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Use of MRI and spectroscopy in evaluation of external beam radiotherapy for prostate cancer
Int. J. Radiation Oncology Biol. Phys., Vol. 60, No. 4, pp. 1047–1055, 2004 Copyright © 2004 Elsevier Inc. Printed in the USA. All rights reserved 0360-3016/04/$–see front matter
doi:10.1016/j.ijrobp.2004.05.015
CLINICAL INVESTIGATION
Prostate
USE OF MRI AND SPECTROSCOPY IN EVALUATION OF EXTERNAL BEAM RADIOTHERAPY FOR PROSTATE CANCER BARBY PICKETT, M.S.,* JOHN KURHANEWICZ, PH.D.,† FERGUS COAKLEY, M.D.,† KATSUTO SHINOHARA, M.D.,‡ BEVERLY FEIN, M.S.R.N.,† AND MACK ROACH III, M.D.*‡ Departments of *Radiation Oncology, †Radiology, and ‡Urology, University of California, San Francisco, School of Medicine, San Francisco, CA Purpose: To characterize the metabolic response in the prostate, the time to resolution of disease, and the correlation between magnetic resonance imaging (MRI) with spectroscopy (MRSI) results, biopsy findings, and serum prostate-specific antigen (PSA) level after external beam radiotherapy. Methods and Materials: A total of 55 patients underwent MRSI before and/or at varying times after external beam radiotherapy. The percentage of the cancerous, healthy, and atrophic voxels was calculated, and the time to resolution of disease was determined and compared with the PSA nadir. Results: Of the 55 patients, 70% had negative MRSI and 30% had positive MRSI findings. A strong correlation was found between negative MRSI and negative biopsy findings (n ⴝ 11) and between positive MRSI and positive biopsy findings (n ⴝ 7). A weak correlation was observed between the PSA level and the MRSI and biopsy findings. The mean time to disease resolution was 40.3 months and the mean time to PSA nadir was 50 months. With time, an increase in atrophy and a decline in cancerous metabolism was found. Conclusion: When used in conjunction with PSA measurement and biopsy, the results of this study suggest that MRSI contributes to a greater level of confidence in determining the outcome and may be a useful adjunct for assessing local control before PSA failure when striving to distinguish the benign “blip” from local recurrence. © 2004 Elsevier Inc. Magnetic resonance imaging, Spectroscopy, Prostate cancer, External beam radiotherapy.
The serum prostate-specific antigen (PSA) test is the most commonly used method of confirming resolution of prostate cancer after definitive radiotherapy (RT). PSA testing is universally used and considered to be a fairly reliable and inexpensive determination of treatment outcome (1). However, bouncing PSA values are common after external beam RT (EBRT) (2). At least one study has suggested that patients with a “bouncing” PSA level tend to present with greater pretreatment PSA levels and that, at 5 years, those with PSA bounces tend to have lower biochemical control rates than patients without (52% vs. 69%, p ⫽ 0.0024). However, because nearly one-half of patients with a bouncing PSA level have disease control, a bouncing PSA level cannot be considered a reliable indicator of relapse. The use of PSA testing to monitor therapeutic efficacy is also not ideal, because PSA is not specific for local recurrences of prostate cancer. Additionally, it can sometimes take ⬎4 years for PSA results to reach a nadir after EBRT
(3). Even when a nadir is achieved, it is often difficult to interpret (1, 4). The PSA response data are difficult to interpret for patients undergoing hormonal deprivation therapy because of the direct effect on PSA production. To date, conventional imaging methods, including transrectal ultrasonography (TRUS), computed tomography (CT), and magnetic resonance imaging (MRI) cannot reliably distinguish healthy from malignant tissue after therapy owing to the induced changes in tissue structure (5). Magnetic resonance imaging with spectroscopy (MRSI) is being used more frequently in patients with newly diagnosed prostate cancer for tumor localization and staging (6). Before therapy, prostate cancer can be identified on the basis of the low-signal intensity on T2-weighted images, the significantly elevated choline/creatine ratios, and the reduced citrate and polyamine peaks on MRSI (6). It is the concordance of the metabolic findings provided by MRSI and the morphologic findings provided by MRI that results in the most confident identification of prostate cancer (7). The regions of cancer defined by combined MRI/MRSI can
Reprint requests to: Barby Pickett, M.S., Department of Radiation Oncology, University of California, San Francisco, School of Medicine, 1600 Divisadero St., H1031, San Francisco, CA 941431708. Tel: (415) 353-7191; Fax: (415) 353-9887; E-mail: [email protected]
Presented at the 45th ASTRO Meeting, Salt Lake City, UT, 2003. Supported by Grants NIH R01-CA79980 and Grant R01CA59897. Received Jan 6, 2004, and in revised form Apr 29, 2004. Accepted for publication May 10, 2004.
INTRODUCTION
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also be registered with CT images for more accurate tumor localization, treatment planning, and visualization of isodose distributions (8). We have previously reported that MRSI may be of value in determining successful treatment after permanent prostate seed implantation (9). Recently we have begun using MRI/MRSI to monitor patients after EBRT. After therapy, the ability to identify prostate cancer on MRI is reduced owing to a diffuse reduction in the T2-weighted signal. The levels of citrate and polyamines are also dramatically reduced on MRSI (6). However, residual prostate cancer can still be identified by a relative increase in the choline/creatine ratio. MRSI can also provide a quantitative measure of successful therapy with the indication of “metabolic atrophy” or lack of cancer. Metabolic atrophy has previously been defined as “spectra containing no significant metabolite peaks, specifically spectra having peak area/ noise ratios of ⬍5 for choline, polyamines, creatine, and citrate” (10). The present study was based on the hypothesis that metabolic atrophy is indicative of successful treatment because growth of normal or abnormal cells cannot occur without metabolism. Therefore, disease resolution (negative MRSI findings), the primary indicator in this study, may be indicative of effective EBRT. A previous study examining the time to metabolic atrophy for permanent prostate implantation patients has suggested that complete metabolic atrophy (CMA) is expected for brachytherapy patients. However, because the dose is much lower in EBRT patients, the time to CMA may not be a suitable endpoint and the time to resolution of disease (TRD) might be more appropriate. The significantly greater prescribed dose used for permanent prostate implantation (144 Gy) vs. for EBRT (68 – 81 Gy) appears to be a contributing factor in achieving CMA. Our purpose, therefore, was to characterize the TRD after EBRT using combined MRI/MRSI studies compared with the results of biopsy and the time to reach a nadir PSA (nPSA). METHODS AND MATERIALS Patient selection The data of patients treated at the University of California, San Francisco, Medical Center between May 1995 and October 2001 were cross-referenced with the MRI/MRSI database to identify patients with pretreatment MRI/MRSI studies and/or posttreatment MRI/MRSI studies as an initial starting point for patient selection. Successful recruitment to this study was complicated by several factors, including the availability of research MRSI times, patients living out of the area, patient discomfort, and those lost to follow-up. All patients included in this study had undergone PSA testing before EBRT and at varying times after treatment. All patients were screened for contraindications and agreed to participate in the institutional review board–approved MRI/MRSI study governed by Health Insurance Portability and Accountability Act (HIPPA) regulations and standards (11). Ultimately, 55 patients were registered for participation. For the purposes of this protocol, we decided that
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patients would be followed until achieving the primary endpoint defined as negative MRSI findings; a positive MRSI study was defined as the presence of an elevated choline/creatine ratio of ⱖ1.5 in three or more contiguous voxels. Patient exclusion All patients interested in participation were initially registered but some were excluded for refusal to return for follow-up studies, claustrophobia, onset of long-term HT prescribed by their primary care physician, and other contraindications specific to MRI safety and rectal area integrity. Each patient was screened for metallic devices and foreign objects and was excluded from entering the MRI suite if any of the following situations existed: some types of penile implants, vascular clips in the brain or body surgically placed within a 6-month period, cardiac pacemakers, and any metal foreign bodies that could have an adverse effect on the patient while he was in the magnet. Hip replacements, although usually made MRI compatible, were found to be directly in the field of the prostate and caused image and spectroscopy artifacts, rendering the data unusable. Patients with current rectal bleeding, painful rectal fissures, Crohn’s disease, ulcerative colitis, rectal procedures requiring end-to-end anastomosis, or a high likelihood of rectal perforation from endorectal probe insertion were also considered ineligible. Patients referred to the magnetic resonance imaging center for participation in a grant-funded protocol were screened for these contraindications before recommendation. EBRT technique Patients were treated with forward planned, static field, intensity-modulated RT or three-dimensional conformal photon beams. Patients with ⬎15% lymph node involvement were treated with four pelvic fields (anterior, posterior, and right and left lateral) used to incorporate the nodes at risk (12). Three-dimensional planning was used to design the posterior lateral margins, minimizing the dose to the rectal wall. Dose–volume histograms determined the weighting of the treated fields. The first conedown treatment to the prostate and seminal vesicles included 18- and 6-MV photon beams to deliver a coplanar arrangement about a second isocenter with the angles distributed 35° anterior and posterior to the lateral gantry position. An anterior field was used to produce a more conformal distribution, minimizing the dose to the femoral heads, but minimally weighted to maintain ⬍50 Gy to 40% of the rectal wall. The lateral beams were heavily weighted for additional rectal wall sparing (13). The prostate and seminal vesicles were treated to 54 Gy (an additional 9 Gy), followed by a second conedown to the prostate only for a final prescribed minimal dose between 68 and 81 Gy. The wide variation in the total minimal dose reflected ongoing departmental and Radiation Therapy Oncology Group protocols and the ability to identify cancer within the prostate for static field, intensity-modulated RT. MRSI was used in 47% of the patients to define the pretreatment tumor
MRSI in evaluation of EBRT for prostate cancer
location in the prostate, referred to as the dominant intraprostatic lesion (14). The doses to the dominant intraprostatic lesion in these patients were escalated to ⬎81 Gy while concurrently delivering a dose of 72–75.6 Gy to the entire prostate. Multileaf collimation and dynamic wedging were used to minimize the patient treatment (beam-on) time. All patients were followed until presentation of negative MRSI studies, biopsy proven recurrence, or metastatic disease. Patient characteristics Fifty-five patients were registered in the study. Of these, 26% had Stage T3 disease and received long-term hormonal therapy (LTHT), 66% had Stage T2 and received short-term neoadjuvant HT (STHT) before EBRT, and 8% had Stage T1 and received EBRT alone. Of the 55 patients, 60% had a Gleason score of ⱕ6, 24% had a Gleason score of 7, and 16% had a Gleason score of ⱖ8. The prescribed minimal dose ranged from 68.4 to 81 Gy, with the maximal dose ranging from 76.2 to 97 Gy. In 18% of the men, forwardplanned EBRT was used concurrently to treat the MRSIdefined cancer to ⬎81 Gy (14). All patients were assessed by MRSI after recovery of testosterone. All patients underwent at least one posttreatment MRSI study, with the TRD measured from the end of EBRT. All patients in the study were reviewed in multidisciplinary MRI/ MRSI conferences, at which time the results were individually assessed for the presence of residual/recurrent cancer. If either the MRI or MRSI data demonstrated evidence of residual disease or the spectra proved to have an inconclusive or a borderline reading, the patient was followed further. Hormonal therapy Our institutional policy regarding the selection of patients for HT in conjunction with EBRT has been previously described (15). HT was discouraged in patients considered low risk, incorporated into the treatment regimen for 4 months for intermediate-risk patients, and incorporated into the treatment regimen for 2 years as adjuvant therapy in high-risk patients. When STHT was prescribed, it generally began 2 months before RT and was discontinued at RT completion. For this study, we paid close attention to the dates HT was started and completed. All men had resolution of all HT-induced symptoms (e.g., “hot flashes”) and/or recovery of testosterone before participation in the study. Prior studies following the course of the metabolic changes after HT have demonstrated a dramatic time-dependent decrease in metabolism, with most men demonstrating a loss of all MRSI-detectable metabolism by 6 months after the initiation of combined HT (10). The metabolic recovery of prostatic metabolism after cessation of HT is also time dependent (16). Additionally, very STHT (ⱕ2 months) has a much less dramatic effect on prostate metabolism (17), and it appears that metabolic recovery is faster with shorter durations of therapy. Three-dimensional MRSI acquisition Three-dimensional proton MRSI was performed using a water and lipid-suppressed double-spin echo point resolved
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spectroscopy (PRESS) sequence (18). The PRESS volume was selected to maximize coverage of the prostate while minimizing inclusion of periprostatic fat and rectal air. Six pairs of very selective outer-volume saturation bands were placed around the prescribed PRESS volume before excitation to improve volume selection further, and three pairs of very selective outer-volume saturation bands were graphically placed to conform the PRESS-selected volume to the shape of the prostate (19). Magnetic field homogeneity was optimized for the selected volume using both automated and manual shimming until a water line width of ⱕ10 Hz was attained. Water and lipid suppression was achieved using either band selective inversion with gradient dephasing pulses or spectral-spatial pulses (20). Data sets were acquired as 16 ⫻ 8 ⫻ 8 phase-encoded spectral arrays (1024 voxels), with a nominal spectral resolution of 0.3 cm3, TR/TE of 1000 ms/130 ms, and 17-min acquisition time. The total examination time was 1 h, including coil placement and patient positioning. Spectroscopic data were processed using a combination of in-house and Interactive Data Language (IDL) (Research Systems, Boulder, CO) software tools. Spectral data were apodized with a 2-Hz gaussian function and Fourier transformed in the time domain and three spatial domains. The resulting data were zero-filled once in the time domain (1024 data points), after which the center 50% of each spectrum was extracted to give 512 data points across a 625-Hz spectral width. Spectra were automatically phased, baseline corrected, and frequency aligned, and the metabolites of interest (i.e., creatine, choline, polyamines, and citrate) were integrated to determine their relative peak areas. The peak area/spectral noise ratios were also calculated for all prostate metabolites (20). Three-dimensional MRSI data analysis Spectroscopic voxels lacking any metabolites and thus having peak area/noise ratios of ⬎5 were considered to be metabolically atrophic. Spectroscopic voxels containing detectable metabolite peaks were labeled as either healthy, equivocal, or cancerous. Healthy metabolism was identified on the basis of the presence of high levels of citrate and lower, approximately equal, levels of choline, creatine, and polyamines similar to those before therapy (21). Equivocal metabolism was identified as regions of MRSI-detectable choline and creatine but with reduced or absent citrate and polyamines. Residual prostate cancer was discriminated from residual healthy and equivocal metabolism on the basis of a choline/creatine peak area ratio of ⱖ1.5 in three or more contiguous voxels (22). Figure 1 shows an axial T2-weighted MRI study of the prostate with spectroscopy voxels overlaid on the corresponding spectra to visualize the choline/citrate peak area ratios used in localizing the cancer. An MRSI study was considered positive if cancerous metabolism was present and negative if healthy and/or equivocal metabolism or metabolic atrophy was observed. Additionally, for negative MRSI cases, the percentage of the prostate gland demonstrating atrophy was calculated on the basis of the total number of voxels interrogated.
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Fig. 1. Axial T2-weighted magnetic resonance imaging of prostate with spectroscopy (MRSI) voxels overlaid on corresponding spectra on right. (a) Pretreatment MRSI findings showing peaks for major metabolites (citrate, choline [Cho], creatine [Cr]). Healthy metabolism (left) characterized by high citrate relative to choline ⫹ creatine; cancerous metabolism (right) characterized by high choline ⫹ creatine relative to citrate. (b) Posttreatment MRSI information showing complete lack of identifiable peaks above baseline noise after successful therapy. Integrity of study confirmed by observation of residual water peaks at correct positions (inset) out of spectral range shown for other metabolites. Endorectal probe present in lower portion of each image, with only spectra covering peripheral zone shown for simplicity.
Gland coverage for MRSI All 55 patients in the study were evaluated for spectroscopic coverage of the prostate. The prostate glands studied ranged in size from 22.5 to 61.7 cm3 (mean, 24.5 cm3; median, 27.5 cm3). The percentage of the gland covered by the MRSI PRESS box ranged from 65% to 100% (mean, 95%; median, 95.2%). Thus, on average, approximately 5% of the gland was inadequately covered by the MRSI study, with this region generally restricted to the very anterior aspect of the central gland (transition zone) and the most superior aspect of the prostatic base. Percentage of cancer before treatment Of the 55 patients in this study, 26 (47%) underwent MRI/MRSI before EBRT for tumor localization. Of these 26 patients, the percentage of cancerous voxels was determined as the ratio of the total number of usable voxels to
determine whether the TRD was affected by the quantity of initial cancer in the prostate. These ratios were tabulated for reference. Time course to nPSA and negative/positive PSA slope All available PSA results for the 55 patients participating in the study and the resulting time to nPSA after therapy were analyzed. The nPSA was determined when the PSA level had stabilized at its lowest value. It should be noted that in many cases, the PSA declined immediately after EBRT, followed by a series of PSA “bounces” or “blips” (due in some cases to testicular recovery) until the nPSA was reached. All PSA values were used to determine the PSA slope. This slope was defined by two endpoints. The first endpoint was the PSA value at EBRT completion. The second endpoint was the PSA value at follow-up. If the slope of the line
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Table 1. Patients grouped by hormonal therapy HT type (n)
Minimal dose (Gy)
Maximal dose (Gy)
Mean TRD for ⫺MRSI/⫹MRSI (mo)
⫺PSA/⫹PSA slope (%)
LTHT (10) STHT (28) NHT (17)
75.7 73.4 74.2
82.5 78.3 80.8
42/32 36/44 41/29
30/70 59/41 62/38
Abbreviations: HT ⫽ hormonal therapy; TRD ⫽ time to disease resolution; MRSI ⫽ MRI with spectroscopy; PSA ⫽ prostate-specific antigen; LTHT ⫽ long-term HT; STHT ⫽ short-term HT; NHT ⫽ no HT.
was in a positive direction, a positive PSA was defined, and if the slope was in the negative direction, a negative PSA was defined. Blood was always drawn at the time of MRSI, and the PSA slope was correlated with the mean TRD for patients grouped by type of HT (Table 1), minimal dose (Table 2), maximal dose (Table 3), percentage of cancer at baseline (Table 4), and MRSI and biopsy results (Table 5). Biopsy technique To minimize the risk of false-negative biopsies, an “extended pattern” biopsy was used in this study. After therapy, patients were referred for biopsy if they experienced a persistent rising PSA level and/or positive MRSI results ⬎36 months after EBRT. The University of California, San Francisco technique includes a previously published highresolution TRUS procedure with variable probe frequency of 5–10 MHz in both transverse and longitudinal scanning planes (23). A 3-day course of antibiotic therapy starting 12 h before biopsy was routinely used. The prostate gland was anesthetized before biopsy with 1% Xylocaine jelly to provide more comfort during the digital rectal examination (23). An 18-gauge biopsy needle loaded in a spring-action automatic biopsy device was used to procure multiple 1.5-cm prostate biopsy specimens. When a biopsy needle is directed at a suspicious lesion, it is important for the needle tip to be placed precisely at the boundary of the lesion before activating the biopsy gun and that the gun is not “tented up” by the needle. In this way, the tissue is not biopsied too deep inside the gland, missing tumor located in the peripheral zone. The excursion of the needle during biopsy was ⬃2.5 cm, and the biopsy notch was ⬃1.5 cm. If no localized lesion was noted on TRUS, extended sextant biopsy, including the medial and lateral aspect of each sextant, was performed. Two additional biopsies were obtained along the anterior capsule of the gland (24). The
Table 2. Patients grouped by minimal dose Minimal dose (Gy) ⱕ72 (18) 73.2–74.4 (12) 75.6 (20) ⬎75.6 (4)
TRUS probe was gently advanced into the rectum to the base of the bladder until the seminal vesicles were visualized. Transverse images were obtained as the probe was moved back from the prostatic base to the prostatic apex. The seminal vesicles were routinely biopsied at the base, regardless of the TRUS findings. If TRUS showed abnormal lesions, TRUS-guided lesion-directed biopsies were added at each lesion. If MRSI lesions were not appreciated on TRUS, geographically guided biopsies were added laterally for a more conclusive biopsy study. RESULTS Overall MRI/MRSI results Overall, 78% of the patients studied had negative MRSI results and 22% had positive MRSI results. Of the MRSI studies with negative findings, the percentage of voxels demonstrating metabolic atrophy increased from ⬃76% within the first 18 months after EBRT to ⬃87% at 19 –30 months, ⬃92% at 31– 42 months, and ⬃97% at ⬎55 months after EBRT. Patients with positive MRSI studies ⬎36 months after treatment were recommended for biopsy in most cases. Overall treatment groups studied Patients were divided into groups to determine whether the type of therapy (RT alone vs. combined with HT; Table 1), radiation dose (minimal [Table 2] vs. maximal [Table 3] dose), or extent of cancer before therapy (Table 4) affected the TRD or PSA slope. Hormonal therapy. Ten patients (18%) underwent LTHT, 28 (51%) underwent STHT, and 17 (31%) did not receive HT. The mean minimal radiation dose was very similar among the three HT groups (75.7, 73.4, and 74.2 Gy, respectively). The TRD vs. the HT type (LTHT, STHT, and
Table 3. Patients grouped by maximal dose
Mean TRD for ⫺MRSI/⫹MRSI (mo)
⫺PSA/⫹PSA slope (%)
32.3/33.5 45.8/37.0 41.6/42.0 65.0/32.3
47/53 50/50 42/58 0/100
Data in parentheses are numbers of patients. Abbreviations as in Table 1.
Maximal dose (Gy) ⬍77 (14) 78–79 (14) 80–81 (13) ⬎81 (14)
Mean TRD for ⫺MRSI/⫹MRSI (mo)
⫺PSA/⫹PSA slope (%)
39.8/38.0 36.8/31.8 43.3/43.0 47.8/32.3
50/50 84/16 36/64 36/64
Data in parentheses are numbers of patients. Abbreviations as in Table 1.
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Table 4. Patients grouped by percentage of pretreatment (baseline) cancer before EBRT Pretreatment cancerous voxels (%)
Mean TRD for ⫺MRSI/⫹MRSI (mo)
⫺PSA/⫹PSA slope (%)
13–29 33–50 54–93
24.3/0 45.3/45.7 66.7/48.4
50/50 22/78 57/43
Abbreviations: EBRT ⫽ external beam radiotherapy; other abbreviations as in Table 1.
no HT) was 42.0, 35.5, and 41.5 months, respectively. The use of HT did not seem to influence the TRD; however, 70% of the patients in the LTHT group had a positive PSA slope at the MRSI study. Table 1 summarizes the data of the patients who underwent HT according to the TRD. Radiation dose. The 55 patients were divided into groups to determine whether a relationship existed between the TRD and the prescribed dose. The data in Table 2 were tabulated to evaluate the TRD by the minimal dose. The data in Table 3 tabulate the TRD according to the maximal dose. No correlation was found between the TRD and the radiation dose. These data suggest that the mean overall TRD of 40.3 months in this study was a reasonable point for all patients, regardless of dose. Percentage of initial cancer. Of the 55 patients in this study, 26 (47%) had usable pretreatment MRSI studies. For the 26 patients, the percentage of cancer in the prostate before treatment ranged from 13% to 93% of the peripheral zone. The TRD for this group of patients is presented in Table 4. When ⬍33% of cancer was present in the prostate before treatment, the median TRD was ⬃24 months. If 33–50% of the voxels studied had cancer present, the median TRD was ⬃44 months, and when ⬎50% of the voxels had cancer present, the median TRD was ⬃67 months. A statistically significant correlation was found between the percentage of initial cancer and the TRD (log–rank test, p ⬍ 0.0001). No correlation with the positive/negative PSA slope was found relative to the quantity of initial cancer present, and no correlation seemed to exist for patients having positive MRSI findings with the percentage of pretreatment cancer. Residual healthy, equivocal, and malignant metabolism In 16% of the patients studied, spectroscopic voxels demonstrating healthy and equivocal metabolism were observed Table 5. Results of combined studies including MRSI, PSA, and biopsy
⫺MRSI ⫹MRSI ⫹PSA, ⫹biopsy ⫹PSA, ⫺biopsy
⫺MRSI (n)
⫹MRSI (n)
⫺PSA (n)
⫹PSA (n)
Total (n)
— — 0 7
— — 4 0
30 8 — —
11 6 — —
41 14 4 7
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in the peripheral zone. In 27% of the patients, healthy and equivocal voxels were observed in the central gland and in regions near the urethra and ejaculatory ducts. No healthy voxels were found in patients who had received HT. Residual cancerous metabolism was found in 20% of the patients. This group of patients experienced persistent “PSA rises” and was referred for biopsy and/or repeat MRSI. (Some patients refused biopsy and have been followed with repeat MRSI and PSA studies.) Results of MRSI studies Of the 55 patients in the study, 43 (78%) had negative MRSI findings at various follow-up points ⬎26 months after EBRT. Of these 43 patients, 40% achieved CMA (i.e., no residual healthy or equivocal metabolism). Of the 12 patients with positive MRSI findings, 4 had a borderline choline signal/noise ratio and were being monitored at last follow-up but had not yet been referred for biopsy. The remaining 8 patients were referred for biopsy and/or repeat MRSI studies. MRSI results compared with biopsy findings and PSA slope Table 5 shows the correlation of negative MRSI, biopsy, and PSA slope data. All 4 patients with positive MRSI findings also had positive biopsy results. Similarly, all 7 patients with negative MRSI findings had negative biopsy findings; however, all 7 patients with negative biopsy and negative MRSI findings had positive PSA results. The MRSI and biopsy findings in our study correlated with each other, but PSA did not have the same relationship. Results of PSA by treatment group In addition to the MRI/MRSI studies, each patient had multiple PSA values, including a pretreatment and at least one posttreatment PSA measurement. The PSA data of 15 patients treated with EBRT alone were graphed to evaluate the TRD relative to the PSA results. This group was unique in that all 15 patients had a baseline pretreatment MRSI study and at least two posttreatment MRSI studies. Figure 2 summarizes the results for these 15 patients who initially presented with positive MRSI findings and then at varying time points had negative MRSI findings after EBRT. Figure 2 also graphs the time to nPSA for each patient to visually understand the differences between the time to nPSA and TRD. The mean TRD for patients treated with EBRT alone was 34 months compared with 48 months for a nPSA. The mean TRD for all 55 patients in the study was 40.3 months compared with 50 months for a nPSA. For all 15 patients with baseline and serial MRSI and PSA studies after EBRT, the metabolism was decreasing or not changing during the transient PSA rises. DISCUSSION The treatment of prostate cancer continues to be somewhat controversial, in part because of the need for long
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Fig. 2. Evaluation of 15 patients who had an initial positive magnetic resonance imaging with spectroscopy (MRSI) findings followed by negative MRSI studies. Data were tabulated for time to resolution of disease and time to PSA nadir (nPSA). In all cases, PSA reached nadir after negative MRSI results.
follow-up times to determine outcomes, including cure (3). If a relatively noninvasive imaging approach (MRSI) could be used to determine successful therapy outcomes, a surrogate endpoint could potentially shorten the time required to determine the success of a treatment. The results of this study suggest that the resolution of metabolic abnormalities as measured by MRSI after EBRT may complement the nPSA as a measure of the therapeutic effectiveness resulting in shorter mean times to nPSA. The spread of points for MRSI studies was influenced because some patients had only one very late point associated with their MRSI study (sometimes ⬎60 months). The inclusion of these late follow-up data likely caused the mean TRD to be overestimated. Only additional serial follow-up with more closely spaced points would be able to prove that the TRD reproducibility occurs before the nPSA after EBRT. Additionally, if these findings hold up with longer clinical follow-up (5–10 years), MRSI could be used as an early surrogate endpoint for the local control of prostate cancer. PSA experience for EBRT patients All 55 patients experienced an initial decline in the PSA level during the first 6 months after EBRT. However, 62% of the patients in this study had a series of PSA blips until an eventual decline or nPSA occurred. Although the typical increases in PSA have been reported in the literature to range, on average, from 0.2 to 3.4 ng/mL, much greater blips are occasionally observed that have lasted for ⱖ18 months (2, 25). However, the presence of a PSA blip does not seem to be generally associated with a greater risk of clinical failure. It is likely that as the cells die, PSA is released into the blood, causing a series of temporary rises, spikes, or blips, delaying the nPSA. Other possible causes of the PSA blips include delayed death of epithelial cells or radiation-induced prostatitis (26). Therefore, the results from a MRI/MRSI examination may help to ease the minds of patients with transient PSA rises. The American Society for Therapeutic Radiology and On-
cology (ASTRO) failure definition of three consecutive PSA rises after a nPSA has been used as the endpoint for biochemical failure for the past 6 years (27). Recently, criticisms have challenged the ASTRO consensus statement because it does not take into consideration laboratory inconsistencies, PSA blips, the timing of PSA measurement, or confusion between the absolute and current nPSA. We identified four definitions from the literature with superior sensitivity, specificity, and positive or negative predictive values after biochemical failure. These biochemical failure definitions include (1) two consecutive rises of at least 0.5 ng/mL; (2) PSA levels at or greater than the absolute nPSA plus 2 ng/mL; (3) PSA levels at or greater than the current nPSA plus 2 ng/mL (28); and (4) the positive or negative slope defined by a line containing the endpoints with the PSA value at the completion of EBRT and at follow-up (3). The PSA values were tabulated using all five biochemical failure definitions along with the number of studies that revealed positive MRSI, positive biopsy, and negative biopsy findings. Table 6 summarizes the results of the patients studied according to the four different definitions for biochemical failure. If the ASTRO definition had been used, twice the number of patients in the study would have been considered to have biochemical failure. The remaining challenging definitions would have considered 12–15 patients to have failure, with two to four failures confirmed by biopsy and three to five with negative biopsies. Of the 29 patients who would have been considered to have biochemical failure by the ASTRO definition, 13 of them did not have failure by any other definition. These men had very small rises or blips after a nPSA, but eventually experienced a decline in the PSA level. A fault of the ASTRO definition is that it has no defined period between PSA measurements. Within this group of patients, the measurements ranged from 2 weeks to 8 months (median, 1 month). All 29 patients were referred to the MRSI center because of the PSA fluctuation. Evaluating other biochemical failure definitions gave us the opportunity to align biochemical failure more realistically by the varying definitions.
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Table 6. Patients (n ⫽ 55) with biochemical failure by each definition cross-tabulated to status BFD
Total (n)
Positive MRSI (n)
Positive biopsy (n)
Negative biopsy (n)
Indicated but no biopsy yet (n)
ASTRO Two rises ⬎0.5 ng/mL Absolute lnPSA⫹2 ng/mL Current nPSA⫹2 ng/mL Positive PSA slope
29* 13* 12 12 15
7 1 1 1 4
3 2 2 2 4
7 4 3 3 5
⬇19 ⬇7 ⬇7 ⬇7 ⬇6
Abbreviations: BFD ⫽ biochemical failure definition; ASTRO ⫽ American Society for Therapeutic Radiology and Oncology; nPSA ⫽ nadir PSA; other abbreviations as in Table 1. * Included patients whose PSA subsequently declined.
Rising PSA levels, or blips, are known to cause unease in the treated patients and physicians alike and can occur within a broad range of periods with varying durations. In this study, viable metabolism continued to decrease during the PSA blips, indicating that these blips were not associated with an increase in residual healthy or cancerous prostatic epithelial cells. Benefits of MRSI over MRI after EBRT Magnetic resonance imaging is limited in imaging the irradiated gland because of the treatment changes that include prostatic shrinkage, the development of diffuse low T2weighted signal intensity in the gland, and the indistinctness of the normal zonal anatomy (29). These changes greatly limit the ability of MRI to depict tumor after RT. Also, even if tumor is detected, MRI does not have the ability to distinguish active tumor from treated tumor. MRSI, which detects abnormal metabolism, rather than abnormal anatomy, has shown considerable promise in the local evaluation of prostate cancer before treatment (8). The preliminary data suggest that MRSI is helpful in the detection of recurrent tumors in the prostate after EBRT, with an area under the receiver operating characteristic curve of 0.81. This is also consistent with the known utility of MRSI to distinguish post-radiation necrosis from viable tumor in brain tumors (30). Use of MRSI for post-EBRT patients In this study, early metabolic responses were observed in patients receiving EBRT, with ⬎80% of the prostate gland demonstrating metabolic atrophy at 24 months. Furthermore, the increase in the amount of metabolic atrophy continued over time, with 78% of patients attaining negative MRSI findings and a mean TRD of 40.3 months after EBRT. A correlation was found between the TRD and the percentage of initial cancer (lower percentages of initial cancer resulted in shorter mean TRDs). MRSI was useful in determining the locations of residual and recurrent cancer, providing a strong correlation between positive MRSI and positive biopsy findings and negative MRSI and negative biopsy findings in all patients studied. Although most pa-
tients were referred for participation in this MRSI study for rising PSA levels, no correlation was found between positive PSA and positive MRSI findings. Regions of residual healthy metabolism (with citrate, low choline and creatine) were observed in 12% of patients after EBRT alone. In the transition zone, the regions of healthy metabolism were typically observed around the urethra and ejaculatory ducts. There may be reason to suspect that treatment of patients before the use of on-line portal imaging and implanted gold markers may have resulted in low-dose regions (healthy voxels) due, in part, to daily organ motion, overblocking, and/or the use of external skin markers (31). Advanced technologies, including implanted gold markers and on-line portal imaging, might decrease the presence of healthy metabolism in low-dose regions, possibly improving local control. A more serious problem would present if low-dose regions (peripherally) existed in areas known to have cancer. CONCLUSION The results of this study summarize the TRD and suggest that cancerous metabolism is generally still detectable in the prostate after EBRT completion. Benign PSA blips were not associated with an increase in metabolic activity, suggesting that these blips are secondary to the death of epithelial cells leaking into the bloodstream. The detection of residual cancer at an early stage after treatment could allow earlier intervention with additional therapy and provide a more quantitative assessment of therapeutic efficacy. The results of this study suggest that when used in conjunction with PSA determination and biopsy, MRSI may provide a greater level of confidence when assessing local control. If supported by additional studies and longer follow-up, MRSI might be a useful adjunct for assessing local control before PSA failure. MRSI could also help distinguish the benign blip from local recurrence after EBRT and be useful in evaluating the complex relationships between treatment and the time to the indication of successful therapy. Longer follow-up is required to confirm these initial observations.
REFERENCES 1. Roach M. Commentary on a multi-institutional analysis of external beam radiotherapy for T1-T2 prostate cancer: “Love
the one you’re with” and “do the right thing.” Int J Radiat Oncol Biol Phys 2003;57:907–909.
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2. Hanlon AL, Pinover WH, Horwitz EM, et al. Patterns and fate of PSA bouncing following 3D-CRT. Int J Radiat Oncol Biol Phys 2001;50:845–849. 3. Takamiya R, Weinberg V, Young CD, et al. A zero PSA slope in post treatment prostate-specific antigen supports cure of patients with long-term follow-up after external beam radiotherapy for localized prostate cancer. Int J Radiat Oncol Biol Phys 2003;56:1073–1078. 4. DeWitt KD, Sandler HM, Weinberg V, et al. What does postradiotherapy PSA nadir tell us about freedom from PSA failure and progression-free survival in patients with low and intermediate-risk localized prostate cancer? Urology 2003;62: 492–496. 5. Roach M. The role of PSA in the radiotherapy of prostate cancer. Oncology 1996;10:1143–1153. 6. Roach M, 3rd, Kurhanewicz J, Carroll P. Spectroscopy in prostate cancer: Hope or hype? Oncology (Huntingt) 2001;15: 1399–1418. 7. Scheidler J, Hricak H, Vigneron DB, et al. Prostate cancer: Localization with three-dimensional proton MR spectroscopic imaging—Clinicopathologic study. Radiology 1999;213:473– 480. 8. Pickett B, Vigneault E, Shinohara K, et al. The use of endorectal magnetic resonance spectroscopy imaging (MRSI) to assess the efficacy of post implant dosimetry for permanent prostate implantation. In: Cox J, editor. Proceedings of the American Society for Therapeutic Radiology and Oncology, 40th Annual Meeting. Phoenix, AZ Vol. 42. Elsevier; 1998. p. 133. 9. Pickett B, Ten Haken RK, Kurhanewicz J, et al. Time to metabolic atrophy after permanent prostate seed implantation based on magnetic resonance spectroscopic imaging. Int J Radiat Oncol Biol Phys 2004;59:665– 673. 10. Mueller-Lisse U, Swanson M, Vigneron DB, et al. Hormone ablation of localized prostate cancer: Time dependent therapy effects on prostate metabolism detected by 3D 1H MR spectroscopy. Magn Reson Med 2001;46:49–57. 11. Kurhanewicz J, PI (Principle Investigator). Magnetic resonance imaging and spectroscopy of the prostate. 2002;UCSF #NIHRO1CA79980. 12. Roach M 3rd, DeSilvio M, Lawton C, et al. Phase III trial comparing whole-pelvic versus prostate-only radiotherapy and neoadjuvant versus adjuvant combined androgen suppression: Radiation Therapy Oncology Group 9413. J Clin Oncol 2003;21:1904–1911. 13. Pickett B, Roach M, Verhey L, et al. The value of nonuniform margins for six-field conformal irradiation of localized prostate cancer. Int J Radiat Oncol Biol Phys 1995;32: 211–218. 14. Pickett B, Vigneault E, Kurhanewicz J, et al. Static field intensity modulation to treat a dominant intra-prostatic lesion to 90 Gy compared to seven field 3-dimensional radiotherapy. Int J Radiat Oncol Biol Phys 1999;44:921–929. 15. Roach M 3rd. Hormonal therapy and radiotherapy for localized prostate cancer: Who, where and how long? J Urol 2003;170:S35–S41. 16. Kurhanewicz J, Swanson MG, Nelson SJ, Vigeron D. Combined magnetic resonance imaging and spectroscopic imaging approach to molecular imaging of prostate cancer. J Magn Reson Imaging 2002;16:451–463.
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17. Mueller-Lisse U, Vigneron DV, Hricak H, et al. Localized prostate cancer: Effect of hormone deprivation therapy measured by combined three-dimensional 1H-MR spectroscopy and MR imaging—Clinico-pathologic case-control study. Radiology 2001;221:380–390. 18. Males R, Vigneron D, Star-Lack J, et al. Clinical application of BASING and spectral/spatial water and lipid suppression pulses for prostate cancer staging and localization by in vivo 3D 1H magnetic resonance spectroscopic imaging. Magn Reson Med 2000;43:17–22. 19. Schricker A, Pauly J, Kurhanewicz J, Swanson MG, Vigneron D. Dualband spectral-spatial RF pulses for prostate MR spectroscopic imaging. Magn Reson Med 2001;56:1079–1087. 20. Star-Lack J, Pauly J, Vigneron D, Kurhanewicz J, Nelson SJ. Improved solvent suppression and increased spatial excitation bandwidths for 3-D PRESS CSI using phase-compensating spectral/spatial spin-echo pulses. J Magn Reson Imaging 1997;7:745–757. 21. Kurhanewicz J, Vigneron DB, Hricak H, et al. Three-dimensional H-1 MR spectroscopic imaging of the in situ human prostate with high (0.24 – 0.7 cm3) spatial resolution. Radiology 1996;198:795–805. 22. Tran TK, Vigneron D, Sailasuta N, et al. Very selective suppression pulses for clinical MR spectroscopic imaging studies of brain and prostate cancer. Magn Reson Med 2000; 43:23–33. 23. Nash P, Bruce J, Indudhara R, Shinohara K. Transrectal ultrasound-guided prostatic nerve blockade eases systematic needle biopsy of the prostate. J Urol 1996;155:607– 609. 24. Meng MV, Franks J, Presti JC, Shinohara K. The utility of anterior horn biopsy. Urol Oncol 2003;21:361–365. 25. Stock RG, Stone NN, Cesaretti JA. Prostate-specific antigen bounce after prostate seed implantation for localized prostate cancer: Descriptions and implications. Int J Radiat Oncol Biol Phys 2003;56:448–453. 26. Cavanagh W, Blasko JC, Grimm PD, et al. Transient elevation of serum prostate-specific antigen following I-125/Pd-103 brachytherapy for localized prostate cancer. Semin Urol Oncol 2002;18:160–165. 27. ASTRO. Consensus statement: Guidelines for PSA following radiation therapy. Int J Radiat Oncol Biol Phys 1997;37:1037– 1041. 28. Thames H, Kuban D, Levy L, Horwitz E. Comparison of alternative biochemical failure definitions based on clinical outcome in 4839 prostate cancer patients treated by external beam radiotherapy between 1986 and 1995. Int J Radiat Oncol Biol Phys 2003;57:929–943. 29. Coakley FV, Hricak H, Wefer AE, et al. Brachytherapy for prostate cancer: Endorectal MR imaging of local treatmentrelated changes. Radiology 2001;219:817–821. 30. Kamada K, Houkin K, Abe H, Sawamura Y, Kashiwaba T. Differentiation of cerebral radiation necrosis from tumor recurrence by proton magnetic resonance spectroscopy. Neuro Med Chir (Tokyo) 1997;37:250 –256. 31. Millender LE, Aubin M, Pouliot J, Shinohara K, Roach M III. Daily electronic portal imaging for morbidly obese men undergoing radiotherapy for localized prostate cancer. Int J Radiat Oncol Biol Phys. 2004;59:6 –10.
doi:10.1016/j.ijrobp.2004.05.015
CLINICAL INVESTIGATION
Prostate
USE OF MRI AND SPECTROSCOPY IN EVALUATION OF EXTERNAL BEAM RADIOTHERAPY FOR PROSTATE CANCER BARBY PICKETT, M.S.,* JOHN KURHANEWICZ, PH.D.,† FERGUS COAKLEY, M.D.,† KATSUTO SHINOHARA, M.D.,‡ BEVERLY FEIN, M.S.R.N.,† AND MACK ROACH III, M.D.*‡ Departments of *Radiation Oncology, †Radiology, and ‡Urology, University of California, San Francisco, School of Medicine, San Francisco, CA Purpose: To characterize the metabolic response in the prostate, the time to resolution of disease, and the correlation between magnetic resonance imaging (MRI) with spectroscopy (MRSI) results, biopsy findings, and serum prostate-specific antigen (PSA) level after external beam radiotherapy. Methods and Materials: A total of 55 patients underwent MRSI before and/or at varying times after external beam radiotherapy. The percentage of the cancerous, healthy, and atrophic voxels was calculated, and the time to resolution of disease was determined and compared with the PSA nadir. Results: Of the 55 patients, 70% had negative MRSI and 30% had positive MRSI findings. A strong correlation was found between negative MRSI and negative biopsy findings (n ⴝ 11) and between positive MRSI and positive biopsy findings (n ⴝ 7). A weak correlation was observed between the PSA level and the MRSI and biopsy findings. The mean time to disease resolution was 40.3 months and the mean time to PSA nadir was 50 months. With time, an increase in atrophy and a decline in cancerous metabolism was found. Conclusion: When used in conjunction with PSA measurement and biopsy, the results of this study suggest that MRSI contributes to a greater level of confidence in determining the outcome and may be a useful adjunct for assessing local control before PSA failure when striving to distinguish the benign “blip” from local recurrence. © 2004 Elsevier Inc. Magnetic resonance imaging, Spectroscopy, Prostate cancer, External beam radiotherapy.
The serum prostate-specific antigen (PSA) test is the most commonly used method of confirming resolution of prostate cancer after definitive radiotherapy (RT). PSA testing is universally used and considered to be a fairly reliable and inexpensive determination of treatment outcome (1). However, bouncing PSA values are common after external beam RT (EBRT) (2). At least one study has suggested that patients with a “bouncing” PSA level tend to present with greater pretreatment PSA levels and that, at 5 years, those with PSA bounces tend to have lower biochemical control rates than patients without (52% vs. 69%, p ⫽ 0.0024). However, because nearly one-half of patients with a bouncing PSA level have disease control, a bouncing PSA level cannot be considered a reliable indicator of relapse. The use of PSA testing to monitor therapeutic efficacy is also not ideal, because PSA is not specific for local recurrences of prostate cancer. Additionally, it can sometimes take ⬎4 years for PSA results to reach a nadir after EBRT
(3). Even when a nadir is achieved, it is often difficult to interpret (1, 4). The PSA response data are difficult to interpret for patients undergoing hormonal deprivation therapy because of the direct effect on PSA production. To date, conventional imaging methods, including transrectal ultrasonography (TRUS), computed tomography (CT), and magnetic resonance imaging (MRI) cannot reliably distinguish healthy from malignant tissue after therapy owing to the induced changes in tissue structure (5). Magnetic resonance imaging with spectroscopy (MRSI) is being used more frequently in patients with newly diagnosed prostate cancer for tumor localization and staging (6). Before therapy, prostate cancer can be identified on the basis of the low-signal intensity on T2-weighted images, the significantly elevated choline/creatine ratios, and the reduced citrate and polyamine peaks on MRSI (6). It is the concordance of the metabolic findings provided by MRSI and the morphologic findings provided by MRI that results in the most confident identification of prostate cancer (7). The regions of cancer defined by combined MRI/MRSI can
Reprint requests to: Barby Pickett, M.S., Department of Radiation Oncology, University of California, San Francisco, School of Medicine, 1600 Divisadero St., H1031, San Francisco, CA 941431708. Tel: (415) 353-7191; Fax: (415) 353-9887; E-mail: [email protected]
Presented at the 45th ASTRO Meeting, Salt Lake City, UT, 2003. Supported by Grants NIH R01-CA79980 and Grant R01CA59897. Received Jan 6, 2004, and in revised form Apr 29, 2004. Accepted for publication May 10, 2004.
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also be registered with CT images for more accurate tumor localization, treatment planning, and visualization of isodose distributions (8). We have previously reported that MRSI may be of value in determining successful treatment after permanent prostate seed implantation (9). Recently we have begun using MRI/MRSI to monitor patients after EBRT. After therapy, the ability to identify prostate cancer on MRI is reduced owing to a diffuse reduction in the T2-weighted signal. The levels of citrate and polyamines are also dramatically reduced on MRSI (6). However, residual prostate cancer can still be identified by a relative increase in the choline/creatine ratio. MRSI can also provide a quantitative measure of successful therapy with the indication of “metabolic atrophy” or lack of cancer. Metabolic atrophy has previously been defined as “spectra containing no significant metabolite peaks, specifically spectra having peak area/ noise ratios of ⬍5 for choline, polyamines, creatine, and citrate” (10). The present study was based on the hypothesis that metabolic atrophy is indicative of successful treatment because growth of normal or abnormal cells cannot occur without metabolism. Therefore, disease resolution (negative MRSI findings), the primary indicator in this study, may be indicative of effective EBRT. A previous study examining the time to metabolic atrophy for permanent prostate implantation patients has suggested that complete metabolic atrophy (CMA) is expected for brachytherapy patients. However, because the dose is much lower in EBRT patients, the time to CMA may not be a suitable endpoint and the time to resolution of disease (TRD) might be more appropriate. The significantly greater prescribed dose used for permanent prostate implantation (144 Gy) vs. for EBRT (68 – 81 Gy) appears to be a contributing factor in achieving CMA. Our purpose, therefore, was to characterize the TRD after EBRT using combined MRI/MRSI studies compared with the results of biopsy and the time to reach a nadir PSA (nPSA). METHODS AND MATERIALS Patient selection The data of patients treated at the University of California, San Francisco, Medical Center between May 1995 and October 2001 were cross-referenced with the MRI/MRSI database to identify patients with pretreatment MRI/MRSI studies and/or posttreatment MRI/MRSI studies as an initial starting point for patient selection. Successful recruitment to this study was complicated by several factors, including the availability of research MRSI times, patients living out of the area, patient discomfort, and those lost to follow-up. All patients included in this study had undergone PSA testing before EBRT and at varying times after treatment. All patients were screened for contraindications and agreed to participate in the institutional review board–approved MRI/MRSI study governed by Health Insurance Portability and Accountability Act (HIPPA) regulations and standards (11). Ultimately, 55 patients were registered for participation. For the purposes of this protocol, we decided that
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patients would be followed until achieving the primary endpoint defined as negative MRSI findings; a positive MRSI study was defined as the presence of an elevated choline/creatine ratio of ⱖ1.5 in three or more contiguous voxels. Patient exclusion All patients interested in participation were initially registered but some were excluded for refusal to return for follow-up studies, claustrophobia, onset of long-term HT prescribed by their primary care physician, and other contraindications specific to MRI safety and rectal area integrity. Each patient was screened for metallic devices and foreign objects and was excluded from entering the MRI suite if any of the following situations existed: some types of penile implants, vascular clips in the brain or body surgically placed within a 6-month period, cardiac pacemakers, and any metal foreign bodies that could have an adverse effect on the patient while he was in the magnet. Hip replacements, although usually made MRI compatible, were found to be directly in the field of the prostate and caused image and spectroscopy artifacts, rendering the data unusable. Patients with current rectal bleeding, painful rectal fissures, Crohn’s disease, ulcerative colitis, rectal procedures requiring end-to-end anastomosis, or a high likelihood of rectal perforation from endorectal probe insertion were also considered ineligible. Patients referred to the magnetic resonance imaging center for participation in a grant-funded protocol were screened for these contraindications before recommendation. EBRT technique Patients were treated with forward planned, static field, intensity-modulated RT or three-dimensional conformal photon beams. Patients with ⬎15% lymph node involvement were treated with four pelvic fields (anterior, posterior, and right and left lateral) used to incorporate the nodes at risk (12). Three-dimensional planning was used to design the posterior lateral margins, minimizing the dose to the rectal wall. Dose–volume histograms determined the weighting of the treated fields. The first conedown treatment to the prostate and seminal vesicles included 18- and 6-MV photon beams to deliver a coplanar arrangement about a second isocenter with the angles distributed 35° anterior and posterior to the lateral gantry position. An anterior field was used to produce a more conformal distribution, minimizing the dose to the femoral heads, but minimally weighted to maintain ⬍50 Gy to 40% of the rectal wall. The lateral beams were heavily weighted for additional rectal wall sparing (13). The prostate and seminal vesicles were treated to 54 Gy (an additional 9 Gy), followed by a second conedown to the prostate only for a final prescribed minimal dose between 68 and 81 Gy. The wide variation in the total minimal dose reflected ongoing departmental and Radiation Therapy Oncology Group protocols and the ability to identify cancer within the prostate for static field, intensity-modulated RT. MRSI was used in 47% of the patients to define the pretreatment tumor
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location in the prostate, referred to as the dominant intraprostatic lesion (14). The doses to the dominant intraprostatic lesion in these patients were escalated to ⬎81 Gy while concurrently delivering a dose of 72–75.6 Gy to the entire prostate. Multileaf collimation and dynamic wedging were used to minimize the patient treatment (beam-on) time. All patients were followed until presentation of negative MRSI studies, biopsy proven recurrence, or metastatic disease. Patient characteristics Fifty-five patients were registered in the study. Of these, 26% had Stage T3 disease and received long-term hormonal therapy (LTHT), 66% had Stage T2 and received short-term neoadjuvant HT (STHT) before EBRT, and 8% had Stage T1 and received EBRT alone. Of the 55 patients, 60% had a Gleason score of ⱕ6, 24% had a Gleason score of 7, and 16% had a Gleason score of ⱖ8. The prescribed minimal dose ranged from 68.4 to 81 Gy, with the maximal dose ranging from 76.2 to 97 Gy. In 18% of the men, forwardplanned EBRT was used concurrently to treat the MRSIdefined cancer to ⬎81 Gy (14). All patients were assessed by MRSI after recovery of testosterone. All patients underwent at least one posttreatment MRSI study, with the TRD measured from the end of EBRT. All patients in the study were reviewed in multidisciplinary MRI/ MRSI conferences, at which time the results were individually assessed for the presence of residual/recurrent cancer. If either the MRI or MRSI data demonstrated evidence of residual disease or the spectra proved to have an inconclusive or a borderline reading, the patient was followed further. Hormonal therapy Our institutional policy regarding the selection of patients for HT in conjunction with EBRT has been previously described (15). HT was discouraged in patients considered low risk, incorporated into the treatment regimen for 4 months for intermediate-risk patients, and incorporated into the treatment regimen for 2 years as adjuvant therapy in high-risk patients. When STHT was prescribed, it generally began 2 months before RT and was discontinued at RT completion. For this study, we paid close attention to the dates HT was started and completed. All men had resolution of all HT-induced symptoms (e.g., “hot flashes”) and/or recovery of testosterone before participation in the study. Prior studies following the course of the metabolic changes after HT have demonstrated a dramatic time-dependent decrease in metabolism, with most men demonstrating a loss of all MRSI-detectable metabolism by 6 months after the initiation of combined HT (10). The metabolic recovery of prostatic metabolism after cessation of HT is also time dependent (16). Additionally, very STHT (ⱕ2 months) has a much less dramatic effect on prostate metabolism (17), and it appears that metabolic recovery is faster with shorter durations of therapy. Three-dimensional MRSI acquisition Three-dimensional proton MRSI was performed using a water and lipid-suppressed double-spin echo point resolved
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spectroscopy (PRESS) sequence (18). The PRESS volume was selected to maximize coverage of the prostate while minimizing inclusion of periprostatic fat and rectal air. Six pairs of very selective outer-volume saturation bands were placed around the prescribed PRESS volume before excitation to improve volume selection further, and three pairs of very selective outer-volume saturation bands were graphically placed to conform the PRESS-selected volume to the shape of the prostate (19). Magnetic field homogeneity was optimized for the selected volume using both automated and manual shimming until a water line width of ⱕ10 Hz was attained. Water and lipid suppression was achieved using either band selective inversion with gradient dephasing pulses or spectral-spatial pulses (20). Data sets were acquired as 16 ⫻ 8 ⫻ 8 phase-encoded spectral arrays (1024 voxels), with a nominal spectral resolution of 0.3 cm3, TR/TE of 1000 ms/130 ms, and 17-min acquisition time. The total examination time was 1 h, including coil placement and patient positioning. Spectroscopic data were processed using a combination of in-house and Interactive Data Language (IDL) (Research Systems, Boulder, CO) software tools. Spectral data were apodized with a 2-Hz gaussian function and Fourier transformed in the time domain and three spatial domains. The resulting data were zero-filled once in the time domain (1024 data points), after which the center 50% of each spectrum was extracted to give 512 data points across a 625-Hz spectral width. Spectra were automatically phased, baseline corrected, and frequency aligned, and the metabolites of interest (i.e., creatine, choline, polyamines, and citrate) were integrated to determine their relative peak areas. The peak area/spectral noise ratios were also calculated for all prostate metabolites (20). Three-dimensional MRSI data analysis Spectroscopic voxels lacking any metabolites and thus having peak area/noise ratios of ⬎5 were considered to be metabolically atrophic. Spectroscopic voxels containing detectable metabolite peaks were labeled as either healthy, equivocal, or cancerous. Healthy metabolism was identified on the basis of the presence of high levels of citrate and lower, approximately equal, levels of choline, creatine, and polyamines similar to those before therapy (21). Equivocal metabolism was identified as regions of MRSI-detectable choline and creatine but with reduced or absent citrate and polyamines. Residual prostate cancer was discriminated from residual healthy and equivocal metabolism on the basis of a choline/creatine peak area ratio of ⱖ1.5 in three or more contiguous voxels (22). Figure 1 shows an axial T2-weighted MRI study of the prostate with spectroscopy voxels overlaid on the corresponding spectra to visualize the choline/citrate peak area ratios used in localizing the cancer. An MRSI study was considered positive if cancerous metabolism was present and negative if healthy and/or equivocal metabolism or metabolic atrophy was observed. Additionally, for negative MRSI cases, the percentage of the prostate gland demonstrating atrophy was calculated on the basis of the total number of voxels interrogated.
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Fig. 1. Axial T2-weighted magnetic resonance imaging of prostate with spectroscopy (MRSI) voxels overlaid on corresponding spectra on right. (a) Pretreatment MRSI findings showing peaks for major metabolites (citrate, choline [Cho], creatine [Cr]). Healthy metabolism (left) characterized by high citrate relative to choline ⫹ creatine; cancerous metabolism (right) characterized by high choline ⫹ creatine relative to citrate. (b) Posttreatment MRSI information showing complete lack of identifiable peaks above baseline noise after successful therapy. Integrity of study confirmed by observation of residual water peaks at correct positions (inset) out of spectral range shown for other metabolites. Endorectal probe present in lower portion of each image, with only spectra covering peripheral zone shown for simplicity.
Gland coverage for MRSI All 55 patients in the study were evaluated for spectroscopic coverage of the prostate. The prostate glands studied ranged in size from 22.5 to 61.7 cm3 (mean, 24.5 cm3; median, 27.5 cm3). The percentage of the gland covered by the MRSI PRESS box ranged from 65% to 100% (mean, 95%; median, 95.2%). Thus, on average, approximately 5% of the gland was inadequately covered by the MRSI study, with this region generally restricted to the very anterior aspect of the central gland (transition zone) and the most superior aspect of the prostatic base. Percentage of cancer before treatment Of the 55 patients in this study, 26 (47%) underwent MRI/MRSI before EBRT for tumor localization. Of these 26 patients, the percentage of cancerous voxels was determined as the ratio of the total number of usable voxels to
determine whether the TRD was affected by the quantity of initial cancer in the prostate. These ratios were tabulated for reference. Time course to nPSA and negative/positive PSA slope All available PSA results for the 55 patients participating in the study and the resulting time to nPSA after therapy were analyzed. The nPSA was determined when the PSA level had stabilized at its lowest value. It should be noted that in many cases, the PSA declined immediately after EBRT, followed by a series of PSA “bounces” or “blips” (due in some cases to testicular recovery) until the nPSA was reached. All PSA values were used to determine the PSA slope. This slope was defined by two endpoints. The first endpoint was the PSA value at EBRT completion. The second endpoint was the PSA value at follow-up. If the slope of the line
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Table 1. Patients grouped by hormonal therapy HT type (n)
Minimal dose (Gy)
Maximal dose (Gy)
Mean TRD for ⫺MRSI/⫹MRSI (mo)
⫺PSA/⫹PSA slope (%)
LTHT (10) STHT (28) NHT (17)
75.7 73.4 74.2
82.5 78.3 80.8
42/32 36/44 41/29
30/70 59/41 62/38
Abbreviations: HT ⫽ hormonal therapy; TRD ⫽ time to disease resolution; MRSI ⫽ MRI with spectroscopy; PSA ⫽ prostate-specific antigen; LTHT ⫽ long-term HT; STHT ⫽ short-term HT; NHT ⫽ no HT.
was in a positive direction, a positive PSA was defined, and if the slope was in the negative direction, a negative PSA was defined. Blood was always drawn at the time of MRSI, and the PSA slope was correlated with the mean TRD for patients grouped by type of HT (Table 1), minimal dose (Table 2), maximal dose (Table 3), percentage of cancer at baseline (Table 4), and MRSI and biopsy results (Table 5). Biopsy technique To minimize the risk of false-negative biopsies, an “extended pattern” biopsy was used in this study. After therapy, patients were referred for biopsy if they experienced a persistent rising PSA level and/or positive MRSI results ⬎36 months after EBRT. The University of California, San Francisco technique includes a previously published highresolution TRUS procedure with variable probe frequency of 5–10 MHz in both transverse and longitudinal scanning planes (23). A 3-day course of antibiotic therapy starting 12 h before biopsy was routinely used. The prostate gland was anesthetized before biopsy with 1% Xylocaine jelly to provide more comfort during the digital rectal examination (23). An 18-gauge biopsy needle loaded in a spring-action automatic biopsy device was used to procure multiple 1.5-cm prostate biopsy specimens. When a biopsy needle is directed at a suspicious lesion, it is important for the needle tip to be placed precisely at the boundary of the lesion before activating the biopsy gun and that the gun is not “tented up” by the needle. In this way, the tissue is not biopsied too deep inside the gland, missing tumor located in the peripheral zone. The excursion of the needle during biopsy was ⬃2.5 cm, and the biopsy notch was ⬃1.5 cm. If no localized lesion was noted on TRUS, extended sextant biopsy, including the medial and lateral aspect of each sextant, was performed. Two additional biopsies were obtained along the anterior capsule of the gland (24). The
Table 2. Patients grouped by minimal dose Minimal dose (Gy) ⱕ72 (18) 73.2–74.4 (12) 75.6 (20) ⬎75.6 (4)
TRUS probe was gently advanced into the rectum to the base of the bladder until the seminal vesicles were visualized. Transverse images were obtained as the probe was moved back from the prostatic base to the prostatic apex. The seminal vesicles were routinely biopsied at the base, regardless of the TRUS findings. If TRUS showed abnormal lesions, TRUS-guided lesion-directed biopsies were added at each lesion. If MRSI lesions were not appreciated on TRUS, geographically guided biopsies were added laterally for a more conclusive biopsy study. RESULTS Overall MRI/MRSI results Overall, 78% of the patients studied had negative MRSI results and 22% had positive MRSI results. Of the MRSI studies with negative findings, the percentage of voxels demonstrating metabolic atrophy increased from ⬃76% within the first 18 months after EBRT to ⬃87% at 19 –30 months, ⬃92% at 31– 42 months, and ⬃97% at ⬎55 months after EBRT. Patients with positive MRSI studies ⬎36 months after treatment were recommended for biopsy in most cases. Overall treatment groups studied Patients were divided into groups to determine whether the type of therapy (RT alone vs. combined with HT; Table 1), radiation dose (minimal [Table 2] vs. maximal [Table 3] dose), or extent of cancer before therapy (Table 4) affected the TRD or PSA slope. Hormonal therapy. Ten patients (18%) underwent LTHT, 28 (51%) underwent STHT, and 17 (31%) did not receive HT. The mean minimal radiation dose was very similar among the three HT groups (75.7, 73.4, and 74.2 Gy, respectively). The TRD vs. the HT type (LTHT, STHT, and
Table 3. Patients grouped by maximal dose
Mean TRD for ⫺MRSI/⫹MRSI (mo)
⫺PSA/⫹PSA slope (%)
32.3/33.5 45.8/37.0 41.6/42.0 65.0/32.3
47/53 50/50 42/58 0/100
Data in parentheses are numbers of patients. Abbreviations as in Table 1.
Maximal dose (Gy) ⬍77 (14) 78–79 (14) 80–81 (13) ⬎81 (14)
Mean TRD for ⫺MRSI/⫹MRSI (mo)
⫺PSA/⫹PSA slope (%)
39.8/38.0 36.8/31.8 43.3/43.0 47.8/32.3
50/50 84/16 36/64 36/64
Data in parentheses are numbers of patients. Abbreviations as in Table 1.
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Table 4. Patients grouped by percentage of pretreatment (baseline) cancer before EBRT Pretreatment cancerous voxels (%)
Mean TRD for ⫺MRSI/⫹MRSI (mo)
⫺PSA/⫹PSA slope (%)
13–29 33–50 54–93
24.3/0 45.3/45.7 66.7/48.4
50/50 22/78 57/43
Abbreviations: EBRT ⫽ external beam radiotherapy; other abbreviations as in Table 1.
no HT) was 42.0, 35.5, and 41.5 months, respectively. The use of HT did not seem to influence the TRD; however, 70% of the patients in the LTHT group had a positive PSA slope at the MRSI study. Table 1 summarizes the data of the patients who underwent HT according to the TRD. Radiation dose. The 55 patients were divided into groups to determine whether a relationship existed between the TRD and the prescribed dose. The data in Table 2 were tabulated to evaluate the TRD by the minimal dose. The data in Table 3 tabulate the TRD according to the maximal dose. No correlation was found between the TRD and the radiation dose. These data suggest that the mean overall TRD of 40.3 months in this study was a reasonable point for all patients, regardless of dose. Percentage of initial cancer. Of the 55 patients in this study, 26 (47%) had usable pretreatment MRSI studies. For the 26 patients, the percentage of cancer in the prostate before treatment ranged from 13% to 93% of the peripheral zone. The TRD for this group of patients is presented in Table 4. When ⬍33% of cancer was present in the prostate before treatment, the median TRD was ⬃24 months. If 33–50% of the voxels studied had cancer present, the median TRD was ⬃44 months, and when ⬎50% of the voxels had cancer present, the median TRD was ⬃67 months. A statistically significant correlation was found between the percentage of initial cancer and the TRD (log–rank test, p ⬍ 0.0001). No correlation with the positive/negative PSA slope was found relative to the quantity of initial cancer present, and no correlation seemed to exist for patients having positive MRSI findings with the percentage of pretreatment cancer. Residual healthy, equivocal, and malignant metabolism In 16% of the patients studied, spectroscopic voxels demonstrating healthy and equivocal metabolism were observed Table 5. Results of combined studies including MRSI, PSA, and biopsy
⫺MRSI ⫹MRSI ⫹PSA, ⫹biopsy ⫹PSA, ⫺biopsy
⫺MRSI (n)
⫹MRSI (n)
⫺PSA (n)
⫹PSA (n)
Total (n)
— — 0 7
— — 4 0
30 8 — —
11 6 — —
41 14 4 7
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in the peripheral zone. In 27% of the patients, healthy and equivocal voxels were observed in the central gland and in regions near the urethra and ejaculatory ducts. No healthy voxels were found in patients who had received HT. Residual cancerous metabolism was found in 20% of the patients. This group of patients experienced persistent “PSA rises” and was referred for biopsy and/or repeat MRSI. (Some patients refused biopsy and have been followed with repeat MRSI and PSA studies.) Results of MRSI studies Of the 55 patients in the study, 43 (78%) had negative MRSI findings at various follow-up points ⬎26 months after EBRT. Of these 43 patients, 40% achieved CMA (i.e., no residual healthy or equivocal metabolism). Of the 12 patients with positive MRSI findings, 4 had a borderline choline signal/noise ratio and were being monitored at last follow-up but had not yet been referred for biopsy. The remaining 8 patients were referred for biopsy and/or repeat MRSI studies. MRSI results compared with biopsy findings and PSA slope Table 5 shows the correlation of negative MRSI, biopsy, and PSA slope data. All 4 patients with positive MRSI findings also had positive biopsy results. Similarly, all 7 patients with negative MRSI findings had negative biopsy findings; however, all 7 patients with negative biopsy and negative MRSI findings had positive PSA results. The MRSI and biopsy findings in our study correlated with each other, but PSA did not have the same relationship. Results of PSA by treatment group In addition to the MRI/MRSI studies, each patient had multiple PSA values, including a pretreatment and at least one posttreatment PSA measurement. The PSA data of 15 patients treated with EBRT alone were graphed to evaluate the TRD relative to the PSA results. This group was unique in that all 15 patients had a baseline pretreatment MRSI study and at least two posttreatment MRSI studies. Figure 2 summarizes the results for these 15 patients who initially presented with positive MRSI findings and then at varying time points had negative MRSI findings after EBRT. Figure 2 also graphs the time to nPSA for each patient to visually understand the differences between the time to nPSA and TRD. The mean TRD for patients treated with EBRT alone was 34 months compared with 48 months for a nPSA. The mean TRD for all 55 patients in the study was 40.3 months compared with 50 months for a nPSA. For all 15 patients with baseline and serial MRSI and PSA studies after EBRT, the metabolism was decreasing or not changing during the transient PSA rises. DISCUSSION The treatment of prostate cancer continues to be somewhat controversial, in part because of the need for long
MRSI in evaluation of EBRT for prostate cancer
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Fig. 2. Evaluation of 15 patients who had an initial positive magnetic resonance imaging with spectroscopy (MRSI) findings followed by negative MRSI studies. Data were tabulated for time to resolution of disease and time to PSA nadir (nPSA). In all cases, PSA reached nadir after negative MRSI results.
follow-up times to determine outcomes, including cure (3). If a relatively noninvasive imaging approach (MRSI) could be used to determine successful therapy outcomes, a surrogate endpoint could potentially shorten the time required to determine the success of a treatment. The results of this study suggest that the resolution of metabolic abnormalities as measured by MRSI after EBRT may complement the nPSA as a measure of the therapeutic effectiveness resulting in shorter mean times to nPSA. The spread of points for MRSI studies was influenced because some patients had only one very late point associated with their MRSI study (sometimes ⬎60 months). The inclusion of these late follow-up data likely caused the mean TRD to be overestimated. Only additional serial follow-up with more closely spaced points would be able to prove that the TRD reproducibility occurs before the nPSA after EBRT. Additionally, if these findings hold up with longer clinical follow-up (5–10 years), MRSI could be used as an early surrogate endpoint for the local control of prostate cancer. PSA experience for EBRT patients All 55 patients experienced an initial decline in the PSA level during the first 6 months after EBRT. However, 62% of the patients in this study had a series of PSA blips until an eventual decline or nPSA occurred. Although the typical increases in PSA have been reported in the literature to range, on average, from 0.2 to 3.4 ng/mL, much greater blips are occasionally observed that have lasted for ⱖ18 months (2, 25). However, the presence of a PSA blip does not seem to be generally associated with a greater risk of clinical failure. It is likely that as the cells die, PSA is released into the blood, causing a series of temporary rises, spikes, or blips, delaying the nPSA. Other possible causes of the PSA blips include delayed death of epithelial cells or radiation-induced prostatitis (26). Therefore, the results from a MRI/MRSI examination may help to ease the minds of patients with transient PSA rises. The American Society for Therapeutic Radiology and On-
cology (ASTRO) failure definition of three consecutive PSA rises after a nPSA has been used as the endpoint for biochemical failure for the past 6 years (27). Recently, criticisms have challenged the ASTRO consensus statement because it does not take into consideration laboratory inconsistencies, PSA blips, the timing of PSA measurement, or confusion between the absolute and current nPSA. We identified four definitions from the literature with superior sensitivity, specificity, and positive or negative predictive values after biochemical failure. These biochemical failure definitions include (1) two consecutive rises of at least 0.5 ng/mL; (2) PSA levels at or greater than the absolute nPSA plus 2 ng/mL; (3) PSA levels at or greater than the current nPSA plus 2 ng/mL (28); and (4) the positive or negative slope defined by a line containing the endpoints with the PSA value at the completion of EBRT and at follow-up (3). The PSA values were tabulated using all five biochemical failure definitions along with the number of studies that revealed positive MRSI, positive biopsy, and negative biopsy findings. Table 6 summarizes the results of the patients studied according to the four different definitions for biochemical failure. If the ASTRO definition had been used, twice the number of patients in the study would have been considered to have biochemical failure. The remaining challenging definitions would have considered 12–15 patients to have failure, with two to four failures confirmed by biopsy and three to five with negative biopsies. Of the 29 patients who would have been considered to have biochemical failure by the ASTRO definition, 13 of them did not have failure by any other definition. These men had very small rises or blips after a nPSA, but eventually experienced a decline in the PSA level. A fault of the ASTRO definition is that it has no defined period between PSA measurements. Within this group of patients, the measurements ranged from 2 weeks to 8 months (median, 1 month). All 29 patients were referred to the MRSI center because of the PSA fluctuation. Evaluating other biochemical failure definitions gave us the opportunity to align biochemical failure more realistically by the varying definitions.
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Volume 60, Number 4, 2004
Table 6. Patients (n ⫽ 55) with biochemical failure by each definition cross-tabulated to status BFD
Total (n)
Positive MRSI (n)
Positive biopsy (n)
Negative biopsy (n)
Indicated but no biopsy yet (n)
ASTRO Two rises ⬎0.5 ng/mL Absolute lnPSA⫹2 ng/mL Current nPSA⫹2 ng/mL Positive PSA slope
29* 13* 12 12 15
7 1 1 1 4
3 2 2 2 4
7 4 3 3 5
⬇19 ⬇7 ⬇7 ⬇7 ⬇6
Abbreviations: BFD ⫽ biochemical failure definition; ASTRO ⫽ American Society for Therapeutic Radiology and Oncology; nPSA ⫽ nadir PSA; other abbreviations as in Table 1. * Included patients whose PSA subsequently declined.
Rising PSA levels, or blips, are known to cause unease in the treated patients and physicians alike and can occur within a broad range of periods with varying durations. In this study, viable metabolism continued to decrease during the PSA blips, indicating that these blips were not associated with an increase in residual healthy or cancerous prostatic epithelial cells. Benefits of MRSI over MRI after EBRT Magnetic resonance imaging is limited in imaging the irradiated gland because of the treatment changes that include prostatic shrinkage, the development of diffuse low T2weighted signal intensity in the gland, and the indistinctness of the normal zonal anatomy (29). These changes greatly limit the ability of MRI to depict tumor after RT. Also, even if tumor is detected, MRI does not have the ability to distinguish active tumor from treated tumor. MRSI, which detects abnormal metabolism, rather than abnormal anatomy, has shown considerable promise in the local evaluation of prostate cancer before treatment (8). The preliminary data suggest that MRSI is helpful in the detection of recurrent tumors in the prostate after EBRT, with an area under the receiver operating characteristic curve of 0.81. This is also consistent with the known utility of MRSI to distinguish post-radiation necrosis from viable tumor in brain tumors (30). Use of MRSI for post-EBRT patients In this study, early metabolic responses were observed in patients receiving EBRT, with ⬎80% of the prostate gland demonstrating metabolic atrophy at 24 months. Furthermore, the increase in the amount of metabolic atrophy continued over time, with 78% of patients attaining negative MRSI findings and a mean TRD of 40.3 months after EBRT. A correlation was found between the TRD and the percentage of initial cancer (lower percentages of initial cancer resulted in shorter mean TRDs). MRSI was useful in determining the locations of residual and recurrent cancer, providing a strong correlation between positive MRSI and positive biopsy findings and negative MRSI and negative biopsy findings in all patients studied. Although most pa-
tients were referred for participation in this MRSI study for rising PSA levels, no correlation was found between positive PSA and positive MRSI findings. Regions of residual healthy metabolism (with citrate, low choline and creatine) were observed in 12% of patients after EBRT alone. In the transition zone, the regions of healthy metabolism were typically observed around the urethra and ejaculatory ducts. There may be reason to suspect that treatment of patients before the use of on-line portal imaging and implanted gold markers may have resulted in low-dose regions (healthy voxels) due, in part, to daily organ motion, overblocking, and/or the use of external skin markers (31). Advanced technologies, including implanted gold markers and on-line portal imaging, might decrease the presence of healthy metabolism in low-dose regions, possibly improving local control. A more serious problem would present if low-dose regions (peripherally) existed in areas known to have cancer. CONCLUSION The results of this study summarize the TRD and suggest that cancerous metabolism is generally still detectable in the prostate after EBRT completion. Benign PSA blips were not associated with an increase in metabolic activity, suggesting that these blips are secondary to the death of epithelial cells leaking into the bloodstream. The detection of residual cancer at an early stage after treatment could allow earlier intervention with additional therapy and provide a more quantitative assessment of therapeutic efficacy. The results of this study suggest that when used in conjunction with PSA determination and biopsy, MRSI may provide a greater level of confidence when assessing local control. If supported by additional studies and longer follow-up, MRSI might be a useful adjunct for assessing local control before PSA failure. MRSI could also help distinguish the benign blip from local recurrence after EBRT and be useful in evaluating the complex relationships between treatment and the time to the indication of successful therapy. Longer follow-up is required to confirm these initial observations.
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