At a glance......
- 1 Causes of Anorexia-Cachexia Syndrome
- 2 Symptom of Anorexia-Cachexia Syndrome
- 3 Diagnostic Criteria of Anorexia-Cachexia Syndrome
- 4 Treatment of Anorexia-Cachexia Syndrome
- 4.1 Hypercaloric Feeding
- 4.2 Glucocorticoids
- 4.3 Progestational Drugs
- 4.4 Cyproheptadine and Other Antiserotonergic Drugs
- 4.5 Branched-chain Amino Acids
- 4.6 Prokinetic Agents
- 4.7 Eicosapentaenoic Acid
- 4.8 Cannabinoids
- 4.9 5′-Deoxy-5-Fluorouridine
- 4.10 Emerging Drugs
- 4.11 Others
- 4.12 Nutritional, Psychological, and Behavioral Therapies
- 4.13 References
- 4.14 People Also Reading
Anorexia-Cachexia Syndrome is a common clinical problem characterized by loss of appetite and weight loss or complex metabolic syndrome of involuntary weight loss associated with cancer and some other palliative conditions a consensus definition of cachexia related to either cancer or chronic disease has been proposed, namely: weight loss with or without fat loss, and additional criteria
Causes of Anorexia-Cachexia Syndrome
Although the etiology of cachexia is not well defined, several hypotheses have been explored including cytokines, circulating hormones, neuropeptides, neurotransmitters, and tumor-derived factors. An emerging view is that the anorexia-cachexia syndrome is caused predominantly by cytokines either produced by cancer or released by the immune system as a response to the presence of cancer, as well as other tumor products that induce profound lipolysis or protein degradation
Symptom of Anorexia-Cachexia Syndrome
- Cancer or chronic disease has been proposed, namely
- Weight loss with or without fat loss,
- Loss of adipose tissue and skeletal muscle mass.
- Decreased muscle strength,
- Reduced muscle mass,
- A cough
- Respiratory secretions.
- Biochemical alterations [anemia, inflammation, and low albumin].
- 80% of patients with upper gastrointestinal cancers
- 60% of patients with lung cancer have had substantial weight loss
- Cachexia is more common in children and elderly patients and becomes more pronounced as the disease progresses
A systematic review of the literature on cachexia suggests that there is a range of pathways involved and that the interactions between weight loss, nutritional intake and anorexia are not straightforward or predictable.
Diagnostic Criteria of Anorexia-Cachexia Syndrome
Cancer cachexia is not difficult to identify. In North Central Cancer Treatment Group research trials involving more than 2,500 patients, simple criteria for anorexia/cachexia have been used:
- A 5-lb weight loss in the preceding 2 months and/or an estimated daily caloric intake of fewer than 20 calories/kg
- A desire by the patient to increase his or her appetite and gain weight
- The physician’s opinion that weight gain would be beneficial for the patient
Recently, other investigators have attempted to provide more detailed or comprehensive definitions of cachexia. For example, Fearon and others recently suggested that weight loss of greater than 2% might also serve to define cachexia in patients already showing evidence of a low body mass index or wasting of skeletal muscle. These definitions are important in stimulating further discussion of this entity and its pathophysiology.
Interestingly, recent studies also suggest that antineoplastic agents may be contributing to some of the body composition changes observed in cachexia. Artoun and others observed that cancer patients treated with sorafenib (Nexavar) manifest notable degrees of muscle wasting over time, with an 8% decrease in lean tissue at 1 year in contrast to placebo-exposed patients.
|Initial||At 6 weeks||At 4 months||At 6 months||At 10 months||Reference and unit|
|Sodium (Na+)||151||138||139||141||138||136–145 mEq/L|
|Potassium (K+)||4.1||3.9||3.56||3.9||3.7||3.5–5.0 mEq/L|
|Leucocytes||5500||4200||8310||6700||7300||4600–10 220 cell/µL|
|Platelets||204 000||218 000||261 000||231 000||256 000||150 000–450 000/µL|
|Luteinizing hormone (LH)||<0.10||<0.10||<0.1||<0.1||<0.1||1.4–8.6 IU/mL|
|Follicle stimulating hormone (FSH)||0.20||0.3||0.14||0.1||0.2||1.5–12.4 IU/mL|
|Free T4 (FT4)||0.533||1.52||1.37||1.52||1.65||0.930–1.700 ng/dL|
|Thyrotropin (TSH)||0.051||<0.005||<0.005||<0.005||<0.005||0.270–4.200 µIU/mL|
|Growth hormone||<0.1||<0.1||0.02–1.23 ng/mL|
|Adrenocorticotropic hormone (ACTH)||3.10||1.4||2.3||7.2–63.3 pg/mL|
[i] Biochemical profile at admission and at 6 weeks and 4-, 6- and 10-month clinical follow-up. Abnormal results marked with bold.
Leptin and Body Weight Regulation of Anorexia-Cachexia Syndrome
The concept that appetite-restraining signal from adipocytes is integral components of the feedback loop between the periphery and the brain for energy homeostasis gained firm ground with the cloning of the ob gene and its encoded protein, leptin, from adipocytes. Leptin is an afferent signal from the periphery to the brain that regulates adipose tissue mass. The level of leptin is positively correlated with body fat mass, and dynamic changes in plasma leptin concentrations in either direction activate the efferent energy regulation pathways. Leptin reduces appetite and increases energy expenditure and evidently elicits these effects via the central nervous system. In the absence of leptin, such as in ob/ob mice, animals fail to restrain their food intake and become massively obese.
Treatment of Anorexia-Cachexia Syndrome
Potentially treatable factors that contribute to breathing problems should be sought and treated if appropriate. These include
- Pulmonary embolus
- Co-morbid lung diseases (eg, Chronic Obstructive Pulmonary Disease – COPD)
- Weakness and muscle wasting due to cachexia-anorexia syndrome
- Pleural effusion
- Pericardial effusion or tamponade
- Ascites or raised intra-abdominal pressure
- Lung toxicity of chemotherapy or radiotherapy
- De-conditioning / reduced physical fitness
- Panic attack
- Need for aids, equipment, increased home support, or modification of daily activities to minimize breathlessness.
Treatment all over
The best way to treat cancer cachexia is to cure cancer, but unfortunately, this remains an infrequent achievement among adults with advanced solid tumors. Therefore, the next therapeutic option is to increase nutritional intake and to inhibit muscle and fat wasting by manipulating the metabolic milieu outlined above with a variety of pharmacological agents.
It is essential to identify causes of reduced food intake, such as nausea and vomiting directly related to treatment, oral mucositis, and gastrointestinal obstruction, as well as to utilize appropriate palliative interventions for relieving these conditions.
A detailed discussion of these issues is beyond the scope of this article but should be considered before choosing the treatment suited to the patient. Treatment should be directed at improving the quality of life, and for many patients, this means improving appetite and food intake.
It was hoped that enteral or parenteral nutritional support would circumvent cancer anorexia and alleviate malnutrition. However, the inability of hypercaloric feeding to increase lean mass, especially skeletal muscle mass, has been repeatedly shown.
The place of aggressive nutritional management in malignant disease also remains ill-defined and most systematic prospective studies that have evaluated total parenteral nutrition combined with chemotherapy or radiotherapy have been disappointing.No significant survival benefit and no significant decrease in chemotherapy-induced toxicity have been demonstrated. Indeed, an increase in infections and mechanical complications has been reported.
However, parenteral nutrition may facilitate administration of complete chemoradiation therapy doses for esophageal cancer and may have beneficial effects in certain patients with decreased food intake because of mechanical obstruction of the gastrointestinal tract. Home parenteral nutrition can also be rewarding for such patients. If the gut can be used for nutritional support, enteral nutrition has the advantage of maintaining the gut mucosal barrier and immunologic function, as well as the advantage of having low adverse side effects and low cost.
The effects of caloric intake on tumor development and growth are still being debated. A clear benefit from nutritional support may thus be limited to a specific, small subset of patients with severe malnutrition who may require surgery or may have an obstructing, but a potentially therapy-responsive tumor. A novel approach is to supplement substances such as omega-3 fatty acids that reduce IL-1 and TNF-α production and may improve the efficacy of nutritional support.
Glucocorticoids are widely used in the palliative setting for symptoms associated with cancer. There have been a number of randomized, placebo-controlled trials demonstrating the symptomatic effects of different types of corticosteroids. Most studies have shown a limited effect of up to four weeks on symptoms such as appetite, food intake, the sensation of well-being, and performance status.
Corticosteroids have been shown to have a significant antinausea effect and to improve asthenia and pain control. However, these studies have failed to show any beneficial effect on body weight. Prolonged treatment may lead to weakness, delirium, osteoporosis, and immunosuppression—all of which are commonly present in advanced cancer patients.
Prednisolone, at a dose of 5 mg three times (15 mg) daily, and dexamethasone, at 3 to 6 mg daily, has been shown to improve appetite to a greater extent than placebo. Methylprednisolone given intravenously at a dose of 125 mg daily may improve quality of life. There is no indication that anyone glucocorticoid is superior in its appetite-stimulating ability. When prescribing, it is recommended to begin with an initial one-week trial and continue treatment if there is a response. The entire daily dose may be given in the morning with breakfast or on a divided schedule after breakfast and lunch. This decreases hypothalamic-pituitary-adrenal (HPA) axis suppression and insomnia associated with use later in the day.
Prescribing an intermediate-acting glucocorticoid (prednisone, prednisolone, methylprednisolone) may cause less HPA axis suppression than a long-acting drug (dexamethasone). Peptic ulceration is a concern, particularly in patients at risk. Prophylactic histamine-2 receptor antagonists are prudent when commencing long-term glucocorticoids. The mechanism of action of glucocorticoids on appetite includes the inhibition of synthesis and/or release of proinflammatory cytokines such as TNF-α and IL-1, which decrease food intake directly or through other anorexigenic mediators, such as leptin, CRF, and serotonin. Glucocorticoids can enhance NPY levels in the hypothalamus, which appear to be responsible, at least in part, for the increased appetite and food intake. NPY-induced feeding is known to be dependent on circulating glucocorticoid levels.
Megestrol acetate 40 mg/ml(MA) and medroxyprogesterone acetate (MPA) are synthetic, orally active derivatives of the naturally occurring hormone progesterone. In several clinical trials, these compounds have been found to improve appetite, caloric intake, and nutritional status.
Megestrol has demonstrated a dose-related benefit from dosages ranging from 160 mg (40 mg orally four times daily) to 1600 mg on appetite, caloric intake, body weight gain (mainly fat), and sensation of well-being, with an optimal dosage of 800 mg daily. Increasing dosages from 160 mg of megestrol to 800 mg per day improves response to a level beyond which no further improvement occurs. It is recommended that a patient is started on the lowest dosage (160 mg/day) and the dose be titrated upwards according to the clinical response.
Quality of life measures such as the Karnovsky index may or may not be influenced by progesterone agents. Medroxyprogesterone has similarly been shown to increase appetite and food intake with stabilization of body weight at a dose of 1000 mg (500 mg twice) daily. Although the drug may be used at 500 to 4000 mg daily, side effects increase above oral doses of 1000 mg daily. Medroxyprogesterone can also be given in a depot formulation. Oncologists are increasingly prescribing megestrol or medroxyprogesterone oral suspensions rather than tablets for their patients because of improved compliance and decreased cost.
There is, at present, considerable evidence of the effect of synthetic progestins on appetite and body weight, the two clinical hallmarks most widely identified in the cancer anorexia-cachexia syndrome. However, further issues to be clarified are the optimal treatment duration, the best time to start treatment during the natural history of the disease, and the eventual impact on the overall quality of life.
Both megestrol and medroxyprogesterone can induce thromboembolic phenomena, breakthrough uterine bleeding, peripheral edema, hyperglycemia, hypertension, adrenal suppression, and adrenal insufficiency (if the drug is abruptly discontinued). Although patients rarely need to stop taking these drugs because of adverse effects, these drugs should not be prescribed in cases of tthe hromboembolic/thrombotic disease, heart disease, or for patients at risk for serious fluid retention.The mechanism of action of progestational drugs remains to be clarified but might be related to glucocorticoid activity. Megestrol may induce appetite via stimulation of NPY in the hypothalamus, modulation of calcium channels in the ventromedial hypothalamus (VMH)—a well-known satiety center which reduces the firing tone of VMH neurons—and inhibition of the activity of proinflammatory cytokines such as IL-1, IL-6, and TNF-α.
Serum levels of such cytokines were reported to be decreased in cancer patients after megestrol or medroxyprogesterone treatment.
Cyproheptadine and Other Antiserotonergic Drugs
Cyproheptadine is an antiserotonergic drug with antihistaminic properties that have been shown to have an appetite-stimulant effect in a number of human conditions.
A randomized, controlled trial found mild appetite stimulation in patients with advanced cancer, although it did not prevent progressive weight loss. Considerable evidence, both in humans and experimental animals, suggests that anorexia may be mediated by increased serotonergic activity in the brain. Its blockade, therefore, might be beneficial in reducing symptoms.
Serotonin (5HT) is a known satiating factor. It suppresses food intake when injected into the VMH of animals, where it may play a critical role in anorexia associated with cancer. Cyproheptadine appeared to stimulate appetite and to decrease diarrhea in patients with advanced carcinoid tumors. 5HT3 receptor antagonists, such as ondansetron and granisetron, have entered widespread clinical use as antiemetics for cancer chemotherapy.
Ondansetron improved the ability of patients to enjoy food although it failed to prevent weight loss. Future clinical trials with other antiserotonergic drugs are needed to define the role of the serotonergic system in the development and treatment of cancer cachexia.
Branched-chain Amino Acids
Peripheral muscle proteolysis, as occurs in cancer cachexia, works to metabolize amino acids required for the synthesis of liver and tumor protein. The administration of amino acids may theoretically serve as a protein-sparing metabolic fuel by providing a substrate for both muscle metabolism and gluconeogenesis.
Branched-chain amino acids (BCAA: leucine, isoleucine, and valine) have been used with the aim of improving nitrogen balance, particularly muscle protein metabolism.
It was reported that BCAA-enriched total parenteral nutrition resulted in improved protein accretion and albumin synthesis.BCAA may also serve to counteract anorexia and cachexia by competing for tryptophan, the precursor of brain serotonin, across the blood-brain barrier and thus blocking the increased hypothalamic activity of serotonin.
It is known that increased plasma levels of tryptophan can lead to increased CSF tryptophan concentrations and increased serotonin synthesis during cancer. Oral supplementation of BCAA successfully decreased the severity of the anorexia in cancer patients.
Many patients with advanced cancer have symptoms of delayed gastric emptying and gastric stasis. Autonomic failure with decreased gastrointestinal motility is a recognized complication of cancer cachexia and is capable of causing anorexia, chronic nausea, early satiety, and constipation leading to the reduced caloric intake.
The prokinetic agent, metoclopramide, 10 mg orally before meals and at bedtimes, may relieve anorexia and early satiety with minimal side effects. It has been the most extensively used drug in patients with cancer for the prevention and treatment of chemotherapy-induced emesis.
Slow-release metoclopramide taken every 12 hours is significantly better than rapid-release metoclopramide taken every six hours, confirming the need for continued gastric stimulation for effective control of chronic nausea and early satiety. The role of other prokinetic agents, including domperidone and potentially erythromycin derivatives that lack antibacterial activity, need to be examined in randomized trials in cancer patients.
The polyunsaturated fatty acid, eicosapentaenoic acid (EPA), has been widely studied in animals and has demonstrated inhibition of lipolysis and muscle protein degradation associated with a cachexia model. It countered the metabolic actions of LMF and PIF by interfering with their second-messenger production (cyclic AMP and arachidonic acid, respectively), and resulted in a reversal of tumor-induced cachexia without changes in food intake in animal models.
In a recent open-label study conducted with pancreatic cancer patients, a supplement of fish oil capsules [18% EPA + 12% DHA (docosahexaenoic acid), 12 tablets per day taken orally] was investigated for three months. Patients showed decreased fatigue and a low body weight gain, as well as a reduction of acute-phase protein while taking the capsules. The reduction of acute-phase response (C-reactive protein) was also related to the suppression of IL-6 production. The effect appeared to be specific to the fish-oil supplement because it was not observed in patients receiving another polyunsaturated fatty acid, γ-linolenic acid.
Although nutritional supplementation alone cannot attenuate the development of weight loss in cachectic patients, the inclusion of EPA significantly increased weight gain and lean body mass, leading to an improvement in performance status.
In a randomized, controlled study, patients with advanced cancer who received a mixed fish-oil preparation showed increased survival relative to patients who received placebo. This improvement was observed in both weight-losing and non-weight-losing subgroups of patients.
Appetite stimulation and body weight gain are well-recognized effects of the use of marijuana and its derivatives. Dronabinol is the synthetic, oral form of tetrahydrocannabinol (THC), which is the active ingredient responsible for this effect.
Dronabinol and Marinol (in the United States) and Nabilone (in Canada) have been used as antiemetics in cancer,
Several studies of THC in advanced cancer-associated anorexia have shown some improvement in mood and appetite with either no or some improvement in body weight.
Randomized, controlled trials are needed to better determine the efficacy and usefulness of THC in cancer cachexia.
It has been shown that almost 20 percent of the cancer patients receiving chemotherapy along with dronabinol as an antiemetic experienced side effects, such as euphoria, dizziness, somnolence, and confusion resulting in a dose reduction or less frequently in the withdrawal of the treatment. The drug could be taken at bedtime to avoid some psychotomimetic effects and might produce long-lasting appetite stimulation for 24-hour periods. The mechanism by which cannabinoids exert their effect has yet to be clarified. It was postulated that they might act via endorphin receptors, by inhibiting prostaglandin synthesis or by inhibiting IL-1 secretion. Recent studies demonstrate that endogenous cannabinoids are present in the hypothalamus, which may tonically activate CB1 cannabinoid receptors to maintain food intake and form part of the neural circuitry regulated by leptin.
The fluorinated pyrimidine nucleoside, 5′;-deoxy-5-fluorouridine (5′-dFUrd) has been shown to effectively attenuate the progression of cachexia in mice bearing murine or human cancer cell lines.
5′-dFUrd is a cytostatic agent that is converted upon metabolization into the active 5-fluororacil (5-FUra) by pyrimidine (thymidine and uridine) phosphorylases, which are very active in tumor tissue. Although concomitant inhibition of tumor growth was observed in these models, it was not sufficient to account for the preservation of body weight. 5prime;-dFUrd reversed a progressive weight loss, hypoglycemia, and increased production of acute phase proteins with no change in tumor size or even some tumor growth.
The mechanisms of the anticachectic activity of 5′-dFUrd include inhibition of production of IL-6 and PIF. Chemotherapy could be expected to have a role in cachexia not only by decreasing tumor mass but perhaps also by modulating the production by cancer cells or immune cells of chemical mediators.
Unfortunately, few studies have been conducted with the aim of trying to define the potential symptomatic role of low-toxicity chemotherapy on cachexia, as well as on asthenia or pain. Such clinical studies are warranted and should include 5′-dFUrd.
The reported clinical trials on emerging drugs are generally small. Larger, randomized studies are necessary to assess the efficacy of these drugs in the treatment of cancer cachexia.
Melatonin is the pineal hormone that is able to decrease the level of circulating TNF-α in patients with advanced cancer. In a recent controlled trial of 100 patients with metastatic solid tumors, loss of more than 10 percent body weight was less common among those treated with melatonin (20 mg daily) than among patients in the placebo group.
Addition of melatonin to the chemotherapy regimen of cisplatin plus etoposide improved the response rate and survival rate, and reduced myelosuppression, neuropathy, and cachexia among lung cancer patients in poor clinical condition.
Initially developed as a sedative and an anti-inflammatory agent, thalidomide was withdrawn from use when its teratogenic effect was recognized. It is now prescribed for new indications, except in susceptible populations (women of child-bearing potential and their spouses, and those with peripheral neuropathy).
Thalidomide also inhibits TNF-α in animals and humans with cancer, AIDS, and other diseases. A significant improvement in well-being and weight gain occurs in AIDS patients with modest doses of thalidomide (300 mg).
It was also reported to improve insomnia and restlessness as well as nausea in advanced cancer patients and it has improved appetite as well, resulting in an enhanced feeling of well-being in one-half to two-thirds of patients studied.
These results together with the recent finding that thalidomide is able to inhibit the growth of the tumor through an inhibition of neoangiogenesis, suggest the unique role of thalidomide both as an anticachectic and antineoplastic agent.
Beta 2 adrenoceptor agonists may have an important effect on protein metabolism in skeletal muscle, favoring protein deposition even in sedentary populations. It was reported that clenbuterol suppresses the activation of muscle proteolysis through its action on the ubiquitin-dependent proteolytic system during tumor growth in tumor-bearing animals.
Although no controlled trials are reported in cancer patients, it was shown to significantly improve muscle strength after knee surgery when compared with placebo.
Non-steroidal Anti-inflammatory Drugs
Non-steroidal anti-inflammatory drugs (NSAIDs) are very widely used in patients with cancer for the treatment of fever and pain. Ibuprofen, taken at a dose of 400 mg three times daily, has been shown to reduce levels of acute phase proteins, IL-6, and cortisol and to normalize whole-body protein kinetics to some extent in cachectic colorectal cancer patients. It may reduce resting energy expenditure and stabilize weight and quality of life in pancreatic cancer patients.
The related anti-inflammatory agent indomethacin, taken at a dose of 50 mg twice daily, has been shown to stabilize performance status and prolong survival of patients with metastatic solid tumors in a large controlled trial. These agents may, therefore, have some role in the palliation of cachexia and fever, although concern remains about gastrointestinal side effects. NSAIDs act by inhibiting prostaglandin production by the rate-limiting enzymes known as cyclooxygenases, COX-1 and COX-2. The recent discovery and introduction into clinical practice of selective inhibitors of COX-2 (celecoxib and rofecoxib) that are devoid of gastrointestinal toxicity yet maintain a high anti-inflammatory activity suggest that these agents will be therapeutic alternatives to conventional NSAIDs.
These COX-2 inhibitors were recently shown to have anti-angiogenic and anti-tumor activities in animal models.
Pentoxifylline, a methylxanthine derivative, is a phosphodiesterase inhibitor that inhibits TNF-α synthesis by decreasing gene transcription. A randomized, controlled trial in patients with solid tumors, however, showed no increase in appetite or body weight gain among patients taking pentoxifylline (400 mg three times daily for two months) compared with patients receiving placebo.
Hydrazine sulfate inhibits phosphoenol-pyruvate carboxykinase, a key enzyme in gluconeogenesis. It was hoped that interrupting the Cori cycle would normalize some aspects of carbohydrate metabolism in cachectic cancer patients. However, large, randomized, placebo-controlled trials did not show any benefit in advanced lung and colorectal cancer patients. Based on its lack of efficacy and significant neurotoxicity, hydrazine sulfate is not used by mainstream oncologists, although it is still promoted by some alternative medicine practitioners.
Anabolic steroids increase muscle mass in noncancer patients, and this has led to their illicit use for athletic advantage. Nandrolone decanoate treatment resulted in a decrease in weight loss in patients with lung cancer. However, in a large, randomized, controlled trial comparing megestrol acetate versus dexamethasone versus fluoxymesterone for the treatment of cancer cachexia, fluoxymesterone was clearly inferior.
Nutritional, Psychological, and Behavioral Therapies
The management of cachexia in advanced cancer patients should first attempt to maximize oral intake by allowing the patient flexibility in type, quantity, and timing of meals.
Professional teams of oncology physicians, nurses, and dietitians, along with patients and families, can diagnose specific needs and plan individualized treatment for improved nutritional health.
Counseling, which any member of the healthcare team may provide, is an effective and inexpensive intervention and should be combined with other nutritional interventions.
Nursing interventions to counteract cachexia should be aimed at minimizing the negative factors of nausea, vomiting, diarrhea, pain, fatigue, changes in taste, or food preferences that may influence appetite.
Encouraging patient and family interaction and providing emotional and educational support may be helpful. When family members can provide the patient’s favorite foods, food intake usually improves and family bonds are strengthened.
Communication among physicians and other healthcare professionals provides the patient with a multidisciplinary approach to care. The patient record will be an excellent resource to document a plan of care and patient responses to treatment. Psychological distress and psychiatric disorders are common among cancer patients and have a prevalence ranging from 10 to 79 percent of patients depending upon the group studied. These problems are also as common among the family members of people with cancer.
The use of psychological and behavioral interventions in cancer is increasing and recent studies have suggested that some of these techniques may affect the quality of life and, perhaps, survival rates.
Evaluations of relaxation, hypnosis, and short-term group psychotherapy have suggested some benefit with regard to anorexia and fatigue, although the population most likely to benefit from these interventions has not yet been determined.
Anorexia and cachexia may result in a secondary depression, or the depression may be a prime contributor to the anorexia and subsequent weight loss. Benzodiazepines can be helpful for persistent fear and anxiety and antidepressant drugs are increasingly used in depressed cancer patients.