Post-operative Adjuvant Treatment for HPV-positive Tumours (PATHOS)

The main objectives of the PATHOS study are: To assess whether swallowing function can be improved following transoral resection of HPV-positive OPSCC, by reducing the intensity of adjuvant treatment protocols. The aim is to personalise treatment, based on disease biology (HPV status and pathology findings), to optimise patient outcomes. To demonstrate the non-inferiority of reducing the intensity of adjuvant treatment protocols in terms of overall survival in the reduced intensity treatment arms.

PATHOS is a multicentre, open-label, parallel-group Phase II/III randomised controlled trial (RCT). The phase II target of 242 patients was reached in December 2018 and there was a seamless transition into Phase III. The protocol was amended in September 2018 to incorporate the changes associated with the phase III transition. The amendment included changes to the outcome measures and sample size calculations. In March 2024, a protocol amendment increasing the target recruitment to Phase III of the study from 1100 to 1269 patients was approved. Patients eligible for the study must have biopsy proven oropharyngeal squamous cell carcinoma (OPSCC) clinically staged T1T3 N0N2b. Their primary tumour, as judged by the local MDT, must be considered resectable via a transoral approach. Having secured informed consent, patients with centrally or locally determined HPV positive tumours will undergo baseline assessment of swallowing function (includes; MDADI score, videofluoroscopy, PSSH\& N, 100 mL water swallow test) and complete QOL questions (EORTC QLQC30 and EORTC QLQH\&N35) prior to surgery. Transoral Laser Microsurgery, Transoral Robotic Surgery \& Endoscopically assisted Transoral Surgery are all accepted transoral techniques for the study. A lateral oropharyngectomy performed with monopolar cautery (The Huet Procedure) can also be used. Following surgery and histopathological assessment of the primary tumour and neck dissection surgical specimens, participants will be allocated into study groups based on the presence or absence of pathological risk factors for recurrence as follows: Group A: Participants with tumours which exhibit no adverse histological features. Participants in this group will not receive any adjuvant treatment as per standard of care. Group B: Participants with T3 tumours (or T1-T2 tumours with additional risk factors), TNM 7th edition pN2a (metastasis in single ipsilateral node 31-60 mm diameter) or pN2b (metastasis in multiple ipsilateral nodes \<61 mm diameter) disease, tumours with evidence of perineural and/or vascular invasion, and/or a histologically normal tissue margin around the primary tumour of 1-5mm and, in the case of TLM, marginal biopsies free of tumour. Patients in this group will be randomised to PORT 60Gy in 30# over 6 weeks (Control Arm B1) or PORT 50Gy in 25# over 5 weeks (Test Arm B2). Group C: Participants with tumours of any T or any N stage, which exhibit the following high-risk pathological features will be included: A histologically normal tissue margin around the primary tumour of \<1mm and, in the case of TLM, marginal biopsies free of tumour and /or extracapsular spread (ECS) of nodal disease. Participants in this group will be randomised to POCRT 60Gy in 30# over 6 weeks with concurrent Cisplatin (Control Arm C1) or PORT 60Gy in 30# over 6 weeks without chemotherapy (Test Arm C2). Participants in groups B and C will be stratified before randomisation by T stage, N stage, smoking history and trial.show_full_description

Inclusion Criteria: * Histologically confirmed or suspected squamous cell carcinoma of the oropharynx. * UICC/AJCC TNM 7th edition stage T1-T3, N0-N2b (or UICC TNM 8th edition stage T1-T3, N0-N1) disease. * Multidisciplinary team (MDT) decision to treat with primary transoral resection and neck dissection. * Patients considered fit for surgery and adjuvant radiotherapy * Aged 18 or over. * Written informed consent provided. Exclusion Criteria: * Known HPV negative squamous cell carcinomas of the head and neck: A negative result for p16 Immunohistochemistry automatically excludes a patient from the trial. If initial p16 testing is positive but High Risk HPV (HR HPV) In-Situ Hybridization (ISH)/Polymerase Chain Reaction (PCR) does not demonstrate the presence of HR HPV DNA, the patient will also be excluded. Patients who are p16+ may complete swallowing assessments, excluding videofluoroscopy, and surgery whilst HR HPV DNA status is being determined (with recourse to central concordance testing, if appropriate, for UK centres). HPV positivity, as determined by p16 and the demonstration of HR HPV DNA is essential before patients undergo videofluoroscopy or randomisation. * T4 and/or T1-T3 tumours where transoral surgery is considered not feasible. * UICC/AJCC TNM 7th edition N2c-N3 nodal disease (or UICC/AJCC TNM 8th edition N2-N3 nodal disease). * Patients for whom transoral surgery and neck dissection is not considered the primary treatment modality. * Current smokers with clinically staged N2b disease (including smokers up to 6 months before diagnosis), even if HPV-positive. Vaping is permitted and should be considered as non-smoking status. * Any pre-existing medical condition likely to impair swallowing function and/ or a history of pre-existing swallowing dysfunction prior to index oropharyngeal cancer. * Patients with distant metastatic disease as determined by routine pre-operative staging radiological investigations e.g., CT thorax and upper abdomen or PET-CT. * Patients with a history of malignancy in the last 5 years, except basal cell carcinoma of the skin or carcinoma in-situ of the cervix. * Women who are pregnant or breastfeeding and fertile women who will not be using contraception during the trial.