May 29, 2008 — Typical presentation, suggested diagnostic tests, and treatment of primary brain tumors in adults are reviewed in an article published in the May 15 issue of the American Family Physician.

"Primary malignant brain tumors are rare, accounting for approximately 2 percent of all cancers in U.S. adults," write Sreenivasa R. Chandana, MD, PhD, from the Michigan State University College of Human Medicine in Lansing, Michigan, and colleagues. "The American Cancer Society estimates that there are more than 18,000 new diagnoses of brain and nervous system cancers causing more than 12,000 deaths each year in the United States. . . . The most common malignant brain tumor is glioblastoma multiforme, and patients with this type of tumor have a poor prognosis."

The only proven environmental risk factor for brain tumor is previous exposure to high-dose ionizing radiation; results were inconclusive for occupational exposures, electromagnetic fields, pesticides, cellular telephones, head trauma, and N-nitroso compounds.

Classification of primary brain tumors by the World Health Organization (WHO) is based on their cellular origin and histologic appearance. Neuroglial tumors, which account for more than 80% of primary brain tumors, originate from astrocytes, oligodendrocytes, or ependymal cells. Grades 1 and 2 gliomas are low grade, whereas grades 3 and 4 are considered high grade.

Meningiomas, which account for approximately 20% of primary brain tumors, originate from meningothelial cells. In the United States, the prevalence of primary central nervous system (CNS) lymphoma has been increasing. This tumor typically occurs in patients with acquired immunodeficiency syndrome or other immunodeficiency syndromes.

Presenting symptoms of primary brain tumors often include persistent headache, seizures, nausea, vomiting, neurocognitive symptoms, and personality changes. Dull, tension-type headache is reported by 77% of patients, and in approximately half of patients, the headache is persistent and can last more than 6 months. Symptoms associated with headache may include seizures in 50% of patients, visual disturbances in 40%, and nausea and vomiting in 38%.

Evaluation for brain tumor is indicated in any patient with chronic, persistent headache associated with protracted nausea, vomiting, seizures, change in headache pattern, neurologic symptoms, or aggravation of headache based on position.

Brain imaging is used to identify the tumor, preferably with magnetic resonance imaging (MRI) as the initial study. Because histopathologic examination is required to confirm the diagnosis, a comprehensive neurosurgical evaluation is essential to obtain tissue for diagnosis and for possible tumor resection. There is no standard staging method for primary brain tumors, which seldom metastasize outside the CNS.

The Glioma Outcomes Project showed that tumor grade, patient age and functional status, and complete surgical resection affected prognosis for survival in patients with recently diagnosed malignant gliomas. Factors associated with better outcomes include age 60 years or younger, score of 70 or greater on the Karnofsky performance scale, near-total or complete surgical resection, presentation with seizure (most likely because of earlier diagnosis), longer duration of disease before diagnosis (most likely because of low proliferative activity of the tumor cells), location in the frontal lobe rather than in the temporal or parietal lobe, and the presence of methyl-guanine and methyl-transferase (MGMT) gene promoter hypermethylation.

Although surgical resection is the cornerstone of treatment, postoperative radiation and chemotherapy may improve survival in patients with high-grade brain tumors. Recent advances in targeted chemotherapy offer novel treatment options for patients who experience recurrence of the primary brain tumor.

Therapies showing some promise in the treatment of recurrent malignant gliomas include the chemotherapy agent irinotecan (Camptosar; Pfizer, Inc). Targeted agents such as bevacizumab (Avastin; Genentech, Inc) targets vascular endothelial growth factor, and gefitinib (Iressa; AstraZeneca), erlotinib (Tarceva; Genentech, Inc), and imatinib (Gleevec; Novartis) target epidermal and platelet-derived growth factor receptors. Radiotherapy and chemotherapy may be particularly helpful in oligodendrogliomas with 1p/19q chromosome deletions.

Steroids are typically the mainstay of treatment of vasogenic edema from brain tumors. Steroid therapy often must be slowly tapered during many months because of symptoms secondary to residual tumor. Prolonged steroid therapy may cause cognitive impairment, hyperglycemia, gastrointestinal tract symptoms, myopathy, and immunosuppression with opportunistic infections.

Despite the high prevalence of seizures in patients with brain tumors, routine use of prophylactic anticonvulsants appears to be unjustified.

Key clinical recommendations for practice, and their accompanying level of evidence rating, are as follows:

1. Patients with symptoms suggestive of brain tumor should undergo gadolinium-enhanced MRI (level of evidence, C).
2. Surgery is the preferred treatment of primary brain tumors, especially for resectable high-grade gliomas (level of evidence, C).
3. In patients with malignant gliomas, radiation with temozolomide (Temodar; Schering-Plough Corp) therapy improves survival (level of evidence, B).

"Primary care physicians play an important role in the perioperative and supportive treatment of patients with primary brain tumors, including palliative care and symptom control," the review authors write. "Hospice care should be considered in patients who are not candidates for surgery or chemotherapy, in patients with deteriorating neurologic deficits despite therapy or tumor recurrence, and in patients with a poor performance status. Primary care physicians in conjunction with the neuro-oncologist and surgeon can help patients and families make decisions about hospice care."

The review authors have disclosed no relevant financial relationships.

Am Fam Physician. 2008;77:1423-1430.

Clinical Context

Study Highlights

• Genetic risk factors include neurofibromatosis 1 and 2, Li-Fraumeni's syndrome, multiple endocrine neoplasia type 1, nevoid basal cell carcinoma syndrome, tuberous sclerosis, Turcot's syndrome, and Von Hippel-Lindau's disease.
• The only proven environmental risk factor is high-dose ionizing radiation.
• Study results for other environmental factors including electromagnetic fields, pesticides, cellular telephones, head trauma, and N-nitroso compounds are inconclusive.
• WHO classification is based on cellular origin and histologic appearance:
  • More than 80% of primary brain tumors are neuroglial tumors derived from astrocytes, oligodendrocytes, or ependymal cells.
  • The most common type of glioma is glioblastoma multiforme.
  • Grades range from low (I and II) to high (III and IV).
  • 20% of primary brain tumors are meningiomas derived from meningothelial cells.
  • Primary CNS lymphoma is associated with immunodeficiency syndromes.
• Clinical presentation is focal in initial stages followed by generalized symptoms as tumor size increases:
  • 1 study found 77% of patients with primary brain tumors had dull, tension-type headache.
  • 50% of patients have persistent headache that could last more than 6 months.
  • Headache is associated with seizures in 50%, visual disturbance in 40%, and nausea and vomiting in 38%.
  • Seizure is most commonly found with low-grade gliomas; type and other symptoms depend on tumor location.
  • Cognitive dysfunction, including changes in memory, attention, orientation, language skills, personality, and activities, can be the initial symptom and is more common with low-grade gliomas.
• Initial evaluation should include funduscopy and complete neurologic examination.
• Preferred initial evaluation is gadolinium-enhanced MRI of the brain vs computed tomography because of higher resolution, visualization of posterior fossa and spine, and low risk for contrast allergy.
• Other imaging modalities useful during management include MR spectroscopy, blood oxygen level–dependent functional MRI, and positron emission tomography.
• Metastasis outside the CNS rarely occurs.
• Standard staging system does not exist.
• The primary treatment is surgical resection, depending on tumor location and extent, histopathologic appearance, and comorbidities.
• Radiation treatment can be external (standard for 5 - 7 weeks or stereotactic radiosurgery in 1 - 3 large doses) or internal (surgical implantation inside the tumor).
• Postsurgical radiation is used for high-grade gliomas but has unclear role for low-grade gliomas.
• Chemotherapy has been used in addition to surgery and radiation:
  • Temozolomide and radiation treatment of high-grade glioma and glioblastoma improves survival.
  • Irinotecan and bevacizumab, gefitinib, erlotinib, and imatinib might be useful for recurrent malignant glioma.
• Postoperative management includes repeated MRI to assess tumor resection within 3 days, monitoring for steroid effects and steroid withdrawal syndrome, and anticoagulation with warfarin or low-molecular-weight heparin (vs inferior vena cava filters) if venous thromboembolism develops.
• Prophylactic anticonvulsant and anticoagulation use is not recommended.
• Factors linked to improved prognosis include age 60 years or younger, seizure as initial symptom, frontal lobe location, low grade, lack of tumor necrosis, longer duration before diagnosis (low proliferative activity), Karnofsky performance score of 70 or greater indicating self-care ability, total or near-total resection, and MGMT gene promoter hypermethylation.

Pearls for Practice

• Typical symptoms of primary brain tumors include persistent headache, nausea, vomiting, seizures, change in headache pattern, neurocognitive symptoms, or positional worsening.
• In a patient with possible brain tumor, the preferred initial imaging study is gadolinium-enhanced MRI. The primary treatment is surgical resection of the tumor and possible postoperative radiation and chemotherapy.

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