Comparing Radiation Therapy to Usual Care for Patients With High-Risk Bone Asymptomatic Metastases

Phase 3

Not yet recruiting

• Conditions: Metastatic Malignant Neoplasm in the Bone; Metastatic Malignant Solid Neoplasm

• Registration Number: NCT06745024
• Lead Sponsor: NRG Oncology

Brief Summary

This phase III trial compares the effect of adding radiation therapy to usual care on the occurrence of bone-related complications in cancer patients with high-risk bone metastases that are not causing symptoms (asymptomatic). High-risk bone metastases are defined by their location (including hip, shoulder, long bones, and certain levels of the spine), or size (2 cm or larger). These bone metastases appear to be at higher risk of complications such as fracture, spinal cord compression, and/or pain warranting surgery or radiation treatment. Radiation therapy uses high energy x-rays to kill cancer cells and shrink tumors. The total dose of radiation can be delivered in a single day or divided in smaller doses for up to 5 days of total treatment. Usual care for asymptomatic bone metastases may include drugs that prevent bone loss, in addition to the treatment for the primary cancer or observation (which means no treatment until symptoms appear). Evidence has shown that preventative radiation therapy may be effective in lowering the number of bone metastases-related complications, however, it is not known if this approach is superior to usual care. Adding radiation therapy to usual care may be more effective in preventing bone-related complications than usual care alone in cancer patients with asymptomatic high-risk bone metastases.

Detailed Description

PRIMARY OBJECTIVE:

I. To determine whether prophylactic radiation therapy (RT) to high-risk asymptomatic bone metastases decreases the occurrence of skeletal-related events (SREs), including pathologic fracture, spinal cord compression, and surgery to bone (not including palliative radiation for pain only), compared to standard of care (SOC).

SECONDARY OBJECTIVES:

I. To compare overall survival (OS) between study arms. II. To compare occurrence of any SREs (including RT for palliation of pain) among enrolled bone metastasis(es) between study arms.

III. To compare occurrence of hospitalizations related to any SREs in enrolled bone metastasis(es) between study arms.

IV. To compare pain-related quality of life (QOL) between study arms. V. To characterize adverse events of RT and compare to SOC.

EXPLORATORY OBJECTIVES:

I. To evaluate overall QOL, functional status, and quality-adjusted life years between study arms.

II. To evaluate any hospitalizations (from any cause) between study arms. III. To characterize differences in primary and secondary endpoints between study arms (a) among the represented racial and ethnic groups (e.g. Black, White, Hispanic/Latino, Asian/Pacific Islander, and Native American) and (b) by sex.

IV. To evaluate the heterogeneity of radiation treatment effect based on cancer-related factors (histology, criteria indicating high-risk for SRE), treatment-related factors (bone modifying agent use, radiation dose/ technique), and patient demographic factors (age, sex, race/ethnicity, and health-related social needs).

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Patients continue to receive SOC systemic anti-cancer therapy or observation and bone modifying agents as determined by the treating physician. Additionally, patients undergo optional blood sample collection on study.

ARM II: Patients continue SOC as in Arm I. Patients also undergo conventional RT or stereotactic body radiation therapy (SBRT) once daily (QD) for up to 5 days (5 fractions) in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo computed tomography (CT) or magnetic resonance imaging (MRI) and optional blood sample collection on study.

After completion of study treatment, patients are followed up at 3, 6, 12 and 24 months.

Study Timeline

• Status Verified: 2024-12
• Study First Submitted: 2024-12-17
• Study First Submitted QC: 2024-12-17
• Last Update Submitted: 2024-12-17
• Study First Posted: 2024-12-20
• Last Update Posted: 2024-12-20
• Study Start: 2025-06-09
• Primary Completion: 2028-10-01
• Study Completion: 2028-10-01

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 280

Inclusion Criteria

• • Patients with polymetastatic cancer defined as more than 5 sites of radiographically-evident systemic metastatic disease (excluding intracranial disease)

  • "High-risk" asymptomatic bone metastasis (Brief Pain Inventory [BPI] score of < 5 on the "maximum" pain item) defined as fulfilling at least one of the following four high-risk criteria:

    • Bulky site of disease in bone ( ≥ 2 cm);
    • Disease involving the hip (acetabulum, femoral head, femoral neck), shoulder (acromion, glenoid, humeral head), or sacroiliac joints;
    • Disease in long bones occupying up to 2/3 of the cortical thickness (humerus, radius, ulna, clavicle, femur, tibia, fibula, metacarpals, phalanges); and/or
    • Disease in junctional spine (C7-T1, T12-L1, L5-S1) and/or disease with posterolateral element (pedicles and/or facet joints) involvement
    • NOTE: Sternum, rib, and scapula are defined as flat bones so lesions in these locations would only be included if bulky

  • Patients with any solid tumor type (excluding multiple myeloma)

  • Patients must have systemic disease evaluation through standard of care diagnostic imaging, including either CT chest/abdomen/pelvis or body positron emission tomography (PET)/CT, with radiology report available

  • Patients with treated brain metastases and no known leptomeningeal disease are eligible if these lesions have been treated prior to enrollment

  • Age ≥ 18

  • Performance status: Eastern Cooperative Oncology Group (ECOG) 0-2 or Karnofsky performance status (KPS) ≥ 60

  • No previous radiotherapy to the intended enrolled sites of disease

  • No epidural spinal cord compression (ESCC) ≥ grade 1c (defined as deformation of the thecal sac with spinal cord abutment) at the enrolled bone metastasis(es)

  • No prior fracture at the enrolled bone metastasis(es)

Exclusion Criteria

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Primary Outcome Measures

Name	Time	Method
Incidence of skeletal-related events (SREs) (Excluding palliative radiation for pain)	From randomization until first SRE up to 24 months	Gray's test will be used to test for statistically significant difference in the distribution of SRE failure times (Gray 1988), accounting for death as a competing risk. The cause specific Cox proportional hazards model will be used to evaluate the treatment effect and stratification variables (Cox 1972). The analysis will be conducted on an intent-to-treat basis using all randomized patients. Analyses of treatment effect will be performed using the Cox proportional hazard model with the stratification factors as fixed covariates. The adjusted estimate of the treatment hazard ratio with a 95% confidence interval will be provided.

Secondary Outcome Measures

Name	Time	Method
Overall survival (OS)	From the time of study entry until death up to 24 months	OS will be compared between the two treatment arms. A stratified Cox proportional hazards model will be used to evaluate the treatment effect and stratification variables (Cox 1972). The analysis will be conducted on an intent-to-treat basis using all randomized patients. The adjusted estimate of the treatment hazard ratio with a 95% confidence interval will be provided.
Hospitalizations for SRE	Up to 24 months	Hospitalization for SRE as an event will be analyzed with a logistic regression model by treatment status, adjusted for stratification factors. The adjusted estimate of the treatment odds ratio with a 95% confidence interval will be provided.
Brief Pain Inventory (BPI) scores	At baseline and up to 24 months	The mean BPI scores at each collected time point (and their 95% confidence intervals) by treatment arm will be estimated. A mixed-effects model will be used to estimate and compare the mean BPI worst pain scores for the treatment arms. Model covariates will include the patients' randomly assigned study treatment, stratification factors, baseline BPI worst pain score, any opioid use, and a treatment-by-assessment time interaction term.
Incidence of adverse events (AEs)	Up to 42 days from registration (Arm I) and up to 30 days from end of treatment (Arm II)	AEs will be collected using the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Descriptive statistics will be used to summarize AEs. These analyses will focus on individuals who initiated their assigned treatment and will summarize maximum grade of AEs occurring during treatment and follow-up classified by CTCAE category. The primary summary of AEs will present counts and percentages, regardless of whether the AE was attributed to any of the study agents.