Is Radiation-before-pathology a Feasible Approach in the Palliative Oncology Setting? A Pragmatic Clinical Trial

Inclusion Criteria: * Age 18 years or older * Willing to provide informed consent * Palliative treatment intent: either metastatic or incurable locally advanced disease * Tissue diagnosis is not required for determination of dose/fractionation scheme * Recent cross-sectional imaging \[for example - Computed Tomography (CT), Magnetic Resonance Imaging (MRI), Positron Emission Tomography/Computed Tomography (PET/CT)\] of the area to be treated, done within the past 3 months * Treating physician considers the pre-test probability of cancer greater than 95 percent based on clinical judgement and radiological findings. * The patient has at least 1 site of cancer amenable to biopsy * As per standard practices, if the radiation oncologist will be radiating the only site available to biopsy, they should proceed with caution. Participants should only be enrolled on trial if the risk of harm from delaying Radiation Therapy (RT) significantly outweighs the risks of possible non-diagnostic tissue. If the participant may potentially be eligible for systemic therapy, the treating radiation oncologist should consult a medical oncologist for an opinion regarding the risks of non-diagnostic molecular testing. The weighing of these priorities should be thoroughly discussed with the participant and the discussion should be documented. * Reasons for radiating a participant with a single lesion prior to biopsy include: * Spinal cord compression (actual or impending) and inoperable * Brain metastasis with significant symptoms or neurologic deficits and inoperable * Other lesions causing neurologic deficit * Pulmonary lesion causing or threatening lung obstruction * Uncontrolled bleeding (including hemoptysis and hematuria) * Superior vena cava obstruction (actual or impending) * Limited upside to molecular testing, as determined by the medical oncologist (for example - participant unfit for available systemic therapies, limited options for systemic therapy) * Radiation is considered urgent (for example - participant should receive radiation prior to biopsy date) o Urgent indications may include but are not limited to the reasons listed previously, as well as the following: * Painful metastases or primary lesion not adequately responding to analgesia * Symptomatic brain metastases * Bleeding * Impending pathologic fracture Exclusion Criteria: * Participant is potentially eligible for curative treatment * Clinical suspicion of lymphoma o Some features may be suggestive of lymphoma, including fever or night sweats (for example - B symptoms excluding weight loss), or imaging showing well-defined, homogenous lymphadenopathy. These findings are not exclusion criteria specifically, but should be considered by the clinician in formulating their differential diagnosis.