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Trial Title:
Prediction of Outcome After Chemoradiotherapy for Head and Neck Cancer Using Functional Imaging and Tumor Biology
NCT ID:
NCT01829646
Condition:
Head and Neck Cancer
Conditions: Official terms:
Head and Neck Neoplasms
Conditions: Keywords:
DWI
DCE MRI
ADC
FDG PET
Hypoxia
Prognostic and predictive model
Study type:
Interventional
Study phase:
N/A
Overall status:
Recruiting
Study design:
Allocation:
N/A
Intervention model:
Single Group Assignment
Primary purpose:
Other
Masking:
None (Open Label)
Intervention:
Intervention type:
Other
Intervention name:
functional MRI
Description:
Functional MRI on day 22 of the chemoradiotherapy treatment. Parameters of these images
will be later on correlated with outcome.
Intervention type:
Other
Intervention name:
Hypoxia gene expression profile.
Description:
Tumour biopsies will be obtained as part of the staging procedure (standard). On this
biopsies we will conduct a hypoxia gene expression profile (15 genes on PCR that can be
analyzed individually or as a group through one binary variable). Hypoxia will be a
parameter in our prognostic/predictive model.
Intervention type:
Other
Intervention name:
Functional MRI before start of treatment.
Description:
As part of the standard staging procedure all patients will undergo an MRI of the neck.
We will however also take DWI and DCE images at this time point. Parameters of these
images will be later on correlated with outcome.
Summary:
Despite uniform histopathological definition the response of locally advanced squamous
cell carcinomas of the head and neck (HNSCC) to ionizing radiation differs greatly with
locoregional recurrences burdening this patient population. The addition of concurrent
chemotherapy and the use of altered fractionation schedules has significantly increased
locoregional control and overall survival over the last decade however, this has come at
the cost of increased acute and late toxicity, preventing further treatment
intensification in all patients. If the investigators want to increase the therapeutic
index of HNSCC, we need to be able to tailor the treatment more individually to each
patient. The project aims at developing a prognostic model for head and neck cancer
patients based on the combination of known clinical parameters with 1) genetic
characteristics of the tumor and 2) parameters derived from diffusion weighted and
dynamic contrast enhanced magnetic resonance imaging (MRI) obtained before and during
treatment. The investigators plan a prospective trial where 120 patients with locally
advanced head and neck cancer treated with chemoradiotherapy will be included. Prior to
treatment biopsy material will be collected for genetic analysis and before and during
treatment functional MRI with diffusion weighted and dynamic contrast enhanced imaging
will be performed. All patients will be followed up multidisciplinary afterwards with
follow-up of tumor status and toxicity.
Detailed description:
1. BACKGROUND AND SETTING
1.1. Introduction
Concurrent (chemo-) radiotherapy (CRT) is the current standard of care for patients
with locally advanced head and neck squamous cell carcinoma (HNSCC). The proximity
of important functional structures with the tumour makes treatment however highly
complex. While locoregional control rates have improved over the last decade,
treatment related toxicity can be severe with xerostomia and dysphagia gravely
complicating the patient's quality of life.
Furthermore, it becomes increasingly clear that while these tumours can be identical
in location and basic histology, their response to treatment differs greatly. This
implies that for a subgroup of patients, equal locoregional control rates could be
achieved using a less intense and consequently less toxic treatment schedule. This
in contrast to the group of patients who develop a locoregional recurrence during
follow up, for whom current treatment is apparently insufficient. These patients
might benefit from a more intense treatment schedule, i.e. a higher dose of
radiation.
These differences in sensitivity to treatment can be explained by variations in
biological, molecular and genetic factors. Clinical parameters alone are
insufficient for response prediction. Identifying the different molecular and
genetic factors, would help us increase the accuracy of response prediction and
based on these factors tailor the treatment more individually to each patient.
Therefore we want to develop a prognostic and predictive model incorporating
well-defined molecular and imaging parameters which show great promise in response
prediction after ionizing radiation.
1.2. Genetic and molecular tumour characteristics
The first parameter we want to investigate further is tumour hypoxia. Hypoxia has
been identified as a factor that increases tumour aggressiveness and decreases
radiosensitivity. In the past, several techniques have been applied to detect
biologically relevant tumour hypoxia, but none of them are used today in routine
clinical practice. Recently, a polymerase chain reaction (PCR) -based hypoxia
classifier gene signature was published by Toustrup et al. This classifier allows us
to study biologically relevant tumour hypoxia and consequently tumour aggressiveness
and resistance to ionizing irradiation. This analysis will be performed on biopsies
obtained prior to treatment. Part of this biopsy material will also be stored into
our biobank. This will facilitate future research on promising molecular and
genetics parameters (such as HPV correlated overexpression of p16 for example) on a
well-defined and structured patient database.
1.3. Imaging parameters
Aside from these important molecular and genetic tumour characteristics, several
functional imaging parameters will also be included in our model. In contrast to
anatomical imaging, functional imaging modalities provide us with a deeper insight
in the tumour's underlying biological activity and microstructure.
Diffusion weighted magnetic resonance imaging (DWI) can characterize tissues based
on the random displacement of water protons. This displacement can be quantified
using the apparent diffusion coefficient (ADC). Preliminary studies in HNSCC have
demonstrated the prognostic and predictive potential of repetitive DWI early during
and after treatment.
Dynamic contrast enhanced magnetic resonance imaging(DCE-MRI) is a second technique,
which shows great promise as an early indicator of response to ionizing radiation.
Many malignant tumors manifest neovascularity or angiogenesis. These processes are
however flawed and as a result these newly synthesized vessels manifest a high
permeability, tortuosity and generally a poor functionality. This might result in
poor oxygen supply to the tumour cells, which may compromise the effectiveness of
radiation treatment of the tumour. Therefore the vascular properties of a tumour,
assessed with DCE-MRI, could prove a prognostic indicator of its aggressiveness.
2. STUDY OBJECTIVES
2.1. Primary objectives
The main objective of this study is to correlate clinical, molecular and
radiological predictors with outcome, as defined by locoregional control and disease
free survival. In this way we will develop a prognostic/predictive model. The
predictive model will be instrumental in the individualization of treatment ensuring
optimized treatment and avoiding under- and overtreatment.
2.2. Secondary objectives
- We want to get new insights in the tumor biology and microstructure by
correlating imaging and molecular/genetic markers in a well-defined patient
population.
- We want to validate the different imaging techniques.
- We want to make a correlation between hypoxia and other predictive biomarkers
in the future, by storing the tissue obtained in this study in our biobank.
3. STUDY DESIGN
We propose to set up a study where we will prospectively include patients with
locally advanced head and neck cancer who will be treated with concurrent
chemoradiotherapy as decided after multidisciplinary consultation. An outline of the
trial is presented in the figure below. All patients recognized eligible
(non-metastatic locally advanced head and neck squamous cell carcinoma, treated with
chemoradiotherapy, karnofsky performance status ≥ 70% and ≥ 18 years old) will be
included after written informed consent. Staging with a laryngoscopy, CT of the
neck, MRI of the neck and a PET-CT will be routinely performed.
The CRT treatment consists of radiotherapy up to 72 Gy using an accelerated
hyperfractionated schedule. Day 1 and day 22 of the treatment Cisplatin at 100mg/m²
will be administered.
Tumour biopsies will be obtained a few days prior to treatment. The hypoxia gene
expression profile will be derived from the tumour material (15 genes on PCR that
can be analyzed individually or as a group through one binary variable).
The tissue used for RNA and DNA extraction needs to be flanked by H&E staining
confirming tumor presence. From the biopsy the two ends will be cut off and fixed in
paraffin. This tissue will be stored in the biobank. The middle part of the tissue
will be stored into RNA-later, and will be used in part to extract DNA and RNA. RNA
will be used to synthesize cDNA to perform the qPCR analysis for the hypoxic
classifier.
Patients will also undergo a DWI MRI and DCE imaging before and 3 weeks into CRT.
Lesions will be quantitatively assessed by manual delineation of regions of interest
(ROI) over the tumour on the native DWI and DCE-MRI images. ADC values and (semi-)
quantitative DCE parameters will be calculated respectively.
All the above described data will be integrated into the prognostic model together
with the available clinical data.
4. DEFINITION OF ENDPOINTS The main endpoint of this study is to validate the above
described prognostic model. Using this prognostic model, we can predict response to
treatment. This will help us to tailor the treatment more individually to each
patient.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
- ≥ 18 years old
- Patients with non-metastatic locally advanced oropharyngeal cancer who will be
treated with chemoradiotherapy, as decided after multidisciplinary consultation.
- A karnofsky performance status ≥ 70%
- Gender: Male - Female
- Informed consent obtained, signed and dated before specific protocol procedures
Exclusion Criteria:
- Prior irradiation to the head and neck region
- Medical contraindications for any of the planned investigations
- Distant metastases
- Pregnant or lactating women
- Mental condition rendering the patient unable to understand the nature, scope, and
possible consequences of the study
- Patient unlikely to comply with the protocol, i.e. uncooperative attitude, inability
to return for follow-up visits, and unlikely to complete the study
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
Accepts Healthy Volunteers
Locations:
Facility:
Name:
Departement of Radiation Oncology
Address:
City:
Leuven
Zip:
3000
Country:
Belgium
Status:
Recruiting
Contact:
Last name:
Daan Nevens, MD
Phone:
016440110
Email:
daan.nevens@uzleuven.be
Investigator:
Last name:
Daan Nevens, MD
Email:
Sub-Investigator
Investigator:
Last name:
Sandra Nuyts, PhD, MD
Email:
Principal Investigator
Start date:
March 2013
Completion date:
March 2026
Lead sponsor:
Agency:
Universitaire Ziekenhuizen KU Leuven
Agency class:
Other
Collaborator:
Agency:
Flemish League Against Cancer
Agency class:
Other
Source:
Universitaire Ziekenhuizen KU Leuven
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT01829646