Predictors of Metastatic Disease After Prostate Brachytherapy

International Journal of

Radiation Oncology biology

physics

www.redjournal.org

Clinical Investigation: Genitourinary Cancer

Predictors of Metastatic Disease After Prostate Brachytherapy Kevin Forsythe, M.D.,* Ryan Burri, M.D.,y Nelson Stone, M.D.,z and Richard G. Stock, M.D.* Departments of *Radiation Oncology and zUrology, Mount Sinai School of Medicine, New York, NY; and yDepartment of Radiation Oncology, New York-Presbyterian Hospital, New York, NY Received Mar 3, 2011, and in revised form May 6, 2011. Accepted for publication Jul 13, 2011

Summary This retrospective review sought to determine predictors for the subsequent development of metastatic disease in localized prostate. The study patients were 1800 men treated by brachytherapy with or without external beam and a six-year median follow-up. The two principal predictors of metastatic disease were Gleason score and post-treatment PSA doubling time. This information may have value in determining the need for and timing of androgen deprivation therapy on failure.

Purpose: To identify predictors of metastatic disease after brachytherapy treatment for prostate cancer. Methods and Materials: All patients who received either brachytherapy alone (implant) or brachytherapy in combination with external beam radiation therapy for treatment of localized prostate cancer at The Mount Sinai Hospital between June 1990 and March 2007 with a minimum follow-up of 2 years were included. Univariate and multivariable analyses were performed on the following variables: risk group, Gleason score (GS), clinical T stage, pretreatment prostate-specific antigen level, post-treatment prostate-specific antigen doubling time (PSADT), treatment type (implant vs. implant plus external beam radiation therapy), treatment era, total biological effective dose, use of androgen deprivation therapy, age at diagnosis, and race. PSA-DT was analyzed in the following ordinate groups: 0 to 90 days, 91 to 180 days, 180 to 360 days, and greater than 360 days. Results: We included 1,887 patients in this study. Metastases developed in 47 of these patients. The 10-year freedom from distant metastasis (FFDM) rate for the entire population was 95.1%. Median follow-up was 6 years (range, 2e15 years). The only two significant predictors of metastatic disease by multivariable analyses were GS and PSA-DT (p < 0.001 for both variables). Estimated 10-year FFDM rates for GS of 6 or less, GS of 7, and GS of 8 or greater were 97.9%, 94.3%, and 76.1%, respectively (p < 0.001). Estimated FFDM rates for PSA-DT of 0 to 90 days, 91 to 180 days, 181 to 360 days, and greater than 360 days were 17.5%, 67.9%, 74%, and 94.8%, respectively (p < 0.001). Estimated 10-year FFDM rates for the low-, intermediate-, and high-risk groups were 98.6%, 96.2%, and 86.7%, respectively. A demographic shift to patients presenting with higher-grade disease in more recent years was observed. Conclusions: GS and post-treatment PSA-DT are both statistically significant independent predictors of metastatic disease. Patients with a high GS and/or short PSA-DT have a higher likelihood of developing metastatic disease and should be considered for systemic therapy. Ó 2012 Elsevier Inc. Keywords: Predictors, Prostate, Brachytherapy, Metastatic, Metastases

Reprint requests to: Richard G. Stock, M.D., Department of Radiation Oncology, Mount Sinai School of Medicine, Box 1236, 1 Gustave L. Levy Place, New York, NY 10029. Tel: (212) 241-7500; Fax: (212) 4107194; E-mail: [email protected] Int J Radiation Oncol Biol Phys, Vol. 83, No. 2, pp. 645e652, 2012 0360-3016/$ - see front matter Ó 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.ijrobp.2011.07.033

Conflict of interest: N. Stone is owner of Prologics LLC and consultant for Nihan Medi-Physics and B&K Medical. The authors report no other conflicts of interest.

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Introduction

International Journal of Radiation Oncology  Biology  Physics Table 1

Patient population characteristics (n Z 1,887)

Characteristic Brachytherapy is an effective treatment modality that can be used alone or in combination with external beam radiation therapy (EBRT) for localized prostate cancer of all risk groups (1e3). The identification and characterization of predictors of metastatic disease in prostate cancer are clinically useful in selecting patients for systemic therapies in the context of a biochemical failure and negative radiologic data (e.g., bone scan, computed tomography [CT] scan, or magnetic resonance imaging [MRI]) because Shipley et al. (4) showed that timely initiation of androgen deprivation therapy (ADT) can increase survival in such a scenario. Other series have identified variables predictive of metastatic disease after treatment with other modalities such as EBRT alone (5) or radical prostatectomy (6), but we sought to identify predictors of metastatic disease in patients treated specifically with brachytherapy. The Mount Sinai Hospital is a relatively high-volume center for prostate brachytherapy, and we present the results of a large retrospective study aimed to support the effectiveness of brachytherapy for prostate cancer and to identify predictors of metastatic disease after prostate brachytherapy.

Methods and Materials Patient selection In this retrospective analysis, we included all patients who were treated for localized prostate cancer with brachytherapy at The Mount Sinai Hospital between June 1990 and March 2007. Definitive radiation therapy consisted of either brachytherapy alone or brachytherapy in combination with EBRT, with the possible addition of ADT. All patients had a minimum follow-up of 2 years (median, 6 years; range, 2e17 years), and a total of 1,887 patients were included in this study. The patient characteristics are presented in Table 1.

Patient characteristics All patients had biopsy-proven prostate cancer that underwent central pathologic review. Initial workup consisted of a history, physical examination, and routine serum chemistries including prostate-specific antigen (PSA) level. For intermediate- and high-risk patients, pelvic imaging (by CT or MRI) and a bone scan were also obtained; all patients in this study had localized disease confined to the prostate at presentation. Patients were stratified into low-, intermediate-, and high-risk groups based on their presenting PSA level, Gleason score (GS), and clinical tumor stage (T stage). The low-risk group was defined as having all of the following low-risk features: PSA level of less than 10 ng/mL, GS of 6 or less, and T stage of T2a or less. The intermediate-risk group was defined as having no highrisk features and at least one of the following intermediate-risk features: PSA level of 10 to 20 ng/mL, GS of 7, and T stage of T2b. The high-risk group was defined as having at least one of the following high-risk features: PSA level greater than 20 ng/mL, GS of 8 or greater, and T stage of T2c or greater.

Gleason score 6 7 8 Pretreatment PSA level <10 ng/mL 10e20 ng/mL >20 ng/mL Clinical T stage T2a T2b T2c Risk group Low Intermediate High PSA doubling time 0e90 d 91e180 d 180e360 d >360 d No PSA failure Treatment type Implant alone Implant þ EBRT Total BED* <180 Gy2 180 Gy2 Use of ADT ADT not used ADT used Treatment era Before January 1, 2000 After January 1, 2000 Age at diagnosis 60 yr >60 yr Race White African American Hispanic East Asian South Asian Pacific Islander Unknown

No. of patients

%

1,285 406 196

68.1 21.5 10.4

1,413 346 128

74.9 18.3 6.8

1,302 385 200

69 20.4 10.6

868 627 392

46 33.2 20.8

44 43 32 63 1,705

2.3 2.3 1.7 3.3 90.4

1,240 647

65.7 34.3

489 1,398

26 74

843 1,044

44.7 55.3

769 1,118

40.8 59.2

425 1,462

22.5 77.5

1,502 224 116 23 8 3 11

79.6 11.9 6.1 1.2 0.5 0.2 0.6

Abbreviations: PSA Z prostate-specific antigen; EBRT Z external beam radiation; BED Z biologically effective dose; ADT Z androgen deprivation therapy. * By convention, the unit Gy2 is used for BED values when an a/b ratio of 2 Gy is used.

Brachytherapy technique Typically, the radiation treatment for low-risk patients consisted of an 125iodine (125I) implant alone, and the radiation treatment for intermediate-risk patients consisted of either a 103palladium (103Pd) implant alone or a 103Pd implant in combination with EBRT.

Volume 83  Number 2  2012 High-risk patients were treated with a 103Pd implant in combination with EBRT. All patients received implants by a real-time transrectal ultrasound-guided technique; this original technique and its subsequent innovations have been previously reported (7e9). For patients receiving 125I implants, the prescription dose was 160 Gy. The prescription dose for a 103Pd implant alone was 124 Gy; when EBRT was added to a 103Pd implant, the implant prescription dose was 100 Gy. The activity range per seed was 0.3 to 0.5 mCi for 125I and 1.0 to 1.5 mCi for 103Pd. All patients underwent post-implant dosimetry as described in the next section.

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followed by 45 Gy of EBRT starting 6 to 8 weeks after the implant, and 6 more months of ADT after the implant.

Follow-up Follow-up consisted of an interval history, physical examination, and PSA level at intervals of 6 months starting after the completion of all radiation therapy. Follow-up time was calculated from the completion of all radiation therapy to the last available follow-up date or date of death.

Post-implant dosimetry Endpoints and variables All patients underwent a CT scan for post-implant dosimetry 1 month after implantation, at which time a doseevolume histogram provided the dose delivered to 90% of the prostate (D90); the significance of the D90 parameter has been previously described (10e12). All doses were defined in accordance with the American Association of Physicists in Medicine Radiation Therapy Committee Task Group No. 43 and National Institute of Standards and Technology 99 guidelines (13, 14). To compare delivered doses among the different treatment types (125I implant alone vs. 103Pd implant alone vs. 103Pd implant in combination with EBRT), we used biologically effective dose (BED) calculations. On the basis of previous work, an a/b ratio of 2 Gy was used (15); by convention, the unit Gy2 is used for BED values when an a/b ratio of 2 Gy is used.

External beam radiation therapy Patients who were treated with EBRT typically started their daily treatments 6 to 8 weeks after their implant and received a dose of 45 Gy. Between 1990 and June 2003, EBRT was delivered by a 6field three-dimensional conformal radiation therapy technique. After June 2003, EBRT was delivered by a 5-field intensitymodulated radiation therapy technique. The target volume included the prostate and seminal vesicles with a 15- to 20-mm margin, and the dose was prescribed typically to encompass the prostate and seminal vesicles with a 5- to 15-mm margin; none of the patients received treatment to the pelvic lymph nodes. Position verification was performed by use of standard port film imaging and orthogonal isocenter verification during the three-dimensional conformal radiation therapy and intensity-modulated radiation therapy eras, respectively.

Androgen deprivation therapy When indicated, ADT typically consisted of a gonadotropinreleasing hormone agonist (e.g., leuprolide or goserelin) with the possible addition of an antiandrogen (e.g., flutamide or bicalutamide). When ADT was given to shrink large prostate glands (i.e., gland size >50 cm3), it was typically given 3 months before implantation and for 2 to 3 months after implantation. When ADT was used in a neoadjuvant and adjuvant manner for intermediateor high-risk patients, it was typically given 3 months before implantation and for 3 to 6 months after implantation (16).

Trimodality therapy Trimodality therapy consisted of 3 months of ADT before implantation, a 103Pd implant (prescription dose, 100 Gy)

For this study, we used the Phoenix definition for biochemical failure (a rise of 2 ng/mL in PSA level above the PSA nadir, without backdating) (17); in the event of a biochemical failure, patients underwent restaging with a bone scan and other imaging of the pelvis (CT scan or MRI). Patients were diagnosed with metastatic disease by either a positive biopsy or a positive bone scan (or both) in the context of a biochemical failure; metastatic disease was presumed to be of prostatic origin in the absence of a biopsy proving otherwise. Freedom from distant metastasis (FFDM) was measured from the time of completion of radiation therapy to the time of diagnosis of metastatic disease. The following factors were analyzed as putative predictors for the development of metastatic disease: risk group (with stratification schema as described earlier), GS (6 vs. 7 vs. 8), PSA level (<10 ng/mL vs. 10e20 ng/mL vs. >20 ng/mL), T stage (T2a vs. T2b vs. T2c), age at diagnosis (60 years vs. >60 years), race (white vs. African American vs. Hispanic vs. East Asian vs. South Asian vs. Pacific Islander vs. unknown), treatment type (implant alone vs. implant plus EBRT), treatment era (before January 1, 2000 vs. after January 1, 2000), total BED (<180 Gy2 vs. 180 Gy2), use of ADT, and post-treatment prostate-specific antigen doubling time (PSA-DT) (0e90 days vs. 91e180 days vs. 180e360 days vs. >360 days). In the event of a biochemical failure, the PSA-DT was calculated by a log-linear method; specifically, the PSA-DT was calculated as the inverse of the slope of a patient’s postebiochemical failure PSA values plotted in log2 as a function of time.

Statistical analyses FFDM was calculated by the Kaplan-Meier method (18); differences in FFDM were compared by use of the log-rank (MantelCox) test and chi-square analysis. Multivariable Cox regression analysis was also performed on the previously mentioned variables to assess their significance in predicting the development of metastatic disease. Spearman correlation tests were used to establish correlations between variables. A two-sided p value <0.05 was considered significant for all tests.

Results The overall FFDM for all patients in this study at 10 years was 95.1% (Fig. 1); among patients in whom metastatic disease developed, the median time to diagnosis of metastatic disease was 4 years.

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International Journal of Radiation Oncology  Biology  Physics Table 2

Univariate analysis of distant metastasis

Variable

Fig. 1. Freedom from distant metastasis (FFDM) for overall study population.

The results of univariate analyses on the putative predictors of metastatic disease are presented in Table 2, and the results of the multivariable analysis are presented in Table 3. The factors of age and race were not found to be significant predictors of metastatic disease by univariate analysis (p Z 0.271 and p Z 0.959, respectively). The following factors were found to be statistically significant predictors of metastatic disease by univariate analysis but were not significant by multivariable analysis: initial PSA level, T stage, treatment type, total BED, use of ADT, and treatment era. Univariate analyses suggested that lower PSA level, lower T stage, less aggressive radiation treatment (i.e., treatment with implant alone, lower BED, or no ADT), and treatment during the earlier years of this study were associated with lower rates of metastases. Multivariable analysis was not performed on the risk group variable because the risk group is defined by the independent variables PSA level, GS, and T stage. However, univariate analysis did correlate the development of metastases with the higher-risk groups; the 10-year FFDM rates for the low-, intermediate-, and high-risk groups were 98.6%, 96.2%, and 86.7%, respectively (p < 0.001). Figures 2 and 3 show the FFDM for the PSA groups and risk groups. Only GS and PSA-DT proved to be statistically significant by both univariate and multivariable analyses. The 10-year FFDM rates for GS of 6 or less, GS of 7, and GS of 8 or greater were 97.9%, 94.3%, and 76.1%, respectively (p < 0.001), correlating higher GSs with increased rates of metastases (Fig. 4). Increased rates of metastases were also correlated with faster (shorter) doubling times (Fig. 5); the 10-year FFDM rates for PSA-DT greater than 360 days, PSA-DT of 181 to 360 days, PSA-DT of 91 to 180 days, and PSA-DT of 0 to 90 days were 94.8%, 74%, 67.9%, and 17.5%, respectively (p < 0.001). To explain why more aggressive treatments (i.e., the use of ADT, the addition of EBRT to an implant, and a higher total BED) were associated with higher rates of metastases, a two-tailed Spearman correlation test was performed, which showed

No. of 10-yr freedom No. patients from of with metastasis p (%) value patients metastases

Gleason score 6 1,285 7 406 8 196 Pretreatment PSA level <10 ng/mL 1,413 10e20 ng/mL 346 >20 ng/mL 128 Clinical T stage T2a 1,302 T2b 385 T2c 200 Risk group Low 868 Intermediate 627 High 392 PSA doubling time 0e90 d 44 91e180 d 43 180e360 d 32 >360 d 63 Treatment type Implant alone 1,240 Implant þ 647 EBRT Total BED* <180 Gy2 489 180 Gy2 1,398 Use of ADT ADT not used 843 ADT used 1,044 Treatment era Before January 769 1, 2000 After January 1,118 1, 2000 Age at diagnosis 60 yr 425 >60 yr 1,462 Race White 1,502 African 224 American Hispanic 116 East Asian 23 South Asian 8 Pacific Islander 3 Unknown 11

15 10 23

97.9 94.3 76.1

<0.001

25 12 11

96 94.3 87.5

<0.001

16 18 14

97.9 91.5 87.9

<0.001

7 11 30

98.6 96.2 86.7

<0.001

25 10 7 4

17.5 67.9 74 94.8

<0.001

14 34

98.3 85

<0.001

12 36

97.3 93.3

<0.001

10 38

98.4 91.9

<0.001

26

97.7

0.049

22

95.1

7 41

96.5 94.7

0.271

36 7

95 95.6

0.959

4 1 0 0 0

93.6 e e e e

Abbreviations: PSA Z prostate-specific antigen; EBRT Z external beam radiation; BED Z biologically effective dose; ADT Z androgen deprivation therapy. * By convention, the unit Gy2 is used for BED values when an a/b ratio of 2 Gy is used.

Volume 83  Number 2  2012 Table 3

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Multivariable analysis of distant metastasis

Variable

p value

Gleason score Pretreatment PSA level Clinical T stage PSA doubling time Treatment type Total BED Use of ADT Treatment era Age at diagnosis Race

0.006 0.723 0.477 <0.001 0.051 0.246 0.483 0.242 0.495 0.925

Abbreviations: PSA Z prostate-specific antigen; BED Z biologically effective dose; ADT Z androgen deprivation therapy.

a significant correlation between higher GSs and more aggressive treatments (p < 0.001 for the correlation between higher GSs and all 3 aggressive treatment variables). Figures 6 and 7 show the correlation between risk groups and more aggressive treatments. We also sought to explain why patients who were treated more recently had higher rates of metastases, and a correlation was observed between patients presenting more recently and all of the higher-risk disease variables: GS (p < 0.001), PSA (p < 0.001), T stage (p < 0.001), and risk group (p < 0.001). Figure 8 shows this for GS, with a decreasing proportion of low-risk patients especially in the last 5 years.

Discussion Overall, the occurrence of metastatic disease after prostate brachytherapy was observed to be low, with a 10-year FFDM rate for all patients of 95.1%. The 10-year FFDM rates were 98.6%,

Fig. 2. Freedom from distant metastasis (FFDM) by risk group (p < 0.001).

Fig. 3. Freedom from distant metastasis (FFDM) by pretreatment prostate-specific antigen (PSA) level. 96.2%, and 86.7% for the low-, intermediate-, and high-risk groups, respectively. These 10-year FFDM rates compare favorably with a published series of 615 patients who were treated with EBRT, in which the 5-year FFDM rates were 100%, 79%, and 66% for the low-, intermediate-, and high-risk groups, respectively (19). Of the putative predictors analyzed in this study, only GS and PSA-DT were found to be significant independent predictors of metastatic disease by multivariable analysis (p Z 0.006 and p <

Fig. 4. Freedom from distant metastasis (FFDM) by Gleason score (GS) (p < 0.001).

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Fig. 5. Freedom from distant metastasis (FFDM) by posttreatment prostate-specific antigen (PSA) doubling time (p < 0.001). 0.001, respectively). D’Amico et al. (20) previously established the validity of using PSA-DT as a surrogate endpoint for distant disease, which has been validated by other studies (5), and this large retrospective study adds to these sets of data. These findings are consistent with the previously reported predictive value of these parameters in patients treated with EBRT alone (5) or radical prostatectomy (6).

Fig. 6. Correlation between risk group and treatment type (p < 0.001). EBRT Z external beam radiation therapy.

International Journal of Radiation Oncology  Biology  Physics

Fig. 7. Correlation between risk group and use of androgen deprivation therapy (ADT) (p < 0.001). More aggressive treatments were associated with higher rates of metastases by univariate analysis; however, the more aggressive treatment variables were not statistically significant on multivariable analysis. This can be explained by the selection bias for administering more aggressive treatments to patients with more aggressive disease; this was statistically proven. It would have been interesting to evaluate the impact of treatment type and use of ADT in higher-risk patients; however, this selection bias precluded such subset analyses (e.g., of the 196 patients with GS 8, 189 received ADT and 173 received EBRT). Interestingly, the large nature of this study enabled us to observe an unexpected association by univariate analysis between the treatment era and the development of metastatic disease: patients who were treated more recently had slightly higher rates of metastatic disease. This observation was the opposite of our a priori expectation, which was based on the assumption that after

Fig. 8. Correlation between Gleason score and date of presentation (p < 0.001).

Volume 83  Number 2  2012 accumulating years of brachytherapy experience, the more recently treated patients would have better outcomes (i.e., a “learning curve” effect). This association, however, was not significant by multivariable analysis (p Z 0.24), and correlation testing showed a shift in patient demographics, with an increasing proportion of patients presenting with higher-risk features in the later years of the study. Patients with low-grade disease previously represented a greater proportion of cases than the intermediateand high-grade cases combined, but in the last several years, the proportion of low-risk patients has steadily fallen (Fig. 8). With increased utilization of the PSA screening test, one would expect an overall downward stage migration as prostate cancers are detected earlier. However, a slight upward shift in Gleason scoring by pathologists when PSA screening became standard was noted in the published literature (21); this was also proven in studies that took biopsy specimens from the late 1980s to early 1990s and had them re-evaluated by pathologists a decade later (22, 23). This upward migration in Gleason scoring led to an apparent improvement in outcomes because some specimens that would have been previously scored as GS 6 were scored as GS 7 (a statistical artifact known as the “Will Rogers phenomenon”). However, this is incongruent with the outcomes of this study, in which more recently treated patients have slightly worse outcomes. In addition, the decrease in low GSs that was observed in this study occurred in the mid 2000s, about a decade later than the documented grade migration. The inconsistency between these two documented trends and the results of this study could be explained as our central pathologic review lagging about a decade behind the national trend in Gleason scoring combined with a decrease in brachytherapy effectiveness at our institution (the inverse of a learning curve). However, we believe that there is a simpler and more plausible explanation: namely, these results could be accounted for by the shunting of lower-risk patients to competing treatment modalities (e.g., EBRT alone, radical prostatectomy, or active surveillance). Because we have not seen an increase in treatment with EBRT alone in our department, we suspect that patients with lower-risk disease are increasingly being referred for radical prostatectomy. Although we are not privy to the demographic data of patients undergoing radical prostatectomy at our institution, we are aware of the increasing number of patients undergoing robotic radical prostatectomy (24). At this time, we do not know whether this trend is peculiar to our institution or whether it represents a greater trend nationwide. Recently, Giberti et al. (25) published a randomized study of 200 patients comparing retropubic radical prostatectomy (RRP) vs. brachytherapy for low-risk prostate cancer. They reported 5-year follow-up data that showed equivalent biochemical control outcomes (RRP, 91.0%; brachytherapy, 91.7%; p Z not significant) and noted higher short-term urinary side effects for brachytherapy, higher short-term sexual side effects for RRP, and equivalent long-term urinary and sexual side effects for both modalities. This study was a good first step toward comparing the treatment modalities for prostate cancer in a randomized, controlled manner; although it might not be easy to randomize patients to surgery vs. radiation in the United States, there is still a need for similar studies to be conducted with larger patient numbers and inclusion of the higher-risk groups. Naturally, this study has inherent limitations because of its retrospective nature, and its results should be considered accordingly. The effectiveness of brachytherapy, like surgical procedures, is heavily operator dependent; the successful results observed in this study may not be able to be extrapolated to

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brachytherapy practitioners who treat a lower volume of patients. Furthermore, we would recommend that brachytherapy procedures only be performed by experienced radiation oncologists and physicists who regularly practice brachytherapy techniques. In terms of variables analyzed, we would have liked to have analyzed the number of positive biopsy cores as a predictor, but this parameter was not routinely captured in our database.

Conclusions The overall incidence of metastatic disease after brachytherapy for prostate cancer is low. Both GS and PSA-DT are statistically significant independent predictors of metastatic disease, so patients who have biochemical failures and either a GS of 8 or greater or a short PSA-DT should be considered for systemic therapies. We have also incidentally observed a decrease in the proportion of patients with low-risk disease being referred for definitive radiation therapy, possibly because of referrals to competing treatment modalities.

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International Journal of Radiation Oncology  Biology  Physics 18. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958;53:457e481. 19. Hanlon AL, Diratzouian H, Hanks GE. Posttreatment prostate-specific antigen nadir highly predictive of distant failure and death from prostate cancer. Int J Radiat Oncol Biol Phys 2002;53:297e303. 20. D’Amico AV, Moul JW, Carroll PR, et al. Surrogate end point for prostate cancer-specific mortality after radical prostatectomy or radiation therapy. J Natl Cancer Inst 2003;95:1376e1383. 21. Jani AB, Master VA, Rossi PJ, et al. Grade migration in prostate cancer: An analysis using the Surveillance, Epidemiology, and End Results registry. Prostate Cancer Prostatic Dis 2007;10:347e351. 22. Smith EB, Frierson Jr HF, Mills SE, et al. Gleason scores of prostate biopsy and radical prostatectomy specimens over the past 10 years: Is there evidence for systematic upgrading? Cancer 2002;94: 2282e2287. 23. Albertsen PC, Hanley JA, Barrows GH, et al. Prostate cancer and the Will Rogers phenomenon. J Natl Cancer Inst 2005;97:1248e1253. 24. Samadi D. RoboticOncology. Available from: URL: http://www. roboticoncology.com/data Accessed on 09/29/2011. 25. Giberti C, Chiono L, Gallo F, et al. Radical retropubic prostatectomy versus brachytherapy for low-risk prostatic cancer: A prospective study. World J Urol 2009;27:607e612.