De-escalation of the adjuvant radiotherapy doses in patients with HPV-related oropharyngeal tumors with high levels of CD8+ tumor infiltrating lymphocytes: a multicentre, randomized, controlled clinical trial

Abstract

BACKGROUND: New epidemiological data indicate that the incidence of oropharyngeal squamous cell carcinomas (OPSCC) is rapidly increasing due to human papillomavirus (HPV). Patients that suffer from a HPV-related OPSCC present distinct characteristics such as younger age, early T-stage but more advanced N-stage, absence of tobacco and alcohol as risk factors, but, more importantly, a significantly better prognosis. Despite their better outcome, these patients are still being treated with the same protocols as not HPV-related tumors and thus, are exposed to the same toxicity and the potentially unnecessary side-effects should not be underestimated. Several protocols of treatment de-escalation are under study in subgroups of patients with different characteristics. In the current study, we will address patients with the best prognosis in order to limit the possibility of negatively affecting the oncologic control. For this purpose we will, incorporate CD8+ tumor infiltrating lymphocytes (TILs) as an additional inclusion criteria. OBJECTIVES: The aim of this study is to prove that de-escalation of the radiotherapeutic adjuvant treatment in patients with HPV-related OPSCC in early stages and displaying additional good prognosis factors, is non-inferior in terms of overall survival. As secondary outcomes we will address local recurrence and post-treatment swallowing dysfunction.

DESIGN AND SETTING: This is designed as a multicentre, randomized, open-labelled non- inferiority clinical trial. It will be performed among four tertiary hospitals of Catalonia.

PARTICIPANTS: patients aged between 18 and 60 years, with HPV-related OPSCC that have high

numbers of CD8+ TILs, are tributary to transoral robotic surgery and have a T-stage <3 and N- stage <N2c.

METHODS: • Participants will be recruited consecutively and aim at 260 patients. • We will assign randomly patients to two treatment groups: standard adjuvant treatment (A) and de-escalated treatment (B) while stratifying by the type of adjuvant treatment required (radio or chemo-radiotherapy) (N=65 patients in each subgroup). • The de-escalation strategy will consist on reducing the protocol of adjuvant radiotherapy in 10 Gy. A follow-up of 5 years will be performed. • Cox hazard ratio will be used for the statistical analyses, in which a confidence interval of 95% will be calculated and significance is defined as a bilateral p<0.05