Medulloblastoma Childhood Cancer Treatment

Introduction

First used by Bailey and Cushing in 19251 , the term medulloblastoma described a series of tumors found in the cerebella of children. Originally classified as a glioma, medulloblastoma is referred to now as a primitive neuroectodermal tumor (PNET). This tumor accounts for approximately 7-8% of all intracranial tumors and 30% of pediatric brain tumors.

Pathophysiology

In the brain, medulloblastoma most often arises in the posterior fossa. The tumor has the propensity of spreading throughout the CNS. Systemic metastases of this tumor, especially to bone, also have been recognized.

Frequency United States

Incidence of medulloblastoma is 1.5-2 cases per 100,000 population, with 350 new cases in the United States each year. Although the majority occur as sporadic cases, hereditary conditions have been associated with medulloblastoma, including (1) Gorlin syndrome (nevoid basal cell carcinoma syndrome), (2) blue rubber-bleb nevus syndrome, (3) Turcot syndrome (eg, glioma polyposis syndrome), and (4) Rubinstein-Taybi syndrome.

International

Incidence of medulloblastoma worldwide seems to approximate that in the United States.

• Hydrocephalus: The most common complication is hydrocephalus due to compression of the normal cerebrospinal fluid (CSF) pathways. Although this is a common complication, only 10-50% of patients with preoperative hydrocephalus will need a long-term ventricular shunt. Some children can be treated with an endoscopic third ventriculostomy.
• Cerebellar dysfunction: Tumor infiltration of the cerebellum usually is in the midline, leading to difficulties with ambulation and truncal ataxia. This is more common than signs attributable to the cerebellar hemisphere (eg, extremity dysmetria).
• Leptomeningeal dissemination: One of the most feared complications of medulloblastoma is dissemination within the CSF. Medical and, less commonly, surgical therapy must be directed at controlling dissemination to cranial nerves and spinal cord and related structures. This dissemination of disease portends to a high-risk stratification.

No specific predilection for a particular racial or ethnic group has been noted.

Medulloblastoma is more common in males than females (1.5:1). Males also tend to have a poorer prognosis.

Although predominantly a pediatric tumor, medulloblastoma can affect patients of any age from neonates to the elderly. Three quarters of all cases occur in children, with a median age of 9 years.

• Hydrocephalus
  • Patients with medulloblastoma most commonly have symptoms related to increased intracranial pressure (as a consequence of hydrocephalus). Symptoms usually precede presentation by no more than 2 months.
  • Presenting symptoms are related to the age of the patient.
    • The younger, nonverbal patient presents with behavioral change.
    • Symptoms in younger children include listlessness, irritability, vomiting, and decreased social interactions.
    • Older children and adults complain of headache, especially upon awakening in the morning.
  • Vomiting without nausea is more common in the morning, since being recumbent (eg, sleeping) increases intracranial pressure.
  • Often, symptoms of headache and vomiting prompt an extensive and lengthy workup of the gastrointestinal tract prior to consideration of the CNS.
  • Patients may develop double vision as the sixth cranial nerve becomes stretched from the hydrocephalus. Visual disturbances more commonly are a result of papilledema.
• Cerebellar symptoms
  • Most commonly found in children, the tumor involves the cerebellar vermis and causes gait ataxia more readily than unilateral symptoms.
  • Adults more commonly harbor the desmoplastic variant of medulloblastoma, which arises in the cerebellar hemisphere. These patients often have symptoms of ipsilateral dysmetria.
  • Head tilt and neck stiffness, caused by meningeal irritation, are complications of tonsillar herniation below the foramen magnum.
  • Alternatively, head tilt can result from trochlear nerve palsy caused by direct tumor compression.
• Leptomeningeal dissemination
  • Presenting symptoms rarely are related to dissemination of tumor in the CSF.
  • Patients can complain of severe weakness from tumor compression of the spinal cord or nerve roots (eg, radiculopathy).

Physical

• Physiognomy
  • Increasing head circumference often is the only presenting symptom in infants.
  • These infants have full anterior fontanelles with widely split cranial sutures.
• Funduscopic examination
  • Visual difficulty usually is due to papilledema; however, it also may originate from cranial nerve palsy.
  • Some studies have found papilledema (the most common physical finding) to be present in as many as 90% of patients.
• Extraocular examination
  • As a consequence of hydrocephalus, the sixth cranial nerve can be compressed at the petroclival ligament, resulting in diplopia and lateral gaze paresis.
  • Fourth cranial nerve palsy can be detected on careful extraocular examination and should be considered in any patient with a head tilt.
  • Patients with fourth cranial nerve dysfunction have greatest difficulty when eyes are rotated medially and depressed (eg, going down stairs). The fourth cranial nerve usually is compressed by direct tumor extension into the cerebral aqueduct.
• Examination of the extraocular muscles may detect nystagmus, which, although nonspecific, can be related to a lesion of the cerebellar vermis.
• Cerebellar signs
  • Medulloblastoma most commonly is located midline. Therefore, unilateral dysmetria is less common than either truncal ataxia or a wide-based gait. Latter symptoms are easily observable on tandem gait.
  • As stated previously, desmoplastic medulloblastoma is more common in adults and usually arises in the cerebellar hemisphere.
  • Signs of ipsilateral cerebellar dysfunction in the arm or the leg are more common in this subtype.
• Torticollis: Head tilt can be a manifestation of either foramen magnum involvement or fourth cranial nerve palsy.

Causes

Debate exists over the cellular origin of medulloblastoma.

• One hypothesis is that the tumor is derived from cells of the external granular layer of the cerebellum.
  • Medulloblastoma cells are cytologically similar to cells of the external granular layer.
  • This is an area of germ cell origin that persists for the first year of life before involuting.
• Another proposed source of medulloblastoma is the posterior medullary velum, from which undifferentiated cells migrate to the external granular layer. These cells persist only for a short time after birth.

Treatment

• For the patient with few neurological signs and little hydrocephalus, the entire presurgical workup can be facilitated on an outpatient basis. Admit patients with significant neurological symptoms (especially those with either change in mental status or imaging evidence of considerable hydrocephalus such as transependymal edema) to the hospital in a monitored setting.
  • The cranium initially can accommodate a small increase of CSF volume with little change in intracranial pressure. However, since the skull is a rigid container with a finite volume (threshold), further increases in ventricular size lead to dramatic increases of intracranial pressure. Decreased mental status is an indication that the ventricular volume is approaching that threshold; enlargement of ventricles beyond the threshold is accompanied by potentially disastrous consequences.
  • Frequent neurologic assessment by the nursing staff is extremely important. Any further decline in mental status is indication for administration of mannitol and emergent neurosurgical consultation for placement of an external ventricular drain.
• Staging
  • Postoperatively, medical care revolves around staging, chemotherapy, and irradiation. Within 48 hours of surgery, a follow-up gadolinium-enhanced MRI is necessary to assess residual tumor size prior to the onset of enhancing reactive gliosis, which may be interpreted as tumor.
  • Staging is dependent upon extent of resection, radiographic evidence of tumor spread, and CSF cytology. Recently, a move away from the Chang TNM staging system to a simplified high-risk/low-risk categorization has occurred. Those patients who undergo gross total resection, with no radiographic evidence of spread and no malignant cells on CSF cytology, are considered in a low-risk category; however, presence of any of the 3 would place the patient into the high-risk group.
• Irradiation
  • Radiation therapy for medulloblastoma is aimed at destroying cells along the entire neuraxis. Local recurrence has been associated with a lower radiation dose at the primary site. Patients receiving less than 5000 centigray (cGy) have over twice the local recurrence rate as those receiving at least this dose.
  • In addition, clinical trials have documented that radiation therapy to only the cranium results in metastasis to the spine (even in the absence of positive cytology or radiographic evidence of spread). Most standard therapy for low-stage disease includes 36 cGy to both the brain and spinal cord with a boost of 18-20 cGy to the primary tumor site. Some institutions use different regimens including higher doses in several fractions. Others recommend proton beam therapy
  • Unfortunately, radiation can have a destructive influence on the developing nervous system. Complications of radiotherapy can include lowered intelligence quotient (IQ) score, small stature, endocrine dysfunction, behavioral abnormalities, and secondary neoplasms (experienced by those fortunate to have prolonged survival).
  • White matter necrosis, which can enlarge and produce significant mass effect, is another feared long-term complication of radiation. Reduction in IQ and neurobehavioral function is related directly to the age at which radiation is administered. Radiotherapy, however, remains the most effective adjunct for medulloblastoma and is used in children despite its consequences.
• Chemotherapy
  • Chemotherapy has evolved from use for advanced recurrent disease to use as a common tool in the modern armamentarium against medulloblastoma. However, despite the common use of chemotherapy today, exact benefits remain unclear.
  • To reduce radiation dose or postpone irradiation until it can be better tolerated, chemotherapy utilization is focusing on young children. Among the several regimens now being used, one of the most aggressive is the "8 drugs in 1 day" protocol, which employs vincristine, carmustine, procarbazine, hydroxyurea, cisplatin, cytarabine, prednisone, and cyclophosphamide.
  • Children's Cancer Group recently reported better results with a vincristine, lomustine, and prednisone (VCP) protocol. The study reported a 63% 5-year progression-free survival rate for VCP as opposed to 45% in the same group for the "8 in 1 day" regimen.
  • Pediatric Oncology Group showed similar survival results in the same age group when chemotherapy was followed by radiation. That study protocol utilized vincristine, cyclophosphamide, etoposide, and cisplatin. Thus far, the greatest benefit from the addition of chemotherapy has been seen in those patients with more advanced disease.
  • New studies are looking at sensitizing the tumor to irradiation with the concomitant use of chemotherapy. Also, the use of presurgical chemotherapy to treat patients in extremis prior to surgery has been reported.
  • Like radiation, chemotherapy involves toxic effects. Adverse effects include renal toxicity, ototoxicity, hepatotoxicity, pulmonary fibrosis, and gastrointestinal disturbances. Most of these effects are transient and reverse with the withdrawal of the drug. However, when methotrexate is used in combination with irradiation, irreversible necrotizing leukoencephalopathy can occur.

Surgical Care

Aside from histologic confirmation, the fundamental goal of surgery is removal of as much tumor as possible. Patients in whom gross total resection is possible are found to have longer recurrence-free intervals than patients who have residual tumor at the end of surgery.

Surgery also has the added benefit of restoring the natural CSF pathways in the brain. A majority of patients will have resolution of their hydrocephalus after surgery.

• At the time of surgery, the extent of subarachnoid spread of the tumor can be assessed. When involved with tumor, the surrounding subarachnoid space is opaque, with a granular appearance often referred to as "sugar coating." This condition is associated with early subarachnoid seeding along the entire neuraxis and early recurrence.
• In one third of cases, the tumor adheres to the floor of the fourth ventricle, precluding gross total resection.
• The purpose of postoperative MRI within 48 hours after surgery is 2-fold. Aside from staging, the MRI delineates any residual tumor; if the surgeon believes the residual tumor is removable, re-exploration of the patient during the same hospitalization for additional tumor removal is a reasonable possibility. The patient spends the first postoperative night in ICU.
• If the surgery entails significant manipulation or invasion of the brain stem, the patient should remain intubated for the first postoperative night and be extubated carefully once lower cranial nerve function has been assessed. However, if the surgeon believes that involvement of the floor of the fourth ventricle was minimal, the patient may be extubated in the operating room.
• If the patient has not had an external ventricular drain placed preoperatively, one usually is placed at the time of surgery.
• Postoperative drainage is maintained for 3 days, after which the drain is clamped and connected to pressure monitoring. If the patient tolerates 24 hours of having the drain clamped, the ventriculostomy is removed.
• Decrease in mental status is an indication for opening the ventriculostomy and continuing drainage. Continued drainage will allow blood and postoperative cellular debris to clear; clamping can be reattempted after an additional 5 days.
• If repeated drainage fails to relieve symptoms, a ventriculoperitoneal shunt must be placed for long-term control of hydrocephalus; however, this is necessary in only approximately 15% of patients. The alternative to shunting is a third ventriculostomy. This can reestablish CSF flow without the potential for peritoneal seeding of tumor.

Consultations

• Oncologist
• Neurosurgeon
• Radiation oncologist

No special diet is beneficial.

No activity restrictions are necessary.

Medulloblastoma is treated primarily with surgical excision followed by radiation therapy and chemotherapy. Few drugs are of benefit in this disease. Exceptions are glucocorticoids, which can aid in decreasing vasogenic edema. Mannitol is useful in the acute setting when the physician is faced with a herniating patient. Chemotherapy is used as adjuvant therapy in some patients. Administration of toxic compounds that affect multiple organ systems is in the realm of the experienced oncologist.

Reduction of vasogenic edema is the role of glucocorticoids in malignant brain tumors. They can be very effective in medulloblastoma and can even alleviate hydrocephalus by reopening CSF pathways in the posterior fossa. Although any of several glucocorticoids can be used, dexamethasone is used most often. Equivalent doses of various glucocorticoids are 0.75 mg for dexamethasone, 4 mg for methylprednisolone and triamcinolone, 5 mg for prednisolone and prednisone, 20 mg for hydrocortisone, and 25 mg for cortisone.

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