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Kufe DW, Pollock RE, Weichselbaum RR, et al., editors. Holland-Frei Cancer Medicine. 6th edition. Hamilton (ON): BC Decker; 2003.

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Holland-Frei Cancer Medicine. 6th edition.

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Treatment of Cachexia

, MD, PhD.

The definitive treatment of cancer cachexia is removal of the causative tumor. Short of achieving this goal, various measures have been undertaken with limited success.

Supportive Care

Patients with anorexia from decreased physical activity, concomitant infection, and toxicities to the alimentary tract from chemotherapy and radiotherapy are managed symptomatically for maintenance of nutritional status and quality of life. Such management includes the use of mouthwash for stomatitis, frequent small volume feedings, antiemetics, antibiotics, transfusions of blood components ,and/or oral and parenteral nutritional supplement. Consideration of the patient's food preferences and service of food in a dining room atmosphere may also be important to stimulate appetite. When a patient is unable to consume a regular diet to obtain adequate nutrition, food supplements, both homemade and commercially available, are an effective means of providing additional calories, protein, fat, vitamins, and minerals, although overall consumption may not increase much. In specific instances, such as the malabsorption syndrome secondary to pancreas carcinoma, exogenous pancreas extract improves fat and protein absorption.63

The effect of frequent nutritional counseling on oral food intake, body weight, response rate, survival, and quality of life was examined in patients with cancer undergoing chemotherapy.240 While the counseling increased daily energy and protein intake as well as triceps skinfold measurements, response rates and overall survival did not differ from control patients who received no intervention.

Pharmacologic Management

Various agents have been administered in attempts to retard or halt progressive cachexia in cancer patients. In addition, a number of agents are currently being studied in animals. These agents are arranged in Table 144-2 based on their major mechanism of action. It is noteworthy that each of these agents exerts a variety of other pharmacologic activities.

Table 144-2. Pharmacologic Treatment of Cancer Cachexia.

Table 144-2

Pharmacologic Treatment of Cancer Cachexia.

Corticosteroids

A number of uncontrolled studies suggest that corticosteroids can alleviate such symptoms as anorexia, asthenia, and pain in patients with cancer. The mechanism of action is unknown. Speculations include a euphoriant activity, inhibition of prostaglandin metabolism, and an inhibitory effect against IL-1. Significant improvements in appetite and a sense of well-being have been reported in randomized trials with prednisolone, methylprednisolone, or dexamethasone.7,241–243 Unfortunately, the improvements were not long-lasting and upon completion of the studies all nutritional parameters returned to their baseline. There were no differences in mortality rate or in survival. In a randomized comparison of dexamethasone and megestrol acetate, both drugs caused a similar degree of appetite enhancement and similar changes in nonfluid weight status, but dexamethasone was found to be less favorable.244 Dexamethasone had more corticosteroid-type toxicity and a higher rate of drug discontinuation because of toxicity and/or patient refusal than megestrol acetate.

Megestrol Acetate

This progestational agent is frequently used in the treatment of patients with metastatic breast cancer. It is generally well tolerated, except that it may cause undesirable weight gain. Subsequently, it was shown that megestrol acetate produced weight gain in a variety of cachectic cancer patients. Significant reduction in serum levels of IL-1α and β, IL-2, IL-6, and TNF-α were observed in cancer patients treated with megestrol acetate, which may bear on the mechanism of improved appetite and body weight gain.245

Recently, 15 randomized clinical trials that included more than 2,000 patients were reviewed in regard to the impact of megestrol on the appetite and weight gain in cancer patients.246 There was a statistically significant advantage for high-dose progestins as regards improved appetite. Although the effect of high-dose progestins on body weight was less impressive, statistical significance was also reached for this outcome. Treatment morbidity was low because of the brief period of the treatment in most of the studies. Thus, the effects of high-dose progestins on appetite and body weight were clearly demonstrated.

Weight gain produced by megestrol acetate was found to be mainly from increased body fat stores rather than accretion of lean tissue.247,248 It has been argued that the gain of adipose tissue as opposed to lean tissue during treatment with megestrol acetate, although suboptimal, should not be considered inherently negative because depletion of body fat is generally an undesirable outcome of cancer.

The addition of megestrol acetate to chemotherapy for patients with melanoma resulted in a high objective response and prolonged median survival as compared to historical controls with chemotherapy alone.249 A recent study of the combination of appetite-stimulating properties of megestrol acetate and the antiinflammatory properties of ibuprofen suggested that this combination stabilized quality of life and produced weight gain in patients with advanced gastrointestinal cancer.250 Additional controlled studies are needed to establish that addition of megestrol alone or a combination of megestrol plus ibuprofen is accompanied by increased tolerance to cancer treatment and improvements in survival.

Medroxyprogesterone Acetate

Medroxyprogesterone acetate is a more widely used synthetic progestogen. Medroxyprogesterone reduced production of cytokines and serotonin that are involved in anorexia/cachexia in cancer patients.251 Two placebo-controlled randomized studies have been reported in which increased appetite resulted.252,253 In one study, significant increases in rapid turnover proteins such as serum thyroid-binding prealbumin and retinol-binding protein were reported.252 In spite of increased appetite, no weight gain was produced in either study.

Cannabinoids (Dronabinol)

While using dronabinol as an antiemetic, it was found that the agent enhanced the appetite in healthy individuals and in cancer patients. To study this phenomenon further, an open dose-ranging study was carried out in patients with cancer.254,255 All patients reported improvement in appetite. Higher doses, 5.0 or 7.5 mg/d, were more effective than the low dose of 2.5 mg/d. Patients in all groups continued to lose weight, although the rate of weight loss decreased with therapy. It is of note that these effects were observed at doses lower than those producing antiemetic effects and without overt psychotropic symptoms.

Recently, a randomized study was carried out to determine whether dronabinol administered alone or with megestrol acetate was more, less, or equal in efficacy to single-agent megestrol acetate for palliating cancer-associated anorexia.256 Megestrol acetate provided superior anorexia palliation among advanced cancer patients compared with dronabinol alone. Combination of megestrol and dronabinol did not appear to have conferred additional benefit.

Cyproheptadine

Cyproheptadine is a serotonin antagonist. In several clinical situations, the agent produced weight gain. A randomized trial in patients with advanced malignant neoplasms showed that cyproheptadine produced a decrease in nausea and mild enhancement in appetite. However, the agent did not abate progressive weight loss in these patients.257

Metoclopramide and Cisapride

In advanced cancer patients with delayed gastric emptying or gastroparesis, oral administration of a prokinetic agent, metoclopramide, 10 mg orally 4 times daily before meals and at bedtime, was shown to be effective in stimulating appetite and relieving other dyspeptic symptoms associated with anorexia.258,259 A controlled-release preparation appears to be more effective than immediate-release drug because of its control of nausea associated with advanced cancer, even without demonstrated abnormalities of the gastrointestinal (GI) tract.260 It was not reported whether patients on metoclopramide had improvements in body weight or survival. Patients with head and neck cancer undergoing radiotherapy were randomized to three groups: megestrol acetate, cisapride, and placebo. Megestrol significantly prevented body weight loss and deterioration of appetite, whereas cisapride lacked these clinical benefits.261

Anabolic Steroids

Anabolic androgenic steroids have been used by athletes to promote muscle growth and strength. In MCG101 sarcoma-bearing mice with progressive cachexia, administration of nandrolone propionate resulted in significant weight gain.262 The weight gain was, however, mainly attributed to water retention, and food intake and survival were not affected. The anabolic steroid did not affect tumor growth. Beneficial effects from anabolic steroid hormones have been reported in patients undergoing chemotherapy.263 Randomized clinical trials were carried out to test whether supplements of nandrolone decanoate influenced the outcome of chemotherapy in patients with non-small-cell lung cancer.264,265 Although the treated experienced less weight loss, response to chemotherapy and survival were comparable. In a three-arm Phase III clinical trial, the fluoxymesterone group showed significantly less appetite enhancement and did not have a favorable toxicity profile as compared to the megestrol acetate and dexamethasone groups.244

Hydrazine Sulfate

Hydrazine sulfate, an inhibitor of the enzyme phosphoenolpyruvate carboxykinase, interrupts gluconeogenesis in animals.266 This observation led to clinical studies of hydrazine sulfate in attempts to prevent or reverse cancer-related cachexia and weight loss. Three recent multicenter group studies were carried out in patients with non-small-cell lung cancer or colorectal cancer.267–269 All three studies failed to show beneficial results in appetite, body weight, quality of life, or survival from hydrazine sulfate.

Pentoxifylline and Lisofylline

These agents are methylxanthine analogs that have antiinflammatory properties. They have profound stimulatory effects on vascular endothelial production of noninflammatory prostaglandins I2 and E2, while inhibiting TNF-α production. Pentoxifylline blocked TNF-α mRNA accumulation.270 Pentoxifylline also prevented muscle atrophy and suppressed increased protein breakdown in tumor-bearing rats by inhibiting the activation of a nonlysosomal, Ca2+-independent ubiquitin-proteasome proteolytic pathway.271 Pentoxifylline suppressed the enhanced expression of ubiquitin, the 14-kDa ubiquitin-conjugating enzyme E2, and the C2 20S proteasome subunit in muscle from cancer-bearing rats.

Prophylactic oral administration of pentoxifylline in allograft recipients together with chemotherapy and radiotherapy resulted in significant reduction in the incidence and severity of treatment-related complications: mucositis, hepatic venoocclusive disease, renal insufficiency, and the incidence of graft-versus-host disease.272 In an initial study in cancer patients, pentoxifylline suppressed TNF-α mRNA levels, increased the sense of well-being, improved appetite, and improved the ability to perform activities of daily living. Patients with normal TNF levels also had a weight gain. However, in a randomized controlled trial in patients with solid tumors, pentoxifylline failed to provide improvement in appetite or body weight compared to a placebo group.273 Likewise, for patients with acute myelocytic leukemia or myelodysplastic syndrome once in complete remission with idarubicin/ara-C chemotherapy, lisofylline provided no favorable effects in terms of rates of infection, overall mortality rates, or outcome.274 Lisofylline did not alter the toxicities of high-dose IL-2, and thus did not impact the overall dose intensity in the treatment of advanced renal cancer and malignant melanoma.275

Thalidomide

Thalidomide has immuno-modulatory activity as well as antiangiogenic properties. Thalidomide also inhibits TNF-α production in patients with leprosy, tuberculosis, AIDS, and cancer.276–278 In patients with HIV and tuberculosis, an improvement in body weight gain from thalidomide was associated with a reduction of TNF-α serum levels.278 In a preliminary study, 72 cancer patients with anorexia and weight loss were given thalidomide 100 mg/d.279 By day 10, 50% to 70% of 37 evaluable patients reported improvements in intensity of various symptoms including anorexia, nausea, fatigue, and sense of well-being. Randomized studies are needed to determine the role of thalidomide in cancer cachexia.

Cytokines, Anticytokine Antibodies, and Miscellaneous Cytokine Inhibitors

In addition to pentoxifylline and thalidomide there are a number of other cytokine inhibitors.

Administration of purified human rIL-6 alone or in combination with subtherapeutic doses of TNF was effective against syngeneic tumors in mice and rat.107 Anti-TNF-α antibody, anti-IL-1 antibody, and anti-IL-1 receptor antibody were reported to have attenuated the cachexia produced by either chronic TNF-α administration or implantation of a tumor in experimental animals.42,90,280 Administration of TNF-α antibody to tumor-bearing rats decreased protein degradation rates in skeletal muscle, heart, and liver, as compared to controls; however, the antibody was unable to prevent a reduction in body weight.281 Decreases in protein degradation in skeletal muscle by TNF-α antibody appear to be caused by inhibition of tumor-induced increases in muscle ubiquitin gene expression.282 The administration of an anti-IL-6 antibody in patients seropositive for human immunodeficiency virus-1 and suffering from an immunoblastic or a polymorphic large-cell lymphoma resulted in partial remission or stabilization of the disease.283 The neutralizing effect of the anti-IL-6 antibody as measured by C-reactive protein levels in the serum was accompanied by abrogation of B clinical symptoms including fever and cachexia. Further studies are needed to determine the therapeutic role of such anticytokine antibodies.

TNF-α is initially expressed as a 233-amino acid membrane-anchored precursor that is cleaved by matrix metalloproteinase-like enzymes to yield the mature 157-amino-acid cytokine.284 This process was specifically prevented by synthetic hydroxamic acid-based metalloproteinase inhibitors.285

All-trans-retinoic acid inhibited the production of TNF by activated peritoneal macrophages.286 Suramin, an antitrypanosomal polyanion, prevented the binding of IL-6 to its cell surface receptor subunits in vitro and inhibited colon-26 mediated cancer cachexia in mice.287

IL-12 was reported to reduce serum levels of IL-6 in mice bearing colon 26 carcinoma and prevented development of cachexia. The IL-12 activity was T-cell dependent and the anticachexia effect resulted from upregulation of IFN-α.288 In patients with gastric and colorectal cancer, the production of IL-12 by peripheral blood mononuclear cells stimulated with phytohemagglutinin or Staphylococcus aureus decreased significantly with advancing disease and was lowest in the patients with distant metastases and cachexia.289

Similarly, a gene transfer of IL-10, another IL-6 inhibitor, prevented cachexia in the same animal model.290 IL-12 and IL-10 may have a role as anticachectic agents in IL-6-producing tumors.

IL-15 treatment partly inhibited skeletal muscle wasting in AH-130-bearing rats by decreasing protein degradative rates to values even lower than those observed in non-tumor-bearing animals.291 These alterations in protein breakdown rates were associated with an inhibition of the ATP-ubiquitin-dependent proteolytic pathway. The cytokine did not modify the plasma levels of corticosterone and insulin in the tumor-bearing hosts.

Branched-Chain Amino Acids

Branched-chain amino acids, used by skeletal muscle but not by the liver, are uniquely effective in regulating nitrogen balance in muscle by reducing protein catabolism and increasing protein synthesis in both injured and tumor-bearing animals. Randomized studies show improved nitrogen retention, improved protein use, and increased protein and albumin synthesis in patients who received parenteral nutritional support with a high content of branched-chain amino acids.292,293 In contrast, a randomized study was carried out examining the effects of a balanced amino acid solution with or without supplementation of α-ketoisocaproate or a branched-chain amino acid solution in patients with gastrointestinal cancer who underwent surgery.294 The balanced amino acid solution itself with an adequate energy supply had an optimal nitrogen-sparing effect. Branched-chain amino acids or α-ketoisocaproate did not improve nitrogen balance or reduce protein degradation.

Interestingly, the tryptophan uptake into the brain is competitive with that of branched-chain amino acids. A trial to reduce tryptophan uptake by increasing plasma levels of branched-chain amino acids resulted in a decrease in the incidence of anorexia in cancer patients.295

Eicosapentaenoic Acid

ω-3 Polyunsaturated fatty acids are an essential component of the diet and are involved in the synthesis of eicosanoids (prostaglandins, leukotrienes, and thromboxanes) and in membrane, receptor, and enzyme functions. Eicosapentaenoic acid (EPA), an ω-3 polyunsaturated fatty acid found in oily fish such as sardines, salmon, and mackerel, possesses antitumor, as well as anticachexia, activities in animal cachexia models.296,297 EPA-induced inhibition of weight loss was accompanied by increases in total body fat and muscle mass. EPA administration resulted in inhibition of proteolysis-inducing factor (PIF)-induced weight loss in mice and decreased glucose use of skeletal muscle.298 EPA appears to exert its effect by interference with second-messenger production by PIF, particularly release of arachidonic acid and its conversion to eicosanoids. EPA also inhibited lipolysis in adipocytes by preventing prostaglandin synthesis and the rise in cyclic adenosine monophosphate (cAMP) in response to the lipid-mobilizing factor.299 EPA reduced acute-phase response mediated by suppression of IL-6.300

Patients with pancreas cancer treated with supplements of fish oil capsules (EPA and docosahexaenoic acid) showed body weight gain accompanied by significant reduction in acute-phase protein production and by stabilization of resting energy expenditure.301 While nutritional supplement alone did not attenuate the development of weight loss in cachectic patients, nutritional supplement enriched with EPA resulted in significant weight gain.302 Significant rises of lean body mass noted in body composition analysis are noteworthy among various therapeutic interventions reported. A randomized controlled study was carried out to investigate the effects of dietary EPA plus vitamin E on the immune systems and survival of well-nourished and of malnourished cancer patients.303 EPA had a considerable immunomodulating effect by increasing the ratio of T-helper cells to T-suppressor cells in the subgroup of malnourished patients. EPA prolonged the survival of both groups of patients. Additional clinical studies are needed to examine whether EPA increases tolerance to surgery, chemotherapy, or radiotherapy, leading to survival advantage in patients with cancer cachexia.

Of note is a recent report indicating a significant increase in colon cancer metastasis in the liver in rats that were fed EPA.304

Indomethacin and Ibuprofen

These agents are inhibitors of prostaglandin synthesis. In clinical trials, indomethacin reduced fever and granulocytosis, and was claimed to have improved the well-being of cancer patients.305,306 In cachectic cancer patients, ibuprofen was reported to decrease C-reactive protein, to produce body weight gain, and to improve survival.307–309

Melatonin

Melatonin is an indole amine primarily secreted from the pineal gland during the hours of darkness. The functions of melatonin are obscure, but it has been claimed to modulate sleep, cardiac rhythms, sexual behavior, the reproductive system, and immunologic functions, as well as antioxidative and antiinflammatory activities. Melatonin decreased the level of circulating TNF in patients with advanced cancer and reduced chemotherapy-induced malaise and asthenia, as well as thrombocytopenia.310–312 Based on observations that melatonin amplified IL-2-induced antitumor effect in animals, a randomized study was carried out in patients with metastatic solid tumors comparing a combination of low-dose IL-2 plus melatonin with best supportive care.313 In the treated group, the percentage of patients with improved performance status, as well as overall survival, was significantly higher than the controls. Another randomized study of chemotherapy with cisplatin plus etoposide plus and/or minus melatonin was carried out in patients with advanced non-small-cell lung cancer with poor clinical status.314 There was no significantly different survival between groups, but the melatonin group had less-frequent myelosuppression, neuropathy, and cachexia. Additional clinical studies are needed to define the role of melatonin in the treatment of cancer cachexia.

Growth Hormone and GHRP-2

Anabolic properties of growth hormone have been examined in animals. Administration of growth hormone to tumor-bearing rats resulted in increased muscle weight, muscle protein content, and preserved host-body composition.315–317 Growth hormone did not stimulate tumor growth.318 The effect of a combination of insulin, growth hormone, and somatostatin on tumor growth, metastasis, and host metabolism was studied in rats bearing MAC-33 mammary tumor.319 The triple therapy supported host anabolism and inhibited tumor growth kinetics. Somatostatin alone is known to have antitumor activity, however, and the contribution of each component to the observed changes was not clear. Growth hormone has not yet been studied in patients with cancer cachexia.

Ghrelin is an endogenous growth hormone secretagogue primarily secreted by oxyntic glands of the stomach; it is capable of stimulating adiposity in rodents. Daily subcutaneous injections of a more stable synthetic ghrelin-receptor agonist GHRP-2 (growth hormone releasing peptide-2) produced dose-dependent increases in food intake and body weight.320 Pre- and posttreatment analysis of body composition indicated increased fat and bone masses but not lean mass. GHRP-2-induced positive energy balance leading to fat gain occurred in the absence of involvement of hypothalamic NPY neurons. Ghrelin receptor agonists may offer a treatment option for syndromes such as anorexia nervosa, cancer cachexia, or acquired immunodeficiency syndrome (AIDS) wasting.

Clenbuterol

Clenbuterol is a β2-adrenoceptor agonist. It prevented muscle protein wasting in tumor-bearing animals and increased muscle mass and function in healthy animals.321–323 There was no change in food intake or tumor growth. In patients after knee surgery, clenbuterol was able to improve muscle strength in a randomized trial.324 Its effects on muscle preservation appeared to occur without the need for exercise. Clenbuterol has not yet been studied in patients with cancer cachexia.

Enteral and Parenteral Nutrition

Cancer cachexia is different from simple starvation in that nutritional support, either enteral or parenteral, has only a limited value. For the correction of cancer-related malnutrition, therefore, enteral and parenteral administration of nutrient solutions must be used discreetly. In patients with oropharyngeal dysfunction from head and neck neoplasm or esophageal obstruction, blenderized food and liquid supplement can often achieve an adequate level of nutritional repletion. When necessary percutaneous gastrostomy or jejunostomy offers bypass feeding. For patients who cannot tolerate the use of the gastrointestinal tract because of nausea, vomiting, obstruction, malabsorption, or absence, it may be necessary to begin total parenteral nutrition (TPN, “hyperalimentation”).

The needs of nutritional support in cancer patients during tumor progression and the role of TPN in cancer surgery, chemotherapy, and radiotherapy should be considered at several different levels.18 Benefits of TPN in patients who underwent cancer surgery included improved wound healing, a decreased rate of infection, fewer major complications, and a decrease in postoperative mortality. In other studies, however, no advantage of TPN was found; one report described an increase in the rate of major postoperative complications.325 TPN in cancer patients with obstructions of the gastrointestinal tract, gastrointestinal fistulae, evisceration, and intraabdominal infection appears justified during and after surgery.326 Although strong data are lacking, when enteral nutrition cannot be encouraged or applied, TPN is considered beneficial in patients who have not been eating for at least 10 days or in those who have lost more than 10% of their usual body weight.327

No significant benefit of TPN was demonstrated, however, in patients undergoing chemotherapy and/or radiotherapy in terms of treatment tolerance, response to chemotherapy or radiotherapy, or in survival.18,327–329 Furthermore, other authors have reported that TPN is detrimental. Controversies related to TPN in the treatment of cancer cachexia have been reviewed.330–332

Because of limited nutritional reserves, children with cancer suffer more often from malnutrition than do adults with neoplasms. Therefore, combined chemotherapy/radiotherapy protocols for children with neuroblastoma and Wilms tumor often incorporate parenteral and enteral nutritional support. Recently, enteral nutritional support has become more popular than TPN mainly for economic reasons. An algorithm for nutritional support has been developed that requires a compelling rationale for choosing parenteral over enteral support in children with a functional GI tract.333 Such a plan results in increased choice of enteral nutritional support.

Chronic submaximal exercise in attempts to increase muscle mass, administration of growth hormone, glutamine, clenbuterol, and acivicin (a glutamine antimetabolite) have all been suggested as adjuncts to TPN.292,293,322,334–337 Clinical studies are needed to document the precise role of these adjunct therapies.

Parenteral nutritional support is an intensive method of clinical care requiring physicians, pharmacists, dietitians, and experienced nurses who, as a team, must make daily rounds to evaluate nutritional status and check for complications. Complications from parenteral nutrition can be multiple (Table 144-3). Among them the complications from infection are the most problematic when long-term nutritional support is used. In addition, the costs of nutrient solutions, prolonged hospitalization, and/or frequent visits to a special clinic or office are formidable medical and financial burdens. For these reasons, careful patient selection is essential before the start of parenteral nutritional support. Parenteral nutritional support in patients with terminal cancer remains highly controversial and must be decided on case by case. Usually TPN in terminal cancer only prolongs the dying process. Therapeutic complications and the financial and psychological impact on the patient and the patient's family cannot be justified unless other definitive therapy is expected to have significant benefits.

Table 144-3. Complications from Parenteral Nutrition.

Table 144-3

Complications from Parenteral Nutrition.

By agreement with the publisher, this book is accessible by the search feature, but cannot be browsed.

Copyright © 2003, BC Decker Inc.
Bookshelf ID: NBK13978

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