Dr. Joseph H. Goodman
Division of Neurosurgery
N007 Upham Hall, 473 W. 12th Avenue
The Ohio State University
Columbus, OH 43210
Phone: 614-293-8586
Fax: 614-293-4281
Projects are approved by an IRB located at: The Ohio State University.
The approving IRB operates under a Multiple Project Assurance (MPA) recognized by DOE or by the Department of Health and Human Services (HHS).
MPA number of the IRB: M-1238
Number of Human Subjects Projects reported: 1
Project Identifier: OSU-95-95H0240
Project Title:
Pharmacokinetics and Biodistribution of Sodium Borocaptate in Patients with Anaplastic Astrocytomas / Glioblastoma Multiforme
Principal Investigator:
Dr. Joseph H. Goodman
Project started in: 1995
Project Funding Information:
Project received funding in Fiscal Year 1997.
Project used human subjects in Fiscal Year 1997.
Funding Sources:
Project does not involve use of multiple protocols/subprojects.
IRB Review:
Type of Review: Full Board
Most Recent Approval: June 16, 1997
IRB Approval Number: 95H0240
Number of Human Subjects who participated in this project/protocol during
FY 1997 (10/1/96 - 9/30/97): 2
Type of Human Subjects Involvement:
A. Objectives
Boron neutron capture therapy (BNCT) is based on the nuclear reaction that occurs when boron-10, which is a non-radioactive constituent of natural elemental boron, is irradiated with low energy (0.025 eV) neutrons to yield high linear energy transfer (LET) helium-4 (alpha particles) and recoiling lithium-7 nuclei. For BNCT to be successful, a large enough number of boron-10 atoms must be delivered to the tumor (35 µg per gm) and enough thermal neutrons must be absorbed by the boron-10 atoms to sustain a lethal boron-neutron capture reaction. The overall goal of the present project is to study the pharmacokinetics and biodistribution in tumor and normal tissues of sodium borocaptate (BSH, NSC #672422) in patients who are undergoing surgical resection of anaplastic astrocytoma or glioblastoma multiforme. This compound has been used in Japan as a capture agent for BNCT in patients with glioblastomas who have had surgical "debulking" of their tumors. The specific goals of the present study are:
1. To determine boron concentrations in surgically resected tumors, peritumoral brain tissue, cerebro-spinal fluid (CSF), dura, bone, muscle, and skin, which ordinarily would be resected at the time of craniotomy, in patients undergoing resection of anaplastic astrocytomas or glioblastoma multiforme after intravenous administration of BSH;
2. To determine the pharmacokinetics of BSH in blood and urine in brain tumor patients before, during, and after surgical resection of their tumors;
3. To document any cardiovascular, hepatic, renal, and hematopoietic toxicity that may occur as a result of BSH administration;
4. To correlate tumor and non-tumor uptake of BSH (i.e., boron content) with the histology of resected tissue samples using direct current plasma atomic emission spectrometry (DCPAES);
5. To define by analytical methods the chemical form of boron in tumor and non-tumor tissues, as well as the metabolites of BSH in blood and urine;
6. To carry out radiodosimetric calculations based on empirically determined boron concentrations and to develop a treatment planning algorithm;
7. Depending upon the results obtained in this study, to develop a treatment protocol that combines surgery and BNCT, using BSH as the capture agent, for patients with anaplastic astrocytoma/glioblastoma multiforme.
In summary, this is a comprehensive, multidisciplinary study on the pharmacokinetics and biodistribution of BSH, the boron compound that at this time has been used as a capture agent in patients with brain tumors and for which there are reported claims of therapeutic efficacy. This is being conducted at The Ohio State University Hospitals with an integrated team that includes neurosurgeons, pathologists, chemists, a pharmacokineticist, radiation oncologists, a medical radiation physicist, and a biostatistician. The present proposal addresses one of the more clinically relevant questions concerning the possible use of BSH as a delivery agent for BNCT of high grade astrocytomas and glioblastomas: Does this boron compound attain a sufficient concentration in the tumor to sustain a lethal boron-neutron capture reaction that will result in selective killing of malignant cells and a concomitant sparing of contiguous normal brain and adjacent normal tissues?
B. Methodology
1. BSH, prepared under an inert atmosphere immediately before administration, is infused intravenously at a constant rate over 1 hour before surgical removal of the tumor.
2. EKG is monitored continuously throughout the infusion, until the time of surgery, during surgery, and for 24 hours after surgery; vital signs are frequently monitored (15 min) during the infusion.
3. Blood is frequently sampled, as described in the protocols submitted, for analysis of boron content, liver enzymes (AST, ALT, and alkaline phosphatase), and creatinine. Standard hematological analyses, including WBC, platelet, hemoglobin, and leukocyte differential counts, are performed.
4. Urine is analyzed for boron content.
5. Tumor and tissue samples collected at the time of surgery are analyzed for boron content. The specimens, records, and data used in this study are obtained specifically for research purposes.
C. Chemical substance to which human subjects are exposed: sodium borocaptate (BSH)
D. Involvement of Human Subjects
Procedures: BSH is infused intravenously prior to surgery to remove the patient's brain tumor. During surgery, tissue samples are taken to be analyzed for boron content. During the patient's hospitalization, blood and urine samples are taken to be analyzed for boron content. This process is described more specifically in the methodology section of this abstract. The patient's progress is followed for 21 days after surgery. All patients in this study receive the best available standard therapy, as determined by their doctor. The study has no effect on the surgical procedure or other treatment of their tumor.
Risks: Although we anticipate no risks to the patients in this study, possible risks to be considered include:
1. Liver dysfunction
2. Cardiac dysrhythmia
3. Renal dysfunction
4. Pulmonary emboli
5. Cerebrovascular accident ("stroke")
6. Fever
7. Bacteremia and/or septicemia
8. Shock
9. Hematoma or pneumothorax from the central line placement
The 1 hour intravenous infusion carried out 3-12 hours before the operative procedure may possibly cause pain, slight bruising, and/or fainting (this varies from person to person) due to the insertion of the venous catheters. The same is true for the blood-sampling procedure. There is a very slight chance that the insertion of the catheter could cause a collapsed lung, which would be treated with a suction tube placed into the chest cavity.
Adverse Effects: We anticipate no adverse effects to the patients in this study. In the unlikely event of such effects occurring, immediate medical treatment is available at The Ohio State University Hospitals and at the Arthur G. James Cancer Hospital and Research Institute.
Consent, Confidentiality: Patients entered into this study will be provided with informed consent forms explaining the risks and benefits involved. Informed consents will be obtained by the principal investigator or his designee. If required, the U.S. Food and Drug Administration may inspect records pertaining to this study. Records obtained during this study may contain patients' names or other personal identifiers and may be made available to the sponsor of this study. Beyond this, participation will remain confidential.