Brain Cancer

New research shows that the oncolytic reovirus, which kills cancer cells by replication within the cell, may also have the potential to prime the immune system to mount a defense against cancer cells

Brain, lung, and ovarian cancers have been chosen as the first cancers to be studied in the pilot phase of The Cancer Genome Atlas (TCGA) project

Modafinil (Provigil) significantly improved cognitive function, mood, and fatigue in patients with brain tumors in a pilot study

Childhood survivors of brain tumors who were diagnosed at age 10 or younger have worse depressive symptomatology and social skills and lower feelings of self-worth than their counterparts who were diagnosed as pre-teens or teenagers

Takeda Pharmaceutical has signed an exclusive licensing agreement with Galaxy Biotech (Mountain View, California) to develop, manufacture, and market HuL2G7, a recombinant humanized anti-hepatocyte growth factor (anti-HGF) monoclonal antibody developed by Galaxy Biotech. HGF is believed to mediate proliferation, metastasis, antiapoptosis, and neoangiogenesis of many types of tumors. In animal models, treatment of intracranial glioma xenografts with HuL2G7 induced substantial tumor regression and prolonged survival (Clin Cancer Res 12:1292-1298, 2006).

EntreMed, Inc.'s lead drug candidate Panzem (2-methoxyestradiol or 2ME2) has received orphan drug status from the FDA for the treatment of glioblastoma multiforme. In vitro studies in glioma cell lines demonstrated Panzem's antiproliferative activity, and in vivo studies in a preclinical model of glioblastoma showed its antitumor activity, EntreMed said in a press release. Panzem is currently being investigated in a phase II trial in patients with glioblastoma multiforme at the Brain Tumor Center at Duke University Medical Center. The agent previously received orphan drug designation for the treatment of multiple myeloma and ovarian cancer.

During the past 18 months, researchers have developed substantial evidence supporting the notion that stem cells play a critical role in the development of at least some cancers, their progression, and the prognosis of patients, including breast, brain, lung, and prostate cancer, multiple myeloma, and melanoma.

Brain metastases from renal cell carcinoma (RCC) cause significant morbidity and mortality. More effective treatment approaches are needed. Traditionally, whole-brain radiotherapy has been used for palliation. With advances in radiation oncology, stereotactic radiosurgery and hypofractionated stereotactic radiotherapy have been utilized for RCC brain metastases, producing excellent outcomes. This review details the role of radiotherapy in various subgroups of patients with RCC brain metastases as well as the associated toxicities and outcomes. Newer radiosensitizers (eg, motexafin gadolinium [Xcytrin]) and chemotherapeutic agents (eg, temozolomide [Temodar]) used in combination with radiotherapy will also be discussed.

Brain metastases from renal cell carcinoma (RCC) cause significant morbidity and mortality. More effective treatment approaches are needed. Traditionally, whole-brain radiotherapy has been used for palliation. With advances in radiation oncology, stereotactic radiosurgery and hypofractionated stereotactic radiotherapy have been utilized for RCC brain metastases, producing excellent outcomes. This review details the role of radiotherapy in various subgroups of patients with RCC brain metastases as well as the associated toxicities and outcomes. Newer radiosensitizers (eg, motexafin gadolinium [Xcytrin]) and chemotherapeutic agents (eg, temozolomide [Temodar]) used in combination with radiotherapy will also be discussed.

After 2 decades of minimal progress, there have been important advances in the treatment of brain tumors with chemotherapy. A trial conducted by the European Organization for Research and Treatment of Cancer (EORTC) and the National Cancer Institute of Canada (NCIC) recently demonstrated the benefit of radiation therapy with concomitant and adjuvant temozolomide (Temodar) chemotherapy for glioblastomas. There is also increasing evidence that chemotherapy may be beneficial for anaplastic and low-grade gliomas, as well as a variety of less common tumors.

When physicians are deciding whether to offer stereotactic radiosurgery to patients with multiple brain metastases who have a fairly good functional status, they should consider the total volume of these metastases instead of their number.

The treatment of malignant gliomashas received significant attentionover the past decade.This likely represents recognition ofthe poor prognosis associated withthese cancers combined with the challengeof developing a treatment strategyfor a neoplasm that, although itrarely metastasizes, has not proven tobe curable by surgical resection. Infact, debate continues about the roleof aggressive surgery in this disease,given that an image-guided biopsycan provide accurate diagnosis whileminimizing any procedure-relatedmorbidity and mortality. Some studieshave strongly suggested a therapeuticbenefit with surgical resection,but the extent of resection is a criticalcomponent.

Glioma is the most common form of primary brain tumor, as well asthe most lethal. Primary treatment strategies for glioma, includingcytoreductive surgery, external-beam irradiation, and systemic chemotherapyhave had generally disappointing results for these tumors. Limitationsof these approaches include tumor invasion into functional braintissue, lack of chemosensitivity, and shortcomings of systemic delivery.Recent attention has focused on locoregional strategies for treatment,as well as new methods for delivering therapy. Identification of tumorspecificsurface targets, biologic agents, and more sophisticated meansto deliver macromolecules to the brain is offering new promise in thetreatment of these tumors. This paper will review the current state ofthe art of available locoregional therapies for glioma, with a particularfocus on convection-enhanced delivery, targeted toxin, and other biologicstrategies.

A variety of novel surgical approaches have been developed in recentyears to manage disease of the cranial base. Few offer the widthand depth of exposure achievable with the extended transbasal approach.This approach combines a bifrontal craniotomy with anorbitonasal or orbitonasoethmoidal osteotomy, and potentially asphenoethmoidotomy to provide broad access to malignancies of theanterior, middle, and posterior skull base. The approach enables the enbloc resection of tumors within the frontal lobes, orbits, paranasal sinuses,and sphenoclival corridors without brain retraction and mayobviate the need for transfacial access. This can be combined with additionalapproaches, based on the tumor's epicenter. Reconstruction isaccomplished with the use of pericranium, and in some instances, atemporalis muscle pedicle or a gracilis microvascular free flap. Complicationsinclude cerebral spinal fluid leakage, pneumocephalus, infection,and cranial neuropathies. However, the morbidity and mortalityassociated with this approach is low. The extended transbasal approachis a relatively novel exposure that enables the skilled cranialbase surgeon to safely excise many malignant lesions previously felt tobe unresectable.

The variability and complexity of central nervous system germ cell tumors have led to controversy in both diagnosis and management. If a germ cell tumor is suspected, the measurement of cerebrospinal fluid and serum alpha-fetoprotein and beta–human chorionic gonadotropin is essential. A histologic specimen is not necessary if the patient has elevated levels; however, if the tumor markers are negative, a biopsy is needed to confirm the diagnosis of a germinoma. Germinomas are extremelyradiosensitive, enabling 5-year survival rates that exceed 90%. Treatment has traditionally included focal and craniospinal axis irradiation; however, multiple ongoing studies are being conducted to examinethe efficacy of reduction or elimination of radiation therapy with the addition of chemotherapy. Nongerminomatous germ cell tumors, on the other hand, are relatively radioresistant with a poorer outcome. The combination of chemotherapy and irradiation is associated with overall survival rates of up to 60%. This article provides a review of the controversies in diagnosis and treatment of central nervous system germ cell tumors.

Statins inhibit the activity of the rate-limiting enzyme in the cholesterolbiosynthetic pathway, HMG-CoA reductase, and are widely prescribedfor lowering plasma lipid levels. Several statins have antitumor effects inexperimental models, and observational studies suggest that this anticanceractivity in the laboratory may translate into effective treatments and/orpreventive strategies for certain human cancers. This paper reviews thelaboratory and clinical evidence that statins have anticancer activity, discussesthe possible mechanisms by which tumor growth may be inhibitedby this class of drugs, and outlines strategies for the evaluation of theseagents in the prevention and treatment of human cancers.

ROCKVILLE, Maryland-The Food and Drug Administration (FDA) has approved a new indication for Temodar capsules (temozolomide, Schering-Plough) for use concurrently with radiotherapy for the treatment of adults with newly diagnosed glioblastoma multiforme (GBM) and as maintenance therapy after radiotherapy. The FDA based its decision on study data that showed a statistically significant overall survival benefit in such patients.

Combined-modality positronemissiontomography (PET)–computed tomography (CT) isbecoming the imaging method ofchoice for an increasing number ofoncology indications. The goal of thispaper is to review the evidence-basedliterature justifying PET-CT fusion.The best evidence comes from prospectivestudies of integrated PETCTscans compared to other methodsof acquiring images, with histopathologicconfirmation of disease presenceor absence. Unfortunately, veryfew studies provide this kind of data.Retrospective studies with similarcomparisons can be used to provideevidence favoring the use of integratedPET-CT scans in specific clinicalsituations. Also, inferential conclusionscan be drawn from studies whereclinical rather than pathologic dataare used to establish disease presenceor absence.

GENEVA, Switzerland-A simple genetic tumor-biopsy test that takes only 2 to 3 days to perform is predictive of which glioblastoma multiforme patients will likely realize a survival benefit from treatment with the alkylating agent temozolomide (Temodar), an international team of scientists has found.

The review by Gururangan andFriedman takes an interestingand informative approach to pediatricbrain tumors in emphasizingthe possible biologic bases for chemotherapyfailure in these neoplasmsin general, and focusing on newer, asyet largely unproven, strategies employing“biologic” therapies to circumventsuch mechanisms of tumor resistance.Many of these newer treatment strategiesare drawn from the work of theauthors and others in the field of adultmalignant gliomas. To date, minimalprogress has been achieved in improvingoutcome for children with malignantsupratentorial gliomas andbrainstem tumors. Hopefully, these newstrategies will have significant benefitin pediatric as well as adult patients.

Central nervous system (CNS) cancers are the second most frequent malignancy in childhood. In recent years, significant advances in surgery, radiotherapy, and chemotherapy have improved survival in children with these tumors. However, a significant proportion of patients with CNS tumors suffer progressive disease despite such treatment.

Sri Gururangan and Henry Friedmanpresent a thoughtful reviewof advances in pediatric neurooncology.Coupled with the recent reviewof pediatric brain tumor biologywritten by Richard Gilbertson, thesearticles highlight the value that thepediatric neuro-oncology communityplaces on translating signal transductionmodifiers into clinical practice.[1]The remainder of this commentaryfocuses on the challenges and opportunitiesassociated with developingmore effective and less toxic therapiesfor children with brain tumors.

NEW ORLEANS-The chemotherapy drug temozolomide (Temodar) combined with radiation therapy more than doubled the 2-year survival rate in patients with glioblastoma multiforme (GBM), compared with radiation alone, according to data presented at the plenary session of the 40th Annual Meeting of the American Society of Clinical Oncology (abstract 2).

The purpose of this paper is to provide an overview of the clinical presentation, diagnosis, and treatment of brain metastases in patients with SCLC, with a focus on current trends and developments in the treatment of this disease.

SALT LAKE CITY-When surgery and chemotherapy have failed, stereotactic radiation therapy (RT) provides good local control of small, low-grade gliomas in children for many years, Karen J. Marcus, MD, said at the American Society for Therapeutic Radiology and Oncology 45th Annual Meeting (abstract 120). In the prospective trial, about two thirds of children in whom surgery or chemotherapy had not controlled the disease were alive with no progression 8 years after stereotactic RT

SEATTLE-Strokes (cerebro-vascular accidents) and second malignancies, especially thyroid carcinoma, are among the many late effects of radiation therapy in children with medulloblastoma, according to the 42-year experience at one institution. Maria Spavor, MD, a clinical fellow in pediatric hematology/oncology, British Columbia Children’s Hospital, Vancouver, presented the findings at the 16th Annual Meeting of the American Society of Pediatric Hematology/Oncology (abstract 1557).

Paraneoplastic disorders of the nervous system are important to the practicing oncologist, because these syndromes, although uncommon, produce significant neurologic dysfunction and disability. The neurologic disorder may be the first manifestation of an unrecognized systemic malignancy, and appropriate diagnosis of the paraneoplastic disorder can lead to a focused search for an underlying cancer. Paraneoplastic disorders may involve any component of the central or peripheral nervous system, and diagnosis requires careful neurologic assessment. The diagnosis is made by recognition of clinical neurologic syndromes and the use of selected laboratory studies as indicated by the clinical picture. Over the past 10 years, the application of molecular biologic techniques to the study of these disorders has elucidated much about the mechanisms that cause neurologic injury. In most cases, disordered humoral and cellular immunity has been demonstrated, and the role of novel targets for autoimmune attack is being clarified. For some paraneoplastic disorders, treatment of the underlying tumor may lead to improvement of the neurologic disorder. For others, various forms of immunosuppressive therapy may be indicated. Unfortunately, for several of the more common paraneoplastic syndromes such as paraneoplastic cerebellar degeneration or limbic encephalitis, treatment is still unsatisfactory, and further research into the exact pathophysiology is clearly needed. [ONCOLOGY 16:1539-1556, 2002]

LOS ANGELES-In a retrospective study, F-18-fluorodeoxyglucose (FDG)- PET images of the brain predicted histological grade and survival in patients with gliomas (see images). At this time, FDG-PET appears to be better than pathological grading for this purpose, Vasantha Padma, MD, of the Wallace-Kettering Neurosciences Institute, Kettering, Ohio, said at the 49th Annual Meeting of the Society of Nuclear Medicine (abstract 400).

Radiation therapy has long been a mainstay in the treatment of ependymoma. Concerns about the long-term effects of radiation therapy have made many parents and caregivers wary of this treatment modality. However, with the advent of conformal radiation and evidence

Glioblastoma multiforme remains virtually incurable, with reported median survivals of less than 2 years with standard treatment.[1] In recent years, thalidomide (Thalomid) has shown activity in high-grade gliomas as a single agent and in combination with nitrosoureas and carboplatin (Paraplatin).[2-4] I will describe three cases in which patients with recurrent, multicentric glioblastoma responded to thalidomide plus chemotherapy after failing initial treatment with conventional radiation and chemotherapy for a single malignant glioma.