Photodynamic Therapy for Prostate Cancer Recurrence After Radiotherapy: A Phase I Study

0022-5347/02/1684-1427/0 THE JOURNAL OF UROLOGY® Copyright © 2002 by AMERICAN UROLOGICAL ASSOCIATION, INC.®

Vol. 168, 1427–1432, October 2002 Printed in U.S.A.

DOI: 10.1097/01.ju.0000030000.81684.7e

PHOTODYNAMIC THERAPY FOR PROSTATE CANCER RECURRENCE AFTER RADIOTHERAPY: A PHASE I STUDY TIMOTHY R. NATHAN*, DOUGLAS E. WHITELAW, STANLEY C. CHANG, WILLIAM R. LEES*, PAUL M. RIPLEY, HEATHER PAYNE, LINDA JONES*, M. CONSTANCE PARKINSON, MARK EMBERTON, ALISON R. GILLAMS, ANTHONY R. MUNDY AND STEPHEN G. BOWN* From the National Medical Laser Center, Department of Surgery and the Institute of Urology, Royal Free and University College Medical School, London, the Departments of Imaging, Radiotherapy and Histopathology, University College London Hospitals, London, United Kingdom, and the Tzu-Chi College of Medicine, Hue-Lin, Taiwan

ABSTRACT

Purpose: Photodynamic therapy, using a photosensitizing drug activated by red light, can destroy localized areas of cancer with safe healing and without the cumulative toxicity associated with ionizing radiation. We used photodynamic therapy in a phase I–II study to treat patients with locally recurrent prostate cancer after radiotherapy. Materials and Methods: Patients with an increasing prostate specific antigen (PSA) and biopsy proven local recurrence after radiotherapy were offered photodynamic therapy. Three days after intravenous administration of the photosensitizer meso-tetrahydroxyphenyl chlorin, light was applied using optical fibers inserted percutaneously through perineal needles positioned in the prostate with imaging guidance. Patients were followed with PSA measurements, prostate biopsies, computerized tomography or magnetic resonance imaging and questionnaires on urinary and sexual function. Results: Photodynamic therapy was given to 14 men using high light doses in 13. Treatment was well tolerated. PSA decreased in 9 patients (to undetectable levels in 2) and 5 had no viable tumor on posttreatment biopsies. After photodynamic therapy, contrast enhanced computerized tomography or magnetic resonance imaging showed necrosis involving up to 91% of the prostate cross section. In 4 men stress incontinence developed (troublesome in 2 and mild in 2) which is slowly improving. Sexual potency was impaired in 4 of the 7 men able to have intercourse before photodynamic therapy, which did not improve. There were no rectal complications directly related to photodynamic therapy, but in 1 patient a urethrorectal fistula developed following an ill-advised rectal biopsy 1 month after therapy. Conclusions: Photodynamic therapy is a new option that could be suitable for organ confined prostate cancer recurrence after radiotherapy. With more precise light dosimetry, it may be possible to destroy essentially all glandular tissue within the prostate with few complications. These results suggest that photodynamic therapy merits further investigation. KEY WORDS: prostatic neoplasms, photochemotherapy, recurrence, radiotherapy

Prostate cancer is now the most commonly diagnosed internal malignancy and the second leading cause of cancer deaths, after lung cancer, among men in the United States.1 The advent of prostate specific antigen (PSA) screening means that increasingly tumors are discovered at an early stage when they are confined to the prostate gland and suitable for cure by radical surgery or radiotherapy. Reported long-term (15-year) cure rates are 19% to 46% for radiotherapy and 40% to 75% for radical prostatectomy.2 However, urinary incontinence and impotence occur in up to 40% and 60% of patients, respectively, after radical prostatectomy3 and up to 7% and 66%, respectively, after radiotherapy.4, 5 Furthermore, tumors detected by screening have a variable biology and a proportion present little threat to survival.6 There is a need for a minimally invasive treatment which destroys organ confined tumor without the risks of radical surgery or radiotherapy or which can be used for tumor recurrence after radiotherapy.

Photodynamic therapy produces localized tissue necrosis with light (most conveniently from a laser) after prior administration of a photosensitizing drug. It does not have the chronic and cumulative toxicity associated with radiotherapy and can be applied to previously irradiated tissue. In vivo studies on the canine prostate have shown that substantial volumes of necrosis can be produced by photodynamic therapy without any unacceptable effects on the surrounding tissue.7, 8 The largest zones of necrosis and the shortest treatment times have been achieved using the photosensitizer meso-tetrahydroxyphenyl chlorin (Foscan, Scotia Pharmaceuticals, Stirling, United Kingdom),7 and so this agent was chosen for clinical assessment. We describe the first phase I–II study to assess the safety and efficacy of percutaneous interstitial photodynamic therapy for patients with localized cancer recurrence following radical radiotherapy. MATERIALS AND METHODS

Accepted for publication April 5, 2002. Supported by the Association for International Cancer Research Patients with 2 or more consecutive increases in PSA dur(St. Andrews, Scotland), the Compassion Relief of Tzu-Chi Founda- ing followup after radical radiotherapy were identified and tion (Hue-Lin, Taiwan) and Scotia Pharmaceuticals (Stirling, United recurrent adenocarcinoma in the prostate gland was conKingdom). * Financial interest and/or other relationship with Scotia Pharma- firmed on transrectal ultrasound guided biopsy (fig. 1, A). Either quadrant or sextant biopsies were taken, depending ceuticals. 1427

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PHOTODYNAMIC THERAPY FOR RECURRENT PROSTATE CANCER

FIG. 1. A, biopsy of patient 6 shows focus of recurrent cancer after radical radiotherapy (arrow). B, biopsy of patient 6, 2 days after therapy reveals several foci with many necrotic cells and marked infiltration of inflammatory cells in fibrous stroma (arrow). Biopsy was taken from lobe of prostate showing almost complete nonenhancement on MRI after therapy. C, biopsy of patient 4, 2 months after therapy reveals small amount of residual cellular necrosis (arrow) in extensive fibrous stroma with much less inflammation than seen 2 days after therapy. H & E, reduced from ⫻30.

on the size of the gland. Patients with locally advanced or extraprostatic disease on a bone scan, or contrast enhanced computerized tomography (CT) or magnetic resonance imaging (MRI) were excluded from study. All patients were considered unsuitable for salvage surgery (radical prostatectomy). After giving informed consent, patients were sensitized with 0.15 mg./kg. intravenous meso-tetrahydroxyphenyl chlorin and kept in reduced room lighting to prevent skin photosensitivity. Three days later with the patient under sedation and using prophylactic urinary catheterization and gentamicin 2 to 8, 15 cm., 19 guage needles were positioned percutaneously in the prostate gland (1 to 2 cm. between needles) with transrectal ultrasound (ATL 5000, Bothel, Washington) or MRI (0.2 Tesla, Viva interventional scanner, Siemens, Erlangen, Germany) guidance. As this was a phase I study no attempt was made to treat the entire gland. The needles were inserted individually into 1 or both lobes based on the location of the biopsies involved with cancer, and the number of needles depended on the size of the gland. The peripheral zone of the affected lobe(s) was treated from base to apex by passing laser fibers (core diameter 0.4 mm., bare tip, except for 1 treatment in which diffuser fibers were used) through the needles to deliver red light at sites 1 cm. apart along the needle track as the needle was withdrawn. The light source was a diode laser (Applied Optronics Corp; New Jersey, wavelength 652 nm., power 100 to 150 mW. per fiber to prevent fiber tip charring) activating up to 4 fibers simultaneously using a beam-splitter. The response was assessed by serial measurements of PSA and contrast enhanced MRI or CT a few days and 2 months after photodynamic therapy. Transrectal ultrasound guided prostate biopsies were repeated 1 to 4 months after therapy. Patients completed simple questionnaires on urinary and sexual function before and after therapy. The rectum was assessed by flexible sigmoidoscopy before and 2 to 5 days after photodynamic therapy. Some patients with a poor response underwent repeat treatment. Those in whom the PSA continued to increase during followup and who were not considered suitable for further photodynamic therapy were offered androgen blockade. The study was approved by the ethical committee of the University College London Hospitals. RESULTS

Photodynamic therapy was given to 14 patients with localized recurrent cancer 22 to 108 months (median 42) after radical external beam radiotherapy (40 to 64 Gy) between April 1996 and June 1999. Median patient age at the time of photodynamic therapy was 70 years (range 58 to 77). In the first 5 patients the light dose was limited to 20 J. per site, which was chosen as it was considered to be a safe dose at which to start clinical studies based on the canine experiments. Small areas of devascularization were detected on

contrast enhanced CT a few days after photodynamic therapy in these patients and there were no complications but the PSA levels did not decrease. Subsequently, 13 patients, including 4 of the original 5, were treated with a higher light dose of at least 50 J. per site, which was generally well tolerated. Three patients asked for the higher dose treatment to be repeated as there was little improvement in PSA and remaining areas of viable tissue were seen on the scans of the areas from which biopsies showed persistent cancer. Only the results of the higher dose treatments are reported. Response of tumor. The tumor response was assessed by followup biopsies, serial measurements of PSA and area of necrosis documented on posttreatment scans (table 1). Biopsies a few days after photodynamic therapy showed edema, hemorrhage and necrosis, most marked in the epithelial components (fig. 1, B). There was marked fibrosis with pigmented macrophages 2 months after therapy and little glandular tissue (fig. 1, C). Table 1 shows the number of biopsy cores with viable cancer and the total number of cores taken before and 1 to 4 months after photodynamic therapy. Serial measurements of PSA from the time of the first high dose photodynamic therapy are shown in figure 2. In all cases PSA eventually started to increase again. Of the 14 patients 13, including 1 with extraprostatic disease after low dose photodynamic therapy who did not receive the higher dose, have now started antiandrogen therapy 3 to 38 months (median 10) after therapy. In 10 cases a contrast enhanced scan 2 to 5 days after photodynamic therapy revealed a marked inflammatory response with edema in the treated area, sometimes spreading into surrounding tissues. The prostate volume increased by a median of 81% (range 14% to 161%) over the pretreatment size. At this time it was difficult to define the extent of necrosis as the appearance was often mottled with patchy uptake of contrast material. In 11 cases a contrast enhanced scan 2 months after photodynamic therapy (14 treatments) revealed that the inflammatory changes had resolved and the prostate had returned close to pretreatment volume (fig. 3). Only 1 prostate was more than 5% smaller after than before photodynamic therapy (16% smaller) but the areas of induced necrosis were much more clearly demarcated. In 5 patients scanned 5 to 26 months after photodynamic therapy the zones of necrosis had become much smaller due to healing. In 2 of these cases the overall size of the gland was the same as that before therapy but in the other 3 with glands of pretreatment size at 2 months, the glands continued to shrink by 17% to 30% below pretreatment size. It was often difficult to measure the extent of necrosis in the plane perpendicular to the plane of the scans, and so quantification was done in 2 dimensions. On the 2-month scan showing the largest cross-sectional area of prostate the total area of the gland and area of necrosis were estimated by measuring maximum dimensions in 2 perpendicular directions and assuming the areas were roughly elliptical. When

Tumor Stage PSA (ng./ml.) Gleason Score Pt. No.

3/4 3/5 1/4 0/5 0/5 0/2** 1/4, 2/6 0/9 2/4 1/4, 1/7, 0/6 2/4, not recorded Not recorded 3/6 2/6 5/5 5/5 6/6 1/4 1/4 4/4 2/4 2/5 2/4 1/6 5/6 3/6 No reduction No reduction 10.9 (9) 0.1 (96) 3.9 (38) 0.1 (99) 8.6 (79) No reduction 16.2 (30) No reduction 5.1 (41) 3.3 (68) 4.3 (62) 1 T3 37.3 3⫹4 77 4⫹5 5 70 10.8 2 T3 35 5⫹4 70 4⫹4 6 48 34.4 3 T2 10.2 2⫹4 71 4⫹3 6 82 12 4 T3 14 3⫹3 59 4⫹5 7 91 2.2 5 T2 17 3⫹4 68 3⫹4 3 40¶ 6.3 6 T3 11.8 Not recorded 67 3⫹4 6 49¶ 8.1 7‡ T3 Not recorded Not recorded 61 3⫹4 4, 4 49, 42 40.0, 20.1 8 T3 15.6 3⫹3 68 3⫹3 8 80 12.3 9 T2 17.6 3⫹3 72 4⫹4 4 48¶ 23.3 10§ T2 27.6 2⫹3 69 2⫹3 4, 4, 2 7, 57, 100¶ 8.8, 15, 26.3 11 T2 37 Not recorded 58 3⫹4 2,㛳 4 8,¶ not recorded 8.7, 10.4 12 T3 21 Not recorded 75 4⫹3 6 53** 10.4 13 T2 24.7 3⫹4 70 3⫹4 2 20 11.2 Excludes 5 treatments performed at low light dose (20 to 25 J.) per site and case treated with low dose but not high dose. * Up to 4 sites were treated with 50 J. along each fiber track using bare tip fibers. † Measurements on scan slices showing the largest cross-sectional area of prostate 2 months after therapy. ‡ Treatment 2 consisted of 75 J. on 8 sites and 50 J. on 5 sites. § Treatment 2 consisted of 75 J. on 8 sites and 50 J. on 5 sites, and treatment 3 consisted of 100 J. on 4 sites and 50 J. on 2 sites. 㛳 For first treatment 2 fibers with 2 cm. diffuser tips were used. ¶ Treatment covered only 1 lobe of prostate. ** Data from 5 days after therapy.

1–4 Mos. After Therapy Before Therapy

PSA 1st High Dose Therapy (ng./ml.) % Necrosis Cross Section† No. Fibers* Gleason Score Before 1st High Dose Therapy Age at Therapy Presentation Before Radiotherapy

TABLE 1. Patient details and response to treatment

PSA Nadir After Therapy (% reduction)

No. Biopsy Cores With Ca/No. Cores Examined

PHOTODYNAMIC THERAPY FOR RECURRENT PROSTATE CANCER

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there was more than 1 discrete zone of necrosis, the area of each was estimated separately and the results were added together. The area of photodynamic therapy induced necrosis varied from 0.9 to 13.4 cm.2 (median 6.3) and the total area of the gland varied from 7.5 to 16.8 cm.2 (median 12.6). The results in table 1 are the percentage of the cross section of the prostate that was necrotic. As each fiber track only crossed any given plane once, table 1 shows the number of fibers used (range 2 to 8, median 4). However, to treat the full depth of the prostate light was delivered at up to 4 positions along each fiber track. The total number of sites treated per photodynamic therapy session ranged from 6 to 32 (median 12). Complications. Urinary Function: The first 5 treatments (low light dose) only caused minor discomfort but the higher dose caused mild to moderate perineal discomfort associated with some irritative urinary symptoms lasting up to a month or so. All patients had American Urological Association-7 documented before photodynamic therapy and during followup. Pretreatment scores ranged from 0 to 19. By 3 months the AUA score had returned to pretreatment levels in 6 patients, but had deteriorated in the others. In 3 other patients the score returned to pretreatment level after a longer period. Specific symptoms are summarized in table 2. The 2 patients with troublesome stress incontinence required up to 4 pads a day, improving to only 1 pad a day after a year. Two others had occasional leakage. Four patients could not be catheterized per urethram before photodynamic therapy of whom 1 had acute retention 24 hours after photodynamic therapy, requiring a suprapubic catheter. In 2 others acute retention developed but resolved in all 3 after a short period of catheterization. In 1 patient prostatitis developed which resolved with antibiotics. Urethral damage (as evidenced by the lack of uptake of contrast material in the urothelium) was seen on scans of 8 patients, often associated with the passage of debris, which may have contributed to later obstruction in 3. Sexual Function: None of the patients had normal potency due to previous radiotherapy, although 7 patients had some sexual function initially, which was lost or impaired after photodynamic therapy in 4 (table 2). In 2 of those with reduced function after treatment, damage to 1 of the neurovascular bundles was detected on the scan. There was no significant recovery of sexual function during followup. Rectum: No patient had any photodynamic therapy related bowel symptoms. Flexible sigmoidoscopy 3 to 5 days after therapy revealed a small area of erythema overlying the prostate in 5 with superficial ulceration in 2. These areas had almost completely resolved when examined again a month later. However, in 1 patient a small residual white area was biopsied 1 month after photodynamic therapy. The next day dysuria and acute retention developed, subsequently shown to be due to a urethrorectal fistula, which was treated with a suprapubic catheter and defunctioning colostomy. The fistula had healed and the colostomy was reversed 3 months later. Five patients had mild episodes of skin photosensitivity, which resolved spontaneously. DISCUSSION

We have shown that percutaneous photodynamic therapy can produce necrosis in recurrent prostate cancer localized to the gland. Contrast enhanced images revealed that up to 91% of the cross section of the prostate was necrotic (up to 49% if only 1 lobe was treated) and in 5 patients posttreatment biopsies did not show cancer. The total number of biopsies taken in each patient was relatively small, and so some areas of persistent cancer may have been missed due to sampling errors. However, our results suggest that the cancer load had been reduced in at least some of the patients. In 2 patients PSA decreased to levels of no biochemical evidence of disease, which were maintained for 26 months in 1, and in 7 others

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FIG. 2. PSA levels immediately before photodynamic therapy and throughout followup. Lines stop at time each patient was started on antiandrogen therapy exception for patient 11, who is not currently on hormone therapy. A, PSA 10 to 20 ng./ml. before radiotherapy. B, PSA 20 to 40 ng./ml. before radiotherapy. Patient 7 did not have PSA measured before radiotherapy.

FIG. 3. Contrast enhanced MRI for patient 6. A, before therapy fairly uniform enhancement is seen. Biopsies only showed cancer in right lobe. Dark area on left was thought to be too poorly enhanced to be cancer and biopsies of this area did not show cancer. B, 2 days after therapy to right lobe there is marked inflammatory response with 70% increase in cross-sectional area of prostate (prostate volume was double that documented before therapy), alteration of fat space and poor definition of prostate capsule. Enhancement pattern is mottled, indicating extensive but poorly defined necrosis, mostly in peripheral zones on right. There is damage to neurovascular bundle on right (white arrow) and small section of rectum is affected (black arrow). C, 2 months after therapy inflammatory changes have resolved and prostate has almost returned to original size. There is now well-defined, uniform zone of necrosis in right lobe (arrow) occupying half of cross-sectional area of gland and including urethra. After therapy PSA decreased to undetectable levels for 26 months. He had borderline sexual function, which was lost after photodynamic therapy but had no rectal symptoms.

13

12

Chronic retention No

Yes

Yes

Acute retention

11

Stress incontinence when colostomy reversed

Yes

Yes

Acute retention

8

Yes

Yes

10

Stress incontinence

7

Increasing outflow obstruction Increasing outflow obstruction

No

No

No

Yes

No

Yes

Yes

Yes

Yes Yes

Yes

No Yes No

No Yes

Urethral Damage on Scan

Yes No

Debris Passed

No

Prostatitis (resolved on antibiotics) Dribbling

6

Increasing urgency, frequency

1 to 6 Mos. After Therapy

9

Dribbling

Stress incontinence Acute retention

⬍1 Mo. After Therapy

4 5

3

1 2

Pt. No.

Urinary Function

No

Yes (7)

No

No

No

No

Yes (10)

Yes (36)

No No

No

No No

Urethral Tumor (mos. after therapy)

Bladder neck incision (7 mos.), leakage

Resolved (1 wk.), incontinence improved (6 mos.)

Dilatation (12 mos.), stress incontinence Dilatation (12 mos.), stress incontinence Improved (1 yr.), worsened after transurethral prostate resection to remove debris Increasing urgency, incontinence (18 mos.), detrusor instability Resolved (8 wks.)

Improved (few mos.)

Progressed (1 yr.)

Improved (1 yr.) Resolved (1 wk.)

Outcome (interval after therapy)

TABLE 2. Complications after photodynamic therapy

Borderline potency/ borderline potency

Impotent/impotent

Acceptable potency/ impotent Borderline potency/ borderline potency

Impotent/impotent

Acceptable potency/ impotent

Impotent/impotent Acceptable potency/ borderline potency Borderline potency/ impotent Impotent/impotent

Impotent/impotent Borderline potency/ borderline potency Impotent/impotent

Sexual Potency Before/After Therapy

—

Erythema, biopsy 1 mo. after therapy caused fistula Erythema

—

—

Erythema

Erythema

—

Erythema —

—

— —

Rectal Changes

PHOTODYNAMIC THERAPY FOR RECURRENT PROSTATE CANCER

1431

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PHOTODYNAMIC THERAPY FOR RECURRENT PROSTATE CANCER

PSA decreased up to 79%. Those with large areas of necrosis but no decrease in PSA almost certainly had undetected extraprostatic disease at the time of treatment. This finding would be consistent with a report that after salvage surgery only 20% to 38% of apparently localized recurrences are organ confined.9 As this is our first report of interstitial photodynamic therapy to the prostate, treatment was applied conservatively and did not cover the entire gland. Therefore, in some cases disease within the prostate may have not been treated. Nevertheless, the results suggest that if better light dosimetry makes it feasible to treat the entire gland accurately and safely, it may be possible to achieve local disease control. The value of photodynamic therapy compared with other salvage therapies will depend as much on the risk of complications as on efficacy. The irritative symptoms described by our patients after therapy were likely due to urethral necrosis but these resolved in a short time as predicted from the canine studies.7 Necrosis may also explain the episodes of acute retention, which resolved within a short period, and dribbling soon after photodynamic therapy. There was probably more damage in the 2 cases of severe stress incontinence soon after therapy, although this did resolve by 1 year. Other urinary problems that occurred longer after photodynamic therapy were most likely due to the underlying disease. The 3 cases of increasing outflow obstruction proved to be due to tumor recurrence in the urethra. The incidence of photodynamic therapy related incontinence in our study (4 of 11, 36%, troublesome 2 and minor 2) compares favorably with that seen in patients after salvage prostatectomy (up to 64%9) or cryotherapy (up to 95%10), although recent results suggest that extensive thermocouple monitoring may reduce this problem with cryotherapy.11 The frequency and urgency in 1 patient 18 months after photodynamic therapy was due to detrusor muscle instability, perhaps related to previous radiotherapy. Prostate radiotherapy is known to harm erectile function.5 None of our patients had completely normal sexual function at presentation, although 7 had some function, which was impaired irreversibly after photodynamic therapy in 4. This result was disappointing but might be avoided by more precise localization of treatment fibers to avoid the damage we detected to the neurovascular bundles. However, some of our patients had reduced sexual potency after therapy without any detectable changes to the neurovascular bundles on scans, and so the problem may be more complex. Limiting treatment in this area might also risk leaving viable cancer. Nevertheless, our results still compare favorably with salvage surgery and cryotherapy, which can render virtually 100% of previously irradiated patients impotent.9, 10 Salvage surgery and cryotherapy have a risk of rectal injury that may necessitate fecal diversion.9 Photodynamic therapy did not produce any clinically important rectal injuries in our patients but an inappropriate rectal biopsy, which included submucosa, taken 1 month after therapy in 1 patient caused a urethrorectal fistula. Experimental studies in the rat have shown that even full thickness photodynamic therapy induced necrosis in the colon does not cause perforation as the mechanical integrity is maintained by submucosal collagen.12 This finding was confirmed in our canine prostate studies.7 This case has alerted us to the risks of taking a rectal biopsy soon after prostate photodynamic therapy but has reassured us that the therapy itself is unlikely to cause a fistula. In the only other clinical report of photodynamic therapy for prostate cancer Windahl et al treated 2 patients with transurethral light delivery using the photosensitizer porfimer sodium following radical transurethral prostate resection for localized carcinoma.13 There were no complications and PSA decreased to 2.5 and 0.2 ng./ml. after 5 months with no histological evidence of tumor at 3 to 6 months. In recent

years there has been a marked increase in the use of interstitial prostate brachytherapy due to the reported low incidence of impotence (15% in those younger than 70 years) and incontinence (5%).14 However, there is no satisfactory treatment following failure of brachytherapy. Photodynamic therapy does not have the cumulative toxicity associated with ionizing radiation and can be applied 1 or more times to previously irradiated tissue. Thus, it could become a useful complementary treatment to brachytherapy or external beam radiotherapy for patients with locally persistent or recurrent disease. CONCLUSIONS

Photodynamic therapy is a minimally invasive technique that can destroy recurrent cancer in the irradiated prostate. The incidence of complications is no worse than that after salvage surgery or cryotherapy, and may be reduced further by refinements in light dosimetry. Photodynamic therapy is worthy of further investigation. REFERENCES

1. Pienta, K. J.: Etiology, epidemiology, and prevention of carcinoma of the prostate. In: Campbell’s Urology, 7th ed. Edited by P. C. Walsh, A. B. Retik, E. D. Vaughan, Jr. and A. J. Wein. Philadelphia: W. B. Saunders Co., vol. 1, chapt. 80, pp. 2489 – 2496, 1998 2. Goluboff, E. T. and Benson, M. C.: External beam radiation therapy does not offer long-term control of prostate cancer. Urol Clin North Am, 23: 617, 1996 3. Fowler, F. J., Jr., Barry, M. J., Lu-Yao, G., Roman, A., Wasson, J. and Wennberg, J. E.: Patient-reported complications and follow-up treatment after radical prostatectomy. The National Medicare Experience: 1988 –1990 (updated June 1993). Urology, 42: 622, 1993 4. Fowler, F. J., Jr., Barry, M. J., Lu-Yao, G., Wasson, J. H. and Bin, L.: Outcomes of external-beam radiation therapy for prostate cancer: a study of Medicare beneficiaries in three surveillance, epidemiology, and end results areas. J Clin Oncol, 14: 2258, 1996 5. Shipley, W. U., Zietman, A. L., Hanks, G. E., Coen, J. J., Caplan, R. J., Won, M. et al: Treatment related sequelae following external beam radiation for prostate cancer: a review with an update in patients with stages T1 and T2 tumor. J Urol, 152: 1799, 1994 6. Albertsen, P. C., Fryback, D. G., Storer, B. E., Kolan, T. F. and Fine, J.: Long-term survival among men with conservatively treated localized prostate cancer. JAMA, 274: 626, 1995 7. Chang, S. C., Buonaccorsi, G., MacRobert, A. and Bown, S. G.: Interstitial and transurethral photodynamic therapy of the canine prostate using meso-tetra-(m-hydroxyphenyl) chlorin. Int J Cancer, 67: 555, 1996 8. Selman, S. H., Albrecht, D., Keck, R. W., Brennan, P. and Kondo, S.: Studies of tin ethyl etiopurpurin photodynamic therapy of the canine prostate. J Urol, 165: 1795, 2001 9. Corral, D. A., Pisters, L. L. and von Eschenbach, A. C.: Treatment options for localized recurrence of prostate cancer following radiation therapy. Urol Clin North Am, 23: 677, 1996 10. Bales, G. T., Williams, M. J., Sinner, M., Thisted, R. A. and Chodak, G. W.: Short-term outcomes after cryosurgical ablation of the prostate in men with recurrent prostate carcinoma following radiation therapy. Urology, 46: 676, 1995 11. Ghafar, M. A., Johnson, C. W., De La Taille, A., Benson, M. C., Bagiella, E., Fatal, M. et al: Salvage cryotherapy using an argon based system for locally recurrent prostate cancer after radiation therapy: the Columbia experience. J Urol, 166: 1333, 2001 12. Barr, H., Tralau, C. J., Boulos, P. B., MacRobert, A. J., Tilly, R. and Bown, S. G.: The contrasting mechanisms of colonic collagen damage between photodynamic therapy and thermal injury. Photochem Photobiol, 46: 795, 1987 13. Windahl, T., Andersson, S. O. and Lofgren, L.: Photodynamic therapy of localised prostatic cancer. Lancet, 336: 1139, 1990 14. Blasko, J. C., Grimm, P. D. and Ragde, H.: Brachytherapy and organ preservation in the management of carcinoma of the prostate. Semin Radiat Oncol, 3: 240, 1993