Online Adaptive Stereotactic Body Radiotherapy for Localized Prostate Cancer (X-SMILE) (X-SMILE)

Online Adaptive Stereotactic Body Radiotherapy for Localized Prostate Cancer in Patients With Lower Urinary Tract Symptoms and/or Prostate Hyperplasia (X-SMILE)

The aim of this phase II international multicenter study is to evaluate the safety, feasibility, and efficacy of CT or MRI-adaptive SBRT, delivered in five weekly fractions, in patients with newly diagnosed localized prostate cancer who have lower urinary tract symptoms and/or prostatic hyperplasia.

Study Overview

• Status: Recruiting
• Conditions: Localized Prostate Carcinoma; Prostate Cancer (Adenocarcinoma); Prostate Hyperplasia; Lower Urinary Track Symptoms
• Intervention / Treatment: Radiation: radiotherapy

Detailed Description

Background: Stereotactic body radiotherapy (SBRT) for localized prostate cancer has demonstrated non-inferior oncological outcomes and toxicity profiles to conventionally or moderately hypofractioned radiotherapy regimens, while offering the advantage of shorter treatment durations. However, SBRT may not be suitable for all patients, particularly those with lower urogenital tract symptoms and/or prostatic hyperplasia.

Methods: This study aims to evaluate the safety and efficacy of weekly computed tomography (CT) or magnetic resonance image-guided (MRI) online adaptive SBRT in patients with intermediate to (very) high-risk localized prostate cancer who present with lower urinary tract symptoms (International Prostate Symptom Score [IPSS] > 12) and/or have prostate hyperplasia (prostate volume >60 mL). The primary outcome measure is urogenital toxicity grade ≥3 within 3 months after completion of SBRT (according to CTCAE V5.0 and RTOG) or discontinuation of therapy. Our aim is to show that the event rate is at 3% below a clinically acceptable threshold, which is set at 20%. Under the null hypothesis, this design with an alpha of 0.05 and power of 80% results in an expected number of cases of 30. In our validation cohort we assume that around 3% of patients will have grade 3 long-term urogenital toxicity (i.e. 2 patients). The rate of treatment discontinuation within 3 months is considered negligible. Our aim is to show with high probability, that the event rate is below a clinically acceptable threshold, which is set at 12%. Under the null hypothesis, this design with an alpha of 0.05 and power of 80% results in an expected number of cases of 75.

• Study Type: Observational
• Enrollment (Estimated): 75

Contacts and Locations

• Study Contact: Name: Radiation Oncology Study Office; Phone Number: +41442554108; Email: RAO_akademischesoffice@usz.ch

Study Locations

• Germany
  • Baden-Wurttemberg
    • Heidelberg, Baden-Wurttemberg, Germany, 69120
      • Not yet recruiting
      • Klinik für Radioonkologie und Strahlentherapie, Universitätsklinikum Heidelberg
      • Contact: Jürgen Debus, Prof. Dr. med. Dr. rer. nat.; Email: juergen.debus@med.uni-heidelberg.de
      • Principal Investigator: Jürgen Debus, Prof. Dr. med. Dr. rer. nat.
  • Bavaria
    • Munich, Bavaria, Germany, 81377
      • Not yet recruiting
      • Klinik und Poliklinik für Strahlentherapie und Radioonkologie, Universitätsklinikum LMU
      • Contact: Claus Belka, Prof. Dr. med.; Email: Claus.Belka@med.uni-muenchen.de
      • Principal Investigator: Claus Belka, Prof. Dr. med.
• Switzerland
  • Canton of Zurich
    • Zurich, Canton of Zurich, Switzerland, 8090
      • Recruiting
      • University Hospital Zurich, Department of Radio-Oncology
      • Contact: Matthias Guckenberger, Prof. Dr. med.; Phone Number: +41 44 255 31 50; Email: matthias.guckenberger@usz.ch
      • Principal Investigator: Matthias Guckenberger, Prof. Dr. med.
      • Principal Investigator: Tiuri E. Kroese, MD PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

This international multicenter prospective phase II study, conducted in collaboration with several academic hospitals in Switzerland and Germany, will include patients with histologically confirmed intermediate to (very) high risk localized prostate cancer with lower urinary tract symptoms and/or prostate hyperplasia. These patients are planned to receive weekly CT or MRI online adaptive SBRT for localized prostate cancer.

Description

Inclusion Criteria:

• histologically confirmed localized prostate cancer
• planned treatment is SBRT according to standard of care and consists of definitive CT or MRI online adaptive SBRT of the prostate according to the PACE trial which includes a total dose to clinical target volume 1 (CTV1, i.e. prostate and proximal 1 cm of the seminal vesicle) of 40.0 Gy in 5 weekly fractions (single dose of 8.0 Gy) and total dose to planning target volume 1 (PTV1) of 37.5 Gy in 5 weekly fractions (single dose of 7.5 Gy) with a compromise for bowel sparing allowed. For patients with unfavorable intermediate to very high-risk disease (according to NCCN guidelines) a total dose to the planning target volume 2 (PTV2, i.e. proximal 1-2 cm of the seminal vesicle) of 32.5 Gy in 5 weekly fractions (single dose of 6.5 Gy) will be delivered.
• intermediate to (very) high risk localized prostate cancer (≤ cT3a and Gleason score ≤ 9 and/or PSA ≤ 20 ng/ml)
• prostate volume > 60 cc and/or IPSS > 12;

Exclusion Criteria:

• Very high risk localized prostate cancer with indication for ADT and ARPI (i.e. Gleason ≥ 8 and cT3a)
• Involvement of seminal vesicles (cT3b)
• Contraindications against definitive CT or MRI-adaptive radiotherapy of the prostate, e.g. inflammatory bowel disease (IBD); previous radiotherapy in the pelvis, previous local radiotherapy of the prostate, contraindication for MRI or CT;
• Patients with severe genitourinary symptoms (e.g. recent urinary retention ≥ grade 3 according CTCAE v.5.0);
• Lymph node metastases or distant metastases (i.e. no localised prostate cancer);
• Participation in a clinical trial which might influence the results of this project.

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Pilot study; For our pilot study, we assumed that around 3% of patients would have grade 3 acute urogenital toxicity (i.e. 1 patient). The rate of treatment discontinuation within 3 months was considered negligible. Our aim was to show with high probability, that the event rate was below a clinically acceptable threshold, which was set at 20%. Under the null hypothesis, this design with an alpha of 0.05 and power of 80% results in an expected number of cases of 30. Dropouts prior to treatment start will be replaced.	Radiation: radiotherapy; Patients with prostate cancer in the medium or high risk range who are planned to receive definitive CT or MRI-adaptive SBRT.
Validation Cohort; For our validation study, we assume that around 3% of patients will have grade 3 long-term urogenital toxicity (i.e. 2 patients). The rate of treatment discontinuation within 3 months is considered negligible. Our aim is to show with high probability, that the event rate is below a clinically acceptable threshold, which is set at 12%. Under the null hypothesis, this design with an alpha of 0.05 and power of 80% results in an expected number of cases of 75. Dropouts prior to treatment start will be replaced.	Radiation: radiotherapy; Patients with prostate cancer in the medium or high risk range who are planned to receive definitive CT or MRI-adaptive SBRT.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
acute grade ≥ III urogenital toxicity	The primary endpoint is acute grade ≥ III urogenital toxicity ≤3 months after completion of radiotherapy (according to the NCI CTCAE V5 or RTOG) or treatment discontinuation related to treatment.	≤ 3 months after completion of radiotherapy

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Gastrointestinal toxicity of grade ≥3	Gastrointestinal toxicity of grade ≥3 within 3 months after completion of radiotherapy (according to CTCAE V5.0 and RTOG)	≤ 3 months after completion of radiotherapy
Mortality	Mortality (related to treatment and/or disease).	≤1 year after initiation of radiotherapy
Urogenital and gastrointestinal toxicities	Number of urogenital and gastrointestinal toxicities within 5 years after completion of radiotherapy and their severity.	≤ 5 years after completion of radiotherapy
Biochemical progression-free survival	Biochemical progression-free survival (determined from the start of therapy until the occurrence of PSA recurrence according to the Phoenix criteria i.e. post- therapeutic PSA nadir + 2 ng/ml),	≤ 5 years after completion of radiotherapy
Hormonal therapy-free survival	Hormonal therapy-free survival (determined from the start of therapy until the start of hormonal therapy,	≤ 5 years after completion of radiotherapy
Overall survival	overall survival (defined from the start of therapy until death or censoring)	5 years after completion of radiotherapy
Quality-of-life questionnaire C-30 from the European Organisation for Research and Treatment of Cancer	Quality-of-life measured using the EORTC QLQ-C30 questionnaire during and after treatment All of the scales and single-item measures range in score from 0 to 100. A high scale score represents a higher response level. Thus a high score for a functional scale represents a high/healthy level of functioning, a high score for the global health status/QoL represents a high QoL, but a high score for a symptom scale/item represents a high level of symptomatology/problems.	≤ 5 years after completion of radiotherapy
Uroflowmetry (optional)	Uroflowmetry prior to the start of radiotherapy (optional study procedure)	Uroflowmetry ≤ 6 weeks prior to the start of radiotherapy
Quality-of-life questionnaire PR25 of the European Organisation for Research and Treatment of Cancer	Quality-of-life measured using the QLQ-PR25 questionnaire during and after treatment All of the scales and single-item measures range in score from 0 to 100. A high score for the Sexual Activity and Sexual Functioning scales represents a high level of functioning, whereas a high score for the Urinary, Bowel, and Hormonal Treatment-Related symptoms scales and Incontinence Aid item represents a high level of symptomatology or problems.	≤ 5 years after completion of radiotherapy

Collaborators and Investigators

• Sponsor: University of Zurich
• Investigators: Principal Investigator: Matthias Guckenberger, University of Zurich; Study Chair: Matthias Guckenberger, Prof. Dr. med., University of Zurich; Principal Investigator: Tiuri E. Kroese, MD, PhD, University of Zurich

Publications and helpful links

General Publications

• Kroese T, Andratschke N, Belka C, Corradini S, Marschner S, Liermann J, Horner-Rieber J, Fink C, Debus J, Silvia F, Tanadini-Lang S, Pouymayou B, Mencarelli A, Fesslmeier D, Schiess A, Guckenberger M, Mayinger M. Online adaptive stereotactic body radiotherapy for localized prostate cancer in patients with lower urinary tract symptoms and/or prostate hyperplasia (X-SMILE). Radiat Oncol. 2025 May 28;20(1):90. doi: 10.1186/s13014-025-02653-4.

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2024
• Primary Completion (Estimated): September 1, 2026
• Study Completion (Estimated): June 30, 2031

Study Registration Dates

• First Submitted: February 6, 2025
• First Submitted That Met QC Criteria: February 13, 2025
• First Posted (Actual): February 19, 2025

Study Record Updates

• Last Update Posted (Actual): February 9, 2026
• Last Update Submitted That Met QC Criteria: February 4, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Keywords: MRI; prostate cancer; radiotherapy; CT; SBRT; prostate hyperplasia; lower urinary tract symptoms; localized prostate cancer; stereotactic radiotherapy
• Additional Relevant MeSH Terms: Urogenital Diseases; Genital Diseases; Genital Neoplasms, Male; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Genital Diseases, Male; Prostatic Diseases; Male Urogenital Diseases; Urological Manifestations; Neoplasms by Histologic Type; Neoplasms, Glandular and Epithelial; Carcinoma; Pathological Conditions, Signs and Symptoms; Signs and Symptoms; Prostatic Neoplasms; Prostatic Hyperplasia; Adenocarcinoma; Lower Urinary Tract Symptoms; Therapeutics; Radiotherapy
• Other Study ID Numbers: RAO-24-014

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Individual participant data that underlie the results reported in this trial after de-identification. Other documents may be shared include the study protocol.
• IPD Sharing Time Frame: Beginning 9 months and ending 36 months after article publication.
• IPD Sharing Access Criteria: Proposals to access study data should send request to matthias.guckenberger@usz.ch. To gain access, data requesters must sign data access agreement.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No