Letter to the Editor: Olanzapine as an Appetite Stimulant in Advanced Cancer – Do the Risks Outweigh the Benefits? A Note of Caution for Clinicians

We read with interest the publication by Othman et al,1 which described the OlAnCa trial. However, we contend that the conclusions presented within the abstract and discussion overstate the results. The primary outcome of this trial was change in anorexia score on the Edmonton Symptom Assessment Scale (ESAS-Anorexia) after 1 week, which was significantly greater in the olanzapine group. However, the effect size was small, with only a 1-point difference between groups, which questions its clinical significance. Similarly, although significant, the rate of >5% body-weight gain in the treatment group was very low (15.4%). For one patient to experience >5% body-weight gain, the number needed to treat is 7.333. However, considering that 20.3% of the treatment group and 11% of the placebo group experienced at least one serious adverse event (SAE), the number needed to harm is 10.753. This trial did not demonstrate an increase in lean body mass (LBM), which is associated with improved function, quality of life (QoL), treatment tolerance, and survival.2 The subjects in this trial were patients with incurable cancer, who were receiving active treatment or supportive care only. While on active treatment, interventions to improve nutritional status have the potential to improve tolerance to treatment and extend life, but in the context of end-of-life care, QoL should be prioritized, with a low tolerance for AEs. Stratifying participants by treatment intent would have provided context for the potential role of olanzapine as an appetite stimulant relative to the distinct intervention goals across the continuum of palliative care. The per-protocol analysis revealed the mean [SD] change in handgrip strength (HGS) was −2.8 [4.9] kg for olanzapine and −0.3 [4.1] kg for placebo. This 2.5 kg difference in rate of deterioration is clinically meaningful, warranting further investigation as a potential AE. Notably, the additional SAEs attributed to olanzapine versus placebo is 5 times that observed with anamorelin following Japanese postmarketing surveillance.3 Anamorelin has been refused marketing authorization in Europe and the United States due to limited efficacy on LBM, no proven effect on HGS or QoL, and the need for further safety outcome data.4 Palliating loss of appetite in advanced cancer is an important end-of-life intervention; however, this study has not adequately explored the risk–benefit ratio in this context. As such, concluding that olanzapine is an appropriate treatment for anorexia in this setting appears overstated. To progress the authorization of drugs for anorexia in cancer cachexia, future trials must focus more on safety and efficacy, and include clinically meaningful endpoints that are relevant to the test cohort.5