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Population-based phase II trial of stereotactic ablative radiotherapy (SABR) for up to 5 oligometastases:… Olson, Robert; Liu, Mitchell; Bergman, Alanah; Lam, Sonya; Hsu, Fred; Mou, Benjamin; Berrang, Tanya; Mestrovic, Ante; Chng, Nick; Hyde, Derek; Matthews, Quinn; Lund, Chad; Glick, Daniel; Pai, Howard; Basran, Parminder; Carolan, Hannah; Valev, Boris; Lefresene, Shilo; Tyldesley, Scott; Schellenberg, Devin Oct 4, 2018

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STUDY PROTOCOL Open AccessPopulation-based phase II trial ofstereotactic ablative radiotherapy (SABR)for up to 5 oligometastases: SABR-5Robert Olson1,2,3* , Mitchell Liu1,4, Alanah Bergman4, Sonya Lam4, Fred Hsu5, Benjamin Mou6, Tanya Berrang7,Ante Mestrovic7, Nick Chng3, Derek Hyde6, Quinn Matthews3, Chad Lund8, Daniel Glick7, Howard Pai7,Parminder Basran7, Hannah Carolan4, Boris Valev3, Shilo Lefresene4, Scott Tyldesley4 and Devin Schellenberg8AbstractBackground: Oligometastases refer to a state of disease where cancer has spread beyond the primary site, but isnot yet widely metastatic, often defined as 1–3 or 1–5 metastases in number. Stereotactic ablative radiotherapy(SABR) is an emerging radiotherapy technique to treat oligometastases that require further prospective population-based toxicity estimates.Methods: This is a non-randomized phase II trial where all participants will receive experimental SABR treatment toall sites of newly diagnosed or progressing oligometastatic disease. We will accrue 200 patients to assess toxicityassociated with this experimental treatment. The study was powered to give a 95% confidence on the risk of lategrade 4 toxicity, anticipating a < 5% rate of grade 4 toxicity.Discussion: SABR treatment of oligometastases is occurring off-trial at a high rate, without sufficient evidence of itsefficacy or toxicity. This trial will provide necessary toxicity data in a population-based cohort, using standardizeddoses and organ at risk constraints, while we await data on efficacy from randomized phase III trials.Trial Registration: Registered through clinicaltrials.gov NCT02933242 on October 14, 2016 prospectively beforepatient accrual.Keywords: Stereotactic ablative radiotherapy, Oligometastases, RadiotherapyBackgroundOligometastases refer to a state of disease where cancerhas spread beyond the primary site, but is not yet widelymetastatic, often defined as 1–3 or 1–5 metastases innumber [1]. It has been proposed that aggressive treat-ment of oligometastases may improve patient outcomes,but only recently have techniques become widelyavailable to do so non-invasively [2, 3]. Ablation ofmetastatic deposits can be achieved through severaltechniques including surgery, radiofrequency ablation, orhigh-dose radiotherapy [4, 5]. Stereotactic ablative bodyradiotherapy (SABR), is an emerging radiotherapy tech-nique that delivers very large, hypofractionated doses ofhighly-conformal radiotherapy to tumor targets with theaid of on-board imaging for accuracy, giving higher ratesof local control [6, 7].Clinical evidence to support the presence of an oligo-metastatic state is controversial, with low quality evi-dence in both the surgical and SABR literature [3, 8, 9].Sufficient level of evidence to support aggressive treat-ment of oligometastases is lacking, and often based onsingle-arm studies without appropriate controls [10].The long-term survival achieved with treatment ofoligometastases may be a result of selection bias ratherthan the result of treatment intervention. There is sparsedata on the subacute or long-term effects of SABR treat-ment. The use of SABR for newly progressive sites (oli-goprogression) is also an area of increased interest thathas the potential for more widespread use of SABR,* Correspondence: rolson2@bccancer.bc.ca1University of British Columbia, Vancouver, Canada2Unviersity of Northern British Columbia, Prince George, CanadaFull list of author information is available at the end of the article© The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, andreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link tothe Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Olson et al. BMC Cancer  (2018) 18:954 https://doi.org/10.1186/s12885-018-4859-7further supporting the argument that more robust dataon SABR efficacy and toxicity is needed [11].Given the lack of robust evidence supporting the useof SABR for oligometastases, BC Cancer (BritishColumbia, Canada) has decided it will not be offeredoutside of a clinical trial. The main focus of this trial isto assess the side effects and quality of life post-SABR ona population scale in BC, and to attain more precise esti-mates of the risk of late effects in long term survivors.This trial provides a clear informed consent process,including the limited evidence for SABR off trial, andpotential harm from SABR, for patients opting to pursueSABR for oligometastases or oligoprogression.Methods/designThis is a non-randomized phase II trial where all partici-pants will receive experimental SABR treatment to allsites of progressing metastatic disease. We will accrue200 patients to assess toxicity associated with thisexperimental treatment using standardize organ at risk(OAR) constraints (see Additional file 1). The study waspowered to give a 95% confidence on the risk of lategrade 4 toxicity, anticipating a < 5% rate of grade 4toxicity. All participants will be accrued with BC Cancer,at each of the 6 BC Cancer regional centres. This studyhas been approved by the joint UBC/BC Cancer ethicsboard. All data will remain confidential and storedwithin the BC Cancer network. Consent will be obtainedby a qualified investigator, who will also be a radiationoncologist who prescribes SABR clinically at BC Cancer.Written consent will be obtained.ObjectivesTo assess quality of life and side effects in patients withup to 5 newly diagnosed or progressing metastaticcancer lesions treated with a comprehensive oligometa-static SABR treatment program. Secondarily we willdocument the disease free and overall survival.Primary endpoints Patient Reported Outcomes, including quality of lifeand side effects Toxicity Assessed by the National Cancer InstituteCommon Toxicity Criteria (NCI-CTC) version 4 foreach organ treatedSecondary endpoints Progression-free survival Time from SABR treatment to disease progressionat any site or death Overall survival Lesion control rate, defined as lack of furtherprogression at the treated site Time to starting or re-starting chemotherapy Number of cycles of further chemotherapy/systemictherapyInclusion criteria Age 18 or older Able to provide informed consent Histologically confirmed malignancy with metastaticdisease detected on imaging. Biopsy of metastasis is preferred, but notrequired. Primary tumour treated radically or controlled byprior palliative radiotherapy or systemic therapy Maximum 5 metastases eligible for SABR (either 5in total or 5 not controlled by prior treatment) Standard of care tests prior to SABR CT simulationwithin 12 weeks: Brain CT or MRI imaging (for tumor sites withpropensity for brain metastasis) Body imaging: CT chest/abdomen/pelvis with bone scanrequired if no PET-CT is performed PET-CT is only required for specific evidence-based indications, and in such cases the CTneck/chest/abdomen/pelvis and bone scan arenot required: MRI spine for patients with vertebral orparaspinal metastases For other indications, at the discretion ofthe treating oncologists, PET-CT scans maybe done but are not required. Liver function tests (AST, ALT, GGT, alkalinephosphatase) for patients with liver metastases Tumor marker testing as appropriate(e.g. CEA for colorectal cancer, PSA for prostatecancer, etc) Pregnancy test for women of child-bearing age ECOG performance status 0–2 All sites of progressive disease can be safely treatedbased on criteria below For non-brainstem mets, maximum size of 3 cm ifusing single fraction radiosurgery. If size is from 3.1 to 4 cm, 25-35Gy/5 can beconsidered All brain mets cases need approval from StereotacticRadiosurgery rounds Maximum size of 6 cm for lesions outside thebrain, except: Bone metastases over 5 cm may be included, ifin the opinion of the local PI it can be treatedsafely (e.g. rib, scapula, pelvis)Olson et al. BMC Cancer  (2018) 18:954 Page 2 of 8 Life expectancy > 6 months In many scenarios this is best estimated by amultidisciplinary opinion from disease siteexperts, preferably obtainted at multidisciplinarytumours rounds. The potential treating SABR radiation oncologistreserves the right to require a multidisciplinarynote documenting life expectancy, othertreatment options and suitability for SABR. Not a candidate for surgical resection at all sites:surgery to all sites not recommended bymultidisciplinary team, or unfit or declining surgery. Not a candidate for an open randomized clinicaltrial comparing SABR and a standard treatment. Prior chemotherapy allowed but no chemotherapy(cytotoxic, immunotherapy or molecularly targetedagents) 48 h prior to first fraction of radiotherapy,during radiotherapy, or for 48 h after last fraction.Certain chemotherapy agents may require a longerbreak prior to or after SABR if protocols dictate.Hormonal therapy during SABR is allowed. Patients with metastases that have been previouslytreated may be eligible for this SABR protocol: If the previous treatment was systemic therapy,the patient may be eligible, if the metastases havedemonstrated a complete radiologic response If the previous treatment was by a local non-radiation means (e.g. prior resection, RFA ormicrowave ablation), then SABR may be consid-ered for residual/recurrent disease If the previous treatment was SABR, the patientis not eligible unless the new site(s) was/were notpreviously treated If the previous treatment was conventional RT,SABR could be considered if it can be deliveredsafely. In such a circumstance it must bepresented in a multidisciplinary setting forapproval.Exclusion criteria Serious medical co-morbidities precludingradiotherapy Bone metastasis in a femoral bone if risk of pendingfracture is high Patients with 1–3 brain metastasis and no diseaseelsewhere (these patients should not be accrued buttreated with stereotactic radiosurgery orradiotherapy as per results of publishedrandomized trials) Complete response to first-line chemotherapy(i.e. no measurable target for SABR) Persistent malignant pleural effusion Inability to treat all sites of progressing disease withablative intent Clinical or radiological evidence of spinal cordcompression Dominant brain metastasis requiring surgicaldecompression Pregnant or lactating womenEvaluationStaging/Testing within 12 weeks of accrual Brain CT or MRI imaging (for tumor sites withpropensity for brain metastasis) Body imaging: CT neck/chest/abdomen/pelvis with bone scanrequired if no PET-CT is performed PET-CT is only required for specific evidence-basedindications, and in such cases the CT neck/chest/ab-domen/pelvis and bone scan are not required: MRI spine for patients with vertebral or paraspinalmetastases Liver function tests (AST, ALT, GGT, alkalinephosphatase) for patients with liver metastases Kidney function tests (Creatinine, eGFR) for adrenaland kidney patients Pulmonary function tests for lung metastases Tumor marker testing as appropriate (e.g. CEA forcolorectal cancer, PSA for prostate cancer, etc) Pregnancy test for women of child-bearing ageAssessment ECOG status Charleson Comorbidity Index (CCI) Patient Reported Outcomes including Quality of Lifeassessment using BC Cancer’s ProspectiveOutcomes and Support Initiative [12] Provider Reported ToxicityInterventionAll patients accrued will be treated with ablative tech-niques (e.g. SABR or surgery) to all sites of active meta-static disease.Dose / fractionation / prescriptionThe Volume of the PTV receiving 100% of the prescrip-tion dose is equal to 95%.The Volume of the PTV receiving 90% of the prescrip-tion dose is greater than 99%.PTV coverage is secondary to OAR)constraints basedon clinical judgement. PTV coverage can be decreasedin order to meet OAR constraints. If the PTV coverageby 100% is < 50% of the PTV volume, then patients willOlson et al. BMC Cancer  (2018) 18:954 Page 3 of 8not be included in the study. Minimum dose to PTVshould be > 50% of prescribed dose.Immobilization Immobilization devices need to be approved by thepracticing Radiation Oncologist(s) and SABR physicsand dosimetry staff within the particular institution. It is left at the discretion of the treating RO/physicsto determine which immobilization device is to beused based on their centre/department specificpolicy.Pre-treatment simulation 4DCT should be acquired for tumors which arelikely to move from respiratory motion, such andlung, liver and adrenal sites. If 4DCT is not possible, 3DCT is acceptable The CT slices thickness should be no greater than3 mm, and pixel sizes should be no greater than1 × 1 mm. For Spine SABR, the CT slice thicknessshould be no greater than 2 mm (eg. 1.25 mm)Intravenous contrast may be used at the discretionof the treating radiation oncologist. Fiducial markers may be used at the discretion ofthe treating radiation oncologist. When available, 4DCT images should be sent toTreatment Planning System: Reconstructed CTs that display entire range ofmotion (e.g., 10 phases) MIP (Maximum Intensity Projection) MIN (Minimum Intensity: for bony lesions) Average CT if used for planning purposesTreatment volumesFor all lesions, the gross tumor volume (GTV) will bedefined as the visible tumor on CT and/or MRI imaging.When used for target definition, MRI and/or PETimaging should be registered with the planning CT. Formobile lesions (e.g. Lung and Liver tumours) an internalGTV (IGTV) or internal CTV (ITV) can be created asper site specific BC Cancer clinical protocols. A ClinicalTarget Volume (CTV) in general will not be used, exceptin liver and vertebral spine. For vertebral lesions, theCTV will be as per the BC Cancer spine SABR protocol,based on definitions of the Canadian Cancer TrialsGroup SC.24 protocol. A Planning Target Volume(PTV) margin of 2–5 mm will be added depending ondisease site and local immobilization and imageguidance practices: no less than a 2 mm margin may beused for spinal stereotactic treatments and brain tumors,and no less than a 5 mm margin for other sites. Forradiosurgery platforms, a PTV margin of 0–1 mm ispermitted. In situations where imaging or immobilizationmay be limited, > 5 mm margins may be considered fornon-spinal bone metastases.Organs at risk visible in the planning CT scan will becontoured.For spinal lesions, a pre-treatment MRI is required toassess the extent of disease and position of the cord.This must be fused with the planning CT scan. A Plan-ning Organ at Risk Volume (PRV) expansion of no lessthan 2 mm will be added to the spinal cord, and doseconstraints for the spinal cord apply to this PRV. Forradiosurgery platforms, a PRV margin of 1 mm is per-mitted for the spinal cord.Relevant organs at risk (OAR) The relevant OARs are dependent on the location ofthe target volume and should be outlined from thesimulation CT. As a general rule, critical structures within 5 cm ofthe PTV should be contoured. Please refer to the Additional file 1 for a list ofstructures that should be considered for differenttreatment sites.Treatment planning / techniqueTechnique 3DCRT, Intensity Modulated radioterhapy (IMRT),volumetric modulated arc therapy (VMAT) ordynamic conformal arcs delivery techniques areallowed. Flattening Filter Free (FFF) beams are encouraged Gating or Dynamic Tumour Tracking is allowedDose calculation algorithm Type II only (3D scatter correction dose algorthms,such as Eclipse AAA, Acuros, or Collapsed Cone) Inhomogeneity Corrections = ONDose grid resolution should be approximately equal tothe CT slice thickness, and no larger than 3 mm with ahigher resolution for Spine SABR.PTV prescription isodose The Volume of the PTV receiving 100% of theprescription dose is equal to 95 % “The Volume ofthe PTV receiving 90% of the prescription dose isgreater than 99 %” PTV coverage may becompromised to achieve dose constraints for criticalOARs at the discretion of the radiation oncologist,but PTV coverage by 100% dose must be > 50% The hotspot should be in the PTV and not in theadjacent normal tissue. The hotspot should generallyOlson et al. BMC Cancer  (2018) 18:954 Page 4 of 8be less than 150% of the prescription dose. For lunglesions, the hotspot should not exceed 167% of theprescription dose.OAR and Normal tissue dose constraints Please refer to Additional file 1 for the OAR doseconstraints. The dose distribution should conform to the PTV asmuch as possible. As a guideline for a single lunglesion, please refer to Additional file 1 for doseconformality indices. For multiple lung lesions, thespecified dose conformality indices might not beachievable.Treatment verification / imaging Collision Check: Recommended for all planscontaining non-coplanar beams Imageverification imaging must be acquired beforeall fractions (e.g. KV, MV, or CBCT). It is recommended that CBCT image guidance isused for all treatment fractions), s indicated in theTable 1 Post treatment fraction imaging should be applied toassess intrafraction motion. If treatment time is expected to exceed 45 min,mid-tx position verification should be performed.Quality assuranceThe contours of the GTV, IGTV, ITV, PTV and allrelevant OAR will be evaluated and signed off upon re-view by a second radiation oncologist. Dose volumehistogram parameters will be evaluated by the planningdosimetrist(s), physicist(s) and radiation oncologist(s).Institutional quality assurance rounds may also evaluatethe radiation plans and delivery of oligometastasesSABR. All plans must be independently verified withmeasurements and/or with quality assurance softwareused in the verification of SABR plans.Data and safety monitoring committeeThere is no independent data and safety monitoringcommittee (DSMC) for this study. The DMSC will bemade up of the study co-investigators. The DSMC willmeet twice annually after study initiation to reviewtoxicity outcomes. If any grade 3–5 toxicity is reported,the DSMC will review the case notes to determine ifsuch toxicity is related to treatment. If the DSMC deemsthat toxicity rates are excessive (> 25% grade 3 toxicity,or > 10% grade 4 or > 3% 5 toxicity), then the DSMCcan, at its discretion, recommend cessation of the trial,dose adjustment, or exclusion of certain treatment sitesthat are deemed as high-risk for complications.Follow-up scheduleSee Table 2 for follow-up schedule:Progressive diseaseParticipants who develop new, untreated metastaticdeposits could be considered for SABR at those sites, ifsuch deposits, or progression at previously stable sites,can be treated safely with SABR. If SABR is not possible,then palliative RT can be delivered if indicated.Participants who have 1st progression at treated sites ordevelop new, untreated metastatic deposits, or progressionat previously stable sites, will undergo re-staging with CTsand bone scans at the discretion of treating oncologist.Follow-up evaluations and questionnaire completions willbe based on schedule 13.1. However, it can be changed atstudy doctor’s discretion. The questionnaires may be donevia mail or telephone call.Patient Reported Outcomes will be collected using thequestionnaires chosen from BC Cancer’s ProspectiveTable 1 Dose and fractionations by site with [secondary options in square brackets]Tumor Location Description Total Dose (Gy) Number of fractions Dose per fraction (Gy) FrequencyLung Tumors 5 cm or less surroundedby lung parenchyma48 [54] 4 [3] 12 [18] Every second dayWithin 2 cm of mediastinum orbrachial plexus60 8 7.5 DailyBone Any bone 35 Gy [24] 5 [2] 7 [12] DailyBrain Stereotactic lesions(no whole brain RT)< 2 cm 24 1 24 Once2–3 cm 18 1 18 Once3-4 cm 15 1 15 OnceIf whole brain treated, thensimultaneous boost to each lesion35Gy to metastases 20 Gywhole brain (optional)5 7 Gy to PTV4 Gy WBRTDailyLiver 54 Gy 3 18 Every second dayAdrenal 60 Gy 8 7.5 dailyLymph Node 40 Gy 5 8 dailyOlson et al. BMC Cancer  (2018) 18:954 Page 5 of 8Outcomes and Support Initiative (POSI: H14–00647)based on body site being treated which is part of stand-ard clinical care, and therefore not outlined in detailhere for the trial. For body sites not yet supported byPOSI, we will using the Functional Assessment ofCancer Therapy (FACT) quality of life questionnairesthat correspond to the tumour site(s) being treated.Physician/registered nurse/other reported outcomes ECOG performance status Outcomes Next local therapy or chemo-/targeted-therapystart date Date of relapse or new metastases Date of death CTCAE version 4.0 toxicity.Measurement of response Survival outcomes: Overall survival will be measuredas time until death from any cause, and progression-free survival as time to either progression or death,whichever occurs first. Lesion control rate will be assessed retrospectivelyas RECIST criteria has not been validated in thesetting of SABR, and is costly to implement in aprospective cohort.Study endpoints and stopping rulesThis study with a sample size of 200 patients has limitedpower to detect an increased incidence of adverse eventsreactions and complicates (see Tables below). For thisreason, the trial’s power is augmented by a Data and SafetyMonitoring Committee (DSMC), which is bound by rulesthat require the suspension/termination of a trial accrualunder certain events as outlined below in Tables 3 and 4.The primary objective of this study is to assess toxicitypost SABR for oligometastases. If any grade 5 SAEsdefinitely, probably, or possibly related to protocol treat-ment occur, all co-investigators will be made awarewithin 1 week of reporting to the principal investigator(PI), and a DSMC meeting will be held within 1 monthof the event. During this time, any other patients ontreatment to the same body site where the grade 5toxicity was interpreted to originate, (e.g. adrenal metas-tases) will have their plan reviewed by the PI to deter-mine if that patients’ treatment should be put on holdprior to DSMC meeting.If 3 or more grade 5 SAEs meet the definition ofunanticipated problem (i.e. unexpected, related andinvolving greater risk occur during this study, thestudy will be temporarily put on hold in order toorganize a DSMC meeting and initiate conversationswith the BCCA/UBC REB. Depending on the resultsof these meetings the study may be permanentlyclosed or significant modifications may be made andre-reviewed by the research ethics board (e.g. removetreatments of adrenal metastases from the study, orTable 2 Evaluation summaryDay Tests and ProceduresEvery 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 questionnaireBlood tests for certain sites (i.e. liver function tests for patients with liver metastases)Assessment of any side effects or adverse eventsMonths 3, 6, 12, 18, and 24 CT scan(s) and/or other imaging (MRI, PET or bone scan)aEvery 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 eventsa imaging is optional for prostate cancer patients with PSA < 5Table 3 Probabilities for exact # of grade 4 toxicity events given true rate of grade 4 toxicities =5%, 4%, 3%, 2% for a sample size = 200# of grade 4toxicity events outof a sample size = 200Probability of exact # of grade4 toxicity events given truerate of grade 4 toxicities = 5%Probability of exact # of grade4 toxicity events given truerate of grade 4 toxicities = 4%Probability of exact # of grade4 toxicity events given truerate of grade 4 toxicities = 3%Probability of exact # of grade4 toxicity events given truerate of grade 4 toxicities = 2%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%Olson et al. BMC Cancer  (2018) 18:954 Page 6 of 8reducing the dose, if toxicity was from this body parttreatment with SABR).For the purpose of reporting this study, we will defineSABR for oligometatases to be reasonable safe with thefollowing a priori endpoints. We will report the 95%confidence interval (see table above) that the upperconfidence is equal to or lower than. In other wordstoxi-cities (with sample size of 200) we have 95% confidencethe toxicity (whatever grade) is < 5% or lower. Likewise,with 6 toxicities, we have 95% confidence the toxicity isless than 6%. < 5% grade 5 toxicity < 10% grade 4 toxicity < 25% grade 3 toxicityNote: Due to attrition from death caused by progres-sion, we anticipate the number at risk beyond a year forlate events will be 100 cases, if 200 are accrued, andtherefore we have provided numbers to demonstrate theestimates of our confidence, which is dependent on thenumber of patients alive at specific time points.DiscussionThis phase II trial is unique, in that SABR in BC duringthe study era is only allowed on study protocol, and there-fore the analysis will be population-based. This will allowfor a more accurate assessment of toxicity assessments,relatively free from selection bias. It is anticipated that thistrial, in combination with results from upcoming random-ized phase II trials [13, 14], will lead to randomized phaseIII trials, where efficacy can be properly assessed.Additional fileAdditional file 1: Dose constraints used for SABR-5 trial. These are basedon the AAPM TG 101, SABR-COMET, SC-24 trials as well as most updated ref-erences. If any structure is not listed, the constraints may be calculated usingthe linear quadratic formula from accepted QUANTEC doses, using analpha-beta ratio of 3 (except neural structure: alpha-beta of 2) for late effects.(DOCX 134 kb)AbbreviationsCTV: Clinical target volume; DSMC: Data & safety monitoring committee;GTV: Gross tumor volume; IGTV: Internal gross tumor volume; IMRT: Intensitymodulated radiotherapy; ITV: Internal clinical tumor volume; NCIC-CTC: NationalCancer Institute Common Toxicity Criteria; OAR: Organs at risk; PTV: Planningtumor volume; SABR: Stereotactic ablative radiotherapy; SAE: Serious adverseevents; VMAT: Volumetric modulated arc therapyAcknowledgementsWe would like to acknowledge the many radiation oncologists who arecurrently accruing patients on this trial.FundingRO received partial funding from the Michael Smith Foundation for HealthResearch. The funders have no role in the design of the study and collection,analysis, interpretation of data, or writing of the manuscript.Availability of data and materialsData will be stored for at least 5 years from end of study, and is availableafter research ethics board approval from the corresponding author onreasonable request.Authors’ contributionsRO is the principal investigator, and oversaw all aspects of study design anddelivery. ML and AB supervised the OAR table creation and editing. SL is thestudy coordinator, and oversaw the data entry form creation and databasedesign. FH, BM, TB, CL, DG, HP, HC, BV, SL, ST, and DS are radiationoncologists who made substantial contributions to the study design. AM,NC, DH, QM, PB are medical physicists who made substantial contributionsto the study design, specifically in the quality assurance and radiotherapyplanning sections. All authors have reviewed and approved this manuscript.Ethics approval and consent to participateThis study was approved by the University of British Columbia ResearchEthics Board. This manuscript presents Version 5, April 17, 2018. Allamendments have been, and will continue to be communicated to allqualified investigators by the Principal Investigator, RO, or his designate, SL.Written consent will be obtained from participants.Consent for publicationNot applicable.Competing interestsThe authors declare that they have no competing interests.Publisher’s NoteSpringer Nature remains neutral with regard to jurisdictional claims inpublished maps and institutional affiliations.Author details1University of British Columbia, Vancouver, Canada. 2Unviersity of NorthernBritish Columbia, Prince George, Canada. 3BC Cancer – Prince George, 1215Lethbridge Street, Prince George, BC V2M7A9, Canada. 4BC Cancer –Vancouver, Vancouver, Canada. 5BC Cancer – Abbotsford, Abbotsford,Canada. 6BC Cancer – Kelowna, Kelowna, Canada. 7BC Cancer – Victoria,Victoria, Canada. 8BC Cancer – Surrey, Surrey, Canada.Received: 30 August 2018 Accepted: 26 September 2018References1. Hellman S, Weichselbaum RR. Oligometastases. JCO. 1995;13:8–10.2. MacDermed DM, Weichselbaum RR, Salama JK. A rationale for the targetedtreatment of oligometastases with radiotherapy. J Surg Oncol. 2008;98:202–6.3. Pastorino U, Buyse M, Friedel G, et al. Long-term results of lungmetastasectomy: prognostic analyses based on 5206 cases. J ThoracCardiovasc Surg. 1997;113:37–49.Table 4 95% confidence interval for true rate of toxicities withsample size = 200# of grade 4 toxicity events Upper limits of one-sided 95%confidence interval for true rateof grade 4 toxicities (sample size = 200)0 1.5%1 2.3%2 3.1%3 3.8%4 4.5%5 5.2%6 5.8%Olson et al. BMC Cancer  (2018) 18:954 Page 7 of 84. Primrose J, Treasure T, Fiorentino F. Lung metastasectomy in colorectal cancer:is this surgery effective in prolonging life? Respirology. 2010;15:742–6.5. Treasure T, Fallowfield L, Lees B, et al. Pulmonary metastasectomy incolorectal cancer: the PulMiCC trial. Thorax. 2012;67:185.6. Milano MT, Katz AW, Schell MC, et al. 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Olson RA, Howard F, Lapointe V, Schellenberg D, Nichol A, Bowering G,Curtis S, Walter A, Brown S, Thompson C, Bergin J, Lomas S, French J,Halperin R, Tyldesley S, Beckham W. Provincial development of a patient-reported outcome initiative to guide patient care, quality improvement, andresearch. Healthc Manage Forum. 2018;31(1):13–7.13. Palma D, Haasbeek C, Rodrigues G, Dahele M, Lock M, Yaremko B, Olson R,Liu M, Panarotto J, Griffioen G, Gaede S, Slotman B, Senan S. Stereotacticablative radiotherapy for comprehensive treatment of oligometastatictumors (SABR-COMET): study protocol for a randomized phase II trial. BMCCancer. 2012;12(1):305.14. Palma D, Olson R, Harrow S, Gaede S, Haasbeek CJA, Mulroy L, Lock M,Rodrigues G, Yaremko B, Schellenberg D, Belal A, Griffioen G, Sashendra S,Swaminath A, Kopek N, Liu M, Bauman G, Moore K, Currie S, Louie A, SenanS. Stereotactic ablative radiotherapy versus standard-of-care palliativetreatment in patients with oligometastatic cancers (SABR-COMET): arandomized, phase II, open-label trial. The Lancet. 2018; under revision.Olson et al. BMC Cancer  (2018) 18:954 Page 8 of 8


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