Background
Investigator-initiated, multicentre, open-label, phase 3 randomised noninferiority trial (INPHOG-SUPP-22-03) conducted across Indian paediatric oncology centres. N=310 patients aged 4-18 years scheduled to receive single- or multiday highly emetogenic chemotherapy (HEC). Median age 13 y; 62.3% male; 51.9% received multiday chemotherapy. Guideline-standard prophylaxis in this setting is dexamethasone plus a 5-HT3 receptor antagonist plus an NK-1 receptor antagonist, but corticosteroids carry clinically relevant toxicity in children (hyperglycaemia, behavioural change, infection risk, and interference with lymphoid malignancy treatment). The trial tested whether olanzapine could replace dexamethasone entirely.
Results
Interventions and follow up: Arm A: Olanzapine + palonosetron + fosaprepitant (OLANZ), dexamethasone-free (n=154)
Arm B: Dexamethasone + palonosetron + fosaprepitant (DEX), standard prophylaxis (n=156)
Primary endpoint: Complete response (CR) to vomiting — no vomiting and no rescue antiemetics — during the overall period (0-120 h after last chemotherapy); prespecified noninferiority margin −15%
mFollow up: Single chemotherapy cycle per patient; per-protocol population n=299 (DEX 151, OLANZ 148)
Results: CR to vomiting, overall period (primary): 63.5% OLANZ vs 56.9% DEX; absolute difference 6.6% (95% CI −4.5 to 17.7) — noninferiority criteria met
CR to vomiting, acute period: 68.9% vs 64.2%
CR to vomiting, delayed period: 79.1% vs 78.8%
CR to nausea, overall period: 53.4% vs 54.3%
CR to nausea, acute period: 59.5% vs 59.6%
CR to nausea, delayed period: 68.9% vs 69.5%
Arm B: Dexamethasone + palonosetron + fosaprepitant (DEX), standard prophylaxis (n=156)
Primary endpoint: Complete response (CR) to vomiting — no vomiting and no rescue antiemetics — during the overall period (0-120 h after last chemotherapy); prespecified noninferiority margin −15%
mFollow up: Single chemotherapy cycle per patient; per-protocol population n=299 (DEX 151, OLANZ 148)
Results: CR to vomiting, overall period (primary): 63.5% OLANZ vs 56.9% DEX; absolute difference 6.6% (95% CI −4.5 to 17.7) — noninferiority criteria met
CR to vomiting, acute period: 68.9% vs 64.2%
CR to vomiting, delayed period: 79.1% vs 78.8%
CR to nausea, overall period: 53.4% vs 54.3%
CR to nausea, acute period: 59.5% vs 59.6%
CR to nausea, delayed period: 68.9% vs 69.5%
Adverse events
Neuropsychiatric: any-grade somnolence 50.7% OLANZ vs 17.2% DEX
Overall tolerability: no new safety signals attributed to olanzapine beyond sedation
Discontinuation: NR
Overall tolerability: no new safety signals attributed to olanzapine beyond sedation
Discontinuation: NR
Conclusions
A completely dexamethasone-free antiemetic regimen built on olanzapine, palonosetron and fosaprepitant was noninferior to standard dexamethasone-containing triple prophylaxis for control of vomiting in children and adolescents receiving highly emetogenic chemotherapy, with numerically higher complete response rates across acute, delayed and overall periods. Nausea control was equivalent. The trade-off is a roughly three-fold increase in any-grade somnolence. These data establish olanzapine as a viable corticosteroid-sparing option in paediatric CINV prophylaxis, which matters most where dexamethasone is contraindicated or undesirable.
Key Limitations
Open-label design with patient- and caregiver-reported vomiting and rescue-medication endpoints is susceptible to reporting bias, and somnolence is not blindable. Only a single chemotherapy cycle was assessed, so durability of benefit and cumulative sedation across multi-cycle regimens are unknown. The prespecified noninferiority margin of −15% is wide for a symptom endpoint and would permit a clinically meaningful loss of vomiting control had the point estimate favoured dexamethasone; the observed 95% CI lower bound (−4.5%) is reassuring but not definitive. Conducted entirely in India, where baseline supportive-care practice, olanzapine dosing conventions and nutritional status may differ from other settings. Olanzapine dose and schedule details, quality-of-life measures, and effects in children with steroid-dependent malignancies were not reported in the abstract. Somnolence at this frequency may limit uptake in outpatient or ambulatory settings.
Clinical Context
MASCC/ESMO 2023 and the paediatric-specific POGO/COG antiemetic guidelines recommend a 5-HT3 receptor antagonist plus dexamethasone plus an NK-1 receptor antagonist (aprepitant/fosaprepitant) as standard prophylaxis for children receiving highly emetogenic chemotherapy, with olanzapine positioned as an add-on agent for breakthrough or refractory CINV rather than as a dexamethasone substitute. Olanzapine is not FDA- or EMA-labelled for CINV in any age group; its antiemetic use is off-label in adults and children alike. Prior randomised paediatric work by the same investigators (Radhakrishnan et al, JCO 2020) showed olanzapine added to standard prophylaxis improved vomiting control. CIVIC POD is the first phase 3 trial to test full dexamethasone replacement, and provides the evidence base guideline panels would need to offer a steroid-free option — particularly relevant in acute lymphoblastic leukaemia, lymphoma and brain-tumour protocols where exogenous corticosteroid confounds therapy or toxicity.