Primary Nervous System Tumors in Adults

Conventional fractionated radiotherapy

Conventional three-dimensional–conformal radiation therapy is provided in daily fractions of 1.8–2.0 Gy. The total dose seldom exceeds 60 Gy to avoid radiation necrosis, or damage to normal brain. “Hyperfractionation” protocols decrease the dose per fraction, but increase the number of fractions per day. With accelerated fractionation, the dose is applied over a shorter period by increasing the number of daily treatments. In theory, this reduces repopulation of tumor cells during irradiation. Fractionation strategies require immobilization devices such as bite blocks and thermoplastic molds that allow reproducible positioning of the patient with each treatment. The use of multiple radiation fields or three-dimensional conformal irradiation limits the exposure of overlying skin and normal brain tissue.

Brachytherapy

In brachytherapy, radiation is delivered by implanting the irradiation source close to or into the target tissue. Interstitial therapy uses iridium-192 or iodine-125 seeds. Scalp infections have been described after therapy with high-activity brachytherapy seeds, and there is a 50% risk of the development of necrosis in the radiation site. Nearly half of patients require surgical removal of this tissue. Intratumoral positioning of miniature x-ray–generating devices or temporary intracavitary placement of a balloon catheter through which radionuclide can be administered are other forms of local radiation delivery. Survival outcomes using this technique have been variable. Given the technical complexity and potential for toxicity, the use of brachytherapy in the treatment of brain tumors is limited in current practice.

Sensitization of tumor cells to ionizing radiation

Hypoxic tumor cells likely evade the lethal effect of irradiation. Rapidly growing tumors such as malignant gliomas contain a fraction of hypoxic cells that may represent one-third of the tumor burden. Fractionation of irradiation allows reoxygenation of tumor tissue during the resting intervals. Pharmacological strategies include nitroimidazoles such as metronidazole, misonidazole, or etanidazole, and the hypoxic cytotoxin tirapazamine. Oxygen delivery to the tumor can be increased by the application of hyperbaric oxygen or the provision of agents that alter the hemoglobin–oxygen dissociation curve (RSR13). Examples for nonhypoxic radiosensitizers are halogenated pyrimidines such as 5-bromodeoxy-uridine and hydroxyurea. Radiosensitization is also provided by certain chemotherapeutic agents (cisplatin or doxorubicin), the antitrypanosomal agent suramin, or the angiogenesis inhibitor thalidomide. Thus far, radiosensitizers have not shown to be of any benefit to brain tumor patients.

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 LINAC 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 and reaches 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 2–4 months after treatment, but maximal at 18 months.

A unique device equipped with a light-weight, high-energy radiation source is available for performing robotic frameless SRS (CyberKnife). The technique uses 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).

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 74.1 ).

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 crosslinks. Gliomas resist these effects by reducing drug uptake, overexpression of cellular sulfhydryl groups, and elimination of alkylated nucleosides by the repair enzyme O-alkyl-guanine-alkyl-transferase (AGAT). Common toxicities of these agents include myelosuppression, nausea, and infertility. Secondary malignancies occur in 5%–10% of patients with a peak incidence 5–7 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 such as acetyl salicylic acid, penicillin G, or probenecid cannot be used concomitantly. Pemetrexed inhibits at least three enzymes involved in folate metabolism and DNA synthesis: thymidylate synthase, DHFR, and glycinamide ribonucleotide formyltransferase.

The deoxycytidine analogue 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 (vinblastine, vincristine), naturally found in Catharanthus 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 ( ). Moreover, this approach is associated with considerable 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 ( ).

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, triethylenethiophosphoramide (thio-TEPA), or cytosine-arabinoside for leptomeningeal metastases. (2) Intracarotid infusion of hypertonic solutions (25% mannitol or 15% glycerol) to produce reversible opening of the BBB. This approach, selectively used in specialized centers, produces 1–2 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. (3) Biodegradable polymers impregnated with bis-chloroethylnitrosourea (carmustine) (BCNU) increase local drug concentration without notable systemic toxicity. Dime-sized wafers of poly [bis (p-carboxyphenoxy)] propane and sebacic acid release the chemotherapeutic agent over 7–10 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 ( ). Complications include infection, wound healing impairment, brain necrosis, and cerebrospinal fluid (CSF) leak.