A phase 3 randomised controlled trial of proton beam therapy for oropharyngeal cancer

Background: The benefits of intensity-modulated proton therapy (IMPT) over intensity-modulated radiation therapy (IMRT) for patients with oropharyngeal squamous cell carcinoma (OPSCC) are controversial. This trial aimed to compare late functional, patient-reported, disease control, and survival outcomes between IMPT and IMRT.<br/> <br/>Methods: In a phase 3 trial (TORPEdO), patients with locally advanced OPSCC were assigned 2:1 to IMPT or IMRT (70 Gy in 33 fractions, over 6.5 weeks) with two cycles of high dose cisplatin (100mg/m², every 3 weeks). Co-primary endpoints at 12 months were gastrostomy tube dependence or severe weight loss (≥20% from baseline) and University of Washington Quality of Life (UW-QoL) mean physical composite score for saliva, taste, chewing, swallowing, speech and appearance.<br/> <br/>Findings: Between February 25, 2020, and June 13, 2023, 205 patients (OPSCC: T3/4 48%, N2(c) 22%) from 20 UK centres were randomised (IMPT n=136; IMRT n=69). At 12 months, gastrostomy tube dependence was &lt;2% in both groups (IMPT: 2/119, IMRT: 1/59), severe weight loss higher for IMPT (IMPT: 20/110 [18%; 97·5% CI: 11–28%], IMRT: 3/53 [6%; 1–17%]), with a combined odds ratio of 2·80, 97·5% CI: 0·75–10·4, p=0·079. Mean UW-QoL physical composite scores at 12 months were 78·3 for IMPT vs 77·1 for IMRT (difference=1·3, 97·5% CI: -3·7–6·2, p=0·56). Four patients had treatment-related SAEs: one IMPT, three IMRT (one with two SAEs). There were no treatment-related deaths. At a median follow-up of 28·3 months (IQR 26·5-39·3), 24-month freedom from loco-regional recurrence rates for IMPT versus IMRT were 94% (99% CI: 86–98%) vs 97% (82–100%); HR=2·6 (99% CI: 0·3–20·3; 95% CI: 0·5–12·4, p=0·24), and overall survival rates: 95% (86–98%) vs 95% (81–99%); HR=1·6 (99% CI: 0·3–8.8; 95% CI 0·4–5·9, p=0·47).<br/><br/>Interpretation: IMRT and IMPT had similar late physical quality of life, gastrostomy tube dependence, local control and overall survival. In healthcare settings where IMPT is not used routinely for OPSCC, IMRT remains the standard of care.<br/><br/>Registration: ISRCTN16424014<br/>Funding: Cancer Research UK<br/>