Cancer and the Nervous System: Management of Primary Nervous System Tumors in Adults

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Chapter 52D Cancer and the Nervous System

Management of Primary Nervous System Tumors in Adults

In the year 2010, approximately 63,000 cases of primary nervous system tumors were expected to occur in the United States (CBTRUS, 2010). The World Health Organization distinguishes between six groups of neoplasms. Meningeal tumors (mostly meningioma) and neuroepithelial tumors (astrocytic tumors including glioblastoma multiforme, oligodendrogliomas, and others) each account for about one-third of nervous system neoplasms. The remaining third is composed of tumors of the sellar region (pituitary adenoma, craniopharyngioma), tumors of peripheral nerves, lymphatic and hematopoietic tumors, and germ cell neoplasms.

Management of patients with primary brain tumors is an interdisciplinary effort that includes neurosurgeons, neurologists, radiation oncologists, medical oncologists, neuroradiologists, and neuropathologists. Neurologists are involved in the clinical diagnosis, treatment with chemotherapeutic agents or new medical strategies, and symptomatic therapy. Over the last 20 years, progress has been made in diagnostic procedures, monitoring of therapeutic efficacy, optimizing standard treatments for selected tumor subtypes, understanding the pathogenesis of primary brain tumors, and developing new treatment concepts. Surgical techniques have been refined and now allow the use of the operating microscope, intraoperative magnetic resonance imaging (MRI), or preoperative mapping using functional MRI and fiber tractography. Surgery is curative for completely resectable meningioma and noninfiltrative gliomas. As surgery has become more precise, so has radiation therapy. Conventional strategies provide cure for patients with germinomas. Highly focused external radiation strategies have improved local tumor control and reduced damage to contiguous normal brain. Chemotherapy improves survival and function of patients with lymphoma or glial brain tumors.

High-grade gliomas remain the biggest therapeutic challenge. Despite the provision of radiation therapy and chemotherapy as adjuvant treatment, fewer than 20% of patients with glioblastoma multiforme are still alive 2 years after diagnosis. Thus tertiary centers are consulted to provide experimental approaches to treat these patients.

Novel therapies must take into account issues specific to brain tumors. The blood-brain barrier (BBB) prevents access to the brain by hydrophilic chemotherapeutic agents and large molecules. Cells of brain tumors are uniquely able to resist chemotherapeutic agents by overexpressing membrane proteins that eliminate these drugs or by inducing enzymes to inactivate them. Even when drugs enter brain tumors, not all cells are sensitive. The hypoxic areas of tumors are in cell-cycle arrest and resistant to cell cycle–dependent agents or radiation. Other factors confounding therapy include corticosteroids that alter the BBB penetration of drugs, the host immunological reaction to the tumor, and the cytotoxic effects of chemotherapy.

This chapter reviews current therapy of brain tumors in adults and provides an approach to specific brain tumors.

Established Treatment Strategies

Surgery

Surgery, the primary modality of management for patients with brain masses, provides indispensable diagnostic information, alleviates mass effect, reduces seizure activity, and may offer cure.

No rational therapy can be provided without a histological diagnosis. Stereotactic biopsy uses targets acquired by computed tomography (CT) or MRI. A stereotactic frame or fiducial markers are placed on the patient’s head, assuring appropriate sampling and diagnosis in over 95% of patients. Functional MRI and diffusion tensor imaging are performed to identify contiguous eloquent areas of the brain and white-matter tracts. The data are co-registered on three-dimensional (3D) MRI reconstructions from which biopsy coordinates are drawn. A probe is then passed through a small drill hole that retrieves cylindrical samples 1 cm in length and 1 to 2 mm in diameter. The procedure is safe and associated with less than a 2% risk of seizure, hemorrhage, or infection.

Some intracranial tumors can be cured by complete surgical resection (noninfiltrative gliomas, pituitary adenoma, and meningioma). Less clear is the benefit of resecting the infiltrating diffuse astrocytoma or “partial” decompression of an aggressive tumor. Resection provides prolonged survival for oligodendrogliomas, and most clinicians support “subtotal” resection in the setting of increased intracranial pressure; steroid-obligating mass effect, hemorrhage, or impending herniation; the presence of necrotic tumor cysts; and uncontrollable seizures. Often the decision to operate depends on preoperative MRI mapping of both gray- and white-matter functions. Aids to the surgeon also include tumor resection based on intraoperative MRI, intraoperative cortical stimulation mapping, and monitoring of somatosensory evoked potentials. It is often argued that surgery will reduce the burden of tumor prone to malignant degeneration, but this view is countered by the occurrence of infiltrates of tumor extending at distances from the main mass. The advocates of subtotal resection often cite the diminished likelihood of sampling error associated with stereotactic biopsy. Following operation, within 48 hours, a contrast-enhanced MRI is recommended as an objective measure of residual tumor. After 48 hours, perioperative changes occur in the brain and prevent accurate determination of residual tumor.

Radiation Therapy

Radiation therapy is commonly provided to treat brain tumors. Some tumors such as germinomas can be cured, and others are slowed in their progression. Survival is improved in many glial and nonglial tumors, and symptoms—including seizures—are reduced. Palliation is the goal for older adult patients or those with leptomeningeal tumor.

The target for radiation cell death is the deoxyribonucleic acid (DNA) molecule. High-energy beams cause breaks in the DNA double strand either by ionization of the target atom or by production of free radicals. The effect of radiation depends on the dose applied, how often it is applied, and how much time is available for the target to repair the damage. Dividing cells are more susceptible to irradiation than nondividing cells, especially during the M-(mitotic) and G2 phase of the cell cycle.

Photons are the most commonly used particles in the radiation therapy of brain tumors. Examples of non-photon irradiation modalities (most of them only available in experimental facilities) include neutrons, protons, and heavy ions (carbon, argon, neon).

Radiation therapy is usually delivered by a linear accelerator (LINAC) that uses high-frequency electromagnetic waves to accelerate electrons to high energies. The electron beam is used directly for the treatment of superficial tumors or indirectly by producing x-ray beams for the treatment of deep-seated lesions. Shielding blocks are built for each patient to restrict the beam to the target volume. The size of the treatment field depends on the tumor type. For infiltrative tumors such as malignant gliomas, therapy is provided to the volume of enhancement or T2 abnormality on MRI and a margin of 1 to 3 cm. For sharply demarcated cystic astrocytomas, a margin of 0.5 cm suffices. On the other hand, whole-brain radiation therapy (WBRT) is provided to treat multifocal infiltrating tumors seen in gliomatosis cerebri or the multiple masses of recurrent brain lymphoma. Strategies, mainly of experimental nature, to improve tumor cell kill and minimize damage to normal tissue include increasing the number of treatment fractions to two or more per day, the use of multiple fields, the use of radiosensitizing agents, or localized high-field strength sources.

The clinician should be aware of radiation therapy complications. Within 10 days of the start of irradiation, patients may become fatigued and experience altered appetite and sleep patterns reflecting brain edema; 6 to 18 months after radiation, contrast-enhanced masses reflect radiation-induced white-matter necrosis. Additional complications include panhypothalamic-pituitary dysfunction, elevated prolactin levels, impotence, or amenorrhea.

Stereotactic Radiosurgery Techniques

Radiosurgery is the name given to single fractions of stereotactic radiosurgery (SRS) and multiple fractions of stereotactic radiation therapy (SRT). These techniques deliver large doses of radiation to well-circumscribed tumor sites while minimizing exposure to normal tissue. Three types of facilities are typically used. LINAC radiosurgery uses a modified linear accelerator to produce high-energy photon beams. Heavy charged particle beams such as helium or protons (proton radiosurgery) offer optimal physical characteristics for stereotactic applications. The beam penetration into tissue reflects the energy imparted to the particle, which penetrates to relatively finite depths (Bragg peak). Gamma Knife provides irradiation using 200 separate and collimated cobalt-60 sources in a hemispherical array aimed at the target. These radiosurgery techniques require some means of fixation of the patient’s head in space. Devices include immobilization masks, rigid frames affixed to the patient’s skull, or fitted mouthpieces. The acute complications of these therapies include cerebral edema and seizures. The major late complication is radiation necrosis manifested as early as 2 to 4 months after treatment, but maximal at 18 months.

A unique device equipped with a light-weight, high-energy radiation source, is now available for performing robotic frameless SRS (CyberKnife). The technique utilizes an image-to-image correlation algorithm for target localization and has been increasingly applied to neoplasms of brain, skull base, and spine. Other devices are available for frameless SRS (Novalis Tx).

Chemotherapy

Standard Cytotoxic Chemotherapy

Chemotherapy is provided to most patients with malignant brain tumors. Less commonly treated are nonresected low-grade but symptomatic tumors prior to or following radiation therapy. Chemotherapy is becoming increasingly important for patients with brain lymphoma or anaplastic oligodendroglial tumors (Table 52D.1).

Alkylating agents are the major compounds used against brain tumors. Their antitumor effect is based on covalent binding of alkyl groups to DNA, which results in intra- and interstrand cross-links. Gliomas resist these effects by reducing drug uptake, overexpressing cellular sulfhydryl groups, and eliminating alkylated nucleosides by the repair enzyme, O6-alkylguanine-alkyltransferase (AGAT). Common toxicities of these agents include myelosuppression, nausea, and infertility. Secondary malignancies occur in 5% to 10% of patients, with a peak incidence 5 to 7 years after exposure.

The antifolates interfere with the synthesis of tetrahydrofolates, one-carbon carriers essential for synthesis of thymidylate and purines. Methotrexate, a potent inhibitor of dihydrofolate reductase (DHFR), is given by vein in gram-equivalent doses to achieve therapeutic concentrations within the brain, spinal fluid, nerve roots, and eye. This mandates the establishment of alkaline diuresis because concentrations in urine can exceed the level of solubility depending on urine pH. Drugs competing for excretion in the proximal tubule (e.g., acetylsalicylic acid, penicillin G, probenecid) cannot be used concomitantly. Pemetrexed inhibits at least three enzymes involved in folate metabolism and DNA synthesis: thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide formyltransferase.

The deoxycytidine analog, cytosine arabinoside, competitively inhibits DNA polymerase A. After incorporation into DNA, there is inhibition of chain elongation and template function.

Microtubular components of the mitotic spindle apparatus can be inhibited within tumor cells with resulting reduction of cell division, intracellular transport, and secretion. The vinca alkaloids, naturally found in Cantharanthus roseus, inhibit polymerization of tubulin and the disassembly of microtubules and thus produce cell-cycle arrest in metaphase. The taxanes (paclitaxel, docetaxel) disrupt microtubule dynamics by stabilization against depolymerization and enhancement of polymerization.

Platinum compounds form bifunctional bonds to DNA to produce intrastrand adducts linking two nucleotides. The cell repair of these links makes use of nucleotide excision DNA repair. Defects in the DNA mismatch repair system may prevent recognition of platinum adducts and result in failure to initiate apoptosis.

Topoisomerase inhibitors catalyze the process of catenation and decatenation, the temporary uncoiling and unlinking of the DNA double strand. The topoisomerases bind to the free ends of the cut DNA molecule, using a specific tyrosine residue. Topoisomerase I introduces single-strand breaks into the DNA molecule. Its inhibitors are derivatives of camptothecin (irinotecan, topotecan). Topoisomerase II catalyzes linking and unlinking by causing double-strand breaks. Etoposide and teniposide, semisynthetic derivatives of podophyllotoxin, a substance found in mayapple extracts, inhibit the re-ligation of DNA from the cleavage complex.

Myeloablative doses of chemotherapy followed by autologous peripheral-blood stem cell transplantation have failed to produce higher response rates in malignant gliomas when compared with conventional adjuvant chemotherapy (Finlay et al., 1996). Moreover, this approach is associated with significant treatment-related morbidity and mortality and thus has not found widespread use. Results of high-dose chemotherapy with peripheral-blood stem cell rescue in patients with chemosensitive brain tumors like anaplastic oligodendroglioma or primary central nervous system lymphoma (PCNSL) are more promising (Abrey et al., 2006).

Delivery Strategies

The BBB is the major anatomical obstacle for chemotherapy of primary brain tumors. It is composed of the endothelial cell layer of cerebral capillaries sealed by intercellular tight junctions, the vascular basal membrane, and astrocytic foot processes. Few studies have measured brain concentrations of systemically administered agents, but delivery strategies developed to circumvent the barrier include the following: (1) intrathecal administration of methotrexate, thiotepa, or cytosine-arabinoside for leptomeningeal metastases, (2) intracarotid infusion of hypertonic solutions (25% mannitol or 15% glycerol) to produce reversible opening of the BBB, and (3) biodegradable polymers impregnated with BCNU. Intracarotid infusion of hypertonic solutions, selectively used in specialized centers, produces 1 to 2 hours of barrier lysis during which hydrophilic chemotherapeutic agents such as methotrexate or cyclophosphamide are provided. The technology obligates general anesthesia and serial angiographic procedures and is associated with toxicity, including seizures and transient encephalopathy. Biodegradable polymers impregnated with BCNU increase local drug concentration without notable systemic toxicity. Dime-sized wafers of p-carboxyphenoxy (polybis) propane and sebacic acid release the chemotherapeutic agent over 7 to 10 days into tumor surrounding the resection site. The polymer-based delivery strategy is associated with median survival improvements of 2 months in patients with malignant glioma (Westphal et al., 2003). Complications include infection, wound healing impairment, brain necrosis, and cerebrospinal fluid (CSF) leak.

New Treatment Strategies

Several methods are under investigation to reduce resistance to alkylating agents. O6-benzylguanine is a potent inhibitor of AGAT that has been co-administered with alkylating agents (Quinn et al., 2005). Inhibitors of poly(adenosine diphosphate–ribose) polymerase (PARP), cell signaling enzymes implicated in cellular responses to DNA injury provoked by genotoxic stress, potentiate the effect of various chemotherapeutic agents, including alkylating compounds and inhibitors of topoisomerase 1.

Various compounds interfering with pathways regulating cell growth have been developed for numerous cancer types. Cell growth control can be attacked at different levels: growth factors, growth factor receptors, intracellular signal transducers, nuclear transcription factors, and cell-cycle control proteins. Various strategies are available to interfere with proteins or the transcription/translation of their encoding genes at each level. Modified peptides or peptidomimetics such as imatinib are molecules designed to bind to the active sites of proteins, such as the tyrosine kinase domain of growth factor receptors. Imatinib, a synthetic inhibitor of the tyrosine kinase receptors, abl and c-kit, has been of value in the therapy of chronic myelogenous leukemia and gastrointestinal stromal tumors. This has inspired the use of similar agents to target analogous brain tumor pathways. Antisense oligonucleotides injected into tumors hybridize with transcripts of growth control genes and inhibit their translation. Ribozymes degrade transcripts with high specificity. Monoclonal antibodies directly target growth-control proteins. Gene therapy may restore the function of mutated cell-cycle control proteins. A summary of new treatment strategies can be found in Box 52D.1.

Epidermal growth factor receptor (EGFR) is an attractive target because it is commonly overexpressed or mutated. However, monotherapy with agents targeting this receptor (gefitinib, erlotinib, tyrphostin) has been disappointing (Rich et al., 2004). Molecular predictors of the rare responses have been identified (Mellinghoff et al., 2005). Inhibition of platelet-derived growth factor receptor (PDGFR) with imatinib has also been unsuccessful. This has led to the development of small-molecule inhibitors with a broader spectrum or “dual” inhibitors. AEE788 and vatalanib interfere with both EGFR and vascular endothelial growth factor receptor (VEGFR) signal transduction. Lapatinib inhibits EGFR and ErbB2, two members of the ErbB family of transmembrane tyrosine kinase receptors. These compounds are currently undergoing clinical evaluation, as are combination regimens using GFR and downstream signal transduction inhibitors (e.g., erlotinib, sirolimus).

A variety of compounds were designed to block intracellular signal transduction such as phosphoinositide-3-kinase/protein kinase B (PI3K/Akt), protein kinase C (PKC), Ras, and the mitogen-activated protein kinase pathway Raf/MEK/ERK. These agents have been used as monotherapy and in combination with classical cytotoxic agents or growth factor receptor inhibitors.

Another therapeutic strategy targets intracellular protein degradation. The proteasome is a cellular protein degradation complex that recognizes and degrades polyubiquitinated substrates such as cell-cycle control proteins. Although a fairly nonspecific apparatus, the overall effect of some proteasome inhibitors such as bortezomib, a dipeptidyl boronic acid derivative, is the induction of apoptosis. The drug is approved for use in multiple myeloma but remains investigational for primary brain tumors.

Histone deacetylase (HDAC) inhibitors interfere with transcription. HDAC induces hyperacetylation of histones, resulting in chromatin relaxation and transcriptional activation. The anticancer properties of various HDACs have been recognized and are likely the complex result of activation of differentiation programs, cell-cycle inhibition, and induction of apoptosis in cancer cells (Johnstone, 2002). Compounds such as phenylacetate, phenylbutyrate, or valproic acid display HDAC-inhibiting properties but are unlikely to play a role as brain cancer therapeutics. Suberoylanilide hydroxamic acid (SAHA) and the fungal tetrapeptide, depsipeptide, are currently undergoing clinical evaluation in malignant gliomas.

Inhibition of angiogenesis or cell invasion represents another promising approach to brain tumor therapy. Gliomas larger than a few millimeters stimulate new blood vessel formation. This induction is affected by promoters including VEGF (hypoxia-inducible endothelial cell mitogen, vascular permeability factor), basic fibroblast growth factor (bFGF), platelet-derived growth factor, EGF, transforming growth factor (TGF), and tenascin. Endogenous inhibitors of angiogenesis include angiostatin, endostatin, thrombospondin, and heparin. Kinase insert domain receptor (KDR) and FMS-related tyrosine kinase 1 are receptors for VEGF. Bevacizumab, a humanized monoclonal antibody with murine complementarity-determining regions binding VEGF, is now approved for use in patients with relapsed glioblastoma. Several small-molecule inhibitors of VEGFR are at various stages of development. Sunitinib is already in clinical use for advanced renal cell cancer. Early experience with cediranib in glioblastoma has been promising, and a phase III study in patients with newly diagnosed disease was completed recently (Batchelor et al., 2007). Other potential therapies targeted to endothelial cells include thalidomide, interleukin (IL)-12, cyclooxygenase II inhibitors, and cilengitide, a cyclic pentapeptide inducing apoptosis of growing endothelial cells through inhibition of their αVβ3 integrin interaction with the matrix proteins, vitronectin and tenascin.

Gene therapy of brain tumors encompasses a wide spectrum of various strategies. A comprehensive review of these approaches goes beyond the scope of this chapter, and the interested reader is referred to excellent review articles (Lam and Breakefield, 2001). Viral vectors create localized inflammation while expressing transgenes that activate cytokines and chemotherapies. Transfection efficiency depends on the agent and the mode of introduction. Cells are killed not only by transfection but by the cellular reaction that damages adjacent tumor cells: the “bystander effect.” The delivery of a therapeutic gene can be enhanced by improving the vector or delivering it through infusional clysis. Ligands or antibodies targeted at receptors expressed on tumor cells (EGFR, transferrin receptor, integrin receptor) can be incorporated into the capsid of adenoviral vectors. Tumor-specific expression systems make use of the human telomerase reverse transcriptase (hTERT) promoter; hTERT is the catalytic subunit of the telomerase ribonucleoprotein and is expressed in glioma cells but not in normal glia cells. Tumor selectivity can also be accomplished by using replication-conditional viral vectors, retroviruses, or placement of genes essential to virus replication under the control of promoters that are selectively active in gliomas (e.g., nestin promoter). Currently used vector systems are either replication-defective or replication-conditional and include recombinant HSV, Ad, retrovirus, and hybrid vectors. Gene therapy delivery involves stereotactic injection into the tumor or intraoperative insertion into the wall of the resection cavity, convection-enhanced delivery, or intraarterial or intraventricular application. Nonviral strategies have made use of naked DNA, polycationic polymers, and liposomes.

Therapies based on immune-mediated strategies aim to increase immune responses to the tumor. Whether primary brain tumors suppress immune reaction, are poorly recognized by the immune system, or are protected by the immunosuppressive effects of concurrent glucocorticoid administration is uncertain. Tumor vaccination makes use of immunogenic peptides, attenuated autologous tumor cells, or dendritic cells loaded with tumor antigens. These tumor antigens create an immune reaction enhanced by irradiation, transfection with cytokine genes, or transfection with major histocompatibility complex (MHC) class II genes. The antigen can be presented in subcutaneous tissues, after which cytotoxic T cells infiltrate the site of injection as well as the brain. A “one-fits-all” immunization strategy targeting a somatic mutant of EGFR (EGFRvIII) has been tested in small phase II studies, with promising results (Sampson et al., 2009).

There are various mechanisms by which gliomas evade recognition by the immune system. Potential mediators include inhibitory cytokines (TGF-β, prostaglandin E, IL-10) and defective cytokine receptors on tumor-infiltrating T lymphocytes. Strategies rendering glioblastoma cells immunogenic have included transfection with antisense TGF-β or decorin, a TGF-β-binding and TGF-β-inhibiting proteoglycan. Cytokines can be linked to bacterial toxins as genetically engineered fusion proteins that enter the tumor cell via binding to selectively expressed receptors. A phase III clinical trial of cintredekin besudotox (IL-13 linked to Pseudomonas exotoxin) administered intracerebrally through convection-enhanced delivery failed to demonstrate a survival benefit (Debinski et al., 1998).

Antibodies alone or conjugated with toxins or radioactive isotopes (iodine-131, yttrium-90) can target epitopes on tumor cells (EGFR, neural cell adhesion molecule, tenascin). These approaches are hampered by insufficient delivery, lack of tumor specificity, and concerns regarding ventricular or subarachnoid exposure.

Oncolytic viruses are modified viruses that preferentially replicate in and destroy cancer cells. For example, ONYX-015 is a replication-competent E1B-attenuated adenovirus. E1B is a viral protein that binds and inactivates p53, a prerequisite for the virus’s ability to replicate in its host cell. Ad lacking E1B can only replicate in TP53-deficient cells. Loss of TP53 function is an early event in the pathogenesis of gliomas and thus renders them susceptible to lytic infection with this attenuated virus (Chiocca et al., 2004). Clinical trials have proven safe, but delivery systems have thus far proven insufficient.

New delivery strategies are designed to circumvent the BBB to treat malignant gliomas. Intraoperative injection of resection margins with various therapeutic agents (viral vectors, oncolytic viruses) does not depend on BBB permeability but is highly inefficient. Tissue penetration can be improved using convection-enhanced delivery. This technique requires intraoperative or stereotactic placement of infusion catheters in the wall of the resection cavity. Using microinfusion pumps, therapeutic agents are provided postoperatively over up to 96 hours. Exposure may be even further enhanced by packaging the therapeutic compound (cytotoxic chemotherapy agent, vector, antibody, etc.) into microspheres from which it is released over a modifiable period of time (Saltzman and Olbricht, 2002). Neuroprogenitor cells may deliver vectors or therapeutic genes to tumors. Animal experiments have shown that systemically administered neural stem cells home to brain tumors. Progenitor cells have been found within experimental brain tumors following injection into the contralateral cerebral hemisphere—an observation that may indicate the stem cells’ ability to track down migratory brain tumor cells (Aboody et al., 2000).

Management of Specific Brain Tumors

Neuroepithelial Tumors

Astrocytic Tumors

Noninfiltrative Tumors

Pilocytic Astrocytoma

Comprising 85% of infratentorial astrocytomas, most pilocytic astrocytomas are benign tumors located in the cerebellum and occur in the first and second decade (Burkhard et al., 2003). The remainder grow in the hypothalamus, the walls of the third ventricle, the optic pathway, and the brainstem. The tumor likely emerges from true astrocytes or subependymal precursors. Pilocytic astrocytoma, usually of the optic nerve, is the most common central nervous system (CNS) tumor associated with neurofibromatosis type 1. The tumor diagnosis is heralded by symptomatic obstructive hydrocephalus, headache, or hypothalamic-pituitary dysfunction. Posterior fossa signs include neck stiffness, head tilt, and incoordination. The masses enhance with gadolinium and appear in proximity to the ventricle or subarachnoid space. Cysts, focal hemorrhage, and calcification are described. Much of the tumor contains benign features: bipolar (piloid) cells with Rosenthal fibers in addition to microcysts surrounded by protoplasmic astrocytes and eosinophilic granular bodies. Three-quarters of patients receive surgical resection. For the unresectable case exhibiting progressive growth or symptoms refractory to treatment, involved field radiation therapy is given with a margin of 0.5 cm. Chemotherapy can be used prior to irradiation or for tumor progression. The 25-year survival rate is between 50% and 94% following surgical resection. Malignant transformation of pilocytic astrocytoma is highly unusual.