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Management of cancer anorexia/cachexia

Management of cancer anorexia/cachexia
Literature review current through: Jan 2024.
This topic last updated: Aug 31, 2023.

INTRODUCTION — The cancer-related anorexia/cachexia syndrome (CACS) is characterized by anorexia and a loss of body weight associated with reduced muscle mass and adipose tissue. In addition to a variable contribution from decreased energy intake, resting energy expenditure can be elevated in CACS in association with increases in both muscle protein breakdown and lipolysis, changes that appear to be due in part to an inflammatory response with the elaboration of cytokines, including tumor necrosis factor-alpha, interleukin (IL) 6, and IL-1 beta. Tumor-elaborated factors may play an important role. Unlike starvation, weight loss in cancer arises both from loss of muscle and fat. (See "Pathogenesis, clinical features, and assessment of cancer cachexia".)

This topic review will cover treatment for patients with CACS. The clinical features and pathogenesis of CACS, diagnostic criteria for CACS, oral and parenteral nutritional support for patients with cancer, and a general discussion of assessment and management of anorexia/cachexia in palliative care patients with advanced life-threatening illness are provided elsewhere. (See "Pathogenesis, clinical features, and assessment of cancer cachexia" and "The role of parenteral and enteral/oral nutritional support in patients with cancer" and "Assessment and management of anorexia and cachexia in palliative care".)

PREVALENCE AND CLINICAL SIGNIFICANCE — The CACS is frequently seen in patients with advanced cancer. One study evaluated 644 consecutive, mostly ambulatory cancer patients; decreased appetite, decreased food intake, and weight loss in excess of 5 percent of premorbid weight were present in more than one-half [1]. Furthermore, 54 percent were underweight when compared with the calculated ideal body weight.

Weight loss in CACS is a marker for both progression of the syndrome and for prognosis [2]. In a multi-institutional, retrospective review of 3047 clinical protocol cancer patients from the Eastern Cooperative Oncology Group, weight loss of more than 5 percent of premorbid weight prior to the initiation of chemotherapy was predictive of early mortality. Weight loss was independent of disease stage, tumor histology, and patient performance status in its predictive value [2]. There was also a trend towards lower response rates with the use of chemotherapy among weight-losing patients. This trend reached statistical significance only among patients with breast cancer.

OVERVIEW OF ASSESSMENT AND MANAGEMENT — All cancer patients should be assessed for nutritional status and weight loss. The clinical assessment for patients with anorexia or cachexia includes a careful history that is focused on nutritional issues including risk factors that compromise the ability to obtain or take in nutrition, and a physical examination focusing on loss of subcutaneous fat, muscle wasting (temporal region, deltoids, and quadriceps with loss of bulk and tone by palpation), edema (sacral or ankle), or ascites. The most commonly used objective measures of nutritional status are serial measurement of body weight and assessment of dietary intake, while subjective information on nutritional status can be provided by malnutritional assessment tools. Laboratory measures of nutritional status (eg, albumin, transferrin) are rarely needed for assessment of nutritional status, although some screening tools (eg, the Nutrition Risk Index) do include a measurement of serum albumin. These issues are all addressed in more detail elsewhere. Of note, substantial data do support that computed tomography-estimated muscle mass is an effective means of determining whether a patient has sarcopenia. (See "Assessment and management of anorexia and cachexia in palliative care", section on 'Clinical assessment'.)

Our approach to management of CACS follows published guidance from the American Society of Clinical Oncology (ASCO) [3,4]:

Communication regarding cachexia management and issues around feeding, particularly in the setting of advanced cancer or end of life care, should involve caregivers as well as patients. (See 'Psychosocial impact and counseling' below.)

Optimizing management of major contributors to anorexia, such as chronic nausea, constipation, taste alterations, dyspnea, and depression (nutrition impact symptoms) may improve appetite. (See 'Treating nutrition impact symptoms' below.)

Referral of patients with CACS to a registered dietician can provide important support to patients and their caregivers, although referral is not mandatory for all patients. The goals include practical and safe advice for feeding; education regarding high-protein, high-calorie, nutrient-dense food; and advice against fad diets and other unproven or extreme diets. (See 'Dietary counseling' below.)

For most patients with advanced cancer and CACS, we suggest not routinely using enteral tube feeding or parenteral nutrition to manage cachexia. A short-term trial of parenteral nutrition may be offered to a very select group of patients, such as those who have a reversible bowel obstruction, short-bowel syndrome, or other issues contributing to malabsorption, but are otherwise reasonably fit. Discontinuation of previously initiated parenteral or enteral nutrition near the end of life is appropriate. (See 'Parenteral or nonvolitional enteral nutrition' below and "The role of parenteral and enteral/oral nutritional support in patients with cancer", section on 'Indications and benefits of nutritional support in cancer patients' and "Assessment and management of anorexia and cachexia in palliative care", section on 'Indications for artificial nutritional support'.)

The decision to use pharmacologic agents for appetite stimulation is highly dependent on the values and preferences of individual patients and other considerations such as degree of anorexia or weight loss, comorbidities, risk of adverse effects, life expectancy, and goals of care. The primary benefits associated with these drugs are increased appetite and modest weight gain, not improved survival. (See 'Potentially beneficial agents' below.)

When it is decided that a pharmacologic agent should be used, we use relatively low doses of olanzapine (2.5 to 5 mg/day). Data supporting the use of this drug come from three clinical trials [5-7]. Consistent with updated ASCO guidelines [4], another option is to use a progesterone analog (megestrol acetate or medroxyprogesterone acetate) or dexamethasone, but potential benefits must be balanced with risks (edema, thromboembolic events, increased mortality). (See 'Progesterone analogs' below and 'Glucocorticoids' below.)

We recommend against the use of hydrazine sulfate. We suggest not using inhaled cannabinoids, cannabis, inhibitors of tumor necrosis factor, insulin, or melatonin. (See 'Not recommended' below.)

Evidence is inconclusive regarding the benefits of many other treatments, including androgens and selective androgen receptor modulators; anamorelin; cyproheptadine; long-chain omega-3 fatty acids; vitamins, minerals, and other dietary supplements; nonsteroidal anti-inflammatory drugs; thalidomide; mirtazapine; and combination approaches, and thus, there is insufficient evidence to recommend either for or against the use of these agents. (See 'Insufficient evidence to recommend for or against' below.)

Outside of the context of a clinical trial, no recommendation can be made for other interventions such as exercise; although, exercise, as tolerated, is generally a good clinical recommendation for most patients. (See 'Exercise' below.)

GENERAL ASPECTS

Psychosocial impact and counseling — Loss of appetite and alterations in appearance as a result of cachexia are distressing to patients and especially to their caregivers and family [8]. Caregivers may misinterpret lack of eating as a failure of the caregiver to provide adequate care, and this may be compounded by familial and/or cultural beliefs that equate feeding and sharing food with the demonstration of love and hope [9,10].

The social benefits of being at the dining table with other family members should be encouraged. The pleasure of tasting food should be emphasized over total caloric intake. In general, patients with anorexia/cachexia syndrome who are able to eat should be recommended to have small, frequent meals that are dense in calories (eg, eggs, liquid nutritional supplements). Other strategies to enhance caloric intake include eating meals that require little preparation (eg, microwaveable) and resting before meals.

Issues around eating and feeding can become more difficult near the end of life; the following discussion points should be emphasized with both patients and their caregivers [3,11]:

Loss of appetite is common in patients with advanced cancer and may be the result of the cancer process itself.

Trying to force a patient to eat is usually counterproductive, potentially leading to increased aspiration, nausea and/or vomiting. Furthermore, when marked appetite loss is present, such efforts can lead to decreased social interactions and increased patient distress and possible avoidance regarding interactions with family and caregivers.

For most patients with advanced cancer and cachexia, providing extra calories by feeding tubes and/or the intravenous route does not improve outcomes.

For caregivers, it might be best to listen to and support the patient in a variety of other ways (eg, giving the patient a massage or applying lip moisturizer) instead of trying to talk them into eating more.

Referral to a registered dietician may provide patients and their caregivers an opportunity to discuss concerns and challenges related to nutrition, appetite, and meal planning. However, referral is not mandatory for all patients.

Treating nutrition impact symptoms — Symptoms such as depression, dysgeusia, pain, excessive drowsiness, nausea, and constipation may contribute to poor oral intake. These nutrition impact symptoms are frequent among patients with CACS, and they are associated with adverse outcomes such as weight loss and shorter survival [12,13]. Retrospective studies suggest clinical benefit from successful treatment of secondary nutrition impact symptoms [12,13]. (See "Assessment and management of anorexia and cachexia in palliative care", section on 'Dietary and lifestyle modifications' and "Assessment and management of anorexia and cachexia in palliative care", section on 'Secondary nutrition impact symptoms'.)

DIETARY COUNSELING — Referral of patients with CACS to a registered dietician can provide important support to patients and their caregivers. The evidence to support benefit from dietary counseling and oral nutritional supplementation or both in terms of weight gain and improved appetite is limited and inconclusive, in part because of a lack of a clear definition of these interventions [14-17]. However, a dietician can help individual patients meet estimated protein and caloric needs as much as possible, and discourage the use of potentially harmful dietary supplement use, and fad, unproven, or extreme diets [3]. One-half or more of cancer patients have reported using dietary supplements during treatment and either pursue or are interested in extreme or unproven forms of dietary restriction [18,19].

PARENTERAL OR NONVOLITIONAL ENTERAL NUTRITION — For most patients with advanced cancer and CACS, we suggest not routinely using enteral tube feeding or parenteral nutrition to manage cachexia. However, there are specific situations in which a patient has a nonfunctioning alimentary tract but does not have extensive organ involvement by a cancer that portends a very poor prognosis [3]. One example is a patient with a relatively indolent malignancy causing a multifocal bowel obstruction. However, even in such situations, the risks, benefits, and cost of total parenteral nutrition (TPN) should be discussed with the patient and caregivers. If such a trial is initiated, benefit should be evaluated after a fixed time period with a specific goal. If no significant benefit has occurred, and when death appears imminent, TPN should be stopped. (See "Stopping nutrition and hydration at the end of life".)

The indications, benefits, and harms of parenteral and enteral nutritional support in advanced cancer are provided in detail elsewhere. (See "The role of parenteral and enteral/oral nutritional support in patients with cancer", section on 'Indications and benefits of nutritional support in cancer patients'.)

PHARMACOLOGIC TREATMENTS

Potentially beneficial agents — There are no US Food and Drug Administration (FDA)-approved medications for treatment of CACS. The decision to use pharmacologic agents for appetite stimulation in cancer patients with cachexia is highly dependent on the values and preferences of the patents and other considerations such as degree of anorexia or weight loss, comorbidities, risk of adverse effects, life expectancy, and goals of care. The primary benefits associated with these drugs are increased appetite and modest weight gain, not improved survival.

If the decision is made to treat, three available, well-studied options are olanzapine, progesterone analogs, and glucocorticoids.

Olanzapine — Olanzapine (2.5 to 5 mg daily) is the preferred option for treating patients with cancer-associated anorexia/cachexia [4]. Supporting evidence comes from several randomized trials:

In a double-blind randomized trial, 124 patients starting chemotherapy for lung, pancreaticobiliary, or stomach cancers were randomly assigned to olanzapine 2.5 mg daily or placebo [6]. Of note, patients in both arms received 5 mg/day of olanzapine for four days with each dose of chemotherapy. At least 5 percent weight gain occurred in 60 percent of patients in the olanzapine arm versus 9 percent of patients in the placebo arm (p <0.001). Substantial appetite improvement was seen in 43 percent of the active therapy arm versus 30 percent of patients receiving a placebo (p <0.001). Grade 3 chemotherapy toxicity was less common with olanzapine (12 percent versus 37 percent, p = 0.002). There was no apparent olanzapine-associated toxicity, with one patient noting potential drug toxicity with olanzapine versus two with placebo.

Additional information came from a report of a randomized placebo-controlled trial of olanzapine in 30 patients with nausea and vomiting associated with advanced cancer who were not receiving chemotherapy or radiation therapy [7]. Appetite scores were unchanged in the placebo group at one week; however, scores improved significantly among those receiving olanzapine.

Earlier evidence to support olanzapine came from a study that involved 80 patients with advanced gastrointestinal or lung cancer who were randomly assigned to megestrol acetate alone at a dose of 800 mg/day or the same dose of megestrol plus olanzapine 5 mg/day for eight weeks [5]. The MD Anderson Symptom Inventory was used to objectively assess appetite. Patients receiving combined therapy had a significantly higher rate of improved appetite (64 versus 5 percent). In this trial, it is worth noting that the appetite stimulation with megestrol acetate was much less than has been noted in other trials. This may be because the patients had advanced cancer and were in a situation in which chemotherapy was not being administered.

Additional support for the potential utility of olanzapine for treatment of cancer cachexia is provided by data demonstrating considerable undesired weight gain among patients receiving olanzapine for psychiatric disorders. While most of the data that support the use of olanzapine for treating cancer-associated anorexia/cachexia come from patients with lung and abdominal cancers, it is reasonable to extrapolate these findings to patients with other types of cancers. One of the manuscripts supporting that olanzapine improved cancer-associated anorexia [7] included patients with breast, gynecologic, prostate, and genitourinary cancers. There are no substantial data that support a difference in the efficacy of olanzapine in any particular type of advanced cancer histology or in patients who are, or are not, receiving concomitant cytotoxic therapy.

Progesterone analogs — Megestrol acetate improves appetite and body weight in patients with cancer cachexia, but the type of weight gain is primarily adipose tissue rather than skeletal muscle [20]. Toxicities include thromboembolic events, edema, and adrenal suppression. Similar findings have been observed with medroxyprogesterone acetate (MPA) [21].

A number of prospective, controlled randomized trials and several systematic reviews and meta-analyses have confirmed the modest efficacy of megestrol acetate and MPA for palliation of CACS [22-29]. The effectiveness of megestrol acetate and its potential superiority to other classes of agents (at least in terms of toxicity) are illustrated by the following observations:

The advantages of progesterone analogs over glucocorticoids and anabolic agents were demonstrated in a trial in which 475 patients with CACS were randomly assigned to treatment with megestrol acetate (800 mg/day), dexamethasone (4 mg/day), or fluoxymesterone (20 mg/day) [24]. The megestrol acetate and dexamethasone had similar efficacy in terms of appetite stimulation and weight gain, and both were superior to fluoxymesterone (which is no longer available). However, toxicity was more common with dexamethasone (myopathy, cushingoid body habitus, and peptic acid disease), which led some patients to discontinue treatment. There was no difference between the treatment groups in survival or quality of life.

A 2013 Cochrane review of megestrol for anorexia/cachexia syndrome concluded that when compared with placebo, megestrol significantly improves appetite, weight, and quality of life, but that there is a lack of benefit when megestrol was compared with other drugs [22]. However, edema, thromboembolic events, and deaths were more frequent in the patients treated with megestrol acetate. The authors concluded that megestrol was associated with increased mortality (relative risk 1.42, 95% CI 1.04-1.94), with greater risk at doses of ≥800 mg/day. A subsequent update concluded that such detrimental effects on survival are nonexistent [30].

Dose of megestrol acetate — Some studies have addressed the optimal dosing of megestrol acetate in patients with cancer [31-34]. In a dose-response trial, there was a positive relationship between appetite stimulation and increasing megestrol acetate doses ranging from 160 to 800 mg/day [31]. A higher dose, 1280 mg/day, was not more effective. The above-mentioned Cochrane review concluded that there was insufficient information to define the optimal dose of megestrol, but that higher doses (>160 mg) were more related to weight gain than were lower doses [22]. On the other hand, mortality was more frequent in patients receiving doses ≥800 mg daily.

Most published studies tested megestrol acetate tablets rather than the oral suspension. However, the liquid form is associated with good compliance, lower expense, and possibly better bioavailability. Our practice is to begin with liquid megestrol acetate at a dose of 400 mg/day in patients who really want appetite stimulation with megestrol acetate (as opposed to olanzapine), despite the risks noted above. While a dose-response trial illustrated that 800 mg per day stimulated appetite a little more than did 480 mg per day, this was with a tablet formulation that is not as bioavailable as is the liquid formulation. Also, cost factors do come into play [31]. A high-potency liquid formulation is available, which contains 625 mg in 5 mL, but may be considerably more expensive.

Side effects — Megestrol acetate may increase the risk of edema and certainly increases thromboembolic problems [22], particularly in patients receiving concomitant chemotherapy [35]. Megestrol may cause symptomatic suppression of the hypothalamic pituitary adrenal axis [36-38]. In the presence of serious infection, surgery, or trauma, this complication may be life threatening if not anticipated and treated. In male patients with cancer, treatment with megestrol may also suppress the gonadal axis, resulting in symptomatic androgen deficiency [38]. (See "Causes of secondary and tertiary adrenal insufficiency in adults".)

Use in prophylaxis — The efficacy of these agents in the treatment of CACS led investigators to study their role for prophylaxis of this problem. The benefit of prophylactic progesterone analogs has not been seen despite several prospective randomized clinical trials, as is illustrated by the following observations:

In one trial, 243 patients with newly diagnosed, extensive-stage small cell lung cancer were randomly assigned to megestrol acetate (800 mg/day) or placebo [35]. Although megestrol reduced nausea somewhat, there was no improvement in tumor response rate, survival, or quality of life. An increased incidence of thromboembolic events was observed in patients treated with megestrol acetate.

A second trial randomly assigned 134 patients with advanced, incurable, nonhormone-sensitive cancer to MPA (500 mg twice daily) or placebo [39]. At 12 weeks, MPA was associated with improved appetite and a mean weight gain of 0.6±4.4 kg compared with a mean weight loss of 1.4±4.6 kg in the placebo-treated group (p = 0.04 for the between group difference). However, there was no improvement in global quality of life.

Glucocorticoids — Glucocorticoids improve appetite to a similar degree to that seen with progesterone analogs. However, given the toxicities and decline in efficacy associated with long-term use, their role as an appetite stimulant often is limited to those with an estimated life expectancy of weeks to a couple of months.

The mechanism of action of corticosteroids in CACS has not been established. Euphorigenic and anti-inflammatory effects, and perhaps stimulation of orexigenic hormones within the hypothalamus, may be responsible for an increase in appetite.

At one time, glucocorticoids were first-line therapy for appetite stimulation in CACS. In the first placebo-controlled trial in CACS, dexamethasone alleviated cancer anorexia on a short-term basis [40]. This finding has subsequently been replicated by other studies, and both prednisolone and methylprednisolone have also been shown to be effective [41,42]. A year 2005 systematic review of six placebo-controlled trials reported improvement in appetite in most of the trials, but only two reported weight findings, with no significant improvement in the glucocorticoid arms [25]. The authors concluded that the optimal dose and duration of glucocorticoid use were unknown.

A reasonable dose of dexamethasone in this setting is 4 mg/day, although lower doses may also be effective.

Many patients treated with glucocorticoids experience an increase in appetite and sense of wellbeing but not weight gain, compared with placebo [40-42]. However, the duration of appetite stimulation is often short-lived. Furthermore, prolonged steroid therapy produces myopathy and a wide variety of other side effects. (See "Major adverse effects of systemic glucocorticoids".)

Insufficient evidence to recommend for or against — The evidence is inconclusive regarding the benefits of many other treatments for cancer cachexia, including androgens and selective androgen receptor modulators; anamorelin; cyproheptadine; long-chain omega-3 fatty acids; vitamins, minerals, and other dietary supplements; nonsteroidal anti-inflammatory drugs (NSAIDs); thalidomide; mirtazapine; and combination therapies. None of these approaches can be recommended at present.

Androgens and selective androgen receptor modulators — Anabolic steroids have been hypothesized to have a selective effect that induces an increase in lean body mass, even while body fat decreases and there is a decrease in overall weight. Two systematic reviews of cachexia management [25,29] have included three randomized trials of androgens or androgen receptor modulators:

In a three-arm trial described above in which 475 patients with CACS were randomly assigned to treatment with megestrol acetate (800 mg/day), dexamethasone (4 mg/day), or fluoxymesterone (20 mg/day), megestrol was better than fluoxymesterone for improving appetite [24]. (See 'Progesterone analogs' above.)

In an early trial of 37 patients with non-small cell lung cancer (NSCLC) receiving chemotherapy, patients who were randomly assigned to four weeks of nandrolone were less likely to lose weight than were those in the control group (12 versus 25 percent) but the difference was not statistically significant [43].

The use of antiandrogen therapy is also supported by a placebo-controlled trial evaluating the benefit of the selective androgen receptor modulator enobosarm (GTx-024) in 159 patients with weight loss due to cancer [44]. Compared with baseline, patients assigned to either of two doses of enobosarm had significant increases in lean body mass for up to 113 days (median 1.2 and 1 kg with 1 and 3 mg daily, respectively), while changes in lean body mass with placebo (median 0.2 kg) were not statistically significant.

Further phase III studies of enobosarm have been completed [45], but published results are not available. Enobosarm is not commercially available in any country.

Modest benefit was also suggested in a small double-blind placebo-controlled trial of weekly injections of testosterone enanthate in 28 patients with cancer-associated loss of muscle mass [46]. Those randomized to testosterone increased lean body mass by 3 percent, compared with a loss of 3 percent in the control group.

Growth hormone and ghrelin analogs (anamorelin) — Recombinant human growth hormone in conjunction with protein restriction increased skeletal muscle mass at the expense of the tumor when used in animals [47]. However, the use of recombinant growth hormone in critically ill adults has been associated with high mortality rates, perhaps because of a diversion of amino acids and energy to skeletal muscle and away from the acute phase response, thus blunting host defenses [48,49].

An alternative approach has been the use of ghrelin, which is a ligand for growth hormone secretagogue receptor and can induce release of growth hormone. Preliminary small, randomized studies have shown that multiple doses of parenteral ghrelin therapy can be safely administered to patients with advanced cancer [50-52]. However, only one of these trials was placebo controlled, and a Cochrane review of all three trials (totaling only 59 cancer patients) concluded that there is insufficient evidence to support or refute any benefit of ghrelin in people with cancer cachexia [53]. (See "Ghrelin".)

On the other hand, studies of anamorelin, an oral ghrelin mimetic, in palliative care populations have been promising [54-61]:

ROMANA 1 (n = 484) and ROMANA 2 (n = 495) were identically designed phase III studies that randomly assigned patients with inoperable stage III or IV NSCLC and cachexia in a 2:1 ratio to receive either anamorelin (100 mg daily) or placebo for 12 weeks in conjunction with chemotherapy [56]. Cachexia was defined as a ≥5 percent weight loss within the past six months or body mass index (BMI) <20 kg/m2. In both studies, patients randomly assigned to placebo continued to lose lean body mass while those receiving anamorelin gained (at 12 weeks, +0.99 versus -0.47 kg with placebo in ROMANA 1; +0.65 versus -0.98 kg with placebo in ROMANA 2). Patients assigned to anamorelin also had a significant increase in body weight (2.2 versus 0.14 kg in ROMANA 1, and 0.95 versus -0.57 kg in ROMANA 2) and significant improvement in anorexia/cachexia symptoms. There were no significant differences in fist-grip strengths between the two study arms, and survival curves were overlapping. The most common adverse events were nausea and hyperglycemia.

In a later extension study of 513 patients who were enrolled in both trials and who continued beyond 12 weeks (ROMANA 3), the improvements in weight and anorexia/cachexia symptoms were maintained over 12 to 24 weeks with no new signals for treatment-emergent adverse effects [62].

Two meta-analysis reported improvements in body weight, lean body mass, and patient-reported quality of life with anamorelin [59,63]. In both, anamorelin did not improve overall survival or hand grip strength, and there were no significant differences between groups for frequency or severity of any adverse events.

Anamorelin has not received approval for use in treating cancer cachexia in the United States or Europe, but it has been approved (December 2020) for use in Japan, largely based upon weight gain observed in phase II trials.

Cyproheptadine — Cyproheptadine is a histamine and serotonin antagonist that has been observed to cause weight gain in observational studies of patients with advanced cancer. In a large, placebo-controlled trial that included 295 patients with the CACS, cyproheptadine (8 mg three times daily) had a mild stimulatory effect on appetite but failed to lead to weight gain [64].

Cyproheptadine may be effective in patients with carcinoid syndrome who have anorexia/cachexia. In these patients, cyproheptadine presumably acts by directly counteracting increased serotonin activity [65]. (See "Staging, treatment, and post-treatment surveillance of non-metastatic, well-differentiated gastrointestinal tract neuroendocrine (carcinoid) tumors".)

Omega-3 fatty acids — Long-chain omega-3 fatty acids are found in marine products, such as fish oil. In vitro studies have shown that these compounds can attenuate the stimulation of adenylate cyclase activity and lipolysis produced by tumor-derived lipid-mobilizing factor [66]. They may also suppress interleukin 6 production in patients with pancreatic cancer cachexia [67].

The effectiveness of omega-3 fatty acids has been assessed in a number of randomized trials, without consistent evidence of a beneficial effect [68-76]. A 2007 Cochrane database meta-analysis concluded that there were insufficient data to establish that supplementation with omega-3 fatty acids was better than placebo [77]; a similar conclusion was reached in a later 2012 systematic review [78]. On the other hand, a separate analysis that was limited to patients with pancreatic cancer suggested that consumption of omega-3 fatty acids may improve weight, lean body mass, and survival [79].

It is, however, reasonable to use these fats as a source of calories for patients with CACS. Natural sources of omega-3 fatty acids, such as salmon, are nutrient-dense foods and can be included in the diet as tolerated [3].

Vitamins, minerals, and other dietary supplements — Information from pilot studies suggested that specific amino acid nutritional formulations with branched chain amino acids, arginine, and glutamine might have had some efficacy in alleviating CACS [80]. However, placebo-controlled clinical trials have yet to be performed. At least one prospective, multicenter, placebo-controlled, randomized, double-blind trial of carnitine supplements (4 g daily) in 72 patients with advanced pancreatic cancer and weight loss reported an increase in BMI, quality of life, and a trend toward improved survival with carnitine supplements [81]. (See "The role of parenteral and enteral/oral nutritional support in patients with cancer", section on 'The perioperative setting'.)

Similarly, benefit from creatine could not be shown in a placebo-controlled randomized trial in 263 patients with CACS and advanced cancer [82].

A year 2017 systematic review evaluated vitamins, minerals, and other dietary supplements including magnesium, vitamin E in combination with omega-3 fatty acids, vitamin D, vitamin C, beta-hydroxy-beta-methylbutyrate, arginine, glutamine, and L-carnitine [83]. Although some studies reported improved lean body mass or BMI, the authors concluded that the evidence was insufficient to concluding that there was benefit to any of these approaches.

NSAIDs — Two meta-analyses addressing the benefit of nonsteroidal anti-inflammatory drugs (NSAIDs) for treatment of cancer cachexia both concluded that NSAIDs improved body weight or quality of life in some studies, but the evidence was insufficient that there is clear evidence of benefit [39,84].

There are conflicting data as to whether NSAIDs enhance outcomes with megestrol in this setting, with one trial demonstrating no benefit from the addition of celecoxib to megestrol in 90 patients with a gastrointestinal cancer and weight loss [85], and a second trial suggesting that combined ibuprofen plus megestrol acetate was better than megestrol plus placebo at maintaining weight [86]. (See 'Combination therapy' below.)

Thalidomide — The use of thalidomide, a potent inhibitor of tumor necrosis factor (TNF)-alpha production, has been associated with weight gain in patients with tuberculosis or HIV infection. (See "Assessment and management of anorexia and cachexia in palliative care", section on 'Other agents'.)

There is insufficient evidence to refute or support the use of thalidomide for cancer cachexia:

A 2012 Cochrane analysis could not perform a meta-analysis due to the small number and high heterogeneity of the studies. However, the narrative review concluded that there is insufficient evidence to support or refute the use of thalidomide for the management of cachexia in patients with advanced cancer [87].

A year 2018 systematic review of pharmacologic agents for cancer cachexia included two randomized trials of thalidomide [29]. One small, placebo-controlled trial of 50 patients with advanced pancreatic cancer suggested modest benefits in preventing weight loss using thalidomide 200 mg/day [88]. However, other endpoints such as survival and quality of life showed no differences between groups. A year 2012 placebo-controlled trial was unable to draw clear conclusions [89].

Mirtazapine — At standard doses, the tetracyclic antidepressant mirtazapine induces weight gain and increases food intake. (See "Serotonin-norepinephrine reuptake inhibitors: Pharmacology, administration, and side effects".)

Benefit in CACS was suggested in a phase II trial in which 17 nondepressed patients with CACS received an eight-week course of mirtazapine (15 to 30 mg by mouth daily) [90]. Four of 17 patients gained 1 kg or more, and 24 percent reported improved appetite. However, a more recent trial was not able to support any benefit for this drug [91].

Combination therapy — The role of combined therapy for treatment of CACS is unclear. Further studies are needed before it can be concluded that any combination of agents is safe and more effective than single-agent therapy.

Combinations that have been tested in controlled trials include the following:

As noted above, olanzapine plus megestrol acetate was better than megestrol acetate alone but was not compared with olanzapine alone [5].

Ibuprofen plus megestrol acetate was reported to be better than megestrol plus placebo at maintaining weight [86].

In another trial, carnitine supplements (4 g/day) and celecoxib (300 mg/day) with or without megestrol acetate were studied and found to result in an identical response for the treatment of cancer cachexia [92].

Combinations of up to four different interventions have been studied preliminarily:

One trial included megestrol acetate plus carnitine supplements, celecoxib, and antioxidants compared with megestrol acetate alone in gynecological malignancies, and the combination arm was associated with improvement in lean body mass, resting energy expenditure, and global quality of life [93].

A randomized Italian trial attempted to address the role of combination therapy in patients with advanced stage cancer and CACS. In this five-arm study, 332 patients were randomly assigned to a four-month course of a progesterone analog (MPA or megestrol acetate), an eicosapentaenoic acid-enriched nutritional supplement, carnitine supplements, thalidomide, or a combination of all four interventions [94]. The combination arm appeared to have provided improved clinical outcomes, thereby suggesting that combination therapy merits further investigation.

Not recommended

Cannabis and cannabinoids — Unless the patient is participating in a clinical trial, we recommend against the use of synthetic cannabinoids, either as a single agent or in combination with megestrol, for treatment of CACS. We also suggest not using inhaled marijuana or ingested cannabidiol (CBD) oil for CACS given the lack of major evidence supporting benefit for this indication.

For the purpose of this review, "marijuana," "medical marijuana," and "cannabis" refer to naturally grown plant materials that are not regulated by the FDA and are procured by patients from legal marijuana dispensaries or street suppliers. The primary psychoactive ingredient is tetrahydrocannabinol (THC).

The term "cannabinoids" refers to several different entities:

CBD is a naturally occurring molecule without psychoactive properties that is found in the cannabis plant. It can be procured by patients from legal marijuana dispensaries or street suppliers (often as CBD oil), and a purified form is available by prescription (Epidiolex) in the United States and approved for treatment of refractory epilepsy. (See "Dravet syndrome: Management and prognosis" and "Lennox-Gastaut syndrome".)

There are three marketed drug products that contain synthetic THC. The only United States-approved cannabinoid (dronabinol [delta 9-THC]) is approved only for chemotherapy-induced nausea and vomiting. A second oral drug, nabilone, is approved in Canada and the UK, but was discontinued in the United States in 2019. Outside the United States, nabiximols, an oromucosal spray containing dronabinol plus CBD and smaller concentrations of other compounds (Sativex), is available and approved to relieve the spasticity associated with multiple sclerosis.

Anecdotal reports and small studies suggest that marijuana and THC supplementation stimulate appetite [95-97], prompting interest in the use of cannabinoids in patients with CACS.

A single phase II randomized double-blind placebo-controlled trial of CBD oil for relief of symptoms in advanced cancer concluded that CBD oil did not add value to the reduction in symptom distress (including loss of appetite) provided by specialist palliative care [98].

Unfortunately, synthetic cannabinoids have not been demonstrated to have activity against CACS in patients with advanced cancer [99,100], despite their activity in patients with advanced HIV disease (see "Assessment and management of anorexia and cachexia in palliative care", section on 'Cannabis and cannabinoids'):

In a cooperative group trial, 469 evaluable patients with anorexia and/or weight loss were randomly assigned to megestrol acetate, dronabinol, or both agents [99]. Significantly more patients had appetite improvement with megestrol acetate (73 versus 47 percent, compared with dronabinol) and nonfluid weight gain of ≥10 percent over baseline (13 versus 5 percent). Combined therapy with both megestrol acetate and dronabinol had no benefit beyond that obtained with megestrol acetate alone.

Similarly, benefit could not be shown in a European trial, in which 243 adults with advanced cancer and CACS were randomly assigned to dronabinol or a placebo [100]. No differences were observed between the groups in terms of appetite, quality of life, or cannabinoid-related toxicity.

Likewise, benefit could not be shown for nabilone (0.5 mg daily for two weeks, then 1 mg daily) in a small double-blind randomized trial of 47 patients with lung cancer [101]. Only 33 were assessable for outcome at eight weeks (the remainder were hospitalized, died, or were lost to follow-up). Although patients receiving nabilone had higher daily caloric intake at eight weeks (1181 versus 965 kcal per day), the difference was not statistically significant, there were no differences in appetite between the groups, and the higher caloric intake did not translate into any weight gain. Although there were reported improvements over baseline in some areas of health-related quality of life at eight weeks in those who received nabilone, there were imbalances between the two groups in baseline measures of several aspects of quality of life, and no significant differences in any aspect of quality of life emerged when the two groups were compared. Treatment-related side effects were not reported.

There are no high-quality published data on the efficacy of inhaled marijuana for patients with CACS.

TNF inhibitors — As noted above, CACS is characterized by anorexia and a loss of body weight associated with reduced muscle mass and adipose tissue and increases in both muscle protein breakdown and lipolysis. These changes appear to be due in part to an inflammatory response with the elaboration of cytokines including TNF-alpha. (See "Pathogenesis, clinical features, and assessment of cancer cachexia", section on 'Cytokines, inflammation, and the hypermetabolic state'.)

Therapeutic strategies targeting TNF that have been explored for treatment of CACS include pentoxifylline, a methylxanthine derivative that can inhibit TNF-alpha production by monocytes and T lymphocytes in vitro and reduce plasma concentrations and mRNA expression of this cytokine in patients with cancer [102,103], and etanercept and infliximab, both monoclonal antibodies that block TNF-alpha. Despite the compelling rationale underlying their use, small, placebo-controlled trials that have tested these three agents individually have failed to demonstrate benefit, reporting no positive effect on appetite or body weight [104-106].

Hydrazine sulfate — We recommend against the use of hydrazine sulfate for managing cancer-associated cachexia. Hydrazine sulfate, an inhibitor of phosphoenolpyruvate kinase, an enzyme involved in gluconeogenesis, was widely touted for the treatment of CACS in the distant past. However, three placebo-controlled clinical trials failed to demonstrate any benefit in patients with advanced cancer [107-109]. Furthermore, central and peripheral neurotoxicity has been described with hydrazine, which is similar to that observed with the hydrazine-derived drug, isoniazid. A fatal case of hepatorenal failure has also been described [110].

Insulin — Treatment with low doses of insulin has been assessed in patients with advanced cancer in an effort to limit the progression of weight loss and improve physical functioning. In a trial in patients with advanced cancer, 138 patients were randomly assigned to intensive supportive care with or without insulin (0.11 units/kg/day) [111]. There was a suggestion of improvement based upon multiple metabolic parameters and overall survival, and there was no evidence to suggest that the insulin stimulated tumor growth.

Additional clinical trials would be required to further assess potential benefits and toxicity of insulin in this setting.

Melatonin — Melatonin has been recommended to correct disturbances in the circadian rhythm; it also down-regulates production of TNF [49]. One study compared supportive care with the administration of melatonin (20 mg per night for three months) [112]. Although there was no difference in food intake, weight loss was significantly less in the melatonin-treated group. In a subsequent study, 70 consecutive patients with advanced NSCLC were randomized to receive chemotherapy with cisplatin and etoposide either alone or with melatonin (20 mg/day) [113]. The degree of cachexia and frequency of myelosuppression and neuropathy were significantly lower in those treated with melatonin, and the one-year survival of this group was increased (15 of 34 versus 7 of 36).

Unfortunately, benefit could not be confirmed in a subsequent double-blind trial in which 100 patients with advanced lung or gastrointestinal cancer, a history of weight loss ≥5 percent, and appetite scores ≥4 on a scale of 1 to 10 (with 10 being the worst appetite) were randomly assigned to melatonin 20 mg daily for 28 days or placebo [114]. The trial was closed after enrolling only 48 patients when a preplanned interim analysis disclosed no significant differences between the groups in appetite, weight, FAACT (Functional Assessment of Anorexia/Cachexia Therapy) scores, quality of life, toxicity, or survival.

EXERCISE — Outside of the context of a clinical trial, no recommendation can be made for other interventions such as exercise in patients with CACS.

The benefits of exercise to improve CACS are uncertain. A 2021 Cochrane review [115] identified four new studies [84,116-118] that had not been included in an earlier review [119]. These studies compared exercise against reasonable comparator arms and found no clear improvements in outcomes with exercise. The authors concluded that there is uncertainty of the effectiveness, acceptability, and safety of exercise for adults with cancer cachexia but assessed the certainty of the body of evidence as limited because of study limitations.

Several adequately powered randomized studies are underway to test exercise as a component of a multimodal cachexia intervention [120,121], and clearly high-quality research is needed and called for based on the conclusions of the meta-analysis cited directly above.

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topics (see "Patient education: Managing loss of appetite and weight loss with cancer (The Basics)")

SUMMARY AND RECOMMENDATIONS

The cancer-related anorexia/cachexia syndrome (CACS) is characterized by anorexia and a loss of body weight associated with reduced muscle mass and adipose tissue. While anorexia/cachexia is frequently seen in advanced cancer, it may also be a prominent feature of other end-stage, life-threatening illnesses. (See 'Introduction' above and "Assessment and management of anorexia and cachexia in palliative care".)

Our approach to management of CACS is as follows:

Communication regarding cachexia management and issues around feeding, particularly in the setting of advanced cancer or end-of-life care, should involve caregivers as well as patients. (See 'Psychosocial impact and counseling' above.)

Optimizing management of major contributors to anorexia, such as chronic nausea, constipation, taste alterations, dyspnea, and depression (nutrition impact symptoms), may improve appetite. (See 'Treating nutrition impact symptoms' above.)

Referral of patients with CACS to a registered dietician can provide practical and safe advice for feeding; education regarding high-protein, high-calorie, nutrient-dense food; and advice against fad diets and other unproven or extreme diets. However, referral is not mandatory for all patients. (See 'Dietary counseling' above.)

For most patients with advanced cancer and CACS, we suggest not routinely using enteral tube feeding or parenteral nutrition to manage cachexia (Grade 2C). A short-term trial of parenteral nutrition may be offered to a very select group of patients (eg, reasonably fit patients with a reversible bowel obstruction, short-bowel syndrome, or other issues contributing to malabsorption). (See 'Parenteral or nonvolitional enteral nutrition' above and "The role of parenteral and enteral/oral nutritional support in patients with cancer", section on 'Indications and benefits of nutritional support in cancer patients' and "Assessment and management of anorexia and cachexia in palliative care".)

For patients with cancer-associated anorexia/cachexia, we suggest olanzapine rather than other agents (Grade 2B). We use a relatively low dose of 2.5 to 5 mg/day. Randomized trials demonstrate improvements in appetite and weight and decreased nausea/vomiting in patients with advanced cancer. Other, less favored, options include a trial with drugs such as megestrol acetate and dexamethasone.

We do not use hydrazine sulfate, synthetic cannabinoids, inhaled cannabis, inhibitors of tumor necrosis factor, insulin, or melatonin for management of cancer-associated anorexia/cachexia.

The evidence is inconclusive for androgens and selective androgen receptor modulators; anamorelin; cyproheptadine; long-chain omega-3 fatty acids; vitamins, minerals, and other dietary supplements; nonsteroidal anti-inflammatory drugs; thalidomide; mirtazapine; and combination approaches, and none of these approaches can be recommended. (See 'Insufficient evidence to recommend for or against' above.)

The benefits and safety of exercise as a treatment for CACS are uncertain. (See 'Exercise' above.)

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Topic 2816 Version 39.0

References

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