Anorexia/Cachexia in Patients with HIV: Lessons for the Oncologist

Anorexia/Cachexia in Patients with HIV: Lessons for the Oncologist Review Article [1] July 01, 1996 By Jamie Hayden Von Roenn, MD [2] and Kevin Knopf, MD [3] Early intervention and attention to nutritional
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Anorexia/Cachexia in Patients with HIV: Lessons for the Oncologist Review Article [1] July 01, 1996 By Jamie Hayden Von Roenn, MD [2] and Kevin Knopf, MD [3] Early intervention and attention to nutritional status are essential in patients with cachexia. Identification of reversible causes of decreased energy intake and/or weight loss is the first step in treatment. When such factors Introduction Anorexia and cachexia are frequent complications of both HIV infection and cancer. Involuntary weight loss and associated malnutrition result in physical and psychological consequences that affect both morbidity and mortality. Numerous investigators have reported on the relationship between involuntary weight loss and adverse outcome in the setting of HIV infection or cancer. Malnutrition adversely affects immune function, increases the risk of infection, and diminishes tolerance to radiation therapy, response to chemotherapy, and overall survival [1]. Whether nutritional status is evaluated using simple clinical nutritional markers, such as serum albumin and percentage of usual body weight, or by sophisticated research techniques, the deleterious effects of malnutrition on the clinical course of HIV infection are well documented. Indeed, malnutrition is a predictor of both risk of hospitalization and survival [2]. Regardless of the clinical setting, death from wasting is directly related to the magnitude of tissue depletion, suggesting that the preservation and/or restoration of body cell mass may enhance survival [3]. Pathogenesis of Wasting The pathogenesis of wasting is incompletely defined. However, it appears to result from complex interactions among decreased energy intake, altered energy expenditure, malabsorption, and hormonal/cytokine and metabolic abnormalities. The respective roles of individual factors, such as altered insulin sensitivity, hypertriglyceridemia, futile cycling of glucose and/or free fatty acids, hypermetabolism or hypometabolism, and alterations in the cytokine milieu, are difficult to identify. Ultimately, weight loss is determined by the balance between energy intake and energy expenditure. Increasingly, data suggest reduced energy intake as the major determinant of involuntary weight loss in patients with HIV infection, and, to a less degree, in those with cancer [1,4,5]. Anorexia is a frequent clinical complaint of patients with malignant disease or HIV infection. Bruera, in a review of 275 consecutive cancer patients admitted to a palliative care unit, noted anorexia to be present in 85% of patients, second in frequency only to the complaint of asthenia and more common than complaints of cancer-related pain [1]. Similarly, anorexia is a highly prevalent symptom in the setting of HIV infection, although its exact prevalence is unknown. In a review of clinical risk factors for malnutrition in 104 HIV-infected patients (including asymptomatic patients, as well as those with AIDS or AIDS-related complex [ARC]), anorexia was identified as the predominant risk factor in 60% of patients [6]. Furthermore, Burger et al reported the benefit of intensified oral nutritional intervention in malnourished HIV-infected outpatients, suggesting that poor spontaneous nutrient intake is an important pathogenetic factor in the development of HIV-related malnutrition [7]. In patients with HIV infection, the degree of weight loss has been closely associated with reduced energy intake. McCorkindale et al noted a correlation between weight loss and decreased oral intake over a 16-month period in asymptomatic patients with HIV infection or early ARC [8]. In an evaluation by Grunfeld et al comparing metabolic parameters and oral intake in HIV-seropositive subjects, seronegative controls, and AIDS patients with and without active secondary infections, a highly significant correlation between 28-day weight loss and caloric intake was identified, while no correlation was seen between resting energy expenditure and weight loss [5]. Similarly, Macallan et al found reduced energy intake, not elevated energy expenditure, to be the primary determinant of Page 1 of 10 weight loss in 27 HIV-seropositive men at different stages of the disease [4]. Although weight loss appears to be progressive over the course of HIV infection, it does not occur continuously. Rather, weight is more often lost in a stepwise fashion in association with opportunistic complications of the underlying immunosuppression. This episodic weight loss is associated with decreased oral intake, which, during its early stages, may be amenable to therapeutic intervention. Although not all investigators agree, a number of studies suggest that attention to oral intake by clinicians results in an improvement in overall nutritional status. McKinley et al demonstrated improved nutritional status in adult outpatients who received nutritional assessment, counseling, and follow-up, compared with outpatients who received no nutritional intervention [9]. In contrast, Chleblowski et al reported progressive weight loss in HIV-infected individuals despite dietary counseling, suggesting the need for earlier intervention and consideration of increased target levels for energy intake [10]. Etiology of Anorexia The etiology of anorexia is incompletely understood. Cytokine Production The endogenous production of cytokines contributes to the development of anorexia and cachexia in both HIV infection and advanced cancer. Experimental therapy in vitro and in vivo with cytokines, such as interferon, tumor necrosis factor (TNF), and interleukin-1 (IL-1), can produce striking anorexia [11-13]. Tumor necrosis factor, although frequently cited as a major cause of anorexia, is not consistently elevated in the serum of patients with cancer cachexia or HIV-related wasting [11-14]. Although individual cytokines can result in significant anorexia when given as single factors in the experimental setting, tolerance to their anorexic effects generally develops and normal food intake resumes [11]. Synergism between cytokines (eg, IL-1 plus interferon-alfa or TNF) may result in irreversible anorexia, metabolic abnormalities, and progressive weight loss. Reversible Causes Food intake may be further decreased by readily identifiable, often reversible causes. Nausea and Vomiting--Chronic nausea is a frequent complaint in patients with HIV infection or cancer. Nausea and vomiting can occur as a result of mechanical obstruction, infectious complications, or as a side effect of medications (see Tables 1 and 2). In the setting of HIV infection, numerous medications are prescribed both for prophylaxis and treatment of opportunistic infections that, alone or in combination, may cause nausea and vomiting; examples include sulfamethoxazole for the treatment of Pneumocystis carinii pneumonia or clarithromycin (Biaxin) as therapy or prophylaxis for Mycobacterium avium complex. Nausea and vomiting occur as both an immediate and late effect of treatment with chemotherapeutic drugs such as cisplatin (Platinol). Radiation therapy, particularly when the treatment field includes the gastrointestinal tract, may also cause significant nausea. In patients with advanced disease, whether cancer or HIV infection, a not infrequent cause of nausea and vomiting is a rapid increase in the dose of narcotic analgesics. In patients receiving high doses of narcotics, nausea may be severe, chronic, and accompanied by other gastrointestinal symptoms, including abdominal pain, constipation, and large bowel distention. Psychosocial or Financial Factors--Decreased oral intake may result from psychosocial or financial factors. Patients have identified anxiety, depression, and/or a sense of isolation as factors interfering with oral intake. Neuropsychiatric symptoms associated with HIV infection and opportunistic pathogens of the central nervous system or central nervous system metastases, including dementia, sensory and motor abnormalities, and psychosis, also may result in decreased caloric intake. Mechanical impediments to food intake secondary to strictures and/or progressive malignant disease further impair nutritional status. Oral and esophageal conditions that result in dysphasia and food aversions, such as esophageal candidiasis, aphthous stomatitis, and therapy-induced mucositis, occur in patients with both cancer and HIV infection. Cytomegaloviral or herpetic esophagitis are most frequently seen in the severely immunocompromised host. Bulky oropharyngeal Kaposi's sarcoma or other aerodigestive tract malignancies may also make eating painful or unpleasant. Early satiety may further compromise oral intake. Early satiety may be secondary to ascites, hepatomegaly, or massive splenomegaly (due to progressive malignancy or organ infiltration by opportunistic infections [eg, cytomegalovirus or M avium complex]). Abdominal fullness, regardless of the cause, has been identified as one of the most important symptoms influencing weight loss in Page 2 of 10 patients with unresectable malignancy [15]. Diarrhea is the most common gastrointestinal tract symptom in patients with HIV infection. It is often difficult to treat and may become a major debilitating aspect of a patient's illness. Not infrequently, diarrhea is associated with decreased oral intake, perhaps because patients attempt to reduce fecal output by restricting food intake, or because unabsorbed nutrients in the gastrointestinal tract suppress appetite. Similarly, diarrhea is a prominent symptom in patients with certain tumors, such as metastatic islet-cell cancers. Appetite Stimulants Anorexia interferes with quality of life and social interaction; the enjoyment of meals with family and friends; and overall performance status. Although weight maintenance and/or improvement in nutritional status have not been proven to enhance survival, there is little doubt that an improvement in appetite favorably affects quality of life. In patients with an intact gastrointestinal tract and the functional ability to swallow, anorexia has been identified as an important target for therapeutic interventions. Because decreased oral intake is a major contributor to the weight loss associated with HIV infection and advanced cancer, pharmacologic interventions, until recently, have focused on appetite stimulation. Corticosteroids Numerous uncontrolled studies have advocated the use of corticosteroids for the treatment of cancer-related anorexia. Prospective, double-blind placebo-controlled trials in patients with cancer-associated anorexia have demonstrated that corticosteroid treatment enhances appetite but does not significantly improve body weight. Moertel et al randomized 116 patients with advanced gastrointestinal malignancies to receive placebo or dexamethasone (0.75 or 1.5 mg orally four times daily) [16]. Although the objective of the trial was to evaluate the antineoplastic effect of dexamethasone, the patients randomized to dexamethasone noted significant improvement in appetite after 2 weeks of therapy. Unfortunately, the appetite improvement disappeared after 4 weeks of treatment and was not associated with weight gain or a survival benefit. A randomized, double-blind, placebo-controlled trial of prednisolone (5 mg orally three times daily) in a similar patient population also reported improved appetite with steroid therapy that failed to translate into weight gain [17]. Bruera et al described the results of a 14-day, randomized, double-blind placebo-controlled, crossover trial of oral methylprednisolone (16 mg twice daily) in patients with cancer anorexia and cachexia. Patients received their initial drug assignment for 5 days, followed, after a 2-day washout period, by treatment with the other medication for 5 additional days [18]. At the completion of the double-blind phase on day 13 of the trial, all patients were placed on 32 mg/d of methylprednisolone, on an open basis, for another 20 days. A statistically significant enhancement of appetite was noted during steroid therapy, but the benefits were short lived. At the completion of the 20-day open phase trial, all of the nutritional parameters had returned to baseline levels. Two randomized prospective trials have evaluated the efficacy of intravenous methylprednisolone for cancer cachexia. Robustelli et al randomized 403 patients to 8 weeks of treatment with methylprednisolone (125 mg IV daily) or placebo [19]. Compared with placebo, methylprednisolone was associated with a significantly greater improvement in patient-reported quality of life and appetite without significant weight gain. An 8-week placebo-controlled trial of methylprednisolone (125 mg IV daily) vs placebo in 173 female patients with terminal cancer also noted significant appetite improvement with corticosteroid treatment [20]. The short-term positive impact of corticosteroids on appetite, coupled with their lack of effect on body weight and potential for serious side effects, has limited the use of these agents as a primary treatment for cancer-associated anorexia and cachexia. Prolonged corticosteroid treatment has been associated with immunosuppression, proximal muscle weakness, delirium, osteoporosis, electrolyte imbalance, hyperglycemia, and fluid retention, to name a few of the long-term effects. To date, corticosteroids have not been well evaluated as a treatment for anorexia in the setting of HIV infection. Cyproheptadine Cyproheptadine is an antihistamine with antiserotonergic properties that is approved in the United States for the treatment of allergic disorders. In early clinical trials with this agent, improvements in appetite and weight gain were noted in geriatric patients, adults with essential anorexia, and Page 3 of 10 adolescents with anorexia nervosa. Because of the suggested appetite enhancement with this agent, a randomized, double-blind, placebo-controlled trial was performed in which 295 patients with advanced cancer were randomized to receive either placebo or oral cyproheptadine (8 mg three times daily) [21]. The median time on the study was slightly over 1 month. Only 25% of the subjects completed the planned 3 months of therapy; the remaining 75% had to discontinue treatment due to clinical deterioration. For treated patients, cyproheptadine led to minimal appetite enhancement without an increase in body weight. Cyproheptadine has not been tested in patients with HIV-associated anorexia. Hydrazine Sulfate Hydrazine sulfate is a metabolic inhibitor that has been evaluated as an antineoplastic agent and as a potential therapy for the amelioration of cancer-associated cachexia and anorexia. Clinical trials failed to show any antineoplastic activity of this agent [22]. However, the purported mechanism of hydrazine sulfate, ie, inhibition of gluconeogenesis, and in vitro data indicating that the drug inhibits the cytolytic activity of TNF in cell culture, suggested hydrazine sulfate as a potential treatment for cancer cachexia [23]. Multiple clinical trials in the 1970s and early '80s arrived at conflicting results regarding the utility of this agent for the treatment of cachexia [22]. Because of the unsettled controversy surrounding hydrazine sulfate, three large randomized clinical trials have recently been performed. Two of the trials randomized patients to hydrazine sulfate or placebo in addition to standard therapy for non-small-cell lung cancer [24,25]. The third trial randomized patients with colorectal carcinoma to receive hydrazine sulfate or placebo without concurrent systemic antineoplastic treatment [26]. All three trials failed to demonstrate benefit from hydrazine sulfate use, either as an antineoplastic agent or for the amelioration of cancer-associated anorexia. These data have dampened enthusiasm for further evaluation of hydrazine sulfate for the treatment of HIV-associated anorexia. Cannabinoid Derivatives The appetite-enhancing effects of marijuana and its derivatives have been well documented. At least one randomized study found dronabinol (delta-9-tetrahydrocannabinol [Marinol]), the primary psychoactive component of marijuana, to be a more effective antiemetic than the phenothiazines and more frequently associated with increased oral intake [27]. Dronabinol has been evaluated in phase II studies for its effect as an appetite stimulant in patients with cancer anorexia. In a 6-week dose-ranging study, 30 patients with unresectable cancer received 2.5 mg of dronabinol daily, 2.5 mg twice daily, or 5 mg once daily [28]. Patients in all treatment groups continued to lose weight, although the rate of weight loss decreased. In the two higher-dose arms, both mood and appetite improved. Five patients discontinued treatment because of adverse effects. A phase II study reported on the effect of 4 weeks of higher-dose dronabinol (2.5 mg orally three times daily) on appetite in patients with advanced cancer and anorexia [29]. Of 18 evaluable patients, 13 reported an improvement in appetite. In contrast to prior studies, only 4 of the 13 patients had significant side effects, including only one case of neuropsychologic toxicity (slurred speech). There were no reports of somnolence or dysphoria. This study suggests that in well-selected patients with advanced cancer, dronabinol may be an effective intervention to stimulate appetite. More recent studies have focused on the appetite-enhancing effect of dronabinol in patients with HIV infection. Gorter et al reported on 10 AIDS patients treated with dronabinol (2.5 mg orally three times daily) in a noncomparative unblinded study. Patients remained on the study from 4 to 20 weeks [30]. Dronabinol resulted in a median weight change of kg/mo, and 7 of the 10 patients gained weight. The appetite-enhancing effect of dronabinol in HIV-infected patients was further evaluated in a multicenter, randomized, double-blind, placebo-controlled study [31]. Patients were randomized to receive placebo or dronabinol (2.5 mg orally twice daily 1 hour before lunch and 1 hour before supper). The primary study end points were changes in appetite, mood, and weight. Of 139 patients enrolled in the trial, 89 were evaluable for response. As compared with placebo, dronabinol resulted in an improvement in appetite, as measured by a visual analog scale (P =.01); a trend toward weight gain after 6 weeks (-.4 vs +.1 kg; P =.21); and an improvement in mood (P =.005), as assessed by a visual analog scale. The dronabinol dose had to be reduced to 2.5 mg once daily in 18% of patients due to neurologic toxicity. After completion of the 6-week randomized study, patients could continue on dronabinol, unblinded, for up to 1 year. Of the 90 patients for whom data are available from the unblinded study extension, appetite stimulation was maintained for at least 6 months and an increase in body weight of equal to or more than 2kg was reported in 38% of patients. Page 4 of 10 Megestrol Acetate Megestrol acetate, a synthetic orally active progestational agent used widely for the treatment of metastatic breast cancer and endometrial cancer, has been reported to stimulate appetite and weight gain. When treated with conventional doses (160 mg/d) of this agent, approximately 30% of breast cancer patients gain weight. A phase I-II study of high-dose megestrol acetate (480 to 1,600 mg/d) for the treatment of advanced breast cancer reported marked appetite stimulation and weight gain of more than 2 kg in 81% of patients [32]. Several controlled randomized studies have subsequently demonstrated the beneficial effect of megestrol acetate on cancer cachexia [33,34]. Across the studies, megestrol acetate-treated patients reported improved appetite and caloric intake, increased body weight, and improved sense of well-being. The observed weight gain appeared to be nonfluid weight, primarily adipose tissue, based on the lack of clinically evident edema or ascites and on body composition studies [35]. Because of the perceived appetite-enhanc
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