In this issue of Cancer Investigation, Kleinberg et al. present their experience using Gliadel® followed by radiotherapy in the treatment of newly diagnosed malignant gliomas. Over the past decade they have treated 46 such patients, the majority of whom have had a glioblastoma multiforme. A subset of these patients could be evaluated for toxicity or complications related to the combination of Gliadel and radiotherapy with the conclusion that this combination is safe and well tolerated. It should be noted that half of these patients did deteriorate neurologically during radiotherapy but improved with an increase in steroid dosing. This is useful information as the group at Johns Hopkins has one of the longest and largest experience in the use Gliadel polymers. The authors importantly emphasize that the use of Gliadel may limit patient participation in future clinical trials. This is a critical consideration for any patient with a newly diagnosed malignant glioma as Gliadel, similar to most advances in the treatment of malignant brain tumors, has achieved only modest success with respect to tumor control.
Local delivery of chemotherapeutic agents as well as a number of other biologic, immunologic, and genetic therapies is an area of active development in neurooncology. Polymer-based therapy is one technique to deliver chemotherapies or other agents that otherwise do not penetrate the blood-brain barrier to the surgical bed. However, this approach should be viewed with caution. Polymer-based therapies deliver high concentrations of drug close to the location where they are placed but significant diffusion into surrounding tissue does not occur. Furthermore, polymers placed in the center of a surgical resection are being placed in a location where the blood-brain barrier is already damaged and relatively permeable, whereas the target of therapy, residual microscopic tumor, is distant from the resection core, distant from the polymer and diffusing therapy, and behind an intact blood-brain barrier. Substances that normally do not penetrate the blood-brain barrier and are, therefore, ideal candidates for polymer-based delivery may cause previously unrecognized neurologic toxicity. Positive-pressure microinfusion or convection enhanced delivery is another strategy being developed to deliver local therapies to malignant brain tumors but with a more specific intent to achieve diffusion of large molecules into brain parenchyma-containing residual microscopic tumor.
These are all novel strategies worthy of trial against a frustrating target. It is reasonable to be hopeful that these approaches may yield further modest gains in the treatment of malignant gliomas. However, the real difficulty is that while most gliomas recur locally this is not a local disease. Viable tumor cells can be found at a significant distance from the primary tumor mass. Therefore, a real breakthrough in treatment will require further understanding of glioma biology with a novel therapeutic approach that can be administered systemically.