Early response evaluation of proton therapy by PET-imaging in squamous cell carcinoma located in the head and neck

Rationale: Proton therapy (PT), currently being introduced in the Netherlands,
delivers radiation dose more conformal than photon radiotherapy, therefore
healthy tissue damage is expected to be lower and at least similar tumouricidal
effects are described. This increases the therapeutic window of radiotherapy
which could be used for intensified treatment to patients prone to locoregional
failure. From photon radiotherapy it is known that stratification of patients
with head and neck squamous cell carcinoma (HNSCC) is possible using different
positron-emission tomography (PET-)techniques. Distribution of tumour hypoxia,
a main cause of resistance to radiotherapy, and glucose metabolic need have
been described. PT, in contrast to photon therapy, results in activation of
endogenous atoms in the irradiated tissues which can be measured using PET and
reflect dose deposition and tissue composition. This provides a unique
application of PET in this treatment modality as quality assurance of proton
therapy and potentially as biomarker of tissue response to proton therapy. The
main hypothesis is that early during PT, PET is capable of discerning a subset
of patients with increased risk of locoregional failure with a univariate
hazard-ratio of at least 4.0. At this time point, treatment intensification
would still be possible.

Objective: To assess whether early changes in hypoxia between baseline and in
the (end of the) second week of proton therapy are predictive for time-to-local
recurrence in patients with HNSCC (primary). Secondary objectives include: to
compare the role of hypoxia-PET to more readily available PET of glucose
metabolism, to describe spatial conformity between the PET-scan and the
location of the recurrence, to determine the potential of adaptive replanning
based on two-timepoint PET-imaging. In a pilot setting the feasibility of
activation PET in a clinical setting for quality assurance of PT-plans and
potential biomarker of PT-induced tissue changes will be explored.

Study design: Prospective, single-arm, observational cohort study with invasive
measurements.

Nature and extent of the burden and risks associated with participation,
benefit and group relatedness: Each PET-acquisition will be performed in
radiotherapy position preferably using fixation devices (mould mask). The
procedures of PET-imaging of 18F-FAZA (hypoxia) and 18F-FDG (glucose
metabolism) each involve preparation (hypoxia: none, glucose metabolism: 6h
fasted), intravenous injection of a radiopharmaceutical, a waiting period in
solitude (hypoxia: 2 h, glucose metabolism: 1 h), followed by PET-acquisition
(hypoxia: 10-20 min, glucose metabolism: 5-10 min). Occurrence of
infusion-related reactions (e.g. allergy) is unlikely. The radiation burden
attached to each of these procedures are 6.8 mSv (hypoxia) and 2.9 mSv (glucose
metabolism). The pilot substudy requires immediate transfer from PT-gantry to
scanner followed by a 30-min PET-acquisition, three times, resulting in a
radiation burden of ~0.5 mSv per procedure. All other procedures are part of
clinical protocol. There will be no individual benefit for enrolled subjects.
Financial compensation for study-related travel expenses have been arranged.
However, where possible, each study procedure will be combined with a regular
visit to the PT-facility.