Determining the dose-effect relation of salivary gland irradiation and functional cell loss with PSMA PET

High dose radiotherapy in the head-neck area can damage salivary glands,
leading to a dry mouth (xerostomia) with detrimental impact on quality of life.
Optimization of radiotherapy to reduce xerostomia is difficult, because many
gland locations cannot be seen with current imaging modalities and biological
dose-effect are currently insufficiently understood. Traditional dose-effect
studies have predominantly been based on subjective symptoms or on poorly
reproducible stimulated salivation in a subset of accessible glands, and are
thus incomplete and potentially inaccurate. Thus, the dose-effect relation
between radiation dose and loss of vital cells in distinct salivary gland types
is unknown, and it may also vary with the use of concurrent chemotherapy or
with standard photon-based RT versus proton therapy (PT). As a result, there
are currently no known sparing strategies or dose constraints for several gland
types, and existing dose constraints for parotid and submandibular glands may
be inaccurate. These issues limit further development of strategies to reduce
xerostomia.

PSMA PET is a new diagnostic instrument which can visualize the presence of
vital acinar cells in salivary gland locations throughout the head and neck,
with a sensitive and quantitative signal. PSMA PET has already contributed to
identification of previously unknown seromucosal gland locations in the head
and neck, for example in the posterior wall of the nasopharynx (torus
tubarius). A reduction of PSMA accumulation in salivary glands is thought to
correlate with loss of vital acinar cells. The PET images can be correlated
with radiotherapy dose distributions in gland-based or voxel-based evaluations.
This makes PSMA PET a suitable instrument to derive the radiobiological
dose-effect relations that are required to develop better and gland-specific
dose constraints for radiotherapy. The results of this study can contribute to
lower toxicity and better quality of life in patients treated with high-dose
radiotherapy in the head and neck.

Primary objective is to determine the gland-based dose-effect relation between
conventionally fractionated radiotherapy (RT) and long-term loss of acinar
cells, per salivary gland type. Secondary objectives are:
- To estimate the dose-effect relation for the acute phase.
- To estimate dose-effect relations in a voxel-based approach (late and acute).
- To estimate the relation of acinar cell loss per gland type for development
of a dry mouth.
- To estimate the detrimental effect of concurrent chemo on function loss per
gland type.
- To estimate the development in time of cell loss in glands during RT.
- To estimate the difference in cell loss after regular RT versus PT

This study is designed as a prospective observational study. 20 patients with
newly discovered squamous cell carcinoma of the head and neck (HNSCC), who have
been referred for high dose (CC)RT, will be included. The relative amount of
remaining vital cells per salivary gland location will be evaluated using
serial PSMA PET/CT scans, and will be correlated with the local radiation dose
to derive the dose-effect relation.

Participation in this study has no significant risks. The complaints and
survival of participating patients are determined by their tumor in the
head-neck area and the response to treatment. Patients will receive 4 low-dose
PSMA PET/CT scans of the head-neck area, with a radiation dose of 3-4 mSv each.
The total dose of 12-16 mSv is well within the range of normal diagnostic
procedures. Participation does not induce a delay in diagnosis or treatment,
and imaging results have no impact on the diagnosis or treatment of the cancer
in the head-neck area.