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15-Year Cause Specific and All-Cause Survival Following Brachytherapy for Prostate Cancer: Negative Impact of Long-Term Hormonal Therapy
Author's Accepted Manuscript 15-Year Cause Specific and All-Cause Survival Following Brachytherapy for Prostate Cancer: Negative Impact of Long-term Hormonal Therapy Nelson N. Stone, Richard G. Stock
PII: DOI: Reference:
S0022-5347(14)03182-6 10.1016/j.juro.2014.03.094 JURO 11358
To appear in: The Journal of Urology Accepted Date: 10 March 2014 Please cite this article as: Stone NN, Stock RG, 15-Year Cause Specific and All-Cause Survival Following Brachytherapy for Prostate Cancer: Negative Impact of Long-term Hormonal Therapy, The Journal of Urology® (2014), doi: 10.1016/j.juro.2014.03.094. DISCLAIMER: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our subscribers we are providing this early version of the article. The paper will be copy edited and typeset, and proof will be reviewed before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to The Journal pertain. All press releases and the articles they feature are under strict embargo until uncorrected proof of the article becomes available online. We will provide journalists and editors with full-text copies of the articles in question prior to the embargo date so that stories can be adequately researched and written. The standard embargo time is 12:01 AM ET on that date.
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15-Year Cause Specific and All-Cause Survival Following Brachytherapy for Prostate Cancer: Negative Impact of Long-term Hormonal Therapy Running Title: 15 Year Survival After Prostate EBRT
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Text pages: 15 Tables: 4 Figures: 2 Word count 2499
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Mailing Address: Nelson N. Stone, MD 350 East 72nd Street, Apt 8A New York, NY 10021 Tel: 845 323 1727 Email: [email protected]
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Nelson N. Stone, MD* and Richard G. Stock, MD^, Departments of Urology* and Radiation Oncology^, Icahn School of Medicine at Mount Sinai, New York, New York.
Funding source: none Financial Interest: R. Stock-none. N. Stone-Prologics LLC (investor interest), Nihon MediPhysics (consultant) Presented at the 2013 AUA Annual Meeting Key Words: prostate cancer, radiation therapy, brachytherapy, hormonal therapy, survival
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Abstract Purpose: We analyzed the factors influencing 15-year cause-specific (CSS) and all-cause survival (ACS) in
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men treated by prostate brachytherapy (PB). Materials and Methods: 1669 men with T1-T3 prostate cancer with a median age of 66 years were treated with PB and followed a mean of 10 years. Treatments were implant alone, implant plus
hormone therapy (HT) or external beam irradiation (EBRT) or implant plus HT plus EBRT. HT was
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administered to 898 (53.8%) men a median of 6 months. Estimates for CSS and ACS were determined by
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Kaplan Meier method with comparisons by logistic regression and Cox proportions hazard rates. Results: 15-year CSS was 94.1%. CSS by the 3 NCCN risk groups was 96.3%, 97.5% and 85.2% (p<0.001). HT did not positively impact CSS. 15-year ACS was 57% and Cox regression demonstrated age (p<0.001, HR 1.09), HT (p=0.032, HR 1.04), diabetes (p=0.013, HR 1.86), atrial fibrillation (p=0.041, HR 2.90), smoking (p=0.030, HR 1.42) and emphysema (p=0.040, HR 8.20) as significant associations. HT
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decreased ACS at 15 years from 60.3% to 54.9% (p=0.009). ACS was not reduced if HT was limited to < 6 months (p=0.005). This difference was present in both younger (age < 66, p=0.017) and older men
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(p=0.05).
Conclusions: PB yields favorable 15-year CSS, especially in high risk patients. ACS is less in patients with
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preexisting diabetes, atrial fibrillation and emphysema. The use of HT for longer than 6 months has a negative effect on ACS even in younger patients without an apparent beneficial effect on CSS.
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Introduction Brachytherapy is a well-established method of treating localized prostate cancer. However few studies
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have documented long-term results, specifically cause-specific and all-cause survival in men who have received either implant alone or in conjunction with hormone therapy or external beam irradiation. While cancer-specific survival at 10 years has been high for low-risk prostate cancer patients, little data
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on 15-year outcomes is available, especially in men with intermediate and high risk disease.
Hormonal therapy is commonly added to a regimen of external radiation therapy. Patients with high
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risk disease are often offered 2-3 years of androgen ablation based on the positive results of several randomized clinical trials (1-2). However, controversies exist on whether longer term HT itself induces morbidity and it possibly may increase mortality (3-4). In the brachytherapy patient, neoadjuvant HT is often prescribed for downsizing a large gland (5). However, patients with high risk disease who receive combination brachytherapy plus external beam irradiation (EBRT) are treated with HT for 2-3 years in
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a similar fashion as men receiving EBRT alone. This treatment plan occurs despite the fact that there are no data that supports the use of long-term HT in patients receiving combination therapy (6).
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In order to better understand these issues we herein report the long-term mortality outcomes in a large
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cohort on prostate cancer patients managed with brachytherapy with and without HT and EBRT.
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Materials and Methods 1669 men with T1-T3 prostate cancer with a median age of 66 years (range 39-85) had permanent
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prostate brachytherapy and were followed a minimum of 5 years and mean of 10 years (range 5-19). The median PSA was 6.9 ng/ml (mean 9.7, range 0.1-300). Treatment began in 1990 and all patients treated up to 2007 were included in the analysis. Follow-up time was censored at the time of death. At the initial consultation details about smoking history (current, quite with pack years), presence of
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diabetes (AODM or type 2), coronary artery disease (CAD), alcohol use, asthma, atrial fibrillation, presence of other cancers, heart disease (any other than CAD), stroke and emphysema were collected.
approved by the institutional review board.
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Responses were prospectively entered into the patient database. The data entry and reporting were
Patients were stratified into 3 NCCN risk groups and treated with implant alone (NCCN 1-low risk), implant plus either hormone therapy (HT) or external beam irradiation (EBRT) (NCCN 2- intermediate
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risk) or implant plus HT plus EBRT (NCCN 3-high risk). There were 759 (45.5%) low, 644 (38.6%) intermediate and 268 (15.9%) high risk patients (Table 1). The median PSA was 6.9 ng/ml (mean 9.7, range 0.1-300). HT was administered to 898 (54%) for a median of 6 months (range 1-34). HT was given
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for 3-6 months as LHRHa with or without an antiandrogen in low risk patients for prostate volume > 50
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cc, for 6 months in patients with NCCN2 if no EBRT was used and for a median of 9 (interquartile range 4.3-9.0) months for NCCN3. 35 patients were treated for more than 9 months if they were found to have stage T3b by biopsy or if they were referred in off protocol. Intermediate and high risk patients had bone scintography and abdominal-pelvic CT. Patients with positive scans were excluded. Brachytherapy was performed with I-125 (160 Gy, TG-43) for NCCN1, Pd-103 (125 Gy, NIST 1999) with 6 months HT or Pd-103 (100 Gy) combined with 45 Gy EBRT (combination therapy) for NCCN2 and 9 months HT with combination therapy for NCCN3. Pd-103 was selected for NCCN2 and NCCN3 because 4
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of its radiobiologic characteristics of short half-life and lower energy (7-8). EBRT was initiated as 3D conformal technique and more recently as IMRT and IGRT. While the technology for targeting improved over time the dose remained fixed at 45 Gy (25 treatments of 1.8 Gy fractions). Within 30
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days post-implant CT based dosimetry was used to calculate the biological effective dose (BED) as previously described (9). BED ranged from 15-282 Gy2 with a median of 198 Gy2 (α/β=2).
Patients were followed every 6 months and were considered biochemical failures if the PSA increased by
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2 ng/ml above a nadir (Phoenix definition). Prostate cancer was selected as the cause of death if the patient had evidence of clinical recurrence. All other causes of death, including men dying with a PSA
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only recurrence were considered to have died from other causes. Statistical analysis was performed using SPSS software (Version 20, Armonk, NY). Neoadjuvant HT use was dichotomized to < 6 months (n=528) and > 6 months (n=370). Chi-square analysis was performed to assess for significant differences between groups and binomial logistic regression models were developed to identify risk factors for
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biochemical freedom from failure, cause specific (CSS) and all cause survival (ACS). Time to death was estimated using the Kaplan-Meier method. Covariates that were significantly associated with CSS and ACS were entered into the Cox proportional hazards model. All statistical tests were two-sided and P
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values less than 0.05 were considered statistically significant.
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Results The 10 and 15 year freedom from biochemical relapse were 89.3% and 67%, respectively. The 10 and
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15-year cause specific survival rates were 98.1% and 94.1% (Figure 1). NCCN risk group, PSA, Gleason score and clinical stage were all predictive of 10 and 15 year CSS (Table 2). Cox regression revealed higher clinical stage (p=0.017, HR 1.53, 95%CI 1.08-2.17) and Gleason grade (p=0.001, HR 1.74, 95%CI 1.27-2.37) to impact negatively on CSS, while the use of neoadjuvant HT and high BED did improve
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CSS. At the time of this analysis 37 (2.2%) men had died of prostate cancer. The number of men dying
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from prostate cancer by Gleason score and NCCN risk category is shown in table 3. All cause survival was 86.8% at 10 years and 57% at 15 years. 238/1669 (14.3%) men had died at the time of this analysis (37 prostate cancer, 201 other causes). On univariate analysis older age, higher PSA, Gleason score and stage, use of HT, and presence of diabetes and heart disease were associated with a decreased 15 year survival. However on Cox regression age, hormone therapy, smoking history,
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diabetes, atrial fibrillation and emphysema were significant covariates (Table 4). An analysis by NCCN category revealed increased time on HT decreased ACS in the NCCN 3 group (p<0.001, HR 1.175, 95% CI 1.086-1.271). HT decreased ACS at 10 years from 89.8 to 84.2% and at 15 years from 60.3% to 54.9%
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(p=0.009). Time on NHT adversely affected ACS dichotomized to < 6 months (n=528) to more than 6
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months (n=370, p=0.005) (Figure 2). This difference persisted in younger (age < 66, p=0.017) and older men (p=0.05). When prostate cancer death was removed for ACS (n=201) these differences remained significant. The 10 year ACS for men treated with 0-6 months of HT vs those treated with > 6 months was 90.9 vs 82.6% and the 15 years was 60.8 vs 56.9% (p=0.004). Exclusion of the significant health risk factors improved all cause survival estimates at 15 years to 60% from 57%. However, the addition of HT still had a negative influence on ACS (p=0.008).
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Discussion Prostate brachytherapy is an established technique for treating localized disease. There are few studies
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that document the long-term prostate cancer specific mortality results. We report favorable 10 and 15 year CSS as 98.1% and 94.1%, respectively. Sylvester et al. reported the 15 year CSS in 215 patients treated with I-125 as 84% (10). Their patient population consisted of only 5.1% men with high risk disease compared to 16.1% in the present study and had a shorter minimum follow-up (3.6 vs 5 years).
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Our study compares favorably to centers reporting CSS for patients treated by radical prostatectomy (RP). Han reported 15-year CSS (mean follow-up 6.3 years) for RP at Johns Hopkins from 1982 to 1990
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as 90% (11). Mullins updated these results in 4,478 men and with a median follow-up of 10 years, the 15 years CSS was 94% (12). Shikanov identified 120,392 men who underwent RP between 1988 and 2003 from the Surveillance, Epidemiology and End Results (SEER) database (13). The 15-year CSS was 95%. Thus it appears that prostate brachytherapy can yield similar 15 year cancer specific survival as
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radical prostatectomy.
Several reports have compared the outcomes of prostatectomy to EBRT and brachytherapy. Hoffman analyzed men aged 55 to 74 years diagnosed with localized PC who underwent either RP (n = 1164) or
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EBRT (n = 491) (14). 45 (3.9%) of the RP and 59 (12%) of the EBRT patients had died from the disease.
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The RP data compare favorably with the current study where 37/1669 (2.2%) have died from prostate cancer. Our data are consistent with Nepple who reported CSS in men treated by RP (n=4459), EBRT (n=1261), or brachytherapy (n=972) (15). At 10 years, EBRT was associated with an increase in prostate cancer mortality compared with RP (HR: 1.66; 95% CI 1.05–2.63); while brachytherapy was not. A possible explanation for these differences comes from the study of Jacob et al (16). In the multivariate Cox model higher radiations doses were associated with both a decrease in metastases and an increase in overall survival. The biologic effective dose (BED) in our brachytherapy patients is considerably higher
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than the radiation dose given to men receiving EBRT, especially when brachytherapy is combined with EBRT in high risk disease (6,9).
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When stratified by NCCN risk group survival rates for the low and intermediate risk patients remain very high (96-99%), with little to no reduction from 10 to 15 years. However, there was a 7% decrease (from 92.5 to 85.2%) over the same period for the high risk group. Shen identified 12,745 patients treated with EBRT (73.5%), brachytherapy (7.1%), or brachytherapy plus EBRT from the SEER database with T1-
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T3N0M0 prostate cancer (17). On multivariate analysis brachytherapy alone was associated with a 33% reduction of prostate cancer death and brachytherapy plus EBRT a 23% compared to EBRT. Johansson
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analyzed 223 patients with early-stage disease, initially untreated prostatic cancer (18). Most cancers had an indolent course during the first 10 to 15 years. However, further follow-up from 15 to 20 years revealed a substantial decrease in cumulative progression-free survival (from 45.0% to 36.0%), survival without metastases (from 76.9% to 51.2%), and prostate cancer– specific survival (from 78.7% to
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54.4%). Fifteen year CSS survival for the high grade tumor was decreased to 28.6%. Albertson performed a 20-year retrospective population-based cohort study using Connecticut Tumor Registry data (19). 767 men aged 55 to 74 years with clinically localized prostate cancer were followed expectantly or treated
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with hormone therapy until death. Death from prostate cancer was 45% (62/137) in Gleason 7 and 66% (53/80) for Gleason 8-10. Bahler investigated 119 men with pathologically confirmed high-grade cancers
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at the time of RP. The overall median follow-up was 73 months. Kaplan-Meier analysis showed at 10 years CSS of 82% (20).
Most agree that aggressive intervention should not be offered to prostate cancer patients if life expectancy is less than 10 years. With a median age of 66 years for our patients, while ACS was 86.8% at 10 years at 15 years there was a substantial decrease to 57%. Using a comorbidity scale such as a Charlson score may improve patient selection (21). Daskivich evaluated 3183 men with prostate cancer
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and found fourteen-year cumulative other-cause mortality rates were 24%, 33%, 46%, and 57% for men with 0, 1, 2, and 3 or more comorbid conditions, respectively (22). In contrast to the Daskivich report, elimination of the significant associations with mortality in the current study only improved ACS from
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57% to 60%. In the Cox regression model the presence of diabetes, atrial fibrillation, smoking, and emphysema at the time of diagnosis decreased all-cause survival by a factor of 1.86, 2.90, 1.42 and 8.20, respectively at 15 years. It may be reasonable to consider active surveillance in men with life
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expectancy less than 15 years if these comorbidities are present, especially in low and intermediate risk
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patients.
Recently studies have emerged that suggest neoadjuvant and adjuvant HT may decrease ACS. In the Cox regression analysis on ACS, use of HT was one of the 5 factors that negatively influenced ACS, with a HR of 1.042 (4% decrease in ACS for every month of HT administered). HT decreased ACS at 10 years from 89.8 to 84.2% and at 15 years from 60.3% to 54.9% (p=0.009). Tsai noted an increase in
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cardiovascular death in men treated by prostatectomy having a median of 4 months of HT (23). Beyer also noted a decrease in overall survival in 2,378 permanent prostate brachytherapy cases treated with HT (24). With median follow-up of 4.1 years, survival was 44% for the hormone naive patients,
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compared with 20% for the hormone cohort (p=0.02). Dosoretz noted similar findings in 2474 men with localized prostate cancer who received NHT (N = 1083) and brachytherapy (25). After a median follow-
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up of 4.8 years treatment with NHT was associated with an increased risk of all-cause mortality (HR 1.24, p=0.04). In our patient population, long term (> 6 months) HT remained significantly associated with poorer ACS in both younger and older men (p= 0.017). While the advantages of HT combined with radiation therapy (EBRT or brachytherapy) for high risk when an adequate dose of radiation is given still remain to be defined, it is clear for the current study that the use of HT for more than 6 months has significant negative consequences (26).
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Bolla et al. randomized 415 men to 70 Gy of EBRT vs EBRT plus 3 years of HT. At 5 years the combination group had an overall survival of 79% vs 62% (p=0.001) (27). The Bolla data differs from the current study because of its short follow-up and relative low dose of radiation (BED 198 Gy2
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compared to 133 Gy2). D’Amico compared 206 men with unfavorable-risk prostate cancer who received EBRT alone or EBRT and HT combined for 6 months (28). With a median follow-up of 7.6 years a significant increase in all-cause mortality was observed in men randomized to RT. However,
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this increase appeared to apply only to men with no or minimal comorbidity. Those receiving
hormone therapy for longer than 6 months in our study were found to have a decreased ACS,
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something not discernable from the limited time on HT in D’Amico’s investigation. Any advantage to long-term HT may be clarified once the randomized TRIP study comparing 6 months of HT to 6 months plus 2 years in men with high risk prostate cancer receiving a combination of brachytherapy plus EBRT
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(29).
Conclusions
Prostate irradiation delivered by brachytherapy results in favorable cause specific survival for all risk
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groups. When combined with EBRT it may be superior to EBRT alone (even with HT) in high risk patients.
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Comorbidities including diabetes, smoking and atrial fibrillation, which have a negative impact on all cause survival, may influence the decision to actively intervene in low and intermediate risk disease. Hormonal therapy, when given for longer than 6 months in the neoadjuvant/adjuvant setting also impacts ACS and warrants further investigation for any benefit in high risk patients.
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(RTOG) trial 86-10 of androgen deprivation adjuvant to definitive radiotherapy in locally advanced carcinoma of the prostate. Int J Radiation Oncology Biol Phys 2001; 50: 1243. 2. Bolla M, Collette L, Blank L et al: Long-term results with immediate androgen
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suppression and external irradiation in patients with locally advanced prostate cancer (an EORTC study): a phase III randomised trial. Lancet 2002; 360: 103.
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3. D’Amico AV, Manola J, Loffredo M et al: 6-Month androgen suppression plus radiotherapy versus radiotherapy alone for patients with clinically localized prostate cancer. JAMA 2004; 292: 821.
4. Oefelein MG: Androgen Suppression Therapy and Prostate Cancer: Balancing the Harms and the Benefits: Cancer 2008; 113: 3275.
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5. Stone NN and Stock RG: The effect of brachytherapy, external beam irradiation and hormonal therapy on prostate volume. J Urol 2007; 177: 925. 6. Stone NN, Potters L, Davis BJ et al: Multicenter Analysis of Effect of High Biologic
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24. Beyer DC, McKeough T and Thomas T: Impact of short course hormonal therapy on overall and cancer-specific survival after permanent prostate brachytherapy. Int J Radiation Oncology Biol Phys. 2005; 61: 1299.
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25. Dosoretz AM, Chen MH, Salenius SA et al: Mortality in men with localized prostate cancer treated with brachytherapy with or without neoadjuvant hormone therapy. Cancer 2010; 116: 837.
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substitute for radiation dose in the treatment of high-risk prostate cancer? Int J Radiation
27. Bolla M, Gonzalez D, Warde P, et al: Improved survival in patients with locally advanced prostate cancer treated with radiotherapy and goserelin. N Engl J Med. 1997; 337: 295.
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28. D'Amico AV , Chen MH, Renshaw AA, et al: Androgen suppression and radiation vs radiation alone for prostate cancer: a randomized trial. JAMA. 2008; 299: 289. 29. Konaka H, Egawa S, Saito S et al: Tri-Modality therapy with I-125 brachytherapy,
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Figure Legends: Figure 1: Cause-specific survival at 10 and 15 years.
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Figure 2: 10 and 15 year all cause survival with hormone therapy use < 6 months vs. > 6 months.
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Median time of HT was 6 months.
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Percent
1239 313 117
74.2 18.8 7
1133 497 39
67.9 29.8 2.3
1128 369 172
67.6 22.1 10.3
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683 417 88 481 898
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757 644 268
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Number
45.3 38.6 16.1
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Variable PSA (ng/ml) <10 ng/ml 10-19.9 > 20 Stage T1c-T2a T2b-c T3 Gleason score <6 7 8-10 NCCN Risk Group 1 2 3 Treatment type Implant alone Implant plus HT Implant plus EBRT Implant plus HT/EBRT Hormone therapy
40.9 24.9 5.3 28.9 53.8
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Table 1: Characteristics of 1669 followed a minimum of 5 years following prostate brachytherapy.
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15 Year Rate (%)
P value
99.3 96.2 92.7
95.8 91.4 81.5
<0.001
99.3 96.7 92.8
96.4 90.1 72
99.5 97.5 80
95.7 97.5 66.7
99.8 97 92.5
96.3 97 85.2
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Table 2: Cause specific survival by treatment characteristics
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10 Year Rate (%)
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<0.001
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Variable PSA (ng/ml) PSA < 10 PSA 10-19.9 PSA > 20 Gleason score <6 7 8-10 Clinical stage T1c-T2a T2b-c T3 NCCN Risk Group 1 2 3
<0.001
<0.001
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Number dead (%) 5/37 (13.5) 8/37 (21.6) 24/37 (64.9) 13/37 (35.15) 11/37 (29.7) 13/37 (35.15)
Number dead of group (%) 5/757 (0.66) 8/644 (1.24%) 24/268 (8.96) 13/1128 (1.15) 11/369 (2.98) 13/172 (7.56)
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Variable NCCN 1 NCCN 2 NCCN 3 Gleason score < 6 Gleason score 7 Gleason score 8-10
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Table 3: Number of patients dying from prostate cancer as percent of prostate cancer deaths by NCCN and Gleason score grouping (first column) and as a percent of total patients in group (second column).
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N
Events Censored (%)
ACS (%)
P value
MV p value HR
95%CI
861 808
69 179
92.0 77.8
75.1 42.2
<0.001
<0.001
1.070-1.116
1365 187 96 21
199 31 17 1
85.4 83.4 82.3 95.2
56.2 60.4 53.2 75.0
0.720
0.906
1239 150 313 56 117 42
87.9 82.1 64.1
58.0 60.3 41.8
0.003
0.331
1128 147 369 64 172 37
87 82.7 78.5
60.8 46.5 43.1
<0.001
1133 127 497 112 39 9
88.8 77.5 76.9
62.5 49.7 25.8
153 696 778
59 93 83
61.4 82.7 89.3
47.4 65.3 51.9
754 545 370
103 78 67
86.3 85.7 81.9
1077 169 592 78
84.3 86.7
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1.093
0.809-1.270
0.995
0.985-1.005
0.709
0.978
0.872-1.097
<0.001
0.217
1.085
0.953-1.235
0.069
0.279
0.998
0.995-1.002
60.3 53.0 51.3
<0.001
0.032
1.042
1.004-1.081
52.8 59.0
0.061
0.030
1.416
1.034-1.942
85.3 82.6
57.7 43.4
0.016
0.013
1.862
1.138-3.039
1589 235 80 10
85.0 87.5
57.2 38.2
0.558
0.527
1.233
0.644-2.363
1016 176 653 72
82.7 89
58.0 53.3
0.303
0.847
0.969
0.705-1.332
1616 242 53 6
85 88.7
57.0 66.3
0.577
0.573
0.789
0.346-2.936
1649 244
85.2
57.2
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1560 229 109 19
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1.014
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Variable Age < 65 >65 Race White Black Hispanic Asian PSA (ng/ml) <10 >10-20 >20 Gleason <6 7 8-10 Stage < T2a T2b-T2c > T3a BED (Gy2) < 150 >150-200 >200 HT (months) 0 1-6 >6 Smoker No Yes Diabetes No Yes CAD No Yes Alcohol Use No Yes Asthma Yes No Atrial Fib No
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80
35.3
0.008
0.041
2.90
1.047-8.0
1627 243 42 5
85.1 88.1
57.2 35.2
0.297
0.897
1.069
0.389-2.936
1616 239 53 9
85.2 83
57.1 65.3
0.030
0.129
0.588
0.296-1.168
1261 199 408 49
84.2 88
57.1 58.6
0.230
0.814
1.041
1.004-1.081
1658 247 11 1
85.1 90.9
56.8 80
0.80
0.612
1.668
0.232-12.01
1665 247 4 1
85.2 75
57 50
0.085
0.040
8.197
1.095-62.5
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4
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20
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Yes Cancer No Yes HD No Yes HBP No Yes Stroke No Yes Emphysema No Yes
Table 4: 15-year all cause survival (ACS) by clinical and co-morbidity variables. Mutivariate (MV) p value determined by Cox regression of all listed variables. In the Cox model Age, PSA, BED and time on hormone therapy were continuous variables. CAD-coronary heart disease, HD-heart disease, HBP-
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hypertension, HT-hormone therapy, BED-biologic effective dose.
94.1%
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98.1%
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Remaining patients: 1669
600
100
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CSS
cause-specific survival
ACS
all-cause survival
HT
hormone therapy
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Key Definitions and Abbreviations
EBRT external beam irradiation
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NCCN national comprehensive cancer network
PII: DOI: Reference:
S0022-5347(14)03182-6 10.1016/j.juro.2014.03.094 JURO 11358
To appear in: The Journal of Urology Accepted Date: 10 March 2014 Please cite this article as: Stone NN, Stock RG, 15-Year Cause Specific and All-Cause Survival Following Brachytherapy for Prostate Cancer: Negative Impact of Long-term Hormonal Therapy, The Journal of Urology® (2014), doi: 10.1016/j.juro.2014.03.094. DISCLAIMER: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our subscribers we are providing this early version of the article. The paper will be copy edited and typeset, and proof will be reviewed before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to The Journal pertain. All press releases and the articles they feature are under strict embargo until uncorrected proof of the article becomes available online. We will provide journalists and editors with full-text copies of the articles in question prior to the embargo date so that stories can be adequately researched and written. The standard embargo time is 12:01 AM ET on that date.
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15-Year Cause Specific and All-Cause Survival Following Brachytherapy for Prostate Cancer: Negative Impact of Long-term Hormonal Therapy Running Title: 15 Year Survival After Prostate EBRT
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Text pages: 15 Tables: 4 Figures: 2 Word count 2499
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Mailing Address: Nelson N. Stone, MD 350 East 72nd Street, Apt 8A New York, NY 10021 Tel: 845 323 1727 Email: [email protected]
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Nelson N. Stone, MD* and Richard G. Stock, MD^, Departments of Urology* and Radiation Oncology^, Icahn School of Medicine at Mount Sinai, New York, New York.
Funding source: none Financial Interest: R. Stock-none. N. Stone-Prologics LLC (investor interest), Nihon MediPhysics (consultant) Presented at the 2013 AUA Annual Meeting Key Words: prostate cancer, radiation therapy, brachytherapy, hormonal therapy, survival
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Abstract Purpose: We analyzed the factors influencing 15-year cause-specific (CSS) and all-cause survival (ACS) in
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men treated by prostate brachytherapy (PB). Materials and Methods: 1669 men with T1-T3 prostate cancer with a median age of 66 years were treated with PB and followed a mean of 10 years. Treatments were implant alone, implant plus
hormone therapy (HT) or external beam irradiation (EBRT) or implant plus HT plus EBRT. HT was
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administered to 898 (53.8%) men a median of 6 months. Estimates for CSS and ACS were determined by
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Kaplan Meier method with comparisons by logistic regression and Cox proportions hazard rates. Results: 15-year CSS was 94.1%. CSS by the 3 NCCN risk groups was 96.3%, 97.5% and 85.2% (p<0.001). HT did not positively impact CSS. 15-year ACS was 57% and Cox regression demonstrated age (p<0.001, HR 1.09), HT (p=0.032, HR 1.04), diabetes (p=0.013, HR 1.86), atrial fibrillation (p=0.041, HR 2.90), smoking (p=0.030, HR 1.42) and emphysema (p=0.040, HR 8.20) as significant associations. HT
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decreased ACS at 15 years from 60.3% to 54.9% (p=0.009). ACS was not reduced if HT was limited to < 6 months (p=0.005). This difference was present in both younger (age < 66, p=0.017) and older men
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(p=0.05).
Conclusions: PB yields favorable 15-year CSS, especially in high risk patients. ACS is less in patients with
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preexisting diabetes, atrial fibrillation and emphysema. The use of HT for longer than 6 months has a negative effect on ACS even in younger patients without an apparent beneficial effect on CSS.
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Introduction Brachytherapy is a well-established method of treating localized prostate cancer. However few studies
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have documented long-term results, specifically cause-specific and all-cause survival in men who have received either implant alone or in conjunction with hormone therapy or external beam irradiation. While cancer-specific survival at 10 years has been high for low-risk prostate cancer patients, little data
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on 15-year outcomes is available, especially in men with intermediate and high risk disease.
Hormonal therapy is commonly added to a regimen of external radiation therapy. Patients with high
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risk disease are often offered 2-3 years of androgen ablation based on the positive results of several randomized clinical trials (1-2). However, controversies exist on whether longer term HT itself induces morbidity and it possibly may increase mortality (3-4). In the brachytherapy patient, neoadjuvant HT is often prescribed for downsizing a large gland (5). However, patients with high risk disease who receive combination brachytherapy plus external beam irradiation (EBRT) are treated with HT for 2-3 years in
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a similar fashion as men receiving EBRT alone. This treatment plan occurs despite the fact that there are no data that supports the use of long-term HT in patients receiving combination therapy (6).
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In order to better understand these issues we herein report the long-term mortality outcomes in a large
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cohort on prostate cancer patients managed with brachytherapy with and without HT and EBRT.
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Materials and Methods 1669 men with T1-T3 prostate cancer with a median age of 66 years (range 39-85) had permanent
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prostate brachytherapy and were followed a minimum of 5 years and mean of 10 years (range 5-19). The median PSA was 6.9 ng/ml (mean 9.7, range 0.1-300). Treatment began in 1990 and all patients treated up to 2007 were included in the analysis. Follow-up time was censored at the time of death. At the initial consultation details about smoking history (current, quite with pack years), presence of
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diabetes (AODM or type 2), coronary artery disease (CAD), alcohol use, asthma, atrial fibrillation, presence of other cancers, heart disease (any other than CAD), stroke and emphysema were collected.
approved by the institutional review board.
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Responses were prospectively entered into the patient database. The data entry and reporting were
Patients were stratified into 3 NCCN risk groups and treated with implant alone (NCCN 1-low risk), implant plus either hormone therapy (HT) or external beam irradiation (EBRT) (NCCN 2- intermediate
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risk) or implant plus HT plus EBRT (NCCN 3-high risk). There were 759 (45.5%) low, 644 (38.6%) intermediate and 268 (15.9%) high risk patients (Table 1). The median PSA was 6.9 ng/ml (mean 9.7, range 0.1-300). HT was administered to 898 (54%) for a median of 6 months (range 1-34). HT was given
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for 3-6 months as LHRHa with or without an antiandrogen in low risk patients for prostate volume > 50
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cc, for 6 months in patients with NCCN2 if no EBRT was used and for a median of 9 (interquartile range 4.3-9.0) months for NCCN3. 35 patients were treated for more than 9 months if they were found to have stage T3b by biopsy or if they were referred in off protocol. Intermediate and high risk patients had bone scintography and abdominal-pelvic CT. Patients with positive scans were excluded. Brachytherapy was performed with I-125 (160 Gy, TG-43) for NCCN1, Pd-103 (125 Gy, NIST 1999) with 6 months HT or Pd-103 (100 Gy) combined with 45 Gy EBRT (combination therapy) for NCCN2 and 9 months HT with combination therapy for NCCN3. Pd-103 was selected for NCCN2 and NCCN3 because 4
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of its radiobiologic characteristics of short half-life and lower energy (7-8). EBRT was initiated as 3D conformal technique and more recently as IMRT and IGRT. While the technology for targeting improved over time the dose remained fixed at 45 Gy (25 treatments of 1.8 Gy fractions). Within 30
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days post-implant CT based dosimetry was used to calculate the biological effective dose (BED) as previously described (9). BED ranged from 15-282 Gy2 with a median of 198 Gy2 (α/β=2).
Patients were followed every 6 months and were considered biochemical failures if the PSA increased by
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2 ng/ml above a nadir (Phoenix definition). Prostate cancer was selected as the cause of death if the patient had evidence of clinical recurrence. All other causes of death, including men dying with a PSA
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only recurrence were considered to have died from other causes. Statistical analysis was performed using SPSS software (Version 20, Armonk, NY). Neoadjuvant HT use was dichotomized to < 6 months (n=528) and > 6 months (n=370). Chi-square analysis was performed to assess for significant differences between groups and binomial logistic regression models were developed to identify risk factors for
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biochemical freedom from failure, cause specific (CSS) and all cause survival (ACS). Time to death was estimated using the Kaplan-Meier method. Covariates that were significantly associated with CSS and ACS were entered into the Cox proportional hazards model. All statistical tests were two-sided and P
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values less than 0.05 were considered statistically significant.
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Results The 10 and 15 year freedom from biochemical relapse were 89.3% and 67%, respectively. The 10 and
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15-year cause specific survival rates were 98.1% and 94.1% (Figure 1). NCCN risk group, PSA, Gleason score and clinical stage were all predictive of 10 and 15 year CSS (Table 2). Cox regression revealed higher clinical stage (p=0.017, HR 1.53, 95%CI 1.08-2.17) and Gleason grade (p=0.001, HR 1.74, 95%CI 1.27-2.37) to impact negatively on CSS, while the use of neoadjuvant HT and high BED did improve
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CSS. At the time of this analysis 37 (2.2%) men had died of prostate cancer. The number of men dying
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from prostate cancer by Gleason score and NCCN risk category is shown in table 3. All cause survival was 86.8% at 10 years and 57% at 15 years. 238/1669 (14.3%) men had died at the time of this analysis (37 prostate cancer, 201 other causes). On univariate analysis older age, higher PSA, Gleason score and stage, use of HT, and presence of diabetes and heart disease were associated with a decreased 15 year survival. However on Cox regression age, hormone therapy, smoking history,
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diabetes, atrial fibrillation and emphysema were significant covariates (Table 4). An analysis by NCCN category revealed increased time on HT decreased ACS in the NCCN 3 group (p<0.001, HR 1.175, 95% CI 1.086-1.271). HT decreased ACS at 10 years from 89.8 to 84.2% and at 15 years from 60.3% to 54.9%
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(p=0.009). Time on NHT adversely affected ACS dichotomized to < 6 months (n=528) to more than 6
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months (n=370, p=0.005) (Figure 2). This difference persisted in younger (age < 66, p=0.017) and older men (p=0.05). When prostate cancer death was removed for ACS (n=201) these differences remained significant. The 10 year ACS for men treated with 0-6 months of HT vs those treated with > 6 months was 90.9 vs 82.6% and the 15 years was 60.8 vs 56.9% (p=0.004). Exclusion of the significant health risk factors improved all cause survival estimates at 15 years to 60% from 57%. However, the addition of HT still had a negative influence on ACS (p=0.008).
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Discussion Prostate brachytherapy is an established technique for treating localized disease. There are few studies
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that document the long-term prostate cancer specific mortality results. We report favorable 10 and 15 year CSS as 98.1% and 94.1%, respectively. Sylvester et al. reported the 15 year CSS in 215 patients treated with I-125 as 84% (10). Their patient population consisted of only 5.1% men with high risk disease compared to 16.1% in the present study and had a shorter minimum follow-up (3.6 vs 5 years).
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Our study compares favorably to centers reporting CSS for patients treated by radical prostatectomy (RP). Han reported 15-year CSS (mean follow-up 6.3 years) for RP at Johns Hopkins from 1982 to 1990
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as 90% (11). Mullins updated these results in 4,478 men and with a median follow-up of 10 years, the 15 years CSS was 94% (12). Shikanov identified 120,392 men who underwent RP between 1988 and 2003 from the Surveillance, Epidemiology and End Results (SEER) database (13). The 15-year CSS was 95%. Thus it appears that prostate brachytherapy can yield similar 15 year cancer specific survival as
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radical prostatectomy.
Several reports have compared the outcomes of prostatectomy to EBRT and brachytherapy. Hoffman analyzed men aged 55 to 74 years diagnosed with localized PC who underwent either RP (n = 1164) or
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EBRT (n = 491) (14). 45 (3.9%) of the RP and 59 (12%) of the EBRT patients had died from the disease.
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The RP data compare favorably with the current study where 37/1669 (2.2%) have died from prostate cancer. Our data are consistent with Nepple who reported CSS in men treated by RP (n=4459), EBRT (n=1261), or brachytherapy (n=972) (15). At 10 years, EBRT was associated with an increase in prostate cancer mortality compared with RP (HR: 1.66; 95% CI 1.05–2.63); while brachytherapy was not. A possible explanation for these differences comes from the study of Jacob et al (16). In the multivariate Cox model higher radiations doses were associated with both a decrease in metastases and an increase in overall survival. The biologic effective dose (BED) in our brachytherapy patients is considerably higher
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than the radiation dose given to men receiving EBRT, especially when brachytherapy is combined with EBRT in high risk disease (6,9).
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When stratified by NCCN risk group survival rates for the low and intermediate risk patients remain very high (96-99%), with little to no reduction from 10 to 15 years. However, there was a 7% decrease (from 92.5 to 85.2%) over the same period for the high risk group. Shen identified 12,745 patients treated with EBRT (73.5%), brachytherapy (7.1%), or brachytherapy plus EBRT from the SEER database with T1-
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T3N0M0 prostate cancer (17). On multivariate analysis brachytherapy alone was associated with a 33% reduction of prostate cancer death and brachytherapy plus EBRT a 23% compared to EBRT. Johansson
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analyzed 223 patients with early-stage disease, initially untreated prostatic cancer (18). Most cancers had an indolent course during the first 10 to 15 years. However, further follow-up from 15 to 20 years revealed a substantial decrease in cumulative progression-free survival (from 45.0% to 36.0%), survival without metastases (from 76.9% to 51.2%), and prostate cancer– specific survival (from 78.7% to
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54.4%). Fifteen year CSS survival for the high grade tumor was decreased to 28.6%. Albertson performed a 20-year retrospective population-based cohort study using Connecticut Tumor Registry data (19). 767 men aged 55 to 74 years with clinically localized prostate cancer were followed expectantly or treated
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with hormone therapy until death. Death from prostate cancer was 45% (62/137) in Gleason 7 and 66% (53/80) for Gleason 8-10. Bahler investigated 119 men with pathologically confirmed high-grade cancers
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at the time of RP. The overall median follow-up was 73 months. Kaplan-Meier analysis showed at 10 years CSS of 82% (20).
Most agree that aggressive intervention should not be offered to prostate cancer patients if life expectancy is less than 10 years. With a median age of 66 years for our patients, while ACS was 86.8% at 10 years at 15 years there was a substantial decrease to 57%. Using a comorbidity scale such as a Charlson score may improve patient selection (21). Daskivich evaluated 3183 men with prostate cancer
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and found fourteen-year cumulative other-cause mortality rates were 24%, 33%, 46%, and 57% for men with 0, 1, 2, and 3 or more comorbid conditions, respectively (22). In contrast to the Daskivich report, elimination of the significant associations with mortality in the current study only improved ACS from
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57% to 60%. In the Cox regression model the presence of diabetes, atrial fibrillation, smoking, and emphysema at the time of diagnosis decreased all-cause survival by a factor of 1.86, 2.90, 1.42 and 8.20, respectively at 15 years. It may be reasonable to consider active surveillance in men with life
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expectancy less than 15 years if these comorbidities are present, especially in low and intermediate risk
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patients.
Recently studies have emerged that suggest neoadjuvant and adjuvant HT may decrease ACS. In the Cox regression analysis on ACS, use of HT was one of the 5 factors that negatively influenced ACS, with a HR of 1.042 (4% decrease in ACS for every month of HT administered). HT decreased ACS at 10 years from 89.8 to 84.2% and at 15 years from 60.3% to 54.9% (p=0.009). Tsai noted an increase in
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cardiovascular death in men treated by prostatectomy having a median of 4 months of HT (23). Beyer also noted a decrease in overall survival in 2,378 permanent prostate brachytherapy cases treated with HT (24). With median follow-up of 4.1 years, survival was 44% for the hormone naive patients,
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compared with 20% for the hormone cohort (p=0.02). Dosoretz noted similar findings in 2474 men with localized prostate cancer who received NHT (N = 1083) and brachytherapy (25). After a median follow-
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up of 4.8 years treatment with NHT was associated with an increased risk of all-cause mortality (HR 1.24, p=0.04). In our patient population, long term (> 6 months) HT remained significantly associated with poorer ACS in both younger and older men (p= 0.017). While the advantages of HT combined with radiation therapy (EBRT or brachytherapy) for high risk when an adequate dose of radiation is given still remain to be defined, it is clear for the current study that the use of HT for more than 6 months has significant negative consequences (26).
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Bolla et al. randomized 415 men to 70 Gy of EBRT vs EBRT plus 3 years of HT. At 5 years the combination group had an overall survival of 79% vs 62% (p=0.001) (27). The Bolla data differs from the current study because of its short follow-up and relative low dose of radiation (BED 198 Gy2
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compared to 133 Gy2). D’Amico compared 206 men with unfavorable-risk prostate cancer who received EBRT alone or EBRT and HT combined for 6 months (28). With a median follow-up of 7.6 years a significant increase in all-cause mortality was observed in men randomized to RT. However,
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this increase appeared to apply only to men with no or minimal comorbidity. Those receiving
hormone therapy for longer than 6 months in our study were found to have a decreased ACS,
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something not discernable from the limited time on HT in D’Amico’s investigation. Any advantage to long-term HT may be clarified once the randomized TRIP study comparing 6 months of HT to 6 months plus 2 years in men with high risk prostate cancer receiving a combination of brachytherapy plus EBRT
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(29).
Conclusions
Prostate irradiation delivered by brachytherapy results in favorable cause specific survival for all risk
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groups. When combined with EBRT it may be superior to EBRT alone (even with HT) in high risk patients.
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Comorbidities including diabetes, smoking and atrial fibrillation, which have a negative impact on all cause survival, may influence the decision to actively intervene in low and intermediate risk disease. Hormonal therapy, when given for longer than 6 months in the neoadjuvant/adjuvant setting also impacts ACS and warrants further investigation for any benefit in high risk patients.
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(RTOG) trial 86-10 of androgen deprivation adjuvant to definitive radiotherapy in locally advanced carcinoma of the prostate. Int J Radiation Oncology Biol Phys 2001; 50: 1243. 2. Bolla M, Collette L, Blank L et al: Long-term results with immediate androgen
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suppression and external irradiation in patients with locally advanced prostate cancer (an EORTC study): a phase III randomised trial. Lancet 2002; 360: 103.
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3. D’Amico AV, Manola J, Loffredo M et al: 6-Month androgen suppression plus radiotherapy versus radiotherapy alone for patients with clinically localized prostate cancer. JAMA 2004; 292: 821.
4. Oefelein MG: Androgen Suppression Therapy and Prostate Cancer: Balancing the Harms and the Benefits: Cancer 2008; 113: 3275.
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5. Stone NN and Stock RG: The effect of brachytherapy, external beam irradiation and hormonal therapy on prostate volume. J Urol 2007; 177: 925. 6. Stone NN, Potters L, Davis BJ et al: Multicenter Analysis of Effect of High Biologic
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Effective Dose on Biochemical Failure and Survival Outcomes in Patients with Gleason
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9. Stock RG, Stone NN, Cesaretti J et al: Biologically effective dose values for prostate brachytherapy: effects on PSA failure and posttreatment biopsies. Int J Radiation Oncology Biol Phys 2006; 64: 527.
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16. Jacob R, Hanlon AL, Horwitz EM et al: The Relationship of Increasing Radiotherapy Dose to Reduced Distant Metastases and Mortality in Men with Prostate Cancer. Cancer 2004; 100: 538.
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17. Shen X, Keith SW, Mishra MV et al: The Impact of Brachytherapy on Prostate
CancereSpecific Mortality for Definitive Radiation Therapy of High-Grade Prostate Cancer: A Population-Based Analysis. Int J Radiation Oncology Biol Phys 2102; 83:
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18. Johansson JE, Andre O, Andersson SO et al: Natural History of Early, Localized Prostate
19. Albertsen PC, Hanley JA and Fine J: 20-Year Outcomes Following Conservative Management of Clinically Localized Prostate Cancer. JAMA 2005; 293: 2095. 20. Bahler CD, Foster RS, Bihrle R et al: Radical prostatectomy as initial monotherapy for
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patients with pathologically confirmed high-grade prostate cancer. B J U Inte 2009; 105: 1372.
21. Charlson ME, Pompei P, Ales KL et al: A new method of classifying prognostic
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22. Daskivich TJ, Fan KH, Koyama T et al: Effect of Age, Tumor Risk, and Comorbidity on Competing Risks for Survival in a U.S. Population–Based Cohort of Men With Prostate Cancer. Ann Intern Med 2013; 158: 709. 23. Tsai HK , D’Amico AV, Sadetsky N et al: Androgen Deprivation Therapy for Localized Prostate Cancer and the Risk of Cardiovascular Mortality. J Natl Cancer Inst 2007; 99: 1516.
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24. Beyer DC, McKeough T and Thomas T: Impact of short course hormonal therapy on overall and cancer-specific survival after permanent prostate brachytherapy. Int J Radiation Oncology Biol Phys. 2005; 61: 1299.
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25. Dosoretz AM, Chen MH, Salenius SA et al: Mortality in men with localized prostate cancer treated with brachytherapy with or without neoadjuvant hormone therapy. Cancer 2010; 116: 837.
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26. Nguyen KH, Horwitz EM, Hanlon AL et al: Does short-term androgen deprivation
Oncology Biol Phys 2003; 57: 377.
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substitute for radiation dose in the treatment of high-risk prostate cancer? Int J Radiation
27. Bolla M, Gonzalez D, Warde P, et al: Improved survival in patients with locally advanced prostate cancer treated with radiotherapy and goserelin. N Engl J Med. 1997; 337: 295.
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28. D'Amico AV , Chen MH, Renshaw AA, et al: Androgen suppression and radiation vs radiation alone for prostate cancer: a randomized trial. JAMA. 2008; 299: 289. 29. Konaka H, Egawa S, Saito S et al: Tri-Modality therapy with I-125 brachytherapy,
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external beam radiation therapy, and short- or long-term hormone therapy for high-risk localized prostate cancer (TRIP): study protocol for a phase III,
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Figure Legends: Figure 1: Cause-specific survival at 10 and 15 years.
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Figure 2: 10 and 15 year all cause survival with hormone therapy use < 6 months vs. > 6 months.
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Median time of HT was 6 months.
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Percent
1239 313 117
74.2 18.8 7
1133 497 39
67.9 29.8 2.3
1128 369 172
67.6 22.1 10.3
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683 417 88 481 898
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757 644 268
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Number
45.3 38.6 16.1
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Variable PSA (ng/ml) <10 ng/ml 10-19.9 > 20 Stage T1c-T2a T2b-c T3 Gleason score <6 7 8-10 NCCN Risk Group 1 2 3 Treatment type Implant alone Implant plus HT Implant plus EBRT Implant plus HT/EBRT Hormone therapy
40.9 24.9 5.3 28.9 53.8
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Table 1: Characteristics of 1669 followed a minimum of 5 years following prostate brachytherapy.
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15 Year Rate (%)
P value
99.3 96.2 92.7
95.8 91.4 81.5
<0.001
99.3 96.7 92.8
96.4 90.1 72
99.5 97.5 80
95.7 97.5 66.7
99.8 97 92.5
96.3 97 85.2
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Table 2: Cause specific survival by treatment characteristics
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10 Year Rate (%)
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<0.001
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Variable PSA (ng/ml) PSA < 10 PSA 10-19.9 PSA > 20 Gleason score <6 7 8-10 Clinical stage T1c-T2a T2b-c T3 NCCN Risk Group 1 2 3
<0.001
<0.001
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Number dead (%) 5/37 (13.5) 8/37 (21.6) 24/37 (64.9) 13/37 (35.15) 11/37 (29.7) 13/37 (35.15)
Number dead of group (%) 5/757 (0.66) 8/644 (1.24%) 24/268 (8.96) 13/1128 (1.15) 11/369 (2.98) 13/172 (7.56)
RI PT
Variable NCCN 1 NCCN 2 NCCN 3 Gleason score < 6 Gleason score 7 Gleason score 8-10
AC C
EP
TE D
M AN U
SC
Table 3: Number of patients dying from prostate cancer as percent of prostate cancer deaths by NCCN and Gleason score grouping (first column) and as a percent of total patients in group (second column).
ACCEPTED MANUSCRIPT
N
Events Censored (%)
ACS (%)
P value
MV p value HR
95%CI
861 808
69 179
92.0 77.8
75.1 42.2
<0.001
<0.001
1.070-1.116
1365 187 96 21
199 31 17 1
85.4 83.4 82.3 95.2
56.2 60.4 53.2 75.0
0.720
0.906
1239 150 313 56 117 42
87.9 82.1 64.1
58.0 60.3 41.8
0.003
0.331
1128 147 369 64 172 37
87 82.7 78.5
60.8 46.5 43.1
<0.001
1133 127 497 112 39 9
88.8 77.5 76.9
62.5 49.7 25.8
153 696 778
59 93 83
61.4 82.7 89.3
47.4 65.3 51.9
754 545 370
103 78 67
86.3 85.7 81.9
1077 169 592 78
84.3 86.7
RI PT
1.093
0.809-1.270
0.995
0.985-1.005
0.709
0.978
0.872-1.097
<0.001
0.217
1.085
0.953-1.235
0.069
0.279
0.998
0.995-1.002
60.3 53.0 51.3
<0.001
0.032
1.042
1.004-1.081
52.8 59.0
0.061
0.030
1.416
1.034-1.942
85.3 82.6
57.7 43.4
0.016
0.013
1.862
1.138-3.039
1589 235 80 10
85.0 87.5
57.2 38.2
0.558
0.527
1.233
0.644-2.363
1016 176 653 72
82.7 89
58.0 53.3
0.303
0.847
0.969
0.705-1.332
1616 242 53 6
85 88.7
57.0 66.3
0.577
0.573
0.789
0.346-2.936
1649 244
85.2
57.2
M AN U
TE D
EP
1560 229 109 19
SC
1.014
AC C
Variable Age < 65 >65 Race White Black Hispanic Asian PSA (ng/ml) <10 >10-20 >20 Gleason <6 7 8-10 Stage < T2a T2b-T2c > T3a BED (Gy2) < 150 >150-200 >200 HT (months) 0 1-6 >6 Smoker No Yes Diabetes No Yes CAD No Yes Alcohol Use No Yes Asthma Yes No Atrial Fib No
ACCEPTED MANUSCRIPT
80
35.3
0.008
0.041
2.90
1.047-8.0
1627 243 42 5
85.1 88.1
57.2 35.2
0.297
0.897
1.069
0.389-2.936
1616 239 53 9
85.2 83
57.1 65.3
0.030
0.129
0.588
0.296-1.168
1261 199 408 49
84.2 88
57.1 58.6
0.230
0.814
1.041
1.004-1.081
1658 247 11 1
85.1 90.9
56.8 80
0.80
0.612
1.668
0.232-12.01
1665 247 4 1
85.2 75
57 50
0.085
0.040
8.197
1.095-62.5
RI PT
4
SC
20
M AN U
Yes Cancer No Yes HD No Yes HBP No Yes Stroke No Yes Emphysema No Yes
Table 4: 15-year all cause survival (ACS) by clinical and co-morbidity variables. Mutivariate (MV) p value determined by Cox regression of all listed variables. In the Cox model Age, PSA, BED and time on hormone therapy were continuous variables. CAD-coronary heart disease, HD-heart disease, HBP-
AC C
EP
TE D
hypertension, HT-hormone therapy, BED-biologic effective dose.
94.1%
EP
TE D
M AN U
SC
98.1%
RI PT
ACCEPTED MANUSCRIPT
AC C
Remaining patients: 1669
600
100
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
ACCEPTED MANUSCRIPT
CSS
cause-specific survival
ACS
all-cause survival
HT
hormone therapy
RI PT
Key Definitions and Abbreviations
EBRT external beam irradiation
AC C
EP
TE D
M AN U
SC
NCCN national comprehensive cancer network