2-fraction Stereotactic Body Proton Therapy (SBPT) With Magnetic Resonance Imaging (MRI) Guidance in Localized Prostate Cancer: A Single-arm Phase II Non-randomized Trial
Phase: NA
Conditions: Prostate Cancer Patients Treated by Radiotherapy
Sponsor: Hong Kong Sanatorium & Hospital

 
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2-fraction Stereotactic Body Proton Therapy 
(SBPT) with Magnetic Resonance Imaging (MRI) 
Guidance in Localized Prostate Cancer: A 
Single-arm Phase II Non-randomized Trial (PT2 
Trial) 
 
NCT number: NCT07130682 
Last updated: 11 Dec 2025 
Last approved: 6 Jan 2026 
 
 

 
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Introduction 
 
Proton therapy (PT) is an advanced form of external beam radiotherapy (EBRT) that 
offers significant potential to enhance the therapeutic ratio compared to photon 
radiotherapy, owing to its unique Bragg peak beam characteristics. This advantage 
applies to a wide range of oncological applications. Hong Kong Sanatorium & Hospital 
(HKSH) established the first proton therapy center in Hong Kong and began offering 
PT as a clinical service in July 2023. However, PT requires substantial capital 
investment, rendering it an expensive treatment option and limiting access for patients 
with socioeconomic challenges. 
 
In addition to technological advancements, such as the development of compact particle 
accelerators and gantry-free treatment solutions, hypofractionation—reducing the 
number of treatment fractions per PT course—offers a practical strategy to improve 
access, lower treatment costs, and maintain clinical outcomes without compromising 
efficacy (1–3). Hypofractionation also benefits patients from remote areas by reducing 
the duration of time they must spend away from home, thereby minimizing financial 
and psychosocial burdens on their support networks (3). 
 
Given the low α/β ratio assumed for prostate cancer and the higher α/β ratios for organs 
at risk, the linear-quadratic model suggests that larger doses per fraction may improve 
the therapeutic ratio, theoretically supporting ultrahypofractionation in clinical practice. 
Ultrahypofractionated radiotherapy using photon beams, known as Stereotactic Body 
Radiation Therapy (SBRT), has been demonstrated to be safe and effective, with Level 
1 evidence from phase III randomized clinical trials such as the PACE-B study (4, 5) 
and the HYPO-RT-PC trial (6, 7). These findings underpin the National Comprehensive 
Cancer Network (NCCN) guidelines (Version 4.2023), which recognize SBRT as a 
standard-of-care treatment option for localized prostate cancer across all risk groups 
(https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1459, 
last 
accessed February 6, 2024). 
 
Ultrahypofractionated PT, referred to here as Stereotactic Body Proton Therapy (SBPT) 
with treatment reduced to five fractions, is being investigated for localized prostate 
cancer. Preliminary results indicate promising outcomes with no significant increase in 
toxicities compared to traditionally fractionated or moderately hypofractionated PT. For 
example, Kubes et al. (2019) reported outcomes for 200 prostate cancer patients (low-
risk: n=93; intermediate-risk: n=103) treated with extreme hypofractionated SBPT 
delivering 36.25 Gy (Relative Biological Effectiveness, RBE) in five fractions, with a 

 
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median follow-up of 30 months. Late gastrointestinal (GI) Grade 2 (G2) toxicity 
occurred in 5.5% of patients, and late genitourinary (GU) G2 toxicity in 4%, with no 
Grade 3 (G3) or higher toxicities observed. Prostate-specific antigen (PSA) relapse was 
noted in 1.08% of low-risk patients and 6.5% of intermediate-risk patients (8). In a 2023 
update, Kubes et al. reported on a larger cohort (n=853) with a median follow-up of 
62.7 months, showing 5-year biochemical disease-free survival (bDFS) rates of 96.5%, 
93.7%, and 91.2% for low-, favorable intermediate-, and unfavorable intermediate-risk 
groups, respectively. Cumulative late toxicity (CTCAE v4.0) included GI G2 in 9.1% 
and G3 in 0.5%, and GU G2 in 4.3%, with no G3 toxicity. PSA relapse occurred in 
6.8% of patients (9). 
 
The efficacy of SBRT for localized prostate cancer can be further enhanced with 
advanced image guidance using magnetic resonance imaging (MRI), or MR-guided 
radiotherapy (MRgRT), facilitated by recently introduced MRI-integrated linear 
accelerators (MR-LINACs) (10, 11). Preliminary clinical outcomes of MR-guided 
SBRT at our institution are encouraging and add to the growing evidence base (12). 
Moreover, emerging evidence suggests that radiotherapy for localized prostate cancer 
can be safely and effectively delivered in fewer than five fractions using SBRT (13). 
Ongoing pilot MRgRT studies, such as NCT03588819 (2SMART) and NCT04984343 
(FORT), are investigating treatment efficacy by reducing fractions from five to two (14). 
Encouraging interim results have recently been published, indicating safety and 
comparable acute toxicity profiles to 5-fraction SBRT (15, 16). 
 
In this study, we hypothesize that 2-fraction (2-fx) SBPT is safe and feasible in clinical 
practice, with similar rates of severe adverse events in low- and intermediate-risk 
prostate cancer patients compared to moderately hypofractionated PT and 5-fx SBPT, 
when guided by planning MRI acquired before and during the PT course. Furthermore, 
reducing the treatment to two fractions could decrease treatment costs by approximately 
50%, significantly improving affordability and increasing access to this advanced 
treatment for more patients. 
 
Methods/Design 
 
This is a phase II, single-arm, non-randomized trial to evaluate clinician-reported and 
patient-reported gastrointestinal (GI) and genitourinary (GU) toxicities at baseline and 
up to 5 years post-treatment in men with low- or intermediate-risk prostate cancer (PCa) 
receiving 2-fraction (offline) Stereotactic Body Proton Therapy (SBPT) guided by 
planning magnetic resonance imaging (MRI). We plan to enroll 35 patients, with an 

 
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anticipated accrual rate of 1–3 patients per month. SBPT will deliver 25 Gy in 2 
fractions to the prostate ± seminal vesicles, with an optional simultaneous dose boost 
to intraprostatic lesions. Treatments will be administered with at least 6 days between 
fractions, ideally completed within 2 weeks. 
 
Objectives 
 
Primary Objective: To demonstrate that 2-fraction SBPT is safe and feasible, resulting 
in similar toxicity rates compared to 5-fraction SBRT. Clinician-reported Grade 2 or 
higher (G2+) GU and GI toxicities, based on the National Cancer Institute (NCI) 
Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 (v5.0), will 
be assessed. Patient-reported GI and GU symptoms post-treatment, and changes in 
scores compared to pre-SBPT baseline, will also be evaluated. 
 
Primary Endpoint 
 
The primary endpoint is clinician-reported G2+ GU and GI adverse events (AEs) at 3 
months and 24 months post-SBPT, as assessed by NCI-CTCAE v5.0. G2+ GU and GI 
AEs within 3 months post-SBPT are classified as acute toxicities, while those occurring 
after 3 months are considered late toxicities. 
 
Secondary Endpoints 
 
1. Changes in patient-reported GI and GU symptoms, measured using the Expanded 
Prostate Cancer Index Composite (EPIC) questionnaire, from baseline to 3 months 
post-SBPT. 
2. Changes in patient-reported GI and GU symptoms, measured using the EPIC 
questionnaire, from baseline to 24 months post-SBPT. 
3. Assessment of disease progression, including biochemical failure (BF), local failure 
(LF), regional failure (RF), and distant metastasis (DM), and time-to-progression 
(TTP), defined as the first occurrence of BF, LF, RF, or DM. 
4. Clinician-reported G2+ GU and GI late events (LEs) at 5 years post-SBPT, based 
on NCI-CTCAE v5.0. 
 
Inclusion Criteria 
 
- 
Men aged ≥ 18 years with histologically confirmed low- or intermediate-risk 
prostate cancer per NCCN guidelines. 

 
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- 
Eastern Cooperative Oncology Group (ECOG) performance status < 2. 
- 
Ability to undergo MRI simulation scans without absolute contraindications, such 
as cardiac implantable electronic devices. 
- 
Ability to complete the EPIC questionnaire. 
 
Exclusion Criteria 
 
- 
History of inflammatory bowel disease or other cancers (except prostate cancer). 
- 
Prior pelvic radiotherapy, chemotherapy, radical prostatectomy, cryosurgery, or 
focal therapy (e.g., high-intensity focused ultrasound [HIFU]) for prostate cancer. 
- 
History of bladder neck or urethral stricture. 
- 
Transurethral resection of the prostate (TURP) < 8 weeks prior to SBPT. 
- 
Prostate volume > 100 cc on MRI. 
- 
Unilateral or bilateral hip replacements. 
- 
Nodal or distant metastases, as indicated by CT, MRI, or prostate-specific 
membrane antigen (PSMA) positron emission tomography (PET) scans. 
- 
Previous androgen deprivation therapy (ADT) lasting more than 6 months. 
 
Patient Selection, Study Enrollment, Randomization, and Blinding 
 
Patients with biopsy-confirmed prostate cancer, who have chosen to receive proton 
therapy, will be informed of their eligibility for this study. Clinicians or research 
nurses/assistants will explain the informed consent form in person. Patients who agree 
to participate must sign the consent form, and a copy will be provided to them. This 
study involves no randomization or blinding; patients are aware of their treatment. 
 
Interventions 
 
Radiation Treatment Planning 
 
Following consent and eligibility confirmation, patients will undergo rectal spacer and 
fiducial marker (Visicoil, IBA Dosimetry GmbH, Schwarzenbruck, Germany) 
implantation per the institutional protocol, prior to simulation scans and treatment 
planning. After 2–3 weeks, without severe complications from implantation, patients 
will undergo same-day CT and subsequent MRI simulation scans (on a 1.5T or 3T MRI 
simulator dedicated for radiotherapy and proton therapy applications) per the 
institutional protocol. Treatment will target the prostate ± seminal vesicles, delivering 
25 Gy in 2 fractions, with at least 6 days between treatments, completed within 2 weeks, 

 
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at the treating physician’s discretion. 
 
Contours 
 
1. The clinical target volume (CTV1) will encompass the entire prostate, as defined 
by the non-contrast axial planning CT scan, for low-risk patients. For intermediate-
risk patients, CTV2 will include the entire prostate plus the proximal two-thirds of 
the seminal vesicles, in addition to CTV1. MRI will be co-registered with the 
planning CT to assist with target contouring. 
2. An optional boost volume may be defined for intraprostatic lesions identified by 
clinical imaging (e.g., MRI, PSMA-PET), at the oncologist’s discretion. 
3. The rectum will be contoured from the bottom of the ischial tuberosities to the 
sigmoid flexure. 
4. Normal structures, including the bladder, urethra (delineation at the treating 
physician’s discretion), femoral heads, and penile bulb, will also be contoured. 
Urethral delineation may use T2 sequences, contouring on axial slices where visible, 
and/or on the sagittal plane from the bladder to the penile urethra. 
 
Treatment Dose Planning Parameters 
 
A setup error of 2-3 mm and a range uncertainty of 3% will be applied in robust 
planning. The CTV will receive a prescribed dose of 25 Gy in 2 fractions. The volume 
of the CTV receiving the prescription dose (V25 Gy) must be ≥ 95% and not exceed 
110% (hotspot). No more than 10% of the urethra volume should receive > 27 Gy. 
 
Table 1: Dose constraints used in the planning of the 2-fraction regimen 
Structure 
Dose Metric 
Planning Dosimetric 
Criterion 
CTV1 
V25 Gy  
> 95% 
Dmax  
< 27.5 Gy 
CTV2 
V20 Gy   
 > 95% 
Urethra 
D10%  
< 27 Gy 
Bowel  
V12 Gy 
< 5 cm3 
Femoral head_L 
V14 Gy  
< 10 cm3 
Femoral head_R 
V14 Gy   
< 10 cm3 
Bladder  
V20.8 Gy  
< 5 cm3 
V14.6 Gy  
< 15 cm3 
Dmax 
< 27Gy 

 
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Penile Bulb 
V19.5 Gy  
< 50% 
Rectum  
V20.8 Gy 
< 1 cm3 
V17.6 Gy  
< 4 cm3 
V13 Gy  
< 7 cm3 
Dmax 
< 27Gy 
 
Adaptive Planning 
 
1. The need for adaptive planning will be assessed for all participants. 
2. Daily MR images will be rigidly registered to the planning CT by aligning relevant 
anatomy (bladder, rectum, prostate ± seminal vesicles). 
3. Organs at risk (OARs) will be auto-contoured on the MR, and CTV simulation 
contours will be rigidly copied to the MR scan. 
4. CTV1/CTV2 and OAR contours will be reviewed and manually adjusted if 
necessary. 
5. The original plan will be recalculated on a synthetic CT generated from the daily 
setup MR to verify compliance with planning dose parameters. 
6. Adaptive planning will be performed if treatment dose parameters fail to meet 
planning or protocol-mandated criteria. 
 
Treatment Delivery and Gating 
 
1. A short MRI scan (~25 seconds) will be used for setup and to assess bladder filling 
and rectal position. 
2. A long MRI scan (~3 minutes) will be used for adaptive planning assessment. 
3. Orthogonal X-ray images will align bony anatomy with the planning CT at the 
patient’s imaging position. 
4. Final couch shifts, based on fiducial marker positions, will be applied before 
treatment delivery. 
5. The fiducial marker with minimal migration will be selected for real-time image-
guided particle therapy (RGPT), using a 1–2 mm tracking boundary during 
treatment. 
 
Concomitant Medication and Supportive Care Guidelines 
 
1. Androgen deprivation therapy (ADT) for 4–6 months may be administered to 
intermediate-risk patients, at the investigator’s discretion and/or patient preference, 
in neoadjuvant (up to 2 months pre-SBPT), concurrent, or adjuvant (post-SBPT) 

 
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settings. 
2. Patients experiencing increased urinary frequency or urgency may receive 
medications (e.g., anticholinergics, alpha-blockers like tamsulosin) at the radiation 
oncologist’s discretion, with documentation in the patient chart. 
3. Rare serious bowel symptoms (e.g., rectal urgency, tenesmus, diarrhea) may be 
managed with medications (e.g., diphenoxylate, loperamide) at the radiation 
oncologist’s discretion, documented in the patient chart. 
 
Follow-Up Phase 
 
Post-SBPT, patients will be followed at 1, 3, 6, and 12 months in the first year, then 
every 6 months until 5 years post-treatment. At each visit, patients will complete the 
EPIC questionnaire (in English or validated Chinese versions), assessing four domains: 
urinary symptoms (subdomains: incontinence, irritative/obstructive), sexual symptoms, 
bowel symptoms, and hormonal symptoms, scored from 0 (worst) to 100 (best). PSA 
levels will be measured at each follow-up (±1 month window). 
 
Clinician-Reported Adverse Events 
 
Adverse events (AEs) will be reported using NCI-CTCAE v5.0. GU toxicities include 
urinary frequency, urgency, incontinence, obstruction, retention, pain, bladder spasm, 
cystitis (noninfective), and hematuria. GI toxicities include proctitis, diarrhea, fecal 
incontinence, rectal hemorrhage, stenosis, ulcer, and small-intestinal obstruction. 
Erectile dysfunction and fatigue will also be graded. Clinical discretion may guide 
management, such as diphenoxylate/loperamide for diarrhea/rectal symptoms, 
phenazopyridine for bladder irritation, anticholinergics/alpha-blockers for urinary 
symptoms, and phosphodiesterase inhibitors (e.g., sildenafil) for erectile dysfunction. 
All AEs and G3+ serious adverse events (SAEs) will be recorded and followed until 
resolution or stabilization. 
 
Data Management and Safety Monitoring 
 
A secure database, maintained by HKSH, will store all treatment, toxicity, efficacy, and 
AE data, accessible only to clinicians, investigators, and core research team members. 
Security measures include firewall technology, role-based access, user authentication 
(ID/password), and restricted data transfer within hospital systems. Data will be 
retained for at least 10 years post-study. 
 

 
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Statistical Analysis 
 
Sample Size and Accrual 
 
We hypothesize that ≤5% of patients will experience G2+ GI or GU late toxicities (≥3 
months) up to 2 years post-treatment. A sample size of 32 patients, using a one-stage 
binomial design, tests the null hypothesis that the G2+ GI or GU toxicity rate is ≥15%, 
with 80% power and a 5% significance level. The target sample size is increased to 35 
to account for a 10% non-compliance rate (e.g., rejection, cancellation, treatment 
violation, dropout/loss to follow-up). The projected accrual rate is 1–3 patients/month, 
with study completion expected in 12–30 months. 
 
Data Analysis 
 
Analysis of Primary Endpoints 
 
GI and GU toxicities will be evaluated throughout follow-up, with occurrence dates 
recorded. Proportions of patients with G2+ GI, GU, or both toxicities will be calculated 
at baseline and each follow-up. Fisher’s exact tests will compare categorical data. 
 
Early Stopping Guidelines/Interim Futility Analysis 
 
An interim futility analysis will occur when half the patients complete 6 months of 
follow-up. If the G2+ GI or GU toxicity rate exceeds 20%, the treatment strategy will 
be deemed unacceptable, and results will be reported to the Institutional Review Board 
(IRB) for review, potentially leading to early study termination. 
 
Analysis of Secondary Endpoints 
 
Patient-reported EPIC score changes will be calculated as baseline scores minus follow-
up scores at 1, 3, 6, and 12 months (year 1), then every 6 months (years 2–5). 
Longitudinal analysis using linear mixed-effects models, adjusted for age, baseline 
domain score, NCCN risk level, Gleason score, baseline PSA, and T-stage, will assess 
each domain. Race will not be included, as most participants are expected to be Chinese. 
Analysis of variance (ANOVA) will compare EPIC score changes at 2 years. Missing 
data impact will be evaluated using multiple strategies, including adjustments for 
patient characteristics (missing at random [MAR]), joint models (missing not at random 
[MNAR]), pattern mixture models, and sensitivity analyses. 

 
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For oncological outcomes (BF, LF, RF, DM), Gray’s cumulative incidence method will 
account for death as a competing risk. Overall survival (OS) will be estimated using the 
Kaplan–Meier method. Cox regression will provide hazard ratios (HRs) for TTP, and 
Fine and Gray’s regression will address competing risks. Adjusted HRs and 95% 
confidence intervals will be reported, adjusting for baseline PSA, EPIC scores, ADT 
use, age, Gleason score, and T-stage as appropriate. 
 
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