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Integrative therapy for brain tumors

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Central nervous system neoplasia in dogs and cats causes significant morbidity and mortality. Though the true prevalence is unknown, a postmortem study looking at the incidence of canine intracranial neoplasia over a 24-year period revealed an overall prevalence of 4.5%.1 A significantly higher prevalence of primary intracranial neoplasms were found in dogs of increasing age and body weight.1

The most common intracranial neoplasias in dogs are gliomas and meningiomas, although undifferentiated sarcomas, pituitary tumors, and ventricular tumors also occur. Golden Retrievers and Boxers have a higher risk of developing primary brain tumors, and dolichocephalic breeds are predisposed to meningiomas. Brachycephalic breeds are more likely to develop gliomas. Cats are less likely than dogs to develop brain neoplasia, but meningiomas (most common), gliomas and others do occur.2

Primary CNS neoplasia should be on the differential list of any older dog or cat with slowly progressive neurologic dysfunction, as well as those that develop new onset seizure activity over the age of five years. The site of the neoplasia usually determines the clinical signs observed; however, hemorrhage and/or edema, or blockage of venous cerebral fluid, can cause additional symptoms.

DIAGNOSIS AND TRADITIONAL TREATMENT

Definitive diagnosis requires histopathology, which may or may not be feasible. A minimum database can help exclude extracranial causes for cerebral dysfunction. Advanced imaging is recommended. MRI is considered superior to computed tomography as it allows visualization of edema, changes in vascularity, hemorrhage, necrosis and overall improved soft tissue detail.2

Goals of traditional treatment include controlling secondary effects such as increased intracranial pressure or edema, and to eradicate the tumor or reduce its size.2 The potential for surgical resection or debulking is determined by the tumor’s size, location, and degree of invasiveness. Surgery is the treatment of choice in feline meningiomas, as they are typically encapsulated and lie over convexities of the cerebrum.3

Traditional forms of radiation therapy and chemotherapy, as well as stereotactic radiosurgery, vaccine therapy, and gene therapy are being offered and explored.

WHAT DOES THE LITERATURE SAY?

A review of the literature does not reveal any placebocontrolled blinded studies on the use of alternative therapies in the treatment of cranial neoplasia in dogs or cats. Since malignant brain tumors affect people and are reportedly the second leading cause of cancer deaths in children and young adults4, there is a very active database of ongoing research as traditional therapies have had less than stellar outcomes. The following discussion presents some of the promising additions to the mainstay of surgical and oncological therapy.

DIET

Dietary management is one strategy that integrative veterinarians often use in an attempt to affect the health of their patients. There is mounting evidence that diet may play a role in the management of brain neoplasia.

Researchers have studied calorically restricted ketogenic diet therapy for malignant brain cancer using a mouse model.5,6 They implanted a malignant mouse astrocytoma and a human malignant glioma into the cerebral cortex of mice, and fed them a standard high carbohydrate diet; a calorie restricted standard high carbohydrate diet; a ketogenic formula; or a calorie restricted ketogenic diet.5 Calorie restriction was defined as 65% to 70% of the recommended daily allowance.

The researchers found that the calorie restricted mice showed a reduction in body weight, but were more physically active and appeared healthier than the unrestricted food group. The calorie restricted groups also had significantly reduced tumor growth (approximately 80% to 86% less) than unrestricted groups. Although plasma glucose levels predicted plasma ketone levels (inverse relationship), it was the glucose levels that were highly significant in predicting tumor growth, with lower levels being associated with smaller tumors.5 Primary brain tumors actively consume glucose and are dependent on glycolysis for energy. Due to mitochondrial defects, tumor cells are unable to metabolize ketone bodies for energy, while normal brain cells are able to utilize ketones for energy. Thus, normal cells were energetically supported with a ketogenic diet, while tumor cells were deprived.6

A ketogenic diet composed roughly of 6:1 (fat: protein + carbohydrate) was shown to increase survival in mice inoculated with brain gliomas when compared to mice given a standard diet. A decrease in the production of reactive oxygen species within the tumor cells was noted. The overall gene expression in the tumors of rodents fed a ketogenic diet was more similar to cells from tumor-free rodents, regardless of their diet.4

A 4:1 commercially available ketogenic diet developed for children with uncontrolled epilepsy (Nutricia KetoCal®) was used in mice inoculated with brain gliomas to determine if a combination of a ketogenic diet plus radiation therapy would have a cumulative effect.7 Mice fed the ketogenic diet lived longer and demonstrated slower tumor growth rates. More impressively, mice fed the ketogenic diet, and that were also irradiated, demonstrated a full regression of their tumors; moreover, the tumors did not recur when the mice where placed back on a standard diet.7

These findings hold promise, and should encourage the integrative veterinarian to include dietary strategies for their patients with cerebral neoplasia. Hopefully, future research will elucidate more specifics and clinical applicability to veterinary species.

HYPERBARIC OXYGEN THERAPY

Melatonin may be helpful In vitro studies have shown that melatonin, at pharmacologic concentrations, inhibits migration and invasion of glioma cells and acts as an antioxidant by inhibiting elevated production of reactive oxygen species in both normoxic and hypoxic conditions.13,14 A small study demonstrated that humans with glioblastoma treated with radiation therapy plus melatonin (20mg/day PO) had significantly improved survival. As well, toxicities from radiation therapy were lower when compared to those treated with radiation therapy only.15 The recommended dose for veterinary patients with gliomas is 0.1 to 0.2 mg/kg once daily, preferably in the evening.

This therapy uses 100% oxygen at elevated atmospheric pressure. It is used to increase oxygen tissue delivery via increased dissolved oxygen in the plasma, and treats various conditions from sepsis to certain non-healing wounds. HBOT has been shown to promote angiogenesis in wounds; for this reason, neoplasia was initially considered a contraindication for its use. In actuality, it appears that decreased oxygen tension selects for more malignant cells and promotes multiple cellular adaptations that promote tumor growth.8 Experimental and clinical studies of various cancers have shown that HBOT does not appear to promote cancer growth or metastasis.8

Stuhr, et al, demonstrated that transplanted gliomas in nude rats exposed to HBOT exhibited a reduced vascular density in the central portion of the tumors; a reduction of vessel diameter throughout the tumors; and an increased number of apoptotic cells, as well as a reduction in tumor growth.9 However, the tumors in this study were transplanted into the necks of the animals and not into the brain, so the clinical relevance of these findings in intracranial tumors is unknown.

Interestingly, Poff, et al, demonstrated a positive effect on survival when HBOT therapy was combined with a ketogenic diet in mice with systemic metastatic cancer – including metastasis to the brain.10 The tumor utilized in the study had been noted to occur spontaneously in the brains of the strain of mice used, and had shown multiple growth characteristics similar to the human glioblastoma multiforme.10 Both the ketogenic diet-only group, and the ketogenic diet plus HBOT therapy group, survived longer than control mice. The HBOT therapy plus ketogenic diet group had the longest mean survival rate, though this was not statistically different from the ketogenic diet-only group in this small sample-sized study. In this study, no effect on survival was seen in mice receiving HBOT therapy and a standard diet.10

HERBALS

Herbal preparations are a cornerstone of Traditional Chinese Medicine as well as other ancient medical practices. Many claims have been made about their beneficial effects through case studies and anecdotal stories, and fortunately research is validating some of these claims.

A review of the literature regarding herbals or portions of herbals specifically targeting brain tumors produces limited results. Two studies that show promise are presented below.

Turmeric curcumin1. Curcumin, an ingredient of turmeric, has been shown to suppress malignant glioma cell growth and induce apoptosis both in vitro and in vivo, using a mouse model.11 Mice were implanted with intracranial glioma cells and treated with intraperitoneal injections of curcumin or solvent DMSO (control) for 20 days. The curcumin group showed a marked reduction in tumor size, and appeared in better health with less weight loss, more activity, better appetite, and no seizures compared to the control group – and showed a significant improvement in survival.11 In vitro work showed that curcumin suppressed gene expression of the tumor cell line in a time- and dose-dependent fashion.11 Curcumin was also shown to inhibit the proliferation of the glioma cells, limit migration of the cells, and induce apoptosis.11

Dang gui angelica sinensis root

2. Angelicae sinensis radix (Dang gui) has traditionally been used in the treatment of menopausal symptoms, gastric mucosal damage and hepatic injury.12 It has also been shown to exhibit cytotoxic activities in tumor cells. Yu-Ling Lin, et al, looked at the methanol extract of Angelica sinensis (AS-M) and its effect on glioblastoma multiforme (GBM) cells. They injected the tumor cells subcutaneously, and also injected the AS-M subcutaneously.12 Treated mice had significantly smaller tumors than the controls. AS-M induced cell cycle arrest and apoptosis in the GBM tumor cells. Mice treated with AS-M showed no systemic deleterious effects, maintaining their body weight, normal morphology of abdominal organs, and normal blood work values.12 The authors hypothesized that intracranial injections of AS-M may be beneficial in human GBM disease.

CONCLUSION

Brain neoplasia presents its own special challenge for treatment due in part to the sensitive nature of brain tissue, its rigid containment within the skull, and the blood/brain barrier. Current treatment strategies are often met with poor outcomes. Innovative therapies are being investigated and these show promise for improved outcomes of this devastating disease.

Dr. Dana Whitlock graduated from the University of California, Davis and did an internship at the University of Georgia, a surgical internship at Dallas Veterinary Surgical Center, an orthopedic fellowship at the University of Tennessee, and surgical training at the University of Missouri. She is a Certified Veterinary Acupuncturist through the Chi Institute in Florida. She currently practices in Oakland, California at the Holistic Veterinary Care and Rehabilitation Center.