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Impact of Hormonal Therapy on Intermediate Risk Prostate Cancer Treated With Combination Brachytherapy and External Beam Irradiation
Impact of Hormonal Therapy on Intermediate Risk Prostate Cancer Treated With Combination Brachytherapy and External Beam Irradiation Richard G. Stock,* Swati Yamalachi, Simon J. Hall and Nelson N. Stone† From the Departments of Radiation Oncology and Urology, Mount Sinai School of Medicine, New York, New York
Abbreviations and Acronyms AST ⫽ androgen suppressive therapy BED ⫽ biologically effective dose D90 ⫽ dose delivered to hottest 90% of prostate EBRT ⫽ external beam irradiation FFBF ⫽ freedom from biochemical failure IMRT ⫽ intensity modulated radiation therapy PSA ⫽ prostate specific antigen Submitted for publication June 3, 2009. Study received institutional review board approval. * Correspondence: Department of Radiation Oncology, Mount Sinai School of Medicine, 1184 5th Ave., New York, New York 10025 (telephone: 212-241-7502; FAX: 212-410-7194; e-mail: richard. [email protected]). † Financial interest and/or other relationship with Prologics, Nihon-MediPhysics, IsoAid and Prostate Cancer Educational Council.
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Purpose: We assessed the impact of androgen suppressive therapy on biochemical failure in patients with intermediate risk prostate cancer treated with brachytherapy and external beam irradiation. Materials and Methods: From 1994 to 2006, 432 patients with intermediate risk prostate cancer as defined by the National Comprehensive Cancer Network were treated with low dose rate brachytherapy and external beam irradiation with or without 9 months of androgen suppressive therapy. Gleason score was 7 in 76% of cases and prostate specific antigen was 1.4 to 20 ng/ml (median 7.6). Of the patients 350 received androgen suppressive therapy and 82 did not. The biologically effective dose was 142 to 280 Gy2 (median 206). Followup was 23 to 155 months (median 56). Results: The overall 8-year biochemical failure-free rate using the Phoenix definition in patients with vs without androgen suppressive therapy was 92% vs 92% (p ⫽ 0.4). The therapy had no significant impact on the biochemical failure-free rate in patients with Gleason score 7 (92% vs 90.5%, p ⫽ 0.55), prostate specific antigen 10 to 20 ng/ml (92% vs 100%, p ⫽ 0.32), T2b-T2c disease (89.5% vs 97%, p ⫽ 0.27) and more than 1 intermediate risk feature (90% vs 100%, p ⫽ 0.2). Conclusions: We addressed the relative importance of radiation dose vs hormonal therapy for intermediate risk prostate cancer. With high biologically effective dose combination treatment androgen suppressive therapy did not have a significant impact on the 8-year biochemical failure-free rate. We question its routine use in this setting. Key Words: prostate, prostatic neoplasms, brachytherapy, radiotherapy, androgen antagonists THE positive interaction between AST and EBRT for intermediate and high risk prostate cancer is well documented in randomized, controlled trials.1–5 The exact mechanism of this interaction and the optimal duration of hormonal therapy are less well established. The consistent factor in trials is that the external beam dose is now considered to be relatively low (68 to 72 Gy). This issue calls into question the relative importance of
radiation dose vs hormonal/radiation interaction to optimize cancer control. The role of AST combined with high dose radiation is not as well tested. Using BED equations the combination of low dose rate brachytherapy and EBRT delivers the highest dose to the prostate of various radiation approaches.6 Hormonal therapy has been added to this combined treatment for patients at high risk in whom the risk of microscopic systemic
0022-5347/10/1832-0546/0 THE JOURNAL OF UROLOGY® Copyright © 2010 by AMERICAN UROLOGICAL ASSOCIATION
Vol. 183, 546-551, February 2010 Printed in U.S.A. DOI:10.1016/j.juro.2009.10.006
IMPACT OF HORMONAL THERAPY ON INTERMEDIATE RISK PROSTATE CANCER
disease is the greatest.7 AST is used in this subset partly to address the risk of systemic disease. In intermediate risk cases the risk of microscopic systemic disease is less but the need for aggressive local treatment is still warranted. Radiation dose is important in this subset.8,9 To our knowledge the relative benefits of dose vs AST is unknown. In this patient subset we retrospectively examined the effects of adjuvant hormonal therapy added to combination EBRT and brachytherapy. AST and other prognostic factors were analyzed to determine their effects on biochemical control in intermediate risk cases. The impact of AST in higher risk subsets of patients at intermediate risk was also tested.
MATERIALS AND METHODS A total of 432 patients classified as at intermediate risk using the National Cancer Care Network classification (www.nccn.org) were treated at Mount Sinai Medical Center with combination low dose rate brachytherapy and EBRT from 1994 to 2006. National Cancer Care Network defines intermediate risk as at least 1 of certain features, including PSA greater than 10 to 20 ng/ml, Gleason score 7 or stage T2b-T2c. In the patients PSA was 1.4 to 20 ng/ml (median 7.6). All cases were staged with bone and computerized tomography, which were negative for nodal or metastatic disease. Table 1 lists presenting disease characteristics. The amount of disease in biopsy specimens could not be quantified since different methods were used by treating urologists to submit biopsy specimens. Specimens were submitted using individual jars for each core or right and left specimen jars. Of the patients 178 underwent bilateral seminal vesicle biopsy and 16 with positive results received hormonal therapy as part of treatment.
Hormonal Therapy AST was administered to shrink prostates greater than 50 cc or at treating physician discretion. There was no set policy on hormonal therapy in intermediate risk cases.
Table 1. Presenting disease characteristics Factors PSA (ng/ml): 4 or Less Greater than 4–10 Greater than 10–20 Gleason score: 6 or Less 7 Clinical T stage: T1c T2a T2b T2c No. intermediate risk features: 1 2 3
No. Pts (%) 27 (6) 254 (59) 151 (35)
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Generally patients with more than 1 risk feature tended to received hormonal therapy. Overall 350 patients (81%) received AST using a luteinizing hormone-releasing hormone with or without an antiandrogen and 82 received no AST. AST was given 3 months before seed implantation and it continued thereafter. Overall hormonal therapy duration was 3 to 24 months (median 9), including less than 6 months in 3% of patients, 6 in 12%, 9 in 81%, 12 in 3% and 24 in 1%.
Radiation Therapy Brachytherapy was administered before EBRT with 103Pd seeds (prescription dose 100 Gy, National Institute of Standards and Technology 1999) in 429 patients and 125I seeds (prescription dose 125 Gy) in 3. All brachytherapy was done using a previously described real-time ultrasound guided technique.10 One month after implantation computerized tomography based dosimetry was done. A dose-volume histogram were generated for the prostate. The 103Pd implant D90 was 30 to 162 Gy (median 106) (National Institute of Standards and Technology 1999). D90 of the 2 125I implants in which dosimetry was done was 132 and 149 Gy, respectively. EBRT was delivered using 3-dimensional conformal and intensity modulated radiation therapy techniques. Five to 7 fields were used and treatment volume consisted of the prostate and seminal vesicles plus margin. Six to 16 MV photons were used. Margins were 0.8 to 1.5 cm. The dose was prescribed to the isodose line covering the clinical planning target volume. The total EBRT dose was 3,960 to 6,120 cGy (median 4,500). All doses were delivered in 1.8 Gy daily fractions. BED was calculated using the implant D90 and the EBRT total dose using an ␣-to- ratio of 2. Derivations of these equations were described previously.6 BED was calculated in 427 patients. Postimplantation dosimetry was not done due to patient noncompliance or a hip prosthesis. BED was 142 to 280 Gy2 (median ⫾ SD 206 ⫾ 18.6). BED was 142 to 179 Gy2 in 7% of cases, 180 to 200 in 32%, 201 to 220 in 40% and greater than 220 in 21%.
Outcomes Patients were followed every 6 months with PSA testing. Followup was 23 to 155 months (median 56). Biochemical failure was determined using the Phoenix definition.11 FFBF curves were calculated using Kaplan-Meier actuarial methods. Comparisons between survival curves were tested using the log rank test. The effect of multiple variables on outcome was tested with Cox regression. Differences in proportions were tested using the Pearson chisquare test.12 This retrospective review was approved by the institutional review board.
105 (24) 327 (76)
RESULTS 134 (31) 74 (17) 156 (36) 68 (16) 203 (47) 179 (41) 50 (12)
Overall FFBF at 8 years in the entire group was 92% (part A of figure). Table 2 lists the effect of pretreatment PSA, Gleason score, clinical stage, seminal vesicle status and number of intermediate risk features on FFBF. No factor significantly affected the FFBF rate. BED did not affect FFBF with an 8-year rate of 95% in 203 patients with BED less than 206
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IMPACT OF HORMONAL THERAPY ON INTERMEDIATE RISK PROSTATE CANCER
A, FFBF. B, hormonal therapy effect on biochemical failure.
Gy2 vs 90% in 224 with BED 206 Gy2 or greater (p ⫽ 0.16). Cox regression analysis with these variables showed that no variable had a significant affect on biochemical failure. Hormonal Therapy Followup was 24 to 155 months (median 57) in patients with hormonal therapy and 23 to 117 (median 54) in those with radiation alone. Table 3 shows the prognostic factor incidence in the AST and nonAST groups. There was an apparent selection bias for choosing hormonal therapy. A significantly greater percent of patients with PSA greater than 10 to 20 ng/ml, Gleason score 7, clinical stage T2c and more than 1 intermediate risk feature was in the AST than in the nonAST group. There was no significant difference in BED in the 2 groups. Overall AST had no significant effect on the FFBF rate with an 8-year rate of 92% in the AST and nonAST groups AST (p ⫽ 0.2, part B of figure). The lowest PSA 5 or more years after treatment in those without PSA failure was significantly lower in the AST vs nonAST group (mean 0.035 ⫾ 0.058 vs 0.185 ⫾ 0.498 ng/ml, p ⬍0.001). Due to differences in the distribution of prognostic factors in the 2 groups the effect of AST was tested in higher risk subgroups, that is patients with a Gleason score of 7, PSA greater than 10 to 20 ng/ml, stage T2b or greater, a Gleason score of 7 and PSA greater than 10 ng/ml, and more than 1 intermediate risk feature (table 2). There was no improvement using hormonal therapy in any subgroup. AST had no impact in the high or low BED group. Of patients with BED less than 206 Gy2 the 172 with AST had an 8-year FFBF rate of 97% vs 86% in the 31 without AST (p ⫽ 0.98). Of patients with BED 206 Gy2 or greater the 174 with AST had an 8-year FFBF rate of 89% vs 94.0% in the 50 without AST (p ⫽ 0.30).
Toxicity Crude comparisons were made between the AST and no AST groups in commonly reported brachytherapy toxicities. Potency was assessed using the Mount Sinai erectile function scoring system in patients who were potent before therapy.13 Impotence (score less than 2), rectal bleeding (Radiation Therapy Oncology Group score 2 or greater) and urinary retention requiring catheterization were noted in 22 of 66 patients at risk, and 5 and 7 of 82 at risk without AST vs 97 of 210 at risk, and 23 and 34 of 350 at risk with AST (chi-square test p ⫽ 0.07, 0.89 and 0.74, respectively).
DISCUSSION Prospective, randomized trials of the role of hormonal therapy in the setting of EBRT have primarily focused on patients with intermediate and high risk features.1–5 These studies were primarily done with relatively low radiation doses in the 70 Gy range (BED 129 Gy2). All studies show a positive outcome of adding hormonal therapy when measuring many disease end points. In the randomized trial by D’Amico et al many patients had primarily intermediate risk features with a score of 7 in 59% and PSA between 10 and 20 ng/ml in 25% with a score of 6 or less.5 This trial showed a survival advantage using 6 months of AST added to 70 Gy EBRT vs EBRT alone. To our knowledge no reported prospective trials address the need for AST in the setting of prostate brachytherapy. Data from retrospective studies are mixed. Most studies do not show a benefit of using AST with brachytherapy without ERBT.14,15 In these series the problem is that AST was primarily used in the neoadjuvant setting for only 3 to 4 months. This duration is probably too short to enhance cancer control. We reported that 6 months of hormonal therapy sandwiched around 103Pd and 125I
IMPACT OF HORMONAL THERAPY ON INTERMEDIATE RISK PROSTATE CANCER
Table 2. Treatment factor effect on FFBF rate overall and in intermediate risk subgroups Factors
No. Pts/No. Failure
Overall PSA (ng/ml): 4 or Less 27/1 Greater than 4–10 254/14 Greater than 10–20 151/10 Gleason score: 6 or Less 105/6 7 327/19 Clinical stage: T2a or Less 208/9 T2b 156/12 T2c 68/4 Seminal vesicle status: Pos 16/2 Neg 162/6 No. intermediate risk features: 1 203/9 2 179/11 3 50/5 Intermediate risk subgroups Gleason score 7: No AST 48/2 AST 279/17 PSA greater than 10–20 ng/ml: No AST 14/0 AST 137/10 Stage T2b or greater: No AST 41/1 AST 183/15 Score 7 ⫹ PSA greater than 10 ng/ml: No AST 2/0 AST 81/8 Greater than 1 intermediate risk feature: No AST 21/0 AST 208/16
% 8-Yr FFBF
p Value 0.88
94 92 93 0.74 94 91 0.39 94 89 95 0.14 93 95.5 0.31 94 91 89 0.55 90.5 92 0.32 100 92 0.27 97 89.5 0.70 100 89 0.2 100 90
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tumor volume measured by biopsy information due to the inconsistent methods in which biopsy material was submitted for evaluation at our institution. Other groups using combination EBRT and brachytherapy also failed to observe a benefit of AST. Dattoli et al did not note that AST improved the outcome in 204 patients with intermediate and high risk features who underwent 103Pd brachytherapy and EBRT.17 The 10-year FFBF rate was 85% with AST vs 78% without AST. In a study of 225 intermediate risk cases Merrick et al found no improvement in biochemical control when adding AST to implantation and EBRT.18 The 6-year FFBF rate was 98%, 96% and 100% for no AST, and cytoreductive and adjuvant AST, respectively. Martinez et al reported on 507 patients with intermediate and high risk features treated with EBRT combined with high dose rate brachytherapy.19 They also did not find that adding 6 months or less of AST improved the biochemical control rate over that of radiation alone with a 5-year FFBF rate of 74% and 76%, respectively. Although the exact mechanism by which AST improves outcomes when combined with EBRT is not known, a large part may be due to its ability to enhance local control. Our study and other reports call into question its beneficial role when higher radiation doses are delivered. A comparison with the randomized study by D’Amico et al using 70 Gy EBRT with 6 months of AST is enlightening.5 The BED equivalent of 70 GY was 129 Gy2, much lower than the median BED in our series, which was 206 Gy2. Those investigators did not report actuarial biochemical failure rates but rather freedom from Table 3. Prognostic factors in patients with and without AST
implants improved the biochemical control rates in intermediate and high risk disease cases.16 This benefit was only seen for low dose implants (D90 less than 140 Gy for 125I and less than 100 Gy for 103Pd), not at higher doses.16 This calls into question the relative importance of dose. Combination brachytherapy and EBRT results in an extremely high BED. In our study 93% of patients had a BED of 180 Gy2 or greater, representing an EBRT equivalent of about 95.4 Gy using 1.8 Gy fractions. In the setting of combination EBRT and brachytherapy perhaps AST, at least given for a relatively short duration, may not have as an important role. In our series 9 months of AST failed to improve biochemical control. Although the study was retrospective and patients with more advanced disease tended to receive AST compared to those treated with radiation alone, the lack of benefit of AST was seen in all higher risk subgroups. The only potential factor that could not be accounted for was
PSA (ng/ml): 4 or Less Greater than 4–10 Greater than 10–20 p Value Gleason score: 6 or Less 7 p Value Clinical stage: T2a or Less T2b T2c p Value No. intermediate risk features: 1 Greater than 1 p Value BED (Gy2): 200 or Less Greater than 200 p Value
No. Without AST (%)
No. With AST (%)
7 (9) 61 (74) 14 (17)
29 (8) 193 (55) 137 (39) 0.001
34 (41.5) 48 (58.5)
71 (20) 279 (80) ⬍0.0001
41 (50) 39 (48) 2 (2)
167 (48) 117 (33) 66 (19) 0.001
61 (74) 21 (26)
142 (41) 208 (59) ⬍0.0001
25 (31) 56 (69)
142 (41) 204 (59) 0.09
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IMPACT OF HORMONAL THERAPY ON INTERMEDIATE RISK PROSTATE CANCER
starting salvage hormonal therapy. In the EBRT and AST groups the 5-year freedom from salvage therapy rate was 82% with salvage therapy started at a median PSA of 9.6 ng/ml. In our series the 5-year FFBF rate was higher at 96% in the implant brachytherapy alone group and we used a more stringent definition of failure, that is the Phoenix definition of PSA nadir plus 2.0 ng/ml. The toxicity profile of 70 Gy plus AST included grade 2 or greater rectal bleeding in 19 of 98 patients (19%) and grade 2 or greater impotence in 32 (33%).5 In our series the toxicity profile in the no AST group included a 33% impotence rate and a grade 2 or greater rectal bleeding rate of 6%. A unique morbidity of a brachytherapy dose escalation approach is urinary retention, which occurred at an 8.5% rate in the implant brachytherapy group. Although this toxicity was not reported by D’Amico et al, retention is rare after EBRT. Dose escalation achieved with an implant and EBRT resulted in much higher biochemical control with a similar morbidity profile while avoiding the potential cardiovascular side effects of AST.
The limitations our study and those mentioned is that they are retrospective and have inherent patient selection bias. The inherent difference in the distribution of prognostic factors in the AST vs nonAST group and the equal biochemical control rates suggest that hormonal therapy may have a role as adjuvant therapy in patients with a higher tumor burden or more aggressive cancer. Significantly lower 5-year PSA in the hormone group also suggests that a benefit to AST may emerge at longer followup. The best way to truly test the effects of hormonal therapy when given with high dose radiation would be in a prospective, randomized trial.
CONCLUSIONS AST given as adjuvant therapy with combined implantation and EBRT in patients at intermediate risk failed to improve biochemical control. Although individualized treatment plans may still include AST, it should not be used routinely without considering its potential associated morbidity.
REFERENCES 1. Bolla M, Collette L, Blank L et al: Long-term results with immediate androgen suppression and external irradiation in patients with locally advanced prostate cancer (an EORTC study): a phase III randomized trial. Lancet 2002; 360: 103. 2. Denham JW, Steigler A, Lamb DS et al: Shortterm androgen deprivation and radiotherapy for locally advanced prostate cancer: results from the Trans-Tasman Radiation Oncology Group 96.01 randomized controlled trial. Lancet Oncol 2005; 6: 841. 3. Pilepich MV, Winter K, John M et al: Phase III Radiation Therapy Oncology group (RTOG) Trial 86-10 of androgen deprivation adjuvant to definitive radiotherapy in locally advanced carcinoma of the prostate. Int J Radiat Oncol Boil Phys 2001; 50: 1243. 4. Pilepich MV, Winter K, Lawton CA et al: Androgen suppression adjuvant to definitive radiotherapy in prostate carcinoma—long term results of Phase III RTOG 85-31. Int J Radiat Oncol Biol Phys 2005; 61: 1285. 5. D’Amico AV, Manola J, Loffredo M et al: 6-Month androgen suppression plus radiation therapy vs radiation therapy alone for patients with clinically localized prostate cancer. JAMA 2004; 292: 821. 6. Stock RG, Stone NN, Cesaretti JA et al: Biologically effective dose values for prostate brachytherapy: effects on PSA failure and post treatment biopsy results. Int J Radiat Oncol Biol Phys 2006; 64: 527.
7. Stock RG, Cahlon O, Cesaretti JA et al: Combined modality treatment in the management of highrisk prostate cancer. Int J Radiat Oncol Biol Phys 2004; 59: 1352.
14. Potters L, Torre T, Ashley R et al: Examining the role of neoadjuvant deprivation in patients undergoing prostate brachytherapy. J Clin Oncol 2000; 18: 1187.
8. Kuban DA, Tucker SL, Dong L et al: Long-term results of the M. D. Anderson randomized doseescalation trial for prostate cancer. Int J Radiat Oncol Biol Phys 2008; 70: 67.
15. Ash D, Al-Qaisieh B, Bottomley D et al: The impact of hormone therapy on post-implant dosimetry and outcome following I-125 implant monotherapy for localized prostate cancer. Radiother Oncol 2005; 75: 303.
9. Stone NN, Potter L, Davis BJ et al: Customized dose prescription for permanent prostate brachytherapy: insights from a multicenter analysis of dosimetry outcomes. Int J Radiat Oncol Biol Phys 2007; 69: 1472. 10. Stock RG, Stone NN, Wesson MF et al: A modified technique allowing interactive ultrasoundguided three-dimensional transperineal prostate implantation. Int J Radiat Oncol Biol Phys 1995; 32: 219. 11. Roach M 3rd, Hanks G, Thames H et al: Defining biochemical failure following radiotherapy with or without hormonal therapy in men with clinically localized prostate cancer; recommendations of the RTOG-ASTRO Phoenix Consensus Conference. Int J Radiat Oncol Biol Phys 2006; 65: 965. 12. Norusis MJ: SPSS 10.0 Guide to Data Analysis. Upper Saddle River: Prentice-Hall 2000. 13. Stock RG, Stone NN and Iannuzzi C: Sexual potency following interactive ultrasound guided brachytherapy for prostate cancer. Int J Radiat Oncol Biol Phys 1996; 35: 267.
16. Lee LN, Stock RG and Stone NN: Role of hormonal therapy in the management of intermediate to high risk prostate cancer treated with permanent radioactive seed implantation. Int J Radiat Oncol Biol Phys 2002; 52: 444. 17. Dattoli M, Wallner K, True L et al: Long-term outcomes after treatment with brachytherapy and supplemental conformal radiation for prostate cancer patients having intermediate and high-risk features. Cancer 2007; 110: 551. 18. Merrick GS, Butler WM, Galbreath RW et al: Does hormonal manipulation in conjunction with permanent interstitial brachytherapy, with or without supplemental external beam irradiation, improve the biochemical outcome for men with intermediate or high-risk features? BJU Int 2003; 91: 23. 19. Martinez A, Galalae R, Gonzalez J et al: No apparent benefit at 5 years from a course of neoadjuvant/concurrent androgen deprivation for patients with prostate cancer treated with high total radiation dose. J Urol 2003; 170: 2296.
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EDITORIAL COMMENT The most vexing question confronting patients with intermediate risk prostate cancer is whether AST should be added to radiotherapy. Phase III trials show that AST improves outcomes but a few patients had intermediate risk disease (references 2 and 5 in article).1 In this retrospective analysis the authors question the role of AST. Are their data compelling enough to recommend abandoning AST in all intermediate risk cases? The short answer is no. Intermediate risk disease includes a heterogeneous group of cases with some at low and some at high risk for failure. The current
cases were relatively favorable with median PSA 7.6 ng/ml and 47% had 1 adverse feature. Patients treated with AST tended to have higher PSA, Gleason score and T stage with lower BED but they did as well as other patients. Radiation Therapy Oncology Group 0815 should allow this question to be answered. Mack Roach, III Department of Radiation Oncology Helen Diller Family Comprehensive Cancer Center University of California-San Francisco San Francisco, California
REFERENCE 1. Roach M 3rd, Bae K, Speight J et al: Short-term neoadjuvant androgen deprivation therapy and external-beam radiotherapy for locally advanced prostate cancer: long-term results of RTOG 8610. J Clin Oncol 2008; 26: 585.
Abbreviations and Acronyms AST ⫽ androgen suppressive therapy BED ⫽ biologically effective dose D90 ⫽ dose delivered to hottest 90% of prostate EBRT ⫽ external beam irradiation FFBF ⫽ freedom from biochemical failure IMRT ⫽ intensity modulated radiation therapy PSA ⫽ prostate specific antigen Submitted for publication June 3, 2009. Study received institutional review board approval. * Correspondence: Department of Radiation Oncology, Mount Sinai School of Medicine, 1184 5th Ave., New York, New York 10025 (telephone: 212-241-7502; FAX: 212-410-7194; e-mail: richard. [email protected]). † Financial interest and/or other relationship with Prologics, Nihon-MediPhysics, IsoAid and Prostate Cancer Educational Council.
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Purpose: We assessed the impact of androgen suppressive therapy on biochemical failure in patients with intermediate risk prostate cancer treated with brachytherapy and external beam irradiation. Materials and Methods: From 1994 to 2006, 432 patients with intermediate risk prostate cancer as defined by the National Comprehensive Cancer Network were treated with low dose rate brachytherapy and external beam irradiation with or without 9 months of androgen suppressive therapy. Gleason score was 7 in 76% of cases and prostate specific antigen was 1.4 to 20 ng/ml (median 7.6). Of the patients 350 received androgen suppressive therapy and 82 did not. The biologically effective dose was 142 to 280 Gy2 (median 206). Followup was 23 to 155 months (median 56). Results: The overall 8-year biochemical failure-free rate using the Phoenix definition in patients with vs without androgen suppressive therapy was 92% vs 92% (p ⫽ 0.4). The therapy had no significant impact on the biochemical failure-free rate in patients with Gleason score 7 (92% vs 90.5%, p ⫽ 0.55), prostate specific antigen 10 to 20 ng/ml (92% vs 100%, p ⫽ 0.32), T2b-T2c disease (89.5% vs 97%, p ⫽ 0.27) and more than 1 intermediate risk feature (90% vs 100%, p ⫽ 0.2). Conclusions: We addressed the relative importance of radiation dose vs hormonal therapy for intermediate risk prostate cancer. With high biologically effective dose combination treatment androgen suppressive therapy did not have a significant impact on the 8-year biochemical failure-free rate. We question its routine use in this setting. Key Words: prostate, prostatic neoplasms, brachytherapy, radiotherapy, androgen antagonists THE positive interaction between AST and EBRT for intermediate and high risk prostate cancer is well documented in randomized, controlled trials.1–5 The exact mechanism of this interaction and the optimal duration of hormonal therapy are less well established. The consistent factor in trials is that the external beam dose is now considered to be relatively low (68 to 72 Gy). This issue calls into question the relative importance of
radiation dose vs hormonal/radiation interaction to optimize cancer control. The role of AST combined with high dose radiation is not as well tested. Using BED equations the combination of low dose rate brachytherapy and EBRT delivers the highest dose to the prostate of various radiation approaches.6 Hormonal therapy has been added to this combined treatment for patients at high risk in whom the risk of microscopic systemic
0022-5347/10/1832-0546/0 THE JOURNAL OF UROLOGY® Copyright © 2010 by AMERICAN UROLOGICAL ASSOCIATION
Vol. 183, 546-551, February 2010 Printed in U.S.A. DOI:10.1016/j.juro.2009.10.006
IMPACT OF HORMONAL THERAPY ON INTERMEDIATE RISK PROSTATE CANCER
disease is the greatest.7 AST is used in this subset partly to address the risk of systemic disease. In intermediate risk cases the risk of microscopic systemic disease is less but the need for aggressive local treatment is still warranted. Radiation dose is important in this subset.8,9 To our knowledge the relative benefits of dose vs AST is unknown. In this patient subset we retrospectively examined the effects of adjuvant hormonal therapy added to combination EBRT and brachytherapy. AST and other prognostic factors were analyzed to determine their effects on biochemical control in intermediate risk cases. The impact of AST in higher risk subsets of patients at intermediate risk was also tested.
MATERIALS AND METHODS A total of 432 patients classified as at intermediate risk using the National Cancer Care Network classification (www.nccn.org) were treated at Mount Sinai Medical Center with combination low dose rate brachytherapy and EBRT from 1994 to 2006. National Cancer Care Network defines intermediate risk as at least 1 of certain features, including PSA greater than 10 to 20 ng/ml, Gleason score 7 or stage T2b-T2c. In the patients PSA was 1.4 to 20 ng/ml (median 7.6). All cases were staged with bone and computerized tomography, which were negative for nodal or metastatic disease. Table 1 lists presenting disease characteristics. The amount of disease in biopsy specimens could not be quantified since different methods were used by treating urologists to submit biopsy specimens. Specimens were submitted using individual jars for each core or right and left specimen jars. Of the patients 178 underwent bilateral seminal vesicle biopsy and 16 with positive results received hormonal therapy as part of treatment.
Hormonal Therapy AST was administered to shrink prostates greater than 50 cc or at treating physician discretion. There was no set policy on hormonal therapy in intermediate risk cases.
Table 1. Presenting disease characteristics Factors PSA (ng/ml): 4 or Less Greater than 4–10 Greater than 10–20 Gleason score: 6 or Less 7 Clinical T stage: T1c T2a T2b T2c No. intermediate risk features: 1 2 3
No. Pts (%) 27 (6) 254 (59) 151 (35)
547
Generally patients with more than 1 risk feature tended to received hormonal therapy. Overall 350 patients (81%) received AST using a luteinizing hormone-releasing hormone with or without an antiandrogen and 82 received no AST. AST was given 3 months before seed implantation and it continued thereafter. Overall hormonal therapy duration was 3 to 24 months (median 9), including less than 6 months in 3% of patients, 6 in 12%, 9 in 81%, 12 in 3% and 24 in 1%.
Radiation Therapy Brachytherapy was administered before EBRT with 103Pd seeds (prescription dose 100 Gy, National Institute of Standards and Technology 1999) in 429 patients and 125I seeds (prescription dose 125 Gy) in 3. All brachytherapy was done using a previously described real-time ultrasound guided technique.10 One month after implantation computerized tomography based dosimetry was done. A dose-volume histogram were generated for the prostate. The 103Pd implant D90 was 30 to 162 Gy (median 106) (National Institute of Standards and Technology 1999). D90 of the 2 125I implants in which dosimetry was done was 132 and 149 Gy, respectively. EBRT was delivered using 3-dimensional conformal and intensity modulated radiation therapy techniques. Five to 7 fields were used and treatment volume consisted of the prostate and seminal vesicles plus margin. Six to 16 MV photons were used. Margins were 0.8 to 1.5 cm. The dose was prescribed to the isodose line covering the clinical planning target volume. The total EBRT dose was 3,960 to 6,120 cGy (median 4,500). All doses were delivered in 1.8 Gy daily fractions. BED was calculated using the implant D90 and the EBRT total dose using an ␣-to- ratio of 2. Derivations of these equations were described previously.6 BED was calculated in 427 patients. Postimplantation dosimetry was not done due to patient noncompliance or a hip prosthesis. BED was 142 to 280 Gy2 (median ⫾ SD 206 ⫾ 18.6). BED was 142 to 179 Gy2 in 7% of cases, 180 to 200 in 32%, 201 to 220 in 40% and greater than 220 in 21%.
Outcomes Patients were followed every 6 months with PSA testing. Followup was 23 to 155 months (median 56). Biochemical failure was determined using the Phoenix definition.11 FFBF curves were calculated using Kaplan-Meier actuarial methods. Comparisons between survival curves were tested using the log rank test. The effect of multiple variables on outcome was tested with Cox regression. Differences in proportions were tested using the Pearson chisquare test.12 This retrospective review was approved by the institutional review board.
105 (24) 327 (76)
RESULTS 134 (31) 74 (17) 156 (36) 68 (16) 203 (47) 179 (41) 50 (12)
Overall FFBF at 8 years in the entire group was 92% (part A of figure). Table 2 lists the effect of pretreatment PSA, Gleason score, clinical stage, seminal vesicle status and number of intermediate risk features on FFBF. No factor significantly affected the FFBF rate. BED did not affect FFBF with an 8-year rate of 95% in 203 patients with BED less than 206
548
IMPACT OF HORMONAL THERAPY ON INTERMEDIATE RISK PROSTATE CANCER
A, FFBF. B, hormonal therapy effect on biochemical failure.
Gy2 vs 90% in 224 with BED 206 Gy2 or greater (p ⫽ 0.16). Cox regression analysis with these variables showed that no variable had a significant affect on biochemical failure. Hormonal Therapy Followup was 24 to 155 months (median 57) in patients with hormonal therapy and 23 to 117 (median 54) in those with radiation alone. Table 3 shows the prognostic factor incidence in the AST and nonAST groups. There was an apparent selection bias for choosing hormonal therapy. A significantly greater percent of patients with PSA greater than 10 to 20 ng/ml, Gleason score 7, clinical stage T2c and more than 1 intermediate risk feature was in the AST than in the nonAST group. There was no significant difference in BED in the 2 groups. Overall AST had no significant effect on the FFBF rate with an 8-year rate of 92% in the AST and nonAST groups AST (p ⫽ 0.2, part B of figure). The lowest PSA 5 or more years after treatment in those without PSA failure was significantly lower in the AST vs nonAST group (mean 0.035 ⫾ 0.058 vs 0.185 ⫾ 0.498 ng/ml, p ⬍0.001). Due to differences in the distribution of prognostic factors in the 2 groups the effect of AST was tested in higher risk subgroups, that is patients with a Gleason score of 7, PSA greater than 10 to 20 ng/ml, stage T2b or greater, a Gleason score of 7 and PSA greater than 10 ng/ml, and more than 1 intermediate risk feature (table 2). There was no improvement using hormonal therapy in any subgroup. AST had no impact in the high or low BED group. Of patients with BED less than 206 Gy2 the 172 with AST had an 8-year FFBF rate of 97% vs 86% in the 31 without AST (p ⫽ 0.98). Of patients with BED 206 Gy2 or greater the 174 with AST had an 8-year FFBF rate of 89% vs 94.0% in the 50 without AST (p ⫽ 0.30).
Toxicity Crude comparisons were made between the AST and no AST groups in commonly reported brachytherapy toxicities. Potency was assessed using the Mount Sinai erectile function scoring system in patients who were potent before therapy.13 Impotence (score less than 2), rectal bleeding (Radiation Therapy Oncology Group score 2 or greater) and urinary retention requiring catheterization were noted in 22 of 66 patients at risk, and 5 and 7 of 82 at risk without AST vs 97 of 210 at risk, and 23 and 34 of 350 at risk with AST (chi-square test p ⫽ 0.07, 0.89 and 0.74, respectively).
DISCUSSION Prospective, randomized trials of the role of hormonal therapy in the setting of EBRT have primarily focused on patients with intermediate and high risk features.1–5 These studies were primarily done with relatively low radiation doses in the 70 Gy range (BED 129 Gy2). All studies show a positive outcome of adding hormonal therapy when measuring many disease end points. In the randomized trial by D’Amico et al many patients had primarily intermediate risk features with a score of 7 in 59% and PSA between 10 and 20 ng/ml in 25% with a score of 6 or less.5 This trial showed a survival advantage using 6 months of AST added to 70 Gy EBRT vs EBRT alone. To our knowledge no reported prospective trials address the need for AST in the setting of prostate brachytherapy. Data from retrospective studies are mixed. Most studies do not show a benefit of using AST with brachytherapy without ERBT.14,15 In these series the problem is that AST was primarily used in the neoadjuvant setting for only 3 to 4 months. This duration is probably too short to enhance cancer control. We reported that 6 months of hormonal therapy sandwiched around 103Pd and 125I
IMPACT OF HORMONAL THERAPY ON INTERMEDIATE RISK PROSTATE CANCER
Table 2. Treatment factor effect on FFBF rate overall and in intermediate risk subgroups Factors
No. Pts/No. Failure
Overall PSA (ng/ml): 4 or Less 27/1 Greater than 4–10 254/14 Greater than 10–20 151/10 Gleason score: 6 or Less 105/6 7 327/19 Clinical stage: T2a or Less 208/9 T2b 156/12 T2c 68/4 Seminal vesicle status: Pos 16/2 Neg 162/6 No. intermediate risk features: 1 203/9 2 179/11 3 50/5 Intermediate risk subgroups Gleason score 7: No AST 48/2 AST 279/17 PSA greater than 10–20 ng/ml: No AST 14/0 AST 137/10 Stage T2b or greater: No AST 41/1 AST 183/15 Score 7 ⫹ PSA greater than 10 ng/ml: No AST 2/0 AST 81/8 Greater than 1 intermediate risk feature: No AST 21/0 AST 208/16
% 8-Yr FFBF
p Value 0.88
94 92 93 0.74 94 91 0.39 94 89 95 0.14 93 95.5 0.31 94 91 89 0.55 90.5 92 0.32 100 92 0.27 97 89.5 0.70 100 89 0.2 100 90
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tumor volume measured by biopsy information due to the inconsistent methods in which biopsy material was submitted for evaluation at our institution. Other groups using combination EBRT and brachytherapy also failed to observe a benefit of AST. Dattoli et al did not note that AST improved the outcome in 204 patients with intermediate and high risk features who underwent 103Pd brachytherapy and EBRT.17 The 10-year FFBF rate was 85% with AST vs 78% without AST. In a study of 225 intermediate risk cases Merrick et al found no improvement in biochemical control when adding AST to implantation and EBRT.18 The 6-year FFBF rate was 98%, 96% and 100% for no AST, and cytoreductive and adjuvant AST, respectively. Martinez et al reported on 507 patients with intermediate and high risk features treated with EBRT combined with high dose rate brachytherapy.19 They also did not find that adding 6 months or less of AST improved the biochemical control rate over that of radiation alone with a 5-year FFBF rate of 74% and 76%, respectively. Although the exact mechanism by which AST improves outcomes when combined with EBRT is not known, a large part may be due to its ability to enhance local control. Our study and other reports call into question its beneficial role when higher radiation doses are delivered. A comparison with the randomized study by D’Amico et al using 70 Gy EBRT with 6 months of AST is enlightening.5 The BED equivalent of 70 GY was 129 Gy2, much lower than the median BED in our series, which was 206 Gy2. Those investigators did not report actuarial biochemical failure rates but rather freedom from Table 3. Prognostic factors in patients with and without AST
implants improved the biochemical control rates in intermediate and high risk disease cases.16 This benefit was only seen for low dose implants (D90 less than 140 Gy for 125I and less than 100 Gy for 103Pd), not at higher doses.16 This calls into question the relative importance of dose. Combination brachytherapy and EBRT results in an extremely high BED. In our study 93% of patients had a BED of 180 Gy2 or greater, representing an EBRT equivalent of about 95.4 Gy using 1.8 Gy fractions. In the setting of combination EBRT and brachytherapy perhaps AST, at least given for a relatively short duration, may not have as an important role. In our series 9 months of AST failed to improve biochemical control. Although the study was retrospective and patients with more advanced disease tended to receive AST compared to those treated with radiation alone, the lack of benefit of AST was seen in all higher risk subgroups. The only potential factor that could not be accounted for was
PSA (ng/ml): 4 or Less Greater than 4–10 Greater than 10–20 p Value Gleason score: 6 or Less 7 p Value Clinical stage: T2a or Less T2b T2c p Value No. intermediate risk features: 1 Greater than 1 p Value BED (Gy2): 200 or Less Greater than 200 p Value
No. Without AST (%)
No. With AST (%)
7 (9) 61 (74) 14 (17)
29 (8) 193 (55) 137 (39) 0.001
34 (41.5) 48 (58.5)
71 (20) 279 (80) ⬍0.0001
41 (50) 39 (48) 2 (2)
167 (48) 117 (33) 66 (19) 0.001
61 (74) 21 (26)
142 (41) 208 (59) ⬍0.0001
25 (31) 56 (69)
142 (41) 204 (59) 0.09
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IMPACT OF HORMONAL THERAPY ON INTERMEDIATE RISK PROSTATE CANCER
starting salvage hormonal therapy. In the EBRT and AST groups the 5-year freedom from salvage therapy rate was 82% with salvage therapy started at a median PSA of 9.6 ng/ml. In our series the 5-year FFBF rate was higher at 96% in the implant brachytherapy alone group and we used a more stringent definition of failure, that is the Phoenix definition of PSA nadir plus 2.0 ng/ml. The toxicity profile of 70 Gy plus AST included grade 2 or greater rectal bleeding in 19 of 98 patients (19%) and grade 2 or greater impotence in 32 (33%).5 In our series the toxicity profile in the no AST group included a 33% impotence rate and a grade 2 or greater rectal bleeding rate of 6%. A unique morbidity of a brachytherapy dose escalation approach is urinary retention, which occurred at an 8.5% rate in the implant brachytherapy group. Although this toxicity was not reported by D’Amico et al, retention is rare after EBRT. Dose escalation achieved with an implant and EBRT resulted in much higher biochemical control with a similar morbidity profile while avoiding the potential cardiovascular side effects of AST.
The limitations our study and those mentioned is that they are retrospective and have inherent patient selection bias. The inherent difference in the distribution of prognostic factors in the AST vs nonAST group and the equal biochemical control rates suggest that hormonal therapy may have a role as adjuvant therapy in patients with a higher tumor burden or more aggressive cancer. Significantly lower 5-year PSA in the hormone group also suggests that a benefit to AST may emerge at longer followup. The best way to truly test the effects of hormonal therapy when given with high dose radiation would be in a prospective, randomized trial.
CONCLUSIONS AST given as adjuvant therapy with combined implantation and EBRT in patients at intermediate risk failed to improve biochemical control. Although individualized treatment plans may still include AST, it should not be used routinely without considering its potential associated morbidity.
REFERENCES 1. Bolla M, Collette L, Blank L et al: Long-term results with immediate androgen suppression and external irradiation in patients with locally advanced prostate cancer (an EORTC study): a phase III randomized trial. Lancet 2002; 360: 103. 2. Denham JW, Steigler A, Lamb DS et al: Shortterm androgen deprivation and radiotherapy for locally advanced prostate cancer: results from the Trans-Tasman Radiation Oncology Group 96.01 randomized controlled trial. Lancet Oncol 2005; 6: 841. 3. Pilepich MV, Winter K, John M et al: Phase III Radiation Therapy Oncology group (RTOG) Trial 86-10 of androgen deprivation adjuvant to definitive radiotherapy in locally advanced carcinoma of the prostate. Int J Radiat Oncol Boil Phys 2001; 50: 1243. 4. Pilepich MV, Winter K, Lawton CA et al: Androgen suppression adjuvant to definitive radiotherapy in prostate carcinoma—long term results of Phase III RTOG 85-31. Int J Radiat Oncol Biol Phys 2005; 61: 1285. 5. D’Amico AV, Manola J, Loffredo M et al: 6-Month androgen suppression plus radiation therapy vs radiation therapy alone for patients with clinically localized prostate cancer. JAMA 2004; 292: 821. 6. Stock RG, Stone NN, Cesaretti JA et al: Biologically effective dose values for prostate brachytherapy: effects on PSA failure and post treatment biopsy results. Int J Radiat Oncol Biol Phys 2006; 64: 527.
7. Stock RG, Cahlon O, Cesaretti JA et al: Combined modality treatment in the management of highrisk prostate cancer. Int J Radiat Oncol Biol Phys 2004; 59: 1352.
14. Potters L, Torre T, Ashley R et al: Examining the role of neoadjuvant deprivation in patients undergoing prostate brachytherapy. J Clin Oncol 2000; 18: 1187.
8. Kuban DA, Tucker SL, Dong L et al: Long-term results of the M. D. Anderson randomized doseescalation trial for prostate cancer. Int J Radiat Oncol Biol Phys 2008; 70: 67.
15. Ash D, Al-Qaisieh B, Bottomley D et al: The impact of hormone therapy on post-implant dosimetry and outcome following I-125 implant monotherapy for localized prostate cancer. Radiother Oncol 2005; 75: 303.
9. Stone NN, Potter L, Davis BJ et al: Customized dose prescription for permanent prostate brachytherapy: insights from a multicenter analysis of dosimetry outcomes. Int J Radiat Oncol Biol Phys 2007; 69: 1472. 10. Stock RG, Stone NN, Wesson MF et al: A modified technique allowing interactive ultrasoundguided three-dimensional transperineal prostate implantation. Int J Radiat Oncol Biol Phys 1995; 32: 219. 11. Roach M 3rd, Hanks G, Thames H et al: Defining biochemical failure following radiotherapy with or without hormonal therapy in men with clinically localized prostate cancer; recommendations of the RTOG-ASTRO Phoenix Consensus Conference. Int J Radiat Oncol Biol Phys 2006; 65: 965. 12. Norusis MJ: SPSS 10.0 Guide to Data Analysis. Upper Saddle River: Prentice-Hall 2000. 13. Stock RG, Stone NN and Iannuzzi C: Sexual potency following interactive ultrasound guided brachytherapy for prostate cancer. Int J Radiat Oncol Biol Phys 1996; 35: 267.
16. Lee LN, Stock RG and Stone NN: Role of hormonal therapy in the management of intermediate to high risk prostate cancer treated with permanent radioactive seed implantation. Int J Radiat Oncol Biol Phys 2002; 52: 444. 17. Dattoli M, Wallner K, True L et al: Long-term outcomes after treatment with brachytherapy and supplemental conformal radiation for prostate cancer patients having intermediate and high-risk features. Cancer 2007; 110: 551. 18. Merrick GS, Butler WM, Galbreath RW et al: Does hormonal manipulation in conjunction with permanent interstitial brachytherapy, with or without supplemental external beam irradiation, improve the biochemical outcome for men with intermediate or high-risk features? BJU Int 2003; 91: 23. 19. Martinez A, Galalae R, Gonzalez J et al: No apparent benefit at 5 years from a course of neoadjuvant/concurrent androgen deprivation for patients with prostate cancer treated with high total radiation dose. J Urol 2003; 170: 2296.
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EDITORIAL COMMENT The most vexing question confronting patients with intermediate risk prostate cancer is whether AST should be added to radiotherapy. Phase III trials show that AST improves outcomes but a few patients had intermediate risk disease (references 2 and 5 in article).1 In this retrospective analysis the authors question the role of AST. Are their data compelling enough to recommend abandoning AST in all intermediate risk cases? The short answer is no. Intermediate risk disease includes a heterogeneous group of cases with some at low and some at high risk for failure. The current
cases were relatively favorable with median PSA 7.6 ng/ml and 47% had 1 adverse feature. Patients treated with AST tended to have higher PSA, Gleason score and T stage with lower BED but they did as well as other patients. Radiation Therapy Oncology Group 0815 should allow this question to be answered. Mack Roach, III Department of Radiation Oncology Helen Diller Family Comprehensive Cancer Center University of California-San Francisco San Francisco, California
REFERENCE 1. Roach M 3rd, Bae K, Speight J et al: Short-term neoadjuvant androgen deprivation therapy and external-beam radiotherapy for locally advanced prostate cancer: long-term results of RTOG 8610. J Clin Oncol 2008; 26: 585.