Functional Imaging during Radiation Therapy for HNC using FDG-PET, HX4-PET and MRI

Although tremendous gains have been achieved over the last few decades with
regard to loco-regional control (LRC) and overall survival (OS) in patients
with head and neck cancer (HNC), the balance between tumor control and toxicity
in patients with HNC treated by means of (chemo)radiation is still very
delicate. The cure rates remain inadequate in patients with locally advanced
tumors, especially HPV negative tumors. Moreover, the toxicity of treatment and
deterioration of quality of life (QoL) are considerable.
Physiological properties of the tumor like hypoxia and cell proliferation
influence the treatment resistance of the tumor. Multiple functional imaging
modalities can describe these physiological properties and have shown their
usage in predicting treatment outcome during radiotherapy. However, the optimal
combination of these modalities and their interplay is not clear. We will
examine which imaging modality or which combination of imaging modalities has
the best prognostic value, and which one can identify the subvolumes of the
tumor with the strongest association with loco-regional failure.

Primary objectives:
To examine the ability of functional imaging signal changes over the course of
treatment to distinguish patients with and without local recurrence

Secundary objectives:
To examine the correlation between the different imaging modalities and the
change in this correlation during treatment
To examine the heterogeneity and spatial distribution within the tumor of the
functional imaging signals and the correlation between the modalities
To examine the prognostic value of change in tumor volume during treatment

Patients will have additional imaging before, during and after the treatment.
Patients are treated with radiotherapy or chemoradiotherapy (possibly with
accelerated fractionation). This treatment will not be altered by the study
design. The week before the treatment patients will receive an additional MRI,
FDG-PET and HX4-PET. These examinations will be repeated during week 2 and 4 of
the treatment. Twelve weeks after the treatment patients will receive a FDG-PET
and MRI. During the standard investigation under general anaesthesia,
additional biopsies will be taken and markers will be placed at the biopsy
location. Before the start of the treatment and 4 and 12 weeks after treatment,
additional blood samples will be taken.
When there is clinical or radiological suspicion of a recurrence, an additional
MRI and FDG-PET in treatment mask will be made.

additional diagnostic scans
- 4 x FDG-PET/CT
- 4 x MRI
- 3 x HX4-PET/CT

Patients included in the study will receive additional imaging with PET/CT and
MRI as listed in the schedule below (table 1 a and 1 b). These imaging
procedures require additional visits to the hospital in the week before
treatment (combined with other appointments where possible), and will be
combined with treatment visits in week 2 and 4. FDG-PET/CT requires 6 hours
fasting. The PET/CT scans come with an additional radiation burden: 4 x low
dose FDG-PET (4 x 2 mSv) + 4 x normal dose CT (4 x 2.5 mSv) + 3 x low dose CT
(3 x 1.25 mSv) and 3 x HX4-PET (3 x 12 mSv), for a total of 57.75 mSv.
Additionally, there will be one extra FDG-PET/CT when a recurrence is suspected
(1x low dose FDG-PET (2 mSv) + 1x normal dose CT (2.5 mSv), expected in 1/5
patients, total of 62.25 mSv). This is not considered a significant risk in the
selected population with cancer and treatment with external beam radiotherapy.
All patients will receive 3 additional MRI*s (1 before and 2 during treatment).
Twelve weeks after treatment and in case of a suspected recurrence, either a
diagnostic CT or MRI will be made. When a CT instead of a MRI is indicated
(tumor below the hyoid), an additional study MRI will be made. The total
additional MRI*s will vary between 3 and 5. 5 additional MRI exams, An
intravenous contrast agent will be injected (15 ml Gadoteric acid) during the
MRI. No adverse effects of this agent have been registered. However, an
allergic reaction can in principle not be excluded. For patients who already
received a similar MRI exam as a part of their treatment, the risk associated
with the repetition of the MRI will be very limited. The FDG-PET scans will
take 1 hour post injection time and 20 minutes scantime, the HX4-PET scans will
take 4 hours post injection time and 30 minutes scantime, the MRI*s 30 minutes
scantime. The additional blood and tissue collection will cause minimal risks.
An extra venipuncture will cause a very small and well treatable risk of
hematoma or infection. The additional biopsies will bring a small change of
infection or bleeding.