Complications of Chemotherapy Protocols for Medulloblastomas and Their Management in Children

The acute toxicities of chemotherapy and infection can be life threatening. Great care is taken to minimize these risks, and fastidious supportive care is essential: Chemotherapy may need to be delayed or reduced to allow tolerance of the regimen.

Bone Marrow Suppression

• Management of infection risk: Usual supportive measures require including Pneumocystis prophylaxis and aggressive management of fever and neutropenia with antimicrobials. RSV prophylaxis in infants. Monitoring should be in a tertiary pediatric center hospital or close proximity to ensure rapid management of fever and neutropenia to avoid sepsis and multi-organ failure.
• Management of anemia and thrombocytopenia: Blood volume and cell counts are maintained with supportive packed red blood cell and platelet transfusions. Consensus Canadian Pediatric Guidelines for platelet transfusion has recommended platelet transfusion when the count is 30 x109/L or below in the following circumstances: residual tumor, presence of an ommaya reservoir or ventriculoperitoneal shunt in situ, intensive chemotherapy, or antiangiogenesis therapy (51). They recommended platelet transfusions for cases of platelet counts of 50 x109/L or less if the patient has a history of a previous intracranial hemorrhage. The use of G-CSF and stem cell support has allowed for intensification of treatment with decreased morbidity and mortality rates.

Gastrointestinal Distress

• Antiemetics for nausea and vomiting: Nausea and vomiting should be treated with the usual supportive regimens including ondansetron, granisetron, dimenhydrinate and nabilone. Dexamethasone should be avoided as an antiemetic due to potential interference with chemotherapy penetration into the brain tumor (10). Chronic nausea and/or poor appetite particularly associated with posterior fossa tumors may respond to cyproheptadine.

Hearing Loss

• Ototoxicity: Cisplatin and high-dose carboplatin are ototoxic. Genetic variants in the genes encoding glutathione S-transferases and megalin in children predispose them to cisplatin-induced ototoxicity (39). The effectiveness of the current chemotherapy protocols has allowed for a dose reduction in this drug in ongoing protocols. Additionally, agents such as sodium thiosulfate and amifostine are being evaluated for efficacy in protection of hearing during chemotherapy. However, the concern is that these agents may also be tumor protective.

Urological Complications

• Nephrotoxicity: Because cisplatin is nephrotoxic, monitoring of renal function and avoidance of additional nephrotoxic agents such as aminoglycosides are recommended. Modification of the dosage may be required.
• Hemorrhagic cystitis: This risk due to cyclophosphamide is minimized by the use of mesna and fluids. If it occurs, it usually resolves with double maintenance fluids. Oxybutynin can be used for bladder spasms. If clots are present, catheterization and bladder flushing will be required with urological consultation. Evaluation to consider for viral infections: CMV, BK virus and adenovirus.

Neurological Complications

• Neuropathy: Vincristine-induced axonal motor and sensory polyneuropathy affecting the limbs is common. It is usually mild to moderate, allowing children to still ambulate independently, although splints and or ankle/foot orthotics may be required. Vincristine-induced autonomic neuropathy is also common, causing constipation in most patients that requires a proactive bowel regimen. Occasionally, this leads to ileus, bowel obstruction, or bladder retention. Occasionally, vincristine induces a mononeuropathy, usually of a cranial nerve. Vincristine-induced generalized dyesthesia or trigeminal pain is usually self limited but may require codeine, gabapentin, amitryptiline, tramadol, carbamazepine, or fentanyl patches. Cisplatin may induce cumulative dose-related (>420 mg/m2 cumulative dose) sensory ganglioneuropathy, particularly affecting vibration and position sense; it can also lead to chorea (43). No preventative strategies have been successful to date.
• Seizures: High-dose methotrexate may cause acute encephalopathy and seizures. Cisplatin rarely has been considered to cause posterior reversible encephalopathy, which may include seizures, and there is one report of focal status epilepticus secondary to infarction. Vincristine rarely causes seizures due to hyponatremia secondary to SIADH. Stopping the offending agent is required as well as symptomatic anticonvulsant therapy.
• Subacute encephalopathy: Subacute encephalopathy secondary to intrathecal or intravenous methotrexate usually presents within 10 days of administration with hemiparesis, aphasia, quadrapresis, and headache. This is associated with diffusion-restricted white matter changes on MRI acutely; T2-weighted and FLAIR white matter increased signal changes may take up to 2 weeks to develop. The clinical deficit is usually completely reversible, although residual white matter signal abnormalities may persist. Some patients have been rechallenged without reoccurrence; however, alternative agents should be considered (40, 45). Screening for MTHFR C677T and MTHFR c.1298A>C gene polymorphisms may allow identification of those at risk of severe neurotoxicity in the future (33, 42).
• Chronic necrotizing encephalopathy: Chronic necrotizing encephalopathy secondary to intravenous high-dose and/or intrathecal methotrexate is well documented in leukemia. The risk is increased with cranial irradiation.