Primary results for the phase III trial of Toxicity Reduction using Proton Beam Therapy for Oropharyngeal Cancer (TORPEdO; CRUK/18/010)

Abstract

Purpose/Objective(s)

To investigate differences in clinical outcomes between intensity-modulated proton therapy (IMPT) and intensity-modulated radiation therapy (IMRT) for patients with locally advanced oropharyngeal squamous cell carcinoma (OPSCC).

Materials/Methods

In this phase 3, randomised, controlled, multicentre trial participants with OPSCC requiring definitive bilateral chemoradiation were assigned in a 2:1 ratio to IMPT or IMRT (70 Gy (RBE) in 33 once daily fractions over 6.5 weeks), with two cycles of concurrent cisplatin chemotherapy (every 3 weeks, 100mg/m²). Co-primary endpoints at 12 months after radiation were: (i) clinician-reported gastrostomy dependence or CTCAE grade 3 weight loss (20% decrease from baseline) and (ii) patient-reported University of Washington quality of life (UW-QOL) physical composite score of saliva, taste, chewing, swallowing, speech and appearance; each tested at the 2.5% significance level. Analysis accounted for tumour (T) and nodal (N) stage, smoking status, chemotherapy received, baseline body mass index and baseline UW-QOL physical composite score. Secondary endpoints included MD Anderson Dysphagia Inventory (MDADI), freedom from loco-regional recurrence and overall survival.

Results

205 participants with locally advanced OPSCC (48% T3/4, 21% N2(c), 31% ≥10 pack year history) from 20 UK centres were allocated to IMPT (n=136) or IMRT (n=69) between March 2020 and June 2023. Treatment was delivered over a median of 44 days (IQR: 44, 44) for both IMPT and IMRT. A second cycle of chemotherapy was not given for 5 (3.8%) and 3 (4.5%) patients receiving IMPT and IMRT, respectively. 178/205 (119 IMPT; 59 IMRT) were evaluable for the clinical co-primary endpoint, with data recorded for gastrostomy dependence or weight loss. Both groups had low rates of gastrostomy dependence: IMPT 2/119 (1.7%) vs IMRT 1/59 (1.7%). A higher rate of grade 3 weight loss was seen for IMPT: 20/110 (18.2%) vs IMRT 3/53 (5.7%); taken together, the odds ratio for IMPT was 2.8 (97.5% CI: 0.8, 10.4, p=0.080). 155/205 participants (100 IMPT; 55 IMRT) were evaluable for the patient reported co-primary endpoint. There was no evidence of a difference in mean UW-QOL physical composite score for IMPT vs IMRT (78.3 vs 77.1, difference=1.3 (to 1 decimal place), 97.5% CI: -3.7, 6.2, p=0.563). MDADI mean composite scores at 12 months for IMPT vs IMRT were 79.4 vs 79.5. At a median follow-up of 27 months, 2-year freedom from loco-regional recurrence for IMPT and IMRT was 94.8% (99% CI: 85.8, 98.2) and 96.8% (81.6, 99.5) and for overall survival 94.4% (85.9, 97.9) and 94.9% (79.1, 98.8), respectively.

Conclusion

For locally advanced OPSCC, IMPT does not reduce long-term gastrostomy dependence or severe weight loss and does not improve long-term patient-reported physical quality of life or swallow function compared with IMRT. There is no requirement for IMPT as an alternative to high quality IMRT.