Administrative information
Title {1} | Stereotactic Multiple Fraction Radiotherapy for Non-Spine Bone Metastases (SMILE) |
Trial Registration {2a and 2b} | Registry: ClinicalTrials.gov Trial ID: NCT05406063 Date of Registration: May 3, 2022 kofam.ch Identifier: SNCTP000004897 Date of Registration: April 6, 2022 |
Protocol Version {3} | Version 1.3, Dated November 10, 2022 |
Funding {4} | The study is funded by Cantonal Hospital Winterthur with additional support from the Swiss Cancer Research Foundation |
Author Details {5a} | Author: Robert Foerster, MD EMBA HSG, Department of Radiation Oncology, Cantonal Hospital Winterthur, Brauerstrasse 15, 8401 Winterthur, Switzerland and Department of Radiation Oncology, Inselspital, University Hospital Bern, University of Bern, Freiburgstrasse 18, 3010 Bern, Switzerland, Email: [email protected] Co-Authors: Daniel R. Zwahlen, MD MBA; Christina Schroeder, MD BSc EMBA; Paul Windisch, MD; Marc-Eric Halatsch, MD (Cantonal Hospital Winterthur); Alex Alfieri, MD (Cantonal Hospital Winterthur, Winterthur, Switzerland and Faculty of Biomedical Sciences, Università della Svizzera Italiana (USI), Lugano, Switzerland); Christoph Meier, MD (Cantonal Hospital Winterthur); Hossein Hemmatazad, MD (Inselspital, University Hospital Bern, University of Bern); Daniel M. Aebersold (Inselspital, University Hospital Bern, University of Bern); André Buchali, MD (University Hospital Ruppin-Brandenburg); Daniel Habermehl, MD (University Hospital of Giessen and Marburg); Nidar Batifi, MSc (Cantonal Hospital Winterthur); |
Name and contact information for the trial sponsor {5b} | Sponsor: Daniel R. Zwahlen, MD MBA, Department of Radiation Oncology, Cantonal Hospital Winterthur, Winterthur, Switzerland |
Role of Sponsor {5c} | The sponsor is involved in study design, data collection, management, analysis, and interpretation. The sponsor also contributes to the report writing and the decision to submit the report for publication. However, they do not have ultimate authority over any of these activities |
Introduction
Background and rationale {6a}
Radiotherapy is a pillar of interdisciplinary management of patients with bone metastases; particularly, it is an established method for the palliation of painful bone metastases. Previous research has shown that patients have an equal benefit from single-fraction and multi-fraction radiotherapy in terms of pain response. However, it has also been shown that retreatment is more common after single-faction radiotherapy [1]. In recent years, stereotactic body radiotherapy (SBRT) has emerged as a modern technology, which has been proven to enable superior pain control over conventional radiotherapy, in terms of a more rapid and longer-lasting pain response [2, 3]. SBRT for bone metastases outside the spine is typically applied within few fractions where a large dose of radiation is delivered per treatment fraction. Previous research has shown that high single radiation doses, however, are also associated with a higher probability for fractures after radiotherapy [4]. Therefore, it seems plausible to apply a multi-fraction approach for SBRT as well to avoid the development of consecutive fractures and the necessity for retreatment. While multi-fraction SBRT seems to be comparable regarding long-term pain control [5], and a survey among international SBRT experts has shown that a 5-fraction schedule is most widely adopted [6], currently it is unclear which multi-fractionation SBRT schedule is best suited for a rapid and enduring palliation of non-spine bone metastases. Additionally, prolonged treatment regimens are potentially more cost intensive and burdensome for the patients, due to the longer treatment time. Therefore, shorter SBRT treatment schedules are preferable. With this trial, we aim to investigate whether multi-fraction SBRT within 3 treatment fractions is non-inferior to the current standard of care of 5-fraction SBRT [7] with regards to pain response at 3 months after radiotherapy.
Objectives {7}
The SMILE study’s primary objective is to assess and compare the pain response at 3 months post-radiotherapy between a 3-fraction regimen (9 Gy per fraction) and a standard 5-fraction regimen (7 Gy per fraction) of SBRT for patients with non-spine bone metastases. The secondary objectives focus on evaluating acute and late toxicities, fracture rates, quality of life, local metastasis control, and long-term pain response [5–9].
Trial design {8}
The SMILE trial is structured as a two-arm, multicenter, randomized, open-label, controlled phase III clinical trial with a non-inferiority design. The research will engage patients across multiple institutions, randomizing them to either the investigational or control arm with the intent of determining the effectiveness and safety of the 3-fraction SBRT regimen [10].
Methods: participants, interventions, and outcomes
Study setting {9}
The SMILE study is conducted in multiple settings, including academic hospitals in Switzerland. 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}
The 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.
The 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 (Fig. 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.
Fig. 1 [Images not available. See PDF.]
Trial design
Intervention description {11a}
Treatment plan
Arm A: Patients will be treated with SBRT delivering 9 Gy × 3 fractions (BED10: 51.3 Gy) to the treatment site.
Arm B: Patients will be treated with SBRT delivering 7 Gy × 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 × 3 fractions.
Arm B (control): The PTV will receive 7 Gy × 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 [14].
Strategies to improve adherence to interventions {11c}
Adherence strategies include close monitoring of treatment attendance and side effects and 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 [15], QLQ-BM22 [16], and EQ-5D-DL [17], 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 (Fig. 2).
Fig. 2 [Images not available. See PDF.]
Schedule of assessments
Sample size {14}
One hundred sixty-two 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 (null hypothesis, H0) [18]. We aim to establish non-inferiority of the intervention as compared to the control. Thus, the non-inferiority margin is chosen to be 10%. Eighty-one 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.
To promote data quality, several processes will be implemented. Key data points, including primary outcomes, will be routinely reviewed for completeness by the Study Office at Cantonal Hospital Winterthur, ensuring that no essential data are missing and minimizing the risk of transcription errors. Additionally, all data collectors, including study nurses and research staff, will participate in comprehensive training sessions. This training will cover correct data entry techniques, an overview of the study protocols, and methods to ensure consistency and accuracy in questionnaire administration and data collection. To further enhance data integrity, regular audits will be conducted by the data monitoring team to identify and resolve any discrepancies in the electronic case report forms (eCRFs), ensuring that data fidelity is maintained across all study sites.
Quality of life assessments will be conducted using validated questionnaires tailored to the needs of palliative care and bone metastasis patients, as part of the data collection process. The EORTC QLQ-C15-PAL is a shortened version of the EORTC QLQ-C30, specifically designed to assess quality of life in palliative care cancer patients [15]. The EORTC QLQ-BM22 is tailored for patients with bone metastases and complements the EORTC QLQ-C30 to address unique symptoms related to bone metastases, such as pain and functional impairment [16]. The EQ-5D is a generic health-related quality of life measure covering mobility, self-care, usual activities, pain/discomfort, and anxiety/depression, widely validated across various populations, including cancer patients [17].
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 [19–24], 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 center 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.
Discussion
This phase III multicenter trial assesses the efficacy and safety of a 3-fraction SBRT regimen for palliating non-spine bone metastases compared to the traditional 5-fraction regimen. This investigation is crucial, given the current paucity of data on optimal fractionation for treating non-spine bone metastases [25]. While SBRT advancements have improved outcomes for spinal metastases, similar progress in non-spine metastases requires further empirical support [1, 2]. Reducing treatment sessions aligns with global health objectives to lessen patient burden—a critical element in enhancing palliative care. Streamlining treatment could notably improve patient adherence and diminish healthcare resource utilization, essential for optimizing the efficiency of cancer care delivery [26]. Moreover, a thorough examination of secondary outcomes such as toxicity profiles and fracture rates will provide essential safety insights, potentially guiding future SBRT protocols [4, 5]. Should the 3-fraction regimen demonstrate non-inferiority to the 5-fraction standard, it might reshape clinical guidelines and establish a new benchmark for managing non-spine bone metastases. The adoption of a less intensive regimen could significantly alter clinical practice, promoting a shift toward more patient-centric treatment approaches [6, 27]. This trial’s outcomes might also stimulate further research into innovative fractionation schedules or combined treatment modalities aimed at improving outcomes in metastatic bone disease [7, 28]. In addition, the findings could serve as a reference for future studies, supporting the development of tailored treatment strategies based on individual clinical profiles and tumor biology. This personalized approach could lead to more precise and effective radiation therapy protocols in palliative care settings, enhancing both treatment efficacy and patient comfort [8, 9]. Moreover, by potentially redefining the standard treatment for non-spine bone metastases, this study underscores the shift towards treatments that not only achieve clinical efficacy but also enhance patient quality of life. The results could drive substantial changes in practice, emphasizing the importance of patient-centered care in the realm of oncology [10]. This trial is set within a broader context of evolving SBRT applications, reflecting a significant trend in oncological treatments toward higher dose intensities over fewer sessions. Similar to developments in other cancer treatments, where dose escalation has been associated with improved outcomes, the SMILE trial’s exploration of an intensified, yet shorter, SBRT regimen could provide crucial insights into the optimal balance of dose and fractionation for bone metastases. Such advancements are not only anticipated to improve patient convenience but also to minimize the long-term side effects associated with radiation therapy, thus preserving patients’ quality of life post-treatment. Furthermore, this study’s exploration of a reduced fractionation schedule could signal a paradigm shift in the approach to radiation therapy, particularly for patients who require palliative care.
Trial status
The current protocol version 1.3 (dated 10 November 2022) was approved by the responsible ethics committee in April 2022 (2022 – 00631). Participant enrollment has been ongoing since June 2022 and is estimated to be completed in May 2026.
Acknowledgements
The authors wish to express their gratitude to Mr. André A. Meichtry from Bern University of Applied Sciences for providing statistical support.
Authors’ contributions {31b}
Initial draft of the protocol: RF. Final manuscript: NB. Principal investigator, initial draft of the protocol: RF; study design and protocol development: CS, DRZ, PW; RF; funding acquisition: AA, CM, DRZ, MEH, RF; regulatory affairs, trial coordination and final manuscript preparation: NB; data collection, patient enrollment, site principal investigators, study implementation: AB, DH, DMA, HH; sponsor: DRZ; all authors read and approved the final manuscript.
Funding {4}
This study is being funded by the Cantonal Hospital Winterthur with additional financial support from the Swiss Cancer Research Foundation. The Swiss Cancer Research Foundation had no role in the design of the study, data collection, analysis, interpretation of the data, or in the writing of the manuscript.
Data availability {29}
Only the study office of the Department of Radiation Oncology at Cantonal Hospital Winterthur will have access to the final trial dataset, in accordance with the Clinical Data Agreement signed by each participating center. Unless specified otherwise, each center agrees not to publish or present its individual results from the multicenter study. If a multicenter publication is not completed within 1 year from the study’s conclusion or termination, centers are permitted to publish their individual study results, provided they adhere to the terms outlined in the agreement. All rights and intellectual property arising directly from the execution of the study and the indications detailed by the protocol shall be the exclusive property of the sponsor. The site commits to assigning all such rights to the sponsor upon their request. Any data required to support the protocol can be supplied on request, subject to the data-sharing policies and agreements governing the study.
Declarations
Ethics approval and consent to participate {24}
Ethics approval has been obtained from Ethics Committee Zurich (BASEC2022 – 0063) and Bern. All methods are carried out in accordance with the current version of the World Medical Association Declaration of Helsinki and ICH-GCP guidelines as well as the local legally applicable requirements. All individual study participants will provide written informed consent to participate in the study. Consent will be obtained by study investigators in conjunction with clinical trials staff.
Consent for publication {32}
Not applicable—no identifying images or other personal or clinical details of participants are presented here or will be presented in reports of the trial results. The participant information materials and informed consent form are available from the corresponding author on request.
Competing interests {28}
The authors declare no competing interests.
Abbreviations
Adverse event
Annual Safety Report/Development Safety Report
Business Administration System for Ethical Committees
Biologically Effective Dose at 10 Gy per fraction
Data management software
Ordinance on Clinical Trials in Human Research
Case report form
Computed tomography
Common Terminology Criteria for Adverse Events
Electronic case report form
European Organisation for Research and Treatment of Cancer
European Quality of Life-5 Dimensions-3 Levels
Federal Act on Data Protection
Federal Office of Public Health
Good Clinical Practice
Human Research Act
International Conference on Harmonisation
International Commission on Radiation Units and Measurements
Intensity-modulated radiotherapy
Karnofsky Performance Status Score
Magnetic resonance imaging
National Clinical Trial
Organs at risk
Positron emission tomography/computed tomography
Planning target volume
Quality of life
Quality of Life Questionnaire
Serious adverse event
Stereotactic body radiotherapy
Stereotactic Multiple Fraction Radiotherapy for Non-Spine Bone Metastases
Università della Svizzera Italiana
Visual analogue scale
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Abstract
Background
The SMILE study addresses a significant need in palliative oncology by evaluating the non-inferiority of a shortened, 3-fraction stereotactic body radiotherapy (SBRT) schedule against the traditional 5-fraction approach for non-spine bone metastases in terms of pain control. Optimizing SBRT could significantly enhance the quality of life for patients by providing effective pain relief while minimizing treatment sessions.
Methods
This international, multicenter phase III trial will randomize 162 patients to receive either a 3-fraction regimen (9 Gy per fraction) or a standard 5-fraction regimen (7 Gy per fraction). Outcomes, assessed at 3 months post-treatment, will focus on pain response, quality of life, and control of metastasis. With a hypothesis-driven design, the study will incorporate intent-to-treat and per-protocol analyses, incorporating appropriate measures for data integrity and handling of missing information.
Discussion
If the 3-fraction SBRT regimen demonstrates non-inferiority, it could streamline palliative care protocols, reduce patient burden, and set a new standard for treatment, reflecting a patient-centered approach in palliative radiation oncology.
Trial registration
The trial has been registered prospectively on ClinicalTrials.gov under the identifier NCT05406063, as of May 3, 2022.
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Details
; Zwahlen, Daniel R. 2 ; Schroeder, Christina 2 ; Windisch, Paul 2 ; Halatsch, Marc-Eric 3 ; Alfieri, Alex 4 ; Meier, Christoph 5 ; Hemmatazad, Hossein 6 ; Aebersold, Daniel M. 6 ; Buchali, André 7 ; Habermehl, Daniel 8 ; Batifi, Nidar 2 1 Cantonal Hospital Winterthur, Department of Radiation Oncology, Winterthur, Switzerland (GRID:grid.452288.1) (ISNI:0000 0001 0697 1703); University Hospital Bern, University of Bern, Department of Radiation Oncology, Inselspital, Bern, Switzerland (GRID:grid.411656.1) (ISNI:0000 0004 0479 0855)
2 Cantonal Hospital Winterthur, Department of Radiation Oncology, Winterthur, Switzerland (GRID:grid.452288.1) (ISNI:0000 0001 0697 1703)
3 Cantonal Hospital Winterthur, Department of Neurosurgery, Winterthur, Switzerland (GRID:grid.452288.1) (ISNI:0000 0001 0697 1703)
4 Cantonal Hospital Winterthur, Department of Neurosurgery, Winterthur, Switzerland (GRID:grid.452288.1) (ISNI:0000 0001 0697 1703); Università Della Svizzera Italiana (USI), Faculty of Biomedical Sciences, Lugano, Switzerland (GRID:grid.29078.34) (ISNI:0000 0001 2203 2861)
5 Cantonal Hospital Winterthur, Department of Orthopedics and Traumatology, Winterthur, Switzerland (GRID:grid.452288.1) (ISNI:0000 0001 0697 1703)
6 University Hospital Bern, University of Bern, Department of Radiation Oncology, Inselspital, Bern, Switzerland (GRID:grid.411656.1) (ISNI:0000 0004 0479 0855)
7 University Hospital Ruppin-Brandenburg, Department of Radiation Oncology, Neuruppin, Germany (GRID:grid.411656.1)
8 University Hospital Giessen and Marburg, Department of Radiation Oncology, Giessen, Germany (GRID:grid.411067.5) (ISNI:0000 0000 8584 9230)