Annual Forum 1988 – Improved Drug Delivery to Brain Tumors

Chair:
Arnold I. Freeman, MD, University of Missouri, Kansas, MO

Participants:
Mark Chasin, Ph.D., Nova Pharmaceuticals, Baltimore, MD
O. Michael Colvin, MD, Johns Hopkins Oncology Center, Baltimore, MD
Mirko Diksic, Ph.D., McGill University, Montreal, Canada
Joseph Fenstermacher, Ph.D., State University of New York, Stony Brook, NY
Jonathan Finley, MB, ChB, Children’s Hospital of Philadelphia, PA
Arnold Freeman, Ph.D., The Children’s Mercy Hospital, Kansas City, MO
Andrew Hertler, MD, Louisiana State University, Shreveport, LA
John T. Kemshead, MD, Institute of Child Health, London, England
Victor Levin, MD, MD Anderson Cancer Center, Houston, TX
Eric Mayhew, Ph.D., Roswell Park Memorial Institute, Buffalo, NY
David Poplack, MD, National Institutes of Health, Bethesda, MD
Joan Shapiro, Ph.D. Memorial Sloan-Kettering, New York, NY
William Shapiro, MD, Memorial Sloan-Kettering, New York, NY
Yukitaka Ushio, MD, Ph.D., Kumamoto University, Kumamoto, Japan


Layout and Goals
Sessions:

  1. Blood-Brain Barrier and its Physiology
  2. Directions of Current Therapy
  3. Targeted Therapy in Brain Tumors
  4. Discussion and Summary

The fourth Annual Forbeck Forum probed the problems of treating brain tumors with chemotherapy. Advances in the cure rate of brain cancers have lagged behind most other childhood cancers. Further, the morbidity of this cancer is often devastating. For example, in children cured of medulloblastoma (a brain tumor in the back if the head), there is often a profound loss of intelligence, which may be so severe as to greatly decrease the quality of life. The brain is unique in that it is in a protected environment so that toxins and other products normally present in the blood cannot gain entry into the brain. The blood brain barrier (BBB) is the prime basis for the protected environment. Unfortunately, this also means that many chemotherapeutic drugs cannot gain entry into the central nervous system. There are, however, techniques which can overcome the BBB. For example, certain “lipid-soluble” drugs cross the BBB. Drugs may be administered in very high doses, thereby “forcing their way” into the CNS, or, them may be administered directly into the artery that bathes the part of the brain where the tumor is located. This achieves a high level of drug in the substance of the brain tumor.


Outcome Report
The Fourth Annual William Guy Forbeck Forum held in November 1988 probed the problems of treating brain tumors with chemotherapy. Advances in the cure rate of brain cancers have lagged behind most other childhood cancers. Further, the morbidity of this cancer is often devastating. For example, in children cured of medulloblastoma (a brain tumor in the back of the head), there is often a profound loss of intelligence, which may be so severe as to greatly decrease the quality of life.

The brain is unique in that it is in a protected environment so that toxins and other products normally present in the blood cannot gain entry into the brain. The blood brain barrier (BBB) is the prime basis for the protected environment. Unfortunately, this also means that many chemotherapeutic agents cannot gain entry into the nervous system. There are, however, techniques which can overcome the BBB. For example, certain “lipid-soluble” drugs cross the BBB. Drugs may be administered in very high doses, thereby ‘forcing their way’ into the CNS, or, they may be administered directly into the artery that bathes the part of the brain where the tumor is located. This achieves a high level of drug in the substance of the brain tumor.

The first session was chaired by Dr. Joseph Fenstermacher and dealt with the basic understanding of the control of drug access to the brain. The thrust of this session was that factors, other than BBB, play a role in drug penetration onto cancer cells. Noted were the capillary density (the number of capillaries per area in the various geographical locations of the brain), the length of the capillary, and the transit time of chemotherapy in the capillaries. Drugs that are highly bound to protein in the blood do not penetrate into the central nervous system. Discussed were mathematic models depicting these problems and pointing toward possible solutions. Also, the benefit of PET scanners to evaluate the metabolism and drug penetration into the brain tumors were evaluated. For example, a patient whose tumor takes up BCNU (an anticancer drug) was shown to have a better response.

The second session was chaired by Dr. William Shapiro and discussed results on recently completed or ongoing studies. These included the use of various drugs in recurrent brain tumors, as well as the use of drugs in a primary adjuvant fashion along with surgery and radiation in an attempt to improve the cure rate. Intra-arterial drug therapy (giving the drug directly into the artery bathing the tumor rather than into a vein), and the benefits of this maneuver, as well as its toxicities, were debated.

At present, standard therapy for high grade gliomas of the brain (the common adult cancer of the brain) is maximal resection, followed by radiation and then BCNU chemotherapy. Unfortunately this program leaves a great deal to be desired. Only 25% of patients with high grade gliomas are alive at 18 months. The smaller the amount of tumor left after surgery, the better the prognosis. It was observed that brain tumors which initially respond to treatment and then recur have become highly resistant to drugs. A new anticancer drug, ACNU (an analog of BCNU), was tested in Japan and has shown that it is effective against brain tumors. The use of bone marrow transplantation in childhood brain tumors was discussed. This technique allows very high doses of drug to be given intravenously. Some impressive responses in far advanced cases were noted.

Dr. John Kemshead chaired the third session which dealt with innovative techniques for the administration of chemotherapy. Intra-arterial chemotherapy was again presented. Discussions included the use of monoclonal antibodies to target drugs, radionucleotides, and toxins, including their use when administered directly into the spinal fluid. Other ideas include discussion of the advantage of using liposomes which are small lipid balls with hollow centers that can be filled with drugs; and the implantation of wafers (containing drugs) directly into the tumor bed (after the tumor has been surgically removed). In this situation, drugs may be directly released into the tumor for long periods of time.

Exciting spinoffs from this meeting included the collaborative evaluation of multidrug resistance in brain tumors and the extension of using wafers in clinical trials.