For patients with aggressive, high-grade gliomas, clinical trials offer access to new experimental therapies studied for their effectiveness. Traditionally, clinical trials have been broken into three phases. Phase 1 clinical trials assess the safety of a new treatment. Phase 2 studies involve more patients and evaluate the efficacy of the treatment. Phase 3 studies are designed to compare the novel treatment to a proven treatment to validate its effectiveness further.
While most clinical trials for high-grade glioma patients study systemically administered chemotherapies managed by a neuro-oncologist, some high-grade glioma clinical trials are now surgically based. In these trials, tumor surgery plays more than its usual cytoreductive role. Examples of surgically based clinical trials include:
- Trials in which biological information is obtained through the surgery;
- Trials in which a therapy is derived from the surgical tissue; and
- Trials in which the surgeon delivers a therapy at the time of the procedure.
The first example of obtaining biological information through the surgery consists of phase 0-like “window of opportunity” clinical trials, first in human studies in which a small number of patients are given a drug for a few days before surgery. Blood is drawn regularly before and during the surgery to obtain pharmacokinetic and pharmacodynamic information, which helps determine how quickly a steady-state concentration of the drug within the tumor is achieved under the prescribed dosing regimen. Cerebrospinal fluid is obtained during surgery to determine whether the agent’s intracranial penetration achieves a steady state after a similar time as occurs systemically. Tumor tissue is analyzed to measure drug levels in the enhancing versus non-enhancing tumor, with levels often 3-4 times higher in the former than the latter, underscoring the difficulty of treating the non-enhancing tumor with systemic chemotherapy. Tumor tissue can also be analyzed for levels of the drug’s target protein and its downstream mediators to determine whether the drug affects the intended target in tumor tissue.
The second example of surgically based clinical trials typically involves immunotherapies in which a vaccine is developed from tumor tissue. The vaccine can be peptide-based — in which an immunostimulatory peptide-like heat shock protein is combined with tumor peptides — or a cellular vaccine in which immune cells like dendritic cells taken from the patient are primed with tumor peptides and then returned to the patient to provide antitumor immunity.
The third example involves the surgical administration of cellular, viral or pharmacologic therapies. These can be delivered into craniotomy walls after resection or directly into the tumor without resection. The advantages of delivering the therapy into craniotomy walls include combining the benefit of cytoreductive surgery with the therapeutic injection. In contrast, the disadvantages of delivering the therapy into the craniotomy walls include the reflux of the agents back into the resection cavity. Needle delivery into the tumor avoids reflux into the resection cavity, but reflux up the injection tract or adjacent cavities from previous surgery must be accounted for. The lack of cytoreductive surgery means needle delivery may be best for smaller focal tumors. Needle delivery into the tumor can be accomplished via direct needle delivery or convection-enhanced delivery involving infusion through a catheter along a pressure gradient over hours or days.
Neurosurgeons play a critical role in designing and developing surgically based clinical trials for high-grade glioma patients. Many of these trials have developed from neurosurgeon-scientists’ basic science research in laboratories using preclinical animal models. There is hope that these trials will lead to discoveries that meaningfully impact the prognosis of patients diagnosed with high-grade gliomas in the future.
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Manish K. Aghi, MD, PhD, FAANS
UCSF Dept. of Neurological Surgery
San Francisco, Calif.