PATHOS: a phase II/III trial of risk-stratified, reduced intensity adjuvant treatment in patients undergoing transoral surgery for Human papillomavirus (HPV) positive oropharyngeal cancer

Abstract

BackgroundHuman papillomavirus-positive oropharyngeal squamous cell carcinoma is increasing in incidence worldwide. Current treatments are associated with high survival rates but often result in significant long-term toxicities. In particular, long-term dysphagia has a negative impact on patient quality of life and health. The aim of PATHOS is to determine whether reducing the intensity of adjuvant treatment after minimally invasive transoral surgery in this favourable prognosis disease will result in better long-term swallowing function whilst maintaining excellent disease-specific survival outcomes.Methods/DesignThe study is a multicentre phase II/III randomised controlled trial for patients with biopsy-proven Human papillomavirus-positive oropharyngeal squamous cell cancer staged T1-T3 N0-N2b with a primary tumour that is resectable via a transoral approach. Following transoral surgery and neck dissection, patients are allocated into three groups based on pathological risk factors for recurrence. Patients in the low-risk pathology group will receive no adjuvant treatment, as in standard practice. Patients in the intermediate-risk pathology group will be randomised to receive either standard dose post-operative radiotherapy (control) or reduced dose radiotherapy. Patients in the high-risk pathology group will be randomised to receive either post-operative chemoradiotherapy (control) or radiotherapy alone. The primary outcome of the phase II study is patient reported swallowing function measured using the MD Anderson Dysphagia Inventory score at 12 months post-treatment. If the phase II study is successful, PATHOS will proceed to a phase III non-inferiority trial with overall survival as the primary endpoint.DiscussionPATHOS is a prospective, randomised trial for Human papillomavirus-positive oropharyngeal cancer, which represents a different disease entity compared with other head and neck cancers. The trial aims to demonstrate that long-term dysphagia can be lessened by reducing the intensity of adjuvant treatment without having a negative impact on clinical outcome. The study will standardise transoral surgery and post-operative intensity-modulated radiotherapy protocols in the UK and develop a gold-standard swallowing assessment panel. An associated planned translational research programme, underpinned by tumour specimens and sequential blood collected as part of PATHOS, will facilitate further empirical understanding of this new disease and its response to treatment.Trial registrationThis study is registered with ClinicalTrials.gov identifier NCT02215265.

Long-Term, Prospective Performance of the MD Anderson Dysphagia Inventory in “Low-Intermediate Risk” Oropharyngeal Carcinoma After Intensity Modulated Radiation Therapy

“…In particular, T1-2N1-2b patients may be eligible for surgical trials such as Eastern Cooperative Oncology Group 3311 (E3311) while both AJCC staging subgroups would be eligible for radiotherapy trials such as NRG Oncology HN002 and Cancer Research UK Post-operative Adjuvant Therapy for HPV-positive Tumours (PATHOS) [39]. From our dataset that included MDADI as the sole PRO instrument, we cannot comment on use of the MDADI as the preferred swallowing-specific PRO in prospective trials.…”

Transoral Robotic Surgery and the Unknown Primary

“…In addition, if the tumour is well lateralised in the tongue base, some tumour boards or head and neck cancer multidisciplinary teams may advocate omitting contralateral neck irradiation. Another benefit from positive identification of a small tongue base cancer is that the patient is now eligible for entry into treatment de-escalation trials, such as PATHOS [39].…”

Radiologic Differences between Human Papillomavirus-Related and Human Papillomavirus-Unrelated Oropharyngeal Carcinoma on Diffusion-Weighted Imaging

“…Thus, there has been a growing importance and need placed on exploring strategies to deintensify therapies in order to reduce the significant morbidity associated with treatment, while not affecting clinical outcomes. Currently, there are a number of ongoing clinical trials studying de-escalation treatment protocols in HPV+ patients, many of which will be reporting results over the next few years [7,8,9]. If such therapeutic strategies prove to be effective, tools used to prognosticate and differentiate between HPV+ and HPV- disease will become imperative for guiding clinical management.…”