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Behavioral Objectives After completing this continuing education article, the pharmacist should be able to:
Primary central nervous system (CNS) tumors are relatively rare malignancies, comprising approximately 1.3% of new cases of cancer in the United States and 2.2% of deaths. It is estimated that in 2004, approximately 18,400 new primary brain tumors will be diagnosed in the United States, resulting in about 12,700 deaths.1 Primary intracranial tumors include at least 25 distinct diseases, divided into a number of categories (Table 1). Grade IV astrocytomas, commonly referred to as glioblastoma multiforme, are the second most common type of brain tumor, accounting for about 21.7% (~4000) new cases. Grades II and III astrocytomas are the third most common type, accounting for approximately 18.4% (~3400) of new cases. Astrocytomas and glioblastoma multiforme together comprise more than 40% of all primary brain tumors. Approximately 90% of astrocytomas are considered to be high grade (malignant), rather than low grade (nonmalignant).2,3
Glial cells are the supporting cells of the central nervous system, holding neurons in place, supplying nutrients and oxygen to the neurons, insulating neurons, and acting as phagocytes. Much smaller and more numerous than neurons, glial cells account for approximately half of the brain's weight. There are 3 types of glial cells: astrocytes, oligodendrocytes, and ependymal cells. Astrocytes are star-shaped cells involved in all 4 glial cell functions. Gliomas are primary brain tumors originating in glial cells. Astrocytic tumors are malignancies that originate in the astrocytes and include pilocytic tumors, low-grade (diffuse, infiltrative, or fibrillary) astrocytoma, anaplastic astrocytomas, and glioblastoma multiforme. In the World Health Organization (WHO) classification of brain tumors, malignant or high-grade diffuse gliomas (anaplastic astrocytoma, anaplastic oligodendroglioma, and anaplastic oligoastrocytoma) are listed as grade III tumors. Glioblastoma multiforme is listed as a grade IV tumor.2 Pilocytic astrocytomas are uncommon, generally noninvasive, and usually curable by surgery alone. Anaplastic astrocytomas and glioblastoma multiforme are the most common primary brain tumors in adults, with glioblastoma comprising more than 50% of all gliomas.4
Grade II astrocytomas are associated with 2 genetic alterations: inactivation of the TP53 tumor suppressor gene and loss of chromosome 22q. TP53 maps to chromosome 17p and encodes the p53 protein, which is important in a variety of cellular activities, such as apoptosis (programmed cell death), cell cycle regulation, and repair of DNA damage. Inactivation of TP53 is reported in about 50% of astrocytomas, and one third of anaplastic astrocytomas and glioblastomas. The mutations are generally missense mutations involving codons 175, 248, and 273 and are believed to be due to spontaneous deamination of 5-methylcytosine residues crucial for DNA binding. These mutations presumably lead to loss of functions mediated by the p53 glycoprotein. The specific gene on chromosome 22q that is involved in development of astrocytomas has not been identified.2
TP53 mutations are involved in both formation of low-grade astrocytomas and transition to malignant glioblastoma, but they occur in only 10% of primary glioblastomas.5 Transformation from low-grade to high-grade astrocytoma involves inactivation of tumor suppressor genes on chromosomes 9p, 13q, and 19q. About two thirds of high-grade tumors show homozygous deletions of the section of chromosome 9p that includes genes CDKN2A and CDKN2B. Loss of chromosome 13q occurs in about one-third of high-grade tumors.2
Distinguishing Properties of Glioma Cells
Overexpression of Growth Factors
A number of factors are overexpressed in malignant gliomas, including:
Loss of Cell Cycle Control
Loss of control is more common in higher-grade gliomas and is responsible for the higher mitotic activity seen in grade III and IV malignancies. The G1-S phase transition, particularly the p16 cyclin dependent kinase (CDK)-4, cyclin D, and pRB (retinoblastoma) proteins, appears to be the part of the cycle primarily involved. Changes in at least 1 of these components is usually seen in anaplastic astrocytomas and occurs in almost all glioblastomas.6
Healthy cells undergo apoptosis, or programmed cell death, as a normal consequence of DNA damage or abnormal proliferation. Many types of malignant cells, including gliomas, are characterized by a loss of this function, with a resultant ability to multiply forever. TP53 mutations, seen in 30% to 50% of astrocytomas and glioblastomas, result in improper regulation of apoptosis in malignant cells.2
Genomic Instability and Malignant Progression
Diffuse low-grade gliomas almost always progress to higher-grade tumors due to the emergence of more malignant clones. TP53 is crucial to protecting cells from DNA damage. TP53 mutations can result in tumor progression by genomic instability. Genomic instability results in increased genomic damage, allowing the gradual emergence of more malignant clones and transformation of low-grade tumors to higher-grade ones.2
Clinical Presentation of Astrocytomas
Like all brain tumors, clinical manifestations of astrocytomas depend on the location and size of the tumor. High-grade astrocytomas cause signs and symptoms associated with local invasion or compression and increased intracranial pressure (ICP). This increased pressure is caused by a large mass or by hydrocephalus caused by restricted outflow of cerebrospinal fluid. Generalized symptoms such as headache and altered mental status are common; a triad of headache, nausea, and papilledema is considered to be a classic presentation, but it does not seem to be present in the majority of cases. Other common indications of high-grade gliomas include seizures and hemiparesis. Nausea or vomiting, motor weakness, and visual or gait disturbances are less common (Table 2).
Signs and Symptoms
The most common neurologic signs of high-grade astrocytomas are hemiparesis (61% - 83%), papilledema (32% - 66%), confusion (18% - 40%), and aphasia (25% - 32%).7,8 As many as 21% of patients with malignant astrocytomas have evidence of meningeal involvement. Common symptoms include back pain (with or without radicular symptoms), cauda equina syndrome, cranial nerve palsies, headache with symptomatic hydrocephalus, and mental status changes.9-12
Headache is the most frequent symptom, often beginning several months before actual diagnosis of the malignancy. Seizures, which may begin as much as a year prior to diagnosis of the tumor, are less common as the initial symptom, but are common at the time of diagnosis. Although symptoms may exist for some time before the actual diagnosis, about 6% of patients with anaplastic astrocytomas or glioblastoma multiforme present with an acute onset of symptoms due to intracranial hemorrhage.8,13
Patients who present with symptoms suggestive of a brain tumor should be referred to their physician for evaluation. The most common diagnostic procedures are computerized tomography (CT) scans and magnetic resonance imaging (MRI). MRI is generally more sensitive than CT and is considered the preferred procedure.14-16 A variety of other procedures, including single photon emission computed tomography (SPECT)17 and fluorodeoxyglucose-positron emission tomography (FDG-PET)18 imaging, may be useful for identifying target areas for biopsy but are not considered standard diagnostic procedures. Although not a standard diagnostic procedure, iodine-123-alpha-methyl-Ltyrosine-single-photon emission tomography (IMT-SPET) imaging has been reported helpful in distinguishing recurrent gliomas from nonmalignant masses.19
The final diagnosis is dependent on obtaining tissue from the suspicious lesion(s) for histologic examination. This requires either a stereotactic biopsy or open surgical resection. These procedures are often performed in conjunction with surgical exploration for possible removal, or debulking, of the tumor. Patients with astrocytomas and glioblastoma multiforme are often candidates for surgical resection, which can be an important prognostic factor. Definitive diagnosis is determined by hematoxylin and eosin chemical staining of the tissue. Immunohistochemical stains or electron microscopy may also be needed. The MIB-1 index, indicating the mitotic rate, is commonly used to assess the grade of the tumor.
Initial therapy of astrocytomas depends on a number of factors, including:
In treating astrocytomas, 3 distinct therapeutic modalities are used, alone or in combination: surgery, radiation, and systemic chemotherapy.
For high-grade (Grade III [anaplastic astrocytoma] and grade IV [glioblastoma multiforme]) astrocytomas, surgery is necessary to confirm the diagnosis, alleviate symptoms of increased intracranial pressure, increase survival, and minimize the use of corticosteroids. The median survival with surgery alone is approximately 4 months. Laws et al reported that extensive surgery was a strong prognostic factor when compared with simple biopsy.20 Other studies indicate aggressive surgery (removal of 98% of the tumor) can improve survival, especially in patients >50 years of age with glioblastoma multiforme and a Karnofsky performance score >70 (Table 3).21,22 While most high-grade astrocytomas cannot be cured by surgery alone, even subtotal resection is useful. Subtotal resection can increase the probability of an accurate histologic diagnosis, provide tissue for special studies, and result in symptomatic improvement. Additionally, tumor debulking can enhance the efficacy of postoperative radiation or chemotherapy.23-25
Low-grade astrocytomas are often treated with either surgery alone or a combination of surgery and radiation therapy. In lower-grade tumors (lowgrade astrocytoma, low-grade oligodendroglioma, pilocytic astrocytoma), the role of surgical debulking of tumors is less certain. Although extensive tumor resections are associated with improved symptom control, it is less certain that a complete resection results in a better prognosis than stereotactic biopsy. Tumors that can be resected safely (eg, located in the polar regions of the brain or dorsal tumors in the brainstem) should be surgically removed. Tumors located in other areas (eg, near motor or language areas) are less amenable to surgical removal.26 Despite these concerns, surgery has an important diagnostic and therapeutic role in these conditions. The primary goal is to obtain tissue for pathologic diagnosis and grading. If feasible, total removal of the tumor should be attempted, because this may delay recurrence, delay or prevent transition to a higher-grade tumor, and increase overall survival.27-30
Radiation has long been the standard therapy for high-grade astrocytomas after surgery. A randomized trial in the 1970s demonstrated that 1-year survival with surgery followed by radiation was superior (24%) to surgery alone (3%) or surgery and chemotherapy with carmustine (12%).31 A wide variety of radiation techniques have been reported as treatment for high-grade astrocytomas and glioblastoma multiforme (Table 4).
Although radiation is considered part of the standard treatment for low-grade astrocytomas, the optimal timing of therapy is still unclear. Some oncologists use radiation immediately after surgery, whereas others wait until there is evidence of tumor recurrence or progression. Due to concerns about the toxicity of radiotherapy, patients with asymptomatic or diffuse low-grade tumors may not receive radiation until the disease relapses or progresses.32 In general, patients who had a diagnostic biopsy or subtotal surgery are more likely to receive immediate radiotherapy. Although 1 study suggested that higher doses of radiation immediately after surgery prolonged survival,33 other studies have failed to confirm this conclusion.28,34
For high-grade tumors, chemotherapy is often used as an adjunct to surgery or/and radiation therapy. Radio-sensitizing agents enhance the efficacy of radiation by a variety of mechanisms, including:
A number of drugs, including cisplatin, fluorouracil, Fluosol, iododeoxyuridine, misonidazole, and paclitaxel, have been studied as radiosensitizers with variable results. At present, no one agent is widely used as a radiosensitizer for patients with astrocytomas.
The primary role for antineoplastic chemotherapy in the management of astrocytomas is in the adjuvant setting. These drugs are usually used in conjunction with, or subsequent to, primary surgery or/and radiation therapy. Of the antineoplastic agents, the nitrosoureas (carmustine, lomustine) have been the agents most commonly used, because of their ability to cross the blood-brain barrier. A number of other single-agent and 2-drug combination trials in astrocytoma and glioblastoma multiforme have reported mixed results (Table 5).31,35-44
Carmustine. For many years, carmustine was the antineoplastic agent most commonly used to treat a variety of brain tumors, including astrocytomas and glioblastoma multiforme.
Carmustine is a nitrosourea alkylating agent that acts by binding to DNA and preventing replication by forming cross-links to the DNA strands. The drug is given intravenously, usually as a short (1- to 3- hour) infusion. Due to its low solubility in water, it must be dissolved in ethanol (3 mL/100 mg of carmustine) prior to dilution in a saline or dextrose solution for infusion. The presence of the ethanol in the solution is partially responsible for the burning sensation some patients report if the drug is infused through a peripheral vein. Use of a central catheter or slow infusion through a running saline or dextrose infusion usually eliminates this problem. Although frank intoxication usually does not occur, patients should be advised of the possible effects of the alcohol. Other toxicities associated with carmustine include nausea and vomiting, prolonged (6-8 weeks) myelosuppression, and severe pulmonary fibrosis (at cumulative doses >1400 mg/m2).45
An early trial suggested that radiation plus carmustine provided better survival than radiation alone; subsequent trials, however, failed to confirm this advantage.46,47 Despite these disappointing results and the toxicity associated with the drug itself, carmustine continued as the agent of first choice.
To avoid the problems associated with intravenous carmustine, alternative methods of delivering the drug have been explored but have not shown a clear improvement in survival. Use of a carmustine-impregnated biodegradable polymer wafer for treatment of recurrent high-grade tumors was approved by the FDA in 1996. These wafers are implanted in the tumor bed during the surgery to remove the tumor and provide a slow-release system that allows the drug to be released gradually into the affected area. A study of the wafer formulation reported a statistically significant improvement in survival.48 Other reports suggested that the carmustine wafers may also prolong survival in newly diagnosed patients with glioblastoma multiforme who undergo optimal resection of the tumor.49,50
PCV Regimen. Unlike other malignancies in which multidrug-combination regimens are the standard of care, very few combination regimens have demonstrated much activity against astrocytomas and glioblastoma multiforme. Although a variety of 2-drug combinations have been studied (Table 5), none has been demonstrated to be clearly superior to single-agent therapy. A combination regimen that is occasionally used consists of procarbazine, lomustine, and vincristine (PCV). As is common with many combination regimens, several variations of the PCV regimen are used (Table 6).51-53
Procarbazine. Procarbazine is an alkylating agent whose exact mechanism of action is uncertain. It appears to inhibit DNA, RNA, and protein synthesis. The drug is administered orally, either as a single daily dose or in divided doses. Because the drug is only available as a 50-mg capsule, dosing schedules may be complicated. Rather than round doses to the nearest 50-mg increment, some oncologists will use varying doses (eg, 50 mg alternating with 100 mg) to achieve an "average" dose equivalent to the desired dose. These more complicated dosing schedules may be confusing to patients and require careful explanation by the pharmacist. Procarbazine is moderately emetogenic and can cause significant myelosuppression. The drug can cause a mild disulfiram-like reaction in some patients. Although not absolutely contraindicated, patients taking procarbazine should be counseled to be cautious if they drink alcohol. The drug also has mild monoamine-oxidaseinhibiting activity. Patients should be cautioned to avoid tyramine-containing foods.54
Lomustine. Lomustine is a nitrosourea alkylating agent, similar to carmustine, that inhibits DNA and RNA synthesis by interacting with DNA polymerases. Although less widely used than carmustine, it has the advantage of being orally administered. A complication of lomustine dosing is the multiple capsules required for each dose (eg, 190 mg = 4 capsules: 1x100 mg + 2x40 mg + 1x10 mg). Because the drug is usually given as a single dose, it is often preferable to dispense all the capsules in a single container clearly labeled for the patient to take all the capsules at one time. Toxicities associated with lomustine include prolonged (6 - 8 weeks) myelo-suppression and severe pulmonary fibrosis (at cumulative doses >600 - 1000 mg). Although the drug is reported to cause a high (>90%) incidence of nausea, the nausea is often relatively mild and of short duration if the drug is taken at bedtime. Although not well described in the literature, many patients report little or no nausea if they take the lomustine dose on an empty stomach at bedtime, 30 to 60 minutes after taking an antiemetic.55
Vincristine. Vincristine is a vinca alkaloid that inhibits formation of the microspindle, causing cell reproduction to stop during the metaphase portion of the cell cycle. It is administered intravenously, either as a rapid (~1 minute) push or as a short (5 - 10 -minute) infusion. Because vincristine can cause the skin to blister, care must be taken to avoid extravasation of the drug into surrounding tissues. Unlike most other antineoplastic agents, vincristine is not myelosuppressive or emetogenic. Its major toxicity is neurologic, which can manifest in a variety of ways, including constipation, loss of reflexes, and paresthesia (tingling or loss of sensation) in the fingers and/or toes.56
Although it has been used for several years, a recent large (nearly 700 patients) trial of the PCV regimen did not show any benefit from using the 3-drug combination in patients with malignant gliomas. Nor did it show any survival benefit for the combination regimen in patients with anaplastic astrocytomas.53
Temozolomide. The most recent advance in the management of malignant astrocytomas and glioblas-toma multiforme has been the introduction of temozolomide. Temozolomide is a prodrug that undergoes a rapid, nonenzymatic conversion in the body to its active moiety. The primary mechanism of antitumor activity is thought to be methylation of specific areas of DNA that initiate transcription. Like lomustine, the drug is given orally, on an empty stomach, as a single dose each day and is well tolerated by most patients. Toxicities associated with temozolomide include nausea, myelosuppression, constipation, fatigue, and CNS symptoms such as headache, convulsions, hemiparesis, and dizziness (which can be difficult to distinguish from the underlying disease).57 A variety of temozolomide dosing regimens have been reported (Tables 5 and 7).
Like lomustine, temozolomide dosing is complicated by the multiple capsules required for each dose (eg, 400 mg = 6 capsules: 1x250 mg + 1x100 mg + 2x20 mg + 2x5 mg). Temozolomide dispensing is further complicated by the fact that, unlike lomustine, it is given daily for multiple (from 5 days to several weeks) days. Because the drug is usually given as a single daily dose, it is sometimes preferable to dispense each day's dose in a single container clearly labeled for the patient to take all the capsules at one time and with each day clearly marked (Figure 1). To facilitate this, the manufacturer provides labels for each day of a 5-day regimen with the medication. These are helpful for patients on the original FDA-approved regimen of 5 days every 4 weeks. For patients taking low doses given concurrently with 5 to 7 weeks of radiation, packaging the medication in individual daily doses is cumbersome. For these patients, it is often preferable to dispense the different-strength capsules in separate containers, each clearly labeled with both the number of capsules of each strength and the total dose to be taken each day (Figure 2). Regardless of the manner in which the drug is packaged, pharmacists must carefully assess the patient's understanding of his or her daily dose and the number of capsules required to provide the correct dose. Patients taking temozolomide concurrently with radiation should also be advised to take the drug every day, even though the radiation is given only 5 days each week.
Although uncommon, malignant astrocytomas and glioblastoma multiforme are severe and usually fatal conditions that respond poorly to current therapy. Recent advances in surgical and radiation techniques and the introduction of temozolomide as adjunctive therapy have made incremental improvements in the overall treatment of these conditions. Pharmacists can play an important role in helping patients with astrocytomas and glioblastomas cope with the symptoms of their disease. In addition, counseling patients on how to handle the complicated drug regimens often used to treat these diseases is of vital importance.
Dominic A. Solimando, Jr, MA, BCOP: President, Oncology Pharmacy Services, Inc.
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1. Which of the following is NOT a sign associated with glioblastoma multiforme?
2. Initial therapy of astrocytomas is influenced by which of the following:
3. Patients receiving carmustine infusions should be advised to avoid which of the following activities:
4. Due to the monoamine oxidase inhibitory activity of procarbazine, which of the following drugs should be avoided by patients receiving the procarbazine, lomustine, and vincristine regimen?
5. Patients should be advised to take lomustine doses:
6. When counseling patients receiving temozolomide, special emphasis should be placed on:
7. The initial therapy of astrocytomas and glioblastoma multiforme always includes:
8. One possible mechanism of action of radiosensitizers is:
9. Which of the follow drugs produces toxicities that can be mistaken for symptoms of the underlying astrocytoma being treated?
10. Concurrent administration of procarbazine and which of the following might result in severe vomiting, facial flushing, and headache?
11. Which of the following drugs is unlikely to cause the patient to require hematopoietic growth factor (filgrastim, sargramostim) support?
12. Patients should be advised to avoid tyramine-containing foods when taking which of the following agents?
13. Which of the following treatments can help reduce the need for corticosteroid use in patients with astrocytomas and glioblastomas?
14. Radiation therapy can be delayed in some patients with which of the following conditions?
15. Which of the following does not influence the choice of initial therapy for astrocytomas?
16. Aggressive surgery can improve survival in which of the following patients?
17. Which of the following can be implanted directly into the tumor bed during surgery?
18. Which of the following can be associated with prolonged myelosuppression and pulmonary toxicity at high doses?
19. Patients should be advised to take temozolomide:
20. Upon receipt of a prescription for temozolomide 270 mg (150 mg/m2) daily for 5 days for a patient, the pharmacist should:
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