Three-dimensional computed tomography-guided monotherapeuticpararectal 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 tomo-

graphy (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� 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� 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� 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

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 ultra-

sound-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 ultra-

sound-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

Radiotherapy and Oncology 60 (2001) 31±35

0167-8140/01/$ - see front matter q 2001 Elsevier Science Ireland Ltd. All rights reserved.

PII: S0167-8140(01)00372-3

www.elsevier.com/locate/radonline

* Corresponding author.

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 peri-

prostatic fat tissue (more often in the distal portion of semi-

nal vesicles). Forty-three out of 362 patients (12%) had

seminal vesicle invasion upstaged with 3-dimensional para-

rectal 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 Glea-

son'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 Amer-

ican Brachytherapy Society considers ultrasound guided,

transperineal brachytherapy alone a relative contraindica-

tion for patients with poor prognosis prostate cancer

(Stage T3, prostate .60 gm, previous transurethral resec-

tion, 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 trans-

rectal 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-dimen-

sional 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 speci-

mens included seminal vesicle wall or epithelium. Forty-

three 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� 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

cm3 (median,55; mean, 59.3).

Two out of 43 patients were not treated with brachyther-

apy. 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 treat-

ment 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 para-

rectal brachytherapy were excluded from this report (two

patients expired from other causes within 1 year post-

brachytherapy and one patient was treated for a second

primary). The remaining 34 patients treated with 3-DCT-

guided 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 poster-

ior 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 mono-

therapeutic 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

P. Koutrouvelis et al. / Radiotherapy and Oncology 60 (2001) 31±3532

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 mono-

therapeutic 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 brachyther-

apy. 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 transur-

ethral prostatectomy (TURP) prior to implant, developed

P. Koutrouvelis et al. / Radiotherapy and Oncology 60 (2001) 31±35 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.

lower urinary-tract infection 2 years after the implant and

his urologist performed a TURP resulting in grade 2 incon-

tinence. 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 semi-

nal vesicles as well to the adjacent fat tissue. Under

combined ultrasound-guided transperineal brachytherapy

and external beam radiation, the dosage to the seminal vesi-

cles 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.

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 prosta-

tectomy [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].

P. Koutrouvelis et al. / Radiotherapy and Oncology 60 (2001) 31±3534

Table 1

Post Treatment PSA (12±56 months, median 24 months) by combined Gleason's and initial PSA (n� 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,� 7 Initial PSA ,20 ng/ml 13 11 85 10 77

Gleason's, � 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

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.

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.

The afterloading needles are not preloaded. If bleeding

results from placement of any of the needles, then adjust-

ments 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 morbid-

ity 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 ischiorec-

tal 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 ischior-

ectal 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 brachyther-

apy 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 prosta-

tectomy 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 prosta-

tectomy for patients with prostate carcinoma: effect of early adjuvant

radiation therapy on biochemical control. Cancer 1998;82(10):1909±

1914.

P. Koutrouvelis et al. / Radiotherapy and Oncology 60 (2001) 31±35 35