Background: Anorexia and cachexia are common in patients with cancer and can be worsened by chemotherapy and there are no FDA approved medications for this condition. Many of the available off-label pharmacotherapy options are problematic: megestrol only modestly improves appetite and has risks of thromboembolism and death, steroids have significant side effects if used long term, and mirtazapine has recently been found to be no better than placebo (1). How does olanzapine impact anorexia and weight gain in patients with newly diagnosed advanced cancer receiving chemotherapy?
Design and Participants: This was a randomized, double-blinded, placebo-controlled trial which enrolled 124 patients newly diagnosed with locally advanced or metastatic gastric, hepatopancreaticobiliary, or lung cancer, who reported loss of appetite within 6 months of diagnosis and were undergoing conventional cytotoxic chemotherapy. The patients were randomized to receive 2.5mg olanzapine or placebo once daily for 12 weeks. The primary end point was the proportion of patients achieving a weight gain of >5% at the end of the study period. Other endpoints assessed included the proportion of patients with weight loss, the proportion of patients with an improvement in appetite on a visual analog scale, and nutrition scores assess by SGA (Subjective Global Assessment).
Results: For the primary outcome, 60% of the olanzapine arm achieved a >5% weight gain during the study period compared to only 9% in the placebo group, with p<0.001. The proportion of patients with improvement in appetite on the visual analog scale over the study period was 43% in the olanzapine group compared to 13% in the placebo group, p<0.001. The nutritional scores assessed by SGA improved in 43% of the olanzapine patients compared to 9% of placebo (<0.0001). The number of cases who were considered severely malnourished at the end of the study was 12% in olanzapine group compared to 39% in the placebo group (P=0.001). Use of olanzapine was also associated with better quality of life scores and lower rates of chemotherapy toxicity.
Commentary: This study is small but well designed and showed a dramatic benefit in weight, appetite, and quality of life. The generalizability of the study is limited in that it only included recently diagnosed patients with certain types of advanced cancer actively undergoing chemotherapy, rather than a broader population of cancer patients. If a significant portion of the benefit is from mitigating chemotherapy side effects, for example, olanzapine may not be as effective in cancer patients who are not on cytotoxic chemotherapy agents. While further study with larger groups of patients and broader inclusion criteria are still needed to increase the strength of evidence, this trial has prompted many clinicians, as well as the American Society of Clinical Oncology (ASCO), to consider olanzapine first line for cancer cachexia. In 2023, ASCO released an update to their Cancer Cachexia guidelines in which they recommend olanzapine above alternative agents: “for adults with advanced cancer, clinicians may offer low-dose olanzapine once daily to improve weight gain an appetite. (2)” They go on to state that clinicians may offer a short-term trial of a progesterone analog or corticosteroids for patients who cannot tolerate low-dose olanzapine.
Bottom Line: Advanced cancer patients with anorexia who took 2.5mg daily of olanzapine while undergoing chemotherapy had improved weight gain, nutritional status, and quality of life compared to those who took a placebo. This study adds to the evidence supporting olanzapine as first line pharmacotherapy over other available agents for cancer anorexia and cachexia.
Source: Sandhya L, Devi Sreenivasan N, 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
References
- Hunter CN, Abdel-Aal HH, Elsherief WA, Farag DE, Riad NM, Alsirafy SA. Mirtazapine in Cancer-Associated Anorexia and Cachexia: A Double-Blind Placebo-Controlled Randomized Trial. J Pain Symptom Manage. 2021;62(6):1207-1215. doi:10.1016/j.jpainsymman.2021.05.017
- Roeland EJ, Bohlke K, Baracos VE, Smith TJ, Loprinzi CL; Cancer Cachexia Expert Panel. Cancer Cachexia: ASCO Guideline Rapid Recommendation Update. J Clin Oncol. 2023;41(25):4178-4179. doi:10.1200/JCO.23.01280
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