Development and validation of a clinically applicable score to classify cachexia stages in advanced cancer patients.

BACKGROUND: Cachexia is a multifactorial syndrome that is highly prevalent in advanced cancer patients and leads to progressive functional impairments. The classification of cachexia stages is essential for diagnosing and treating cachexia. However, there is a lack of simple tools with good discrimination for classifying cachexia stages. Therefore, our study aimed to develop a clinically applicable cachexia staging score (CSS) and validate its discrimination of clinical outcomes for different cachexia stages. METHODS: Advanced cancer patients were enrolled in our study. A CSS comprising the following five components was developed: weight loss, a simple questionnaire of sarcopenia (SARC-F), Eastern Cooperative Oncology Group, appetite loss, and abnormal biochemistry. According to the CSS, patients were classified into non-cachexia, pre-cachexia, cachexia, and refractory cachexia stages, and clinical outcomes were compared among the four groups. RESULTS: Of the 297 participating patients, data from 259 patients were ultimately included. Based on the CSS, patients were classified into non-cachexia (n = 69), pre-cachexia (n = 68), cachexia (n = 103), and refractory cachexia (n = 19) stages. Patients with more severe cachexia stages had lower skeletal muscle indexes (P = 0.002 and P = 0.004 in male and female patients, respectively), higher prevalence of sarcopenia (P = 0.017 and P = 0.027 in male and female patients, respectively), more severe symptom burden (P < 0.001), poorer quality of life (P < 0.001 for all subscales except social well-being), and shorter survival times (P < 0.001). CONCLUSIONS: The CSS is a simple and clinically applicable tool with excellent discrimination for classifying cachexia stages. This score is extremely useful for the clinical treatment and prognosis of cachexia and for designing clinical trials.

Cachexia: clinical features when inflammation drives malnutrition.

Cachexia is a clinically relevant syndrome which impacts on quality of life, morbidity and mortality of patients suffering from acute and chronic diseases. The hallmark of cachexia is muscle loss, which is triggered by disease-associated inflammatory response. Cachexia is a continuum and therefore a staging system is needed. Initially, a three-stage system (i.e. pre-cachexia, cachexia and refractory cachexia) was proposed. More recent evidence supports the use of a five-stage classification system, based on patient's BMI and severity of weight loss, to better predict clinical outcome. Also, large clinical trials in cancer patients demonstrated that cachexia emerging during chemotherapy has greater influence on survival than weight loss at baseline. Therefore, becoming widely accepted is the importance of routinely monitoring patients' nutritional status to detect early changes and diagnose cachexia in its early phases. Although cachexia is associated with the presence of anabolic resistance, it has been shown that sustained yet physiological hyperaminoacidaemia, as well as the use of specific nutrients, is able to overcome impaired protein synthesis and revert catabolism. More importantly, clinical evidence demonstrates that preservation of nutritional status during chemotherapy or improvement of body weight after weight loss is associated with longer survival in cancer patients.

Comparing two classifications of cancer cachexia and their association with survival in patients with unresected pancreatic cancer.

There is no universally accepted definition of cancer cachexia. Two classifications have been proposed; the 3-factor classification requiring ≥ 2 of 3 factors; weight loss ≥ 10%, food intake ≤ 1500 kcal/day, and C-reactive protein ≥ 10 mg/l, and the consensus classification requiring weight loss >5% the past 6 mo, or body mass index <20 kg/m(2) or sarcopenia, both with ongoing weight loss >2%. Precachexia is the initial stage of the cachexia trajectory, identified by weight loss ≤ 5%, anorexia and metabolic change. We examined the consistency between the 2 classifications, and their association with survival in a palliative cohort of 45 (25 men, median age of 72 yr, range 35-89) unresected pancreatic cancer patients. Computed tomography images were used to determine sarcopenia. Height/weight/C-reactive protein and survival were extracted from medical records. Food intake was self-reported. The agreement for cachexia and noncachexia was 78% across classifications. Survival was poorer in cachexia compared to noncachexia (3-factor classification, P = 0.0052; consensus classification, P = 0.056; when precachexia was included in the consensus classification, P = 0.027). Both classifications showed a trend toward lower median survival (P < 0.05) with the presence of cachexia. In conclusion, the two classifications showed good overall agreement in defining cachectic pancreatic cancer patients, and cachexia was associated with poorer survival according to both.

Diagnostic criteria for the classification of cancer-associated weight loss.

PURPOSE: Existing definitions of clinically important weight loss (WL) in patients with cancer are unclear and heterogeneous and do not consider current trends toward obesity. METHODS: Canadian and European patients with cancer (n = 8,160) formed a population-based data set. Body mass index (BMI) and percent WL (%WL) were recorded, and patients were observed prospectively until death. Data were entered into a multivariable analysis controlling for age, sex, cancer site, stage, and performance status. Relationships for BMI and %WL to overall survival were examined to develop a grading system. RESULTS: Mean overall %WL was -9.7% ± 8.4% and BMI was 24.4 ± 5.1 kg/m(2), and both %WL and BMI independently predicted survival (P < .01). Differences in survival were observed across five categories of BMI (< 20.0, 20.0 to 21.9, 22.0 to 24.9, 25.0 to 27.9, and ≥ 28.0 kg/m(2); P < .001) and five categories of %WL (-2.5% to -5.9%, -6.0% to -10.9%, -11.0% to -14.9%, ≥ -15.0%, and weight stable (± 2.4%); P < .001). A 5 × 5 matrix representing the five %WL categories within each of the five BMI categories was graded based on median survival and prognostic significance. Weight-stable patients with BMI ≥ 25.0 kg/m(2) (grade 0) had the longest survival (20.9 months; 95% CI, 17.9 to 23.9 months), and %WL values associated with lowered categories of BMI were related to shorter survival (P < .001), as follows: grade 1, 14.6 months (95% CI, 12.9 to 16.2 months); grade 2, 10.8 months (95% CI, 9.7 to 11.9 months); grade 3, 7.6 months (95% CI, 7.0 to 8.2 months); and grade 4, 4.3 months (95% CI, 4.1 to 4.6 months). Survival discrimination by grade was observed within specific cancers, stages, ages, and performance status and in an independent validation sample (n = 2,963). CONCLUSION: A robust grading system incorporating the independent prognostic significance of both BMI and %WL was developed.

Validation of the Consensus-Definition for Cancer Cachexia and evaluation of a classification model--a study based on data from an international multicentre project (EPCRC-CSA).

BACKGROUND: Weight loss limits cancer therapy, quality of life and survival. Common diagnostic criteria and a framework for a classification system for cancer cachexia were recently agreed upon by international consensus. Specific assessment domains (stores, intake, catabolism and function) were proposed. The aim of this study is to validate this diagnostic criteria (two groups: model 1) and examine a four-group (model 2) classification system regarding these domains as well as survival. PATIENTS AND METHODS: Data from an international patient sample with advanced cancer (N = 1070) were analysed. In model 1, the diagnostic criteria for cancer cachexia [weight loss/body mass index (BMI)] were used. Model 2 classified patients into four groups 0-III, according to weight loss/BMI as a framework for cachexia stages. The cachexia domains, survival and sociodemographic/medical variables were compared across models. RESULTS: Eight hundred and sixty-one patients were included. Model 1 consisted of 399 cachectic and 462 non-cachectic patients. Cachectic patients had significantly higher levels of inflammation, lower nutritional intake and performance status and shorter survival. In model 2, differences were not consistent; appetite loss did not differ between group III and IV, and performance status not between group 0 and I. Survival was shorter in group II and III compared with other groups. By adding other cachexia domains to the model, survival differences were demonstrated. CONCLUSION: The diagnostic criteria based on weight loss and BMI distinguish between cachectic and non-cachectic patients concerning all domains (intake, catabolism and function) and is associated with survival. In order to guide cachexia treatment a four-group classification model needs additional domains to discriminate between cachexia stages.

Pre-cachexia and cachexia at diagnosis of stage III non-small-cell lung carcinoma: an exploratory study comparing two consensus-based frameworks.

Despite the development of consensus-based frameworks to define cancer cachexia, the validity and usefulness of these frameworks are relatively unknown. The aim of the present study was to study the presence of pre-cachexia and cachexia in patients with stage III nonsmall-cell lung carcinoma (NSCLC) by using a cancer-specific framework and a general framework for cachexia, and to explore the prognostic value of pre-cachexia and cachexia. In forty patients at diagnosis of stage III NSCLC, weight loss, fat-free mass, handgrip strength, anorexia and serum biochemistry, assessed before the first chemotherapy, were used to define 'cancer cachexia' or 'cachexia'. The cancer-specific framework also classified for pre-cachexia and refractory cachexia. Additionally, quality of life was assessed by the European Organisation for Research and Treatment of Cancer­Quality of Life Questionnaire C30. Groups were compared using independent t tests, ANOVA, Kaplan­Meier and Cox survival analyses. Based on the cancer-specific framework, pre-cachexia was present in nine patients (23%) and cancer cachexia was present in seven patients (18%). Cancer cachexia was associated with a reduced quality of life (P = 0.03) and shorter survival (hazard ratio (HR) = 2.9; P = 0.04). When using the general framework, cachexia was present in eleven patients (28%), and was associated with a reduced quality of life (P = 0.08) and shorter survival (HR = 4.4; P = 0.001). In conclusion, pre-cachexia and cachexia are prevalent in this small population of patients at diagnosis of stage III NSCLC. For both frameworks, cachexia appears to be associated with a reduced quality of life and shorter survival. Further studies are warranted to more extensively explore the validity and prognostic value of these new frameworks in cancer patients.

Terminology in cancer cachexia: importance and status.

PURPOSE OF REVIEW: This article reviews the current status of the definition of cancer cachexia, and comments on future initiatives to refine it and to use it as a foundation for a cancer cachexia classification system. RECENT FINDINGS: There has been a plethora of work by expert panels defining cachexia. Stemming from this work, an expert panel has published a definition of cancer cachexia and a three level staging system: precachexia, cachexia, and refractory cachexia. Colleagues in the cancer pain field have put forward a sophisticated pain classification system. Work to develop a similar classification system for cachexia is now commencing. Aside from improved communication, these efforts may also enable the oncology community to better appreciate the importance of cancer cachexia and to participate in interdisciplinary treatment programmes to combat cachexia. SUMMARY: The quest to determine the pathophysiology of cancer cachexia and to use this knowledge to identify patient subsets will further research. Equally important, the fruits of this endeavour will lead to a higher priority for addressing cachexia with consequent development of a multimodal approach to management.

Definition and classification of cancer cachexia: an international consensus.

To develop a framework for the definition and classification of cancer cachexia a panel of experts participated in a formal consensus process, including focus groups and two Delphi rounds. Cancer cachexia was defined as a multifactorial syndrome defined 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 progressive functional impairment. Its pathophysiology is characterised by a negative protein and energy balance driven by a variable combination of reduced food intake and abnormal metabolism. The agreed diagnostic criterion for cachexia was weight loss greater than 5%, or weight loss greater than 2% in individuals already showing depletion according to current bodyweight and height (body-mass index [BMI] <20 kg/m(2)) or skeletal muscle mass (sarcopenia). An agreement was made that the cachexia syndrome can develop progressively through various stages--precachexia to cachexia to refractory cachexia. Severity can be classified according to degree of depletion of energy stores and body protein (BMI) in combination with degree of ongoing weight loss. Assessment for classification and clinical management should include the following domains: anorexia or reduced food intake, catabolic drive, muscle mass and strength, functional and psychosocial impairment. Consensus exists on a framework for the definition and classification of cancer cachexia. After validation, this should aid clinical trial design, development of practice guidelines, and, eventually, routine clinical management.

Evolving classification systems for cancer cachexia: ready for clinical practice?

INTRODUCTION: Involuntary weight loss, the defining factor of cachexia, is a common consequence of advanced cancer. DISCUSSION: This review summarizes the actual cachexia definitions and classification systems (NCCTG-studies, Loprinzi et al.; PG-SGA, Ottery et al.; Cachexia Consensus Conference, Evans et al; Cancer Cachexia Study Group, Fearon et al.; and SCRINIO Working group, Bozzetti et al.).We describe the ongoing development of a new classification system for cancer cachexia, which is based on literature reviews and Delphi processes within the European Palliative Care Research Collaborative. The review describes the evolving understanding of the pathophysiological mechanisms of cachexia and outlines an overview on treatment options. CONCLUSION: In this review an outlook on the requirements of a new decision guiding instrument is given and the challenges in clinical decision making in palliative are discussed.

Defining and classifying cancer cachexia: a proposal by the SCRINIO Working Group.

BACKGROUND: Although cancer cachexia is widely diffuse in the cancer patient population, there is no objective definition and classification of this syndrome. The purpose of this study is to propose a simple and quick classification that relies on the severity of the body weight loss and presence/absence of symptoms that are associated with cancer cachexia. METHODS: The authors used a database of an ongoing multicenter prospective investigation on the screening of the nutrition risk of 1307 cancer outpatients from different (mainly Italian) university or scientific institutes or hospitals. The database included demographic, oncologic, clinical, and nutrition data. The patients were divided into 4 classes based on combinations of body weight loss (< 10%, precachexia; > or = 10%, cachexia) and the presence/absence of at least 1 symptom of anorexia, fatigue, or early satiation. The authors verified statistically whether these 4 classes were associated with the distribution of main clinical, nutrition, and oncologic variables, after adjustment for treatment status, by using the Cochrane-Mantel-Hanszel test for count data and ANOVA for continuous data. RESULTS: Moving from "asymptomatic precachexia" (class 1) to "symptomatic cachexia" (class 4), there were statistically significant trends (P < .0001) in the percentage of gastrointestinal vs nongastrointestinal tumors, severity of cancer stage, percentage of weight loss, number of symptoms per patient, Eastern Cooperative Oncology Group (ECOG) performance status, and nutritional risk score. CONCLUSIONS: The statistical analysis has validated the classification by identifying stages with different severity of cachexia. This classification could be adopted within a comprehensive oncologic approach to the weight-losing patients, until more specific diagnostic techniques are available in clinical practice.

Cachexia: a new definition.

On December 13th and 14th a group of scientists and clinicians met in Washington, DC, for the cachexia consensus conference. At the present time, there is no widely agreed upon operational definition of cachexia. The lack of a definition accepted by clinician and researchers has limited identification and treatment of cachectic patient as well as the development and approval of potential therapeutic agents. The definition that emerged is: "cachexia, is a complex metabolic syndrome associated with underlying illness and characterized 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). Anorexia, inflammation, insulin resistance and increased muscle protein breakdown are frequently associated with cachexia. Cachexia is distinct from starvation, age-related loss of muscle mass, primary depression, malabsorption and hyperthyroidism and is associated with increased morbidity. While this definition has not been tested in epidemiological or intervention studies, a consensus operational definition provides an opportunity for increased research.

A proposed nomenclature and diagnostic criteria for protein-energy wasting in acute and chronic kidney disease.

The recent research findings concerning syndromes of muscle wasting, malnutrition, and inflammation in individuals with chronic kidney disease (CKD) or acute kidney injury (AKI) have led to a need for new terminology. To address this need, the International Society of Renal Nutrition and Metabolism (ISRNM) convened an expert panel to review and develop standard terminologies and definitions related to wasting, cachexia, malnutrition, and inflammation in CKD and AKI. The ISRNM expert panel recommends the term 'protein-energy wasting' for loss of body protein mass and fuel reserves. 'Kidney disease wasting' refers to the occurrence of protein-energy wasting in CKD or AKI regardless of the cause. Cachexia is a severe form of protein-energy wasting that occurs infrequently in kidney disease. Protein-energy wasting is diagnosed if three characteristics are present (low serum levels of albumin, transthyretin, or cholesterol), reduced body mass (low or reduced body or fat mass or weight loss with reduced intake of protein and energy), and reduced muscle mass (muscle wasting or sarcopenia, reduced mid-arm muscle circumference). The kidney disease wasting is divided into two main categories of CKD- and AKI-associated protein-energy wasting. Measures of chronic inflammation or other developing tests can be useful clues for the existence of protein-energy wasting but do not define protein-energy wasting. Clinical staging and potential treatment strategies for protein-energy wasting are to be developed in the future.

Mecanismos de la caquexia / Mechanisms of cachexia

Se revisan los elementos fisiopatológicos que constituyen esta frecuente complicación, compartida por muchas enfermedades distintas (no sólo neoplásicas). Se trata de un síndrome complejo, las alteraciones se dan desde en los niveles metabólico (celular), nivel neurohumoral (con la modificación del apetito y de la ingesta) y nivel somatotrópico-hormonal (resistencia a las hormonas anabólicas), configurando un cuadro que gradualmente se conoce parcialmente. La acción predominante de citokinas y de sustancias que promueven la movilización de proteínas (PIF) y lípidos (LMF), en el contexto de un estado inflamatorio juegan un rol central.