Stesura Seveso Archivio Italiano di Urologia e Andrologia 2022; 94, 2166 ORIGINAL PAPER No conflict of interest declared. intensity-modulated radiotherapy that has shown that increasing dose improves biochemical disease-free sur- vival with acceptable acute and long-term complications (1, 2). Recently, injection of a hydrogel spacer (Space OAR) between the rectum and the prostate and the use of intraprostatic fiducials have been suggested to reduce rec- tal toxicity and improve selective prostate radiation ther- apy (3-8) resulting particularly useful in men candidate to hypofractionated radiotherapy (HRT) (9-11). In this study, the incidence of ED in men with organ-confined PCa sub- mitted to HRT has been prospectively evaluated. MATERIALS AND METHODS From April 2018 to September 2020, 56 patients (median age 70 years; range = 58-82) with organ-confined PCa (cT1c stage) were treated by HRT directed to the prostate and seminal vesicle. All the patients were previously sub- mitted to multiparametric magnetic resonance imaging (mpMRI) (13) and transperineal prostate biopsy (14-15). The median PSA was 8.3 ng/ml (range = 4.5-23.1); 20 patients (35.7%) were at low risk (Grade Group 1/Gleason score 6), 28 (50%) at favorable intermediate risk (Grade Group 2/Gleason score 3 + 4) and only 8 (22.3%) at unfa- vorable intermediate risk (Grade Group 3/Gleason score 4 + 3) (6); moreover, all patients were without evidence of disease spread to the lymph nodes or the bones. All patients were selected for a hydrogel injection Space OAR before HRT. The injection of hydrogel was per- formed under sedation by transrectal ultrasound guid- ance, furthermore, three gold fiducials were inserted transperineally at the prostate base and mid-gland (8). Patients were simulated 2 weeks after placement; CT sim- ulation was obtained at 3 mm slice thickness using an immobilization device, extending from L1 to below the ischial tuberosities. CT-MRI image registration was accomplished using the MIM-software (Maestro, version 7.0.5, MIM Software Inc., Cleveland, OH, USA). The whole prostate and seminal vesicle were delineated as the clini- cal target volume (CTV). Non-uniform planning target vol- ume (PTV) was defined by adding margins to CTV; the margin was 8 mm in the anterior, lateral, superior and inferior directions, while it was 4 mm in the posterior direction. The rectum, urinary bladder, bowel, femoral Introduction: The incidence of erectile dys- function (ED) in men with organ-confined prostate cancer (PCa) submitted to hypofractionated radiothera- py (HRT) has been prospectively evaluated. Materials and methods: From April 2018 to September 2020, 56 patients (median age 70 years) with cT1c PCa were treated by HRT directed to the prostate and seminal vesicle. Median PSA was 8.3 ng/ml; 20 patients (35.7%) vs. 28 (50%) vs. 8 (22.3%) had a PCa Grade Group 1 vs. 2 vs. 3, respectively. All patients underwent hydrogel injection of Space OAR and intraprostatic fiducials before HRT. The prescription dose was 60 Gy in 20 fractions 5 days/week over 4 weeks. During the follow up, PSA, genitourinary (GU) and gastrointestinal (GI) toxicities were evaluated. The sexual function was evaluated by International Index of Erectile Function - 5 (IIEF-5) before, 6 and 18 months from HRT; 32/56 (57.1%) men referred a normal sexual activity before HRT (median IIEF-5 score: 22). Results: Median PSA level at median follow up of 18 months was 0.92 ng/ml and none used adjuvant therapy. One man (1.8%) referred a tardive grade 1 GU complication. At a median follow up of 6 and 18 months, 20/32 (62.5%) kept pretreatment sexual potency (median IIEF-5 score: 21). The 12/32 men who worsened the sexual function following HRT had a median age higher than patients without ED (78 vs. 67 years). Conclusions: The use of hydrogel injection and intraprostatic fiducials followed by HRT allowed to kept pretreatment sexual potency in 62.5% of the cases. KEY WORDS: Prostate cancer; Erectile dysfunction; Hypofractionated radiotherapy; Intraprostatic fiducials; Hydrogel injection. Submitted 10 April 2022; Accepted 23 April 2022 INTRODUCTION Prostate cancer (PCa) is the most commonly diagnosed male malignancy and radical prostatectomy or external radiotherapy (RT) are currently recommended as defini- tive treatment alone or combination in men with a life expectancy greater than 10 years. Radiation damage to neural and vascular tissue, such as the neurovascular bun- dles (NVBs) and internal pudendal arteries (IPAs), during radiotherapy for PCa may cause erectile dysfunction (ED). The advances in physics, engineering and imaging have been channeled into the development of image-guided Erectile dysfunction following hydrogel injection and hypofractionated radiotherapy for prostate cancer: Our experience in 56 cases Pietro Pepe 1, Maria Tamburo 2, Paolo Panella 1, Ludovica Pepe 1, Giulia Marletta 2, Michele Pennisi 1, Francesco Marletta 2 1 Urology Unit, Cannizzaro Hospital, Catania, Italy; 2 Radiotherapy Unit, Cannizzaro Hospital, Catania, Italy. DOI: 10.4081/aiua.2022.2.166 Summary 167Archivio Italiano di Urologia e Andrologia 2022; 94, 2 Erectile dysfunction and hypofractionated radiotherapy heads and penile bulb were contoured as organs at risk. The rectum was delineated from the rectosigmoid flexure to the anus; the treatment planning system was Monaco- Elekta (Elekta AB, Stockholm, Sweden). The prescription dose was 60 Gy in 20 fractions 5 days/week over 4 weeks, the CTV was planned to receive at least 100% of the pre- scription dose and the PTV at least 95% with maximum dose at CTV < 110% of the prescription dose. Dose-vol- ume constraints were: dose given to 30% of rectal volume < 46 Gy, dose given to 50% of rectal volume < 37 Gy, dose given to 30% urinary bladder volume < 46 Gy, dose given to 30% urinary bladder volume < 37 Gy, dose given to 5% left/right femoral head volume < 43 Gy. Patients were treated with volumetric modulated arc therapy (VMAT) using the LINAC Sinergy Elekta and pretreatment verifi- cation of the prostate was conducted using a kilovoltage cone-beam CT during each treatment session. Patients were followed every 3 months for 2 years, and thereafter every 6 months. PSA relapse was determined according to the Phoenix consensus definition (nadir PSA value plus 2 ng/ml). Genitourinary (GU) and gastrointestinal (GI) toxic- ities were evaluated following RTOG/EORT score. Acute toxicity was defined as that occurred within 3 months after the initiation of radiotherapy, while late toxicity was observed after 3 months. The sexual function was evalu- ated by International Index of Erectile Function-5 (IIEF-5) (12) before (baseline), 6 and 18 months from HRT. None of the patients used 5-phosphodiesterase inhibitors or prostaglandins to improve sexual activity. The median prostate volume was 69.4 cm2; clinical (comorbidities, drug therapy) and laboratory data collect- ed before prostate biopsy are reported in Table 1. Thirty- two (57.1%) men referred a normal sexual activity before HRT (median IIEF-5 score: 22; range 20-25) and among them 12 (37.5%) vs. 18 (56.2%) vs. 2 (6.3%) men had a PCA Grade Group equal to 1 vs. 2 vs. 3, respectively. RESULTS All patients tolerated well the injection of Space OAR plus intraprostatic fiducials and completed the HRT treatment. Median PSA level at median follow up of 18 months was 0.92 ng/ml (range: 0.01-3.6 ng/ml) and none used adju- vant therapy. Only one man (1.8%) referred a tardive grade 1 GU complication, the remain 55 (98.2%) had no tardive side effects. Among the 32/56 (57.1%) men who had a normal sexual activity before HRT (median IIEF-5 score: 22; range 20- 25), at a median follow up of 6 and 18 months, 20/32 (62.5%) kept pretreatment sexual potency (median IIEF-5 score: 21; range = 19-25) (Table 2). The 12/32 men who worsened the sexual function following HRT had a median age higher than patients without DE (78 vs. 67 years). DISCUSSION However the advent of modern technology using advanced prostate targeting and penile-bulb sparing tech- niques, ED is a prevalent side effect of PCa treatment; Hunt et al. (16) in a recent systematic review of the litera- ture reported in 2,714 patients at 2-year follow-up a median increase of ED equal to 17%, 26%, 23%, and 23%, in men who underwent three-dimensional confor- mal radiation therapy, intensity-modulated radiotherapy, low dose rate of brachytherapy, and stereotactic body radiation therapy, respectively. Goy et al. (17) reported in 1,503 men with intermediate risk PCa who underwent radical prostatectomy vs. external radiotherapy vs. brachytherapy a prevalence of ED at 10 years of follow up equal to 24.3%, 6.6%, 8.2%, respectively; in addition, ED was not significantly different in men submitted to stan- dard dose radiation therapy (38.1%) vs. dose escalated radiation therapy (49.7%) (18). Recently, the introduc- tion in clinical practice of the so-called precision medicin Table 1. Clinical findings and drugs therapy in the 56 patients submitted to hypofractionated radiotherapy. Clinical findings No (%) of patients Median age (years) 70 (range: 58-82) PSA 4.1-10 ng/mL 43 PSA > 10 ng/mL 13 Abnormal DRE - LUTS 42 Qmax 12 IPSS (median) 11 (4-29) Comorbidities: 35 Diabetes mellitus 9 Hypertension 23 Gastritis 12 Cardiovascular ischemic disease 6 Other 9 Drug therapy (overall): 495 (88.3) Oral hypoglycemic 6 Antihypertensive 25 Antiplatelet agents 34 Diuretic 10 Proton pomp inhibitor 23 Alfa-blockers 50 Other 15 DRE: digital rectal examination; LUTS: lower urinary tract symptoms; IPSS: international prostate symptoms score. Table 2. International Index Erectile Function (IIEF-5) in 56 patients before (baseline) and after 6 and 18 months from hypofractionated radiotherapy. IEFF-5 (score: 5-25) Baseline 6 months 18 months median age: 70 years (%) (%) (%) Absence of erectile dysfunction (ED) (22-25) 32 (57.1) 20 (62.5) 20 (62.5) median age: 67 years Mild ED (17-21) 4 (7.1) 3 (5.3) 2 (3.5) median age: 72 years Mild-moderate ED (12-16) 4 (7.1) 5 (8.9) 5 (8.9) median age Moderate ED (8-11) 4 (7.1) 3 (5.3) 2 (3.5) median age: 76 years Severe ED (5-7) 12 (21.5) 13 (23.2) 14 (25) median age: 78 years Archivio Italiano di Urologia e Andrologia 2022; 94, 2 P. Pepe, M. Tamburo, P. Panella, L. Pepe, G. Marletta, M. Pennisi, F. Marletta 168 decreased the risk of complications; in fact, neurovascu- lar-sparing magnetic resonance-guided adaptive radio- therapy seems to reduce the risk of ED following external radiotherapy (19). At the same time, CT-MRI image regis- tration using dedicated software, the use of intraprostatic fiducials and hydrogel spacer could help to better focalize radiation therapy into the prostate; therefore, these devices used before radiotherapy could better preserve neurovascular bundle reducing the risk of ED. In our series, to our knowledge the first that evaluated ED following HRT in men submitted hydrogel spacer and intraprostatic fiducials injection, we reported among 32/56 (57.1%) men who had a normal sexual activity before HRT, at a median follow up 18 months, a restored pretreatment sexual potency in 20/32 (62.5%) (median IIEF-5 score: 21; range = 19-25). In addition, the 12/32 men who worsened the sexual function following HRT had a median age high- er than patients without DE (78 vs. 67 years). Regarding our results some considerations should be done. Firstly, the true sexual activity of the couple administering a sexual questionnaire to the partners was not investigated. 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Correspondence Pietro Pepe, MD (Corresponding Author) piepepe@hotmail.com Paolo Panella, MD ppanella5@gmail.com Ludovica Pepe, MD ludopepe97@gmail.com Michele Pennisi, MD michepennisi2@virgilio.it Urology Unit, Cannizzaro Hospital, Via Messina 829, Catania (Italy) Maria Tamburo, MD marinellatamburo@virgilio.it Giulia Marletta, MD marlettagiulia1@gmail.com Francesco Marletta, MD francescomarletta1@gmail.com Radiotherapy Unit, Cannizzaro Hospital, Catania (Italy)