Published online before print May 16, 2007, 10.1148/radiol.2441060398
(Radiology 2007;244:196-204.)
© RSNA, 2007
Prostate Gland: MR Imaging Appearance after Vascular Targeted Photodynamic Therapy with Palladium-Bacteriopheophorbide1
Masoom A. Haider, MD, FRCPC,
Sean R. H. Davidson, MASc,
Ashwini V. Kale, DMRD,
Robert A. Weersink, PhD,
Andrew J. Evans, MD, PhD, FRCPC,
Ants Toi, MD, FRCPC,
Mark R. Gertner, PhD,
Arjen Bogaards, PhD,
Brian C. Wilson, PhD,
Joseph L. Chin, MD, FRCSC,
Mostafa Elhilali, MD, FRCSC, and
John Trachtenberg, MD, FRCSC
1 From the Joint Department of Medical Imaging (M.A.H., A.V.K., A.T.), Department of Pathology and Laboratory Medicine (A.J.E.), and Department of Surgical Oncology (J.T.), Princess Margaret Hospital, University Health Network and Mount Sinai Hospital, University of Toronto, 610 University Ave, Toronto, ON, Canada M5G 2M9; Biophysics and Bioimaging Division, Ontario Cancer Institute, University Health Network, Toronto, Ontario, Canada (S.R.H.D., R.A.W., M.R.G., A.B., B.C.W.); Divisions of Urology and Surgical Oncology, University of Western Ontario, London, Ontario, Canada (J.L.C.); and Department of Surgery, McGill University, Montreal, Quebec, Canada (M.E.). Received March 2, 2006; revision requested May 3; revision received July 13; accepted August 23; final version accepted December 1. Supported by Steba-Biotech and Negma; the U.S. National Institutes of Health under program project grant CA43892 and the Muzzo Fund; and the Princess Margaret Hospital Foundation.
Address correspondence to M.A.H.
 |
ABSTRACT
|
|---|
Purpose: To prospectively evaluate the magnetic resonance (MR) imaging appearance of the prostate and periprostatic tissues after vascular targeted photodynamic therapy (VTP) with palladium-bacteriopheophorbide for locally recurrent carcinoma after external beam radiation therapy.
Materials and Methods: Informed consent was obtained from all patients, and approval was obtained from the ethics review boards of all participating institutions. Nonenhanced T2-weighted and dynamic gadolinium-enhanced T1-weighted MR imaging examinations were performed at baseline and 1 week, 4 weeks, and 6 months after VTP in 25 men (age range, 58–83 years; mean age, 73 years) as part of a prospective phase I/II trial. Percentage of MR-depicted necrosis was defined as the volume of nonenhancing prostatic tissue 1 week after VTP divided by the volume of the prostate. Patterns of intra- and extraprostatic necrosis were recorded. Pearson correlation coefficients were used to test correlations between necrosis and prostate-specific antigen level.
Results: Contrast material–enhanced T1-weighted MR images obtained 1 week after therapy showed necrosis in all patients. Treatment margins were irregular in 21 of 25 patients. T2-weighted images showed no clear treatment boundaries in any patient. Extraprostatic necrosis involved the puborectalis or levator ani muscles in 22, obturator internus muscle in 12, periprostatic veins in three, pubic bone marrow in four, and anterior rectal wall in nine of the 25 patients. The neurovascular bundle appeared to be spared in all patients. Percentage of MR-depicted intraprostatic necrosis was correlated with percentage decrease in prostate-specific antigen level (from baseline) at 4 weeks (r = 0.41, P = .04) and 12 weeks (r = 0.45, P = .02).
Conclusion: Contrast-enhanced MR imaging depicts irregular margins of intraprostatic treatment effect. This finding suggests varied tissue sensitivities to VTP with palladium-bacteriopheophorbide.
© RSNA, 2007
Clinical trial registration no. NCT00308919.
|
INTRODUCTION
|
|---|
There is a 20%–60% prevalence of biochemical progression of prostate cancer after external beam radiation therapy; positive biopsy results are reported 2 or more years after therapy for up to 50% of patients (1–5). Without salvage therapy, the median time to development of distant metastases is approximately 3 years (6). Androgen deprivation therapy is a therapeutic option, but it is not curative. The only curative option for these patients involves local salvage therapy, which is the only treatment that has reportedly facilitated cancer control for 10 years or longer (7). However, local salvage therapy is not commonly performed because of the relatively high rate of complications, including rectal injury (3%), urinary incontinence (56%), and anastomotic stricture (23%) (8). As a result, attempts have been made to perform less invasive methods such as thermal therapy (ie, cryotherapy [9,10] and microwave ablation [11]). Although small patient numbers have prevented investigations to determine the long-term effectiveness of these methods, these techniques have the potential to be effective and are associated with lower complication rates compared with radical prostatectomy if they are performed with minimal damage to the surrounding tissues such as the rectum, neurovascular bundle, and urethral sphincter.
Although thermal salvage therapies have been explored, there are other options. Photodynamic therapy (PDT) is a cancer treatment that involves the administration of a photosensitizing agent followed by the exposure of the target tissue to light, which stimulates the production of reactive oxygen species that cause cell death (12). PDT is used to treat many cancer sites, including the esophagus, lung, oropharynx, and bladder (13–15). The use of first-generation PDT agents to treat prostate cancer has been limited because of their long intravascular half-life, which results in prolonged skin sensitivity and spectral properties that limit the depth of treatment.
Palladium-bacteriopheophorbide (WST09, Tookad; Steba-Biotech N.V., The Hague, the Netherlands, and Negma, Toussus-le-Noble, France) is a relatively new PDT agent with properties that may make it favorable for treating prostate cancer, such as a short intravascular half-life and a near-infrared (763-nm) absorption band, which allow deeper light penetration in tissue (15,16). Unlike thermal therapies, PDT with palladium-bacteriopheophorbide has been shown to offer some degree of tumor selectivity and preservation of tissue architecture (17). The primary mode of inducing necrosis with this agent has been shown to be related to the rapid induction of vascular occlusion (18–20), so this therapy might be termed vascular targeted PDT (VTP). Thus, it would seem reasonable that contrast material–enhanced magnetic resonance (MR) imaging would be well suited for monitoring the therapeutic response. This has been previously demonstrated in an animal trial, in which the lack of prostatic enhancement at MR imaging was shown to correspond to histologically proved necrosis (21). Although there have been brief descriptions of MR imaging findings after PDT (22), we undertook our study to prospectively evaluate the MR imaging appearance of the prostate and periprostatic tissues after VTP with palladium-bacteriopheophorbide for locally recurrent carcinoma after external beam radiation therapy.
|
MATERIALS AND METHODS
|
|---|
Funding for the cost of the MR examinations, contrast material, and image interpretations in our study was provided by Negma. J.L.C. received remuneration from Negma for performing surgical procedures. M.E. is a consultant and investigator for Negma. The principal author (M.A.H.) had control over the inclusion of any data and information that might represent a conflict of interest for those authors who are consultants for Negma.
Patients
Informed consent was obtained from all patients, and approval was obtained from the ethics review boards of all three involved institutions (University Health Network; Royal Victoria Hospital, Montreal, Quebec, Canada; and London Health Sciences Center, London, Ontario, Canada). Twenty-eight men (age range, 58–83 years; mean age, 72 years) with histologically proved locally recurrent or persistent prostate cancer after external beam radiation therapy underwent VTP with palladium-bacteriopheophorbide as part of a prospective multi-institutional phase I/II trial from April 2004 through February 2005. The three participating institutions recruited 18, four, and six patients, respectively. Histologic proof of local recurrence was obtained with systematic, transrectal, ultrasonographically (US) guided prostate biopsy, which revealed cancer in at least one core specimen. The carcinoma stage after radiation therapy was T1N0M0 or T2N0M0. Cancer staging was performed by using digital rectal examination, computed tomography, and bone scanning. Failed external beam radiation therapy was defined on the basis of three consecutive elevations in serum prostate-specific antigen (PSA) level from a nadir value.
Patients were excluded if they were receiving any hormone treatment or taking photosensitizing medications, had undergone or were undergoing chemotherapy for prostatic carcinoma, had undergone transurethral resection of the prostate, had extensive cystitis and/or proctitis caused by radiation therapy, and/or had renal, hepatic, or hematologic disorders. Patients with cystitis and proctitis were excluded to avoid any potential effect on the hyperemic bladder or rectum from the PDT agent. Three patients did not complete imaging follow-up, and two of these three patients did not undergo post-VTP biopsy. Thus, 25 men (age range, 58–83 years; mean age, 73 years) were included in the image analysis and 26 were included in the response analysis. One patient was eliminated from analysis because he did not undergo biopsy or 6-month follow-up MR imaging.
Surgical Procedure
Three urologists (J.T., M.E., and J.L.C., with 27, 37, and 23 years prostate surgery experience, respectively) performed the VTP procedures. Patients were anesthetized and placed in the lithotomy position, and the prostate was visualized with transrectal US (Panther2002 ADI console with model 8558/S/T biplanar transrectal probe; B-K Medical Systems, Herlev, Denmark) on a model RTP-6000 precision stabilizer frame with a modified brachytherapy insertion template (Radiation Therapy Products, Seattle, Wash). By using trocars, the surgeon guided two to six closed-end catheters (15 gauge in diameter, 20 cm in length) through the perineum to the locations in the prostate determined at pretreatment planning (23). Optical fibers with cylindrically diffusing tips (Ceralas model CD 403; CeramOptec, Bonn, Germany) for light delivery were inserted. To minimize the risk of VTP-induced rectal injury, a hydrodissection procedure was performed (24). For this, a 5–10-mm separation between the rectal wall and the prostate was created by inserting a tube (model VSSW-5.5–38-17; Cook Canada, Stouffville, Ontario, Canada) into the space between the rectum and the prostate with US guidance and injecting sterile saline into the tube through a syringe. This space was maintained with a saline drip bag and a pressure cuff during VTP treatment. Light fiber positions were mapped on each transverse US image by measuring the perpendicular distance from the posterior prostate surface and from the midline to the fiber for the purpose of MR imaging correlation.
Palladium-bacteriopheophorbide was administered in a dose of 2 mg per kilogram of body weight. Light delivery began 6 minutes after the start of the infusion and lasted for approximately 30 minutes. The light doses and number of diffusing fibers were escalated according to the phase I/II protocol. The site of fiber placement and the expected treatment effect were determined with use of in-house treatment-planning software (23).
Imaging Protocol
Nonenhanced T2-weighted, dynamic gadolinium-enhanced T1-weighted, and delayed contrast-enhanced T1-weighted MR images were obtained 4–36 days (mean, 12.8 days) before VTP and 1 week (range, 6–8 days), 4 weeks (range, 24–35 days; mean, 29 days), and approximately 6 months (range, 159–465 days; mean, 7.2 months) after treatment. All examinations were preformed by using a 1.5-T MR imaging system (EchoSpeed, Excite, or Excite HD; GE Medical Systems, Milwaukee, Wis) and a four- or eight-channel phased-array surface coil. To minimize the risk of inducing a rectoprostatic fistula after therapy, an endorectal coil was not used. The following parameters were used to obtain nonenhanced T2-weighted images: 5600/98 (repetition time msec/echo time msec), echo train length of 16, bandwidth of 31.25 kHz, field of view of 20 cm, section thickness of 3 mm, no intersection gap, three acquired signals, no phase wrap, left-to-right phase-encoding direction, and matrix of 256 x 256.
Acquisition of the T2-weighted images was followed by the acquisition of dynamic contrast-enhanced T1-weighted images with use of a three-dimensional fast spoiled gradient-echo sequence and the following parameters: 8.8 (minimum)/4.2, 18° flip angle, bandwidth of 31.25 kHz, matrix of 256 x 160, fat saturation, no phase wrap, seven phases, and temporal resolution of 95 seconds per phase with no temporal gap between acquisitions; the first two phases were acquired before contrast material injection. With use of a power injector (Medrad, Indianola, Pa), 0.1 mmol/kg gadopentetate dimeglumine (Magnevist; Bayer Schering Pharma, Berlin, Germany) was injected at a rate of 4 mL/sec at the start of the third phase and followed by a 20-mL saline flush. Contrast material was injected to help distinguish necrotic from viable tissue. Delayed imaging was performed 10 minutes after the contrast material injection by using a conventional spin-echo T1-weighted pulse sequence with the following parameters: 650/20, bandwidth of 15 kHz, field of view of 20 cm, section thickness of 3 mm, no intersection gap, one acquired signal, matrix of 256 x 192, and fat saturation.
All necrosis and prostate contouring (discussed in following section) was performed by a radiology fellow (A.V.K.) and was checked by a staff radiologist (M.A.H.) with 10 years experience reading prostate MR images. In cases of discrepancy, the staff radiologist was assumed to be correct. This same staff radiologist performed all other imaging assessments. The radiologist and radiology fellow were blinded to the treatment data, PSA levels, and biopsy results.
Intraprostatic Treatment Effect 1 Week after VTP
Regions of necrosis were defined as areas with a visually obvious lack of enhancement on the T1-weighted images obtained 10 minutes after contrast material injection 1 week after VTP and that were new compared with findings on the baseline images. This definition was based on the findings in prior in vivo normal canine prostate studies, in which such changes were shown to correspond to regions of tissue necrosis (21). Lack of enhancement was assessed qualitatively by reviewing the dynamic contrast-enhanced and 10-minute contrast-enhanced images. A region of interest was drawn along the intraprostatic necrosis margins on each MR image section. This enabled calculation of the volume of intraprostatic necrosis. The prostate volume was derived by contouring the prostate on corresponding T2-weighted images. Percentage volume of necrosis was defined as the volume of necrosis divided by the volume of the prostate. Boundaries were classified as smooth or irregular. Signal intensity changes on T2-weighted images were described as increased, decreased, or mixed compared with the signal intensity on the baseline images. For both the contrast-enhanced T1-weighted and the nonenhanced T2-weighted MR images, the boundary was judged to be well defined along the entire border, well defined around a part of the border, or poorly defined. Areas of high signal intensity seen on T1-weighted images obtained before contrast material injection were considered evidence of hemorrhage. The intraprostatic urethra normally exhibited a ring of enhancement before VTP. A break in this ring after VTP was considered evidence of urethral wall involvement.
Quantitative analysis of enhancement was performed by using the dynamic contrast-enhanced MR images obtained at baseline and 1 week after VTP. For each section location in the dynamic contrast-enhanced series, an image was generated from the enhancement index calculated for each voxel: Et = 100·[(St/S0) – 1], where t is the time since injection of the contrast material, Et is the enhancement index at time t, St is the signal intensity at time t, and S0 is the baseline signal intensity.
From the enhancement index maps, a section that showed both enhancing and nonenhancing areas was chosen. A region of interest was then drawn in the apparent nonenhancing region as well as in the prostate outside of this region. Each region of interest encompassed the largest possible area of visually obvious enhancing and nonenhancing tissue and ranged in maximal diameter from 0.5 to 4.2 cm. The same regions of interest were then used on a similar section of the pretreatment enhancement index maps so that pretreatment enhancement could be compared with posttreatment enhancement. All-region-of-interest measurements were performed by using ImageJ software (National Institutes of Health, Bethesda, Md), and enhancement maps were constructed by using IDL v6.0 software (ITT Visual Information Solutions, Boulder, Colo). The purposes of this analysis were to quantitatively assess the degree of enhancement in areas that visually appeared to lack enhancement, assess the enhancement changes between pre- and post-VTP MR imaging, and determine if there was a change in enhancement of the background prostate tissue after VTP that was not visually obvious.
Extraprostatic Treatment Effect 1 Week after VTP
Extraprostatic necrosis was defined as an area showing lack of enhancement on the dynamic contrast-enhanced and 10-minute contrast-enhanced T1-weighted images and that was new compared with findings on the baseline images of the area outside the prostate. Assessment of necrosis in fat was not possible because of the inherent poor enhancement of this tissue. Specific structures assessed were the periprostatic veins, neurovascular bundle, obturator internus muscles, levator ani muscle, puborectalis muscle, bone marrow, and rectal wall.
MR Findings 4 Weeks and 6 Months after VTP
Intraprostatic necrosis boundaries were assessed in a manner similar to the assessment of the 1-week posttreatment image findings. Extraprostatic tissues were assessed for any changes in enhancement pattern compared with the enhancement patterns seen on images obtained 1 week after VTP. Because the boundaries of necrosis were poorly defined at 6 months and the volume of necrosis was smaller at 4 weeks, quantitative analysis of enhancement was not performed at these time points. The volume of necrosis at 4 weeks was compared with the volume of necrosis at 7 days.
Treatment Response and PSA Level
Patients underwent systematic transrectal US-guided biopsy 6 months after VTP with six to eight core specimens. Because of the small size of the prostate after radiation therapy and to minimize the risk of rectoprostatic fistula, more core specimens were not obtained. A 6-month time point was chosen to allow healing of any potential rectal injury from VTP. If there was no cancer at 6-month biopsy, the patient was considered to be a responder. PSA levels were measured at baseline and at 4 and 12 weeks after VTP. Percentage decrease in PSA level from baseline was correlated with percentage volume of necrosis at MR imaging performed 1 week after VTP.
Statistical Analyses
Statistical analysis was performed by using SPSS v11 software (SPSS, Chicago, Ill). P values lower than .05 were considered to indicate significance. For correlations between PSA level and MR-depicted necrosis, Pearson correlation coefficients were used and tested for difference from zero. Correlation coefficient values of 0.4–0.6 were considered to indicate a moderate correlation, while values of 0.7–1.0 were considered to indicate a strong correlation (25). Paired t tests were used to compare differences in mean enhancement indexes before and after therapy, mean enhancement indexes in different regions, and volumes of necrosis at 1 week and 4 weeks after VTP.
|
RESULTS
|
|---|
Intraprostatic Treatment Effect 1 Week after VTP
Intraprostatic necrosis was seen at MR imaging in all 25 patients, with the percentage of necrosis ranging from 0.9% to 80%. On the basis of the light fluence, the nature of the diffusion fibers, and the assumption of homogeneous drug distribution and tissue sensitivity, one would expect an ovoid smooth-bordered region of treatment effect around each fiber (23) (Fig 1a). The contrast-enhanced T1-weighted MR images, however, showed treatment margin irregularity in 21 of 25 patients and well-defined boundaries in all patients. In some cases, these features produced an appearance of islands of perfused (ie, spared) tissue surrounded by treated regions (Fig 1b). Previous animal studies have revealed structural and functional resistance of the urethra to VTP (16,26). On the basis of treatment plans with the assumption of equal sensitivity between prostatic and urethral tissues, one would expect urethral necrosis in all but one patient in our study. In our study, however, complete urethral preservation was seen in 10 of 25 patients, confirming urethral resistance to VTP. However, the urethra was not immune to VTP in all cases and demonstrated loss of wall enhancement in 15 patients (Fig 2a).
View larger version (108K):
[in this window]
[in a new window]
[Download PPT slide]
|
Figure 1a: Expected necrosis boundary determined by using treatment-planning software and necrosis effect observed at contrast-enhanced T1-weighted MR imaging. (a) On color fluence map superimposed on transverse contrast-enhanced T1-weighted MR image (650/20), the expected necrosis boundary determined by using treatment-planning software, which assumes homogeneous drug distribution and tissue sensitivity to PDT, is outlined in red. The margin of the prostate is outlined in blue. Blue dots (A, B, D, E) indicate optical fiber locations, and the yellow circle outlines the urethra. The rectum is outlined in green. (b) Corresponding 10-minute contrast-enhanced transverse fat-saturated T1-weighted MR image (650/20) obtained 1 week after VTP shows islands of spared enhancing tissue within the expected area of necrosis (small arrow) and irregular treatment boundaries (large arrow).
|
|
View larger version (168K):
[in this window]
[in a new window]
[Download PPT slide]
|
Figure 1b: Expected necrosis boundary determined by using treatment-planning software and necrosis effect observed at contrast-enhanced T1-weighted MR imaging. (a) On color fluence map superimposed on transverse contrast-enhanced T1-weighted MR image (650/20), the expected necrosis boundary determined by using treatment-planning software, which assumes homogeneous drug distribution and tissue sensitivity to PDT, is outlined in red. The margin of the prostate is outlined in blue. Blue dots (A, B, D, E) indicate optical fiber locations, and the yellow circle outlines the urethra. The rectum is outlined in green. (b) Corresponding 10-minute contrast-enhanced transverse fat-saturated T1-weighted MR image (650/20) obtained 1 week after VTP shows islands of spared enhancing tissue within the expected area of necrosis (small arrow) and irregular treatment boundaries (large arrow).
|
|
View larger version (174K):
[in this window]
[in a new window]
[Download PPT slide]
|
Figure 2a: Comparison of transverse (a) 10-minute gadolinium-enhanced fat-saturated T1-weighted MR image (650/20) and (b) nonenhanced T2-weighted MR image (5600/98) in defining regions of necrosis. (a) T1-weighted image obtained 1 week after VTP shows irregular but well-defined necrosis boundaries with partial loss of urethral wall enhancement (arrow). (b) Corresponding T2-weighted image shows mixed signal intensity within the treated areas, with poor boundary definition.
|
|
Unlike the contrast-enhanced MR images, the nonenhanced T2-weighted MR images did not show treatment boundaries well. The T2-weighted images showed poorly defined necrosis margins in 23 of 25 patients, with partial boundary definition in two cases (Fig 2b); thus, it was impossible to assess necrosis volumes. In all cases, there was mixed signal intensity change at T2-weighted imaging performed 1 week after VTP.
View larger version (169K):
[in this window]
[in a new window]
[Download PPT slide]
|
Figure 2b: Comparison of transverse (a) 10-minute gadolinium-enhanced fat-saturated T1-weighted MR image (650/20) and (b) nonenhanced T2-weighted MR image (5600/98) in defining regions of necrosis. (a) T1-weighted image obtained 1 week after VTP shows irregular but well-defined necrosis boundaries with partial loss of urethral wall enhancement (arrow). (b) Corresponding T2-weighted image shows mixed signal intensity within the treated areas, with poor boundary definition.
|
|
The mean enhancement index at all time points in the regions with no visually obvious enhancement ranged from 1%–6% compared with 99%–156% in the remainder of the prostate (P < .001) (Fig 3a). After VTP, the enhancement index decreased 97%–149% in the regions of necrosis (P < .001). There was no significant difference between the pre- and post-VTP enhancement indexes in the remainder of the prostate (P = .83) (Fig 3b). Thus, quantitative analysis revealed two classes of enhancement change: marked reduction in enhancement and no change in enhancement from baseline.
View larger version (12K):
[in this window]
[in a new window]
[Download PPT slide]
|
Figure 3a: Dynamic contrast enhancement curves at 1 week after VTP. MR-depicted necrosis was defined as an area with no visually obvious enhancement. (a) Graph of enhancement versus time for the prostate 1 week after VTP shows a marked difference in enhancement between areas of MR-depicted necrosis and the surrounding regions of enhancement in the background prostate tissue. (b) Graph shows the changes in enhancement in similar regions before and after VTP as a function of time after contrast material injection. The background prostate tissue shows no change, while the areas of MR-depicted necrosis show a marked decrease in enhancement compared with the enhancement at pre-VTP MR imaging. Error bars represent 95% confidence intervals of the mean enhancement or enhancement change value across the entire study population. Enhancement index was defined as the percentage signal intensity increase from the signal intensity at precontrast MR imaging.
|
|
View larger version (12K):
[in this window]
[in a new window]
[Download PPT slide]
|
Figure 3b: Dynamic contrast enhancement curves at 1 week after VTP. MR-depicted necrosis was defined as an area with no visually obvious enhancement. (a) Graph of enhancement versus time for the prostate 1 week after VTP shows a marked difference in enhancement between areas of MR-depicted necrosis and the surrounding regions of enhancement in the background prostate tissue. (b) Graph shows the changes in enhancement in similar regions before and after VTP as a function of time after contrast material injection. The background prostate tissue shows no change, while the areas of MR-depicted necrosis show a marked decrease in enhancement compared with the enhancement at pre-VTP MR imaging. Error bars represent 95% confidence intervals of the mean enhancement or enhancement change value across the entire study population. Enhancement index was defined as the percentage signal intensity increase from the signal intensity at precontrast MR imaging.
|
|
Extraprostatic Treatment Effect 1 Week after VTP
At 1 week after VTP, an extraprostatic treatment effect was seen at MR imaging in 22 of 25 patients. There was some loss of rectal enhancement in nine patients. In seven of these nine patients, the effect was limited to the outer rectal wall (muscularis propria), and in two patients, there was also partial involvement of the mucosa (Fig 4). One of these patients developed clinical symptoms of a rectourethral fistula, but the fistula tract could not be defined with MR imaging or cystoscopy. The fistula eventually resolved. The anterior puborectalis muscle showed loss of enhancement anteroinferiorly in all patients who exhibited an extraprostatic treatment effect. Fourteen of 22 patients had involvement of other extraprostatic tissues: In 12 of these 14 patients, the anteroinferior obturator internus muscle was involved (Fig 5), and three of these 14 patients had periprostatic vein thrombosis. The intraprostatic and extraprostatic necroses were not always contiguous. Definitive loss of enhancement of the vessels in the region of the neurovascular bundle was not seen in any patient, and the periprostatic vessels were most often spared despite necrosis development on either side. These findings suggest resistance of the macroscopic vasculature to treatment (Fig 6). In all patients, the extraprostatic treatment effect was poorly assessed on the T2-weighted MR images.
View larger version (168K):
[in this window]
[in a new window]
[Download PPT slide]
|
Figure 4a: Transverse 10-minute contrast-enhanced fat-saturated T1-weighted MR images (650/20) demonstrate partial rectal wall involvement with healing at 6 months. (a) Image obtained 1 week after VTP shows loss of enhancement in the outer layer of the rectal wall (muscularis propria), with sparing of the mucosa (black arrowheads). The urethral wall (white arrow) is spared, and the levator ani muscles (white arrowheads) on the left and right sides of the prostate exhibit loss of enhancement. There is an island of spared tissue (open arrow) within the treated region. (b) On image obtained at 6 months, the rectal wall (white arrow) has returned to normal enhancement, and there is enhancement of the levator ani muscles (arrowheads) consistent with healing. The prostate has shrunk; the treated area (open arrows) is much smaller and enhancing slightly.
|
|
View larger version (164K):
[in this window]
[in a new window]
[Download PPT slide]
|
Figure 4b: Transverse 10-minute contrast-enhanced fat-saturated T1-weighted MR images (650/20) demonstrate partial rectal wall involvement with healing at 6 months. (a) Image obtained 1 week after VTP shows loss of enhancement in the outer layer of the rectal wall (muscularis propria), with sparing of the mucosa (black arrowheads). The urethral wall (white arrow) is spared, and the levator ani muscles (white arrowheads) on the left and right sides of the prostate exhibit loss of enhancement. There is an island of spared tissue (open arrow) within the treated region. (b) On image obtained at 6 months, the rectal wall (white arrow) has returned to normal enhancement, and there is enhancement of the levator ani muscles (arrowheads) consistent with healing. The prostate has shrunk; the treated area (open arrows) is much smaller and enhancing slightly.
|
|
View larger version (159K):
[in this window]
[in a new window]
[Download PPT slide]
|
Figure 5a: Transverse 10-minute contrast-enhanced fat-saturated T1-weighted MR images (650/20) show extraprostatic treatment effect in bone marrow and muscle. (a) Image obtained 4 weeks after VTP shows normal bone marrow. There is evidence of extraprostatic necrosis in the right obturator internus muscle (arrows), which was also seen on the 1-week posttreatment images. (b) Image obtained 6 months after VTP shows enhancement (arrows) suggestive of infarction within the marrow. There is also return of enhancement to the obturator internus muscle, consistent with healing.
|
|
View larger version (138K):
[in this window]
[in a new window]
[Download PPT slide]
|
Figure 5b: Transverse 10-minute contrast-enhanced fat-saturated T1-weighted MR images (650/20) show extraprostatic treatment effect in bone marrow and muscle. (a) Image obtained 4 weeks after VTP shows normal bone marrow. There is evidence of extraprostatic necrosis in the right obturator internus muscle (arrows), which was also seen on the 1-week posttreatment images. (b) Image obtained 6 months after VTP shows enhancement (arrows) suggestive of infarction within the marrow. There is also return of enhancement to the obturator internus muscle, consistent with healing.
|
|
View larger version (170K):
[in this window]
[in a new window]
[Download PPT slide]
|
Figure 6: Sparing of neurovascular bundle. Transverse 10-minute contrast-enhanced fat-saturated T1-weighted MR image (650/20) obtained 7 days after VTP shows intraprostatic and extraprostatic necrosis. Despite the necrosis (arrowhead) adjacent to the neurovascular bundle, there is no evidence of thrombosis of the vessels in the region of the neurovascular bundle (arrows).
|
|
MR Imaging Findings 4 Weeks and 6 Months after VTP
Maximal necrosis was visualized at MR imaging 1 week after VTP in 23 of 25 patients. The volume of necrosis measured at MR imaging 1 week after VTP was significantly higher than that measured at 1 month (P < .001; mean volume decrease, 2.7 cm3). This finding suggests that 1-week MR imaging is superior to 4-week MR imaging for assessment of maximal treatment response. Four patients developed pubic marrow enhancement changes that suggested bone infarction. These changes were not visible 1 week after VTP, were partially visible at 4 weeks, and were most evident at 6-month MR imaging (Fig 5b). There was a region of increased signal intensity on the nonenhanced fast spoiled gradient-echo MR images of the treated areas at 1 week in one patient and at 4 weeks in 11 patients, suggesting hemorrhagic necrosis.
The treated areas were well defined on the contrast-enhanced T1-weighted images obtained 6 months after VTP in only seven of 25 patients. These regions were shrunken and exhibited some mild enhancement. In the regions of extraprostatic necrosis seen at 1 week, there was a complete return of enhancement in 16 and a partial return of enhancement in six of 22 patients (Figs 4b, 5b), suggesting healing. In two patients, a urine-filled cavity had formed in the prostatic bed, suggesting sloughing or resorption of the prostate. Thus, 6-month MR imaging was of little value in assessing treatment response, but it did reveal effects such as marrow infarction and changes associated with healing.
Treatment Response and PSA Level
The percentage of MR-depicted intraprostatic necrosis at 1 week after VTP was moderately correlated with the percentage decrease in PSA level from baseline at 4 weeks (r = 0.41, P = .04) and 12 weeks (r = 0.45, P = .02). There were no correlations with absolute PSA levels.
Six-month post-VTP biopsy results were available for 26 of 28 patients. Eight of these patients were responders: Biopsy revealed no cancer. With the assumption that 100% specificity for response would be required, an MR-depicted necrosis threshold of greater than 55% yielded a sensitivity of 62% (five of eight responders). For an assessment based on 4-week PSA levels performed to obtain an early measure of response, using a PSA level criterion of less than 0.4 ng/mL yielded a sensitivity of 38% (three of eight responders) (Fig 7). With use of the 12-week PSA level, the PSA level threshold of less than 0.5 ng/mL yielded the same sensitivity, 38% (three of eight responders). The percentage decrease in PSA level from baseline at 4 weeks was of little value: The threshold of a greater than 95% decrease yielded a sensitivity of 13% (one of eight responders).
|
DISCUSSION
|
|---|
PDT with palladium-bacteriopheophorbide involves the intravenous administration of a photosensitizing drug, which is followed by drug activation by means of illumination of the target tissue with light of a particular wavelength. This process results in the production of reactive oxygen species that cause cell death and tissue ablation. On the basis of the rapid effect of palladium-bacteriopheophorbide and its short half-life, one would expect early post-VTP MR imaging to reveal the maximal treatment effect. In our study, the volume of necrosis depicted at MR imaging was significantly higher at 1 week than at 1 month, confirming that palladium-bacteriopheophorbide has an early effect on prostatic tissue. The reduced size of the treated area over time combined with the presence of fibrosis in these areas at 6-month biopsy was consistent with gradual healing.
On the basis of models of light and drug delivery that assume homogeneous light and drug distribution around a laser fiber, one would expect a smooth cylindrical or ellipsoidal boundary of treatment effect. In our study, we found that the majority of patients had marked irregularity at the treatment boundary, with tendrils of enhancing tissue extending close to the fiber and areas of enhancing viable tissue interposed between nonenhancing necrotic regions. These findings suggest the possibility of tissue selectivity or varied tissue response to the light-drug combination in VTP in the human prostate. Preclinical studies have revealed that squamous cell carcinoma and vascularized tissues have higher sensitivity to PDT with palladium-bacteriopheophorbide (17,20). Thus, the irregular boundaries seen on MR images of the prostate may be related to variations in the geometry of the blood supply or to the varied distribution of fibrotic tissue, normal tissue, and cancerous tissue in the irradiated prostate (27). If in fact these irregular boundaries are indicative of tumor selectivity, then this selectivity could give VTP an advantage over thermal therapies that are nonselective.
Regions of extraprostatic effect were not always contiguous with regions of intraprostatic treatment effect. This finding supports the concept that variations in tissue sensitivity and in light and drug distributions affected the areas of treatment effect. Of note was the relative sparing of the periprostatic veins, which were thrombotic in only three of 25 patients. Despite the proximity of the neurovascular bundle to the treatment fibers and the associated high drug concentration in this area, no thrombosis in the region of the neurovascular bundle was seen at MR imaging. This finding suggests that with VTP, there may be a reduced chance of complications, such as impotence, compared with the chance of complications associated with thermal methods. As with thermal methods and salvage prostatectomy, with the described VTP there may be the potential for rectal injury. This potential was supported by the MR imaging evidence of rectal wall involvement in nine of 25 patients in our study. Further refinements of treatment delivery methods are underway to help minimize this risk.
Nonenhanced T2-weighted imaging did not depict the treated areas well. One might expect the development of high signal intensity at T2-weighted imaging owing to tissue necrosis and increased edema and free water in tissue, but this was not the case. This lack of high signal intensity may have been related to the presence of coagulative and hemorrhagic necrosis, which has been previously demonstrated in association with PDT with palladium-bacteriopheophorbide in canine prostate models (16) and was supported by the high signal intensity at nonenhanced T1-weighted imaging in our study.
Contrast-enhanced T1-weighted MR imaging performed 1 week after VTP enabled the prediction of 6-month biopsy results negative for cancer better than did PSA assessment; at this time, however, there are insufficient data to draw any definitive conclusions regarding the value of MR imaging versus PSA measurement in predicting outcome.
The principal limitation of our study was the absence of whole-mount histopathologic specimen correlation to validate the regions of treatment effect seen on MR images. However, validation has been performed by using similar pulse sequences in the canine prostate (21), and contrast enhancement changes were expected on the basis of the known mechanism of action of the drug. We qualitatively assessed lack of enhancement as a measure of necrosis, and such assessment may be subject to interobserver variability. However, quantitative analysis revealed a marked difference in enhancement between areas judged to be necrotic and background prostate tissue, which suggests that interobserver variability was probably low.
The use of a 20-cm field of view may have limited our assessment of very small areas of tissue necrosis. This field of view was chosen because we did not know the degree of extraprostatic effect to expect and wanted to be sure that we covered all of the central pelvic soft tissue. An endorectal coil was not used because of the concern of inducing a rectoprostatic fistula. Finally, we used negative 6-month biopsy results as a measure of response, and this may have caused us to miss small foci of residual cancer. The true measure of response should be based on longer-term measures of residual or recurrent tumor.
The use of VTP for primary prostate cancer is of interest. At this time, it is unclear whether the response of nonirradiated human prostate tissue would be similar to that of irradiated prostate tissue. There is a difference in vascularity and tissue composition between these tissues that might affect their sensitivity to VTP; further trials to determine the dose-related response to VTP for primary therapy of prostate cancer are underway. It should be noted, however, that in a previous study (26), no qualitative differences at histopathologic analysis or differences in size of the PDT-induced lesions between irradiated and nonirradiated tissues were observed in normal dog prostate tissue treated with VTP.
In conclusion, VTP with palladium-bacteriopheophorbide for recurrent prostate carcinoma after external beam radiation therapy yields irregular margins of treatment effect at contrast-enhanced MR imaging, suggesting varied tissue sensitivities to this mode of treatment.
|
ADVANCE IN KNOWLEDGE
|
|---|
- The potential varied tissue response seen with palladium-bacteriopheophorbide photodynamic therapy in the prostate is demonstrated at contrast-enhanced MR imaging.
|
ACKNOWLEDGMENTS
|
|---|
We acknowledge the input of Diego Provvedini, MD, and Patrick Cohen, MD.
|
FOOTNOTES
|
|---|
Abbreviations: PDT = photodynamic therapy • PSA = prostate-specific antigen • VTP = vascular targeted PDT
See Materials and Methods for pertinent disclosures.
Author contributions: Guarantor of integrity of entire study, M.A.H.; study concepts/study design or data acquisition or data analysis/interpretation, all authors; manuscript drafting or manuscript revision for important intellectual content, all authors; manuscript final version approval, all authors; literature research, M.A.H., B.C.W.; clinical studies, M.A.H., S.R.H.D., A.V.K., R.A.W., A.T., M.R.G., A.B., B.C.W., J.L.C., M.E., J.T.; statistical analysis, M.A.H., S.R.H.D., A.V.K., B.C.W., J.L.C.; and manuscript editing, M.A.H., S.R.H.D., R.A.W., A.J.E., A.T., B.C.W., J.L.C., M.E., J.T.
|
References
|
|---|
- Nichol A, Chung P, Lockwood G, et al. A phase II study of localized prostate cancer treated to 75.6 Gy with 3D conformal radiotherapy. Radiother Oncol 2005;76:11–17.[CrossRef][Medline]
- Zietman AL, DeSilvio ML, Slater JD, et al. Comparison of conventional-dose vs high-dose conformal radiation therapy in clinically localized adenocarcinoma of the prostate: a randomized controlled trial. JAMA 2005;294:1233–1239.[Abstract/Free Full Text]
- Pollack A, Zagars GK, Antolak JA, Kuban DA, Rosen II. Prostate biopsy status and PSA nadir level as early surrogates for treatment failure: analysis of a prostate cancer randomized radiation dose escalation trial. Int J Radiat Oncol Biol Phys 2002;54:677–685.[CrossRef][Medline]
- Zelefsky MJ, Leibel SA, Gaudin PB, et al. Dose escalation with three-dimensional conformal radiation therapy affects the outcome in prostate cancer. Int J Radiat Oncol Biol Phys 1998;41:491–500.[CrossRef][Medline]
- Crook JM, Bahadur YA, Bociek RG, Perry GA, Robertson SJ, Esche BA. Radiotherapy for localized prostate carcinoma: the correlation of pretreatment prostate specific antigen and nadir prostate specific antigen with outcome as assessed by systematic biopsy and serum prostate specific antigen. Cancer 1997;79:328–336.[CrossRef][Medline]
- Lee WR, Hanks GE, Hanlon A. Increasing prostate-specific antigen profile following definitive radiation therapy for localized prostate cancer: clinical observations. J Clin Oncol 1997;15:230–238.[Abstract/Free Full Text]
- Bianco FJ Jr, Scardino PT, Stephenson AJ, Diblasio CJ, Fearn PA, Eastham JA. Long-term oncologic results of salvage radical prostatectomy for locally recurrent prostate cancer after radiotherapy. Int J Radiat Oncol Biol Phys 2005;62:448–453.[CrossRef][Medline]
- Ward JF, Sebo TJ, Blute ML, Zincke H. Salvage surgery for radiorecurrent prostate cancer: contemporary outcomes. J Urol 2005;173:1156–1160.[CrossRef][Medline]
- Izawa JI, Perrotte P, Greene GF, et al. Local tumor control with salvage cryotherapy for locally recurrent prostate cancer after external beam radiotherapy. J Urol 2001;165:867–870.[CrossRef][Medline]
- Chin JL, Pautler SE, Mouraviev V, Touma N, Moore K, Downey DB. Results of salvage cryoablation of the prostate after radiation: identifying predictors of treatment failure and complications. J Urol 2001;165:1937–1941.[CrossRef][Medline]
- Chen JC, Moriarty JA, Derbyshire JA, et al. Prostate cancer: MR imaging and thermometry during microwave thermal ablation-initial experience. Radiology 2000;214:290–297.[Abstract/Free Full Text]
- Ackroyd R, Kelty C, Brown N, Reed M. The history of photodetection and photodynamic therapy. Photochem Photobiol 2001;74:656–669.[CrossRef][Medline]
- Radu A, Wagnieres G, van den Bergh H, Monnier P. Photodynamic therapy of early squamous cell cancers of the esophagus. Gastrointest Endosc Clin N Am 2000;10:439–460.[Medline]
- Metz JM, Friedberg JS. Endobronchial photodynamic therapy for the treatment of lung cancer. Chest Surg Clin N Am 2001;11:829–839.[Medline]
- Jichlinski P, Leisinger HJ. Photodynamic therapy in superficial bladder cancer: past, present and future. Urol Res 2001;29:396–405.[CrossRef][Medline]
- Chen Q, Huang Z, Luck D, et al. Preclinical studies in normal canine prostate of a novel palladium-bacteriopheophorbide (WST09) photosensitizer for photodynamic therapy of prostate cancers. Photochem Photobiol 2002;76:438–445.[CrossRef][Medline]
- Borle F, Radu A, Fontolliet C, van den Bergh H, Monnier P, Wagnieres G. Selectivity of the photosensitiser Tookad for photodynamic therapy evaluated in the Syrian golden hamster cheek pouch tumour model. Br J Cancer 2003;89:2320–2326.[CrossRef][Medline]
- Gross S, Gilead A, Scherz A, Neeman M, Salomon Y. Monitoring photodynamic therapy of solid tumors online by BOLD-contrast MRI. Nat Med 2003;9:1327–1331.[CrossRef][Medline]
- Kelleher DK, Thews O, Scherz A, Salomon Y, Vaupel P. Perfusion, oxygenation status and growth of experimental tumors upon photodynamic therapy with Pd-bacteriopheophorbide. Int J Oncol 2004;24:1505–1511.[Medline]
- Borle F, Radu A, Monnier P, van den Bergh H, Wagnieres G. Evaluation of the photosensitizer Tookad for photodynamic therapy on the Syrian golden hamster cheek pouch model: light dose, drug dose and drug-light interval effects. Photochem Photobiol 2003;78:377–383.[CrossRef][Medline]
- Huang Z, Haider MA, Kraft S, et al. Magnetic resonance imaging correlated with the histopathological effect of Pd-bacteriopheophorbide (Tookad) photodynamic therapy on the normal canine prostate gland. Lasers Surg Med 2006;38:672–681.[CrossRef][Medline]
- Moore CM, Nathan TR, Lees WR, et al. Photodynamic therapy using meso tetra hydroxy phenyl chlorin (mTHPC) in early prostate cancer. Lasers Surg Med 2006;38:356–363.[CrossRef][Medline]
- Weersink RA, Bogaards A, Gertner M, et al. Techniques for delivery and monitoring of TOOKAD (WST09)-mediated photodynamic therapy of the prostate: clinical experience and practicalities. J Photochem Photobiol B 2005;79:211–222.[CrossRef][Medline]
- Sherar MD, Gertner MR, Yue CK, et al. Interstitial microwave thermal therapy for prostate cancer: method of treatment and results of a phase I/II trial. J Urol 2001;166:1707–1714.[CrossRef][Medline]
- Zou KH, Tuncali K, Silverman SG. Correlation and simple linear regression. Radiology 2003;227:617–622.[Abstract/Free Full Text]
- Huang Z, Chen Q, Trncic N, et al. Effects of Pd-bacteriopheophorbide (TOOKAD)-mediated photodynamic therapy on canine prostate pretreated with ionizing radiation. Radiat Res 2004;161:723–731.[CrossRef][Medline]
- Sheaff MT, Baithun SI. Effects of radiation on the normal prostate gland. Histopathology 1997;30:341–348.[CrossRef][Medline]
This article has been cited by other articles:
|
|
|
|
 
H. Patel, R. Mick, J. Finlay, T. C. Zhu, E. Rickter, K. A. Cengel, S. B. Malkowicz, S. M. Hahn, and T. M. Busch
Motexafin Lutetium-Photodynamic Therapy of Prostate Cancer: Short- and Long-Term Effects on Prostate-Specific Antigen
Clin. Cancer Res.,
August 1, 2008;
14(15):
4869 - 4876.
[Abstract]
[Full Text]
[PDF]
|
|
|
TOP
ABSTRACT
INTRODUCTION
), as compared with the three of eight responders predicted by using early PSA levels. 
= nonresponders. PSA level is plotted on a logarithmic scale.