The COMPLETE study
HolistiC early respOnse assessMent for oroPharyngeaL cancer paTiEnts

In the Netherlands 300 patients with HPV negative squamous cell carcinoma of
the oropharynx (OPC) are diagnosed each year. Despite improvements of the
chemoradiation treatment in the last decades, the incidence of locoregional
failure (LRF) remains disappointingly high (37% at two years) and long-term
toxicity is substantial for patients that survive.
Stratification of patients into poor and good responders, prior to or early
during treatment, would provide opportunities for personalized treatment: e.g.
intensified treatment for patients with a poor response. However, within the
HPV negative patient population no accurate prognostic models are available for
accurate patient stratification. Apparently, important driving forces that
determine if a tumor responses to treatment, are not yet known.

Therefore, this project focuses on a holistic approach to gain insight in novel
potential prognostic biomarkers to predict response to treatment for HPV
negative oropharyngeal cancer patients. The response of a tumor to treatment
depends on its entire, complex, multi-layered landscape: on total tumor load
and the presence of different tumor regions (the macroscopic *layer*), on tumor
pathology and micro-environment (the microscopic *layer*) and on the genetic
characteristics of the tumor cells (the molecular *layer*). To fill the current
knowledge gap, the overall aim is to acquire a complete picture of the tumor,
using a holistic approach that assesses this entire multi-layered landscape.
Moreover, since a tumor is a dynamic system that evolves as the result of
treatment, pretreatment characteristics may not be sufficient. Therefore the
tumor landscape will be studied pretreatment but also how it evolves during
treatment. The macroscopic landscape will be studied using Intra-voxel
Incoherent Motion (IVIM) Diffusion Weighted MR Imaging (DWI). The microscopic
landscape using a biopsy that will be treated ex vivo. And the molecular
landscape using circulating tumor DNA.

Primary objective: to determine if the change in mean diffusion coefficient (an
IVIM DWI parameter) early during treatment, improves the performance of a
prognostic model for local regional control (LRC) two years after treatment of
HPV negative oropharyngeal cancer patients.

Secondary objectives:
1. to determine if the change in mean diffusion coefficient (an IVIM DWI
parameter) early during treatment, improves the performance of a prognostic
model for local regional control response three months after treatment of HPV
negative oropharyngeal cancer patients.
2. To determine if IVIM DWI, ctDNA, ex vivo sensitivity characteristics and
combinations thereof can be identified as potential novel prognostic markers,
using an explorative approach.
3. To build a repository of imaging data and liquid biopsies to allow future
identifications of biomarkers of treatment response.

Observational study

In this study patients will undergo 1 additional MRI scan during radiotherapy.
This MRI scan will not affect the course of the treatment. In correspondence to
the MRI scan that is part of the standard clinical protocol, patients will be
scanned with radiotherapy mask and intravenous contrast (gadolinium) is used.
At the same day the MRI scan is acquired, a blood sample (30 ml) will be taken
and stored. Due to the intravenous injection of contrast there is a risk of a
small bruising near the place of injection.