Diagnosis and treatment of brain tumors (Proceedings)
The Past: Surgery, Irradiation and Chemotherapy
The major goals of therapy for a brain tumor have been to control secondary effects, such as increased intracranial pressure or cerebral edema, and to eradicate the tumor or reduce its size. Beyond general efforts to maintain homeostasis, palliative therapy for dogs or cats with a brain tumor has consisted of glucocorticoids for edema reduction, and in some cases (e.g., lymphoma), for retardation of tumor growth. Some animals with a brain tumor will demonstrate dramatic improvement in clinical signs for weeks or months with sustained glucocorticoid therapy. Should seizure therapy be needed, phenobarbital or bromide are the drugs best suited for the control of generalized seizures.
Three major methods of therapy for a brain tumor have been available for use in dogs and cats: surgery, irradiation, and chemotherapy.Surgery
In association with the availability of CT and MRI, and the development of advanced neurosurgical, anesthetic, and critical care techniques, complete or partial surgical removal of intracranial neoplasms has been practiced with increasing frequency. Neurosurgical intervention is an essential consideration in the management of intracranial neoplasms of cats or dogs, whether for complete excision, partial removal, or biopsy.
The use of radiation therapy for the treatment of primary brain tumors of dogs and cats is well established. Irradiation may be used either alone or in combination with other treatments. Radiation therapy also is recommended for the treatment of secondary brain tumors. Metastases, pituitary macroadenomas or macrocarcinomas, and skull tumors have been successfully managed by means of either radiation therapy alone or as an adjunct to surgery. Lymphoma may also be sensitive to radiation therapy.
Traditionally, cytotoxic drugs have had a limited role in the treatment of dogs or cats with brain tumors, and progress in the development of truly effective chemotherapeutic protocols for humans or companion animals has been slow. Several factors affect the use of chemotherapeutic agents for the treatment of brain tumors in dogs or cats. The first, unique to the brain, is that the blood-brain barrier may prevent exposure of all or some of the tumor to a chemotherapeutic agent injected parenterally. Second, tumor cell heterogeneity may be such that only certain cells within a tumor are sensitive to a given agent. Third, a tumor may be sensitive only at dosages that are toxic to the normal brain or other organs
The Present: Therapeutic Delivery Strategies for Canine Brain Tumors
Development of novel therapeutic strategies to combat primary brain tumors has followed closely behind elucidation of the basic molecular and genetic mechanisms underlying both tumorigenesis and subsequent progression. Despite the wealth of data documenting successful treatment of experimental tumors, translation into the clinical setting has been slow. Many existing therapeutics are rendered ineffective in the treatment of brain tumors due to the inability to effectively deliver and sustain them within the brain. The major obstacle to therapeutic delivery via the vascular route (following either orally administration or direct vascular administration) is the blood brain barrier (BBB).
Transport across the brain vascular endothelium is essentially trans-cellular, therefore the ideal substance to be transported should be:
Unfortunately, a majority of chemotherapeutic agents are large positively charged, hydrophilic molecules. Many therapeutic molecules such as cyclosporine, doxorubicin and vincristine have poor BBB penetration despite being lipophilic (cyclosporine A is more lipophilic than diazepam). This is the result of additional "barriers" such as high levels of degrading enzymes within the endothelial cells, and high concentrations of efflux transporter proteins such as P-glycoprotein, multiple organic anion transporter proteins (MOAT) and multi-drug-resistance proteins (MRP).