The Role of Neuroimaging in Diagnosis and Treatment of Adult Gliomas of the Brain

Rennette Timbrell, RT(T), M.Rad (South Africa)

  ^*Supervisor-Radiation Therapy, Radiation Oncology Department, University of Colorado Hospital Denver, Aurora, Colorado.
   Address correspondence to: Rennette Timbrell, RT(T), M.Rad (South Africa), Supervisor-Radiation Therapy, Radiation Oncology Department, PO Box 6510, MS-F-706, University of Colorado Hospital Denver, Aurora, CO 80045. E-mail: Rennette.Timbrell@uch.edu.

Disclosure: Ms Timbrell reports having no significant financial or advisory relationships with corporate organizations related to this activity.

ABSTRACT

Brain tumors are amongst the most devastating of all malignant diseases and are difficult to diagnose, as well as challenging to treat. Over the last 50 years, the incidence of brain tumors has appeared to be steadily rising, with the National Cancer Institute estimating that 21 810 men and women in the United States will be diagnosed with cancer of the brain and other central nervous system (CNS) tumors in 2008; of these individuals, 57% will die from their disease.

The epidemiology of brain tumors is complex and appears to be dependant on age, with gliomas occurring mainly in the adult population. They are the most common type of primary brain tumor in adults, accounting for 50% of all primary CNS tumors. For the most part, there are no risk factors associated with brain tumors, the exception being hereditary cancer syndrome, which is associated with selected tumors. Although there are theories attempting to relate environmental factors, such as cell phone usage, to an increased risk of developing a brain tumor, no association has been established.

Neuroimaging has assumed an important role in the care of patients suffering from brain tumors. Advances in CNS imaging technology have resulted in improvements in the accuracy of diagnosis and treatment of these patients. This article will provide a summary of the incidence, pathological classification, diagnosis, and staging of brain tumors. The role of imaging in the diagnosis and treatment of gliomas will be discussed with particular reference to computed tomography, magnetic resonance imaging, and positron emission tomography. In addition, current treatment strategies, including surgical and radiation therapy procedures, chemotherapy, and targeted therapies, will be reviewed.

Introduction
Brain tumors are considered among the most devastating of all cancers and are relatively uncommon, accounting for less than 2% of all primary cancers.¹ They may occur in the meninges, the pituitary or pineal glands, the cranial nerves, the lining of the cavities of the brain, the parenchymal tissue of the central nervous system (CNS), and as metastatic spread from primary tumors. Gliomas, which are the most common type of primary brain tumor in adults, arise in the neuroglial and ependymal cells, whereas tumors arising from nerve cells of the CNS are extremely rare.

Brain tumors are difficult to diagnose and challenging to treat. The prognosis for patients with brain tumors is dismal, and even with multimodal treatment, average survival is less than 1 year after diagnosis and less than 10% of patients survive beyond 2 years.² They are associated with an increased level of morbidity and mortality, due in part to their anatomical position within the cranium. Because the cranium is a rigid bony structure, it does not allow for expansion of the brain and the increased intracranial pressure associated with edema and tumor growth.

Although there have been developments in multimodal treatment over the last decade, including surgery, radiation therapy, and chemotherapy, they have not resulted in much improvement to the dismal prognosis of brain tumors. Rather, current management of brain tumors has embraced developments in neurosurgery and neuroimaging technology, particularly computed tomography (CT) and magnetic resonance imaging (MRI), to increase the accuracy of diagnosis and treatment. In addition, progress in molecular and biologic treatment strategies has played an important role in attempting to improve the outlook for patients with brain tumors.

Epidemiology and Pathological Classification of Gliomas
Brain tumors account for 80% to 90% of all primary tumors of the CNS, including the brain and spinal cord. In general, the incidence of primary brain tumors is higher in whites than in blacks and mortality is higher in males than in females. Over the last decade some studies have indicated an increase in the incidence of brain tumors in the elderly population that may be partially attributable to the greater availability of diagnostic tests.³

In 2008, it is estimated that in the United States there will be 21 810 new cases and 13 070 deaths from tumors of the brain and other nervous system tumors.⁴ Very little is known about the etiology of brain tumors. The clearest risk factor is the presence of a hereditary tumor syndrome, such as neurofibromatosis. Although there are theories attempting to relate environmental factors, such as cell phone usage, to an increased risk of developing a brain tumor, no association has been established.³

Gliomas are the most common primary tumor of the CNS, accounting for an incidence of 40% to 50% in the adult population. They occur most commonly in the cerebrum and most frequently between the ages of 40 to 74 years.⁵ Glioblastoma, also known as glioblastoma multiforme (GBM), is the most common glioma and the most malignant form of astrocytoma.

Primary brain tumors are classified according to their predominant cell type and graded based upon the presence or absence of pathological features.⁶ Gliomas arise in the supportive parenchymal cells or glial cells of the brain, which are made up of astrocytes, oligodendrocytes, ependymal cells, and microglial cells, and make up almost 50% of the brain substance and ependymal cells that line the cavities of the brain (Table 1). According to the World Health Organization (WHO), the 3 main types of gliomas are astrocytomas, oligodendrogliomas, and mixed oligoastrocytomas, and they can usually be distinguished by their histological features.⁷ The degree of malignancy is indicated by the tumor's histological grade, which is based on several features, including invasion, tumor necrosis, endothelial proliferation, pleomorphism, and mitotic activity. There are 4 grades, based on these cytomorphological characteristics, beginning with Grade 1 or low grade, which is the least malignant, and then Grades 2 through 4 which are progressively more malignant.¹ Grade 4 tumors are referred to as high grade.

Astrocytoma
These tumors are the most common types of gliomas, and they arise from the astrocytes in the brain parenchyma. They spread locally by invasion of the surrounding tissue, presenting a challenge for accuracy in diagnosis and treatment.

There are 4 grades of astrocytic tumors based on histopathology:

Grade 1: Pilocytic astrocytoma is a slow growing, low-grade tumor that occurs mainly in children and young adults.

Grade 2: Diffuse astrocytoma is an infiltrating tumor of low mitotic activity. These tumors may recur after treatment and have a tendency to progress to higher grades of malignancy.⁴

Grade 3: Anaplastic astrocytoma (high-grade astrocytoma) may arise from a diffuse astrocytoma or de novo glioma without indication of a less malignant precursor.

Grade 4: Glioblastoma, which is also known as GBM, may develop from a Grade 2 or Grade 3 glioma or de novo glioma without indication of a less malignant precursor.

High-grade glioblastomas are 4 times more common than anaplastic astrocytomas⁷ and account for 50% to 60% of all astrocytic tumors. These tumors arise more commonly in males than in females with a sex ratio of 3:2, and they occur more frequently in older patients with a mean age of onset of 53 years. GBMs are aggressive and highly malignant but almost never spread systemically.⁷ They grow rapidly by direct extension and are always much larger than suggested by imaging studies, such as CT and MRI,¹ a fact that significantly impacts the choice of treatment. The prognosis for patients with GBM is less than 1 year. These tumors are associated with several specific genetic abnormalities but none are specific only to GBM.

Genetic alterations, which play an important role in glioma development, include a loss or mutation of the tumor suppressor gene TP53 located on chromosome 17p. TP53 mutation and allelic loss of chromosome 17p is observed in at least 33% of all grades of adult astrocytoma.³  A chromosome 10 loss is associated with GBM in 65% to 90% of cases.

Oligodendroglioma
The incidence of oligodendroglioma is less common than astrocytoma and occurs almost exclusively in adults with a peak age of incidence of 50 to 60 years.⁸ These tumors are quite uncommon in very young and elderly patients. The prognosis is for oligodendroglioma is better than the prognosis for astrocytoma, with a mean survival of 10 years. The frontal, parietal, and temporal lobes of the brain are common sites of occurrence. Because these tumors grow slowly, calcification within the tumor is common and is visible in CT images.

The tumor is derived from supportive cells and may also present as oligoastrocytoma, which is a tumor of mixed histology. After a period of years, these tumors have a tendency to transform into a higher-grade tumor, known as anaplastic oligodendroglioma, with approximately 50% of oligodendroglial tumors being of the anaplastic type. It is interesting to note that anaplastic oligodendrogliomas appear to be associated with specific chromosomal alterations, and they have a better response to both radiation therapy and chemotherapy. The allelic loss of chromosomes 1p and 19q affects 40% to 80% of mixed oligodendrogliomas. Anaplastic oligodendrogliomas have proven to be the first brain tumor for which molecular genetic analysis has practical clinical ramifications.³ Patients with the anaplastic type mixed tumor and chromosome loss have a better response to chemotherapy with 50% of such tumors demonstrating neuroradiologic responses.³

Ependymoma
Ependymomas arise from the cells of tissue lining the cavities of the CNS, notably the ventricles, the central canal of the spinal cord, and the filum terminale, with the most frequent site of occurrence being the fourth ventricle.³ They occur most commonly in children and young adults, with the most malignant ependymomas occurring in children.⁸

They may spread by direct invasion of surrounding tissue, in addition to seeding (or spreading) along the cerebrospinal fluid (CSF) pathways. For this reason, diagnosis procedures include CSF analysis and radiation therapy treatment fields include the whole brain and spinal cord. The most aggressive type of ependymoma is ependymoblastoma.

Diagnosis and Management of Glioma
Clinical Features
Brain tumors are often difficult to diagnose, particularly when a tumor is situated in a critical area of the brain, and symptoms of a tumor often do not manifest right away. In general, the major symptoms include partial or generalized seizures, which are more common with slow growing tumors; headaches, nausea, and vomiting caused by raised intracranial pressure (ICP); and focal symptoms due to the site and size of the tumor. The most common general symptom for almost all brain tumors is a headache. The brain itself is not pain sensitive and tumor headache is thought to arise from the dura and intracranial vessels. Headaches related to raised ICP tend to be worse in the mornings because ICP increases with recumbency,³ whereas tumor-related headaches tend to be worse at night and may cause the patent to wake up.⁹ This nocturnal pattern is thought to be due in part to transient increases in PCO₂, a potent vasodilator during sleep.⁹ Headaches associated with tumors may be mild and intermittent or constant and severe, and when accompanied by nausea and vomiting, are suggestive of a brain tumor.

Seizures occur commonly with gliomas, particularly the lower-grade tumors, and may also occur with cerebral metastases. Patients who present with seizures usually have smaller primary brain tumors compared to those who present with other symptoms. This may be attributable to a seizure being an indication for neuroimaging, leading to earlier diagnosis.⁹ Other general symptoms include subtle mood and personality changes, cognitive dysfunction, drowsiness, loss of energy, nausea, and vomiting.

Focal symptoms are a result of the site of the tumor in the brain and will reflect functional changes related to the anatomical position of the tumor in the brain. Some examples are indicated in Table 2. It is beyond the scope of this article to provide a detailed account of the various anatomical sites and the corresponding symptoms. In general, sensory and motor changes may occur, including vision and visual spatial changes, epilepsy, cranial nerve palsies, grand mal seizures, and hemiparesis. Muscle weakness related to edema may occur in the lower or upper extremities and is frequently found in patients with brain tumors.⁹

Diagnostic Procedures
Diagnosis of malignant brain tumors is challenging because of the difficulty in differentiating neoplasms from other neurologic diseases, including abscesses, fungal infections, tuberculosis, venous thrombosis, and cytercersosis.¹⁰ Once a full clinical history has been taken, diagnosis is usually made from neuroradiologic imaging procedures, namely CT and MRI, although the gold standard for diagnosis is based on the histologic examination of appropriately sampled tissue.¹¹ Some authors have argued that the only test needed to diagnose a brain tumor is MRI.^9,12  Ideally, diagnosis by neuroimaging should be used to interpret the diagnosis comparatively to proven histology in order to facilitate treatment decisions.¹³

Surgical intervention for biopsy or surgical removal of a tumor is performed with the objective of obtaining a positive histology and attaining a surgical cure. When a surgical cure is not possible, maximal tumor bulk resection with minimal risk to the patient becomes the primary goal.³ Whether for biopsy alone or for resection, surgical procedures can be hazardous to the patient's health because of pathological classification, site, and size of the tumor. For example, for deep-seated tumors in the brain stem or thalamus, even biopsy may be ruled out completely. Over the years, there have been technological advances in surgical biopsies, procedures, and instrumentation, such as the use of CT or MRI guided techniques, which have improved the safety of these procedures. Stereotactic image-guided surgery for many small- and deep-seated brain lesions, such as neoplasms, cyst, abscesses, and hematomas,¹⁴ is well established for diagnosis and resection. The use of stereotactic biopsy for malignant tumors is controversial because it does not usually help alter the prognosis in the vast majority of patients who undergo this procedure.¹⁴ Other controversial issues relevant to surgical biopsy include sampling errors that may occur because of inadequate or non-diagnostic tissue samples.

Cerebrospinal fluid analysis is helpful to assess secondary spread of tumors, especially for ependymoma and GBM. However, in the presence of raised ICP, lumbar puncture may be contraindicated.

Treatment Options
The treatment of malignant gliomas is multimodal, incorporating surgery, radiation therapy, and chemotherapy. Newer treatment strategies, such as biologic markers and targeted treatment, are being used in an effort to improve the poor prognosis. The following sections discuss these different treatment options.

Surgery
Surgical resection is the initial treatment for malignant glioma, especially for low-grade glioma. The goal of surgical resection is maximal resection with preservation of neurologic function.

Benefits of curative resection should be weighed against the risk of causing serious neurologic damage to the patient. However, there is evidence to suggest that aggressive resection is associated with improved functional status and with possible prolonged survival.¹⁵

Many tumors are not amenable to total resection because of the site and grade of the tumor, in addition to the age and performance status of the patient. For instance, high-grade malignant gliomas have poorly defined margins with infiltration of neoplastic cells along white-matter fibers and perivascular spaces that can extend well beyond the tumor margin.¹⁵ For this reason, total resection for cure is not possible. In these instances, another surgical option includes tumor debulking prior to adjuvant radiation therapy or chemotherapy to reduce symptoms of edema and hydrocephalus.

Despite advances in neurodiagnostic imaging, which have contributed significantly to noninvasive histopathologic confirmation of diagnosis, surgical biopsy may be undertaken to confirm a diagnosis; this may be done using a stereotactic image-guided procedure or an open operation. Recent advances in preoperative functional neuroimaging, microsurgery, intraoperative cortical mapping, and image-guided, computer-aided stereotactic procedures have increased the safety of surgical procedures and assisted neurosurgeons in achieving maximal resection, especially in critical sites of the brain.

Preoperative positron emission tomography (PET) scanning and functional MRI may be used to optimize the extent of the tumor volume and minimize the operative injury to "eloquent" (speech) areas of the brain. The functional MRI allows for functional mapping of the brain tissue assisting in localization of cortical areas, such as the motor cortex and diffusion tensor imaging allows for visualization of the subcortical tracts that carry eloquent task information from speech, motor, and visual pathways.¹⁵  

Intraoperative techniques with image-guided stereotactic procedures using a specially designed frame or a frameless set-up may be used for diagnosis. The frame is a set of rigid fiducial bars fixed to the patient's skull to minimize any movement.³ The frameless procedure involves placing fiducial markers on the patients scalp at the time of preoperative CT or MRI imaging. The intraoperative stereotactic procedures are best done in specially designed operating rooms with CT and/or MRI units to guide the resection in "realtime."¹⁵  Another surgical procedure is the "awake" craniotomy combining frameless computer-guided stereotaxis with intraoperative cortical stimulation and repetitive neurologic and language assessment. This method facilitates aggressive resection while minimizing the postoperative neurologic dysfunction.¹⁵  

Despite suggestions that aggressive resection may result in prolonged survival and improved functional status, introduction of improved surgical procedures has not decreased the frequent incidence of local recurrence even after aggressive surgical intervention.

Radiation Therapy
Radiation therapy is indicated as adjuvant treatment for patients who have had partial resection where there is an increased risk of tumor recurrence, or as primary treatment for patients with unresectable gliomas. Radiation therapy has been shown to improve local control and survival after resection,¹⁵ although the tolerance of normal brain tissue to radiation therapy is a limiting factor in achieving complete local control.

Radiation therapy involves treatment of the tumor volume as seen on the enhancing MRI plus a margin of 2 to 3cm of apparently normal tissue around the tumor. This "normal" brain tissue may be infiltrated by microscopic tumor and will be included in the target/tumor volume to be treated.

In the past, whole brain irradiation was used for malignant gliomas. This technique has largely been replaced with limited radiation portals. Three-dimensional conformal treatment is used most commonly; with this technique the dose delivery is designed to conform to the tumor/target volume while limiting the dose to any normal tissue outside of the target volume. Certain gliomas, notably ependymoma, will require that the whole cerebrospinal axis be included in the treatment portal because of the potential spread of tumor cells (or seeding) in CSF pathways.

Technological advances in neuroimaging, treatment planning, and delivery have contributed to the development of sophisticated procedures to limit dose to the normal brain tissue while ensuring a high dose to the tumor/target volume. One such procedure is stereotactic radiosurgery (SRS), which is a method of highly focal, closed skull external irradiation that uses imaging compatible to stereotactic devices used for precise target localization.³ With SRS, a high dose of radiation is delivered in a single fraction using a 3-dimensional coordinate system to locate intracranial targets precisely. CT images are fused with MRI images to locate the exact site and size of the lesion for accurate treatment planning and delivery. This is particularly important because there is an associated increase in radiation toxicity to normal brain tissue when using SRS. It is used for newly diagnosed GBM despite the argument that there is little evidence of it having a significant impact on treatment outcomes and prognosis in malignant glioma.^15-17

Chemotherapy
The median survival after surgery and postoperative radiation therapy for patients with GBM is less than 1 year¹⁸ and almost all of these tumors recur despite aggressive treatment. Even patients who undergo total resection for glioma have a high recurrence rate because of the infiltrative nature of malignant glioma.¹⁵ Advances in intraoperative and neurosurgical procedures may allow safer resection of many inaccessible tumors but there are those tumors that remain inaccessible or are only partially resectable due to their location and to the highly infiltrative nature of gliomas.

For these patients and those with recurrent GBM or anaplastic astrocytoma, chemotherapy offers systemic treatment, and studies have shown that adjuvant chemotherapy may improve survival in addition to the improved survival rate offered by radiation therapy treatment alone. However, the results with chemotherapy in general have been disappointing. There are several reasons for this, with the most notable reason being that the doses of chemotherapeutic agents that can be given within the range of acceptable toxicity to patients are not high enough and patients develop an intrinsic resistance to these drugs.³ Another reason is the blood-brain barrier (BBB), which protects the CNS from toxic substances in the bloodstream, only allows a small portion of any systemically delivered drug to find its way to the brain. This has led to the development of alternate drug administration techniques,³ which include the following¹⁵:

• Intra-arterial drug administration
• Disruption of the BBB by hyperosmolar solutions or biomolecules
• High-dose chemotherapy
• Direct intratumoral injection of free drug, or the use of a drug embedded in a controlled-release, biodegradable matrix delivery system

The nitrosureas are the most widely used chemotherapy agents, either alone (carmustine) or in combination with other drugs, such as vincristine, procarbazine, and lomustine. The development and use of temozolomide, an alkylating agent that is less toxic than other agents, has been shown to be of benefit for patients with recurrent high-grade glioma¹⁸ and for elderly patients,¹⁵ resulting in a modest improvement in the survival of these groups of patients.

Neuroimaging in the Management of Adult Patients with Glioma
Neuroimaging features are of particular importance in the management of patients with brain tumors, and it is vital to obtain a differential diagnosis so that appropriate care and management of the patient can be planned. The technological advances in neuroimaging have contributed significantly to these decisions.

The role of neuroimaging includes refining the diagnosis based on imaging characteristics and anatomic site, precise anatomic localization for surgical or radiotherapeutic planning, measurement of residual tumor size after surgery, radiation therapy and chemotherapy, and detection of late effects of therapy.^3,19 For instance, MRI contributes to the histopathologic classification of a glioma with an accuracy rate that approaches that of neuropathologic diagnosis,²⁰ a procedure that is subject to an increase in sampling errors. Noninvasive assessment of tumor viability and activity also will aid in testing new therapies,²¹ with special emphasis on imaging techniques that provide information about tumor angiogenesis and metabolic activity. An example is magnetic resonance spectroscopy imaging (MRSI), which reflects the biologic characteristics of glioma, such as rate of cell proliferation and cell necrosis, and contributes toward more accurate delineation of the tumor. This increased accuracy may result in improved treatment outcomes.

Diagnosis
Although CT with a contrast agent and MRI with or without the addition of gadolinium contrast are the major imaging procedures for diagnosis, MRI remains the procedure of choice.³ Plain film skull X rays, cerebral angiography, and isotope brain scanning are rarely performed to confirm suspicion of a brain tumor, whereas PET with fluorodeoxyglucose (FDG) may be used to detect malignant tumors with a high metabolic rate. PET-FDG is not a US Food and Drug Administration approved part of the routine workup tests used to confirm suspicion of a brain tumor, although this test may be used to differentiate recurrent tumors from radiation necrosis.⁹

Even though MRI has replaced CT as the modality of choice for diagnosis, CT is still used for select cases in which MRI is contraindicated; examples of when MRI is contraindicated include patients with pacemakers or iron-containing implants, when a patient suffers from claustrophobia and open MRI is not available, or when the patient's condition is unstable due to acute hemorrhage and thus the speed of CT would be preferable to MRI. Other instances in which CT is superior to MRI include for detection of calcifications and for bony or vascular involvement.

However, in most cases, the soft tissue contrast resolution with MRI is superior to CT and standard T1- and T2-weighted MRIs detect brain tumors with high sensitivity.¹⁹ A typical MRI examination will include several sequences that are chosen to provide information relative to the clinical diagnosis of the patient. These may include proton density, diffusion-, and perfusion-weighted images, as well as fluid-attenuated inversion recovery (FLAIR), in which free water appears as dark and edematous tissue remains bright. Most tumors are hypointense (dark) on T1-weighted images and hyperintense (bright) on FLAIR, T2-weighted, and proton density weighted images.

The destruction of the blood-brain barrier (BBB) plays an important role in diagnosis and classification of brain tumors. In the presence of highly proliferative tumors, such as anaplastic astrocytoma or GBM, the BBB is destroyed allowing for passage of the contrast media into the brain during contrast-enhanced CT and MRI. In general, most low-grade gliomas do not enhance on CT or MRI, whereas almost all enhancing lesions are high-grade tumors.^3,19 A promising imaging tool for measuring physiological tumor properties, such as vascular permeability, is the dynamic contrast-enhanced perfusion MRI. Using this tool to assess changes in tumor vessel permeability allows for the prediction of pathologic tumor grade.¹⁹

Planning for Surgical Biopsy or Resection and/or Planning for Radiation Therapy
Computed tomography is the primary imaging source for treatment planning with radiation therapy because CT remains the only method for directly measuring the electron densities in the tissue necessary for computing the planned dose distribution.²² CT images are fused with MRI and/or PET for treatment planning.

Magnetic resonance imaging allows for review of the images in the 3 orthogonal planes-sagittal, coronal and axial-which assists in accurate delineation of the site and size of the tumor for either surgical procedures or radiation therapy. Accuracy in delineation is imperative to preserve as much healthy brain tissue as possible when either surgery for biopsy or resection and/or radiation treatment is planned. Accuracy in delineation becomes especially important when preservation of functional brain tissue is at risk. In selected patients and specialized institutions, MRSI and PET are being used in conjunction with MRI to define the real extent or size of a tumor.¹⁹ Comparison of CT and MRI studies have shown that isolated tumor cell infiltration may extend to the periphery of T2-weighted MRI abnormalites.³

When using new treatment delivery technologies in radiation therapy where dose escalation with decreased tumor volume is the primary goal, the demand for accuracy in tumor localization and delineation to limit the toxicity to the brain tissue is important. A similar rationale applies to surgical biopsy and resection techniques using CT- or MRI-guided stereotactic procedures.

To assist with accuracy in treatment, clinicians are using MRSI more frequently. This technique provides information about tumor activity based on levels of cellular metabolites including choline, which is increased in tumors; N-acetylaspartate, which is decreased in gliomas; and lactate, the presence of which indicates cellular breakdown or tumor necrosis.^9,23 Studies have indicated that functional imaging should be incorporated into treatment planning techniques, especially for high-grade gliomas,^23,24 for which the accuracy of tumor outline may be increased. In 45% of patients with low-grade gliomas who were studied, tumor cells were found outside the T2-imaging abnormality with a median of treatment volume increase of 2.3 cm³.^3,23 The same is usually true for high-grade gliomas, in which MRSI has been found to both over- and underestimate the volume of microscopic residual tumor.³ Some studies have even indicated that MRSI shows that tumors on average are 14% larger than seen on conventional MRI technology.  

Figures 1 through 3 provide examples of the changes in treatment volume for radiation therapy treatment planning, using both T1- and T2-weighted MRI in a 50-year-old female patient with a GBM who is undergoing radiation therapy.

Evaluation of Therapeutic Response and Differentiation Between Tumor Recurrence and Radiation Necrosis
Malignant gliomas are rapidly progressive brain tumors. Multiple studies investigating patterns of recurrence after completion of treatment in GBM and anaplastic astrocytoma concluded that local failure was the most common pattern of recurrence.²⁵ The poor prognosis, even after treatment, has lead to development of new treatment strategies that depend on the assessment of tumor response to estimate the efficacy of treatment.

Currently, tumor progression is defined by new or enlarging contrast enhancement on post-treatment MRI studies²⁶; however, imaging for tumor response with standard contrast-enhanced MRI is limited because residual tumor and post-surgical changes can result in abnormal enhancement.¹⁹ In addition, it is difficult to differentiate between radiation injury (tissue necrosis) and recurrent tumor with standard contrast-enhanced MRI, yet it is important in order to plan further management. Dynamic contrast-enhanced MRI, by quantitating the uptake of gadolinium-contrast agent into the lesion, can distinguish the slow rate of uptake of radiation injury from the rapid rate of uptake often seen in malignant tumors.³

Use of imaging to evaluate the response of a tumor to treatment is especially helpful for monitoring the results of biologic therapies, such as the response after the use of antiangiogenic agents. In this example, dynamic contrast-enhanced MRI is useful as a surrogate marker.^19,27

Current Developments in Treatment Strategies for Malignant Glioma    
The standard treatment modalities for malignant glioma-surgery, radiation therapy and chemotherapy-offer some effect on survival but overall, the outlook for patients is still poor with most patients surviving less than 1 year after diagnosis and less than 10% of patients surviving beyond 2 years.²⁸ This dismal prognosis provides the impetus for ongoing investigations in search of improved therapeutics, which currently are focused on the molecular level of cancer mechanics and genetic aberrations of malignant cells.²⁷

Targeted Therapy
Advances in the understanding of molecular biology have led to developments in targeted therapy. This includes the study of small-molecule inhibitors that target oncogenic pathways that are important in the biology of gliomas. One promising target is the vascular endothelial growth factor receptor (VEGFR) found on cellular surfaces, which plays a role in the development of the abnormal vasculature observed in some tumors. Several antiangiogenic agents have been introduced, including bevacizumab, a monoclonal antibody that binds with VEGF and prevents interaction with the receptors on the cell surface. Studies using bevacizumab have been promising. Another antiangiogenic substance, thalidomide, has been studied either alone or with the chemotherapy drug, carmustine. Currently, most of the study results using these VEGFR agents remain uncertain.²

Another important target is the epidermal growth factor receptor, which is overexpressed in the majority of patients with malignant glioma. Targeted therapy using small-molecule growth factor inhibitors, such as erlotinib and gifitinib, are currently under investigation and the role of these substances are being evaluated.²

Biologic Approaches
Gene therapy, oncolytic virotherapy, and immunotherapy are major investigational biologic approaches to the treatment of gliomas that have demonstrated promise in preclinical and early clinical trials.²⁷

Gene therapy involves the transfer or modification of a gene in tumor cells to stimulate a local immune response or to correct genetic alterations present as a result of the malignancy and uncontrolled proliferation. The most promising study of immunotherapy is the use of interferons that stimulate antiviral and cytotoxic activity. Other avenues of research involve the use of anticancer vaccines to stimulate the host immune system to recognize cancer cells as foreign by using competent viruses to infect and lyse cells, with or without genetic transfer.² These strategies are being investigated in clinical trials and although there have been some promising results, most procedures remain experimental.²⁸

Conclusions
Malignant gliomas are some of the most difficult and challenging tumors to treat. The developments in technological and biologic advances in neuroimaging have played a significant role in noninvasive diagnosis and histopathologic grading of gliomas. Although surgical biopsy to confirm pathology is preferred, the role of neuroimaging in confirming pathology is accepted as one of significance. In addition, neuroimaging procedures have become standard procedure for the treatment planning for radiation therapy, playing a significant role in increasing the accuracy of tumor delineation for treatment and decreasing the volume of normal tissue included in the treatment fields. Modern neuroimaging also has improved the accuracy for stereotactic surgical biopsy and removal of glioma in suitable adult patients.

Unfortunately, despite the technological advances in neurodiagnostic imaging procedures and surgical and radiation therapy techniques, there has been only a modest improvement in the treatment outcomes for these tumors over the last 3 to 4 decades. The prognosis for patients with high-grade gliomas remains poor with less than 10% survival at 2 years, even after aggressive treatment that includes surgery, radiation therapy, and adjuvant chemotherapy. Research and clinical trials focused on molecular targets and the biology of tumors have become the main focus of a growing body of literature dedicated to solving the limitations encountered in the treatment of malignant gliomas.²

References
1. Souhami R, Tobias J. Cancer and its management. 5th ed. Oxford, England: Blackwell Publishing Inc; 2005: 174-184.

2. Selznick LA, Shamji MF, Fecci P, et al. Molecular strategies for the treatment of malignant glioma-genes, viruses and vaccines. Neurosurg Rev. 2008;31:141-155.

3. DeVita VT Jr, Hellman S, Rosenberg SA. Cancer: Principles and Practice of Oncology. 7th ed. Philadelphia, PA: Lippincott, Williams and Wilkins; 2005: Chapter 39.

4. Adult brain tumors treatment (PDQ). The National Cancer Institute Web site. Available at: http://www.cancer.gov/cancertopics/pdq/treatment/adultbrain/HealthProfessional/page2. Accessed October 8, 2008.

5. Rubin P. Clinical Oncology: A Multidisciplinary Approach for Physicians and Students. 7th ed. Philadelphia, PA: WB Saunders; 1993.

6. Schiff D, Batchelor T. Classification of brain tumors. Available at: http://www.uptodate.com/patients/content/topic.do?topicKey=~k99dFx546bx7cV. Accessed August 27, 2008.

7. Behin A, Hoang-Xuan K, Carpenter A, et al. Primary brain tumors in adults. Lancet. 2003;361:323-331.

8. Bomford CK, Kunkler IH, Sheriff SB. Walter and Miller's Textbook of Radiotherapy. 5th ed. London, England: Churchill and Livingston; 1993: 473.

9. Wong E, Wu J. Clinical presentation and diagnosis of brain tumors. Available at: http://www.uptodate.com/patients/content/topic.do?topicKey=~LKuOlZzqcYWzAo6. Accessed September 26, 2008.

10. Omuro A, Leite C, Mokhtari K, et al. Pitfalls in the diagnosis of malignant glioma. Lancet Neurol. 2006;5:937-948.

11. Brat DJ, Prayson RA, Rykan TC, et al. Diagnosis of malignant glioma: the role of neuropathology. J Neurooncol. 2008;89:287-311.

12. DeAngelis LM. Brain tumors. N Engl J Med. 2001;344:114-123.

13. Munkandan S, Holder C, Olson J. Neuroradiological assessment of newly diagnosed glioblastoma. J Neurooncol. 2008;89:259-269.

14. Stranjalis G, Protopapa D, Sakas D, et al. Stereotactic biopsy in the era of advanced neuroimaging: does the minimal therapeutic gain justify is current wide use? Minim Invasive Neurosurg. 2003;46:90-93.

15. Batchelor T, Shih HA, Carter B. Clinical manifestations, prognosis, and management of malignant gliomas. Available at: http://www.uptodate.com/patients/content/topic.do?topicKey=~MOY.EcXspAc6KM&selectedTitle=3~69&source=search_result. Accessed November 12, 2008.

16. Ask the experts: surgery and radiosurgery. GliomaEd.com Web site. Available at: http://www.gliomaed.com/expert_question.asp. Accessed September 26, 2008.

17. Tsoa MN, Mehta MP, Whelan TJ, et al. The American Society for Therapeutic Radiology and Oncology (ASTRO): evidence-based review of radiosurgery for malignant glioma. Int J Radiat Oncol Biol Phys. 2005;63:47-55.

18. Sridhar T, Gove A, Bolangiu I, et al. Concomitant (without adjuvant) temozolomide and radiation to treat glioblastoma. A retrospective study. Clin Oncol. In press.

19. Jacobs A, Kracht LW, Grossman A, et al. Imaging in neurooncology. Neuro Rx. 2005;2:333-347.

20. Dean B, Drayer B, Bird CR, et al. Gliomas: classification with MR imaging. Radiology.1990;174:411-415.

21. Aberle DR, Chiles C, Hillman B, et al. Imaging and cancer: research strategy of the American College of Radiology Imaging Network. Radiology. 2005;235:741-751.

22. Imaging for Radiation Therapy Planning. In: Van Dyk J, ed. The Modern Technology of Radiation Oncology. Madison, WI: Medical Physics Publishing; 1999.

23. Pirzkall A, McKnight TR, Graves EE, et al. MR-spectroscopy guided target delineation for high grade gliomas. Int J Radiat Oncol Biol Phys. 2001;50:915-928.

24. Ling CC, Humm J, Larson S, et al. Towards multi-dimensional radiotherapy (MD-CRT): biological imaging and biological conformity. Int J Radiat Oncol Biol Phys. 2000;47:551-560.

25. Tada T, Minakuchi K, Koda M, et al. Patterns of recurrence after complete remission with definitive radiotherapy in the treatment of malignant glioma. Int J Clin Oncol. 1998;3:36-40.

26. Aiken AH, Chang SM, Larson D, et al. Longitudinal magnetic resonance imaging features of glioblastoma multiforme treated with radiotherapy with or without brachytherapy. Int J Radiat Oncol Biol Phys. 2008;5:1340-1346.

27. Gossman A, Hellbich T, Kuriyama N, et al. Dynamic contrast enhanced magnetic resonance imaging as a surrogate marker of tumor response to antiangiogenic therapy in a xenograft model of glioblastoma multiforme. J Magn Reson Imaging. 2002;15:223-240.

28. Batchelor T, Supko J. Experimental treatment approaches for malignant gliomas. Available at: http://www.uptodate.com/patients/content/topic.do?topicKey=~FFpwp.sZ/j6sMTk&selectedTitle=2~150&source=search_result. Accessed August 27, 2008.