Comparing Radiation Therapy to Usual Treatment for Patients With High-Risk Bone Metastases That Are Not Causing Pain, PREEMPT Trial

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), (b) by sex, and (c) by health-related social needs.

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) for RT planning and optional blood sample collection on study.

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

• Best Practice (Other), also known as standard of care, standard therapy: Given SOC systemic anti-cancer therapy
• Biospecimen Collection (Procedure), also known as Biological Sample Collection, Biospecimen Collected, Specimen Collection: Undergo blood sample collection
• Bone Metastases Treatment (Other): Given bone modifying agent
• Computed Tomography (Procedure), also known as CAT, CAT Scan, Computed Axial Tomography, Computerized Axial Tomography, Computerized axial tomography (procedure), Computerized Tomography, Computerized Tomography (CT) scan, CT, CT Scan, Diagnostic CAT Scan, Diagnostic CAT Scan Service Type, tomography: Undergo CT
• Conventional Radiotherapy (Procedure), also known as 2-Dimensional Conventional Radiation Therapy, 2D Conventional Radiotherapy, 2D Radiotherapy, 2D-RT, Radiation, 2D Conventional: Undergo conventional RT
• Magnetic Resonance Imaging (Procedure), also known as Magnetic Resonance, Magnetic Resonance Imaging (MRI), Magnetic resonance imaging (procedure), Magnetic Resonance Imaging Scan, Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance, MR, MR Imaging, MRI, MRI Scan, MRIs, NMR Imaging, NMRI, Nuclear Magnetic Resonance Imaging, sMRI, Structural MRI: Undergo MRI
• Patient Observation (Other), also known as Active Surveillance, deferred therapy, expectant management, Observation, Watchful Waiting: Undergo SOC observation
• Questionnaire Administration (Other): Ancillary studies
• Stereotactic Body Radiation Therapy (Radiation), also known as SABR, SBRT, Stereotactic Ablative Body Radiation Therapy: Undergo SBRT

Primary outcomes

• 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 outcomes

• 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.

Other outcomes

• Overall quality of life, functional status, and quality-adjusted life years [At baseline and up to 24 months]: Comparison of overall quality of life between the arms will be evaluated using the European Quality of Life Five Dimension Five Level (EQ-5D-5L) scale. Analyses of the EQ-5D-5L is primarily descriptive and involves estimating differences in mean scores for each treatment group with confidence intervals. A mixed-effects model will be used to estimate and compare the mean scores for the treatment groups across time. Model adjustment covariates will include the patients' randomly assigned study treatment, stratification factors, baseline EQ-5D-5L score and assessment time.
• Hospitalizations (from any cause) [Up to 24 months]: Hospitalizations from any cause 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.
• Treatment differences by race and ethnicity, sex, and health-related social needs [Up to 24 months]: Differences in primary and secondary endpoints will be characterized descriptively only. Estimates of the primary outcome treatment effect and the corresponding 95% confidence interval will be provided by sex, race, and ethnicity.
• Heterogeneity of radiation treatment effects [Up to 24 months]: Sociodemographic variables collected at baseline will be evaluated for potential interaction with radiation treatment.

Sex: All, ages: 18 Years to any

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(es) (defined as pain score of < 5 on a 0-10 scale using question #3 from the Brief Pain Inventory \[BPI\]) 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.

NOTES:

* Patients may have up to 3 individual high-risk bone metastases enrolled in the study. Sternum, rib, and scapula are defined as flat bones so lesions in these locations would only be included if bulky (per high-risk criteria #1)
* Question #3 from the Brief Pain Inventory (BPI): "On a scale of 0-10, 0 being no or least amount of pain, and 10 being the worst pain imaginable, what score would you rate your worst pain in the last 24 hours."

  * The pain score can be lesion-specific and does not need to refer to overall pain.
  * The remaining questions on the BPI are not required to confirm eligibility

    * Patients with any solid tumor type (excluding multiple myeloma and lymphoma)
    * 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)

526 more sites not listed.

• Results publication: Lapen K, Zhang Z, White C, Barker CA, Kotecha R, McIntosh AF, Nipp RD, Iyengar P, Yang JT, Yerramilli D, Gillespie EF. Predictors of Skeletal-Related Events and Quality-of-Life Dimensions Among Patients With High-Risk Asymptomatic Bone Metastases With or Without Early Radiation Therapy: Secondary Analysis of a Multicenter Randomized Phase II Clinical Trial. J Natl Compr Canc Netw. 2026 Mar 9;24(4):e257126. doi: 10.6004/jnccn.2025.7126. PMID 41825136

• Erin F Gillespie, Principal investigator, NRG Oncology

NIH grants: UG1CA189867