Patients
This study was approved by the ethics committee of Institutional Review Board of our hospital. Between Nov 2018 and May 2019, 53 consecutive patients with histologically proven untreated CC scheduled to undergo CCRT treatment were enrolled in this retrospective study. The exclusion criteria were contradictions for MR scanning or CCRT. There was no dropout in our research.
CCRT treatment
All patients were treated with a combination of EBRT and intracavitary brachytherapy (ICBT). EBRT was delivered to the whole pelvis, with a total dose of 50 Gy (daily dose of 2 Gy, 5 times per week) and accompanied by concurrent chemotherapy: six cycles of weekly cisplatin (40 mg/m2) or three cycles of cisplatin (75 mg/m2) at 3-week intervals. ICBT was initiated after an EBRT dose of 46-50 Gy. ICBT was delivered once or twice a week in 4-5 fractions, with a fractional dose of 6-7 Gy at point A. The median dose of ICBT was 28 Gy and the median biological effective dose (BED) was 47.8 Gy (range, 23.3-64.7 Gy) to point A.
MRI protocol
All patients underwent MR examination at two time-points: within 1 week before (T0) and the 3rd day during (T1) CCRT. All MR examinations were performed on a 3.0 T MRI scanner (GE Healthcare 750 Discovery, Milwaukee, Wisconsin, USA) using an 8-channel phase array coil. Routine MRI protocols included sagittal T2WI (repetition time [TR]/echo time [TE]: 4,763 /85 ms; slice thickness/spacing: 4 /0.4 mm; field of view [FOV]: 28 cm; number of excitations [NEX]: 4), coronal T2WI (TR/TE: 4171 /85 ms; slice thickness/spacing: 5 / 0.5 mm; FOV: 32 cm; NEX: 4), axial T2WI with fat suppression (TR/TE: 4580 /85 ms; slice thickness/spacing: 4 /1 mm; FOV: 34 cm; NEX: 4), axial T1WI (TR/TE: 601 /minimum ms; slice thickness/spacing: 3 /1 mm; FOV: 32 cm; NEX: 2). Axial multi-b-values DWI with 11 b-values of 0, 10, 20, 40, 80, 150, 200, 400, 800, 1000 and 1200 s/mm2 was performed with a single-shot echo-planar sequence (TR/TE: 3883 /59 ms; slice thickness/spacing: 5 /0.5 mm; FOV: 36 cm; matrix, 128×160; NEX 1 to 6 with the increasing of b-values, total scan time 6:34 min).
Treatment response assessment
Treatment response was assessed at one month after the completion of the entire CCRT by using convention MR scanning according to the evaluation criteria in solid tumors (RECIST v1.1[25]) as follows: (1) complete response (CR): no residual tumor showed on the MR images; (2) partial response (PR): the largest diameter of residual tumor was at least 30% less than the original size; (3) progressive disease (PD): there was an at least 20% increase in the longest diameter of tumor compared with the pretreatment size; (4) stable disease (SD): there was neither a decrease sufficient to qualify for PR nor an increase sufficient to qualify for PD. All patients were dichotomized into two groups, CR group and non-CR group. The CR group consisted of patients with CR, while non-CR group consisted of patients with PR, SD and PD.
Image analysis
Two radiologists with 15 and 2 years’ experience in gynecologic imaging performed post-process and image analysis independently. Readers were blinded to the pathological findings and therapeutic responses. All functional parameters maps were post-processed by using the MADC program on the Advantage Workstation (AW 4.6 version, GE, US). The regions of interest (ROIs) containing all the tumor region and avoiding obvious necrotic areas were manually delineated along the margin of tumor on the three consecutive maximal tumor slices on axial DWI images with b=1000 s/mm2. The mean value of parameters of the three ROIs was used for statistical analysis.
The mono-exponential model was applied to calculate ADC value from all 11 b values by using the following equation [1]:
S/S0= exp(-b.ADC) (1)
Where S0 and S represent the signal intensity obtained with the b=0 and b>0 s/mm2.
The bi-exponential model, also called intravoxel incoherent motion (IVIM), was applied to calculate Dslow, Dfast, and fp values with the following equation [26]:
Sb/S0= (1−fp).exp(-b.Dslow)+fp.exp(-b.Dfast) (2)
Where Sb represents the mean signal intensity with diffusion gradient b, and S0 represents the mean signal intensity at b=0 s/mm2. The fp (perfusion fraction) represents the ratio of water movement within capillaries compared with the total volume of water in a voxel. Dslow (pure diffusion coefficient) represents pure molecular diffusion where a physiological perfusion effect is excluded. Dfast (pseudo-diffusion coefficient) represents the average blood velocity and mean capillary segment length. Considering that Dfast is much greater than Dslow with one order of magnitude, the effects of Dfast on the signal decay at large b-values (>200 s/mm2) can be ignored.
The stretched exponential model was used to calculate DDC and α by using the following equation [3]:
S/ S0= exp(-(b.DDC) α) (3)
Where S0 and S represents the signal intensity obtained with the b=0 and b>0 s/mm2. DDC represents the distributed diffusion coefficient reflecting the mean intravoxel diffusion rate, while α represents intravoxel diffusion heterogeneity index corresponding to intravoxel water molecular diffusion heterogeneity with a range from 0 to 1[27].
Statistical analysis
All statistical analyses were performed using SPSS (Version 17.0, SPSS Inc., Chicago, IL, USA) and GraphPad Prism 5 (GraphPad Prism Software Inc., San Diego, California, USA). An intra-class correlation coefficient (ICC) was calculated to evaluate interobserver reliability of the measurements. Change of MRI parameters(Δ) was defined as (parameter-T1-parameter-T0)。All quantitative values are presented as the mean ± standard deviation (SD). Clinical characteristics of cervical cancer patients with different treatment outcome was compared using Chi-square test. The Kolmogorov–Smirnov test was conducted to analyze the normal distribution of all metrics. Comparisons between CR group and non-CR group, and between different time-points were performed by using independent t test (Dslow, DDC and α, which conformed to normal distribution) and Mann–Whitney U test (ADC, Dfast and fp, which did not conform to normal distribution). Two-tailed p values were used and p values less than 0.05 were considered as statistically significant. The area under the curve (AUC) of the receiver operating characteristic (ROC) curves for the significant parameters were calculated and compared. The cut-off values were selected by using the maximized values of the Youden indexes. The values that corresponded to the highest Youden index were chosen as the optimal threshold values.