Radiosensitizers and DIPG

Radiation therapy remains the only effective treatment for brainstem gliomas in children. Because its effectiveness is transient for most patients, attempts to improve the benefits of radiation therapy have been a focus of clinical research. These efforts have included increases in the total dose of radiotherapy delivered, and alterations in the fractionation of radiation received (i.e., times per day radiation is given and the dose at each delivery). These modifications to date have not resulted in improved survival. The use of multiple small doses of radiation per day to allow for a higher total daily dose (called hyperfractionated radiation therapy) resulted in increased toxicity. Radiation damage to the brainstem (called radionecrosis) is associated with increased neurologic deficits.

Radiosensitizers

Radiosensitization is another means to improve the therapeutic balance between efficacy and toxicity of radiation therapy. This research has been explored over the past two decades, and continues to be studied. Radiosensitizers are defined as compounds that, when combined with radiation, achieve greater tumor inactivation than would have been expected from just the additive effects of the two modalities of treatment. The premise that underlies radiosensitization is that the toxicities of the chemical agent used and the radiation do not significantly overlap, thereby not increasing toxicity. Also, the chemical agent chosen should not make the radiation therapy more toxic to the normal brain cells within the region of the brain receiving the radiation. Optimally, the benefits of radiosensitization should allow the tumor site to be exposed to an effectively higher dose of radiation without increased toxicity. In reality, this hoped-for synergistic effect of radiosensitization is a balance between how much more effective the radiosensitizers make radiation in killing more tumor cells, compared with how much more damaging the treatment will be to normal cells that are exposed to the radiotherapy.

Another basic concept that has been difficult to prove with brainstem gliomas is that increasing the effective dose of radiation therapy actually improves disease control. At best, most radiosensitizers increase the dose intensity of radiotherapy by 20% to 30%, yet it is unclear whether such an increase results in improved long-term disease control.

Types of Radiosensitizers

Hypoxic Cell Sensitizers

The largest early experience with radiosensitizers was the use of agents that act to sensitize hypoxic cells to radiation therapy. The use of these agents was based on the assumption that a chronic state of tumor hypoxia (when tumor cells exist in an environment low in oxygen) occurs in brainstem gliomas. Using agents that make these hypoxic tumor cells more sensitive to radiation therapy may provide a therapeutic advantage by killing more hypoxic cells and sparing better oxygenated cells (in theory, normal cells) from the damaging effects of radiation. A series of hypoxic cell sensitizers have been utilized for other cancers, but they have not been used in brainstem gliomas due to concerns about toxicity, including enhanced neurologic toxicity, and lack of any clear benefit when used on other types of tumors.

An alternative means to radiosensitize hypoxic cells is to make the tumor less hypoxic—in other words, get more oxygen to the cells. Different methods that have been used to accomplish this include hyperbaric oxygen, the use of red blood cell transfusions, and the delivery of oxygen carrier substances.

Radiosensitization with Molecular-Targeted Drugs and Other "Biologic Agents"

Over the past decade, a host of biologic agents have become available and tested in children with brain tumors. Molecularly targeted agents have included:

1. Antiangiogenesis drugs;
2. Agents that block growth factor receptors;
3. Drugs that interfere with intracellular signaling essential for tumor growth.

The lack of biologic information about brainstem gliomas has hindered, to a great degree, a biologic rationale for deciding which drug,  or drug combinations would be most effective if combined with radiation. In phase 1 trials to date, these biologic agents have demonstrated minimal ability to shrink tumors, although some have resulted in possible prolonged stable disease. Because of the relative low toxicity of many of these agents and, in some cases, theoretic evidence that they may be at least additive—if not synergistic—with concurrent radiotherapy, multiple studies have utilized biologics with, and following, radiation therapy. There is great interest in continuing such approaches, with the caveat that experimental evidence for independent efficacy or synergy is often minimal, at best.

Summary

Radiosensitization remains an appealing approach for the treatment of children with newly diagnosed brainstem gliomas. As outlined, although there are theoretic benefits to their use, there is little evidence to date to validate improved efficacy. Work continues with standard chemotherapeutic agents, hypoxic and non-hypoxic radiosensitizers, and biologic agents. Until more is known about the basic biology of brainstem gliomas, most studies will remain empiric. Delivery of agents to the brainstem remains an extremely critical and potentially limiting factor. In addition, as better agents are developed, their selective capabilities of killing tumor cells and relatively sparing the normal surrounding brain cells will remain a critical issue.