Robotic Stereotactic Body Radiotherapy (SBRT) for Low- and Intermediate Risk Localized Prostate Cancer. Feasibility, Outcome and Toxicity.

Robotic Stereotactic Body Radiotherapy (SBRT) for Low- and Intermediate Risk Localized Prostate Cancer. 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Feasibility, Outcome and Toxicity. Arne Grün, Dirk Böhmer, Carolin Senger, Goda Kalinauskaite, Markus Kufeld, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-1337836/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background To analyze outcome and toxicity of 41 consecutive patients with localized low- and intermediate risk prostate cancer treated with CyberKnife-Stereotactic Body Radiotherapy. Patients and Methods Patient selection and treatment protocol was according to (but not on) the PACE-trial protocol. Staging was in accordance with the German S3-guideline for prostate cancer. Prior to treatment, four gold-fiducials were implanted into the prostate. All patients received MRI-based prostate SBRT with 4 x 9.5 Gy (n=10) or 5 x 7.25 Gy (n=31). Toxicity was scored using the IPSS, ICIQ and IIEF-5 questionnaires. FU was every 3 months for 2 years and every 6 months onwards. Results With a median follow-up of 40.7 months, overall survival was 100% and progression-free survival 98%. One patient had a biochemical recurrence and was subsequently diagnosed and treated for lymphatic oligo-metastases. There was a non-statistical increase in toxicity after SBRT. Due to a TUR-P for urinary retention, there was one case of grade 3 toxicity. Mean PSA dropped from 9.4 ng/ ml to a mean of 2.4 ng/ml in year two of follow up and 0.1 ng/ml in year five with the greatest decrease within 6 months after SBRT. Conclusion In a cohort of 41 patients with predominantly intermediate risk localized prostate cancer, we could show that Cyberknife-Stereotactic Body Radiotherapy is feasible with very good tumor control and an only moderate and statistically non-significant increase in toxicity. Our results strengthen the case for Stereotactic Body Radiotherapy as a primary treatment option for patients with low and intermediate risk prostate cancer. Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Background Hypofractionation increases the therapeutic ratio in prostate cancer (PC) irradiation due to the purported low alpha/beta ratio 1 compared to that of the surrounding tissue. The use of Stereotactic Body Radiotherapy (SBRT) is increasing 2 for it allows dose escalation while at the same time maintaining very small safety margins and hence sparing adjacent normal tissue. While Fuller et al. emulated the heterogeneous dose distribution of high-dose-rate (HDR)-brachytherapy 3 , King et al. and Katz et al. went for a more homogenous approach comparable to intensity-modulated radiotherapy (IMRT) 4 . A 2019 meta-analysis of >6000 pts. treated on prospective protocols showed high rates of bPFS (biochemical Progression-free Survival) over all risk groups with very low genito-urinary- (GU) and gastro-intestinal (GI)-toxicity. The five-year bPFS rate was 95.3% (96.7% for low and 92.1% for intermediate risk group) and GU and GI toxicity ≥grade 3 was less than 2.5% 5 . Similar results could be shown in a study with long-term FU 6 . With the recent publication of the HYPO-RT-PC trial (ISRCTN45905321) 7 and early toxicity reporting from the PACE-B trial 8 , comparative data has been added to the growing body of evidence supporting the use of ultra-hypofractionation in selected low- and intermediate risk pts. We retrospectively analyze our first 41 consecutive patients (pts.) with localized low- and intermediate-risk prostate cancer treated with CyberKnife-SBRT with regard to feasibility, outcome and toxicity. Methods Between and 2011 and 2019 41 pts. were treated with CyberKnife (Accuray, Inc., Sunnyvale, CA, USA) SBRT for localized low- and intermediate risk PC. Staging was in accordance with the German S3-guideline for prostate cancer. Three out of 41 pts. received a staging PSMA-PET-CT with either Ga-68 PSMA or F18-PSMA. The pts. were classified into four risk groups as low (PSA ≤10ng/mL, Gleason ≤ 6, T stage ≤2a), favorable intermediate (iPSA >10-20 ng/ mL, Gleason 7a, T stage 2b), unfavorable intermediate (iPSA 11-20 ng/mL, Gleason 7b, T stage 2b) and high (iPSA >20 ng/mL, Gleason >7, T stage 2c) risk. Contouring, margins and treatment planning was according to the international randomized multicenter PACE-protocol ( Prostate Advances in Comparative Evidence ) (NCT01584258) which allowed for two different fractionation schemas. Six pts. had bridging-ADT, no pt. had ADT following SBRT. Prior to treatment, 4 gold fiducials were implanted under ultrasound-guidance. The implantation was performed by radiation oncologists experienced in prostate cancer brachytherapy (DB and AG). We initially used single fiducials but later switched to two pairs of Fleximark® gold on titanium fiducials with two nodes and 20 mm spacing preloaded in a 18 GA by 20 cm sterile needle (Riverpoint Medical, LLC, 825 NE, 25 th Avenue, Portland, OR, 97232, USA). Image registration of an axial MRI and the planning CT (slice thickness 1 mm, supine position, hands on chest, kneefix, feetfix) was performed using the Registration Software within Multiplan® (Accuray Inc., Sunnyvale, California, USA). The prostate and base of seminal vesicles (in intermediate risk) constituted the clinical target volume (CTV), the PTV was 2 mm isometrically for the pts. receiving 4 x 9.5 Gy and 5mm isometrically/3mm towards the rectum for the rest. The first ten pts. (24.4%) were treated using 4 x 9.5 Gy with inhomogeneous (60% Isodose) planning with a bladder catheter for urethra-sparing. We found the catheter placement to be the greatest source of dissatisfaction for our patients and hence switched to the 5-fraction approach (5 x 7.25 Gy, 85% Isodose) with homogenous planning and without catheter placement. Treatment quality-assurance was according to statutory provisions and current clinical standards 9 . Patients were treated every other day 10 . Bladder, urethra (if visible on the MRI), rectum, bowel, penile bulb and femoral heads constituted the OARs. We evaluated toxicity and PSA-levels at follow-up (FU) visits every three months during the first year and about every 6 months from the second year on. At the time of this analysis, we invited all patients to a FU visit or to fill out the questionnaires and send them by mail. PFS was defined as PSA relapse, any new manifestation of the disease or the initiation of ADT. Biochemical relapse was defined as PSA-nadir + 2 ng/mL. GU- and gastrointestinal GI-adverse events were scored using the International Prostate Symptom Score (IPSS), the International Consultation on Incontinence Questionnaire (ICIQ) of the International Index of Erectile Function (IIEF-5) and the Common Terminology Criteria of Adverse Events (CTCAE). The analysis is registered at the Charité ethics board under EA4/056/21. Results Mean age and BMI at the time of treatment was 69.2 years (47-81 years) and 25.4 kg/m². All patients had ECOG ≤1. Mean initial PSA was 9.4 ng/ ml (median 7.4 ng/ ml) and initial PSA groups were 20 ng/mL in 80%, 17.5% and 2.5%. Distribution of T-stage was T1, T2a, T2b and T2c in 80.6%, 11.1%, 0% and 5.6%. 24.4% of the patients had Gleason 6, 7a (56.1%) and 7b (19.5%). Risk group allocation was 9.8% low risk, 63.4% favorable-intermediate, 24.4% unfavorable-intermediate and 2.4% high risk. Six pts. (15%) had ADT prior or during SBRT, no pt. had ADT after completion of SBRT (Table 1) . Median volumes for prostate, CTV and PTV were 57.84, 69.74 and 92.74 cc. Fixed vs. iris collimator-use was 31.7% and 68.3%. Average irradiation time was 60 minutes and 10 seconds per fraction. The mean dose to the testes was 1.08 Gy. IPSS initial scores were low, mild, severe in 64.7, 11.8 and 23.5%. ICIQ groups 0, 1-5 and 6-10 initially were 72.4, 24.1, 3.45%. IIEF groups prior to SBRT were 22-25, 17-21, 12-16, 8-11 and <8 in 46.4, 10.7, 28.6, 3.57 and 10.7%. There was a moderate but not significant increase in adverse events (AE) after SBRT (Table 2, Figures 1, 2, 3) . One pt. had urinary retention during FU and was subjected to TUR-P. Unfortunately, we were not contacted prior to the procedure; hence, we do not know if medication or a temporary catheter placement would have sufficed, nevertheless it was scored as a grade 3 AE. Ten pts. were treated with 4 x 9.5 Gy, subsequently we switched to 5 x 7.25 Gy (Figure 4) . Overall survival was 100%, PFS was 98% (Figure 5) . After a median FU of 46.3 months (median 40.7 months; range 8.5 - 102.0 months), we saw a decrease in median PSA from 9.4 ng/ ml to 2.4 ng/ml (median 0.4 ng/ml) in year 2 of FU and o.1 ng/ml (median 0.0m ng/ml) in year five. (Figure 6) . There was no statistically significant difference in the survival- and toxicity-outcomes between the pts. receiving 39 Gy or 37.25 Gy. One pt. had a biochemical recurrence 28 months after therapy (the first PSA increase was at 25 months and the second confirmatory one at 28 months) and was subsequently treated for lymphatic oligo-metastases with ADT and SBRT. Discussion In our cohort, at a median FU of 41 months OS was 100% and PFS was 98% although the retrospective nature of this analysis and the rather small pt. cohort are bias-prone. In a pooled analysis of 1100 pts. including all risk groups the 5-years biochemical progression-free survival was 93%, 84% and 81% for low-, intermediate and high-risk patients 6 . Our median FU-time of 41 months is short with respect to the nature of PCA-recurrences although other studies have not shown a dramatic decline in PFS over longer FU-periods 6 . One of our pts. had a PSA recurrence. The pt. was diagnosed with lymph-node metastases in a PSMA-PET-CT and was salvaged with ADT and SBRT. Six pts. had bridging-ADT prior to SBRT, no pt. had ADT following SBRT. Katz et al. could show in 304 low- and intermediate-risk patients with a five year actuarial FU that ADT did not affect outcomes 11 . We saw a PSA decline from 9.4 ng/ ml to 2.4 ng/ml (median 0.4 ng/ml) in year 2 of FU and o.1 ng/ml (median 0.0 ng/ml) in year five. PSA fall-off occurs early and more steeply than in conventional EBRT 12 . Aluwini et al. saw a 53% decrease at three months and 81% at six months 13 . Continued decreases in PSA two to three years after treatment can regularly be seen 14 . Katz et al. could report on a PSA nadir of less than one ng/ml in 97% of 304 treated patients at 17 to 30 months median FU. At a median FU of five years, Freeman and King reported a median PSA nadir of 0.3 ng/ ml 15 . At ten years median FU, it was 0.1 ng/ ml in strictly low-risk cases 16 . GU and GI toxicity was mostly grade 1 and 2. Acute GU- or GI-toxicity ≥grade 3 is very rare (≤1%) 4 . Overall, there was an increase in mild but a decrease in severe IPSS scores. Arscott et al. witnessed an increase in bother with voiding symptoms of approximately 10%, which declined fast, there was a second less prominent peak at about 1 years post SBRT 17 . In a cohort of 204 pts. with 12% baseline dysuria of whom 1% felt that to be a moderate to big bother, post SBRT dysuria peaked at 1 month and 6-12 months post treatment. While 43% of patients reported a one-month peak in dysuria, only 9% felt it to be a moderate to big problem. Dysuria subsided to baseline values at 18 months post SBRT 18 . We saw a slight but continuous increase of ICIQ and decrease if IIEF scores. In a series of 204 pts. 79.3% never leaked and 72.9% said they have total urinary control. There were 16.3% patients with a frequency of ≤1 leak per day and 26.1% describing occasional dribbling. Only 1% of the patients though described that to be a moderate to big problem while most checking at “no problem” [75.9% or “small problem” (23.2%)]. At 36 months there is an increase with 29.9% ≤1 leak per day and 5.7% with >1 leak per day. Occasional dribbling has increased to 29.9% with 4.5% frequent dribbling. The portion of patients describing the issue as not problematic falls from 75% to 58% in the same time. Still most of the patients (87.7%) check no - or small problem 19 . In the Phase II cohort initially described by King, baseline erectile dysfunction (ED) medication was used by 3% of their patients progressing to 25% at last FU with a median time to initiation of ED medication of 18 months after RT 20 . They saw a progressive decrease in all EPIC sexual subdomains by 49%. The sexual bother score on the other hand decreased by only 25% and plateaued at 20 months. Age played an important role as pts. younger or older than 70 years remained a satisfactory erectile function in 60 vs. 12% of cases (p.0008). Freeman et al. 21 and Dess et al. corroborated age as an independent factor for erectile dysfunction. The latter could determine baseline health-related quality of life (HRQoL), age and body mass index as independent predictors for ED at 60 months 22 . In a series of 216 men with a median age of 66.8 years receiving prostate SBRT, 49.5% were found to have baseline erectile dysfunction and 36.1% already using sexual aids (mostly PDE5 inhibitors). Two years post RT 77.8% had erections satisfactory for sexual activity. Sexual aid usage prior to SBRT was associated with increased probability of potency preservation in uni- and multivariate analysis 23 . Conclusion SBRT is a comfortable and cost-effective 24 treatment approach. It shows very good tumor control and self-limiting, medically manageable toxicity. Based on meta-analyzed data from prospective comparative trials like HYPO-RT and PACE-B, we propose SBRT as a primary option for selected pts. with localized low- to intermediate-risk prostate cancer 25 . Abbreviations SBRT – Stereotactic Body Radiotherapy PC – Prostate Cancer HDR – High Dose Rate IMRT – Intensity Modulated Radiotherapy bPFS/ PFS – biochemical Progression-Free Survival GU- genito-urinary GI- gastro-intestinal FU- Follow-up PSMA-PET - Prostate-Specific Membrane Antigen Positron Emission Tomography PSA- Prostate-Specific Antigen ADT- Androgen Deprivation Therapy DB – Dirk Böhmer AG- Arne Grün GA - Gauge MRI – Magnetic Resonance Tomography CT – Computed Tomography CTV – Clinical Target Volume PTV- Planning Target Volume OARs – Organs At Risk IPSS – International Prostate Symptom Score ICIQ – Incontinence Questionnaire CTCAE – Common Terminology Criteria of Adverse Events BMI – Body Mass Index AE – Adverse Events EBRT – External Beam Radiotherapy ED – Erectile Dysfunction EPIC – Expanded Prostate Cancer Index Composite HRQoL – Health-Related Quality of Life PDE5 – Phopho-Diesterase RT - Radiotherapy Declarations Conflict of Interest: All authors declare that they have no conflict of interest Ethical Approval and Consent to participate All treatments were conducted according to Good Clinical Practice and the German Radiation Protection Laws. The analysis is registered at the Charité ethics board under EA4/056/21. All patients gave written consent for the use of their data for scientific purposes. Consent for publication All patients gave written consent for the use of their data for scientific purposes including publication. Availability of supporting data This manuscript contains no individual`s personal data in any form. All data supporting the results reported in this article are available on a secured data server owned by the Charité University Medicine, Berlin, Germany. The datasets used and analyses of all data of this manuscript are available from the corresponding author on reasonable request. Competing interests Not applicable Funding There was no funding for data analyses. The manuscript was edited and proof-read by San Francisco Edit, 1755 Jackson Street, Suite 610, San Francisco, CA 94109. Manuscript proof-reading was funded by a scientific grant of Varian Medical Systems, Palo Alto, California, USA. Authors' contributions AG and VHE had full access to all patient related data. AG was responsible for the design of the study, performed database set-up, and data integrity checks. VHE was responsible for data collection and database set-up and statistics. AG and VHE are responsible for interpretation of data. AG and VHE prepared the manuscript. GK, CS, MK and VB substantially revised and edited the manuscript. All authors approved the submitted version of the manuscript and its publication. Acknowledgement We thank all patients for their valuable and much appreciated contribution to this manuscript. Thanks to all technicians, nurses, physicists, and physicians who were responsible for preparation, planning, and daily treatment of all participants. Special thanks go to Prof. Dr. Volker Budach, Head of the Department for Radiation Oncology, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Germany. References Dasu A, Toma-Dasu I. Prostate alpha/beta revisited - an analysis of clinical results from 14 168 patients. Acta Oncol. 2012; 51: 963-74. Vogel, MME, Dewes, S, Sage, EK et al. Patterns of care for prostate cancer radiotherapy—results from asurvey among German-speaking radiation oncologists. Strahlenther Onkol 2021. https://doi.org/10.1007/s00066-020-01738-1. Fuller DB, Naitoh J, Lee C, Hardy S, Jin H. Virtual HDR CyberKnife treatment for localized prostatic carcinoma: dosimetry comparison with HDR brachytherapy and preliminary clinical observations. Int J Radiat Oncol Biol Phys. 2008; 70: 1588-97. King CR, Brooks JD, Gill H, Pawlicki T, Cotrutz C, Presti JC Jr. Stereotactic body radiotherapy for localized prostate cancer: interim results of a prospective phase II clinical trial. Int J Radiat Oncol Biol Phys. 2009; 73: 1043-8. Jackson WC, Silva J, Hartman HE, Dess RT, Kishan AU, Beeler WH, Gharzai LA, Jaworski EM, Mehra R, Hearn JWD, Morgan TM, Salami SS, Cooperberg MR, Mahal BA, Soni PD, Kaffenberger S, Nguyen PL, Desai N, Feng FY, Zumsteg ZS, Spratt DE. Stereotactic Body Radiation Therapy for Localized Prostate Cancer: A Systematic Review and Meta-Analysis of Over 6,000 Patients Treated On Prospective Studies. Int J Radiat Oncol Biol Phys. 2019; 104: 778-89. Kishan AU, Dang A, Katz AJ et al. Long-term Outcomes of Stereotactic Body Radiotherapy for Low-Risk and Intermediate-Risk Prostate Cancer. JAMA Netw Open 2019; 2: e188006. doi: 10.1001/jamanetworkopen.2018.8006. PMID: 30735235; PMCID: PMC6484596. Widmark A, Gunnlaugsson A, Beckman L et al. Ultra-hypofractionated versus conventionally fractionated radiotherapy for prostate cancer: 5-year outcomes of the HYPO-RT-PC randomised, non-inferiority, phase 3 trial. Lancet. 2019; 394: 385-395. doi: 10.1016/S0140-6736(19)31131-6. Epub 2019 Jun 18. PMID: 31227373. Brand DH, Tree AC, Ostler P et al. Intensity-modulated fractionated radiotherapy versus stereotactic body radiotherapy for prostate cancer (PACE-B): acute toxicity findings from an international, randomised, open-label, phase 3, non-inferiority trial. Lancet Oncol 2019; 11: 1531-1543. https://doi.org/10.1016/s1470-2045(19)30569-8 Schmitt, D, Blanck, O, Gauer, T et al. Technological quality requirements for stereotactic radiotherapy. Strahlenther Onkol 2020; 196, 421-443. https://doi.org/10.1007. King CR, Brooks JD, Gill H, Presti JC Jr.Long-term outcomes from a prospective trial of stereotactic body radiotherapy for low-risk prostate cancer. Int J Radiat Oncol Biol Phys. 2012; 82: 877-82. Katz AJ, Santoro M, Diblasio F, Ashley R. Stereotactic body radiotherapy for localized prostate cancer: disease control and quality of life at 6 years. Radiat Oncol. 2013; 8: 118. Leborgne F, Fowler J. Late outcomes following hypofractionated conformal radiotherapy vs. standard fractionation for localized prostate cancer: A nonrandomized contemporary comparison. Int J Radiat Oncol Biol Phys 2009; 74: 1441-6. Aluwini S, van Rooij P, Hoogeman M, Bangma C, Kirkels WJ, Incrocci L, Kolkman-Deurloo IK. CyberKnife stereotactic radiotherapy as monotherapy for low- to intermediate-stage prostate cancer: early experience, feasibility, and tolerance. J Endourol. 2010; 24:865-9. Friedland JL, Freeman DE, Masterson-McGary ME, Spellberg DM. Stereotactic body radiotherapy: an emerging treatment approach for localized prostate cancer. Technol Cancer Res Treat. 2009; 8: 387-92. Freeman DE, King CR. Stereotactic body radiotherapy for low-risk prostate cancer: five-year outcomes. Radiat Oncol. 2011; 6: 3. Katz A. Stereotactic Body Radiotherapy for Low-Risk Prostate Cancer: A Ten-Year Analysis. Cureus. 2017; 9: e1668. Arscott WT, Chen LN, Wilson N, Bhagat A, Kim JS, Moures RA, Yung TM, Lei S, Collins BT, Kowalczyk K, Suy S, Dritschilo A, Lynch JH, Collins SP1. Obstructive voiding symptoms following stereotactic body radiation therapy for prostate cancer. Radiat Oncol. 2014; 9: 163. Janowski EM, Kole TP, Chen LN, Kim JS, Yung TM, Collins BT, Suy S, Lynch JH, Dritschilo A, Collins. Dysuria Following Stereotactic Body Radiation Therapy for Prostate Cancer. Front Oncol. 2015; 5: 151. Chen LN, Suy S, Wang H, Bhagat A, Woo JA, Moures RA, Kim JS, Yung TM, Lei S, Collins BT, Kowalczyk K, Dritschilo A, Lynch JH, Collins SP. Patient-reported urinary incontinence following stereotactic body radiation therapy (SBRT) for clinically localized prostate cancer. Radiat Oncol. 2014; 9: 148. Wiegner EA, King CR. Sexual function after stereotactic body radiotherapy for prostate cancer: results of a prospective clinical trial. Int J Radiat Oncol Biol Phys. 2010; 78: 442-8. Freeman D, Dickerson G, Perman M. Multi-institutional registry for prostate cancer radiosurgery: a prospective observational clinical trial. Front Oncol. 2015; 4: 369. Dess RT, Hartman HE, Aghdam N, Jackson WC, Soni PD, Abugharib AE, Suy S, Desai NB, Zumsteg ZS, Mehra R, Morgan TM, Feng FY, Hamstra DA, Schipper MJ, Collins SP, Spratt DE. Erectile function after stereotactic body radiotherapy for localized prostate cancer. BJU Int. 2018; 121: 61-68. Obayomi-Davies O, Chen LN, Bhagat A, Wright HC, Uhm S, Kim JS, Yung TM, Lei S, Batipps GP, Pahira J, McGeagh KG, Collins BT, Kowalczyk K, Bandi G, Kumar D, Suy S, Dritschilo A, Lynch JH, Collins SP1. Potency preservation following stereotactic body radiation therapy for prostate cancer. Radiat Oncol. 2013; 8: 256. Pan HY, Jiang J, Hoffman KE, Tang C, Choi SL, Nguyen QN, Frank SJ, Anscher MS, Shih YT, Smith BD. Comparative Toxicities and Cost of Intensity-Modulated Radiotherapy, Proton Radiation, and Stereotactic Body Radiotherapy Among Younger Men With Prostate Cancer. J Clin Oncol. 2018; 36: 1823-30. Wolf, F, Sedlmayer, F, Aebersold, D et al. Ultrahypofractionation of localized prostate cancer. Strahlenther Onkol 2021; 197, 89-96. https://doi.org/10.1007/s00066-020-01723-8. Tables Tables are only available as a download in the Supplemental Files section. Additional Declarations No competing interests reported. Supplementary Files Table1Patientcharacteristics.pptx Table2Toxicity.pptx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-1337836","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":83036544,"identity":"e9c9b7c5-930c-4960-8432-fb0995455305","order_by":0,"name":"Arne Grün","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA9ElEQVRIiWNgGAWjYHAD5gPMQJIHxJQgUgtbAlgLDwlaeAyYGaDW4NXCP/vswQcMv+4l9kv3fPxcUHNPxp69gfHGBzxaJM7lJRsw9hUnzpxzdrP0jGPFPDw8B5gtZ+Cz5gyPmQRjT0Lihhu525h52BJ4eCQS2KR58OiQP8Nj/gOkZf+NnGfMPP+AWuQfsEn/waPFAGgLA8MPoC0SOWzMvG0gWxjYpPG5y/AMj7FEYkOC8YwbacbSvH1ALWcSmy178GiRO8Nj+OHDnwTZ/hnJDz/zfEuwZ28/fPDGD3zWgEBiGwqXsYGQBiDA59tRMApGwSgYBQCZYUZq9mbCVAAAAABJRU5ErkJggg==","orcid":"","institution":"Charité - University Medicine Berlin","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Arne","middleName":"","lastName":"Grün","suffix":""},{"id":83036545,"identity":"cd4ce51e-8e35-43c1-a34c-1a3a14f93033","order_by":1,"name":"Dirk Böhmer","email":"","orcid":"","institution":"Charité - University Medicine Berlin","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Dirk","middleName":"","lastName":"Böhmer","suffix":""},{"id":83036546,"identity":"40127520-34ec-4c58-a264-9176b7df5ce4","order_by":2,"name":"Carolin Senger","email":"","orcid":"","institution":"Charité - University Medicine Berlin","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Carolin","middleName":"","lastName":"Senger","suffix":""},{"id":83036547,"identity":"daa43a73-9a7e-4881-8a88-57addb6842ef","order_by":3,"name":"Goda Kalinauskaite","email":"","orcid":"","institution":"Charité - University Medicine Berlin","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Goda","middleName":"","lastName":"Kalinauskaite","suffix":""},{"id":83036548,"identity":"03f08b19-123a-4457-9e40-639068199dd5","order_by":4,"name":"Markus Kufeld","email":"","orcid":"","institution":"European Cyberknife Center München Großhadern","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Markus","middleName":"","lastName":"Kufeld","suffix":""},{"id":83036549,"identity":"44cdfdf8-c005-4ce2-a4e2-405c4e1ec809","order_by":5,"name":"Volker Budach","email":"","orcid":"","institution":"Charité - University Medicine Berlin","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Volker","middleName":"","lastName":"Budach","suffix":""},{"id":83036552,"identity":"ab40bf55-19ed-4782-a143-575a819d717d","order_by":6,"name":"Vincent Ehrhardt","email":"","orcid":"","institution":"University Medical Center Hamburg-Eppendorf","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Vincent","middleName":"","lastName":"Ehrhardt","suffix":""}],"badges":[],"createdAt":"2022-02-08 07:59:17","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-1337836/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-1337836/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":18199223,"identity":"af3a9ed4-c868-47bf-8d35-49b6b63787b8","added_by":"auto","created_at":"2022-02-14 15:29:43","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":20120,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eA and B. IPSS. A: \u003c/strong\u003estacked bar plot of IPSS results prior to therapy, during follow-up and at the time of last FU-contact with the patient. The results of the test are grouped according to severity (0-7 points: mild symptoms; 8-19 points: moderate symptoms; 20-35 points: severe symptoms). Although statistically not significant (Bowker test), there is a trend between the initial results and the last toward an increase of moderate symptoms (green) while severe symptoms (blue)\u0026nbsp;seem to be decreasing. Both effects can be acrredited to the treatment, one as the therapy related irritation of the uriniray tract and the other as a decrease in gland size which might be beneficiial with regard to obstructive symptoms. \u003cstrong\u003eB: \u003c/strong\u003ecross-table comparing the intial IPSS results (columns) with the results at last contact (lines). Patients on the diagonal from top left to bottom right did not change i.e. six pts. with IPSS of 0-7 prior to therapy had the same result at the last FU-contact. Nine pts. with IPSS 0-7 at the outset had an IPSS of 8-19 at the time of the last FU-visit.\u003c/p\u003e\u003cp\u003e\u003cbr\u003e\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-1337836/v1/d4a2ef2101a9296e422c8642.png"},{"id":18199594,"identity":"7e3799c6-b6d5-47b9-bc5d-d6149cef8799","added_by":"auto","created_at":"2022-02-14 15:32:43","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":20574,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eA and B. ICIQ. A: \u003c/strong\u003estacked bar plot of ICIQ results prior to therapy, during follow-up and at the time of last FU-contact. The results of the test are grouped according to severity (0 points: no incontinence; 1-5 points: mild incontinence; 6-10 points: moderate incontinence; \u0026gt;11 points: severe incontinence). Although statistically not significant, there is a trend between the initial results and the last toward a decrease in number of pts. with no incontinence and a temporary increase of moderate symptoms. At last FU-contact there is an overall increase in symptom severerity.\u003c/p\u003e\u003cp\u003e\u003cbr\u003e\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-1337836/v1/be009d81aed8e325a22aff86.png"},{"id":18199218,"identity":"b3c83831-08e1-4969-8cbc-48c5704b710c","added_by":"auto","created_at":"2022-02-14 15:29:43","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":19617,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eA and B. IIEF-5. A: \u003c/strong\u003estacked bar plot of IIEF results prior to therapy, during follow-up and at the time of last FU-contact. The results of the test are grouped according to severity (22-25 points: no erectile dysfunction; 17-21 points: mild erectile dysfunction; 12-16 points: mild to moderate erectile dysfunction; 8-11 points: moderate erectile dysfunction; \u0026lt;8 points severe erectile dysfunction). Although statistically not significant (Bowker test), there is a trend between the initial results and the last toward an increase of severe symptoms (violet) and a decrease in number of pts. with no erectile dysfunction (red). \u003cstrong\u003eB: \u003c/strong\u003ecross-table comparing the intial IIEF results (columns) with the results at last FU-contact (lines). Patients on the diagonal from top left to bottom right did not change.\u003c/p\u003e\u003cp\u003e\u003cbr\u003e\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-1337836/v1/fc5d5acfd398a4c6d94b82d0.png"},{"id":18199222,"identity":"6692fce9-e3e9-43c3-bfb2-19ee7440644f","added_by":"auto","created_at":"2022-02-14 15:29:43","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":488232,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eHeterogenous and homogenous dose distribution. \u003c/strong\u003eSagittal, frontal and axial planes of a plan with (a) inhomogenous and (b) homogenous dose prescription. Visible in (a) is the bladder catheter and the dose sparing surrounding the urethra (bold light-green is the prescription isodose). The homogenous dose approach foregoes the use of a bladder catheter and the prescription isodose (bold light-green line)\u0026nbsp;encompasses the PTV in all planes.\u003c/p\u003e\u003cp\u003e\u003cbr\u003e\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-1337836/v1/4c9adb701d85d214718c7383.png"},{"id":18199220,"identity":"b60f2a0a-74e1-4919-9c01-e39510a8ce8c","added_by":"auto","created_at":"2022-02-14 15:29:43","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":47263,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSurvival. \u003c/strong\u003eKaplan-Meier plots of Progression-free (A) and overall survival (B) in months. Median survival was not reached. One patients had a recurrence 28 months after therapy, was treated for it and is alive.\u003c/p\u003e\u003cp\u003e\u003cbr\u003e\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-1337836/v1/684c6e18e5e4c126e4ec6e74.png"},{"id":18199730,"identity":"df09104c-0421-49cb-b3f7-ced4160fbe6b","added_by":"auto","created_at":"2022-02-14 15:35:43","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":35333,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ePSA response. \u003c/strong\u003eSpaghetti-plot of all PSA counts during FU. The main decrease occurs during the first 3-6 months but further continuous decrease can be seen. One patients shows a sudden increase in PSA and is subsequently diagnosed with lymphatic oligo-metastases in a PSMA-PET-CT. He went on to receive SBRT as metastases directed therapy and ADT.\u0026nbsp;\u003c/p\u003e\u003cp\u003e\u003cbr\u003e\u003c/p\u003e","description":"","filename":"6.png","url":"https://assets-eu.researchsquare.com/files/rs-1337836/v1/986204276d097b2b3b4dc409.png"},{"id":20495832,"identity":"17224268-561c-4130-a436-81034da01b50","added_by":"auto","created_at":"2022-04-19 11:59:27","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":954582,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-1337836/v1/5fbadf9a-7907-43d1-b10f-034f0d4ece74.pdf"},{"id":18199216,"identity":"15d3c2ee-e656-4203-8c0e-ba548f722f62","added_by":"auto","created_at":"2022-02-14 15:29:43","extension":"pptx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":35325,"visible":true,"origin":"","legend":"","description":"","filename":"Table1Patientcharacteristics.pptx","url":"https://assets-eu.researchsquare.com/files/rs-1337836/v1/7b7e43d4aaad13a9ce3f3056.pptx"},{"id":18199592,"identity":"36af0ed0-050d-4a06-9239-5b1a49d5d0cb","added_by":"auto","created_at":"2022-02-14 15:32:43","extension":"pptx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":36495,"visible":true,"origin":"","legend":"","description":"","filename":"Table2Toxicity.pptx","url":"https://assets-eu.researchsquare.com/files/rs-1337836/v1/ca1be3f5b8102dbf4db744a0.pptx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Robotic Stereotactic Body Radiotherapy (SBRT) for Low- and Intermediate Risk Localized Prostate Cancer. Feasibility, Outcome and Toxicity.","fulltext":[{"header":"Background","content":"\u003cp\u003eHypofractionation increases the therapeutic ratio in prostate cancer (PC) irradiation due to the purported low alpha/beta ratio\u003csup\u003e1\u003c/sup\u003e compared to that of the surrounding tissue. The use of Stereotactic Body Radiotherapy (SBRT) is increasing\u003csup\u003e2\u003c/sup\u003e for it allows dose escalation while at the same time maintaining very small safety margins and hence sparing adjacent normal tissue. While Fuller et al. emulated the heterogeneous dose distribution of high-dose-rate (HDR)-brachytherapy\u003csup\u003e3\u003c/sup\u003e, King et al. and Katz et al. went for a more homogenous approach comparable to intensity-modulated radiotherapy (IMRT)\u003csup\u003e4\u003c/sup\u003e. A 2019 meta-analysis of \u0026gt;6000 pts. treated on prospective protocols showed high rates of bPFS \u0026nbsp;(biochemical Progression-free Survival) over all risk groups with very low genito-urinary- (GU) and gastro-intestinal (GI)-toxicity. The five-year bPFS rate was 95.3% (96.7% for low and 92.1% for intermediate risk group) and GU and GI toxicity \u0026ge;grade 3 was less than 2.5%\u003csup\u003e5\u003c/sup\u003e. Similar results could be shown in a study with long-term FU\u003csup\u003e6\u003c/sup\u003e. With the recent publication of the HYPO-RT-PC trial (ISRCTN45905321)\u003csup\u003e7\u003c/sup\u003e and early toxicity reporting from the PACE-B trial\u003csup\u003e8\u003c/sup\u003e, comparative data has been added to the growing body of evidence supporting the use of ultra-hypofractionation in selected low- and intermediate risk pts. We retrospectively analyze our first 41 consecutive patients (pts.) with localized low- and intermediate-risk prostate cancer treated with CyberKnife-SBRT with regard to feasibility, outcome and toxicity.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eBetween and 2011 and 2019 41 pts. were treated with CyberKnife (Accuray, Inc., Sunnyvale, CA, USA) SBRT for localized low- and intermediate risk PC.\u0026nbsp;Staging was in accordance with the German S3-guideline for prostate cancer.\u0026nbsp;Three out of 41 pts. received a staging PSMA-PET-CT with either Ga-68 PSMA or F18-PSMA. The pts. were classified into four risk groups as low (PSA \u0026le;10ng/mL, Gleason \u0026le; 6, T stage \u0026le;2a), favorable intermediate (iPSA \u0026gt;10-20 ng/ mL, Gleason 7a, T stage 2b), unfavorable intermediate (iPSA 11-20 ng/mL, Gleason 7b, T stage 2b) and high (iPSA \u0026gt;20 ng/mL, Gleason \u0026gt;7, T stage 2c) risk. Contouring, margins and treatment planning was according to the international randomized multicenter\u0026nbsp;PACE-protocol (\u003cem\u003eProstate Advances in Comparative Evidence\u003c/em\u003e) (NCT01584258) which allowed for two different fractionation schemas. Six pts. had bridging-ADT, no pt. had ADT following SBRT. Prior to treatment, 4 gold fiducials were implanted under ultrasound-guidance.\u0026nbsp;The implantation was performed by radiation oncologists experienced in prostate cancer brachytherapy (DB and AG).\u0026nbsp;We initially used single fiducials but later switched to\u0026nbsp;two pairs of Fleximark\u0026reg; gold on titanium fiducials with two nodes and 20 mm spacing preloaded in a 18 GA by 20 cm sterile needle (Riverpoint Medical, LLC, 825 NE, 25\u003csup\u003eth\u003c/sup\u003e Avenue, Portland, OR, 97232, USA).\u0026nbsp;Image registration of an axial MRI and the planning CT\u0026nbsp;(slice thickness 1 mm, supine position, hands on chest, kneefix, feetfix)\u0026nbsp;was performed using the Registration Software within Multiplan\u0026reg; (Accuray Inc., Sunnyvale, California, USA).\u0026nbsp;The prostate and base of seminal vesicles (in intermediate risk) constituted the clinical target volume (CTV), the PTV was 2 mm isometrically for the pts. receiving 4 x 9.5 Gy and 5mm isometrically/3mm towards the rectum for the rest. The first ten pts. (24.4%) were treated using 4 x 9.5 Gy with inhomogeneous (60% Isodose) planning with a bladder catheter for urethra-sparing.\u0026nbsp;We found the catheter placement to be the greatest source of dissatisfaction for our patients and hence switched to the 5-fraction approach (5 x 7.25 Gy, 85% Isodose) with homogenous planning and\u0026nbsp;without catheter placement.\u0026nbsp;Treatment quality-assurance was according to statutory provisions and current clinical standards\u003csup\u003e9\u003c/sup\u003e. Patients were treated every other day\u003csup\u003e10\u003c/sup\u003e. Bladder, urethra (if visible on the MRI), rectum, bowel, penile bulb and femoral heads constituted the OARs. We evaluated toxicity and PSA-levels at follow-up (FU) visits every three months during the first year and about every 6 months from the second year on. At the time of this analysis, we invited all patients to a FU visit or to fill out the questionnaires and send them by mail. PFS was defined as PSA relapse, any new manifestation of the disease or the initiation of ADT. Biochemical relapse was defined as PSA-nadir + 2 ng/mL. GU- and gastrointestinal GI-adverse events were scored using the International Prostate Symptom Score (IPSS), the International Consultation on Incontinence Questionnaire (ICIQ) of the International Index of Erectile Function (IIEF-5) and the Common Terminology Criteria of Adverse Events (CTCAE). The analysis is registered at the Charit\u0026eacute; ethics board under EA4/056/21.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eMean age and BMI at the time of treatment was 69.2 years (47-81 years) and 25.4 kg/m\u0026sup2;. All patients had ECOG \u0026le;1. Mean initial PSA was 9.4 ng/ ml (median 7.4 ng/ ml) and initial PSA groups were \u0026lt;11 ng/mL, 11-20 ng/mL and \u0026gt;20 ng/mL in 80%, 17.5% and 2.5%. Distribution of T-stage was T1, T2a, T2b and T2c in 80.6%, 11.1%, 0% and 5.6%. 24.4% of the patients had Gleason 6, 7a (56.1%) and 7b (19.5%). Risk group allocation was 9.8% low risk, 63.4% favorable-intermediate, 24.4% unfavorable-intermediate and 2.4% high risk. Six pts. (15%) had ADT prior or during SBRT, no pt. had ADT after completion of SBRT \u003cstrong\u003e(Table 1)\u003c/strong\u003e. Median volumes for prostate, CTV and PTV were 57.84, 69.74 and 92.74 cc. Fixed vs. iris collimator-use was 31.7% and 68.3%. Average irradiation time was 60 minutes and 10 seconds per fraction. The mean dose to the testes was 1.08 Gy. IPSS initial scores were low, mild, severe in 64.7, 11.8 and 23.5%. ICIQ groups 0, 1-5 and 6-10 initially were 72.4, 24.1, 3.45%. IIEF groups prior to SBRT were 22-25, 17-21, 12-16, 8-11 and \u0026lt;8 in 46.4, 10.7, 28.6, 3.57 and 10.7%. There was a moderate but not significant increase in adverse events (AE) after SBRT \u003cstrong\u003e(Table 2, Figures 1, 2, 3)\u003c/strong\u003e.\u0026nbsp;One pt. had urinary retention during FU and was subjected to TUR-P. Unfortunately, we were not contacted prior to the procedure; hence, we do not know if medication or a temporary catheter placement would have sufficed, nevertheless it was scored as a grade 3 AE.\u0026nbsp;Ten pts. were treated with 4 x 9.5 Gy, subsequently we switched to 5 x 7.25 Gy \u003cstrong\u003e(Figure 4)\u003c/strong\u003e. Overall survival was 100%, PFS was 98% \u003cstrong\u003e(Figure 5)\u003c/strong\u003e. After a median FU of 46.3 months (median 40.7 months; range\u0026nbsp;8.5 - 102.0 months), we saw a decrease in median PSA from 9.4 ng/ ml to 2.4 ng/ml (median 0.4 ng/ml) in year 2 of FU and o.1 ng/ml (median 0.0m ng/ml) in year five. \u003cstrong\u003e(Figure 6)\u003c/strong\u003e. There was no statistically significant difference in the survival- and toxicity-outcomes between the pts. receiving 39 Gy or 37.25 Gy. One pt. had a biochemical recurrence 28 months after therapy (the first PSA increase was at 25 months and the second confirmatory one at 28 months) and was subsequently treated for lymphatic oligo-metastases with ADT and SBRT.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn our cohort, at a median FU of 41 months OS was 100% and PFS was 98% although the retrospective nature of this analysis and the rather small pt. cohort are bias-prone. In a pooled analysis of 1100 pts. including all risk groups the 5-years biochemical progression-free survival was 93%, 84% and 81% for low-, intermediate and high-risk patients\u003csup\u003e6\u003c/sup\u003e. Our median FU-time of 41 months is short with respect to the nature of PCA-recurrences although other studies have not shown a dramatic decline in PFS over longer FU-periods\u003csup\u003e6\u003c/sup\u003e. One of our pts. had a PSA recurrence. The pt. was diagnosed with lymph-node metastases in a PSMA-PET-CT and was salvaged with ADT and SBRT. Six pts. had bridging-ADT prior to SBRT, no pt. had ADT following SBRT. Katz et al. could show in 304 low- and intermediate-risk patients with a five year actuarial FU that ADT did not affect outcomes\u003csup\u003e11\u003c/sup\u003e. We saw a PSA decline\u0026nbsp;from 9.4 ng/ ml to 2.4 ng/ml (median 0.4 ng/ml) in year 2 of FU and o.1 ng/ml (median 0.0 ng/ml) in year five.\u0026nbsp;PSA fall-off occurs early and more steeply than in conventional EBRT\u003csup\u003e12\u003c/sup\u003e. Aluwini et al. saw a 53% decrease at three months and 81% at six months\u003csup\u003e13\u003c/sup\u003e. Continued decreases in PSA two to three years after treatment can regularly be seen\u003csup\u003e14\u003c/sup\u003e. Katz et al. could report on a PSA nadir of less than one ng/ml in 97% of 304 treated patients at 17 to 30 months median FU. At a median FU of five years, Freeman and King reported a median PSA nadir of 0.3 ng/ ml\u003csup\u003e15\u003c/sup\u003e. At ten years median FU, it was 0.1 ng/ ml in strictly low-risk cases\u003csup\u003e16\u003c/sup\u003e. GU and GI toxicity was mostly grade 1 and 2. Acute GU- or GI-toxicity \u0026ge;grade 3 is very rare (\u0026le;1%)\u003csup\u003e4\u003c/sup\u003e\u003csup\u003e\u0026nbsp;\u003c/sup\u003e. Overall, there was an increase in mild but a decrease in severe IPSS scores. Arscott et al. witnessed an increase in bother with voiding symptoms of approximately 10%, which declined fast, there was a second less prominent peak at about 1 years post SBRT\u003csup\u003e17\u003c/sup\u003e. In a cohort of 204 pts. with 12% baseline dysuria of whom 1% felt that to be a moderate to big bother, post SBRT dysuria peaked at 1 month and 6-12 months post treatment. While 43% of patients reported a one-month peak in dysuria, only 9% felt it to be a moderate to big problem. Dysuria subsided to baseline values at 18 months post SBRT\u003csup\u003e18\u003c/sup\u003e. We saw a slight but continuous increase of ICIQ and decrease if IIEF scores. In a series of 204 pts. 79.3% never leaked and 72.9% said they have total urinary control. There were 16.3% patients with a frequency of \u0026le;1 leak per day and 26.1% describing occasional dribbling. Only 1% of the patients though described that to be a moderate to big problem while most checking at \u0026ldquo;no problem\u0026rdquo; [75.9% or \u0026ldquo;small problem\u0026rdquo; (23.2%)]. At 36 months there is an increase with 29.9% \u0026le;1 leak per day and 5.7% with \u0026gt;1 leak per day. Occasional dribbling has increased to 29.9% with 4.5% frequent dribbling. The portion of patients describing the issue as \u003cem\u003enot problematic\u0026nbsp;\u003c/em\u003efalls from 75% to 58% in the same time. Still most of the patients (87.7%) check \u003cem\u003eno\u003c/em\u003e- or \u003cem\u003esmall problem\u003csup\u003e19\u003c/sup\u003e\u003c/em\u003e. In the Phase II cohort initially described\u0026nbsp;by King, baseline erectile dysfunction (ED) medication was used by 3% of their patients progressing to 25% at last FU with a median time to initiation of ED medication of 18 months after RT\u0026nbsp;\u003csup\u003e20\u003c/sup\u003e. They saw a progressive decrease in all EPIC sexual subdomains by 49%. The sexual bother score on the other hand decreased by only 25% and plateaued at 20 months. Age played an important role as pts. younger or older than 70 years remained a satisfactory erectile function in 60 vs. 12% of cases (p.0008). Freeman et al.\u003csup\u003e21\u003c/sup\u003e and Dess et al. corroborated age as an independent factor for erectile dysfunction. The latter could determine baseline health-related quality of life (HRQoL), age and body mass index as independent predictors for ED at 60 months\u003csup\u003e22\u003c/sup\u003e. In a series of 216 men with a median age of 66.8 years receiving prostate SBRT, 49.5% were found to have baseline erectile dysfunction and 36.1% already using sexual aids (mostly PDE5 inhibitors). Two years post RT 77.8% had erections satisfactory for sexual activity. Sexual aid usage prior to SBRT was associated with increased probability of potency preservation in uni- and multivariate analysis\u003csup\u003e23\u003c/sup\u003e.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eSBRT is a comfortable and cost-effective\u003csup\u003e24\u003c/sup\u003e treatment approach. It shows very good tumor control and self-limiting, medically manageable toxicity. Based on meta-analyzed data from prospective comparative trials like HYPO-RT and PACE-B, we propose SBRT as a primary option for selected pts. with localized low- to intermediate-risk prostate cancer\u003csup\u003e25\u003c/sup\u003e.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eSBRT \u0026ndash; Stereotactic Body Radiotherapy\u003c/p\u003e\n\u003cp\u003ePC \u0026ndash; Prostate Cancer\u003c/p\u003e\n\u003cp\u003eHDR \u0026ndash; High Dose Rate\u003c/p\u003e\n\u003cp\u003eIMRT \u0026ndash; Intensity Modulated Radiotherapy\u003c/p\u003e\n\u003cp\u003ebPFS/ PFS \u0026ndash; biochemical Progression-Free Survival\u003c/p\u003e\n\u003cp\u003eGU- genito-urinary\u003c/p\u003e\n\u003cp\u003eGI- gastro-intestinal\u003c/p\u003e\n\u003cp\u003eFU- Follow-up\u003c/p\u003e\n\u003cp\u003ePSMA-PET - Prostate-Specific Membrane Antigen Positron Emission Tomography\u003c/p\u003e\n\u003cp\u003ePSA- Prostate-Specific Antigen\u003c/p\u003e\n\u003cp\u003eADT- Androgen Deprivation Therapy\u003c/p\u003e\n\u003cp\u003eDB \u0026ndash; Dirk B\u0026ouml;hmer\u003c/p\u003e\n\u003cp\u003eAG- Arne Gr\u0026uuml;n\u003c/p\u003e\n\u003cp\u003eGA - Gauge\u003c/p\u003e\n\u003cp\u003eMRI \u0026ndash; Magnetic Resonance Tomography\u003c/p\u003e\n\u003cp\u003eCT \u0026ndash; Computed Tomography\u003c/p\u003e\n\u003cp\u003eCTV \u0026ndash; Clinical Target Volume\u003c/p\u003e\n\u003cp\u003ePTV- Planning Target Volume\u003c/p\u003e\n\u003cp\u003eOARs \u0026ndash; Organs At Risk\u003c/p\u003e\n\u003cp\u003eIPSS \u0026ndash; International Prostate Symptom Score\u003c/p\u003e\n\u003cp\u003eICIQ \u0026ndash; Incontinence Questionnaire\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCTCAE \u0026ndash; Common Terminology Criteria of Adverse Events\u003c/p\u003e\n\u003cp\u003eBMI \u0026ndash; Body Mass Index\u003c/p\u003e\n\u003cp\u003eAE \u0026ndash; Adverse Events\u003c/p\u003e\n\u003cp\u003eEBRT \u0026ndash; External Beam Radiotherapy\u003c/p\u003e\n\u003cp\u003eED \u0026ndash; Erectile Dysfunction\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eEPIC \u0026ndash;\u0026nbsp;Expanded Prostate Cancer Index Composite\u003c/p\u003e\n\u003cp\u003eHRQoL \u0026ndash; Health-Related Quality of Life\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePDE5 \u0026ndash; Phopho-Diesterase\u003c/p\u003e\n\u003cp\u003eRT - Radiotherapy\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eConflict of Interest:\u0026nbsp;\u003c/h2\u003e\n\u003cp\u003eAll authors declare that they have no conflict of interest\u003c/p\u003e\n\u003ch2\u003eEthical Approval and Consent to participate\u0026nbsp;\u003c/h2\u003e\n\u003cp\u003eAll treatments were conducted according to Good Clinical Practice and the German Radiation Protection Laws. The analysis is registered at the Charit\u0026eacute; ethics board under EA4/056/21. All patients gave written consent for the use of their data for scientific purposes.\u0026nbsp;\u003c/p\u003e\n\u003ch2\u003eConsent for publication\u0026nbsp;\u003c/h2\u003e\n\u003cp\u003eAll patients gave written consent for the use of their data for scientific purposes including publication.\u003c/p\u003e\n\u003ch2\u003eAvailability of supporting data\u0026nbsp;\u003c/h2\u003e\n\u003cp\u003eThis manuscript contains no individual`s personal data in any form. All data supporting the results reported in this article are available on a secured data server owned by the Charit\u0026eacute; University Medicine, Berlin, Germany. The datasets used and analyses of all data of this manuscript are available from the corresponding author on reasonable request.\u0026nbsp;\u003c/p\u003e\n\u003ch2\u003eCompeting interests\u0026nbsp;\u003c/h2\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003ch2\u003eFunding\u0026nbsp;\u003c/h2\u003e\n\u003cp\u003eThere was no funding for data analyses. The manuscript was edited and proof-read by San Francisco Edit, 1755 Jackson Street, Suite 610, San Francisco, CA 94109. Manuscript proof-reading was funded by a scientific grant of Varian Medical Systems, Palo Alto, California, USA.\u0026nbsp;\u003c/p\u003e\n\u003ch2\u003eAuthors\u0026apos; contributions\u0026nbsp;\u003c/h2\u003e\n\u003cp\u003eAG and VHE had full access to all patient related data. AG was responsible for the design of the study, performed database set-up, and data integrity checks. VHE was responsible for data collection and database set-up and statistics. AG and VHE are responsible for interpretation of data. AG and VHE prepared the manuscript. GK, CS, MK and VB substantially revised and edited the manuscript. All authors approved the submitted version of the manuscript and its publication.\u003c/p\u003e\n\u003ch2\u003eAcknowledgement\u0026nbsp;\u003c/h2\u003e\n\u003cp\u003eWe thank all patients for their valuable and much appreciated contribution to this manuscript. Thanks to all technicians, nurses, physicists, and physicians who were responsible for preparation, planning, and daily treatment of all participants. Special thanks go to Prof. Dr. Volker Budach, Head of the Department for Radiation Oncology, Charit\u0026eacute; \u003cem\u003e\u0026ndash;\u0026nbsp;\u003c/em\u003eUniversit\u0026auml;tsmedizin Berlin, corporate member of Freie Universit\u0026auml;t Berlin, Humboldt-Universit\u0026auml;t zu Berlin, and Berlin Institute of Health, Germany.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003e Dasu A, Toma-Dasu I. Prostate alpha/beta revisited - an analysis of clinical results from 14 168 patients. Acta Oncol. 2012; 51: 963-74.\u003c/li\u003e\n \u003cli\u003e Vogel, MME, Dewes, S, Sage, EK et al. Patterns of care for prostate cancer radiotherapy\u0026mdash;results from asurvey among German-speaking radiation oncologists. Strahlenther Onkol 2021. https://doi.org/10.1007/s00066-020-01738-1.\u003c/li\u003e\n \u003cli\u003e Fuller DB, Naitoh J, Lee C, Hardy S, Jin H. Virtual HDR CyberKnife treatment for localized prostatic carcinoma: dosimetry comparison with HDR brachytherapy and preliminary clinical observations. Int J Radiat Oncol Biol Phys. 2008; 70: 1588-97.\u003c/li\u003e\n \u003cli\u003e King CR, Brooks JD, Gill H, Pawlicki T, Cotrutz C, Presti JC Jr. Stereotactic body radiotherapy for localized prostate cancer: interim results of a prospective phase II clinical trial. Int J Radiat Oncol Biol Phys. 2009; 73: 1043-8.\u003c/li\u003e\n \u003cli\u003e Jackson WC, Silva J, Hartman HE, Dess RT, Kishan AU, Beeler WH, Gharzai LA, Jaworski EM, Mehra R, Hearn JWD, Morgan TM, Salami SS, Cooperberg MR, Mahal BA, Soni PD, Kaffenberger S, Nguyen PL, Desai N, Feng FY, Zumsteg ZS, Spratt DE. Stereotactic Body Radiation Therapy for Localized Prostate Cancer: A Systematic Review and Meta-Analysis of Over 6,000 Patients Treated On Prospective Studies. Int J Radiat Oncol Biol Phys. 2019; 104: 778-89.\u003c/li\u003e\n \u003cli\u003e Kishan AU, Dang A, Katz AJ et al. Long-term Outcomes of Stereotactic Body Radiotherapy for Low-Risk and Intermediate-Risk Prostate Cancer. JAMA Netw Open 2019; 2: e188006. doi: 10.1001/jamanetworkopen.2018.8006. PMID: 30735235; PMCID: PMC6484596.\u003c/li\u003e\n \u003cli\u003e Widmark A, Gunnlaugsson A, Beckman L et al. Ultra-hypofractionated versus conventionally fractionated radiotherapy for prostate cancer: 5-year outcomes of the HYPO-RT-PC randomised, non-inferiority, phase 3 trial. Lancet. 2019; 394: 385-395. doi: 10.1016/S0140-6736(19)31131-6. Epub 2019 Jun 18. PMID: 31227373.\u003c/li\u003e\n \u003cli\u003e Brand DH, Tree AC, Ostler P et al. Intensity-modulated fractionated radiotherapy versus stereotactic body radiotherapy for prostate cancer (PACE-B): acute toxicity findings from an international, randomised, open-label, phase 3, non-inferiority trial. Lancet Oncol 2019; 11: 1531-1543. https://doi.org/10.1016/s1470-2045(19)30569-8\u003c/li\u003e\n \u003cli\u003e Schmitt, D, Blanck, O, Gauer, T et al. Technological quality requirements for stereotactic radiotherapy. Strahlenther Onkol 2020; 196, 421-443. https://doi.org/10.1007.\u003c/li\u003e\n \u003cli\u003e King CR, Brooks JD, Gill H, Presti JC Jr.Long-term outcomes from a prospective trial of stereotactic body radiotherapy for low-risk prostate cancer. Int J Radiat Oncol Biol Phys. 2012; 82: 877-82.\u003c/li\u003e\n \u003cli\u003e Katz AJ, Santoro M, Diblasio F, Ashley R. Stereotactic body radiotherapy for localized prostate cancer: disease control and quality of life at 6 years. Radiat Oncol. 2013; 8: 118.\u003c/li\u003e\n \u003cli\u003e Leborgne F, Fowler J. Late outcomes following hypofractionated conformal radiotherapy vs. standard fractionation for localized prostate cancer: A nonrandomized contemporary comparison. Int J Radiat Oncol Biol Phys 2009; 74: 1441-6.\u003c/li\u003e\n \u003cli\u003e Aluwini S, van Rooij P, Hoogeman M, Bangma C, Kirkels WJ, Incrocci L, Kolkman-Deurloo IK. CyberKnife stereotactic radiotherapy as monotherapy for low- to intermediate-stage prostate cancer: early experience, feasibility, and tolerance. J Endourol. 2010; 24:865-9.\u003c/li\u003e\n \u003cli\u003e Friedland JL, Freeman DE, Masterson-McGary ME, Spellberg DM. Stereotactic body radiotherapy: an emerging treatment approach for localized prostate cancer. Technol Cancer Res Treat. 2009; 8: 387-92.\u003c/li\u003e\n \u003cli\u003e Freeman DE, King CR. Stereotactic body radiotherapy for low-risk prostate cancer: five-year outcomes. Radiat Oncol. 2011; 6: 3.\u003c/li\u003e\n \u003cli\u003e Katz A. Stereotactic Body Radiotherapy for Low-Risk Prostate Cancer: A Ten-Year Analysis. Cureus. 2017; 9: e1668.\u003c/li\u003e\n \u003cli\u003e Arscott WT, Chen LN, Wilson N, Bhagat A, Kim JS, Moures RA, Yung TM, Lei S, Collins BT, Kowalczyk K, Suy S, Dritschilo A, Lynch JH, Collins SP1. Obstructive voiding symptoms following stereotactic body radiation therapy for prostate cancer. Radiat Oncol. 2014; 9: 163.\u003c/li\u003e\n \u003cli\u003e Janowski EM, Kole TP, Chen LN, Kim JS, Yung TM, Collins BT, Suy S, Lynch JH, Dritschilo A, Collins. Dysuria Following Stereotactic Body Radiation Therapy for Prostate Cancer. Front Oncol. 2015; 5: 151.\u003c/li\u003e\n \u003cli\u003e Chen LN, Suy S, Wang H, Bhagat A, Woo JA, Moures RA, Kim JS, Yung TM, Lei S, Collins BT, Kowalczyk K, Dritschilo A, Lynch JH, Collins SP. Patient-reported urinary incontinence following stereotactic body radiation therapy (SBRT) for clinically localized prostate cancer. Radiat Oncol. 2014; 9: 148.\u003c/li\u003e\n \u003cli\u003e Wiegner EA, King CR. Sexual function after stereotactic body radiotherapy for prostate cancer: results of a prospective clinical trial. Int J Radiat Oncol Biol Phys. 2010; 78: 442-8.\u003c/li\u003e\n \u003cli\u003e Freeman D, Dickerson G, Perman M. Multi-institutional registry for prostate cancer radiosurgery: a prospective observational clinical trial. Front Oncol. 2015; 4: 369.\u003c/li\u003e\n \u003cli\u003e Dess RT, Hartman HE, Aghdam N, Jackson WC, Soni PD, Abugharib AE, Suy S, Desai NB, Zumsteg ZS, Mehra R, Morgan TM, Feng FY, Hamstra DA, Schipper MJ, Collins SP, Spratt DE. Erectile function after stereotactic body radiotherapy for localized prostate cancer. BJU Int. 2018; 121: 61-68.\u003c/li\u003e\n \u003cli\u003e Obayomi-Davies O, Chen LN, Bhagat A, Wright HC, Uhm S, Kim JS, Yung TM, Lei S, Batipps GP, Pahira J, McGeagh KG, Collins BT, Kowalczyk K, Bandi G, Kumar D, Suy S, Dritschilo A, Lynch JH, Collins SP1. Potency preservation following stereotactic body radiation therapy for prostate cancer. Radiat Oncol. 2013; 8: 256.\u003c/li\u003e\n \u003cli\u003e Pan HY, Jiang J, Hoffman KE, Tang C, Choi SL, Nguyen QN, Frank SJ, Anscher MS, Shih YT, Smith BD. Comparative Toxicities and Cost of Intensity-Modulated Radiotherapy, Proton Radiation, and Stereotactic Body Radiotherapy Among Younger Men With Prostate Cancer. J Clin Oncol. 2018; 36: 1823-30.\u003c/li\u003e\n \u003cli\u003e Wolf, F, Sedlmayer, F, Aebersold, D et al. Ultrahypofractionation of localized prostate cancer. Strahlenther Onkol 2021; 197, 89-96. https://doi.org/10.1007/s00066-020-01723-8.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables are only available as a download in the Supplemental Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-1337836/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-1337836/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eBackground To analyze outcome and toxicity of 41 consecutive patients with localized low- and intermediate risk prostate cancer treated with CyberKnife-Stereotactic Body Radiotherapy. \u003c/p\u003e\u003cp\u003ePatients and Methods Patient selection and treatment protocol was according to (but not on) the PACE-trial protocol. Staging was in accordance with the German S3-guideline for prostate cancer. Prior to treatment, four gold-fiducials were implanted into the prostate. All patients received MRI-based prostate SBRT with 4 x 9.5 Gy (n=10) or 5 x 7.25 Gy (n=31). Toxicity was scored using the IPSS, ICIQ and IIEF-5 questionnaires. FU was every 3 months for 2 years and every 6 months onwards. \u003c/p\u003e\u003cp\u003eResults With a median follow-up of 40.7 months, overall survival was 100% and progression-free survival 98%. One patient had a biochemical recurrence and was subsequently diagnosed and treated for lymphatic oligo-metastases. There was a non-statistical increase in toxicity after SBRT. Due to a TUR-P for urinary retention, there was one case of grade 3 toxicity. Mean PSA dropped from 9.4 ng/ ml to a mean of 2.4 ng/ml in year two of follow up and 0.1 ng/ml in year five with the greatest decrease within 6 months after SBRT. \u003c/p\u003e\u003cp\u003eConclusion In a cohort of 41 patients with predominantly intermediate risk localized prostate cancer, we could show that Cyberknife-Stereotactic Body Radiotherapy is feasible with very good tumor control and an only moderate and statistically non-significant increase in toxicity. Our results strengthen the case for Stereotactic Body Radiotherapy as a primary treatment option for patients with low and intermediate risk prostate cancer.\u003c/p\u003e","manuscriptTitle":"Robotic Stereotactic Body Radiotherapy (SBRT) for Low- and Intermediate Risk Localized Prostate Cancer. Feasibility, Outcome and Toxicity.","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2022-02-14 15:29:41","doi":"10.21203/rs.3.rs-1337836/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"f74b78f1-b76e-4776-b147-6397859f92cb","owner":[],"postedDate":"February 14th, 2022","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2022-04-19T11:59:23+00:00","versionOfRecord":[],"versionCreatedAt":"2022-02-14 15:29:41","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-1337836","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-1337836","identity":"rs-1337836","version":["v1"]},"buildId":"WrCJVZZCHTDjtuVLN7oU0","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}