Effects of S-pindolol in mouse pancreatic and lung cancer cachexia models.

BACKGROUND: It is known that S-pindolol attenuates muscle loss in animal models of cancer cachexia and sarcopenia. In cancer cachexia, it also significantly reduced mortality and improved cardiac function, which is strongly compromised in cachectic animals. METHODS: Here, we tested 3 mg/kg/day of S-pindolol in two murine cancer cachexia models: pancreatic cancer cachexia (KPC) and Lewis lung carcinoma (LLC). RESULTS: Treatment of mice with 3 mg/kg/day of S-pindolol in KPC or LLC cancer cachexia models significantly attenuated the loss of body weight, including lean mass and muscle weights, leading to improved grip strength compared with placebo-treated mice. In the KPC model, treated mice lost less than half of the total weight lost by placebo (-0.9 ± 1.0 vs. -2.2 ± 1.4 g for S-pindolol and placebo, respectively, P < 0.05) and around a third of the lean mass lost by tumour-bearing controls (-0.4 ± 1.0 vs. -1.5 ± 1.5 g for S-pindolol and placebo, respectively, P < 0.05), whereas loss of fat mass was similar. In the LLC model, the gastrocnemius weight was higher in sham (108 ± 16 mg) and S-pindolol tumour-bearing (94 ± 15 mg) mice than that in placebo (83 ± 12 mg), whereas the soleus weight was only significantly higher in the S-pindolol-treated group (7.9 ± 1.7 mg) than that in placebo (6.5 ± 0.9). Grip strength was significantly improved by S-pindolol treatment (110.8 ± 16.2 vs. 93.9 ± 17.1 g for S-pindolol and placebo, respectively). A higher grip strength was observed in all groups; whereas S-pindolol-treated mice improved by 32.7 ± 18.5 g, tumour-bearing mice only show minimal improvements (7.3 ± 19.4 g, P < 0.01). CONCLUSIONS: S-pindolol is an important candidate for clinical development in the treatment of cancer cachexia that strongly attenuates loss of body weight and lean body mass. This was also seen in the weight of individual muscles and resulted in higher grip strength.

Cancer-associated cachexia - understanding the tumour macroenvironment and microenvironment to improve management.

Cachexia is a devastating, multifactorial and often irreversible systemic syndrome characterized by substantial weight loss (mainly of skeletal muscle and adipose tissue) that occurs in around 50-80% of patients with cancer. Although this condition mainly affects skeletal muscle (which accounts for approximately 40% of total body weight), cachexia is a multi-organ syndrome that also involves white and brown adipose tissue, and organs including the bones, brain, liver, gut and heart. Notably, cachexia accounts for up to 20% of cancer-related deaths. Cancer-associated cachexia is invariably associated with systemic inflammation, anorexia and increased energy expenditure. Understanding these mechanisms is essential, and the progress achieved in this area over the past decade could help to develop new therapeutic approaches. In this Review, we examine the currently available evidence on the roles of both the tumour macroenvironment and microenvironment in cancer-associated cachexia, and provide an overview of the novel therapeutic strategies developed to manage this syndrome.

The atypical ß-blocker S-oxprenolol reduces cachexia and improves survival in a rat cancer cachexia model.

BACKGROUND: Beta-blockers and selected stereoisomers of beta-blockers, like bisoprolol and S-pindolol (ACM-001), have been shown to be effective in preclinical cancer cachexia models. Here, we tested the efficacy of stereoisomers of oxprenolol in two preclinical models of cancer cachexia-the Yoshida AH-130 rat model and the Lewis lung carcinoma (LLC) mouse model. METHODS AND RESULTS: In the Yoshida AH130 hepatoma rat cancer cachexia model and compared with placebo, 50 mg/kg/d S-oxprenolol (HR: 0.49, 95% CI: 0.28-0.85, P = 0.012) was superior to 50 mg/kg/d R-oxprenolol (HR: 0.83, 95% CI 0.38-1.45, P = 0.51) in reducing mortality (= reaching ethical endpoints). Combination of the three doses (12.5, 25 and 50 mg/kg/d) that had a significant effect on body weight loss in the S-oxprenolol groups vs the same combination of the R-oxprenolol groups lead to a significantly improved survival of S-oxprenolol vs R-oxprenolol (HR: 1.61, 95% CI: 1.08-2.39, P = 0.0185). Interestingly, there is a clear dose dependency in S-oxprenolol-treated (5, 12.5, 25 and 50 mg/kg/d) groups, which was not observed in groups treated with R-oxprenolol. A dose-dependent attenuation of weight and lean mass loss by S-oxprenolol was seen in the Yoshida rat model, whereas R-oxprenolol had only had a significant effect on fat mass. S-oxprenolol also non-significantly reduced weight loss in the LLC model and also improved muscle function (grip strength 428 ± 25 and 539 ± 37 g/100 g body weight for placebo and S-oxprenolol, respectively). However, there was only a minor effect on quality of life indicators food intake and spontaneous activity in the Yoshida model (25 mg/kg/S-oxprenolol: 11.9 ± 2.5 g vs placebo: 4.9 ± 0.8 g, P = 0.013 and also vs 25 mg/kg/d R-oxprenolol: 7.5 ± 2.6 g, P = 0.025). Both enantiomers had no effects on cardiac dimensions and function at the doses used in this study. Western blotting of proteins involved in the anabolic/catabolic homoeostasis suggest that anabolic signalling is persevered (IGF-1 receptor, Akt) and catabolic signalling is inhibited (FXBO-10, TRAF-6) by S-pindolol, but not he R-enantiomer. Expression of glucose transporters Glut1 and Glut 4 was similar in all groups, as was AMPK. CONCLUSIONS: S-oxprenolol is superior to R-oxprenolol in cancer cachexia animal models and shows promise for a human application in cancer cachexia.

Formoterol reduces muscle wasting in mice undergoing doxorubicin chemotherapy.

Background: Even though doxorubicin (DOX) chemotherapy promotes intense muscle wasting, this drug is still widely used in clinical practice due to its remarkable efficiency in managing cancer. On the other hand, intense muscle loss during the oncological treatment is considered a bad prognosis for the disease's evolution and the patient's quality of life. In this sense, strategies that can counteract the muscle wasting induced by DOX are essential. In this study, we evaluated the effectiveness of formoterol (FOR), a ß2-adrenoceptor agonist, in managing muscle wasting caused by DOX. Methods and results: To evaluate the effect of FOR on DOX-induced muscle wasting, mice were treated with DOX (2.5 mg/kg b.w., i.p. administration, twice a week), associated or not to FOR treatment (1 mg/kg b.w., s.c. administration, daily). Control mice received vehicle solution. A combination of FOR treatment with DOX protected against the loss of body weight (p<0.05), muscle mass (p<0.001), and grip force (p<0.001) promoted by chemotherapy. FOR also attenuated muscle wasting (p<0.01) in tumor-bearing mice on chemotherapy. The potential mechanism by which FOR prevented further DOX-induced muscle wasting occurred by regulating Akt/FoxO3a signaling and gene expression of atrogenes in skeletal muscle. Conclusions: Collectively, our results suggest that FOR can be used as a pharmacological strategy for managing muscle wasting induced by DOX. This study provides new insights into the potential therapeutic use of FOR to improve the overall wellbeing of cancer patients undergoing DOX chemotherapy.

Effects of Cigarette Smoke on Adipose and Skeletal Muscle Tissue: In Vivo and In Vitro Studies.

Chronic obstructive pulmonary disease (COPD), often caused by smoking, is a chronic lung disease with systemic manifestations including metabolic comorbidities. This study investigates adaptive and pathological alterations in adipose and skeletal muscle tissue following cigarette smoke exposure using in vivo and in vitro models. Mice were exposed to cigarette smoke or air for 72 days and the pre-adipose cell line 3T3-L1 was utilized as an in vitro model. Cigarette smoke exposure decreased body weight, and the proportional loss in fat mass was more pronounced than the lean mass loss. Cigarette smoke exposure reduced adipocyte size and increased adipocyte numbers. Adipose macrophage numbers and associated cytokine levels, including interleukin-1ß, interleukine-6 and tumor necrosis factor-α were elevated in smoke-exposed mice. Muscle strength and protein synthesis signaling were decreased after smoke exposure; however, muscle mass was not changed. In vitro studies demonstrated that lipolysis and fatty acid oxidation were upregulated in cigarette smoke-exposed pre-adipocytes. In conclusion, cigarette smoke exposure induces a loss of whole-body fat mass and adipose atrophy, which is likely due to enhanced lipolysis.

Lack of Synergy Between ß-Agonist Treatment and a Blockage of Sarcoplasmic Calcium Flow in a Rat Cancer Cachexia Model.

BACKGROUND: During cancer cachexia, both skeletal muscle and adipose tissue losses take place. The use of ß2-agonists, formoterol in particular, has proven to be very successful in the treatment of the syndrome in pre-clinical models. The object of the present research was to study the effects of a combination of formoterol and dantrolene, an inhibitor of the ryanodine receptor 1 (RyR1), on body weight loss and cachexia in tumour-bearing animals. METHODS: Rats were separated into two groups: controls (C) and tumour bearing (TB). TB group was further subdivided into four groups: untreated (saline as a vehicle), treated with Formoterol (TF) (0,3 mg/kg body weight in saline, subcutaneous (s.c.), daily), treated with Dantrolene (TD) (5 mg/kg body weight in saline, subcutaneous (s.c.), daily), and double-treated treated (TFD) with Formoterol (0,3 mg/kg body weight, subcutaneous (s.c.), daily) and Dantrolene (5 mg/kg body weight, subcutaneous (s.c.), daily). 7 days after tumour transplantation, muscle weight, grip force, and total physical activity were specified in all experimental groups. RESULTS: While formoterol had, as in previous studies, a very positive effect in reducing muscle weight loss, dantrolene had no effects, neither on skeletal muscle nor on any of the parameters studied. Finally, the combined treatment (formoterol and dantrolene) did not result in any significant benefit on the action of the ß2-agonist. CONCLUSION: It is concluded that, in the preclinical cachectic model used, no synergy exists between ß2-agonist treatment and the blockade of sarcoplasmic-calcium flow.

Differential structural features in soleus and gastrocnemius of carnitine-treated cancer cachectic rats.

Muscle wasting is associated with chronic diseases and cancer. Elucidation of the biological mechanism involved in the process of muscle mass loss and cachexia may help identify therapeutic targets. We hypothesized that l-carnitine treatment may differentially revert muscle fiber atrophy and other structural alterations in slow- and fast-twitch limb muscles of rats bearing the Yoshida ascites hepatoma. In soleus and gastrocnemius of tumor-bearing rats (108 AH-130 Yoshida ascites hepatoma cells inoculated intraperitoneally) with and without treatment with l-carnitine (1 g/kg body weight for 7 days, intragastric), food intake, body and muscle weights, fiber typing and morphometry, morphological features, redox balance, autophagy and proteolytic, and signaling markers were explored. Levels of carnitine palmitoyl transferase were also measured in all the study muscles. l-Carnitine treatment ameliorated the atrophy of both slow- and fast-twitch fibers (gastrocnemius particularly), muscle structural alterations (both muscles), and attenuated oxidative stress, proteolytic and signaling markers (gastrocnemius). Despite that carnitine palmitoyl transferase-1 levels increased in both muscle types in a similar fashion, l-carnitine ameliorated muscle atrophy and proteolysis in a muscle-specific manner in cancer-induced cachexia. These data reveal the need to study muscles of different fiber type composition and function to better understand whereby l-carnitine exerts its beneficial effects on the myofibers in muscle wasting processes. These findings also have potential clinical implications, since combinations of various exercise and muscle training modalities with l-carnitine should be specifically targeted for the muscle groups to be trained.

The animal cachexia score (ACASCO).

BACKGROUND: None of the published studies involving cancer cachexia experimental models have included a measure of the severity of the syndrome like the scoring system previously developed for human subjects. The aim of the present investigation was to define and validate a cachexia score usable in both rat and mouse tumor models. METHODS: In order to achieve this goal, we included in the study one rat model (Yoshida AH-130ascites hepatoma) and two mouse models (Lewis lung carcinoma and Colon26 carcinoma). The Animal cachexia score (ACASCO) includes five components: (a) body and muscle weight loss, (b) inflammation and metabolic disturbances, (c) physical performance, (d) anorexia, and (e) quality of life measured using discomfort symptoms and behavioral tests. RESULTS: Using the ACASCO values, three cut-off values were estimated by applying hierarchical cluster analysis. Four groups were originally described, one exactly below the observed mean, a second exactly over the mean, and two other groups adjusted to every cue (inferior and superior). The three cut-off values were estimated through maximization of the classification function. This was accomplished by using a similarity matrix based on the metric properties of the variables and assuming multinormal distribution. The results show that the four groups were: no cachexia, mild cachexia, moderate cachexia and advanced cachexia. CONCLUSIONS: The results obtained allow us to conclude that the score could be very useful as an endpoint in pre-clinical studies involving therapeutic strategies for cancer cachexia. The potential usefulness of ACASCO relates to the primary endpoint in pre-clinical cancer cachexia drug evaluations.

Autophagy Exacerbates Muscle Wasting in Cancer Cachexia and Impairs Mitochondrial Function.

Cancer cachexia is a multifactorial syndrome characterized by anorexia, weight loss and muscle wasting that impairs patients' quality of life and survival. Aim of this work was to evaluate the impact of either autophagy inhibition (knocking down beclin-1) or promotion (overexpressing TP53INP2/DOR) on cancer-induced muscle wasting. In C26 tumor-bearing mice, stress-induced autophagy inhibition was unable to rescue the loss of muscle mass and worsened muscle morphology. Treating C26-bearing mice with formoterol, a selective ß2-agonist, muscle sparing was paralleled by reduced static autophagy markers, although the flux was maintained. Conversely, the stimulation of muscle autophagy exacerbated muscle atrophy in tumor-bearing mice. TP53INP2 further promoted atrogene expression and suppressed mitochondrial dynamics-related genes. Excessive autophagy might impair mitochondrial function through mitophagy. Consistently, tumor-induced mitochondrial dysfunction was detected by reduced ex vivo muscle fiber respiration. Overall, the results evoke a central role for muscle autophagy in cancer-induced muscle wasting.

Mediators of cachexia in cancer patients.

Alterations in amino acid and protein metabolism-particularly in skeletal muscle-are a key feature of cancer that contributes to the cachexia syndrome. Thus, skeletal muscle protein turnover is characterized by an exacerbated rate of protein degradation, promoted by an activation of different proteolytic systems that include the ubiquitin-proteasome and the autophagic-lysosomal pathways. These changes are promoted by both hormonal alterations and inflammatory mediators released as a result of the systemic inflammatory response induced by the tumor. Other events, such as alterations in the rate of myogenesis/apoptosis and decreased regeneration potential also affect skeletal muscle in patients with cancer. Mitochondrial dysfunction also contributes to changes in skeletal muscle metabolism and further contributes to the exacerbation of the cancer-wasting syndrome. Different inflammatory mediators-either released by the tumor or by the patient's healthy cells-are responsible for the activation of these catabolic processes that take place in skeletal muscle and in other tissues/organs, such as liver or adipose tissues. Indeed, white adipose tissue is also subject to extensive wasting and "browning" of some of the white adipocytes into beige cells; therefore increasing the energetic inefficiency of the patient with cancer. Recently, an interest in the role of micromRNAs-either free or transported into exosomes-has been related to the events that take place in white adipose tissue during cancer cachexia.

Therapeutic strategies against cancer cachexia.

Cancer cachexia has two main components: anorexia and metabolic alterations. The main changes associated with the development of this multi-organic syndrome are glucose intolerance, fat depletion and muscle protein hypercatabolism. The aim of this paper is to review the more recent therapeutic approaches designed to counteract the wasting suffered by the cancer patient with cachexia. Among the most promising approaches we can include the use of ghrelin agonists, beta-blockers, beta-adrenergic agonists, androgen receptor agonists and anti-myostatin peptides. The multi-targeted approach seems essential in these treatments, which should include the combination of both nutritional support, drugs and a suitable program of physical exercise, in order to ameliorate both anorexia and the metabolic changes associated with cachexia. In addition, another very important and crucial aspect to be taken into consideration in the design of clinical trials for the treatment of cancer cachexia is to staging cancer patients in relation with the degree of cachexia, in order to start as early as possible this triple approach in the course of the disease, even before the weight loss can be detected.

Cancer cachexia, a clinical challenge.

PURPOSE OF REVIEW: The aim of this article is to review the metabolic background of the cachectic syndrome and to analyze the recent therapeutic approaches designed to counteract the wasting suffered by the cancer patient with cachexia. RECENT FINDINGS: The main changes associated with the development of this multiorganic syndrome are glucose intolerance, fat depletion and muscle protein hypercatabolism. Among the most promising approaches for the treatment of cachexia include the use of ghrelin agonists, beta-blockers, beta-adrenergic agonists, androgen receptor agonists and antimyostatin peptides. The multitargeted approach seems essential in these treatments, which should include the combination of both nutritional support, drugs and a suitable program of physical exercise, in order to ameliorate both anorexia and the metabolic changes associated with cachexia. In addition, another very important aspect for the design of clinical trials for the treatment of cancer cachexia is to staging cancer patients in relation with the degree of cachexia, in order to start as early as possible, this triple approach in the course of the disease, even before weight loss can be detected. SUMMARY: Cancer cachexia has two main components: anorexia and metabolic alterations and both have to be taken into consideration for the treatment of the syndrome.

Inter-tissue communication in cancer cachexia.

Cachexia is a systemic condition that occurs during many neoplastic diseases, such as cancer. Cachexia in cancer is characterized by loss of body weight and muscle and by adipose tissue wasting and systemic inflammation. Cancer cachexia is often associated with anorexia and increased energy expenditure. Even though the cachectic condition severely affects skeletal muscle, a tissue that accounts for ~40% of total body weight, it represents a multi-organ syndrome that involves tissues and organs such as white adipose tissue, brown adipose tissue, bone, brain, liver, gut and heart. Indeed, evidence suggests that non-muscle tissues and organs, as well as tumour tissues, secrete soluble factors that act on skeletal muscle to promote wasting. In addition, muscle tissue also releases various factors that can interact with the metabolism of other tissues during cancer. In this Review, we examine the effect of non-muscle tissues and inter-tissue communication in cancer cachexia and discuss studies aimed at developing novel therapeutic strategies for the condition.

Effects of the beta2 agonist formoterol on atrophy signaling, autophagy, and muscle phenotype in respiratory and limb muscles of rats with cancer-induced cachexia.

Muscle mass loss and wasting are characteristic features of patients with chronic conditions including cancer. Beta-adrenoceptors attenuate muscle wasting. We hypothesized that specific muscle atrophy signaling pathways and altered metabolism may be attenuated in cancer cachectic animals receiving treatment with the beta2 agonist formoterol. In diaphragm and gastrocnemius of tumor-bearing rats (intraperitoneal inoculum, 108 AH-130 Yoshida ascites hepatoma cells, 7-day study period) with and without treatment with formoterol (0.3 mg/kg body weight/day/7days, subcutaneous), atrophy signaling pathways (NF-κB, MAPK, FoxO), proteolytic markers (ligases, proteasome, ubiquitination), autophagy markers (p62, beclin-1, LC3), myostatin, apoptosis, muscle metabolism markers, and muscle structure features were analyzed (immunoblotting, immunohistochemistry). In diaphragm and gastrocnemius of cancer cachectic rats, fiber sizes were reduced, levels of structural alterations, atrophy signaling pathways, proteasome content, protein ubiquitination, autophagy, and myostatin were increased, while those of regenerative and metabolic markers (myoD, mTOR, AKT, and PGC-1alpha) were decreased. Formoterol treatment attenuated such alterations in both muscles. Muscle wasting in this rat model of cancer-induced cachexia was characterized by induction of significant structural alterations, atrophy signaling pathways, proteasome activity, apoptotic and autophagy markers, and myostatin, along with a significant decline in the expression of muscle regenerative and metabolic markers. Treatment of the cachectic rats with formoterol partly attenuated the structural alterations and atrophy signaling, while improving other molecular perturbations similarly in both respiratory and limb muscles. The results reported in this study have relevant therapeutic implications as they showed beneficial effects of the beta2 agonist formoterol in the cachectic muscles through several key biological pathways.

Formoterol attenuates increased oxidative stress and myosin protein loss in respiratory and limb muscles of cancer cachectic rats.

Muscle mass loss and wasting are characteristic features of patients with chronic conditions including cancer. Therapeutic options are still scarce. We hypothesized that cachexia-induced muscle oxidative stress may be attenuated in response to treatment with beta2-adrenoceptor-selective agonist formoterol in rats. In diaphragm and gastrocnemius of tumor-bearing rats (108 AH-130 Yoshida ascites hepatoma cells inoculated intraperitoneally) with and without treatment with formoterol (0.3 mg/kg body weight/day for seven days, daily subcutaneous injection), redox balance (protein oxidation and nitration and antioxidants) and muscle proteins (1-dimensional immunoblots), carbonylated proteins (2-dimensional immunoblots), inflammatory cells (immunohistochemistry), and mitochondrial respiratory chain (MRC) complex activities were explored. In the gastrocnemius, but not the diaphragm, of cancer cachectic rats compared to the controls, protein oxidation and nitration levels were increased, several functional and structural proteins were carbonylated, and in both study muscles, myosin content was reduced, inflammatory cell counts were greater, while no significant differences were seen in MRC complex activities (I, II, and IV). Treatment of cachectic rats with formoterol attenuated all the events in both respiratory and limb muscles. In this in vivo model of cancer-cachectic rats, the diaphragm is more resistant to oxidative stress. Formoterol treatment attenuated the rise in oxidative stress in the limb muscles, inflammatory cell infiltration, and the loss of myosin content seen in both study muscles, whereas no effects were observed in the MRC complex activities. These findings have therapeutic implications as they demonstrate beneficial effects of the beta2 agonist through decreased protein oxidation and inflammation in cachectic muscles, especially the gastrocnemius.

Novel targeted therapies for cancer cachexia.

Anorexia and metabolic alterations are the main components of the cachectic syndrome. Glucose intolerance, fat depletion, muscle protein catabolism and other alterations are involved in the development of cancer cachexia, a multi-organ syndrome. Nutritional approach strategies are not satisfactory in reversing the cachectic syndrome. The aim of the present review is to deal with the recent therapeutic targeted approaches that have been designed to fight and counteract wasting in cancer patients. Indeed, some promising targeted therapeutic approaches include ghrelin agonists, selective androgen receptor agonists, ß-blockers and antimyostatin peptides. However, a multi-targeted approach seems absolutely essential to treat patients affected by cancer cachexia. This approach should not only involve combinations of drugs but also nutrition and an adequate program of physical exercise, factors that may lead to a synergy, essential to overcome the syndrome. This may efficiently reverse the metabolic changes described above and, at the same time, ameliorate the anorexia. Defining this therapeutic combination of drugs/nutrients/exercise is an exciting project that will stimulate many scientific efforts. Other aspects that will, no doubt, be very important for successful treatment of cancer wasting will be an optimized design of future clinical trials, together with a protocol for staging cancer patients in relation to their degree of cachexia. This will permit that nutritional/metabolic/pharmacological support can be started early in the course of the disease, before severe weight loss occurs. Indeed, timing is crucial and has to be taken very seriously when applying the therapeutic approach.

A Rat Immobilization Model Based on Cage Volume Reduction: A Physiological Model for Bed Rest?

Bed rest has been an established treatment in the past prescribed for critically illness or convalescing patients, in order to preserve their body metabolic resource, to prevent serious complications and to support their rapid path to recovery. However, it has been reported that prolonged bed rest can have detrimental consequences that may delay or prevent the recovery from clinical illness. In order to study disuse-induced changes in muscle and bone, as observed during prolonged bed rest in humans, an innovative new model of muscle disuse for rodents is presented. Basically, the animals are confined to a reduced space designed to restrict their locomotion movements and allow them to drink and eat easily, without generating physical stress. The animals were immobilized for either 7, 14, or 28 days. The immobilization procedure induced a significant decrease of food intake, both at 14 and 28 days of immobilization. The reduced food intake was not a consequence of a stress condition induced by the model since plasma corticosterone levels -an indicator of a stress response- were not altered following the immobilization period. The animals showed a significant decrease in soleus muscle mass, grip force and cross-sectional area (a measure of fiber size), together with a decrease in bone mineral density. The present model may potentially serve to investigate the effects of bed-rest in pathological states characterized by a catabolic condition, such as diabetes or cancer.

Validation of the CAchexia SCOre (CASCO). Staging Cancer Patients: The Use of miniCASCO as a Simplified Tool.

The CAchexia SCOre (CASCO) was described as a tool for the staging of cachectic cancer patients. The aim of this study is to show the metric properties of CASCO in order to classify cachectic cancer patients into three different groups, which are associated with a numerical scoring. The final aim was to clinically validate CASCO for its use in the classification of cachectic cancer patients in clinical practice. We carried out a case -control study that enrolled prospectively 186 cancer patients and 95 age-matched controls. The score includes five components: (1) body weight loss and composition, (2) inflammation/metabolic disturbances/immunosuppression, (3) physical performance, (4) anorexia, and (5) quality of life. The present study provides clinical validation for the use of the score. In order to show the metric properties of CASCO, three different groups of cachectic cancer patients were established according to the results obtained with the statistical approach used: mild cachexia (15 ≤ × ≤ 28), moderate cachexia (29 ≤ × ≤ 46), and severe cachexia (47 ≤ × ≤ 100). In addition, a simplified version of CASCO, MiniCASCO (MCASCO), was also presented and it contributes as a valid and easy-to-use tool for cachexia staging. Significant statistically correlations were found between CASCO and other validated indexes such as Eastern Cooperative Oncology Group (ECOG) and the subjective diagnosis of cachexia by specialized oncologists. A very significant estimated correlation between CASCO and MCASCO was found that suggests that MCASCO might constitute an easy and valid tool for the staging of the cachectic cancer patients. CASCO and MCASCO provide a new tool for the quantitative staging of cachectic cancer patients with a clear advantage over previous classifications.