Sophie F. Riches

Diffusion-weighted magnetic resonance imaging: a potential non-invasive marker of tumour aggressiveness in localized prostate cancer

AIM To evaluate diffusion-weighted magnetic resonance imaging (DW-MRI) as a marker for disease aggressiveness by comparing tumour apparent diffusion coefficients (ADCs) between patients with low- versus higher-risk localized prostate cancer. METHOD Forty-four consecutive patients classified as low- [n = 26, stageT1/T2a, Gleason score < or = 6, prostate-specific antigen (PSA)< 10 (group 1)] or intermediate/high- [n = 18, stage > or = T2b and/or Gleason score > or = 7, and/or PSA > 10 (group 2)] risk, who subsequently were monitored with active surveillance or started neoadjuvant hormone and radiotherapy, respectively, underwent endorectal MRI. T2-weighted (T2W) and DW images (5 b values, 0-800 s/mm(2)) were acquired and isotropic ADC maps generated. Regions of interest (ROIs) on T2W axial images [around whole prostate, central gland (CG), and tumour] were transferred to ADC maps. Tumour, CG, and peripheral zone (PZ = whole prostate minus CG and tumour) ADCs (fast component from b = 0-100 s/mm(2), slow component from b = 100-800 s/mm(2)) were compared. RESULTS T2W-defined tumour volume medians, and quartiles were 1.2 cm(3), 0.7 and 3.3 cm(3) (group 1); and 6 cm(3), 1.3 and 16.5 cm(3) (group 2). There were significant differences in both ADC(fast) (1778 +/- 264 x 10(-6) versus 1583 +/- 283 x 10(-6) mm(2)/s, p = 0.03) and ADC(slow) (1379 +/- 321 x 10(-6) versus 1196 +/- 158 x 10(-6) mm(2)/s, p = 0.001) between groups. Tumour volume (p = 0.002) and ADC(slow) (p = 0.005) were significant differentiators of risk group. CONCLUSION Significant differences in tumour ADCs exist between patients with low-risk, and those with higher-risk localized prostate cancer. DW-MRI merits further study with respect to clinical outcomes.

Combined Use of Diffusion-Weighted MRI and 1H MR Spectroscopy to Increase Accuracy in Prostate Cancer Detection

OBJECTIVE The objective of our study was to establish the sensitivity and specificity for prostate cancer detection using a combined 1H MR spectroscopy and diffusion-weighted MRI approach. SUBJECTS AND METHODS Forty-two men (mean age +/- SD, 69.3 +/- 4.7 years) with prostate cancer were studied using endorectal T2-weighted imaging, 2D chemical shift imaging (CSI), and isotropic apparent diffusion coefficient (ADC) maps. Regions of interest (ROIs) were drawn around the entire gland, central gland, and peripheral zone tumor, diagnostically defined as low signal intensity on T2-weighted images within a sextant that was biopsy-positive for tumor. Lack of susceptibility artifact on a gradient-echo B0 map through the slice selected for CSI and no high signal intensity on external array T1-weighted images confirmed the absence of significant hemorrhage after biopsy. CSI voxels were classified as nonmalignant or as tumor (ROI included > or = 30% or > or = 70% tumor). Choline-citrate (Cho/Cit) ratios and average ADCs were calculated for every voxel. A plot of Cho/Cit ratios versus ADCs yielded a line of best separation of tumor voxels from nonmalignant voxels. Receiver operating characteristic (ROC) curves were plotted for Cho/Cit ratios alone, ADCs alone, and a combination of the two. RESULTS The Cho/Cit ratios were significantly higher (p < 0.001) and the ADCs were significantly lower (p < 0.006) in tumor-containing voxels than in non-tumor-containing voxels. When voxels containing 30% or more tumor were considered positive, the area under the ROC curves using combined MR spectroscopy and ADC (0.81) was similar to that of Cho/Cit alone (0.79) and better than ADC alone (0.66). When voxels containing 70% or more tumor were considered positive and cutoffs to achieve a 90%-or-greater sensitivity chosen, a combination of Cho/Cit and ADC achieved a significant improvement in specificity compared with Cho/Cit alone (p < 0.0001) or ADC alone (p < 0.0001). CONCLUSION When voxels containing > or = 70% tumor are considered positive, the combined use of MR spectroscopy and diffusion-weighted MRI increases the specificity for prostate cancer detection while retaining the sensitivity compared with MR spectroscopy alone or diffusion-weighted MRI alone.

A Study of Diffusion-Weighted Magnetic Resonance Imaging in Men with Untreated Localised Prostate Cancer on Active Surveillance

BACKGROUND Markers that predict the behaviour of localised prostate cancer are needed to identify patients that require treatment. OBJECTIVE We have analysed the apparent diffusion coefficient (ADC) generated from diffusion-weighted magnetic resonance imaging (DW-MRI) with respect to repeat biopsy findings and time to radical treatment in patients in a prospective study of active surveillance. DESIGN, SETTING, AND PARTICIPANTS Some 86 men recruited between 2002 and 2006 were followed for a median of 29 mo. Patients had clinical stage T1/T2a N0/Nx M0/Mx adenocarcinoma of the prostate, prostate-specific antigen (PSA) level<15 ng/ml, Gleason score≤7, primary Gleason grade≤3, and positive biopsy cores (pbc)≤50%. MEASUREMENTS All patients had DW-MRI in addition to standard MRI sequences. Tumour regions of interest (ROIs) were identified using T2-weighted fast-spin echo images as focal areas of restricted diffusion. Univariate analyses including all clinical variables and tumour ADC data were performed with respect to repeat biopsy findings and time to radical treatment. Receiver operating curves (ROC) compared predictive variables. RESULTS AND LIMITATIONS Patients in the study had a median age of 66 yr and a median initial PSA level of 6.7 ng/ml. Some 39 patients (45%) received deferred radical treatment, and 34 patients (40%) had adverse histology on repeat biopsy. According to univariate analysis, tumour ADC was a significant predictor of both adverse repeat biopsy findings (p<0.0001; hazard ratio [HR]: 1.3; 95% confidence interval [CI]: 1.1-1.6), and time to radical treatment (p<0.0001; HR: 1.5; 95% CI: 1.2-1.8). ROC curves for ADC showed an area under the curve (AUC) of 0.7 for prediction of adverse repeat biopsy findings and an AUC of 0.83 for prediction of radical treatment. CONCLUSIONS In patients with low-risk, localised disease, tumour ADC on DW-MRI may be a useful marker of prostate cancer progression and may help to identify patients who stand to benefit from radical treatment. This possibility warrants further study.

Diffusion-weighted imaging of the prostate and rectal wall: comparison of biexponential and monoexponential modelled diffusion and associated perfusion coefficients

This study compares parameters from monoexponential and biexponential modelling of diffusion‐weighted imaging of normal and malignant prostate tissue and normal rectal wall tissues. Fifty men with Stage Ic prostate cancer were studied using endorectal T2‐weighted imaging and diffusion‐weighted imaging with 11 diffusion‐sensitive values (b‐values = 0, 1, 2, 4, 10, 20, 50, 100, 200, 400, 800 s/mm2). Regions of interest were drawn within non‐malignant central gland and peripheral zone, malignant prostate tissue and normal rectal wall tissue. Both a monoexponential and biexponential model was fitted over various b‐value ranges, giving an apparent diffusion coefficient (ADC) from the monoexponential model and a diffusion coefficient, perfusion coefficient and perfusion fraction from the biexponential model. In all tissues, over the full range of b‐values, the ADC from the monoexponential model was significantly higher than the corresponding diffusion coefficient from the biexponential model. As the minimum b‐value increased, the ADC decreased and was equal to the diffusion coefficient for some b‐value ranges. The biexponential model best described the data when low b‐values were included, suggesting that there is a fast perfusion component. Neither model could distinguish between benign prostate tissues on the basis of diffusion coefficients, but the rectal wall tissue and malignant prostate tissue had significantly lower diffusion coefficients than normal prostate tissues. Perfusion coefficients and fractions were highly variable within the population, so their clinical utility may be limited, but removal of this variable perfusion component from reported diffusion coefficients is important when attributing clinical differences to diffusion within tissues. Copyright

MRI in the Detection of Prostate Cancer: Combined Apparent Diffusion Coefficient, Metabolite Ratio, and Vascular Parameters

OBJECTIVE The purpose of this study was to compare apparent diffusion coefficients, metabolic ratios, and vascularity values within histologically defined prostate tumors with those in nontumor tissue to determine which functional parameter or combination of parameters is best for differentiating tumor from nontumor tissue. SUBJECTS AND METHODS Twenty patients due for prostatectomy underwent endorectal MRI at 1.5 T. Transverse T2-weighted, diffusion-weighted, 2D chemical shift, and dynamic contrast-enhanced images were acquired. After prostatectomy, the gland was sectioned transversely. Fresh slices and stained whole-mount sections with histologically defined tumor outlines were photographed. The tumor outlines were mapped onto images, and the apparent diffusion coefficient (ADC), choline-to-citrate (Cho/cit) ratio, and vascularity of the histologically defined tumor, normal peripheral zone, and central gland were quantitatively measured. Area under the receiver operating characteristics (ROC) curve (A(z)) was used to determine the sensitivity and specificity of parameter combinations in cancer detection. RESULTS In tumor regions larger than 1 cm(2), the Cho/cit ratio was higher in tumor than in nontumor tissue (p < 0.001), in the peripheral zone alone (p = 0.007), and in the central gland alone (p = 0.005). ADC was lower and tumor vascularity greater in tumor than in nontumor tissue (ADC, p = 0.003; initial area under the gadolinium plasma concentration-time curve [initial gadolinium AUC], p = 0.012; forward rate constant [K(trans)], p = 0.011; return rate constant [k(ep)], p = 0.036). No single parameter had a significantly greater A(z) (ADC, 0.71; Cho/cit ratio, 0.79; initial gadolinium AUC, 0.60; K(trans), 0.62; k(ep), 0.65). Pairs of parameters, however, did increase A(z): ADC and initial gadolinium AUC (A(z) = 0.94) versus ADC (p = 0.001) and initial gadolinium AUC (p < 0.001); ADC and Cho/cit ratio (A(z) = 0.94) versus ADC (p = 0.001) and Cho/cit ratio (not significant); and Cho/cit ratio and initial gadolinium AUC (A(z) = 0.88) versus Cho/cit ratio (not significant) and initial gadolinium AUC (p < 0.001). All three functional techniques together had an A(z) of 0.95, showing no further improvement. CONCLUSION The combination of two functional parameters is associated with significant improvement in prostate cancer detection over use of any parameter alone. Use of a third parameter does not increase the rate of detection.

Relationship Between Imaging Biomarkers of Stage I Cervical Cancer and Poor-Prognosis Histologic Features: Quantitative Histogram Analysis of Diffusion-Weighted MR Images

OBJECTIVE The purpose of this study was to determine whether histogram analysis of apparent diffusion coefficient (ADC) values from diffusion-weighted MRI can be used to differentiate cervical tumors according to their histologic characteristics. SUBJECTS AND METHODS Sixty patients with International Federation of Gynecology stage I cervical cancer underwent MRI at 1.5 T with a 37-mm-diameter endovaginal coil. T2-weighted images (TR/TE, 2000-2368/90) followed by diffusion-weighted images (TR/TE, 2500/69; b values, 0, 100, 300, 500, and 800 s/mm(2)) were acquired. An expert observer drew regions of interest around a histologically confirmed tumor on ADC maps by referring to the T2-weighted images. Pixel-by-pixel ADCs were calculated with a monoexponential fit of data from b values of 100-800 s/mm(2), and ADC histograms were obtained from the entire tumor volume. An independent samples Student t test was used to compare differences in ADC percentile values, skew, and kurtosis between squamous cell carcinoma and adenocarcinoma, well or moderately differentiated and poorly differentiated tumors, and absence and presence of lymphovascular space invasion. RESULTS There was no statistically significant difference in ADC percentiles between squamous cell carcinoma and adenocarcinoma, but the median was significantly higher in well or moderately differentiated tumors (50th percentile, 1113 ± 177 × 10(-6) mm(2)/s) compared with poorly differentiated tumors (50th percentile, 996 ± 184 × 10(-6) mm(2)/s) (p = 0.049). Histogram skew was significantly less positive for adenocarcinoma compared with squamous cell carcinoma (p = 0.016) but did not differ between tumor grades. There was no significant difference between any parameter with regard to lymphovascular space invasion. CONCLUSION Median ADC is lower in poorly compared with well or moderately differentiated tumors, while lower histogram-positive skew in adenocarcinoma compared with squamous cell carcinoma is likely to reflect the glandular content of adenocarcinoma.

Diffusion-weighted magnetic resonance imaging for monitoring prostate cancer progression in patients managed by active surveillance

OBJECTIVES We studied patients managed by active surveillance to determine whether there was a difference over time in apparent diffusion coefficients (ADCs) derived from diffusion-weighted MRI in those who progressed to radical treatment (progressors, n = 17) compared with those who did not (non-progressors, n = 33). METHODS 50 consecutive patients (Stage T1/2a, Gleason grade ≤ 3+4, prostate-specific antigen (PSA) <15 ng ml⁻¹, <50% cores positive) were imaged endorectally (baseline and 1-3 years follow-up) with T₂ weighted (T₂W) and echo-planar diffusion-weighted MRI sequences. Regions of interest drawn on ADC maps with reference to the T₂W images yielded ADC(all) (b = 0-800), ADC(fast) (b = 0-300) and ADC(slow) (b = 300-800) for whole prostate (minus tumour) and tumour (low signal-intensity peripheral zone lesion in biopsy-positive octant). RESULTS Tumour and whole prostate ADC(all) and ADC(fast) were significantly reduced over time in progressors (p = 0.03 and 0.03 for tumours, respectively; p = 0.02 and 0.007 for the whole prostate, respectively). There were no significant changes in ADC over time in non-progressors. A 10% reduction in tumour ADC(all) indicated progression with a 93% sensitivity and 40% specificity (A(z) of receiver operating characteristic (ROC) curve = 0.68). Percentage reductions in whole prostate ADC(all), ADC(fast) and ADC(slow) were also significantly greater in progressors than in non-progressors (p = 0.01, 0.03 and 0.008, respectively). CONCLUSION This pilot study shows that DW-MRI has potential for monitoring patients with early prostate cancer who opt for active surveillance.

Apparent Diffusion Coefficient as a Predictive Biomarker of Prostate Cancer Progression: Value of Fast and Slow Diffusion Components

OBJECTIVE The purpose of our study was to investigate whether fast and slow components of the apparent diffusion coefficient (ADC) from diffusion-weighted MR images could predict prostate cancer progression in patients managed by active surveillance. SUBJECTS AND METHODS Eighty-one patients managed by active surveillance underwent diffusion-weighted MRI in addition to T2-weighted MRI using an endorectal technique. ADCs from tumor regions of interest were calculated using all b values (ADC(all)), b = 0-300 s/mm(2) (ADC(fast)), and b = 300-800 s/mm(2) (ADC(slow)). These parameters and tumor volumes were compared in those upgraded at subsequent biopsy (n = 14) versus those histologically stable (n = 41) and in evaluable patients who progressed to radical treatment (n = 16) versus those who did not (n = 64). Coxs regression was used to analyze the effect of parameter mean on time to treatment. RESULTS ADC(all), ADC(fast), and ADC(slow) in patients upgraded on repeat biopsy were significantly lower than those who were stable (1,070 ± 110 vs 1,356 ± 357 × 10(-6)mm(2)/s, p < 0.001; 1,283 ± 188 vs 1,526 ± 397 × 10(-6)mm(2)/s, p = 0.004; 843 ± 74 vs 1,105 ± 285 × 10(-6) mm(2)/s, p < 0.001, respectively). Tumor volume was significantly higher in the upgraded group (0.86 ± 0.9 vs 0.26 ± 0.25 cm(3), p = 0.02). The lower ADC(slow) in patients who subsequently progressed to radical treatment approached significance (922 ± 256 vs 1,054 ± 235 × 10(-6) mm(2)/s, p = 0.053; hazard ratio, 0.991 for time to treatment). Tumor volume was significantly higher in the treated group (0.86 ± 0.85 cm(3) vs 0.32 ± 0.33 cm(3), p = 0.02). ADC(slow) and tumor volume were significant but independent predictors of upgrade on biopsy (p = 0.01 and 0.002, respectively). CONCLUSION Both fast and slow diffusion components were significantly lower in tumors that were subsequently upgraded on histology. Both tumor volume and the true diffusion ADC(slow) were significant but independent predictors of histologic progression.

Diffusion-Weighted MRI for Locally Recurrent Prostate Cancer After External Beam Radiotherapy

OBJECTIVE The objectives of our study were to establish the apparent diffusion coefficients (ADCs) of tumor and nontumor irradiated tissues in patients with suspected postradiation recurrence of prostate cancer and to determine the sensitivity and specificity of a combination of T2-weighted and diffusion-weighted imaging (DWI) for detecting local recurrence. MATERIALS AND METHODS Twenty-four patients with rising prostate-specific antigen levels after having completed radiation therapy 30-130 months earlier (median, 62 months) underwent endorectal T2-weighted imaging and DWI (b = 0, 100, 300, 500, and 800 s/mm(2)) followed by transrectal ultrasound (TRUS)-guided biopsy. Images were scored prospectively as positive for tumor if a region of low signal intensity on T2-weighted imaging within the prostate corresponded with a focally restricted area on the ADC map. A region of interest (ROI) was drawn around the suspicious lesion on a single slice of the ADC map and a corresponding ROI was drawn around presumed nontumor irradiated peripheral zone and central gland tissues on the opposite side of the prostate. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were determined against TRUS-guided biopsy reference standard (octant, n = 17; sextant, n = 5; two samples, n = 1; 12 samples, n = 1). RESULTS Sixteen of 24 patients (66.7%) had positive histology findings. The median tumor ROI area was 0.37 cm(2) (quartiles, 0.30 and 0.82 cm(2)). The sensitivity, specificity, PPV, and NPV for detecting tumor were 93.8%, 75%, 88.2%, and 85.7%, respectively. A cutoff ADC of 1216 × 10(-6) mm(2)/s could predict tumor with 100% sensitivity and 96% specificity (area under the receiver operating characteristic curve = 0.992). CONCLUSION An ADC derived from DWI is a useful adjunct to T2-weighted MRI for detecting local tumor recurrence larger than 0.4 cm(2) within the prostate.

Nine-year Follow-up for a Study of Diffusion-weighted Magnetic Resonance Imaging in a Prospective Prostate Cancer Active Surveillance Cohort

BACKGROUND In active surveillance (AS) for prostate cancer there are few data on long-term outcomes associated with novel imaging markers. OBJECTIVE To determine long-term outcomes with respect to the apparent diffusion coefficient (ADC) derived from diffusion-weighted magnetic resonance imaging (DW-MRI) in a prospective AS cohort. Early results have already been published; we now present findings with long-term follow-up. DESIGN, SETTING, AND PARTICIPANTS A subset of patients (n=86) underwent pre-enrolment DW-MRI in a prospective AS study between 2002 and 2006. Inclusion criteria were untreated prostate cancer, clinical T1/T2a/N0M0, Gleason ≤ 3+4, and prostate-specific antigen (PSA) <15 ng/ml. Protocol follow-up was by biopsy at 18-24 mo and then every 24 mo, with regular PSA measurement. INTERVENTION Men underwent baseline DW-MRI in addition to standard sequences. ADC was measured from the index lesion on T2-weighted images. To avoid influencing treatment decisions, DW-MRI sequence results were not available to the AS study investigators. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Baseline ADC was analysed with respect to time to radical treatment (TRT) and time to adverse histology (TAH). Kaplan-Meier analysis and univariate and multivariate regression analyses were performed. RESULTS AND LIMITATIONS The median follow-up was 9.5 yr (interquartile range 7.9-10.0 yr). On univariate analysis, ADC below the median was associated with shorter TAH (hazard ratio [HR] 2.13, 95% confidence interval [CI] 1.17-3.89; p<0.014) and TRT (HR 2.54, 95% CI 1.49-4.32; p<0.001). Median TRT was 9.3 yr (95% CI 7.0-11.6 yr) for patients with ADC above the median and only 2.4 yr (95% CI 1.5-6.0 yr) for ADC below the median. For TRT, addition of ADC to a multivariate model of baseline variables resulted in a significant improvement in model fit (HR 1.33, 95% CI 1.14-1.54; p<0.001). Receiver operating characteristic analysis for TRT revealed an area under the curve of 0.80 (95% CI 0.70-0.88). The number of variables included in the multivariate model was limited by sample size. CONCLUSIONS Long-term follow-up for this study provides strong evidence that ADC is a useful marker when selecting patients for AS. Routine DW-MRI is now being evaluated in our ongoing AS study for initial assessment and as an alternative to repeat biopsy. PATIENT SUMMARY Before entering a study of close monitoring for the initial management of prostate cancer, patients had a type of magnetic resonance imaging scan that looks at the movement of water within cancers. These scans may help in predicting whether patients should receive close monitoring or whether immediate treatment should be given.