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 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 the 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.
In 2006, the guidelines published in Europe and the United States defined cachexia as “a syndrome of complex metabolic disorders associated with underlying disease, characterized by a decrease in muscle mass with or without adipose tissue loss”. The clinical symptoms of cachexia include weight loss in adults and failure to thrive in children. With regard to differential diagnosis, cachexia was defined as a condition that differs from starvation, age-related muscle loss, depression, malabsorption, hyperthyroidism, anorexia, increased inflammatory response, insulin resistance, and increased protein catabolism (6).
In 2011, the European Palliative Care Research Collaborative (EPCRC) guidelines for cancer cachexia were published, stating that:
“Cancer cachexia is difficult to improve with conventional nutritional support and leads to progressive dysfunction, with or without adipose tissue loss. It is a complex metabolic disorder syndrome characterized by marked loss of muscle tissue. Pathophysiologically, it is characterized by decreased oral intake, decreased protein levels due to metabolic disorders, and a negative energy balance” (20, 21).
In 2017, the classification of malnutrition issued by the European Society for Clinical Nutrition and Metabolism (ESPEN) defined cachexia as a condition synonymous with “chronic disease-related malnutrition with inflammation” (22).
As mentioned above, cancer-associated cachexia is known to differ from both starvation (i.e., a form of malnutrition not caused by a disease) and malabsorption (i.e., a form of malnutrition caused by a disease but not accompanied by inflammation). A state of cachexia presenting as a mild metabolic disorder with the absence of obvious cachexia symptoms is termed “pre-cachexia”. The cachexia special interest group (SIG), which is ESPEN’s SIG on cachexia-anorexia in chronic wasting diseases, has defined this concept and emphasized the importance of addressing pre-cachexia in clinical management.
In addition, due to the severity of this metabolic disorder, a terminal state known as “late cachexia” or “severe cachexia” may occur, wherein there is no more room for improvement in nutritional status. In the EPCRC guidelines, this state is termed “refractory cachexia” and is defined as “a cachexic condition that causes irreversible nutritional disorders due to highly resistant or rapidly progressing cancer”.
The EPCRC guidelines propose three disease stages namely “pre-cachexia”, “cachexia”, and “refractory cachexia”. A set of diagnostic criteria for each stage is also proposed for future implementation within clinical guidelines. Further consideration is necessary before implementing these clinical definitions and diagnostic criteria. However, this development itself is significant in managing the nutrition of cancer patients before and after cachexia (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.
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 the 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. Loss of appetite is observed in approximately 40% of cancer patients and has a prevalence of 80% in patients with advanced-stage cancer (9). Some causes of loss of appetite in cancer patients are nausea, the cancer itself, pain, anxiety, and depression. Recently, it has been suggested that anorexia is caused by an increased inflammatory response. In other words, in the state of cancer cachexia, macrophages, mononuclear cells, and lymphocytes release large amounts of inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α), interleukin-1β, and interleukin-6 (3, 28). These cytokines, which are peptides present in the hypothalamus, promote feeding behavior and suppress the action of neuropeptide Y as well as the secretion of corticotropin-releasing hormone, which is an antifeedant hormone (3). In advanced cancer, chronic pain caused by nerve compression and bone metastasis results in anorexia (3). For instance, the combined symptomology of gastrointestinal cancer exerting pressure on the ganglia coupled with abdominal pain causes a strong decrease in appetite.
Abnormal energy metabolism. Increased energy expenditure is one of the main factors leading to cancer cachexia. The resting energy expenditure (REE) of cancer patients is approximately 48% higher than that of healthy people (29). According to the current literature, increased REE in cancer patients may be mediated by several mechanisms, such as an increase in uncoupling protein levels, variations in cytokine levels, and release of LMFs (30-32). Changes in intracellular energy production as well as activation of the Cori cycle, involving recycling of lactic acid, are also considered potential mechanisms.
Even in the presence of abundant oxygen, tumor cells also perform anaerobic respiration, that is, respiration that produces energy without the use of oxygen. This is known as the Warburg effect (33, 34). Anaerobic respiration is less efficient than normal aerobic respiration in terms of energy production. Therefore, cancer cells consume more glucose than normal for survival, and thus, energy production is unbalanced. It is believed that this mechanism contributes greatly to the increased energy expenditure observed in cancer patients.
Increased insulin resistance and abnormal metabolism. Cancer patients present with abnormalities in carbohydrate, lipid, and protein metabolism. In particular, glucose metabolism and gluconeogenesis are enhanced in the liver (35, 36), and decreased sensitivity to insulin or insulin resistance is observed in the skeletal muscles. This impaired glucose tolerance is observed before a decrease in muscle mass becomes apparent (37). With regard to lipid metabolism, lipid mobilization in peripheral tissues is enhanced, and fat accumulation in the body is reduced in cachexia. In addition, fatty acids released from lipid tissues reduce insulin receptor sensitivity, thus leading to insulin resistance. The underlying mechanism of enhanced fatty acid release in cancer patients may be the increased lipoprotein lipase activity, which is involved in the release of fatty acids from adipose tissue. However, several aspects of this mechanism remain unclear (38).
We also note that protein metabolism disorders are changes directly related to the loss of muscle mass. In the muscles, proteolysis is increased while protein synthesis is suppressed in patients with cancer cachexia. In other words, there is an increase in the catabolic reaction and a decrease in the anabolic reaction, thus causing muscle atrophy. On the other hand, in the liver, protein synthesis is increased to counteract the increase in proteolysis in the skeletal muscles (39).
Changes in the neuroendocrine system. In cancer cachexia, blood levels of the anabolic hormone insulin-like growth factor-1 (IGF-1) may decrease, thereby causing muscle atrophy (40). It has also been reported that leptin concentrations, which regulate appetite, are decreased in cachexia, while blood concentrations of ghrelin are increased (41). Since leptin is mainly produced in the adipose tissue, the decrease in leptin concentration reflects a decrease in fat mass occurring due to cancer cachexia. However, in cancer cachexia, the assimilation of protein is decreased, and it is hypothesized that blood ghrelin concentrations increase as a compensatory reaction. Ghrelin, a hormone mainly produced in the stomach, is involved in the promotion of anabolic and growth factor secretion as well as in the enhancement of appetite. Its clinical application to cancer cachexia has previously been determined (42-44).
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 are 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).
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.
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. Even for cancer patients, oral and enteral nutrition is recommended, whichever is possible. Enteral nutrition is considered an auxiliary means of treatment based on the principles of nutritional management. The ESPEN guidelines, which mention nutritional pathways, designate oral and enteral nutrition as the first choice in the nutritional treatment of cancer patients. If oral intake is difficult, for example, due to the presence of head and neck or esophageal cancer, tube feeding from a gastric fistula via a nasogastric tube or percutaneous endoscopic gastrostomy is recommended (47). Enteral nutrition is recommended only when oral intake or dietary supplementation is not possible (20).
Energy dosing. The optimal energy dose for cancer patients is set to a normal nutritional level when the metabolic disorder is mild, and the dose is reduced when the metabolic disorder becomes severe. The REE of cancer patients varies depending on the type of cancer and the degree of progression (48, 49). According to the ESPEN guidelines, REE increases in cases with a high inflammatory response. In general, the total energy expenditure (TEE) of cancer patients decreases due to a decrease in physical activity. This decrease in TEE is translated into changes in weight. A TEE of 25 kcal/kg/day is recommended. In addition, patients should actively refrain from nutritional administration at the end of cancer treatment.
Refractory cachexia is defined as a stage that does not respond to nutritional administration. It is considered appropriate to reduce the nutritional dose towards the terminal stage of cancer when metabolic disorders become severe. In the terminal stage of cancer, even if active nutrition is administered, nutrition is not used effectively and instead becomes an excess metabolic load that may be harmful to the body.
Infusion management at the end of life. In Japan, infusion is often performed for patients with decreased oral intake at the end of life. However, various metabolic disorders occur at the terminal stage of cancer, and infusion often leads to an increase in edema, pleural effusion, ascites, and airway secretions. When infusing at the end of life, it is important to comply with clinical recommendations regarding treatment indications and to take careful measures based on the patient’s and family’s intentions. Infusion is generally judged to be beneficial to the patient at the end of life and is indicated if the patient or his/her family approves. Careful follow-up is required to maximize the benefits and minimize the risks of this intervention.
Nutrition therapy. Providing nutritional guidance, counseling, and health education to patients is thought to have a positive effect on their nutritional status and QOL (50-52). Because the patients and families are not aware of the importance of nutritional management, patients often have inadequate nutritional intake, which worsens their nutritional status. Thus, appropriate nutritional guidance from a doctor or a registered dietitian regarding dietary content, intake methods, and the use of dietary supplements is necessary (53, 54).
Exercise therapy. Patients with cancer are less physically active due to the confluence of various factors. Consequently, they are more likely to develop skeletal muscle atrophy due to the lack of exercise. Loss of muscle mass causes fatigue and creates a vicious cycle of reduced activity and further muscle atrophy. Moreover, anabolic stimulation by muscle contraction is required to maintain the body’s protein at acceptable levels (55, 56). Thus, it is important for clinicians to recommend light exercises, such as walking, to prevent loss of muscle mass (50, 51). However, the effectiveness of exercise therapy has not been verified at the advanced stage of cachexia, and excessive exercise may lead to exhaustion when sufficient nutritional intake cannot be secured or when metabolic disorders are severe. This is burdensome for the patient and necessitates the administration of extra medical care (57-59).
Patients who can complete an exercise program can obtain complete physical function and a greatly improved QOL. Unfortunately, a high dropout rate is a substantial limitation of exercise therapy for cancer patients. Additionally, attending group interventions and/or high-intensity exercise prescriptions using recommended training equipment increases the number of hospital visits and causes a heavy burden on patients.
At present, there have been a few randomized controlled trials of non-pharmaceutical treatments, such as nutrition therapy and exercise therapy, in patients with cancer cachexia (60, 61). In one randomized controlled trial of patients with advanced cancer, nutritional therapy alone did not prove to be consistently effective in terms of the effects on body weight, survival, and other outcomes (62, 63). As mentioned above, nutritional support for cancer patients includes not only dietary interventions and infusions but also nutritional guidance and exercise therapy. Currently, it is difficult to address cachexia, which is a complex metabolic disorder syndrome. However, an effective multidisciplinary approach administered by the medical care team has been shown to delay the progression of this disorder and ultimately, improve the QOL and prognosis of cancer patients (64, 65).
Drug Treatment
Non-steroidal anti-inflammatory drugs. Although non-steroidal anti-inflammatory drugs are useful analgesic aids to medical narcotics, their single-agent administration-based anti-inflammatory effects have not been shown to improve metabolism and nutritional status. However, these drugs may prevent the development of cachexia when used as a part of a multimodal treatment. Unfortunately, at present, these drugs are known to cause adverse events in cases of severe cachexia. Unnecessary administration should therefore be avoided.
Corticosteroids. Corticosteroids are powerful anti-inflammatory drugs that are often used together with progesterone preparations in the treatment of anorexia in cachexic patients in Europe and the United States. Corticosteroids demonstrated efficacious results with regard to maintaining body weight and QOL. However, because side effects occur at a high rate with long-term use, their indicated use is limited to end-of-life care (66, 67).
Anti-cytokine therapy. As the mechanism of cachexia has been gradually elucidated, attempts have been made to improve malnutrition caused by cachexia through the use of drugs and specialized nutrients. Because inflammatory cytokines play an important role in metabolic disorders and anorexia occurring within cachexia, treatments, such as anti-cytokine therapy, have been attempted in previous researches.
Eicosapentaenoic acid. In addition to its anti-inflammatory effects, eicosapentaenoic acid has been reported to reduce PIF production, inhibit skeletal muscle decomposition, and improve QOL in cachexia patients. In Japan, eicosapentaenoic acid is widely used to treat cancer patients with favorable results (68).
Branched-chain amino acids, L-carnitine, CoQ10. Branched-chain amino acids suppress protein breakdown and promote protein synthesis in the brain. Moreover, they also control the metabolism of pseudoneurotransmitters in vivo to improve “greed”. It has been reported that L-carnitine promotes fatty acid metabolism at the cellular level when used in combination with coenzyme Q10 (CoQ10) and also improves the symptoms of anorexia (69). However, additional detailed studies on the effects of these various nutrients are necessary.
Gastrointestinal hypermotility drugs. Gastrointestinal hypermotility drugs, such as metoclopramide, are effective in treating appetite loss and gastrointestinal peristalsis in cancer patients, and their use is recommended within current medical guidelines. However, side effects and serious complications associated with these medications have been reported. Thus, these drugs should be used in compliance with the relevant indications.
Oral supplements. The use of oral supplements (ONS) is currently the first nutritional care strategy that is recommended for increasing oral nutritional intake (51, 70). There has been an increase in the number of ONS listed in the National Health Insurance (NHI) price list. In addition, many nutritional supplements, which are treated as food according to national regulations, are sold over the counter. The wide variety of ONS available as prescriptions or in the general market includes 1) supplements with different flavors, 2) supplements with fortified nutrients, high nutrient concentrations, and/or high protein levels, and 3) supplements with different textures. To improve compliance with and effective administration of ONS, it is necessary to educate patients regarding the appropriate method of intake and to provide a sufficient explanation of the significance of these 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 over-expressing 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).
The chemical structure of anamorelin hydrochloride.
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 factor-1 (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).
A depiction of anamorelin’s ghrelin-like mechanism of action. Anamorelin activates growth hormone secretagogue receptor 1a (GHS-R1a), 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.
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.
Acknowledgements
This work was supported by JSPS KAKENHI Grant Number JP20K08997 and JP22H04990.
Footnotes
Authors’ Contributions
Conceptualization and design: H.W. and T.O. Literature review/writing/revision: H.W. and T.O. All Authors have read and agreed to the published version of the manuscript.
Conflicts of Interest
The Authors have no actual or potential conflicts of interest to declare in relation to this study.
- Received November 23, 2022.
- Revision received December 5, 2022.
- Accepted December 6, 2022.
- Copyright © 2023 The Author(s). Published by the International Institute of Anticancer Research.
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).
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