Cachexia definition and diagnosis

The term cachexia derives from the Greek words ‘kakos’ and ‘hexis’, which mean ‘bad conditions’. However, a more clinically relevant definition was needed in order to design useful clinical trials and improve our understanding of the pathogenic mechanisms. In 2008, an international consensus defined cachexia as ‘a complex metabolic syndrome associated with underlying illness and characterised by loss of muscle with or without loss of fat mass. The prominent clinical feature of cachexia is weight loss in adults (corrected for fluid retention) or growth failure in children (excluding endocrine disorders)’⁽ Reference Evans, Morley and Argilés ^{8 )}. Although Evans et al. focused their definition mainly on chronic diseases⁽ Reference Evans, Morley and Argilés ^{8 )}, it is important to note that cachexia, i.e. disease-associated malnutrition characterised by muscle loss, is prevalent also in patients with acute and critical illness, although the identification of the specific contributions of inflammation and disuse to muscle loss is almost impossible⁽ Reference Schefold, Bierbrauer and Weber-Carstens ^{9 )}. According to the Evans et al. consensus, cachexia is diagnosed in the presence of significant weight loss (i.e. >5 % in the previous 12 months or less) associated with at least three of the following markers: decreased muscle strength, fatigue, anorexia, low fat-free mass index and abnormal biochemistry⁽ Reference Evans, Morley and Argilés ^{8 )}.

Although supported by clinical reasoning and molecular evidence, the Evans et al. definition and its attending diagnostic criteria may not precisely assess the clinical conditions of cachectic patients nor predict their outcome, since they were not validated by a large prospective clinical trial. However, many studies have consistently confirmed that the main clinical feature of cachexia is muscle loss, independently of the underlying disease⁽ Reference Palus, von Haehling and Springer ^{10 )}. Therefore, it should not be surprising that in daily practice the recent and specific definition of cancer cachexia is frequently used also to define cachexia associated with other acute or chronic diseases. In fact, cancer cachexia has been defined as ‘a multifactorial syndrome characterised by an ongoing loss of skeletal muscle mass (with or without loss of fat mass) that cannot be fully reversed by conventional nutritional support and leads to functional impairment. The pathophysiology is characterised by a negative protein and energy balance driven by a variable combination of reduced food intake and abnormal metabolism’⁽ Reference Fearon, Strasser and Anker ^{11 )}. This definition elaborated for cancer wasting highlights the key features of cachexia, and therefore is applied to other acute and chronic diseases in which muscle loss develops. Supporting the use of this definition under different clinical conditions, experimental evidence shows that most of the molecular pathways responsible for cancer cachexia are also activated during other diseases⁽ Reference Cohen, Nathan and Goldberg ^{12 )}.

Cancer cachexia is a progressive disease. Therefore, the clinical phenotypes of cachectic patients may vary amply, ranging from reduced food intake and minimal weight loss to severe anorexia, wasting and fatigue. To correctly identify cachectic patients, it has been proposed that cachexia is divided into three stages: pre-cachexia, cachexia and refractory cachexia⁽ Reference Fearon, Strasser and Anker ^{11 )} (Table 1). This classification highlights the importance of the early recognition and treatment of cachexia, before reaching the stage of refractory cachexia when treatments appear futile.

Table 1. Clinical features and diagnostic criteria of cachexia stages⁽ Reference Fearon, Strasser and Anker ^{11 )}

This conceptual framework has been recently validated in a large cohort of cancer patients⁽ Reference Blum, Stene and Solheim ^{13 )}. Results prospectively obtained show that by applying the definition of cachexia to cancer patients, cachectic patients have shorter survival⁽ Reference Blum, Stene and Solheim ^{13 )}. More importantly, by stratifying cancer patients according to the stages of cachexia, survival of refractory cachectic patients is shorter than cachectic and pre-cachectic patients⁽ Reference Blum, Stene and Solheim ^{13 )}. Interestingly, no significant difference in survival was observed between cancer patients with no cachexia and cancer patients with pre-cachexia, which underscores the clinical benefits associated with the early recognition and treatment of nutritional deterioration during disease.

Sarcopenia and cachexia

Muscle loss is the key feature of cachexia. However, muscle loss is not exclusively found in cachectic patients. Ageing is characterised by the profound rearrangement of human metabolism and thus body composition⁽ Reference Laviano, Gori and Rianda ^{14 )}. Age-dependent muscle loss is defined as sarcopenia. To differentiate age-dependent from disease-associated muscle loss, it has been proposed that muscle paucity of cachexia is defined as myopenia⁽ Reference Fearon, Evans and Anker ^{15 )}. Although it is acknowledged that sarcopenia and myopenia recognise different pathogenic mechanisms, in clinical practice it could be extremely difficult to ascertain the specific contribution of sarcopenia and cachexia to muscle loss in elderly patients suffering from chronic diseases. Therefore, in clinical practice, the term myopenia is scarcely used and sarcopenia is often used also to define disease-associated muscle loss.

BMI as a contributory factor in determining outcome

Muscle loss is the key feature of cachexia. When body composition analysis is not available, involuntary weight loss allows diagnosis of cachexia⁽ Reference Fearon, Strasser and Anker ^{11 )}. Robust data show that the severity of weight loss is a reliable, yet negative, prognostic factor in cancer patients and in other clinical conditions as well⁽ Reference Martin, Senesse and Gioulbasanis ^{16 )}. However, BMI also influences survival in cancer patients, higher BMI being associated with longer survival⁽ Reference Martin, Senesse and Gioulbasanis ^{16 )}. In order to obtain a more accurate classification of weight loss, and therefore of cachexia, which encompasses muscle and fat mass changes, Martin et al. classified a large cohort of cancer patients (n 8160) not only according to the severity of weight loss but BMI as well⁽ Reference Martin, Senesse and Gioulbasanis ^{16 )}. In particular, anthropometric characteristics of patients were used to fill a 5 × 5 matrix as outlined in Table 2.

Table 2. Conceptual framework for classification of cancer patients based on their weight loss and BMI and relative class of risk for shorter survival (adapted from⁽ Reference Martin, Senesse and Gioulbasanis ^{16 )})

By assessing the mean survival time for each class of patients, Martin et al. found five specific patterns, with significant different survival, ranging from zero, with the longest survival, to four, with the shortest survival (Table 2)⁽ Reference Martin, Senesse and Gioulbasanis ^{16 )}. Based on these robust data, it could be proposed that cancer cachexia could be classified in five-stages, stage-0 being pre-cachexia and stage-4 being refractory cachexia. Whether this classification can be applied to other clinical conditions in which cachexia develops is presently being tested.

Pathogenesis and clinical features

The pathogenesis of cachexia is complex and involves a number of mechanisms. The main driving mechanism is the increased inflammatory response which triggers a cascade of molecular events, ranging from increased muscle proteolysis without compensatory anabolism and increased lipolysis, to functional impairment of the hypothalamic areas controlling food intake⁽ Reference Argilés, Busquets and Stemmler ^{4 ,} Reference Cohen, Nathan and Goldberg ^{12 )}. Of specific interest is the investigation of the early events leading to progressive muscle loss. In this regard, recent data in experimental models of cancer seem to suggest that hyperactivation of lipase activity yields to increased circulating levels of NEFA, which infiltrate muscles, causing or exacerbating proteolysis⁽ Reference Arner ^{17 )}. Whether this early crosstalk between adipose tissue and muscle mass is operating also in cachexia of diseases other than cancer, remains to be tested⁽ Reference Fearon ^{18 )}.

Muscle loss is the key feature of cachexia. However, cachexia cannot be defined as a syndrome involving only muscularity. In fact, other tissues and organs are affected by the presence of cachexia. Gut barrier dysfunction, myocardial decreased innervations, reduced hepatic synthesis of albumin and increased thermogenesis are just a few alterations observed and described in cachectic patients⁽ Reference Argilés, Busquets and Stemmler ^{4 )}. Also, it appears that sexual dimorphisms exist when the impact of cachexia on muscle function is considered. Consistent evidence shows that in the presence of cancer-associated moderate weight loss, muscle function loss is similar between males and females⁽ Reference Stephens, Gray and MacDonald ^{19 ,} Reference Norman, Stobäus and Reiß ^{20 )}. In contrast, when weight loss is severe, muscle function is more preserved in females than in males⁽ Reference Stephens, Gray and MacDonald ^{19 ,} Reference Norman, Stobäus and Reiß ^{20 )}. This evidence highlights the relevance of sexual hormones in the pathogenesis and clinical feature of cachexia.

Obesity paradox in cachexia

As previously mentioned, high BMI is associated with better outcome in cancer patients⁽ Reference Martin, Senesse and Gioulbasanis ^{16 )}. This evidence appears to support the concept that obesity may exert a protective role in chronic diseases⁽ Reference Lainscak, von Haehling and Doehner ^{21 )}. However, it has also been proposed that the obesity paradox may not be a true phenomenon, since large adipose tissue is frequently associated with large muscularity, which may be the real reason for the better outcome. To address this uncertainty, Gonzalez et al. analysed the survival of cancer patients⁽ Reference Gonzalez, Pastore and Orlandi ^{22 )}. When stratified according to BMI, the longest survival was observed for those cancer patients with BMI > 25. However, when muscle mass and fat mass were measured, the shortest survival was observed for those patients with obesity and muscle loss, i.e. with sarcopenic obesity⁽ Reference Gonzalez, Pastore and Orlandi ^{22 )}. These results demonstrate that adipose tissue plays a protective role only in the presence of normal or increased muscle mass. In fact, the combination of obesity and sarcopenia or myopenia is a severe negative prognostic factor in patients with chronic diseases⁽ Reference Koo, Park and Park ^{23 ,} Reference Prado, Lieffers and McCargar ^{24 )}.

Clinical relevance of cachexia

Cachexia is clinically relevant since it impacts on patients’ quality of life, morbidity and mortality⁽ Reference LeBlanc, Nipp and Rushing ^{25 –} Reference Habedank, Meyer and Hetzer ^{27 )}. Nevertheless, the assessment of patients’ nutritional status does not represent a priority in many clinical settings⁽ Reference Schindler, Pernicka and Laviano ^{28 )}. It could be speculated that the lack of interest in the evaluation of the presence of cachexia could be related to the fact that other prognostic factors are usually considered by healthcare professionals in their clinical practice, making the diagnosis of cachexia apparently futile. However, it should be noted that cachexia is a more robust prognostic factor than the traditional ones, at least in cancer. In a large cohort of gastrointestinal and lung cancer patients (n 1473), a survival model containing conventional variables (i.e. cancer diagnosis, stage, age and performance status) revealed a c statistic of 0·73⁽ Reference Martin, Birdsell and Macdonald ^{29 )}. However, a survival model tested in the same cohort and including only BMI, weight loss, muscle index and muscle attenuation revealed a c statistic of 0·92⁽ Reference Martin, Birdsell and Macdonald ^{29 )}. These results suggest that cachexia is a powerful predictor of outcome in cancer, possibly superior to conventional variables. Confirming this concept, Stene et al. have recently demonstrated in advanced lung cancer patients that increase in muscle mass during chemotherapy, but not sarcopenia at baseline, is a significant prognostic factor predicting better survival⁽ Reference Stene, Helbostad and Amundsen ^{30 )}. These results point the importance of monitoring cachexia during the clinical journey of cancer patients, and likely of patients with other acute and chronic diseases.

Consistent evidence shows that weight loss during therapy is associated with worse outcome independently of the presence of sarcopenia at baseline, at least in cancer patients. Lu et al. have showed in 384 patients with gastric cancer that weight loss as minimal as 3 % during chemotherapy was associated with reduced survival independently from the presence of weight loss before starting anti-cancer therapies⁽ Reference Lu, Yang and Yu ^{31 )}. Kimura et al. regularly assessed 134 newly diagnosed non-small-cell lung cancer patients during their journey and demonstrated that at all time points, patients with cancer cachexia had shorter survival times than those without cachexia⁽ Reference Kimura, Naito and Kenmotsu ^{32 )}. Therefore, the nutritional status of patients suffering from chronic diseases should be regularly monitored in order to early detect any change which may negatively influence patients’ outcome.

The mechanisms by which cachexia negatively influences clinical outcome remain to be fully elucidated. In cancer patients, it has been shown that cachexia is associated with increased incidence of dose-limiting toxicity which yields to incomplete delivery of the planned treatment schedules⁽ Reference Mir, Coriat and Blanchet ^{33 –} Reference Lieffers, Bathe and Fassbender ^{35 )}. This effect could be related to the different distribution volume of drugs caused by sarcopenia when dosing is calculated based on the body surface area⁽ Reference Laviano, Rianda and Rossi Fanelli ^{36 )}. The impairment of drug distribution volume may also represent a contributing factor for increased morbidity in other clinical conditions as well.

Anabolic potential in cachexia

Cachexia is associated with worse outcome⁽ Reference LeBlanc, Nipp and Rushing ^{25 –} Reference Habedank, Meyer and Hetzer ^{27 )}. In order to develop effective therapies, it should be first assessed whether anabolic potential is still exploitable in patients with acute and chronic diseases. To address this key issue, Prado et al. measured muscle mass of 368 cancer patients at different time points during their clinical journey⁽ Reference Prado, Sawyer and Ghosh ^{37 )}. Results obtained showed that the overall frequency of muscle gain was 15·4 %, and muscle was stable in 45·6 % of intervals between any two scans, which made the maintenance or gain of muscle the predominant behaviour⁽ Reference Prado, Sawyer and Ghosh ^{37 )}. Also, multinomial logistic regression revealed that being within 90 d (compared with >90 d) from death was the principal risk factor for muscle loss⁽ Reference Prado, Sawyer and Ghosh ^{37 )}. The authors then concluded that ‘a window of anabolic potential exists at defined early phases of the disease trajectory (>90 d survival), creating an opportunity for nutritional intervention to stop or reverse cachexia. Cancer patients within 90 d of death have a low likelihood of anabolic potential’⁽ Reference Prado, Sawyer and Ghosh ^{37 )}. Based on these results, it could be speculated that refractory cachexia coincides with the last 90 d of survival, at least in cancer patients. Also, these results highlight the importance of starting any anti-cachexia therapy early in the clinical course of the underlying disease.

Confirming the possibility that cachexia can be prevented and treated, Stene et al. have demonstrated that muscle mass does increase during chemotherapy, which is associated with longer survival⁽ Reference Stene, Helbostad and Amundsen ^{30 )}. Also, Lu et al. reported that cancer patients increasing their body weight during chemotherapy significantly improve their survival, even if they were losing weight at baseline⁽ Reference Lu, Yang and Yu ^{31 )}. Similarly, Kimura et al. reported an intermediate survival time for those patients who became cachectic or reverted from cachexia during chemotherapy, when compared with persistently cachectic and persistently well-nourished cancer patients⁽ Reference Kimura, Naito and Kenmotsu ^{32 )}. It is acknowledged that the study designs of these trials does not allow us to ascertain whether body weight gain is the consequence of effective nutrition therapy or effective anti-cancer therapies leading to reduced tumour mass and decreased inflammatory response. Nevertheless, it remains imperative that supportive care is started early to maintain body weight or facilitate recovery from weight loss.

Further supporting the relevance and potential of anti-cachexia therapies, the concept of anabolic resistance associated with increased inflammatory response has been recently challenged. In their elegant study, Winter et al. tested whether insulin-mediated resistance of protein anabolism could underlie the muscle degradation associated with cancer cachexia and whether a sustained, physiological elevation of amino acids with hyperinsulinaemia would compensate for it⁽ Reference Winter, MacAdams and Chevalier ^{38 )}. Results obtained in lung cancer patients showed that cachexia was associated with insulin resistance and impaired whole-body protein anabolism. However, they also revealed that patients’ anabolic protein response was stimulated normally by hyperaminoacidaemia⁽ Reference Winter, MacAdams and Chevalier ^{38 )}. Therefore, ample provision of amino acids appears a promising and effective strategy to overcome the protein anabolic resistance of cachexia. Similarly, Deutz et al. showed that the use of selected nutrients, including leucine and n 3 fatty acids, is able to stimulate protein synthesis in cancer patients, reverting catabolism⁽ Reference Deutz, Safar and Schutzler ^{39 )}.

Thus, cachexia is a syndrome which increases morbidity and mortality, but it can be effectively prevented and treated.