Radiation Treatment for Localized Prostate Cancer and the Risk of Developing Myelodysplastic Syndromes (MDS)
Authors: Mukherjee Sudipto , Reddy Chandana , Ciezki Jay , Tiu Ramon V. , Copelan Edward A. , Advani Anjali S. , Saunthararajah Yogen , Paulic Katarina , Maciejewski Jaroslaw P. , Bolwell Brian J. , Klein Eric A. , Sekeres Mikkael A. 
Published: October 2019

Abstract
Abstract 120

Background:
Both environmental radiation exposure and use of therapeutic radiation (XRT) in primary solid tumor malignancies increase the risk of secondary MDS. No data exist on the risk of developing secondary MDS in prostate cancer patients (pts) being treated with radiotherapy. Establishing this risk has important clinical implications, as prostate cancer is the leading cancer in men and radiation therapy has increasingly become the preferred modality for treatment of localized prostate cancer.

Methods:
We performed a prospective case control study of 11,015 pts with localized prostate adenocarcinoma newly diagnosed between 1986 and 2011 at Cleveland Clinic who underwent treatment with either radical prostatectomy (control group) or definitive radiotherapy (external beam radiotherapy [EBRT] or prostate interstitial brachytherapy [PI] – case group), to investigate the risk of radiation-related MDS. Data on demographics, surgery, radiation treatment, and follow-up were collected from merged prostate cancer and MDS databases. Cytogenetic risk groups were per International Prognostic Scoring System (IPSS) for MDS. Univariate and multivariate analyses were performed using the Fine and Gray competing risk model with MDS as a time-dependent endpoint (which incorporates differences in duration of follow-up) and death from any cause as the competing event, comparing radiotherapy groups to the surgical cohort as the reference group, controlling for age and follow-up frequency. Hazard ratios (HR) with 95% confidence intervals (CIs) are reported.

Results:
For all pts, median age was 64 years (yrs, range, 37 – 88) at the time of prostate cancer diagnosis: 69 yrs in EBRT, 67 yrs in PI, and 60 yrs in surgery pts, respectively (p<0.0001); 5119 (46%) were treated with XRT, 5896 (54%) with prostatectomy. None of the pts had a previous history of another malignancy. Among XRT pts, 2183 (43%) were treated with EBRT, 2936 (57%) with PI. Median follow-up was 3.0 yrs [(range, 0.0 – 25.2): 6.8 yrs in the EBRT group, 2.5 yrs in the PI group and 1.8 yrs in the surgery group, (p<0.0001)] following prostate intervention, longer (4.6 yrs) in pts treated since 1996, when PI was first performed [6.6 yrs in the EBRT group, 3.8 yrs in the PI group and 4.3 yrs in the surgery group, (p<0.0001)]. In the entire cohort, 30 pts developed MDS: 24 in the XRT group and 6 in the surgery group. MDS World Health Organization classification was: RA/RARS (n=12), RCMD (n=3), RAEB-1 (n=3), RAEB-2 (n=3), CMML (n=2), MDS-U (n=3) and unknown (n=4). IPSS cytogenetic risk classification was: good risk (n=17), intermediate risk (n=5), poor risk (n= 4) and unknown (n = 4). For MDS pts within the XRT group, median age at MDS diagnosis was 79 yrs (range, 74 – 89) for EBRT, 80 yrs (range, 64 – 100) for PI. The median time to develop MDS was 8.9 yrs (range, 0.9 – 20.2): 9.1 for EBRT, 8.2 for PI, and 13.0 for prostatectomy pts, respectively (p=0.05). In univariate analyses, older pts (HR=1.14; CI, 1.09 – 1.2; p<0.0001), and those treated with XRT (HR=3.3; CI, 1.35 – 8.08; p=0.009): EBRT (HR=2.6; CI, 1.0 – 6.9; p=0.05), PI (HR=5.87; CI, 2.1 – 16.3; p=0.0007) were significantly more likely to develop MDS. In multivariate analysis though, while advanced age (HR=1.13; CI, 1.0 – 1.2; p < 0.0001) remained significantly associated with MDS development, XRT did not (HR=1.56; CI, 0.56 – 4.38; p=0.4), though a trend remained for PI (HR=2.85; CI, 0.9 – 8.8; p = 0.07).

Conclusions:
Pts who underwent definitive radiation treatment for localized prostate cancer did not appear to have a significantly increased risk of subsequent MDS, in analyses that controlled for age and incorporated length of follow-up. A trend for MDS development was present for those undergoing XRT with PI. These findings are encouraging for both patients and providers who have concerns about the potential effects of XRT on development of MDS.

Disclosures:
Maciejewski: Celgene: Membership on an entity's Board of Directors or advisory committees. Sekeres:Celgene: Consultancy, Honoraria, Speakers Bureau.