Ask AI
Back Back
Advances in the Management of Cancer Cachexia
Cancer Cachexia: A Clinical Unmet Need in Oncology Practice

Released: April 02, 2026

Jann Arends
Jann Arends, MD
Activity Information

Activity

Progress
1
Course Completed
Continue
Key Takeaways
  • Several easy-to-use tools are digitally available that can aid rapid diagnosis of patients with cancer and cachexia (eg, the Malnutrition Screening Tool, Nutritional Risk Screening 2002, and the Malnutrition Universal Screening Tool).
  • Multidisciplinary treatment should be individualized to include nutritional counselling, appetite stimulation, adapted exercise, and symptom control, as needed.
  • No biologic or pharmacologic agents are approved for cachexia in the EU/US; phase II/III trials with olanzapine, S-pindolol, and various agents targeting inflammatory cytokines (eg, GDF-15) are ongoing or planned.

Overview
Cachexia is a multifactorial syndrome that is frequently observed among patients with advanced cancer, with an incidence of approximately 30% to 80%. It is particularly common among patients with advanced upper gastrointestinal or lung cancer. The presence of cachexia is associated with a decrease in quality of life and response to anticancer treatments, an increase in the rate of complications, and overall, a significantly increased mortality rate. Therefore, effective approaches for the prevention and/or identification and prompt treatment of cachexia is an important clinical goal that should be carefully integrated into the routine care of patients with cancer.

Cancer cachexia is best understood to be synonymous with cancer-related multiorgan dysfunction involving inflammation-associated malnutrition. It occurs as an adverse event of a chronically inadequate activation of the immune response to the presence of malignant tumor cells. If the system is unable to eliminate the abnormal malignant cells, the cancer progresses despite infiltration by lymphocytes, macrophages, and other immune cells and despite the system being bathed in secreted proinflammatory mediators. The resulting stromal mixture comprising malignant and immune cells releases inflammatory mediators such as cytokines into the circulatory system of the patient. Persistent systemic inflammation involving elevated levels of proinflammatory cytokines triggers neuroimmunologic signals that cause changes in metabolism and alterations in the function of multiple tissues and organs.

In the central nervous system, these signals induce conditions such as anorexia and fatigue and peripherally tip the metabolic balance away from anabolism toward systemic catabolism causing accelerated loss of muscle mass, reduced physical function, and functional loss in multiple organs. Of importance, patient-specific characteristics such as gastrointestinal, psychological, social, and emotional factors may also contribute to the development of cancer cachexia.

Signs, Symptoms, and Diagnosis of Cancer Cachexia
The typical signs of cachexia include loss of appetite, weight loss, loss of muscle mass and strength, and a raised basal body temperature and heart rate. The most frequently observed symptoms include fatigue, weakness, lethargy, anorexia, and early satiety. Yet, cachexia remains underdiagnosed, overlooked, or misdiagnosed in many patients with cancer. Recent data using electronic medical records of patients from hospitals in Europe demonstrated that even though cachexia was present in 29% of the patients with gastrointestinal or lung cancer, a diagnosis of cachexia was documented in less than 4% of these patients. Of note, one half of these diagnoses appeared to be misclassified. This further supports the need to correctly identify and recognize cachexia, and the measures generally used by healthcare professionals are still severely inadequate, requiring more effort, and perhaps, training.

To improve awareness, all patients with cancer need to be routinely screened for the risk of malnutrition with screening repeated regularly. This is especially necessary when the patient’s cancer progresses or the patient’s condition worsens. There are several available tools that are easy to use and can aid to rapidly diagnose and identify patients with cachexia. Examples of such tools are questionnaires including the Malnutrition Screening Tool (MST), Nutritional Risk Screening 2002 (NRS-2002), and the Malnutrition Universal Screening Tool (MUST), which are most conveniently used when digitally available. Of note, these questionnaires can be used by nonnutrition experts and even by the patients’ themselves. Abnormal results from these questionnaires should be immediately followed by an in-depth nutritional assessment, which is best performed by an experienced nutritionist.

Importance of Nutritional Assessment and Determination of Sarcopenia
Nutritional assessment should aim to screen for nutrition impact symptoms; quantify food intake; measure body weight, muscle mass, and strength; and determine performance index and functional status of the patient. In addition, laboratory markers of systemic inflammation should be evaluated. It is advisable to also screen for symptom-based psychological and social distress.

Nutritional assessment should include checks for diagnostic criteria for serious nutritional problems. This includes the determination of obesity based on a BMI of >30 kg/m². In particular, it should include assessments for malnutrition defined by the Global Leadership Initiative on Malnutrition (GLIM) criteria as involuntary weight loss of >5% body weight within 6 months, a low BMI (<20 kg/m2 if younger than 70 years of age, <22 kg/m2 if older than 70 years of age) or sarcopenia (involuntary loss of skeletal muscle strength and mass).

Nutritional assessment should consider that there are 2 different types of malnutrition. The first type is malnutrition without inflammation, which is the same as starvation-type malnutrition as a result of either inadequate food intake or malabsorption. The second type is malnutrition with ongoing systemic inflammation, which is also called disease-associated malnutrition. Cachexia develops as a result of cancer-associated systemic inflammation.  Currently, cachexia is coded using ICD-10 code R64.

The presence of sarcopenia is frequently observed in cases of malnutrition, but it is important to note that sarcopenia may occur by itself (eg, in elderly individuals) or in patients with obesity. The diagnosis of sarcopenia is based on reduced muscle strength and mass (stratified by the age and sex of the patient) and the grading of sarcopenia considers decreased physical performance. Anthropometric measurements, CTs, and MRIs are some of the techniques that can be used to determine if a patient has sarcopenia or not. Because several and potentially interacting mechanisms may lead to weight loss and sarcopenia, knowledge of the factors relevant in each patient’s case is important for treatment. Understanding the interplay of the different conditions contributing to cancer cachexia will significantly enhance prompt recognition and accurate diagnosis that will, in turn, lead to optimal therapeutic solutions for patients.

Management of Patients With Cancer Cachexia
Once cachexia is diagnosed, a multimodal treatment approach should be initiated. Being a multifactorial syndrome, the treatment of cancer cachexia requires the involvement of a multidisciplinary team of experts to achieve holistic health and wellness. Treatment should be individualized to include nutritional counseling, appetite stimulation, adapted exercise, and symptom control, as needed. Patients should be counseled to consume sufficient calories corresponding to 1.2-1.3 times the estimated resting energy expenditure or approximately 20-30 kcal/kg/day. If this is not well tolerated, the use of oral supplements may be offered.

Enteral feeding tubes and/or parenteral nutrition may be considered, but these approaches should not be routinely used. To modulate inflammation and support anabolism, high-protein intake (≥1.2-1.5 g/kg/day) should be recommended, and it may be combined with omega-3 fatty acid supplementation. Professionally guided and individualized exercise therapy combining resistance training with aerobic exercise should be recommended to preserve lean muscle mass and maintain functional independence.

To date, no biologic or pharmacologic agent has been approved for the treatment of patients with cancer cachexia in the United States or Europe. However, it is important to note that anamorelin, an oral selective agonist of the ghrelin receptor, is approved in Japan for patients with cancer cachexia, although it is still under investigation for cancer cachexia in other parts of the world. A multicenter, randomized phase II trial is investigating anamorelin compared with placebo in the prevention of cancer-induced anorexia and weight loss for patients with advanced pancreatic cancer who are receiving first-line anticancer therapy (NCT04844970).

The efficacy and safety of several other agents have been studied, and many new and emerging treatment modalities are currently being investigated for patients with cancer cachexia. The use of corticosteroids (dexamethasone) or progestins (megestrol acetate) has demonstrated appetite improvement, increased food intake, and weight gain in patients with cancer and cachexia. However, the prolonged use of corticosteroids results in the loss of efficacy, and both dexamethasone and megestrol acetate are associated with unwanted adverse effects such as thromboembolism or osteoporosis.

Prior work has involved investigations into the efficacy and safety of antipsychotic agents for patients with cancer and cachexia. For instance, the atypical antipsychotic agent, olanzapine, demonstrated improvement in appetite, body weight, and quality of life for patients with advanced cancer and cachexia. An ongoing placebo-controlled, randomized phase III trial is investigating 2 doses of olanzapine (2.5 mg/day or 5 mg/day) vs placebo for patients with advanced cancer-related anorexia–cachexia syndrome (NCT06517199).

S-pindolol, a β-receptor agonist/antagonist, was investigated in the multicenter, double-blind randomized phase II ACT-ONE trial. In this trial, patients with advanced colorectal cancer (CRC) or non-small-cell lung cancer and cachexia with a life expectancy of >3 months were randomly assigned to receive high-dose S-pindolol (10 mg twice daily), low-dose S-pindolol (2.5 mg twice daily), or placebo. In comparison to placebo, treatment with high-dose S-pindolol resulted in the significant reversal of weight loss, improvement in lean body mass, and increased hand grip strength. Based on these results, the planned phase II/III IMPACT trial will investigate the utility of S-pindolol in patients with CRC and cachexia.

Several cytokine-targeting agents are also being clinically studied for patients with cancer and cachexia. Interleukin (IL)-6 is a proinflammatory cytokine and is known to be a key mediator in the development of cachexia in patients with advanced cancer. Therefore, targeting the IL-6/JAK/STAT3 signaling pathway with ruxolitinib is another interesting therapeutic strategy that is currently being studied in a phase I trial for the treatment of patients with cachexia and stage IV lung cancer (NCT04906746). Bermekimab is a monoclonal antibody that targets IL-1α, another proinflammatory cytokine implicated in the development of cachexia in patients with cancer. It has been studied in a placebo-controlled, randomized phase III trial for patients with refractory, advanced CRC and cachexia (NCT02138422). Treatment with bermekimab resulted in significant improvements in lean body mass and anorexia compared with those who received placebo.

Growth differentiation factor 15 (GDF-15) is another inflammatory cytokine that has been associated with weight loss and reduced lean body mass. The activation of the GDF-15 signaling pathway has been implicated in the development of cancer cachexia. Ponsegromab is a humanized monoclonal antibody that specifically targets GDF-15. In a randomized phase II trial for patients with cachexia, elevated GDF-15 levels and lung cancer, pancreatic cancer, or CRC, treatment with ponsegromab led to significant improvements in weight gain, reduced cachexia symptoms, and improvements in overall physical activity level compared with those who received placebo. Based on the encouraging results observed, the ongoing randomized phase III RIVER-mPDAC trial is investigating ponsegromab vs placebo for patients with cachexia and metastatic pancreatic ductal adenocarcinoma after completion of first-line chemotherapy (NCT06989437). In fact, there are several ongoing studies investigating different agents targeting the GDF-15 signaling pathway for patients with cancer cachexia. These agents include rilogrotug, visugromab, NGM-120, and JMT-203 (NCT05865535, NCT07112196, NCT07033026, NCT06868849).

Overall Conclusions
The management of cachexia in patients with advanced cancer remains a challenging and unmet clinical need. Early diagnosis and management of cancer cachexia is key to achieving optimal treatment outcomes and improving overall survival and quality of life for our patients. With improved understanding and continued research, this field will continue to advance, and we will be better able to recognize the signs and symptoms early and promptly apply treatment using a multidimensional and individualized treatment approach. With multiple promising agents on the horizon, treatment and possibly the prevention of cancer cachexia may soon be within reach.

Your Thoughts
What are some of the biggest challenges that you face related to the care of your patients with advanced cancer and cachexia? Answer the polling question and join the conversation in the discussion box below.

Continue

Poll

1.

How often do you discuss participation in clinical trials evaluating investigational therapies for cancer cachexia with your patients?

Submit