Novel Concepts and Treatments in Cancer Cachexia

Oct 27, 2016   |  Timothy C. Tan, MBBS, PhD, FACC; Patsie Polly, PhD

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Background

Cancer-induced cachexia is an insidious, complex, paraneoplastic syndrome, affecting up to 50% of patients with cancer and the majority of patients with terminal cancer. The reported prevalence of cachexia can be as high as 86% in the last 1-2 weeks of life.1-4 Approximately 45% of patients suffering from cancer-induced cachexia lose more than 10% of their original body weight over the course of their disease progression, with death usually ensuing once there is more than 30% weight loss.3,5,6 It is well-accepted that cachexia is indirectly responsible for the death of at least 20% of patients with cancer.7-10

Clinical Definition and Manifestation

Cancer-induced cachexia is often, but not always, accompanied by anorexia11 and is characterized by a hypercatabolic/hypermetabolic state, which causes negative protein and energy balance. The result is an involuntary loss of lean body mass, with or without loss of fat mass.1 Clinically, cachexia is defined as weight loss of at least 5% that occurs within a period of 12 months due to an underlying disease including cancer and is not due to a reduction in edema, diet, or lifestyle.5 Also associated are alterations in immune responses, (elevated systemic cytokines), body composition (reduced fat and muscle mass), dysregulated physiological systems (altered metabolic regulation), and a reduction in response to chemotherapy.12-17 Although cachexia is common in chronic disease states, muscle mass loss and associated metabolic changes appear in rodent models of cancer cachexia and are most profound and rapid in certain patients with cancer.18 Typically, patients experience lethargy, loss of appetite, and increased disability associated with a significant weight loss due to wasting of lean body mass. Patients with pancreatic or gastric cancer have been reported to have the highest frequency of cachexia, and patients with non-Hodgkin's lymphoma, breast cancer, acute non-lymphocytic leukemia, and sarcomas have the lowest frequency of cachexia.19 The variations in the spectrum of severity of cachexia have been attributed to variations in tumor phenotype or host genotype, thereby implying a role for the host-tumor interaction.20

Cancer-Induced Cardiac Cachexia

Current evidence is emerging that supports a causative link between the presence of cancer and cardiac myopathy, independent of cancer treatments. These emerging cardiac myopathies may have a potentially significant role in the development of symptomatic heart failure (HF) and impaired survival.21 Studies in various animal models of cancer-induced cachexia have revealed loss in cardiac tissue weight, evidence of cardiac remodeling, and impairment of cardiac function. Patients with gastrointestinal, pancreatic, and non-small-cell lung cancer who died were also found to have reduced heart mass and evidence of left ventricular (LV) remodeling, compared with non-cachectic patients with cancer and controls.22 A study from Canada that examined 16,500 patients with cancer found a 7.5% incidence of a new diagnosis of HF within the 365 days preceding death, when cachexia is likely to be most prominent and supports a cardiopathology due to cancer.23 Likewise, another study in the United Kingdom recently reported higher mortality rates due to a cardiac event in patients with colorectal cancer following elective and non-elective colorectal resection that could not solely be attributed to preexisting cardiac disease.24

Clinical Significance

The underlying pathogenic mechanisms of cancer cachexia can occur early during tumor growth and may be at play even in the absence of weight loss. Hence, a significant proportion of patients with cancer are potentially at risk, particularly those with certain cancers known to negatively influence nutritional status and those with metastatic disease.16 The clinical manifestations of cancer-induced cachexia are diverse and include anemia, anorexia, and altered immune function. In more advanced stages of cachexia, the ability of patients to react appropriately to stress may be impaired, which increases the risk of infections and toxicity from their chemotherapy.25 All these factors contribute to fatigue, impaired quality of life, and reduced survival, particularly in the significant proportion of patients with aggressive or metastatic cancer who continue to also suffer from effects from their cancer.16 The potential of a cancer-induced cardiac pathology, in addition to all the other conditions seen in cachexia, is of clinical significance because this pathology may potentially further augment the morbidity and mortality associated with cancer treatments. As supportive care continues to play a critical role in the management of patients with cancer,26 the identification of cancer-induced cardiac dysfunction would allow appropriate measures to be instituted to improve the quality of life and potentially survival for patients with cancer.

Pathophysiology of Cancer-Induced Cardiac Cachexia

The pathophysiology of cancer-induced cardiac cachexia is currently still being elucidated. The complex clinical nature of cancer-induced cachexia suggests a multifactorial etiology, which is underpinned by complex pathophysiology; therefore, elucidating the underlying mechanism for cachexia has been challenging. This is also compounded by the fact that the different cancer types can have differing cytokine profiles, which potentially can result in a spectrum of severity in symptoms of cachexia.2,14,27,28 Because there have been very few studies in humans, a large part of our current understanding of the underlying pathophysiology has come from animal studies. One hypothesis implicates inflammatory cytokines as the cause for skeletal muscle cachexia and is postulated to also cause cardiac cachexia. Animal studies and studies involving human pancreatic cancer and patients with colorectal carcinoma have identified elevated serum pro-inflammatory cytokines such as tumor necrosis factor-alpha, interleukin-1, and interleukin-6.2,27,29,30 The elevated levels of inflammatory cytokines have been proposed to result from the host-tumor interaction, which creates a systemic chronic inflammatory state. Elevated levels of these inflammatory cytokines have been implicated in inflammation, muscle wasting, weight loss, reduced quality of life, and shortened survival31 by inducing muscle and lipoatrophy, aberrant lipid and protein metabolism, and aberrant zinc metabolism. Gene array experiments in animal models of cancer cachexia have revealed the upregulation of inflammatory processes in skeletal and cardiac tissue.32 This hypothesis is also supported by the findings of elevated levels of acute-phase response proteins such as C-reactive protein (established as an accurate measure of pro-inflammatory cytokine activity)33 and fibrinogen in patients. The host-tumor interaction also potentially results in the release of a number of other factors apart from the pro-inflammatory cytokines, such as proteolysis-inducing factor and lipid-mobilizing factor, which induces protein degradation34 and breakdown of adipose tissue by tumor cells,35 respectively. Other mechanisms reported in cancer-induced cachexia that may be implicated in the cardiac dysfunction seen in cancer cachexia include impaired energy supply at a cellular level due to mitochondrial dysfunction36 and decreased oxidative capacity,37 disrupted protein synthesis,38 changes in membrane fluidity and oxidative modification of mitochondrial proteins,39 and imbalance in protein metabolism with reduced rates of anabolism of new proteins and enhanced rates of catabolism due to abnormalities in the neurohormonal mediated systems.40 Although the pro-inflammatory cytokines have been postulated to potentially modulate some of these processes, the exact molecular mechanisms or triggers underpinning cancer cachexia induction are still unclear.

Treatments for Cancer-Induced Cardiac Cachexia

Currently, cancer cachexia cannot be cured, and most treatment strategies are limited to symptom management and palliation rather than prolongation of life. To date, all of the information on the efficacy of potential treatments has come from animal studies.22 One potential treatment approach may be an angiotensin-converting enzyme (ACE) inhibitor because the treatment of patients with congestive HF (in combination with digoxin and a diuretic) increased subcutaneous fat and muscle bulk.41 Another potential treatment approach may be an aldosterone antagonist because a study involving patients suffering from either non-small-cell lung or colorectal cancer revealed significantly increased plasma levels of aldosterone and brain natriuretic peptide in those with cachexia. Interestingly, treatment of a hepatoma rat model (AH130) of cancer-induced cachexia with an aldosterone antagonist and a beta-blocker, but not an ACE inhibitor, attenuated many of the deleterious cardiac effects (i.e., impairment in LV systolic function and cardiac remodeling) but did not improve heart function to the level of healthy controls. A number of agents including statins, celecoxib, thalidomide, angiotensin receptor antagonists (ARBs), ACE inhibitors, beta2 agonists, resveratrol, and rosiglitazone have been trialed in other animal models for the treatment of cachexia, with some showing potentially promising results on cardiac function and remodeling (Table 1). There have yet to be any trials addressing their effectiveness in treatment or prevention of cancer-induced cardiac atrophy in humans. Given the multifactorial process of this disease entity, it is evident that treatment approaches will likely have to be multidisciplinary in nature.

Table 1: Clinical Therapies Trialed for Treating Cardiac Dysfunction in Animal Models of Cancer Cachexia

Study

Drug

Model

Effect

Saitoh M, et al.44

Erythropoietin (used for treatment of anemia in patients with cancer)

Yoshida AH130 hepatoma model (rat)
  • Ameliorated decrease in LV mass
  • Ameliorated decrease in LV function

Musolino V, et al.45

Megestrol acetate (used as appetite stimulant in patients with cancer)

Yoshida AH130 hepatoma model (rat)
  • Improved survival
  • Reduced wasting in cardiac muscle
  • Improved cardiac function

Stevens SC, et al.46

Losartan (ARB)

C26 colon carcinoma (mouse)
  • Improved cardiac systolic function

Springer J, et al.22

Bisoprolol (beta1 selective antagonist)

Yoshida AH130 hepatoma model (rat)
  • Preserved LV function
  • Decreased mortality

Springer J, et al.22

Spironolactone (aldosterone antagonist)

Yoshida AH130 hepatoma model (rat)
  • Preserved LV function
  • Decreased mortality

Springer J, et al.22

Imidapril (ACE inhibitor)

Yoshida AH130 hepatoma model (rat)
  • No improvement in systolic function
  • Did not have any effect on cardiac remodelling

Trobec K, et al.47

Rosiglitazone (Peroxisome proliferator-activated receptor gamma activator)

Yoshida AH130 hepatoma model (rat)
  • Improved cardiac function
  • No effect on cardiac mass
  • Decreased mortality

Toledo M, et al.48

Formoterol (beta2-adrenoceptor-selective agonist)

Yoshida AH130 hepatoma model (rat) and Lewis Lung Carcinoma (mouse)
  • Increased cardiac mass

Elkina Y, et al.49

Tandospirone (5-HT1A receptor agonist -antidepressant and anxiolytic)

Yoshida AH130 hepatoma model (rat)
  • Preserved cardiac mass
  • Preserved LV systolic function

Palus S, et al.50

Simvastatin (3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitor)

Yoshida AH130 hepatoma model (rat)
  • Improved cardiac function
  • Decreased mortality

Current Challenges in the Field

The effects of cancer-induced cachexia on cardiac structure and function have not been widely studied in humans. Previous studies relating to patients with cancer have focused predominantly on the treatment of the malignancy and the characterization of the potential cardiotoxic effects of the therapies.24,36 Although there have now been reports of impairment in cardiac function in rodent models of cancer cachexia, to date there have not been any detailed assessments of cardiac function in patients with cancer that focus specifically on the effects of the cancer on the heart. Clinically, the diagnosis of cachexia is also difficult because the manifestation of this syndrome is typically latent, and its development often proceeds for a long time before its clinical manifestation.42,43 Additionally, inherent challenges involved in determining the relative contribution of underlying heart disease unrelated to cancer compared with that induced by cancer itself contribute to the lack of clinical data on the pathogenesis, epidemiology, and impact of cardiac cachexia in cancer.36 Finally, there is no defined cure at the moment; present treatment approaches are largely focused on palliation of symptoms rather than prolongation of life. Treatment targeting the preclinical stages of this disease entity is also likely going to be more effective than treatment targeting advanced stages of the disease, but the lack of definitive information regarding the underlying mechanisms precludes early diagnosis and treatment of this condition. Current treatments that are effective are also very limited; therefore, improving our understanding of the pathophysiologic mechanisms leading to cardiac atrophy in cancer will ultimately help identify potential biomarkers for early detection of this condition and potential novel therapeutic targets.

Novel Approaches to Understanding Molecular Pathways in Cardiac Cancer Cachexia

In recent years, there have been a number of scientific breakthroughs in the fields of tumor biology and genomics that have translated into novel antineoplastic therapeutic approaches. Likewise, genome-wide approaches may potentially be used to provide insights into molecular expression and signaling pathways in cancer-induced cardiac cachexia. Most interestingly, microarray analysis of ribonucleic acid gene expression profiles and proteomics of several thousand proteins of interest have revealed dynamic aspects and unique adaptations in cancer cachexia, which has improved our understanding of the genetic basis of this disease process. Further categorization of the identified cardiac gene effectors in cachectic mice has revealed two themes: 1) effectors and potential drugs that regulate inflammatory processes and 2) wound healing and tissue remodeling, implicated in HF.32

Conclusion

Cancer-induced cachexia is a complex syndrome that can have a detrimental effect on patients' lives. Therefore, it requires a systematic approach to assessment, treatment, and management. The involvement of the heart, which may be secondary to cancer presence and independent to cancer treatments, may potentially affect morbidity, quality of life, and ultimately survival in patients with cancer. Limited information regarding the underlying mechanisms precludes early diagnosis and treatment of this condition. Improving our understanding of the pathophysiologic mechanisms leading to cardiac myopathy due to cancer will ultimately help identify potential biomarkers for early detection of this condition and new therapeutic targets, which in turn should affect survival outcomes for patients with cancer. Although novel approaches to gene and protein expression are invaluable in understanding the potential mechanisms underlying the cardiac pathology and identifying potential drug targets, more research to elucidate the mechanisms involved and clinical trials to determine effectiveness of current available potential treatments are required.

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Keywords: Acute-Phase Proteins, Adipose Tissue, Anemia, Angiotensin Receptor Antagonists, Anti-Anxiety Agents, Antidepressive Agents, Cachexia, Carcinoma, Hepatocellular, Carcinoma, Lewis Lung, Cardiotoxicity, Heart Failure, Heart Diseases, Interleukin 1 Receptor Antagonist Protein, Interleukin-6, Leukemia, Lymphoid, Myocardium, Natriuretic Peptide, Brain, Paraneoplastic Syndromes


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