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PROSTATE BRACHYTHERAPY: TREATMENT STRATEGIES
0022-5347/99/1622-042YO
THEJOURNAL OF UROLOGY Copyright 0 1999 by AMERICAN UROLOGICAL ASSOCIATION, INC.
Vol. 162,421-426, August 1999 Printed in U.S.A.
PROSTATE BRACHYTHERAPY: TREATMENT STRATEGIES NELSON N. STONE From the Departments
of
AND
RICHARD G. STOCK
Urology and Radiation Oncology, Mount Sinai School of Medicine, Mount Sinai Medical Center,
New York,New York ABSTRACT
Purpose: Patients who present with localized and locally advanced prostate cancer may be candidates for prostate brachytherapy. We evaluated the treatment outcomes in a diverse group of prostate cancer patients who presented with low, moderate and high risk features. Materials and Methods: A total of 301 patients who presented with T1 to T3 prostate cancer were treated with brachytherapy alone or combined with hormonal therapy and/or external beam irradiation. Of these patients 109 at low risk with prostate specific anti en (PSA) 10 ng./ml. or less, Gleason score 6 or less and clinical stage T2a or less were treated with f5. 1. ~ alone, ~ e 152 at moderate risk with PSA greater than 10 ngJml., Gleason score greater than 6 or stage T2b or greater were treated with lZ5iodineor 103palladiumor combined implant alone with 5 months of hormonal therapy, and 40 at high risk with PSA greater than 15 ng./ml., Gleason 8 or greater, clinical stage T2c to T3 or positive seminal vesicle biopsy (20) were treated with combination brachytherapy, external beam irradiation and 9 months of hormonal therapy. Patients with a positive seminal vesicle biopsy (T3c disease) and negative pelvic lymph nodes were included in the h g h risk group, and the walls of the seminal vesicles were also treated with implantation. Followup was performed every 6 months with digital rectal examination and ultrasound evaluation. Prostate biopsy was routinely recommended 2 years after completion of the radiation. Failure was defined as PSA increase on 2 consecutive determinations above 1 ngJml. or evidence of local recurrence on digital rectal examination, transrectal ultrasound or biopsy. Kaplan-Meier projections were used to calculate progression-free survival rates. Results: Of the 109 patients a t low risk followed from 1 to 7 years (median 18 months) 91% were free of PSA failure at 4 years. No patient experienced urinary incontinence following implantation, although grade 1to 2 radiation proctitis occurred in 5 (4.5%).Of the 152 patients at moderate risk 73 received implantation and 79 received implantation combined with hormonal therapy. The 4-year biochemical freedom from failure rate for the hormone group was 85%versus 58% for the no hormone group (p = 0.08). The difference was more significant for those with Gleason score 7 or greater (90 versus 43%, p = 0.01) and for those with PSA greater than 10 ng./ml. (87 versus 59%, p = 0.04). Grade 1to 2 radiation proctitis occurred in 1of the 79 patients (1.3%) receiving hormonal therapy and in 3 (4%) treated with implantation only. There were no cases of urinary incontinence. Of the 40 patients a t high risk 71% were free of biochemical failure at 3 years. Of the 4 patients with failure (10%) 3 (75%)originally had positive seminal vesicle biopsies. Five patients experienced gastrointestinal complications, although none was grade 3 o r 4. The actuarial freedom from grade 2 proctitis was 82%. No patient experienced urinary incontinence. Prostate biopsies were negative in 87% of the low risk, 96.8 (hormone group) versus 68.6% (no hormone group) of the moderate risk (p = 0.0023) and 86% of the high risk patients. Conclusions: Brachytherapy appears to offer comparable results t o external beam irradiation and radical prostatectomy when patients are stratified by disease extent. Adopting a strategy of implant alone, implant with hormonal therapy or implant with hormonal therapy and external beam irradiation in patients who present with low to high risk features can improve the overall results in the more advanced cases.
'
KEY WORDS:prostatic neoplasms, brachytherapy, radiation
Reports on the efficacy and low morbidity of prostate brachytherapy have generated increased interest in this new treatment modality for patients and physicians. With longterm data recently becoming available, this procedure is now being widely embraced by urologists and radiation oncologists.' Selection of appropriate candidates for implant alone or combined with external beam irradiation and/or hormonal therapy has not been adequately studied. We describe the ultrasound guided approach to permanent prostate seed implantation, and detail the efficacy and morbidity outcomes of the procedure in a diverse group of patients with low, moderate and high risk prostate cancer.
TECHNIQUE
Preplanned implant. Holm et a1 first described the use of transrectal ultrasound to plan seed placement," and physicians at the Northwest Hospital perfected this technique which uses axial images to generate a treatment plane.'." The implant needles, guided by the preplan, are inserted through the template and perineum, and into the prostate. Transrectal ultrasound is used not to direct seed placement, but rather to recreate the preplan and ensure that the implant needles are placed accordingly. Seeds are inserted via preloaded needles, polyglycolic acid strands or the Mick applicator.
42 1
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PROSTATE BRACHYTHERAPY
For early implants uniform seed spacing was used,4 while later implants were performed with peripheral weighting to decrease the dose to the urethra.5 The Northwest Hospital series has the longest followup and compares favorably with radical prostatectomy.6 Urinary complications can be significant and result from the high dose delivered to the center of the gland close to the urethra from the uniformly spaced seeds. Patients who undergone a prior transurethral resection of the prostate and who were treated with this technique had a 12% incontinence rate.6 Based on these data, such patients were not considered suitable for a preplanned uniform implant. In addition, pubic arch interference also limited this technique. Rectal complications and erectile dysfunction were low. Real-time interactive prostate implantation. Real-time interactive seed implantation is the newest technique to be used for prostate brachytherapy and takes advantage of the ability of transrectal ultrasound to provide precision targeting.7-9 Before implantation the prostate volume is measured. Using an activity per volume table, the appropriate amount of activity is ordered and brought to the operating room. With the patient in the dorsal lithotomy position and a Foley catheter in place, a C-arm fluoroscopic image intensifier is positioned over the bladder and prostate. An electronic phased array biplanar probe is positioned in the rectum to ensure that the entire prostate is visible. The perineum is then prepared and the template is attached to the stepping unit. Using transverse imaging serial contours of the prostate are measured at 5 mm. intervals from base to apex. This planimetry volume is used when calculating the amount of activity to implant. The treatment plan is created in the operating room. The total activity is divided by activity per seed (usually 0.3 to 0.5 mCi. per seed for 125iodine[I] and 1.0 to 1.5 mCi. per seed for lo3palladiurn [Pdl) to give the total number of seeds to implant. After the volume measurements are completed, imaging is switched to longitudinal, and measurements are made anterior and posterior t o the urethra, and posterior from base to apex. These longitudinal measurements are used to determine the spacing between the seeds. Current isotope choices for permanent prostate seed implantation are 1251 and lo3Pd. 1251 is selected for patients with Gleason score 6 or less on biopsy and lo3Pd is used in ' also selected for patients with Gleason 7 or greater. lo3Pd is high risk patients who are t o receive a combination of seed implant and external beam irradiation (implant is done first with 67% of the full dose followed 2 months later with external beam at 45 Gy.). The details of this implant technique have been previously described?g A month after implantation the patient returns for evaluation with a 3-dimensional (D) computerized tomography (CT) dosimetric system. CT images of the prostate are taken at 3 to 5 mm. intervals from the base of the bladder to the sphincter to assess the quality of the implant. These images are then digitized and reconstructed in 3-D to give dose volume histograms and dose surface histograms of the prostate, rectal wall and bladder base, respectively. This information is critically important for evaluating the adequacy of the implant and helps newly trained physicians assess and improve their technique.10
might best benefit from prostate brachytherapy. 13-18 Eventually, an analysis of the effect of PSA, stage and grade on outcome confirmed the same prognostic significance of these factors following brachytherapy.9 Based on these results, low risk patients who might best benefit with implant alone were identified. Low risk was defined as stage T2a or less, Gleason sum less than 7 and PSA 10 ng./ml. or less. These patients had significantly improved outcome compared to higher risk patients when treated with Ip51implant alone.'" Patients with more advanced localized disease were found to benefit from the addition of hormonal therapy to the external beam regimen.""zl While the addition of neoadjuvant hormonal therapy appeared to offer an advantage in patients with large prostates who underwent seed implantation, no substantial information was available to evaluate its benefit in high risk patients undergoing brachytherapy.Z2 The addition of neoadjuvant hormonal therapy in patients who presented with stage T2b or greater, PSA greater than 10 ng./ml. or Gleason score 7 or greater might yield similar favorable results as seen in the combination hormonal therapy, external beam studies. Also patients who presented with PSA greater than 20 ng./ml. responded poorly to implant alone.'* Data on external beam irradiation and radical prostatectomy revealed high recurrence rates in patients with poor prognostic factors,13.23.24 and prostatectomy data indicated poor outcomes for patients with pathologically involved seminal vesicle disease. Based on these data an aggressive treatment regimen was developed, which included hormonal therapy, brachytherapy and conformal external beam irradiation to treat patients with PSA greater than 15 ng./ml., Gleason score 8 to 10, clinical stage T2C t o T3 or positive seminal vesicle biopsies. MATERIALS AND METHODS
A total of 301 patients who presented with T1 to T3 prostate cancer were treated with brachytherapy alone or combined with hormonal therapy andor external beam irradiation (table 1). There were 109 patients at low risk with PSA 10 ng./ml. or less, Gleason score 6 or less and clinical stage T2a or less treated with 1251 alone, 152 at moderate risk with PSA greater than 10 ng./ml., Gleason score greater than 6 or stage T2b or greater treated with Ip51or In3Pd implant alone or combined with 5 months of hormonal therapy, and 40 at high risk with PSA greater than 15 ng./ml., Gleason 8 or greater, or clinical stage T2c t o T3 or positive seminal vesicle biopsy (20) treated with combination brachytherapy, external beam irradiation and 9 months of hormonal therapy. Low risk patients were implanted with lZ5Ito a dose of 160 Gy. (TG43 guidelines) and moderate risk patients were implanted with '1 for Gleason score of 6 or less or ""Pd to a dose of 115 Gy. for Gleason 7 or greater. Hormonal therapy was administered for 3 months before and for 2 months after implant in 79 of the moderate risk patients, while 73 received implantation alone. High risk patients received an implant of lo3Pd t o a dose of 56 t o 86 Gy. combined with external beam irradiation to a dose or 4,500 to 7,040 cGy. Conformal 3-D external beam irradiation was delivered via 6 fields (2 anterior oblique, 2 posterior oblique and 2 lateral fields) with a 2 cm. margin to the prostate and seminal vesicles. High risk patients were treated according to an institutional review
PATIENT SELECTION
In the past few data were available to help guide patient selection for brachytherapy. Cases were often staged with little more than a bone scan and CT. The addition of bilateral ultrasound guided seminal vesicle biopsy and laparoscopic lymph node dissection helped t o identify further patients with extraprostatic disease.11,l2 Studies reporting the prognostic significance of prostate specific antigen (PSA) and grade in predicting outcome after external beam irradiation and prostatectomy also helped further define which patients
TABLE1. Clinical features of patients treated with brachytherapy according to risk category Clinical Feature
Low Risk
Moderate Risk
High Risk
Stage T2a or Less TZbT2c T2c-T3c Grade 6 or Less 7 or Greater 8 or Greater PSA (ng./ml.) 10 or Less Greater than 10 Greater than 15 Low risk patients must have all features to be included in that category, while moderate or high risk patients need only 1 feature prescnt.
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board approved lo3Pd dose escalation study, and received 3 months of hormonal therapy before implant and continued androgen withdrawal therapy for 6 months after implant (total 9 months). Patients on the institutional review board protocol also received a higher dose of external beam irradiation t o 5,940 and 7,040 cGy. and the implant dose was also escalated from 56 to 76 to 86 Gy. as part of this protocol. Those patients with a positive seminal vesicle biopsy (T3c disease) and negative pelvic lymph nodes were included in the high risk group and additionally the walls of the seminal vesicles were also treated with implantation. Hormonal therapy was administered as a combination of leuprolide acetate and 250 mg. flutamide every 8 hours in all patients. All cases were staged with routine bone scans and CT. All patients with PSA greater than 10 ng./ml., Gleason 7 or greater or clinical stage T2b or greater also underwent bilateral seminal vesicle biopsy. Those patients with PSA greater than 15 ng./ml., Gleason score greater than 7 or a positive seminal vesicle biopsy underwent laparoscopic pelvic lymph node dissection before treatment,22.23 and those with positive nodes were excluded from implantation. Followup was performed every 6 months with PSA, digital rectal examination and ultrasound evaluation. Prostate biopsies, including 6 from the prostate and 6 from the seminal vesicles for patients with a positive seminal vesicle biopsy, were routinely recommended 2 years after completion of treatment regardless of disease status. Followup was started at completion of therapy (date of implant or completion of external beam irradiation). PSA failure was defined as 2 elevations above 1 ng./ml. Comparisons between survival rates were calculated using the log rank test, and differences in proportions were tested using the Pearson chi-square method. RESULTS
1
0 0
1
2
3
4
Years [ ] No. of patients at risk
FIG. 1. Four-year freedom from PSA failure in low risk patients with PSA 10 ng./ml. or less, Gleason 6 or less and clinical stage T2a or less. TABLE3. Clinical features of 152 moderate risk patients Variable
No. Pts. Treated With Hormones (7%)
No. Pts. No Hormones (7O)
PSA (ng./ml.): 1 (1.3) 2 (2.7) 0-4 4.1-10 8 (11) 24 (30.4) 10.1-20 37 (46.8) 38 (52) Greater than 20 17 (21.5) 25 (34.3) Gleason score: 16 (20.2) 12 (16.4) 2-4 21 (26.6) 37 (50.7) 5-6 40 (50.6) 24 (32.9) 7 or Greater Clinical stage: Tlb 1 (1.3) 2 (2.7) Tlc 15 (19) 10 (13.7) T2a 12 (15.2) 14 (19.2) T2b 33 (41.8) 38 (52.1) T2c 18 (22.7) 9 (12.3) Hormonal group was treated for 3 months before and 2 months after implant with leuprolide and flutamide.
The 109 patients at low risk received I ' ' ' alone, and followup ranged from 1 to 7 years (median 18 months). PSA ranged from 1.3 to 10 ng./ml. (median 6.41, a third of the patients had Gleason scores 2 to 4 and an equal number had Tlc and T2a lesions (table 2). The 4-year freedom from PSA failure rate was 91% (fig. 1).No patient experienced urinary incontinence following implantation. Grade 1 t o 2 radiation proctitis occurred in 5 men (4.5%) and there were no cases of of grade 3 or 4 radiation proctitis and no cases of urinary grade 3 or 4 radiation proctitis. incontinence. The 152 patients a t moderate risk were followed a median The 40 patients at high risk underwent a combination of of 27 months (range 12 to 74) and were treated with either hormonal therapy and lo3Pd implantation followed by exterimplantation alone (73) or implant combined with hormonal nal beam irradiation. PSA ranged from 2.1 to 202 ng./ml. therapy (79). The patients were equally distributed with (median 20),32 had Gleason score 7 or greater (80%) and 34 regard to stage, PSA and Gleason score (table 3). The 4-year had clinical stage T2b or greater (85%).Of the 40 patients 20 biochemical freedom from failure rate for the hormone group had biopsy confirmed seminal vesicle involvement (table 4). was 85% versus 58%for the no hormone group (p = 0.08, fig. Followup ranged from 6 to 42 months (median 13). The 2, A). The difference was more significant for those with 3-year biochemical freedom from failure rate in these high Gleason score 7 or greater (90 versus 43%, p = 0.01, fig. 2, B ) risk patients was 71% (fig. 3). Of the 4 patients (10%) with and for those with PSA greater than 10 ng./ml. (87 versus failure 3 (75%) originally had positive seminal vesicle biop59%, p = 0.04, fig. 2, C). Grade 1 to 2 radiation proctitis sies. The time to failure in these 4 patients ranged from 226 occurred in 1patient receiving hormonal therapy (1.3%)and to 712 days (mean 446). The last PSA value in the 36 patients in 3 treated only with implantation (4%).There were no cases without failure was less than 0.05 ng./ml. in 21 (58.3%),0.05 to 0.2 in 13 (36.1%)and greater than 0.2 to 0.5 in 2 (5.6%).All 5 patients who received 5,940 cGy. external beam dose had gastrointestinal complications. There were no grade 3 or TABLE2. Clinical features of 109 low risk patients 4 gastrointestinal complications. The actuarial freedom from Variable No. F'ts. (70) grade 2 proctitis was 82%. No patient experienced urinary incontinence. Prostate biopsies were negative in 87% of the PSA (ng./ml.): 0-4 17 (15.6) low risk, 96.8 (hormone group) versus 68.6% (no hormone Greater than 4-10 92 (84.4) group) of the moderate risk (p = 0.0023) and 86% of the high Gleason score: risk patients (table 5). 2 4 33 (30.3) 5-6 Clinical stage: Tlb Tlc T2a
76 (69.7)
1 (0.9) 56 (51.4) 52 (47.7)
DISCUSSION
The rationale for using brachytherapy alone in low risk patients evolved from the experience at several centers
424
PROSTATE BRACHYTHERAPY A
C
6
f
5 E
"1
E
E
E
e
g
E
FIG.2. Effect of hormonal therapy on PSA failure. Four-year biochemical freedom from failure for moderate risk patients treated with or without hormones ( p = 0.08, A), with Gleason 7 or greater (p = 0.01, B )and with PSA 10 ng./ml. or greater (p = 0.04, C ) . TABLE4. Clinical features of 40 high risk patients Variable PSA (ng./ml.): 0-4 Greater than P 1 0 Greater than 10-20 Greater than 20-50 Greater than 50 Gleason score: 2 4 56
7
aio
No. F'ts. (Bi 1 (2.51 8 (20) 11 (27.5) 14 (35) 6 (15) 1 (2.5) 7 (17.51 19 (47.5) 13 (32.51
Clinical stage: 5 (12.5) Tlc 1 (2.51 T2a 5 (12.51 T2b 22 (55) T2c 7 (17.51 T3 External beam dose (cGy.): 4,500 8 (20) 5,040 3 (7.5) 5,940 28 (70) 7,020 1 (2.51 Implant dose (cGy.1: 5,700 13 (32.51 7,600 13 (32.5) 8,600 14 (35) The highest dose given was combination of 86 Gy. of Io3Pdfollowed by 5,940 cGy. e&mal beanirradiation in 6 patients
n
25 n = 40 3 year freedom from failure = 71'b
0
0
6
12
18
24
30
36
1
Months [ ] No. of patients at rlsk
FIG. 3. Three-year freedom from PSA failure in high risk patients with PSA greater than 15 ng./ml., Gleason 8 or greater, or clinical stage T2c to T3 or positive seminal vesicle biopsy treated with combination brachytherapy,external beam irradiation and 9 months of hormonal therapy. TABLE5. Prostate biopsy results in low to high risk Datients No. Nee. Biousv (B) No. Pos. Biousv (%)
where implants have been performed for a considerable time. Ragde et a1 reported on 126 men followed a mean of 69 months who received a 1251 implant.6 While the results were not stratified by the presenting risk factors, most of their cases would fit into the definition of low risk. Median PSA was 5.0 ng./ml., which is similar to the low risk median 6.4 ng./ml. in our study. In addition, 85.3%of their patients had clinical T2a or less disease, all had Gleason 6 or less and 78.7% had PSA 10 ng./ml. or less. One might argue that their patients represented an even more favorable group than ours because 44.3% had PSA from 0 to 4 ng./ml. compared to only 15.6%in our series. Nonetheless, the 7-year actuarial PSA progression-free outcome was 87%for PSA 1.0 ng./ml. or less and 79%for PSA 0.5 ng./ml. or less. These numbers compare favorably to our own report of 91% freedom from PSA progression. The progression-free results in these low risk paalone also compare favorably to what tients treated with 1251 has been reported for similar groups of patients treated with radical prostatectomy or external beam irradiation. In a group of clinically similar patients who underwent radical retropubic prostatectomy, Catalona and Bigg reported a 78% success rate (PSA 0.6 ng./ml. or less) at 5 years,25 and Partin et a1 reported an 83%freedom from PSA failure rate (PSA 0.3 ng./ml. or less) at 5 years.26 DAmico et a1 evaluated the effect of presenting risk features on 867 and 757 consecutive prostate cancer patients treated with external beam irradiation or radical retropubic prostatectomy.27 Patients were separated into a low risk
Low risk
20 (87) 3 (13) Moderate risk with hormones 30 (96.8) 1 (3.2) Moderate risk without hormones 35 (68.6) 16 (31.4) High risk 6 (86) 1 (14) The difference in positive biopsy results between the moderate risk patients treated with and without hormonal therapy was significant ( p = 0.0023).
group defined as PSA greater than 4 to 10 ng./ml. and Gleason score 4 or less. The 2-year PSA failure-free survival was 87%for the radical prostatectomy cases with organ confined disease and 92%for those who received external radiation. Vicini et al performed a n extensive review of patients who received external beam irradiation and analyzed the data by presenting PSA.28.29 Biochemical control rates for 6 centers that reported data for patients who presented with initial PSA 4.0 ng./ml. or less ranged from 69 to 93%. For patients with PSA 4 to 10 ng./ml. the success rate was 44 t o 84%. They also analyzed 5 brachytherapy series with presenting PSA between 4 and 10 ng./ml. and found a 55 t o 90% success rate. Patients who present with moderate risk disease do not do as well as those with low risk disease regardless of the treatment modality. DAmico et al defined an intermediate risk category as PSA greater than 4 to 10 ng./ml. and Gleason score 5 to 7 or PSA greater than 10 to 20 ng./ml. and Gleason score 7 or lessz7 The 2-year success rate for radiation therapy and radical prostatectomy was 81 and 77%, respectively. Kupelian et al re-
PROSTATEBRACHYTHERAPY
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ported a 60 to 70% 5-year success rate with these 2 treatment recognize that followup for biochemical control in this study modalities when cases were stratified by PSA greater than 10 t o is relatively short and that longer followup will be needed to 20 ng./ml.30x31Biochemical control rates for patients with PSA substantiate these findings. Brachytherapy also has few side greater than 10 to 20 ng./ml. reported in 6 conventional radia- effects, even when combined with conventional doses of extion therapy series ranged from 27 to 72%.2s,29The same study ternal beam irradiation. reported brachytherapy results from 5 centers with reported success rates ranging from 45 to 89%. Our own data also suggest inferior results compared to patients with low risk disease. REFERENCES The 4-vear success rate for the imdant alone cases was onlv 1. Ragde, H., Elgamal, A. A., Snow, P. B., Brandt, J., Bartolucci, 58% whch contrasted to 85%for those treated with a combinaA. A,, Nadir, B. S. and Korb, L. J.: Ten-year disease free tion of hormonal therapy and seed implantation. The difference survival after transperineal sonography-guided iodine-125 was more significant in patients with PSA greater than 10 brachytherapy with or without 45-gray external beam irrading./ml. (87 versus 59%, p = 0.04) and in patients with Gleason ation in the treatment of patients with clinically localized, low score 7 or greater (90 versus 43%, p = 0.01). to high grade prostate carcinoma. Cancer, 8 3 989, 1998. 2. Holm, H. H., Juul, N., Pedersen, J. F., Hansen, H. and Stoyer, I.: The most difficult cases to treat successfully are those with Transperineal 125 iodine seed implantation in prostatic carcilocally advanced prostate cancer at presentation. We previnoma guided by transrectal ultrasonography. J. Urol., 130 ously reported a 58% 2-year and 34% 4-year freedom from 283, 1983. biochemical progression in men who presented with initial 3. Blasko, J. C., Wallner, K., Grimm, P. D. and Ragde, H.: PSA PSA greater than 20 ng./ml. treated with implant alone with based disease control following ultrasound guided 1-125 imor without hormonal therapy.9- 19 Freedom from failure rates plantation for stage Tlfl’2 prostatic carcinoma. J . Urol., 154: for similar patients treated with conventional external beam 1096, 1995. irradiation or conformal radiation therapy range from 8 to 4. Quimby, E. H.: The grouping of radium tubes in packs and 37%.”2727.28 Radical prostatectomy success rates in these plaques to produce the desired distribution of radiation. AJR, 27: 18, 1932. high risk patients are equally disappointing, as Kupelian et 5. Paterson, R. and Parker, H. M.: A dosage system for gamma-ray a1 reported a 25% likelihood of freedom from failure at 5 therapy, Parts 1 and 2. Brit. J. Rad., 7: 592, 1943. years in this setting.30.31 6. Ragde, H., Blasko, J. C., Grimm, P. D., Kenny, G. M., Sylvester, We elected to combine brachytherapy with external beam J. E., Hoak, D. C., Landin, K. and Cavanagh, W.: Interstitial irradiation and neoadjuvant and adjuvant hormonal therapy iodine-125 radiation without adjuvant therapy in the treatto attempt to improve the poor results in these high risk ment of clinically localized prostate cancer. Cancer, 8 0 442, patients. The rationale for the combination of seed implant 1997. and external beam irradiation evolved from the dose re7. Stone, N. N., Stock, R. G., DeWyngaert, J. K. and Tabert, A,: sponse data in high risk patients treated with external beam Prostate brachytherapy: improvements in prostate volume measurements and dose distribution using interactive ultraalone and from the initial favorable reports of combination sound guided implantation and three-dimensional dosimetry. irradiation from several centers.31-34 The addition of comRad. Oncol. Invest., 3 185, 1995. plete hormonal therapy also evolved from randomized stud8. Stock, R. G., Stone, N. N., Wesson, M. F. and DeWyngaert, J. K.: ies documenting the advantage of androgen withdrawal in A modified technique allowing interactive ultrasound guided locally advanced prostate cancer treated with external beam three-dimensional transperineal prostate implantation. Int. J . irradiation.20.21 The favorable 3-year freedom from PSA failRad. Oncol. Biol. Phys., 3 2 219, 1995. ure in this group of high risk patients (50% of whom had 9. Stock, R. G., Stone, N. N., DeWyngaert, J. K., Lavagnini, P. and biopsy proved T3c disease) suggests that tri-modal therapy Unger, P. D.: Prostate specific antigen findings following in(seeds plus external beam plus hormonal therapy) may offer teractive ultrasound guided transperineal brachytherapy for early stage prostate carcinoma. Cancer, 77: 2386, 1996. a significant improvement over standard monotherapy with radiation or radical prostatectomy alone. The data also sug- 10. Stock, R. G., Stone, N. N., Tabert, A,, Iannuzzi, C. and DeWyngaert, K.: A dose response study for 1-125 prostate gest that this treatment is successful at eradicating all local implants. Int. J . Rad. Oncol. Biol. Phys., 41: 101, 1998. disease with a 2-year negative biopsy rate of 86%. 11. Stock, R. G., Stone, N. N., Ianuzzi, C. and Unger, P.: Seminal Our data also suggest that brachytherapy can be accomvesicle biopsy and laparoscopic pelvic lymph node dissection: plished with low morbidity. No patient had incontinence, implications for patient selection in the radiotherapeutic mancystitis or significant radiation proctitis (grade 3 or higher). agement of prostate cancer. Int. J. Rad. Oncol. Biol. Phys., 3 3 The incidence of grade 1 to 2 radiation proctitis in the low to 815, 1995. moderate risk patients ranged from 1.3to 4.5%. Patients who 12. Stone, N. N., Stock, R. G. and Unger, P.: Indications for seminal vesicle biopsy and laparoscopic pelvic lymph node dissection in received a combination of seeds and external beam irradiamen with localized carcinoma of the prostate. J. Urol., 154 tion had a n actuarial 18% incidence of grade 1to 2 proctitis. 1392, 1995. There was no grade 2 proctitis in 11 of the 40 patients who received external beam irradiation to a dose of less than 13. Zeitman, A. L., Coen, J. J., Shipley, W. U., Willet, C. G. and Efrid, J . T.: Radical radiation therapy in the management of %940 cGy. Thus, this higher incidence of grade 2 proctitis prostatic adenocarcinoma: the initial prostate specific antigen was only found in those patients receiving high doses of value as a predictor of treatment outcome. J . Urol., 151: 640, external beam irradiation. This study is part of a n ongoing 1994. institution review board approved dose escalation trial to 14. Zagars, G. K.: Prostate specific antigen as an outcome variable determine whether an external dose beyond the conventional for T1 and T2 prostate cancer treated by radiation therapy. J. Urol., 152: 1786, 1994. dose of 4,500 cGy. offers an advantage in these high risk 15. Lee, W. R., Hanks, G. E., Schultheiss, T. E., Corn, B. W. and patients.”-3.5 Hunt, M. A.: Localized prostate cancer treated by external -
~~
~
CONCLUSIONS
Brachytherapy appears to offer comparable results to external beam irradiation and radical prostatectomy when cases are stratified by disease extent. Adopting a strategy of Implant alone, implant with hormonal therapy or implant with hormonal theraDv and external beam irradiation in Patients who presen[&ith low t o high risk features can Improve the overall results in the more advanced cases. We
beam radiotherapy alone: serum prostate-specific antigen driven outcome analysis. J. Clin. Oncol., 13 464, 1995. 16. Hanks, G. E., Lee, W. R. and Schultheiss, T. E.: Clinical and biochemical evidence of control of prostate cancer at 5 years after external beam radiation. J. Urol., 154: 456, 1995. 17. Zagars, G. K. and Pollack, A,: Radiation therapy for T1 and T2 prostate cancer: prostate-specific antigen and disease control. Urology, 4 5 476, 1995. 18. Zeitman, A. L., Edelstein, R. A., Coen, J. J., Babayan, R. K. and Krane. R. J.: Radical Drostatectomv for adenocarcinoma of the
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analysis of clinical and pathological factors that predict for prostate: the influence of preoperative and pathologic findings on biochemical disease free outcome. Urology, 43 828, 1994. prostate specific antigen failure after radical prostatectomy for 19. Stock, R. G. and Stone, N. N.: The effect of prognostic factors on prostate cancer. J . Urol., 154: 131, 1995. therapeutic outcome following transperineal prostate brachy- 28. Vicini, F. A,, Honvitz, E. M., Kini, V. R., Stromber, J. S. and therapy. Sem. Surg. Oncol., 1 3 454, 1997. Martinez, A. A.: Radiotherapy options for localized prostate 20. Pilepich, M. V., Krall, J . M., Al-Sarraf, M., Madhu, J. J., Doggett, cancer based upon pretreatment serum prostate-specific antiR. L. S., Sause, W. T., Lawton, C. A,, Abrams, R. S.,Rotman, gen levels and biochemical control: a comprehensive review of M., Rubin, P., Shipley, W. U.,Grignon, D., Caplan, R. and Cox, the literature. Int. J . Rad. Oncol. Biol. Phys., 40 1101, 1998. J. D.: Androgen deprivation with radiation therapy compared 29. Vicini. F. A.. Honvitz. E. M.. Gonzalez, J . and Martinez, A. A.: with radiation therapy alone for locally advanced prostatic Treatment options for localized prostate cancer based upon carcinoma: a randomized comparative trial of the radiation pretreatment prostate specific antigen levels. J. Urol., 158: therapy oncology group. Urology, 45 616, 1995. 319, 1997. 21. Laverdiere, J., Gomez, J. L., Cusan, L., Suburu, E. R., Diamond, 30. Kupelian, P., Katcher, J., Levin, H., Zippe, C. and Klein, E. I.: P., LeMay, M., Canadas, B., Fortin, A. and Labrie, F.: BenefiCorrelation of clinical and pathologic factors with rising cial effect of combination therapy administered prior and folprostate-specific antigen profiles after radical prostatectomy lowing external beam radiation therapy in localized prostate alone for clinically localized prostate cancer. Urology, 48 249, cancer. Int. J . Rad. Oncol. Biol. Phys., 37: 247, 1997. 1996. 22. Blasko, J . C., Ragde, H., Grimm, P. D., Sylvester, J. and 31. Kupelian, P., Katcher, J., Levin, H., Zippe, C., Suh, J., Macklis, Cavanagh, W.: Potential for neoadjuvant hormonal therapy R. and Klein, E.: External beam radiotherapy versus radical with brachytherapy for prostate cancer. Mol. Urol., 1: 207, prostatectomy for clinical stage T1-2 prostate cancer: thera1997. peutic implications of stratification by pretreatment PSA lev23. Hanks, G. E., Hanlon, A. L., Hudes, G., Lee, W. R., Winlove, S. els and biopsy Gleason scores. Cancer J . Sci. Amer., 3: 78, and Schultheiss, T.: Patterns of failure analysis of patients 1997. with high pretreatment prostate-specific antigen levels treated by radiation therapy. The need for improved systemic 32. Hanks, G. E., Martz, K. L. and Diamond, J. J.: The effect of dose on local control of prostate cancer. Int. J. Rad. Oncol. Biol. and regional therapy. Int. J. Rad. Oncol. Biol. Phys., 14: 1093, Phys., 1 5 1299, 1988. 1996. 24. Kuban, D. A,, El-Mahdi, A. M. and Schellhammer, P. F.: 33. Critz, F. A,, Levinson, A. K., Williams, W. H. and Holloday, D. A,: Prostate-specific antigen nadir: the optimum level after irraProstate-specific antigen for pretreatment and post-treatment diation for prostate cancer. J . Clin. Oncol., 14: 2893, 1996. evaluation of outcome after definitive irradiation for prostate 34. Dattoli, M., Wallner, K., Sorace, R., Koval, J., Cash, J., Acosta, cancer. Int. J. Rad. Oncol. Biol. Phys., 3 2 307, 1995. R., Brown, C., Ethridge, J., Binder, M., Brunelle, R., Kinvan, 25. Catalona, W. J . and Bigg, S. W.: Nerve-sparing radical prostaN., Sanchez, S., Stein, D. and Wasserman, S.: Pd-103 brachytectomy: evaluation of results after 250 patients. J. Urol., 1 4 3 therapy and external beam irradiation for clinically localized, 538, 1990. high-risk prostatic carcinoma. Int. J . Rad. Oncol. Biol. Phys., 26. Partin, A. W., Pound, C. R., Quentin Clemens, J., Epstein, J. I. 3 5 875. 1996. and Walsh, P. C.: Serum PSA after anatomic radical prostatectomy. The Johns Hopkins experience after 10 years. Urol. 35. Blasko, J.'C., Ragde, H., Cavanagh, W., Sylvester, J. and Grimm, P. D.: Long-term outcomes of external beam irradiation and Clin. N. Amer., 20 713, 1993. 27. DAmico, A. V., Whittington, R., Malkowicz, S. B., Schultz, D., 1-125/Pd-103 brachytherapy boost for prostate cancer. Int. J. Rad. Oncol. Biol. Phys., 3 6 198, 1996. Schnall, M., Tomaszewski, J . E. and Wein, A,: A multivariate ~
~~~~~
QUESTIONS AND RESPONSES Dr. C. A. Olsson. You reported in your series a 15% positive biopsy rate. What do you in this situation? Dr. N. N . Stone. We reported negative prostate biopsies in 87% of the low risk, 96.8 versus 68.6% of the moderate risk (p = 0.0023, favoring neoadjuvant hormonal therapy) and 86% of the high risk patients. The options for treating brachytherapy failure cases which have a documented local recurrence (positive biopsy) and no evidence of systemic disease include another seed implant, external beam irradiation, salvage radical prostatectomy and hormonal therapy. The decision of which to recommend depends on the situation and the results of post-implant dosimetry. The dosimetry should describe the radiation dose to the prostate, rectum, bladder and urethra. In most cases the radiation dose to the rectum and bladder is much lower than that received by a patient initially treated with external beam (the dose to 30% of the rectum averages only 40% of the prescription dose). A repeat implant might be considered if the original implant was done poorly (as defined by dosimetry) and rectal doses were low. Salvage external beam irradiation might be considered if the biopsies were positive outside of the prostate and the rectal doses were low. Finally, salvage radical prostatectomy might be considered if the dose to the prostate was adequate, and the rectal and bladder dose was low. Doctor Olsson. What is the morbidity of a salvage prostatectomy following a radiation seed failure? Are most failures at 2 years associated with distant relapse? Doctor Stone. The morbidity of a salvage prostatectomy following a seed implant would in theory be similar to the morbidity following external beam irradiation. If post-implant dosimetry reveals low dose to the rectum and bladder neck then the radical should be no more difficult than in a previously untreated patient, and this is in fact the case. The urologist will need to know the dosimetry before undertaking the salvage radical prostatectomy. Local failure a t 2 years in low risk patients is most often not associated with systemic relapse. The likelihood of local failure in a moderate risk patient who received neoadjuvant therapy is only 3.2%.Local failure in high risk patients is almost always associated with systemic relapse.
THEJOURNAL OF UROLOGY Copyright 0 1999 by AMERICAN UROLOGICAL ASSOCIATION, INC.
Vol. 162,421-426, August 1999 Printed in U.S.A.
PROSTATE BRACHYTHERAPY: TREATMENT STRATEGIES NELSON N. STONE From the Departments
of
AND
RICHARD G. STOCK
Urology and Radiation Oncology, Mount Sinai School of Medicine, Mount Sinai Medical Center,
New York,New York ABSTRACT
Purpose: Patients who present with localized and locally advanced prostate cancer may be candidates for prostate brachytherapy. We evaluated the treatment outcomes in a diverse group of prostate cancer patients who presented with low, moderate and high risk features. Materials and Methods: A total of 301 patients who presented with T1 to T3 prostate cancer were treated with brachytherapy alone or combined with hormonal therapy and/or external beam irradiation. Of these patients 109 at low risk with prostate specific anti en (PSA) 10 ng./ml. or less, Gleason score 6 or less and clinical stage T2a or less were treated with f5. 1. ~ alone, ~ e 152 at moderate risk with PSA greater than 10 ngJml., Gleason score greater than 6 or stage T2b or greater were treated with lZ5iodineor 103palladiumor combined implant alone with 5 months of hormonal therapy, and 40 at high risk with PSA greater than 15 ng./ml., Gleason 8 or greater, clinical stage T2c to T3 or positive seminal vesicle biopsy (20) were treated with combination brachytherapy, external beam irradiation and 9 months of hormonal therapy. Patients with a positive seminal vesicle biopsy (T3c disease) and negative pelvic lymph nodes were included in the h g h risk group, and the walls of the seminal vesicles were also treated with implantation. Followup was performed every 6 months with digital rectal examination and ultrasound evaluation. Prostate biopsy was routinely recommended 2 years after completion of the radiation. Failure was defined as PSA increase on 2 consecutive determinations above 1 ngJml. or evidence of local recurrence on digital rectal examination, transrectal ultrasound or biopsy. Kaplan-Meier projections were used to calculate progression-free survival rates. Results: Of the 109 patients a t low risk followed from 1 to 7 years (median 18 months) 91% were free of PSA failure at 4 years. No patient experienced urinary incontinence following implantation, although grade 1to 2 radiation proctitis occurred in 5 (4.5%).Of the 152 patients at moderate risk 73 received implantation and 79 received implantation combined with hormonal therapy. The 4-year biochemical freedom from failure rate for the hormone group was 85%versus 58% for the no hormone group (p = 0.08). The difference was more significant for those with Gleason score 7 or greater (90 versus 43%, p = 0.01) and for those with PSA greater than 10 ng./ml. (87 versus 59%, p = 0.04). Grade 1to 2 radiation proctitis occurred in 1of the 79 patients (1.3%) receiving hormonal therapy and in 3 (4%) treated with implantation only. There were no cases of urinary incontinence. Of the 40 patients a t high risk 71% were free of biochemical failure at 3 years. Of the 4 patients with failure (10%) 3 (75%)originally had positive seminal vesicle biopsies. Five patients experienced gastrointestinal complications, although none was grade 3 o r 4. The actuarial freedom from grade 2 proctitis was 82%. No patient experienced urinary incontinence. Prostate biopsies were negative in 87% of the low risk, 96.8 (hormone group) versus 68.6% (no hormone group) of the moderate risk (p = 0.0023) and 86% of the high risk patients. Conclusions: Brachytherapy appears to offer comparable results t o external beam irradiation and radical prostatectomy when patients are stratified by disease extent. Adopting a strategy of implant alone, implant with hormonal therapy or implant with hormonal therapy and external beam irradiation in patients who present with low to high risk features can improve the overall results in the more advanced cases.
'
KEY WORDS:prostatic neoplasms, brachytherapy, radiation
Reports on the efficacy and low morbidity of prostate brachytherapy have generated increased interest in this new treatment modality for patients and physicians. With longterm data recently becoming available, this procedure is now being widely embraced by urologists and radiation oncologists.' Selection of appropriate candidates for implant alone or combined with external beam irradiation and/or hormonal therapy has not been adequately studied. We describe the ultrasound guided approach to permanent prostate seed implantation, and detail the efficacy and morbidity outcomes of the procedure in a diverse group of patients with low, moderate and high risk prostate cancer.
TECHNIQUE
Preplanned implant. Holm et a1 first described the use of transrectal ultrasound to plan seed placement," and physicians at the Northwest Hospital perfected this technique which uses axial images to generate a treatment plane.'." The implant needles, guided by the preplan, are inserted through the template and perineum, and into the prostate. Transrectal ultrasound is used not to direct seed placement, but rather to recreate the preplan and ensure that the implant needles are placed accordingly. Seeds are inserted via preloaded needles, polyglycolic acid strands or the Mick applicator.
42 1
422
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For early implants uniform seed spacing was used,4 while later implants were performed with peripheral weighting to decrease the dose to the urethra.5 The Northwest Hospital series has the longest followup and compares favorably with radical prostatectomy.6 Urinary complications can be significant and result from the high dose delivered to the center of the gland close to the urethra from the uniformly spaced seeds. Patients who undergone a prior transurethral resection of the prostate and who were treated with this technique had a 12% incontinence rate.6 Based on these data, such patients were not considered suitable for a preplanned uniform implant. In addition, pubic arch interference also limited this technique. Rectal complications and erectile dysfunction were low. Real-time interactive prostate implantation. Real-time interactive seed implantation is the newest technique to be used for prostate brachytherapy and takes advantage of the ability of transrectal ultrasound to provide precision targeting.7-9 Before implantation the prostate volume is measured. Using an activity per volume table, the appropriate amount of activity is ordered and brought to the operating room. With the patient in the dorsal lithotomy position and a Foley catheter in place, a C-arm fluoroscopic image intensifier is positioned over the bladder and prostate. An electronic phased array biplanar probe is positioned in the rectum to ensure that the entire prostate is visible. The perineum is then prepared and the template is attached to the stepping unit. Using transverse imaging serial contours of the prostate are measured at 5 mm. intervals from base to apex. This planimetry volume is used when calculating the amount of activity to implant. The treatment plan is created in the operating room. The total activity is divided by activity per seed (usually 0.3 to 0.5 mCi. per seed for 125iodine[I] and 1.0 to 1.5 mCi. per seed for lo3palladiurn [Pdl) to give the total number of seeds to implant. After the volume measurements are completed, imaging is switched to longitudinal, and measurements are made anterior and posterior t o the urethra, and posterior from base to apex. These longitudinal measurements are used to determine the spacing between the seeds. Current isotope choices for permanent prostate seed implantation are 1251 and lo3Pd. 1251 is selected for patients with Gleason score 6 or less on biopsy and lo3Pd is used in ' also selected for patients with Gleason 7 or greater. lo3Pd is high risk patients who are t o receive a combination of seed implant and external beam irradiation (implant is done first with 67% of the full dose followed 2 months later with external beam at 45 Gy.). The details of this implant technique have been previously described?g A month after implantation the patient returns for evaluation with a 3-dimensional (D) computerized tomography (CT) dosimetric system. CT images of the prostate are taken at 3 to 5 mm. intervals from the base of the bladder to the sphincter to assess the quality of the implant. These images are then digitized and reconstructed in 3-D to give dose volume histograms and dose surface histograms of the prostate, rectal wall and bladder base, respectively. This information is critically important for evaluating the adequacy of the implant and helps newly trained physicians assess and improve their technique.10
might best benefit from prostate brachytherapy. 13-18 Eventually, an analysis of the effect of PSA, stage and grade on outcome confirmed the same prognostic significance of these factors following brachytherapy.9 Based on these results, low risk patients who might best benefit with implant alone were identified. Low risk was defined as stage T2a or less, Gleason sum less than 7 and PSA 10 ng./ml. or less. These patients had significantly improved outcome compared to higher risk patients when treated with Ip51implant alone.'" Patients with more advanced localized disease were found to benefit from the addition of hormonal therapy to the external beam regimen.""zl While the addition of neoadjuvant hormonal therapy appeared to offer an advantage in patients with large prostates who underwent seed implantation, no substantial information was available to evaluate its benefit in high risk patients undergoing brachytherapy.Z2 The addition of neoadjuvant hormonal therapy in patients who presented with stage T2b or greater, PSA greater than 10 ng./ml. or Gleason score 7 or greater might yield similar favorable results as seen in the combination hormonal therapy, external beam studies. Also patients who presented with PSA greater than 20 ng./ml. responded poorly to implant alone.'* Data on external beam irradiation and radical prostatectomy revealed high recurrence rates in patients with poor prognostic factors,13.23.24 and prostatectomy data indicated poor outcomes for patients with pathologically involved seminal vesicle disease. Based on these data an aggressive treatment regimen was developed, which included hormonal therapy, brachytherapy and conformal external beam irradiation to treat patients with PSA greater than 15 ng./ml., Gleason score 8 to 10, clinical stage T2C t o T3 or positive seminal vesicle biopsies. MATERIALS AND METHODS
A total of 301 patients who presented with T1 to T3 prostate cancer were treated with brachytherapy alone or combined with hormonal therapy andor external beam irradiation (table 1). There were 109 patients at low risk with PSA 10 ng./ml. or less, Gleason score 6 or less and clinical stage T2a or less treated with 1251 alone, 152 at moderate risk with PSA greater than 10 ng./ml., Gleason score greater than 6 or stage T2b or greater treated with Ip51or In3Pd implant alone or combined with 5 months of hormonal therapy, and 40 at high risk with PSA greater than 15 ng./ml., Gleason 8 or greater, or clinical stage T2c t o T3 or positive seminal vesicle biopsy (20) treated with combination brachytherapy, external beam irradiation and 9 months of hormonal therapy. Low risk patients were implanted with lZ5Ito a dose of 160 Gy. (TG43 guidelines) and moderate risk patients were implanted with '1 for Gleason score of 6 or less or ""Pd to a dose of 115 Gy. for Gleason 7 or greater. Hormonal therapy was administered for 3 months before and for 2 months after implant in 79 of the moderate risk patients, while 73 received implantation alone. High risk patients received an implant of lo3Pd t o a dose of 56 t o 86 Gy. combined with external beam irradiation to a dose or 4,500 to 7,040 cGy. Conformal 3-D external beam irradiation was delivered via 6 fields (2 anterior oblique, 2 posterior oblique and 2 lateral fields) with a 2 cm. margin to the prostate and seminal vesicles. High risk patients were treated according to an institutional review
PATIENT SELECTION
In the past few data were available to help guide patient selection for brachytherapy. Cases were often staged with little more than a bone scan and CT. The addition of bilateral ultrasound guided seminal vesicle biopsy and laparoscopic lymph node dissection helped t o identify further patients with extraprostatic disease.11,l2 Studies reporting the prognostic significance of prostate specific antigen (PSA) and grade in predicting outcome after external beam irradiation and prostatectomy also helped further define which patients
TABLE1. Clinical features of patients treated with brachytherapy according to risk category Clinical Feature
Low Risk
Moderate Risk
High Risk
Stage T2a or Less TZbT2c T2c-T3c Grade 6 or Less 7 or Greater 8 or Greater PSA (ng./ml.) 10 or Less Greater than 10 Greater than 15 Low risk patients must have all features to be included in that category, while moderate or high risk patients need only 1 feature prescnt.
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board approved lo3Pd dose escalation study, and received 3 months of hormonal therapy before implant and continued androgen withdrawal therapy for 6 months after implant (total 9 months). Patients on the institutional review board protocol also received a higher dose of external beam irradiation t o 5,940 and 7,040 cGy. and the implant dose was also escalated from 56 to 76 to 86 Gy. as part of this protocol. Those patients with a positive seminal vesicle biopsy (T3c disease) and negative pelvic lymph nodes were included in the high risk group and additionally the walls of the seminal vesicles were also treated with implantation. Hormonal therapy was administered as a combination of leuprolide acetate and 250 mg. flutamide every 8 hours in all patients. All cases were staged with routine bone scans and CT. All patients with PSA greater than 10 ng./ml., Gleason 7 or greater or clinical stage T2b or greater also underwent bilateral seminal vesicle biopsy. Those patients with PSA greater than 15 ng./ml., Gleason score greater than 7 or a positive seminal vesicle biopsy underwent laparoscopic pelvic lymph node dissection before treatment,22.23 and those with positive nodes were excluded from implantation. Followup was performed every 6 months with PSA, digital rectal examination and ultrasound evaluation. Prostate biopsies, including 6 from the prostate and 6 from the seminal vesicles for patients with a positive seminal vesicle biopsy, were routinely recommended 2 years after completion of treatment regardless of disease status. Followup was started at completion of therapy (date of implant or completion of external beam irradiation). PSA failure was defined as 2 elevations above 1 ng./ml. Comparisons between survival rates were calculated using the log rank test, and differences in proportions were tested using the Pearson chi-square method. RESULTS
1
0 0
1
2
3
4
Years [ ] No. of patients at risk
FIG. 1. Four-year freedom from PSA failure in low risk patients with PSA 10 ng./ml. or less, Gleason 6 or less and clinical stage T2a or less. TABLE3. Clinical features of 152 moderate risk patients Variable
No. Pts. Treated With Hormones (7%)
No. Pts. No Hormones (7O)
PSA (ng./ml.): 1 (1.3) 2 (2.7) 0-4 4.1-10 8 (11) 24 (30.4) 10.1-20 37 (46.8) 38 (52) Greater than 20 17 (21.5) 25 (34.3) Gleason score: 16 (20.2) 12 (16.4) 2-4 21 (26.6) 37 (50.7) 5-6 40 (50.6) 24 (32.9) 7 or Greater Clinical stage: Tlb 1 (1.3) 2 (2.7) Tlc 15 (19) 10 (13.7) T2a 12 (15.2) 14 (19.2) T2b 33 (41.8) 38 (52.1) T2c 18 (22.7) 9 (12.3) Hormonal group was treated for 3 months before and 2 months after implant with leuprolide and flutamide.
The 109 patients at low risk received I ' ' ' alone, and followup ranged from 1 to 7 years (median 18 months). PSA ranged from 1.3 to 10 ng./ml. (median 6.41, a third of the patients had Gleason scores 2 to 4 and an equal number had Tlc and T2a lesions (table 2). The 4-year freedom from PSA failure rate was 91% (fig. 1).No patient experienced urinary incontinence following implantation. Grade 1 t o 2 radiation proctitis occurred in 5 men (4.5%) and there were no cases of of grade 3 or 4 radiation proctitis and no cases of urinary grade 3 or 4 radiation proctitis. incontinence. The 152 patients a t moderate risk were followed a median The 40 patients at high risk underwent a combination of of 27 months (range 12 to 74) and were treated with either hormonal therapy and lo3Pd implantation followed by exterimplantation alone (73) or implant combined with hormonal nal beam irradiation. PSA ranged from 2.1 to 202 ng./ml. therapy (79). The patients were equally distributed with (median 20),32 had Gleason score 7 or greater (80%) and 34 regard to stage, PSA and Gleason score (table 3). The 4-year had clinical stage T2b or greater (85%).Of the 40 patients 20 biochemical freedom from failure rate for the hormone group had biopsy confirmed seminal vesicle involvement (table 4). was 85% versus 58%for the no hormone group (p = 0.08, fig. Followup ranged from 6 to 42 months (median 13). The 2, A). The difference was more significant for those with 3-year biochemical freedom from failure rate in these high Gleason score 7 or greater (90 versus 43%, p = 0.01, fig. 2, B ) risk patients was 71% (fig. 3). Of the 4 patients (10%) with and for those with PSA greater than 10 ng./ml. (87 versus failure 3 (75%) originally had positive seminal vesicle biop59%, p = 0.04, fig. 2, C). Grade 1 to 2 radiation proctitis sies. The time to failure in these 4 patients ranged from 226 occurred in 1patient receiving hormonal therapy (1.3%)and to 712 days (mean 446). The last PSA value in the 36 patients in 3 treated only with implantation (4%).There were no cases without failure was less than 0.05 ng./ml. in 21 (58.3%),0.05 to 0.2 in 13 (36.1%)and greater than 0.2 to 0.5 in 2 (5.6%).All 5 patients who received 5,940 cGy. external beam dose had gastrointestinal complications. There were no grade 3 or TABLE2. Clinical features of 109 low risk patients 4 gastrointestinal complications. The actuarial freedom from Variable No. F'ts. (70) grade 2 proctitis was 82%. No patient experienced urinary incontinence. Prostate biopsies were negative in 87% of the PSA (ng./ml.): 0-4 17 (15.6) low risk, 96.8 (hormone group) versus 68.6% (no hormone Greater than 4-10 92 (84.4) group) of the moderate risk (p = 0.0023) and 86% of the high Gleason score: risk patients (table 5). 2 4 33 (30.3) 5-6 Clinical stage: Tlb Tlc T2a
76 (69.7)
1 (0.9) 56 (51.4) 52 (47.7)
DISCUSSION
The rationale for using brachytherapy alone in low risk patients evolved from the experience at several centers
424
PROSTATE BRACHYTHERAPY A
C
6
f
5 E
"1
E
E
E
e
g
E
FIG.2. Effect of hormonal therapy on PSA failure. Four-year biochemical freedom from failure for moderate risk patients treated with or without hormones ( p = 0.08, A), with Gleason 7 or greater (p = 0.01, B )and with PSA 10 ng./ml. or greater (p = 0.04, C ) . TABLE4. Clinical features of 40 high risk patients Variable PSA (ng./ml.): 0-4 Greater than P 1 0 Greater than 10-20 Greater than 20-50 Greater than 50 Gleason score: 2 4 56
7
aio
No. F'ts. (Bi 1 (2.51 8 (20) 11 (27.5) 14 (35) 6 (15) 1 (2.5) 7 (17.51 19 (47.5) 13 (32.51
Clinical stage: 5 (12.5) Tlc 1 (2.51 T2a 5 (12.51 T2b 22 (55) T2c 7 (17.51 T3 External beam dose (cGy.): 4,500 8 (20) 5,040 3 (7.5) 5,940 28 (70) 7,020 1 (2.51 Implant dose (cGy.1: 5,700 13 (32.51 7,600 13 (32.5) 8,600 14 (35) The highest dose given was combination of 86 Gy. of Io3Pdfollowed by 5,940 cGy. e&mal beanirradiation in 6 patients
n
25 n = 40 3 year freedom from failure = 71'b
0
0
6
12
18
24
30
36
1
Months [ ] No. of patients at rlsk
FIG. 3. Three-year freedom from PSA failure in high risk patients with PSA greater than 15 ng./ml., Gleason 8 or greater, or clinical stage T2c to T3 or positive seminal vesicle biopsy treated with combination brachytherapy,external beam irradiation and 9 months of hormonal therapy. TABLE5. Prostate biopsy results in low to high risk Datients No. Nee. Biousv (B) No. Pos. Biousv (%)
where implants have been performed for a considerable time. Ragde et a1 reported on 126 men followed a mean of 69 months who received a 1251 implant.6 While the results were not stratified by the presenting risk factors, most of their cases would fit into the definition of low risk. Median PSA was 5.0 ng./ml., which is similar to the low risk median 6.4 ng./ml. in our study. In addition, 85.3%of their patients had clinical T2a or less disease, all had Gleason 6 or less and 78.7% had PSA 10 ng./ml. or less. One might argue that their patients represented an even more favorable group than ours because 44.3% had PSA from 0 to 4 ng./ml. compared to only 15.6%in our series. Nonetheless, the 7-year actuarial PSA progression-free outcome was 87%for PSA 1.0 ng./ml. or less and 79%for PSA 0.5 ng./ml. or less. These numbers compare favorably to our own report of 91% freedom from PSA progression. The progression-free results in these low risk paalone also compare favorably to what tients treated with 1251 has been reported for similar groups of patients treated with radical prostatectomy or external beam irradiation. In a group of clinically similar patients who underwent radical retropubic prostatectomy, Catalona and Bigg reported a 78% success rate (PSA 0.6 ng./ml. or less) at 5 years,25 and Partin et a1 reported an 83%freedom from PSA failure rate (PSA 0.3 ng./ml. or less) at 5 years.26 DAmico et a1 evaluated the effect of presenting risk features on 867 and 757 consecutive prostate cancer patients treated with external beam irradiation or radical retropubic prostatectomy.27 Patients were separated into a low risk
Low risk
20 (87) 3 (13) Moderate risk with hormones 30 (96.8) 1 (3.2) Moderate risk without hormones 35 (68.6) 16 (31.4) High risk 6 (86) 1 (14) The difference in positive biopsy results between the moderate risk patients treated with and without hormonal therapy was significant ( p = 0.0023).
group defined as PSA greater than 4 to 10 ng./ml. and Gleason score 4 or less. The 2-year PSA failure-free survival was 87%for the radical prostatectomy cases with organ confined disease and 92%for those who received external radiation. Vicini et al performed a n extensive review of patients who received external beam irradiation and analyzed the data by presenting PSA.28.29 Biochemical control rates for 6 centers that reported data for patients who presented with initial PSA 4.0 ng./ml. or less ranged from 69 to 93%. For patients with PSA 4 to 10 ng./ml. the success rate was 44 t o 84%. They also analyzed 5 brachytherapy series with presenting PSA between 4 and 10 ng./ml. and found a 55 t o 90% success rate. Patients who present with moderate risk disease do not do as well as those with low risk disease regardless of the treatment modality. DAmico et al defined an intermediate risk category as PSA greater than 4 to 10 ng./ml. and Gleason score 5 to 7 or PSA greater than 10 to 20 ng./ml. and Gleason score 7 or lessz7 The 2-year success rate for radiation therapy and radical prostatectomy was 81 and 77%, respectively. Kupelian et al re-
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ported a 60 to 70% 5-year success rate with these 2 treatment recognize that followup for biochemical control in this study modalities when cases were stratified by PSA greater than 10 t o is relatively short and that longer followup will be needed to 20 ng./ml.30x31Biochemical control rates for patients with PSA substantiate these findings. Brachytherapy also has few side greater than 10 to 20 ng./ml. reported in 6 conventional radia- effects, even when combined with conventional doses of extion therapy series ranged from 27 to 72%.2s,29The same study ternal beam irradiation. reported brachytherapy results from 5 centers with reported success rates ranging from 45 to 89%. Our own data also suggest inferior results compared to patients with low risk disease. REFERENCES The 4-vear success rate for the imdant alone cases was onlv 1. Ragde, H., Elgamal, A. A., Snow, P. B., Brandt, J., Bartolucci, 58% whch contrasted to 85%for those treated with a combinaA. A,, Nadir, B. S. and Korb, L. J.: Ten-year disease free tion of hormonal therapy and seed implantation. The difference survival after transperineal sonography-guided iodine-125 was more significant in patients with PSA greater than 10 brachytherapy with or without 45-gray external beam irrading./ml. (87 versus 59%, p = 0.04) and in patients with Gleason ation in the treatment of patients with clinically localized, low score 7 or greater (90 versus 43%, p = 0.01). to high grade prostate carcinoma. Cancer, 8 3 989, 1998. 2. Holm, H. H., Juul, N., Pedersen, J. F., Hansen, H. and Stoyer, I.: The most difficult cases to treat successfully are those with Transperineal 125 iodine seed implantation in prostatic carcilocally advanced prostate cancer at presentation. We previnoma guided by transrectal ultrasonography. J. Urol., 130 ously reported a 58% 2-year and 34% 4-year freedom from 283, 1983. biochemical progression in men who presented with initial 3. Blasko, J. C., Wallner, K., Grimm, P. D. and Ragde, H.: PSA PSA greater than 20 ng./ml. treated with implant alone with based disease control following ultrasound guided 1-125 imor without hormonal therapy.9- 19 Freedom from failure rates plantation for stage Tlfl’2 prostatic carcinoma. J . Urol., 154: for similar patients treated with conventional external beam 1096, 1995. irradiation or conformal radiation therapy range from 8 to 4. Quimby, E. H.: The grouping of radium tubes in packs and 37%.”2727.28 Radical prostatectomy success rates in these plaques to produce the desired distribution of radiation. AJR, 27: 18, 1932. high risk patients are equally disappointing, as Kupelian et 5. Paterson, R. and Parker, H. M.: A dosage system for gamma-ray a1 reported a 25% likelihood of freedom from failure at 5 therapy, Parts 1 and 2. Brit. J. Rad., 7: 592, 1943. years in this setting.30.31 6. Ragde, H., Blasko, J. C., Grimm, P. D., Kenny, G. M., Sylvester, We elected to combine brachytherapy with external beam J. E., Hoak, D. C., Landin, K. and Cavanagh, W.: Interstitial irradiation and neoadjuvant and adjuvant hormonal therapy iodine-125 radiation without adjuvant therapy in the treatto attempt to improve the poor results in these high risk ment of clinically localized prostate cancer. Cancer, 8 0 442, patients. The rationale for the combination of seed implant 1997. and external beam irradiation evolved from the dose re7. Stone, N. N., Stock, R. G., DeWyngaert, J. K. and Tabert, A,: sponse data in high risk patients treated with external beam Prostate brachytherapy: improvements in prostate volume measurements and dose distribution using interactive ultraalone and from the initial favorable reports of combination sound guided implantation and three-dimensional dosimetry. irradiation from several centers.31-34 The addition of comRad. Oncol. Invest., 3 185, 1995. plete hormonal therapy also evolved from randomized stud8. Stock, R. G., Stone, N. N., Wesson, M. F. and DeWyngaert, J. K.: ies documenting the advantage of androgen withdrawal in A modified technique allowing interactive ultrasound guided locally advanced prostate cancer treated with external beam three-dimensional transperineal prostate implantation. Int. J . irradiation.20.21 The favorable 3-year freedom from PSA failRad. Oncol. Biol. Phys., 3 2 219, 1995. ure in this group of high risk patients (50% of whom had 9. Stock, R. G., Stone, N. N., DeWyngaert, J. K., Lavagnini, P. and biopsy proved T3c disease) suggests that tri-modal therapy Unger, P. D.: Prostate specific antigen findings following in(seeds plus external beam plus hormonal therapy) may offer teractive ultrasound guided transperineal brachytherapy for early stage prostate carcinoma. Cancer, 77: 2386, 1996. a significant improvement over standard monotherapy with radiation or radical prostatectomy alone. The data also sug- 10. Stock, R. G., Stone, N. N., Tabert, A,, Iannuzzi, C. and DeWyngaert, K.: A dose response study for 1-125 prostate gest that this treatment is successful at eradicating all local implants. Int. J . Rad. Oncol. Biol. Phys., 41: 101, 1998. disease with a 2-year negative biopsy rate of 86%. 11. Stock, R. G., Stone, N. N., Ianuzzi, C. and Unger, P.: Seminal Our data also suggest that brachytherapy can be accomvesicle biopsy and laparoscopic pelvic lymph node dissection: plished with low morbidity. No patient had incontinence, implications for patient selection in the radiotherapeutic mancystitis or significant radiation proctitis (grade 3 or higher). agement of prostate cancer. Int. J. Rad. Oncol. Biol. Phys., 3 3 The incidence of grade 1 to 2 radiation proctitis in the low to 815, 1995. moderate risk patients ranged from 1.3to 4.5%. Patients who 12. Stone, N. N., Stock, R. G. and Unger, P.: Indications for seminal vesicle biopsy and laparoscopic pelvic lymph node dissection in received a combination of seeds and external beam irradiamen with localized carcinoma of the prostate. J. Urol., 154 tion had a n actuarial 18% incidence of grade 1to 2 proctitis. 1392, 1995. There was no grade 2 proctitis in 11 of the 40 patients who received external beam irradiation to a dose of less than 13. Zeitman, A. L., Coen, J. J., Shipley, W. U., Willet, C. G. and Efrid, J . T.: Radical radiation therapy in the management of %940 cGy. Thus, this higher incidence of grade 2 proctitis prostatic adenocarcinoma: the initial prostate specific antigen was only found in those patients receiving high doses of value as a predictor of treatment outcome. J . Urol., 151: 640, external beam irradiation. This study is part of a n ongoing 1994. institution review board approved dose escalation trial to 14. Zagars, G. K.: Prostate specific antigen as an outcome variable determine whether an external dose beyond the conventional for T1 and T2 prostate cancer treated by radiation therapy. J. Urol., 152: 1786, 1994. dose of 4,500 cGy. offers an advantage in these high risk 15. Lee, W. R., Hanks, G. E., Schultheiss, T. E., Corn, B. W. and patients.”-3.5 Hunt, M. A.: Localized prostate cancer treated by external -
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CONCLUSIONS
Brachytherapy appears to offer comparable results to external beam irradiation and radical prostatectomy when cases are stratified by disease extent. Adopting a strategy of Implant alone, implant with hormonal therapy or implant with hormonal theraDv and external beam irradiation in Patients who presen[&ith low t o high risk features can Improve the overall results in the more advanced cases. We
beam radiotherapy alone: serum prostate-specific antigen driven outcome analysis. J. Clin. Oncol., 13 464, 1995. 16. Hanks, G. E., Lee, W. R. and Schultheiss, T. E.: Clinical and biochemical evidence of control of prostate cancer at 5 years after external beam radiation. J. Urol., 154: 456, 1995. 17. Zagars, G. K. and Pollack, A,: Radiation therapy for T1 and T2 prostate cancer: prostate-specific antigen and disease control. Urology, 4 5 476, 1995. 18. Zeitman, A. L., Edelstein, R. A., Coen, J. J., Babayan, R. K. and Krane. R. J.: Radical Drostatectomv for adenocarcinoma of the
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analysis of clinical and pathological factors that predict for prostate: the influence of preoperative and pathologic findings on biochemical disease free outcome. Urology, 43 828, 1994. prostate specific antigen failure after radical prostatectomy for 19. Stock, R. G. and Stone, N. N.: The effect of prognostic factors on prostate cancer. J . Urol., 154: 131, 1995. therapeutic outcome following transperineal prostate brachy- 28. Vicini, F. A,, Honvitz, E. M., Kini, V. R., Stromber, J. S. and therapy. Sem. Surg. Oncol., 1 3 454, 1997. Martinez, A. A.: Radiotherapy options for localized prostate 20. Pilepich, M. V., Krall, J . M., Al-Sarraf, M., Madhu, J. J., Doggett, cancer based upon pretreatment serum prostate-specific antiR. L. S., Sause, W. T., Lawton, C. A,, Abrams, R. S.,Rotman, gen levels and biochemical control: a comprehensive review of M., Rubin, P., Shipley, W. U.,Grignon, D., Caplan, R. and Cox, the literature. Int. J . Rad. Oncol. Biol. Phys., 40 1101, 1998. J. D.: Androgen deprivation with radiation therapy compared 29. Vicini. F. A.. Honvitz. E. M.. Gonzalez, J . and Martinez, A. A.: with radiation therapy alone for locally advanced prostatic Treatment options for localized prostate cancer based upon carcinoma: a randomized comparative trial of the radiation pretreatment prostate specific antigen levels. J. Urol., 158: therapy oncology group. Urology, 45 616, 1995. 319, 1997. 21. Laverdiere, J., Gomez, J. L., Cusan, L., Suburu, E. R., Diamond, 30. Kupelian, P., Katcher, J., Levin, H., Zippe, C. and Klein, E. I.: P., LeMay, M., Canadas, B., Fortin, A. and Labrie, F.: BenefiCorrelation of clinical and pathologic factors with rising cial effect of combination therapy administered prior and folprostate-specific antigen profiles after radical prostatectomy lowing external beam radiation therapy in localized prostate alone for clinically localized prostate cancer. Urology, 48 249, cancer. Int. J . Rad. Oncol. Biol. Phys., 37: 247, 1997. 1996. 22. Blasko, J . C., Ragde, H., Grimm, P. D., Sylvester, J. and 31. Kupelian, P., Katcher, J., Levin, H., Zippe, C., Suh, J., Macklis, Cavanagh, W.: Potential for neoadjuvant hormonal therapy R. and Klein, E.: External beam radiotherapy versus radical with brachytherapy for prostate cancer. Mol. Urol., 1: 207, prostatectomy for clinical stage T1-2 prostate cancer: thera1997. peutic implications of stratification by pretreatment PSA lev23. Hanks, G. E., Hanlon, A. L., Hudes, G., Lee, W. R., Winlove, S. els and biopsy Gleason scores. Cancer J . Sci. Amer., 3: 78, and Schultheiss, T.: Patterns of failure analysis of patients 1997. with high pretreatment prostate-specific antigen levels treated by radiation therapy. The need for improved systemic 32. Hanks, G. E., Martz, K. L. and Diamond, J. J.: The effect of dose on local control of prostate cancer. Int. J. Rad. Oncol. Biol. and regional therapy. Int. J. Rad. Oncol. Biol. Phys., 14: 1093, Phys., 1 5 1299, 1988. 1996. 24. Kuban, D. A,, El-Mahdi, A. M. and Schellhammer, P. F.: 33. Critz, F. A,, Levinson, A. K., Williams, W. H. and Holloday, D. A,: Prostate-specific antigen nadir: the optimum level after irraProstate-specific antigen for pretreatment and post-treatment diation for prostate cancer. J . Clin. Oncol., 14: 2893, 1996. evaluation of outcome after definitive irradiation for prostate 34. Dattoli, M., Wallner, K., Sorace, R., Koval, J., Cash, J., Acosta, cancer. Int. J. Rad. Oncol. Biol. Phys., 3 2 307, 1995. R., Brown, C., Ethridge, J., Binder, M., Brunelle, R., Kinvan, 25. Catalona, W. J . and Bigg, S. W.: Nerve-sparing radical prostaN., Sanchez, S., Stein, D. and Wasserman, S.: Pd-103 brachytectomy: evaluation of results after 250 patients. J. Urol., 1 4 3 therapy and external beam irradiation for clinically localized, 538, 1990. high-risk prostatic carcinoma. Int. J . Rad. Oncol. Biol. Phys., 26. Partin, A. W., Pound, C. R., Quentin Clemens, J., Epstein, J. I. 3 5 875. 1996. and Walsh, P. C.: Serum PSA after anatomic radical prostatectomy. The Johns Hopkins experience after 10 years. Urol. 35. Blasko, J.'C., Ragde, H., Cavanagh, W., Sylvester, J. and Grimm, P. D.: Long-term outcomes of external beam irradiation and Clin. N. Amer., 20 713, 1993. 27. DAmico, A. V., Whittington, R., Malkowicz, S. B., Schultz, D., 1-125/Pd-103 brachytherapy boost for prostate cancer. Int. J. Rad. Oncol. Biol. Phys., 3 6 198, 1996. Schnall, M., Tomaszewski, J . E. and Wein, A,: A multivariate ~
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QUESTIONS AND RESPONSES Dr. C. A. Olsson. You reported in your series a 15% positive biopsy rate. What do you in this situation? Dr. N. N . Stone. We reported negative prostate biopsies in 87% of the low risk, 96.8 versus 68.6% of the moderate risk (p = 0.0023, favoring neoadjuvant hormonal therapy) and 86% of the high risk patients. The options for treating brachytherapy failure cases which have a documented local recurrence (positive biopsy) and no evidence of systemic disease include another seed implant, external beam irradiation, salvage radical prostatectomy and hormonal therapy. The decision of which to recommend depends on the situation and the results of post-implant dosimetry. The dosimetry should describe the radiation dose to the prostate, rectum, bladder and urethra. In most cases the radiation dose to the rectum and bladder is much lower than that received by a patient initially treated with external beam (the dose to 30% of the rectum averages only 40% of the prescription dose). A repeat implant might be considered if the original implant was done poorly (as defined by dosimetry) and rectal doses were low. Salvage external beam irradiation might be considered if the biopsies were positive outside of the prostate and the rectal doses were low. Finally, salvage radical prostatectomy might be considered if the dose to the prostate was adequate, and the rectal and bladder dose was low. Doctor Olsson. What is the morbidity of a salvage prostatectomy following a radiation seed failure? Are most failures at 2 years associated with distant relapse? Doctor Stone. The morbidity of a salvage prostatectomy following a seed implant would in theory be similar to the morbidity following external beam irradiation. If post-implant dosimetry reveals low dose to the rectum and bladder neck then the radical should be no more difficult than in a previously untreated patient, and this is in fact the case. The urologist will need to know the dosimetry before undertaking the salvage radical prostatectomy. Local failure a t 2 years in low risk patients is most often not associated with systemic relapse. The likelihood of local failure in a moderate risk patient who received neoadjuvant therapy is only 3.2%.Local failure in high risk patients is almost always associated with systemic relapse.