PET-MRI based molecular imaging as a response marker in cervical cancer: A Systematic

PET-MRI based molecular imaging as a response marker in cervical cancer: A
Systematic Review

ABSTRACT
Therapeutic strategies continue to evolve for treatment of women with
cervical cancer. However there is dearth of validated biomarkers of
therapeutic response and overall survival. In recent year development of
molecular imaging techniques using Magnetic Resonance Imaging (MRI) and
Positron Emission Tomography (PET) has allowed evaluation of imaging
biomarkers of proliferation, angiogenesis, perfusion and hypoxia as
prognostic imaging biomarkers. The present systematic review summarises the
current role of multifunctional PET and MRI as a response biomarker for
cervical cancer.



















INTRODUCTION

Last decade has seen significant improvements in therapeutics for cervical
cancer with the integration of concurrent chemo-radiation 1, image guided
external 2,3 and image guided intracavitary brachytherapy 4,5. While new
techniques promise improved local control 6 and potentially overall
survival, there is a dearth of validated biomarkers of response to chemo
radiation and clinical prediction of response still hinges on Federation
Internationale et de Obstetrique (FIGO) stage, tumour volume 7 and lymph
node status 8. Investigations into tumour microenvironment, 9-11 DNA repair
kinetics, 12,13 single gene expression 14-16 and multigene predictors 17,18
are still not mature and seek validation. In the last decade developments
in radionuclide and magnetic resonance imaging (MRI) have generated
interest in evaluation of functional imaging metrics as predictive and
prognostic markers. Availability of radionuclides other than fluoro
deoxyglucose (FDG) positron emission tomography (PET) like [18F]
–flouromisonidazole (18 F- F-Miso), 19 [18 F]
Fluoroazomycinarabinofuranoside (FAZA), 20 [18 F] Fluoro-L-Thymidine (FLT)
21 and multiparametric MRI 22 techniques like dynamic contrast enhanced MRI
(DCE-MRI), diffusion weighted (DW) MR, MR Spectroscopy (MRS), Blood Oxygen
Level Dependent (BOLD) MR imaging provides an opportunity for non-invasive
three dimensional investigation of tumour cellularity, perfusion,
proliferation and hypoxia and it's correlation with therapeutic response.
The present review is being undertaken to summarize the status of
multiparametric PET and MRI as predictive/prognostic imaging biomarker for
cervical cancer.

MATERIALS AND METHODS

Published data for this review was identified by systematically searching
PUBMED database (http://www.ncbi.nlm.nih.gov/pubmed) from 1966 – August
2012 with the following Medical Subject Heading (MeSH) terms: "cervical
cancer", "MRI", "DW-MRI", "DCE-MRI", "MR Spectroscopy", " BOLD", "PET",
"FDG", "F-Miso", "FAZA PET", "FLT PET", "Cu-ATSM PET" using Boolean search
algorithms. Any study reporting the use of multiparametric MRI or PET for
response prediction either alone or in combination with other biomarkers or
imaging modalities was reviewed. A preliminary search identified 248
potential articles. All pertinent articles in English language were
retrieved and relevant studies were considered for the purpose of this
review. Original studies were included only if they dealt with response
assessment of cervical cancer. Studies dealing with endometrial or uterine
cancers or describing only anatomical MRI for diagnosis and response
evaluation or using MRI for external beam radiation or brachytherapy
planning were excluded. Initial abstract screening eliminated 142 studies.
Subsequently two authors (SC, TD) independently reviewed each study for its
relevance and inclusion in this review.

RESULTS AND DISCUSSION

PET markers of therapeutic response

FDG PET as a response biomarker

In cervical cancer increased glucose utilisation is mainly through over
expression of Glucose Transporter-1 (GLUT-1) 23,24. Statistically
significant correlation has been demonstrated between expression of GLUT-1
and standardized uptake value (SUV) in primary and recurrent cervical
cancer specimens as compared to normal cervical tissue25. FDG PET scan
thereby provides an opportunity for non-invasive imaging of GLUT-1, a
marker hailed to be predictive of metastasis free survival in patients with
cervical cancer23. Systematic evaluation of 18FDG PET as a response
biomarker has essentially been conducted in the last decade by Washington
University Medical Center. Various metabolic parameters have been evaluated
as a prognostic marker for cervical cancer and the results are elucidated
in the sections below

Tumour SUV max as a prognostic biomarker

Yilmaz et al. 26 evaluated correlation of baseline SUV Max in cervical
tumours with extent of local tumour, presence of lymph node or distant
metastasis and concluded that higher SUV max at baseline predicts for
higher metastatic lymph node potential. Chung et al. 27 evaluated the
prognostic significance of SUV max in patients undergoing radical surgery
for cervical cancer. Within a cohort of 75 women with stage early cervical
cancer (stage IB-IIA)disease, high SUV max at baseline was found to be
independent predictor of recurrence following surgery (Hazard 1.17 (95% CI
1.03-1.34, p=0.01).

In another study Xue . 28 reported a mean SUV of 10.8 +/-5.8 in a cohort of
96 women with cervical cancer. No correlation was seen with baseline FIGO
stage, PET defined tumour volume or presence of lymph node metastasis.
Though the SUV max was higher for patients with loco-regional or distant
failure than those without disease recurrence (12.9 vs. 9.7), this
difference was deemed statistically non-significant. While SUV max lower
than the population median (10.2) was associated with improved 5 year
disease free survival (DFS) (71% vs. 52%, p=0.02), no difference was
observed in overall survival (OS) between the two cohorts. On multivariate
analysis SUV max was identified to be borderline significant for predicting
DFS (p=0.05). In a larger study by the same group (n=287) a mean SUV max of
11.6 was reported for squamous histology and 9.7 for non-squamous
histology. A higher SUV max at diagnosis was predictive of persistent FDG
uptake in cervix at 3 month post- therapy scan (p=0.04). A higher primary
SUV max also increased the risk of pelvic recurrence (p=0.02) with weak
association with distant metastasis (p=0.09). In the aforementioned study
multivariate analysis evaluating correlation of SUV max, tumour volume,
histology, lymph node status the only predictive factor for cause specific
survival (CSS) (p=0.01) and OS (p=0.01) was SUV max. On sub categorization
of patients according to baseline SUV max (Group 1 SUV max 5.2, group 2
SUV max 5.2-13.3, group 3 SUV max >13.3) the 5 year OS was 95%, 70% and 44%
respectively (p3.3 predicted for poor 5 year OS 30.

Metabolic Volume as a prognostic marker

Metabolic tumour volume derived from FDG PET has the ability to integrate
tumour volume and biological heterogeneity as a single index. The role of
metabolic tumour volume as a prognostic marker has been evaluated both
within surgical and chemo-radiation cohort. Chung et a. 31 measured
metabolic tumour volume in 63 patients scheduled to undergo surgery for
cervical cancer and used SUV>2.5 to define metabolic tumour volume. A cut
off value of 23.4 ml was identified to predict for recurrence. On
univariate analysis metabolic tumour volume,SUV max >9.5, lymph node
metastasis, parametrial involvement and lymph vascular space invasion was
identified to be predictive of DFS. However on multivariate analysis only
metabolic tumour volume predicted for DFS. Miller et al. 32 evaluated the
prognostic values of PET based metabolic tumour volume as a prognostic
marker in women undergoing chemo-radiation for cervical cancer. Using
thresholding techniques relying on edge detection authors concluded that
metabolic tumour volume