Title
Radiation Therapy For High-Risk Asymptomatic Bone Metastases: A Pragmatic Multicenter Randomized Phase 3 Clinical Trial (Preempt)

Description
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.

Objective
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).

Treatment 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.

Key Eligibility 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)

Applicable Disease Sites
Sarcoma

Participating Institutions
DN Greenwald Center; Johnson Creek, UW Cancer Center; Oconomowoc Memorial Hospital, Waukesha Memorial; UW Cancer Center at ProHealth; UW Health Eastpark Medical Center; UW Health University Hospital; Waukesha Memorial Hosp