Cancer Cachexia

Original Editor - Ashmita Patrao Top Contributors - Ashmita Patrao, Kim Jackson, Uchechukwu Chukwuemeka, Vidya Acharya, Chelsea Mclene and Rishika Babburu

Definition

Cancer cachexia or cancer-associated fatigue is defined as a multi-factorial syndrome characterized 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 characteristic feature is the negative protein-energy balance that occurs due to a reduction in food intake and an abnormal metabolism.

Classification

There are 3 stages of relevance clinically, forming a spectrum, however, not all of these subjects traverse the entire spectrum.

1. Precachecia: The early clinical signs like anorexia and metabolic signs like impaired glucose test precede weight loss (≤5%). The progression varies and depends on the cancer type and staging, low food intake, systemic inflammation, and poor response to anti-cancer therapy.
2. Cachexia: A stable weight loss of more than 5% over 6 months OR a Body mass index (BMI) of lesser than 20 kg/m² OR sarcopenia and ongoing weight loss of more than 2%, but not yet entered the refractory stage classified as cachexia.
3. Refractory cachexia: Very advanced cancer OR rapidly progressive cancer, unresponsive to anticancer therapy. Associated with active catabolism and the factors associated with active management of weight loss here no longer stand appropriate. Low-performance status and a life expectancy of less than 3 months are characteristic.

Pathophysiology

Diagnosis of Cancer Cachexia

• BMI <20 and any degree of weight loss >2%
• Weight loss >5% over the past 6 months (in the absence of simple starvation)
• Appendicular skeletal muscle index consistent with sarcopenia (males <7·26 kg/m²; females <5·45 kg/m²) and any degree of weight loss >2%

Assessment

Muscle mass and strength

Cross-sectional imaging CT or MRI, dual-energy X-ray imaging, bioimpedance analysis, and anthropometry mainly including the mid-arm girth are used to check for muscle mass. Handgrip dynamometer and manual muscle testing are used for strength assessment.

Anorexia and reduced food intake

Quantification of protein may be relevant. The mechanisms behind this may be chemosensory disturbances, reduced upper gastrointestinal mobility, and distal tract dysmobility. The secondary causes include stomatitis, constipation, dyspnoea, pain and poor dietary habits.

Hypercatabolism

This could be due to tumor-mediated side effects or systemic inflammation. Contributing factors include insulin resistance, duration high dose corticosteroid, an elevation in resting energy expenditure, and hypogonadism.

Psychosocial and Functional aspects

Patient-reported outcomes for physical functioning including European Organisation for Research and Treatment of Cancer, Quality of life Questionnaire, Patient completed Eastern Cooperative Oncology Group questionnaire. This can be followed by activity meters and checklists. The psychosocial aspects could be identified by routine questions about the person's psychological status.

Management

There are 4 basic steps of treatment strategies:

1. Correcting the cause of the impaired nutritional intake
2. Adequate nutritional support
3. Multimodal cancer cachexia intervention:
4. Detecting any related psycho-social distress and treating the same

Multimodal anabolic interventions are best in symptom management. Individualized nutrition and exercise optimize the drug effects Counselling including behavioural change, anticancer or antineoplastic treatment, total parenteral nutrition, prokinetics, progestins, cannabinoids, Eicosapentaenoic acid, Cyclo-oxygenase inhibitors, Corticosteroids and exercise interventions are the treatments.

Exercise Interventions

Mechanisms

Exercise can increase muscle mass, muscle function, strength, and cardiovascular fitness and reduce fatigue indirectly improving the quality of life by reducing fatigue levels. There are several suggested mechanisms for the same. They include:

Exercise and inflammation

Acute exercise induces an immune response which increases the cytokine levels in the body, however, these cytokines do not produce the pro-inflammatory effect. IL-6 is the typical cytokine released and expected in elevated levels, along with IL-10 and IL-1ra, This triggers an anti-inflammatory response which is speculated to reduce the systemic inflammation due to cancer, hence attenuating the cachexia process. Right from moderate intensity concentric exercises to vigorous intensity eccentric exercises, these interventions increase the rate of transcription and express the IL-6 protein which is necessary for the contracting muscle.

Inflammation and exercise in the adipose tissue

Endurance exercise blocks the effect of TNF-α, an inflammatory cytokine that stimulates lipolysis and supports the inflammatory cascade.

Exercise and oxidative stress

Exercising enhances the antioxidative enzymes such as super-oxide dismutase, and glutathione peroxidase in the skeletal muscle and mitochondrial superoxide dismutase and catalase in the lungs and diaphragm. Also, the non-enzymatic antioxidant levels increase in the body thus protecting the tissues from damage.

Exercise and insulin sensitivity

It has been speculated that insulin resistance occurs in response to tumour growth and as the normal inflammatory response. Exercises reduces the TNF-α factor hence improving the body's sensitivity to insulin. Also, glucose transport proteins like Glutathione-4 increase in the skeletal muscles increasing the glucose transport into the muscle. Creatinine phosphate that prevents the action of glutathione reduces while exercising.

Exercises

• High-intensity interval training for 8 weeks has an impact on stage III and stage IV non-small cell lung cancer in patients who are receiving chemotherapy. These patients had a high risk of respiratory failure due to cancer cachexia and exercise training helped improve their lung capacity.
• Progressive resistance exercise training (2-3 days a week for 12 weeks) improved the patients' compliance and lean body mass by 1-2 Kg. However, its effectiveness is yet to be determined in the head and neck cancer group receiving radiation therapy.
• Aerobic exercises are beneficial in terms they increases mitochondrial biogenesis and reduce proteolysis by reducing inflammation.
• Pedometer-based exercises(7 weeks) help in improving the skeletal mass, functional capacity, and quality of life in cancer cachexia on chemotherapy.
• Resistance exercises in patients with prostate cancer receiving androgen deprivation therapy and radiation therapy prevent loss of muscle mass and strength