Title: TORPEdO -a phase III trial of intensity-modulated proton beam therapy versus intensity-modulated radiotherapy for multi-toxicity reduction in HPV related oropharyngeal cancer
Funder: Cancer Research UK

Abstract: Background: HPV-related oropharyngeal cancer is highly curable, but treatment with concurrent chemoradiotherapy is associated with severe acute and late side-effects, which can have a profound detrimental impact on long-term quality-of-life (QoL). Compared with standard radiotherapy, the superior dosimetric properties of protons with sharp lateral penumbra and distal fall-off reduce radiation doses to normal tissues beyond the target volume, which should lessen treatment-related side-effects and improve patient QoL. Aims: 1. Assess whether intensity-modulated proton therapy (IMPT) compared with intensity-modulated radiotherapy (IMRT) reduces toxicities and improves QoL for patients with HPV-related oropharyngeal squamous cell carcinoma. 2. Validate a biomarker (normal tissue complication probability [NTCP] model) as a predictor of benefit from IMPT versus IMRT. 3. As the UK’s first clinical trial of PBT, define methodology and processes for future UK-led trials of this cutting edge therapy. Methods: A phase III multicentre trial in TNM 8 stage I-III HPV-related oropharyngeal cancer patients (excluding T1-2 node negative or single ipsilateral node 3cm, and N3 disease) requiring concurrent cisplatin chemoradiotherapy, including bilateral neck treatment. 110 patients will be randomised in a 1:1 ratio to standard IMRT at the recruiting centre versus IMPT at The Christie or UCLH. Radiotherapy doses 70/56 Gy (or relative biological effective [RBE] equivalent) in 35 fractions over 7 weeks shall be used. The trial is designed (90% power, 2-sided 5% significance) to detect a clinically meaningful 10 point improvement in mean UW-QoL physical composite score 12 months after treatment (primary endpoint). Secondary endpoints include: longitudinal HR-QoL using patient reported outcome questionnaires (UW-QoL, EORTC QLQ-C30, QLQ-H&N43, MDADI, MDASI); acute and late (up to 5 years) severe (grade 3-5) CTCAEv5.0 toxicities; tube feeding dependence, quantitative measures of lymphopenia, hearing loss and trismus; resection, loco-regional tumour control and overall survival rates; and cost-effectiveness expressed as Cost per Quality Adjusted Life Year(s). Translational physics and biology will be integrated to the study. How the results of the research will be used: A significant improvement in late HR-QoL in favour of IMPT would change clinical practice. Cost-effectiveness analyses will underpin the case for a change in clinical practice. Validation of an NTCP-biomarker will further refine patient selection for IMPT. Results will be shared with international collaborators to facilitate meta-analyses of endpoints and translational work to strengthen the case for changes to clinical practice. The trial will also provide the evidence base for toxicity reduction to support future studies of IMPT dose escalation in poorer prognosis patients.

Lay abstract: Background: HPV-related oropharyngeal cancer is highly curable, but treatment with concurrent chemoradiotherapy is associated with severe acute and late side-effects, which can have a profound detrimental impact on long-term quality-of-life (QoL). Compared with standard radiotherapy, the superior dosimetric properties of protons with sharp lateral penumbra and distal fall-off reduce radiation doses to normal tissues beyond the target volume, which should lessen treatment-related side-effects and improve patient QoL. Aims: 1. Assess whether intensity-modulated proton therapy (IMPT) compared with intensity-modulated radiotherapy (IMRT) reduces toxicities and improves QoL for patients with HPV-related oropharyngeal squamous cell carcinoma. 2. Validate a biomarker (normal tissue complication probability [NTCP] model) as a predictor of benefit from IMPT versus IMRT. 3. As the UK’s first clinical trial of PBT, define methodology and processes for future UK-led trials of this cutting edge therapy. Methods: A phase III multicentre trial in TNM 8 stage I-III HPV-related oropharyngeal cancer patients (excluding T1-2 node negative or single ipsilateral node 3cm, and N3 disease) requiring concurrent cisplatin chemoradiotherapy, including bilateral neck treatment. 110 patients will be randomised in a 1:1 ratio to standard IMRT at the recruiting centre versus IMPT at The Christie or UCLH. Radiotherapy doses 70/56 Gy (or relative biological effective [RBE] equivalent) in 35 fractions over 7 weeks shall be used. The trial is designed (90% power, 2-sided 5% significance) to detect a clinically meaningful 10 point improvement in mean UW-QoL physical composite score 12 months after treatment (primary endpoint). Secondary endpoints include: longitudinal HR-QoL using patient reported outcome questionnaires (UW-QoL, EORTC QLQ-C30, QLQ-H&N43, MDADI, MDASI); acute and late (up to 5 years) severe (grade 3-5) CTCAEv5.0 toxicities; tube feeding dependence, quantitative measures of lymphopenia, hearing loss and trismus; resection, loco-regional tumour control and overall survival rates; and cost-effectiveness expressed as Cost per Quality Adjusted Life Year(s). Translational physics and biology will be integrated to the study. How the results of the research will be used: A significant improvement in late HR-QoL in favour of IMPT would change clinical practice. Cost-effectiveness analyses will underpin the case for a change in clinical practice. Validation of an NTCP-biomarker will further refine patient selection for IMPT. Results will be shared with international collaborators to facilitate meta-analyses of endpoints and translational work to strengthen the case for changes to clinical practice. The trial will also provide the evidence base for toxicity reduction to support future studies of IMPT dose escalation in poorer prognosis patients.

Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES;7.1 INDIVIDUAL CARE NEEDS
Health categories: CANCER AND NEOPLASMS