Erectile Dysfunction and Absorbed Dose to Penile Base Structures in a Randomized Trial Comparing Ultrahypofractionated and Conventionally Fractionated Radiation Therapy for Prostate Cancer

Journal Pre-proof Erectile dysfunction and absorbed dose to penile base structures in a randomized trial comparing ultra-hypofractionated and conventionally fractionated radiotherapy for prostate cancer Elisabeth Rasmusson, M.D, Adalsteinn Gunnlaugsson, M.D. Ph.D, Elinore Wieslander, Ph.D, Medical Physicist, Peter Höglund, M.D, Professor, Anders Widmark, M.D, Professor, Per Fransson, Ph. D, Elisabeth Kjellén, M.D, Associate Professor, Per Nilsson, Associate Professor, Medical Physicist PII:

S0360-3016(20)30128-0

DOI:

https://doi.org/10.1016/j.ijrobp.2020.01.022

Reference:

ROB 26165

To appear in:

International Journal of Radiation Oncology • Biology • Physics

Received Date: 11 October 2019 Revised Date:

13 January 2020

Accepted Date: 21 January 2020

Please cite this article as: Rasmusson E, Gunnlaugsson A, Wieslander E, Höglund P, Widmark A, Fransson P, Kjellén E, Nilsson P, Erectile dysfunction and absorbed dose to penile base structures in a randomized trial comparing ultra-hypofractionated and conventionally fractionated radiotherapy for prostate cancer, International Journal of Radiation Oncology • Biology • Physics (2020), doi: https:// doi.org/10.1016/j.ijrobp.2020.01.022. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Elsevier Inc. All rights reserved.

Erectile dysfunction and absorbed dose to penile base structures in a randomized trial comparing ultra-hypofractionated and conventionally fractionated radiotherapy for prostate cancer

Short running title: Ultra-hypofractionation: erectile dysfunction Authors: Elisabeth Rasmussona,e , M.D. Adalsteinn Gunnlaugssona,e , M.D. Ph.D Elinore Wieslandera, Ph.D. Medical Physicist Peter Höglundb, Professor. M.D.* Anders Widmarkc, Professor. M.D. Per Franssond , Ph. D Elisabeth Kjelléna,e, Associate Professor. M.D. Per Nilsson a,f. Associate Professor. Medical Physicist. a

Department of Haematology, Oncology and Radiation Physics, Skane University Hospital, Lund, Sweden b Lund University, Faculty of Medicine, Department of Laboratory Medicine, Clinical Pharmacology, Lund, Sweden c Department of Oncology, Umeå University Hospital, Umeå, Sweden d Umeå University, Department of Nursing, Umeå, Sweden e Lund University, Faculty of Medicine, Department of Clinical Sciences, Lund, Oncology and Pathology, Lund, Sweden f Lund University, Faculty of Medicine, Department of Clinical Sciences Lund, Radiation Physics, Lund, Sweden *Deceased 9 Sept 2019 Corresponding author: Elisabeth Rasmusson Mail: Skane University Hospital, Oncology, Klinikgatan 5 22242 Lund SWEDEN E-mail: [email protected] Telephone number: +46 46 172540, +46 709 981910 Author responsible for statistical analyses: Per Nilsson and Peter Höglund (Deceased 9 Sept. 2019) Mail: Skane University Hospital, Oncology, Klinikgatan 5 22242 Lund SWEDEN E-mail: [email protected], [email protected] Telephone number: +46 768 871567 Conflict of interest: None Funding: Regional funds (Region Skåne), Berta Kamprad Foundation, The Swedish Research Council Acknowledgement: The HYPO-RT-PC Study group

Abstract Purpose To study the relationships between absorbed dose to penile base structures and erectile dysfunction (ED) in patients treated with ultra-hypofractionated (UHF) radiotherapy (RT) or conventionally fractionated (CF) RT for prostate cancer. Materials/Methods This dose-response study comprises 673 patients (57%) of the 1180 per-protocol patients included in the XXXXXXXXXX trial (median follow up 5 years) where patients were randomised to CF (39x2.0 Gy, 8 weeks) or UHF (7x6.1Gy, 2.5 weeks). No ADT was allowed. Only patients with erectile function enough for intercourse at baseline and complete RT data were included in this study. Erectile function was assessed by physician at regular follow-ups. The main endpoint was severe ED (EDs). The penile bulb (PB) and crus were retrospectively delineated on the treatment planning CT scans. Dose-volume descriptors were derived from EQD2 converted dose matrices (α/β=3 Gy). Uni- and multivariable Cox proportional hazard regression and logistic regression were used to find predictors for EDS. Results No significant difference in EDs was found between CF and UHF. During the follow up period EDs occurred in 27% of the patients in both treatment groups. Average (median) PB mean dose, Dmean, was 24.5 (20.2) in CF and 18.7 (13.1) Gy3 in UHF. Age was the only significant predictor for EDs in Cox analyses. All dose-volume variables contributed significantly in univariable logistic regression at 2 year follow-up. Age and near maximum dose (D2%) were significant predictors for EDs in multivariable logistic regression analyses at both 1 and 2 years.

Conclusions The frequency of EDS was similar in the CF and UHF treatment groups. Age at radiotherapy was the strongest predictor for EDs followed by dose to PB, most evident for younger patients. We propose D2 % < 50 Gy3 and Dmean <20 Gy3 to PB as primary objectives to be applied in the treatment planning process.

Introduction Erectile dysfunction (ED) is a common side effect after radiation therapy (RT) for prostate cancer. According to the literature, at least 50 % of the patients develop radiation induced ED (RiED) in five years after radiotherapy. The largest decline in erectile function occurs within the first year and increases with time predominantly during the first few years (1-3).

Based on the high radiation-fraction sensitivity of prostate cancer several trials with hypofractionated RT have been performed as a mean of increasing the therapeutic ratio. Hypofractionation is generally categorised as moderate hypofractionation (MHF) or ultrahypofractionation (UHF) with fraction sizes in the range of 2.4-3.4 Gy and ≥5 Gy, respectively (4). Recently, four large randomised studies on MHF (CHHiP(5), HYPRO (6), NRG Oncology RTOG0415 (7), and PROFIT (8)) have been published with median followup of five years or more. These studies all indicate that MHF is safe and results in disease control comparable to what is accomplished with CF and they have therefore changed the clinical practice in many RT centres (4). No significant differences in ED between CF and MHF have been reported in these trials (5, 9, 10).

Ultra-hypofractionation of prostate cancer is still considered experimental although many studies are ongoing and the results so far seem promising (4). Five-year outcomes from one large randomized UHF study have recently been reported; the XXXXXXXXXXXX XXXXXXXXXX study (11). The UHF schedule (6.1 Gy/fraction) in this trial was found to be non-inferior to CF regarding failure-free survival with similar late side-effects in the treatment arms.

Studies on erectile function after RT in relation to dose to critical erectile structures are mainly focused on PB and crus as organs-at-risk (OAR), with contradictory results. For example a study by Roach et al. (12) on 158 patients supported dose response while a study by Van der Wielen et al. (13) on 96 patients did not. Most reported studies have a limited number of patients and some studies include patients with hormonal treatment. Structure delineation, endpoint and follow-up differ (12-15). The QUANTEC review by Roach et al. concludes that “the bulb might be a surrogate for yet to be determined structures” and that “it is prudent to keep the mean dose to 95% of the bulb to less than 50 Gy” (16).

The aim of the present work was to study the relationship between absorbed dose to penile base structures and ED in patients treated in the XXXXXXXXXX study, i.e. with UHF-RT or CF-RT for prostate cancer. Specifically, we investigated if any dose-volume objectives can be recommended to reduce the risk of ED.

Materials and Methods The XXXXXXXXXX-trial 1200 patients (< 75 years of age) with verified intermediate-to-high-risk prostate cancer were included in the multicentre XXXXXXXXXX phase III trial (11). Patients were randomized to CF (39x2.0 Gy=78.0 Gy in 8 weeks) or UHF (7x6.1Gy=42.7 Gy in 2.5 weeks). The treatment schedules were designed to be equieffective for late normal tissue complications under the linear-quadratic model (α/β=3 Gy). No ADT was allowed. 1180 patients were treated per protocol. The clinical target volume (CTV) was the prostate as outlined on CT (MR guidance was recommended). The seminal vesicles were not included in the CTV. Mandatory organs at risk were rectum, anal canal, urinary bladder and femoral heads while it was optional to delineate

the PB and hence no dose-volume objectives were applied to this structure. Treatment planning dose-volume constraints/objectives can be found in the study protocol (xxxxxxxxxxxx). The constraints/objectives were linearly scaled from CF to UHF rather than EQD2 corrected.

Radiotherapy was given with 3D-CRT (80%) or VMAT (20%) using image guidance based initially on the BeamCath® technique (10%) and then implanted markers (90%). For the UHF patients treated with BeamCath® technique (17) a CTV−planning target volume (PTV) margin of 6 mm was added (4 mm dorsal) and all fractions were given with BeamCath®. For the CF patients four fractions were given with BeamCath® with these margins and the remaining fractions (35) with wider (10-15 mm) margins and no IGRT. For the patients treated with implanted markers, an isotropic margin of 7 mm was added to the CTV to generate the PTV, in both treatment arms. The study was approved in XXXXXX by the Ethics Committee in XXXX (03-513, 2003-1223) and in XXXXXXX by the XXXXXXX XXXXXXX XXXXXX Committees on Health Research Ethics (M-20090180, 2009-11-19). Follow-up of ED and patient inclusion Patients were followed-up at end of RT, at three, six, nine and 12 months after start of RT and then every six months. At these visits erectile function was assessed as: “enough for intercourse”, “not enough for intercourse” (EDM) or “severe erectile dysfunction” (EDS). Only patients with erectile function “enough for intercourse” at randomization and available dose distributions were included in this study.

Delineation of PB and crus

The treatment planning CT-scans, and MRI-scans when available, were imported into the treatment planning system (Eclipse 13.6, Varian) for delineation. The PB and crus were delineated by the same radiation oncologist (the first author (XX)) on the treatment planning CT scans (Figure A1). The PB was defined according to RTOG recommendations as the bulbous portion of the corpora spongiosa near the divergence of the corpora cavernosa (18). Crus was defined as the divergent proximal portions of the corpora cavernosa, originating under the ischio-pubic rami as two separate structures and merging under the pubic arch (18, 19).

Dose distributions The delineated structures (PB and crus) and the original dose distributions were imported into the software package Medical Interactive Creative Environment (MICE version 1.0.4, available at https://www.micetoolkit.com). The analyses were performed for equivalent doses converted, voxel by voxel, to 2 Gy with α/β=3 Gy (EQD23). Dose-volume descriptors (mean dose (Dmean (Gy3)), median dose (D50% (Gy3)), near maximum dose (D2 %( Gy3)) and V5-65Gy3 (%) in 5 Gy3 steps) were derived for PB and crus. Data analysis and statistical methods Uni- and multivariable Cox proportional hazard regression and logistic regression were used to find predictors for severe ED (EDS) and for severe or moderate ED (EDS/M). In the Cox regression analyses patients were censored in case of hormonal treatment (after relapse) or at the last follow-up. We also performed the time-to-event analyses with hormonal treatment and death as competing events. The following rules for defining time to event (EDS or EDS/M) were used:

1. The patient had to have EDS/EDS/M at two consecutive follow-ups or more, without later recovery. Time to EDS/EDS/M was set at the first date of these events. 2. If missing data before the date of event, the time to EDS/EDS/M was set to midway between last follow-up before the event and the date of event. Statistical analyses were made using IBM SPSS Statistics version 24 and R version 3.4.3.

Results

In total 673 patients were included in the study (330 and 343 in the CF and UHF arms, respectively), i.e. 57% of the 1180 per-protocol patients in the trial (Figure 1). No statistically significant differences in patient characteristics and treatment techniques were found between the two treatment arms for the study cohort (Table 1).

Dose distributions There was a strong correlation between the dose-volume descriptors studied (r>0.85) for both PB and crus. To avoid problems with collinearity in the multivariable analyses only the most significant dose descriptor was included. There was also a strong correlation between the dose distributions in PB and crus (r>0.8). Dose-response analyses were therefore restricted to PB. Average (median) Dmean in PB was 24.5 (20.2) in CF and 18.7 (13.1) Gy3 in UHF, respectively. Corresponding figures for average (median) D2% was 52.1 (63.3) in CF and 46.0 (54.4) Gy3 in UHF. Complementary data on the PB volume and selected dose-volume descriptors are presented in Table A1. The EQD2 doses are consistently lower for patients in the UHF compared to the CF group treated with fiducials, primarily due to the linearly scaled dose-volume objectives/constraints

but also due to the differences in margins for the patients treated with BeamCath®. PB mean dose-volume histograms (DVH) per treatment arm are presented in Figure A2 for all patients and separately for patients treated with BeamCath® and gold fiducials. As expected, the DVHs with dose in percentage units are similar for the two treatment arms when using fiducials while they differ substantially for the BeamCath® technique due to the described differences in CTV-PTV margins.

Time to EDs EDs occurred in 181 (27%) patients (89 (27%) in CF and 92 (27%) in UHF) during the follow up period. Treatment group (UHF vs. CF), clinical variables (T-stage, Gleason score, PSA at randomization, age at RT), treatment technique (VMAT vs. 3DCRT) and the dose-volume descriptors were tested as predictors for time to EDs in Cox proportional hazard regressions. There was no significant difference in the development of EDs over time between CF and UHF (Figure 2a).The only statistically significant predictor was age, both in univariable and multivariable analyses. Of the tested dose-volume descriptors, D2%, was the strongest predictor for time to EDs (p=0.08) (Table 2). When adjusting for hormonal treatment and death as competing events we obtained similar results (Table A3). Including only patients treated with implanted gold fiducials, i.e. excluding patients treated with BeamCath® technique, gave results consistent with those for the whole patient material (Table A4).

EDs at 12 and 24 months EDs was present in 74 (11%) (37 in each treatment arm) and in 105 (18%) (53 in CF and 52 in UHF) patients at 12 and 24 months, respectively. Age was the only clinical statistically significant predictor for EDs. All dose-volume descriptors studied were significantly associated with EDs in univariable analyses at 24 months but only D2% at 12 months (Table

2), the strongest single dose predictor at both follow-up times. Dose-volume histograms (DVH), derived from median Vx-values for patients with and without EDs at 24 months are presented in Figure 3a. In multivariable analyses, age together with D2 % was significant predictors for EDS at both 12 and 24 months. This was also the case when excluding patients treated with BeamCath® (Table A4).

EDS at 36, 48 and 60 months Only age contributed significantly to EDS at 36, 48 and 60 months in the logistic regression analyses.

EDs in “young” patients. Further analyses showed that the association between dose and EDs was strongest for the younger patients in the study cohort. Based on receiver-operating characteristic (ROC) of D2% and Dmean for EDs at12 and 24 months we found the largest area under the ROC curve (AUC) for patients aged 65 years or younger. The cumulative incidence of EDs for patients ≤ 65 and > 65 years are shown in Figure 2b. The dose-response analyses described above were repeated for the younger group. A strong significant association between dose and EDs was found at both 12 and 24 months and also when analyzed over time with Cox regression (Table 2). As for the whole patient group, D2% was the strongest dose predictor. Median DVHs for patients with and without EDs at 24 months are presented in Figure 3b. ROC curve analyses on D2% for patients ≤65 years resulted in AUC values of 0.714 and 0.735 for EDs at 12 and 24 months, respectively. The best D2% cut-off value for predicting EDs, based on maximum Youden index, was 50 Gy3 at both 12 and 24 months. The cumulative

incidence of EDs for patients 65 years or younger with D2 %< 50 Gy3 and D2%≥50 Gy3 is shown in Figure 2c. Corresponding ROC curve analyses on Dmean for patients ≤65 years resulted in AUC values of 0.716 for EDs at both 12 and 24 months. The best cut-off value for predicting EDs was 20 Gy3 at both 12 and 24 months. The dose-response relationship for D2% and EDs at 24 months is shown in Figure 4 for patients younger and older than 65 years.

EDS/M EDS/M occurred in 340 (51%) patients (166 (50%) in CF and 174 (51%) in UHF) during the follow up period. The only statistically significant predictor for time to EDS/M and EDS/M at 12 and 24 months was age. For young patients (≤65 years) D2% was significantly associated with time to EDS/M and for EDS/M at 24 months (data not shown).

Discussion The XXXXXXXXXXXX XXXXXXXXXX trial is the first published prospective randomized phase III study comparing CF with UHF. As previously presented there were no significant differences in ED between the two treatment arms after a median follow-up time of five years (11). In the present work we have evaluated the risk of ED for the patients treated within the trial with special focus on the impact of radiation doses to the penile base. Our results show that age at radiotherapy is the strongest predictor of ED followed by the “near maximum” dose (D2%) to the PB. However, it should be stressed that all studied dosevolume parameters were significantly associated with EDs at 24 months. This implies that a volume dependence cannot be ruled out and hence that dose-volume parameters other than

D2% could also be of importance when defining treatment planning dose-volume objectives for the PB. We found, however, that the best cut-off dose to prevent EDs was at near maximum dose of 50 Gy3 to the PB, established on results for younger patients (≤65 years). We therefore suggest this as a dose volume objective. Based on ROC analysis, and that a volume dependence cannot be excluded, we suggest to add mean dose of 20 Gy3 to the PB as dose volume objective. Another argument for mean dose as treatment planning objective is that it might be more robust to differences in outlining, as the cranial part included in the penile bulb volume will have major impact on D2%. The median DVHs for patients with and without EDs (figure 3) support these dose volume objectives for D2% and Dmean. Compared to the recommendation made by the QUANTEC group, i.e. to keep the mean dose to the PB below 50 Gy (to 95% of the volume) our results suggest to keep the near maximum dose at the same level and the mean dose substantially lower. The QUANTEC recommendation is based on few studies. The largest included study (with evaluation of doseresponse association) is on 158 patients by Roach et al. (12) where the mean dose to the PB is higher than in our material. The low mean dose in our study can explain why the near maximum dose (D2%) was a better predictor of ED than the mean dose and also why the doseresponse relationship was quite weak. To our knowledge there are only two publications concerning hypofractionation and doseresponse relationship with ED. Mc Donald et al.(20) published a study on 41 patients treated with moderate hypofractionation and reported reduced radiation tolerance of penile structures with a mean dose at 20 Gy as cut-off. Murray et al. (21) recently presented dose-ED data for 233 patients without severe ED at baseline, treated within the CHHiP trial. They propose that a mean PB dose <20 Gy increases potency preservation, in line with our findings.

In the present study the frequency of ED and its development over time was similar in the CF and UHF arms despite the fact that EQD23 -corrected doses to the erectile tissue were, as expected, lower in the UHF arm. A complementary analysis with EQD22 correction (α/β= 2 Gy) resulted in more equal dose distributions to the PB between the arms. This might indicate that the α/β of the tissues involved in the pathogenesis of RiED is lower than 3 Gy, supporting radiation injury to slow reacting structures, such as nerves and vessels. An interesting approach to further spare the erectile tissues is vessel-sparing radiotherapy, where a reduced dose to the internal pudendal artery (IPA), has shown promising results which implicates that vessel injury could be an important cause of RiED (22) .

It is not surprising that age was strongly correlated to ED. This correlation has been reported in several epidemiological studies such as the large MALES study, where the prevalence of ED was found to be 30 % in the age group of 60-69 years and 37 % for 70-75 years (23). The largest European study EMAS, where a cohort from XXXXXX was included, found 64% ED (severe +moderate) in the age-group over 70 years, almost twice as high as for the age group of 60-69 years (38%) (24). The annual incidence is increasing with age and was reported to be about 5% in the ages between 60-69 in the Massachusetts male aging study(25). In the XXXXXX study 58 % of the patients had a good erectile function at baseline, in line with these epidemiological studies. Given the median age of the HYPO-RT-PC study population one can estimate that approximately 5% of the HYPO-RT-PC patient population can be expected to lose their erectile function each year, to be taken into account when interpreting the effect of radiation dose on ED. We observed a stronger dose-response effect among the younger patients (less than 65 years). This might reflect the fact that ED-development in older patients is more multifactorial with several competing factors (e.g. comorbidities, medications, etc.).

However, despite the impact of age, we observed modest but significant dose-response effects between radiation doses to the penile base on ED, so sparing of these structures is still recommended in all age groups, while preserving the dose coverage of the CTV.

There are some limitations to our study. To measure ED is a delicate matter. Inaccuracy in the assessment of ED could cause an inaccurate evaluation of the dose-volume effects on erectile tissues. We chose to work with ED scored by physician. This three level endpoint is not based on a validated protocol which is a weakness of the study. Patient reported outcome measurements (PROM) could add valuable information on the relationship between dose to the penile bulb and ED. There were several reasons for not including PROM data in the present paper. The main reason was that we primarily performed time-to-event analyses in order to get an understanding of the development of ED after radiotherapy. For these analyses we demanded two consecutive follow-ups or more, without later recovery, for defining time to event. The PROM registrations were performed at fewer time points with larger dropout at each follow-up occasion and it was therefore not suitable for this approach. Another limitation of the study is that comorbidities were not registered. Comorbidities are expected to increase with increasing age and might have influenced the strong association of ED with age. Delineation on CT-scans is more uncertain than using MRI, especially for crus, but was used due to lack of MRI support for the OARs. However we consider that the prospective nature of this trial, large sample size, absence of androgen deprivation therapy (ADT) and multiple follow-up assessments ensures a high quality of our data to draw reliable conclusions.

Moderate hypofractionation has become standard of care after the publication of several large studies, mentioned earlier, with advantages both for the patients and for the workload of radiotherapy departments. Ultra-hypofractionation shows promising results and could be the next generation of treatment for prostate cancer. Dose-volume objectives/constraints are a prerequisite for good treatment results and must be renewed as new fractionation schedules evolves. This study contributes to increased knowledge in this field. Future work should involve other possibly involved OAR as for example IPA and nerve bundles.

Conclusions There was no statistically significant difference in ED between CF and UHF. Age at radiotherapy was the strongest predictor for ED followed by dose to the PB, most evident for younger patients. We propose to keep the “near maximum” dose D2 % (PB) < 50 Gy3 and/or the mean dose Dmean (PB) <20 Gy3 as objectives to be applied in the treatment planning process.

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15. Rivin del Campo E, Thomas K, Weinberg V, Roach M, 3rd. Erectile dysfunction after radiotherapy for prostate cancer: a model assessing the conflicting literature on dose-volume effects. International journal of impotence research. 2013;25(5):161-5. 16. Roach M, 3rd, Nam J, Gagliardi G, El Naqa I, Deasy JO, Marks LB. Radiation dose-volume effects and the penile bulb. International journal of radiation oncology, biology, physics. 2010;76(3 Suppl):S130-4. 17. Bergstrom P, Lofroth PO, Widmark A. High-precision conformal radiotherapy (HPCRT) of prostate cancer--a new technique for exact positioning of the prostate at the time of treatment. International journal of radiation oncology, biology, physics. 1998;42(2):305-11. 18. Wallner KE, Merrick GS, Benson ML, Butler WM, Maki J, Tollenaar BG. Penile bulb imaging. International journal of radiation oncology, biology, physics. 2002;53(4):928-33. 19. Buyyounouski MK, Horwitz EM, Uzzo RG, Price RA, McNeeley SW, Azizi D, et al. The radiation doses to erectile tissues defined with magnetic resonance imaging after intensity-modulated radiation therapy or iodine-125 brachytherapy. International journal of radiation oncology, biology, physics. 2004;59(5):1383-91. 20. McDonald AM, Baker CB, Shekar K, Popple RA, Clark GM, Yang ES, et al. Reduced radiation tolerance of penile structures associated with dose-escalated hypofractionated prostate radiotherapy. Urology. 2014;84(6):1383-7. 21. Murray J, Gulliford S, Griffin C, Wilkins A, Syndikus I, Staffurth J, et al. Evaluation of erectile potency and radiation dose to the penile bulb using image guided radiotherapy in the CHHiP trial. Clinical and Translational Radiation Oncology. 2019. 22. Spratt DE, Lee JY, Dess RT, Narayana V, Evans C, Liss A, et al. Vessel-sparing Radiotherapy for Localized Prostate Cancer to Preserve Erectile Function: A Single-arm Phase 2 Trial. European urology. 2017;72(4):617-24. 23. Rosen RC, Fisher WA, Eardley I, Niederberger C, Nadel A, Sand M. The multinational Men's Attitudes to Life Events and Sexuality (MALES) study: I. Prevalence of erectile dysfunction and related health concerns in the general population. Current medical research and opinion. 2004;20(5):607-17. 24. Corona G, Lee DM, Forti G, O'Connor DB, Maggi M, O'Neill TW, et al. Agerelated changes in general and sexual health in middle-aged and older men: results from the European Male Ageing Study (EMAS). The journal of sexual medicine. 2010;7(4 Pt 1):136280. 25. Johannes CB, Araujo AB, Feldman HA, Derby CA, Kleinman KP, McKinlay JB. Incidence of erectile dysfunction in men 40 to 69 years old: longitudinal results from the Massachusetts male aging study. The Journal of urology. 2000;163(2):460-3.

Figure Captions 1. Flow chart showing the patient selection process for the study. 2. Figure 2. Cumulative incidence of EDs for a) UHF and CF (HR= hazard ratio for UHF vs. CF), b) patients younger and older than 65 years at start of radiothetapy and c) D2% to PB less than or larger than 50 Gy in patients aged 65 years or younger. 3. Figure 3. Median DVHs for patients with and without EDs at 2 years for a) all patients b) patients ≤65 years. 4. Figure 4. Risk of EDs vs D2% for patients younger and older than 65 years with 95% confidence intervals.

Table 1. Baseline demographics, clinical characteristics, and radiotherapy (RT) details for the study cohort (n=673). CF

U-HF

(n=330)

(n=343)

p value

Age at start of RT (years) Median (range)

68

(54−76)

68

(51-76)

0.34

PSA (ng/mL) Median (IQR)

7.9

(5.5−12.0)

8.6

(5.9-12.0)

0.22

≤10 ng/mL >10 ng/mL

210 120

(64%) (36%)

212 131

(62%) (38%)

0.63

Gleason score ≤6 7 ≥8

52 256 22

(16%) (78%) (7%)

58 264 21

(17%) (77%) (6%)

0.89

Clinical T stage T1c T2 T3a

168 148 14

(51%) (45%) (4%)

186 142 15

(54%) (41%) (4%)

0.66

Risk group Intermediate risk a High risk

295 35

(89%) (11%)

307 36

(90%) (11%)

1.00

MRI support Yes No

210 118

(64%) (36%)

195 146

(57%) (43%)

0.082

RT technique 3DCRT VMAT/IMRT

249 81

(75%) (25%)

269 74

(78%) (22%)

0.36

IGRT technique BeamCath® Fiducial markers

29 301

(9%) (91%)

34 309

(10%) (90%)

0.69

Table 2. Univariable and multivariable predictors for physician assessed severe erectile dysfunction for all patients (n=673) and for patients 65 years and younger at start of radiotherapy (n=194). Cox regression Univariable HR 95% CI

UHF vs. CF

0.959

Age

1.092

D2% (Gy3)

1.005

Dmean (Gy3)

1.005

V5-65 Gy3 (%)

>1

0.7161.283 1.0561.130 0.9991.010 0.9981.013 ---

p

Multivariable HR 95% CI

0.78

1.003

<0.001

1.091

0.083

1.004

0.7491.344 1.0551.129 0.9991.010

p

Logistic regression, 12 months Univariable Multivariable OR 95% CI p OR 95% CI All patients (n=673)

0.98

0.969

<0.001

1.101

0.13

1.011

0.17

1.009

n.s.

>1

0.5971.573 1.0411.164 1.0011.021 0.9961.021 ---

0.90

1.038

<0.001

1.101

0.024

1.011

0.6341.699 1.0401.164 1.0011.020

p

Logistic regression, 24 months Univariable Multivariable OR 95% CI p OR 95% CI

0.88

0.957

0.001

1.111

0.027

1.011

0.18

1.013

n.s.

>1

0.6281.460 1.0571.167 1.0031.019 1.0021.024 ---

0.84

1.018

<0.001

1.110

0.009

1.010

0.6611.568 1.0561.167 1.0031.019

p

0.94 <0.001 0.010

0.025 <0.05

Age ≤65 years (n=194) UHF vs. CF

0.759

Age

1.277

D2% (Gy3)

1.019

Dmean (Gy3)

1.018

V5-65 Gy3 (%)

>1

0.3981.446 1.0851.503 1.0051.034 1.0021.034 ---

0.40

0.778

0.003

1.287

0.010

1.019

0.4081.483 1.0871.524 1.0051.035

0.45

0.363

0.003

1.270

0.011

1.052

0.025

1.032

<0.05

>1

0.1081.222 0.9651.671 1.0091.098 1.0041.060 ---

0.10

0.374

0.089

1.297

0.018

1.053

0.1071.314 0.9591.753 1.0081.100

0.12

0.528

0.091

1.173

0.020

1.049

0.027

1.034

<0.05

>1

0.1951.431 0.9451.456 1.0141.085 1.0091.060 ---

0.21

0.527

0.15

1.209

0.005

1.051

0.007 <0.05

0.1861.497 0.9561.530 1.0151.089

0.23 0.11

0.005