Radiation Therapy for DIPG

Radiation therapy is the standard treatment for children with diffuse intrinsic pontine gliomas (DIPGs). This type of therapy uses high-energy x-rays, similar to those used in a computed tomography (CT) scanner but at much higher doses. These x-rays deposit energy within the tumor, causing damage to the DNA of cells. The tumor cells are then unable to repair the damage, and ultimately die when the tumor cells try to divide.

The Radiation Therapy Process

Before starting radiation, parents of a child with a DIPG consult with the radiation oncologist to discuss the planned therapy and potential side effects. After this initial consultation, the child undergoes a planning session (also referred to as a simulation). At that time, a mask will be custom-made for the child. The mask allows accurate, consistent positioning of the head for each treatment and helps the child remain still during treatment. The mask is made out of a special type of plastic that becomes moldable when heated in a water bath. After the mask is completed, a special CT scan is performed. This entire process takes approximately 1 hour.

After the planning session, the radiation oncologist uses the CT scan to define the area that corresponds to the tumor and the regions of the brain that should not receive radiation. With the assistance of dosimetrists (who specialize in calculating the dose of radiation to ensure the tumor gets enough radiation) and physicists (who develop and direct quality-control programs for radiation equipment and procedures), a radiation therapy plan is developed to maximally treat the tumor while minimizing the amount of radiation delivered to normal brain tissues and surrounding tissues.

Radiation therapy is an effective palliative treatment that improves symptoms in about 80% of children with DIPGs.

Radiation therapy is then delivered daily, Monday through Friday, for about 6 weeks to a total dose of about 54 Gray (Gy). Smaller daily fractions accumulating to the total dose over weeks is intended to allow normal tissues the chance to repair some radiation-induced DNA damage while still destroying the tumor.

As radiation patients must lie still and alone on a table, some children are too young or too ill to tolerate the radiation treatments while awake. In these cases, the planning session and treatments can be performed under general anesthesia. A commonly used anesthetic agent in radiation therapy is propofol. Propofol is an intravenous anesthetic that allows for rapid induction and recovery, and—most importantly—does not require intubation (insertion of a tube) for protection of the airway. Even with daily use, the risks of complications with propofol are very low. Typically, the child is brought into the room awake, with the parents, and the anesthesia is initiated. After induction of anesthesia, the parents leave the room and the radiation therapy procedures are performed.

Effectiveness of Radiation Therapy

Radiation therapy is an effective palliative treatment that improves symptoms in about 80% of children with DIPGs. The dose of radiation therapy is limited by the tolerance of the surrounding normal brain tissue. However, given the high rate of response, in the 1980’s a number of institutions increased the dose of radiation therapy from 54 Gy to greater than 70 Gy and had promising preliminary results. To escalate the dose of radiation delivered, smaller doses per treatment were used (referred to as hyperfractionation). These smaller doses allow greater recovery of normal tissues, and thus a higher total dose can be given. However, a Pediatric Oncology Group randomized trial showed that while the higher dose of radiation was well tolerated by most children, there was unfortunately no difference in survival rates.

Medical professionals have an interest in exploring agents that may be given along with radiation to improve the effects of this therapy; these agents are referred to as radiosensitizers. Some types of chemotherapy, such as carboplatin, can be used as radiosensitizers. Other experimental agents are also being studied. For example, arsenic trioxide given concurrently with radiation therapy is undergoing clinical trials to determine safety and to provide information that can be used for studies of effectiveness.

Possible Complications of Radiation Therapy

A common complication of radiation therapy in children with a DIPG is radiation necrosis—cell death of brain tissue. This may cause swelling and potentially lead to neurologic symptoms such as headache, nausea, vomiting, cranial neuropathies, and ataxia (loss of muscle movement coordination).  Radiation necrosis can be very difficult to distinguish from tumor recurrence by manifesting clinical symptoms or by imaging. Steroids are typically used for the symptomatic treatment of radiation necrosis. However, steroids can also cause side effects, including behavioral issues, insomnia, and weight gain. These steroid-related complications can significantly impact the child’s quality of life. The exact mechanism of radiation necrosis is poorly understood, but vascular endothelial growth factor (VEGF) appears to play a role. Bevacizumab is a monoclonal antibody that interferes with VEGF and is being studied as a possible treatment for radiation necrosis.

Technologies for Delivering Radiation Therapy

Many different technologies are used to deliver radiation therapy. The most common radiation therapy machine is a linear accelerator, in which high-energy electrons impact a target to generate high-energy x-rays. There are a number of different manufacturers, but most of the machines only have slight technical differences. Some machines provide the ability to perform a CT scan for localization; these machines include Tomotherapy (TomoTherapy Incorporated, Madison, WI), Trilogy (Varian Medical Systems, Inc., Palo Alto, CA), and Synergy (Elekta, Stockholm, Sweden). The Novalis Tx (BrainLAB, Westchester, IL) uses orthogonal planar x-ray imaging for localization. There is no clinical difference in any of these machines. From a technical standpoint, the Cyberknife (Accuray, Sunnyvale, CA) is the most different from other machines. The Cyberknife mounts a linear accelerator on a robotic arm and is primarily used to treat small tumors throughout the body. Due to the relatively large size of the brainstem tumor in children with DIPGs, Cyberknife is typically not an option.  

Proton radiation therapy (PRT) is a form of radiation therapy that has very limited availability. PRT uses protons to deliver therapeutic radiation. Protons differ significantly from the photons used in conventional radiation therapy because they have no mass or charge, compared to protons, which have mass and are positively charged. The mass and charge of protons results in a phenomenon called the Bragg Peak, which results in no energy deposited after a certain depth in tissue depending on the energy of the proton (higher energies go deeper). This technique allows protons to potentially deliver less radiation therapy to normal tissues, with fewer late effects of therapy. Numerous theoretical modeling studies have shown benefit to using proton radiation. For children with DIPGs, the potential benefit of protons is unfortunately minimal. The difference in normal tissue radiated between PRT and current photon radiation therapy techniques is small, and late effects in these children is not yet a significant concern due to the extremely low survival rate in this population. 

Summary

In summary, radiation therapy is the current standard treatment for children with a DIPG. Radiation therapy improves clinical symptoms in the majority of children, but that improvement is temporary. The most active areas of research are exploring the addition of therapeutic agents to a backbone of standard radiation therapy.