Title: PATHOS: Post-operative adjuvant treatment for HPV-positive tumours
Funder: Cancer Research UK

Abstract: Background: Human papillomavirus positive oropharyngeal cancer (HPV-positive OPSCC) is increasing in incidence. Prognosis is good with 3y overall survival rates of over 90%. However, current treatments cause serious side effects, particularly swallowing dysfunction which affects long term quality of life. Minimally invasive surgery - Transoral Laser Microsurgery (TLM) or Transoral Robotic Surgery (TORS) - result in good swallowing outcomes, although function is impaired by adjuvant (post-operative) radiotherapy or chemoradiotherapy. Radiotherapy doses of 60Gy Gray and the use of concurrent chemotherapy can increase the risk of late swallowing dysfunction. PATHOS phase II has been recruiting ahead of target in the UK since opening in October 2015 (currently 15% ahead). EORTC & CR-UK negotiations have resulted in full endorsement of PATHOS by the EORTC and a commitment to roll-out the trial into 22 centres in 6 European Countries. The phase III application is strongly supported by the H&N CSG and CTRad. Aims: To demonstrate that reduced intensity adjuvant treatment results in 1. Non-inferior survival outcomes 2. Better swallowing function outcomes. Methods: Patients with T1-T3 N1-N2b HPV-positive OPSCC, who are suitable for TLM/TORS, will be recruited. HPV positivity will be confirmed by p16 immunohistochemistry and High-Risk HPV In Situ Hybridization or PCR. Following surgery with TLM/TORS, tumours will be stratified on the basis of pathological risk factors for recurrence. Patients with no adverse pathological features will receive no adjuvant treatment (Group A). Patients with intermediate risk features (T3 or N2 stage, perineural invasion, vascular invasion) will be randomised to 60Gy in 30 fractions radiotherapy (control) or 50Gy in 25 fractions (de-intensification) (Group B). Patients with surgical margins 1mm and/or lymph node extracapsular spread will be randomised to adjuvant chemoradiotherapy (control) or 60Gy radiotherapy alone (de-intensification) (Group C). The phase II protocol will remain unchanged for phase III to allow inclusion of phase II data in the phase III analysis. The primary endpoint is overall survival. ~1000 randomised patients will be required to show that de-intensified adjuvant treatment results in non-inferior survival in Group C whilst demonstrating, using a swallowing panel, the functional superiority of de-intensification of adjuvant treatment schedules in both Groups B and C. Early stopping rules are defined to terminate the trial in the event of higher locoregional recurrence or death rates following de-intensification. How the results of this research will be used: If positive, PATHOS will result in a global change in practice for patients with HPV-positive OPSCC.

Lay abstract: Background: Human papillomavirus positive oropharyngeal cancer (HPV-positive OPSCC) is increasing in incidence. Prognosis is good with 3y overall survival rates of over 90%. However, current treatments cause serious side effects, particularly swallowing dysfunction which affects long term quality of life. Minimally invasive surgery - Transoral Laser Microsurgery (TLM) or Transoral Robotic Surgery (TORS) - result in good swallowing outcomes, although function is impaired by adjuvant (post-operative) radiotherapy or chemoradiotherapy. Radiotherapy doses of 60Gy Gray and the use of concurrent chemotherapy can increase the risk of late swallowing dysfunction. PATHOS phase II has been recruiting ahead of target in the UK since opening in October 2015 (currently 15% ahead). EORTC & CR-UK negotiations have resulted in full endorsement of PATHOS by the EORTC and a commitment to roll-out the trial into 22 centres in 6 European Countries. The phase III application is strongly supported by the H&N CSG and CTRad. Aims: To demonstrate that reduced intensity adjuvant treatment results in 1. Non-inferior survival outcomes 2. Better swallowing function outcomes. Methods: Patients with T1-T3 N1-N2b HPV-positive OPSCC, who are suitable for TLM/TORS, will be recruited. HPV positivity will be confirmed by p16 immunohistochemistry and High-Risk HPV In Situ Hybridization or PCR. Following surgery with TLM/TORS, tumours will be stratified on the basis of pathological risk factors for recurrence. Patients with no adverse pathological features will receive no adjuvant treatment (Group A). Patients with intermediate risk features (T3 or N2 stage, perineural invasion, vascular invasion) will be randomised to 60Gy in 30 fractions radiotherapy (control) or 50Gy in 25 fractions (de-intensification) (Group B). Patients with surgical margins 1mm and/or lymph node extracapsular spread will be randomised to adjuvant chemoradiotherapy (control) or 60Gy radiotherapy alone (de-intensification) (Group C). The phase II protocol will remain unchanged for phase III to allow inclusion of phase II data in the phase III analysis. The primary endpoint is overall survival. ~1000 randomised patients will be required to show that de-intensified adjuvant treatment results in non-inferior survival in Group C whilst demonstrating, using a swallowing panel, the functional superiority of de-intensification of adjuvant treatment schedules in both Groups B and C. Early stopping rules are defined to terminate the trial in the event of higher locoregional recurrence or death rates following de-intensification. How the results of this research will be used: If positive, PATHOS will result in a global change in practice for patients with HPV-positive OPSCC.

Research activity codes: 6.4 SURGERY;7.1 INDIVIDUAL CARE NEEDS
Health categories: CANCER AND NEOPLASMS