Cancer of the Central Nervous System
Jay F. Dorsey, Andrew B. Hollander, Michelle Alonso-Basanta, Lukasz Macyszyn, Leif-Erik Bohman, Kevin D. Judy, Amit Maity, John Y.K. Lee, Robert A. Lustig, Peter C. Phillips and Amy A. Pruitt
Summary of Key Points
Incidence
• An estimated 66,290 new primary tumors of the central nervous system (CNS) will be diagnosed in the United States in 2012, of which approximately one third will be malignant.
• An estimated 4200 new childhood (ages 0 to 19 years) primary benign and malignant CNS tumors will be diagnosed in 2012. Brain tumors are the second most common malignancy among children, second only to leukemias.
• Radiation exposure is the best established risk factor for brain tumors. Hereditary syndromes including neurofibromatosis type 1 and 2, tuberous sclerosis, von Hippel–Lindau, and Li-Fraumeni are associated with higher risk of brain tumors.
Pathology and Classification
• Taking all age groups into account, histologic types of CNS tumors include meningiomas (35%), glioblastomas (16%), other astrocytomas (7%), tumors of cranial and paraspinal nerves (9%), tumors of the sellar region (14%), oligodendrogliomas (2%), ependymomas (2%), and embryonal tumors including medulloblastomas (1%).
• Among children 14 years or younger, histologic tumor types include pilocytic astrocytomas (17%), glioblastomas (3%), other astrocytomas (9%), ependymomas (6%), oligodendrogliomas (1%), embryonal tumors including medulloblastomas (15%), craniopharyngiomas (4%), and germ cell tumors (4%).
• Most brain tumors are supratentorial; notable exceptions include brainstem gliomas, cerebellar pilocytic astrocytomas, medulloblastomas, and ependymomas that involve the posterior fossa.
• Glioblastoma (World Health Organization grade IV astrocytoma) and brainstem gliomas in children carry the poorest prognosis. Pilocytic astrocytomas carry the best prognosis.
Clinical Manifestations
• General signs and symptoms from mass effect, increased intracranial pressure, edema, or shift or destruction of surrounding brain tissue may include changes in personality and cognitive function, headaches, nausea, vomiting, seizures, and papilledema.
• Focal signs and symptoms may include focal seizures, visual changes, speech abnormalities, gait abnormalities, and cranial nerve deficits.
• Posterior fossa tumors often compress the fourth ventricle, causing hydrocephalus, and frequently manifest with ataxia and intractable nausea and vomiting.
• Brainstem gliomas often manifest with a combination of cranial nerve palsies and “long tract” signs such as hemianesthesia or hemiparesis coupled with ataxia in cases with cerebellar involvement.
• Pineal region tumors (germ cell tumors, pineocytomas, and pineoblastomas, as well as gliomas of this region) may compress the aqueduct of Sylvius, causing hydrocephalus. Compression of the pretectal area produces Parinaud syndrome, with paralysis of upgaze, ptosis, and loss of pupillary light reflexes, along with retraction-convergence nystagmus.
Diagnostic Studies
• Magnetic resonance imaging with gadolinium contrast is the most sensitive technique.
• Computed tomography scanning is good for visualizing intratumoral calcifications and bone erosion but poor at visualizing the posterior fossa.
• Positron emission tomography and advanced magnetic resonance imaging techniques may help discriminate between tumor recurrence and radiation necrosis or pseudoprogression.
• Magnetic resonance spectroscopy may help distinguish a high-grade tumor from a low-grade tumor or radiation necrosis.
Therapy
• For most brain tumors, tissue diagnosis is required (an exception may be selected brainstem gliomas).
• Treatment for brain tumors is highly dependent on histologic type. For many tumors (e.g., gliomas, meningiomas, primitive neuroectodermal tumors [PNETs], and ependymomas), maximal surgical resection that is safely feasible is the primary treatment.
• For some tumors (e.g., glioblastomas, PNETs, and germ cell tumors), radiation therapy is an essential adjunct treatment after surgery.
• For some tumors (e.g., acoustic neuromas and glomus tumors), either irradiation or surgery can offer successful control; the decision between the two is based on assessment of adverse effects.
• Chemotherapy is assuming an increasingly important role in the management of many brain tumors (e.g., glioblastomas, germ cell tumors, anaplastic oligodendrogliomas, PNETs, and CNS lymphomas).
1. Which of the following statements is true regarding the European Organization for Research and Treatment of Cancer (EORTC) 22981/26981/National Cancer Institute of Canada (NCIC) CE.3 cooperative group trial that compared radiation therapy alone with radiation in addition to temozolomide for patients with glioblastoma?
A Temozolomide was given only during radiotherapy.
B No overall survival benefit was found with the addition of temozolomide, but the progression-free survival was increased.
C Methylguanine DNA-methyltransferase (MGMT) promoter methylation was a favorable prognostic factor only in patients who received temozolomide.
D Patients with MGMT promoter methylation had better median overall survival with the addition of temozolomide to radiotherapy than with radiation alone.
2. A patient is diagnosed with glioblastoma. She undergoes maximal safe resection followed by radiation with concurrent and adjuvant temozolomide. Four weeks after completion of radiotherapy, repeat imaging shows an increase in the size of the contrast-enhancing lesion. The patient has no new symptoms. What is the most appropriate next step in management?
A Refer the patient back to neurosurgery for reresection
B Discontinue all current treatment because the lesion has not responded
C Continue current treatment with adjuvant temozolomide and then obtain follow-up imaging in 1 to 2 months
D Consider initiation of bevacizumab because the patient has recurrent disease
3. A 38-year-old man, previously in good health, presents with severe headache for several weeks. He denies visual disturbances, as well as nausea and vomiting. He notes some fatigue for several months, as well as decreased libido and impotence. His prolactin level is >500 ng/mL. MRI shows a pituitary tumor with extension outside the sella. What is the best initial treatment of this patient’s pituitary adenoma?
A Transsphenoidal surgical resection of the adenoma
B Medical therapy with cabergoline
D Symptom management only, such as opioids for headache and phosphodiesterase inhibitors for impotence
4. A 7-year-old previously healthy boy presents to his pediatrician with several weeks of headache, which is worse in the morning, and new-onset nausea and ataxia for the past 2 days. MRI demonstrates a large mass appearing to arise from the vermis of the cerebellum. It has increased T2 and reduced T1 signal with heterogeneous enhancement. Which of the following is true regarding medulloblastoma?
A 17p deletion, resulting in isochromosome i(17q), is a negative prognostic marker.
B Postoperative small residual tumor burden (<1.5 cm3) has no apparent adverse effect on survival.
C Ventriculoperitoneal shunting should be avoided because medulloblastoma will likely disseminate to the abdomen via the shunt.
D Only involved field radiation is required because medulloblastoma rarely disseminates to the spinal cord.
1. Answer: D. This trial compared radiation therapy alone to radiation with concomitant and adjuvant temozolomide (concomitant daily temozolomide at 75 mg/m2/day followed by six cycles of maintenance temozolomide at 150-200 mg/m2/day on days 1 to 5 every 28 days). The addition of temozolomide increased 2-year median overall survival. Patients receiving radiation only had a 10.4% 2-year overall survival compared with 26.5% for patients receiving temozolomide with radiation. Five-year overall survival was 9.8% for the patients who received radiation and temozolomide and 1.9% for the radiation-only group. Of the patients enrolled in this trial, 206 had tumor samples assessed for MGMT promoter methylation. Methylation occurred in 45% of samples and was found to be an independent prognostic factor regardless of treatment (2-year overall survival was 23.9% for patients with MGMT promoter-methylation vs. a 1.8% 2-year survival for unmethylated patients, treated with radiation alone). Answer D is correct because patients with MGMT promoter methylation who were treated with temozolomide and radiation had 48.9% 2-year survival versus 23.9% for patients treated with radiation alone (see Table 66-7). Even among patients with unmethylated MGMT, a trend toward increased survival is recognized for those receiving temozolomide. These data have made irradiation plus adjuvant temozolomide the standard of care for all patients with glioblastoma regardless of MGMT status.
2. Answer: C. Pseudoprogression is defined as an increase in contrast enhancement or edema on magnetic resonance imaging (MRI) without true tumor progression, a phenomenon made more common by the addition of temozolomide to radiotherapy, particularly in patients with glioblastoma who have MGMT promoter methylation. The first postradiation MRI shows increased contrast enhancement in up to 50% of patients, in half of whom the enhancement eventually subsides. The phenomenon is often asymptomatic. Given the frequency of pseudoprogression after temozolomide chemoradiation therapy, and especially in patients without new clinical signs or symptoms, adjuvant temozolomide should be continued. Although bevacizumab is an option for the treatment of recurrent glioblastoma, this patient should not be presumed to have recurrence in this scenario.
3. Answer: B. This patient has a prolactin-secreting pituitary adenoma. Most patients with hyperprolactinemia due to prolactinoma can be treated with medical therapy. Bromocriptine and cabergoline, which are dopamine agonists, effectively lower prolactin levels in 70% to 90% of patients, and thus reverse symptoms such as impotence in men and menstrual irregularities in women caused by hyperprolactinemia. Tumor shrinkage and a decrease in prolactin levels can take anywhere from days to weeks to months to occur. Unfortunately, the action of dopamine agonists is reversible; therefore when the drug is discontinued, regrowth of the tumor with an increase in the prolactin level is usually seen. Therefore lifelong administration is the rule, and many patients can tolerate prolonged treatment for years. Surgery is not the primary mode of management for patients with prolactinomas. However, a transsphenoidal surgical approach can be considered in certain settings, such as a patient with visual field deficits that are not improved with the use of bromocriptine. Still, surgical cure rates of macroprolactinomas are significantly lower than that of other types of pituitary adenomas, and recurrence rates after surgical resection of prolactinoma is high. Radiation therapy may be indicated for patients with prolactinomas who are unable to tolerate adverse effects of medical therapy and are unable to undergo surgical resection or who fail to benefit from surgery. The response to treatment is generally seen as a slow decrease in prolactin levels and control of tumor growth. Stereotactic radiosurgery is generally the preferred technique because this treatment is as efficacious as fractionated therapy and is more convenient for patients. Fractionated radiation therapy is indicated when treating a tumor that is near radiation-sensitive normal tissue, such as the optic chiasm.
4. Answer: B. One of the goals of surgery should be complete or near-complete tumor removal, because complete tumor removal favorably influences prognosis. However, efforts to remove residual tumor adherent to or invading the brainstem may cause considerable postoperative neurologic deficits and a small residual tumor burden (e.g., less than 1.5 cm3) has no apparent adverse effect on survival outcomes. The most common molecular genetic abnormality, occurring in 40% to 50% of childhood primitive neuroectodermal tumors (PNETs), is a deletion of the short arm of chromosome 17, typically resulting in the formation of an isochromosome i(17q). Putative tumor suppressor locations have been identified on 17p and 9q. Multivariate analysis has not clearly identified a clinical prognostic significance for 17p deletion, either altering clinical outcome or associated with higher metastatic stage. The incidence of tumor dissemination to the abdomen by ventriculoperitoneal shunt is extremely low, possibly because the peritoneal environment is not conducive to neuroectodermal tumor growth, or possibly because concomitant systemic chemotherapy may effectively prevent tumor implantation or growth. PNET/medulloblastoma (MB) commonly is associated with seeding of the spinal cord. Accordingly, three tumor staging studies are important for PNET/MB: (1) neuraxis staging evaluation by spinal MRI (performed preoperatively or 10 to 14 days after surgery) to identify metastatic tumor aggregates; (2) cerebrospinal fluid cytologic examination (performed intraoperatively or 10 to 14 days after surgery) to identify leptomeningeal tumor spread; and (3) postoperative neuroimaging to assess residual tumor. Radiation treatment approaches for PNET/MB are determined by assignment of the patient to either a standard- or a high-risk category. High-risk patients receive 36 Gy of radiation to the craniospinal axis and chemotherapy followed by a boost to the posterior fossa tumor site to a total dose of approximately 5580 cGy. Standard-risk patients typically receive a lower craniospinal dose, (e.g., 2340 cGy) followed by a posterior fossa boost to 5580 cGy. The lower craniospinal RT dose for standard risk is intended to decrease the risk of neurocognitive and other radiation-associated toxicities.
