Sonic Hedgehog Medulloblastoma Treatment

The occurrence of an SHH medulloblastoma is treated by the following steps:

• Surgery to remove as much of the tumor as can be seen with the naked eye and can be safely removed with the least risk of neurological damage
• Radiation to the brain and spine
• Chemotherapy

The exact treatment is planned based upon the risk of recurrence, which in turn is determined by factors such as:

• Age
• Residual tumor following surgery
• Metastatic tumor

Risk Classes

In children, the presence of one of the following factors indicates high risk of recurrence:

• Diagnosis at age 3 or below
• Residual tumor volume more than 1.5 sq. cm
• Evidence of distant metastasis

The absence of any of these indicates an average risk. In adults, evidence of metastasis is the only established risk factor.

Surgery

The aims of surgery include:

• Palliation of symptoms due to hydrocephalus
• Obtaining tissue for biopsy
• Achieving minimum volume of residual tumor without causing neurological damage

This is assisted by MRI scanning and other computerized imaging tools which help the surgeon work out the ideal approach to the tumor before the actual procedure and to track its removal during surgery.

Magnification and ultrasound ablation help to remove tumor tissue while sparing normal tissue.

Difficulties may arise when the tumor grows into the brain stem, as is seen in a third of patients. Debulking is performed when total removal is impossible.

The use of steroids such as the glucocorticoids dexamethasone help relieve swelling around the tumor. A ventriculostomy may be performed by placing a shunt to drain CSF from the brain, if the tumor cannot be completely removed.

Radiation Therapy

Even if significant residual tumor is not present, radiation therapy may be resorted to in order to destroy the microscopic tumor cells that remain in the brain surrounding the tumor site, and which may cause recurrence of the tumor.

The age, location of the tumor and the residual tumor volume, as well as the presence of metastasis, determine the type of therapy implemented. It is usually not given to children under three years of age to minimize neurological damage.

The radiation is usually administered five days a week for about 6 weeks and may be associated with skin darkening, loss of hair, ulceration of the mouth and other adverse effects.

Higher-intensity radiation is delivered to the tumor periphery and cavity, from where the tumor was removed.

Low-dose radiation, focused stereotactic radiotherapy, conformal radiation, and proton beam radiation therapy are all various innovative techniques being studied to minimize radiation toxicity.

Chemotherapy

In children below three years, surgical removal of a medulloblastoma is followed by  chemotherapy to kill any residual cancer cells.

These drugs inhibit cell division and hence act much faster on rapidly dividing tissues, such as tumor cells, compared to slow-growing normal tissues. They also kill epithelial and bone marrow cells, unfortunately, which accounts for their adverse effects.

Chemotherapy is also used as an adjunct to surgery and radiation therapy to increase the survival rate following treatment by reducing the risk of distant metastasis through the blood stream. Combined chemotherapy helps to reduce the risk of resistance by killing cells in different ways.

Each chemotherapy cycle is separated from the next by 3-4 weeks to allow the normal tissues to recover in between. Four to nine cycles are given, depending on the clinical context.

The importance of staging is the propensity of medulloblastomas to spread along the brain-spinal cord axis by dropping cells into the CSF or by crossing the ependymal barrier into the brainstem.

Various imaging techniques are used to stage the tumor, along with a lumbar puncture to test a specimen of CSF for the presence of tumor cells.

Recurrent medulloblastomas are treated by chemotherapy as well as specific antibodies to vascular endothelial growth factor (VEGF). Specific SHH inhibitors such as vismodegib, LDE225, saridegib, or erismodegib are still being evaluated clinically, especially because of the rapid emergence of resistance to SHH inhibitors.

Other promising avenues include growth-phase inhibitors. One particularly high-risk group is those patients with TP53 mutations, accounting for a fifth of these cases.

Patients with tumors associated with GLI2 amplification are at high risk. These are ideal targets for smoothened inhibitors such as vismodegib and sodinegib, and other mTOR or AKT inhibitors which act in combination to counteract recurrent mutations affecting GLI activation pathways in SHH medulloblastomas in adult patients.