Background
Methods/design
Objectives
Primary endpoints
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Patient Reported Outcomes, including quality of life and side effects
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Toxicity Assessed by the National Cancer Institute Common Toxicity Criteria (NCI-CTC) version 4 for each organ treated
Secondary endpoints
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Progression-free survival
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Time from SABR treatment to disease progression at any site or death
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Overall survival
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Lesion control rate, defined as lack of further progression at the treated site
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Time to starting or re-starting chemotherapy
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Number of cycles of further chemotherapy/systemic therapy
Inclusion criteria
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Age 18 or older
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Able to provide informed consent
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Histologically confirmed malignancy with metastatic disease detected on imaging.
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Biopsy of metastasis is preferred, but not required.
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Primary tumour treated radically or controlled by prior palliative radiotherapy or systemic therapy
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Maximum 5 metastases eligible for SABR (either 5 in total or 5 not controlled by prior treatment)
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Standard of care tests prior to SABR CT simulation within 12 weeks:
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Brain CT or MRI imaging (for tumor sites with propensity for brain metastasis)
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Body imaging:
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CT chest/abdomen/pelvis with bone scan required if no PET-CT is performed
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PET-CT is only required for specific evidence-based indications, and in such cases the CT neck/chest/abdomen/pelvis and bone scan are not required:
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MRI spine for patients with vertebral or paraspinal metastases
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For other indications, at the discretion of the treating oncologists, PET-CT scans may be done but are not required.
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Liver function tests (AST, ALT, GGT, alkaline phosphatase) for patients with liver metastases
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Tumor marker testing as appropriate (e.g. CEA for colorectal cancer, PSA for prostate cancer, etc)
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Pregnancy test for women of child-bearing age
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ECOG performance status 0–2
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All sites of progressive disease can be safely treated based on criteria below
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For non-brainstem mets, maximum size of 3 cm if using single fraction radiosurgery.
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If size is from 3.1 to 4 cm, 25-35Gy/5 can be considered
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All brain mets cases need approval from Stereotactic Radiosurgery rounds
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Maximum size of 6 cm for lesions outside the brain, except:
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Bone metastases over 5 cm may be included, if in the opinion of the local PI it can be treated safely (e.g. rib, scapula, pelvis)
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Life expectancy > 6 months
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In many scenarios this is best estimated by a multidisciplinary opinion from disease site experts, preferably obtainted at multidisciplinary tumours rounds.
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The potential treating SABR radiation oncologist reserves the right to require a multidisciplinary note documenting life expectancy, other treatment options and suitability for SABR.
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Not a candidate for surgical resection at all sites: surgery to all sites not recommended by multidisciplinary team, or unfit or declining surgery.
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Not a candidate for an open randomized clinical trial comparing SABR and a standard treatment.
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Prior chemotherapy allowed but no chemotherapy (cytotoxic, immunotherapy or molecularly targeted agents) 48 h prior to first fraction of radiotherapy, during radiotherapy, or for 48 h after last fraction. Certain chemotherapy agents may require a longer break prior to or after SABR if protocols dictate. Hormonal therapy during SABR is allowed.
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Patients with metastases that have been previously treated may be eligible for this SABR protocol:
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If the previous treatment was systemic therapy, the patient may be eligible, if the metastases have demonstrated a complete radiologic response
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If the previous treatment was by a local non-radiation means (e.g. prior resection, RFA or microwave ablation), then SABR may be considered for residual/recurrent disease
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If the previous treatment was SABR, the patient is not eligible unless the new site(s) was/were not previously treated
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If the previous treatment was conventional RT, SABR could be considered if it can be delivered safely. In such a circumstance it must be presented in a multidisciplinary setting for approval.
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Exclusion criteria
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Serious medical co-morbidities precluding radiotherapy
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Bone metastasis in a femoral bone if risk of pending fracture is high
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Patients with 1–3 brain metastasis and no disease elsewhere (these patients should not be accrued but treated with stereotactic radiosurgery or radiotherapy as per results of published randomized trials)
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Complete response to first-line chemotherapy (i.e. no measurable target for SABR)
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Persistent malignant pleural effusion
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Inability to treat all sites of progressing disease with ablative intent
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Clinical or radiological evidence of spinal cord compression
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Dominant brain metastasis requiring surgical decompression
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Pregnant or lactating women
Evaluation
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Brain CT or MRI imaging (for tumor sites with propensity for brain metastasis)
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Body imaging:
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CT neck/chest/abdomen/pelvis with bone scan required if no PET-CT is performed
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PET-CT is only required for specific evidence-based indications, and in such cases the CT neck/chest/abdomen/pelvis and bone scan are not required:
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MRI spine for patients with vertebral or paraspinal metastases
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Liver function tests (AST, ALT, GGT, alkaline phosphatase) for patients with liver metastases
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Kidney function tests (Creatinine, eGFR) for adrenal and kidney patients
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Pulmonary function tests for lung metastases
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Tumor marker testing as appropriate (e.g. CEA for colorectal cancer, PSA for prostate cancer, etc)
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Pregnancy test for women of child-bearing age
Assessment
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ECOG status
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Charleson Comorbidity Index (CCI)
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Patient Reported Outcomes including Quality of Life assessment using BC Cancer’s Prospective Outcomes and Support Initiative [12]
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Provider Reported Toxicity
Intervention
Dose / fractionation / prescription
Immobilization
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Immobilization devices need to be approved by the practicing Radiation Oncologist(s) and SABR physics and dosimetry staff within the particular institution.
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It is left at the discretion of the treating RO/physics to determine which immobilization device is to be used based on their centre/department specific policy.
Pre-treatment simulation
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4DCT should be acquired for tumors which are likely to move from respiratory motion, such and lung, liver and adrenal sites.
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If 4DCT is not possible, 3DCT is acceptable
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The CT slices thickness should be no greater than 3 mm, and pixel sizes should be no greater than 1 × 1 mm. For Spine SABR, the CT slice thickness should be no greater than 2 mm (eg. 1.25 mm) Intravenous contrast may be used at the discretion of the treating radiation oncologist.
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Fiducial markers may be used at the discretion of the treating radiation oncologist.
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When available, 4DCT images should be sent to Treatment Planning System:
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Reconstructed CTs that display entire range of motion (e.g., 10 phases)
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MIP (Maximum Intensity Projection)
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MIN (Minimum Intensity: for bony lesions)
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Average CT if used for planning purposes
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Treatment volumes
Relevant organs at risk (OAR)
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The relevant OARs are dependent on the location of the target volume and should be outlined from the simulation CT.
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As a general rule, critical structures within 5 cm of the PTV should be contoured.
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Please refer to the Additional file 1 for a list of structures that should be considered for different treatment sites.
Treatment planning / technique
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3DCRT, Intensity Modulated radioterhapy (IMRT), volumetric modulated arc therapy (VMAT) or dynamic conformal arcs delivery techniques are allowed.
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Flattening Filter Free (FFF) beams are encouraged
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Gating or Dynamic Tumour Tracking is allowed
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Type II only (3D scatter correction dose algorthms, such as Eclipse AAA, Acuros, or Collapsed Cone)
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Inhomogeneity Corrections = ON
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The Volume of the PTV receiving 100% of the prescription dose is equal to 95 % “The Volume of the PTV receiving 90% of the prescription dose is greater than 99 %” PTV coverage may be compromised to achieve dose constraints for critical OARs at the discretion of the radiation oncologist, but PTV coverage by 100% dose must be > 50%
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The hotspot should be in the PTV and not in the adjacent normal tissue. The hotspot should generally be less than 150% of the prescription dose. For lung lesions, the hotspot should not exceed 167% of the prescription dose.
OAR and Normal tissue dose constraints
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Please refer to Additional file 1 for the OAR dose constraints.
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The dose distribution should conform to the PTV as much as possible. As a guideline for a single lung lesion, please refer to Additional file 1 for dose conformality indices. For multiple lung lesions, the specified dose conformality indices might not be achievable.
Treatment verification / imaging
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Collision Check: Recommended for all plans containing non-coplanar beams
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Imageverification imaging must be acquired before all fractions (e.g. KV, MV, or CBCT).
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It is recommended that CBCT image guidance is used for all treatment fractions), s indicated in the Table 1
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Post treatment fraction imaging should be applied to assess intrafraction motion.
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If treatment time is expected to exceed 45 min, mid-tx position verification should be performed.
Tumor Location | Description | Total Dose (Gy) | Number of fractions | Dose per fraction (Gy) | Frequency | |
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Lung | Tumors 5 cm or less surrounded by lung parenchyma | 48 [54] | 4 [3] | 12 [18] | Every second day | |
Within 2 cm of mediastinum or brachial plexus | 60 | 8 | 7.5 | Daily | ||
Bone | Any bone | 35 Gy [24] | 5 [2] | 7 [12] | Daily | |
Brain | Stereotactic lesions (no whole brain RT) | < 2 cm | 24 | 1 | 24 | Once |
2–3 cm | 18 | 1 | 18 | Once | ||
3-4 cm | 15 | 1 | 15 | Once | ||
If whole brain treated, then simultaneous boost to each lesion | 35Gy to metastases 20 Gy whole brain (optional) | 5 | 7 Gy to PTV 4 Gy WBRT | Daily | ||
Liver | 54 Gy | 3 | 18 | Every second day | ||
Adrenal | 60 Gy | 8 | 7.5 | daily | ||
Lymph Node | 40 Gy | 5 | 8 | daily |
Quality assurance
Data and safety monitoring committee
Follow-up schedule
Day | Tests and Procedures |
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Every 3 months for the first 2 years | Follow-up appointment with study doctor, physical examination by study doctor (or family doctor if appointment is over videolink or phone) and complete questionnaire Blood tests for certain sites (i.e. liver function tests for patients with liver metastases) Assessment of any side effects or adverse events |
Months 3, 6, 12, 18, and 24 | CT scan(s) and/or other imaging (MRI, PET or bone scan)a |
Every 6 months for years 2–6 | Follow-up appointment with study doctor, physical examination by study doctor (or family doctor if appointment is over videolink or phone) and complete questionnaire. Assessment of any side effects or adverse events |
Progressive disease
Physician/registered nurse/other reported outcomes
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ECOG performance status
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Outcomes
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Next local therapy or chemo-/targeted-therapy start date
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Date of relapse or new metastases
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Date of death
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CTCAE version 4.0 toxicity.
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Measurement of response
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Survival outcomes: Overall survival will be measured as time until death from any cause, and progression-free survival as time to either progression or death, whichever occurs first.
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Lesion control rate will be assessed retrospectively as RECIST criteria has not been validated in the setting of SABR, and is costly to implement in a prospective cohort.
Study endpoints and stopping rules
# of grade 4 toxicity events out of a sample size = 200 | Probability of exact # of grade 4 toxicity events given true rate of grade 4 toxicities = 5% | Probability of exact # of grade 4 toxicity events given true rate of grade 4 toxicities = 4% | Probability of exact # of grade 4 toxicity events given true rate of grade 4 toxicities = 3% | Probability of exact # of grade 4 toxicity events given true rate of grade 4 toxicities = 2% |
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0 | 0.004% | 0.03% | 0.2% | 1.8% |
1 | 0.04% | 0.2% | 1.4% | 7.2% |
2 | 0.2% | 1% | 4.3% | 14.6% |
3 | 0.7% | 2.7% | 8.8% | 19.6% |
4 | 1.7% | 5.6% | 13.4% | 19.7% |
5 | 3.6% | 9.1% | 16.2% | 15.8% |
6 | 6.1% | 12.3% | 16.3% | 10.5% |
# of grade 4 toxicity events | Upper limits of one-sided 95% confidence interval for true rate of grade 4 toxicities (sample size = 200) |
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0 | 1.5% |
1 | 2.3% |
2 | 3.1% |
3 | 3.8% |
4 | 4.5% |
5 | 5.2% |
6 | 5.8% |
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< 5% grade 5 toxicity
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< 10% grade 4 toxicity
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< 25% grade 3 toxicity