Trial Title:
Prognostic and Diagnostic Added Value of Medical Imaging in Gynecological Cancer (PRODIGYN)
NCT ID:
NCT05855941
Condition:
Cervix Cancer
Endometrial Cancer
Epithelial Ovarian Cancer
Conditions: Official terms:
Ovarian Neoplasms
Carcinoma, Ovarian Epithelial
Endometrial Neoplasms
Uterine Cervical Neoplasms
Conditions: Keywords:
Positron Emission Tomography-Computed Tomography
Magnetic Resonance Imaging
Cervix Cancer
Endometrial Cancer
Epithelial Ovarian Cancer
Study type:
Observational
Overall status:
Recruiting
Study design:
Time perspective:
Prospective
Intervention:
Intervention type:
Diagnostic Test
Intervention name:
FDG-PET/CT and FDG-PET/MRI
Description:
Intravenous injection of FDG 3 MBq/kg. Intravenous injection of Dotarem 279.3 mg/ml, 0.2
ml/kg.
Arm group label:
Cervix cancer
Arm group label:
Endometrial cancer
Arm group label:
Ovarian cancer
Summary:
The goal of this observational study is to learn about the added diagnostic and
prognostic value of advanced medical imaging procedures in cervical cancer, endometrial
cancer and ovarian cancer. The main questions it aims to answer are:
- Does advanced medical imaging predict survival?
- Can advanced medical imaging improve radiotherapy target planning?
- Are advanced medical imaging results associated with risk markers found in tumor
tissue?
Participants will
- Undergo four additional imaging procedures, as compared to clinical routine
examinations, two at baseline and two after three months.
- Be subject to clinical follow-up for five years.
Detailed description:
This study has a retrospective and a prospective part, where the main aims are to:
1. Retrospectively validate the added value of radiological staging to clinical staging
according to the International Federation of Gynecology and Obstetrics (FIGO) tumor
classification system, in cervical cancer, endometrial cancer, and epithelial
ovarian cancer.
2. Prospectively identify prognostic biomarkers with 18F-2-fluoro-2-deoxy-D-glucose
fluorodeoxyglucose (FDG)-positron emission tomography (PET)/CT and FDG-PET/MRI in
cervical cancer, endometrial cancer, and epithelial ovarian cancer
3. Assess the possible effect of PET/MRI on radiotherapy target delineation in cervical
cancer
4. Improve non-invasive lymph node staging in endometrial cancer
5. Develop a machine learning decision support tool for characterization of ovarian
lesions
Material and methods (retrospective):
All eligible patients from the multi-disciplinary gynecological tumor conference at Umea
University Hospital during 2013-2022, with newly diagnosed cervical, endometrial, or
epithelial ovarian cancer, known cFIGO, >18 years old, and no other known current or
previous malignancy within the last 10 years, will be included in a retrospective
evaluation of radiological stage (rFIGO) based on all pre-operative imaging (MRI, CT and
FDG-PET/CT), clinical stage (cFIGO) based on examination under anesthesia (EUA), and
histopathological stage (pFIGO) based on available surgical and histopathological
findings. The analysis will be carried out in two cohort groups - 2016-01-01-2018-05-31,
and 2018-06-01-2022-06-01, before and after the implementation of the 2018 revised FIGO
classification, after which the cFIGO may be influenced to larger extent by imaging
results. For all epithelial ovarian cancer patients, Ovarian-Reporting and Data System
(O-RADS) score will be annotated for each MRI examination.
Agreement between rFIGO and cFIGO will be evaluated, and if feasible, compared to pFIGO.
The investigators will thus be able to validate rFIGO in cervical cancer with cFIGO up to
Ib2, and in endometrial and epithelial ovarian cancer treated with surgery.
The added value of rFIGO in terms of metastasis assessment and change of therapy, as well
as pattern and incidence of radiotherapy side effects will be evaluated in patients who
were considered inoperable.
Hypotheses (retrospective):
1. The degree of agreement is high between rFIGO T stage and cFIGO T stage in cervical,
endometrial, and epithelial ovarian cancer.
2. There is high sensitivity, specificity, accuracy, and negative and positive
predictive values of rFIGO to predict pFIGO in ovarian cancer of epithelial subtype.
3. There is an added value of rFIGO for metastasis assessment and change of patient
management in cervical cancer stages >Ib2, and in endometrial and epithelial ovarian
cancer patients who are considered inoperable.
Material and methods (prospective)
All eligible patients with newly diagnosed cervical cancer stage >1a, endometrial cancer
type 2 and/or minimum stage 1, or strongly suspected epithelial ovarian cancer,
consecutively referred to the gynecological- oncological department of Umea University
Hospital, with written informed consent, will be included in a prospective study of the
diagnostic and prognostic value of FDG-PET/CT and FDG-PET/MRI at baseline and at therapy
response evaluation after 3 months. The subgroup of patients with cervical and
endometrial cancer treated with radiotherapy, will undergo one additional stand-alone MRI
with dedicated tumor protocol after one week of treatment for early response evaluation.
Patient demographics and age of menarche, menopause and parity will be collected to
characterize the study population. Furthermore, for epithelial ovarian cancer, levels of
tumor markers cancer antigen (CA)-125 and CA-19-9 as well as risk of malignancy index
will be collected.
The FDG-PET/CT will be performed according to clinical routine with intravenous injection
of FDG 3 megabecquerel (MBq)/kg, 60 minutes post-injection (with the addition of Sharp
Inversion Recovery (IR) reconstruction to be used for comparison with the FDG-PET/MRI),
but without intravenous iodine contrast agent, since the FDG-PET/MRI will be performed
120 minutes after the same FDG-injection and will be prioritized for administration of
gadolinium-based contrast agent.
The FDG-PET/MRI will be designed according to standard clinical MRI protocol, dedicated
for each cancer type as described in detail below, with preparatory administration of 2
ml Buscopan 20 mg/ml and gadolinium-based contrast agent Dotarem 279.3 mg/ml, 0.2 ml/kg
body weight (maximum 20 ml). If renal function is moderately impaired (relative GFR 45-59
ml/min/1.73 m2), the dose will be reduced to 0.1 ml/kg. If relative GFR is <45
ml/min/1.73 m2 the examination will be performed without iv contrast agent. The total
examination time is estimated to approximately 40 minutes.
Cervical cancer: T2-weighted (T2W) (sagittal, axial, coronal oblique, axial oblique), T1
Dixon all (axial), diffusion-weighted imaging (DWI) (b 100, 800, axial), optional Gd+ T1
Dixon (axial).
Endometrial cancer: T2W (sagittal, axial, axial oblique), T1Dixon all (axial oblique),
DWI (b 100, 800, axial oblique), Gd+T1 Dixon (axial oblique, sagittal oblique).
Ovarian cancer: T2W (sagittal, axial, coronal), T1 Dixon all (axial), DWI (b 100, 800,
axial), Gd+T1Dixon (axial, sagittal).
Clinical evaluation will take place at 3 months, 6 months, 1 year and 5 years after start
of treatment with collection of clinical data progression-free survival (PFS, defined as
the time from start of treatment to progression or specific cancer-related death),
overall survival (OS, defined as the time from start of treatment to death from any
cause), and pattern and incidence of any radiotherapy side effects.
In FDG-PET/CT, pathological uptake of the suspected primary tumor will be visually
categorized into 1 = uptake < mediastinal background, 2 = uptake > mediastinal background
and < liver background, 3 = moderate uptake > liver background, or 4 = intense uptake >
liver background. From the PET/CT and PET/MRI examinations, primary tumor PET parameters
will also be quantified in maximum standardized uptake value (SUVmax), mean standardized
uptake value (SUVmean), functional tumor volume (FTV) and total lesion glycolysis (TLG).
In addition, the categorical parameters tumor heterogeneity, suspected radiological lymph
node metastases (present or not, N1 or N0) will be reported for both, and distant
metastases (M1 or M0) will be reported for PET/CT. CT and MRI parameters volume,
delineation, contrast enhancement and diffusion restriction, as well as tumor
heterogeneity will also be assessed. Interpretation of rFIGO will be reported for both
PET/MRI and PET/CT.
At the 3 months´evaluation, the same imaging parameters will be evaluated and absolute
differences in continuous parameters as well as up-grading or down-grading of categorical
parameters will be analyzed. The patients treated with radiotherapy or chemotherapy will
be categorized into responders, defined as complete or partial metabolic response, and
non-responders, defined as stable metabolic disease or progressive metabolic disease,
according to PERCIST criteria (see References). The feasibility of FDG-PET/MRI for
radiotherapy dose planning guidance will be compared to standard imaging-based guidance
regarding target delineation of gross tumor volume (GTV), and the prognostic difference
between the group of early responders (any perceptible response) at one week´s
stand-alone MRI evaluation, compared to non-responders (stable or progressive disease),
will be assessed.
In the histopathological analysis, prognostic factors will be recorded and if applicable,
immunohistochemical stainings for P53, Ki-67, ER, D240 and CD31, as well as molecular
analysis of microsatellite instability (MSI), breast cancer susceptibility gene (BRCA)-,
and polymerase-epsilon (POLE)-mutations and possible additional genes of emerging
interest will be performed.
For the study participants with endometrial cancer scheduled for surgery with sentinel
node algorithm, imaging characteristics of suspected lymph nodes will be described in
terms of visually quantified pathological FDG-PET uptake according to the four previously
mentioned categories, and PET parameters SUVmax, SUVmean, FTV, TLG and tumor
heterogeneity. CT and MRI parameters size, shape, delineation, contrast enhancement,
diffusion restriction and tumor heterogeneity will also be assessed. The lymph node with
the highest metabolic activity (SUVmax) will be selected for each affected lymph node
region: external iliac, internal iliac, common iliac, obturator and infrarenal paraaortic
regions. In addition, the same parameters will be analyzed for the primary tumor to
evaluate its predictive value of lymph node metastases. Regarding histopathology in this
sub-study, as a starting point morphological patterns detected on hematoxylin-eosin
stained glass will be recorded. These patterns will then guide further
immunohistochemical and molecular analyses to highlight the changes that have occurred in
the metastatic lymph nodes.
For the ovarian cancer dataset, the investigators will develop a machine learning method
for diagnostic decision support and prognostic prediction. The modeling data set will
consist of the various MRI data from different MRI scanners and protocols, annotated with
O-RADS (MRI), from ovarian cancer patients from the previous retrospective part of the
PRODIGYN study. The matching dataset of controls will be acquired from the non-ovarian
(cervical and endometrial) cancer patient cohort from the above-mentioned retrospective
study. After training, validation and testing, the investigators will apply the machine
learning method for O-RADS (MRI) risk categorization on the prospective study dataset and
compare the diagnostic performance of the machine learning method with two radiologists,
by area under the receiver operating characteristic curve (AUC-ROC) analysis, with ground
truth histopathology. The prognostic predictive performance will be assessed using O-RADS
4 and 5 lesion labeling as markers of poor prognostic outcome, with ground truth PFS and
OS.
Hypotheses (prospective):
1. FDG-PET/CT and FDG-PET/MRI biomarkers can predict PFS and OS in cervical,
endometrial, and epithelial ovarian cancer
2. FDG-PET/CT and FDG-PET/MRI metrics at follow-up of therapy response have higher
prognostic impact than baseline
3. Early tumor response on MRI after radiotherapy predicts better prognosis
4. Early response patterns in organs at risk may predict serious adverse events
5. Target delineation of GTV in cervical cancer is significantly different with
FDG-PET/MRI compared to local standard MRI
6. Degree of agreement, sensitivity, specificity and accuracy of FDG-PET/CT and
FDG-PET/MRI are high for lymph node metastases on regional and on patient basis in
endometrial cancer
7. Primary tumor FDG-PET/CT and FDG-PET/MRI imaging characteristics can predict
aggressive histological type II, MSI phenotype and presence of lymph node metastases
in endometrial cancer
8. FDG-PET/MRI can be used to distinguish BRCA-mutated from non-BRCA-mutated ovarian
cancer by differences in growth pattern and metabolic activity
9. The histopathological immune response in sentinel nodes can predict prognosis and
correlate with FDG-PET/CT and FDG-PET/MRI biomarkers in endometrial cancer
10. There is an added value of FDG-PET/CT and FDG-PET/MRI to the sentinel node
algorithm, for detection of para-aortic lymph node metastases in endometrial cancer
11. The machine learning method performs similarly to radiologists in O-RADS 1-4 but is
inferior in O-RADS 5
Criteria for eligibility:
Study pop:
Consecutive patients from the Northern Swedish regions of Vasterbotten, Vasternorrland,
Jamtland-Harjedalen and Norrbotten, referred to the gynecological- oncological department
of Umea University Hospital with newly diagnosed cervical cancer stage >1a, endometrial
cancer type 2 and/or minimum stage 1, or strongly suspected epithelial ovarian cancer.
Sampling method:
Non-Probability Sample
Criteria:
Inclusion Criteria:
- Previously untreated primary cervical, endometrial, or strongly suspected epithelial
ovarian cancer.
- Known clinical FIGO stage.
- >18 years old.
- No other known current or previous malignancy within the last 10 years.
Exclusion Criteria:
- Imaging findings suggestive of other primary malignancy.
- Previously included suspected epithelial ovarian cancer, later confirmed to be other
diagnosis than epithelial ovarian cancer or "cancer abdominis".
- MRI incompatible devices or patient unable to undergo MRI.
Gender:
Female
Minimum age:
18 Years
Maximum age:
N/A
Locations:
Facility:
Name:
Centre for Gynecology and Obstetrics, Umea University Hospital
Address:
City:
Umea
Country:
Sweden
Status:
Recruiting
Contact:
Last name:
Erika Figaro
Start date:
May 23, 2023
Completion date:
May 2032
Lead sponsor:
Agency:
Region Västerbotten
Agency class:
Other
Collaborator:
Agency:
Umeå University
Agency class:
Other
Source:
Region Västerbotten
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05855941
