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Cancer Cachexia in Oncology Practice
Cancer Cachexia to the Frontline of Oncology Practice

Released: September 22, 2025

Ester Oneda
Ester Oneda, MD
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Key Takeaways
  • Early recognition and systematic screening for cancer cachexia are essential, using simplified multifactorial tools to identify patients at risk and intervene before the condition becomes irreversible.
  • Multimodal management, including the integration of nutrition, exercise, and selected pharmacologic agents, remains the cornerstone of care and is feasible even during systemic cancer treatment.
  • There are several promising novel therapies on the horizon, but future clinical trials need to ensure appropriate patient selection and well-defined patient-centered endpoints while prioritizing multimodal treatment strategies to achieve meaningful clinical benefit.

Overview
Cancer cachexia is not a simple nutritional problem. It is a multifactorial syndrome characterized by progressive skeletal muscle loss (with or without fat depletion) and is driven by systemic inflammation and tumor–host interactions. Unlike malnutrition, cachexia cannot be reversed by nutritional support alone. Its prevalence is substantial, affecting approximately 60%-80% of patients with advanced gastrointestinal and lung cancers. Yet it remains underrecognized and undertreated, with devastating consequences for treatment tolerance, quality of life, and survival.

Early recognition of cancer cachexia is crucial. Patients often present with unintentional weight loss, anorexia, fatigue, and muscle wasting, and these symptoms can be staged as pre-cachexia, cachexia, or refractory cachexia according to the 2011 international consensus by Fearon and colleagues. Of note, the use of interventions in the earlier phases of the syndrome may stabilize the condition, whereas at the refractory stages, cancer cachexia is largely irreversible.

The Need for Systematic Screening
Screening for cachexia needs to become standard practice in oncology. Simple tools such as the Malnutrition Screening Tool (MST) and the Nutritional Risk Screening 2002 (NRS-2002) can be used at diagnosis and repeated before each treatment cycle. The red flags for cancer cachexia—including ≥5% unintentional weight loss in 6 months, anorexia, fatigue, functional decline, elevated C-reactive protein, and hypoalbuminemia—are integrated into prognostic tools such as the modified Glasgow Prognostic Score (mGPS). A positive mGPS should prompt a full assessment of multiple parameters, including weight trajectory, muscle strength, functional tests, and levels of inflammatory biomarkers. The role of many inflammatory or endocrine biomarkers such as growth differentiation factor-15 (GDF-15) and proinflammatory cytokines (interleukin[IL]-6 and tumor necrosis factor-alpha) in cancer cachexia is still under investigation and yet to be validated. Therefore, tests for these biomarkers should not be routinely prescribed. miniCASCO is a simplified tool proposed for the classification of cancer cachexia. It accounts for multiple factors including weight loss, body composition, nutritional intake, inflammation, level of physical activity, and overall well-being. It is particularly useful in both clinical practice and research settings. It offers a practical framework for therapeutic decision-making and patient stratification in clinical trials.

Multimodal Management Paradigm
Because cachexia arises from overlapping metabolic, inflammatory, and functional factors, no single treatment modality is sufficient for its assessment. To obtain optimal results, the management of cancer cachexia should be multimodal. In all, nutritional counselling remains central to treatment, with protein intake of 1.0-1.5 g/kg/day (up to approximately 2.0 g/kg/day in selected cases) to support muscle mass and function. This should be supported with the use of oral supplements or enteral nutrition when needed. In addition, omega-3 fatty acid supplementation can aid weight stabilization and improve quality of life.

Exercise is equally important. Supervised resistance training, with or without aerobic activity, improves muscle strength, body composition, and functional capacity. Exercise is feasible even during systemic therapy.

Of note, pharmacologic interventions for cancer cachexia are currently limited. Megestrol acetate induces modest appetite increases and weight gain but is associated with risks of edema and thrombosis. Corticosteroids may transiently improve appetite and well-being but are not appropriate for long-term use. In addition, the American Society of Clinical Oncology endorsed low-dose olanzapine, an antipsychotic agent, as an option to improve appetite, promote weight gain, and enhance quality of life in select patients. However, the design of randomized controlled trials of olanzapine varies with differences in treatment dose, duration, concomitant therapies, and endpoints.

Multimodal Interventions in Clinical Trials and Therapies on the Horizon
The most promising advances for the management of cancer cachexia are emerging from integrated and combination approaches. The phase III MENAC trial investigated the combination of nutrition, omega-3 fatty acid supplementation, exercise, and anti-inflammatory therapy vs standard of care (routine oncology and palliative care). The primary endpoint was change in body weight and the key secondary endpoints included change in muscle mass and physical activity. MENAC demonstrated feasibility and safety of the multimodal approach. The study showed evidence for weight stabilization although functional outcomes showed mixed results. Defining key and important endpoints for cancer cachexia trials is challenging, and there is no consensus from regulatory bodies. However, the findings from the MENAC trial underscore the need for more trials designed around appetite-directed approaches, anti–protein degradation strategies, specifically drugs that block catabolism, and exercise. The key endpoints of the trials need to be carefully thought out and should reflect patient-centered outcomes such as functional independence, treatment tolerance, and quality of life, rather than weight gain alone.

For patients with cancer cachexia, novel and emerging agents are at different stages of development. For instance, anamorelin, an oral selective agonist of the ghrelin receptor, was investigated in the randomized, placebo-controlled phase II O-7643-04 trial for Japanese patients with unresectable stage III/IV non-small-cell lung cancer (NSCLC) and cachexia. It demonstrated improvements in lean body mass and anorexia symptoms, but treatment was not associated with an increase in motor function. Based on these results, anamorelin gained approval in Japan for patients with cancer cachexia. It is the first-in-class agent to be investigated in phase III trials of cancer cachexia. In the randomized, placebo-controlled, phase III ROMANA 1 and ROMANA 2 trials for patients with stage III/IV NSCLC and cachexia, anamorelin failed to demonstrate increased handgrip strength over 12 weeks, but improvements were seen in the coprimary endpoint of lean body mass. Anamorelin is not approved for use in Europe or in the United States.

Other pharmacologic agents are under investigation in early-phase clinical trials. Therapies targeting GDF-15, a cytokine implicated in appetite suppression and metabolic dysregulation, are particularly exciting. Ponsegromab, a humanized anti–GDF-15 monoclonal antibody, was investigated in a randomized, phase II trial in which patients with cancer cachexia and elevated GDF-15 levels (≥1500 pg/mL) received 3 different subcutaneously administered doses (100 mg, 200 mg, and 400 mg) vs placebo. The primary endpoint of the trial was change from baseline in body weight at 12 weeks. Key secondary endpoints included appetite and cachexia symptoms, safety, and digital measures of physical activity. The trial demonstrated clinically meaningful weight gain, appetite improvement, and overall physical activity level. However, a remaining important question is whether blocking a single cytokine will be sufficient for the management of cancer cachexia, given the redundancy of inflammatory pathways involved in homeostasis. It is anticipated that the ongoing phase IIb/III randomized, double-blind, multinational trial investigating the efficacy, safety and tolerability of systemic chemotherapy with or without ponsegromab as first-line therapy for patients with cachexia and metastatic pancreatic ductal adenocarcinoma will shed more light on this (NCT06989437).

Espindolol is a novel beta-blocker that showed improved handgrip strength, reversed weight loss, and a trend towards overall survival benefit in the randomized, placebo-controlled phase II ACT-ONE trial in patients with advanced colorectal cancer or NSCLC and cachexia.

IL-6 blockade with tocilizumab alone or in combination with corticosteroids has also shown encouraging early results with improvements in weight and increased albumin levels, although confirmatory trials are awaited.

Other investigational strategies have shown promise in preclinical or animal models, but translation to clinical benefit in humans with cancer cachexia has been limited. Among the most promising are myostatin/activin inhibitors such as domagrozumab, beta-2 agonists such as formoterol (in combination with megestrol acetate), melanocortin-4 receptor antagonists such as TCMCB07, and monoclonal antibodies against IL-1 alpha such as bermekimab.

Conclusions
For oncologists, nurses, dietitians, and all other allied healthcare professionals, the priority is clear: patients must be routinely screened for cancer cachexia. Once a diagnosis is made, the syndrome should be staged, and patients should be promptly managed. Integrating cachexia management into oncology practice today can preserve muscle mass, sustain functional independence, and improve tolerance to systemic therapies. At the same time, healthcare professionals should remain updated about ongoing research. Careful trial design with meaningful patient selection criteria and key endpoints is essential to translating these therapies into real clinical benefit. Cancer cachexia remains 1 of oncology’s most pressing unmet needs. Raising awareness, adopting systematic screening, and implementing multimodal interventions are achievable now. As clinical trials evolve, the oncology community has the responsibility to bring the care of cachexia from the sidelines to the frontline of cancer management.

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