PROSTATE CANCER WITH LARGE GLANDS TREATED WITH 3- DIMENSIONAL COMPUTERIZED TOMOGRAPHY GUIDED PARARECTAL BRACHYTHERAPY: UP TO 8 YEARS OF FOLLOWUP

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1 /03/ /0 Vol. 169, , April 2003 THE JOURNAL OF UROLOGY Printed in U.S.A. Copyright 2003 by AMERICAN UROLOGICAL ASSOCIATION DOI: /01.ju e8 PROSTATE CANCER WITH LARGE GLANDS TREATED WITH 3- DIMENSIONAL COMPUTERIZED TOMOGRAPHY GUIDED PARARECTAL BRACHYTHERAPY: UP TO 8 YEARS OF FOLLOWUP PANOS G. KOUTROUVELIS, NIKO LAILAS, STUART KATZ, JAMES SEHN, GUILLERMO GIL-MONTERO AND NABIL KHAWAND From the Uro-Radiology Prostate Institute, Vienna, Virginia ABSTRACT Purpose: We report post-brachytherapy results in patients with cancer in a large prostate. Materials and Methods: From June 1, 1994 to June 30, 2000, 331 consecutive patients with a large prostate of 50 to 180 cm. 3 (median 69) were treated with 3-dimensional computerized tomography guided brachytherapy. Patient age was 42 to 90 years (median 69). Of these patients 327 were available for followup for 2 to 8 years (median 4.5). Patients were stratified according to risk profile. The high risk group had 1 or more high risk factors (prostate specific antigen [PSA] greater than 20 ng./ml., Gleason greater than 7, stage T2b, T3a or T3b) or 2 intermediate risk factors (PSA 10 to 20 ng./ml. and Gleason 7). The high risk group was further stratified into subgroups with a similar risk profile. The intermediate risk group had only 1 high risk factor (PSA 10 to 20 ng./ml. or Gleason 7). The low risk group had PSA less than 10 ng./ml., Gleason less than 7 and stage T1a, b, c or T2a. A dose of 144 Gy. with 125 I or 120 Gy. with 103 Pd was achieved in 90% to 100% of the target. A total of 31 patients (9%) had previously undergone transurethral resection and 198 (60%) were treated with 3 months of neoadjuvant androgen ablation. Results: Biochemical disease-free survival was achieved in 90% of the 182 patients at high risk, 96% of the 52 at intermediate risk and 99% of the 93 at low risk. Seven patients (2%) required catheterization during year 1 for urinary retention, 11 (3%) required transurethral prostate resection 1 to 4 years after implantation, 3 patients (1%) had grade 1 or 2 incontinence after repeat transurethral prostate resection and 4 (1%) had grade 3 or 4 rectal complications. Conclusions: The 3-dimensional computerized tomography guided pararectal permanent implant results in a high level of biochemical control with low morbidity at 2 to 8 years in patients with prostate cancer who have a large prostate. There was less favorable biochemical control in patients with PSA greater than 20 ng./ml., Gleason 7 or greater and seminal vesicle invasion. KEY WORDS: prostatic neoplasms; prostate; brachytherapy; tomography, x-ray computed; imaging, three-dimensional Brachytherapy for localized prostate cancer is a desirable option for patients who do not elect surgery due to medical contraindication or for reasons related to morbidity, such as incontinence and impotence. Prostate volume is a common selection criterion for transrectal ultrasound guided transperineal brachytherapy. In 1997 the committee of the American Brachytherapy Society recommended that a relative contraindication to transrectal ultrasound guided transperineal brachytherapy was a prostate of greater than 60 cm We first performed brachytherapy for prostate cancer in a large prostate in 1994 using a 3-dimensional (3-D) stereotactic system, posterior pararectal approach and computerized tomography (CT) guidance. We reported our 5-year results in March 2000 in 203 patients with a prostate volume of greater than 60 cm The reason that we decided to treat large volume prostates was the ability of our posterior pararectal CT guided stereotactic method to achieve adequate source placement in large prostates of 60 to 180 cm. 3 without pubic arch interference. Also, the use of permanent radioactive sources of 125 Ior 103 Pd at a low dose rate and high attenuation minimizes radiation injury to adjacent organs (rectum and bladder). Furthermore, we have the ability to identify and spare the urethra during implantation. Radiation oncologists believe that large prostate volume is a contraindication to ultrasound guided transperineal brachytherapy because of the technical difficulty of achieving Accepted for publication November 1, good coverage in large prostate glands and the high likelihood of postimplantation morbidity. However, transperineal implantation using the transrectal ultrasound guided method in large prostates has been reported. 3 5 We report brachytherapy in a large prostate in 331 patients from June 1994 to June Four patients were excluded from analysis due to death or insufficient followup. Up to 8 years of followup are available on 327 patients with a large prostate of 50 to 180 cm. 3 treated with 3-D CT guided posterior pararectal brachytherapy. Some of these extremely large prostates were referred by radiation oncologists because they did not want to use a large field size for external beam radiation therapy. Of these patients with a large prostate 31 had undergone transurethral prostate resection 1 to 3 years previously except 2 who underwent that procedure 4 months before implantation. We have reported our experience treating patients with transurethral prostate resection before brachytherapy. 6 METHODS AND MATERIALS A total of 331 consecutive patients with cancer in a large volume (50 to 180 cm. 3 ) prostate were treated from June 1994 to June 2000 with 3-D CT guided posterior pararectal brachytherapy using 125 Ior 103 Pd seeds. Table 1 lists patient characteristics. For staging purposes all patients underwent digital rectal examination, transrectal ultrasound guided biopsy of the prostate, CT of the abdomen and pelvis, and bone scan. Of the 331

2 1332 PROSTATE CANCER TREATED WITH BRACHYTHERAPY TABLE 1. Prostate cancer with large volume treated with 3-D CT brachytherapy from June 1994 to June 2000 in 331 patients Mean/median age (range) 68/69 (42 90) Prostate vol. (cm. 3 ): No (%) 95 (29) No (%) 140 (42) No (%) 59 (18) No. greater than 100 (%) 37 (11) Mean/median (range) 73/68 (50 180) PSA (ng./ml.): No. less than 10 (%) 189 (57) No (%) 99 (30) No. greater than 20 (%) 43 (13) No. 10 or greater (%) 142 (43) Mean/median (range) 13/8.6 ( ) No. Gleason (%): Less than (70) 7 76 (23) Greater than 7 23 (7) No. transurethral prostate resection 1 5 yrs. before 31 (9) implantation (%) No. neoadjuvant androgen ablation 3 mos. before implantation 198 (60) (%) No. 125 I (%) 150 (45) No. 103 Pd (%) 181 (55) No American Joint Committee on Ca stage (%): T1a, T1b, T1c, T2a 169 (51) T2b, T3a 138 (42) T3b (biopsy proved seminal vesicle invasion) 24 (7) men 211 (63%) underwent seminal vesicle biopsy. In 24 of the 211 patients (11%) who underwent 3-D CT guided pararectal biopsy of the seminal vesicle results were positive (stage T3b). In patients with a Gleason score of 8 or greater and/or prostate specific antigen (PSA) greater than 20 ng./ml. a Prostascint (Cytogen, Princeton, New Jersey) scan or laparoscopic pelvic lymphadenectomy was performed. However, routine lymphadenectomy was not performed before brachytherapy. No lymphadenectomy was performed in patients who underwent a Prostascint scan to evaluate results. The sensitivity of Prostascint is reportedly 60% and specificity is 72% in patients with positive lymphadenectomy. 7 All patients were treated at our institution. In 1994 one of us (P. G. K.) developed the posterior pararectal method of brachytherapy using a 3-D stereotactic system and CT guidance. 8 CT is used for pretreatment planning, performing the implantation procedure with the 3-D stereotactic system and postimplantation dosimetry. Three-D CT guided planning and dosimetry are performed with Varian BrachyVision (Vavian Medical Systems International AG, Baden, Swizterland) (fig. 1). Precise placement of the after loading needles is achieved with the 3-D stereotactic system. The rectum is constricted with tannic acid before implantation. The 3-D stereotactic template is adjusted as needed to avoid needle penetration through the rectum or obstruction of needle insertion by the coccyx or sacrum. The 8 10 cm. 2 stereotactic template can cover a large target and has perforations 2.5 mm. apart in either direction for fine needle correction when needed. The procedure is performed using epidural or spinal anesthesia. The patient returns home the same day. A Mick applicator is used for loose seeds. An attachment to the 3-D stereotactic template is used for instant loading and seed implantation in a strand and/or loose seeds with spacers. No pre-loaded needles are used. The correct position of the needles is verified by computerized tomography before implantation. Patients with seminal vesicle invasion (stage T3b) were treated with brachytherapy including the whole seminal vesicle. Our experience with brachytherapy in patients with seminal vesicle invasion has previously been reported. 9 Extracapsular extension in localized prostate cancer has been reported in 35% of patients after radical prostatectomy. 10 The treatment target includes 5 to 10 mm. outside of the capsule except the portion on the prostate adjacent to the anterior rectal wall. Before termination of the implant CT of the prostate is performed to verify good coverage of the target with seeds (fig. 2). After implantation x-ray dosimetry was performed before the CT dosimetry era. In the last 4 years postimplantation CT dosimetry has been performed immediately and 2 weeks after implantation when possible (figs. 3 to 6). We performed it 2 weeks after implantation for more accurate dosimetry after edema subsided. The prescribed dose is 120 Gy. with 103 Pd or 144 Gy. with 125 I for the target, including 5 to 10 mm. surrounding fat. Biochemical disease-free survival was based on an American Society for Therapeutic Radiology and Oncology definition as no 3 consecutive increases in PSA with a minimal increase of 1.5 ng./ml. above the nadir. The Kaplan-Meier product limit method was used to calculate the disease-free survival rate. 11, 12 The log rank test was used to compare survival curves. RESULTS Followup, including PSA data, was determined at office visits every 3 months during year 1, every 6 months during year 2 and yearly thereafter. In addition, data were collected from direct telephone contact and patient responses to yearly written questionnaires. The prescribed dosage of 120 Gy. using 103 Pd and 144 Gy. using 125 I seeds to 90% to 100% of target volume was TABLE 2. Risk profile and biochemical results in patients with large prostate volume treated with 3-D CT guided brachytherapy at 8 years of followup No. Pts./No. Risk Factors No Biochemical Disease Evidence (%) High risk (3 risk factors): Stage T3b, Gleason 7 or greater, PSA ng./ml. 3/3 (100) Stage T3b, Gleason 7 or greater, PSA greater than 20 13/10 (77) ng./ml. Stage T2b, 3a, Gleason 7 or greater, PSA greater than 14/13 (93) ng./ml. Stage T2b, 3a, Gleason 7 or greater, PSA greater, 9/8 (89) than 20 ng./ml. Subtotal 39/34 (87) High risk (2 risk factors): Stage T3b, Gleason 7 or greater, PSA less than 10 ng./ 4/4 (100) ml. Stage T3b, PSA ng./ml., Gleason less than 7 1/1 (100) Gleason 7 or greater, PSA ng./ml., stage T1a, b, 14/13 (93) c, T2a Gleason 7 or greater, PSA greater than 20 ng./ml., 1/1 (100) Stage T2b, 3a, Gleason 7 or greater, PSA less than 10 26/23 (89) ng./ml. Stage T2b, 3a, PSA ng./ml., Gleason less than 7 28/23 (82) Stage T2b, 3a, PSA greater than 20 ng./ml., Gleason 12/10 (83) less than 7 Subtotal 86/75 (87) High risk (1 risk factor): Stage T3b, PSA less than 10 ng./ml., Gleason less 3/3 (100) than 7 Stage T2b, 3a, PSA less than 10 ng./ml., Gleason less 45/45 (100) than 7 PSA greater than 20 ng./ml., Gleason less than 7, 8/7 (88) Gleason greater than 7, PSA less than 10 ng./ml., 1/0 (0) Subtotal 57/55 (96) High risk total 182/164 (90) Intermediate risk: Gleason 7, PSA less than 10 ng./ml., stage T1a, b, c, 13/13 (100) T2a PSA ng./ml., Gleason less than 7, stage T1a, b, 39/37 (95) c, T2a Intermediate risk total 52/50 (96) Low risk PSA less than 10 ng./ml., Gleason less than 7, 93/92 (99) High, intermediate low risk total 327/306 (94) Median followup 4.5 years.

3 PROSTATE CANCER TREATED WITH BRACHYTHERAPY 1333 FIG. 1. Pre-implant CT dosimetry of 60 cm. 3 prostate with Varian BrachyVision. Green dots at center represent lesser activity seeds of 0.32 mci. per seed to decrease dose to anterior rectal wall and urethra. Blue squares represent higher activity seeds of 0.38 mci. at prostate periphery. Purple isodose line represents 160% of prescribed dose of 144 Gy. of 125 I seeds. Orange isodose line represents 100% of prescribed dose. The yellow isodose line represents 50% of prescribed dose, that is 72 Gy. FIG. 2. CT verification of seed coverage in prostate during implant. Urethra in this 130 cm. 3 prostate is at posterior periphery prostate few mm. from anterior rectal wall. There is excellent seed coverage of target. achieved in all patients treated with 3-D stereotactic CT guided posterior pararectal brachytherapy, as calculated by postimplantation CT dosimetry. Followup PSA results were available at 2 to 8 years (median 4.5) in 327 patients treated with CT guided posterior pararectal brachytherapy. Biochemical results were stratified according to the risk profile (table 2). Patients were stratified into groups at high, intermediate and low risk. The high risk group of 182 patients had 1 or more high risk factors (PSA greater than 20 ng./ml., Gleason greater than 7, stage T2b, T3a or biopsy proven seminal vesicle invasion T3b), or 2 intermediate risk factors (PSA 10 to 20 ng./ml. and Gleason 7). Stages T2b and T3a were stratified together because they clinically overlapped. The intermediate risk group of 52 patients had only 1 high risk factor (PSA 10 to 20 ng./ml. or Gleason 7). The low risk group of 93 patients had favorable factors (PSA less than 10 ng./ml., Gleason less than 7 and stage T1a, b, c or T2a). The high risk

4 1334 PROSTATE CANCER TREATED WITH BRACHYTHERAPY FIG. 3. Post-implant dosimetry and cumulative dose volume histogram of seminal vesicles (light blue) shows 160% isodose line (blue), 100% isodose line (pink) covering seminal vesicles and 5 to 10 mm. outside in fat tissue, and 50% isodose line (yellow). Of target of seminal vesicles 95% received prescribed dose of 144 Gy. FIG. 4. Post-implant CT dosimetry of large prostate with protrusion of mid-lobe within bladder before termination of implant procedure shows good coverage. Bladder is filled with intravenous contrast medium. Balloon of Foley catheter was punctured during procedure and balloon air is visible in bladder dome. Patient has no rectum due to previous colectomy for colorectal cancer. group was stratified further into 3 groups according to the number of risk factors. For meaningful biochemical statistical comparison these 3 high risk groups were also subdivided into subgroups with a similar risk profile (table 2). Patients at high risk with seminal vesicle invasion and PSA less than 20 ng./ml. had excellent biochemical results (table 2). However, a greater number of patients in these subgroups with a similar risk profile is required to compare results with those of other treatment methods, including surgery or external beam radiation therapy. Biochemical disease-free results were achieved in 164 (90%) of the 182 patients at high risk, 50 (96%) of the 52 at intermediate risk and 92 (99%) of the 93 at low risk. Overall a biochemical disease-free result was achieved in 306 of 327 men (94%) (table 2). The 8-year disease-free survival rate for the high, intermediate and low risk groups was 83%, 95%, and 99%, respectively (fig. 7). Significant differences were noted in disease-free survival in patients at low and high risk (p 0.010). There was no significant difference in the low and intermediate risk groups (p 0.364). There was also no significant difference in patients with or without preimplantation hormone therapy (p 0.705). Of the men treated with brachytherapy 20% experienced transient treatment related symptoms of dysuria, nocturia and/or frequent urination 2 to 4 weeks in duration. They were treated with -blockers and Pyridium, and/or steroids

5 PROSTATE CANCER TREATED WITH BRACHYTHERAPY 1335 FIG. 5. Post-implant CT dosimetry at 2 weeks in patient with large prostate (red), seminal vesicle (light blue) invasion and protrusion of mid lobe within bladder (yellow). Note rectum (blue), and 160% (blue), 100% (pink) and 50% (yellow) isodose lines. FIG D post-implant reconstruction of large prostate (red) and seminal vesicles (light blue). Note rectum (blue) and protrusion of mid lobe within bladder (yellow). (Radiation Therapy Oncology Group grading criterion I or II). Seven patients (2%) required catheterization during year 1 for urinary retention (grading criterion III) and 11 (3%) required transurethral prostate resection 1 to 4 years after implantation (grading criterion IV). Three patients (1%) had grade 1 or 2 incontinence after repeat transurethral prostate resection and 4 (1%) had grade 3 or 4 rectal complications. The average decrease in prostate gland volume in 127 patients from 6 months to 1 year was 54%. Prostate volume was measured at the date of implantation. No data are available on prostate volume at the time of hormone therapy initiation. DISCUSSION We report on 331 patients with prostate cancer and a large prostate treated with the 3-D CT guided stereotactic posterior pararectal method. Although these 331 patients had a large prostate, 182 (55%) had a high risk profile. The results of this study show that this method results in a high level of clinical and biochemical control at 2 to 8 years of followup (median 4.5). There are limited publications on transperineal brachytherapy for prostate glands greater than 50 cm. 3. Such brachytherapy was performed in a small number of patients. 3 5 Morbidity was not related to the size of the prostate. However, 2 of 33 patients with a large gland of 50 to 60 cm. 3 had a prostate fistula and 12 were in acute postimplantation urinary retention requiring catheterization within 24 hours, while 15% required catheterization after 1 month and only 1 required it after 1 year. 5 In our study low urinary morbidity was probably due to the difference in technique in the 3-D CT guided posterior approach and the ultrasound guided transperineal approach. A portion of the urethra in these large prostates is in the periphery of the prostate (fig. 2). We are able to identify and spare the urethra (fig. 2). We also use seeds with less activity placed near the urethra and anterior rectal wall adjacent to the prostate (fig. 1). Preoperative serum PSA does not reflect the biochemical failure rate after radical prostatectomy in men with large volume cancer. 13 Also, with brachytherapy we noted that large volumes with PSA greater than 20 ng./ml. was not statistically different than large volumes with PSA less than 20 ng./ml. (table 2). However, patients with a large volume prostate and the 3 high risk factors of stage T3b, Gleason 7 or greater and PSA greater than 20 ng./ml. had a greater biochemical control failure rate (table 2). No biochemical failure was observed after year 4 after implantation (fig. 6). Threedimensional stereotactic CT pararectal brachytherapy allows implantation of patients with a large prostate gland with or without a rectum and implantation with protrusion of the mid lobe of the large prostate into the bladder (figs. 4 and 5). CONCLUSIONS Three-dimensional CT guided pararectal permanent implantation results in a high level of biochemical control (94%) with low morbidity at 2 to 8 years in patients with prostate cancer who have a large prostate. There was less favorable

6 1336 PROSTATE CANCER TREATED WITH BRACHYTHERAPY FIG. 7. Actuarial disease-free survival biochemical control in patients with PSA greater than 20 ng./ml., Gleason 7 or greater and seminal vesicle invasion. REFERENCES 1. Nag, S., Baird, M., Blasko, J., Beyer, D., Dattoli, M., Grado, G. et al: American Brachytherapy Society survey of current clinical practice for permanent brachytherapy of prostate cancer. J Brachyther Int, 13: 243, Koutrouvelis, P., Lailas, N., Goldson, A., Bondy, H., Hendricks, F., Katz, S. et al: 3-D CT-guided brachytherapy for localized prostate cancer in patients with large volumes: 5-year followup. J Brachyther Int, 16: 1, Stone, N. N. and Stock, R. G.: Prostate brachytherapy in patients with prostate volumes / 50 cm. (3): dosimetric analysis of implant quality. Int J Radiat Oncol Biol Phys, 46: 1199, Wang, H., Wallner, K., Sutlief, S., Blasko, J., Russell, K. and Ellis, W.: Transperineal brachytherapy in patients with large prostate glands. Int J Cancer, 90: 199, Sherertz, T., Wallner, K., Wang, H., Sutlief, S. and Russell, K.: Long-term urinary function after transperineal brachytherapy for patients with large prostate glands. Int J Radiat Oncol Biol Phys, 51: 1241, Koutrouvelis, P. G., Lailas, N., Goldson, A., Bondy, H., Hendricks, F., Katz, S. et al: CT-guided ischiorectal brachytherapy of prostate cancer in patients with prior TURP. J Brachyther Int, 15: 65, Manyak, M. J., Hinkle, G. H., Olsen, J. O., Chiaccherini, R. P., Partin, A. W., Piantadosi, S. et al: Immunoscintigraphy with indium-111-capromab pendetide: evaluation before definitive therapy in patients with prostate cancer. Urology, 54: 1058, Koutrouvelis, P. G.: Three-dimensional stereotactic posterior ischiorectal space computerized tomography guided brachytherapy of prostate cancer: a preliminary report. J Urol, 159: 142, Koutrouvelis, P. G., Lailas, N., Hendricks, F., Gil-Montero, G., Sehn, J. and Katz, S.: Three-dimensional computed tomography-guided monotherapeutic pararectal brachytherapy of prostate cancer with seminal vesicle invasion. Radiother Oncol, 60: 31, Sohayda, C., Kupelian, P. A., Levin, H. S. and Klein, E. A.: Extent of extracapsular extension in localized prostate cancer. Urology, 55: 382, Collet, D.: Modelling Survival Data in Medical Research. London: Chapman & Hall, Kaplan, E. L. and Meier, P.: Nonparametric estimation from incomplete observations. J Am Stat Assoc, 53: 457, Noguchi, M., Stamey, T. A., McNeal, J. E. and Yemoto, C. M.: Preoperative serum prostate specific antigen does not reflect biochemical failure rates after radical prostatectomy in men with large volume cancers. J Urol, 164: 1596, 2000