Radiation and Chemotherapy for Malignant Glioma

Man Receiving Radiation Therapy for Cancer Treatment. Mask over patient?s face. Patient is lying under a linear accelerator or linac.
undefined

Primary brain tumors develop directly in the brain, rather than spreading from another source such as a lung cancer.  The most common sort of primary brain tumors come from glial cells that normally support nerve cell function.  When glial cells become cancerous, they are called a glioma. 

There are many types of glial cells, including astrocytes, oligodendrocytes, microglia, and ependymal cells.  Astrocytomas are the most common type of glioma.

 Gliomas are further categorized into four grades by signs of cell division under the microscope.  Grades III and IV are the highest grades, with the worst prognosis and greatest need for aggressive treatment if possible.  Grade IV glioma, also called glioblastoma multiforme or GBM, has a particularly poor prognosis.   

The first step in the treatment of high-grade glioma is neurosurgery to remove as much of the tumor as possible.  Sometimes, though, this is impossible-- the patient may be too sick to tolerate surgery, for example, or the tumor may be in an area like the brainstem where surgery would be too dangerous.  Even if surgery is performed, malignant gliomas are so aggressive that almost all patients will have a recurrence after surgery.  Fortunately, other options are available to supplement neurosurgery, and even replace it if surgery is impossible.    

Radiation:

The benefit of radiation therapy (RT) in patients with malignant glioma was first demonstrated in the 1970s.

  At the time, the entire brain was irradiated, a process called whole-brain radiation therapy (WBRT).   The maximum dose of radiation seems to be 50 to 60 Gray (Gy), with no additional benefit but increased side effects above this dose.  Those side effects can include radiation necrosis—the death of normal brain tissue due to radiation.

  Other complications include blood vessel narrowing, hair loss, headache and more. 

To minimize side effects, radiation is now focused more tightly on the tumor, with a 1 to 3-centimeter margin, using a technique called involved-field radiation therapy (IFRT).  The margin is based on about 90 percent of recurrences occurring between 2 cm of the original tumor site after radiation. 

Other techniques include 3D conformal radiotherapy (3D-CRT), which uses special software to make treatment plans to reduce irradiation of normal brain.  Intensity-modulated RT (IMRT) varies radiation across treatment fields, which is useful when the tumor is against sensitive brain areas.  Whereas the previous methods are usually used to deliver several small doses of radiation during a series of visits, stereotactic radiosurgery (SRS) delivers precise, high dose radiation to small targets in the brain.  The benefit of SRS remains poorly defined when used in combination with chemotherapy, though it is sometimes used to treat tumors inaccessible to conventional surgery.

 

Radiation may also be delivered by placing radioisotope seeds in the resection cavity or the tumor itself, leading to continuous dose delivery.  Randomized clinical trials have shown marginal benefit at best for this technique. The current standard of care is treatment with intensity-modulated RT in most cases of malignant glioma.

Chemotherapy:

Temozolamide, also called Temodar, is the recommended drug in patients with GBM.  When comparing people who did or didn’t receive temozolomide after radiation therapy, there was a significant overall survival (27 vs 11 percent at one year).  Methylation of the methyl guanine methyl transferase (MGMT) promoter is a genetic factor that is predictive of benefit with chemotherapy, increasing the survival rates over three-fold at two years.

Chemotherapy with temozolomide is usually given daily for five days every 28 days, that is with 23 days break after the 5 days of administration.  This is done for 6 to twelve cycles.  Temozolomide increases the risk of hematologic complications such as thrombocytopenia, and so blood tests are needed 21 and 28 days into each cycle of treatment.  Other side effects include nausea, fatigue, and a decreased appetite. 

A combination of chemotherapeutics called procarbazine, lomustine, and vincristine (PCV) is another option in the treatment of brain tumor.  The number of blood cells that fight infection may be reduced by this treatment, as may the cells that prevent bruising and bleeding. Fatigue, nausea, numbness and tingling may also occur.  

Wafers of the drug carmustine (Gliadel) are sometimes implanted at the time of surgical resection.  However, data are lacking regarding the efficacy and safety of this approach in newly diagnosed glioblastoma in combination with other therapies.  The drug is more convincingly effective in grade III glioma, but the technique is still considered experimental.  Potential side effects include infection and potentially fatal brain swelling.

Bevacizumab (Avastin) is an antibody that binds to vascular endothelial growth factor (VEGF).  The drug thereby attempts to interfere with the production of new blood vessels that provide nutrients to the growing tumor.  However, there is no proven benefit to bevacizumab in combination with temozolomide and RT.  The drug has been associated with neutropenia, hypertension, and thromboembolism. Further studies are exploring potential benefits in subgroups of patients.

Older Patients:

Treatment recommendations often differ for older patients who are at higher risk of side effects.  A lower dose of radiation may be recommended for those who are deemed unsuitable for treatment with both radiation and chemotherapy.  For those with MGMT-methylated tumors, temozolomide alone may be a reasonable alternative.  

Relapse:

The treatment of malignant glioma that has relapsed after treatment is controversial and depends heavily on individual patients and physicians.  Repeating radiation therapy increases the risk of radiation necrosis, though some research has suggested a survival benefit in anaplastic astrocytoma, but not clearly in GBM.  Treatment with bevacizumab may be more appropriate in such treatments.  Whenever possible, patients should consider enrolling in a clinical trial. 

Sources: 

Buatti J, Ryken TC, Smith MC, et al. Radiation therapy of pathologically confirmed newly diagnosed glioblastoma in adults. J Neurooncol 2008; 89:313.

Greenberg HS, Chandler WF, Sandler HS. Brain Tumors (Contemporary Neurology Series 54), Oxford University Press, New York 1999.

Paulino AC, Mai WY, Chintagumpala M, et al. Radiation-induced malignant gliomas: is there a role for reirradiation? Int J Radiat Oncol Biol Phys 2008; 71:1381.

Selker RG, Shapiro WR, Burger P, et al. The Brain Tumor Cooperative Group NIH Trial 87-01: a randomized comparison of surgery, external radiotherapy, and carmustine versus surgery, interstitial radiotherapy boost, external radiation therapy, and carmustine. Neurosurgery 2002; 51:343.

Continue Reading