Assessment of Response to Radiotherapy for Prostate Cancer: Value of Diffusion-Weighted MRI at 3 T
Abstract
OBJECTIVE. The objective of our study was to investigate the changes of apparent diffusion coefficient (ADC) values in prostate cancers before and after radiotherapy at 3 T using a phased-array coil.
MATERIALS AND METHODS. Forty-nine patients with biopsy-proven prostate cancer who received radiotherapy underwent diffusion-weighted imaging (DWI) at 3 T and were included in the study. Biopsies in all patients were performed before the initial MRI examination (range, 15–35 days before MRI; mean, 23.4 days). All 49 patients underwent DWI (b values = 0 and 1,000 s/mm2) before and 1–5 months after the completion of radiotherapy. The changes in ADC values were measured for cancers and benign tissues before and after therapy. Additionally, the changes in serum prostate-specific antigen (PSA) levels were evaluated before and after therapy.
RESULTS. A total of 57 cancers (peripheral zone, n = 45; transition zone, n = 12) were found in 46 patients. For the tumors, the mean ADC value after therapy (1.61 × 10–3 mm2/s) was increased compared with the mean ADC value before therapy (1.0 × 10–3 mm2/s) (p < 0.001). After radiotherapy, the mean ADC values of benign peripheral zones and of benign transition zones were statistically significantly decreased compared with those before radiotherapy (p < 0.05). Before treatment, a significant difference of ADC values between the tumors and benign tissues was found (p < 0.001), whereas there was no significant difference of ADC values between them after treatment (p > 0.1). The median PSA level after therapy (0.49 ng/mL) was decreased compared with the median PSA level before therapy (20.0 ng/mL).
CONCLUSION. With the use of a 3-T MR scanner, our preliminary results suggest that ADC values may be useful as an imaging biomarker for monitoring therapeutic response of prostate cancer to radiotherapy.
Introduction
Determination of the serum prostate-specific antigen (PSA) level has been widely used for screening, diagnosis, determination of prognosis, and selection of the appropriate treatment for men with clinically localized prostate cancer [1–4]. Radiotherapy for prostate cancer is currently one of the common treatment strategies if the cancer is detected at an early stage and invasive surgical resection can be avoided [5, 6]. After radiotherapy, monitoring PSA levels is used to determine the effectiveness of treatment as an early and accurate surrogate. However, PSA monitoring has been shown to have a limited role in defining cancer cure within the first 5 years after radiotherapy because, although a lower PSA nadir after radiotherapy has been associated with cancer cure, the treatment ultimately fails in 5–25% of patients—even in those with the most optimal biochemical response. In addition, the most appropriate biochemical definitions of treatment failure after radiotherapy remain controversial because of substantial differences in the diagnostic accuracies of biochemical levels for predicting clinical outcome. Moreover, no pattern of PSA kinetics after radiotherapy has conclusively differentiated between local and distant failure [7–9]. To the contrary, a functional MR technique such as diffusion-weighted imaging (DWI) may detect and localize prostate cancer before radiotherapy and then may provide qualitative or quantitative information for measuring therapeutic response in patients with prostate cancer during and after radiotherapy.
With the introduction of higher-field-strength MR scanners and the parallel imaging technique for prostate MRI, DWI has been shown to have several potential benefits for the assessment of tumor localization and staging. In comparison with the use of conventional MRI, DWI can noninvasively show the changes of cellularity in malignant tumors in the body; apparent diffusion coefficient (ADC) maps can show the mobility of water in tissues.
After the treatment of malignant tumors, the cellularity and cell membrane integrity in necrotic tumor cells are reduced and there is a subsequent increase in water mobility, whereas viable tumor cells restrict diffusion of water molecules. To date, several clinical studies on the usefulness of DWI as a measurement of treatment response have been reported [10–13]. For the evaluation of changes of ADC values after radiotherapy in localized prostate cancer, to our knowledge, few investigations have been reported [14]. Therefore, the purpose of this study was retrospectively to investigate the changes of ADC values in prostate cancers before and after radiotherapy at 3 T using a phased-array coil.
Materials and Methods
Patients
The ethics committee of our institute approved this study. Written informed consent was waived because of the retrospective nature of the analysis. Between January 2006 and May 2008, 49 patients with biopsy-proven prostate cancer underwent external beam radiotherapy and MR examinations at 3 T before and after radiotherapy in our hospital. The median patient age was 67.5 years (age range, 42–81 years).
Radiotherapy was administered at 2 Gy/fraction to a total dose of 66–74 Gy (median dose, 70 Gy) with the use of a 15-MV linear accelerator. Thirty-nine patients were treated with the use of 3D conformal radiotherapy to the prostate only or to the prostate and seminal vesicles. In 10 patients, a whole-pelvis irradiation dose of 46 Gy was administered, and an additional 20–28 Gy was administered to the prostate only or to the prostate and seminal vesicles using a cone-down boost technique.
All patients underwent a transrectal sonography–guided biopsy within 5 weeks before radiotherapy. Biopsies in all patients were performed before the initial MRI examination (range, 15–35 days; mean, 23.4 days). The median Gleason score before therapy was 7 (range, 4–10). Table 1 presents the distributions of Gleason scores. All MR scans were obtained before the start of radiotherapy and 1–5 months (mean, 3.5 months) after the completion of therapy. Twenty-seven patients received simultaneous hormone therapy.
| Gleason Score | No. of Patients (n = 49) |
|---|---|
| 4 | 3 |
| 5 | 0 |
| 6 | 10 |
| 7 | 20 |
| 8 | 11 |
| 9 | 3 |
| 10 | 2 |
Clinical response was determined from measurements of serum PSA levels. The mean serum PSA level was 42.5 ng/mL (range, 4.25–456 ng/mL) before biopsy and 0.87 ng/mL (range, 0.34–1.4 ng/mL) after the completion of radiotherapy.
MR Techniques
All images were collected using a 3-T MR system (Intera Achieva, Philips Healthcare) equipped with a phased-array coil (six-channel). All patients underwent DWI in addition to imaging studies using a routine prostatic MR protocol. Before undergoing scanning, each patient received an intramuscular injection of 20 mg of butyl scopolamine (Buscopan, Boehringer Ingelheim) to suppress bowel peristalsis; no bowel preparation was performed. T2-weighted turbo spin-echo images were acquired in three orthogonal planes (axial, sagittal, and coronal). The T2-weighted imaging parameters were as follows: TR range/TE range, 2,690–3,800/80–90; slice thickness, 3 mm; interslice gap, 0.3–1 mm; 512 × 304 matrix; field of view (FOV), 18 cm; number of signals acquired (NSA), 3; sensitivity-encoding (SENSE) factor, 2; voxel size, 0.35 × 0.59 × 3 mm; slice number, 20; and acquisition time of each plane, 4 minutes 22 seconds.
DW images were acquired in the axial plane using the single-shot echo-planar imaging technique. The scanning parameters were as follows: 2,740–2,750/83–85; slice thickness, 3 mm; interslice gap, 1 mm; matrix, 112 × 110; FOV, 20 cm; SENSE factor, 2; and NSA, 3. Diffusion-encoding gradients were applied as a bipolar pair at b values of 0 and 1,000 s/mm2 along the three orthogonal directions of motion-probing gradients. ADC maps were automatically constructed on a pixel-by-pixel basis (0 and 1,000 s/mm2). The acquisition time of DWI was within 2 minutes.
Data Analysis and ADC Measurement
All images were retrospectively analyzed in consensus by two genitourinary radiologists with 6 and 3 years of experience, respectively, who were aware of the clinical and histologic findings. Each reader had completed a genitourinary fellowship and had interpreted more than 700 MR examinations of the prostate at the time of the study.
The localization of prostate cancer was determined by consensus of the two readers based on a comparison of digital rectal examination findings, the pathologic results of biopsies, and the presence of a focal low-signal-intensity area in the peripheral zone and transition zone on ADC maps with or without the use of T2-weighted images. ADC maps were processed using workstation software (PRIDE tool, Philips Healthcare). With the use of MRIcro software (version 1.37, Rorden and Brett, 2000), ADC values in tumors and in the peripheral zone and transition zone of benign tissue before and after radiotherapy were calculated by placement of regions of interest (ROIs) (Fig. 1A, 1B). When the ROIs were drawn, great care was taken to exclude both the neurovascular bundle and the urethra to reduce any error in ADC calculations.
Before radiotherapy, ROIs of the tumors in the peripheral zone and transition zone were drawn on ADC maps to include as much of the tumor as possible. ADC values in tumors were assessed twice in the same site, and the average was calculated. If a tumor was located in several imaging slices of ADC maps, ADC values were measured on each image of the ADC maps and the average was calculated. Tumors with a transverse greatest diameter of more than 0.5 cm were included to reduce false-positive findings. High-resolution T2-weighted images corresponding to the ADC maps were observed in the transverse orientation to assist in the identification of the detailed anatomy of the prostate. For measurement of ADC values in the peripheral zone and transition zone of benign tissue, ROIs at the contralateral side of the tumor were selected. In three different sites of benign tissue, ADC values were measured and the average was calculated.
After the completion of radiotherapy, there was no visible residual tumor in most cases, particularly for patients with a good response. In this situation, the ROI was drawn on what was considered the normal residual prostate by two radiologists in consensus; usually the ROI was drawn in the same area as that initially used in the pretherapy MR examination. ROIs were assessed twice in the same site, and the average was calculated. For benign tissues, the ROIs were drawn on the same area that was initially used in preradiotherapy images, and the average was calculated.
Before radiotherapy, the mean ROIs were 208 mm2 for tumors (range, 10–979 mm2) and 28 mm2 for benign tissue (range, 17–43 mm2). After radiotherapy, the mean ROIs were 97.4 mm2 for tumors (range, 10–404 mm2) and 22 mm2 for benign tissue (range, 14–32 mm2).
Statistical Analysis
Statistical analysis was performed using SAS software (version 8, SAS Institute). The paired Student's t test was used to compare the ADC values of tumors and benign tissues before and after radiotherapy and to compare the mean PSA levels before and after radiotherapy. The comparison of mean ADC values of tumors and benign tissues before radiotherapy was performed using the paired Student's t test. A correlation in the degree of change between serum PSA levels and ADC values was performed by use of Pearson's correlation. Two-tailed tests were used to calculate all p values. A p value of < 0.05 was considered statistically significant.
Results
In 46 of 49 patients, 57 cancers (peripheral zone, n = 45; transition zone, n = 12) were found; in the remaining three patients, all of whom had a Gleason score of 4, no focal mass was seen on ADC maps. On the ADC maps obtained before therapy, the mean size of the tumors was 2.2 cm (range, 0.8–3.2 cm).
In 57 tumors of 46 patients, the mean ADC value before therapy was 1.0 × 10–3 mm2/s, which is significantly lower than the mean ADC value after therapy (1.61 × 10–3 mm2/s) (p < 0.001) (Table 2). After the completion of radiotherapy, there was no visible tumor in 42 patients. However, in the remaining four patients who had one tumor each, residual tumor was seen on ADC maps 1–5 months after the completion of radiotherapy. The mean ADC value of those tumors was 1.08 × 10–3 mm2/s.
| ADC Value × 10-3mm2/s, mean ± SD (range) | ||
|---|---|---|
| Time of ADC Measurement | Tumors | Benign Tissues |
| Before radiotherapy | ||
| Overall | 1.00 ± 0.19 (0.73-1.58)a | |
| Peripheral zone | 1.03 ± 0.20 (0.77-1.58)a | 2.05 ± 2.07 (1.58-2.72)b |
| Transition zone | 0.88 ± 0.13 (0.73,1.08)a | 1.72 ± 0.24 (1.24-2.27)b |
| After radiotherapy | ||
| Overall | 1.61 ± 0.27 (0.89-2.46) | |
| Peripheral zone | 1.62 ± 0.29 (0.89-2.47) | 1.77 ± 0.27 (1.35-2.48) |
| Transition zone | 1.57 ± 0.18 (1.31-1.91) | 1.59 ± 0.23 (1.22-2.33) |
a
Comparison of the mean ADC values of tumors before and after radiotherapy, p < 0.001.
b
Comparison of the mean ADC values of benign tissues before and after radiotherapy, p < 0.05.
Of the four patients with residual tumors, follow-up ADC maps obtained 7 months after the completion of radiotherapy showed that residual tumor had disappeared in two patients; however, in the other two patients who had one tumor each, the mean ADC value did not increase after radiotherapy. There was no change in one patient (from 0.96 × 10–3 before therapy to 0.96 × 10–3 mm2/s after therapy) and a decrease in the other patient (from 1.04 to 0.89 × 10–3 mm2/s) (Figs. 2 and 3A, 3B, 3C, 3D). These two patients showed a decrease in PSA level (from 21.12 ng/mL before therapy to 3.2 ng/mL after therapy and from 16.62 ng/mL before therapy to 12.09 ng/mL after therapy, respectively) and a considerable rise in PSA level after the completion of radiotherapy.
Before radiotherapy, the mean ADC values of tumors in both the peripheral zone and transition zone were statistically lower than the corresponding values of benign tissues (p < 0.001). After radiotherapy, a significant difference of ADC values between the tumors and benign tissues was not found (p > 0.1) (Table 2). The mean ADC values of the peripheral zone and transition zone of benign tissue were statistically decreased compared with the corresponding values before radiotherapy (p < 0.05).
Figure 4 shows the changes in PSA levels before and after radiotherapy. The median PSA level before therapy was 20.0 ng/mL, which is significantly higher than the median PSA level after therapy of 0.49 ng/mL (p < 0.001). A correlation in the degree of changes between the PSA levels and ADC values was not found (p > 0.05).
Discussion
DWI as a functional imaging technique can measure the mobility of water within tissues in addition to depicting tumor size and shape [15]. To date, several studies have shown that the ADC values of prostate cancer are lower than the ADC values of benign noncancerous tissue [16–19]. Changes in ADC values are inversely correlated with changes in cellularity: Increases in ADC values reflect an increase in the mobility of water through a decrease in cellular size or number, and decreases in ADC values reflect a decrease in free extracellular water by an increase of total cellular size or number, as can be seen with tumor progression, fibrosis, or edema [15, 20].
Takayama et al. [14] recently reported that ADC values of prostate cancer significantly increased after radiotherapy. In our study, DWI performed at 3 T with a phased-array coil was used to evaluate the changes of ADC values of prostate cancer before and after radiotherapy. As in the previous study [14], our results showed that the ADC values of prostate cancer increased statistically in both the peripheral zone and transition zone after radiotherapy. One potential explanation for this change was that an increase of the ADC after radiotherapy might be correlated with cellularity increases because of a decrease in the size and number of neoplastic glands, although tumors might still exist [21]. The results of our study for malignant tumors after therapy were found to be equivalent to those of previous studies for other malignant tumors after treatment such as hepatocellular carcinomas [22], rectal cancers [12], brain tumors [10, 11], and breast cancers [13].
Compared with the use of 1.5 T, the use of 3 T has several advantages [23]. Theoretically, the signal-to-noise ratio (SNR) increased twofold on moving from 1.5 to 3 T, and an increased SNR can be translated into improvements in spatial, temporal, and spectral resolution. A limited SNR at 1.5 T may impair MR sensitivity for subtle changes in ADC values of the prostate. The increase in SNR from 3-T imaging enables either an increase in spatial resolution or an increase in the SNR of the ADC maps, so a possible increase in the accuracy of MRI for prostate cancer localization and of the measurements of ADC values in prostate cancers using ROIs may be expected. Therefore, we think that the potential measurement error for tumor ADC values at 3 T might be lower than that at 1.5 T.
In our study, after undergoing radiotherapy of prostate cancer, all patients except two showed an increase in the mean ADC values of tumors in both the peripheral zone and the transition zone. In the remaining two patients, each of whom had one tumor, an increase in the ADC values was not shown: The ADC value of one tumor was slightly decreased, and the ADC value of the remaining tumor showed no change. As determined at subsequent follow-up of the two patients, local treatment had failed; the patients underwent salvage high-intensity focused ultrasound ablation.
As compared with a previous study [14] that showed no significant changes of ADC values in benign prostate tissue after radiotherapy, our results showed a statistically significant decrease in the ADC values for the peripheral zone and transition zone of benign noncancerous tissue. After radiotherapy, benign prostate tissue might show histologic changes of acinar distortion and atrophy as well as stromal fibrosis with granulation tissue formation that may cause a decrease of ADC values. Furthermore, a decrease of ADC values in benign prostate tissue after radiotherapy might result from a decrease in the extracellular space due to inflammatory swelling of cells associated with radiotherapy.
Before radiotherapy, the ADC values of prostate cancer in our study were lower than the corresponding values of noncancerous benign prostate tissue, as described in previous investigations [17–19, 24]. Lower ADC values in prostate cancer reflect the restriction of water mobility due to the dense, high cellularity of prostate cancer. Thus, prostate cancer possibly showing a higher ADC value was automatically excluded from this study because accurate localization of the cancer on ADC maps was not possible. In three patients in our study who had Gleason score 4, the use of DWI could not delineate localized prostate cancer and ADC values could not be measured.
In our study, the mean ROIs for tumors and benign tissue were different before and after radiotherapy. The reason is that the size and volume of the prostate were markedly decreased after radiotherapy as compared with before radiotherapy.
There are several limitations to this study. First, we did not perform frequent follow-up MR examinations in all patients. Patients underwent MR examinations before radiotherapy and 1–5 months after radiotherapy. As shown in previous studies of other body tumors, DWI findings can reflect cellular changes in malignant tissues earlier than 1–5 months after therapy, as early as 24 hours after treatment. For future studies, earlier and more frequent examinations should be performed during and after radiotherapy to assess the dynamic changes of ADC values. Second, all patients underwent a transrectal sonography–guided biopsy with the pretreatment MR examinations, which might have affected the ADC values in benign prostate tissues due to hemorrhage or inflammatory changes. Third, we could not evaluate for any correlation between MR images and histopathologic findings because we did not obtain surgical specimens. With the use of a preclinical animal study, a detailed correlation between MR images and histopathologic findings should be determined during or after radiotherapy. Fourth, this study was retrospective in design with the use of some different parameters such as TR and TE. These differences in imaging parameters might have affected ADC values of tumor and benign prostate tissues. Finally, the images in our study were interpreted by consensus of two readers instead of by separate analyses. However, the aim of this study was not to evaluate the diagnostic performance for detecting localized cancer on DWI but to determine ADC changes in prostate cancer and normal prostate tissue before and after radiotherapy using 3 T. Moreover, the interreader agreement of MRI including DWI is not perfect for the detection of localized prostate cancer. Thus, the localization of prostate cancer in this study was determined by consensus of two readers.
In conclusion, with the use of a 3-T MR scanner, our preliminary results suggest that ADC values may be useful as an imaging biomarker for monitoring therapeutic responses of prostate cancer to radiotherapy. However, larger, more definitive studies with clinical endpoints such as early response assessment within 7 days after the initiation of radiotherapy or pretherapeutic prediction of biochemical failure after radiotherapy should be performed.
Footnotes
Address correspondence to C. K. Kim ([email protected]).
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Submitted: August 31, 2009
Accepted: December 7, 2009
First published: November 23, 2012
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