor (p = 0.002 and 0.04, respectively). Fourteen patients relapsed from 10 to 120 months (median 39 months) after diagnosis. In nine patients the ependymoma recurred only at the original tumor site. Three patients experienced both local and distant relapse, whereas two others had only a distant relapse. All relapses of the Grade II ependymoma initially occurred at the primary tumor site. Histological grade and extent of resection were significantly associated with tumor dissemination (p = 0.0034 and 0.0011, respectively). The field of postoperative radiation had no impact on patient survival or lesion recurrence. CONCLUSIONS: Tumor grade and resection are the two important prognostic factors with respect to patient survival, tumor recurrence, and tumor dissemination. Considering that relapses were predominantly local and that there was no apparent benefit from prophylactic radiation, the authors concluded that postoperative radiation should be focused on local control, especially for Grade II ependymomas.

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Cancer Invest. 2005;23(4):363-76.
Current concepts and controversies in the treatment of parenchymal brain metastases: improved outcomes with aggressive management.
Bajaj GK, Kleinberg L, Terezakis S.
Department of Radiation Oncology and Molecular Radiation Sciences, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland 21231, USA.

The multimodality management of brain metastases has undergone significant refinement in the last decade. Although brain metastases remain a significant source of morbidity and mortality for many cancer patients, aggresive management has led to pronounced gains in neurological functioning, disease free survival and overall survival compared to standard treatment regimens consisting of only whole brain radiation therapy. Representative studies reviewing the role of aggressive management approaches including surgical resection with or without whole brain radiation therapy or non-surgical approaches employing stereotactic radiosurgery alone or in combination with whole brain radiation therapy are highlighted. Additionally, the emerging role of systemic agents showing distinct clinical activity in patients with brain metastases are also discussed. As we continue to gain advances in systemic therapies for metastatic disease, local control of brain metastases in these patients is likely to become more critical in improving survival and quality of life, thereby calling for a more aggressive multi-modal approach to this population of patients.

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Curr Treat Options Neurol. 2005 Jul;7(4):323-336.
Treatment of Medical Complications in Patients with Brain Tumors.
Pruitt AA.
Department of Neurology, University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA 19104, USA. pruitt@mail.med.upenn.edu.

Patients with primary brain tumors and those with cerebral metastases are at risk throughout their illness for several major medical problems, including vasogenic edema, seizures, and symptomatic venous thrombosis. In turn, the corticosteroids, anti-epileptic drugs, and anticoagulants used to treat these problems may produce significant adverse effects and result in important drug-drug interactions that may complicate chemotherapy. Although few Class I studies address any of these issues, guidelines can be offered to maximize quality of life and minimize hospital readmissions. Optimal management of brain edema involves minimizing corticosteroid use and tapering the steroid dose slowly to avoid steroid withdrawal symptoms. Prophylaxis of Pneumocystis pneumonia is necessary for patients requiring corticosteroids for more than 1 month. Anti-epileptic drugs (AEDs) should be avoided unless patients experience seizures. If possible, non-CTY (P450) enzyme-inducing drugs should be chosen. AED levels should be obtained frequently during corticosteroid taper. Multimodality venous thrombosis prophylaxis should begin at the time of the original surgery with external leg compression and unfractionated subcutaneous heparin or a low molecular weight heparin (LMWH). Brain tumor patients with symptomatic venous thrombosis or pulmonary embolism can be anticoagulated safely with warfarin or with LMWH, and LMWHs are preferable from the standpoints of efficacy, safety, and convenience for long-term outpatient treatment of venous thrombosis. Clinicians should be aware of potential drug-drug interactions between prescribed AEDs and chemotherapy and possible interactions with complementary and alternative therapies chosen by their patients. They also should be aware of interventions to minimize late sequelae of brain tumors and their treatment, including cognitive decline, depression, and increased stroke risk.

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Curr Treat Options Neurol. 2005 Jul;7(4):293-303.
The Treatment of Malignant Gliomas.
Gilbert MR, Loghin M.
Department of Neuro-Oncology, M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA. mrgilbert@mdanderson.org.

The optimal management of patients with malignant gliomas begins with the accurate determination of the pathologic diagnosis based on adequate sampling of the tumor. Clear differences in prognosis and therapeutic options have been established for the various tumor grades and cellular classification. Current recommendations, on the basis of the results of a recent phase III randomized trial, are that patients with glioblastoma should have maximal surgical resection followed by concurrent radiation and chemotherapy with temozolomide. It is further recommended that patients then be treated with 6 to 12 months of adjuvant temozolomide. However, despite the shown improvement in survival with this chemoradiation regimen, the impact on outcome is modest. It is increasingly evident that a greater understanding of the molecular mechanisms of gliomagenesis is needed to improve treatments for these patients. Recent and ongoing investigations strongly indicate that specific molecular markers tremendously impact prognosis and often can predict response to treatment. For example, allelic loss of the 1p and 19q chromosome arms predicts a dramatic improvement in response to treatment and survival for tumors histologically classified as anaplastic oligodendroglioma. Future advances for treating primary brain tumors likely will be directly related to our ability to molecularly subcategorize tumors and customize therapy based on the molecular profile within each histologic type and grade of tumor. This is evident in preliminary data indicating that inactivation of the methyl guanine methyltransferase gene by hypermethylation of the promoter region specifically predicts a better tumor response rate to chemotherapies that alkylate DNA as their mechanism of action. Similarly, elucidation of overly active signal transduction pathways within tumor cells may provide an opportunity to select the optimal therapeutic regimen composed of modulators of these pathways, analogous to restricting the use of trastuzumab to breast cancers expressing the Her-2 receptor. Advances in treating primary malignant brain tumors will likely depend on collaborative clinical trials that are designed to select patients on the basis of histologic and molecular characteristics and to determine the optimal biologic dose of the best agent that can treat each specific tumor type.

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Clin Cancer Res. 2005 Jun 1;11(11):3987-4002.
Boron neutron capture therapy of cancer: current status and future prospects.
Barth RF, Coderre JA, Vicente MG, Blue TE.
Department of Pathology, The Ohio State University, Columbus, Ohio 43210, USA. barth.1@osu.edu

BACKGROUND: Boron neutron capture therapy (BNCT) is based on the nuclear reaction that occurs when boron-10 is irradiated with low-energy thermal neutrons to yield high linear energy transfer alpha particles and recoiling lithium-7 nuclei. Clinical interest in BNCT has focused primarily on the treatment of high-grade gliomas and either cutaneous primaries or cerebral metastases of melanoma, most recently, head and neck and liver cancer. Neutron sources for BNCT currently are limited to nuclear reactors and these are available in the United States, Japan, several European countries, and Argentina. Accelerators also can be used to produce epithermal neutrons and these are being developed in several countries, but none are currently being used for BNCT. BORON DELIVERY AGENTS: Two boron drugs have been used clinically, sodium borocaptate (Na(2)B(12)H(11)SH) and a dihydroxyboryl derivative of phenylalanine called boronophenylalanine. The major challenge in the development of boron delivery agents has been the requirement for selective tumor targeting to achieve boron concentrations ( approximately 20 microg/g tumor) sufficient to deliver therapeutic doses of radiation to the tumor with minimal normal tissue toxicity. Over the past 20 years, other classes of boron-containing compounds have been designed and synthesized that include boron-containing amino acids, biochemical precursors of nucleic acids, DNA-binding molecules, and porphyrin derivatives. High molecular weight delivery agents include monoclonal antibodies and their fragments, which can recognize a tumor-associated epitope, such as epidermal growth factor, and liposomes. However, it is unlikely that any single agent will target all or even most of the tumor cells, and most likely, combinations of agents will be required and their delivery will have to be optimized. CLINICAL TRIALS: Current or recently completed clinical trials have been carried out in Japan, Europe, and the United States. The vast majority of patients have had high-grade gliomas. Treatment has consisted first of "debulking" surgery to remove as much of the tumor as possible, followed by BNCT at varying times after surgery. Sodium borocaptate and boronophenylalanine administered i.v. have been used as the boron delivery agents. The best survival data from these studies are at least comparable with those obtained by current standard therapy for glioblastoma multiforme, and the safety of the procedure has been established. CONCLUSIONS: Critical issues that must be addressed include the need for more selective and effective boron delivery agents, the development of methods to provide semiquantitative estimates of tumor boron content before treatment, improvements in clinical implementation of BNCT, and a need for randomized clinical trials with an unequivocal demonstration of therapeutic efficacy. If these issues are adequately addressed, then BNCT could move forward as a treatment modality.

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Strahlenther Onkol. 2005 Jun;181(6):372-377.
Temozolomide Combined with Irradiation as Postoperative Treatment of Primary Glioblastoma Multiforme Phase I/II Study.
Combs SE, Gutwein S, Schulz-Ertner D, van Kampen M, Thilmann C, Edler L, Wannenmacher MM, Debus J.
Department of Radiation Oncology, University of Heidelberg, Heidelberg, Germany.

BACKGROUND AND PURPOSE: : The role of radiochemotherapy in the treatment of primary glioblastoma multiforme is still discussed controversially. To evaluate the feasibility and toxicity of irradiation and concomitant administration of 50 mg/m(2) temozolomide in patients with primary malignant glioma, this phase I/II study was conducted. PATIENTS AND METHODS: : 53 Patients with histologically confirmed WHO grade IV malignant glioma were enrolled into the study. All patients were treated with radiation therapy up to a total dose of 60 Gy using conventional fractionation of 5 x 2.0 Gy/week. Temozolomide was administered orally each therapy day at a dose of 50 mg/m(2). RESULTS: : Prior to radiochemotherapy, complete resection (n = 14), subtotal resection (n = 22) or a biopsy (n = 17) of the tumor was performed. The median time interval between surgery and radiochemotherapy was 21 days. Treatment-related toxicity was very mild. Acute toxicity > grade 2 was observed in one patient who developed grade 4 hemotoxicity. Minor side effects of chemotherapy included nausea and vomiting. No severe late effects were observed. Median progression-free and overall survival were 8 and 19 months, respectively. The overall survival rate was 72% at 1 and 26% at 2 years. Age and extent of surgery significantly influenced survival. CONCLUSION: : The combination of temozolomide plus radiation therapy is feasible and safe in terms of toxicity. Overall survival times were relatively long compared to survival times reported for radiotherapy alone. The application of 50 mg/m(2) of temozolomide can be performed throughout the whole time course without interruption due to side effects and might largely contribute to the prolonged overall survival. Further evaluation is warranted as to which dose of temozolomide is optimal with regard to tumor response and toxicity.

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J Clin Neurosci. 2005 May;12(4):389-98.
Photodynamic therapy of high grade glioma - long term survival.
Stylli SS, Kaye AH, Macgregor L, Howes M, Rajendra P.
Department of Neurosurgery and Department of Surgery, Royal Melbourne Hospital, University of Melbourne, Melbourne.

Haemetaporphyrin derivative (HpD) mediated photodynamic therapy (PDT) has been investigated as an adjuvant treatment for cerebral glioma. This study records the survival of patients at the Royal Melbourne Hospital with residences in the State of Victoria, utilizing the Victorian Cancer Registry database for patients treated with adjuvant PDT following surgical resection of the tumour. For primary (newly diagnosed) tumours, median survival from initial diagnosis was 76.5 months for anaplastic astrocytoma (AA) and 14.3 months for glioblastoma multiforme (GBM). Seventy-three percent of patients with AA and 25% with GBM survived longer than 36 months. For recurrent tumour, median survival from the time of surgery was 66.6 months for AA and 13.5 months for GBM. Fifty-seven percent of patients with recurrent AA and 41% of patients with recurrent GBM survived longer than 36 months. Older age at the time of diagnosis was associated with poorer prognosis. Laser light doses above the sample median of 230 J/cm(2) were associated with better prognosis in the 136 patients studied (primary tumour patients - (HR=0.50[0.27,0.95],p=0.033); recurrent tumour patients (HR=0.75[0.42,1.31],p=0.312). There was no mortality directly associated with the therapy, three patients had increased cerebral oedema thought to be related to photodynamic therapy that was controlled with conventional therapies.

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J Neurooncol. 2005 May;72(3):241-4.
A phase I trial of surgery, Gliadel wafer implantation, and immediate postoperative carboplatin in combination with radiation therapy for primary anaplastic astrocytoma or glioblastoma multiforme.
Limentani SA, Asher A, Heafner M, Kim JW, Fraser R.
Carolinas Hematology-Oncology Associates, 1100 South Tryon Street, Charlotte, North Carolina, 28203, USA, steven.limentani@carolinashealthcare.org.

Two types of chemotherapy used in the treatment of patients with malignant glioma are carboplatin and Gliadel((R)) wafer [(3.85% 1,3-bis-(2-chloroethyl)-1-nitrosourea (BCNU)]. To date there have been no published data examining their concurrent use in this disease. The purpose of this study was to evaluate combination chemotherapy with Gliadel wafer and carboplatin in patients with high-grade, malignant glioma. In this prospective phase I study, 16 patients underwent surgery, Gliadel wafer implantation (up to 8 wafers), intravenous carboplatin given postoperatively (day 3 or 4) at a dose escalation range of area under the curve (AUC)=2-6, and external beam radiation. Median age was 55 years (range 27-66 years). Fourteen (88%) patients had glioblastoma multiforme and 2 (12%) had anaplastic astrocytoma. Performance status was as follows: Eastern Cooperative Oncology Group (ECOG)=0 (2 patients), ECOG=1 (13 patients), and ECOG=2 (2 patients). Three patients were treated at each dosing level (AUC=2-6), and 4 patients were treated at an AUC=5. Carboplatin was administered to all patients by postoperative day 4. Radiation was begun on day 14-36. No grade 3 or 4 toxicities were noted in this study. Median progression-free and overall survival was 266 and 679 days, respectively. We conclude that administering systemic carboplatin is safe and well tolerated in the postoperative period immediately following resection and implantation of Gliadel wafer for the treatment of malignant glioma. Further evaluation in a phase II setting, at maximal carboplatin dose to establish potential efficacy, with this combination is warranted.

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Bull Cancer. 2005 Apr;92(4):343-54.
[New place of the chemotherapy in gliomas]
[Article in French]
Chinot O.
Unite de Neuro-Oncologie, CHU Timone et Laboratoire de cancerologie experimentale, Inserm EMI 0359, Faculte de Medecine Nord, Universite de la Mediterranee, Assistance Publique-Hopitaux de Marseille. olivier.chinot@ap-hm.fr

During these last 25 years, despite numerous phases III studies, standard of treatment in glioblastoma multiforme (GBM) consisted of surgery and post-operative radiotherapy, while benefit of chemotherapy was a matter of debate. A phase III study, conducted by EORTC and NCI Canada and involving 573 patients, concluded clearly to the benefit of adding temozolomide during and after radiotherapy as adjuvant treatment. Using this schedule, median survival increase from 12,1 to 14,6 months, and 2 year survival rate from 8 to 26%. In the same time, for anaplastic oligodendroglioma (AO) the phase III study conducted by Cairncross, that compared radiotherapy to a schedule that deliver a chemotherapy with PCV followed by radiotherapy, failed to determine a significant benefit on overall survival, despite the particular chemosensitivity of theses tumors. Moreover, these two studies did underlined impact of biological markers (methylation of the promoter of O6 methylguanine DNA transferase (MGMT) gene for GBM and chromosomes 1p and 19q deletion for AO), that may become decisional markers in the future. We review here the new place of chemotherapy in the adjuvant treatment of GBM and anaplastic gliomas, as well as the impact of these pivotal studies on second lines therapies, and future clinical research.

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J Neurosurg. 2005 Apr;102(4):678-91.
Stereotactic radiosurgery for pituitary adenomas: an intermediate review of its safety, efficacy, and role in the neurosurgical treatment armamentarium.
Sheehan JP, Niranjan A, Sheehan JM, Jane JA Jr, Laws ER, Kondziolka D, Flickinger J, Landolt AM, Loeffler JS, Lunsford LD.
Department of Neurological Surgery, University of Virginia Health System, Charlottesville, Virginia 22908, USA. jps2f@virginia.edu

OBJECT: Pituitary adenomas are very common neoplasms, constituting between 10 and 20% of all primary brain tumors. Historically, the treatment armamentarium for pituitary adenomas has included medical management, microsurgery, and fractionated radiotherapy. More recently, radiosurgery has emerged as a viable treatment option. The goal of this research was to define more fully the efficacy, safety, and role of radiosurgery in the treatment of pituitary adenomas. METHODS: Medical literature databases were searched for articles pertaining to pituitary adenomas and stereotactic radiosurgery. Each study was examined to determine the number of patients, radiosurgical parameters (for example, maximal dose and tumor margin dose), duration of follow-up review, tumor growth control rate, complications, and rate of hormone normalization in the case of functioning adenomas. A total of 35 peer-reviewed studies involving 1621 patients were examined. Radiosurgery resulted in the control of tumor size in approximately 90% of treated patients. The reported rates of hormone normalization for functioning adenomas varied substantially. This was due in part to widespread differences in endocrinological criteria used for the postradiosurgical assessment. The risks of hypopituitarism, radiation-induced neoplasia, and cerebral vasculopathy associated with radiosurgery appeared lower than those for fractionated radiation therapy. Nevertheless, further observation will be required to understand the true probabilities. The incidence of other serious complications following radiosurgery was quite low. CONCLUSIONS: Although microsurgery remains the primary treatment modality in most cases, stereotactic radiosurgery offers both safe and effective treatment for recurrent or residual pituitary adenomas. In rare instances, radiosurgery may be the best initial treatment for patients with pituitary adenomas. Further refinements in the radiosurgical technique will likely lead to improved outcomes.

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J Neurosurg. 2005 Apr;102(4):650-7.
Long-term neurological, visual, and endocrine outcomes following transnasal resection of craniopharyngioma.
Chakrabarti I, Amar AP, Couldwell W, Weiss MH.
Department of Neurological Surgery, University of Southern California, Los Angeles, California 90032, USA. Ichakrab@usc.edu

OBJECT: The authors report on a cohort of patients with craniopharyngioma treated principally through transnasal (TN) resection and followed up for a minimum of 5 years. More specifically, they evaluate the role of the TN approach in the management of craniopharyngioma. METHODS: Between 1984 and 1994, 68 patients underwent TN resection of craniopharyngiomas at the University of Southern California. The tumor was at least partially cystic in 88% of cases. Four tumors were purely intrasellar, 53 had intra- and suprasellar components, and 11 were exclusively suprasellar. During the same period, 18 patients underwent transcranial (TC) resection of purely suprasellar craniopharyngiomas. Long-term neurological, visual, and endocrine outcomes were reviewed for all patients. In 61 (90%) of 68 patients in the TN group, total resection was achieved, according to 3-month postoperative magnetic resonance images, although four patients suffered a recurrence. Three (43%) of the seven tumors that had been partially resected were enlarged on serial imaging. Fifty-four (87%) of 62 patients with preoperative visual loss experienced improvement in one or both eyes, but two patients (3%) with exclusively suprasellar tumors experienced postoperative visual worsening in one or both eyes. New instances of postoperative endocrinopathy (that is, not present preoperatively) occurred as follows: hypogonadism (eight of 22 cases), growth hormone (GH) deficiency (four of 18 cases), hypothyroidism (11 of 49 cases), hypocortisolemia (nine of 52 cases), and diabetes insipidus (DI; four of 61 cases). One case each of hypocortisolemia and hypothyroidism resolved after surgery. Hyperphagia occurred in 27 (40%) of 68 patients. One patient had short-term memory loss. Postoperative complications included one case of cerebrospinal fluid leak. Among the 18 patients in the TC group, 11 had complete resections. In one case (9%) the tumors recurred. Three (43%) of the seven subtotally resected tumors grew during the follow-up interval. Vision improved in 11 (61%) of 18 cases and worsened in three (17%) as a result of surgery. New instances of postoperative endocrinopathy occurred as follows: hypogonadism (one of six cases), GH deficiency (four of seven cases), hypothyroidism (11 of 14 cases), hypocortisolemia (eight of 15 cases), and DI (nine of 16 cases). No instance of preoperative endocrinopathy was corrected through TC surgery. Four patients (22%) exhibited short-term memory loss and 11 (61%) had hyperphagia after surgery. When compared with those in the TC group, patients in the TN group had shorter hospital stays. CONCLUSIONS: Use of the TN approach can render good outcomes in properly selected patients with craniopharyngioma, particularly when the tumor is cystic. Even in mostly suprasellar cases, an extended TN approach can afford complete resection. Note that endocrine function often worsens after surgery and that postoperative obesity can be a significant problem.

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Int J Clin Oncol. 2005 Apr;10(2):74-80.
Surgical treatment of brain metastasis.
Fujimaki T.
Department of Neurosurgery, Teikyo University School of Medicine, 2-11-1 Kaga, Tokyo 173-8605, Japan. tfujimak-tky@umin.ac.jp

Treatment modalities for brain metastasis or metastatic brain tumor include surgery, conventional irradiation, stereotactic radiosurgery (SRS), chemotherapy, and supportive care with corticosteroid. In most cases, these treatments are used in combination. For a single metastasis, surgery followed by whole-brain radiation therapy (WBRT) has been the standard treatment. SRS has become increasingly popular and challenges the standard procedure, but there are still insufficient data for the outcomes of combinations including SRS. For the treatment of multiple metastases, WBRT is the standard procedure. For tumors larger than 3 cm, and in life-threatening situations such as a large metastasis to the cerebellum, surgery is the only feasible approach. Histological examination is sometimes useful for characterizing metastatic tumors from unknown primary sites. Thus, although brain metastasis invariably indicates a stage 4 cancer, some patients can benefit from surgery.

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N Engl J Med. 2005 Mar 10;352(10):987-96.
Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma.
Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO; European Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups; National Cancer Institute of Canada Clinical Trials Group.
Multidisciplinary Oncology Center, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland. roger.stupp@chuv.hospvd.ch

BACKGROUND: Glioblastoma, the most common primary brain tumor in adults, is usually rapidly fatal. The current standard of care for newly diagnosed glioblastoma is surgical resection to the extent feasible, followed by adjuvant radiotherapy. In this trial we compared radiotherapy alone with radiotherapy plus temozolomide, given concomitantly with and after radiotherapy, in terms of efficacy and safety. METHODS: Patients with newly diagnosed, histologically confirmed glioblastoma were randomly assigned to receive radiotherapy alone (fractionated focal irradiation in daily fractions of 2 Gy given 5 days per week for 6 weeks, for a total of 60 Gy) or radiotherapy plus continuous daily temozolomide (75 mg per square meter of body-surface area per day, 7 days per week from the first to the last day of radiotherapy), followed by six cycles of adjuvant temozolomide (150 to 200 mg per square meter for 5 days during each 28-day cycle). The primary end point was overall survival. RESULTS: A total of 573 patients from 85 centers underwent randomization. The median age was 56 years, and 84 percent of patients had undergone debulking surgery. At a median follow-up of 28 months, the median survival was 14.6 months with radiotherapy plus temozolomide and 12.1 months with radiotherapy alone. The unadjusted hazard ratio for death in the radiotherapy-plus-temozolomide group was 0.63 (95 percent confidence interval, 0.52 to 0.75; P<0.001 by the log-rank test). The two-year survival rate was 26.5 percent with radiotherapy plus temozolomide and 10.4 percent with radiotherapy alone. Concomitant treatment with radiotherapy plus temozolomide resulted in grade 3 or 4 hematologic toxic effects in 7 percent of patients. CONCLUSIONS: The addition of temozolomide to radiotherapy for newly diagnosed glioblastoma resulted in a clinically meaningful and statistically significant survival benefit with minimal additional toxicity. Copyright 2005 Massachusetts Medical Society.

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N Engl J Med. 2005 Mar 10;352(10):978-86.
Treatment of early childhood medulloblastoma by postoperative chemotherapy alone.
Rutkowski S, Bode U, Deinlein F, Ottensmeier H, Warmuth-Metz M, Soerensen N, Graf N, Emser A, Pietsch T, Wolff JE, Kortmann RD, Kuehl J.
Department of Pediatric Oncology, Children's Hospital, University of Wurzburg, Wurzburg, Germany. rutkowski@mail.uni-wuerzburg.de

BACKGROUND: The prognosis for young children with medulloblastoma is poor, and survivors are at high risk for cognitive deficits. We conducted a trial of the treatment of this brain tumor by intensive postoperative chemotherapy alone. METHODS: After surgery, children received three cycles of intravenous chemotherapy (cyclophosphamide, vincristine, methotrexate, carboplatin, and etoposide) and intraventricular methotrexate. Treatment was terminated if a complete remission was achieved. Leukoencephalopathy and cognitive deficits were evaluated. RESULTS: Forty-three children were treated according to protocol. In children who had complete resection (17 patients), residual tumor (14), and macroscopic metastases (12), the five-year progression-free and overall survival rates (+/-SE) were 82+/-9 percent and 93+/-6 percent, 50+/-13 percent and 56+/-14 percent, and 33+/-14 percent and 38+/-15 percent, respectively. The rates in 31 patients without macroscopic metastases were 68+/-8 percent and 77+/-8 percent. Desmoplastic histology, metastatic disease, and an age younger than two years were independent prognostic factors for tumor relapse and survival. Treatment strategies at relapse were successful in 8 of 16 patients. There were no major instances of unexpected toxicity. In 19 of 23 children, asymptomatic leukoencephalopathy was detected by magnetic resonance imaging. After treatment, the mean IQ was significantly lower than that of healthy controls within the same age group but higher than that of patients in a previous trial who had received radiotherapy. CONCLUSIONS: Postoperative chemotherapy alone is a promising treatment for medulloblastoma in young children without metastases. Copyright 2005 Massachusetts Medical Society.

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Med Clin (Barc). 2005 Feb 26;124(7):271-3.
[Radiation therapy with synchrotron radiation and cysplatine-based chemotherapy as a treatment of gliomas.]
[Article in Spanish]
Ferrer S.
ALBA Edificio Ciencias. C-3 central UAB. Bellaterra. Barcelona. Espana.

The application of synchrotron radiation in medicine dates back to more than one decade. In particular, a team of researchers led by Dr. F. Esteve has been working for several years in the Grenoble Synchrotron (ESRF) on radiotherapy treatments to heal brain tumors. The team has recently obtained a very promising new result. Gliomas the commonest brain tumor in the adult and the mean survival in advanced disease patients is lower than one year. Conventional radiation therapy is used palliatively since it is one of the most radiotherapy-resistant tumors. Moreover, chemotherapy and surgery have no utility in most cases. Experiments at the Grenoble Synchrotron have been carried out in mice with gliomas and they consist of injecting cysplatine into the tumors so that an intense monochromatic radiation is applied afterwards. Half-life of sick untreated mice is 28 days. With the use of cysplatine alone, it expands to 48 days. However, the association of two treatments supposes a half-life of 206 days (six times greater than in untreated mice). After one year of treatment, 34% of animals remain alive, which constitutes a result never seen before in this type of radio-resistant tumors.

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J Neurosurg. 2005 Feb;102(2):209-15.
Resection of brain metastases previously treated with stereotactic radiosurgery.
Vecil GG, Suki D, Maldaun MV, Lang FF, Sawaya R.
Department of Neurosurgery, Brain and Spine Tumor Center, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030-4009, USA.

OBJECT: To date, no report has been published on outcomes of patients undergoing resection for brain metastases who were previously treated with stereotactic radiosurgery (SRS). Consequently, the authors reviewed their institutional experience with this clinical scenario to assess the efficacy of surgical intervention. METHODS: Sixty-one patients (each harboring three or fewer brain lesions), who were treated at a single institution between June 1993 and August 2002 were identified. Patient charts and their neuroimaging and pathological reports were retrospectively reviewed to determine overall survival rates, surgical complications, and recurrence rates. A univariate analysis revealed that patient preoperative recursive partitioning analysis (RPA) classification, primary disease status, preoperative Karnofsky Performance Scale score, type of focal treatment undergone for nonindex lesions, and major postoperative surgical complications were factors that significantly affected survival (p < or = 0.05). In contrast, only the RPA class and focal (conventional surgery or SRS) treatment of nonindex lesions significantly (or nearly significantly) affected survival in the multivariate analysis. Major neurological complications occurred in only 2% of patients. The median time to distant recurrence after resection was 8.4 months; that to local recurrence was not reached. The overall median survival time was 11.1 months, with 25% of patients surviving 2 or more years. Conventional surgery facilitated tapering of steroid administration. Conclusions. The complication, morbidity, survival, and recurrence rates are consistent with those seen after conventional surgery for recurrent brain metastases. Our results indicate that in selected patients with a favorable RPA class in whom nonindex lesions are treated with focal modalities, surgery can provide long-term control of SRS-treated lesions and positively affect overall survival.

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J Neurooncol. 2005 Feb;71(3):301-5.
A Phase II trial of paclitaxel and topotecan with filgrastim in patients with recurrent or refractory glioblastoma multiforme or anaplastic astrocytoma.
Pipas JM, Meyer LP, Rhodes CH, Cromwell LD, McDonnell CE, Kingman LS, Rigas JR, Fadul CE.
Neuro-Oncology Program, Dartmouth-Hitchcock Medical Center/Norris Cotton Cancer Center, 1 Medical Center Drive, New Hampshire, Lebanon, NH, USA, 03756, j.marc.pipas@hitchcock.org.

Purpose: Therapy for high-grade gliomas remains unsatisfactory. Paclitaxel and topotecan have separately demonstrated activity against gliomas. We conducted a Phase II trial of these agents in combination with filgrastim (G-CSF) in patients with recurrent or refractory glioblastoma multiforme or anaplastic astrocytoma.Patients and Methods: Adult patients with radiographic evidence of recurrent or progressive tumor following primary therapy were eligible for study. Patients received paclitaxel 175 mg/m(2) IV over 3 h on day 1 and topotecan 1.0 mg/m (2) IV over 30 min on days 1-5. Filgrastim 5 mug/kg was given days 6-14 for neutrophil support. Treatment cycles were repeated every 21 days.Results: Twenty patients were enrolled on study, and seventeen were considered evaluable for response. Two patients (12/%) exhibited partial remission and seven patients (41/%) exhibited stable disease in response to therapy. Hematologic toxicity was common with 25 /% of patients experiencing grade III or IV leukopenia despite G-CSF support. Two patients died of infectious complications on protocol, prompting suspension of further accrual.Conclusion: Paclitaxel and topotecan with G-CSF support exhibits modest activity in adults with recurrent or refractory glioblastoma and anaplastic astrocytoma. The significant hematotoxicity encountered, however, cannot justify further investigation of this combination in patients with high grade brain tumors.

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Neuro-oncol. 2005 Jan;7(1):41-8.
Sequential chemotherapy, high-dose thiotepa, circulating progenitor cell rescue, and radiotherapy for childhood high-grade glioma.
Massimino M, Gandola L, Luksch R, Spreafico F, Riva D, Solero C, Giangaspero F, Locatelli F, Podda M, Bozzi F, Pignoli E, Collini P, Cefalo G, Zecca M, Casanova M, Ferrari A, Terenziani M, Meazza C, Polastri D, Scaramuzza D, Ravagnani F, Fossati-Bellani F.
Pediatric Oncology Unit, Istituto Nazionale Tumori, Milan, Italy. maura.massimino@istitutotumori.mi.it

Childhood malignant gliomas are rare, but their clinical behavior is almost as aggressive as in adults, with resistance to therapy, rapid progression, and not uncommonly, dissemination. Our study protocol incorporated sequential chemotherapy and high-dose thiotepa in the preradiant phase, followed by focal radiotherapy and maintenance with vincristine and lomustine for a total duration of one year. The induction treatment consisted of two courses of cisplatin (30 mg/m2) plus etoposide (150 mg/m2) x 3 days and of vincristine (1.4 mg/m2) plus cyclophosphamide (1.5 g/m2) plus high-dose methotrexate (8 g/m2), followed by high-dose thiotepa (300 mg/m2 x 3 doses), with harvesting of peripheral blood progenitor cells after the first cisplatin/etoposide course. From August 1996 to March 2003, 21 children, 14 females and 7 males, with a median age of 10 years were enrolled, 18 presenting with residual disease after surgery. Histologies were glioblastoma multiforme in 10, anaplastic astrocytoma in nine, and anaplastic oligodendroglioma in two; sites of origin were supratentorial areas in 17, spine in two, and posterior fossa in two. Of the 21 patients, 12 have died (10 after relapse, with a median time to progression for the whole series of 14 months; one with intratumoral bleeding at 40 months after diagnosis; and one affected by Turcot syndrome for duodenal cancer relapse). Four of 12 relapsed children had tumor dissemination. At a median follow-up of 57 months, overall survival and progression-free survival at four years were 43% and 46%, respectively. Sequential and high-dose chemotherapy can be afforded in front-line therapy of childhood malignant glioma without excessive morbidity and rather encouraging results.

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J Neurooncol. 2005 Jan;71(2):181-187.
A study of sequential high dose cyclophosphamide and high dose carboplatin with peripheral stem-cell rescue in resistant or recurrent pediatric brain tumors.
Foreman NK, Schissel D, Le T, Strain J, Fleitz J, Quinones R, Giller R.
The Children's Hospital, Denver, The University of Colorado, Health Sciences Center, Denver, Colorado, USA.

Purpose: To determine the maximum tolerated dose (MTD) of carboplatin with autologous hematopoietic stem-cell rescue, in children with poor-prognosis brain tumors.Patients and methods: A previously determined dose of cyclophosphamide with stem-cell rescue was used as a first course. In a second course, carboplatin was given for 3days with stem-cell rescue to 20 children. The starting dose of carboplatin was 400mg/m(2)/day with increments of 75mg/m(2)/day in subsequent cohorts. Toxicity and tumor response were recorded.Results: There were two grade IV toxicities at the dose level of 775mg/m(2)/day. There were no toxic deaths. Thus, the MTD of carboplatin was 700mg/m(2)/day for 3days. There were six complete responses (33%, 95% confidence interval [CI], 13-59%), two partial responses (11%; 95% CI, 1-35%), four with stable diseases (22%; 95% CI, 6-48%) and six progressed (33%; 95% CI, 13-59%) out of 18 assessable. Seven of the eight responses were in primitive neuroectodermal tumors (PNETs) or Germinomas. One child with a metastatic anaplastic astrocytoma had a CR. The median duration of tumor response was 10 months (range: 1.5-87months) with two children disease free at 66 and 87months. Actuarial survival is 21%. Median follow-up of survivors is 35months (range: 15-87months).Conclusion: The MTD of carboplatin with stem-cell rescue is 700mg/m(2)/day for 3days. Sequential stem-cell supported cyclophosphamide and carboplatin was tolerable in children with brain tumors and produced responses in PNETs and Germinomas.

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Curr Opin Neurol. 2004 Dec;17(6):681-6.
Update of stereotactic radiosurgery for brain tumors.
Suh JH, Vogelbaum MA, Barnett GH.
Departments of Radiation Oncology and Neurosurgery, Brain Tumor Institute, Cleveland Clinic Taussig Cancer Center, Cleveland Clinic Foundation, Cleveland, Ohio, USA.

PURPOSE OF REVIEW: This paper will review the recent publications of stereotactic radiosurgery for brain tumors. RECENT ADVANCES: Despite its controversial beginning, stereotactic radiosurgery has rapidly gained acceptance among neurosurgeons, radiation oncologists, and neuro-oncologists as a valuable treatment option for patients with certain benign and malignant brain tumors. Over the past year, a number of publications have confirmed the efficacy and safety of this treatment modality as the sole treatment modality or as part of the multimodality management of brain tumor patients. These publications ranged from the first multi-institutional phase III trial of radiosurgery for patients with brain metastases to numerous retrospective papers about treatment outcomes. Also, a number of these publications have explored the use of newer imaging modalities to improve treatment outcomes while others reported on the rare complication of radiation-associated second tumors. SUMMARY: Recent publications of stereotactic radiosurgery have increased our understanding of the use of this technology. Future studies are needed to further improve outcomes, minimize toxicities and increase our understanding of this treatment modality.

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J Clin Oncol. 2004 Nov 1;22(21):4282-9.
Phase II study of fenretinide (NSC 374551) in adults with recurrent malignant gliomas: A North American Brain Tumor Consortium study.
Puduvalli VK, Yung WK, Hess KR, Kuhn JG, Groves MD, Levin VA, Zwiebel J, Chang SM, Cloughesy TF, Junck L, Wen P, Lieberman F, Conrad CA, Gilbert MR, Meyers CA, Liu V, Mehta MP, Nicholas MK, Prados M; North American Brain Tumor Consortium.
Department of Neuro-Oncology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Unit 431, Houston TX 77030, USA. vpuduval@mdanderson.org

PURPOSE: Fenretinide induces apoptosis in malignant gliomas in vitro. This two-stage phase II trial was conducted to determine the efficacy of fenretinide in adults with recurrent malignant gliomas. PATIENTS AND METHODS: Twenty-two patients with anaplastic gliomas (AG) and 23 patients with glioblastoma (GBM) whose tumors had recurred after radiotherapy and no more than two chemotherapy regimens were enrolled. Fenretinide was given orally on days 1 to 7 and 22 to 28 in 6-week cycles in doses of 600 or 900 mg/m(2) bid. RESULTS: Six of 21 (29%) patients in the AG arm and two of 23 (9%) patients in the GBM arm had stable disease at 6 months. One patient with AG treated at 900 mg/m(2) bid dosage had a partial radiologic response. Median progression-free survival (PFS) was 6 weeks for the AG arm and 6 weeks for the GBM arm. PFS at 6 months was 10% for the AG arm and 0% for the GBM arm. Grade 1 or 2 fatigue, dryness of skin, anemia, and hypoalbuminemia were the most frequent toxicities reported. The trial was closed after the first stage because of the inadequate activity at the fenretinide doses used. The first-administration mean plasma C(max) for fenretinide was 832 +/- 360 ng/mL at the 600 mg/m(2) bid dosage and 1,213 +/- 261 ng/mL at the 900 mg/m(2) bid dosage. CONCLUSION: Fenretinide was inactive against recurrent malignant gliomas at the dosage used in this trial. However, additional studies using higher doses of the agent are warranted based on the tolerability of the agent and the potential for activity of a higher fenretinide dosage, as suggested in this trial.

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Mol Ther. 2004 Nov;10(5):967-72.
AdvHSV-tk gene therapy with intravenous ganciclovir improves survival in human malignant glioma: a randomised, controlled study.
Immonen A, Vapalahti M, Tyynela K, Hurskainen H, Sandmair A, Vanninen R, Langford G, Murray N, Yla-Herttuala S.
Department of Neurosurgery, University of Kuopio, A.I. Virtanen Institute, Finland.

Malignant glioma is a devastating brain tumor with no effective treatment. This randomised, controlled study involved 36 patients with operable primary or recurrent malignant glioma. Seventeen patients were randomized to receive AdvHSV-tk gene therapy (3 x 10(10) pfu) by local injection into the wound bed after tumor resection, followed by intravenous ganciclovir (GCV), 5 mg/kg twice daily for 14 days. The control group of 19 patients received standard care consisting of radical excision followed by radiotherapy in those patients with primary tumors. The primary end-point was survival as defined by death or surgery for recurrence. Secondary end-points were all-cause mortality and tumour progression as determined by MRI. Overall safety and quality of life were also assessed. Findings were also compared with historical controls (n = 36) from the same unit over 2 years preceding the study. AdvHSV-tk treatment produced a clinically and statistically significant increase in mean survival from 39.0 +/- 19.7 (SD) to 70.6 +/- 52.9 weeks (P = 0.0095, log-rank regression vs. randomized controls). The median survival time increased from 37.7 to 62.4 weeks. Six patients had increased anti-adenovirus antibody titers, without adverse effects. The treatment was well tolerated. It is concluded that AdvHSV-tk gene therapy with GCV is a potential new treatment for operable primary or recurrent high-grade glioma.

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Semin Oncol. 2004 Oct;31(5):666-75.
Current treatment of medulloblastoma: recent advances and future challenges.
Rood BR, Macdonald TJ, Packer RJ.
Division of Hematology/Oncology, Center for Cancer Research, Children's National Medical Center, Washington, DC 20010, USA. Brood@cnmc.org

Medulloblastoma (MB) is the most common malignant brain tumor of childhood, yet it makes up only 1% of adult brain tumors. MB is uniquely sensitive to chemotherapy and radiation, but successful surgical resection continues to be an important component of therapeutic success. Progress in the treatment of MB has occurred in multiple areas from improved neurosurgical techniques, refined dosing and delivery of radiation, and optimized chemotherapy. Tumors are currently risk-stratified as average risk or high risk depending on clinical factors such as age, extent of resection, and presence of metastases. Molecular biology is beginning to improve upon clinical prognostication and may soon provide the means to accurately predict response to therapy. Treatment for average-risk MB has achieved a level of success that allows efforts to be focused on the limitation of adverse treatment effects. Therapy for high-risk and relapsed MB has been positively affected by the advent of high-dose chemotherapy with stem cell rescue. In addition, molecular targets are being elucidated and new therapeutic agents are being tested for safety and efficacy. Treatment for this disease has evolved a great deal over the preceding decades, but a great deal of work remains to be done to effect reliable cures while reducing long-term sequelae of therapy.

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Semin Oncol. 2004 Oct;31(5):635-44.
Current management of glioblastoma multiforme.
Grossman SA, Batara JF.
Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA. grossman@jhmi.edu

Glioblastoma multiforme is the most common primary brain tumor in adults. Despite major research efforts and progress in neuroimaging, neurosurgery, and radiation and medical oncology, the overall survival of patients with this disease has changed little over the past 30 years. Surgery and radiation therapy remain critical components in the care of patients with glioblastoma multiforme. Treatment with chemotherapy has been hampered by the apparent resistance of these tumor cells to available agents and challenges in delivering agents to the tumor cells. The blood-brain barrier can restrict entry of some agents and the effect of antiepileptic drugs inducing hepatic P450 can significantly affect the pharmacology of a wide range of antineoplastic agents. As a result, new agents and novel approaches are required. Translational research efforts should: (1) pursue a broad research agenda until productive avenues are identified; (2) quantify the delivery of novel agents to the malignant brain tumor cells; (3) determine the maximum tolerated dose (MTD) and preliminary efficacy data on novel agents before initiating combination therapies; (4) optimize trial designs; and (5) improve psychosocial and supportive care for patients with this devastating illness.

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Semin Oncol. 2004 Oct;31(5):618-34.
Anaplastic astrocytoma: diagnosis, prognosis, and management.
See SJ, Gilbert MR.
Department of Neurology, National Neuroscience Institute, Singapore General Hospital, Singapore.

The designation of a tumor as anaplastic astrocytoma (AA) reflects a distinct histologic classification of malignant glioma characterized by an abundance of pleomorphic astrocytes with evidence of mitosis. Although these tumors are malignant, they have a better prognosis and a higher likelihood of response to treatment than glioblastoma. Despite advances in brain tumor imaging, making an accurate diagnosis requires the evaluation of tumor tissue and is essential for treatment planning. Currently, most patients undergo maximal surgical debulking of tumor followed by external beam radiation, often with subsequent adjuvant chemotherapy. However, despite the use of these treatment modalities, most tumors recur within a few years and these recurrent tumors are more refractory to subsequent therapies. This review examines the diagnosis, prognosis, and treatment of AAs. Ongoing clinical research investigations are also summarized, reflecting advances in our knowledge of the molecular pathogenesis of these tumors and providing hope for significant improvements in patient outcomes.

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Lakartidningen. 2004 Sep 30;101(40):3078-80.
[Gamma knife surgery improves the treatment of intracranial tumors]
[Article in Swedish]
Lippitz B.
Gamma Knife Center, Sophiahemmet, Stockholm, Sweden. bodo.lippitz@sophiahemmet.se

Radiosurgery is considered one of the most revolutionary recent developments in the therapy of certain intracranial tumors. It is generally accepted that radiosurgery with the Gamma Knife or stereotactic Linac is the least invasive effective treatment for cerebral metastases. The Gamma Knife provides so far the highest possible and practically applicable precision of radiation. Radiosurgery of brain metastases with a size of less than 12 cm3 results in excellent local tumor control rates and very low associated morbidity. The Gamma Knife has been shown to be highly effective also against multiple metastases and is likewise effective even for tumors that are relatively resistant to traditional external beam radiation therapy. Radiosurgery replaces open tumor operation in some indications. As an additive therapy it allows the conventional surgeon to operate less radically resulting in a lower complication rate. The goal is short hospitalization time and increased quality of life.

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Cancer Invest. 2004;22(3):405-16.
Dendritic cell-based immunotherapy of malignant gliomas.
Parajuli P, Sloan AE.
Department of Neurosurgery, Wayne State University and Karmanos Cancer Institute, Detroit, Michigan 48201, USA. pparajuli@neurosurgery.wayne.edu

The failure of conventional treatment modalities for gliomas, in spite of tremendous progress in research in the past two decades, has led to increasing interest in alternative treatment strategies, including immunotherapy. It has become evident that vaccination with dendritic cells (DC), designed to express tumor antigens, is a potent strategy to elicit anti-tumor immune response in both pre-clinical and clinical settings. Various methods have been applied in order to induce DC to express tumor antigens including: pulsing with isolated tumor peptides or whole tumor lysate; fusion with tumor cells; and pulsing with apoptotic tumor cells. Herein, we review the recent progress in DC biology with regard to tumor immunity and discuss current DC-based strategies and future prospects in immunotherapy for malignant gliomas.

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Expert Opin Biol Ther. 2004 Sep;4(9):1453-71.
Monoclonal antibodies for brain tumour treatment.
Boskovitz A, Wikstrand CJ, Kuan CT, Zalutsky MR, Reardon DA, Bigner DD.
Department of Pathology, Duke University Medical Center, Durham, NC 27710, USA.

Conventional treatment of brain tumours includes surgical, radiotherapeutic and chemotherapeutic modalities. Nonetheless, the outcome of patients with brain tumours, in particular glioblastoma, remains poor. Immunotherapy with armed or unarmed monoclonal antibodies targeting tumour-specific antigens has emerged in the last two decades as a novel potential adjuvant treatment for all types of neoplasia. Many challenges to its implementation as a safe and viable therapy for brain tumours still need to be addressed; nevertheless, results from ongoing Phase I/II clinical trials are encouraging, as disease stabilisation and patient survival prolongation have been observed. Advances in preclinical and clinical research indicate that treatment of brain tumours with monoclonal antibodies can be increasingly adjusted to the characteristics of the targeted tumour and its environment. This aspect relies on the careful selection of the target antigen and corresponding specific monoclonal antibody, and antibody format (size, class, affinity), conjugation to the appropriate toxin or radioactive isotope (half-life, range), and proper compartmental administration.

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Pediatr Blood Cancer. 2004 Aug;43(2):126-33.
Intensive cisplatin and cyclophosphamide-based chemotherapy without radiotherapy for intracranial germinomas: failure of a primary chemotherapy approach.
Kellie SJ, Boyce H, Dunkel IJ, Diez B, Rosenblum M, Brualdi L, Finlay JL.
Oncology Unit, The Children's Hospital at Westmead, Sydney, NSW, Australia. stewartk@chw.edu.au

PURPOSE: High rates of overall and event-free survival have been reported in patients with intracranial germinomas treated with craniospinal radiotherapy. More recently, similar results have been reported with chemotherapy combined with radiotherapy to more localized treatment volumes. Our interest in exploring chemotherapy without radiotherapy in patients with CNS germinomas was based on concerns about the late sequelae of radiotherapy to the brain or neuraxis and also the well documented success of chemotherapy alone in patients with disseminated extracranial germinomas. The primary objective of this study was to determine whether intensive cisplatin and cyclophosphamide-based combination chemotherapy, without radiotherapy, was effective in patients with CNS germinomas. PATIENTS AND METHODS: Nineteen patients were enrolled, ranging in age from 1 to 24 years (median, 14 years). Thirteen were male. Nine had diabetes insipidus. Therapy comprised two courses of Regimen 'A' (cisplatin, etoposide, cyclophosphamide, and bleomycin) followed by MRI evaluation. Patients achieving a complete remission (CR) completed all planned therapy with two courses of regimen 'B' (carboplatin, etoposide, and bleomycin). Patients achieving less than a CR received two courses of Regimen 'B' followed by another evaluation. Those in CR after four courses of treatment received one additional course of Regimen 'A' and Regimen 'B', while those not in CR after four treatment courses underwent second look surgery and/or radiation therapy. RESULTS: Eleven of 11 patients with residual postoperative disease assessable for response achieved a CR. With a median follow-up of 6.5 years, eight out of 19 (0.42) patients remain in CR 1 without radiotherapy and another three patients are in stable second or subsequent remissions. Three patients died from treatment-related toxicity and another died in CR 1 from an uncharacterized leukoencephalopathy. The 5-year event-free survival (EFS) was 0.47 +/- 0.23 and 5-year overall survival (OS) was 0.68 +/- 0.22. CONCLUSIONS: Intensive cisplatin and cyclophosphamide-based chemotherapy was effective in achieving remissions, however, the long-term outcome using this treatment program was unsatisfactory and associated with unacceptable morbidity and mortality, particularly in patients with diabetes insipidus. Copyright 2004 Wiley-Liss, Inc.

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AJNR Am J Neuroradiol. 2004 Aug;25(7):1211-7.
CT and MR imaging after placement of the GliaSite radiation therapy system to treat brain tumor: initial experience.
Matheus MG, Castillo M, Ewend M, Smith JK, Knock L, Cush S, Morris DE.
Department of Radiology, University of North Carolina School of Medicine, Chapel Hill, NC, USA.

BACKGROUND AND PURPOSE: The GliaSite system delivers local, high radiation after brain tumor resection. We describe the imaging appearance of the device and the changes it causes. METHODS: Eight patients with brain tumors were treated with this system. After surgery, all underwent MR imaging, and one underwent CT. Five were examined 1 month after radioactive unloading and every 2 months thereafter (total, 6-9 months). Initial studies were assessed for balloon appearance and complications; subsequent studies, for signal intensity and enhancement. Three patients underwent multivoxel proton MR spectroscopy, and one underwent MR perfusion study. Spectra were reviewed for metabolites suggesting tumor; perfusion studies were reviewed for increased relative cerebral blood volume and flow. RESULTS: CT showed the hyperattenuating balloon with considerable artifact. All MR images showed the device and adjacent brain. Follow-up studies showed enhancement and T2 hyperintensity in five patients. In one, enhancement progressively disappeared with no evidence of tumor recurrence. Another patient had progressive enhancement and low relative cerebral blood volume and flow; biopsy showed necrosis and inflammation. One patient had progressive enhancement and high choline levels (proved anaplastic astrocytoma). In another, T2 signal intensity and contrast enhancement progressed owing to tumor and bacterial infection. The last patient had a high choline level (proved radionecrosis); enhancement progressed over 5 months. In three, the device was removed early because of bleeding, mass effect, and therapeutic changes (no follow-up). CONCLUSION: Good balloon visualization was possible with MR imaging. After brachytherapy, all patients developed T2 hyperintensity; stable or progressive enhancement occurred with tumor recurrence and radionecrosis. High choline levels were suggestive of, but not necessarily diagnostic of, tumor.

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Br J Cancer. 2004 Aug 2;91(3):425-9.
Temozolomide in paediatric high-grade glioma: a key for combination therapy?
Verschuur AC, Grill J, Lelouch-Tubiana A, Couanet D, Kalifa C, Vassal G.
Department of Paediatric Oncology, Institut Gustave Roussy, 39 rue Camille Desmoulins, 94805 Villejuif, France. a.c.verschuur@amc.uva.nl

This report describes a single-centre study with temozolomide (TMZ) (200 mg m(-2) day(-1) x 5 per cycle of 28 days) in children with (recurrent) high-grade glioma. Magnetic resonance imaging was performed every two cycles. In all, 20 patients were treated between 1998 and 2001 after the UKCCSG/SFOP TMZ phase II trial. All patients had measurable disease. Totally, 15 patients had a relapse after surgery+/-radiotherapy+/-chemotherapy. Overall, five patients received TMZ after surgery or biopsy, awaiting radiotherapy. There were one clinically malignant grade II glioma, 11 grade III and eight grade IV gliomas. Seven tumours had oligodendroglial features. Mean age at start of TMZ was 12.0 years (range 3-20.5 years). In total, eight patients had >8 cycles (range 3-30). One VGPR (currently in CR after surgery), three PRs (with a PFS of 4, 4 and 11 months, respectively) and one MR (PFS 14 months) were observed. Three out of five responses occurred after >4 courses. The overall response rate was 20%. Median progression-free survival (PFS) was 2.0 months (range 3 weeks-34+ months). PFS rate was 20% after 6 months. Median overall survival (OS) was 10 months. Nine patients showed a clinical improvement. Three patients vomitted shortly after TMZ administration, eight patients (13 cycles) experienced grade III/IV thrombocytopenia, occurring predominantly during the fourth week of the first two cycles. Five patients experienced neutropenia, and three patients febrile neutropenia. TMZ is a well-tolerated ambulatory treatment for children with malignant glial tumours. This drug warrants further study in these highly chemoresistant tumours and should be studied either as upfront therapy or in combination therapy.

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Oncologist. 2004;9(4):442-50.
Conformal radiation therapy for childhood CNS tumors.
Kirsch DG, Tarbell NJ.
Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.

Radiation therapy plays a central role in the management of many childhood brain tumors. By combining advances in brain tumor imaging with technology to plan and deliver radiation therapy, pediatric brain tumors can be treated with conformal radiation therapy. Through conformal radiation therapy, the radiation dose is targeted to the tumor, which can minimize the dose to normal brain structures. Therefore, by limiting the radiation dose to normal brain tissues, conformal radiation therapy offers the possibility of limiting the long-term side effects of brain irradiation.In this review, we describe different approaches to conformal radiation therapy for pediatric central nervous system tumors including: A) three-dimensional conformal radiation therapy; B) stereotactic radiation therapy with arc photons; C) intensity-modulated radiation therapy; and D) proton beam radiation therapy. We discuss the merits and limitations of these techniques and describe clinical scenarios in which conformal radiation therapy offers advantages over conventional radiation therapy for treating pediatric brain tumors. Copyright AlphaMed Press

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J Neurosurg. 2004 Aug;101(2):227-32.
Endoscope-assisted microsurgical resection of epidermoid tumors of the cerebellopontine angle.
Schroeder HW, Oertel J, Gaab MR.
Department of Neurosurgery, Ernst Moritz Arndt University, Greifswald, Germany. henry.schroeder@uni-greifswald.de

OBJECT: Epidermoid tumors located in the cerebellopontine angle (CPA) are challenging lesions because they grow along the subarachnoid spaces around delicate neurovascular structures and often extend into the middle cranial fossa. The purpose of this study was to determine the value of endoscopic assistance in the microsurgical resection of these lesions, in which total removal is the therapy of choice. METHODS: Eight patients harboring an epidermoid tumor of the CPA were treated using an endoscope-assisted microsurgical technique. A retrosigmoid suboccipital approach was used in five patients and a pterional transsylvian approach was chosen in the other three. In four patients the lesion was resected microsurgically and the endoscope was used repeatedly to verify complete tumor removal, whereas most of the tumor mass was removed with the aid of an operating microscope in the other four. Tumor parts extending into other cranial compartments that were not visible through the microscope were removed under endoscopic view by using rigid rod-lens scopes with 30 and 70 degrees angles of view. All epidermoids were completely evacuated and the membranes were widely resected. Large tumors occupying both the middle and posterior cranial fossa were removed through a single small opening without enlarging the craniotomy. Permanent hearing loss and permanent hypacusis were observed in one patient each. One patient with facial and one with abducent nerve palsy recovered within 6 and 4 months, respectively. A transient weakness of the chewing muscles was encountered in one patient. Postoperative magnetic resonance imaging revealed no residual tumor in any patient. To date no recurrences have been-observed (follow up range 12-98 months). CONCLUSIONS: The endoscope-assisted microsurgical technique enables safe removal even when tumor parts are not visible in a straight line. Tumor extensions into adjacent cranial compartments can be removed with the same approach without retracting neurovascular structures or enlarging the craniotomy.

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Cancer. 2004 Aug 15;101(4):825-33.
Initial treatment of melanoma brain metastases using gamma knife radiosurgery: an evaluation of efficacy and toxicity.
Radbill AE, Fiveash JF, Falkenberg ET, Guthrie BL, Young PE, Meleth S, Markert JM.
Department of Medicine, Children's Hospital, Boston, Massachusetts, USA.

BACKGROUND: Melanoma is the primary malignancy that is most likely to metastasize to the brain. Because such an event carries an almost uniformly poor prognosis, the current study reviewed outcomes and identified associated prognostic indicators for 51 consecutive patients receiving gamma knife (GK) radiosurgery in the initial treatment of 188 intracranial melanoma metastases. METHODS: Data were collected retrospectively from a single-center GK radiosurgery database and from primary patient medical records and radiographs. RESULTS: At presentation, 71% of patients had multiple intracranial metastases, and extracranial metastases were present in 66% of patients. Thirty-two patients (63%) were initially treated with GK radiosurgery alone, whereas the remainder received GK radiosurgery in combination with surgery and/or whole-brain radiotherapy (WBRT). Overall median survival from time of GK radiosurgery was 26 weeks. Subgroup analysis revealed a median survival of 77 weeks for patients presenting with a single lesion, compared with 20 weeks for patients presenting with multiple lesions (P = 0.003). Patients in recursive partitioning analysis (RPA) Class I survived a median of 57 weeks, compared with a median survival of 20 weeks for patients in RPA Class II or III (P = 0.002). Although long-term imaging follow-up revealed that a majority of patients experienced distant brain metastases, multivariate analysis showed that distant metastases occurred significantly sooner in patients with extracranial metastases (P = 0.0004). Addition of initial WBRT had no significant effect on the time to development of new brain metastases (P = 0.13). Local control (crude) was observed in 81% of lesions initially treated with GK. Patients experienced improved or stable symptoms for a median of 37 weeks post-GK radiosurgery. CONCLUSIONS: Survival analyses supported the use of GK radiosurgery in the initial treatment of patients with melanoma brain metastases, with best results occurring in patients presenting with a single lesion. Copyright 2004 American Cancer Society.

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Am J Clin Oncol. 2004 Aug;27(4):420-4.
Survival in relation to radiotherapeutic modality for brain metastasis: whole brain irradiation vs. gamma knife radiosurgery.
Datta R, Jawahar A, Ampil FL, Shi R, Nanda A, D'Agostino H.
Department of Radiology/Radiation Oncology, LSU Health Sciences Center-Shreveport, Shreveport, LA 71130, USA. rdatta@lsuhsc.edu

The purpose of this report is to evaluate and compare the survival of patients with brain metastasis (BRM) treated by whole brain irradiation (WBI) using linear energy accelerator (LINAC) and by stereotactic radiosurgery using gamma knife. This study consists of a series of 67 patients with BRM treated with WBI between 1998 and 1999 and 53 patients with BRM treated with gamma knife radiosurgery (GKRS) between 2000 and 2001. A retrospective study of the data was performed and the overall survival between these 2 groups was analyzed. The comparability of these 2 groups was tested by chi2 and t test values. Log-rank test was used in the survival comparison. The 1-year survival rate was 26.3% and 22.6%, and corresponding mean survival was 7.8 months and 6.7 months for WBI and GKRS groups, respectively. There was no statistically significant difference between these 2 groups' survival. It was evident from imaging defined lesions that with GKRS the lesions were reduced, stabilized, or disappeared in 89% of cases. Survival of patients with BRM treated with WBI or GKRS was similar in these series. The present study suggests that good tumor response by GKRS does not translate in longer patient survival.

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Tumori. 2004 May-Jun;90(3):294-8.
Primary cerebral lymphoma: a retrospective study in 22 immunocompetent patients.
Caroli E, Acqui M, Ferrante L.
Neurological Sciences Department, Neurosurgery, Policlinico S Andrea, University La Sapienza, Rome, Italy. manucarol2000@yahoo.it

AIMS AND BACKGROUND: Primary CNS lymphomas are uncommon tumors in immunocompetent patients. We describe the radiological features that should orient towards performing a biopsy and analyze the results in our series of patients. METHODS: We reviewed 22 immunocompetent patients with primary central nervous system lymphoma admitted in our Institute between 1977 and 1997. The follow-up period ranged from 2 months (patient deceased) to 69 months. Fourteen patients underwent surgical removal of the tumor and the remainder a biopsy. All patients received radiotherapy and 8 patients radiotherapy plus chemotherapy. RESULTS: Two of the 14 patients treated by surgical removal of the tumor died. There was no mortality related to biopsy procedures. Patients treated with radiotherapy had 1-year, 2-year and 5-year survival rates of 66%, 41.6% and 16.6%, compared to 87.5%, 62.5% and 50%, respectively, for patients who received radiotherapy and chemotherapy. CONCLUSIONS: At present, there is no definite treatment for these highly malignant brain tumors. The most favorable results seem related to biopsy followed by radiotherapy plus chemotherapy versus surgical removal, which is related to a high risk of severe postoperative deficit for both the deep location and infiltrating nature of these lesions.

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Rev Neurol (Paris). 2004 May;160(5 Pt 1):539-45.
[Results of salvage stereotactic radiosurgery in 14 patients with grade III or IV gliomas]
[Article in French]
Noel G, Ben Ammar CN, Feuvret L, Valery CA, Cornu P, Boisserie G, Simon JM, Hasboun D, Tep B, Delattre JY, Sanson M, Baillet F, Mazeron JJ.
Service de Cancerologie / Radiotherapie, Paris. noel@ipno.in2p3.fr

AIMS: To determine local control and overall survival rates of 14 patients treated for a grade III or IV glioma relapsing in a previously irradiated area and re-irradiated by stereotactic radiosurgery. PATIENTS AND METHODS: From January 1997 to October 2001, 14 patients (median age 52 Years, age range 49-58 Years, Karnofski performance score 80 to 100) received radiosurgery for a relapse of grade III (3 patients) and or grade IV (10 patients) malignant gliomas. Before relapse, all patients had undergone surgery and had been given with a classical radiation protocol. Median maximum diameter and Volume of the tumors were 38.5mm (24-86mm) and 7cm3 (2-35cm3), respectively. RESULTS: Median maximal dose at the isocenter and median minimal dose at the periphery of the lesion were 21Gy (16-38Gy) and 13Gy (9-17Gy), respectively. Mean follow-up was 8.5 Months (1-29). Median overall survival was 11.6 Months; 6-Month, 1- and 2-Year overall survival rates were 85p.100, 36p.100 and 12p.100, respectively. At univariate analysis, only histological grade was a significant prognostic factor of overall survival (p=0.03). Median disease-free survival was 8.2 Months while 6-Month and 1-Year disease-free survival rates were 69p.100 and 14p.100, respectively. According to univariate analysis, histological grade (p=0.033) and minimal dose delivered at the margin of the target Volume (p=0.02) were prognostic factors for disease-free survival. Two patients developed a symptomatic radionecrosis. CONCLUSION: Radiosurgery of relapsed primitive high-grade brain tumors is efficient and overall survival rates were encouraging.

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Cancer. 2004 Apr 15;100(8):1705-11.
Stereotactic radiosurgery for multiple brain metastases from breast carcinoma.
Muacevic A, Kreth FW, Tonn JC, Wowra B.
Department of Neurosurgery, Ludwig-Maximilians-University, Klinikum Grosshadern, Munich, Germany. amuacevi@helios.med.uni-muenchen.de

BACKGROUND: The current study analyzed the feasibility and outcome of stereotactic radiosurgery (SRS) for treatment of brain metastases from breast carcinoma. METHODS: During an 8-year period, 151 patients with a combined total of 620 brain metastases from breast carcinoma underwent 197 outpatient SRS procedures. Sixty-three percent of all patients had multiple brain metastases. The median tumor volume was 2.2 cm(3) (range, 0.1-20.9 cm(3)). The mean prescribed tumor dose was 19 +/- 4 grays. Local/distant tumor recurrences were treated with additional radiosurgical therapy for patients with stable systemic disease. All patients were categorized according to the Radiation Therapy Oncology Group classification. Survival time and freedom from local tumor recurrence were analyzed using the Kaplan-Meier method. Prognostic factors were identified using the Cox proportional hazards model. RESULTS: The overall median survival duration was 10 months after SRS. Ninety-four percent of patients did not experience local brain tumor recurrence after radiosurgery. In addition, 70.2% of patients did not have disease recurrence in the brain. Most patients died of systemically progressing malignancy. A Karnofsky performance score > 70 and recursive partitioning analysis Class I were related to prolonged survival in the univariate and multivariate analyses. Age, whole-brain radiotherapy, surgery, number of metastases, chemotherapy, and latency period from diagnosis of the primary tumor to the development of brain metastases did not reach prognostic relevance in the multivariate model. Patients with RPA I, II, and III survived 34.9, 9.1, and 7.9 months, respectively. There was no treatment related permanent morbidity and mortality. The transient morbidity rate was 17%. Sixteen patients exhibited symptomatic transient complications related to treatment. CONCLUSIONS: The results of the current study indicate that SRS is a feasible treatment concept for selected patients with multiple brain metastases from breast carcinoma. Copyright 2004 American Cancer Society.

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Cancer. 2004 Apr 15;100(8):1750-7.
Oral topotecan in children with recurrent or progressive high-grade glioma: a Phase I/II study by the German Society for Pediatric Oncology and Hematology.
Wagner S, Erdlenbruch B, Langler A, Gnekow A, Kuhl J, Albani M, Volpel S, Bucsky P, Emser A, Peters O, Wolff JE.
Department of Pediatric Oncology, Krankenhaus der Barmherzigen Bruder, Klinik St. Hedwig, Regensburg, Germany. sabine.wagner@barmherzige-regensburg.de

BACKGROUND: Continuous oral treatment with topotecan may be more effective than the typical 1-day and 5-day treatment schedules. In previous studies of continuous treatment with topotecan, increased intestinal side effects were reported in adult patients; however, the experience in pediatric patients and patients with high-grade glioma is quite limited. METHODS: Thirty-two pediatric patients with recurrent high-grade glioma (16 females and 16 males; median age, 9.5 years) were enrolled in the current Phase I/II study. Tumor locations included the cerebral cortex (n = 5), pons (n = 18), and other sites (n = 9). An injectable formulation of topotecan was administered orally, in ice-cold orange juice, once daily. The starting dose of 0.4 mg/m(2) per day was escalated on a patient-by-patient basis. At each patient's maximum dose, blood samples were obtained for the determination of plasma hydroxytopotecan and topotecan lactone concentrations and for the calculation of pharmacokinetic quantities. RESULTS: The toxicity criteria for a maximum tolerated topotecan dose were met in only 19 patients. The primary toxicity type was hematologic. The median maximum tolerated dose was 0.9 mg/m(2) per day (n = 19). The calculated maximum total plasma topotecan concentration was 3.8 ng/mL (n = 7), with an area under the concentration-time curve of 38.4 ng. hours/mL and a half-life of 4.1 hours, which would result in the complete disappearance of topotecan from the plasma after 12 hours. Objective responses were observed in 2 of 13 evaluable patients and lasted for 2.5 and 9 months, respectively (continuous clinical remission, 1 of 14 patients; partial response, 2 of 14 patients; stable disease, 7 of 14 patients; progressive disease, 4 of 14 patients). CONCLUSIONS: Oral topotecan (median dose, 0.9 mg/m(2) per day) administered once daily was well tolerated and somewhat effective in children with recurrent high-grade glioma. A schedule in which the daily dose is split so that dosing is performed twice daily may be superior to the current schedule. Copyright 2004 American Cancer Society.

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J Neurooncol. 2004 Mar-Apr;67(1-2):201-7.
Evaluation of photodynamic therapy near functional brain tissue in patients with recurrent
brain tumors.
Schmidt MH, Meyer GA, Reichert KW, Cheng J, Krouwer HG, Ozker K, Whelan HT.
Department of Neurosurgery University of Utah, Salt Lake City, UT, USA.

INTRODUCTION: Photodynamic therapy (PDT) involves the selective retention of a photosensitizer that upon activation with light mediates tumor cell destruction via the production of singlet oxygen. This study evaluates the toxicity of PDT and a new light-delivery device based on light-emitting diode (LED) technology in selected patients with brain tumors. METHODS: Twenty patients with recurrent malignant brain tumors received 22 treatments with PDT. Sixteen tumors were supratentorial and four tumors were infratentorial. Patients received IV Photofrin 24 h prior to light exposure starting at 0.75 mg kg(-1). Laser and LED arrays were used to deliver 100 J cm(-2) of light to the sensitized tumors. Fourteen patients received PDT with a laser-balloon adapter, two via interstitial optical fibers and five patients had LED based PDT. At the maximum Photofrin dose of 2.0 mg kg(-1) five patients received laser-balloon adapter light and five patients received LED light. In addition, three patients received LED light with 0.25 mg kg(-1) of Visudine, a benzoporphyrin derivative (BPD). Quantitative analysis of toxicity and time to progression was performed. RESULTS: Two patients had toxicity consisting of ataxia and facial weakness after treatment with interstitial fibers. Escalating doses of Photofrin were tolerated to the maximum dose of 2.0 mg kg(-1). BPD did not result in additional toxicity. PDT in the posterior fossa or near eloquent brain was tolerated using the LED or laser-balloon adapter. All patients had tumor responses as documented by MRI scan and the mean time to tumor progression after PDT was 67 weeks. CONCLUSION: PDT with LED balloon adapters (also tunable dye laser) has acceptable toxicity in brain tumor patients. Future studies using more effective photosensitizers could improve local recurrence control.

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Curr Opin Oncol. 2004 Mar;16(2):161-6.
Management of brain metastases in patients with melanoma.
Tarhini AA, Agarwala SS.
Department of Medicine and Division of Hematology/Oncology, Melanoma Center, University of Pittsburgh Cancer Institute, 5150 Centre Avenue, Pittsburgh, PA 15232, USA.

PURPOSE OF REVIEW: Melanoma is the third most common metastatic brain tumor in the United States and is a major cause of morbidity and mortality. The development of more effective therapies for melanoma brain metastases is a major unmet clinical need and is summarized in this review. RECENT FINDINGS: Management strategies include symptomatic treatment with corticosteroids and anticonvulsants, and definitive therapy in the form of whole-brain radiation therapy, surgical resection, stereotactic radiosurgery, and systemic therapy. The data on whole-brain radiation therapy show little impact on survival, but there is evidence that it may improve neurologic deficits. Surgery may provide a survival advantage in combination with whole-brain radiation therapy in the management of a single brain melanoma metastasis, compared with whole-brain radiation therapy alone. Stereotactic radiosurgery may offer a survival advantage (in a select group of patients with limited disease) when used alone or in combination with whole-brain radiation therapy, compared with whole-brain radiation therapy alone. Fotemustine, temozolomide, and thalidomide are three agents with high central nervous system penetration that are being actively investigated as part of systemic therapy. SUMMARY: The currently available therapeutic options offer palliative relief of symptoms in most patients and a survival advantage in selected patients with melanoma and brain metastases. An urgent need exists to further define these treatments in the context of randomized trials, several of which are under way in the United States and abroad.

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Cancer. 2004 Feb 15;100(4):807-13.
Second-line treatment with carboplatin for recurrent or progressive oligodendroglial tumors after PCV (procarbazine, lomustine, and vincristine) chemotherapy: a phase II study.
Soffietti R, Nobile M, Ruda R, Borgognone M, Costanza A, Laguzzi E, Mutani R.
Neuro-Oncology Service, Department of Neuroscience, San Giovanni Battista Hospital, University of Turin, Turin, Italy. riccardo.soffietti@unito.it

BACKGROUND: The efficacy of second-line chemotherapy for patients with recurrent or progressive oligodendroglial tumors is limited. In the current study, the authors investigated the use of carboplatin as a second-line chemotherapeutic agent against these types of tumors. METHODS: Twenty-three patients with recurrent or progressive oligodendrogliomas or oligoastrocytomas after first-line PCV (procarbazine, lomustine, and vincristine) chemotherapy were enrolled in a single-institution Phase II study of second-line carboplatin chemotherapy. All patients had undergone surgery, and most also had undergone conventional radiotherapy. Carboplatin was administered at a dose of 560 mg/m2 intravenously every 4 weeks. Responses were evaluated according to conventional criteria, based on magnetic resonance imaging (MRI) findings. RESULTS: Three of 23 patients (13%) had partial responses, with neurologic improvement. Twelve patients (52%) had stable disease; in 2 of these 12 patients, a minor response was seen on MRI. Eight patients (35%) had progressive disease. The median time to tumor progression was 3 months for all patients and 9 months for patients who experienced responses to treatment. Progression-free survival rates at 6 and 12 months were 34.8% and 8.7%, respectively. Among the salvage treatment plans followed after carboplatin chemotherapy were supportive care alone, radiotherapy, third-line chemotherapy, and reoperation. The median survival duration from the start of carboplatin administration was 16 months. Myelotoxicity was severe, with Grade 3 or 4 thrombocytopenia in 60% of patients and Grade 3 or 4 neutropenia in 48% of patients. CONCLUSIONS: When administered according to a monthly schedule, carboplatin exhibited modest activity in adult patients with recurrent or progressive oligodendroglioma or oligoastrocytoma who experienced treatment failure after PCV chemotherapy; the current treatment regimen also was associated with severe toxicity. Further improvement of second-line chemotherapy for the patient group examined in the current study is necessary. Copyright 2004 American Cancer Society.

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J Clin Oncol. 2004 Feb 15;22(4):706-13.
Change in neurocognitive functioning after treatment with cranial radiation in childhood.
Spiegler BJ, Bouffet E, Greenberg ML, Rutka JT, Mabbott DJ.
Department of Psychology, The Hospital for Sick Children, 555 University Ave, Toronto, ON M5G 1X8, Canada.

PURPOSE: To evaluate the pattern of stability and change over time across multiple domains of neurocognitive function in radiated survivors of posterior fossa (PF) tumors. PATIENTS AND METHODS: Thirty-four children (25 males) treated for malignant PF tumors were observed with serial clinical neuropsychologic assessments. Thirty patients were treated for medulloblastoma and four patients were treated for ependymoma. Twelve patients were treated with reduced-dose and 21 patients were treated with standard-dose cranial radiation. All patients received an additional boost to the PF. One patient was treated with PF radiation only. Standardized neuropsychologic tests were administered at different times after diagnosis for each child. The rate of change in scores was determined using a mixed model regression. RESULTS: Results showed a 2- to 4-point decline per year in intelligence scores. For our relatively young sample, intellectual function declined quickly in the first few years after treatment, and then more gradually. Significant declines in visual-motor integration, visual memory, verbal fluency, and executive functioning were also documented. No decline was evident for verbal memory and receptive vocabulary. CONCLUSION: Cranial radiation is associated with a decline in multiple neurocognitive domains, with a few notable exceptions. Our results must be interpreted in the context of common limitations of clinical research, including patient variability, changes in test versions, small sample size, and clinical referral bias.

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J Clin Oncol. 2003 Jul 1;21(13):2525-8.
Phase II study of first-line chemotherapy with temozolomide in recurrent oligodendroglial tumors: the European Organization for Research and Treatment of Cancer Brain Tumor Group Study 26971.
van den Bent MJ, Taphoorn MJ, Brandes AA, Menten J, Stupp R, Frenay M, Chinot O, Kros JM, van der Rijt CC, Vecht ChJ, Allgeier A, Gorlia T; European Organization for Research and Treatment of Cancer Brain Tumor Group.
Department of Neuro-Oncology, University Hospital Rotterdam/Rotterdam Cancer Center, the Netherlands. m.vandenbent@erasmusmc.nl

PURPOSE: Oligodendroglial tumors are chemotherapy-sensitive tumors, with two thirds of patients responding to combination chemotherapy with procarbazine, lomustine, and vincristine (PCV). Temozolomide (TMZ), a new alkylating and methylating agent, has demonstrated high response rates in patients with recurrent anaplastic astrocytoma. We investigated TMZ as first-line chemotherapy in recurrent oligodendroglial tumors (OD) and mixed oligoastrocytomas (OA) after surgery and radiation therapy. PATIENTS AND METHODS: In a prospective, nonrandomized, multicenter, phase II trial, patients were treated with 200 mg/m2 of TMZ on days 1 through 5 in 28-day cycles for 12 cycles. Patients with a recurrence after prior surgery and radiotherapy, and with measurable and enhancing disease on magnetic resonance imaging (MRI) were eligible for this study. Patients with large lesions and mass effect or with new clinical deficits were not eligible. Pathology and the MRI scans of all responding patients were centrally reviewed. RESULTS: Thirty-eight eligible patients were included. In three patients, pathology review did not confirm the presence of an OD or OA. TMZ was generally well tolerated. The most frequent side effects were hematologic; only one patient discontinued treatment for toxicity. In 20 (52.6%) of 38 patients (95% exact confidence interval, 35.8% to 69.0%), a complete (n = 10) or partial response to TMZ was observed. The median time to progression was 10.4 months for all patients and 13.2 months for responding patients. At 12 months from the start of treatment, 40% of patients were still free from progression. CONCLUSION: TMZ provides an excellent response rate with good tolerability in chemotherapy-naive patients with recurrent OD. A randomized phase III study comparing PCV with TMZ is warranted.

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J Clin Oncol. 2003 Jul 1;21(13):2508-18.
Phase I trial of adenovirus-mediated p53 gene therapy for recurrent glioma: biological and clinical results.
Lang FF, Bruner JM, Fuller GN, Aldape K, Prados MD, Chang S, Berger MS, McDermott MW, Kunwar SM, Junck LR, Chandler W, Zwiebel JA, Kaplan RS, Yung WK.
Department of Neurosurgery, The University of Texas M.D. Anderson Cancer Center, Houston 77030, USA. flang@mdanderson.org

PURPOSE: Advances in brain tumor biology indicate that transfer of p53 is an alternative therapy for human gliomas. Consequently, we undertook a phase I clinical trial of p53 gene therapy using an adenovirus vector (Ad-p53, INGN 201). MATERIALS AND METHODS: To obtain molecular information regarding the transfer and distribution of exogenous p53 into gliomas after intratumoral injection and to determine the toxicity of intracerebrally injected Ad-p53, patients underwent a two-stage approach. In stage 1, Ad-p53 was stereotactically injected intratumorally via an implanted catheter. In stage 2, the tumor-catheter was resected en bloc, and the postresection cavity was treated with Ad-p53. This protocol provided intact Ad-p53-treated biologic specimens that could be analyzed for molecular end points, and because the resection cavity itself was injected with Ad-p53, patients could be observed for clinical toxicity. RESULTS: Of fifteen patients enrolled, twelve underwent both treatment stages. In all patients, exogenous p53 protein was detected within the nuclei of astrocytic tumor cells. Exogenous p53 transactivated p21CIP/WAF and induced apoptosis. However, transfected cells resided on average within 5 mm of the injection site. Clinical toxicity was minimal and a maximum-tolerated dose was not reached. Although anti-adenovirus type 5 (Ad5) titers increased in most patients, there was no evidence of systemic viral dissemination. CONCLUSION: Intratumoral injection of Ad-p53 allowed for exogenous transfer of the p53 gene and expression of functional p53 protein. However, at the dose and schedule evaluated, transduced cells were only found within a short distance of the injection site. Although toxicity was minimal, widespread distribution of this agent remains a significant goal.

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J Clin Oncol. 2003 Jul 1;21(13):2519-24.
Effects of radiotherapy on cognitive function in patients with low-grade glioma measured by the folstein mini-mental state examination.
Brown PD, Buckner JC, O'Fallon JR, Iturria NL, Brown CA, O'Neill BP, Scheithauer BW, Dinapoli RP, Arusell RM, Curran WJ, Abrams R, Shaw EG.
Mayo Clinic, Division of Radiation Oncology, Rochester, MN 55905, USA.

PURPOSE: To assess the neurocognitive effects of cranial radiotherapy on patients with low-grade gliomas, we analyzed cognitive performance data collected in a prospective, intergroup clinical trial. METHODS: Patients included 203 adults with supratentorial low-grade gliomas randomly assigned to a lower dose (50.4 Gy in 28 fractions) or a higher dose (64.8 Gy in 36 fractions) of localized radiotherapy. Folstein Mini-Mental State Examination (MMSE) scores and neurologic function scores (NFS) at baseline and key evaluations were analyzed. Median follow-up was 7.4 years in 101 patients still alive. A change of more than three MMSE points was considered clinically significant. RESULTS: In patients without tumor progression, significant deterioration from baseline occurred at years 1, 2, and 5 in 8.2%, 4.6%, and 5.3% of patients, respectively. Most patients with an abnormal baseline MMSE score (< 27) experienced significant increases. Baseline variables such as radiation dose, conformal versus conventional radiotherapy, number of radiation fields, age, sex, tumor size, NFS, seizures, and seizure medications did not predict cognitive function changes. CONCLUSION: In this population, most low-grade glioma patients maintained a stable neurocognitive status after focal radiotherapy as measured by the MMSE. Patients with an abnormal baseline MMSE were more likely to have an improvement in cognitive abilities than deterioration after receiving radiotherapy. Only a small percentage of patients had cognitive deterioration after radiotherapy. However, more discriminating neurocognitive assessment tools may identify cognitive decline not apparent with the use of the MMSE.

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J Neurosurg. 2003 Jun;98(6):1263-70.
Increased locoregional blood flow in brain tumors after cervical spinal cord stimulation.
Clavo B, Robaina F, Catala L, Valcarcel B, Morera J, Carames MA, Ruiz-Egea E, Panero F, Lloret M, Hernandez MA.
Department of Radiation Oncology Research Unit, Dr. Negrin Hospital, Las Palmas, Canary Islands, Spain. bernardinoclavo@terra.es

OBJECT: Patients with high-grade gliomas have poor prognoses following standard treatment. Generally, malignant brain tumors have a decreased blood flow that results in increased resistance to radiation and reduced delivery of chemotherapeutic agents and oxygen. The aim of the present study was to assess the effect of spinal cord stimulation (SCS) on locoregional blood flow in high-grade tumors in the brain. METHODS: Fifteen patients (11 with Grade III and four with Grade IV brain tumors) had SCS devices inserted prior to scheduled radiotherapy. Both before and after SCS, the patients underwent the following procedures: 1) single-photon emission computerized tomography (SPECT) scanning; 2) middle cerebral artery (MCA) blood flow velocity measurements (centimeters/second) with the aid of transcranial Doppler (TCD) ultrasonography; and 3) common carotid artery (CCA) blood flow volume quantification (milliliters/minute) based on time-domain processing by using color Doppler ultrasonography. The indices demonstrated on SPECT scanning before SCS were significantly lower (p < 0.001) in tumor sites compared with those in peritumoral sites (32%) and healthy contralateral areas (41%). Poststimulation results revealed the following: 1) a mean increase of 15% in tumor blood flow in 75% of patients (p = 0.033), as demonstrated on SPECT scanning: 2) a mean increase of greater than 18% in systolic and diastolic blood flow velocities in both tumorous and healthy MCAs in all but one patient (p < 0.002), as exhibited on TCD ultrasonography; and 3) a mean increase of greater than 60% in blood flow volume in tumorous and healthy CCAs in all patients (p < 0.013), as revealed on color Doppler ultrasonography studies. CONCLUSIONS: Preliminary data show that SCS can modify locoregional blood flow in high-grade malignant tumors in the brain, thus indicating that SCS could be used to improve blood flow, oxygenation, and drug delivery to such tumors and could be a useful adjuvant in chemoradiotherapy.

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Vopr Onkol. 2003;49(2):170-5.
[Antigen-specific immunotherapy as a component of combined therapy for malignant brain tumors]
[Article in Russian]
Ostanin AA, Tsentner MI, Khonina NA, Leplina OIu, Shevela EIa, Nikonov SD, Stupak VV, Chernykh ER.
Institute of Clinical Immunology, Russian Academy of Medical Sciences, Siberian Branch, Institute of Traumatology and Orthopedics, Ministry of Health of the RF, Novosibirsk.

The purpose of the present research was to study immunity in the course of complex treatment for malignant gliomas of the brain and to evaluate extracorporeal antigen-specific immunotherapy (EASIT), a pilot procedure which was carried out according to an approved protocol. Initially, lowered HLA-DR+ monocyte count and in vitro inhibition of proliferative activity were reported in all patients. Inductive EASIT started in early postoperative period aborted immune disturbances caused by surgery. In 1998-2000, the procedure was performed in 33 patients with anaplastic astrocytoma (AA) (20) and glioblastoma (GB) (13). Mean dose of cell infusion was 2.43(0.18 x 109/patient and was well tolerated. There are 22 survivors and 9 patients died (GB--4 and AA--5; overall mortality--29%). Mean relapse-free survival was 14.2 mo (22); stable remission during 12-18 mo--37.5% (3/8)(GB) and 64% (9/14) (AA) Complete rehabilitation of immunity was generally reported 12 mo after the course of EASIT. Hence, complex treatment (surgery + EASIT) enhanced its efficacy in the management of brain tumors.

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J Neurooncol. 2003 May;62(3):321-8.
Locoregional radioimmunotherapy in selected patients with malignant glioma: experiences, side effects and survival times.
Goetz C, Riva P, Poepperl G, Gildehaus FJ, Hischa A, Tatsch K, Reulen HJ.
Neurochirurgische Klinik der Ludwig-Maximilians-Universitat, Munchen, Germany. cgoetz@nc.med.uni-muenchen.de

Prognosis of malignant glioma is very unfavourable mainly due to minimal tumour remnants in the peritumoural tissue. Intralesionally applied radioimmunotherapy is a possible therapeutical option with the potential to improve survival of patients with malignant glioma. We investigated side effects and survival after surgery, conventional radiotherapy and additional radioimmunotherapy with labelled tenascin-antibodies in patients with malignant glioma. METHODS: Since 1995, 37 patients were treated with radioimmunotherapy after resection and radiotherapy of a malignant glioma. Patients received antibodies labelled with yttrium-90 and iodine-131 in different doses into the tumour cavity via a previously implanted ommaya-reservoir. Treatment was applied in up to 8 cycles (mean 2.96 cycles) in time intervals of 6-8 weeks. Mean age was 46 years, histology was anaplastic astrocytoma in 13 patients and glioblastoma in 24 patients. RESULTS: For the whole group median survival time has not yet been reached. For glioblastoma the median survival time is 17 months, 5-year survival probability for anaplastic astrocytoma is 85% approximately. Quality of life was acceptable. Acute side effects following treatment were headache, seizures and worsening of pre-existing neurological symptoms. Late side effects were skin necrosis and, in 1 case, a delayed aphasia probably due to a vascular lesion. CONCLUSION: Radioimmunotherapy prolonged survival time in a selected group of patients with malignant gliomas as compared to a historical control group. Patients with anaplastic astrocytomas seem to have more benefit from this therapy than patients with glioblastomas.

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Ned Tijdschr Geneeskd. 2003 May 10;147(19):904-8.
[Surgical treatment of tumor metastases in the lungs, brain or liver]
[Article in Dutch]
van den Berkmortel FW, Ruers TJ, Bootsma GP, Verhagen AF, de Mulder PH.
Afd. Medische Oncologie, Universitair Medisch Centrum St Radboud, Postbus 9101, 6500 HB Nijmegen. f.vandenberkmortel@onco.umcn.nl

Metastases are generally an expression of widespread disease and therefore warrant systemic treatment. However, clinical observations have revealed that local surgical treatment might be beneficial in the case of organ-confined metastatic disease. Randomised studies have revealed that in the case of brain metastases, metastasectomy followed by radiotherapy, has a favourable outcome with respect to both the quality of life and overall survival. Retrospective non-randomised studies in selected patient groups show prolonged post-treatment survival in the case of both lung and liver metastasectomy. The most important prognostic factors for metastasectomy are: disease control elsewhere in the body, tumour species, the patient's general condition, and the possibility of a total resection of the metastasis. These factors form the basis of the separate decision-making process for each individual patient.

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Neurosurgery. 2003 Jun;52(6):1318-26; discussion 1326.
Brain metastases treated with radiosurgery alone: an alternative to whole brain radiotherapy?
Hasegawa T, Kondziolka D, Flickinger JC, Germanwala A, Lunsford LD.
Department of Neurological Surgery, University of Pittsburgh School of Medicine, University of Pittsburgh Medical Center, 200 Lothrop Street, Pittsburgh, PA 15213, USA.

OBJECTIVE: Whole brain radiotherapy (WBRT) provides benefit for patients with brain metastases but may result in neurological toxicity for patients with extended survival times. Stereotactic radiosurgery in combination with WBRT has become an important approach, but the value of WBRT has been questioned. As an alternative to WBRT, we managed patients with stereotactic radiosurgery alone, evaluated patients' outcomes, and assessed prognostic factors for survival and tumor control. METHODS: One hundred seventy-two patients with brain metastases were managed with radiosurgery alone. One hundred twenty-one patients were evaluable with follow-up imaging after radiosurgery. The median patient age was 60.5 years (age range, 16-86 yr). The mean marginal tumor dose and volume were 18.5 Gy (range, 11-22 Gy) and 4.4 ml (range, 0.1-24.9 ml). Eighty percent of patients had solitary tumors. RESULTS: The overall median survival time was 8 months. The median survival time in patients with no evidence of primary tumor disease or stable disease was 13 and 11 months. The local tumor control rate was 87%. At 2 years, the rate of local control, remote brain control, and total intracranial control were 75, 41, and 27%, respectively. In multivariate analysis, advanced primary tumor status (P = 0.0003), older age (P = 0.008), lower Karnofsky Performance Scale score (P = 0.01), and malignant melanoma (P = 0.005) were significant for poorer survival. The median survival time was 28 months for patients younger than 60 years of age, with Karnofsky Performance Scale score of at least 90, and whose primary tumor status showed either no evidence of disease or stable disease. Tumor volume (P = 0.02) alone was significant for local tumor control, whereas no factor affected remote or intracranial tumor control. Eleven patients developed complications, six of which were persistent. Nineteen (16.5%) of 116 patients in whom the cause of death was obtained died as a result of causes related to brain metastasis. CONCLUSION: Brain metastases were controlled well with radiosurgery alone as initial therapy. We advocate that WBRT should not be part of the initial treatment protocol for selected patients with one or two tumors with good control of their primary cancer, better Karnofsky Performance Scale score, and younger age, all of which are predictors of longer survival.

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Neurocirugia (Astur). 2003 Apr;14(2):127-39.
[Treatment of intracranial germ cell tumours and other tumours of the pineal region]
[Article in Spanish]
Regueiro CA.
Servicio de Oncologia Radioterapica. Hospital Universitario Clinica Puerta de Hierro, Madrid, Spain.

The management of patients with central nervous system germ-cell tumours is evolving, and a definitive standard has not been achieved. A large amount of data indicate that radiotherapy alone results in long-term relapse free survival rates of about 90% in patients with germinoma. Various prospective trials evaluated the results of combinations of chemotherapy and reduced dose and/or volume radiotherapy. The survival rates of combined treatment approaches were similar to the rates achieved with craniospinal radiotherapy alone. Nevertheless, the relapse rates were probably higher due to the significant number of relapses that arouse outside the volume treated with radiotherapy. Additional studies are necessary to determine the appropriate radiotherapy volumes and the role of combined treatments. Chemotherapy alone results in high relapse rates and can not be recommended. Mature teratomas are benign germ cell tumours that can be controlled with complete surgical resection in over 90% of cases. Non-germinoma germ cell tumours are a heterogeneous group of tumours that includes very aggressive tumours such as mixed and pure choriocarcinomas, yolk sac tumours, and embryonal carcinomas; and tumours with intermediate aggressiveness such as mixed tumours with germinoma and teratoma, immature teratomas and teratomas with malignant transformation. Both radiotherapy alone and chemotherapy alone result in quite low rates of tumour control and current treatment approaches include chemotherapy and radiotherapy, with surgical removal of the tumour in some patients. Pineocytomas are benign tumours that are controlled in most cases by complete surgical resection or partial surgical resection and local field irradiation. Current treatment approaches for pineoblastomas include surgery, chemotherapy, and craniospinal irradiation with a local boost. Chemotherapy alone was used to delay irradiation in infants with very little success.

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J Clin Oncol. 2003 Jul 1;21(13):2529-36.
Survival and neurologic outcomes in a randomized trial of motexafin gadolinium and whole-brain radiation therapy in brain metastases.
Mehta MP, Rodrigus P, Terhaard CH, Rao A, Suh J, Roa W, Souhami L, Bezjak A, Leibenhaut M, Komaki R, Schultz C, Timmerman R, Curran W, Smith J, Phan SC, Miller RA, Renschler MF.
University of Wisconsin-Madison, Department Human Oncology Radiation Oncology, 53792, USA. mehta@mail.humonc.wisc.edu

PURPOSE: This phase III randomized trial evaluated survival as well as neurologic and neurocognitive function in patients with brain metastases from solid tumors receiving whole-brain radiation therapy (WBRT) with or without motexafin gadolinium (MGd). PATIENTS AND METHODS: Patients were randomly assigned to 30 Gy of WBRT +/- 5 mg/kg/d MGd. Survival and time to neurologic progression determined by a blinded events review committee (ERC) were coprimary end points. Standardized investigator neurologic assessment and neurocognitive testing were evaluated. RESULTS: Four hundred one (251 non-small-cell lung cancer) patients were enrolled. There was no significant difference by treatment arm in survival (median, 5.2 months for MGd v 4.9 months for WBRT; P =.48) or time to neurologic progression (median, 9.5 months for MGd v 8.3 months for WBRT; P =.95). Treatment with MGd improved time to neurologic progression in patients with lung cancer (median, not reached for MGd v 7.4 months for WBRT; P =.048, unadjusted). By investigator, MGd improved time to neurologic progression in all patients (median, 4.3 months for MGd v 3.8 months for WBRT; P =.018) and in lung cancer patients (median, 5.5 months for MGd v 3.7 months for WBRT; P =.025). MGd improved neurocognitive function in lung cancer patients. CONCLUSION: The overall results did not demonstrate significant differences by treatment arm for survival and ERC time to neurologic progression. Investigator neurologic assessments demonstrated an MGd treatment benefit in all patients. In lung cancer patients, ERC- and investigator-determined time to neurologic progression demonstrated an MGd treatment benefit. MGd may improve time to neurologic and neurocognitive progression in lung cancer.

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J Clin Oncol. 2003 Jun 15;21(12):2299-304.
Phase II trial of thalidomide and carmustine for patients with recurrent high-grade gliomas.
Fine HA, Wen PY, Maher EA, Viscosi E, Batchelor T, Lakhani N, Figg WD, Purow BW, Borkowf CB.
Neuro-Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 10 Center Drive, MSC 1911, Building 10, Room 12S245, Bethesda, MD 20892-1911, USA. hfine@mail.nih.gov

PURPOSE: The use of thalidomide as an antiangiogenic agent has met with only limited success in the treatment of malignant gliomas. On the basis of preclinical data demonstrating synergistic antitumor activity when antiangiogenic agents are combined with cytotoxic agents, we explored the clinical activity of the combination of thalidomide and carmustine (BCNU) in patients with recurrent high-grade gliomas. PATIENTS AND METHODS: Patients with a histologic diagnosis of high-grade glioma and radiographic evidence of tumor progression after standard surgery, radiation, and chemotherapy were eligible for the study. Patients received BCNU 200 mg/m2 on day 1 of every 6-week cycle, and 800 mg/d of thalidomide that was escalated to a maximal dose of 1,200 mg/d as tolerated. RESULTS: A total of 40 patients (38 with glioblastomas, two with anaplastic gliomas) were accrued to the study. The combination of thalidomide and BCNU was well tolerated; mild myelosuppression and mild to moderate sedation were the most common side effects. The median progression-free survival (100 days) and the objective radiographic response rate (24%) for patients with glioblastoma compared favorably with data from historical controls. CONCLUSION: This is one of the first clinical trials to evaluate the strategy of combining a putative antiangiogenic agent with a cytotoxic agent in patients with primary brain tumors. Our data demonstrate that thalidomide in combination with BCNU is well tolerated and has antitumor activity in patients with recurrent high-grade gliomas. Although the combination seems to be more active than either agent alone, such conclusions await confirmatory trials.

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Int J Radiat Oncol Biol Phys. 2003 Jul 1;56(3):793-800.
Hypofractionated stereotactic radiotherapy alone without whole-brain irradiation for patients with solitary and oligo brain metastasis using noninvasive fixation of the skull.
Aoyama H, Shirato H, Onimaru R, Kagei K, Ikeda J, Ishii N, Sawamura Y, Miyasaka K.
Department of Radiology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.

PURPOSE: To evaluate the efficacy and toxicity of hypofractionated stereotactic radiotherapy (HSRT) using noninvasive fixation of the skull on solitary or oligo brain metastatic patients as an alternative to stereotactic radiosurgery (SRS) using invasive fixation. PATIENTS AND METHODS: The subjects were 87 patients who had 4 or fewer brain metastases (50 solitary, 37 oligometastases). Treatment was conducted on 159 metastases by using a linac-based stereotactic system. The median isocentric dose was 35 Gy in 4 fractions. Whole-brain irradiation was not applied as an initial treatment. For the salvage treatment of metachronous brain metastases, repeat HSRT or whole-brain irradiation was applied. RESULTS: The actuarial 1-year local tumor control rate was 81%. Treatment-related complications were observed in 4 patients in the early period (<3 months) and in 2 patients in the late period. The median survival period was 8.7 months. Metachronous brain metastases occurred in 30 patients, and none of the 18 patients who were eligible for salvage HSRT refused to receive it again. CONCLUSIONS: Hypofractionated stereotactic radiotherapy achieved tumor control and survival equivalent to those of SRS reported in the literature. The results suggested that HSRT could be an alternative for solitary or oligo brain metastatic patients with less toxicity and less invasiveness compared to SRS.

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Neurosurgery. 2003 Jun;52(6):1411-22; discussion 1422-4.
The neurosurgeon as local oncologist: cellular and molecular neurosurgery in malignant glioma therapy.
Dunn IF, Black PM.
Brain Tumor Laboratories and Department of Neurosurgery, Brigham and Women's Hospital, Boston, MA, USA.

Malignant gliomas are among the most challenging of all cancers to treat successfully, being characterized not only by aggressive proliferation and expansion but also by inexorable tumor invasion into distant brain tissue. Although considerable progress has been made in the treatment of these tumors with combinations of surgery, radiotherapy, and chemotherapy, these efforts have not been curative. Neurosurgeons as oncologists have increasingly turned their attention to therapies on a molecular scale. Of particular interest to neurosurgeons is the ability to deliver therapy locally to the tumor site or to take advantage of existing immunological mediators, enhancing drug concentrations or therapeutic cell numbers while bypassing the blood-brain barrier to maximize efficacy and minimize systemic toxicity. Exciting local-therapy approaches have been proposed for these devastating tumors. In this review, we discuss the potential applications of bioreactors, neural stem cells, immunotherapies, biodegradable polymers, and convection-enhanced drug delivery in the treatment of malignant gliomas. These approaches are at different stages of readiness for application in clinical neurosurgery, and their eventual effects on the morbidity and mortality rates of gliomas among human patients are difficult to ascertain from successes in animal models. Nevertheless, we are entering an exciting era of "nanoneurosurgery," in which molecular therapies such as those discussed here may routinely complement existing surgical, radiological, and chemotherapeutic approaches to the treatment of neuro-oncological disease. The potential to deploy any of a number of eloquently devised molecular therapies may provide renewed hope for neurosurgeons treating malignant gliomas.

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Minim Invasive Neurosurg. 2003 Apr;46(2):72-7.
Image-guided removal of supratentorial cavernomas in critical brain areas: application of neuronavigation and intraoperative magnetic resonance imaging.
Gralla J, Ganslandt O, Kober H, Buchfelder M, Fahlbusch R, Nimsky C.
Department of Neurosurgery, University Erlangen-Nurnberg, Erlangen, Germany.

In a retrospective study the postoperative results of 26 patients operated on for supratentorial cavernous hemangiomas either deep-seated or near eloquent brain areas are summarized. An exact surgical approach to these lesions is essential to prevent neurological deterioration. Three different navigation systems were used and compared according to their clinical applicability. Complete removal of the lesion was obtained in all patients of this series. In six cases (23 %) functional data from magnetoencephalography or functional magnetic resonance imaging were integrated into the navigational setup. In 14 cases (54 %) intraoperative magnetic resonance imaging was performed. The follow-up time was 3 - 26 months (mean: 10 months). In the postoperative course one patient (3.8 %) developed a hemiparesis, another one developed quadrantopia. Nineteen patients presented with preoperative seizure history, 16 of these (84 %) had no further or rare seizures after surgery. The better results in seizure control were achieved in those patients with shorter duration of seizure history before surgery. The study indicates that the application of neuronavigation allows surgery on supratentorial cavernous hemangiomas in critical brain areas with low morbidity. The intraoperative visualization of eloquent cortex areas by integration of functional data allows a fast identification and exemption of eloquent brain areas, preventing neurological deterioration. Furthermore, the intraoperative MR resection control ensures a complete resection and illustrates the minimal invasive approach.

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J Neurooncol. 2003 Mar-Apr;62(1-2):197-210.
Common challenges and problems in clinical trials of boron neutron capture therapy of brain tumors.
Gupta N, Gahbauer RA, Blue TE, Albertson B.
Division of Radiation Oncology, The Ohio State University, Columbus, OH, USA. gupta.6@osu.edu

Clinical trials for binary therapies, like boron neutron capture therapy (BNCT), pose a number of unique problems and challenges in design, performance, and interpretation of results. In neutron beam development, different groups use different optimization parameters, resulting in beams being considerably different from each other. The design, development, testing, execution of patient pharmacokinetics and the evaluation of results from these studies differ widely. Finally, the clinical trials involving patient treatments vary in many aspects such as their dose escalation strategies, treatment planning methodologies, and the reporting of data. The implications of these differences in the data accrued from these trials are discussed. The BNCT community needs to standardize each aspect of the design, implementation, and reporting of clinical trials so that the data can be used meaningfully.

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J Neurooncol. 2003 Mar-Apr;62(1-2):123-34.
Boron neutron capture therapy of brain tumors: clinical trials at the finnish facility using boronophenylalanine.
Joensuu H, Kankaanranta L, Seppala T, Auterinen I, Kallio M, Kulvik M, Laakso J, Vahatalo J, Kortesniemi M, Kotiluoto P, Seren T, Karila J, Brander A, Jarviluoma E, Ryynanen P, Paetau A, Ruokonen I, Minn H, Tenhunen M, Jaaskelainen J, Farkkila M, Savolainen S.
Department of Oncology, University of Helsinki, Finland. heikki.joensuu@hus.fi

Two clinical trials are currently running at the Finnish dedicated boron neutron capture therapy (BNCT) facility. Between May 1999 and December 2001, 18 patients with supratentorial glioblastoma were treated with boronophenylalanine (BPA)-based BNCT within a context of a prospective clinical trial (protocol P-01). All patients underwent prior surgery, but none had received conventional radiotherapy or cancer chemotherapy before BNCT. BPA-fructose was given as 2-h infusion at BPA-dosages ranging from 290 to 400 mg/kg prior to neutron beam irradiation, which was given as a single fraction from two fields. The average planning target volume dose ranged from 30 to 61 Gy (W), and the average normal brain dose from 3 to 6 Gy (W). The treatment was generally well tolerated, and none of the patients have died during the first months following BNCT. The estimated 1-year overall survival is 61%. In another trial (protocol P-03), three patients with recurring or progressing glioblastoma following surgery and conventional cranial radiotherapy to 50-60 Gy, were treated with BPA-based BNCT using the BPA dosage of 290 mg/kg. The average planning target dose in these patients was 25-29 Gy (W), and the average whole brain dose 2-3 Gy (W). All three patients tolerated brain reirradiation with BNCT, and none died during the first three months following BNCT. We conclude that BPA-based BNCT has been relatively well tolerated both in previously irradiated and unirradiated glioblastoma patients. Efficacy comparisons with conventional photon radiation are difficult due to patient selection and confounding factors such as other treatments given, but the results support continuation of clinical research on BPA-based BNCT.

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J Neurooncol. 2003 Mar-Apr;62(1-2):111-21.
A critical examination of the results from the Harvard-MIT NCT program phase I clinical trial of neutron capture therapy for intracranial disease.
Busse PM, Harling OK, Palmer MR, Kiger WS 3rd, Kaplan J, Kaplan I, Chuang CF, Goorley JT, Riley KJ, Newton TH, Santa Cruz GA, Lu XQ, Zamenhof RG.
Department of Radiation Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA. pbusse@caregroup.harvard.edu

A phase I trial was designed to evaluate normal tissue tolerance to neutron capture therapy (NCT); tumor response was also followed as a secondary endpoint. Between July 1996 and May 1999, 24 subjects were entered into a phase I trial evaluating cranial NCT in subjects with primary or metastatic brain tumors. Two subjects were excluded due to a decline in their performance status and 22 subjects were irradiated at the MIT Nuclear Reactor Laboratory. The median age was 56 years (range 24-78). All subjects had a pathologically confirmed diagnosis of either glioblastoma (20) or melanoma (2) and a Karnofsky of 70 or higher. Neutron irradiation was delivered with a 15 cm diameter epithermal beam. Treatment plans varied from 1 to 3 fields depending upon the size and location of the tumor. The 10B carrier, L-p-boronophenylalanine-fructose (BPA-f), was infused through a central venous catheter at doses of 250 mg kg(-1) over 1 h (10 subjects), 300 mg kg(-1) over 1.5 h (two subjects), or 350 mg kg(-1) over 1.5-2 h (10 subjects). The pharmacokinetic profile of 10B in blood was very reproducible and permitted a predictive model to be developed. Cranial NCT can be delivered at doses high enough to exhibit a clinical response with an acceptable level of toxicity. Acute toxicity was primarily associated with increased intracranial pressure; late pulmonary effects were seen in two subjects. Factors such as average brain dose, tumor volume, and skin, mucosa, and lung dose may have a greater impact on tolerance than peak dose alone. Two subjects exhibited a complete radiographic response and 13 of 17 evaluable subjects had a measurable reduction in enhanced tumor volume following NCT.

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J Neurooncol. 2003 Mar-Apr;62(1-2):101-9.
Assessment of the results from the phase I/II boron neutron capture therapy trials at the Brookhaven National Laboratory from a clinician's point of view.
Diaz AZ.
Roswell Park Cancer Institute, Buffalo, NY 14263, USA. aidnag.diaz@roswellpark.org

Boron neutron capture therapy (BNCT) represents a promising modality for a relatively selective radiation dose delivery to the tumor tissue. The key to effective BNCT of tumors such as glioblastoma multiforme (GBM) is the homogeneous preferential accumulation of 10B in the tumor, including the infiltrating GBM cells, as compared to that in the vital structures of the normal brain. Provided that sufficiently high tumor 10B concentration (approximately 10(9) boron-10 atoms/cell) and an adequate thermal neutron fluence (approximately 10(9) neutrons/cm2) are achieved, it is the ratio of the 10B concentration in tumor cells to that in the normal brain cells and the blood that will largely determine the therapeutic gain of BNCT.

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Surg Neurol. 2003 Apr;59(4):250-68.
Principles of treatment of the pineal region tumors.
Konovalov AN, Pitskhelauri DI.
Burdenko Neurosurgery Institute, Moscow, Russia.

BACKGROUND: A pineal region tumor is an uncommon deep-seated, heterogeneous group of mass lesions of the brain, and the management strategy of any types of these tumors remains controversial. It is the purpose of this communication to present results of our experience in treating patients with these neoplasms. METHODS: From 1976 to 1999 about 700 patients with tumors of the pineal region and posterior third ventricle were managed at the Burdenko Neurosurgery Institute. In more than 330 cases the tumor was removed. In this paper we present results of 287 patients with histologically verified pineal region tumors for the period from 1976 to 1999. All of them had verified tumor histology, excluding only five cases in which stereotactic biopsy procedures were uninformative. There are four main groups of tumors: the germ cell tumors-87 (31%); the pineal parenchymal tumors-75 (27%); the glial tumors-77 (27%); and miscellaneous-43 (15%). There were 255 surgical procedures for tumor removal performed in 244 and stereotactically guided biopsies in 61 patients, 168 (58%) with obstructive hydrocephalus who underwent cerebrospinal fluid shunting. Radiation therapy was administered in 145 (51%) and chemotherapy in 16 patients. Follow-up data were collected in 209 cases (80%). Survival was calculated with the Kaplan-Meier product limit method. RESULTS: The occipital transtentorial and infratentorial supracerebellar approaches were the most commonly used on our series-138 (54%) and 87 (34%), respectively. In the remaining cases, subchoroidal approach, approach through the fourth ventricle, and the combined approaches were used. A total tumor removal was achieved in 148 operations (58%), subtotal in 74 (29%) and partial in 33 (13%). The projected 5-year and 10-year survival rates for patients with malignant pineal tumors, who received irradiation after tumor resection or underwent radiation therapy alone, were: 95% and 88% for pure germinomas, 80% and 50% for high grade gliomas, 44% and 0% for malignant pineal parenchymal tumors, and 20% and 0% for malignant germ cell tumors, respectively. CONCLUSIONS: Benign pineal tumors should be cured with surgery alone. Malignant tumors should be treated with aggressive resection followed with irradiation and chemotherapy. Pure germinomas, which are exquisitely radiosensitive, can be cured by conventional radiation therapy alone.

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Neurochirurgie. 2003 May;49(2-3 Pt 1):83-9.
[Use of polyester urethane (Neuro-Patch) as a dural substitute. Prospective study of 70 cases]
[Article in French]
Raul JS, Godard J, Arbez-Gindre F, Czorny A.
Service de Neurochirurgie, CHU Jean-Minjoz, Besancon. Jean-Sebastien.Raul@iml-ulp.u-strasbg.fr

Between October 1995 and March 1998, 70 patients were treated with a microporous polyester urethane dura substitute (Neuro-Patch), after brain or spinal surgery. These patients were assessed clinically and radiologicaly 10 days, 6 weeks and 1 year after surgery. Radiological evaluation used CT scan or MRI. All dura substitutes were fixed by continuous suture to the surrounding dura-mater. We studied the handling properties, the incidence of infection and of CSF leakage. Eleven patients underwent craniotomy again. This gave us the opportunity to examine the adhesion to the brain tissue and the integration of the dura substitute. Six sheets underwent histological examination. Our results show good handling properties of the material; 3 infections; 6 out of 9 radiological CSF leakage occurred from infratentorial surgery. During reoperation, no adhesion to the brain tissue or injury to the brain while detaching the dura substitute was noticed. An excellent histological integration was observed: pores of the Neuro-Patch were colonized by fibroblasts synthesizing collagen, and there was no immune or inflammatory reaction, with an actual 4 to 6 years follow-up. A Neuro-Patch can therefore be recommended as a dura substitute to repair spinal or cranial dural defects.

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Gan To Kagaku Ryoho. 2003 Apr;30(4):455-9.
[Brain tumors]
[Article in Japanese]
Hatano M, Mizuno M, Yoshida J.
Dept. of Neurosurgery, Nagoya University Graduate School of Medicine.

Brain tumors generally arise as the culmination of a multistep process that involves a variety of genetic abnormalities. Theoretically, replacement of abnormal genes with normal genes is essential to brain tumor treatment. However, it is very difficult to replace all damaged genes. Currently, most clinical protocols for gene therapy in brain tumors include transfer of a gene which can induce tumor cells to die or which can enhance the environment to generate a systemic immune response against the tumor. The former strategy includes suicide gene therapies, tumor suppressor gene therapy and oncolytic virus therapy. The latter adopts immunogene therapy. In this report, we also focus on other gene therapies, such as therapies to control the cell cycle or apoptosis, and promote antiangiogenesis. Gene therapy is generally accepted to be rather safe in recent years. In fact, the current single-gene therapies for brain tumor are limited and probably restricted to a few tumors. Several agents with different mechanisms of action would be necessary to kill heterogenously mixed tumor cells. Further molecular techniques and basic studies may overcome the malignancy of cancers.

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Cancer. 2003 May 1;97(9):2262-6.
Temozolomide as an alternative to irradiation for elderly patients with newly diagnosed malignant gliomas.
Glantz M, Chamberlain M, Liu Q, Litofsky NS, Recht LD.
Southwestern Vermont Cancer Center, Bennington, Vermont, USA.

BACKGROUND: The optimal treatment for elderly patients (defined as patients 70 years of age or older) with malignant gliomas (MG) remains controversial. Some physicians advocate withholding therapy following diagnosis based on the observation that elderly patients do not tolerate adjuvant radiotherapy. The availability of temozolomide (TMZ), a new alkylating agent with antiglioma efficacy, offers another potential therapeutic option for these patients. The drug can be administered orally at home with minimal morbidity. METHODS: The authors retrospectively reviewed a cohort of 86 consecutive elderly MG patients from three institutions, 32 of whom received monthly TMZ in lieu of radiation. RESULTS: Initial Karnofsky performance score was the only predictor of survival in this cohort. No difference in survival was noted between these two groups. Toxicity was minimal in the chemotherapy-treated group and a higher percentage of patients receiving chemotherapy died at home. CONCLUSIONS: The authors concluded that TMZ is as effective as irradiation as a treatment of elderly patients with MG. It is an alternative and, perhaps, a superior therapeutic option to irradiation, based on its ease of administration and low morbidity. Copyright 2003 American Cancer Society.DOI 10.1002/cncr.11323

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Zh Vopr Neirokhir Im N N Burdenko. 2003 Jan-Mar;(1):2-6; discussion 6-7.
[Supratentorial cavernomas: clinical picture, diagnosis, treatment]
[Article in Russian]
Belousova OB, Filatov IuM, Shishkina LV, Sazonova OB.

The study was undertaken to examine the clinical picture, diagnosis, morphology and substantiate management policy for patients with supratentorial cavernomas. Examination was made in 160 patients with this abnormality, 87 of them were operated on. The histological structure of cavernomas was shown to be heterogeneous. Different types of their clinical course are analyzed and the optimum diagnostic criteria of the diseases substantiated. Removal of supratentorial cavernomas is the method of choice, which eliminates a risk for rehemorrhage and positively affects the course of the convulsive syndrome. Exceptions are the cavernomas that are located in the functionally important brain regions difficult to reach. In these cases, the indication for surgery may be severe rehemorrhage or drug-untreated frequent seizures. Removal of cavernomas does not rule out a long-term use of anticonvulsants. They may be discontinued only on the basis of clinical and electroencephalographic control.

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Strahlenther Onkol. 2003 Apr;179(4):219-32.
Radiochemotherapy of malignant glioma in adults. Clinical experiences.
Kortmann RD, Jeremic B, Weller M, Plasswilm L, Bamberg M.
Department for Radiation Oncology, University of Tubingen, Germany. rdkortma@med.uni-tuebingen.de

BACKGROUND: Standard treatment in patients with malignant glioma consists of surgery and postoperative radiotherapy. A high early recurrence rate, particularly in glioblastoma, has led to the investigation of additional chemotherapy. MATERIAL AND METHODS: Recent results of radiochemotherapy published in the literature were reviewed with respect to outcome in phase II and III trials. Based on these experiences, aspects of future strategies were discussed. RESULTS: 3 decades of intensive research had, unfortunately, little impact on the overall results. While early prospective studies established adjuvant nitrosoureas, particularly BCNU, as suitable adjuvant to surgery and postoperative radiotherapy, further studies largely concentrated on combined chemotherapeutic protocols, mostly procarbazine, CCNU and vincristine (PCV), which was shown to prolong survival in anaplastic astrocytoma. The recent MRC study, however, showed no effect for adjuvant PCV in grade III and IV malignant glioma. Only in high-grade glioma with an oligodendroglial component, additional chemotherapy may be of a decisive benefit. The introduction of newer drugs such as paclitaxel, temozolomide, or gemcitabine demonstrated no decisive advantage. Different modes of application and sequencing of radiotherapy and chemotherapy are presently actively investigated, but failed to substantially improve outcome. CONCLUSIONS: Therefore, search for newer and more effective drugs continues, as well as for "optimal" administration and sequencing, especially from the standpoint of accompanying acute and late toxicity. Finally, recent endeavors focused on basic research such as angiogenesis, migration and invasion, or induction of cell differentiation, but these strategies are still away from broader clinical investigation.

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Strahlenther Onkol. 2003 Apr;179(4):213-8.
[Treatment for central neurocytoma: a meta-analysis based on the data of 358 patients]
[Article in German]
Rades D, Fehlauer F, Schild S, Lamszus K, Alberti W.
Abteilung fur Strahlentherapie und Radioonkologie, Universitatsklinikum Hamburg-Eppendorf, Hamburg, Deutschland. Rades.Dirk@gmx.net

BACKGROUND: Central neurocytomas are described as uncommon benign CNS lesions. Uncertainty exists about the most appropriate treatment regimen. This retrospective analysis compares four therapies for local control and overall survival: complete resection alone (KR), complete resection plus radiotherapy (KR-RT), incomplete resection alone (IR), and incomplete resection plus radiotherapy (ITR-RT). MATERIAL AND METHODS: The cases published in the literature since 1982 were reviewed for age, gender, extent of resection, atypical neurocytoma, radiotherapy, local control, and overall survival (minimum follow-up 12 months). From direct contact with the authors additional data were obtained providing more detailed information about the patients and a longer follow-up. Statistical analysis was performed with the Kaplan-Meier analysis and the log-rank test. RESULTS: Complete data were obtained from 358 patients (KR 118, KR-RT 35, IR 91, IR-RT 114). Local control was significantly better after KR, KR-RT and IR-RT than after IR (Figure 1). No significant difference was found between KR, KR-RT and IR-RT. Median time to progression was 36 (KR), 39 (KR-RT), 21 (IR) and 32 (IR-RT) months. The comparison of the four groups for overall survival demonstrated that KR provided a significantly better overall survival than IR (Figure 2). Overall survival rates were 99.2% and 86.1%, respectively. CONCLUSIONS: Complete resection is much more effective for the treatment of central neurocytoma than incomplete resection. After complete resection the additional benefit of postoperative radiotherapy remains unclear. After incomplete resection postoperative radiotherapy significantly improved local control, but not overall survival.

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J Clin Oncol. 2003 Apr 15;21(8):1581-91.
Results of a randomized study of preradiation chemotherapy versus radiotherapy alone for nonmetastatic medulloblastoma: The International Society of Paediatric Oncology/United Kingdom Children's Cancer Study Group PNET-3 Study.
Taylor RE, Bailey CC, Robinson K, Weston CL, Ellison D, Ironside J, Lucraft H, Gilbertson R, Tait DM, Walker DA, Pizer BL, Imeson J, Lashford LS; International Society of Paediatric Oncology; United Kingdom Children's Cancer Study Group.
Cookridge Hospital, Leeds, West Yorkshire, LS16 6QB, United Kingdom. Roger.Taylor@Leedsth.nhs.uk

PURPOSE: To determine whether preradiotherapy (RT) chemotherapy would improve outcome for Chang stage M0-1 medulloblastoma when compared with RT alone. Chemotherapy comprised vincristine 1.5 mg/m2 weekly for 10 weeks and four cycles of etoposide 100 mg/m2 daily for 3 days, and carboplatin 500 mg/m2 daily for 2 days alternating with cyclophosphamide 1.5 g/m2. PATIENTS AND METHODS: Patients aged 3 to 16 years inclusive were randomly assigned to receive 35 Gy craniospinal RT with a 20 Gy posterior fossa boost, or chemotherapy followed by RT. RESULTS: Of 217 patients randomly assigned to treatment, 179 were eligible for analysis (chemotherapy + RT, 90 patients; RT alone, 89 patients). Median age was 7.67 years, and median follow-up was 5.40 years. Overall survival (OS) at 3 and 5 years was 79.5% and 70.7%, respectively. Event-free survival (EFS) at 3 and 5 years was 71.6% and 67.0%, respectively. EFS was significantly better for chemotherapy and RT (P =.0366), with EFS of 78.5% at 3 years and 74.2% at 5 years compared with 64.8% at 3 years and 59.8% at 5 years for RT alone. There was no statistically significant difference in 3-year and 5-year OS between the two arms (P =.0928). Multivariate analysis identified use of chemotherapy (P =.0248) and time to complete RT (P =.0100) as having significant effect on EFS. CONCLUSION: This is the first large multicenter randomized study to demonstrate improved EFS for chemotherapy compared with RT alone. It is anticipated that this regimen could reduce ototoxicity and nephrotoxicity compared with cisplatin-containing schedules. The importance of avoiding interruptions to RT has been confirmed.

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J Clin Oncol. 2003 Apr 15;21(8):1485-91.
Phase III study comparing three cycles of infusional carmustine and cisplatin followed by radiation therapy with radiation therapy and concurrent carmustine in patients with newly diagnosed supratentorial glioblastoma multiforme: Eastern Cooperative Oncology Group Trial 2394.
Grossman SA, O'Neill A, Grunnet M, Mehta M, Pearlman JL, Wagner H, Gilbert M, Newton HB, Hellman R; Eastern Cooperative Oncology Group.
1650 Orleans St, Room G93, The Sydney Kimmel Cancer Center at Johns Hopkins, Baltimore, MD 21231, USA. grossman@jhmi.edu

PURPOSE: This phase III Eastern Cooperative Oncology Group-Southwest Oncology Group intergroup study was conducted to determine whether three 72-hour infusions of carmustine (BiCNU) and cisplatin administered monthly before external-beam radiotherapy would improve the survival of patients with newly diagnosed glioblastoma multiforme. The control arm consisted of radiation with standard adjuvant BiCNU. PATIENTS AND METHODS: A total of 223 patients were accrued from 1996 to 1999. Of these, 219 patients were eligible; 109 were randomly assigned to the experimental arm, and 110 were randomly assigned to the control arm. Randomization was stratified by age, performance status, and extent of resection. RESULTS: The median age of the patients was 55 years; 55% were male, 93% were white, 26% had a biopsy only, and 84% were ambulatory. Treatment arms were well balanced with respect to baseline characteristics. Median follow-up time of the 15 patients still alive at the time of analysis was 3.3 years (range, 2 to 5 years). Median survival times for the standard and experimental arms were 11.2 and 11.0 months (P =.33, two-sided log-rank test), and survival at 1 year was 45% versus 44%, respectively. Fifty-six percent of patients received all three cycles of BiCNU/cisplatin, 12% received two cycles, and 31% received only one cycle. Toxicity was primarily hematologic and was more common in the experimental arm (P <.01). CONCLUSION: This study demonstrates that 72-hour infusions of BiCNU and cisplatin followed by radiation do not improve median survival, survival at 1 year, or time to progression. Furthermore, this treatment requires more time in the hospital and is associated with more serious toxicities than standard therapy.

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Curr Neurol Neurosci Rep. 2003 May;3(3):193-9.
Ependymomas.
Chamberlain MC.
Department of Neurology, USC/Norris Cancer Center, 1441 Eastlake Avenue, Suite 3459, Los Angeles, CA 90033-0804, USA. chamberl@usc.edu

Ependymomas are uncommon neoplasms of the central nervous system (CNS), and as a consequence, few randomized, clinical trials have been performed, thereby limiting treatment guidelines. A review of the literature would permit the following conclusions regarding treatment. The best management of newly diagnosed ependymoma entails a complete resection corroborated by postoperative contrast-enhanced magnetic resonance imaging (MRI). If an incomplete resection is documented, a second attempt at gross total resection should be considered, given the prognostic significance of complete resection. Small volume residual disease is best managed with involved-field radiotherapy unless postoperative staging (cerebrospinal fluid cytology, neuraxis MRI) documents metastatic disease, which is best managed by craniospinal irradiation. The role of chemotherapy is uncertain and in general would be reserved for patients having previously failed surgery and radiotherapy. Disease-free survival following recurrence is unusual (<15% at 5 years) and suggests intensification of initial adjuvant treatment may best prevent relapse.

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AORN J. 2003 Mar;77(3):583-9.
Brain tumor resections guided by magnetic resonance imaging.
Kanan A, Gasson B.
MRT Department, Brigham and Women's Hospital, Boston, USA.

A major goal of surgical treatment of intracranial tumors is to achieve complete resection of the lesion while also preserving normal brain tissue and function. Conventional stereotactic systems used today to localize intracranial lesions are based on previously acquired imaging data sets. These data sets cannot provide surgeons with information about dynamic changes that occur during surgery. The recent development of intraoperative magnetic resonance imaging allows surgical resection to be performed through the eyes of the surgeon with concurrent magnetic resonance images. This advancement has revolutionized the way neurosurgical procedures are being performed.

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Neurosurg Clin N Am. 2003 Jan;14(1):167-71.
Long-term management and outcome for pituitary tumors.
Ciric I.
Division of Neurosurgery, Evanston Hospital, 2650 Ridge Avenue, Room 4222, Evanston, IL 60201, USA. iciric@ENH.org

As we enter the twenty-first century, neurosurgeons and endocrinologists are armed with a greater variety of treatment options for pituitary adenomas, both secreting and nonsecreting. These include an ever-increased availability of different drugs that can be used for suppression of hypersecretion of pituitary adenomas in conjunction with their shrinkage (at least for the duration of the treatment), surgical techniques that have greatly improved, and newer techniques, such as endoscopic microsurgery, that have been added to the surgeon's armamentarium. Radiation therapy techniques have also improved in terms of structuring the radiation field as well as in terms of dosimetry and delivery.

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Neurosurg Clin N Am. 2003 Jan;14(1):147-66.
Radiotherapy and stereotactic radiosurgery for pituitary tumors.
Petrovich Z, Jozsef G, Yu C, Apuzzo ML.
Department of Radiation Oncology, Keck School of Medicine, University of Southern California, 1441 Eastlake Avenue, NOR G356, Los Angeles, CA 90033-0804, USA. zpetrovi@hsc.usc.edu

Based on a review of the literature and our medical center experience, we believe that transphenoidal surgery is the procedure of choice in most patients with pituitary adenomas. Conversely, SRS is a procedure of choice for those with cavernous sinus involvement. Patients with incomplete surgical excision should be considered either for a planned stereotactic treatment or for external beam radiotherapy. The same applies to patients with recurrent tumors. We favor stereotactic treatment in patients who have tumors that are less than 35 mm in diameter and at least 3 mm from the chiasm or optic nerves. Other patients should be considered for three-dimensional conformal radiotherapy. Radiotherapy provides a good treatment alternative in those patients who either refuse surgery or have contraindications to this therapy. Contemporary radiotherapy and SRS for pituitary adenomas is safe and effective treatment. This treatment should be undertaken in medical centers with appropriate expertise and instrumentation.

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Neurosurg Clin N Am. 2003 Jan;14(1):123-38.
Postoperative endocrine management of pituitary tumors.
Singer PA, Sevilla LJ.
Division of Endocrinology and Metabolism, Keck School of Medicine, University of Southern California, 1355 San Pablo Street, Room 118, Los Angeles, CA 90033, USA. psinger@hsc.usc.edu

Pituitary tumors are common and are often associated with endocrine abnormalities. Furthermore, pituitary surgery itself may result in additional hormonal changes, including impairment of anterior pituitary hormone secretion and, more commonly, abnormalities of ADH regulation. Endocrine management of patients with pituitary or other sellar lesions involves acute hospital-based and longer term office-based evaluation and treatment. In the immediate postoperative period, careful attention must be directed toward sodium and water balance as well as toward recognition of changes in endocrine function. Postoperative measurement of serum hormone levels also helps to determine if resection of a hypersecreting tumor has been successful. To minimize postoperative morbidity, perioperative endocrine assessment and management of patients undergoing pituitary surgery should consist of a team approach, involving both the neurosurgeon and the endocrinologist.

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Int J Radiat Oncol Biol Phys. 2003 Jun 1;56(2):511-8.
Radiation therapy for intracranial germ cell tumors.
Haas-Kogan DA, Missett BT, Wara WM, Donaldson SS, Lamborn KR, Prados MD, Fisher PG, Huhn SL, Fisch BM, Berger MS, Le QT.
Department of Radiation Oncology, University of California, San Francisco, CA 94143, USA. hkogan@radonc17.ucsf.edu

PURPOSE: To review the combined experiences of University of California, San Francisco, and Stanford University Medical Center in the treatment of intracranial germ cell tumors (GCT) and to assess the impact of craniospinal radiation (CSI) on patterns of relapse, progression-free survival (PFS), and overall survival (OS). PATIENTS AND METHODS: Ninety-three patients received radiation for newly diagnosed intracranial GCTs, including 49 germinomas, 16 nongerminomatous GCTs (NGGCT), and 28 with no biopsy. Median follow-up for surviving patients was 4.5 years (range 0.25-34). Tests for variables correlating with OS and PFS were conducted using Cox proportional hazards model. RESULTS: Five-year PFS and OS rates were 60% +/- 15% and 68% +/- 14% for patients with NGGCT and 88% +/- 5% and 93% +/- 4% for those with germinoma. Of 6 patients with localized NGGCT who did not receive CSI, 1 experienced an isolated spinal recurrence but was salvaged. Of 41 patients with localized germinoma, 6 who received CSI and 35 who did not, no isolated spinal cord relapses occurred. Twenty-one patients with localized germinoma received neither CSI nor whole brain radiation. Of these, none of 18 with ventricular radiation relapsed. One of 3 patients with primary tumor radiation relapsed intracranially but had only received 11 Gy at initial treatment. On multivariate analysis, germinoma histology but not CSI correlated with improved PFS and OS. CONCLUSION: CSI is not indicated in the treatment of localized germinomas. For patients with localized germinomas treated with radiation alone, we recommend ventricular irradiation followed by primary tumor boost to a total of 45-50 Gy.

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Przegl Lek. 2002;59(12):1018-23.
[Thyrotropin—TSH secreting pituitary tumor]
[Article in Polish]
Zielinski G, Podgorski JK, Warczynska A, Koziarski A, Zgliczynski W.
Klinika Neurochirurgii Wojskowego Instytutu Medycznego 00-909 Warszawa, ul Szaserow 128. grzegorz.zielinskiL14@inetia.pl

Thyrotropin-releasing pituitary tumors represent 0.9 to 2.8% of all pituitary adenomas. They cause secondary or central hyperthyroidism. The diagnosis of these tumors has been increasing in the past 20 years. It was produced by introduction of the sensitive immunoradio-metric assay of TSH and better radiological imaging (magnetic resonance imaging). TSH--secreting pituitary adenomas are aggressive and invasive neoplasms. Most reports describe a poor outcome after pharmacological therapy, surgery and radiation therapy. Presently the diagnosis of thyrotropin-secreting pituitary tumor is based on the lack of: a. inhibition of TSH levels in the presence of increased free thyroid hormones; b. response of TSH to stimulation with TRH; c. and presence of a abnormal, neoplastic(adenomatous) intrasellar or parasellar mass. Surgical excision (selective adenomectomy) by the transsphenoidal route is the first treatment. Craniotomy should be reserved for parasellar tumors with significant lateral extension. Pharmacological pretreatment with long acting somatostatin analogues is recently a standard before surgery. This medical treatment of the TSH-omas is effective in reducing TSH and free thyroid hormone plasma levels. Administration of the somatostatin analogues causing tumor mass shrinkage and changes consistency. This pretreatment is effective therapy and improves surgical outcome especially in patients harbouring macroadenomas. Radiotherapy is noncurative and produces long term complications (hypopituitarism). Authors present and discuss current cure criteria of TSH-omas with reference to their clinical experience.

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Neurol Neurochir Pol. 2002 Nov-Dec;36(6):1149-56.
[Embolization of supratentorial angiomas. Own experience]
[Article in Polish]
Kolasa P, Kaurzel Z.
Oddzialu Neurochirurgii, Zakladu Radiologii, Specjalistycznego Szpitala im. M. Kopernika w Lodzi.

Embolization of intracerebral angiomas has been performed in our Center since 1995. Main criteria for the treatment include bleeding into the central nervous system (CNS), epilepsy, and other neurological symptoms. METHOD: CNS angiography and angioma location were performed using the Seldinger technique. A highly selective microcatheterization of particular angioma feeders was carried out then in the DVM system. After a radiological confirmation of the precise location of the catheter end in the angioma, embolization of the angioma feeders and nidus was performed with the Histoacryl-Lipiodol mixture. RESULTS: One hundred endovascular treatment procedures were performed in 58 patients with cerebral angiomas of IV and V grade according to the Spetzler-Martin scale. The total angioma occlusion was attained in 35 patients (63.3%), and partial--in 18 (31.8%) cases. There were four early deaths (6.8%) and one late (1.8%), not related to the surgical procedure. CONCLUSION: Embolization is a new and effective method of treatment of extensive supratentorial angiomas.

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Neuroimaging Clin N Am. 2002 Nov;12(4):553-70.
Viruses in the treatment of brain tumors.
Fecci PE, Gromeier M, Sampson JH.
Departments of Neurosurgery and Pathology, Duke University Medical Center, Durham, NC 27710, USA.

The grave outlook for malignant glioma patients in spite of improvements to current modalities has ushered in new approaches to therapy. Viruses have emerged on the scene and gained attention for their ability to play essentially two roles: first, as vectors for therapeutic gene delivery and second, as engineered infectious agents capable of selectively lysing tumor cells. To date, clinical brain tumor trials using viruses for gene delivery have employed retroviral or adenoviral vectors to introduce ganciclovir susceptibility to tumors in the form of the HSV1-TK gene. Clinical oncolytic studies, on the other hand, have evaluated a conditionally replicating HSV as an antineoplastic agent. Despite some promise afforded by these trials, further studies are warranted; the investigation of additional viruses to play these roles is inevitable and is now precedented.

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