Three-dimensional computed tomography-guided monotherapeutic pararectal brachytherapy of prostate cancer with seminal vesicle invasion

Radiotherapy and Oncology 60 (2001) 31±35 www.elsevier.com/locate/radonline Three-dimensional computed tomography-guided monotherapeutic pararectal brachytherapy of prostate cancer with seminal vesicle invasion Panos Koutrouvelis*, Niko Lailas, Fred Hendricks, Guillermo Gil-Montero, James Sehn, Stuart Katz Uro-Radiology Prostate Institute, 8320 Old Courthouse Road, #150 Vienna, Virginia 22182, USA Received 12 July 2000; received in revised form 2 January 2001; accepted 4 April 2001 Abstract Purpose: To treat patients with prostate cancer and seminal vesicle invasion with monotherapeutic three dimensional computed tomography (3-DCT)-guided posterior pararectal brachytherapy. Methods and materials: Three hundred and sixty two patients with clinical stage T1 a,b or T2 a,b of prostate cancer were referred for 3- DCT-guided brachytherapy. Each underwent ftirther staging with 3-D CT-guided pararectal biopsy of the seminal vesicles under local anesthesia during the pre-treatment CT-planning. Forty-three patients (12%) were upstaged to T3 cnomo disease. In the set of 43 patients, Eight had Gleason's score#6, 24 Gleason's score ˆ 7, and 11 patients $ 8. Initial PSA was,10 ng/ml in 14 patients, 10±20 ng/ml in 11 patients, and.20 in 18 patients. Of the 43 patients, 37 patients were treated monotherapeutically with 3-D CT-guided brachytherapy. No patients received hormone therapy after the implant. The prescribed dosage to the seminal vesicles and prostate is 120 Gy with Pd-103 seeds and 144 Gy with 1±125 seeds. Results: The prescribed dosage was achieved in all 37 patient's throughout the seminal vesicles whose range of target radiation extended 5±10 mm outside the target in the adjacent fat as calculated with post-implant CT-dosimetry with Varian Brachy Vision or MMS software. Prostate Speci c Antigen (PSA) outcome data were available in 34 patients treated with monotherapy and follow up ranged from 12±56 months (median, 24 months). Decreased PSA levels were strati ed into six groups based on the presenting Gleason's score and initial PSA. In the rst group (with Gleason's score # 6 and initial PSA,20 ng/ml), PSA levels decreased to less than 0.5 ng/ml in all seven patients (100%) after brachytherapy. In the second group (with Gleason's ˆ 7 and initial PSA, 20 ng/ml), PSA levels decreased to less than 1 ng/ml in 11 of 13 patients (85%); additionally PSA levels decreased to less than 0.5 ng/ml in ten patients (77% in this group). In the third group (with Gleason's score ˆ 7 and initial PSA. 20 ng/ml), PSA decreased to less than 0.5 ng/ml in four out of eight patients (50%). All of the patients in the fourth group (with Gleason's score $ 8 and initial PSA, 20 ng/ml) decreased their PSA levels to less than 0.5 ng/ml in three of three patients. PSA decreased less than 0.5 ng/ml in two out of three patients (67% in the last group with Gleason's score $ 8 and initial PSA. 20 ng/ml). There were no patients with Gleason's score of 1±6 and greater than 20 ng/ml initial PSA. Patients, irrespective of the Gleason's score and PSA, had an overall response of decreased PSA (less than 1 ng/ml) of 79%. Conclusion: 3-D CT-guided brachytherapy delivers adequate dosage to the seminal vesicles. Clinical and biochemical results are encouraging in patients with low initial PSA levels regardless of their Gleason's scores, but longer-term data in a greater number of patients is necessary. q 2001 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Prostate; Cancer; Seminal vesicle; Brachytherapy 1. Introduction * Corresponding author. The incidence of seminal vesicle invasion with localized prostate cancer reported after radical prostatectomy is 13-14% [11,18]. However, clinical staging with biopsy of the seminal vesicles is not routinely performed in all patients of prostatic adenocarcinoma during the initial transrectal ultrasound-guided biopsy of the prostate or prior to initiation of any treatment, surgical or radiation therapy. In our protocol we include biopsy of seminal vesicles for clinical staging of adenocarcinoma of the prostate in all patients who are referred for 3-dimensional CT-guided posterior brachytherapy and have had no transrectal ultrasound-guided seminal vesicle biopsy performed prior to referral. The procedure is performed under local anesthesia during the pre-treatment CT planning. The 3-dimensional stereotactic system is adjusted to avoid the coccyx and spare 0167-8140/01/$ - see front matter q 2001 Elsevier Science Ireland Ltd. All rights reserved. PII: S0167-8140(01)00372-3

32 needle penetration of the rectum. Veri cation of needle position with CT is made prior to biopsy. Three biopsies of each seminal vesicle are performed: one near the junction of each seminal vesicle with the base of the prostate (S1), one in the mid-portion of each seminal vesicle (S2) and nally, the distal portion of each seminal vesicle (S3). Seminal vesicle invasion of prostate adenocarcinoma occurs through direct extension of the tumor through the ejaculatory ducts, through invasion of the capsule in the prostate base or through the perineural invasion in the periprostatic fat tissue (more often in the distal portion of seminal vesicles). Forty-three out of 362 patients (12%) had seminal vesicle invasion upstaged with 3-dimensional pararectal biopsy (T3cNoMo). Pathological seminal vesicle invasion has been reported after radical prostatectomy in 63 out of 375 patients (13%) T3cNoMo [18]. Seminal vesicle involvement is a poor prognostic feature in patients who have undergone radical prostatectomy in 3± 5 years, particularly in patients with high grade tumor Gleason's score $ 7, PSA. 10, and/or distal portion of seminal vesicle involvement [2,3,4,18]. The range of success after radical prostatectomy with seminal vesicle invasion at eight large centers is reported to be 5±60% [13]. External beam radiation (EBRT) has been used to treat patients with prostatic cancer and seminal vesicle invasion (T3cNoMo). Although EBRT may not be suf cient to provide long term control of stage T3c prostate cancer [1,5], large radiation eld with EBRT to include seminal vesicles increases the dose to the rectum by 40±50% [6]. Because of the low risk of invasion of the seminal vesicles in the low risk patients (6% of 192 patients with PSA, 10ng/ml and Gleason's score # 6) and because of the high dosage to the rectum with a large radiation eld, monotherapeutic EBRT has not been recommended [6]. Furthermore, the Clinical Research Committee of the American Brachytherapy Society considers ultrasound guided, transperineal brachytherapy alone a relative contraindication for patients with poor prognosis prostate cancer (Stage T3, prostate.60 gm, previous transurethral resection, PSA. 10 ng/ml, Gleason's score. 6, extensive intraprostatic calci cation) [12]. The combined method of EBRT and booster with brachytherapy covering only the portion of seminal vesicles near the base of the prostate has been performed with transrectal ultrasound-guided transperineal approach [16]. Dosage of the seminal vesicles using combined treatment as calculated with dose volume histograms was not adequate [16]. We report 37 patients with prostate cancer and seminal vesicle invasion treated with monotherapeutic 3-dimensional stereotactic CT-guided pararectal brachytherapy with excellent coverage of the entire seminal vesicles. 2. Methods and materials Three-hundred and sixty-two patients staged at T1 a,b or T2 a,b prostate cancer were referred for 3-DCT-guided brachytherapy. Each underwent further staging with 3- DCT-guided pararectal biopsy of the seminal vesicles. Three biopsies were performed of each seminal vesicle. The position of the needles during biopsy was veri ed with CT. (Fig. 1). Pathologists reported 98% of the specimens included seminal vesicle wall or epithelium. Fortythree patients (12%) were found to have seminal vesicle involvement and were upstaged to T3c disease. Of these 43 patients, eight patients had Gleason's score # 6, 24 patients ˆ 7, and 11 patients had Gleason's score $ 8. Initial PSA was,10 ng/ml in 14 patients, 10±20 ng/ml in 11 patients, and.20 ng/ml in 18 patients. The age of patients ranged from 52 to 82 years (median, 70; mean, 68). Initial PSA ranged from 1.4 to 80 ng/ml (median, 14.5; mean, 20.5). Initial volume ranged from 24 to 110 cm 3 (median,55; mean, 59.3). Two out of 43 patients were not treated with brachytherapy. One of the two had brachytherapy performed elsewhere 3 years prior and developed a prostatourethrorectal stula and was treated with systemic therapy. The other one had a Gleason's score of 8 and failed external radiation therapy and was treated with systemic therapy. Four patients out of the remaining 41 patients had combined method of treatment or salvage brachytherapy and are excluded from the analysis of this report. Three patients of the remaining 37 patients treated with monotherapeutic 3-DCT-guided pararectal brachytherapy were excluded from this report (two patients expired from other causes within 1 year postbrachytherapy and one patient was treated for a second primary). The remaining 34 patients treated with 3-DCTguided method of brachytherapy are included in the analysis of this report. The 3-DCT-guided method has been reported [7±10]. The senior author developed the 3-dimesional CT-guided posterior method in 1994. CT is used for pretreatment planning, the execution of the implant procedure in conjunction with the 3-dimensional stereotactic system and for post-implant dosimetry. Precise placement of the afterloading needles is achieved with the 3-dimensional stereotactic system. The correct position of the needles is veri ed with CT prior to implant. The template is large enough to cover a large target and has perforations that are 2.5 mm apart in either direction for ne needle correction if needed. The procedure is performed under epidural anesthesia. The patient is able to return 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 implant of seeds in rapid strand and/or loose seeds with spacers. The afterloading needles are not preloaded to avoid seed placement in vessels and reduce seed migration to a minimum. Post-implant CT dosimetry is performed immediately after the procedure. Dosage to the prostate and seminal vesicles under the monotherapeutic method, is 120 Gy with Palldium-103 and 144 Gy with iodine-125, includes 5±10 mm outside the target. Three-dimensional CT-guided planning and dosimetry is

33 Fig. 1. CT image of 3-D CT-guided stereotactic pararectal biopsy needle placement into the seminal vesicles. The rectum and coccyx is spared. performed with Varian Brachy Vision, and post-implant CT dosimetry is performed with Varian/MIVIS or Varian BrachyVision (Figs. 2 and 3). 3. Results Follow-up was determined by of ce visits every 3 months during the rst year, every 6 months during the second year, and yearly thereafter. In addition, data were collected from direct telephone contact and patient responses to written annual questionnaires. Prescribed dosage (120 Gy using Palladium-103 seeds and 144 Gy using Iodine-125 seeds) to the entire seminal vesicles was achieved in all 37 patients treated with monotherapeutic 3-D stereotactic CT-guided brachytherapy as calculated with postimplant CT-dosimetry with Varian Brachytherapy or Varian MMS. Follow-up PSA results were available 12±56 months (median, 24 months) in 34 patients treated with brachytherapy. We have established a PSA level less than 1 ng/ml as a nadir. PSA levels were strati ed into six groups based on the presenting Gleason's score and initial PSA. In the group (with Gleason's score~6 and initial PSA,20 ng/ml), PSA levels decreased to less than 0.5 ng/ml in all seven patients (100%) after brachytherapy. In the group with Gleason's 7 and initial PSA,20 ng/ml, PSA levels decreased to less than 1 ng/ml in 11 of 13 patients (85%) and PSA, 0.5 ng/ml in ten patients (77%). In the group with Gleason's score 7 and initial PSA. 20 ng/ml, PSA decreased to less than 0.5 ng/ml in four out of eight patients (50%). In the group with Gleason's score $ 8 and initial PSA, 20 ng/ml PSA levels decreased to less than 0.5 ng/ml in three of three patients. PSA decreased less than 0.5 ng/ml in two out of three patients in the last group 67% with Gleason's score $ 8 and initial PSA. 20 nglml. There were no patients with a Gleason score of 1±6 and greater then 20 nglml initial PSA. (Table 1). Patients (n 34), irrespective of the Gleason's score and PSA, had an overall response from CT guided brachytherapy of 79% (decreased PSA less than 1 ng/ml). Twenty percent of patients treated with brachytherapy experience transient treatment-related symptoms of frequency of urination and burning sensation lasting 2±4 weeks and were treated with alpha-blockers and Pyridium and/or steroids. None of the 37 patients treated for seminal vesicle involvement required a catheter after the implant procedure. One patient of the 37 patients, who had transurethral prostatectomy (TURP) prior to implant, developed

34 Fig. 2. Post-implant CT dosimetry (Varian Brachy Vision) of the seminal vesicles with Pd-103 seeds. Seminal vesicles are colored in pink. The 100% isodose level of the prescribed dose of 120 Gy is outlined in blue and extends 5±10 mm outside the seminal vesicles. The 50% isodose level of the prescribed dose of 120 Gy is outlined in yellow. Anterior rectal wall is outlined in blue and urinary bladder in yellow at bottom. lower urinary-tract infection 2 years after the implant and his urologist performed a TURP resulting in grade 2 incontinence. Transient rectal symptoms of diarrhea and/or constipation occurred after implant in 20% of the patients lasting 1±4 weeks. Two patients experienced post-implant delayed effect of radiation with grade 3 rectal complications 12 months after the implant with rectal bleeding and pain. 4. Discussion Under the 3-D CT-guided pararectal approach, brachytherapy delivers adequate dosage to the entire seminal vesicles as well to the adjacent fat tissue. Under combined ultrasound-guided transperineal brachytherapy and external beam radiation, the dosage to the seminal vesicles has been reported to be inadequate [16]. In addition, with CT-guided monotherapeutic brachytherapy, the dosage to the adjacent organs (bladder and rectum) is 20±40% of the prescribed dose. This is less than the dosage given under combined methods of treatment or radical EBRT. Fig. 3. Dose volume histogram for patient in Fig. 2. One hundred per cent of the target volume of the prostate and seminal vesicles are shown to have received the prescribed dose of 120 Gy. The urethra received 100% of the target dose. The rectum and urinary bladder received in the range of 20± 50% of the target dose. Studies have reported extra capsular extension to range from 15±60% in patients with clinically organ-con ned disease and may have local recurrence after radical prostatectomy [14,15,17]. Furthermore, patients who underwent radical prostatectomy with negative surgical margins and negative lymph nodes have a better prognosis in spite of seminal vesicle invasion. PSA of. 10 ng/ml and Gleason's score. 7 had adverse prognostic failure [17]. Table 1 Post Treatment PSA (12±56 months, median 24 months) by combined Gleason's and initial PSA (n ˆ 34) N PSA,1 ng/mi % PSA, 0.5 ng/ml % Gleason's, 1Ð6 & initial PSA,,20 ng/ml 7 7 100 7 100 Gleason's, 1Ð6 & Initial PSA,.20 ng/ml 0 NA NA NA NA Gleason's, ˆ 7 Initial PSA,20 ng/ml 13 11 85 10 77 Gleason's, ˆ 7 Initial PSA.20 ng/ml 8 4 50 4 50 Gleason's, $ 8 Initial PSA,20 ng/ml 3 3 100 3 100 Gleason's, $ 8 Initial PSA.20 ng/ml 3 2 67 2 67

35 The afterloading needles are not preloaded. If bleeding results from placement of any of the needles, then adjustments to the needles are made to avoid seed placement in the venous plexus; therefore, little, if any, seed migration occurs. There is no signi cant seed migration with loose seeds outside the capsule of the prostate, however we prefer seeds in rapid strand. This is con rmed with CT of the pelvis and chest radiographs taken 3±6 months after implant in all patients. In the absence of infection, high initial PSA (greater than 20) is a poor prognostic indicator without and with seminal vesicle invasion. Although these patients may have negative bone scan, negative CT and negative MRI of the upper and lower abdomen, they may have microscopic systemic disease. We perform pelvic lymph node resection and/or nuclear Prostascint scan for patients with seminal vesicle invasion and high PSA. If positive we recommend EBRT and hormone therapy rather than monotherapy with brachytherapy. However, high-risk patients with Gleason's score $ 7 and PSA,20 have had good results and have good coverage with radioactive seeds. 5. Conclusions 3-DCT-guided monotherapeutic brachytherapy delivers adequate dosage to the seminal vesicles. Clinical and biochemical results are encouraging in patients with low initial PSAs regardless of their Gleason's scores, but longer-term data in a greater number of patients is necessary. References [1] Cadeddu JA, Partin AW, DeWeese TL, Walsh PC. Long-term results of radiation therapy for prostate cancer recurrence following radical prostatectomy. J Urol. 1998;159(1):173±178. [2] Debras B, Guillonneau B, Bougaran J, Chambon E, Vallancien G. Prognostic signi cance of seminal vesicle invasion on the radical prostatectomy specimen. Rationale for seminal vesicle biopsies. Eur Urol. 1998;33(3):271±277. [3] Epstein J, Partin A, Sauvageot J, Walsh P. Prediction of progression following radical prostatectomy. A multivariate analysis of 721 men with long-term follow-up. Am J Surg Pathol 1996;20(3):286±292. [4] Gademan G. Radiotherapy of prostatic cancer. Radiologe 1994;34(3):134±143. [5] Holzman M, Carlton Jr. CE, Scardino PT. The frequency and morbidity of local tumor recurrence after de nitive radiotherapy for stage C prostate cancer. J Urol 1991;146(6):1578±1582. [6] Katcher J, Kupelian PA, Zippe C, Klein EA, Sohn JW. Indications for excluding the seminal vesicles when treating clinically localized prostatic adenocarcinoma with radiotherapy alone. Int Radiat Oncol Biol Phys. 1997;37(4):871±876. [7] Koutrouvelis PG. Three-dimensional stereotactic posterior ischiorectal space computerized tomography guided brachytherapy of prostate cancer: a preliminary report. J Urol 1998;159:142±145. [8] Koutrouvelis PG, Lailas N, Goldson A, et al. 3-D Ct-Guided ischiorectal brachytherapy of prostate cancer in patients with prior TURP. J Brachytherapy Int 1999;15:65±72. [9] Koutrouvelis P, Lailas N, Goldson A, et al. 3-D Ct-Guided brachytherapy for localized prostate cancer in patients with large volumes: 5-year followup.. J. Brachytherapy Int 2000;16:1±10. [10] Koutrouvelis P, Lailas N, Katz S, et al. High & low risk prostate cancer treated with 3-D CT-guided monotherapeutic brachytherapy: 1-5 year followup. J Endo Urol 2000;14(4):357±366. [11] Linzer DG, Stock RG, Stone NN, Ratnow R, Ianuzzi C, Unger P. Seminal vesicle biopsy: accuracy and implications for staging of prostate cancer. Urology 1996;48(5):757±761. [12] Nag S, Baird M, Blasko J, et al. American Brachytherapy Society survey of current clinical practice for permanent brachytherapy of prostate cancer. J Brachytherapy Int 1997(13):243±251. [13] Potter SR, Epstein JI, Partin AW. Seminal vesicle invasion by prostate cancer: prognostic signi cance and therapeutic implications. Rev Urol 2000;2(3):190±195. [14] Rosen M, Goldstone L, Lapin S, Wheeler T, Scardino PT. Frequency and location of extracapsular extension and positive surgical margins in radical prostatectomy specimens. J Urol 1992;148(2 Pt 1):331±337. [15] Sohayda C, Kupelian P, Levin H, Klein E. Extent of extracapsular extension in localized prostate cancer. Urology. 2000;55(3):382±386. [16] Stock RG, Lo YC, Gaildon M, Stone NN. Does prostate brachytherapy treat the seminal vesicles? A dose-volume histogram analysis of seminal vesicles in patients undergoing combined PD-103 prostate implantation and external beam irradiation. Int J Radiat Oncol Biol Phys. 1999;45(2):385±389. [17] Te hli MV, Gheiler EL, Tiguert R, et al. Prognostic indicators in patients with seminal vesicle involvement following radical prostatectomy for clinically localized prostate cancer. J Urol :160(3 Pt 1998;1:802±806. [18] Valicenti RK, Gomella LG, Ismail M, Mulholland SG, Peterson RO, Corn BW. Pathologic seminal vesicle invasion after radical prostatectomy for patients with prostate carcinoma: effect of early adjuvant radiation therapy on biochemical control. Cancer 1998;82(10):1909± 1914.