To determine whether the effect of androgen deprivation therapy (ADT) on the risk of biochemical failure varies at different doses of radiation in patients treated with definitive external beam radiation for intermediate risk prostate cancer (IRPC).
Ludwig et al BMC Cancer (2015) 15:190 DOI 10.1186/s12885-015-1180-6 RESEARCH ARTICLE Open Access The role of androgen deprivation therapy on biochemical failure and distant metastasis in intermediate-risk prostate cancer: effects of radiation dose escalation Michelle S Ludwig1*, Deborah A Kuban2, Xianglin L Du4, David S Lopez4, Jose-Miguel Yamal5 and Sara S Strom3 Abstract Background: To determine whether the effect of androgen deprivation therapy (ADT) on the risk of biochemical failure varies at different doses of radiation in patients treated with definitive external beam radiation for intermediate risk prostate cancer (IRPC) Methods: This study included 1218 IRPC patients treated with definitive external beam radiation therapy to the prostate and seminal vesicles from June 1987 to January 2009 at our institution Patient, treatment, and tumor information was collected, including age, race, Gleason score, radiation dose, PSA, T-stage, and months on ADT Results: The median follow-up was years A total of 421(34.6%) patients received ADT, 211 (17.3%) patients experienced a biochemical failure, and 38 (3.1%) developed distant metastasis On univariable analyses, higher PSA, earlier year of diagnosis, higher T-stage, lower doses of radiation, and the lack of ADT were associated with an increased risk of biochemical failure No difference in biochemical failure was seen among different racial groups or with the use of greater than months of ADT compared with less than months On multivariate analysis, the use of ADT was associated with a lower risk of biochemical failure than no ADT (HR, 0.599; 95% CI, 0.367-0.978; P < 0.04) and lower risk of distant metastasis (HR, 0.114; 95% CI, 0.014-0.905; P = 0.04) Conclusions: ADT reduced the risk of biochemical failure and distant metastasis in both low- and high dose radiation groups among men with intermediate-risk PCa Increasing the duration of ADT beyond months did not reduce the risk of biochemical failures Better understanding the benefit of ADT in the era of dose escalation will require a randomized clinical trial Keywords: Prostate cancer, Dose escalation, Androgen deprivation therapy, Intermediate risk prostate cancer Background The addition of Androgen Deprivation Therapy (ADT) to radiation therapy for locally advanced prostate cancer has demonstrated an improvement in local control and overall survival benefit in a number of randomized controlled trials [1-6] Many of these trials were conducted in an era where lower doses of radiation were used and when patients were not evaluated in the risk groups that are now used to make clinical decisions In all of the * Correspondence: Michelle.Ludwig@bcm.edu Department of Radiology, Baylor College of Medicine, One Baylor Plaza, MS: BCM360 Room 165B, Houston, TX 77030, USA Full list of author information is available at the end of the article described trials that established the need for ADT with external beam radiation, a dose of 70 Gy or less was used In 2002, results from a randomized trial by Pollack et al., showed that a 78 Gy dose improved survival and other several similar dose-escalation studies changed the recommended practice patterns by increasing the dose of prostate radiation [7-10] In the face of this new standard of higher radiation doses, there is a need to evaluate the benefit of adding ADT in terms of optimal patient selection and optimal timing and duration of ADT ADT can cause adverse physical and psychological side effects in patients, such as decrease in muscle mass, increase in diabetes, decrease in bone density, depression, © 2015 Ludwig et al This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited The Creative Commons Public Domain Dedication waiver (http:// creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated Ludwig et al BMC Cancer (2015) 15:190 loss of libido, and others, so its use must be carefully balanced between benefit and risk [11,12] Current National Comprehensive Cancer Network (NCCN) guidelines reflect this uncertainty by recommending “consideration of 4-6 months of ADT” if radiation therapy is given as definitive treatment for intermediate and high risk prostate cancer [13] Given the adverse physical and quality of life effects of ADT and the unknown benefit of ADT in the era of radiation dose escalation, an evaluation of its benefit is needed We conducted a retrospective clinical review of prostate cancer patients to determine whether the effect of ADT on the risk of biochemical failure and distant metastasis was the same at different doses of radiation in intermediate risk prostate cancer and whether the duration or timing of ADT resulted in improved outcomes Page of for the first two years, then every six months for the next years, and then annually after five years Their medical records were analyzed in a retrospective fashion and institutional approval was received prior to initiating the study The biochemical 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 [14] Patients lost to follow-up were censored at the last visit The interval to biochemical failure was calculated from the completion date of radiation therapy Metastatic failures were outside of the pelvis, in nonregional lymph nodes, bone, or other places Coding of metastatic disease was based on chart review Statistical analysis Methods Patient selection and pretreatment evaluation This study included intermediate risk prostate cancer (defined according to NCCN criteria) patients who were treated at our institution with definitive external beam radiation therapy from June 1987 to January 2009 [13] The proposal approval was granted by the University of Texas Health Science Center at Houston Committee for The Protection of Human Subjects #HSC-SPH-12-0475 The data were collected under the MD Anderson Cancer Center IRB as Protocol RCR02-127 All patients had biopsyproven 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 The bone scans and pelvic computerized tomography for staging were performed if the patient’s pretreatment PSA was ≥10 or Gleason score was ≥8 Treatment All patients were treated with definitive external beam radiation therapy to the prostateand seminal vesicles Prior to 2000, conventional four-field techniques were used with doses prescribed to the isocenter After 2000, intensity-modulated radiation therapy was used to treat the prostate and seminal vesicles Lymph nodes were not included in the clinical target volume Radiation prescription doses ranged from 60 to 78 Gy, depending on the year of treatment ADT was delivered either as total androgen blockade or a lutenizing hormone releasing hormone (LHRH) agonist alone, given at the discretion of the treating radiation oncologist Follow-up and endpoints Follow-up evaluation consisted of digital rectal examination and serum PSA measurements every 3-6 months Descriptive measures were calculated for all variables, and the patients were divided into ADT and no ADT groups Univariable analyses were conducted to determine the relationship between all variables and the outcome of biochemical failure or distant metastasis, using Cox proportional hazards models Comparisons between the use of ADT and the other variables were assessed using a t-test All variables were analyzed as continuous variables except for radiation dose, which was considered a binary variable (low dose radiation was defined as receiving < = 70 Gy, and high dose radiation was defined as > 70 Gy) and ADT (yes or no) and timing of ADT (neoadjuvant or adjuvant) Five and ten year rates of biochemical failure were calculated for the overall and four major groups Radiation dose was evaluated for effect modification by both addition of an interaction term in the models and by stratification by dose of radiation 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 In the absence of definitive guidelines for placing patients on ADT, the decision is left to the treating physician As such, this decision is likely to be influenced by patient factors (e.g., age and comorbidity) and tumor factors (PSA, t-stage, Gleason score), which are all known to contribute to outcomes of biochemical, local, and distant failures In order to address this selection bias, propensity score analysis was utilized16 In our application, the propensity score estimates the conditional probability of a Ludwig et al BMC Cancer (2015) 15:190 Page of patient receiving a hormonal treatment given other covariates To create the scores, 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 backwards stepwise procedure The propensity score-adjusted result has been shown to remove 90% of the bias in a continuous distribution [15] Matching on the propensity score and using the propensity score as a covariate in the Cox model were used for the outcome of biochemical failures Matching was then conducted; a 1:1 matched pair design without replacement was used to account for the nonrandom treatment allocation Case patients (with ADT) were matched with control patients (no ADT) Since matching results in a violation of the independence assumption for a Cox model, a frailty term was used for the matched pairs in creation of the model Results and discussion A total of 1218 patients with intermediate risk prostate cancer were included in our study Table shows the characteristics of the patients by ADT status The mean age for all patients was 68.5 years Median follow up was years A total of 421 (34.6) patients received adjuvant ADT, with 211 (17.3%) patients experiencing a biochemical failure, and (3.1%) experiencing distant metastasis Five year rates of biochemical failure were 9.7% and ten year rates were 16.1% Of the patients who received ADT, a total of 271 (64.4%) patients received months or less, and 150 (35.6%) patients were on ADT for longer than months Radiation dose was divided into low Table Distribution of baseline variables by concurrent ADT status Variable ADT No ADT (cases) (unmatched controls) Total p-value no ADT p-value (unmatched) (matched controls) (matched) n = 421 n = 797 Mean age 68.63 68.5 0.75 68.4 0.67 Mean PSA 8.47 8.18 0.28 8.12 0.252 Gleason Score (mean) 6.9 6.38