Patients
Informed consents were waived by the institutional Ethics Committee for this retrospective study. All patients with pathologically diagnosed squamous cell uterine cervical cancer in our institute from 2009 to 2013 were reviewed, and 152 consecutive patients were found to meet the following inclusion criteria: (a) the tumor was in stage IB to IVA, (b) the patient received concurrent chemoradiation in our radiation department, (c) pre-treatment pelvic MR was performed in our hospital and was within 30 days before treatment started, and (d) valid follow-up information could be acquired from the medical records. After retrieving MR images and clinical medical records, 49 patients were excluded, including 32 with sagittal instead of axial DWI, 8 with poor quality DWI images, 5 with a tumor with a long diameter of less than 1 cm, 1 with small cell lung cancer, and 3 with a follow-up time of less than 2 years. We recorded the relevant clinical information, including age, grade, FIGO stage, and serum levels of squamous cell carcinoma antigen (SCC-Ag). In total, 103 subjects were enrolled in the study. The follow-up time was defined as from the date of first radiation to either the recurrence date or the last visit date with no events. The median follow-up time for the whole cohort was 48.9 months (range 2.0–94.6 months). Among them, 55 patients free of recurrence or metastasis at the end of the follow-up period (median follow-up time 59.7 months).
Treatment and outcome evaluation
All patients underwent standard radiotherapy in combination with concurrent cisplatin-containing chemotherapy. Radiotherapy consisted of external beam radiation (40–50.4Gy in 1.8-2Gy daily fractions using 10-MV photons) and intracavitary brachytherapy (30–35 Gy to point A by 5 Gy fractions in 3 weeks). Six courses of cisplatin-based chemotherapy (40 mg/m2 dosage) were delivered weekly at the same time with radiotherapy.
The primary outcome was DFS, defined as the period of time from the first radiation treatment to the date of developing any recurrence (local or distant relapse, metastasis). Patients with persistent disease were considered to have relapsed on the first day of completing radiation therapy. Recurrence data were taken from the medical records, with evidence based on the diagnosis by the treating physician and imaging (18F-fluorodeoxyglucose [18F-FDG] positron emission tomography/computed tomography [PET/CT], MRI, CT) or biopsy results. Recurrence group and non-recurrence group were divided based on DFS ≤ 2 year and DFS > 2 years.
MR imaging
All examinations were performed on 1.5-T MR scanners (GE optima 1.5 T MR360 and GE signa 1.5 T EchoSpeed Plus) with four-channel or eight-channel torso phased-array body coil. The scanning range was set to cover the entire pelvis from the level of the anterior superior iliac spine to the inferior level of the symphysis pubis. All patients were required to fast at least 2 h before the examination. After excluding the contradictions, patients were asked to inject 5 ml of anisodamine about 20–30 min before the examination to reduce bowel motion artifacts.
MR sequences included T1WI, T2WI, and DWI. The standard MR scan protocol was kept identical each time and was as follows: (a) axial T1WI: fast spin-echo (FSE) sequence, repetition time (TR) = 726 ms, echo time (TE) = 12 ms, matrix size = 288 × 256, field of view (FOV) = 26–36 cm, slice thickness/intersection gap = 8/1 mm, number of excitations (NEX) = 1; (b) axial T2WI: FSE-XL, TR = 5182 ms, TE = 80 ms, matrix size = 352 × 320, FOV = 26–30 cm, slice thickness/intersection gap = 8/1 mm, NEX = 2; (c) sagittal T2WI: FSE-XL, TR = 4138 ms, TE = 102 ms, matrix size = 320 × 288, FOV = 24–36 cm, slice thickness/intersection gap = 5/1 mm, NEX = 4; (d) axial DWI: single-shot echo-planar imaging sequence, TR = 3500 ms, TE = minimum time, matrix size = 128 × 128, FOV = 36 cm, slice thickness/intersection gap = 8/1 mm, NEX = 4, b-value = 0 and 1000 s/mm2. All slice lines of DWI were copied from the axial T2WI to make sure the images were all at the same table position.
Image analysis
All images were retrieved from local PACS (Huahai, China). By putting axial T2WI and DWI images side by side and also referring to the sagittal T2WI, ROIs were drawn manually slice by slice on DWI images along the edge of the lesions in order to cover as much tumor area as possible without excluding cystic, hemorrhagic or necrotic areas (Fig. 1). ROIs were initially drawn by a junior radiology resident (Z.B.) with 3 years’ experience in MR reading and then reviewed and corrected by a senior attending radiologist (C.K.) with more than 10 years’ experience in gynecologic imaging. Both radiologists were blinded to patients’ outcomes during the data collection period. Whole lesion ROIs were thus achieved to acquire volumetric data of tumors.
Axial DWI images were loaded into a post-processing workstation (GE AW 4.6) and parametric ADC maps were generated automatically in the FUNCTOOL program. Parametric maps along with DWI and ROIs were all transferred to house-made radiomics software based on the 3D Slicer platform. ROIs were registered to the parametric maps. Histograms and corresponding ADC parameters values were automatically generated by the software. Excel software was used to sum up the parameters values of ROI at all slices of the tumor respectively and then calculate the average value. The HA program in the software was generated the following 8 parameters for ADC values: mean, median, maximum, minimum, 10th percentile, 90th percentile, kurtosis, and skewness. The maximal diameter of tumor (MDT) was calculated on two-dimensional axial ADC metrics.
Statistical analyses
Continuous variables are presented as mean ± SD. Categorical variables are presented as counts and percentages. The clinical variables and ADC parameter values were compared between the recurrence and non-recurrence groups using the Wilcoxon rank-sum test or the chi-square test. Univariate and multivariate Cox regression analyses were used to evaluate the potential prognostic value of ADC parameters and relevant clinical variables (i.e., age, MDT, grade, FIGO stage, SCC-Ag) for DFS. For the multivariate analysis, parameters were selected by using stepwise selection and by considering the following covariates with a P-value less than 0.3 in the univariate analysis. The receiver operating characteristic (ROC) curve was drawn to determine the cutoff value of the parameters using the maximum Youden index. The Kaplan–Meier survival curve was drawn and log-rank estimates were obtained. All statistical analyses were performed using SPSS 22.0. All reported values are two-tailed, and P-values < 0.05 were considered statistically significant.