Cachexia, a disease that can result from cancer-related fatigue, is characterized by

INTRODUCTION

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Cancer cachexia is a highly relevant clinical challenge for the practicing oncologist. Formed from the Greek words kakós (bad) and hexis (condition), cachexia is estimated to affect more than half of all patients with cancer.1 Symptomatic and physiologic sequels of cachexia include anorexia, muscle wasting, fatigue, anemia, edema, and taste changes, leading to decreased physical function, increased treatment-related toxicity, and poor prognosis.2 Despite the ubiquity of cachexia in clinical oncology practice, challenges remain regarding its prevention, early identification, and intervention.

To recognize cancer cachexia and intervene early, oncologists must understand at least the basics of its complex pathophysiology. In brief, cancer cachexia is a multifactorial syndrome characterized by involuntary loss of weight and skeletal muscle, leading to progressive functional impairment.3 Three main factors drive this syndrome: (1) metabolic dysregulation, which creates a negative energy balance; (2) increased catabolic drive for fat and protein breakdown; and (3) neurohormonal dysregulation (Fig 1).3 Attempts to prevent the onset and progression of cachexia have targeted these known pathophysiologic factors. To date, the approaches to identifying, diagnosing, preventing, and treating cancer cachexia have been limited and, unfortunately, are often ineffective.

FIG 1. Cancer cachexia pathophysiology and targeted treatments. APP, acute phase proteins; CRF, corticotropin-releasing factor; GH, growth hormone; IL-1, interleukin-1; LMF, lipid mobilizing factor; TNF-α, tumor necrosis factor α.

DEFINING CANCER CACHEXIA

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Despite the prevalence of cancer cachexia, establishing a clinically meaningful definition for use in clinical practice has been challenging. Traditionally, cachexia has been defined by a specified percentage of weight loss over time (ie, ≥ 5% weight loss in the preceding 6 months). However, assessment of weight loss alone does not reflect the complete scope of pathophysiologic changes or the clinical impact.4 To date, Fearon et al1 have completed the most exhaustive international effort to define cancer cachexia beyond weight loss. According to this new consensus definition, cancer cachexia is a “multifactorial syndrome defined by ongoing loss of skeletal muscle mass (with or without loss of fat mass) that cannot be fully reversed by conventional nutritional support and leads to progressive functional impairment.”(p490) This is a clear shift in how cancer cachexia is defined and requires that oncologists assess muscle loss, not simply weight loss. Cancer cachexia is composed of three distinct stages: (1) precachexia, (2) cachexia, and (3) refractory cachexia (Fig 2). Notably, the last stage—refractory cachexia—has been the focus of many clinical trials of novel, interventional agents. This is a particularly difficult phase in which to demonstrate the efficacy of cachexia therapy because refractory cachexia is characterized by a catabolic state that is not responsive to anticancer treatment, a low performance status, and a prognosis of survival of less than 3 months.1 It is this terminal stage of cachexia that is most frequently recognized by oncologists, yet it is also the stage at which interventions are the least likely to be effective, and it predicts limited survival.2 Weight-loss measures alone, however, ignore other changes such as occult muscle loss and/or fat gain, although when weight loss is present, it is useful for detecting patients at risk for poor outcomes.2 A recent study found that weight loss used as a screening tool can effectively detect patients at risk for worse physical function and quality of life (QoL) in non–small-cell lung cancer (NSCLC).6 However, prior evidence suggests that once patients experience a weight loss greater than 5%, they are already at a markedly increased risk of mortality.2 For this reason, more sensitive criteria are needed beyond weight loss to detect patients in the early stages of cachexia. These types of evaluations require measurements other than standard weight, such as instruments for muscle mass and/or physical activity.

FIG 2. Select summary of investigational pharmacologic agents for cancer-related cachexia with therapeutic agents aligned to represent the phase of cachexia tested on the basis of inclusion criteria compared with the consensus definition of cachexia. Adapted from Fearon et al1 and Ma et al.5 ActRII, [myostatin] activing receptor type II; BMI, body mass index; JAK, Janus kinase; NSCLC, non–small-cell lung cancer.

BODY COMPOSITION MATTERS MORE THAN WEIGHT

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Although it is a key challenge in identifying and treating cancer, cachexia has been accurately discriminating the constituents of body weight change. Gained weight might be desirable and may consist of functional muscle mass, but it may also be composed largely of fat (as induced by corticosteroids and progestins) or of additional water in the form of edema, ascites, or pleural effusion. The most common method for evaluating body composition in cancer cachexia clinical trials has been dual x-ray absorptiometry (DXA). DXA is used to measure total appendicular lean tissue including the extremities and is taken to be representative of muscle mass. However, DXA has several limitations in the oncology setting—varied availability, additional burden of a nonstandard scan, and increased study-related cost—and for these reasons, it is limited as a screening tool within oncology care. Because of these limitations, the International Cachexia Consensus recommends computed tomography (CT) or magnetic resonance imaging as a first choice over DXA for analyzing body composition.1 CT images acquired during routine patient care can be used to quantify body composition among patients with advanced cancer.7,8 For example, transverse CT images, typically at standard landmarks (eg, third lumbar) routinely present in CTs of the abdomen, have established correlates of whole-body fat and muscle mass equivalent to DXA.9 Therefore, standard CT scans obtained during routine cancer care have the potential to be used to screen for and measure changes in body composition in patients with cancer and can even be used to estimate corresponding muscle mass. This computerized technology could be used to screen patients for early muscle loss and to identify the subset of patients with precachexia who have the greatest potential to benefit from interventions (Fig 2).10 In the clinical setting, oncologists can collaborate with radiologists to assess and quantify changes in body composition on standard radiologic assessments. Although widespread adoption of muscle and fat quantification on CT has not yet occurred in cancer radiology, automated segmentation of axial lumbar CT images for muscle and adipose tissue will greatly facilitate this enterprise.11

BODY COMPOSITION PREDICTS TOXICITY

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Cancer cachexia has marked effects on QoL, physical function, and mortality. One reason for these effects may be related to the increased toxicity related to cancer-directed treatments with body composition changes.12 Drug doses are typically administered on the basis of body surface area, which does not account for muscle loss (ie, sarcopenia), fat gain, or water retention.13 Consequently, the volume of distribution of cancer treatments can be impacted not only from a change in lean body mass, but also from changes in fat mass and total body water. This change in volume of distribution may decrease the effectiveness and/or increase toxicities of cancer-directed therapies. Body composition changes as a predictor of toxicity have been documented in breast,14 lung,15 esophageal,16 and colon17 cancers. Across disease sites, sarcopenic patients are at risk for treatment-related toxicity, surgical complications, and poor survival.12 The most striking example of increased treatment-related toxicity and mortality is in obese patients with low muscle mass, a state known as sarcopenic obesity.6 Identification of these patients may be particularly clinically challenging because the sarcopenia is masked by an obese body mass index (BMI).

BIOMARKERS ARE NOT QUITE READY FOR PRIME TIME

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When identifying and monitoring patients with cancer who have cachexia, it is important to acknowledge the potential role of biomarkers. Potential biomarkers can be derived from different body compartments, including plasma, urine, tumors, skeletal muscle, and even within the patient’s genome.18 Given the established role of inflammation in pathogenesis of cancer and its related adverse effects, cytokines have been an area of intense research.19 However, cytokine profiles are unique among cancer types and stages.18 One potential serum biomarker commonly used in clinical practice is C-reactive protein which, when combined with additional factors of weight loss and nutritional intake, has identified patients at risk for cancer cachexia.18 To date, C-reactive protein is the most cost-effective, practical, and scientifically robust cachexia biomarker with a demonstrated role in prognostication; in addition, recent evidence suggests that it can independently predict QoL parameters independent of performance status.1,18,20 Given the complex pathophysiology of cancer cachexia, additional biomarkers have been identified, including serum parathyroid hormone-related protein, insulin, and cortisol. Urine levels of lipid mobilizing factor are also a promising biomarker requiring further investigation and clinical correlation.18 Tumor specimens have also been evaluated. For example, detection of interleukin-6 (IL-6) and IL-1β in tumor biopsy specimens have correlated with cancer cachexia.18 Muscle biopsy has also been evaluated for detection of β-dystroglycan levels, and it has demonstrated the ability to detect cachexia among patients with upper gastrointestinal cancer.21 However, the intrusive nature of muscle biopsies significantly limits them as a practical screening and monitoring approach. Further investigations are needed to identify more sensitive and specific biomarkers that can be practically implemented and interpreted in a busy clinical setting.

MEASURING PHYSICAL ACTIVITY

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To date, no clinical trials have led to approval by the US Food and Drug Administration (FDA) for the prevention or treatment of cancer cachexia. Prior evidence suggests that measuring weight loss alone is inadequate for detecting patients with or at risk for cancer cachexia,4 although this is the most frequently used variable based on ease of implementation and minimal cost within clinical trials. Unfortunately, clear guidance on how to best capture FDA-required co-primary end points of change in lean body mass and physical activity in cancer cachexia clinical trials is lacking. Thus, recent clinical trials have used varied measures and end points (Fig 2). Cancer cachexia trials frequently require participants to complete more than four or five physical activity assessments (eg, power and speed on a stair climb, handgrip strength, 6-minute walk test, timed up and go), thereby increasing patient burden, impeding recruitment, fueling ambiguous findings, limiting comparisons, and restricting consensus building (Fig 2). For instance, the largest phase III study of cancer cachexia evaluating anamorelin in advanced NSCLC highlights the difficulties with capturing a relevant physical activity end point.22 More than 900 patients with NSCLC who have cachexia (≥ 5% weight loss within the prior 6 months or BMI < 20 kg/m2 and Eastern Cooperative Oncology Group performance status [ECOG PS] of 0 to 2) were randomly assigned to placebo or anamorelin. Physical activity was captured by handgrip strength from baseline over the 12-week study period. Although patients assigned to anamorelin experienced an unprecedented increase in lean body mass compared with placebo (with a median increase of 0.99 kg [95% CI, 0.61 to 1.36] v −0.47 kg [95% CI, −1.00 to 0.21; P < .0001] in ROMANA 1 and 0.65 kg [95% CI, 0.38 to 0.91] v −0.98 kg [95% CI, −1.49 to −0.41; P < .0001] in ROMANA 2), handgrip strength showed no change.22 Consequently, anamorelin has not received FDA approval to date, despite its impact on improving cachexia-related QoL in this randomized controlled trial.

MANAGING CACHEXIA BEYOND WEIGHT LOSS

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Pharmacologic Approaches in Current Use

Progestins

Megestrol acetate is a progesterone derivative that is approved by FDA exclusively for the treatment of anorexia, cachexia, or unexplained significant weight loss in AIDS patients. Its precise mechanism of stimulating appetite is uncertain, but it is thought to be related to altered neuropeptide Y release.23 Oral doses range from 400 to 800 mg/d. An updated Cochrane review evaluated megestrol acetate for the treatment of anorexia-cachexia syndrome in cancer. When compared with placebo, it yields improved appetite and a small effect on overall weight but no improvement in overall QoL.24 In contrast, when compared with dexamethasone, megestrol acetate failed to improve appetite, weight gain, or QoL. Unfortunately, megestrol acetate appears to induce weight gain primarily by increasing adipose tissue and body fluid, with a loss of lean body mass.25 Limited data are available regarding safety with use for more than 4 months, but common adverse effects include diarrhea, rash, edema, thromboembolic disease, impotence, and adrenal insufficiency.26 These risks are not inconsequential because patients are often also receiving chemotherapies, tyrosine kinase inhibitors, and supportive care agents (eg, opioids), and they have underlying cancers (eg, pancreatic cancer) that also increase the risk of dermatologic adverse effects, embolic events, and endocrine disorders. Thus, this is not a particularly promising treatment of cancer cachexia.

Cannabinoids

Dronabinol is a synthetic oral derivative of delta-9-tetrahydrocannabinol that also has limited FDA approval for anorexia associated with weight loss in AIDS. Endorphin receptor activation through prostaglandin and IL-1 inhibition is a possible mechanism of action in this setting.23 An oral dose of 5 mg/d is used to treat anorexia. However, when compared with megestrol acetate in patients with advanced cancer, megestrol was superior for the treatment of anorexia.23 Furthermore, a phase III study in patients with advanced cancer randomly assigned to dronabinol 2.5 mg twice per day, placebo, or cannabis extract (2.5 mg dronabinol plus cannabidiol 1 mg) for 6 weeks showed no significant differences in appetite, QoL, or cannabinoid-related toxicity. In fact, the study was closed early because of insufficient differences between study arms.27 Notably, as with megestrol acetate, weight gain with the use of dronabinol is not associated with increases in lean body mass.28 Adverse effects such as dizziness, euphoria, hallucinations, and somnolence have an incidence of 3% to 10%, whereas the incidence for nausea and vomiting is more than 5%.29

Corticosteroids

Corticosteroids have also been used to stimulate appetite. Oral dexamethasone 0.75 to 1.5 mg four times per day has been assessed in randomized clinical studies in patients with cancer, and patients showed an improvement in appetite and a trend toward nonfluid weight gain.23,30 A second randomized, double-blind, placebo-controlled study evaluated 32 mg per day of oral methylprednisolone in patients with cancer.31 A secondary end point of this study demonstrated an improvement in fatigue and improved appetite after 7 days compared with placebo.31 However, the well-recognized adverse effects of corticosteroids associated with duration of use and total cumulative dose limit their use. Cushing syndrome, hyperglycemia, adrenal insufficiency, myopathy, infection risk, osteoporosis, and neuropsychological effects are frequently associated adverse effects.32 Moreover, corticosteroid use is discouraged with many new immunotherapies (eg, ipilimumab, nivolumab, pembrolizumab).

Cytokines and neurohormones

As previously described, the pathophysiology of cancer cachexia involves several factors, including metabolic dysregulation, increased fat and protein breakdown, decreased nutrient absorption, and neurohormonal dysregulation of compensatory feeding stimuli. Proinflammatory cytokines such as IL-1, IL-6, and tumor necrosis factor α contribute to suppressing appetite within the hypothalamus (Fig 1).33 Investigational agents have been developed to block the action of these cytokines. Cytokines also inhibit growth hormones and contribute, in part, to skeletal muscle wasting. Investigational agents targeting specific growth hormones (ie, ghrelin) and other investigational agents targeting different metabolic pathways are in development. A select summary of investigational agents is summarized in Figure 2.

A THREE-STEP APPROACH FOR THE BUSY ONCOLOGIST

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Step 1: Recognize Cachexia Early

For the practicing oncologist, the first step—identifying, monitoring, and treating cancer cachexia as early as possible—is critical. This requires educating the entire oncology team, including nurses and advanced practice providers, to recognize cachexia beyond changes in weight and BMI. Cancer cachexia is particularly under-recognized in obese patients with sarcopenic obesity. It is not only weight that matters, it is the type of weight that matters most. For example, in patients with cancer who are receiving treatment and who have weight that remains stable or is increased, sarcopenia may be present but obscured by the accumulation of fluid (eg, ascites). Third-spacing of fluid in the setting of low oncotic pressure is a key indicator of nutritional deficiency and active inflammation, which are hallmarks of cancer cachexia even if there is no overt weight loss.

Oncologists must also recognize the limitations of relying solely on ECOG PS or Karnofsky PS to assess physical function.34,35 Oncologists are the gatekeepers to treatment; thus, patients and/or loved ones frequently tell us what we want to hear for fear that we may reduce, delay, or even stop treatment. We therefore must also use objective tests whenever possible. Although evidence-based physical activity assessments such as the 6-minute walk test are safe, feasible, and sensitive to small functional status changes,36 often these tests are not performed because of practical constraints such as time and space. Consequently, we recommend the routine use of patient-reported outcomes, which are already frequently incorporated into clinical practices and can be completed prior to appointments, in waiting areas, and with help from our nursing colleagues. One example is the Functional Assessment of Anorexia/Cachexia Treatment (FAACT). This 12-item measure of patients’ perceptions of appetite is also used to assess QoL in the phase III study of anamorelin.22 The FAACT scale has separate domains for assessment of physical function and can easily be implemented in clinical practice.6 Patient-reported outcomes should be routinely incorporated into the assessment of our patients and combined with additional objective criteria.

Step 2: Refer and Collaborate

Cachexia is a multifactorial syndrome that requires early intervention and multimodal management (Fig 3). Despite our best intentions, oncologists cannot do it all. Therefore, the second step—identifying and referring to other experts, including pain anesthesiologists, palliative care specialists, dieticians, physical therapists, and occupational therapists among others—is most effective in treating cancer cachexia,

FIG 3. Multimodal approach to cancer cachexia.

Cancer and its treatment sequelae can cause uncontrolled symptoms such as pain, nausea, diarrhea, and mucositis, each of which can significantly contribute to cachexia. Although oncologists are capable of assessing and effectively palliating these symptoms, additional help and expertise may sometimes be required.37 Early consultation with pain and/or palliative care services is a vital resource available to oncologists and their patients. For example, neurolytic celiac plexus blocks used to treat cancer-related pain in the setting of pancreatic cancer improves pain and decreases opioid use and associated adverse effects.38 Evaluation by a gastroenterologist may also be helpful in assessing interventions such as stenting, venting, and gastrostomy. Consultative palliative care, when incorporated into standard oncology care regardless of prognosis, has been shown to reduce symptom burden and improve QoL.39 Guidelines from ASCO recommend early integration of palliative care along with standard oncology care for any patient with cancer who has a high symptom burden.40

Step 3: Nutrition and Exercise

The third step relates to nutrition and exercise. Despite the intense focus of many patients and caregivers on diet in the context of a cancer diagnosis, nutritional interventions play a limited role in the treatment of cancer cachexia. A meta-analysis examined the effect of oral interventions, including dietary advice, nutritional supplements, or both in malnourished patients with cancer.41 Thirteen studies (N = 1,414) were identified, but differences among studies resulted in statistical heterogeneity. After removing data that contributed to statistical heterogeneity, oral nutritional interventions had no impact on weight gain, energy intake, overall QoL, or mortality versus routine care. With regard to dietary supplements, omega-3 fatty acids are the most studied supplement, but data are conflicting for their use in cancer cachexia. A systematic review demonstrated insufficient evidence to establish whether oral eicosapentaenoic acid is better than placebo in patients with advanced cancer.23 Of note, a contrasting systematic review demonstrated a benefit in patients with unresectable pancreatic cancer, showing improvement in body weight, lean body mass, and overall survival.42 Numerous additional supplements have been studied, but to date there are no well-established supplemental regimens for patients with cancer cachexia.43

With regard to physical activity, small studies have demonstrated that physical exercise improves physical functioning and QoL and decreases fatigue in patients with cancer, although no studies have been specifically directed at patients with cachexia.44 One clinical trial examined the effects of physical exercise versus usual care in patients with advanced and incurable cancer.45 Physical exercise (ie, warm-up session, circuit training, and stretching) consisting of 60 minutes twice a week for 8 weeks demonstrated significant improvement as measured by the Shuttle Walk Test and hand grip strength. However, two systematic reviews have concluded that there is insufficient evidence to determine the safety and efficacy of exercise in patients with cancer.46 In one review, the authors noted that the majority of reviewed studies did not use the definitions of precachexia, cachexia, and refractory cachexia as proposed by Fearon et al,1 which complicates the ability to determine the proportion of patients who meet the criteria for precachexia and cachexia. Despite minimal proven benefit, there is no evidence of overt harm associated with a well-balanced, high-caloric diet, and physical activity. Therefore, inclusion of nutritional and exercise interventions in the approach to cancer cachexia is appropriate and should be encouraged (Fig 3).

In conclusion, cancer cachexia has a remarkable impact on the experiences of patients with cancer. Despite decades of research, few interventions are available. Further research and development in this area are sorely needed, as are efforts to promote earlier detection of precachexia, when interventions are more likely to be most effective. Novel methods for detecting cachexia and sarcopenia are showing early promise, and several new compounds are in various phases of testing. As our understanding of cancer and its treatment continues to evolve, so too will our ability to effectively target cancer cachexia. We anticipate this will require an individually tailored multifaceted approach. For example, this multifaceted approach is part of ongoing collaborative investigations in the management of patients with cachexia. The MENAC (NCT02330926; Multimodal Intervention for Cachexia in Advanced Cancer Patients Undergoing Chemotherapy) study uses multimodal intervention consisting of nutritional supplements and advice, a home-based self-assisted exercise program, and anti-inflammatory medication (ibuprofen) to treat cancer cachexia. Through the early recognition of cachexia and integration of a polymodal treatment strategy, we can optimize aggressive cancer treatment, minimize toxicity, and improve QoL.

Copyright © 2016 by American Society of Clinical Oncology

Conception and design: Andrew R. Bruggeman, Arif H. Kamal, Thomas W. LeBlanc, Vickie E. Baracos, Eric J. Roeland

Collection and assembly of data: Andrew R. Bruggeman, Thomas W. LeBlanc, Joseph D. Ma, Eric J. Roeland

Data analysis and interpretation: Joseph D. Ma, Vickie E. Baracos, Eric J. Roeland

Manuscript writing: All authors

Final approval of manuscript: All authors

Accountable for all aspects of the work: All authors

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Cancer Cachexia: Beyond Weight Loss

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or jop.ascopubs.org/site/misc/ifc.xhtml.

Andrew R. Bruggeman

No relationship to disclose

Arif H. Kamal

Consulting or Advisory Role: INSYS Therapeutics

Thomas W. LeBlanc

Honoraria: Helsinn Therapeutics

Consulting or Advisory Role: EPI-Q, Boehringer Ingelheim, Flatiron Health, Pfizer

Research Funding: Helsinn Therapeutics (Inst), Opus Science/Celgene (Inst)

Joseph D. Ma

Employment: Intercept Pharmaceuticals (I)

Stock or Other Ownership: Amgen

Vickie E. Baracos

No relationship to disclose

Eric J. Roeland

Consulting or Advisory Role: Eisai (Inst), Helsinn Healthcare (Inst), Heron Therapeutics

Speakers’ Bureau: TEVA Pharmaceuticals, Eisai, Depomed

Research Funding: XBiotech (Inst), AstraZeneca (Inst), Merck (Inst)

Travel, Accommodations, Expenses: Eisai, Teva, Helsinn Healthcare

REFERENCES

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What is cancer cachexia characterized by?

What does cachexia result from?

What defines cachexia?

What diseases are associated with cachexia?