Standard arm (Arm 1)

Radiotherapy for patients in the standard arm should follow the principles of palliative radiotherapy as per the individual institution, with the goal of alleviating symptoms or preventing imminent complications. Recommended dose fractionations in this arm will include 8 Gy in 1 fraction, 20 Gy in 5 fractions, and 30 Gy in 10 fractions.

Patients in this arm should not receive ablative treatments or radical-intent treatments (e.g. surgery), unless there is a clearly known clinical benefit (e.g. stereotactic radiation to a new brain metastasis when other disease is controlled on systemic therapy, or treatment of the prostate in the setting of low-burden disease elsewhere). Even when some lesions are treated in this manner, patients should not receive treatment to all lesions in the standard arm. If the investigator judges that all lesions would be treated with ablative therapies on Arm 1 as part of standard of care, the patient should not be randomized.

Systemic therapy will be pre-specified based on the standard of care approach for that patient, and it may include systemic therapy (cytotoxic, targeted, hormonal, or immunotherapy) or observation. See Systemic Therapy Section for the timing of systemic therapy.

Experimental arm (Arm 2)

Arm 2 consists of treatment to the primary tumor and metastases, with SABR preferred, but other options all allowable (e.g. surgery, RFA, fractionated radiation, chemoradiation) if those are deemed to be preferable by the treating oncologists (see Dose/Fractionation for the Primary Tumor and Metastases Section).

Pre-planning procedure

It is recommended (but not required) to complete a radiation pre-plan before enrollment. In cases that are very clearly plannable (e.g. a small lung primary tumor and two bone metastases, or a primary tumor to be resected on Arm 2 with a single metastasis to be treated with SABR), the pre-plan can be omitted.

If a patient undergoes pre-planning but cannot be randomized due to failure to generate an acceptable plan, the baseline information of such patients will be captured (i.e. the Eligibility Checklist and Baseline Form), but they will not be followed for outcomes. If there are lesions that will not be treated with radiation (e.g. they will be resected), then those are to be ignored on the pre-plan.

Institutions may use diagnostic images rather than radiation planning images for pre-planning. To minimize the risk of progression or development of new lesions between the diagnostic images and the eventual CT simulation, the diagnostic images must be less than 4 weeks old by the time of randomization (i.e. after the pre-plan is done). If randomized to Arm 2, CT simulation and planning must occur such that radiation starts within 2 weeks of randomization.

Institutions may send treatment plans to the coordinating centre if the sites wish to have their plans reviewed (this is not mandatory) or if requested by the coordinating centre.

Dose/fractionation for the primary tumor and metastases Treatment of the primary tumor

The primary tumor and any involved regional nodes may be treated with SABR (using the dose fractionations in Treatment of Metastases Section) or with other local modalities (surgery, fractionated radiation [e.g. 40 Gy in 15 fractions], or chemoradiation) at the discretion of the treating team and/or the local multidisciplinary tumor board. Because of the convenience in using SABR for all lesions, non-SABR modalities should only be used if they are likely to provide a benefit over SABR (e.g. better local control with chemoradiation for stage III intrathoracic lung cancer, or with surgery for a colorectal primary).

If SABR is being used, most primary tumors will be treatable with the fractionations in Treatment of Metastases Section. However, tumors in the esophagus, stomach, small intestine or colon should be treated with either fractionated radiation or a lower SABR dose (e.g. 25 Gy in 5 fractions) to minimize the risk of perforation.

Treatment of metastases

Each lesion may be treated with 1, 3, or 5 fractions, depending on the local practice of the enrolling institution and treating physician. All doses are prescribed to the periphery of the planning target volume (PTV). Acceptable fractionations are listed in Table 2.

Table 2 Radiation fractionation options for metastatic lesions

Note for vertebral metastases: for centres that standardly treat vertebral metastases with 24 Gy in 2 fractions and would prefer to use that fractionation, this is allowable. Organ at risk (OAR) dose constraints should be the same as was used for the SC-24 trial and can be found in the supplemental appendix of the SC-24 trial publication [22]. However, as noted in Volume Definition (Arm 2) section, it is recommended that the spine target volumes consist of the lesion only plus an additional margin, rather than the whole vertebral body, to avoid large volumes of bone marrow irradiation.

Non-SABR treatments may be used for metastases (e.g. resection or RFA) if they are thought to provide an advantage in the treatment of a specific metastases (e.g. resecting a lesion to collect tissue for molecular biomarkers, resecting a lesion in a location not easily amenable to SABR, or resecting a lesion that was previously radiated but progressing).

Immobilization

Treatment will be setup using reproducible positioning and verified using an online protocol for all patients in this study. Immobilization may include a custom immobilization device, such as thermoplastic shell or vacuum bag, as per individual institutional practice when delivering SABR. Some institutions do not use immobilization devices and have demonstrated high degrees of accuracy; this is acceptable in this study.

Imaging/localization/registration

All patients in Arm 2 will undergo planning CT simulation. Axial CT images will be obtained throughout the region of interest. For institutions using stereotactic radiosurgery platforms, real-time tumor tracking and orthogonal imaging systems are permitted.

Patients may be treated with MRI-guided delivery if deemed appropriate by the treating oncologist, and may use daily plan adaptation as has been described previously.4–74D-CT Procedures Section will not apply to these patients.

4D-CT procedures

Four-dimensional (4D) CT will be used for tumors in the lungs, liver, or adrenals. For patients undergoing 4D-CT, physics will review the 4D-CT images and will perform standard quality assurance (QA) procedures indicated on the 4D-CT template designed specifically for SABR. Motion measurements in all 3 directions are required and each institution must have a strategy for motion management.

Volume definitions (Arm 2)

For SABR, the gross tumor volume (GTV) will be defined as the visible tumor on CT and/or MRI imaging ± PET. No additional margin will be added for microscopic spread of disease (i.e. clinical target volume [CTV] = GTV). For vertebral body lesions, although current guidelines consider the entire vertebral body as the CTV, that is not preferred in this trial due to the risk of large cumulative amounts of bone marrow being irradiated. It is preferred that vertebral PTVs consist of the GTV (as defined on CT and MRI) with a small margin for motion, and NOT include the whole uninvolved vertebral body, unless the number of spinal lesions/levels being treated is small (e.g. 1–3). A PTV margin of 2–5 mm will be added depending on site of disease, immobilization, and institutional setup accuracy: 2 mm margins should be used for spinal stereotactic treatments, 0–2 mm for brain tumors, and 5 mm for other sites.

For fractionated radiotherapy, target volumes are the same as for SABR, except that a CTV of up to 5 mm is allowed, but not required.

Targets should be named based on the organ involved, and numbered from cranially to caudally for each organ. For example, in a patient with 1 brain and 3 lung lesions, there would be: GTV_brain_1, GTV_lung_1, GTV_lung_2, and GTV_lung_3, and corresponding PTV_brain_1, PTV_lung_1, PTV_lung_2, and PTV_lung_3, representing the lesions from superior to inferior. In order to keep track of which lesions are being treated on each day, we strongly recommend use of a lesion tracking sheet, to specify which isocentres are being treated on which date; this sheet is available from the Principal Investigator upon request.

For spinal lesions, a pre-treatment MRI is required to assess the extent of disease and position of the cord. This must be fused with the planning CT scan. A planning organ at risk volume (PRV) expansion of 2 mm will be added to the spinal cord, and dose constraints for the spinal cord apply to this PRV. Alternatively, the thecal sac may be used as the PRV. For radiosurgery platforms, a PRV margin of 1 mm is permitted for the spinal cord.

OAR doses

OAR doses are listed in Appendix 1 [23]. OAR doses may not be exceeded. In cases where the PTV coverage cannot be achieved without exceeding OAR doses, the PTV coverage is to be compromised. All OARs within 5 cm of the PTV must be contoured. This can be tested for each PTV by creating a 5 cm expansion to examine which OARs lie within that expansion.

Treatment planning

Treatment can be delivered using static beams (either 3-dimensional (3D)-conformal radiotherapy or intensity-modulated) or rotational therapy (volumetric modulated arc therapy [VMAT], or tomotherapy). Priority will be placed on generating clinically acceptable plans while minimizing complexity, planning time, and treatment time.

Dose constraints may not be exceeded. If a dose constraint cannot be achieved due to overlap of the target with an OAR, the dose can be reduced, the number of fractions can be increased, or the target coverage compromised in order to meet the constraint. The decision as to whether to reduce the dose to the whole target, or part of the target (i.e. by compromising the PTV coverage), is left to the discretion of the treating physician. In cases where the target coverage must be reduced, the priority for dose coverage is the GTV (e.g. attempt to cover as much of the GTV as possible with the prescription dose). For vertebral tumors, note that the spinal cord constraints apply to the PRV (see 4D-CT Procedures Section).

For all targets, doses should be prescribed to 60–90% isodose line surrounding the PTV, and all hotspots should fall within the GTV. 95% of the PTV should be covered by the prescription dose, and 99% of the PTV should be covered by 90% of the prescription dose.

Doses must be corrected for tissue inhomogeneities. Several non-overlapping 6/10 MV beams (on the order of 7–11 beams) or 1–2 VMAT arcs combined possibly with a few non-coplanar beams should be utilized. Non-coplanar beams can be used to reduce 50% isodose volume.

The number of isocentres is at the discretion of the treating physician, physicists, and dosimetrists. Generally, metastases can be treated with separate isocenters if they are well-separated.

The scheduling and sequence of treating the primary and each metastasis is at the discretion of individual physicians, but in general should begin with the brain, due to risks associated with progression.

Treatment should start within two weeks of randomization, and treatment of all lesions (including the primary and metastases) should be delivered in as short a time-frame as feasible, although there is no strict requirement for a maximum treatment period.

Quality assurance (Arm 2)

The following requirements must be completed for each patient:

Prior to treatment, plans for each patient must be peer-reviewed, either by discussion at QA rounds or by another individual radiation oncologist.

All radiotherapy plans must meet target dose levels for OARs (Appendix 1). Prior to plan approval, the dose to each OAR must be verified by the physicist or treating physician.

All dose delivery for intensity-modulated plans (including arc-based treatments) will be confirmed before treatment by physics staff.

Systemic therapy

Patients treated with prior systemic therapy are eligible for this study. Cytotoxic agents must be held commencing 2 weeks prior to radiation and lasting until 1 week after the last fraction. Molecularly targeted agents must be held for at least 48 h before the first fraction until 48 h after the last fraction. Immunotherapy and hormone therapy are exempted from these requirements and are allowed during treatment but patients who are on hormone therapy with cyclin-dependent kinase (CDK) 4/6 inhibitors must stop the latter during this three-week period. Use of chemotherapy schemes containing potent enhancers of radiation damage (e.g. gemcitabine, doxorubicin) and vascular endothelial growth factor inhibitors (e.g. bevacizumab) are discouraged within the first month after radiation.

Further radiotherapy for progressive disease at new metastatic sites

Patients in Arm 1 who develop new, untreated metastatic deposits should be treated with standard of care approaches. SABR to those sites is not permitted, except for unique scenarios where it would be considered standard of care (e.g. all disease controlled on systemic therapy with a newly developed brain metastasis).

Patients in Arm 2 who develop new, untreated metastatic deposits should be considered for SABR at those sites, as appropriate, if such deposits can be treated safely with SABR, and if the treating institution offers SABR for that body site. If SABR is not possible, then palliative radiotherapy can be delivered if indicated. Patients in Arm 2 who develop progression at lesion previously treated with SABR may be considered for palliative radiation or repeat SABR if safe and dose constraints can be met.

QA for participating institutions

Prior to opening the study, each participating institution will be required to send to one of the Principal Investigators a mock treatment plan for the anatomic sites that will be treated (e.g. lung, brain, liver, adrenal), to ensure that the treatment plans are designed in compliance with the protocol. The Principal Investigators will provide pertinent CT datasets. Alternatively, a pre-plan for a patient enrolled on this trial may be used for credentialing. Each participating institution can choose which tumor sites will be treated at their individual institution (i.e. some institutions may only choose to treat a subset of the eligible metastatic sites). Sites that have prior accreditation for SABR through a clinical trial (e.g. SABR-COMET, or organ-specific SABR trials) are exempt from this requirement for the organ sites that have been accredited in those trials.