During its evolution, cancer induces changes in patients’ energy metabolism that strongly affect the overall clinical state and are responsible for cancer-related cachexia syndrome. To better understand the mechanisms underlying cachexia and its metabolic derangements, research efforts should focus on the events that are driven by the immune system activation during the evolution of neoplastic disease and on the phenomena of “resistance” and “tolerance” typically involved in the human body immune response against stress, pathogens, or cancer. Indeed, the growth of a tumor that overcomes the mechanisms of resistance underlines a lack of efficacy of the specific immune response, which is followed by a macrophage-mediated chronic inflammatory response with related symptoms, whose persistence leads to the phenomena of tolerance. In the case where resistance is not able to eliminate the cancer, tolerance mechanisms can utilize the symptoms of cachexia (anemia, anorexia, and fatigue) to counteract unregulated cancer growth. Thus, cancer cachexia should be considered the evidence of symptoms related to tolerance, and it should be considered as the final attempt by the body to counteract cancer growth. These notions are also sustained by the evidence that cancer cachexia may be reversible if the resistance and tolerance phases are supported by appropriate antineoplastic treatments. In fact, in clinical practice, several patients exhibiting symptoms of cachexia (weight loss ≥ 5-10 % of ideal weight in the last 3-6 months) exhibit a significant resolution of the phenomena and associated symptoms with the reduction of tumor burden. Once a patient, even in an advanced stage of the disease, achieves a clinical response, especially a complete response, they might regain their appetite with a resolution of anorexia, gain weight with the improvement of lean body mass, and become free of other symptoms associated to cachexia, such as anemia and immunodepression. Viceversa, the irreversible form of cachexia that leads to death develops when the available therapies are not able to control the disease and the resistance mechanisms fail with the prevalence of the tolerance phenomena. Accordingly, there is no doubt that anticachectic therapies have an irreplaceable role in cases of reversible cancer cachexia where, if harmoniously associated with effective antineoplastic therapies, they can contribute to preserve the quality of life and improve prognosis. Such anticachectic treatments should be based on targeting the complex immunological, inflammatory, and metabolic pathways involved in the complex pathogenesis of cachexia. Meanwhile, the role of the anticachectic therapies is very different in the stage of irreversible cachexia when the available antineoplastic treatments are not able to control the disease. At this stage, they can be useful only to improve the quality of life, allowing the patient and their family to get a better awareness of the final phases of life, thereby opening to the best spiritual remodulation of the final event, death. Therefore, a better knowledge of the mechanisms of resistance and tolerance as crucial events involved in the pathogenesis and development of cancer cachexia surely could help clinicians to be aware of the relevance of cachexia incidence in the evolution of cancer disease and improve its early recognition and effective treatment.
1. Introduction
During its evolution, cancer induces changes in patients’ energy metabolism that strongly affect the overall clinical state
[1]. A plethora of symptoms that involve various organs and systems are linked with cancer-associated metabolic changes, including anorexia, nausea, weight loss with reductions in lean mass and adipose tissue, and increased energy metabolism with changes in glucose, lipid, and protein metabolism. These changes are often responsible for cancer-related cachexia syndrome—a condition associated with malignancy identified by involuntary weight loss accompanied by chronic inflammation, fatigue, anorexia, and anemia
[2]. This syndrome affects cancer patients with metastatic disease with a variable incidence among different tumor types and is responsible for about half of all cancer deaths worldwide
[3], although it may be reversible in some phases of the neoplastic disease. A consensus agreement defined cancer cachexia as a multifactorial syndrome characterized by the ongoing loss of skeletal muscle mass (with or without the loss of fat mass) that cannot be fully reversed by conventional nutritional support, and thus, ultimately leads to progressive functional impairment
[4]. The consensus diagnostic criteria for cachexia are ≥5% weight loss, or ≥2% weight loss in individuals already showing decreases in body weight and height (body mass index (BMI) < 20 kg/m
2) or skeletal muscle mass (sarcopenia)
[4]. Researchers agree that cancer cachexia syndrome can develop progressively through various stages, from pre-cachexia to cachexia and refractory cachexia. Cachexia severity can be classified according to the degree of depletion of energy stores and protein (based on BMI) in combination with the degree of ongoing weight loss
[4]. Assessments to guide disease classification and clinical management should include the following domains: anorexia or reduced food intake, catabolic drive, i.e., inflammation and tumor growth, muscle mass and strength, and functional or psychosocial impairment.
Despite the evidence presented above, early, and accurate diagnosis is lacking in clinical practice and a standardized effective treatment has not yet been established. Meanwhile, based on the relevant clinical impact of this syndrome, a therapeutic approach based on the depth of knowledge of its complex pathogenesis must be implemented.
2. Role of Inflammation, Oxidative Stress, and Energy Pathways-Related Biomarkers for Early Detection of Cancer Cachexia
The inflammatory response with alterations of energy metabolism associated with the pathogenesis of cachexia leads to changes of circulating levels of several related parameters in cancer patients. Several papers from our group demonstrated that serum levels of proinflammatory cytokines, and particularly IL-6, are positively associated with ROS levels and inversely with antioxidant enzymes in advanced cancer patients
[5][6][7][102,116,117]. The inflammatory response is also inversely related to leptin levels that, together with IL-6, may be a useful prognostic marker of disease outcome as demonstrated by us in a population of advanced ovarian cancer
[7][117]. Indeed, leptin is closely associated with cytokine levels, mainly IL-6, and has been identified as a mediator of the metabolic and immunological changes observed in advanced cancer patients
[8][118]. Leptin changes closely reflected changes in IL-6, according to tumor objective response or progression
[7][117]. It could thus be hypothesized that the changes observed with leptin parallel the changes in energy metabolism that are induced by cytokines, long before the metabolic changes induce a significant loss in body weight. Then, IL-6 and leptin could represent early markers of the main symptoms and metabolic alterations associated with the pathogenesis of cancer cachexia. The search for parameters useful to diagnose cachexia according to its degree, and to improve its recognition in the early stages to improve a more effective therapeutic approach, is a recognized need by researchers operating in this field
[4]. In this regard, recently Argiles JM et al.
[9][119] developed and validated a tool to assess the different stages of cachexia, which includes several important parameters of inflammation/metabolic disturbances/immunosuppression (i.e., CRP, IL-6, albumin, lactate, triglycerides, urea, hemoglobin, ROS, and glucose tolerance test/insulinemia). Their results showed that CASCO may represent a new valid tool for the quantitative staging of cachectic cancer patients
[9][119].
3. Perspective for a Targeted Metabolic-Driven Therapeutic Approach for Cancer Cachexia
Muscle wasting during the evolution of neoplastic disease involves reduced protein synthesis and an associated increase in muscle degradation. Moreover, the increased proliferation rate of cancer cells and the chronic inflammatory response evoked by the defective immune response in the resistance phase are associated with increased energy expenditure, altered energy metabolism, and the concomitant onset of cancer-related anorexia. These events evoke energy stress with consequent protective inhibition of the PI3K/AKT/mTOR pathway and halted protein synthesis. Chronic inflammation induces proteolysis, particularly mediated by IL-6, with the release of amino acids. This effect is useful for supporting the increased energy demand through β-oxidation and is probably also an attempt to reactivate mTOR. Importantly, IL-6 is considered a mediator of cancer anorexia and the main inducer of cancer anemia, and both conditions eventually inhibit the mTOR axis, thereby establishing a vicious cycle that augments muscle wasting. Strategies to reverse this condition should consider two factors: counteracting anorexia and anemia, and inhibiting the activity of inflammatory cytokines, particularly IL-6.
These observations justify a multitargeted therapy approach for neoplastic cachexia, as we have emphasized in our previous publications, where specific modulators of inflammation, energy metabolism, and associated oxidative stress find their broad etiopathogenic rationale.
3.1. Drugs Targeting Inflammation
Approved drugs to treat cachexia include progestins (megestrol acetate and medroxyprogesterone acetate) for their ability to stimulate appetite and body weight demonstrated in several clinical trials
[10][120]. Their mechanism of action is mediated mainly by their capacity to decrease the synthesis of proinflammatory cytokines, downregulate the ubiquitin-proteasome pathway, and stimulate the orexigenic neuropeptide Y
[10][120]. However, these drugs do not seem to exert a significant impact on muscle mass, while they may have significant adverse effects, such as thromboembolic phenomena, peripheral edema, hyperglycemia, hypertension, adrenal suppression, and adrenal insufficiency. Therefore, their use should warrant a careful evaluation of their potential toxicities especially in hospitalized and elderly patients
[11][12][121,122].
Among anti-inflammatory agents, a COX-2 inhibitor, which has been tested alone
[13][14][123,124] and in combination regimens for cancer cachexia
[15][16][125,126], should be able to improve several features of cancer cachexia including loss of body weight, muscle strength, and lean body mass in parallel with a decrease in circulating levels of pro-inflammatory cytokines, particularly IL-6 and CRP. Notably, these compounds exert their anticachectic effect through their ability to downregulate the proinflammatory cascade (prostaglandin, TNF, IL-6) and the Cox-2-mediated activation of proteolytic pathways, as well as inhibiting the GH-IGF1-mediated protein anabolism
[17][127]. Notable, in experimental models associated with muscle wasting, celecoxib was able to prevent the rise in blood levels of lactate, the inhibition of the peripheral response to insulin and hepatic glycolysis, and tended to attenuate the decrease in food intake
[18][128].
Specific therapeutic targets against proinflammatory cytokines (IL-6, TNFα, IL-1, etc.) have been proposed for testing in clinical trials, based on the preclinical investigation. However, none of these drugs has been yet approved for the indication of cancer cachexia
[2]. IL-6 represents the main target cytokine for the treatment of muscle wasting and a preclinical animal study with the IL-6 inhibitor tocilizumab showed promising results
[19][129]. Additionally, in preliminary clinical trials in patients with lung cancer and cachexia, the humanized anti-IL-6 antibody tocilizumab is safe and effective against cachexia-related symptoms
[20][21][130,131]. Interestingly, considering the mediating role of the JAK/STAT3 pathway in IL-6-induced muscle wasting, the role of the recently developed JAK and STAT3 inhibitors (i.e., ruxolitinib) on muscle mass and function should be further investigated especially when considering the significant benefit obtained specifically in ameliorating the cachectic symptoms in a large clinical trial in patients with multiple myeloma
[22][132].
Among nutraceuticals, curcumin also proved to be useful as an anticachectic agent
[23][24][133,134]. Its efficacy may be mainly due to the ability to inhibit STAT-3-induced NF-kb signaling and increase sirtuin-1 activity, thereby counteracting muscle proteolysis and wasting
[25][135].
Additionally, lactoferrin can lessen inflammation associated with M1 macrophage polarization
[26][136] and positively modulate the related changes in iron metabolism (iron trafficking and storage), mobilizing iron from deposits and increasing its availability for erythropoiesis
[27][137].
3.2. Drugs Targeting Oxidative Stress
Additionally, antioxidants such as glutathione, N-acetyl cysteine, and quercetin, can revert cancer-induced muscle wasting by reducing both oxidative stress and inflammation by modulating the ROS-mediated activation of the inflammasome pathway. Indeed, ROS may affect the protein synthesis and degradation involved in muscle wasting and they are a known modulator of the PI3K/Akt/mTORC1 pathway, calpain and ubiquitin-proteasome mediated proteolysis, and autophagic degradation of muscle mass
[28][138]. Moreover, in an animal experimental model, ROS-induced alterations affected muscle quality and function
[29][139].
3.3. Modulators of Energy Metabolic Pathways
6.3. Modulators of Energy Metabolic Pathways
L-carnitine was also shown to effectively improve lean body mass in cachectic cancer patients, most likely for its ability to increase oxidative mitochondrial energy metabolism and exert antioxidant effects. In a randomized double-blinded trial, 72 patients with advanced pancreatic adenocarcinoma received 4 g carnitine or placebo for 12 weeks, and the treatment group achieved an improvement in body cell mass
[30][140]. Another study by our group showed that treatment with
l-carnitine (6 g/day) in a population of 12 patients with different cancer types at advanced stage led to an increase in lean mass and appetite associated with a decrease in fatigue and oxidative stress over 4 weeks of treatment
[31][141]. The metabolic role of
l-carnitine as an anticachectic agent is likely related to its ability to modulate the carnitine/carnitine palmitoyl transferase system. This is the rate-limiting step of fatty acid oxidation/ketogenesis, which is activated in catabolic states such as cachexia, in association with gluconeogenesis, and decreased lipogenesis
[32][142]. In experimental preclinical models,
l-carnitine was shown to ameliorate cancer cachexia and increase muscle mass by increasing the activities of carnitine palmitoyl transferase I and II
[33][34][143,144]. Moreover,
l-carnitine can modulate peroxisome proliferator-activated receptor gamma-1 alpha, a master regulator of metabolism, which induces hepatic gluconeogenesis and fatty acid oxidation in the catabolic state
[33][143].
Among nutritional supplements, amino acids have been tested as a targeted therapy of cancer cachexia for their critical role in promoting protein synthesis in muscle tissue. The emerging role of some amino acids, in particular branched-chain amino acids (BCAAs), in reversing the anabolic muscle resistance is being reported
[35][145]. Noteworthy, hydroxyl-methyl butyrate (HMB) can up-regulate the phosphorylation of mTOR and downregulate the Akt/FoxO and MuRF1 which controls autophagy and ubiquitin-dependent proteolytic systems
[17][127].
Accordingly, amino acids are demonstrated to ameliorate muscle loss in cancer cachexia [146]. Interestingly, in advanced cancer patients, HMB combined with other amino acids in supplements resulted in a significant gain in lean body mass as demonstrated by randomized clinical trials [147,148] and a systematic review [149].
4Discussion and Conclusions
The implementation of the knowledge of the early mechanisms involved in the onset of cancer cachexia and the development of its complex metabolic alterations may certainly improve a timely diagnosis and a more adequate treatment aimed to specifically target its pathogenetic mechanisms [150]. DThe recognition of the mechanisms of resistance and tolerance, involved in different phases of the immune response against tumor, ascussion and Conclusion crucial events involved in the pathogenesis and development of cancer cachexia surely could help clinicians to be aware of the relevance of cachexia incidence in the evolution of cancer disease and improve its early recognition. Consistently, more effective treatment with agents targeting the inflammatory pathways, the related changes in the oxido-reductive status, and the relevant energy metabolism derangements could be early started and offer a greater advantage in the prevention and treatment of this syndrome. There is no doubt that anticachectic therapies have an irreplaceable role in cases of reversible cachexia where, if harmoniously associated with effective antineoplastic therapies, they can effectively contribute to maintain a quality of life and promote the efficacy of the treatment. Meanwhile, the role of these therapies is very different in the different stages of irreversible cachexia that leads to death, where anticachectic therapy can be useful only to improve the quality of life. Allowing the patient and his family to get a better awareness of the final stages of life, thereby opening to the best spiritual remodulation of the final event, death. Thus, in this context, the increase in the number of days obtained with the use of these therapies certainly has its clinical significance but its spiritual role must also emerge.
The implementation of the knowledge of the early mechanisms involved in the onset of cancer cachexia and the development of its complex metabolic alterations may certainly improve a timely diagnosis and a more adequate treatment aimed to specifically target its pathogenetic mechanisms. The recognition of the mechanisms of resistance and tolerance, involved in different phases of the immune response against tumor, as crucial events involved in the pathogenesis and development of cancer cachexia surely could help clinicians to be aware of the relevance of cachexia incidence in the evolution of cancer disease and improve its early recognition. Consistently, more effective treatment with agents targeting the inflammatory pathways, the related changes in the oxido-reductive status, and the relevant energy metabolism derangements could be early started and offer a greater advantage in the prevention and treatment of this syndrome. There is no doubt that anticachectic therapies have an irreplaceable role in cases of reversible cachexia where, if harmoniously associated with effective antineoplastic therapies, they can effectively contribute to maintain a quality of life and promote the efficacy of the treatment. Meanwhile, the role of these therapies is very different in the different stages of irreversible cachexia that leads to death, where anticachectic therapy can be useful only to improve the quality of life. Allowing the patient and his family to get a better awareness of the final stages of life, thereby opening to the best spiritual remodulation of the final event, death. Thus, in this context, the increase in the number of days obtained with the use of these therapies certainly has its clinical significance but its spiritual role must also emerge.
