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Duration of Androgen Deprivation Therapy Influences Outcomes for Patients Receiving Radiation Therapy Following Radical Prostatectomy
EURURO-6211; No. of Pages 8 EUROPEAN UROLOGY XXX (2015) XXX–XXX
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Platinum Priority – Prostate Cancer Editorial by XXX on pp. x–y of this issue
Duration of Androgen Deprivation Therapy Influences Outcomes for Patients Receiving Radiation Therapy Following Radical Prostatectomy William C. Jackson a, Matthew J. Schipper a, Skyler B. Johnson a, Corey Foster a, Darren Li a, Howard M. Sandler b, Ganesh S. Palapattu c, Daniel A. Hamstra a, Felix Y. Feng a,* a
Department of Radiation Oncology, University of Michigan Medical Center, Ann Arbor, MI, USA;
b
Department of Radiation Oncology, Cedars-Sinai,
Los Angeles, CA, USA; c Department of Urology, University of Michigan Medical Center, Ann Arbor, MI, USA
Article info
Abstract
Article history: Accepted May 5, 2015
Background: Limited data exist to guide the use of androgen deprivation therapy (ADT) for men treated with radiation therapy (RT) after radical prostatectomy (RP). The optimal duration of ADT in this setting is unknown. Objective: To determine if the duration of ADT influences clinical outcomes for men receiving post-RP RT. Design, setting, and participants: A total of 680 men who received adjuvant radiation therapy (n = 105) or salvage radiation therapy (n = 575) between 1986 and 2010 at a single tertiary care institution were reviewed retrospectively. Median follow-up post-RT was 57.8 mo. Intervention: RT was delivered using three-dimensional conformal or intensitymodulated RT in 1.8-Gy fractions. For patients treated with ADT, >80% were treated with a gonadotropin-releasing hormone agonist with or without a nonsteroidal antiandrogen. Outcome measurements and statistical analysis: Biochemical failure (BF), distant metastasis (DM), prostate cancer–specific mortality (PCSM), and overall mortality were assessed using Kaplan-Meier analysis and propensity score analysis. Results and limitations: Overall, 144 patients (21%) received ADT with post-RP RT, most of whom had high-risk disease features such as Gleason score 8–10, seminal vesicle invasion, or pre-RT prostate-specific antigen >1 ng/ml. Median ADT duration was 12 mo (interquartile range: 6.0–23.7). Patients who received <12 mo of ADT had an association with increased BF (hazard ratio [HR]: 2.27; p = 0.003) and DM (HR: 2.48; p = 0.03) compared with patients receiving 12 mo of ADT. The 5-yr rates of DM were 6.0% and 23% for 12 and <12 mo of ADT, respectively. On propensity score analysis controlling for pretreatment and treatment-related factors, each month of ADT was associated with a decreased risk for BF (HR: 0.95; p = 0.0004), DM (HR: 0.88; p = 0.0004), and PCSM (HR: 0.90; p = 0.037). These findings are limited by the retrospective nature of our analysis. Conclusions: For men with high-risk disease features receiving ADT with post-RP RT, the duration of ADT is associated with clinical outcomes. Our findings suggest that for these men an extended course of ADT 12 mo may be preferable. Validation of our findings is needed. Patient summary: We evaluated outcomes for men with high-risk disease features treated with androgen deprivation therapy (ADT) and radiotherapy after radical prostatectomy. Longer durations of ADT resulted in improved patient outcomes. # 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved.
Associate Editor: Matthew Cooperberg Keywords: Prostate cancer Androgen deprivation therapy Postprostatectomy radiotherapy
* Corresponding author. Department of Radiation Oncology, University of Michigan Medical Center, 1500 E. Medical Center Drive, Ann Arbor, MI 48109, USA. Tel. +1 734 936 4302. E-mail address: [email protected] (F.Y. Feng). http://dx.doi.org/10.1016/j.eururo.2015.05.009 0302-2838/# 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Jackson WC, et al. Duration of Androgen Deprivation Therapy Influences Outcomes for Patients Receiving Radiation Therapy Following Radical Prostatectomy. Eur Urol (2015), http://dx.doi.org/10.1016/j.eururo.2015.05.009
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1.
Introduction
receiving 64.0–70.2 Gy. Whole pelvis radiation therapy (WPRT) fields were treated in 17% of patients, typically in 1.8 Gy fractions to 45 Gy. For
The addition of androgen deprivation therapy (ADT) to external-beam radiation therapy (EBRT) as definitive treatment for high-risk localized prostate cancer (PCa) has been demonstrated to improve patient outcomes in multiple randomized controlled trials [1–8]. An advantage in overall survival (OS) has been associated with both the use of short-term ADT (4–6 mo) [3,6,8] and long-term ADT (2–3 yr) [2] for men treated with definitive radiation therapy (RT). Both Radiation Therapy Oncology Group (RTOG) 9202 and European Organization for Research and Treatment of Cancer (EORTC) 22961 compared short-term ADT with long-term ADT and found improved outcomes among those randomized to long-term ADT [1,5]. Despite a significant amount of evidence suggesting that the addition of ADT to EBRT for the definitive treatment of localized PCa improves patient outcomes, little is known regarding the use of ADT for patients receiving RT after radical prostatectomy (RP). Several retrospective analyses identified an association between the use of ADT with post-RP RT and decreased rates of biochemical recurrence [9–14]. Early results from RTOG 9601, which randomized salvage RT patients to RT with or without the addition of 2 yr of ADT, found improved freedom from prostate-specific antigen (PSA) progression and a reduction in the development of metastases in those treated with the addition of ADT [15]. Although limited evidence suggests that there is indeed a role for the addition of ADT to RT for patients receiving RT post-RP, there are no data to guide the duration of ADT use in this setting. The ongoing Radiotherapy and Androgen Deprivation in Combination After Local Surgery (RADICALS) trial will hopefully shed light on this issue [16]; however, preliminary results are not expected in the near future because the trial plans to continue recruiting until at least mid-2016. Given the lack of knowledge concerning the optimal duration of ADT when added to post-RP RT, we sought to assess retrospectively whether the duration of ADT in this setting had an impact on biochemical failure (BF), distant metastasis (DM), prostate cancer–specific mortality (PCSM), and overall mortality (OM) in a cohort of patients who were treated with RT and ADT after RP. 2.
Patients and methods
those patients treated with ADT, >80% were treated with a gonadotropinreleasing hormone (GnRH) agonist with or without the addition of a nonsteroidal antiandrogen. The remaining patients were treated with a nonsteroidal antiandrogen with or without a 5a-reductase inhibitor.
2.3.
End points
Primary outcomes measured included BF, DM, PCSM, and OM. The time to all end points was determined from the start date of RT. ADT duration was calculated from the day of initiation of ADT to the last day of ADT effectiveness (i.e., a 3-mo injection of a GnRH agonist contributed 3 mo). Serum testosterone values were not routinely evaluated. BF was defined as a serum PSA value of at least 0.2 ng/ml greater than the post-SRT nadir followed by a second higher serum PSA value [17] or any PSA value of at least 0.5 ng/ml greater than the post-SRT nadir [18,17]. DM was defined as the presence of any clinical, pathologic, or radiologic evidence of metastasis. PCSM was defined as any death in a patient with metastatic or hormone-refractory PCa. OM was defined as any death, independent of the cause.
2.4.
Statistical analysis
Patient characteristics were compared between treatment groups using one-way analysis of variance and chi-square methods for continuous and categorical variables, respectively. Survival outcomes were summarized with Kaplan-Meier methods. A propensity score analysis was performed to assess the impact of ADT use and ADT duration on patient outcomes while accounting for the nonrandomized nature of treatment assignment in these data. Specifically, the probability of treatment assignment (propensity score) was calculated using logistic regression. The inverse of this propensity was then used to fit weighted Cox models [19]. A robust sandwich variance estimator [20] was used to estimate the covariance matrix and calculate a p value for a score test of no treatment effect. To calculate the propensity score, we used a stepwise logistic regression with outcome equal to treatment (ADT use vs no ADT use, ADT duration <12 mo vs ADT duration 12 mo). For the ADT use versus no use ADT propensity, we used a 0.2 level of significance to select variables for inclusion in the propensity score model. The identified model included Gleason score (2–6, 7, and 8–10), pre-RT PSA, and positive SMs. The same three variables were used to calculate the propensity of long-term ADT use (12 mo) even though in this case, pre-RT PSA was not significant at the 0.2 level (p = 0.7). This propensity score was then used to perform adjusted analyses of the impact of ADT duration (both as a long- vs short-term variable and as a continuous covariate) on patient outcomes. We also performed sensitivity analyses in which the propensity score was built using all covariates regardless of statistical significance. The
2.1.
Patient selection
A total of 680 patients who received either adjuvant (n = 105) or salvage RT (n = 575) post-RP at a single institution between 1986 and 2010 (with 75% treated after 1999) were reviewed retrospectively through an analysis
resulting estimates of treatment effect and statistical significance were similar and are not presented. All statistical analyses were performed using SAS v.9.3 (SAS Institute, Cary, NC, USA) and MedCalc v.12.3.0.0 (MedCalc Software, Mariakerke, Belgium).
approved by the institutional review board. Salvage radiation therapy (SRT) was defined as RT given for a persistently elevated PSA post-RP or for
3.
Results
3.1.
Patient characteristics
biochemical recurrence post-RP. All other RT was considered adjuvant radiation therapy (ART). Of the 680 patients treated with post-RP RT, 144 (21%) received ADT with RT and are the focus of this analysis.
2.2.
Treatment and follow-up
RT was delivered using three-dimensional conformal RT or intensitymodulated RT typically in 1.8-Gy fractions, with >95% of patients
A total of 144 patients (21%) received concurrent ADT with post-RP RT. The median follow-up post-RT was 57 mo (interquartile range [IQR]: 32.7–86.5), with median followup of 57 mo (n = 114) for living patients, and 58 mo
Please cite this article in press as: Jackson WC, et al. Duration of Androgen Deprivation Therapy Influences Outcomes for Patients Receiving Radiation Therapy Following Radical Prostatectomy. Eur Urol (2015), http://dx.doi.org/10.1016/j.eururo.2015.05.009
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Table 1 – Patient characteristics stratified by use of concurrent androgen deprivation therapy
Age, yr, median (IQR) Follow-up post-RT, mo, median (IQR) CCI, median (IQR) Range Pre-RT PSA, ng/dl, median (IQR) Range Pre-SRT PSA DT, mo, median (IQR) PSA nadir post-RT, ng/dl, median (IQR) RT dose, Gy, median (IQR) WPRT, % ADT during RT, % ART, % ADT duration, mo Median (IQR) GS, % 2–6 7 8–10 pT stage, % T1–T2a T2b–T2c T3–T4 SVI, % Positive SM, % ECE, % LNI, %
Without concurrent ADT (n = 536)
Concurrent ADT (n = 144)
64.7 (59.0–69.7) 56.7 (19.9–102.7) 3 (2–4) 0–7 0.5 (0.3–1.0) 0–18.4 8.1 (4.4–15.9) 0 (0–0.2) 68.4 (64.8–68.4) 15 0.0 13
63.9 (58.1–69.4) 57.8 (31.6) 3 (2–4) 1–8 0.9 (0.3–2.5) 0–27.1 6.9 (3.6–13.5) 0 (0–0) 68.4 (64.8–70.2) 27 100 23
0 (0–0)
p value
p = 0.7* p = 0.7* p = 0.8* p < 0.001* p = 0.1* p = 0.3* p = 0.017y p = 0.001z p < 0.0001z p = 0.007z
11.9 (6.0–23.7)
NA
22 58 20
20 45 35
p = 0.001z
9.0 22 69 18 54 56 2.9
4.0 18 78 29 63 67 16
p = 0.07z p = 0.006z p = 0.047z p = 0.022z p < 0.0001z
ADT = androgen-deprivation therapy; ANOVA = analysis of variance; ART = adjuvant radiation therapy; CCI = Charlson Comorbidity Index; ECE = extracapsular extension; GS = Gleason score; IQR = interquartile range; LNI = lymph node involvement; NA = not applicable; PSA = prostate-specific antigen; PSA DT = prostate-specific antigen doubling time; RT = radiation therapy; SM = surgical margin; SRT = salvage radiation therapy; SVI = seminal vesicle invasion; WPRT = whole pelvic radiation therapy. * ANOVA. y ANOVA; mean RT dose 66.9 Gy for those not receiving ADT versus 67.5 Gy for those treated with ADT. z Chi-square.
(n = 30) mo for deceased patients. Table 1 lists patient characteristics comparing those who did and did not receive ADT with RT. Patients receiving ADT had a higher pre-RT PSA and were more likely to have a Gleason score (GS) of 8–10, seminal vesicle invasion (SVI), positive SMs, and lymph node involvement (LNI). They were also more likely to receive ART and WPRT. Furthermore, 67% of patients treated with ADT had at least one of the high-risk features of GS 8–10, SVI, or pre-RT PSA 1 ng/ml (previously identified high-risk features associated with recurrence [21]) compared with only 48% of patients not receiving ADT (p = 0.0001), and 20% of patients treated with ADT had multiple of these high-risk features present compared with only 11% of patients who did not receive ADT (p = 0.004). Thirty-one patients (21%) received ADT and ART; 113 patients (79%) received ADT and SRT. For those receiving ART, median time from RP to RT was 5.1 mo (IQR: 3.7–6.5) compared with 26.2 mo (IQR: 10.2–52.0) for SRT. Patients treated with ART were generally more likely to have a higher GS, SVI, positive SMs, and LNI (Supplementary Table 1). For those treated with ADT, median ADT duration was 11.9 mo (IQR: 6.0–23.7). For patients treated with <12 mo of ADT, median ADT duration was 6.0 mo (IQR: 4.4–6.9), and for those treated with 12 mo of ADT, median duration was 23.7 mo (IQR: 17.9–25.4). Table 2 lists the patient
characteristics comparing those treated with <12 and 12 mo of ADT, with patients receiving 12 mo more likely to have LNI and to receive WPRT. Of patients treated with ADT, 53 experienced BF, 23 developed metastatic disease, 13 died from PCa, and 30 experienced a death from any cause. There was no significant difference in the use of short- or long-term ADT as a function of treatment year (p = 0.4). Last, patient baseline characteristics remained balanced between treatment groups after propensity score weighting (Supplementary Table 1). 3.2.
Univariate analysis
Figure 1 shows the Kaplan-Meier analysis of both ADT use and duration. Patients treated with the addition of ADT to post-RP RT were less likely to experience BF (HR: 0.74; 95% confidence interval [CI], 0.56–0.98; p = 0.04). Five-year rates of BF were 39% (95% CI, 32–51) and 52% (95% CI, 48–59) for those treated with and without the addition of ADT to post-RP RT, respectively (p = 0.01). We did not observe a difference between those treated with and without ADT with regard to DM, PCSM, or OM (Fig. 1B– 1D). The finding on univariate analysis that ADT use was not significantly associated with DM, PCSM, or OM is not unexpected given that patients treated with ADT had decidedly more aggressive disease features than patients who did not (Table 1). However, given that ADT use was
Please cite this article in press as: Jackson WC, et al. Duration of Androgen Deprivation Therapy Influences Outcomes for Patients Receiving Radiation Therapy Following Radical Prostatectomy. Eur Urol (2015), http://dx.doi.org/10.1016/j.eururo.2015.05.009
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Table 2 – Patient characteristics stratified by duration of androgen deprivation therapy
Age, yr, median (IQR) Follow-up post-RT, mo CCI median (IQR) Range Pre-RT PSA, ng/dl, median (IQR) Range Pre-SRT PSA DT, mo, median (IQR) PSA nadir post-RT, ng/dl, median (IQR) RT dose, Gy, median (IQR) WPRT, % ART, % ADT duration, mo, median (IQR) GS, % 2–6 7 8–10 pT stage, % T1–T2a T2b–T2c T3–T4 SVI, % Positive SM, % ECE, % LNI, %
12 mo ADT (n = 70)
<12 mo ADT (n = 74)
63.8 (58.2–69.5) 58.3 (32.0–86.3) 3 (2–4) 1–7 0.7 (0.3–3.2) 0–10.4 4.8 (2.5–16.2) 0 (0–0) 64.8 (64.8–70.2) 33 27 23.7 (17.9–25.4)
64.7 (58.3–69.8) 57.3 (33.9–87.7) 3 (3–4) 1–8 1.1 (0.4–2.4) 0–27.1 7.2 (4.6–13.2) 0 (0–0.1) 68.4 (64.8–70.2) 16.2 16.2 6.0 (4.4–6.9)
p value
p = 0.5* p = 0.8* p = 0.5* p = 0.9* p = 0.9* p = 0.7* p = 0.1* p = 0.033y p = 0.2y p < 0.001y
14 50 36
26 41 33
p = 0.2y
3.0 16 81 30 67 69 28
5.0 21 74 24 57 63 3.0
p = 0.6y p = 0.5y p = 0.3y p = 0.6y p = 0.017y
ADT = androgen-deprivation therapy; ART = adjuvant radiation therapy; CCI = Charlson Comorbidity Index; ECE = extracapsular extension; GS = Gleason score; IQR = interquartile range; LNI = lymph node involvement; PSA = prostate-specific antigen; PSA DT = prostate-specific antigen doubling time; RT = radiation therapy; SM = surgical margin; SVI = seminal vesicle invasion; WPRT = whole pelvic radiotherapy. * Analysis of variance. y Chi-square.
Table 3 – Results of propensity score analysis for both androgen deprivation therapy use and duration ADT use, any vs none Outcome Time Time Time Time
to to to to
BF DM PCSM OM
ADT duration, <12 mo vs 12 mo
ADT duration, continuous, mo
Estimated HR
p value
95% CI
Estimated HR
p value
95% CI
Estimated HR
p value
95% CI
0.69 0.66 0.59 1.06
0.042 0.14 0.6 0.8
0.49–0.99 0.38–1.14 0.39–1.70 0.65–1.75
0.39 0.21 0.36 0.49
0.004 0.017 0.14 0.12
0.20–0.74 0.06–0.76 0.09–1.38 0.20–1.19
0.95 0.88 0.90 0.95
0.004 0.004 0.037 0.11
0.91–0.98 0.82–0.99 0.82–0.99 0.90–1.01
ADT = androgen-deprivation therapy, BF = biochemical failure, CI = confidence interval, DM = distant metastasis, HR = hazard ratio, OM = overall mortality; PCSM = prostate cancer–specific mortality.
associated with improved rates of BF despite these patients having more aggressive disease, we continued with our primary objective to assess the impact of duration of ADT. For those treated with ADT, patients receiving <12 mo of ADT with post-RP RT were more likely to experience BF (HR: 2.27; 95% CI, 1.31–3.87; p = 0.003) and DM (HR: 2.48; 95% CI, 1.10–5.63; p = 0.03) than those receiving 12 mo (Fig. 1D–F). Five-year rates of BF for those receiving <12 mo of ADT were 48% (95% CI, 36–62) compared with 32% (95% CI, 21–53) for 12 mo (p = 0.01). Similarly, 5-yr rates of DM were increased for those treated with <12 mo of ADT compared with 12 mo (23% [95% CI, 10–36] vs 6.0% [95% CI, 0.10–12], respectively; p = 0.03). The associated benefit for BF and DM seen with ADT use 12 mo was present despite patients receiving 12 mo of ADT having more aggressive disease (Table 2). On univariate analysis a statistically significant difference was not observed with
regard to PCSM or OM for those treated with <12 and 12 mo of ADT. 3.3.
Propensity score analysis
To further assess the impact of ADT use and duration on patient outcomes, we next performed a propensity score analysis as described in the ‘‘Patients and Methods’’ section (results in Table 3). Variables considered for inclusion in the propensity score model included pre-RT PSA, GS, SVI, extracapsular extension (ECE), SMs, the use of ART versus SRT, the use of WPRT, RT dose, as well RT start date, with GS, pre-RT PSA, and positive SMs reaching statistical significance and thus included in the propensity score. In the propensity score adjusted analysis, ADT use (any vs none) was associated with decreased BF (HR: 0.69; 95% CI, 0.49–0.99; p = 0.042). As an exploratory analysis,
Please cite this article in press as: Jackson WC, et al. Duration of Androgen Deprivation Therapy Influences Outcomes for Patients Receiving Radiation Therapy Following Radical Prostatectomy. Eur Urol (2015), http://dx.doi.org/10.1016/j.eururo.2015.05.009
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A
E
Freedom from Biochemical Failure
Freedom from Biochemical Failure 100
Survival probability (%)
Survival probability (%)
100 80 60 40 HR: 0.74 (95% CI, 0.56–0.98, p < 0.05) RT and ADT RT alone
20 0
0
12
Number at risk Group: RT alone 503 Group: RT and ADT 148
24
36 48 Time, mo
60
72
256
199
151
107
81
60
125
86
66
46
37
29
19
B
12
24
36 48 Time, mo
60
72
84
36
28
20
15
20
15
48
36
24
20
24
20
84
Freedom from Metastasis
Survival probability (%)
Survival probability (%)
60 40 p = 0.8 RT and ADT RT alone
20 0
12
Number at risk Group: RT alone 509 Group: RT and ADT 145
24
36 48 Time, mo
60
72
351
307
266
221
190
155
138
116
99
79
64
51
38
60 40 HR:0.40 (95% CI, 0.18–0.91, p = 0.03) ADT duration <12 mo ADT duration >12 mo
20
12
24
36 48 Time, mo
60
72
Number at risk Group: ADT duration <12 mo 72 68 Group: ADT duration >12 mo 68 66
0
56
48
39
28
23
17
57
48
37
33
25
19
G
Prostate Cancer-specific Survival
Prostate Cancer-specific Survival 100
Survival probability (%)
100 Survival probability (%)
80
0
84
419
C 80 60 40 p = 0.9 RT and ADT RT alone
20 0
12
Number at risk Group: RT alone 496 Group: RT and ADT 139
24
36 48 Time, mo
60
72
490
476
458
438
421
367
139
138
133
131
127
123
110
80 60 40 p= 0.2 ADT duration <12 mo ADT duration >12 mo
20 0
84
494
D
12
24
36 48 Time, mo
60
72
84
Number at risk Group: ADT duration <12 mo 67 67 Group: ADT duration >12 mo 67 67
0
67
64
64
62
59
51
66
64
62
60
59
54
H
Overall Survival
Overall Survival 100
Survival probability (%)
100 Survival probability (%)
0
100
80
80 60 40 p = 0.9 RT and ADT RT alone
20 0
HR: 0.44 ( 95% CI, 0.26–0.76, p = 0.003) ADT duration <12 mo ADT duration >12 mo
20
F
Freedom from Metastasis
0
40
Number at risk Group: ADT duration <12 mo 73 61 Group: ADT duration >12 mo 70 60
100
0
60
0
84
360
80
0
Number at risk Group: RT alone 530 Group: RT and ADT 149
12
24
36 48 Time, mo
60
72
84
526
521
506
484
463
444
388
149
148
141
138
133
128
115
80 60 40 p = 0.2 ADT duration <12 mo ADT duration >12 mo
20 0
12
24
36 48 Time, mo
60
72
84
Number at risk Group: ADT duration <12 mo 74 74 Group: ADT duration >12 mo 70 70
0
74
69
68
65
62
54
69
67
65
63
61
56
Fig. 1 – Kaplan-Meier analysis of androgen deprivation therapy (ADT) use and duration. (A) Freedom from biochemical failure (BF), (B) freedom from metastasis, (C) cause-specific survival, and (D) overall survival (OS) for patients stratified by ADT use with radiation therapy. (E) Freedom from BF, (F) freedom from metastasis, (G) cause-specific survival, and (H) OS for patients treated with ADT stratified by ADT duration. ADT = androgen deprivation therapy; BF = biochemical failure; CI = confidence interval; HR = hazard ratio; OS = overall survival; RT = radiation therapy.
propensity score analysis was performed to assess the impact of ADT treatment on DM, PCSM, and OM. ADT use was not significantly associated with DM, PCSM, or OM. Lastly we sought to assess the impact of ADT duration on BF, DM, PCSM, and OM, which was the primary goal of our
analysis from the outset. Recognizing that patients treated with longer durations of ADT had more aggressive disease than patients treated with shorter durations, we again performed a propensity score analysis controlling for the same variables as the previously described model (Table 3)
Please cite this article in press as: Jackson WC, et al. Duration of Androgen Deprivation Therapy Influences Outcomes for Patients Receiving Radiation Therapy Following Radical Prostatectomy. Eur Urol (2015), http://dx.doi.org/10.1016/j.eururo.2015.05.009
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assessing first ADT duration 12 mo versus <12 mo, as well as continuous ADT duration in months. ADT duration 12 mo was significantly associated with decreased BF (HR: 0.39; 95% CI, 0.20–0.74; p = 0.004) and DM (HR: 0.21; 95% CI, 0.06–0.76; p = 0.017). Statistical significance was not met for PCSM (HR: 0.36; 95% CI, 0.09–1.38; p = 0.14) or OM (HR: 0.49; 95% CI, 0.20–1.19; p = 0.12). Continuous ADT duration in months was significantly associated with reduced BF (HR: 0.95; 95% CI, 0.91–0.98; p = 0.004), DM (HR: 0.88; 95% CI, 0.82–0.99; p = 0.004), and PCSM (HR: 0.90; 95% CI, 0.82–0.99; p = 0.037). Statistical significance was again not reached for OM (HR: 0.95; 95% CI, 0.90–1.01; p = 0.11). 4.
Discussion
In this retrospective analysis we demonstrate that increasing durations of ADT are associated with decreased development of metastases and PCSM among patients receiving ADT with post-RP RT despite patients receiving longer durations of ADT harboring more aggressive disease features. Although statistical significance was not reached for PCSM or OM when comparing <12 mo with 12 mo, and continuous ADT duration was not statistically significantly associated with OM, the HRs and CIs for these results all favor a net benefit with longer durations of ADT (Table 3). Our findings suggest that for patients with high-risk disease features including GS 8–10, SVI, and pre-RT PSAs >1, which are previously identified predictors of recurrence [21], receiving ADT with post-RP RT, an extended course of ADT, such as 12–24 mo, may be preferable. This may be consistent with the hypothesis that patients experience BF after post-RP RT secondary to the presence of micrometastatic disease outside of the RT treatment field rather than solely a failure of RT to eradicate pelvic disease. Our findings are also consistent with the results from RTOG 9202 and EORTC 22961 that both assessed ADT duration when added to RT for the definitive treatment of PCa and provide evidence that improved patient outcomes arise from treating with long-term ADT compared with short-term ADT, at least in high-risk patients, in this setting [1,5]. In RTOG 9202, all patients were treated with 4 mo of ADT with RT and then randomized to either 2 additional years of ADT or no additional ADT. Those treated with 2 additional years of ADT had statistically significant decreased rates of BF (52% vs 62%), distant metastases (15% vs 23%), and improved disease-specific survival (89% vs 84%) at 10 yr post-RT [5]. Similarly, results from EORTC 22961, in which all patients received 6 mo of ADT and then were randomized to an additional 2.5 yr of ADT or to no additional ADT, demonstrated that short-term ADT was inferior to longterm ADT with respect to OS at 5 yr (15% vs 19%) [1]. The analysis of RTOG 9202 included a multivariate analysis to which we can compare our findings. Twenty-eight months of ADT use compared with 4 mo resulted in an HR of 0.66 (95% CI, 0.50–0.86) for PCSM in RTOG 9202, which approximates to a 1.52-fold (95% CI, 1.17–1.98) reduction in risk. In our analysis, each increasing month of ADT use
was associated with an HR of 0.0.90 for PCSM that approximately equates to a relative risk reduction of 12. Although the impact of ADT duration would appear to be larger in our analysis, given our relatively small sample size one would expect a larger variance in estimated treatment effect, and in fact an approximate 1.5-fold reduction in PCSM is within our 95% CI, and as such further lends plausibility to our findings. Given the advantage of long-term ADT compared with short-term ADT in patients with high-risk PCa, it is not unreasonable to hypothesize as we have that patients requiring RT following RP may also benefit from a longer duration of ADT. Unfortunately, limited data exist to guide even the use of ADT in patients treated with RT following RP. Several retrospective analyses have demonstrated decreased rates of BF with the addition of ADT at the time of SRT, although results are conflicting as to which subgroups of patients benefit most from the addition of ADT [9–14]. Median ADT duration in these studies ranged from 3 to 20 mo, with a variety of ADT regimens used. A number of these analyses have further demonstrated that ADT use was prognostic for decreased BF on multivariate analysis [10,11,13,14]. In the present analysis, we demonstrate similar findings to the previous analyses with ADT resulting in decreased rates of BF post-RT on univariate and multivariate analysis. This consistency with previous reported results further helps support the validity of our finding concerning duration of ADT. Preliminary results from RTOG 9601 suggest a benefit to 2 yr of a nonsteroidal antiandrogen with RT, with decreased rates of BF and a 5.2% reduction in development of metastases at 7 yr in those treated with the addition of a nonsteroidal antiandrogen [15]. However, use of an antiandrogen alone is not a common treatment regimen. A more contemporary ADT regimen is being assessed in the ongoing RTOG 0534 Short-term Androgen Deprivation with Pelvic Lymph Node or Prostate Bed Only Radiotherapy (SPPORT) trial, in which patients are randomized to either no ADT or 4–6 mo of an luteinizing hormone-releasing hormone agonist and a nonsteroidal antiandrogen with or without pelvic lymph node RT. Given the different ADT regimens used in each trial, it will be difficult to compare outcomes between the two trials, and thus while both may independently shed light on the benefits of both short- and long-term ADT use with post-RP RT, neither alone nor in combination will provide an answer to the optimal duration of ADT use. However, the ongoing RADICALS trial may provide guidance for the appropriate duration of ADT use in post-RP RT [16]. RADICALS randomizes patients to either no ADT or 6 versus 24 mo of ADT. Patients are treated with either an antiandrogen or a GnRH agonist, and the chosen treatment regimen (antiandrogen vs GnRH agonist) will be used as a stratification variable. Thus the RADICALS trial represents the most likely source to provide level 1 evidence regarding the appropriate duration of ADT for patients being treated with post-RP RT. Our findings led us to hypothesize that increasing durations of ADT with post-RP RT may be of benefit,
Please cite this article in press as: Jackson WC, et al. Duration of Androgen Deprivation Therapy Influences Outcomes for Patients Receiving Radiation Therapy Following Radical Prostatectomy. Eur Urol (2015), http://dx.doi.org/10.1016/j.eururo.2015.05.009
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particularly in patients with the most aggressive pathologic features, but given the retrospective design of our analysis and small number of overall events, external validation is a necessity. A second limitation of this analysis is that we were unable to assess the impact of ADT duration on patient quality of life, or if undesirable ADT associated side effects may have had an impact on OM. In the setting of definitive RT for localized PCa, longer courses of ADT have been demonstrated to result in decreased tolerability compared with shorter courses, leading to worse quality of life including increases in fatigue, insomnia, hot flushes, as well as decreased sexual interest and sexual activity [1,22]. Although ADT use was not associated with decreased OS in our analysis—in fact, after controlling for pathologic risk features, longer duration ADT was associated with improved all-cause mortality—the potential benefits of ADT use need to be weighed against the potential detriments to overall quality of life. Along this same line of thought, we were unable to assess whether a particular subset of patients may benefit from shorter durations of ADT use; however, for patients in our analysis with high-risk features such as GS 8–10, SVI, or a pre-RT PSA >1 ng/ml who were ultimately treated with ADT, increasing durations of ADT use was associated with decreased DM and improved PCSM and OM. The ongoing RADICALS trial will better delineate if a population exists that benefits from shorter durations of ADT use, such as 6 mo opposed to 24 mo. Another limitation of our analysis is that testosterone levels were not routinely followed for men treated with ADT. It is well established that testosterone levels may remain depressed for months to years following even shortcourse ADT such as 6 mo [23], bringing into question when the effectiveness of ADT truly ceases following a specified treatment course. Future analysis of ADT use in this setting should monitor testosterone levels until normalization of serum testosterone following cessation of ADT to assess if normalization of serum testosterone would serve as a more appropriate time point from which to begin analysis. A final limitation of this analysis is that a minority of patients (21%) were treated with the combination of RT and ADT, and, as such, a selection bias certainly exists. Not surprisingly, patients treated with RT and ADT had more aggressive pathologic features than those who were not, and thus it becomes difficult to ascertain whether these findings would apply to patients with less aggressive disease. Nevertheless, our findings support the notion that for patients with aggressive disease features including GS 8–10, SVI, and pre-RT PSA >1 ng/ml at the time of post-RP RT, there may indeed be a benefit to a longer course of ADT such as 24 mo over a shorter course such as 6 mo.
7
patients therefore may help to treat micrometastatic disease that may be present at the time of post-RP RT. The ongoing RTOG 9601, SPPORT, and RADICALS trials will hopefully bring clarity to the benefits of ADT with post-RP RT, with the RADICALS trial further elucidating the ideal duration of ADT use in this setting. Until results from these trials become publicly available, our findings suggest that when considering adding ADT to post-RP RT in patients with high-risk disease features such as those included in the present analysis, a longer course of treatment 12 mo may be preferable. Author contributions: Felix Y. Feng had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Jackson, Sandler, Palapattu, Hamstra, Feng Acquisition of data: Jackson, Johnson, Foster, Li Analysis and interpretation of data: Jackson, Johnson, Feng, Hamstra. Drafting of the manuscript: Jackson, Feng, Hamstra. Critical revision of the manuscript for important intellectual content: Sandler, Foster, Palapattu, Schipper. Statistical analysis: Schipper, Jackson, Johnson, Feng, Hamstra. Obtaining funding: None. Administrative, technical, or material support: None. Supervision: Sandler, Palapattu, Hamstra, Feng. Other (specify): None. Financial disclosures: Felix Y. Feng certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: None. Funding/Support and role of the sponsor: None.
Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j. eururo.2015.05.009. References [1] Bolla M, de Reijke TM, Van Tienhoven G, et al. Duration of androgen suppression in the treatment of prostate cancer. N Engl J Med 2009;360:2516–27. [2] Bolla M, Van Tienhoven G, Warde P, et al. External irradiation with or without long-term androgen suppression for prostate cancer with high metastatic risk: 10-year results of an EORTC randomised study. Lancet Oncol 2010;11:1066–73. [3] D’Amico AV, Chen MH, Renshaw AA, Loffredo M, Kantoff PW. Androgen suppression and radiation vs radiation alone for prostate cancer: a randomized trial. JAMA 2008;299:289–95.
5.
Conclusions
We demonstrate that in patients with high-risk disease features, such as GS 8–10, SVI, or pre-RT PSA >1 ng/ml, treatment with 12 mo of ADT with post-RP RT is associated with improved outcomes compared with treatment <12 mo. Longer durations of ADT in these high-risk
[4] Denham JW, Steigler A, Lamb DS, et al. Short-term androgen deprivation and radiotherapy for locally advanced prostate cancer: results from the Trans-Tasman Radiation Oncology Group 96.01 randomised controlled trial. Lancet Oncol 2005;6:841–50. [5] Horwitz EM, Bae K, Hanks GE, et al. Ten-year follow-up of radiation therapy oncology group protocol 92-02: a phase III trial of the duration of elective androgen deprivation in locally advanced prostate cancer. J Clin Oncol 2008;26:2497–504.
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[6] Jones CU, Hunt D, McGowan DG, et al. Radiotherapy and short-term
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[17] Stephenson AJ, Scardino PT, Kattan MW, et al. Predicting the outcome of salvage radiation therapy for recurrent prostate cancer after radical prostatectomy. J Clin Oncol 2007;25:2035–41. [18] Stephenson AJ, Kattan MW, Eastham JA, et al. Defining biochemical recurrence of prostate cancer after radical prostatectomy: a pro-
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Please cite this article in press as: Jackson WC, et al. Duration of Androgen Deprivation Therapy Influences Outcomes for Patients Receiving Radiation Therapy Following Radical Prostatectomy. Eur Urol (2015), http://dx.doi.org/10.1016/j.eururo.2015.05.009
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Platinum Priority – Prostate Cancer Editorial by XXX on pp. x–y of this issue
Duration of Androgen Deprivation Therapy Influences Outcomes for Patients Receiving Radiation Therapy Following Radical Prostatectomy William C. Jackson a, Matthew J. Schipper a, Skyler B. Johnson a, Corey Foster a, Darren Li a, Howard M. Sandler b, Ganesh S. Palapattu c, Daniel A. Hamstra a, Felix Y. Feng a,* a
Department of Radiation Oncology, University of Michigan Medical Center, Ann Arbor, MI, USA;
b
Department of Radiation Oncology, Cedars-Sinai,
Los Angeles, CA, USA; c Department of Urology, University of Michigan Medical Center, Ann Arbor, MI, USA
Article info
Abstract
Article history: Accepted May 5, 2015
Background: Limited data exist to guide the use of androgen deprivation therapy (ADT) for men treated with radiation therapy (RT) after radical prostatectomy (RP). The optimal duration of ADT in this setting is unknown. Objective: To determine if the duration of ADT influences clinical outcomes for men receiving post-RP RT. Design, setting, and participants: A total of 680 men who received adjuvant radiation therapy (n = 105) or salvage radiation therapy (n = 575) between 1986 and 2010 at a single tertiary care institution were reviewed retrospectively. Median follow-up post-RT was 57.8 mo. Intervention: RT was delivered using three-dimensional conformal or intensitymodulated RT in 1.8-Gy fractions. For patients treated with ADT, >80% were treated with a gonadotropin-releasing hormone agonist with or without a nonsteroidal antiandrogen. Outcome measurements and statistical analysis: Biochemical failure (BF), distant metastasis (DM), prostate cancer–specific mortality (PCSM), and overall mortality were assessed using Kaplan-Meier analysis and propensity score analysis. Results and limitations: Overall, 144 patients (21%) received ADT with post-RP RT, most of whom had high-risk disease features such as Gleason score 8–10, seminal vesicle invasion, or pre-RT prostate-specific antigen >1 ng/ml. Median ADT duration was 12 mo (interquartile range: 6.0–23.7). Patients who received <12 mo of ADT had an association with increased BF (hazard ratio [HR]: 2.27; p = 0.003) and DM (HR: 2.48; p = 0.03) compared with patients receiving 12 mo of ADT. The 5-yr rates of DM were 6.0% and 23% for 12 and <12 mo of ADT, respectively. On propensity score analysis controlling for pretreatment and treatment-related factors, each month of ADT was associated with a decreased risk for BF (HR: 0.95; p = 0.0004), DM (HR: 0.88; p = 0.0004), and PCSM (HR: 0.90; p = 0.037). These findings are limited by the retrospective nature of our analysis. Conclusions: For men with high-risk disease features receiving ADT with post-RP RT, the duration of ADT is associated with clinical outcomes. Our findings suggest that for these men an extended course of ADT 12 mo may be preferable. Validation of our findings is needed. Patient summary: We evaluated outcomes for men with high-risk disease features treated with androgen deprivation therapy (ADT) and radiotherapy after radical prostatectomy. Longer durations of ADT resulted in improved patient outcomes. # 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved.
Associate Editor: Matthew Cooperberg Keywords: Prostate cancer Androgen deprivation therapy Postprostatectomy radiotherapy
* Corresponding author. Department of Radiation Oncology, University of Michigan Medical Center, 1500 E. Medical Center Drive, Ann Arbor, MI 48109, USA. Tel. +1 734 936 4302. E-mail address: [email protected] (F.Y. Feng). http://dx.doi.org/10.1016/j.eururo.2015.05.009 0302-2838/# 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Jackson WC, et al. Duration of Androgen Deprivation Therapy Influences Outcomes for Patients Receiving Radiation Therapy Following Radical Prostatectomy. Eur Urol (2015), http://dx.doi.org/10.1016/j.eururo.2015.05.009
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1.
Introduction
receiving 64.0–70.2 Gy. Whole pelvis radiation therapy (WPRT) fields were treated in 17% of patients, typically in 1.8 Gy fractions to 45 Gy. For
The addition of androgen deprivation therapy (ADT) to external-beam radiation therapy (EBRT) as definitive treatment for high-risk localized prostate cancer (PCa) has been demonstrated to improve patient outcomes in multiple randomized controlled trials [1–8]. An advantage in overall survival (OS) has been associated with both the use of short-term ADT (4–6 mo) [3,6,8] and long-term ADT (2–3 yr) [2] for men treated with definitive radiation therapy (RT). Both Radiation Therapy Oncology Group (RTOG) 9202 and European Organization for Research and Treatment of Cancer (EORTC) 22961 compared short-term ADT with long-term ADT and found improved outcomes among those randomized to long-term ADT [1,5]. Despite a significant amount of evidence suggesting that the addition of ADT to EBRT for the definitive treatment of localized PCa improves patient outcomes, little is known regarding the use of ADT for patients receiving RT after radical prostatectomy (RP). Several retrospective analyses identified an association between the use of ADT with post-RP RT and decreased rates of biochemical recurrence [9–14]. Early results from RTOG 9601, which randomized salvage RT patients to RT with or without the addition of 2 yr of ADT, found improved freedom from prostate-specific antigen (PSA) progression and a reduction in the development of metastases in those treated with the addition of ADT [15]. Although limited evidence suggests that there is indeed a role for the addition of ADT to RT for patients receiving RT post-RP, there are no data to guide the duration of ADT use in this setting. The ongoing Radiotherapy and Androgen Deprivation in Combination After Local Surgery (RADICALS) trial will hopefully shed light on this issue [16]; however, preliminary results are not expected in the near future because the trial plans to continue recruiting until at least mid-2016. Given the lack of knowledge concerning the optimal duration of ADT when added to post-RP RT, we sought to assess retrospectively whether the duration of ADT in this setting had an impact on biochemical failure (BF), distant metastasis (DM), prostate cancer–specific mortality (PCSM), and overall mortality (OM) in a cohort of patients who were treated with RT and ADT after RP. 2.
Patients and methods
those patients treated with ADT, >80% were treated with a gonadotropinreleasing hormone (GnRH) agonist with or without the addition of a nonsteroidal antiandrogen. The remaining patients were treated with a nonsteroidal antiandrogen with or without a 5a-reductase inhibitor.
2.3.
End points
Primary outcomes measured included BF, DM, PCSM, and OM. The time to all end points was determined from the start date of RT. ADT duration was calculated from the day of initiation of ADT to the last day of ADT effectiveness (i.e., a 3-mo injection of a GnRH agonist contributed 3 mo). Serum testosterone values were not routinely evaluated. BF was defined as a serum PSA value of at least 0.2 ng/ml greater than the post-SRT nadir followed by a second higher serum PSA value [17] or any PSA value of at least 0.5 ng/ml greater than the post-SRT nadir [18,17]. DM was defined as the presence of any clinical, pathologic, or radiologic evidence of metastasis. PCSM was defined as any death in a patient with metastatic or hormone-refractory PCa. OM was defined as any death, independent of the cause.
2.4.
Statistical analysis
Patient characteristics were compared between treatment groups using one-way analysis of variance and chi-square methods for continuous and categorical variables, respectively. Survival outcomes were summarized with Kaplan-Meier methods. A propensity score analysis was performed to assess the impact of ADT use and ADT duration on patient outcomes while accounting for the nonrandomized nature of treatment assignment in these data. Specifically, the probability of treatment assignment (propensity score) was calculated using logistic regression. The inverse of this propensity was then used to fit weighted Cox models [19]. A robust sandwich variance estimator [20] was used to estimate the covariance matrix and calculate a p value for a score test of no treatment effect. To calculate the propensity score, we used a stepwise logistic regression with outcome equal to treatment (ADT use vs no ADT use, ADT duration <12 mo vs ADT duration 12 mo). For the ADT use versus no use ADT propensity, we used a 0.2 level of significance to select variables for inclusion in the propensity score model. The identified model included Gleason score (2–6, 7, and 8–10), pre-RT PSA, and positive SMs. The same three variables were used to calculate the propensity of long-term ADT use (12 mo) even though in this case, pre-RT PSA was not significant at the 0.2 level (p = 0.7). This propensity score was then used to perform adjusted analyses of the impact of ADT duration (both as a long- vs short-term variable and as a continuous covariate) on patient outcomes. We also performed sensitivity analyses in which the propensity score was built using all covariates regardless of statistical significance. The
2.1.
Patient selection
A total of 680 patients who received either adjuvant (n = 105) or salvage RT (n = 575) post-RP at a single institution between 1986 and 2010 (with 75% treated after 1999) were reviewed retrospectively through an analysis
resulting estimates of treatment effect and statistical significance were similar and are not presented. All statistical analyses were performed using SAS v.9.3 (SAS Institute, Cary, NC, USA) and MedCalc v.12.3.0.0 (MedCalc Software, Mariakerke, Belgium).
approved by the institutional review board. Salvage radiation therapy (SRT) was defined as RT given for a persistently elevated PSA post-RP or for
3.
Results
3.1.
Patient characteristics
biochemical recurrence post-RP. All other RT was considered adjuvant radiation therapy (ART). Of the 680 patients treated with post-RP RT, 144 (21%) received ADT with RT and are the focus of this analysis.
2.2.
Treatment and follow-up
RT was delivered using three-dimensional conformal RT or intensitymodulated RT typically in 1.8-Gy fractions, with >95% of patients
A total of 144 patients (21%) received concurrent ADT with post-RP RT. The median follow-up post-RT was 57 mo (interquartile range [IQR]: 32.7–86.5), with median followup of 57 mo (n = 114) for living patients, and 58 mo
Please cite this article in press as: Jackson WC, et al. Duration of Androgen Deprivation Therapy Influences Outcomes for Patients Receiving Radiation Therapy Following Radical Prostatectomy. Eur Urol (2015), http://dx.doi.org/10.1016/j.eururo.2015.05.009
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Table 1 – Patient characteristics stratified by use of concurrent androgen deprivation therapy
Age, yr, median (IQR) Follow-up post-RT, mo, median (IQR) CCI, median (IQR) Range Pre-RT PSA, ng/dl, median (IQR) Range Pre-SRT PSA DT, mo, median (IQR) PSA nadir post-RT, ng/dl, median (IQR) RT dose, Gy, median (IQR) WPRT, % ADT during RT, % ART, % ADT duration, mo Median (IQR) GS, % 2–6 7 8–10 pT stage, % T1–T2a T2b–T2c T3–T4 SVI, % Positive SM, % ECE, % LNI, %
Without concurrent ADT (n = 536)
Concurrent ADT (n = 144)
64.7 (59.0–69.7) 56.7 (19.9–102.7) 3 (2–4) 0–7 0.5 (0.3–1.0) 0–18.4 8.1 (4.4–15.9) 0 (0–0.2) 68.4 (64.8–68.4) 15 0.0 13
63.9 (58.1–69.4) 57.8 (31.6) 3 (2–4) 1–8 0.9 (0.3–2.5) 0–27.1 6.9 (3.6–13.5) 0 (0–0) 68.4 (64.8–70.2) 27 100 23
0 (0–0)
p value
p = 0.7* p = 0.7* p = 0.8* p < 0.001* p = 0.1* p = 0.3* p = 0.017y p = 0.001z p < 0.0001z p = 0.007z
11.9 (6.0–23.7)
NA
22 58 20
20 45 35
p = 0.001z
9.0 22 69 18 54 56 2.9
4.0 18 78 29 63 67 16
p = 0.07z p = 0.006z p = 0.047z p = 0.022z p < 0.0001z
ADT = androgen-deprivation therapy; ANOVA = analysis of variance; ART = adjuvant radiation therapy; CCI = Charlson Comorbidity Index; ECE = extracapsular extension; GS = Gleason score; IQR = interquartile range; LNI = lymph node involvement; NA = not applicable; PSA = prostate-specific antigen; PSA DT = prostate-specific antigen doubling time; RT = radiation therapy; SM = surgical margin; SRT = salvage radiation therapy; SVI = seminal vesicle invasion; WPRT = whole pelvic radiation therapy. * ANOVA. y ANOVA; mean RT dose 66.9 Gy for those not receiving ADT versus 67.5 Gy for those treated with ADT. z Chi-square.
(n = 30) mo for deceased patients. Table 1 lists patient characteristics comparing those who did and did not receive ADT with RT. Patients receiving ADT had a higher pre-RT PSA and were more likely to have a Gleason score (GS) of 8–10, seminal vesicle invasion (SVI), positive SMs, and lymph node involvement (LNI). They were also more likely to receive ART and WPRT. Furthermore, 67% of patients treated with ADT had at least one of the high-risk features of GS 8–10, SVI, or pre-RT PSA 1 ng/ml (previously identified high-risk features associated with recurrence [21]) compared with only 48% of patients not receiving ADT (p = 0.0001), and 20% of patients treated with ADT had multiple of these high-risk features present compared with only 11% of patients who did not receive ADT (p = 0.004). Thirty-one patients (21%) received ADT and ART; 113 patients (79%) received ADT and SRT. For those receiving ART, median time from RP to RT was 5.1 mo (IQR: 3.7–6.5) compared with 26.2 mo (IQR: 10.2–52.0) for SRT. Patients treated with ART were generally more likely to have a higher GS, SVI, positive SMs, and LNI (Supplementary Table 1). For those treated with ADT, median ADT duration was 11.9 mo (IQR: 6.0–23.7). For patients treated with <12 mo of ADT, median ADT duration was 6.0 mo (IQR: 4.4–6.9), and for those treated with 12 mo of ADT, median duration was 23.7 mo (IQR: 17.9–25.4). Table 2 lists the patient
characteristics comparing those treated with <12 and 12 mo of ADT, with patients receiving 12 mo more likely to have LNI and to receive WPRT. Of patients treated with ADT, 53 experienced BF, 23 developed metastatic disease, 13 died from PCa, and 30 experienced a death from any cause. There was no significant difference in the use of short- or long-term ADT as a function of treatment year (p = 0.4). Last, patient baseline characteristics remained balanced between treatment groups after propensity score weighting (Supplementary Table 1). 3.2.
Univariate analysis
Figure 1 shows the Kaplan-Meier analysis of both ADT use and duration. Patients treated with the addition of ADT to post-RP RT were less likely to experience BF (HR: 0.74; 95% confidence interval [CI], 0.56–0.98; p = 0.04). Five-year rates of BF were 39% (95% CI, 32–51) and 52% (95% CI, 48–59) for those treated with and without the addition of ADT to post-RP RT, respectively (p = 0.01). We did not observe a difference between those treated with and without ADT with regard to DM, PCSM, or OM (Fig. 1B– 1D). The finding on univariate analysis that ADT use was not significantly associated with DM, PCSM, or OM is not unexpected given that patients treated with ADT had decidedly more aggressive disease features than patients who did not (Table 1). However, given that ADT use was
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Table 2 – Patient characteristics stratified by duration of androgen deprivation therapy
Age, yr, median (IQR) Follow-up post-RT, mo CCI median (IQR) Range Pre-RT PSA, ng/dl, median (IQR) Range Pre-SRT PSA DT, mo, median (IQR) PSA nadir post-RT, ng/dl, median (IQR) RT dose, Gy, median (IQR) WPRT, % ART, % ADT duration, mo, median (IQR) GS, % 2–6 7 8–10 pT stage, % T1–T2a T2b–T2c T3–T4 SVI, % Positive SM, % ECE, % LNI, %
12 mo ADT (n = 70)
<12 mo ADT (n = 74)
63.8 (58.2–69.5) 58.3 (32.0–86.3) 3 (2–4) 1–7 0.7 (0.3–3.2) 0–10.4 4.8 (2.5–16.2) 0 (0–0) 64.8 (64.8–70.2) 33 27 23.7 (17.9–25.4)
64.7 (58.3–69.8) 57.3 (33.9–87.7) 3 (3–4) 1–8 1.1 (0.4–2.4) 0–27.1 7.2 (4.6–13.2) 0 (0–0.1) 68.4 (64.8–70.2) 16.2 16.2 6.0 (4.4–6.9)
p value
p = 0.5* p = 0.8* p = 0.5* p = 0.9* p = 0.9* p = 0.7* p = 0.1* p = 0.033y p = 0.2y p < 0.001y
14 50 36
26 41 33
p = 0.2y
3.0 16 81 30 67 69 28
5.0 21 74 24 57 63 3.0
p = 0.6y p = 0.5y p = 0.3y p = 0.6y p = 0.017y
ADT = androgen-deprivation therapy; ART = adjuvant radiation therapy; CCI = Charlson Comorbidity Index; ECE = extracapsular extension; GS = Gleason score; IQR = interquartile range; LNI = lymph node involvement; PSA = prostate-specific antigen; PSA DT = prostate-specific antigen doubling time; RT = radiation therapy; SM = surgical margin; SVI = seminal vesicle invasion; WPRT = whole pelvic radiotherapy. * Analysis of variance. y Chi-square.
Table 3 – Results of propensity score analysis for both androgen deprivation therapy use and duration ADT use, any vs none Outcome Time Time Time Time
to to to to
BF DM PCSM OM
ADT duration, <12 mo vs 12 mo
ADT duration, continuous, mo
Estimated HR
p value
95% CI
Estimated HR
p value
95% CI
Estimated HR
p value
95% CI
0.69 0.66 0.59 1.06
0.042 0.14 0.6 0.8
0.49–0.99 0.38–1.14 0.39–1.70 0.65–1.75
0.39 0.21 0.36 0.49
0.004 0.017 0.14 0.12
0.20–0.74 0.06–0.76 0.09–1.38 0.20–1.19
0.95 0.88 0.90 0.95
0.004 0.004 0.037 0.11
0.91–0.98 0.82–0.99 0.82–0.99 0.90–1.01
ADT = androgen-deprivation therapy, BF = biochemical failure, CI = confidence interval, DM = distant metastasis, HR = hazard ratio, OM = overall mortality; PCSM = prostate cancer–specific mortality.
associated with improved rates of BF despite these patients having more aggressive disease, we continued with our primary objective to assess the impact of duration of ADT. For those treated with ADT, patients receiving <12 mo of ADT with post-RP RT were more likely to experience BF (HR: 2.27; 95% CI, 1.31–3.87; p = 0.003) and DM (HR: 2.48; 95% CI, 1.10–5.63; p = 0.03) than those receiving 12 mo (Fig. 1D–F). Five-year rates of BF for those receiving <12 mo of ADT were 48% (95% CI, 36–62) compared with 32% (95% CI, 21–53) for 12 mo (p = 0.01). Similarly, 5-yr rates of DM were increased for those treated with <12 mo of ADT compared with 12 mo (23% [95% CI, 10–36] vs 6.0% [95% CI, 0.10–12], respectively; p = 0.03). The associated benefit for BF and DM seen with ADT use 12 mo was present despite patients receiving 12 mo of ADT having more aggressive disease (Table 2). On univariate analysis a statistically significant difference was not observed with
regard to PCSM or OM for those treated with <12 and 12 mo of ADT. 3.3.
Propensity score analysis
To further assess the impact of ADT use and duration on patient outcomes, we next performed a propensity score analysis as described in the ‘‘Patients and Methods’’ section (results in Table 3). Variables considered for inclusion in the propensity score model included pre-RT PSA, GS, SVI, extracapsular extension (ECE), SMs, the use of ART versus SRT, the use of WPRT, RT dose, as well RT start date, with GS, pre-RT PSA, and positive SMs reaching statistical significance and thus included in the propensity score. In the propensity score adjusted analysis, ADT use (any vs none) was associated with decreased BF (HR: 0.69; 95% CI, 0.49–0.99; p = 0.042). As an exploratory analysis,
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A
E
Freedom from Biochemical Failure
Freedom from Biochemical Failure 100
Survival probability (%)
Survival probability (%)
100 80 60 40 HR: 0.74 (95% CI, 0.56–0.98, p < 0.05) RT and ADT RT alone
20 0
0
12
Number at risk Group: RT alone 503 Group: RT and ADT 148
24
36 48 Time, mo
60
72
256
199
151
107
81
60
125
86
66
46
37
29
19
B
12
24
36 48 Time, mo
60
72
84
36
28
20
15
20
15
48
36
24
20
24
20
84
Freedom from Metastasis
Survival probability (%)
Survival probability (%)
60 40 p = 0.8 RT and ADT RT alone
20 0
12
Number at risk Group: RT alone 509 Group: RT and ADT 145
24
36 48 Time, mo
60
72
351
307
266
221
190
155
138
116
99
79
64
51
38
60 40 HR:0.40 (95% CI, 0.18–0.91, p = 0.03) ADT duration <12 mo ADT duration >12 mo
20
12
24
36 48 Time, mo
60
72
Number at risk Group: ADT duration <12 mo 72 68 Group: ADT duration >12 mo 68 66
0
56
48
39
28
23
17
57
48
37
33
25
19
G
Prostate Cancer-specific Survival
Prostate Cancer-specific Survival 100
Survival probability (%)
100 Survival probability (%)
80
0
84
419
C 80 60 40 p = 0.9 RT and ADT RT alone
20 0
12
Number at risk Group: RT alone 496 Group: RT and ADT 139
24
36 48 Time, mo
60
72
490
476
458
438
421
367
139
138
133
131
127
123
110
80 60 40 p= 0.2 ADT duration <12 mo ADT duration >12 mo
20 0
84
494
D
12
24
36 48 Time, mo
60
72
84
Number at risk Group: ADT duration <12 mo 67 67 Group: ADT duration >12 mo 67 67
0
67
64
64
62
59
51
66
64
62
60
59
54
H
Overall Survival
Overall Survival 100
Survival probability (%)
100 Survival probability (%)
0
100
80
80 60 40 p = 0.9 RT and ADT RT alone
20 0
HR: 0.44 ( 95% CI, 0.26–0.76, p = 0.003) ADT duration <12 mo ADT duration >12 mo
20
F
Freedom from Metastasis
0
40
Number at risk Group: ADT duration <12 mo 73 61 Group: ADT duration >12 mo 70 60
100
0
60
0
84
360
80
0
Number at risk Group: RT alone 530 Group: RT and ADT 149
12
24
36 48 Time, mo
60
72
84
526
521
506
484
463
444
388
149
148
141
138
133
128
115
80 60 40 p = 0.2 ADT duration <12 mo ADT duration >12 mo
20 0
12
24
36 48 Time, mo
60
72
84
Number at risk Group: ADT duration <12 mo 74 74 Group: ADT duration >12 mo 70 70
0
74
69
68
65
62
54
69
67
65
63
61
56
Fig. 1 – Kaplan-Meier analysis of androgen deprivation therapy (ADT) use and duration. (A) Freedom from biochemical failure (BF), (B) freedom from metastasis, (C) cause-specific survival, and (D) overall survival (OS) for patients stratified by ADT use with radiation therapy. (E) Freedom from BF, (F) freedom from metastasis, (G) cause-specific survival, and (H) OS for patients treated with ADT stratified by ADT duration. ADT = androgen deprivation therapy; BF = biochemical failure; CI = confidence interval; HR = hazard ratio; OS = overall survival; RT = radiation therapy.
propensity score analysis was performed to assess the impact of ADT treatment on DM, PCSM, and OM. ADT use was not significantly associated with DM, PCSM, or OM. Lastly we sought to assess the impact of ADT duration on BF, DM, PCSM, and OM, which was the primary goal of our
analysis from the outset. Recognizing that patients treated with longer durations of ADT had more aggressive disease than patients treated with shorter durations, we again performed a propensity score analysis controlling for the same variables as the previously described model (Table 3)
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assessing first ADT duration 12 mo versus <12 mo, as well as continuous ADT duration in months. ADT duration 12 mo was significantly associated with decreased BF (HR: 0.39; 95% CI, 0.20–0.74; p = 0.004) and DM (HR: 0.21; 95% CI, 0.06–0.76; p = 0.017). Statistical significance was not met for PCSM (HR: 0.36; 95% CI, 0.09–1.38; p = 0.14) or OM (HR: 0.49; 95% CI, 0.20–1.19; p = 0.12). Continuous ADT duration in months was significantly associated with reduced BF (HR: 0.95; 95% CI, 0.91–0.98; p = 0.004), DM (HR: 0.88; 95% CI, 0.82–0.99; p = 0.004), and PCSM (HR: 0.90; 95% CI, 0.82–0.99; p = 0.037). Statistical significance was again not reached for OM (HR: 0.95; 95% CI, 0.90–1.01; p = 0.11). 4.
Discussion
In this retrospective analysis we demonstrate that increasing durations of ADT are associated with decreased development of metastases and PCSM among patients receiving ADT with post-RP RT despite patients receiving longer durations of ADT harboring more aggressive disease features. Although statistical significance was not reached for PCSM or OM when comparing <12 mo with 12 mo, and continuous ADT duration was not statistically significantly associated with OM, the HRs and CIs for these results all favor a net benefit with longer durations of ADT (Table 3). Our findings suggest that for patients with high-risk disease features including GS 8–10, SVI, and pre-RT PSAs >1, which are previously identified predictors of recurrence [21], receiving ADT with post-RP RT, an extended course of ADT, such as 12–24 mo, may be preferable. This may be consistent with the hypothesis that patients experience BF after post-RP RT secondary to the presence of micrometastatic disease outside of the RT treatment field rather than solely a failure of RT to eradicate pelvic disease. Our findings are also consistent with the results from RTOG 9202 and EORTC 22961 that both assessed ADT duration when added to RT for the definitive treatment of PCa and provide evidence that improved patient outcomes arise from treating with long-term ADT compared with short-term ADT, at least in high-risk patients, in this setting [1,5]. In RTOG 9202, all patients were treated with 4 mo of ADT with RT and then randomized to either 2 additional years of ADT or no additional ADT. Those treated with 2 additional years of ADT had statistically significant decreased rates of BF (52% vs 62%), distant metastases (15% vs 23%), and improved disease-specific survival (89% vs 84%) at 10 yr post-RT [5]. Similarly, results from EORTC 22961, in which all patients received 6 mo of ADT and then were randomized to an additional 2.5 yr of ADT or to no additional ADT, demonstrated that short-term ADT was inferior to longterm ADT with respect to OS at 5 yr (15% vs 19%) [1]. The analysis of RTOG 9202 included a multivariate analysis to which we can compare our findings. Twenty-eight months of ADT use compared with 4 mo resulted in an HR of 0.66 (95% CI, 0.50–0.86) for PCSM in RTOG 9202, which approximates to a 1.52-fold (95% CI, 1.17–1.98) reduction in risk. In our analysis, each increasing month of ADT use
was associated with an HR of 0.0.90 for PCSM that approximately equates to a relative risk reduction of 12. Although the impact of ADT duration would appear to be larger in our analysis, given our relatively small sample size one would expect a larger variance in estimated treatment effect, and in fact an approximate 1.5-fold reduction in PCSM is within our 95% CI, and as such further lends plausibility to our findings. Given the advantage of long-term ADT compared with short-term ADT in patients with high-risk PCa, it is not unreasonable to hypothesize as we have that patients requiring RT following RP may also benefit from a longer duration of ADT. Unfortunately, limited data exist to guide even the use of ADT in patients treated with RT following RP. Several retrospective analyses have demonstrated decreased rates of BF with the addition of ADT at the time of SRT, although results are conflicting as to which subgroups of patients benefit most from the addition of ADT [9–14]. Median ADT duration in these studies ranged from 3 to 20 mo, with a variety of ADT regimens used. A number of these analyses have further demonstrated that ADT use was prognostic for decreased BF on multivariate analysis [10,11,13,14]. In the present analysis, we demonstrate similar findings to the previous analyses with ADT resulting in decreased rates of BF post-RT on univariate and multivariate analysis. This consistency with previous reported results further helps support the validity of our finding concerning duration of ADT. Preliminary results from RTOG 9601 suggest a benefit to 2 yr of a nonsteroidal antiandrogen with RT, with decreased rates of BF and a 5.2% reduction in development of metastases at 7 yr in those treated with the addition of a nonsteroidal antiandrogen [15]. However, use of an antiandrogen alone is not a common treatment regimen. A more contemporary ADT regimen is being assessed in the ongoing RTOG 0534 Short-term Androgen Deprivation with Pelvic Lymph Node or Prostate Bed Only Radiotherapy (SPPORT) trial, in which patients are randomized to either no ADT or 4–6 mo of an luteinizing hormone-releasing hormone agonist and a nonsteroidal antiandrogen with or without pelvic lymph node RT. Given the different ADT regimens used in each trial, it will be difficult to compare outcomes between the two trials, and thus while both may independently shed light on the benefits of both short- and long-term ADT use with post-RP RT, neither alone nor in combination will provide an answer to the optimal duration of ADT use. However, the ongoing RADICALS trial may provide guidance for the appropriate duration of ADT use in post-RP RT [16]. RADICALS randomizes patients to either no ADT or 6 versus 24 mo of ADT. Patients are treated with either an antiandrogen or a GnRH agonist, and the chosen treatment regimen (antiandrogen vs GnRH agonist) will be used as a stratification variable. Thus the RADICALS trial represents the most likely source to provide level 1 evidence regarding the appropriate duration of ADT for patients being treated with post-RP RT. Our findings led us to hypothesize that increasing durations of ADT with post-RP RT may be of benefit,
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particularly in patients with the most aggressive pathologic features, but given the retrospective design of our analysis and small number of overall events, external validation is a necessity. A second limitation of this analysis is that we were unable to assess the impact of ADT duration on patient quality of life, or if undesirable ADT associated side effects may have had an impact on OM. In the setting of definitive RT for localized PCa, longer courses of ADT have been demonstrated to result in decreased tolerability compared with shorter courses, leading to worse quality of life including increases in fatigue, insomnia, hot flushes, as well as decreased sexual interest and sexual activity [1,22]. Although ADT use was not associated with decreased OS in our analysis—in fact, after controlling for pathologic risk features, longer duration ADT was associated with improved all-cause mortality—the potential benefits of ADT use need to be weighed against the potential detriments to overall quality of life. Along this same line of thought, we were unable to assess whether a particular subset of patients may benefit from shorter durations of ADT use; however, for patients in our analysis with high-risk features such as GS 8–10, SVI, or a pre-RT PSA >1 ng/ml who were ultimately treated with ADT, increasing durations of ADT use was associated with decreased DM and improved PCSM and OM. The ongoing RADICALS trial will better delineate if a population exists that benefits from shorter durations of ADT use, such as 6 mo opposed to 24 mo. Another limitation of our analysis is that testosterone levels were not routinely followed for men treated with ADT. It is well established that testosterone levels may remain depressed for months to years following even shortcourse ADT such as 6 mo [23], bringing into question when the effectiveness of ADT truly ceases following a specified treatment course. Future analysis of ADT use in this setting should monitor testosterone levels until normalization of serum testosterone following cessation of ADT to assess if normalization of serum testosterone would serve as a more appropriate time point from which to begin analysis. A final limitation of this analysis is that a minority of patients (21%) were treated with the combination of RT and ADT, and, as such, a selection bias certainly exists. Not surprisingly, patients treated with RT and ADT had more aggressive pathologic features than those who were not, and thus it becomes difficult to ascertain whether these findings would apply to patients with less aggressive disease. Nevertheless, our findings support the notion that for patients with aggressive disease features including GS 8–10, SVI, and pre-RT PSA >1 ng/ml at the time of post-RP RT, there may indeed be a benefit to a longer course of ADT such as 24 mo over a shorter course such as 6 mo.
7
patients therefore may help to treat micrometastatic disease that may be present at the time of post-RP RT. The ongoing RTOG 9601, SPPORT, and RADICALS trials will hopefully bring clarity to the benefits of ADT with post-RP RT, with the RADICALS trial further elucidating the ideal duration of ADT use in this setting. Until results from these trials become publicly available, our findings suggest that when considering adding ADT to post-RP RT in patients with high-risk disease features such as those included in the present analysis, a longer course of treatment 12 mo may be preferable. Author contributions: Felix Y. Feng had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Jackson, Sandler, Palapattu, Hamstra, Feng Acquisition of data: Jackson, Johnson, Foster, Li Analysis and interpretation of data: Jackson, Johnson, Feng, Hamstra. Drafting of the manuscript: Jackson, Feng, Hamstra. Critical revision of the manuscript for important intellectual content: Sandler, Foster, Palapattu, Schipper. Statistical analysis: Schipper, Jackson, Johnson, Feng, Hamstra. Obtaining funding: None. Administrative, technical, or material support: None. Supervision: Sandler, Palapattu, Hamstra, Feng. Other (specify): None. Financial disclosures: Felix Y. Feng certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: None. Funding/Support and role of the sponsor: None.
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5.
Conclusions
We demonstrate that in patients with high-risk disease features, such as GS 8–10, SVI, or pre-RT PSA >1 ng/ml, treatment with 12 mo of ADT with post-RP RT is associated with improved outcomes compared with treatment <12 mo. Longer durations of ADT in these high-risk
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