Risk for Developing Myelodysplastic Syndromes in Prostate Cancer Patients Definitively Treated With Radiation

JNCI J Natl Cancer Inst ( r isk for Developing Myelodysplastic Syndromes in Prostate c ancer Patients Definitively t reated With r adiation Sudipto Mukherjee 0 Chandana A. Reddy 0 Jay P. Ciezki 0 May Abdel-Wahab 0 Ramon V. Tiu 0 Edward Copelan 0 Anjali A. Advani 0 Yogen Saunthararajah 0 Katarina Paulic 0 Sean Hobson 0 Jaroslaw P. Maciejewski 0 Brian J. Bolwell 0 Matt Kalaycio 0 Robert Dreicer 0 Eric A. Klein 0 Mikkael A. Sekeres 0 0 Desk R35 , 9500 Euclid Ave, Cleveland, OH 44195 ( Background Exposure to ionizing radiation has been linked to myelodysplastic syndromes (MDS); it is not clear whether therapeutic radiation doses used for prostate cancer pose an increased MDS risk. We performed a retrospective cohort study of prostate cancer patients diagnosed between 1986 and 2011 at Cleveland Clinic, comparing those who underwent definitive treatment with radical prostatectomy (RP) to radiotherapy either external beam radiotherapy (EBRT) or prostate interstitial brachytherapy (PI) and to populationbased registries. Competing risk regression analyses were used to determine the cumulative risk of developing MDS. All statistical tests were two-sided. Of 10 924 patients, 5119 (47%) received radiation (n = 2183 [43%] in EBRT group and n = 2936 [57%] in PI group) and 5805 (53%) were treated with RP. Overall, 31 cases of MDS were observed, with age-adjusted incidence rates no higher than in population-based registries. In univariate analyses, advancing age (hazard ratio [HR]  =  1.14; 95% confidence interval [CI] = 1.09 to 1.20; P < .001) and radiotherapy exposure (HR = 3.44; 95% CI = 1.41 to 8.37; P = .007) were statistically significantly associated with development of MDS. In multivariable analyses, although advanced age (HR = 1.13; 95% CI = 1.06 to 1.19; P < .001) remained statistically associated with MDS, radiation did not, although a small non-statistically significant trend existed for PI-treated patients. MDS rates were no higher than in population-based registries. With relatively short follow-up, prostate cancer patients definitively treated with radiation did not appear to have a statistically increased risk of subsequent MDS. Results Conclusions Prostate cancer is the most common cancer affecting men in the United States, with an estimated 238 590 new cases and 29 270 deaths in 2013 ( 1 ). Clinically localized and locally advanced prostate cancer comprise more than 80% of all newly diagnosed cases ( 1 ). Radical prostatectomy (RP), external beam radiation therapy (EBRT), and prostate interstitial brachytherapy (PI) are all considered definitive treatment options for these patients, with 5-year relative survival rates approaching 100% ( 1 ). Ionizing radiation is a known carcinogen. Over the past two decades, several single registry ( 2–8 ) and Surveillance, Epidemiology, and End Results (SEER)–based studies ( 9–13 ) have reported variably increased risk of secondary hematological malignancies, mostly leukemias and lymphomas ( 9–11,14,15 ), after radiation to the prostate, particularly in long-term survivors. Myelodysplastic syndromes (MDS), a myeloid malignancy, is the most common bone marrow failure condition in the United States, with an age-adjusted incidence rate (AAIR) of 4.4 per 100 000 persons ( 16 ). MDS is a heterogeneous group of clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis leading to peripheral cytopenias and their related complications, with an increased risk of progression to acute myeloid leukemia. Although the majority of MDS cases arise de novo, approximately 14% are defined as therapy-related MDS (t-MDS) ( 17 ), occurring on average 5 to 7 years after treatment with cytotoxic chemotherapy, radiation, or both. Exposure to ionizing radiation has been linked to subsequent development of MDS in several cancer cohorts ( 18–20 ), but the risk of MDS in radiation-treated prostate cancer patients remains unclear. Delivery of external beam radiation to the prostate results in inadvertent irradiation of the surrounding pelvic bones, estimated to contain more than 50% of the total body reserve of active bone marrow mass ( 21,22 ). With PI, the potential effect of radiation on bone marrow is unclear. Recent evidence of circulating bone marrow–resident hematopoietic stem cell trafficking through extramedullary sites and homing back to the bone marrow (23) has led to the hypothesis that these bone marrow–resident hematopoietic stem cells are exposed to radiation from implanted [125I] iodine seeds as they pass through the prostate. Considering that prostate cancer patients constitute the second largest group of radiationtreated cancer patients in the United States ( 24 ) and the likelihood of exposure of a large volume of active marrow during EBRT as well as the putative mutagenic effects on circulating bone marrow– resident hematopoietic stem cells from implanted 125I seeds, there remains a concern for an increased risk of MDS in this (...truncated)