Definition and classification of cancer cachexia: an international consensus

Introduction:

- Cachexia has been recognised for a long time as an adverse effect of cancer.

- It is associated with reduced physical function, reduced tolerance to anticancer therapy, and reduced survival.

Definition of Cancer Cachexia:

- Cancer cachexia is 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 progressive 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.

Stage:

1) Precahexia

- Early clinical and metabolic signs (eg, anorexia and impaired glucose tolerance) can precede substantial involuntary weight loss (ie, ≤5%)

- Risk of progression varies and depends on factors such as cancer type and stage, the presence of systemic inflammation, low food intake, and lack of response to anticancer therapy

2) Cachexia

- >5% loss of stable body weight over the past 6 months OR BMI <20 kg/m² and ongoing weight loss of >2%

- Not entered the refractory stage yet

3) Refractory cachexia

- Clinically refractory as a result of very advanced cancer (preterminal) or the presence of rapidly progressive cancer unresponsive to anticancer therapy

- Associated with active catabolism, or presence of factors that render active management of weight-loss no longer possible/appropriate.

- Characterized by a low performance status (WHO score 3 or 4) and life expectancy < 3 months.

- Burden and risk of artificial nutritional support are likely to outweigh any potential benefit

- Therapeutic interventions focus: alleviating the consequences and complications of cachexia—eg, symptom control (appetite stimulation, management of nausea or eating-related distress of patients and families) and the alleviation of cachexia-related suffering

 Severity of depletion, classified according to:

- Rate of ongoing loss of weight +

- Concurrent degree of depletion of energy stores +

- Body protein mass (which can be compounded by a low initial reserve)

Assessment:

1) Anorexia or reduced food intake

- Food intake should be assessed routinely (especially protein).

- Assess underlying factors contribute to food intake, including decreased central drive to eat, chemosensory disturbances (eg, in taste and smell), decreased upper gastrointestinal motility (eg, early satiety and nausea), and distal tract dysmotility (after treatment of constipation).

- Secondary causes of impaired food intake such as stomatitis, constipation, dyspnoea, pain, and poor dietary habits should be recognised early, because they might prove readily reversible

2) Catabolic drivers

- The most widely accepted index of systemic inflammation is serum C-reactive protein (CRP).

- However cachexia can exist without overt systemic inflammation, so indirect indices reflecting the catabolic drive such as responsiveness to chemotherapy and the rate of progression should also be assessed.

- Other potential factors contributing to catabolism, including insulin resistance, prolonged high-dose corticosteroid therapy, hypogonadism, and increased resting energy expenditure.

3) Muscle mass and strength

- Patients with sarcopenia seem prone to toxic effects during chemotherapy, requiring dose reductions or treatment delays (which could then reduce treatment efficacy

- Order of preference for muscle mass assessment: cross-sectional imaging (CT or MRI), DEXA, anthropometry (mid-arm muscle area), bioimpedance analysis

- For practical reasons in testing muscle strength, upper-limb hand-grip dynamometry was preferred to lower-limb extension strength testing.

- While focusing on skeletal muscle, it is important not to forget the potentially vital parts played by other tissues, such as cardiac muscle, the immune system, and the liver.

4) Functional and psychosocial effects

- To estimate the effect on physical functioning, routine assessment of physical activity is recommended. Method of choice: EORTC QLQ-C30 or Eastern Cooperative Oncology Group questionnaire. Other method (order of preference): physician reported activity (eg, Karnofsky score) followed by objective methodologies, such as activity meter and checklists of specific activities

- Psychosocial effect of cachexia should also be assessed routinely by questions such as: “how much do you feel distressed about your inability to eat” or “have you experienced feelings of pressure, guilt or relational stress with regard to food intake and weight-loss”

- PG-SGA can provide some, but not all of the information needed for a detailed assessment.

Fearon et al. Lancet Oncol 2011; 12: 489–95. DOI:10.1016/S1470-2045(10)70218-7

Cachexia: A new definition

Definition:

- a complex metabolic syndrome associated with underlying illness and characterized by loss of muscle with or without loss of fat mass.

Prominent clinical feature:

- Weight loss in adults (corrected for fluid retention) or growth failure in children (excluding endocrine disorders).

- Wasting disease (associated with Anorexia, inflammation, insulin resistance and increased muscle protein breakdown)

(Note: wasting disease is distinct from starvation, age-related loss of muscle mass, primary depression, malabsorption and hyperthyroidism)

­(Note: Cachexia is generally associated with loss of appetite so losses of body weight and muscle are accelerated. In such cases, the process of cachexia may be misinterpreted as caused by malnutrition)

Cause:

- Complex and not completely understood at the present time

Discussion

1) Weight loss

- Body weight changes: highly predictive of morbidity and mortality in cachectic patients

- At least a 5% loss of edema-free body weight during the previous 12 months or less.

[The time frame may be disease specific and is likely to be shorter in cancer (3e6 months) and longer in chronic kidney or heart failure or COPD (12 months)]

- If history of weight loss cannot be documented, BMI of <20 kg/m² was considered sufficient to establish a diagnosis of cachexia.

- Degree: weight loss within previous 12 months (or less) is >5% (mild), >10% (moderate) or >15% (severe)

2) Skeletal muscle

- Accelerated or exaggerated loss of skeletal muscle mass distinguishes cachexia from the weight loss due solely to reduced energy intake.

- Every effort should be made to quantify body composition, and in particular, appendicular skeletal muscle mass.

- Other criteria: decreased muscle strength, fatigue, anorexia, low muscle mass, biochemical abnormalities (inflammation, anaemia or hypoalbuminemia)

3) Nutritional factor

- It is important to distinguish cachexia from starvation, malabsorption, hyperthyroidism, dehydration or sarcopenia (though these conditions may represent a pre-cachectic state) and from subcutaneous fat loss (lipoatrophy)

- Although malnutrition is often present in cachexia, the clinical characteristic of cachexia is that it cannot be successfully treated with nutrition alone.

(Refeeding a patient with cachexia does not correct the underlying problem. Even with total parenteral nutrition, weight stabilization does not prevent the continuing loss of skeletal muscle mass or correct the underlying abnormality in the metabolic state)

- Cachexia is often associated with loss of appetite. However, anorexia can occurs in other conditions that are not associated with cachexia. For this reason, cachexia should only be diagnosed in the presence of weight loss if at least three of the five conditions identified in Table 1.

Evans et al. Clin Nutr 2008; 27, 793-799. doi:10.1016/j.clnu.2008.06.013