• Login
    • AAHPM |  Publications |  AAHPM Quarterly | Spring 2025 |  Cancer Cachexia: The State of the Art and New Directions

    Cancer Cachexia: The State of the Art and New Directions

    Dan Partain, MD FAAHPM, and Leslie Siegel, PharmD

    Cancer cachexia is a devastating complication of cancer that has adverse prognostic implications and negatively impacts patient well-being.1 Cachexia is a complex neurohormonal state defined as an irreversible loss of skeletal muscle exceeding 5% of total body mass. There is emerging evidence that cachexia may be partially reversible.2 Although cachexia is associated with other serious illnesses such as advanced cardiovascular or pulmonary disease, the pathophysiology for cancer-associated cachexia has been most closely associated with specific biomarkers, including growth differentiation factor 15 (GDF-15). As researchers more fully understand the complex physiology involved in cachexia, novel therapeutics are being developed to offer a targeted therapeutic approach.

    Existing Therapies

    There are currently no FDA approved medications for the treatment of cachexia. Prior to initiating medications for the treatment of cachexia, providers should optimize all other symptoms that may negatively affect nutritional status including pancreatic insufficiency, nausea, dysgeusia, and pain. The American Society of Clinical Oncology (ASCO) 2020 guidelines for management of cachexia do not give any medication a strong recommendation due to equivocal evidence of benefit. However, following promising results from a recent clinical trial, olanzapine has garnered more interest as a first-line therapy for cachexia.3 Per ASCO, patients who have a contraindication or are unable to tolerate low-dose olanzapine may benefit from a short course of progesterone analogs or steroids; long-term complications often prohibit chronic use. Additional medications that are often used outside of guidelines include mirtazapine, omega-3 supplements, growth hormones, and non-steroidal anti-inflammatory drugs. Furthermore, nutritional support may be pursued in combination with medication therapy.

    Emerging Therapies

    Ponsegromab

    GDF-15 is an inflammatory cytokine that is upregulated in a variety of cancers such as gastrointestinal and lung.4 GDF-15 has been associated with cachexia, and ponsegromab is a novel monoclonal antibody that binds to circulating GDF-15. Ponsegromab has shown promise in a recent phase 2 clinical trial where patients treated with ponsegromab experienced improved weight, muscle mass, and physical activity at 12 weeks.5 Benefits beyond 12 weeks are unknown. Although all patients in the study had elevated GDF-15 levels, it is unclear what proportion of patients with cancer cachexia have elevated GDF-15 levels.

    Anamorelin

    Ghrelin is a hormone produced in the gastrointestinal tract that prompts hunger. Anamorelin is a ghrelin agonist, which was approved in 2021 in Japan for the treatment of cancer-related cachexia. Clinical trials have found increased total weight and improved reported symptoms with anamorelin.6 A recent extension study also reports that positive effects may continue to be seen at 24 weeks. Unfortunately, anamorelin has not been shown to improve hand grip strength, which is a marker for improved physical function, and this gap in patient-centered outcomes has posed a barrier to entering the US market.

    Discussion

    Cancer cachexia is a serious complication of advanced cancer that can lead to total person suffering and increases the risk of both morbidity and mortality. Existing treatments have unclear benefits; they have been shown to increase non-lean mass gain and may be associated with significant side effects. Of the many treatments that are under active investigation, ponsegromab appears to show the most promise as a treatment for cachexia due to improved muscle mass and patient function. Although this research is aligned with the palliative care ethos of total person care and represents a growing focus on quality of life and other patient-centered outcomes, more data is needed for us to advocate for a comprehensive paradigm shift.

    Last, it remains important for palliative care clinicians to not lose sight of the fact that despite emerging therapies for serious illnesses, our communication skills and total person care remain the most important treatments we can offer our patients. We are reminded of the enthusiasm for immune checkpoint inhibitor (ICI) therapy. Many years on, we still experience the daily value of high-quality palliative care, as we now know that ICI therapy is not a panacea. Nevertheless, these new medications are exciting developments.

    Resources

    1. Roeland EJ, Bohlke K, Baracos VE, et al. Management of cancer cachexia: ASCO guideline. J Clin Oncol. 2020;38(21):2438-2453. doi:10.1200/JCO.20.00611.
    2. Gunchick V, Brown E, Liu J, et al. Morphomics, survival, and metabolites in patients with metastatic pancreatic cancer. JAMA Netw Open. 2024;7(10):e2440047. doi:10.1001/jamanetworkopen.2024.40047.
    3. Sandhya L, Sreenivasan ND, Goenka L, et al. Randomized double-blind placebo-controlled study of olanzapine for chemotherapy-related anorexia in patients with locally advanced or metastatic gastric, hepatopancreaticobiliary, and lung cancer. J Clin Oncol. 2023;41(14):2617-2627. doi:10.1200/JCO.22.01997.
    4. Baracos VE. Cancer cachexia and the brain stem. N Engl J Med. 2024;391(24):2373-2376. doi:10.1056/NEJMe2411334.
    5. Groarke JD, Crawford J, Collins SM, et al. Ponsegromab for the treatment of cancer cachexia. N Engl J Med. 2024;391(24):2291-2303. doi:10.1056/NEJMoa2409515.
    6. Laird BJA, Skipworth R, Bonomi PD, et al. Anamorelin efficacy in non-small-cell lung cancer patients with cachexia: insights from ROMANA 1 and ROMANA 2. J Cachexia Sarcopenia Muscle. 2025;16(1):e13732. doi:10.1002/jcsm.13732.

    Dan Partain, MD FAAHPM, is a palliative care consultant at the Mayo Clinic in Rochester, MN, and a newly inducted FAAHPM for 2025. His clinical interests include complex pain and symptom management and promoting equitable palliative care for patients coming from international settings and those with non-English language preferences.

    Leslie Siegel, PharmD, has served as a palliative care pharmacist at the Mayo Clinic in Rochester, MN, since 2022. Prior to that she completed her pain medicine and palliative care pharmacy residency at The Ohio State University. Her clinical interests include oncologic palliative care and serving patients with concurrent substance use disorders.