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10.1136/bmjopen-2023-082899
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Protocol
Urology
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Two-fractionated stereotactic magnetic resonance-guided adaptive radiation therapy for patients with prostate cancer (SMART PRO trial): protocol for a confirmatory clinical trial
http://orcid.org/0000-0002-0421-5805
Zenda Sadamoto 12szenda@east.ncc.go.jp

Kashihara Tairo 3tkashiha@ncc.go.jp

Saito Tetsuo 4tetsuosaito1977@gmail.com

Okamoto Hiroyuki 3hiokamot@ncc.go.jp

Kadoya Noriyuki 5kadoya.n@rad.med.tohoku.ac.jp

Chiba Takahiro 3tachiba@ncc.go.jp

Noda Shin-ei 6nodashin@saitama-med.ac.jp

http://orcid.org/0000-0003-2446-7716
Kawaguchi Takashi 7tkawa@toyaku.ac.jp

Jingu Keiichi 5kjingurad@yahoo.co.jp

Shibuya Keiko 8kshibuya@omu.ac.jp

Uno Takashi 9unotakas@faculty.chiba-u.jp

Igaki Hiroshi 3hiigaki@ncc.go.jp

1 Department of Radiation Oncology, National Cancer Center Hospital East, Kashiwa, Japan
2 Department of Supportive and Palliative Care Research Support Office, National Cancer Center Hospital East, Kashiwa, Japan
3 Department of Radiation Oncology, National Cancer Center Hospital, Chuo-ku, Japan
4 Division of Integrative Medical Oncology, Saiseikai Kumamoto Hospital, Kumamoto-Shi, Kumamoto, Japan
5 Department of Radiation Oncology, Tohoku University Graduate School of Medicine, Sendai, Japan
6 Department of Radiation Oncology, Saitama Medical University, Iruma-gun, Japan
7 Department of Practical Pharmacy, Tokyo University of Pharmacy and Life Sciences, Hachioji, Japan
8 Department of Radiation Oncology, Osaka Metropolitan University Graduate School of Medicine School of Medicine, Osaka, Japan
9 Diagnostic Radiology and Radiation Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan
Dr; tkashiha@ncc.go.jp
None declared.

2024
24 8 2024
14 8 e08289906 12 2023
01 8 2024
Copyright © Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
2024
https://creativecommons.org/licenses/by-nc/4.0/ This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

Abstract

Introduction

In an MRI-guided linear accelerator (MR-LINAC) system, the planned doses for organs at risk and for tumours are assessed by MR imaging and re-contouring at every treatment. This allows treatment to be safer and more precise by ensuring that it is suitable for the state of the patient’s organs on that day, as well as by allowing images to be acquired during radiation therapy to prevent radiation while organs are in motion.

Here, we will conduct a confirmatory study of two-fractionated stereotactic magnetic resonance-guided adaptive radiation therapy for patients with localised prostate cancer.

Methods and analysis

This will be a single-arm study to demonstrate the safety and efficacy of ultra-hypofractionated radiation (26 Gy/2 Fr) using an MR-LINAC system in patients with very low-intermediate risk prostate cancer.

The primary endpoint will be the incidence of grade ≥2 acute urinary tract adverse events occurring within 90 days of the start of radiation therapy.

The sample size has been determined to be 58.

Ethics and dissemination

This study is performed in accordance with Ethical Guidelines for Medical and Health Research Involving Human Subjects, published by Japan’s Ministry of Education, Science and Technology and the Ministry of Health, Labour and Welfare and the modified act on the Protection of Personal Information as well as the Declaration of Helsinki. This study was approved by the institutional ethics committee of the National Cancer Center on 20 November 2021.

The findings of this trial will be submitted to an international peer-reviewed journal and the key findings will be presented at an international scientific conference.

Authorship will be ascribed in accordance with the International Committee of Medical Journal Editors guidance.

Trial registration number

UMIN000049746.

Radiation oncology
Prostate disease
Quality of Life
Magnetic resonance imaging
Safety
http://dx.doi.org/10.13039/100009619 Japan Agency for Medical Research and Development AMED23ck0106745h0002
==== Body
pmcStrengths and limitations of this study

This study is multicentre clinical study.

Treatment regimen is ultra-hypofractionated radiation (26 Gy/2 Fr) using an MR-LINAC system.

Treatment can be completed in 2 days to ensure patient comfort.

Quality assurance of radiotherapy is strictly maintained.

This study is a small-scale, non-randomised study.

Introduction

Most patients with prostate cancer are diagnosed with clinically localised disease, and the majority have low-risk or intermediate-risk disease as defined by the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology (NCCN Guidelines); Prostate Cancer V.4.2022.

In the 2022 NCCN Guidelines, radiotherapy is recommended for patients with low-intermediate risk when life expectancy is 10 years or more. In prostate cancer, tumours have a low alpha/beta ratio, and from a radiobiological point of view, greater treatment response can be achieved by increasing the radiation dose per fraction.16

In common CT-based radiation therapy equipment, alignment is often performed via cone-beam CT imaging at each treatment using a metal marker implanted in the prostate gland as a landmark.7 However, this method has the following disadvantages: the inability to check organ motion during treatment and to change the treatment plan in the event of organ misalignment or deformation of the organs, and difficulty in delineating the boundary between the spacer and the rectal wall and prostate on cone-beam CT. Both of these are directly related to a loss of safety and efficacy with this radiation therapy. In an MRI-guided linear accelerator (MR-LINAC) system, on the other hand, the planned doses for organs at risk and for tumours are assessed by MRI and re-contouring at every treatment, allowing treatment to be planned anew if the treatment plan is inadequate.8 9 It is thus possible to ensure safer and more precise treatment by, for example, ensuring a treatment that is suitable for the state of the patient’s organs on that day, as well as by allowing images to be acquired during radiation therapy to prevent radiation while organs are in motion.10

The 2STAR trial,11 a clinical trial of stereotactic radiotherapy in which 26 Gy was delivered in two fractions using a CT-based linear accelerator to patients with localised prostate cancer, had a high rate of grade 2 or higher acute urinary tract adverse events (40%).

Here, we will conduct a confirmatory study of two-fractionated stereotactic magnetic resonance-guided adaptive radiation therapy for patients with localised prostate cancer.

Methods and analysis

Objective and trial design

The objective will be to confirm the safety and efficacy of stereotactic body radiation therapy using an MR-LINAC system for very low to low-risk or intermediate-risk prostate cancer.

This protocol has been reviewed by the Institutional Review Board of the National Cancer Center Hospital, Japan (https://www.ncc.go.jp/en/index.html) (study number 2022–190), and the study has been registered in the UMIN Clinical Trial Registry. At this point, no data-sharing plan has been accepted.

Patient and public involvement

None.

Study setting

This will be a single-arm study to demonstrate the safety and efficacy of ultra-hypofractionated radiation (26 Gy/2 Fr) using the MR-LINAC system in patients with prostate cancer. If the results of this study are favourable, it is assumed that MRI-based treatment planning will become a standard method.

All participants will be recruited from five hospitals: National Cancer Center Hospital, Tohoku University Hospital, Osaka Metropolitan University Hospital, Chiba University Hospital and Saitama Medical University International Medical Center.

Eligibility criteria

Inclusion criteria

Patients fulfilling all of the following criteria will be eligible for inclusion in the study.

(1) Histopathologically confirmed prostate cancer, (2) clinical stage T1c-2cN0M0, (3) any pre-enrolment Prostate-specific antigen (PSA) level <20 ng/mL, (4) Gleason score of 6–7, (5) very low to low risk or intermediate risk per the NCCN Guidelines risk classification (2022 version), (6) with or without measurable lesions, (7) 18 years to <80 years of age on the date of enrolment, (8) Eastern Cooperative Oncology Group (ECOG) performance status of 0–1, (9) able to undergo MRI, (10) no history of surgical treatment of the prostate gland (such as transurethral resection of the prostate, subcapsular prostatectomy, orchidectomy), HIFU (high-intensity focused ultrasound therapy) or chemotherapies other than hormonal therapy, (11) International Prostate Symptom Score ≤19 within 28 days prior to enrolment (may be same day of the week 4 weeks prior to enrolment), (12) if implanted, SpaceOAR is properly implanted in the Denovier space, with no marked worsening of post-implant voiding symptoms, (13) no history of radiation therapy in the area exposed to radiation in this study, including treatment for other types of cancer, (14) no hormone-refractory tumours, (15) written informed consent to participate in the study provided personally by the patient, (16) willing to undergo study treatment after being informed of other treatment options.

Exclusion criteria

Patients meeting any of the following criteria will be excluded from the study.

(1) Infectious disease requiring systemic treatment, (2) psychiatric disorder or psychiatric symptoms interfering with activities of daily living, making it difficult to participate in the study, (3) poorly controlled diabetes mellitus despite ongoing use of insulin or oral hypoglycaemic agents, (4) inflammatory bowel disease such as Crohn’s disease or ulcerative colitis, (5) abdominal or pelvic surgery other than appendectomy or inguinal hernia, (6) active scleroderma or systemic lupus erythematosus, (7) inappropriate for participation in the study in the opinion of the investigator, (8) current use of anticoagulant/antiplatelet medication.

Intervention (radiotherapy for prostate cancer)

Stereotactic body radiation therapy will be performed using an MR-LINAC system. A dose of 13 Gy will be administered two times, for a total dose of 26 Gy. The prescription dose will ensure that 26 Gy/2 Fr is delivered to 95% of the clinical target volume (CTV) − (urethra+1 mm). The first and second treatments will be given 7−14 days apart (up to a maximum of 30 days) (figure 1).

Figure 1 Treatment schema and radiotherapy in detail. Pretreatment simulation is performed using an MRI-guided linear accelerator (MR-LINAC) system. A dose of 13 Gy will be administered two times, for a total dose of 26 Gy. The first and second treatments will be given 7–14 days apart. PTV, planning target volume.

If the urethra cannot be visualised by LINAC MR imaging, urethral catheterisation will be recommended during planned imaging and treatment to visualise the urethra. The dose distribution will be calculated on the MRI taken before the start of irradiation on the treatment bed, and irradiation will be started after its validity is confirmed.

Radiation should be stopped if bowel gas movement, for example, results in a change in position during treatment. MR images will be acquired to assess deviations in the treatment plan or during treatment.

Target volume

Contouring will be performed with reference to the RTOG Contouring Atlas,12 however, the individual judgement of the physician in charge will be allowed.

The prostate gland will be considered to be the gross tumour volume (GTV).

The CTV will be the prostate gland (same as GTV), but inclusion of the seminal vesical base will be recommended in intermediate-risk patients. Contouring of the seminal vesicle base will be recommended as follows1; include approximately 1 cm in the longitudinal direction of the seminal vesicle,2 adipose tissue between the seminal vesicle and the prostate may be included,3 as a general guide, include approximately 1 cm from the seminal vesicle root.

The inclusion of the seminal vesicle base will be recommended when there is a 10% or greater probability of seminal vesicle invasion, as determined using the following Partin table13 (table 1), but the final decision will be left to the site or investigator. The planning target volume (PTV) should be the CTV+3 to 5 mm in all directions. PTV margins may differ depending on direction.

Table 1 Partin table

Clinical T1c				
PSA	GS:6	GS:3+4	GS:4+3	
 4.1–6.0	Group 1	Group 1	Group 1	
 6.1–10.0	Group 1	Group 1	Group 1	
 >10.0	Group 1	Group 2	Group 2	
Clinical T2a				
PSA				
 4.1–6.0	Group 1	Group 1	Group 1	
 6.1–10.0	Group 1	Group 1	Group 2	
 >10.0	Group 1	Group 2	Group 2	
Clinical T2b/T2c				
PSA				
 4.1–6.0	Group 1	Group 1	Group 2	
 6.1–10.0	Group 1	Group 2	Group 2	
 >10.0	Group 1	Group 2	Group 3	
Group 1: group with less than 10% probability of seminal vesicle invasion, as determined using the Partin table.

Group 2: group with 10% to less than 25% probability of seminal vesicle invasion as determined using the Patin table.

Group 3: group with ≥25% probability of seminal vesicle invasion, as determined using the Partin table.

GS, Gleason scorePSAprostate-specific antigen

Definition of organs at risk and dose constraints

The bladder, rectum, intestine (colon, small intestine) and urethra will be defined as organs at risk, and dose constraints will be established. All organs will be considered to be solid. The bladder extends from the neck to the base. The rectum extends from the anus (at the level of the ischial tuberosity) to the rectosigmoid junction. The dose constraints for normal tissue will be as follows. A portion of the bladder and rectum may be irradiated with a dose equivalent to the PTV. However, these kinds of high-dose areas should be minimised via careful planning. Caution should be exercised to ensure that organs at risk are not exposed to the maximum dose (table 2).

Table 2 Dose constraints

Contour	Dose constraint (target)	Dose constraint (acceptable)	
Entire PTV	≥95	%	23	Gy	≥93	%	23	Gy	
≤2	%	30	Gy	≤5	%	30	Gy	
Intraurethral PTV	≥98	%	22	Gy	≥96	%	22	Gy	
≤5	%	26	Gy	≤10	%	26	Gy	
CTV − (urethra+1 mm)	≥95	%	26	Gy					
Femoral head	≤ 5	cc	14	Gy	≤10	cc	14	Gy	
Rectum	≤0.1	cc	24	Gy	≤0.5	cc	24	Gy	
≤0.5	cc	20.8	Gy	≤1	cc	20.8	Gy	
≤2	cc	17.6	Gy	≤4	cc	17.6	Gy	
≤4	cc	13	Gy	≤7	cc	13	Gy	
Bladder	≤5	cc	20.8	Gy	≤10	cc	20.8	Gy	
≤10	cc	14.6	Gy	≤20	cc	14.6	Gy	
Intestine (colon, small intestine)	≤0.1	cc	20	Gy	≤0.5	cc	20	Gy	
≤1	cc	16	Gy	≤2	cc	16	Gy	
Urethra*+1 mm	≤0.1	cc	26	Gy	≤0.5	cc	26	Gy	
* The urethra should be contoured with a urethral catheter. If no urethral catheter is placed, it should be depicted as a circle 4 mm in diameter on the axial image.

CTV, clinical target volumePTV, planned target volume

Permitted concomitant therapies

Anti-flatulence/antidiarrhoeal agents for loose stool/diarrhoea will be permitted. non-steroidal anti-inflammatory drugs (NSAIDs) and local steroid treatments (steroid suppositories or ointments for anal anti-inflammatory analgesia) will be permitted for anal pain and haemorrhoids, for example, or radiation therapy-induced anorectal disorders. The use of anticholinergics and α1 blockers, for example, will be permitted for urination disorders.

Prohibited concomitant therapies

A luteinizing hormone-releasing hormone (LHRH) analogue alone (or LHRH antagonist alone) or an LHRH analogue (or LHRH antagonist) + antiandrogen may be used for androgen deprivation therapy. The protocol treatment will not include androgen deprivation therapy.

Concomitant chemotherapy will not be permitted. Antitumour therapy such as chemotherapy, immunotherapy or additional radiation therapy will not be permitted until recurrence following the completion of radiation therapy.

Endpoints

Primary endpoint (safety)

The primary endpoint will be the incidence of grade ≥2 acute urinary tract adverse events (occurring within 90 days of the start of radiation therapy).

All urinary tract toxicities, including voiding pain and haematuria, will be assessed as urinary tract adverse events.

Reports of stereotactic body radiation therapy (SBRT) for prostate cancer in the past indicate that acute phase adverse events peak primarily around 2–4 weeks after the start of radiation therapy.

Secondary endpoints

Secondary endpoints will be the rate of other acute adverse events, rate of 5-year late adverse events associated with radiotherapy (from 91 days after radiotherapy initiation), minimum PSA after radiotherapy completion, 5-year PSA recurrence-free rate, 5-year clinical progression-free rate, 5-year disease-specific survival rate, 5-year metastasis-free survival rate, 5-year overall survival rate, PSA recurrence-free duration, clinical progression-free survival, disease-specific survival, overall survival, patient-reported outcomes and health economic evaluation using EuroQol 5 Dimension (EQ-5D). Acute and late adverse events will be evaluated by their physicians. Patient-reported outcomes will be collected electronically.

Participant timeline

Patients will be registered online before protocol treatment is started.

The following assessments should be performed prior to the start of any treatment (tests required for staging): prostate needle biopsy: biopsy Gleason score, number of positive biopsies/number of biopsies, maximum core involvement (%), PSA value, pelvic CT or MRI, bone scintigraphy (as needed), medical history, comorbidities, Charlson Comorbidity Index, tumour, node, metastases classification and NCCN risk classification.

After protocol treatment starts, objective and subjective evaluation with regard to adverse events and general examination will be performed weekly, namely at 7 days and 14 days after protocol treatment. With regard to follow-up period, the outpatient interval will be changed to between less than 2 years and more than 2 years after protocol treatment. The assessment schedule from enrolment to 5 years after protocol treatment is shown in table 3.

Table 3 Assessment schedule

Time schedule	Pretreatment	During radiotherapy	Follow-up (<2 years)	Follow-up (≥2 years)	
Check interval		Weekly	1, 3, 6, 9, 12, 15, 18, 21 and 24 months after treatment	30, 36, 42, 48, 54 and 60 months after treatment	
Prostate needle biopsy	X				
Medical history	X				
Charlson Comorbidity Index	X				
TNM staging	X				
Performance status	X				
Adverse events	X	X	X	X	
Subjective symptoms	X	X	X	X	
Objective symptoms	X	X	X	X	
IPSS	X		X	X	
EPIC/EQ-5D	X		X	X	
Imaging (CT/MRI)	X		X	X	
EPICExpanded Prostate Cancer Index CompositeEQ-5DEuroQol 5 DimensionIPSSInternational Prostate Symptom ScoreTNMtumour, node, metastases

Sample size

A previous single-arm non-inferiority confirmatory study evaluated treatment consisting of 26 Gy/2 Fr dose fractions delivered via the MR-LINAC system. This was expected to be non-inferior, as demonstrated on the basis of the incidence of grade ≥2 acute phase genitourinary adverse events, versus a historical control, namely a clinical study of ultra-hypofractionated radiation (36.25 Gy/5 Fr) using CT-based radiation therapy equipment. The reported incidence of grade ≥2 acute phase genitourinary adverse events with 36.25 Gy/5 Fr CT-based radiation therapy was 23.1%, and a precision-based sample size calculation was therefore implemented assuming an expected incidence of 23.1%, a threshold of 30.6% and one-sided alpha of 10%.

If adverse events occur in up to 12 of 52 per-protocol subjects (23.07%) in the present study, the upper limit of the 80% CI based on normal approximation would be 30.590% or less. Based on this required number of per-protocol patients of 52, the sample size was determined to be 58, assuming that some of the enrolled subjects will not complete the planned radiation therapy.14

Planned enrolment period was 3 years.

Allocation

Not applicable.

Masking

This will not be a blinded study for clinicians and patients.

Data collection methods

The investigators will maintain individual records for each patient as source data, including a copy of the informed consent, medical records, laboratory data, image data, patient diary and other records or notes. All data will be collected by the supportive and palliative care research support section at the National Cancer Center Hospital East. Clinical data entry, data management and central monitoring will be performed using an electronic data capture (EDC) system, Viedoc 4 (PCG Solutions, Sweden). Patient-reported outcomes will be collected using electronic Patient Reported Outcome (ePRO), Viedoc Me.

Statistical methods of analysis

Non-inferiority versus the above-noted standard treatment (ultra-hypofractionated radiation (36.25 Gy/5 Fr) using CT-based radiation therapy equipment) will be demonstrated if the upper limit of the 80% CI based on normal approximation falls below 30.6%. When this non-inferiority is shown, superiority versus 26 Gy/2 Fr treatment using CT-based radiation therapy equipment (reported incidence of grade ≥2 acute phase genitourinary adverse events of 40%) will also be shown because the upper limit of the 80% CI naturally falls below 40%. Moreover, if non-inferiority versus 36.25 Gy/5 Fr CT-based radiation therapy is demonstrated, then superiority versus this 5 Fr CT-based radiation therapy will also be assessed by testing whether the upper limit of the 80% CI for the incidence of grade ≥2 acute phase adverse events falls below 23.1%.

Safety profile will be analysed among the per-protocol population who receive full-dose radiotherapy. Other endpoints related to survival will be analysed using the entire population of subjects in the study.

Handling of missing values and outliers

In principle, all analyses will be performed without imputation of missing values or outliers. However, if it is found before data lock that missing values or outliers may significantly affect analysis results, countermeasures will be described in a statistical analysis plan.

Data management, monitoring and auditing

Central data monitoring reports will be compiled by the clinical data managers twice a year and reported to the principal and site investigators. An effectiveness safety committee has been established and this will also review the safety data if serious adverse events occur.

For data management at participating institutions, source documents, a linkable anonymising correspondence table, etc will be appropriately managed under the responsibility of the site investigator. Since the Case Report Form (CRF) will be managed electronically using the electronic CRF (eCRF), the site investigator, subinvestigator and study collaborators will pay maximum attention to password self-management.

Study-related data will be stored at participating institutions for 10 years after the end-of-study report, but preferably for as long as possible. After the retention period, any study-related sample or information will be discarded only after being anonymised. After completion of the study, the raw data collection or data set created for analysis at the data centre will be returned to the study representative and stored by the study representative.

Auditing will be carried out by each institution’s audit system.

Protocol amendments

Modifications to the study protocol will be communicated to the Institutional Review Board (IRB) at the National Cancer Center Hospital. The IRB will revise the informed consent materials to be given to participants and adapt them to accord with our institution’s guidelines. The protocol was amended as V.1.1 as of December 2023.

Confidentiality

Personal information such as name, address and medical ID will not be collected.

Access to data

Only clinical data managers at the central data centre will have access to reported case data through the EDC system during the conduct of the study. The data manager will transfer the final data set to the principal investigator after statistical analysis and the data will be stored in the electronic format.

Ethics and dissemination

This study is performed in accordance with Ethical Guidelines for Medical and Health Research Involving Human Subjects, published by Japan’s Ministry of Education, Science and Technology and the Ministry of Health, Labour and Welfare and the modified act on the Protection of Personal Information as well as the Declaration of Helsinki. This study was approved by the institutional ethics committee of the National Cancer Center on 20 November 2021.

The findings of this trial will be submitted to an international peer-reviewed journal and the key findings will be presented at an international scientific conference.

Authorship will be ascribed in accordance with the International Committee of Medical Journal Editors guidance.

Discussion

This clinical trial will not be conducted as a randomised controlled trial due to the potential difficulties in accumulating patients for randomised controlled trials. In recent years, many studies have reported the superiority of MR linear accelerators over CT linear accelerators,15 16 however, few facilities in Japan have MR linear accelerators. Given these concerns, we decided to collect validative data in a single arm in this study. As secondary endpoints, electronic patient-reported outcomes will be collected in this study. This will also enable medical economic evaluation via the calculation of Quality-adjusted life years (QALYs), which will greatly contribute to the insurance approval of MR-guide technology fees.

Trial status

The study is ongoing, and patients are currently being enrolled. Enrolment started in January 2023. As of August 2023, a total of 20 patients had been enrolled. We thus expect to complete recruitment by March 2025.

Acknowledgements

The authors thank in advance all the patients, investigators and institutions involved in this study.

Review Process File
24 8 2024

Funding: This study is supported by the Japan Agency for Medical Research and Development (AMED23ck0106745h0002).

Prepub: Prepublication history for this paper is available online. To view these files, please visit the journal online (https://doi.org/10.1136/bmjopen-2023-082899).

Patient consent for publication: Consent obtained directly from patient(s).

Provenance and peer review: Not commissioned; externally peer reviewed.

Patient and public involvement: Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
==== Refs
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