The Latest Treatments for Cancer Cachexia

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The Latest Treatments for Cancer Cachexia: An Overview (2023)
HAYATO WATANABE and TAKASHI OSHIMA


Abstract

Cancer cachexia demonstrates the same pathology as cachexia found in patients with disease-associated malnutrition presenting with inflammation. In advanced cancer, a decrease in skeletal muscle mass progresses with an increase in cancer cell mass. Moreover, cancer cachexia causes systemic edema and cachexia, reduces the efficacy of chemotherapy, and negatively affects cancer prognosis. Early nutritional intervention and multidisciplinary care are essential to ensure sufficient nutritional requirements and minimize anabolic resistance factors. In addition, preventive care that minimizes deterioration of nutritional status and loss of skeletal muscle mass is required for the effective treatment of cachexia. Therefore, the current review sought to comprehensively describe the available evidence for the effective pharmaceutical treatment of cancer-associated cachexia. Steroids have traditionally been used for cachexia drug therapy. However, their effects are limited, and it is difficult to radically restore the highly reduced muscle mass inherent to cancer-associated cachexia. Recently, anamorelin hydrochloride, an endogenous ligand for the growth hormone release-promoting factor receptor, which has a similar pharmacological action to that of ghrelin, was developed to treat weight loss accompanied by anorexia. This medication also treats cachexia and was the first drug to be approved for this purpose. Anamorelin hydrochloride is expected to bring new advancements into the field of clinical oncology as an effective therapeutic drug for cancer cachexia, a devastating complication that, so far, has no definitive and effective treatment.




As cancer progresses, many patients develop characteristic symptoms, such as loss of appetite, weight loss, malaise, and poor physical fitness, all of which work synergistically toward increasing the likelihood of malnutrition. Various other factors also contribute to decreased oral nutritional intake and overall energy intake.
Malnutrition is associated with absolute nutritional deficiencies (1). Although there are differences in clinical findings depending on the stage of cancer progression, in general, more than half of all cancer patients have moderate to severe anorexia. In addition, weight loss is observed in 30-80% of cancer patients (2)

Hyponutrition in cancer patients impedes daily activity and reduces the quality of life (QOL). In addition, malnutrition or hyponutrition decreases tolerability to curative cancer treatments, such as surgery and chemotherapy, leading to significant reductions in therapeutic effects. This adversely and severely affects cancer prognoses (3-5). Even mild nutritional disorders presenting in cancer patients, such as “constant nutritional status due to starvation”, a diagnosis that is limited to loss of appetite, cause irreversible nutritional disorders when associated with advanced cancer progression, which involves infiltration into critical organs and metabolic disorders. If not for these cancer-associated complications, recovery from mild nutritional disorders would be easily attainable with appropriate nutritional intake. However, unlike in simple starvation, patients with advanced cancer physiologically and behaviorally resist nutritional management and treatment. Thus, these patients tend to develop metabolic disorders, such as cachexia, that are characterized by marked muscle and weight loss as cancer progresses (6)

Cachexia is characterized by low nutrition and skeletal muscle mass against the setting of chronic diseases, such as cancer, chronic heart failure, chronic obstructive pulmonary disease (COPD), chronic renal failure, chronic rheumatoid arthritis, and severe burn injuries.
The state of malnutrition results in severe weight loss (6, 7). Cancer cachexia is found in approximately 80% of patients with advanced cancer (8- 10) and accounts for approximately 30% of cancer-associated deaths (11-14). In contrast to “starvation undernutrition,” in which skeletal muscle mass, which is essential for supporting basic life functions, is reversibly preserved and adipose tissue is preferentially reduced, cancer-associated cachexia reduces skeletal muscle mass starting from an early stage (15). In addition to the typical cachexia symptoms of weight loss and loss of appetite, cancer-associated cachexia also leads to a diminished therapeutic effect of chemotherapy and increased side effects thus, leading to a greater likelihood of discontinuation of treatment and a lower survival rate (16, 17)


*Therefore, the current review sought to comprehensively describe the evidence for the effective pharmaceutical treatment of cancer-associated cachexia. In particular, this review discusses the importance of nutritional management in palliative cancer medicine, with a focus on new treatments for cachexia, a topic that has recently gained attention in the fields of medicine and research.




Definition of Cachexia


The term cachexia has long been used to describe a state of weakness caused by malnutrition (18, 19). Cachexia is a terminal stage of malnutrition that occurs not only in cancer but also in various chronic wasting diseases. Physiological and behavioral treatment resistance associated with cachexia worsens the prognosis and QOL of patients.

Cachexia is characterized by the extensive loss of skeletal muscle, termed sarcopenia or myopenia, and adipose tissue. This cancer-associated presentation is opposite to that of the physiological presentation of simple starvation. However, because this cachexia is a complicated condition and can undergo considerable modification due to nutritional and pharmaceutical management, the findings of metabolic analyses are not straightforward. Thus, it is difficult to set a standardized definition that everyone agrees upon. In addition, elucidating the mechanisms underlying this condition and developing effective treatment methods remain to be a challenge.





Mechanisms and Primary Symptoms of Cachexia

The mechanisms underlying the development of cachexia are not well understood. However, these mechanisms are gradually being elucidated through recent progress using biochemical and biological analyses. For example, the involvement of proteolysis-inducing factor (PIF), which is released from tumors and reflects abnormalities of the neuroendocrine system, is gradually being revealed. The activation of inflammatory cytokines resulting from the interactions between the cancer cells and host cells varies. Inflammatory pathways are deeply involved in various metabolic disorders and loss of appetite (23) and play a central role in the mechanisms underlying cachexia (20). In recent years, cachexia has been regarded as a systemic inflammatory reaction mediated by various cytokines (17, 22).

Cancer-associated cachexia is characterized by a unique competitive response in the tumor involving the release of PIF and lipid mobilizing factor (LMF).
Disease presentation is largely affected by factors, such as the rate of tumor progression, biological attitudes, and side effects of anticancer treatment, which can include cachexia.

As cancer progresses, cachexia generally develops into irreversible malnutrition that gradually causes death (24, 25). However, some cancer types are less likely to produce cachexia (26, 27), and the rate of progression varies across individuals. The malnutrition caused by cachexia is a metabolic abnormality occurring due to a chronic inflammatory reaction throughout the body as well as increased catabolism. This includes symptoms of increased skeletal muscle decomposition, insulin resistance, and increased lipid decomposition (2, 8). When this metabolic disorder becomes severe, nutritional intake is not effectively utilized and malnutrition gradually becomes irreversible. Therefore, it is extremely important to provide nutritional support early on at the stage where the progress of cachexia is not extensive, that is, wherein the degree of metabolic abnormality is mild.



-Loss of appetite

-Abnormal energy metabolism

-Increased insulin resistance and abnormal metabolism

-Changes in the neuroendocrine system





Diagnostic Criteria for Cancer Cachexia

The diagnostic criteria for cachexia were described in the guidelines published in both the United States and Europe in 2008 (Figure 2). When cachexia occurs due to underlying diseases, including cancer, chronic heart failure, COPD, chronic renal failure, chronic inflammation, septicemia, anorexia, inflammation, insulin resistance, sexual dysfunction, and anemia is frequently observed in the disease presentation. Moreover, tissue loss and muscle exhaustion can lead to weight loss, weakness, and fatigue. The diagnostic criteria for cachexia are defined as the presence of three or more of the following five items: 1) muscle weakness, 2) fatigue, 3) decreased appetite, 4) low lean body mass, and 5) abnormal biochemical data [e.g., C-reactive protein (CRP), Hb (hemoglobin), and albumin (Alb) levels] (5) (Figure 2).




Non-pharmaceutical Therapies for Cancer Cachexia

Current medical guidelines recommend monitoring and performing preventive nutritional interventions in the case of pre-cachexia, in which weight loss is significant due to loss of appetite (45, 46).


-Nourishment route

-Energy dosing

-Infusion management at the end of life

-Nutrition therapy


-Exercise therapy




Drug Treatment


-Non-steroidal anti-inflammatory drugs


-Corticosteroids

-Anti-cytokine therapy

-Eicosapentaenoic acid

-Branched-chain amino acids, L-carnitine, CoQ10

-Gastrointestinal hypermotility drugs

-Oral supplements





Anamorelin hydrochloride

Anamorelin hydrochloride is an orally administered low molecular weight drug that exhibits ghrelin-like action via growth hormone secretagogue receptor 1a (GHS-R1a), which is a G-protein coupled receptor that is distributed in many tissues including the pituitary gland, hypothalamus, stomach, pancreas, and myocardium (Figure 3) (71-75). In transgenic rats overexpressing the antisense GHS receptor gene and with attenuated expression of the GHS receptor in the arcuate nucleus, GHS-R1a secretes growth hormone (GH) from the pituitary gland and hypothalamus. This mechanism is involved in increasing appetite (76).

Ghrelin is a peptide hormone identified as an endogenous agonist of GHS-R1a. In addition to promoting GH secretion and appetite, ghrelin also promotes weight gain, fat production, glucose metabolism suppression, gastrointestinal motility regulation, and cytokine production. Ghrelin is thought to play an important role in maintaining the homeostasis of in vivo energy metabolism by antagonizing leptin-like signals that suppress appetite (72, 77-81). However, the elimination half-life of ghrelin in human plasma is as short as 10 minutes, and the route of administration is limited to intravenous or subcutaneous routes (82).

In contrast, anamorelin hydrochloride is a ghrelin-like agent that has an elimination half-life of approximately nine hours and can be administered orally. Anamorelin hydrochloride promotes GH secretion in the pituitary gland and increases appetite in the hypothalamus. GH secreted from the pituitary gland secretes insulin-like growth factor1 (IGF-1) from the liver and promotes muscle protein synthesis thus leading to an increase in muscle mass and weight in humans (Figure 4) (83).

*Anamorelin hydrochloride was introduced in Japan in January 2021 after undergoing three domestic and international trials (ONO-7643-04, ONO-7643-05, HT-ANAM-301/302) (84- 87). After its introduction, manufacturing and marketing approval for cancer cachexia was obtained from regulatory bodies. Anamorelin hydrochloride is the only approved therapeutic agent that can renew appetite via oral administration.





Conclusion

This review details the current state of knowledge regarding cancer cachexia and its latest treatments. Anamorelin hydrochloride, which is an endogenous ligand for GHS-R1a that has the same pharmacological action as ghrelin, was developed for the treatment of weight loss accompanied by a loss of appetite. It is also approved for treating cancer-associated cachexia. Since this medication has emerged as a therapeutic agent, cancer cachexia treatment has entered a new era. It is strongly believed that this new treatment method will continue to improve cancer cachexia symptomology as well as enhance treatment results in cancer patients.
 

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Figure 1. The spectrum of cachexia. Cancer-related cachexia is known to be distinct from both starvation and malabsorption. The state of cachexia, which presents as a mild metabolic derangement without overt cachectic symptoms, is termed “pre-cachexia". As cachexia progresses, a terminal state occurs in which nutritional status cannot be improved. This condition is called refractory cachexia, which is often caused by cancer diseases that have strong catabolic effects and do not respond to anticancer drug treatment, and the expected survival period is less than 3 months.
Screenshot (20286).png
 
Figure 2. Diagnostic criteria for cachexia. This figure is a conceptual representation of the definition of cachexia. In particular, cachexia results from an adaptation to an underlying illness, such as cancer. The illness creates an environment that may be characterized by inflammation, loss of appetite or anorexia, low levels of testosterone and other anabolic hormones, and anemia. Decreased food intake and anorexia result in the loss of body and muscle mass. In addition, inflammation, insulin resistance, and low levels of anabolic hormones result in muscle wasting.
Screenshot (20287).png
 
Figure 3. The chemical structure of anamorelin hydrochloride.
Screenshot (20288).png



Anamorelin hydrochloride is an orally administered low molecular weight drug that exhibits ghrelin-like action via growth hormone secretagogue receptor 1a (GHS-R1a), which is a G-protein coupled receptor that is distributed in many tissues including the pituitary gland, hypothalamus, stomach, pancreas, and myocardium (Figure 3) (71-75). In transgenic rats overexpressing the antisense GHS receptor gene and with attenuated expression of the GHS receptor in the arcuate nucleus, GHS-R1a secretes growth hormone (GH) from the pituitary gland and hypothalamus. This mechanism is involved in increasing appetite (76)

Ghrelin is a peptide hormone identified as an endogenous agonist of GHS-R1a. In addition to promoting GH secretion and appetite, ghrelin also promotes weight gain, fat production, glucose metabolism suppression, gastrointestinal motility regulation, and cytokine production. Ghrelin is thought to play an important role in maintaining the homeostasis of in vivo energy metabolism by antagonizing leptin-like signals that suppress appetite (72, 77-81). However, the elimination half-life of ghrelin in human plasma is as short as 10 minutes, and the route of administration is limited to intravenous or subcutaneous routes (82)

In contrast, anamorelin hydrochloride is a ghrelin-like agent that has an elimination half-life of approximately nine hours and can be administered orally. Anamorelin hydrochloride promotes GH secretion in the pituitary gland and increases appetite in the hypothalamus. GH secreted from the pituitary gland secretes insulin-like growth factor1 (IGF-1) from the liver and promotes muscle protein synthesis thus leading to an increase in muscle mass and weight in humans (Figure 4) (83)

*Anamorelin hydrochloride was introduced in Japan in January 2021 after undergoing three domestic and international trials (ONO-7643-04, ONO-7643-05, HT-ANAM-301/302) (84- 87). After its introduction, manufacturing and marketing approval for cancer cachexia was obtained from regulatory bodies. Anamorelin hydrochloride is the only approved therapeutic agent that can renew appetite via oral administration
 
Figure 4. A depiction of anamorelin’s ghrelin-like mechanism of action. Anamorelin activates growth hormone secretagogue receptor 1a (GHSR1a), which in turn promotes growth hormone (GH) secretion in the pituitary gland and increases appetite in the hypothalamus. GH secreted by the pituitary gland leads to insulin-like growth factor-1 (IGF-1) secretion from the liver and promotes muscle protein synthesis, thereby leading to increased muscle mass and weight.
Screenshot (20290).png
 




 
Drug Treatment


-Non-steroidal anti-inflammatory drugs


-Corticosteroids

-Anti-cytokine therapy

-Eicosapentaenoic acid

-Branched-chain amino acids, L-carnitine, CoQ10

-Gastrointestinal hypermotility drugs

-Oral supplements

They are so afraid of anabolics like nandrolone or oxandrolone.
 
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