Proton Image-guided Radiation Assignment for Therapeutic Escalation via Selection of locally advanced head and neck cancer patients

Patients with HPV-negative locally advanced head and neck squamous cell
carcinoma (HNSCC) have poor survival (3- and 5-year overall survival (OS): 53%
and 42%, resp.) and local-regional control rates (~30%) despite multimodality
treatment. Recurrent or residual tumor predominantly originates in the regions
that receive the highest radiotherapy dose (i.e., CTV70). Hence, higher
radiation doses to the tumor have potential improve the cure rates for these
patients. Introduced in the Netherlands in 2018, proton therapy can reduce
radiation dose to the normal tissue surrounding the tumor, and thus toxicities,
while delivering the same dose to the tumor tissues. Yet, proton therapy
remains to be deployed to achieve higher tumor doses with similar (or even
lower) normal tissue dose compared to conventional photon therapy. For this
study we propose a novel design to achieve tumor radiation dose-escalation with
proton therapy plus standard of care concomitant chemotherapy, in combination
with mid-treatment image-guided tumor boost dose adaptation, hybrid
hyper-fraction and selective critical structure sparing to prevent toxicities
(arising from both the high- and intermediate- dose regions) and improve
locoregional control.

To assess the safety & feasibility of image-guided mid-treatment
hyper-fractioned dose-escalation with proton therapy for the treatment of
locally advanced HPV-negative squamous cell oropharyngeal cancer

Single arm Bayesian Phase I intervention study

Radiation dose escalation of the prescribed dose to the gross tumor volume
(80.5Gy)

Participants will receive a higher radiotherapy dose to the gross tumor volume.
To minimize the risk of toxicities within target volumes receiving the highest
dose, a hybrid hyper-fractionated fractionation schedule is used, meaning that
participants are irradiated twice per day in week 5-7 of treatment (note,
treatment in week 1-4 are according to current clinical standard). Moreover,
dose escalation is only applied tumor tissue that is detectable at the end of
week 4 of treatment, which means that patients will undergo an additional MRI
scan in week 4 during treatment to define the remaining tumor volume.
The PIRATES treatment strategy is designed to minimize the risk of
(life-threatening) toxicities. Specifically, previous randomized studies have
demonstrated that these toxicities were not observed after full-treatment
hyper-fractionation schedules to a total dose of around 80 Gy. By integrating
this approach with adaptive proton therapy, the risk is considered minimal.
Moreover, the target population is locally advanced OPC patients that are at
high-risk of treatment failure at the primary tumor site and pathologic lymph
nodes. The potential benefit of hybrid hyper-fractionated dose escalation with
protons for these patients is improved locoregional tumor control without
enhancing severe toxicity.