1. Corresponding author Name; 2015 North Jefferson St; email@floridaproton.org; 904-588- 1800 Three-Year Analysis of Urinary Toxicity in Two Prospective Trials of Image-guided Proton Therapy for Early- and Intermediate-Risk Prostate Cancer: Outcomes in Men with Moderate to Severe Pretreatment Urinary Obstructive Symptoms Randal H. Henderson, MD, MBA; Zuofeng Li, DSc; Bradford S Hoppe, MD; Robert B Marcus, MD; William M Mendenhall, MD; R Charles Nichols, MD; Christopher G Morris, MD; Christopher R Williams, MD; Joseph Costa, DO; Nancy P Mendenhall, MD University of Florida Proton Therapy Institute, Jacksonville, FL Introduction To assess the impact of moderate-to-severe pretreatment urinary obstructive symptoms on late urinary function and genitourinary (GU) toxicity in patients treated with image- guided proton therapy for early- and intermediate-risk prostate cancer. Methods One hundred seventy-one prostate cancer patients accrued to two prospective institutional review board-approved trials of 78 cobalt gray equivalent (CGE) in 39 fractions for low–risk disease or dose escalation from 78 to 82 CGE for intermediate-risk disease. Minimum potential follow-up was 3 years. Thirty-two patients had pretreatment International Prostate Symptom Score (IPSS) of >15. The IPSS was followed for changes over time and analyzed as a pretreatment factor against CTCAE v3.0 acute and late GU toxicity. Results One low-risk and 1 intermediate-risk patient had disease progression out of the total 171 patients. Multivariate analysis showed a correlation between GU 2+ symptoms and pre-treatment GU symptom management (p=0.0003), but no correlation with dose-volume parameters for the bladder and bladder wall. A total of 58, 54, and 60 patients received alpha-blockers before, during, and after proton therapy, respectively. There were 18 and 5 patients who received their first prescription for alpha-blockers during and after radiotherapy, respectively. Patients with pretreatment IPSS scores of >15 had a decline in median score from 18 prior to treatment to a median score of 11.5 at 36 months follow-up. Pretreatment IPSS >15 versus <15 was not associated with a higher incidence of grade 2+ acute GU toxicity (12% vs. 9%, p=0.7491). The Kaplan- Meyer 3-year freedom from grade 2+ late GU toxicity was 63% versus 85% (p =0.0164) and from grade 3 late toxicity it was 100% versus 97% in the two groups respectively (p=0.3318), and 98% overall. There were no late grade 4 events and all late grade 3 complications have resolved with time. Conclusions Outcomes at 3 years with image-guided proton therapy in doses up to 82 CGE, based on organ-constraints and the techniques used in this study, continue to suggest high efficacy and minimal toxicity. Patients with a pretreatment IPSS score of >15 had significant improvement in median IPSS scores at 36 months, while patients with pretreatment scores of <15 had no change in median scores. The low toxicity and improvement in IPSS score in patients with moderate to severe pretreatment urinary obstructive symptoms may be useful in decisions regarding the choice of treatment for this group of patients.