Abstract
The optimum use of androgen deprivation therapy (ADT) in high-risk prostate cancer patients has not been defined in the setting of dose-escalated external beam radiation therapy. A retrospective analysis of 1,290 patients with high-risk prostate cancer from June 1987 through March 2010 treated with external beam radiation therapy was performed. Median follow-up was 7.2 years, and 797 patients received ADT, with 384 patients experiencing a biochemical failure and 145 with distant metastasis. ADT was associated with lower risk of biochemical failure and distant metastasis than no ADT after adjusting for age, prostate-specific antigen (PSA), Gleason score, year of diagnosis, tumor stage, and radiation dose. ADT was associated with a greater reduction in biochemical failure in the low-dose radiation group than in the high-dose group. Patients with >24 months of ADT had a lower risk of PSA failures than those with <24 months. ADT was associated with decreased risk of biochemical failure and distant metastasis in all patients. The effect of ADT on reducing risk of biochemical failure was greater among men with low-dose radiation. There was a benefit in PSA and distant metastasis-free survival with >24 months of ADT in all patients who received ADT.
Keywords: prostate cancer, oncology/cancer, hormone replacement therapy, physiological and endocrine disorders, outcomes research, research
Introduction
The timing and duration of androgen deprivation therapy (ADT) for patients receiving external beam radiation therapy (EBRT) for high-risk prostate cancer (PCa) has been an oft-studied topic. Several randomized controlled trials have demonstrated a local control and overall survival benefit by adding ADT to EBRT (Bolla et al., 2010; D’Amico, Chen, Renshaw, Loffredo, & Kantoff, 2008; Jones et al., 2011; Pilepich et al., 2005; Roach et al., 2008; See & Tyrrell, 2006). Results from these trials may not be applicable today, since they used lower doses of radiation and different risk group classifications than the current standards. A number of dose-escalation studies starting in the early 2000s changed the recommended doses of radiation from 65 Gy to 70 Gy to the higher doses of >70 Gy (Dearnaley et al., 2007; Pollack et al., 2002; Shipley et al., 1995; Zietman et al., 2010). With the new standard of higher radiation doses, there is a need to evaluate the benefit of adding ADT in terms of optimal patient selection, timing, and duration of ADT.
ADT is now being used more frequently in patients being treated with EBRT (Park et al., 2005; Shahinian, Kuo, Freeman, Orihuela, & Goodwin, 2005). Many adverse side effects are associated with ADT, such as metabolic syndrome, increased risk of diabetes, cardiovascular disease, as well as a decline in quality of life, which is worse with longer durations of ADT (Green et al., 2004; Keating, O’Malley, & Smith, 2006; Nanda, Chen, Braccioforte, Moran, & D’Amico, 2009). Current National Comprehensive Cancer Network (NCCN) guidelines reflect this uncertainty by recommending “consideration of ADT” if radiation therapy is given as definitive treatment for high-risk PCa (NCCN, 2011).
Given the adverse effects of ADT, it is vital to understand its potential benefits in order to help patients and oncologists make informed decisions regarding its use. The aims of the current study were to determine the effect of ADT on the risk of biochemical failure and distant metastasis at different doses of radiation among high-risk PCa and to evaluate whether the duration of ADT affected the outcomes.
Materials
Patient Selection and Pretreatment Evaluation
This review included high-risk PCa patients treated with definitive EBRT from June 1987 to March 2010. Institutional approval was received prior to initiating the study. Patients were categorized as high risk based on having T3a or greater stage, or Gleason 8-10, or prostate-specific antigen (PSA) > 20 according to the NCCN criteria (NCCN, 2011). The variable “race” was based on patient self-report. All patients had biopsy-proven adenocarcinoma of the prostate with no metastatic disease at the time of diagnosis. The initial evaluation consisted of a history and physical, digital rectal exam to evaluate tumor stage (based on the 1992 American Joint Committee on Cancer staging system), serum PSA measurement, and biopsy with Gleason histologic grading. Pretreatment evaluation included bone scans and pelvic computerized tomography for staging if the pretreatment PSA was ≥10 or the Gleason score was ≥8.
Treatment
All patients received definitive EBRT to the prostate and seminal vesicles. Prior to 2000, 3-dimensional conformal radiation therapy was used with doses prescribed to the isocenter. After 2000, intensity-modulated radiation therapy was used to treat the prostate and seminal vesicles with doses prescribed to the planning target volume. Lymph nodes were not included in the clinical target volume. Radiation prescription doses ranged from 60 Gy to 78 Gy, depending on the year of treatment.
ADT was given neoadjuvantly and/or concurrently with radiation. This was delivered either as a luteinizing hormone-releasing hormone agonist alone, or in combination with an antiandrogen, given at the discretion of the treating radiation oncologist. Duration of ADT was recorded in months.
Follow-Up and Endpoints
After EBRT, patients returned for a digital rectal examination and serum PSA measurements every 3 to 6 months for the first 2 years, then every 6 months for the next 3 years, then annually after 5 years. The biochemical (PSA) failures were coded by the “Phoenix” definition, or a rise in ≥2 ng/mL above the lowest PSA achieved after treatment, with the actual date of failure coded as the date of the PSA test (Roach et al., 2006). Patients lost to follow-up were censored at the last visit. Time was calculated from the completion date of radiation therapy.
Statistical Analysis
To compare baseline characteristics of the patients by ADT status, chi-square tests were used for categorical variables (number of failures, T-stage, radiation dose, length of ADT, radiation technique, and race) and t tests were used for continuous variables (age, pretreatment PSA, Gleason score, year of diagnosis). The main exposure variables (ADT and dose of radiation) were evaluated for effect modifiers by both addition of an interaction term in the models and by stratification by dose of radiation and use of ADT. After stratification, the log-rank test for homogeneity of survival curves was used to test the difference in effect of ADT among the two strata. Multivariable Cox proportional hazards models were constructed to include possible confounders and effect modifiers when appropriate, and variables were removed from the model one by one to evaluate the change in hazards of the main effect variables. If a significant change was noted in the main outcome variable being tested (about 10%-20%), the variable being tested remained in the model as a confounder. The proportional hazards assumption was tested for each variable in the model. Two-sided p values ≤.05 were considered statistically significant. Statistical analyses were performed using Stata version 11 IC and SPSS version 21.
To address the selection bias inherent in a retrospective trial design, propensity score analysis was utilized (Rosenbaum & Rubin, 1983). A logistic model was used to estimate the probability of receiving ADT. Gleason score, age, year of diagnosis, T-stage, and pretreatment PSA were included into the multivariable logistic regression model, as these factors had been decided a priori to affect a clinician’s decision to place a patient on ADT, and variable selection was conducted using a backward stepwise procedure. Quintiles of the propensity scores were used to stratify patients into five homogeneous groups with respect to their likelihood of being given ADT. The comparison of prognostic factors across the quintiles was done with analysis of variance and chi-squared tests to evaluate the effectiveness of the propensity score stratification. A stratified Cox regression analysis based on the propensity score was then conducted with separate estimates for all of the variables in each of the five strata. A weighted average of the stratum-specific estimates was calculated.
Results
The analysis included 1,290 patients. The mean age was 68 years. Median follow-up was 7.2 years, and 797 patients received adjuvant ADT. A total of 384 (29.77%) patients experienced biochemical failure and 145 (11.2%) experienced distant metastasis. Of the patients who received ADT, a total of 377 (47.3%) patients received 2 years or less, and 420 (52.7%) patients were on ADT for longer. Radiation dose was divided into low (≤70 Gy, n = 593, 46%) or high (>70 Gy, n = 609, 54%). The type of radiation received was highly correlated with radiation dose, as 462 of the 463 patients who were treated with intensity-modulated radiation therapy were also given high-dose radiation. Radiation technique was not evaluated as a variable for the remainder of the analyses. A majority (n = 992, 77%) of the patients were White. Differences in baseline characteristics existed between the groups that received ADT and those that did not receive ADT (see Table 1) in all variables except for age. Patients receiving ADT had higher mean pretreatment PSA (18.2 vs. 25.74, p = .006), higher rates of biochemical and distant failures, and higher mean Gleason scores (6.6 vs. 7.82, p < .001), than patients who did not receive ADT.
Table 1.
Baseline Variables by Treatment Modality and Testing of Distribution.
| No ADT |
% | ADT |
% | Total | p Value | |
|---|---|---|---|---|---|---|
| (n = 493) | (n = 797) | |||||
| PSA Failure | ||||||
| No | 241 | 49 | 665 | 83 | 906 | <.001 |
| Yes | 252 | 51 | 132 | 17 | 384 | |
| Distant Failure | ||||||
| No | 420 | 85 | 725 | 91 | 1,145 | <.001 |
| Yes | 73 | 15 | 72 | 9 | 145 | |
| Age (M) | 68.22 | 68 | 68 | .59 | ||
| Pretreatment PSA (M) | 18.12 | 25.74 | 22.8 | <.001 | ||
| Gleason Score (M) | 6.6 | 7.89 | 7.39 | <.001 | ||
| Year of Diagnosis (M) | 1992 | 2000 | 1997 | <.001 | ||
| T-stage | ||||||
| T1a-T2a | 101 | 20 | 285 | 36 | <.001 | |
| T2b-T2c | 64 | 13 | 149 | 19 | ||
| T3 | 319 | 65 | 335 | 42 | ||
| T4 | 9 | 2 | 28 | 4 | ||
| Radiation Dose (high vs. low) | <.001 | |||||
| High (>70 Gy) | 97 | 20 | 600 | 75 | 697 | |
| Low (≤70 Gy) | 396 | 80 | 197 | 25 | 593 | |
| Length of Concurrent ADT | ||||||
| Short (≤24 months) | 337 | 42 | 337 | |||
| Long (>24 months) | 420 | 53 | 420 | |||
| Race | ||||||
| White | 413 | 84 | 579 | 73 | 992 | <.001 |
| Black | 48 | 10 | 99 | 12 | 147 | |
| Hispanic | 19 | 4 | 78 | 10 | 97 | |
| Other | 13 | 3 | 41 | 5 | 54 | |
| Radiation Type | ||||||
| 3-D Conformal | 472 | 96 | 335 | 42 | 827 | <.001 |
| IMRT | 21 | 4 | 442 | 55 | 463 | |
Note. PSA = prostate-specific antigen; ADT = androgen deprivation therapy; IMRT = intensity-modulated radiation therapy.
In univariable analyses (see Table 2), younger age (hazard ratio [HR], 0.98; 95% confidence interval [CI: 0.965, 0.993]; p = .003), higher pretreatment PSA (HR, 1.006; 95% CI [1.004, 1.008]; p ≤ .001) earlier year of diagnosis (HR, 0.892; 95% CI [0.871, 0.913]; p < .001), higher T-stage (HR, 1.17; 95% CI [1.041, 1.318]; p = .009), lower doses of radiation (HR, 0.366; 95% CI [0.29, 0.46]; p < .001), and the lack of hormone use (HR, 0.345; 95% CI [0.279, 0.427]; p < .001) were associated with increased risk of biochemical failure (see Table 2). Gleason score, race, and the length of hormone use were not statistically significant.
Table 2.
Univariable Analysis of Association With Biochemical Failure and Distant Metastasis.
| Variable | Biochemical failure |
Distant metastasis |
||||
|---|---|---|---|---|---|---|
| Hazard ratio | 95% CI | p Value | Hazard ratio | 95% CI | p Value | |
| Age | 0.98 | [0.965, 0.993] | .003 | 0.958 | [0.936, 0.980] | <.001 |
| Pretreatment Prostate-Specific Antigen | 1.006 | [1.004, 1.008] | <.001 | 1.007 | [1.004, 1.010] | <.001 |
| Gleason Score | 0.945 | [0.885, 1.008] | .088 | 1.248 | [1.109, 1.404] | <.001 |
| Year of Diagnosis | 0.892 | [0.871, 0.913] | <.001 | 0.957 | [0.923, 0.993] | .019 |
| T-stage | 1.17 | [1.041, 1.318] | .009 | 1.293 | [1.055, 1.585] | .013 |
| Radiation Dose (high vs. low) | 0.366 | [0.29, 0.46] | <.001 | 0.593 | [0.287, 1.226] | .158 |
| Adjuvant Hormone Use (yes vs. no) | 0.345 | [0.279, 0.427] | <.001 | 0.653 | [0.454, 0.941] | .022 |
| Length of Hormone Use (short vs. long) | 0.823 | [0.579, 1.170] | .278 | 0.839 | [0.520, 1.354] | .473 |
| Race | 0.678 | [0.318, 1.444] | .263 | |||
| White | 1 (ref) | 1 (ref) | ||||
| Black | 1.296 | [0.667, 2.516] | .444 | 1.316 | [0.418, 4.146] | .639 |
| Hispanic | 1.709 | [0.841, 3.476] | .139 | 1.915 | [0.573, 6.402] | .291 |
| Other | 0.881 | [0.393, 1.977] | .759 | 0.755 | [0.180, 3.160] | .701 |
Univariable analysis for distant metastasis (see Table 2) demonstrated that younger age (HR, 0.958; 95% CI [0.936, 0.980]; p < .001), higher pretreatment PSA (HR, 1.007; 95% CI [1.004, 1.010]; p < .001), higher Gleason score (HR, 1.248; 95% CI [1.019, 1.404]; p < .001), earlier year of diagnosis (HR, 0.957; 95% CI [0.923, 0.993]; p = .019), higher T-stage (HR, 1.293; 95% CI [1.055, 1.585]; p = .013), and the lack of ADT (HR, 0.128; 95% CI [0.040, 0.409]; p < .001) were associated with an increased risk of distant metastasis. No difference in distant metastasis was seen among different racial groups, different doses of radiation (HR, 0.593; 95% CI [0.284, 1.226]; p = .022), or with the use of greater than 24 months of ADT compared with less than 24 months (HR, 0.839; 95% CI [0.520, 1.354]; p = .473).
A logistic regression model was created to predict the use of ADT. Younger age (odds ratio [OR], 0.97; p = .023), higher pretreatment PSA (OR, 1.045; p < .001), higher Gleason score (OR, 1.55; p < .001), and later year of diagnosis (OR, 1.56; p < .001) were all associated with the use of ADT. T-stage did not have an association with the use of ADT (OR, 1.154; p = .167). These results were used to estimate the probability of being placed on ADT (propensity score). Stratifying the patients into propensity score quintiles resulted in an improved balancing of patient characteristics between the ADT/no ADT groups compared with the initial differences prior to stratification. The only significant differences remaining were within the ADT/no ADT groups demonstrating a higher mean PSA in the ADT arm in Quintile 2 (p = .005), later year of diagnosis for the ADT arm in Quintiles 3 (p = .006) and 4 (p = .036), and higher radiation dose for the ADT arms in Quintile 2 (p = .002) and Quintile 5 (p < .001).
Despite unfavorable clinical prognostic factors, patients treated with ADT had a lower risk of biochemical failure than patients without ADT (HR, 0.324; 95% CI [0.243, 0.433]; p < .001). An interaction term of adjuvant hormone use and radiation dose was significant when added to the model (HR, 3.07; p < .001), meaning that an effect modification could be present; that is, the effect of ADT could be different at different doses of radiation. To test the presence of effect modification, a stratified Cox analysis was conducted by dividing the patients into low- and high-dose groups (see Table 3). This stratified analysis identified that the effect of hormone use on the risk of biochemical failure differed among the doses of radiation, signifying that effect modification does exist. A log-rank test for homogeneity of ADT use among the two strata was significant at p < .001, displaying that the effect of ADT causing a greater reduction in biochemical failure in the low-dose radiation group (HR, 0.284; p < .001) than in the high-dose group (HR, 0.478; p = .012). To evaluate if a benefit existed to giving more than 24 months of ADT, a Cox analysis was conducted only in patients who received ADT (see Table 4). This suggests that those receiving over 24 months of ADT have a reduced risk of biochemical failures compared with those receiving less than 24 months of ADT (HR, 0.619; 95% CI [0.412, 0.910]; p = .015). Since a benefit was seen at all three dose levels of ADT (none, <24 months, >24 months), the variable ADT use was analyzed at the three levels for the remainder of the analyses.
Table 3.
Stratified Cox Multivariable Analysis for Time to Prostate-Specific Antigen Failure.
| Hazard ratio | 95% CI | p Value | |
|---|---|---|---|
| Radiation dose ≤ 70 Gy | |||
| Age | 0.976 | [0.960, 0.933] | .007 |
| Pretreatment Prostate-Specific Antigen | 1.007 | [1.004, 1.010] | <.001 |
| Gleason Score | 1.177 | [1.084, 1.277] | <.001 |
| Year of Diagnosis | 0.91 | [0.860, 0.964] | .001 |
| T-stage | 0.901 | [0.776, 1.047] | .175 |
| Adjuvant Hormone Use (yes vs. no) | 0.284 | [0.196, 0.410] | <.001 |
| Radiation dose > 70 Gy | |||
| Age | 0.965 | [0.938, 0.994] | .018 |
| Pretreatment Prostate-Specific Antigen | 1.011 | [1.008, 1.015] | <.001 |
| Gleason Score | 1.612 | [1.293, 2.008] | <.001 |
| Year of Diagnosis | 0.976 | [0.915, 1.482] | .468 |
| T-stage | 1.184 | [0.946, 1.482] | .14 |
| Adjuvant Hormone Use (yes vs. no) | 0.478 | [0.269, 0.852] | .012 |
Table 4.
Cox Analysis of Prostate-Specific Antigen Failure in Patients Who Received Androgen Deprivation Therapy.
| Variable | Hazard ratio | 95% CI | p Value |
|---|---|---|---|
| Age | 0.967 | [0.945, 0.990] | .005 |
| Pretreatment Prostate-Specific Antigen | 1.007 | [1.005, 1.010] | <.001 |
| Gleason Score | 1.417 | [1.200, 1.674] | <.001 |
| Year of Diagnosis | 1.029 | [0.963, 1.099] | .395 |
| T-stage | 1.159 | [0.947, 1.418] | .153 |
| Radiation Dose (high vs. low) | 0.693 | [0.981, 1.230] | .211 |
| Length of Hormone Use (short vs. long) | 0.619 | [0.412, 0.910] | .015 |
A Cox multivariable analysis was conducted within each propensity score quintile (see Table 6). Weighted averages of the strata were then calculated to create the adjusted analysis. In the stratified (see Table 4) and the weighted average of the propensity score quintile-adjusted Cox multivariate analyses presented in Table 6, the models show that when adjusting for the variables in the analysis, there is a significant improvement in PSA-recurrence-free survival to ADT (HR, 0.248; 95% CI [0.196, 410]; p < .001 when dose ≤ 70 Gy and, HR, 0.478; 95% CI [0.269, 0.852]; p < .012 when dose >70 Gy, and HR, 0.506; 95% CI [0.419, 0.611]; p < .001 in the stratified Cox weighted average) as well as improvement in distant metastasis-free survival (see Table 5) with giving ADT (HR, 0.781; 95% CI [0.617, 0.988]; p < .004 in the initial Cox, HR, 0.693; 95% CI [0.524, 0.916]; p < .001 in the stratified Cox). Two additional techniques, matching and using the propensity score as a covariate, were utilized as a sensitivity analysis (see Appendix B).
Table 6.
Multivariable Cox Analysis for Time to Biochemical Failure in High Risk by Quintiles.
| Variable | Quintile 1 |
Quintile 2 |
Quintile 3 |
Quintile 4 |
Quintile 5 |
Weighted averages of strata |
||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Hazard ratio | 95% CI | p Value | Hazard ratio | 95% CI | p Value | Hazard ratio | 95% CI | p Value | Hazard ratio | 95% CI | p Value | Hazard ratio | 95% CI | p Value | Hazard ratio | 95% CI | p Value | |
| Age | 0.972 | [0.947, 0.998] | .034 | 0.968 | [0.938, 0.998] | .039 | 0.971 | [0.928, 1.016] | .199 | 0.96 | [0.924, 0.997] | .037 | 0.997 | [0.945, 1.051] | .899 | 0.98 | [0.956, 0.995] | .009 |
| Pretreatment Prostate-Specific Antigen | 1.042 | [1.029, 1.055] | <.001 | 1.026 | [1.007, 1.046] | .006 | 1.003 | [0.970, 1.036] | .867 | 1.032 | [1.011, 1.054] | .003 | 1.003 | [0.998, 1.009] | .251 | 1.007 | [1.003, 1.010] | .001 |
| Gleason Score | 1.181 | [1.050, 1.329] | .006 | 1.369 | [1.112, 1.686] | .003 | 1.132 | [0.750, 1.707] | .556 | 2.283 | [1.550, 3.642] | <.001 | 1.457 | [0.958, 2.214] | .078 | 1.202 | [1.016, 1.306] | <.001 |
| Year of Diagnosis | 0.919 | [0.815, 1.036] | .168 | 0.918 | [0.788, 1.070] | .272 | 0.874 | [0.628, 1.217] | .425 | 1.176 | [0.934, 1.480] | .167 | 0.823 | [0.683, 0.992] | .041 | 0.905 | [0.852, 0.961] | .001 |
| T-stage | 0.858 | [0.690, 1.067] | .169 | 1.089 | [0.867, 1.367] | .465 | 0.932 | [0.614, 1.416] | .742 | 1.149 | [0.851, 1.553] | .365 | 1.085 | [0.708, 1.662] | .709 | 0.998 | [0.869, 1.124] | .859 |
| Radiation Dose (high vs. low) | 0.534 | [0.187, .524] | .241 | 0.706 | [0.424, 1.176] | .181 | 0.351 | [0.143, 0.864\ | .023 | 1.172 | [0.361, 3.802] | .792 | 4.992 | [0.842, 29.607] | .077 | 0.728 | [0.519, 1.023] | .067 |
| Adjuvant Hormone Use (none, short, long) | 0.391 | [0.193, 0.796] | .01 | 0.423 | [0.317, 0.563] | <.001 | 0.482 | [0.326, 0.714] | <.001 | 0.546 | [0.317, 0.940] | .029 | 0.974 | [0.497, 1.909] | .938 | 0.506 | [0.419, 0.611] | <.001 |
Table 5.
Cox Models for Distant Failure: Initial, Stratified by Quintiles.
| Variable | Initial Cox |
Stratified by propensity score quintiles |
||||
|---|---|---|---|---|---|---|
| Hazard ratio | 95% CI | p Value | Hazard ratio | 95% CI | p Value | |
| Age | 0.961 | [0.939, 0.984] | .001 | 0.97 | [0.946, 0.995] | .017 |
| Pretreatment Prostate-Specific Antigen | 1.006 | [1.003, 1.009] | .001 | 0.999 | [0.993, 1.005] | .818 |
| Gleason Score | 1.407 | [1.239, 1.597] | .001 | 1.389 | [1.208, 1.597] | <.001 |
| Year of Diagnosis | 0.94 | [0.881, 1.003] | .062 | 0.841 | [0.763, 0.928] | .001 |
| T-stage | 1.265 | [1.023, 1.563] | .03 | 1.229 | [0.994, 1.519] | .057 |
| Radiation Dose (high vs. low) | 0.999 | [0.600, 1.663] | .996 | 1.012 | [0.582, 1.757] | .967 |
| Adjuvant Hormone Use (none, short, long) | 0.781 | [0.617, 0.988] | .04 | 0.693 | [0.524, 0.916] | .01 |
Discussion
These results identified that the addition of ADT to external beam radiation increased PSA-recurrence-free survival as well as distant metastasis-free survival even in the dose-escalation setting. Even though patients who received ADT were more likely to have higher pretreatment PSAs and higher Gleason scores, known adverse prognostic factors, these patients had reduced biological failures and distant metastasis compared with those who did not receive ADT. When controlling for the imbalances in prognostic factors using Cox and propensity score analyses, ADT seemed to decrease the risk of biochemical failures by 67.5% and a 21.9% reduction in distant metastasis. In addition, a 38.1% reduction in PSA recurrence was seen in patients who received greater than 24 months of ADT compared with those who received less than 24 months.
A number of trials evaluated the benefits of combining radiation and ADT in high-risk patients, which led to a standard of care of around 24 months of ADT for high-risk patients treated with EBRT. Pilepich et al. (2005; RTOG 85-31) evaluated high-risk PCa patients treated with 65 Gy to 70 Gy of radiation ± indefinite ADT, and found a reduction in local failures at 10 years (23% vs. 38%) as well as an overall survival benefit to adding ADT (Pilepich et al., 2005). In the RTOG 86-10 study, 65 Gy to 70 Gy of radiation was given to patients with bulky disease, ± short-term (4 months) ADT and improvements in biochemical control (65% vs. 80%) were seen on the ADT arm (Roach et al., 2008). The EORTC 22863 trial evaluated high-risk patients ± 3 years of ADT given with 70 Gy of radiation, and reported that the combined arm also revealed an improvement in disease-free survival (47.7% vs. 22.7%; Bolla et al., 2010). High-risk patients in RTOG 94-08 study, which randomized patients to radiation ± 4 months of ADT, reported an improvement in biochemical failure with ADT (28% vs. 47%) at 10 years (Jones et al., 2011). D’Amico et al. (2007) evaluated intermediate and high-risk patients who received 70 Gy ± 6 months of ADT and realized that ADT resulted in a reduction in PSA recurrence (19% vs. 54%). A large series of studies were conducted as part of the Early PCa Trialists’ Group, and the 7-year update indicated that patients with locally advanced cancers had a 59% improvement in PSA progression-free survival (See & Tyrrell, 2006).
Once the benefit of adding hormone therapy to radiation therapy was established, researchers began to investigate the optimum duration of hormone therapy. The Irish Clinical Oncology Research Group 97-01 study was conducted from 1997 to 2001 (Armstrong et al., 2011). This study randomized 261 patients with localized, node-negative, intermediate- to high-risk, PSA > 20 disease to 70 Gy of radiation with either a short (4-month) or long (8-month) course of neoadjuvant hormone therapy (luteinizing hormone-releasing hormone with flutamide). At 102 months of follow-up, there was no statistically significant difference between the two groups in terms of overall survival, biochemical-free survival, or cancer-specific survival. The Canadian Multicenter study was conducted from 1995 to 2001 (Crook et al., 2009). A total of 378 men with clinically localized cT1-T4 (43% intermediate risk) were randomized to receive either 3 or 8 months of hormone therapy (flutamide and goserelin) prior to definitive radiation to 66 Gy. Overall, no difference was seen in biochemical failure both arms. D’Amico et al. (2007) analyzed a total of 311 men with a median age of 70 years, who had been enrolled on three prospective randomized trials from 1987 to 2000, who received 6 months or 3 years of hormone therapy with definitive radiation therapy. Radiation doses were between 66 Gy and 70 Gy and ADT was given in some cases as combined androgen blockade and in other cases from single-agent therapy only. They discovered that after adjusting for known prognostic factors, the use of 3 years of hormone therapy did not improve survival compared with 6 months of hormone therapy.
No trials have yet been completed which incorporate higher doses of radiation and the current risk classification as per NCCN guidelines. The current trial, RTOG 99-10, does use modern risk stratification schemes, comparing 8 weeks versus 28 weeks of androgen suppression followed by a 70 Gy dose of radiation and closed to accrual in May of 2004, but results have not yet been presented. The suggestion based on our study findings is, for the present, to provide ADT to high-risk patients in conjunction with EBRT before the definitive results from large randomized clinical trials become available in the future.
Limitations of this study are inherent in the retrospective, nonrandomized setting. This bias is seen in the discrepancy in baseline PSA values, Gleason scores, and T-stage, and efforts were made to minimize the bias by use of the propensity score. As mentioned previously, some of the imbalances seen actually favored patients that did not receive ADT, that is, lower Gleason score and lower PSA. Even after controlling for this bias using propensity score adjustment, patients who did not receive ADT had an increased risk of biochemical failures as compared with those who received ADT. It is likely that ADT does have a significant biologic effect in reduction of biochemical failures. Another weakness is that the duration and type of ADT usage was not standardized. Additionally, this retrospective study was conducted in a specialized cancer center with little variation in terms of the race mix of the patient population. In addition, no information was available in the database regarding comorbidities and obesity, all of which may affect the results or limit their generalizability. Strengths of our study are long follow-up, and standardization of the pathology as well as the radiation treatment. Furthermore, the method of propensity scores was used to reduce bias in this retrospective study design.
This study supports the use of ADT for all high-risk PCa patients treated with EBRT, particularly in those receiving lower dose of radiation. The relative risk reduction for biochemical failures with the use of ADT differs slightly by levels of radiation dose, with less benefit from ADT among patients who received in high doses of radiation. Additional benefit is seen in giving longer than 24 months of EBRT, but delineation of patients within the high-risk category who would stand to benefit from longer courses of ADT would require a randomized clinical trial.
Footnotes
Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.
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