Whole lesion histogram analysis of apparent diffusion coefficient predicts therapy response in locally advanced rectal cancer

Table 1 Magnetic resonance imaging sequences and data acquisition parameters

Parameter	Magnetic resonance imaging sequences
	T2 FSE sagittal	T2 FSE axial	T2 FSE coronal	T1 FSE axial	DWI axial	T1 + GD axial	T1 + GD coronal	T1 + GD coronal
Repetition time in ms	5325	9890	7509	850	7750	435	295	265
Echo time in ms	102	102	102	Min	Min	Min	Min	Min
Slices, n	30	40	30	40	40	40	40	30
FOV	24	20	20	20	20	20	20	24
Slices thickness in mm	4	4	4	4	4	4	4	4
Broadband in Hz/Px	62.5	62.5	50	62.5	-	50	50	50
Phase	384	384	416	384	60	320	320	320
Acquisition time in min:s	2:35	3:08	2:45	3:53	5:18	2:31	2:16	2:02

DWI: Diffusion-weighted imaging; FSE: Fast spin-echo; GD: Gadolinium; MRI: Magnetic resonance imaging.

Table 2 Clinical and pathological characteristics of the patients’ studies

Characteristics	n (%)
Sex
Female	23 (48)
Male	25 (52)
RECIST 1.1
Partial response	22 (46)
Stable disease	13 (27)
Progressive disease	13 (27)
Ryan’s classification
0	18 (38)
1	10 (21)
2	9 (19)
3	11 (22)
Treatment response
Complete responders after nCRT	18 (38)
Non-responders’ patients after nCRT	30 (62)
Tumor location
Upper third	7 (15)
Middle third	14 (29)
Lower third	20 (41)
Diffuse	7 (15)
ypT stage
T0	4 (8)
T1s	4 (8)
T1a	2 (4)
T2	8 (17)
T3	20 (42)
T4b	10 (21)
ypN stage
N0	20 (42)
N1a	14 (29)
Nic	14 (29)
Degree of differentiation
Well-differentiated adenocarcinoma	6 (13)
Moderately differentiated adenocarcinoma	35 (73)
Poorly differentiated adenocarcinoma	7 (14)
Surgical approach
Low anterior resection	16 (33)
Intersphincteric resection	26 (54)
Abdominoperineal resection	6 (13)

nCRT: Neoadjuvant chemoradiation therapy.

Table 3 Median and interquartile range of pre- and post-neoadjuvant chemoradiation therapy parameters, as well as of changes between pre- and post-treatment values

	Responders	Non-responders	P value
Pre-nCRT parameters
pre-nCRT ADCmean	0.75 (0.60-0.90)	0.85 (0.70-0.90)	0.146
10th percentile	0.20 (0.17-0.23)	0.20 (0.17-0.26)	0.812
25th percentile	0.32 (0.29-0.35)	0.32 (0.23-0.41)	1.000
50th percentile	0.40 (0.35-0.40)	0.40 (0.30-0.50)	0.698
75th percentile	0.56 (0.47-0.58)	0.57 (0.45-0.63)	0.391
90th percentile	0.71 (0.55-0.77)	0.76 (0.50-0.80)	0.556
Skewness	1.10 (0.90-1.14)	1.19 (0.88-1.37)	0.135
Kurtosis	0.89 (0.83-0.92)	0.92 (0.83-0.95)	0.296
ROI ADCmean	0.92 (0.80-1.20)	0.91 (0.83-0.93)	0.562
Post- nCRT parameters
post- nCRT ADCmean	1.20 (0.98-1.52)	1.10 (0.90-1.30)	0.065
10th percentile	0.36 (0.30–0.37)	0.32 (0.31–0.34)	0.0361
25th percentile	0.41 (0.40-0.52)	0.42 (0.41-0.50)	0.476
50th percentile	0.66 (0.56-0.70)	0.65 (0.51-0.66)	0.127
75th percentile	0.71 (0.67-0.80)	0.70 (0.66-0.75)	0.050
90th percentile	0.89 (0.80-0.95)	0.80 (0.79-0.89)	0.105
Skewness	0.92 (0.60–1.14)	2.00 (1.15–2.67)	< 0.0011
Kurtosis	0.65 (0.59–0.72)	0.90 (0.80–0.90)	< 0.0011
ROI ADCmean	2.50 (1.50-2.70)	2.00 (1.80-2.30)	0.056
Changes between pre-treatment and post-treatment
∆%ADCmean	57% (14%–103%)	27% (0%–59%)	0.0321
∆%ADC10th	86% (37%–118%)	48% (11%–88%)	0.0201
∆%ADC25th	39% (19%-57%)	22% (0%-58%)	0.905
∆%ADC50th	70% (31%-86%)	31% (2%-65%)	0.067
∆%ADC75th	40% (20%-61%)	37% (0%-57%)	0.288
∆%ADC90th	27% (11%-58%)	9% (7%-119%)	0.061
∆skewness	–0.20 (–0.40–0.00)	0.49 (0.10–0.50)	< 0.0011
∆%kurtosis	41% (18%–54%)	2.5% (1.4%–5.9%)	< 0.0011
ROI ∆%ADCmean	55% (48%–60%)	23% (15%–30%)	0.0201

¹Statistically significant difference. ADC: Apparent diffusion coefficient; nCRT: Neoadjuvant chemoradiation therapy; ROI: Region of interest.

Table 4 Diagnostic performance of the best magnetic resonance imaging histogram derived parameters to detect responder patients

	Cutoff	Sensitivity	Specificity	PPV	NPV	Accuracy	AUC (95%CI)
∆%kurtosis	11.85%	94.4%	96.7%	94.4%	96.7%	96.0%	0.991 (0.925-1.000)
Post-nCRT kurtosis	0.78	93.3%	99.0%	90%	99.0%	96.0%	0.985 (0.957-1.000)
∆skewness	0.16	66.7%	99.0%	64.3%	99.0%	79.2%	0.885 (0.795-0.975)
Post-nCRT skewness	1.59	63.3%	99.0%	62.0%	99.0%	77.1%	0.815 (0.795-0.634)
Post-nCRT ADC10th	0.34×10-3 mm2/s	66.7%	73.3%	60.0%	79.0%	71.0%	0.681 (0.509-0.852)
∆%ADCmean	56.00%	56.0%	77.0%	56.0%	73.3%	66.7%	0.686 (0.500-0.820
∆%ADC10th	74.21%	61.1%	70.0%	55.0%	75.0%	66.7%	0.589 (0.483-0.815)
ROI ∆%ADCmean	55.00%	61.0%	69.0%	52.0%	72.0%	65.3%	0.583 (0.425-0.715)

ADC: Apparent diffusion coefficient; AUC: Area under the receiver operating characteristic curve; nCRT: Neoadjuvant chemoradiation therapy; NPV: Negative predictive value; PPV: Positive predictive value; ROI: Region of interest.

Table 5 Diagnostic odds ratios of magnetic resonance imaging parameters in differentiating respond and non- respond patients in locally advanced rectal cancer

	Diagnostic odds ratio	95%CI
∆%kurtosis	376.0	228.9-842.1
Post-nCRT kurtosis	375.3	225.7-887.7
∆skewness	192.2	69.0-253.3
Post-nCRT skewness	168.6	54.0-251.7
Post-nCRT ADC10th	5.48	1.0-19.6
∆%ADCmean	4.26	1.0-14.4
∆%ADC10th	3.65	1.0-12.5
ROI ∆%ADCmean	3.47	1.0-11.2

ADC: Apparent diffusion coefficient; nCRT: Neoadjuvant chemoradiation therapy; ROI: Region of interest.

Table 6 Intraobserver variability

		ICC	95%CI
Basal
Test1 and test2, reader1	ROI ADCmean	0.850	0.742–0.800
Test1 and test2, reader2	ROI ADCmean	0.890	0.850-0.820
After treatment
Test1 and test2, reader1	ROI ADCmean	0.800	0.750-0.819
Test1 and test2, reader2	ROI ADCmean	0.823	0.800-0.850
Basal
Test1 and test2, reader1	ADCmean	0.850	0.756-0.920
Test1 and test2, reader2	ADCmean	0.777	0.745-0.812
After treatment
Test1 and test2, reader1	ADCmean	0.845	0.830-0.850
Test1 and test2, reader2	ADCmean	0.823	0.800-0.833
Basal
Test1 and test2, reader1	10th percentile	0.820	0.880-0.950
Test1 and test2, reader2	10th percentile	0.880	0.800-0.920
After treatment
Test1 and test2, reader1	10th percentile	0.780	0.740-0.853
Test1 and test2, reader2	10th percentile	0.853	0.723-0.901
Basal
Test1 and test2, reader1	25th percentile	0.803	0.800-0.922
Test1 and test2, reader2	25th percentile	0.863	0.801-0.895
After treatment
Test1 and test2, reader1	25th percentile	0.788	0.750-0.837
Test1 and test2, reader2	25th percentile	0.820	0.780-0.846
Basal
Test1 and test2, reader1	50th percentile	0.850	0.840-0.920
Test1 and test2, reader2	50th percentile	0.845	0.790-0.860
After treatment
Test1 and test2, reader1	50th percentile	0.821	0.800-0.913
Test1 and test2, reader2	50th percentile	0.833	0.800-0.897
Basal
Test1 and test2, reader1	75th percentile	0.821	0.790-0.860
Test1 and test2, reader2	75th percentile	0.859	0.820-0.920
After treatment
Test1 and test2, reader1	75th percentile	0.851	0.790-0.880
Test1 and test2, reader2	75th percentile	0.837	0.791-0.856
Basal
Test1 and test2, reader1	90th percentile	0.850	0.820-0.890
Test1 and test2, reader2	90th percentile	0.880	0.850-0.960
After treatment
Test1 and test2, reader1	90th percentile	0.831	0.800-0.902
Test1 and test2, reader2	90th percentile	0.901	0.850-0.975
Basal
Test1 and test2, reader1	Skewness	0.920	0.900-0.940
Test1 and test2, reader2	Skewness	0.901	0.880-0.923
After treatment
Test1 and test2, reader1	Skewness	0.931	0.920-0.950
Test1 and test2, reader2	Skewness	0.889	0.877-0.910
Basal
Test1 and test2, reader1	Kurtosis	0.920	0.890-0.950
Test1 and test2, reader2	Kurtosis	0.910	0.850-0.960
After treatment
Test1 and test2, reader1	Kurtosis	0.890	0.850-0.960
Test1 and test2, reader2	Kurtosis	0.880	0.840-0.982

ADC: Apparent diffusion coefficient; ICC: Intraclass correlation coefficient; ROI: Region of interest.

Table 7 Interobserver variability (intraclass correlation coefficient and 95% confidence intervals)

Pre-treatment	Reader one vs reader two	Post-treatment	Reader one vs reader two
ROI ADCmean	0.985 (1.900-0.999)	ROI ADCmean	0.889 (0.850-0.950)
ADCmean	0.989 (0.980–0.994)	ADCmean	0.990 (0.985-0.995)
10th percentile	0.972 (0.951–0.984)	10th percentile	0.992 (0.986–0.996)
25th percentile	0.970 (0.947–0.983)	25th percentile	0.950 (0.940-0.982)
50th percentile	0.986 (0.976–0.992)	50th percentile	0.987 (0.945-0.995)
75th percentile	0.989 (0.980–0.994)	75th percentile	0.990 (0.982–0.994)
90th percentile	0.989 (0.980–0.994)	90th percentile	0.972 (0.987–0.996)
Skewness	0.990 (0.982–0.994)	Skewness	0.993 (0.987–0.996)
Kurtosis	0.992 (0.986–0.995)	Kurtosis	0.972 (0.951–0.984)

ADC: Apparent diffusion coefficient; ROI: Region of interest.