Single Fraction and Multifraction Arc-Based Radiotherapy for Painful Bone Metastases

Single-fraction radiotherapy (SFRT) is an established standard treatment for palliation of painful bone metastases. However, multifraction radiotherapy (MFRT) continues to be widely used in clinical practice because of concerns regarding durability of pain control and retreatment. With the increasing use of modern arc-based radiotherapy techniques such as volumetric modulated arc therapy (VMAT), there is a need to evaluate whether single-fraction radiotherapy can provide effective pain palliation while reducing treatment burden and improving resource utilisation.

The SMART trial is a prospective, single-centre, randomised, open-label, parallel-group pilot feasibility study comparing VMAT-based SFRT (8 Gy in 1 fraction) with VMAT-based MFRT (20 Gy in 5 fractions) in patients with painful bone metastases, including spinal metastases.

Approximately 70 participants will be randomised in a 1:1 ratio to receive either SFRT or MFRT. Both treatment schedules will be delivered using VMAT with daily image-guided radiotherapy using cone-beam computed tomography (CBCT)-based image guidance.

Stratified block randomisation will be used according to the site of metastasis (spine versus non-spine) to maintain balance between the two treatment groups. Within each stratum, computer-generated variable block randomisation using block sizes of 4 and 6 will be used. Allocation will be concealed using sequentially numbered, opaque, sealed envelopes.

Pain will be assessed using the Numeric Rating Scale (NRS-11) and Wong-Baker FACES Pain Scale at baseline and during follow-up. Participants will be assessed at 2 weeks, 4 weeks and 12 weeks after radiotherapy.

The primary aim of this pilot study is to assess the feasibility of conducting a randomised controlled trial at the participating tertiary oncology centre. Feasibility will include recruitment, treatment completion, follow-up completion and completeness of study data.

The primary efficacy outcome will be overall pain response at 4 weeks following radiotherapy. Secondary outcomes will include pain response at other follow-up time points, retreatment rates, pain flare, treatment-related toxicity, patient convenience and resource utilisation.

The study is not powered to provide a definitive non-inferiority conclusion. A non-inferiority margin of 15% has been prespecified to guide estimation of the treatment effect and inform the design and sample size of a future definitive randomised trial. The primary efficacy analysis will compare overall pain response between the two treatment groups using the intention-to-treat population.

The study will generate preliminary feasibility and clinical outcome data to inform the design of a future definitive randomised controlled trial evaluating single-fraction versus multifraction radiotherapy for painful bone metastases.

• Single-Fraction Radiotherapy (8Gy x 1#) (Radiation): VMAT-based external beam radiotherapy planned to deliver 8 Gy in a single fraction with CBCT-based image guidance for the palliation of painful bone metastasis
• Multifraction Radiotherapy (20 Gy in 5 #) (Radiation): VMAT-based external beam radiotherapy planned to deliver 20 Gy in Five fractions of 4 Gy each with daily CBCT-based image guidance for the palliation of painful bone metastasis

Primary outcomes

• Percentage of target sample recruited [From study initiation through completion of the recruitment period.]: The percentage of the planned target sample successfully recruited during the recruitment period. Recruitment feasibility will be interpreted using predefined traffic-light criteria: Green ≥80% (feasibility achieved), Amber 70-79% (borderline feasibility requiring review), and Red <70% (feasibility not achieved and requiring review).
• Percentage of participants completing assigned radiotherapy [From randomisation through completion of assigned radiotherapy.]: The percentage of randomised participants who complete the assigned radiotherapy treatment according to the study protocol. Treatment completion feasibility will be interpreted using predefined traffic-light criteria: Green ≥90% (feasibility achieved), Amber 80-89% (borderline feasibility requiring review), and Red <80% (feasibility not achieved and requiring review).
• Percentage of participants completing 3-month follow-up [From randomisation through 3 months after radiotherapy.]: The percentage of randomised participants who complete the required study follow-up through 3 months after radiotherapy. Follow-up feasibility will be interpreted using predefined traffic-light criteria: Green ≥80% (feasibility achieved), Amber 70-79% (borderline feasibility requiring review), and Red <70% (feasibility not achieved and requiring review).
• Percentage of participants with complete required study data [From study initiation through 3 months after radiotherapy.]: The percentage of participants with complete required study data according to the study data collection requirements. Data completeness will be interpreted using predefined traffic-light criteria: Green ≥90% (feasibility achieved), Amber 80-89% (borderline feasibility requiring review), and Red <80% (feasibility not achieved and requiring review).
• Percentage of participants with major protocol deviations [From randomisation through 3 months after radiotherapy.]: The percentage of participants with major protocol deviations during the study. A major protocol deviation is a significant departure from the study protocol that may affect participant safety, treatment allocation, assessment of the primary outcome, or validity of the study results. Protocol adherence will be interpreted using predefined traffic-light criteria: Green <10% major protocol deviations (feasibility achieved), Amber 10-20% (borderline feasibility requiring review), and Red >20% (feasibility not achieved and requiring review).

Secondary outcomes

• Percentage of participants achieving overall pain response at 4 weeks. [4 weeks after radiotherapy]: Overall pain response will be assessed using the NRS-11 and analgesic use. Pain response is defined as a reduction of at least 2 points in pain from baseline with no escalation in analgesic use. The percentage of participants achieving pain response will be compared between the SFRT and MFRT groups.
• Percentage of participants requiring retreatment [From completion of radiotherapy through 3 months after radiotherapy]: The percentage of participants requiring repeat radiotherapy to the treated sitefor persisten or recurrence of pain will be recorded and compared between the SFRT and MFRT groups.
• Percentage of participants experiencing pain flare [From completion of radiotherapy through 10 days after radiotherapy.]: Pain flare following radiotherapy will be recorded and compared between the SFRT and MFRT groups. Pain flare is defined as increase in NRS pain score by ≥2 points without reduction in analgesic use, or Increase in analgesic requirement by ≥25% without improvement in pain score, followed by return to the baseline pain level or analgesic requirement within 10 days after radiotherapy.
• Percentage of participants achieving overall pain response at 2 weeks and 3 months [2 weeks and 3 months after radiotherapy]: Overall pain response will be assessed using the NRS-11 and analgesic use. Pain response is defined as a reduction of at least 2 points in pain from baseline with no escalation in analgesic use. The percentage of participants achieving pain response will be recorded at 2 weeks and 3 months after radiotherapy and compared between the SFRT and MFRT groups.
• Change in analgesic requirement from baseline [At 2 weeks, 4 weeks, and 3 months after radiotherapy]: Change in analgesic requirement from baseline will be assessed using the patient's analgesic consumption and expressed as oral morphine equivalent dose (OMED). The change in analgesic requirement will be recorded and compared between the SFRT and MFRT groups.

Other outcomes

• Number of participants receiving radiotherapy to new painful metastatic sites [From completion of radiotherapy through 3 months after radiotherapy]: The number of participants who receive radiotherapy to new painful metastatic sites during the 3-month follow-up period will be recorded descriptively. This outcome reflects the occurrence of new painful metastatic disease during follow-up and is not intended to assess the efficacy of SFRT versus MFRT.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* Age ≥18 years
* Histologically proven malignancy
* Radiological evidence of bone or spine metastases
* Pain score ≥4 on Numeric Rating Scale (NRS-11)
* ECOG Performance Status 0-3
* Life expectancy ≥3 months.
* Ability to provide written informed consent

Exclusion Criteria:

* Spinal cord compression requiring emergency therapy
* Previous radiotherapy to same site
* Unstable pathological fracture requiring surgery
* Pregnancy
* Inability to provide consent
* Oligometastatic bone metastases requiring Stereotactic Body Radiotherapy (SBRT)

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• Balaji Subramanian Sitaraman, MBBS, DNB, Principal investigator, Royal Hospital, Ministry of Health, Oman