Pharmacological Intervention

6. Pharmacological Intervention

In addition to treating the underlying malignancy with surgery, radiation therapy, chemotherapy or a combination of these modalities, additional medications may be indicated and necessary to reverse weight loss and improve quality of life. In order to choose the most effective drugs and provide the optimal care for the individual patient it is important to determine the cause for the inadequate food intake and weight loss.

Causes of Dysorexia and Anorexia

Anorexia is the failure of the usual appetite signals and can be a direct or indirect effect of the cancer itself or the cancer treatment, specifically chemotherapy. Decreased or loss of appetite may be a direct result of abdominal pain or discomfort, and early satiety due to restricted gastric accommodation or delayed emptying secondary to tumor infiltrate. Primary intestinal tumors may lead to complete or incomplete obstruction, ileus, malabsorption, diarrhea or constipation which again can lead to discomfort, bloating, anorexia or nausea (Uomo et al., 2006).

Chemotherapy may contribute to further decreasing appetite by its effects on the vomiting center as well as the effect on the gastrointestinal tract. Certain chemotherapeutic drugs such as vincristine can cause ileus and constipation, which again may feed into the cycle of anorexia and depression (Ogilvie et al., 2001). The direct cytotoxic effects on the intestinal epithelial lining may lead to sloughing and make possible bacterial translocation and secondary intestinal bacterial overgrowth.

Chemotherapy induced gastroenteritis can induce nausea, vomiting and diarrhea. The risk for sepsis is especially important if the patient experiences concurrent myelosuppression. If there is a potential for sepsis, broad-spectrum antibiotics with good gram positive and gram negative coverage are indicated in these patients.

Analgesia

Pain and discomfort may contribute to anorexia and weight loss. It is often difficult to determine whether veterinary patients are in pain, especially visceral pain. Visceral pain is commonly reported in human cancer patients with abdominal organ cancer, especially pancreatic cancer. Cancer cachexia is more common in pancreatic cancer than in any other cancer type and up to 80% of the patients are reported to be cachetic (Splinter, 1992; Ryan et al., 1998). Pain medications are routinely provided to palliate these patients (Li et al., 2004).

It is feasible that cats with alimentary lymphoma experience some degree of discomfort or pain, however, the effectiveness of pain medications in improving appetite and reversing the cycle of weight loss in these patients has not been evaluated, and pain medications may not be routinely prescribed. Pain is easier to recognize and therefore more likely to be treated in cats with visible non-resectable solid tumors that invade or destroy bone or that compress nerves. Palliative care with the focus of treating the cancer pain with oral or parenteral pain medication and/or palliative radiation therapy is routinely offered to cats with oral squamous cell carcinoma or osteosarcomas. It is the authors’ subjective impression that some of these cats improve and increase their voluntary food intake with such measures. However, there are no studies to confirm these observations.

Anti-inflammatory Drugs

The systemic effects of cancer and metabolic changes associated with cancer cachexia syndrome are mediated by a complex network of pro-inflammatory cytokines (Jatoi et al., 2001; Walker, 2001). Anti-inflammatory drugs may therefore have a role in reversing some of these effects. Nonsteroidal anti-inflammatory drugs (NSAIDs) include several different drugs with anti-cycloxogenase activity. These drugs have both analgesic and well as anti-inflammatory effects, and may therefore provide dual benefits to patients suffering from a painful non-resectable tumor and/or the systemic inflammatory effects of the tumor and cancer cachexia syndrome. In addition, the effects against cycloxogenase-2 may have direct anti-cancer effects, especially in tumors overexpressing this enzyme. The direct anti-cancer affects of NSAIDs have been reported only in dogs at this point (Schmidt et al., 2001; Knapp et al., 2002; Mustaers et al., 2003; Mohammed et al., 2004; Mustaers et al., 2005). NSAIDs have been reported to improve some of the symptoms associated with cancer cachexia syndrome and improve quality of life in human pancreatic and other gastrointestinal cancer patients (Wigmore et al., 1995; McMillian et al., 1997; McMillian et al., 1999).

Appetite Stimulating Drugs

The use of appetite stimulating drugs and anti-depressants may also be indicated in some patients. It can be very difficult and often impossible to distinguish between anorexia resulting from nausea and anorexia as part of the cancer cachexia syndrome. Therefore anti-emetics should always be considered first or in conjunction with drugs to stimulate appetite. Administering appetite stimulating drugs without providing effective anti-emetics may worsen nausea and cause more vomiting with the potential of creating a learned food aversion. It is also important to rule out and treat any physical causes of nausea, vomiting and subsequent anorexia such as gastrointestinal tumors, intestinal obstruction or chemotherapy-induced gastroenteritis prior to prescribing appetite stimulating drugs.

Megestrol acetate is effective in feline cancer patients and used to improve appetite and promote weight gain. (© Yves Lanceau/RC/Norwegian Forest Cat).

Megestrol acetate is the most effective and commonly prescribed drug to combat weight loss and cachexia in human oncology. A large meta-analysis found that cancer patients receiving megestrol acetate were significantly more likely to gain or maintain weight than those who did not receive the drug (Berenstein et al., 2005). The exact mechanism of action of megestrol acetate is complex and thought to involve stimulation of appetite by both direct and indirect pathways as well as antagonism of the metabolic effects on the principal catabolic cytokines (Uomo et al., 2006). Megestrol acetate is also effective in feline cancer patients and used to improve appetite and promote weight gain.

However, corticosteroids are used more commonly in the USA, especially in feline lymphoma. Corticosteroids are part of the chemotherapy protocol for lymphoma and used for their cytotoxic effects, however, corticosteroids have additional benefits including appetite stimulation and anti-inflammatory effects which might be beneficial in combating the cancer cachexia syndrome.

Cyproheptadine, an anti-serotonergic, is another appetite stimulant used relatively frequently in cats and still favored by many veterinarians despite the fact that prospective trials in human cancer patients found no improvement in nutritional status in patients receiving cyproheptadine versus placebo (Kardinal et al., 1990).

Appetite stimulating drugs are often used in conjunction with other palliative measures in cats. Some seem to benefit from these measures, but it may be impossible to determine which of the palliative drugs is indeed effective in patients where many different strategies to improve appetite are instituted simultaneously; the improvement may in fact be a result of synergistic or complimentary additive effects of a combination of drugs. A combination of drugs or a multimodality approach may indeed be necessary to maintain weight or reverse weight loss.

Nevertheless, it is important to assess all of the above potential contributing factors, i.e., tumor stage and direct gastrointestinal involvement, presence of nausea, pain or discomfort, chemotherapy induced gastroenteritis, or the presence of the cancer cachexia syndrome, so that the most appropriate drugs or drug combinations are administered. There may be a practical limitation to how many different oral medications a cat will tolerate, and forceful administration of excessive unnecessary medications may make the situation worse. Table 6 and Table 7 include drugs with recommended dosages used to decrease nausea, stimulate appetite, improve nutritional status and combat weight loss in cats with cancer.

Conclusion

The primary goals of cancer therapy are to prolong life and maintain a good quality of life. Ensuring adequate nutrition is a requirement for both goals to be fulfilled. Human cancer studies have found that cachectic patients have a worse outcome, more complications and a lower response to therapy. The situation is likely similar in cats, as illustrated by one recently published investigation, where:
- remission was positively correlated with a higher BCS
- cats with solid tumors and lymphoma that had an underweight body condition had significantly shorter survival times than cats with a higher BCS (Baez et al., 2007).

Weight loss and the associated reduced quality of life may not only have a negative impact on treatment, but may also have direct consequences for survival, because it may lead to a decision to euthanize. The ability, interest, and willingness to eat voluntarily are major components of having a good quality of life. Most owners and veterinarians will likely agree that a cat that does not eat voluntarily or adequately over long periods of time may not feel well and may be suffering.

Therefore, providing effective nutritional support and offering the appropriate palliative medications to decrease nausea, improve appetite and facilitate voluntary food intake become crucial for prolonging survival. On our service we have found that the majority of cats with lymphoma lose weight in the induction phase of chemotherapy (Bachman et al., 2000). A significant proportion of cats with lymphoma die or are euthanized within the first months of starting chemotherapy. These facts suggest that more focus should be directed towards ensuring adequate nutrition and preventing weight loss in these patients. Early nutritional intervention may not only improve quality of life in cats with cancer but may also have positive impact on survival.