Study Setting {9}
The SMILE study is conducted in multiple settings, including academic hospitals in Switzerland and Germany. The study sites are chosen based on their capacity to administer advanced radiotherapy treatments and manage the comprehensive data collection required for this trial. This allows for diverse participant demographic and robust data on the efficacy of different treatment regimens.
Eligibility Criteria {10}
Inclusion Criteria include:
- Age 18 years or older.
- Histologically or radiologically confirmed diagnosis of non-spine bone metastases.
- Pain or pain free with the use of analgesics
- Able and willing to give informed consent.
Exclusion criteria include:
- Pregnant women
- Women of childbearing potential or sexually active males not willing to use effective contraception while on treatment and 3 months after the end of treatment,
- Lesions > 5 cm in maximum diameter,
- Prior radiotherapy to the intended treatment site,
- Prior treatment with radioactive isotopes within 30 days of randomization,
- Spinal column, hands, feet, or head as intended treatment site,
- Fracture at the intended treatment site,
- Surgery required or previous surgery at the intended treatment site,
- Instability of the intended treatment site (Mirels' score ≥ 9) [10, 11].
- Significant medical conditions that would pose a risk to participant safety or interfere with the study outcomes.
Who Will Take Informed Consent? {26a}
Informed consent will be obtained by trained personnel who will explain all aspects of the study in accordance with ethical guidelines. This includes detailed discussions on the purpose of the study, procedures to be followed, potential risks and benefits, and the voluntary nature of participation.
Additional Consent Provisions for Collection and Use of Participant Data, a general consent form {26b}
Participants will be asked for additional consent for the use of their data for future research related to bone metastases treatment. This will ensure that all data can be used to their fullest potential in improving treatment strategies and outcomes.
Interventions
Explanation for the Choice of Comparators {6b}
The choice of comparators in this study is based on the current standards and emerging data in the management of non-spine bone metastases. Two different fractionation schedules of Stereotactic Body Radiation Therapy (SBRT) are compared: a more conventional 5-fraction regimen and a shorter 3-fraction regimen (Figure 1). This comparison is intended to explore whether the shorter regimen can offer comparable pain relief and quality of life improvements with potentially fewer side effects and reduced treatment burden.
Intervention Description {11a}
Treatment plan
Arm A: Patients will be treated with SBRT delivering 9 Gy x 3 fractions (BED10: 51.3 Gy) to the treatment site.
Arm B: Patients will be treated with SBRT delivering 7 Gy x 5 fractions (BED10: 59.5 Gy) to the treatment site.
Immobilization
The patient will be placed in a stable supine position using an immobilization device that will ensure set-up reproducibility and patient comfort during simulation and throughout radiation therapy delivery. A variety of immobilization devices can be used including vacuum bag, alpha cradle, or stereotactic frames that surround the patient on three sides and large rigid pillows (conforming to patient’s external contours) with reference to the treatment delivery coordinate system. Immobilization will subsequently be performed in an identical fashion to that used during simulation and treatment. Patient immobilization should meet the accuracy requirement of image-guidance. Patient immobilization should be comfortable enough to prevent any uncontrolled movements during treatment delivery, which may require extended periods of time. The immobilization device allows patient and tumor imaging such as computed tomography (CT) and/or fluoroscopy and/or magnetic resonance (MR) imaging and does not interfere with dose calculation or delivery. All patients immobilized in the treatment position within the immobilization device will undergo a treatment planning CT with a ≤2 mm slice width that should cover the target and OARs. Whenever necessary, the treatment planning CT scan will be performed with intravenous contrast and/or oral bowel or esophageal contrast to aid in target volume and OAR definition. After image acquisition, treatment planning CT and MR and/or PET/CT image datasets will be transferred to a treatment planning system for co-registration. The treatment planning CT scans will be the primary image platform utilized for target volume and OAR delineation and treatment planning.
Target volume delineation
Arm A (investigation) and arm B (control):
The gross tumor volume (GTV) will be delineated based on the extension of the metastasis on planning CT and co-registered MRI and/or PET/CT. The GTV plus a 5 mm intraosseous circumferential margin will constitute the clinical target volume (CTV). In cases of associated soft tissue disease and/or significant cortical bone disruption, an extraosseous CTV margin of 5 mm should be added. All CTVs should be manually cropped to respect anatomic barriers. This target volume delineation is in accordance with the recommendations published by Nguyen TK et al. [12]. An additional margin of 5 mm is added to derive the planning target volume (PTV).
Organs at risk delineation and dose constraints
Organs at risk (OAR) will be contoured at the level of the intended treatment site according to institutional standards and at least 2 cm cranially and caudally of the maximum PTV extension. Lungs, liver, heart, and kidneys need to be fully delineated. Dose constraints for OARs should adhere to published data by Gerhard SG et al. [13].
Dose prescription
Arm A (investigation): The PTV will receive 9 Gy x 3 fractions.
Arm B (control): The PTV will receive 7 Gy x 5 fractions.
The dose prescription will adhere to ICRU dose prescription standards with 95% of the PTVs receiving between 95% and 107% of the prescription dose. An inhomogeneous dose prescription is not allowed.
Dose coverage of the PTVs may be reduced up to 80% of the respective volume receiving between 95% and 107% of the prescription dose to meet OAR dose constraints. A reduction of the prescription dose is not allowed.
Treatment planning and delivery
Treatment planning should be carried out as 3D-conformal planning with a type C dose calculation algorithm utilizing static, rotational or robotic intensity modulated radiotherapy.
On-board imaging is required before the delivery of every treatment fraction to account for set-up errors and to allow for online positional correction.
Criteria for Discontinuing or Modifying Allocated Interventions {11b}
Intervention may be discontinued or modified due to severe adverse events, patient request, or significant changes in the patient's condition, including improved or worsened symptoms. Specific criteria include toxicity as assessed by Common Terminology Criteria for Adverse Events (CTCAE) or patient intolerance to treatment.
Strategies to Improve Adherence to Interventions {11c}
Adherence strategies include close monitoring of treatment attendance and side effects, regular follow-up appointments. Adherence will be further supported by regular communication with the treatment team.
Relevant Concomitant Care Permitted or Prohibited During the Trial {11d}
During the trial, standard supportive care measures, including analgesics and anti-inflammatory medications, are permitted. However, other forms of radiation therapy or treatments that could interfere with the evaluation of the primary endpoints are prohibited. This ensures the integrity of the trial outcomes.
Provisions for Post-Trial Care {30}
After the completion of the trial, all patients will be monitored for long-term side effects and continued pain management. Provisions for post-trial care include follow-up visits and continued access to care teams to manage any ongoing or emerging issues related to the treatment received during the trial.
Outcomes {12}
The primary outcome is the pain response at the treatment site, assessed by a ≥2 point improvement on the Visual Analogue Scale (VAS) at 3 months post-treatment. Secondary outcomes include acute and late toxicities, fracture rates, quality of life assessments using EORTC QLQ-C15-PAL, QLQ-BM22, and EQ-5D-DL, local metastasis control, and long-term pain response.
Participant Timeline {13}
The participant timeline involves initial screening, randomization, treatment administration, and follow-up assessments at 3, 6, and 12 months post-treatment. A schematic diagram of the timeline is recommended to visually depict these stages.
Sample Size {14}
162 patients will be enrolled. This is an international multicenter, open label, randomized, controlled phase 3 non-inferiority clinical trial. We assume a pain response of 80% for patients in arm B (control) based on previous research and a pain response of 70% for patients in arm A (intervention) at 3 months after radiotherapy (hull hypothesis, H0). We aim to establish non-inferiority of the intervention as compared to the control. Thus, the non-inferiority margin is chosen to be 10%. 81 patients will have to be enrolled per study arm to reach 80% power at a conservative 1-sided significance level of 2.5% with a possible drop rate of 10% for allowing to reject H0 and, hence, the conclusion of non-inferiority (alternate hypothesis, H1) of arm A (intervention) to arm B (control).
Statistical analyses will be done in three populations: 1) Intent-to-Treat population (ITT) including all patients who were randomized and received at least one fraction of radiation therapy; 2) Per Protocol population (PP) including all patients of the ITT who have received study treatment according to randomization without significant protocol violations and 3) safety-analysis set including all patients who were randomized and received at least one fraction of radiation therapy.
In case of poor accrual, the enrolment of 128 patients (64 patient per study arm) will be sufficient to reach 80% power at a significance level of 5% with a possible drop rate of 10%.
Recruitment {15}
Recruitment strategies include utilizing referrals from oncologists, information sessions at participating clinical sites, and advertisements in patient advocacy group newsletters. The study aims to ensure a diverse participant pool reflective of the population typically affected by bone metastases.
Assignment of Interventions: Allocation
Sequence generation {16a}
The allocation sequence will be automatically generated by the data management software, CASTOR EDC®. Stratification factors include the center, radioresistance vs. radiosensitivity of the histology, lesion size (≤2 cm vs. >2 cm), type of bone (long bones vs. others), and gender. This ensures a balanced distribution of these factors across treatment arms.
Concealment mechanism {16b}
The allocation sequence is managed and concealed within the CASTOR EDC® system. Only the study office in Winterthur has the capability to trigger the randomization once a participating center enrolls a patient, ensuring that the sequence remains concealed from the clinical teams until the point of assignment.
Implementation {16c}
Upon the enrollment of a patient by a participating center, the study office in Winterthur initiates the randomization process through CASTOR EDC®. This centralized control maintains consistency and integrity in the assignment of participants to their respective intervention arms across all centers.
Assignment of Interventions: Blinding
Who will be blinded {17a}
This is an open-label study, and as such, blinding of participants and healthcare providers is not applicable. However, to maintain objectivity in the evaluation of study outcomes, statisticians and data analysts will remain blinded to the allocation. Additionally, the centers are blinded to each other’s aggregate data to avoid any potential bias in patient management and outcome assessments.
Procedure for unblinding if needed {17b}
In this open-label study, formal blinding procedures for participants and healthcare providers do not apply. However, the blinding of statisticians and data analysts is crucial and will be maintained rigorously. Should unblinding be necessary for any reason related to safety concerns, a controlled and documented process will be executed via the CASTOR EDC® system.
Data Collection and Management
Plans for Assessment and Collection of Outcomes {18a}
Data will be prospectively collected from medical files and quality of life (QoL) questionnaires (source data) of the participating patients by the co-investigators and their delegated personnel, such as Study Nurses and responsible investigative staff. Data are recorded on electronic case report forms (eCRFs) through the CASTOR EDC® website, with access provided to all participating centers. The unique subject identification number will be the only identifier recorded in the CRFs, which must be completed in English, although trade names for concomitant medications may be entered in the local language.
Plans to Promote Participant Retention and Complete Follow-up {18b}
The participants' retention and complete follow-up are ensured by the follow-up schedule set at 3 months, 6 months, and 12 months post-treatment. Procedures at each study visit include physical examinations, Karnofsky Performance Status scoring, pain and medication recording, and imaging per institutional standards, ensuring continuous engagement and monitoring of participants.
Data Management {19}
Data will be managed by the study office of the Department of Radiation Oncology at Cantonal Hospital Winterthur who ensures that the CRFs are stored on the CASTOR EDC® website. The investigator on each site or center will maintain a personal patient identification list to enable records to be identified, ensuring the confidentiality and integrity of the data.
Confidentiality {27}
All records identifying patients will be kept confidential and will not be made publicly available to the extent permitted by applicable laws or regulations. In compliance with Federal regulations, the ICH Guidelines for Good Clinical Practice (E6 R2), and the World Medical Association Declaration of Helsinki, the investigator and institution will permit authorized representatives of regulatory agencies and the IEC/IRB direct access to review the subject's original medical records for verification of study-related procedures and data.
Plans for Collection, Laboratory Evaluation, and Storage of Biological Specimens for Genetic or Molecular Analysis in this Trial/Future Use {33}
N/a. This trial does not involve the collection, laboratory evaluation, or storage of biological specimens for genetic or molecular analysis. Any changes regarding this will be documented and communicated as per protocol amendments.
Statistical methods
Statistical methods for primary and secondary outcomes {20a}
Statistical analyses will be conducted to evaluate the primary outcome of pain response at 3 months post-radiotherapy. A non-inferiority margin of 10% is set, with the hypothesis that the pain response in the intervention arm (A) will be no worse than 10% compared to the control arm (B). The secondary outcomes will include safety profiles and quality of life assessments. Details of the statistical analysis plan will be available in the full study protocol, accessible through the Department of Radiation Oncology at Cantonal Hospital Winterthur.
Interim analyses {21b}
N/a; no interim analyses will be performed.
Methods for additional analyses (e.g. subgroup analyses) {20b}
Subgroup analyses will not be conducted.
Methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data {20c}
The analysis will include an intent-to-treat (ITT) population, defined as all patients randomized and having received at least one fraction of radiation therapy, regardless of subsequent adherence. A per-protocol (PP) analysis will also be conducted, including only those patients who completed the treatment as per the protocol without significant deviations. Missing data will be handled using multiple imputation techniques to address potential biases due to incomplete data.
Plans to give access to the full protocol, participant level-data and statistical code {31c}
The full protocol, along with the participant-level dataset and the statistical code, will be made available publicly after the trial's conclusion. Data will be de-identified to protect participant confidentiality, and access will be provided through a controlled access database to ensure data integrity and security.
Oversight and Monitoring
Composition of the Coordinating Centre and Trial Steering Committee {5d}
The trial is coordinated by the Department of Radiation Oncology at Cantonal Hospital Winterthur, which provides comprehensive oversight for the trial. The trial steering committee, located at this institution, includes both clinical and methodological experts who meet quarterly to review trial progress and ensure strict adherence to the protocols.
Composition of the Data Monitoring Committee, Its Role and Reporting Structure {21a}
The study does not establish a traditional independent Data Monitoring Committee due to its scope and scale. Instead, monitoring responsibilities are managed by the Department of Radiation Oncology at Cantonal Hospital Winterthur. This includes conducting site initiation visits, ongoing oversight of data entries, regular data quality checks, and a closing monitoring visit with all participating centers. An annual safety report is produced and distributed to all centers to keep them informed of safety issues and trial progress.
Adverse Event Reporting and Harms {22}
Adverse events are systematically collected, assessed, and managed by the study office in Winterthur according to predefined criteria. All serious adverse events are immediately reported to this office, which in turn notifies the relevant ethics committee and regulatory authorities as required. The study also ensures that all participating centers are compliant with Good Clinical Practice (GCP) standards, with regular checks for GCP understanding and certification among study participants.
Frequency and Plans for Auditing Trial Conduct {23}
Regular auditing of trial conduct is planned to ensure adherence to protocols and regulatory standards. Audits will be conducted quarterly. These audits will be coordinated by the Department of Radiation Oncology at Cantonal Hospital Winterthur and will involve thorough reviews of study documentation, data management processes, and site activities.
Plans for Communicating Important Protocol Amendments {25}
Any important protocol modifications will be promptly communicated to all relevant parties, including investigators, trial participants, and ethics committees. Amendments to eligibility criteria, outcomes, or analyses will be documented in detail and submitted for review and approval by the appropriate regulatory bodies. Communication channels will include direct notification of investigators and participants, updates to trial registries, and publication in relevant journals.
Dissemination Plans {31a}
The investigators and sponsor are committed to transparently communicating trial results to various stakeholders. Findings will be disseminated through peer-reviewed publications, conference presentations, and reports to trial participants. Additionally, trial results will be shared with healthcare professionals and the public via open-access databases and other data-sharing platforms. There are no publication restrictions, and efforts will be made to ensure that results are accessible to all interested parties.