Role of Diet in Cancer

The impact of diet on the development of cancer as well as the role of nutrition in the treatment of cancer is well researched although hotly debated in human oncology. Research continues to investigate varying approaches to oncologic nutrition, with recommendations remaining individualized and tailored for every patient. Whole food, minimally processed diets, rich in phytonutrients and low in carbohydrates are a generally agreed upon approach in human oncology, with further recommendations regarding whole grains, elimination of animal products, amount of fats or carbohydrates remaining controversial. Limited data exists within veterinary oncology investigating the role nutrition plays in the development or treatment of cancer.

The role of diet in the prevention of cancer was investigated in a population of Scottish terriers, a breed predisposed to the development of transitional cell carcinoma [11]. This survey study evaluated each dog’s diet a year prior to diagnosis and compared data to non-neoplastic counterparts. A statistically significant decrease in risk of developing transitional cell carcinoma occurred in dogs fed green-leafy and yellow-orange vegetables as well as for dogs fed vegetables at least three times per week [11]. Few studies have examined the effects of dietary substrate (protein, fat, carbohydrate) and plant based dietary intake and cancer [12]. Two epidemiological studies revealed contradictory information to human findings, showing dogs with increased protein intake having increased survival times following diagnosis and intake of fat and carbohydrate not relevant to progression of the disease [13, 14]. Although more recent epidemiological data shows that more than 50% of owners of pets with cancer incorporate a nontraditional feeding program after diagnosis [15], additional studies have not been performed to evaluate the role of dietary modifications in the treatment of cancer, with current data guiding clinical decisions greater than twenty years old.

Protein, Carbohydrate and Fat Ratios

Currently, feeding recommendations for the veterinary cancer patient is driven by known metabolic derangements of tumorous tissues as well as identified abnormalities in amino acid, fatty acid, substrate and vitamin/mineral imbalances. The well-researched derangement of cancer cells to increase metabolic pathways that utilize glucose coupled with a limited fatty acid metabolism is known as the Warburg effect, after Otto Warburg’s seminal work suggesting glycolysis as the primary pathway for energy production in neoplastic cells [12]. This altered glucose metabolism concurrent with insulin resistance and hyperlactatemia support the recommendation for minimizing carbohydrate levels in veterinary cancer patients [16]. Alterations in fatty acid ratios as well as lipid metabolism in veterinary cancer patients, support the addition of dietary unsaturated fatty acids to minimize loss of lean body mass as well as possibly reduce tumor growth rate [12]. Current nutritional recommendations suggest providing foods with an omega-6:omega-3 ratio as close to 1:1 as possible alongside concurrent omega-3 supplementation. Alterations in protein metabolism, as well as inhibitory effects of certain amino acids like arginine against neoplastic cell proliferation [17] support recommendations to increase protein levels in excess of adult maintenance requirements, assuming renal and hepatic function is adequate to tolerate increased amounts. As cancer progresses, alterations in normal patient metabolism may occur causing simultaneous loss of both protein and fat stores with concurrent cytokine stimulation and insulin resistance, known as cancer cachexia. Cachexic patients need high energy in the form of fat, and additional carbohydrates may need to be reintroduced at this stage [18].

Highly Processed Foods

The high temperatures used in commercial pet food processing facilitate chemical reactions in proteins and carbonyl groups of reducing sugars which result in the formation of advanced glycation end products (AGEs). The release of these byproducts into systemic circulation has been associated with multiple degenerative diseases such as cardiovascular disease, osteoarthritis, autoimmune, and cancer. In a study quantifying the amount of these end products found in commercial pet foods, canned pet foods contained the most, followed by pelleted and extruded foods. Average daily intake (mg/kg body weight^0.75) of byproducts was 122 times higher for dogs and 38 times higher for cats than average intake for adult humans [19]. These inflammatory byproducts are currently under investigation for their effects on animal health and are the reasons to advocate for minimally processed and fresh food diets in patients with conditions such as cancer.

For additional information regarding the byproducts of commercial pet food processing, specifically those related to Malliard Reaction products and AGEs, please refer to Chapter 12 in Section V (Integrative Nutrition) of this textbook [20–22].

Dietary Modification for Cancer Patients

As each veterinary patient has their unique metabolic requirements and nutritional needs, feeding recommendations for every oncologic patient should be tailored and individualized. Using a foundational recommendation of high protein, low carbohydrate, supplemented with omega-3 fatty acids and as minimally processed as the owner can provide should serve as a basis that can be modified for the specific needs of each patient.

Vitamin D3

Vitamin D3 (cholecalciferol) has been examined for its benefits as a preventive agent and as a treatment for many types of cancer. In animal models, dietary vitamin D3 demonstrates chemo-preventative effects against breast cancer equivalent to those elicited by calcitriol without causing hypercalcemia [23]. The anticancer effect of vitamin D3 is thought to be due to induction of cell differentiation and antiproliferation. A positive feedback signaling loop between the serine-protein kinase ATM (ataxia telangiectasia mutated) and the VDR (vitamin D receptor) was identified as critical for cancer chemoprevention by vitamin D3.

In a 2016 veterinary study, low serum vitamin D3 levels were shown to be associated with an increased risk of developing cancer in canine patients [24]. The optimal serum vitamin D3 level was determined to be 100–120 ng/mL based on iPTH and c-CRP variations plateauing at this level. In the author’s practice, serum vitamin D3 levels are routinely monitored and supplementation with oral vitamin D3 initiated with a target serum range of 100–120 ng/mL, although higher serum concentrations have been maintained in individual patients with no accompanying hypercalcemia to date. In a recent study, oral vitamin D3 supplementation at five times the recommended allowance (2–3 ug/kg) was not effective for rapidly raising serum 25(OH)D concentrations in healthy, adult dogs, although supplementation was well tolerated and caused no toxicity [25]. A current clinical trial is underway investigating oral vitamin D3 supplementation as part of a multi-herb treatment regimen for dogs with hemangiosarcoma [26].

Omega-3 Fatty Acids

Preliminary findings suggest fish oil supplementation increases chemotherapy efficacy, improves survival, and helps to maintain weight and muscle mass in patients with various cancers [27, 28]. An EPA-enriched oral supplement improved tolerability of chemotherapy in patients with advanced colorectal cancer and when combined with chemotherapy, fish oil supplementation may delay tumor progression in patients with colorectal cancer [29]. Omega-3 fatty acids are thought to have anticoagulant effects at doses greater than three grams in humans, however, results from clinical studies are mixed [30, 31]. In a study of 32 dogs with lymphoma fed kibble-based diets supplemented with omega-3 fatty acids and arginine, an increase in disease free interval and survival time was noted to be longer than those in the control group [32]. The amount of EPA in the fish oil diet (on a DM basis) was 29 g/kg of diet (13.2 g/lb of diet), and that of DHA was 24 g/kg of diet (10.9 g/ lb of diet) [32].

The Antioxidant Debate

Use of antioxidants during conventional cancer treatment is among the most controversial areas in integrative oncology. Agents including anthracyclines, platinum compounds, alkylating agents and radiation therapy exert their anticancer effects through the generation of free radicals or reactive oxygen species. The theoretical concern exists that antioxidants may render these treatments less effective. A secondary hypothesis also exists that antioxidants may improve efficacy of chemo/radiation therapy by increasing tumor response and decreasing toxicity to normal cells. This is supported by evidence that chemo/radiation therapy can reduce levels of normal tissue antioxidants. Systematic reviews on antioxidant use with chemo/radiation therapy in humans have shown similar mixed conclusions. Heterogenous patient populations, variations in administration/dosages/genetic coding, as well as patient antioxidant status are hurdles to a consensus in the available literature regarding safety [33–35].

In a review article evaluating 33 published papers and 2,446 human patients, various antioxidants were evaluated to determine their effect on chemotherapeutic toxicity. The majority (73%) of studies reported evidence of decreased toxicities, nine (27%) reported no difference in toxicities between the two groups, and five (15%) reported the antioxidant group completed more full doses of chemotherapy or had less-dose reduction than control groups. With the exception of one, all of the antioxidant supplemented groups, reported tumor responses that were the same or better than the control. One study (3%), however, reported increased toxicity (myelosuppression) in the antioxidant (vitamin A) group versus control; although controls had a significantly increased risk of disease progression and death compared to the vitamin A group [35]. Additional systematic reviews and meta-analyses have reported similar results [33, 36].

Routine examples of current use of pharmaceutical and nutraceutical antioxidants alongside chemotherapy should also be noted. Mesna, a chemotherapy adjuvant, is used alongside cyclophosphamide and ifosfamide to prevent sterile hemorrhagic cystitis and hematuria through its free radical scavenging activity. Dexrazoxane, used for its cardioprotective effects against doxorubicin or as an antidote when extravascular injection has occurred, minimizes cardiac damage and tissue necrosis via free radical scavenging and antioxidant activity. Denamarin®, a nutraceutical shown to delay hepatotoxicity with lomustine administration, minimizes hepatotoxicity through prevention of glutathione depletion [37]. These agents are used routinely as antioxidants, showing similar results to those reported in larger studies of lessened toxicities from conventional treatments without concern for negative implications to conventional therapies. It should also be noted that not all chemotherapy agents work via the creation of free radicals. Common classes of antineoplastic agents and degree of dependence on formation of free radicals for anticancer activity is detailed in Table 22.1.

The use of the single high dose antioxidant beta-carotene may be an exception, including supplementation alongside radiation therapy. In a report on 540 head and neck cancer patients undergoing radiation therapy, patients were randomly assigned into two arms, one receiving supplementation with α-tocopherol (400 IU/d) and β-carotene (30 mg/d) while the second arm was receiving placebo. Patients were administered these supplements throughout radiation and for three years thereafter. Patients in the treatment group reported significantly less side effects, however, rate of local recurrence was significantly higher in the supplement arm (hazard ratio, 1.37; 95% CI, 0.93 to 2.02) [38]. In a meta-analysis of twelve trials evaluating effects of antioxidant supplementation on primary cancer incidence and mortality, beta carotene supplementation was also found to increase cancer incidence and cancer mortality among smokers [39]. Additional trials evaluating the use of antioxidants concurrently with radiation therapy have not found similar concerning results with other antioxidants. Agents such as selenium, vitamin E and vitamin C have demonstrated anticarcinogenic effects, regression of radiation induced fibrosis, and protection against radiation induced proctitis [39–41].

Herbal Formulas

Among the 520 new drugs approved in the United States between 1983 and 1994, 157 were derived from natural products; accounting for more than 60% of antibacterial and anticancer drugs developed (Table 22.2) [34].

The use of combinations of medicinal herbs according to traditional practices (e.g. Traditional Chinese Medicine (TCM), Ayurvedic Medicine, Western Herbal Medicine) are commonly used in the treatment of patients with cancer, both human and animal. Herbal medicines are chosen for various reasons with multiple goals in mind, alongside conventional therapy, or when declined or when no longer an option. Each herb and botanical agent have tens to thousands of active constituents, which increase exponentially when combined with other herbs into commonly used formulas, allowing the targets and goals of therapy to be multifactorial. Addressing cancer-related clinical signs, adverse treatment side effects, modulating pain/inflammation/immune function, mitigating or reversing multidrug resistance, and improving quality of life are a few of the many possible goals when using herbal formulas for cancer patients.

Medicinal herbs commonly used in the treatment of cancer are comprised of various chemical constituents. Some of the many categories include: alkaloids (e.g. berberine, matrine, colchicine), flavonoids (e.g. baicalein, wogonin, luteolin, apigenin, tectorigenin), terpenoids (e.g. oridonin, ursolic acid, oleanolic acid, artemisinin, saikogenin), anthraquinones, polyphenols, organic acids (e.g. ursolic acid, oleanolic acid), polysaccharides, and saponins (e.g. saikosaponin, pulsatilla saponins). Studies indicate that the active compounds from these herbs regulate a wide range of signaling pathways, kinase activity and gene expression, which are involved in cell proliferation, cell cycle arrest, apoptosis, invasion, and metastasis as well as modulation of tumor microenvironments [42, 43].

As cancer is a complex systemic disease, effective herbal approaches must not be directed to the Western/conventional diagnosis, but rather to the patient and their specific presentation, clinical signs, and needs. A tailored, personalized approach addressing underlying/chronic medical issues, as well as pattern imbalances and root causes taught in traditional schools of herbal medicine will create the most effective herbal plan.

Turmeric

Turmeric (Curcuma longa) is a rhizomatous plant in the ginger family that is native to South Asia but is cultivated in tropical areas around the world. The rhizome is used as a spice in regional cuisines, and as a coloring agent in food and cosmetics. It has long been used in traditional medicine for improving circulation and digestion. Turmeric extracts are widely marketed as dietary supplements to improve arthritis, memory, and cancer prevention, among others.

Turmeric, as well as its most well-studied polyphenol extract, curcumin, have powerful antioxidant, anti-inflammatory, and antitumor activity, documented to inhibit more than seventy oncogenes. Curcumin has been shown to inhibit transformation, proliferation, invasion, angiogenesis, and metastasis of tumors. It also downregulates many abnormal cell signaling proteins used by cancer cells to become more virulent and spread. More than 100 proteins, enzymes and receptors, including NF-Kβ, VEGF, TNF-α, COX-2, IL-1, 6, and 8, STAT 3 and 5, and 5-LOX have been found to be switched off by curcumin [44]. It inhibits gastric and bowel cancers [44–47] and is used as part of most cancer protocols. Curcumin, used as a single constituent extract, carries a risk of interference with cytochrome P450 enzymes and therefore chemotherapy drugs such as alkylating agents, doxorubicin and toceranib phosphate (Palladia®), as well as those that can enhance bleeding tendencies or gastrointestinal toxicity should be cautioned in combination. Further investigation is required to determine the optimal dosing strategies to achieve desired effects. Suggested dosing varies on formulation and intended use and are listed below in Box 22.1. Currently, there are no clinical trials or published research investigating the use of turmeric or curcumin in veterinary cancer patients.

Milk Thistle

Milk thistle (Silybum marianum) is a plant originally native to Southern Europe and Asia, but now found throughout the world. Silymarin, which is derived from the milk thistle plant, is primarily used to manage liver disease, but additional studies suggest antioxidant and anticancer effects. Found in veterinary products such as Denamarin and Denosyl (Nutramax Laboratorites), this synthetic formulation has been shown to delay onset of chemotherapy-induced hepatotoxicity in patients receiving lomustine chemotherapy [37].

Silibinin, a flavonoid isolated from milk thistle, demonstrated antioxidant and anti-inflammatory effects by inhibiting release of hydrogen peroxide and production of tumor necrosis factor alpha [49]. Other studies indicate the flavonoids in milk thistle exert anticancer effects by arresting G1 and S phases of the cell cycle [50]. Generally well tolerated and considered safe in combination with most medications, there are limited concerns for combination with chemo-radiation therapy.

Cannabis

The Cannabis sativa plant has been used in herbal remedies for centuries. Over 480 biologically active components have been identified in cannabis, with the two best-studied being delta-9-tetrahydrocannabinol (often referred to as THC), and cannabidiol (CBD). Various other cannabinoids are being studied for their medicinal and therapeutic effects.

At the time of publication, the US Drug Enforcement Administration (DEA) lists cannabis and its cannabinoids as Schedule I controlled substances, meaning they cannot legally be prescribed, possessed, or sold under federal law. The use of cannabis to treat some medical conditions is legal under state laws in many jurisdictions for licensed physicians, however, veterinarians are not included in these regulations. Dronabinol, a synthetic form of THC, is approved by the FDA for cancer treatment-related conditions such as nausea. Recently, the FDA has approved Epidiolex, which contains a purified form of CBD for the treatment of seizures associated with Lennox-Gastaut syndrome, Dravet syndrome or tuberous sclerosis in humans one year of age and older [51]. There are currently no FDA approved cannabis products for veterinary patients.

Studies from the 1970s discovered that dogs have the highest number of THC receptors in the brain, even more so than humans. For this reason, human dosing strategies should not be extrapolated to canine patients and considered safe. Although considered to have a high margin of safety, with no human deaths ever recorded, deaths in dogs have been seen after ingestion of food products containing concentrated medical-grade THC butter. The minimum lethal oral dose for dogs for THC is more than 3 g/kg [52]. Hemp-based CBD extracts have been found to be effective in treating refractory epilepsy and osteoarthritis in dogs [53–55]. Varying dosing strategies have been reported ranging from 2 mg/kg BID to 20–50 mg per day [53–56]. In vivo trials have proven efficacy of CBD in inducing apoptosis in various canine neoplastic cell lines. [57] CBD is a potent competitive inhibitor of cytochrome p450, even more so than Bergapten found in grapefruit juice, and therefore should be cautioned when used alongside medications that are metabolized by these same pathways such as chemotherapy and antiepileptic agents. [58, 59] A study evaluating the safety and efficacy of CBD oil use during chemotherapy in dogs with lymphoma is currently underway [60]. For additional information regarding use of cannabis in the veterinary patient as well as rapidly changing regulations in this growing field, visit https://veterinarycannabissociety.org.

Medicinal Mushrooms

Various medicinal mushroom species have been researched and utilized for their cancer prevention and treatment properties for centuries. More than 100 species of medicinal mushrooms are used in Asia routinely, including Ganoderma lucidum (Reishi), Trametes versicolor or Coriolus versicolor (Turkey Tail), Lentinus edodes (Shiitake), and Grifola frondosa (Maitake). Studies have examined the effects of mushrooms on immune response pathways and on direct antitumor mechanisms. Innate immune effects are believed to be mediated primarily by the presence of high-molecular-weight polysaccharides, known as beta-glucans, although other constituents may be involved [61]. Beta-glucans have been found to stimulate monocytes, natural killer cells, and dendritic cells, leading to their reported benefits in immune system response, improved quality of life, increased survival, increased apoptosis and reduction in side effects of conventional treatment [62, 63].

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