US Pharm
. 2013;38(3)(Oncology suppl):3-7.

ABSTRACT: Central nervous system (CNS) malignancies account for only 2% of all cancers but have a high mortality rate. Management strategies for CNS neoplasms include surgery, radiation, chemotherapy, and various combinations of each modality. Management and prognostic features are determined on an individual basis according to age, performance status, and histology. Symptoms may have an insidious onset and range from mild to severe, including headaches, seizures, cerebral edema, and psychiatric disturbances. Management of symptoms and complications to improve the quality of life of patients is a key role of the pharmacist.

In 2012, approximately 22,910 people in the United States were diagnosed with a central nervous system (CNS) neoplasm.1 Although brain tumors account for only 2% of all malignancies, they result in a disproportionately high mortality, and about 13,700 persons will die annually as a result of their disease.1 Brain neoplasms are a heterogeneous collection of neoplasms, including astrocytomas, gliomas, and CNS lymphomas. Within each histology, there are a variety of presentations that range from low- to high-grade malignancies.

Patients typically present with mild symptoms such as headache, nausea, and dizziness, but more serious symptoms may include seizures, cerebral edema, and psychiatric disturbances. Patients with CNS malignancies are at a higher risk for venous thromboembolism, which may occur during the course of the disease as well. Key areas for pharmacist intervention in the interdisciplinary management of CNS malignancy often involve managing symptoms and optimizing the quality of life for patients. Principles of management and prognostic features are carefully determined on an individual basis according to age, performance status, and histologic subtype of the malignancy.2

Epidemiology

The incidence of CNS malignancies has been increasing over the last 30 years. CNS neoplasms most commonly arise from glial tissue, in particular from astrocytes and oligodendrocytes.3 Most patients present between the fifth and seventh decade of life, with a median age at diagnosis of 64 years.1,3-6

The overall age-adjusted incidence for primary brain and other CNS malignancies was 6.5 per 100,000 adults per year from 2005 to 2009.3 Caucasian men represent the highest risk group, with an incidence of 8.4 per 100,000. Of the CNS malignancies, high-grade gliomas account for the largest percentage.7 Five-year survival rates for anaplastic astrocytomas (AAs) are about 27%, as compared to glioblastomas (GBMs), with <5% of treated patients alive after 5 years.

The World Health Organization (WHO) classification system is based on histologic findings and is commonly used to stratify brain tumors. High-grade gliomas (HGGs) are classified as either WHO grade III (AAs) or WHO grade IV (GBMs) and account for 7% and 54% of all malignancies of glial origin, respectively. Low-grade gliomas (LGGs; WHO grade II) are less common in adults, representing approximately 15% of primary brain tumors diagnosed each year.8

Low-grade astrocytomas and oligodendrogliomas (WHO grade II) are slow-growing brain neoplasms with up to 3,000 reported cases annually. The typical age range for presentation for low-grade astrocytomas is 35 to 44 years, which is a younger cohort as compared to the higher-grade brain tumors. Patients with low-grade astrocytomas and gliomas can have significant extended survival, with 26% of patients surviving up to 20 years after diagnosis.4,5,7-9

Pilocytic astrocytomas, which occur most commonly in children, are classified as WHO grade I. These tumors are typically managed with surgical excision and are associated with a very good prognosis and extended survival.1  

Primary CNS lymphomas (PCNSLs) are estimated to account for 3% of all primary CNS malignancies.1 As compared to other patients with non-Hodgkin’s lymphoma, CNS lymphoma patients present with a primary extranodal brain, spinal cord, or leptomeningeal mass without evidence of systemic involvement. The incidence of this unique presentation of lymphoma has increased in the past 20 years. The median age of presentation of PCNSL in immunocompetent patients is 55 years, versus 33 years in immunocompromised patients. Although equally distributed among males and females for immunocompetent patients, there is a clear male predominance in immunocompromised PCNSL.1,4,6,10 Diffuse large B-cell lymphoma is found in 90% of PCNSL patients.1,4,6,9,10

Risk Factors

Risk factors that have been associated with an increased risk of developing a CNS neoplasm include exposure to ionizing radiation, neurofibromatosis type 1, Li-Fraumeni syndrome, Epstein-Barr virus (EBV), and HIV infection. Other risk factors have been studied with inconclusive results, including cellular phone use, other viruses, and head trauma. Recent epidemiologic studies suggest an inverse relationship between immunoglobulin E (IgE) levels and the risk of glioma development. Gliomas were shown to be 1.5 to 4 times less likely to occur in patients with allergies. Viral infections with EBV and HIV are most highly linked with the development of PCNSL, and are not associated with other types of CNS malignancies.6,11

Pathology, Molecular Targets, and Staging

The exact cell origin for gliomas remains unknown; however, newer evidence suggests that neural stem cells may undergo malignant transformation and give rise to tumors. PCNSLs are derived from postgerminal center B cells and are most commonly involved with the supratentorial region of the brain. PCNSL typically expresses common B-cell markers such as CD20, CD45, and CD10. In addition, about 96% of PCNSLs are MUM1-positive, a marker of germinal center B cells.1,4,6,10

Tumor histology remains part of the WHO classification system and is the current standard for diagnosis and subtyping of brain tumors. CNS malignancies are classified according to the predominant cell type and graded upon certain characteristics such as mitotic activity, nuclear atypia, necrotic presence, and endothelial cell proliferation (TABLE 1).1,4-6


Molecular factors are becoming more important in the characterization of CNS malignancies. Findings from recent, ongoing studies may help improve classification, prognostication, and treatment of CNS tumors.6 Astrocytomas and gliomas are commonly found to have a p53 mutation. Other pathways considered in the tumor development of high- and low-grade gliomas are isocitrate dehydrogenase 1 or 2 (IDH1, IDH2), platelet-derived growth factor (PDGF), and epidermal growth factor receptor (EGFR) amplification.

IDH1 and IDH2 mutations are considered a positive prognostic factor; however, the impact either mutation has on response to treatment is unknown, and routine testing is not yet recommended. Mutation in p53 is found in over 66% of low-grade astrocytomas that transform into AAs.8 Mutations of the p53 gene at 17p13.1 lead to altered p53 expression and change the autoregulatory feedback that helps control neovascularization, cell death, and differentiation leading to tumorigenesis.

In a study of 103 patients with WHO grade II tumors, expression of the PDGF receptor was correlated with a poorer prognosis and was typically associated with oligodendrogliomas.6 The ability of PDGF to dedifferentiate mature cells, or its role in the promotion of cancer stem cells, is not clearly understood and will need more investigation. Additionally, abnormalities in EGFR signaling are observed in many GBMs. Mutations leading to EGFR overexpression upregulate vascular endothelial growth factor and angiogenesis, resulting in tumor growth.

Chromosomal deletions of 1p and 19q are associated with oligodendroglioma. The loss of both genes has been reported in 50% to 80% of all oligodendroglioma patients and is associated with a good prognosis.6 Patients with the co-deletion of chromosomes 1p and 19q receiving chemotherapeutic regimens of PCV (procarbazine, carmustine, and vincristine) or temozolomide have been shown to have a better progression-free and overall survival than patients with other histologic subtypes of gliomas. Studies have also suggested tumors with this co-deletion behave in a more indolent manner even before initiation of treatment.6

The DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT) is often expressed in high-grade gliomas and indicates resistance to alkylating agents such as temozolomide. Methylation of the MGMT gene results in a decreased MGMT transcription, which increases cell susceptibility to temozolomide and other alkylating agents. MGMT methylation has been shown to predict sensitivity to temozolomide in glioblastoma patients.12

Presentation

HGGs and LGGs often present with a combination of generalized symptoms including headaches, mood and personality changes, psychomotor slowing, and generalized tonic-clonic seizures. Headaches with HGGs are often more severe and associated with nausea from increased pressure and cranial edema. Seizures are a common symptom for all gliomas, but are present in 81% of LGGs and are more frequently associated with oligodendrogliomas.1,4,6

PCNSLs may differ in presentation depending on location in the CNS and immunologic status. Generally, both immunocompetent and immunocompromised patients tend to present with focal neurologic deficits and neuropsychiatric symptoms. In addition, immunocompetent patients have severe headache and nausea resulting from increased intracranial pressure along with ocular symptoms and seizures. Immunocompromised patients may present with personality changes.1,4,6,10

Diagnosis and Management

Once a tumor is suspected, imaging with contrast-enhanced MRI is the preferred modality used to detect the presence of a mass lesion. CT and PET scanning may also be used, but as with most malignancies, tissue examination and biopsies provide a definitive pathologic diagnosis. During the diagnostic workup, patients are also evaluated and categorized as high or low risk. TABLE 2 outlines the different categories, with Karnofsky performance status (KPS) scale, histology, tumor size, and chromosomal deletions weighing in to determine risk. The cornerstones of CNS malignancy management include surgical excision, radiation therapy, and chemotherapy. Depending on the histology and tumor type, the use of these modalities will vary.13,14 The management of LGGs, GBMs, anaplastic gliomas, and PCNSLs will be discussed in further detail below.

LGGs: Patients are categorized clinically in three ways to help in decision making. Patients are considered to either be able to have a maximal safe resection or not. If a patient has completed a maximal safe resection, he or she is further evaluated as low or high risk, as in TABLE 2. Low-risk patients may be followed up with observation and an MRI every 3 to 6 months for 5 years.1 High-risk patients can be offered fractionated external beam radiation therapy (EBRT) or chemotherapy followed by MRI observation as above. In a patient who is not maximally debulked with surgery and continues to experience symptoms, fractionated EBRT or chemotherapy is considered, followed by observation and MRI follow-up. In a patient who is not maximally debulked but is stable with symptom improvement, fractionated radiation therapy, chemotherapy, or observation can be considered with MRI follow-up. Due to the indolent nature of LGGs, if observation if deemed appropriate due to clinical circumstances, follow-up with MRI scans is indicated. TABLE 3 summarizes the approaches to management of LGGs.

Upon recurrence or progressive disease in an LGG, treatment depends on whether the patient has received prior fractionated EBRT. Patients who have and are resectable continue on to surgery. Patients who have had prior radiation therapy may have a second surgery to resect a recurrence, followed by chemotherapy with agents such as temozolomide, a platinum-based regimen, or combination procarbazine, lomustine (CCNU), and vincristine.1,15

In those who have had prior radiation therapy, additional radiation may be possible if the new brain lesion is outside the previous radiation field. Patients may be candidates for supportive or palliative care, depending on their clinical and functional status. Decisions are based on the patient’s preference, prior response to therapies, and functional status.1,4

Anaplastic Gliomas: These are typically categorized into patients with good performance status (KPS ≥70) or those with poor performance status (KPS <70).1 For either type, fractionated radiation is a valid choice for therapy; however, in the patients with good performance status, chemotherapy may be combined with radiation therapy. Additionally, chemotherapy may be an option for all patients, but may be more likely utilized in patients with the 1p and 19q co-deletion. In patients with poor performance status, palliative or supportive care may be offered versus chemotherapy. Follow-up typically includes an MRI after radiation therapy to assess the outcomes of the intervention, then one every 2 to 4 months for 2 to 3 years, then less frequently to monitor for growth of the tumor.1

GBMs: Management includes surgery, if possible, with the option of placing carmustine wafers in the site of the surgical excision. Adjuvant therapy with carmustine wafers can be used in patients following their initial surgery or following surgery for recurrences of GBMs. Carmustine wafers are designed to distribute the chemotherapy to the site of local removal. Benefits with local control are noted from this therapy, as well as survival benefits when combined with postsurgery temozolomide and radiation therapy.4,16,17

Patients with GBMs are categorized into those with good (KPS ≥70) or poor (KPS <70) performance status.1 Patients with good performance status who are ≤70 years typically receive fractionated radiation with concurrent temozolomide therapy following surgery. Those patients with good performance status who are >70 years may be candidates for concurrent radiation and temozolomide following surgery as well, but may be at higher risk for toxicity. Concomitant radiotherapy and temozolomide provides a statistically significant survival benefit. Patients receiving radiotherapy and temozolomide had a 2-year survival rate 10% higher than those patients receiving radiotherapy alone. However, hematologic toxicities such as severe neutropenia and thrombocytopenia limit the use of the regimen in certain GBM patients.14,16,17 Options for patients with poor performance status include fractionated radiation therapy, chemotherapy, or best supportive care as warranted based on the patient’s clinical situation. MRI follow-up for GBMs is similar to follow-up for anaplastic gliomas.1

Recurrence for anaplastic gliomas and GBM is evaluated to determine if the recurrence is amenable to surgery or not. Typically, surgical resection will be done again if possible, and carmustine wafers may be inserted into the area where the tumor has been removed for patients with GBM. Radiation may also be considered, but this will depend on the patient’s history of prior radiation. If patients have unresectable or diffuse recurrences, systemic chemotherapy along with supportive care is offered to patients based on performance status. Options for systemic chemotherapy for AA and GBM are outlined in TABLE 4. Typically the options for both types of cancer are similar. Initial regimens would usually include bevacizumab with one chemotherapy agent.18 Adverse effects associated with bevacizumab therapy include impaired wound healing, proteinuria, hypertension, bowel perforation, and bleeding. Upon further recurrence, therapy options include temozolomide, nitrosourea therapy, PCV, or other platinum-based regimens.1,4 Adverse effects associated with temozolomide and nitrosourea therapy include myelosuppression and the effects of neutropenia, anemia, and thrombocytopenia.14-17 Platinum therapy is associated myelosuppression, infusion reactions, and nephrotoxicity.

PCNSLs: Management includes chemotherapy and radiation and not surgical excision. The standard of care for patients with PCNSL is high-dose methotrexate in combination with several other chemotherapy agents. Management may include concurrent radiation therapy with the high-dose methotrexate, at a more moderate dose of methotrexate, along with vincristine, procarbazine, cytarabine, and/or rituximab therapy. 1 If radiation therapy is deferred until after chemotherapy, a higher dose of methotrexate is typically used with rituximab and/or temozolomide therapy.1,19,20 Patients receiving high-dose methotrexate therapy typically undergo aggressive urinary alkalization with sodium bicarbonate and required post-therapy leucovorin rescue. Patients are often given colony-stimulating growth factors in between cycles of therapy to maintain their white blood cell counts.14

Patients who have a recurrence of PCNSL are often managed again with high-dose methotrexate therapy, temozolomide +/- rituximab, or high-dose cytarabine.19,20 In patients with complete responses to therapy following relapse, hematopoietic stem cell transplantation is often considered to maintain the tumor response.1

Additional CNS tumor types that patients may develop include medulloblastomas, spinal cord tumors, ependymomas, and meningiomas, to name a few. Various modalities of therapy are used depending on the tumor type. Spinal cord tumors and meningiomas are typically managed with radiation therapy and potentially surgical excision. Medulloblastomas and ependymomas are managed with chemotherapy agents including platinums, bevacizumab, vincristine, cyclo-phosphamide, etoposide, and temozolomide in various combinations as indicated by the tumor type, as well as by clinical status and prior therapy.1,21

Symptom Management

Patients with CNS malignancies are typically symptomatic at presentation and recurrence. The management of these symptoms is critical for patient quality of life and that of their families. CNS symptoms of confusion, headache, and disorientation are typically associated with the mass effects of CNS lesions. Initiation of high-dose corticosteroids will often improve patient symptoms and alleviate symptoms associated with early radiation therapy. The corticosteroid of choice is often dexamethasone.1 Patients are titrated down following completion of radiation therapy. However, patients with persistent or recurrent disease may require daily doses to manage symptoms. Observation for gastrointestinal intolerance and other side effects will be necessary. Patients in whom seizure activity has been observed or suspected, the use of anticonvulsant therapy is warranted. The classic agent used to manage seizures is phenytoin; however, newer anticonvulsants such as levetiracetam, pregabalin, lamotrigine, and topiramate are commonly used to avoid the drug interactions and therapeutic drug monitoring associated with phenytoin use. Seizure prophylaxis for patients who have not had a seizure is not recommended, with the exception that patients undergoing a surgical resection may be placed on an anticonvulsant to avoid perioperative seizures.1,21

Additional symptoms that are problematic for patients with CNS malignancies include endocrinopathies due to therapy-related toxicity, direct effects of the tumor, and adverse effects of supportive medication, severe fatigue, venous thromboembolism, and depression. Patients may benefit from physical therapy, exercise therapy, occupational therapy, and speech therapy services.1 Venous thromboembolism prophylaxis is warranted in patients with CNS malignancies who are admitted to the hospital, but it is not currently recommended for outpatients while at home. If patients develop an embolism, full therapeutic anticoagulation with low-molecular-weight heparin therapy is recommended.22 If patients are exhibiting signs and symptoms of anxiety and depression, therapeutic intervention with antidepressants and/or anxiolytic medications is recommended.23

Conclusion

CNS malignancies are often insidious in their presentation, with nondescript symptoms in patients from the third to eighth decade of life. As tumors progress, the level of CNS impairment can rapidly increase. Early management for almost all tumor types includes surgical excision and further therapy with radiation, chemotherapy, or a combination of both. Patients are often stratified according to the grade of the tumor and performance status to determine the most appropriate therapy options. The prognosis for patients with CNS malignancies is varied, but without complete resection and/or response to therapy, survival is limited. Management of patients with PCNSL differs from other CNS malignancies and primarily involves aggressive chemotherapy. Upon tumor progression, patients with brain tumors often experience significant symptoms that will require management.

Pharmacists should monitor patients for toxicities associated with therapy in addition to complications associated with the disease itself, including seizures, fatigue, venous thromboembolism, depression, and endocrinopathies. Future directions for these malignancies include further identification of prognostic factors and molecular targets of therapy that will benefit patients.

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