Nutritional Considerations for Cancer and Cachexia

3. Nutritional Considerations for Cancer and Cachexia

Energy Sources

Carbohydrate is often the most abundant energy source found in companion animal diets, particularly dry type canine diets. Since neoplastic tissue thrives on glucose as its primary energy substrate, the strategy is to force the neoplasia to use other substrates which may help in decreasing cell proliferation. During cachexia it may be important to provide extra dietary protein to help attenuate the cachectic process. Therefore, choosing a diet high in fat and protein with low carbohydrate may be helpful. Many premium dry and canned products, in particular specialty foods for active or stressed canines, may be used. Most of these products contain higher quality and quantities of protein and fat as compared to adult maintenance diets.

When changing commercial food, the guaranteed analysis for protein and fat content must be examined. Good guidelines are at least 35% protein and at least 25% fat on a dry matter basis for dogs. The guaranteed analysis can be used to estimate what percentage of protein, fat and carbohydrate are in the chosen food but it should be converted to a dry matter basis (Table 3). Canned foods are often around 70 - 75% water, therefore the "as fed" percentages of protein and fat listed in the guaranteed analysis are much lower than in dry foods, but when examined for protein, fat and caloric content based on dry matter, they can actually be better than extruded products.

Contraindications for feeding such a diet include dogs and cats with congenital or acquired hypertriglyceridemia, a history of pancreatitis, or chronic renal disease.

Amino Acids and Fatty Acids

It has been well documented that dietary amino acid alterations may be beneficial as an intervention to retard tumor growth in animal models (Mills et al., 1998; Epner et al., 2002). Further developments in this area will likely lead to a better understanding of how manipulating amino acid metabolism can retard tumor progression and aid in quality of life and survival time of the patient with neoplasia.

Increased dietary arginine has been shown to slow tumor progression in a number of animal models (Burns et al., 1984; Milner et al., 1979; Robinson et al., 1999). This effect may be either due to the ability of arginine to form nitric oxide through NO synthase activity in neoplastic cells leading to retarded cell division, and/or its ability to increase cellular immune surveillance properties (Reynolds et al., 1990; Robinson et al., 1999). The exact mechanism has yet to be elucidated, but providing up to 2% of dietary proteins as arginine may be beneficial to the canine cancer patient (Olgivie et al., 2000) (Figure 4).

Figure 4. The potential role of arginine in cancer. Supplementing the arginine concentration in the diet to at least 2% of the amino acids may prove beneficial in dogs with cancer (Olgivie et al., 2000).

Glutamine may also have suppressive effects on tumorigenesis. Glutamine appears to have a profound immuno-stimulatory role, which leads to greater whole body immunomodulation, and this immunomodulatory function may reduce tumor or metastasis growth rates (Souba, 1993; Kaufmann et al., 2003). Glutamine has also been shown to improve gastrointestinal function and may be considered as a potential GI nutrient to optimize enterocyte function (Souba, 1993). However, glutamine in foods appears to be very labile, particularly if they are exposed to excessive temperatures or in liquid format. After absorption, glutamine is rapidly transaminated by the liver, therefore its efficacy in pet foods for long term clinical cases of neoplasia is uncertain (Bergana et al., 2000). Branched Chain Amino Acids (BCAA - isoleucine, leucine, valine) are increasingly used as a supplement in critically ill patients due to the potential benefits cited in human literature. The use of BCAA's as anti-tumorigenic amino acids has been debated (Danner & Priest, 1983; Blomgren et al., 1986; Saito et al., 2001), but it is likely that dietary supplementation with certain BCAA's (leucine) may be beneficial in conjunction with other amino acids like arginine in retarding tumor growth (Wakshlag et al., 2004).

Interestingly, recent literature has demonstrated the beneficial effects of BCAAs for their anti-proteolytic effects during cachexia by increasing lean body mass and preventing excessive lean body wasting in cancer patients. Leucine, as a single amino acid supplement, has been shown to have profound effects of increasing protein synthesis in skeletal muscle when compared to dietary increases of other amino acids, shifting the balance towards anabolism rather than catabolism (Kadawaki & Kanazawa, 2003; Anthony et al., 2001) (Figure 5).

Figure 5. Proposed actions of leucine on skeletal muscle protein synthesis (Anthony et al., 2001; Kadawaki & Kanazawa, 2003).

Recent clinical studies in humans have revealed increased survival times, improved nitrogen balance, and increased quality of life when diets supplemented with up to 12 grams of BCAAs were fed daily (Ventrucci et al., 2001; Hiroshige et al., 2001; Inui, 2002; Gomes-Marcondes et al., 2003). Though there is no literature in veterinary medicine to support the use of BCAA's, experimental diets with up to 5% of dry matter as BCAAs or the addition of 3% leucine have been used without adverse effects in rodent models. Therefore a safe non-toxic dose for veterinary patients may be approximately 100 - 200 mg/kg.

Fatty Acids

Increased intake of omega-3 fatty acids has shown strong correlation with remission and survival times, and decreased growth rate of carcinomas in animal models (Thomson et al., 1996; Olgivie et al., 2000; Togni et al., 2003). In addition, human clinical studies have shown positive effects of omega 3 fatty acids supplementation on body weight, quality of life, disease free intervals and survival times in cancer cachexia patients. These changes may also be true for canine cancer patients (Olgivie et al., 2000; Wigmore et al., 2000; Barber et al., 2001; Fearon et al., 2003) (Figure 6).

Figure 6. Proposed actions of omega 3 versus 6 fatty acids on skeletal muscle degradation. Omega-3 fatty acidsupplementation, in particular eicosapentaenoic acid (EPA), has been shown to decrease 15-hydroxytetraenoic acid (15-HETES) concentration thereby suppressing proteolytic activity (i.e. proteasome activity) in skeletal muscle in a model of cancer cachexia (Belezario et al., 1991; Smith et al., 1999).

EPA and DHA can have a profound negative effect on cachexia. Furthermore, they may also attenuate tumor growth through their ability to decrease arachidonic acid metabolism by preventing the promitogenic production of PGE2 in neoplastic cells (Yuri et al., 2003) (Figure 7). Fish oils (e.g., Menhaden oil) are the richest source of the omega-3 fatty acids EPA and DHA (Table 4) and have been shown to be useful in ameliorating cachexia in human clinical trials (Wigmore et al., 2000; Fearon et al., 2003). Some "premium" dog foods are supplemented with omega 3 fatty acids to achieve a 10:1 - 5:1 ratio of omega 6 to omega 3 fatty acids. The addition of fish oil can significantly alter the omega 6 to 3 ratio beyond what is already found in most pet foods (Olgivie et al., 2000). Though not detrimental to most patients, ratios lower than 1:1 have been associated with increased clotting times and decreased vitamin E concentrations within cellular membranes (Valk et al., 2000; Hendriks et al., 2002).

Figure 7. Proposed actions of omega 3 versus 6 fatty acids on tumor cell proliferation. EPA slows tumor growth by decreasing the production of promitogenic agents from arachidonic acid.

Only one canine clinical study has been performed with the use of fish oil at a ratio of 0.3:1 and the results showed increased survival times and disease free intervals in dogs with lymphoma, with no discernable side effects (Olgivie et al., 2000). The clinical evaluation of fish oil supplementation in multiple other neoplastic conditions is presently underway and unpublished data suggest that fish oil may be promising for the management of several neoplastic conditions.

Vitamins and Minerals

Supplemental feeding of common dietary antioxidants such as β-carotene, retinoids and vitamins C and E have all been associated with decreased risk of carcinogenesis in animal models and in epidemiological cohort studies. Selenium is the only mineral with similar anti-carcinogenic effects. The standing hypothesis is that many of these compounds, except for retinoids, act primarily as antioxidants to decrease cell damage (Figure 8), in particular DNA damage, thus lowering the incidences of functional mutations in DNA resulting in lower incidences of cancer.

Figure 8. Antioxidants. Antioxidants help the organism combat the destructive effects of free radicals, which are unstable elements continuously produced by the organism. The role of antioxidants constitutes one of the dominant themes in current medical research, particularly in the prevention or treatment of certain cancers.

Many of these vitamins and minerals are present in adequate concentrations in most dog feeds, and their usefulness in neoplasia once already diagnosed, are largely undetermined. There are multiple human epidemiologic longevity and relative risk studies in progress, using many of these potential anti-carcinogenic agents. However, to date the indiscriminate use of these antioxidants as supplements cannot be supported in veterinary medicine because of the very different dietary patterns and metabolism of these substances in veterinary as compared to human patients.

β-Carotene, and other natural carotenoids and polyphenol compounds have been linked to cancer prevention through their ability to scavenge free radicals within cells in vitro (Duthie et al., 2003; Cooper, 2004). β-carotene has been one of the most widely studied antioxidants in cancer prevention due to its potent antioxidant capabilities. Studies in humans predisposed to neoplasia (lung cancer) have shown that β-carotene supplementation may actually increase the relative risk of neoplasia (Bendich, 2004; Russell, 2004). Considering these recent findings supplemental β-carotene in human medicine has evolved into a cautionary tale of micro-nutrient supplementation.

Sources of carotenoids, (β-carotene, lutein, lycopene, xanthene), generally found in red, green, yellow and orange colored fruits and vegetables, are receiving significant attention because of their beneficial effects in specific cancers (Wu et al., 2004; Murtaugh et al., 2004). However, their benefit in companion animals is confounded by the fact that carotenoids are absorbed differently in dogs than in humans. Dogs have a far better capacity to cleave β-carotene into retinal than humans, and absorb very little intact β-carotene (Baskin et al., 2000). In light of these findings safety and efficacy data is needed in veterinary medicine before recommendations can be made for supplementing cancer patients with these potentially beneficial antioxidants.

Vitamins C and E are both potent antioxidants which have been shown in human clinical trials to reduce the risk of carcinogenesis (Henson et al., 1991; Sung et al., 2003; Virtamo et al., 2003). Much like β-carotene, these antioxidants have been proven to be preventative rather than therapeutic. Vitamin C (ascorbic acid) has been associated with augmenting the effects of certain chemotherapeutic agents such as vincristine (Osmak et al., 1997). While ascorbic acid supplements may help in some cases of drug resistant chemotherapy, it has also been argued that their use may have tumor promoting effects for some neoplasias, and anti-neoplastic activities for others (Seifried et al., 2003; Lee et al., 2003). No controlled studies have been performed to assess its efficacy in the veterinary patient. Ascorbic acid is synthesized in the dog therefore the relative risk of neoplasia due to deficiency over the lifetime of the animal is not an known. Vitamin E, on the other hand, is required in the diet and further investigation into its efficacy as an anti-neoplastic agent is warranted.

Retinoids (Retinoic acid and retinoic acid derivatives) have been extensively used in the treatment of acute promyelocytic leukemias, and have been associated with increased remission rates in human mammary cancer (Paik et al., 2003; Altucci et al., 2004). They attach to nuclear receptors initiating transcription of genes, promoting cellular differentiation or apoptosis of neoplastic cells. These findings have lead to the use of natural and synthetic retinoid derivatives in the treatment of human cancer. In time such approaches may cross over to veterinary medicine as experimental clinical data is collected regarding efficacy of these retinoids in various neoplastic conditions in animals. Considering the highly potent effects of retinoids, such as retinoic acid which is a known teratogen, and due to toxic effects, e.g., cervical spondylosis in cats, as well as anorexia and clotting disorders, recommendations cannot be made at this time for their use in the small animal cancer therapy (Hayes, 1982).

Selenium is the only mineral known to have anti-tumorigenic and preventative properties. There is conclusive evidence that higher serum selenium concentrations are associated with lower incidences of skin, lung and prostate carcinomas in humans (Duffield-Lillico et al., 2003; Reid et al., 2002; Nelson et al., 1999; Clark et al., 1996). These actions are thought to be separate from the antioxidant properties of selenium via its role in glutathione peroxidase.

The AAFCO dog food nutrient profile recommended concentration of selenium is met in most commercial pet foods, but the NRCrecommendation has recently tripled, therefore the selenium intake of many companion animals may be low normal or deficient. In light of this, and the human clinical studies showing that selenium supplementation has the greatest effects in reducing the relative risk of cancer in those people with low normal serum selenium concentrations (Clark et al., 1996; Nelson et al., 1999; Reid et al., 2002; Duffield-Lillico et al., 2003), it may be wise to supplement (2 - 4 µg/kg BW/day) animals with a history of neoplasia or a predisposition to develop cancer. At this conservative recommended dose the risks for toxicity are minimal and such supplementation will likely ensure adequate seleniumintake.

Overall, when using specific nutrients pharmacologically one may be able to retard tumor growth, enhance quality of life and ameliorate body condition to a certain extent. Yet, it can be difficult to address the specific needs for each neoplastic condition due to the complex nature of cancer, and the various nutrient compositions of the variety of feeds that are available. To properly address these nutritional issues, the practitioner needs to know the food consumption and the dry matter content of various nutrients in the given feed, before an effort to alter ratios or total intake of many of the aforementioned nutrients can be made. Table 5 provides some guidelines for nutritional intervention that should be beneficial in most aggressive neoplastic conditions and can be used once the practitioner has calculated contents of various nutrients in the given food.