By Katherine Skorupski, DVM, Dipl. ACVIM (Oncology)
Studies of human cancer patients indicate that up to 81 percent take vitamins, nutraceuticals or herbal supplements, yet up to 68 percent of their physicians are unaware of such use.
However, one difficulty in gaining such knowledge lies in a lack of published evidence for many supplements. Some have been studied and others have not, and there is a great need for prospective clinical trials to test the efficacy of nutraceuticals and supplements.
Further, unlike pharmaceuticals, supplement quality isn’t monitored or controlled by the U.S. Food and Drug Administration or other oversight agency. Recent reports of fraud have surfaced in the supplement industry; some were found to contain little or no active ingredient(s). One veterinary study of commercially available SAMe supplements found significant variation in actual SAMe content depending on brand.
Because similar data is not available for other supplements, it can be difficult for veterinarians to make specific brand recommendations.
Although there is much left to learn about supplement, herb and nutraceutical use in veterinary medicine, the available evidence has expanded in recent years. Here, I summarize the evidence for or against their use in pets with cancer.
Omega-3 Fatty Acids
Omega-3 fatty acids, eicosapentaenoic acid and docosahexaenoic acid, serve as natural anti-inflammatories in cells by inhibiting cyclooxygenase. Their use has been studied in a variety of human diseases, including asthma, inflammatory bowel disease and rheumatoid arthritis. There is evidence in cancer patients that these fatty acids can help prevent or reverse cancer cachexia, especially in people with gastrointestinal cancers. Studies also have shown that fatty acid supplementation may reduce postoperative infections and acute radiation side effects in human cancer patients undergoing surgery or radiation therapy.
Omega-3 fatty acids also may be able to kill cancer directly and have been shown to reduce cellular proliferation, angiogenesis and invasion, and increase programmed cell death. In addition, they have been shown to be protective against cancer development in human patients predisposed to colon cancer and are being studied as part of combination treatments for people with colon, breast and prostate cancer.
Despite their exciting potential, limited research exists on omega-3 fatty acid supplementation in veterinary cancer patients. One study evaluated the effects of a diet supplemented with high doses of omega-3 fatty acids in dogs with lymphoma. Improved outcome was seen in a subset of dogs receiving the diet, but not in all patients. Importantly, fatty acid supplementation was well tolerated and did not affect doxorubicin pharmacokinetics in these patients.
Another study in dogs with nasal carcinoma undergoing radiation found lower levels of inflammatory mediators in dogs receiving fatty acid supplements, which might translate to fewer radiation side effects. Further research into potential benefits of omega-3 fatty acid supplementation in pets with cancer is needed to better define their role. The optimal doses of fatty acids necessary to benefit cancer patients also is not known, but may be higher than labeled doses at approximately 100 milligrams/kilograms per day. Side effects are rare, even at high doses, but can include coagulopathy, diarrhea or a fishy odor.
Valproic acid, a short, branched-chain fatty acid that has been studied for use as an anti-epileptic, functions as a histone deacetylase inhibitor, which prevents tight winding of DNA. This may make DNA more accessible to certain chemotherapy drugs.
A preliminary in vitro study of canine osteosarcoma cells showed it to work synergistically with doxorubicin to increase cell killing, and a clinical study found it to be well tolerated in dogs when combined with doxorubicin. Further study into the best chemotherapy combination and its effects on chemotherapy efficacy is necessary.
Yunnan baiyao, a proprietary herbal mixture whose primary ingredient is thought to be panax notoginseng, is believed to slow or stop bleeding and has been advocated for use in dogs with bleeding nasal tumors, bladder tumors, hemangiosarcoma and other cancers.
Despite widespread use in veterinary medicine, published research is limited and results are conflicting. An in vitro study found that Yunnan baiyao may kill hemangiosarcoma cells directly, while a clinical trial evaluating blood clotting via TEG and mucosal bleeding times in dogs found no difference between treatment groups.
Anecdotally, Yunnan baiyao is very safe even with chronic dosing. Additional published research into its role in cancer treatment is expected soon.
The Yun Zhi mushroom Coriolus versicolor, also known as the cloud mushroom or turkey tail mushroom, is an herb that may inhibit cancer cell growth through cell cycle inhibition, immunomodulation and gene modulation. Some human studies suggest that it can improve long-term survival when combined with other cancer treatment modalities.
In veterinary medicine, a randomized clinical trial in dogs with splenic hemangiosarcoma was conducted using the brand I’m-Yunity, and dogs were treated with varying doses of the product after splenectomy. Results indicated that the herb is well tolerated, and dogs at the highest dose level had a longer time to cancer progression, though no difference in survival was found. Further study into the ideal dose and duration of this herb and how it can best be combined with chemotherapy is necessary.
Curcumin, the principal compound in turmeric, has been shown to inhibit cancer cell growth in vitro by many mechanisms, including inhibition of cell-signaling pathways. Unfortunately, curcumin and its metabolites are poorly bioavailable and travel with minimal absorption through the GI tract. For this reason, most over-the-counter forms of the supplement are not expected to be clinically useful. Efforts have been made to develop injectable forms of the drug, and studies of liposome-encapsulated formulations currently are underway. Liposome encapsulation can help curcumin concentrate to high levels in tissues, especially lung tissue. This may be particularly useful in treating primary and metastatic lung cancers. More information on potential new formulations, doses and cancer response data is expected soon.
SAMe and Milk Thistle
Hepatic function is important in the activation or metabolism of many chemotherapeutic agents, including vincristine, cyclophosphamide, doxorubicin and toceranib (Palladia). Some chemotherapeutic agents also can be directly hepatotoxic, and CCNU is the most severe hepatotoxin used in veterinary oncology. Up to 84 percent of dogs that receive CCNU therapy will develop elevations in liver enzymes during therapy, and 7 percent will develop liver failure.
SAMe and silybin, the most potent flavonoid from the milk thistle plant, have shown efficacy in human and veterinary patients with toxic hepatopathies. Limited study has been done of their roles in human patients with chemotherapy-induced hepatopathy, and they reduced liver enzyme elevations and allowed patients to receive chemotherapy on schedule.
A study was conducted to explore a possible role for SAMe and silybin in veterinary cancer patients. A randomized clinical trial evaluating Denamarin (containing both SAMe and silybin) in dogs prescribed CCNU found that dogs not taking the supplement had significantly greater increases in all liver values compared to dogs that were taking it. Dogs on Denamarin also were more likely to complete their prescribed treatment course. These results and the excellent safety profile of Denamarin make it a good option to support patients receiving potentially hepatotoxic chemotherapy.
When prescribing, it is important to consider how an herb or supplement could potentially affect an individual cancer patient and whether contraindications exist. For example, some herbs have estrogenic properties that could impact mammary or ovarian cancers. Soy products, flax seed oil and black cohosh are some examples.
Other herbs may inhibit platelet aggregation and may be contraindicated in patients undergoing surgery or with low platelet counts. Garlic, grape seed and ginsengs are examples.
Some herbs are photosensitizers that may increase acute radiation toxicity. Examples include St. John’s wort and shitake mushroom.
Echinacea is an immune stimulant that potentially should be avoided in lymphoma patients and those on immunosuppressive drugs. Shark cartilage can inhibit angiogenesis and may be contraindicated in patients undergoing surgery or in hypercalcemic patients due to its composition.
Like drugs, herbal supplements can interact with drugs and other supplements in several ways. Many interactions occur through effects on cytochrome p450 enzymes or the p-glycoprotein pump responsible for drug distribution and metabolism. Specific herbs of concern include St. John’s wort, ginsengs (including Yunnan baiyao), garlic, ginkgo and Echinacea. Studies have found each of these to affect metabolism of one or more chemotherapy drugs.
Herbal supplements also may have antioxidant properties that may interfere with cancer killing by chemotherapy or radiotherapy. Garlic, grape seed extract, vitamins E and C, ginsengs and red clover are herbs with antioxidant properties. While many know about negative effects of reactive oxygen species, their activity is essential to the action of some cancer therapies. Radiation therapy causes cell death exclusively through DNA damage by free radicals and, without this, radiation therapy would be ineffective. Additionally, some chemotherapy agents are known to have free radical production or oxidative effects as part of their mechanism of cancer killing.
While some have attempted to study interactions between antioxidants and chemotherapy in humans in a clinical setting, the results of these studies are difficult to interpret. This is due to variability in dosing and duration of antioxidant use and frequent use of multiple antioxidants at once. As a result, antioxidant use with chemotherapy is still controversial in human medicine.
There is stronger evidence against antioxidant use during radiation therapy in humans. Multiple randomized trials of human head and neck cancer have shown higher recurrence rates and mortality in patients receiving supplementation with vitamins A or E.
Although there is no data available to directly guide recommendations in veterinary species, caution is recommended when combining antioxidant supplements with cancer treatment.
Dr. Katherine Skorupski is an associate professor of clinical medical oncology at the University of California, Davis School of Veterinary Medicine.