INTRATHECAL CHEMOTHERAPY OF GLIOMAS: RATIONALE AND CURRENT STATUS

Intrathecal injection of drugs to treat central nervous system disease, particularly infections, is an old concept based upon the rationale of rapidly getting a high dose of an active agent where it is most needed, as well as bypassing the blood-brain barrier, which excludes, or tends to exclude, certain substances from the brain and the cerebrospinal fluid. It also has the advantage of allowing certain substances to be used which, if given intravenously, would be detoxified too rapidly in the body to get into the brain. For tumors such as meningeal leukemia, medulloblastoma, and ependymomas that are in the arachnoid and are not closely related to the bloodstream, the only way to get a cytotoxic agent to the tumors is via the cerebrospinal fluid, either by direct injection or from the bloodstream and then into the cerebrospinal fluid, Here, the intrathecal injection offers a great advantage. The possible effectiveness of intrathecal treatment of large solid tumors depends very much on their location. If the tumor is on the ventricular surface or the external surface of the brain, then there is a chance of entry of the drug directly from the cerebrospinal fluid; but if the tumor is not on the surface of the brain, the effectiveness of intrathecal therapy as opposed to blood-transported drugs must be measured by the rate of diffusion of the antitumor agent through the brain compared with the rate of entry of the drug into the tumor from the bloodstream. If the intrathecal route is to be the most efficient route to these tumors, the tumors must exhibit a blood-tumor barrier similar to the blood-brain barrier. The evidence on this point is, unfortunately, scanty. Another situation in which intrathecal therapy might be extremely useful occurs immediately following surgery, when there are tumor cells floating in the cerebrospinal fluid which might seed the meninges, or when the last layer of tumor cells cannot be removed, as in a medulloblastoma. The bathing of a tumor bed with the antitumor agent in the cerebrospinal fluid offers a chance of getting the antitumor agent where the remaining cells are located in a dosage that might not be possible through the intravascular route. Even without the blood-brain barrier phenomenon, the intrathecal route does offer certain advantages in providing a high concentration to the tumors with less risk of general toxicity than the intravascular routes offer. This is true in the case of drugs that are rapidly detoxified, and also in the case of drugs that are bound to the blood proteins and can only move into the brain in the unbound form. Although the free, unbound drug will rapidly leave the cerebrospinal fluid, there will be a higher concentration presented to the tumor or surface of the brain than would be possible by the vascular route, even by arterial injection, since the systemic circulation time is only two seconds, whereas the intrathecal circulation time may be as long as three to five hours.