In this study the safety & feasibility of image-guided mid-treatment hyper-fractioned dose-escalation with proton therapy will be assessed for the treatment of locally advanced HPV-negative squamous cell oropharyngeal cancer

For this study, the investigators propose a novel design to safely achieve tumor radiation dose escalation with proton therapy plus standard-of-care concomitant chemotherapy. Through mid-treatment image guidance, the tumor boost dose is determined; subsequently, only that GTV boost will receive a total dose of 80 Gy through hybrid hyperfractionation. This refers to twice-daily radiation in the last 15 fraction days. The combination of boost dose hyperfractionation and proton therapy is anticipated to prevent critical normal tissue damage within both the high- and intermediate-dose regions. This novel treatment approach aims to minimize critical toxicities while improving locoregional control for head and neck cancer patients who are at a higher risk of disease relapse.

Inclusion Criteria:

In order to be eligible to participate in this study, a subject must meet all of the following criteria:

• Biopsy proven diagnosis of squamous cell carcinoma originating in the oropharynx.

• Routine staging procedures, including CT of the head and neck region and chest, head and neck FDG-PET/CT and MRI (treatment planning allowed), and endoscopic evaluation when indicated.

• Negative for p16

• Locally advanced disease, specifically meeting all following criteria:

  • Stage III-IV
  • T-stage 2-4
  • All N-stages (N0-3)
  • M0

• Eligible for primary concurrent chemoradiation using conventionally fractionated radiotherapy 70 Gy combined with weekly cisplatin

• Eastern Cooperative Oncology Group (ECOG) performance score ≥2

• Age ≥18 years

• Written informed consent

Exclusion Criteria:

A potential subject who meets any of the following criteria will be excluded from participation in this study; patients that:

• underwent definitive resection of their primary tumor or nodal disease, except for incisional or excisional biopsies.

received radiation therapy in the head and neck area in the past

• have no detectable tumor anymore at both the primary site and lymph nodes at week 4 in treatment, because there will not be a volume to boost.
• are unable or unwilling to give written, informed consent
• have contra-indications for chemotherapy. This is at the discretion of the treating medical oncologist.
• are unable to tolerate intravenous contrast for both CT and MRI, having an estimated GFR < 60 ml/min/1.73 m2 or any contraindications to gadolinium-based contrast agents.
• have any evidence of iron overload on pre-imaging laboratory studies.
• have other serious illnesses or medical conditions present at entry in the study, including (but not limited to): immunodeficiency virus (HIV) infection or other conditions of persistent immunodeficiency, neurologic or psychiatric disorders, active disseminated intravascular coagulation, unstable cardiac disease despite treatment or uncontrolled diabetes mellitus.
• Women who are pregnant or breast feeding

All participants receive the experimental treatment