Potential improvement of survival statistics for glioblastoma multiforme (WHO IV)

Neurosurgery

A glioblast is a highly malignant tumor with cells that can spread throughout the brain. The current forms of treatment include surgical removal of the primary tumor followed by postsurgical radiation and the subsequent administration of chemotherapy. The present-day neurosurgical treatment of a glioblast involves removing the maximum amount of malignant tumor tissue without involving critical areas of the brain that if resected would result in a serious postoperative neurological defect.

Radiation

Following surgical excision of a glioblast in which complete or incomplete removal of the tumor has been performed; the malignant tumor bed and surrounding brain areas receive conventional radiation therapy often in 30 treatments of radiation in a cumulative dosage of 60 gy. Additional radiation may be applied to other areas of the brain by directing multiple beams of radiation to specific brain locations; however, there is the possibility that additional radiation can be harmful to brain tissue. Furthermore, it does not appear that increased radiation therapy for a glioblast will have a significant influence on future survival statistics for this tumor.

Chemotherapy

If there is to be improvement in the poor statistics associated with a glioblast, it seems likely that chemotherapy will be a major factor in the treatment. The chemotherapeutic agents needed for effective destruction of malignant tumor cells will require easy access into brain tissue over an indefinite period of time.

The ultimate question is can the present-day treatment of a glioblast by surgery, radiation therapy, and chemotherapy be improved? There appears to be a possibility that this can be accomplished.

An Interventional proposal

The initial procedure over the years for the treatment of a glioblast has been the surgical removal of the primary tumor and as much as possible of infiltrating malignant tissue surrounding the primary tumor. Success of this procedure has been limited by tumor tissue present in, or adjacent to, a critical brain area, a problem that has remained unresolved.

A recent article suggested that “there does not presently appear to be surgical techniques that would increase patients’ survival rates following the excision of a primary glioblastoma WHO IV.”[1] This statement must be corrected since there are now two relatively new neurosurgical procedures that have the potential to improve the treatment outcome of patients with a glioblast.

5-Aminovolumic acid (ALA)

One of the new procedures that have the potential to improve the progression-free period that follows the initial resection of glioblast is the intraoperative utilization of the drug 5-ALA. This drug was first described in 1983 and was approved for glioblast treatment by the FDA on July 3, 2017. Recently, the first 5-ALA fluorescence-guided brain tumor surgery symposium was held in the USA at the Mount Sinai Hospital in New York City on November 20, 2018.[17-23]

5-ALA, when administered 3 h before surgery for a glioblast, results in the fluorescence of malignant tissue within the brain. At the time of surgery, the drug causes a distinct red coloration in malignant brain tissue predominantly around the area of the primary tumor. The distinct red coloration loses its intensity at the site of a primary malignant tumor with the fluorescent red coloration decreasing to pink at the margin of the lesion. Fluorescence-guided surgery enables neurosurgeons to distinguish tissue infiltrated by malignant cells from normal brain tissue. The red and pink coloration of malignant tumor at the margin of a tumor resection allows for a more complete resection of malignant brain tissue. The visual distinction observed between normal and malignant tissue at the time of surgery can result in the surgical removal of a greater amount of malignant brain tissue than was previously possible. Fluorescence-guided surgery has made this achievable.

The amount of 5-ALA that is necessary for fluorescence has been proposed at a dosage level of 5, 10, and 20 mg/kg. The optimal dosage of the drug is presently being investigated by various studies which undoubtedly will be significant.

Omentum

A second new neurosurgical procedure that may improve the survival statistics of a glioblast is the use of the omentum. It has been shown over the past several decades that when an intact vascularized omental pedicle is placed directly on the brain of animals[3,4] and humans,[5-15] blood vessels from the omentum penetrate directly and deeply into the underlying brain. The inner lining in these omental blood vessels is completely free of cellular material.[2] In contrast, in the normal brain, blood–brain barrier (BBB vessels) contains strongly compacted endothelial cells that line the inside of the blood vessel, which prevent unwanted material, including particular chemotherapeutic agents, from entering the brain.[16] Chemotherapeutic agents flowing through omental blood vessels will have the potential to freely pass through the wall of an omental blood vessel and perfuse throughout the entire brain as shown in Figure 1.

Close

Figure 1:: India Ink given intravenously shows the dye in the omentum located on a monkey brain. Note the omental blood vessels delivering blood and India Ink into the depth of the underlying brain. It is expected that chemotherapeutic agents will also have the ability, when present in omental capillary blood flow, to deliver drugs to malignant cells distant from a primary glioma. Blood brain barrier vessels will not be necessary in the process.

Export to PPT

Omental blood flow studies have shown that placing the omentum on the brain of humans allows for increased blood flow throughout the entire brain.[6] The blood flow through these omental vessels would be expected to allow chemotherapeutic agents to perfuse the brain and, most importantly, to come in contact with glioblast cells present throughout the brain. The postsurgical contribution of 5-ALA and the subsequent placement of the omentum on the brain of patients with a glioblast raise the possibility and the hope that the combination of 5-ALA and the omentum may improve the survival statistics of a glioblast.