CADTH Health Technology Review

Stereotactic Ablative Radiotherapy for the Treatment of Oligometastatic Cancer: A Clinical Review as Part of a Health Technology Assessment

This is the baseline clinical review for a living systematic review. Please see the CADTH project page to access the latest version of the report and for the version history

Clinical Review

Authors

Clinical Review

Dr. Chantelle C. Lachance, PhD, (CADTH) led the protocol development for the clinical review; screened and selected studies; extracted, critically appraised, and interpreted data; contributed to synthesis; wrote the clinical review; revised the review based on reviewers’ feedback; and provided final approval of the version of the report submitted for publication.

Dr. Khai Tran, PhD, (CADTH) assisted with protocol development for the clinical review; screened and selected studies; extracted, critically appraised, and interpreted data; contributed to synthesis; contributed to the preparation of the clinical review; and provided final approval of the version of the report submitted for publication.

Elizabeth Carson, MSc, (CADTH) contributed to protocol development for the clinical review; provided methodological oversight and support; provided critical review of the contents of the report; and provided final approval of the version of the report submitted for publication.

Dr. Joanne Kim, PhD, (CADTH) contributed to the study design during protocol development for the clinical review; provided methodological oversight and support; provided critical review of the contents of the report; and provided final approval of the version of the report submitted for publication.

Dr. David Palma, MD, MSc, PhD, FRCPC, (London Health Sciences Centre, Schulich School of Medicine & Dentistry, University of Western Ontario) provided clinical expert opinion throughout the duration of the review, helped interpret data, and reviewed draft reports.

Dr. Shaun Loewen, MD, PhD, FRCPC, (Tom Baker Cancer Centre, Cumming School of Medicine, University of Calgary) provided clinical expert opinion throughout the duration of the review, helped interpret data, and reviewed draft reports.

Patient Engagement

Tamara Rader, MLIS, (CADTH) led patient engagement activities, wrote the summary of those activities included in the report, and provided final approval to the version of the report submitted for publication.

Research Information Science

Danielle MacDougall, MLIS, (CADTH) designed and executed the literature search strategies, wrote the literature search methods section and appendix, and managed the report referencing.

Caitlyn Ford, MLIS, (CADTH) designed and executed draft literature search strategies and assisted with designing final search strategies.

Contributors

The authors are grateful to Michelle Clark, Program Officer, for her involvement in detailed scoping for this project; Diksha Kumar, for contributing to screening and selection of studies; Brit Cooper-Jones, for leading knowledge mobilization activities; Paula Murray, Project Management Officer, for project management support; David Kaunelis, Research Information Specialist – Methods, for his assistance with the literature search methodology; Dr. Matthew Bryan, Scientific Advisor, for statistical support; Dr. Laura Weeks, Director, Health Technology Assessment and Program Development, for her methodology support and project oversight; and Chris Kamel, Director, Health Technology Assessment and Rapid Response, for his feedback on the protocol for this report. Further, we would like to thank the patient volunteer who shared their insights into and experiences of oligometastatic cancer and treatment with stereotactic ablative body radiotherapy confidentially; and the stakeholders who submitted feedback on the draft report.

External Reviewer

Dr. Rathod kindly provided comments on a draft version of this report.

Dr. Shrinivas Rathod, MBBS, MD, FRCPC

CancerCare Manitoba, University of Manitoba

Winnipeg, Manitoba

Conflicts of Interest

There are no conflicts of interest to declare relevant to this report.

Summary

Key Messages

• Oligometastatic cancer (cancer with a limited number of metastases) represents an intermediate state between cancer confined to a single location in the body and cancer that has metastasized — or spread — widely.

• One treatment option, for which there is growing interest, is stereotactic ablative radiotherapy, also known as SABR.

  • SABR precisely delivers a high dose of radiation to ablate tumours at specific sites while minimizing the radiation dose to surrounding normal tissues.

  • SABR may be used independently or alongside other treatment options in the management of oligometastatic cancer.

• This CADTH clinical review evaluated the evidence regarding the clinical effectiveness and safety of SABR with or without standard of care (SOC) for people with oligometastatic cancer and found the following:

  • SABR in addition to SOC may offer a benefit in terms of overall survival (OS) and progression-free survival (PFS).

  • The findings for the effectiveness of SABR alone compared with SOC were mixed and deemed inconclusive.

  • There are insufficient data related to adverse events (AEs) at the present time to draw conclusions regarding the safety of SABR relative to SOC alternatives.

• Note that this is the baseline report of a living systematic review (LSR) that is being updated every 3 months to ensure the findings remain up to date as new evidence emerges. Please refer to the CADTH project page for the latest version of the report and for the version history.

Abstract

Context and Decision Problem(s)

Oligometastatic cancer (cancer with a limited number of metastases) represents an intermediate state between cancer confined to a single location in the body and cancer that has metastasized — or spread — widely. Treatment options for oligometastatic cancer may include surgery, conventional radiotherapy, or systemic therapy, depending on factors such as the type, location, and ease of access of each lesion. SABR is an additional treatment option for which there is growing interest. SABR precisely delivers a high dose of radiation to ablate tumours at specific sites while minimizing the radiation dose to surrounding normal tissues. SABR may be used independently or alongside other treatment options in the management of oligometastatic cancer.

While interest in the use of SABR for oligometastatic cancer is high, there remain key questions. What is the clinical effectiveness and safety of SABR for patients with oligometastatic cancer? What would form appropriate patient selection criteria and what would be the optimal dose or regimen? What is the cost-effectiveness of SABR, and what are the key implementation considerations? The purpose of this CADTH Health Technology Assessment (HTA) was to address these questions, starting with a review of the clinical evidence, which is presented here.

Clinical Effectiveness and Safety Evidence

Because the evidence on SABR for oligometastatic cancer is rapidly evolving, CADTH is using a “living systematic review” (LSR) format for the clinical review. The status of the LSR is being updated every 3 months to ensure the findings reflect the latest up-to-date evidence on the topic.

CADTH compared SABR plus SOC with SOC alone, and compared SABR alone with SOC alone, for people with oligometastatic cancer. Outcomes identified as important by patient and clinical expert input were OS, PFS, and AEs. Additional outcomes of interest included freedom from progression, health-related quality of life (QoL), lesional control (LC), and systemic therapy use after treatment.

A total of 3 randomized controlled trials (RCTs) and 6 nonrandomized studies were identified. The findings suggested there may be OS and PFS benefits associated with SABR plus SOC compared with SOC alone. However, the findings from the studies comparing SABR alone with SOC were mixed and deemed inconclusive. With regard to AEs, there are limited available data to assess whether SABR with or without SOC is more or less harmful than SOC alone. There was a lack of literature identified to inform conclusions for other outcomes of interest.

Conclusions and Implications for Decision- or Policy-Making

The current clinical evidence suggests that SABR plus SOC may offer survival benefits for patients with oligometastatic cancer. To inform patient selection criteria, future research on the effectiveness of SABR in patients with different characteristics would clarify who might benefit most from this treatment. Evidence on the optimal regimen or dose of SABR for the treatment of oligometastases is also needed. Additional studies are expected to be identified during the LSR phase of this project. Finally, this clinical review represents 1 component among many that decision-makers will consider when making the decision about the expanded use of SABR in Canada. CADTH is currently undertaking an Environmental Scan of implementation considerations that will contribute to this HTA to further support decision-making.

Introduction

Background and Rationale

Cancer and Oligometastatic State

Cancer is the leading cause of death in Canada, comprising 30% of all death events.³ In 2020, there will be an estimated 225,800 new cancer cases and 83,300 deaths.³ Tumour metastasis is the main cause of cancer-related death.^4-6 The development of metastases is a potential complication among patients with cancer.⁷ Metastasis occurs when cancer cells, originating from 1 part of the body, move from the place of origin (primary tumour) and spread to another location to form 1 or more tumours.^4,7 The extent of systemic disease and the number, size, and location(s) of lesions can affect the overall prognosis for a patient.⁸

In 1995, Hellman and Weichselbaum first introduced the term oligometastatic state and proposed that the process of cancer metastasis occurs along a continuum — from localized to widespread metastatic disease.^9,10 Oligometastases may represent a paradigm shift in the treatment intent for metastatic cancer: if a limited number of metastases can be treated, then the outcome may be curative.¹¹ Hellman and Weichselbaum described 2 different clinical scenarios that would both be considered oligometastases “tumours early in the chain of progression with metastases limited in number and location;” and “patients with oligometastases who had widespread metastases that were mostly eradicated by systemic drugs, the chemotherapy having failed to destroy those remaining because of the number of tumour cells, the presence of drug-resistant cells, or the tumour foci being located in some pharmacologically privileged site.”⁹ Moreover, as these 2 classes of oligometastases represent different clinical scenarios, they are associated with different prognoses and may also require different treatments.¹² Current definitions of oligometastatic disease in the literature are heterogeneous, although the European and American societies for radiotherapy and oncology recently published a consensus definition as 1 to 5 metastatic lesions, with control of the primary tumour being optional but where all metastatic sites must be safely treatable.¹³

Since the publication of this seminal paper by Hellman and Weichselbaum,⁹ the concept of oligometastasis has been generally accepted; however, specific criteria that define an oligometastatic state, such as the number of metastases and organ sites, are still unclear.^12,14 Oligometastasis includes situations where the primary tumour is present, not present (i.e., removed), treated, or untreated; therefore, a patient can have oligometastases regardless of the state of the primary tumour.¹⁵ Moreover, patients can be described as having synchronous oligometastatic disease (maximum 6-month interval between the diagnosis of oligometastatic disease and the primary cancer diagnosis) and metachronous oligometastatic disease (more than a 6-month interval between the diagnosis of oligometastatic disease and the primary cancer diagnosis).¹² Imaging is currently the most relevant diagnostic method for defining oligometastatic cancer, which is broadly understood as a limited number of metastatic lesions.^12,16

Stereotactic Ablative Radiotherapy

Treatment options for patients presenting with oligometastatic cancer may include, but are not limited to, surgery, conventional radiotherapy, systemic therapy (e.g., chemotherapy, hormone therapy), observation, and ablative therapies such as cryoablation, microwave ablation, radiofrequency ablation, and SABR.^11,17-19 SOC is variable according to the type of cancer. The notion of using targeted therapies such as surgery or radiation therapy to eliminate oligometastatic disease has been termed metastasis-directed therapy or local consolidative therapy.^9,20,21 Metastasis-directed therapy has been shown to improve survival relative to SOC (observation or maintenance systemic therapy) in RCTs of patients with oligometastatic prostate cancer²² and non–small cell lung cancer.²¹ In those studies, the choice of surgery or radiation therapy, particularly SABR, was determined by the multidisciplinary team and patient characteristics. Though there are multiple treatment options within the class of metastasis-directed therapies, and surgical resection is considered the gold standard for the treatment of certain oligometastases (e.g., partial liver resection for metastases from colorectal cancer), SABR may be an alternative non-invasive treatment option for achieving LC.¹⁷

SABR, also known as stereotactic body radiation therapy (SBRT), is a method of precisely delivering high doses of radiation to ablate tumours at specific sites while sparing radiation dose to surrounding normal tissue.^23-25 First developed in Sweden in the early 1990s,²⁶ SABR builds on the treatment delivery paradigm used to treat brain tumours with intracranial stereotactic radiosurgery, but it targets tumours outside of the brain (e.g., lungs, liver, bone, and lymph nodes).²³ SABR relies on an imaging component to map the treatment area using CT (CT) scans or MRI (MRI), tumour motion reduction, and reproducible patient set-up strategies (e.g., respiratory compression, body immobilization devices [e.g., alpha-cradle or vacuum-lock system]), and advanced radiotherapy-delivery techniques using conventional linear accelerators or novel precision delivery systems.²³ Newer technology with the potential for application in this area includes C-arm S-band linear accelerator systems, robotic X-band CyberKnife, image-guided Gamma Knife Icon system, proton-based applications, and MR Linac.^27,28 SABR is considered an alternative to surgical resection and is often the preferred option for patients with cancer that is medically inoperable. Treatment advantages include limited recovery time before resuming systemic therapy and the ability to treat areas with metastatic involvement that are either not surgically accessible or include more than 1 organ, or patients at high risk of post-operative complications.¹²

SABR in Canada

The availability of SABR has increased across Canada. In 2014, a survey of 41 Canadian radiotherapy centres reported that 5 provinces (British Columbia, Alberta, Manitoba, Ontario, Quebec) had centres with SABR capacity and substantial growth was expected.²⁹ Currently, all provinces in Canada have SABR capability.³⁰ SABR is also available in some northern centres (e.g., Northeast Cancer Centre in Ontario).³¹ Canadian centres are using SABR to treat primary tumours and oligometastases in different areas of the body, such as the lungs, liver, bone, and lymph nodes.^29,32 However, there is variation in patient selection criteria for SABR treatment across radiotherapy centres, and not all centres offer SABR for the treatment of oligometastases.²⁹

CADTH received input from Canadian jurisdictions that identified several common considerations regarding the use and implementation of SABR for oligometastatic cancer. There is a desire to determine the appropriate use of SABR across Canada regarding which patients should be treated with SABR to achieve the greatest benefit (e.g., location and number of metastases) and how those patients should be managed (e.g., radiation dose fractionation, treatment sites, immobilization methods, tumour-tracking methods, and image guidance strategies). Decision-makers are also seeking more information regarding the long-term outcomes of treatment with SABR. In addition to patient treatment and management, jurisdictions expressed interest in gathering information regarding the implementation of the technology, including how other jurisdictions have successfully operationalized the use of technology for oligometastatic cancer (e.g., billing codes, time to treatment, length of individual treatment sessions, staffing), and in a review of resource and infrastructure considerations (e.g., requirements for additional staff training, software, or equipment upgrades). An understanding of patients’ and clinicians’ perspectives (e.g., acceptability, feasibility) and ethical considerations (e.g., a shifting risk-benefit profile compared with standard care) will also become salient if expanded use of SABR is pursued. Equity issues relating to accessing SABR as a result of the specialized nature of therapy and its delivery in urban centres may also emerge. All of the jurisdictions that responded expressed an interest in an economic analysis of the expanded use of this technology.

Moreover, the use of SABR for the ablation of oligometastases is an active area of research. Specifically, a 2019 paper identified 64 ongoing studies examining SABR for oligometastatic cancer.³³ In the summer of 2016, the National Health Service (UK) produced a policy document stating that it would not routinely commission SABR for oligometastatic cancer, given there was inconclusive evidence to support the provision of treatment.³⁴ However, recently identified evidence has suggested the potential for improved health outcomes, such as OS and PFS, with the use of SABR for oligometastases.³⁵ A CADTH HTA is warranted for critically reviewing the current evidence of SABR in the treatment of patients with oligometastatic cancer.

Decision Problem

Based on the context, jurisdictional feedback, and results of a detailed scoping exercise, the aim of a CADTH HTA on this topic was to inform the following decision problem:

• Should the use of SABR be expanded to include the treatment of patients with oligometastatic cancer?

  • If so, what are the appropriate patient selection criteria?

  • If so, what is the optimal regimen or dose?

• What is the value for money and affordability of SABR for oligometastatic cancers?

• What are the main challenges to and enablers of the implementation of SABR in Canada?

Objective

The clinical evidence regarding SABR is still developing; therefore, a staged approach to this HTA was followed, as proposed in the Scoping Brief.¹ CADTH first conducted a clinical review using systematic review methods to synthesize and critically appraise the current evidence of SABR for the treatment of patients with oligometastatic cancer. An Environmental Scan is also being conducted to explore considerations for the implementation of SABR for this purpose.

The scoping review did not identify any qualitative literature on the topics of oligometastatic cancer or SABR. Given the paucity of published evidence, engaging directly with patients who have experience with SABR is a more relevant method for capturing patients’ experiences with this health technology.

Similarly, the scoping review did not identify any literature reporting ethical considerations related to the use of SABR for the treatment of oligometastatic cancer. Ethical considerations were acknowledged and discussed among the broader review team, such as the potential to exacerbate existing equity considerations regarding access to cancer treatments, and the aforementioned challenges in defining an oligometastatic state. However, in consultation with ethics experts and in the absence of published literature, it was determined that a full ethical analysis would not be warranted.

As previously noted, jurisdictions have expressed an interest in an economic analysis of the expanded use of SABR for oligometastatic cancer. At the time of the protocol development in 2020, CADTH was aware of several Canadian groups conducting analyses addressing the economic considerations regarding the use of SABR for the treatment of oligometastatic cancer. To avoid duplication of effort, CADTH will monitor ongoing Canadian economic analyses and attempt to broker existing work to meet the economic evidence needs of stakeholders.

The objective of this report is to address the decision problem by assessing the clinical effectiveness and safety of SABR in the treatment of patients with oligometastatic cancer through a systematic review of the literature. As the clinical evidence regarding SABR is still developing and there are several ongoing clinical trials, CADTH will use an LSR approach to regularly update the review. The deliverable for this report is the baseline review of an LSR of the clinical evidence. The results of the Environmental Scan will be incorporated in the report upon subsequent updates to this review. An analytical framework (Figure 1) guiding the clinical review can be found in Appendix 1.

Research Questions

This clinical review addressed the following research questions:

1. What is the clinical effectiveness of SABR alone or in combination with other therapies for the treatment of patients, of any age, with oligometastatic cancer?

2. What is the safety of SABR alone or in combination with other therapies for the treatment of patients, of any age, with oligometastatic cancer?

Opportunities for Stakeholder Feedback

Stakeholders (i.e., clinicians, policy-makers, researchers, health associations) have been given the opportunity to provide feedback on the draft of the list of included studies and a draft report of the baseline clinical review. No unpublished data were identified as part of the feedback process. Additionally, CADTH will periodically (e.g., annually) seek input from decision-makers in Canadian jurisdictions to determine whether there is continued interest in this topic to inform whether to maintain or transition the review out of living mode.

Methods

The conduct of the clinical review was informed by a CADTH Rapid Response report,³⁶ an informal scoping review of the existing literature (Scoping Brief),¹ discussion with clinical experts, and patient engagement. A protocol³⁷ was written a priori, using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Protocols (PRISMA-P)³⁸ for guidance on clarity, transparency, and completeness, and the protocol was followed throughout the study process. Any deviations from the prospectively registered protocol were disclosed in the final report (Table 1: Protocol Amendments) and updates were made to the PROSPERO submission accordingly (registration number: CRD42020167767).

Study Design

This clinical review was designed as an LSR to answer research questions 1 and 2, enabling continual surveillance and updates to the analysis contingent on following a priori stopping rules (see Project Protocol³⁷ for more details). The LSR model will allow for ongoing assessment of the clinical effectiveness and safety of SABR, and the incorporation of the results from several ongoing clinical trials identified during the scoping process with expected completion dates ranging from the year 2020 through 2029 as well as the results of any other relevant trials or studies that may be currently under way.

This review aims to comprehensively explore the clinical effectiveness and safety of SABR for oligometastatic cancer for different primary tumours and any metastatic sites amenable to SABR, as outlined in research questions 1 and 2. Specifically, CADTH decided to conduct an LSR in consideration of the methods outlined in the Cochrane Handbook for Systematic Reviews of Interventions.³⁹

This report presents the baseline review for the LSR, which is in keeping with the same core methods and review steps as a standard systematic review. Thus, standard systematic review methods (e.g., screening, data extraction, risk-of-bias assessment) were followed. The clinical review is now considered in living mode with the publication of this baseline review. Details on the updating and ending of the LSR can be found in the protocol.³⁷

Literature Search Methods

The literature search for clinical studies was performed by an information specialist using a peer-reviewed search strategy according to the PRESS Peer Review of Electronic Search Strategies checklist (www.cadth.ca/resources/finding-evidence/press).⁴⁰ The complete search strategy is presented in Appendix 2.

Published literature was identified by searching the following bibliographic databases: MEDLINE All (1946‒) through Ovid, Embase (1974‒) through Ovid, and the Cochrane Central Register of Controlled Trials (CENTRAL) through Ovid. The search strategy comprised both controlled vocabulary, such as the National Library of Medicine’s MeSH (Medical Subject Headings), and keywords. The main search concepts were SABR and oligometastatic cancer. The following clinical trial registries were searched: the US National Institutes of Health’s clinicaltrials.gov, the Health Canada Clinical Trials Database, and the Canadian Cancer Trials Database.

No filters were applied to limit the retrieval by study type. Retrieval was limited to publications published between January 1, 1990 and March 20, 2020. Conference abstracts were excluded from the search results, though they were reviewed by clinical team members for forecasting purposes.

The initial search was completed on March 20, 2020. Monthly alerts were conducted until the end of the stakeholder feedback period for the baseline review (January 18, 2021). Since then, alerts are run every 3 months to support the LSR phase of the HTA. The clinical trial registries search was updated before the completion of the stakeholder feedback period for the baseline review. Following the completion of the baseline report, the clinical trial registries search will be updated every 6 months.

Grey literature (literature that is not commercially published) was identified by searching sources listed in relevant sections of the Grey Matters: A Practical Tool for Searching Health-Related Grey Literature checklist (www.cadth.ca/grey-matters),⁴¹ which includes the websites of regulatory agencies, HTA agencies, clinical guideline repositories, systematic review repositories, patient-related groups, and professional associations. Google was used to search for additional internet-based materials. These searches were supplemented through contacts with experts, as appropriate. The grey literature search was updated before the completion of the stakeholder feedback period. Grey literature will be updated every 6 months during the LSR phase of the HTA. See Appendix 2 for more information on the grey literature search strategy.

Selection and Eligibility Criteria

Studies were included if they met the eligibility criteria, including the specific population, intervention, comparators, and outcomes (PICO), presented in Table 2. The inclusion criteria were informed by the CADTH Rapid Response report,³⁶ the informal scoping review of the existing literature,¹ patient engagement, and consultation with clinical experts.

For this clinical review, the population of interest was patients with oligometastatic cancer, described by study authors as having limited metastatic lesions using terminology such as “oligo,” “limited,” or “few.” Studies that did not state clearly that the patient population was restricted to or included oligometastatic patients were excluded. Oligometastasis includes situations where the primary tumour is present, not present (i.e., removed), treated, or untreated.¹⁵ Since a participant can have oligometastases regardless of the state of the primary tumour, the status of the primary tumour was not part of the eligibility criteria.¹⁵ Moreover, this review included patients with an imaging-based diagnosis of a limited number of metastases identified at presentation or before initial therapy, or a limited number of metastases identified after initial therapy of the primary tumour, or a metastatic relapse of a limited number of metastases where initial metastatic sites are controlled or resolved, or a known metastatic site that responded to previous treatment (local treatment or systemic treatment or both) that showed interval growth (or regrowth) with or without a systemic-free interval.^12,44-47 Studies of patients with a history of widespread metastatic disease (i.e., patients with induced oligometastatic cancer, including induced oligoprogression and induced oligopersistence) were excluded based on clinical expert input indicating that the nature of their disease progression is clinically different than the intended oligometastatic population for this review.¹² Studies that included patients with a history of metastases but did not report enough detail to determine whether this represents a history of oligometastasis (i.e., limited or few metastases) versus a history of widespread metastatic disease were also excluded. Studies with mixed populations (i.e., comprising both individuals who met and those who did not meet the eligibility criteria) were considered eligible for inclusion if the results pertaining to the population of interest were reported separately.

The intervention of interest was SABR (synonym: SBRT), with or without 1 or more concurrent or neoadjuvant therapies. Stereotactic radiosurgery for brain-only metastases was excluded, as ablative therapy to the central nervous system is more clinically established and not the focal area of interest for this HTA.⁴⁸ Studies of metastasis-directed therapy that did not report results specific to SABR were also excluded. For instances where the intervention was SABR in combination with 1 or more concurrent or neoadjuvant therapies, the study was eligible for inclusion if the comparator also included the same concurrent or neoadjuvant therapies to explore the true effects of SABR.

For the clinical effectiveness outcomes for research question 1, the data at all time points as reported in the included studies were included, but different time points were not combined. In cases where studies used more than 1 tool to assess health-related QoL, all data were included. The “systemic therapy use” outcomes were meant to explore whether there was a difference in the need for systemic therapy subsequent to treatment with SABR (e.g., in terms of the number of cycles or total duration of systemic therapy) compared with the use of systemic therapy in patients who do not receive SABR.

For the safety outcomes for research question 2, data that allowed for comparisons between the intervention and comparator groups were of interest and included, irrespective of the tools used to measure or describe the AEs (e.g., frequencies or prevalence of individual or grades of AEs [e.g., grades 1 to 2 versus grades 3 to 5] reported for each group were in scope, but non-quantifiable lists of AEs for both groups were not in scope).

If there were multiple publications fulfilling the inclusion criteria from the same study (i.e., same population), all publications were included; in those cases, data from multiple publications were extracted and discussed as 1 single study.

Study Selection

Study selection was conducted using the systematic review management software DistillerSR (Evidence Partners, Ottawa, Canada). Two reviewers independently screened titles and abstracts of all retrieved citations (i.e., literature searches of academic databases, clinical trial registries, grey literature searches, citations identified by clinical content experts, and stakeholder feedback) against the eligibility criteria (Table 2). Exclusion by both reviewers was required for a record to be excluded at the title and abstract level. Articles that were judged to be potentially relevant by at least 1 reviewer from their title or abstract were retrieved for full-text screening. The same 2 reviewers independently examined all full-text articles against the eligibility criteria and compared their included and excluded studies from the full-text review. Consensus was required for inclusion in the review. Discrepancies were resolved by discussion between the 2 reviewers, through the involvement of a third reviewer, or by consultation with a clinical expert as needed.

Studies identified via monthly database search alerts and semi-annual clinical trial registry and grey literature search alerts meeting the selection criteria of the review were incorporated into the analysis if they were identified before the end of the stakeholder feedback period for this baseline review. Since the stakeholder feedback period, database search alerts have been scheduled every 3 months, and clinical registry and grey literature search alerts will continue on a semi-annual basis, as part of the LSR protocol. Any studies identified after the stakeholder feedback period will be retained to be screened along with the next set of results from database search alerts (conducted every 3 months as part of the LSR process).

Lists of included studies and excluded studies were generated. The study selection process was documented in a PRISMA⁴⁹ flow chart (Appendix 3).

Data Extraction

Reviewers used Microsoft Excel to document and tabulate all relevant information from the included studies. Using the data-extraction spreadsheet, 2 reviewers extracted data independently and then compared and combined their data. Discrepancies were resolved through discussion until consensus was reached; when necessary, a third reviewer or clinical experts were also involved.

The following relevant information was extracted, where available:

• Study level: Description of publication (e.g., first author’s last name, title, publication year, journal), study characteristics (e.g., clinical trial registry identification number, trial acronym, objectives, study design, year of the conducted study, sample size, study setting, country of the conducted study, study funding source).

• Patient level: Number of patients, age (mean, standard deviation), proportion of women or female patients (as reported by study authors), clinical situation of the diagnosis (e.g., limited metastases at presentation or before initial therapy, after therapy, relapse), number of metastases (mean, standard deviation), location of primary tumour site, status of primary tumour (e.g., treated versus untreated), previous treatment (e.g., for the primary tumour or for metastases), location(s) of metastases, number of metastases per metastatic site

• Intervention level: type (SABR, co-intervention), dose, total duration of treatment, frequency of treatment (e.g., single dose, multiple fractions or treatment), equipment type (brand)

• Comparator level: type (e.g., surgery, conventional radiotherapy, chemotherapy, immunotherapy, hormone therapy, other ablative treatment [cryoablation, radiofrequency ablation, and so forth], targeted therapy [e.g., targeting specific mutations, proteins], no treatment), dose, total duration of treatment, frequency of treatment (i.e., number of cycles), and equipment type (brand)

• Outcome level: Description of outcomes (e.g., subgroup definition, measurement method, unit of measurement, length of follow-up), results, and conclusions of outcomes and subgroups of interest

Data were extracted for all relevant outcomes for this study at any duration of follow-up. Measures of treatment effects (e.g., risk ratios, odds ratios, or risk differences for dichotomous outcomes, mean differences or standardized mean differences for continuous outcomes, and hazard ratios [HRs] for survival outcomes), and any results of statistical tests reported on those measures were extracted. Data from figures were extracted if explicit numerical data were reported. No attempts were made to contact study authors, as no relevant data were deemed conflicting or missing and needed for meta-analyses, which were the 2 conditions pre-specified in the protocol for contacting the corresponding authors.³⁷

As mentioned, if a study was reported in multiple publications and each publication provided unique results, data from these publications were extracted and discussed as 1 single study.

Critical Appraisal

The risk of bias of the primary studies was systematically evaluated using the methods described in version 2 of the Cochrane risk-of-bias tool for randomized trials (RoB 2)⁵⁰ and the Risk of Bias Assessment Tool for Nonrandomized Studies (RoBANS),^51,52 including cohort studies.

The RoB 2 tool⁵⁰ allowed for the assessment of 5 sources of bias or “domains”: bias arising from the randomization process, bias due to deviations from intended interventions, bias due to missing outcome data, bias in measurement of the outcome, and bias in selection of the reported result. Each question within each domain was answered with a yes, probably yes, probably no, no, or no information. Afterwards, a judgment of “low risk of bias,” “high risk of bias,” or “some concerns” was assigned for each domain, with rationale for each decision included in the comments box field.⁵⁰ An overall risk-of-bias judgment for each study was provided as “high risk of bias” if the study had at least 1 domain that was at “high risk of bias;” “some concerns” if the study had at least 1 domain that indicated “some concerns” but no domain that was at “high risk of bias;” or “low risk of bias” where the study had “low risk of bias” for all domains, as per the RoB guidance.⁵⁰

The RoBANS tool^51,52 allowed for the assessment of the risk of 5 types of bias across 8 domains: the possibility of the target group comparisons, target group selection, confounder, exposure measurement, blinding of assessors, outcome assessment, incomplete outcome data, and selective outcome reporting. For each item, a risk-of-bias judgment of “low,” “high,” or “unclear” was assigned with rationale for each decision included in the comments box field.⁵¹ An overall risk-of-bias judgment for each study was provided as “high risk of bias,” where the study had at least 1 domain that was at “high risk of bias;” “some concerns,” where the study had at least 1 domain that was “unclear” but no domain that was at “at high risk of bias;” or “low risk of bias,” where the study had “low risk of bias” for all domains. As the RoBANS guidance did not provide a specific approach for making study-level judgments, this was borrowed from the RoB 2 guidance for methodological consistency.

For sources of bias that may differ across outcomes within a single primary study (i.e., bias due to deviations from missing outcome data and measurement of the outcome in RCTs; outcome assessment and incomplete outcome data in nonrandomized studies), the risk of bias was assessed for individual outcomes within individual studies.

The risk-of-bias assessments of the included studies was performed by 1 reviewer and verified by a second reviewer. All disagreements were resolved through discussion between the 2 reviewers. The tools were used as a guide to evaluate the risk of bias in the included studies; additional insight beyond the items on the instruments has also been provided, when applicable. Summary scores were not calculated; rather, the strengths and limitations of each included study and how they affect the study findings were described narratively. Results of the risk-of-bias assessment were not used to exclude studies from this review.

Data Analysis and Synthesis

Narrative Synthesis

Narrative syntheses were performed. The narrative syntheses included presentation of study characteristics (e.g., the total number of studies included, study designs, publication years, countries in which the studies were conducted, and PICO elements, including dose) and findings within the main text and summary tables. All data analyses and narrative syntheses for this review were conducted separately for each outcome. Under each outcome, all intervention-comparator comparisons were grouped under 1 of 2 different categories — SABR plus SOC versus SOC alone and SABR alone versus SOC alone — which allowed us to summarize the effects of SABR alone or in combination with 1 or more concurrent therapies separately.

For assessing safety outcomes (research question 2), AEs were reported as described in each respective publication. In some studies, the number of patients experiencing an AE or complication was reported, whereas in other studies, the number of unique AEs or complications (i.e., events) was reported; in both cases, some individuals may have experienced more than 1 AE or complication.

The direction and size of any observed effects and any results of statistical tests that reported on those effects were summarized across studies, including an assessment of the likelihood of clinical benefit (i.e., research question 1, clinical effectiveness) or harm (i.e., research question 2, safety). If relevant statistical comparisons were not conducted in the primary studies, this was explicitly stated; the direction of findings was summarized subjectively where possible in the text (e.g., whether the outcome variable changed numerically over time or was numerically different between groups) and overall findings were described as “uncertain” or “unclear.”

The following subgroups were of interest for both narrative and quantitative syntheses for research question 1:

• age

• sex or gender

• location of primary tumour site

• number of metastases sites (e.g., number of metastatic locations; single [e.g., lung only] versus multiple sites [e.g., lung, kidney, adrenal])

• number of metastases (e.g., total, regardless of metastatic location; 5 or fewer versus 3 or fewer metastases)

• location of metastases (e.g., metastatic site specific [e.g., prostate only, lung only])

• previous treatment of primary tumour (i.e., yes, no)

• previous treatment of metastases (i.e., yes, no)

Any relevant data on these subgroups of interest were extracted and analyzed.

A narrative summary of the results of the critical appraisal for each included study was provided. Specifically, tables were developed to present the answers to the questions within the critical appraisal tools, along with a narrative description of the strengths and limitations of the included studies within the main text of the report to provide the reader with an overview of the quality of the literature.

Meta-Analysis

The possibility of conducting meta-analyses was considered for OS, PFS, and AE outcomes (i.e., the outcomes identified as most important by the interviewed patient and clinical experts consulted) and all subgroups of interest. Specifically, clinical, methodological, and statistical characteristics of the included studies were explored, in consultation with clinical and statistical experts, to determine if the data were sufficiently homogeneous for pooling. Meta-analyses were deemed inappropriate and not conducted, and the reasons for these decisions were documented.

Reporting of Findings

The systematic review was prepared in consideration of relevant reporting guidelines (i.e., PRISMA statement,⁵³ Synthesis Without Meta-analysis [SWiM] guideline,⁵⁴ and Guidance for Reporting Involvement of Patients and the Public – Short Form [GRIPP2-SF] reporting checklist⁵⁵), and meets the criteria outlined in A Measurement Tool to Assess Systematic Reviews 2 (AMSTAR 2) checklist.⁵⁶

Patient Engagement

CADTH involves patients, patient families, and patient groups to improve the quality and relevance of our assessments, ensuring that those affected by the assessments have an opportunity to contribute to them. CADTH has adopted the CADTH Framework for Patient Engagement in Health Technology Assessment.⁵⁷ The framework includes Standards for Patient Involvement in Individual Health Technology Assessments and is used to support and guide our activities involving patients. CADTH engaged 1 adult cancer patient who has lived experience with SABR treatment for their oligometastatic cancer.

Invitation to Participate and Consent

A person with SABR experience was identified through CADTH’s informal network of radiation oncologists. A CADTH patient engagement officer contacted potential participants by phone to explore their interest in becoming involved. The preliminary request described CADTH and the purpose and scope of this review, the purpose of the engagement, and the nature of the engagement activities. The patient engagement officer obtained this person’s informed consent.

Engagement Activities

The objective of patient engagement is to inform the research team about the experience of SABR and to raise considerations and perspectives that are not available in clinical trials. The purpose is not to analyze the views and comments of the patient; rather, the patient’s perspectives are used to help interpret the clinical evidence. A patient was and will be invited to reflect on their personal experiences at several time points during assessment, including:

• before clinical protocol finalization

• during drafting of the initial baseline clinical review

• upon completion of the baseline clinical review

• during the clinical review update(s) as part of the LSR phase

• upon transitioning the clinical review out of living mode.

The patient perspectives gained through engagement helped ensure the relevance of outcomes of interest for the clinical assessment and added comments on other key concepts that were initially identified through prior scoping activities. The involvement of patients prompted the research team to consider the possible need to explore avenues of analysis that may have otherwise been missed or underdeveloped. The involvement of patients enabled the research team to consider the evidence alongside an understanding of the wider experiences of patients and caregivers.

Once preliminary findings of the initial baseline review were available, the participant was invited to be interviewed. The conversation explored the patient’s perceptions of key findings, including whether the findings were understandable, and whether they reflect personal experiences or understandings. Final conversations will be held with the participant upon completion of the final baseline clinical review. CADTH will share the key results of the full assessment and describe how engagement activities were used. A similar process for patient engagement will be followed during any updating of the clinical review during the LSR phase and when the clinical review transitions out of living mode.

Reporting

The reporting of this section follows the GRIPP2-SF reporting checklist.⁵⁵

Results

Quantity of Research Available

A total of 2,859 citations were identified in the literature search. Following screening of titles and abstracts, 2,726 citations were excluded and 133 were retrieved for full-text review. An additional 10 potentially relevant reports were retrieved from other sources (i.e., search alerts). Of these 143 potentially relevant articles, 131 publications were excluded for various reasons, and 9 unique studies (3 RCTs and 6 nonrandomized studies) in 12 publications met the inclusion criteria and were included in this review. One RCT (i.e., SABR-COMET) had 3 publications,^32,58,59 and 1 nonrandomized study had 2 publications.^60,61 No unique studies that met the inclusion criteria were submitted by stakeholders. Nine studies in 12 publications were relevant to research question 1,^32,58-68 and 6 studies in 8 publications were relevant to research question 2.^{32,58,62,63,66-68} The study selection process (Figure 2) is outlined in Appendix 3 using a PRISMA flow chart. Lists of included and excluded citations, with details describing the rationale for those excluded, are presented in Appendix 4 and Appendix 5, respectively. CADTH acknowledges that there are randomized trials of metastasis-directed therapy for oligometastatic cancer that are not limited to SABR. However, given the focus of this HTA on SABR specifically, studies of metastasis-directed therapy that did not report results specific to SABR were excluded and can be found in Appendix 5.

Heterogeneity and Decisions Regarding Meta-Analysis

The included studies were generally considered to be too heterogeneous in terms of clinical, methodological, or statistical characteristics to be pooled in meta-analyses for OS, PFS, and AE outcomes and for the subgroups of interest. In 1 instance, a meta-analysis might have been appropriate for 2 studies but was deemed unlikely to add any statistical value to the narrative synthesis, as the point estimates from those studies matched closely in their direction, magnitude, and statistical significance. Thus, findings for all outcomes were synthesized narratively for this baseline review. The complete list of relevant studies for each comparison and the detailed rationale for not conducting meta-analyses is found in Appendix 6. In brief, sources of heterogeneity included differences across the studies in:

• different study designs (i.e., RCTs and nonrandomized studies needing to be analyzed separately, leading to a small numbers of studies)

• data unavailability (e.g., 2 relevant studies for the comparison of interest, but HRs reported for only 1 study)

• data variability (e.g., the AEs that were reported included different AE grades, treatment versus non–treatment-related AEs, or event data versus patient data)

• discordant results (i.e., large variability in the direction, magnitude, and statistical significance of the results).

Study Characteristics

Additional details regarding the characteristics of included studies are provided in Appendix 7.

Study Design, Year of Publication, Sample Size, and Funding

Question 1: Clinical Effectiveness

Three RCTs (in 5 publications^{32,58,59,62,63}) and 6 nonrandomized studies (1 prospective cohort study⁶⁴ and 5 retrospective cohort studies in 6 publications^60,61,65-68) were identified regarding the clinical effectiveness of SABR (with or without SOC) versus SOC comparators. These studies were published between 2013 and 2020. Figure 3 identifies the number of publications by study year.

The sample size of the included studies ranged from 26 to 506 patients (RCTs: 29 to 99 patients; nonrandomized studies: 26 to 506 patients). Of the included studies, 3 received public funding,^{32,58,59,63,66} 1 disclosed that no financial support was provided to undertake the research,⁶⁷ and 5 studies did not report the source of funding.^{60,61,64,65,68,69} No studies reported being sponsored by industry.

Question 2: Safety

Three RCTs (in 4 publications^32,58,63,69) and 3 nonrandomized studies (all retrospective cohort studies^66-68) were identified regarding the safety of SABR (with or without SOC) versus SOC comparators. These studies were published between 2016 and 2020 (Figure 3).

The sample size of the included studies ranged from 26 to 506 patients (RCTs: 29 to 99 patients; nonrandomized studies: 26 to 506 patients). Of the included studies, 3 received public funding,^32,58,63,66 1 disclosed that no financial support was provided to undertake the research,⁶⁷ and 2 did not report the source of funding.^68,69

Country of Origin

Question 1: Clinical Effectiveness

Two RCTs were conducted in the US^63,69 and 1 RCT (in 3 publications)^32,58,59 was conducted at multiple institutions across Canada, the Netherlands, UK, and Australia. The nonrandomized studies were conducted in Turkey,⁶⁵ the Netherlands,^60,61,64 Italy,⁶⁸ and China.⁶⁷ One additional nonrandomized study⁶⁶ was conducted across multiple institutions across Belgium, Italy, France, Switzerland, UK, and Spain.

Question 2: Safety

Two RCTs were conducted in the US^63,69 and 1 RCT (in 2 publications)^32,58 was conducted across multiple institutions across Canada, the Netherlands, UK, and Australia. The nonrandomized studies were conducted in China⁶⁷ and Italy.⁶⁸ One additional nonrandomized study⁶⁶ was conducted across multiple institutions across Belgium, Italy, France, Switzerland, the UK, and Spain.

Patient Population

Question 1: Clinical Effectiveness

The median patient age ranged from 63⁶⁶ to 71⁶⁷ years, and males were more represented overall, given the prevalence of patients with primary prostate cancer in the included studies.

Consistent with our inclusion criteria, all studies included patients with oligometastatic cancer, as described by study authors as having limited metastatic lesions using terminology such as “oligo,” “limited,” or “few.”^32,58-68 The location of the primary tumour and metastatic sites varied widely across studies and, in some cases, within a study (i.e., in a single study, the included population may have included patients with different primary tumour locations or metastatic sites).

Type of primary tumour included breast,^32,58,64 lung,^{32,58-61,64,69,70} kidney,^60,61,64 colorectal,^{32,58-61,67,68} prostate,^{32,58,59,63-66,70} sarcoma,^60,61 and other (non-specified).^32,58-61,64 Most studies included patients who had some previous treatment of the primary tumour (3 RCTs,^{32,58,59,62,63} 6 nonrandomized studies^60,61,64-68).

All studies allowed for up to 5 metastatic lesions per patient with the exception of 2 studies,^63,67 which included patients with up to 3 metastatic lesions. Locations of the metastases included bone,^{32,58,59,63-65,69} lymph nodes,^{32,58,59,65-67,69} soft tissue,^63,64 brain,^32,58,59 nasopharynx,⁶⁹ adrenal,^32,58,59,69 lung,^{32,58-61,68,69} liver,^{32,58,59,64,69} and other.⁶⁴ Of note, in the RCT (SABR-COMET) that included patients with brain metastases (n = 1 metastatic lesion in the SABR intervention group; n = 3 metastatic lesions in the control group), all of those patients also had metastases in locations other than the brain.^32,58,59

Three nonrandomized studies^60,61,67,68 included patients with metastasis to a single location in either the lung^60,61,68 or liver.⁶⁷ Six studies (3 RCTs,^32,58,63,69 3 nonrandomized studies^64-66) included patients with metastasis to multiple locations, 5 studies^{32,58,63-65,69} included patients with metastases in the bone and other sites, and 1 study⁶⁶ had patients with metastases in the lymph nodes of the pelvic and extra-pelvic areas.

Seven studies included at least some patients who had received previous treatment for metastases^{32,58-61,64,66-69}; the remaining 2 studies were unclear in their reporting of any history of treatment for oligometastases.^63,65

Question 2: Safety

The median patient age ranged from approximately 63⁶⁶ to 71⁶⁷ years, and males were more represented overall, given the prevalence of patients with primary prostate cancer in the included studies.

All studies included patients with oligometastatic cancer.^{32,58,63,66-69} The location of the primary tumour and metastatic sites varied widely across studies and, in some cases, within a study. Types of primary tumour included breast,^32,58 lung,^32,58,69 colorectal,^32,58,67,68 prostate,^32,58,63,66 and other (non-specified).^32,58 Three RCTs^32,58,63,69 and 3 nonrandomized studies^66-68 included patients who all had any previous treatment of the primary tumour. Two studies included patients with metastasis to a single location (i.e., lung metastases^67,68); 3 studies included patients with metastasis in the bone and other sites, including lung, liver, brain, adrenal, mediastinum, axilla and nasopharynx^32,58,63,69; and 1 study had patients with metastasis in the lymph nodes of pelvic and extra-pelvic areas.⁶⁶ As noted previously, 4 patients in 1 RCT (SABR-COMET)^32,58,59 with brain metastases (1 in the SABR group and 3 in the control group) also had metastases in locations other than the brain. Five studies included at least some patients who had previous treatment of metastases,^32,58,66-69 and 2 studies were unclear in their reporting of any history of treatment for oligometastases.^63,67

Interventions and Comparators

Question 1: Clinical Effectiveness

The intervention of interest was SABR of any dose or fractionation alone or in combination with 1 or more concurrent or neoadjuvant therapies (i.e., SABR alone or in combination with SOC). In the included studies, 5 examined SABR alone,^{60,61,63,64,67,68} 2 examined SABR with systemic therapy,^32,58,59,69 and 2 examined SABR with or without systemic therapy (i.e., hormonotherapy, androgen deprivation therapy [ADT]) at the discretion of the physician.^65,66 The dose used when administering SABR was study-dependent and varied based on the protocol used in consideration of the location(s) of the targeted metastatic site(s), and the frequency and number of fractions per lesion per patient (see Appendix 7).

SABR was compared with SOC. The SOC comparators in the included studies comprised no therapy (i.e., observation),⁶³ surgery,^60,61,68 systemic therapy (i.e., maintenance chemotherapy),⁶⁹ conventional radiotherapy (i.e., 3-dimensional conformal radiation therapy [3DCRT]),^64,67 conventional radiotherapy (i.e., conventional fractionation radiotherapy or elective nodal radiotherapy [ENRT]) with or without systemic therapy (i.e., hormonotherapy, ADT) at the discretion of the physician,^65,66 and palliative SOC.^32,58,59 Specifically, palliative SOC offered to the SABR-COMET trial’s control group included systemic therapy and palliative (not radical) radiotherapy to alleviate symptoms or prevent anticipated complications of progression.^32,58,59

For the 2 studies^65,66 that had common treatments (i.e., systemic therapy) provided in both the intervention and control groups, the effects of those treatments were assumed to be the same in both groups, allowing the comparison of interest to distill down to SABR versus SOC for the sake of categorization in this review.

Question 2: Safety

Among 7 included studies, 4 examined SABR alone,^63,67,68 2 examined SABR with systemic therapy,^32,58,69 and 1 examined SABR with or without systemic therapy (i.e., ADT) at the discretion of the physician.⁶⁶

The comparators included observation,⁶³ surgery,⁶⁸ systemic chemotherapy (i.e., maintenance chemotherapy),⁶⁹ conventional radiotherapy (i.e., 3DCRT),⁶⁷ a combination of radiotherapy with palliative intent and systemic therapy,^32,58 and radiotherapy (i.e., ENRT) with or without systemic therapy (i.e., ADT) at the discretion of the physician.⁶⁶

Outcomes

Question 1: Clinical Effectiveness

All studies captured at least 1 key outcome (i.e., OS, PFS) to answer this research question. Seven studies examined OS (2 RCTs,^32,58,69 5 nonrandomized studies^{60,61,64,65,67,68}), and 7 studies examined PFS (3 RCTs,^32,58,63,69 4 nonrandomized studies^{60,61,64,65,68}).

Additional outcomes of interest included health-related QoL (3 studies: 2 RCTs^32,58,59,63 and 1 nonrandomized study⁶⁴) and LC (2 studies: 1 RCT,^32,58 1 nonrandomized study^60,61). The 2 RCTs assessed health-related QoL using validated tools such as the Brief Pain Inventory (Short Form)⁶³ and the Functional Assessment of Cancer Therapy–General (FACT-G).^32,58,59 The nonrandomized study⁶⁴ measured QoL using validated questionnaires: European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 15 Palliative (QLQ-C15-PAL), Brief Pain Inventory, and the EuroQol 5-Dimensions questionnaire (EQ-5D). None of the included studies explored freedom from progression or systemic therapy use after treatment with SABR.

In the included studies, the length of follow-up was variable and also reported inconsistently (i.e., some studies reported total follow-up,^{58,60,61,63,65-67,69} and others reported follow-up separately for the intervention and comparator^32,64,68). The shortest follow-up point for a key outcome was a median follow-up of 9.6 months (interquartile range [IQR], 2.4 to 30.2 months)⁶⁹; the longest follow-up point was a median follow-up of 91 months (IQR, 69.6 to 117.6 months).⁶¹

Question 2: Safety

Six studies examined AEs (3 RCTs,^32,58,63,69 3 nonrandomized studies^66-68). The studies used version 3 or version 4 of the Common Terminology Criteria for Adverse Events (CTCAE) or the Radiation Therapy Oncology Group (RTOG) assessment tool to evaluate AEs for SABR compared with its comparators. Reporting on AEs varied among studies: 3 reported AE grades of 1 or higher,^63,67,69 1 reported AE grades of 2 or higher,^32,58 1 reported AE grades of 0 or higher,⁶⁸ and 1 reported AE grades of 3 or higher.⁶⁶

Critical Appraisal of Individual Studies

A summary of the critical appraisal for RCTs can be found in Table 3 and in Table 4 for nonrandomized studies. Appendix 8 presents details of the critical appraisal of both the included RCTs (Table 18) and nonrandomized studies (Table 19). Overall, each of the included studies exhibited some risk of bias, described subsequently.

Risk of Bias in RCTs

The risk of bias in 3 RCTs (from 5 publications^{32,58,59,63,69}) was assessed with RoB 2 (Table 3).

For 2 of the included RCTs,^32,58,59,63 there was a high risk of bias arising from the randomization process. Though both studies used a computerized random allocation sequence, no information was provided about whether the allocation sequence was concealed until participants were enrolled and assigned to the intervention.^32,58,59,63 Moreover, some baseline differences between intervention groups may suggest a problem with the randomization process, although no statistical comparisons were conducted for them: in Phillips et al.,⁶³ the control arm had a higher Gleason score (from the grading classification system that helps in evaluating the prognosis of patients with prostate cancer) and a higher proportion of patients in the intervention arm received prior ADT; in SABR-COMET,^32,58,59 the intervention arm had a higher proportion of patients with prostate cancer. Generally, the methods described in the third RCT by Iyengar et al.⁶⁹ were brief in nature, making the risk of bias for various categories uncertain; therefore, it is possible the risk of bias is higher or lower than what was reported (i.e., the quality of the reporting might have impacted the critical appraisal). Due to the lack of information provided by Iyengar and colleagues,⁶⁹ there were some concerns of bias arising from the randomization process. Iyengar et al.⁶⁹ did not provide details about whether the allocation sequence was random and, if so, concealed until participants were enrolled and assigned to the intervention groups. However, the authors reported no significant differences in baseline characteristics between the 2 arms, which might argue against there being any serious problem with the randomization process.⁶⁹

There were some concerns of bias due to deviations from intended interventions for all 3 RCTs.^{32,58,59,63,69} All 3 RCTs were open-label studies, meaning both the participants and the individuals delivering the interventions were aware of the intervention assignments during the trial, which could have led to some deviations. However, although 1 patient from the control group in the SABR-COMET study^32,58,59 withdrew consent for further follow-up to pursue SABR, this single deviation was unlikely to have affected the balance between the groups or the results due to the relatively large sample size. Similarly, Iyengar et al.⁶⁹ reported that 2 patients crossed over from the control arm to the intervention arm, but these deviations were unlikely to have affected the interpretation of the results. For the other RCT,⁶³ no information was provided about whether there were deviations from the intended intervention that arose because of the trial context.

The included RCTs^{32,58,59,63,69} used appropriate analyses to estimate the effect of intervention assignments using an intention-to-treat (ITT) analysis. For all outcomes of interest for all included RCTs,^{32,58,59,63,69} outcome data were available for all or nearly all participants randomized. Thus, there was a low risk of bias due to missing outcome data for all included RCTs.

The level of risk of bias in the measurement of the outcome depended on the RCT being assessed and the type of outcome explored, ranging from low risk to some concerns. Generally, the method of measurement and analysis for all included outcomes for all RCTs was likely appropriate (e.g., the Kaplan–Meier method was used to estimate survival outcomes, CTCAE was used to classify AEs, FACT-G was used to assess QoL).^{32,58,59,63,69} However, none of the studies reported having adjusted for multiplicity in their outcome measures, suggesting that the type I error rate might have been inflated if multiple testing was conducted. For 1 RCT, outcome assessors were aware of the intervention received by study participants⁶³; however, this was unclear for the other 2 RCTs.^32,58,59,69 However, it is unlikely that the measurement or ascertainment of the outcomes would have been different between the intervention groups.^{32,58,59,63,69} For outcomes that inherently have some subjectivity in the assessment (e.g., outcomes that involve assessment of a radiograph or clinical examination based on medical records, such as LC, AEs, and QoL outcomes), it is possible that the assessment of these outcomes could have been influenced by the knowledge of the intervention received.

There was a low risk of bias in the selective reporting of outcomes for the included RCTs,^{32,58,59,63,69} as data analyses and reported results were all in accordance with a pre-specified analysis plan indicated in the corresponding protocols.^{32,58,59,63,69}

One RCT^32,58,59 reported a similar median follow-up between the treatment arms, but the range was wider in the comparator arm. The other 2 RCTs^63,69 reported only the median follow-up of the total population with a wide IQR, without providing follow-up details for each treatment arm. Therefore, it was unclear whether there was any difference in the follow-up duration between the treatment arms in those studies.

Overall risk-of-bias judgment revealed that 2 RCTs^32,58,59,63 were considered to have an overall high risk of bias and 1 RCT⁶⁹ as having some concerns of bias overall.

Risk of Bias in Nonrandomized Studies

The risk of bias in 6 nonrandomized studies (from 7 publications)^60,61,64-68 was assessed using RoBANS^51,52 (Table 4).

The risk of selection bias from the domain related to the possibility of the target group comparisons varied between the included studies: 1 study was considered to be at low risk of bias because pertinent baseline characteristics were balanced between groups,⁶⁷ and 4 studies were considered to be at high risk of bias because the intervention groups differed in some of the main baseline characteristics.^{60,61,64,66,68} For instance, 1 study^60,61 had older patients (i.e., higher in median age) receiving SABR, 2 studies (in 3 publications)^60,61,64 had higher proportions of patients in the SABR group who had received prior treatment for metastatic disease and had imbalances in the primary tumour location between groups, 1 study⁶⁶ had a higher proportion of patients receiving adjuvant ADT in the comparator group compared with SABR, and 1 study⁶⁸ had a higher proportion of patients in the SABR group who had been diagnosed with metastases at a later period compared with surgery. Given various differences in baseline characteristics, it is difficult to predict the direction of bias. The remaining study⁶⁵ was considered to have an unclear risk of bias because the baseline characteristics were not reported for each group, preventing comparison.⁶⁵

All nonrandomized studies were at low or unclear risk of selection bias for the target group selection domain. Studies were considered to be at low risk of bias when the participant recruitment strategy (e.g., standard of inclusion or exclusion, selection method) was the same for both groups.^64,67,68 Studies were considered to have an unclear risk of bias when the participant recruitment strategy was not clearly described (e.g., unknown whether participants selected from different institutions were balanced between groups).^60,61,65,66

All nonrandomized studies were at a low risk or unclear risk of selection bias due to confounders: low-risk studies confirmed confounders and considered them during the planning and analysis stages,^{60,61,64,66,68} and the studies with unclear risk of bias were not clear for at least 1 outcome if confounders were confirmed or considered during the planning and analysis stages.^65,67

For all included nonrandomized studies,^60,61,64-68 there was a low risk of performance bias (i.e., exposure measurement domain), since the data were obtained from medical records — and for reasons of detection bias (i.e., blinding of assessor’s domain) — as the main end points were time-to-event (survival) outcomes (i.e., objective outcomes).

For all outcomes of all included nonrandomized studies,^60,61,64-68 the outcome assessment was probably appropriate (i.e., low risk of confirmation bias), since outcome data were confirmed with medical records. One study⁶⁴ reported having adjusted for multiplicity but only for QoL outcome measures, and no other study reported having adjusted for multiplicity in its outcome measures, suggesting the type I error rate might have been inflated if multiple testing was conducted.

When considering attrition bias via the incomplete outcome data domain, 2 studies were at low risk of bias, given there were no missing data in the analysis of all reported outcomes,^60,61,68 and 3 studies had an unclear risk of bias, as it was unclear whether all participant data were included in the analyses.^65-67 One study⁶⁴ had a low risk of attrition bias for OS and PFS outcomes (i.e., all data included in analyses), but a high risk of bias for pain response and QoL outcomes because not all patient data were included in the analyses for these outcomes (i.e., study authors excluded all patients with no pain at baseline).

One study had been publicly registered a priori (ClinicalTrials.gov NCT02356497; low risk of reporting bias).⁶⁴ The remaining studies did not mention having or registering a protocol a priori; therefore, it is unclear whether there was any selective outcome reporting (i.e., reporting bias) for these studies.^60,61,65-68

Regarding follow-up duration, 2 studies^64,68 reported that the median follow-up in the intervention group was much shorter compared with that in the comparator group. Four studies^60,61,65-67 reported the median follow-up of the total population. It was therefore unclear whether there was any difference in the duration of follow-up between the treatment arms in those studies.

Overall risk-of-bias judgment revealed that 4 studies^{60,61,64,66,68} were considered to have an overall high risk of bias and that 2 studies^65,67 had some concerns of bias overall.

Data Analysis and Synthesis

Table 5 presents a high-level summary of the findings of the included studies on the clinical effectiveness and safety of SABR for the treatment of patients with oligometastatic cancer, which were grouped into 2 main comparisons (i.e., SABR + SOC versus SOC alone, and SABR versus SOC). Appendix 9 presents the main study findings with regard to OS (Table 20), PFS (Table 21), health-related QoL (Table 22, Table 23), and AEs (Table 24).

Due to the limited amount of available data, subgroup analyses were not possible.

Question 1: Clinical Effectiveness

SABR With SOC Versus SOC Alone

Overall Survival

From 2 RCTs using ITT analyses,^32,58,69 with an overall risk of bias of either high or with some concerns and considering multiple metastatic sites and up to 5 oligometastases in patients previously treated for their primary tumour, there is some evidence suggesting an OS benefit associated with SABR plus SOC compared with SOC alone (Table 6). The initial findings from the SABR-COMET RCT (N = 99 patients)³² found longer median OS and a lower HR for OS in the SABR plus systemic therapy (n = 66 patients) compared with systemic therapy (n = 33; i.e., systemic therapy with patients being allowed to receive radiotherapy with palliative intent) in patients with multiple primary tumour locations. The median OS was 41 months (95% confidence interval [CI], 26 to not reached) for SABR plus systemic therapy and 28 months (95%CI, 19 to 33) for systemic therapy alone. The unadjusted HR was 0.57 (95% CI, 0.30 to 1.10; P = 0.09) with a median follow-up of 26 months (IQR, 23 to 37) for SABR plus systemic therapy and 25 (IQR, 19 to 54) months for systemic therapy. A longer surveillance period (median follow-up for both arms was 51 months; IQR, 46 to 58 months) revealed a significant difference in OS in favour of SABR plus systemic therapy compared with systemic therapy alone (unadjusted HR was 0.47; 95% CI, 0.27 to 0.81; P = 0.006).⁵⁸ the Iyengar et al. RCT⁶⁹ of 29 patients with primary lung cancer provided limited OS findings for their study: for the SABR plus maintenance chemotherapy intervention arm (n = 14), median OS was not reached during the investigation period (i.e., more than half the patients were still alive); for the maintenance chemotherapy arm, median OS was nearly 1 year for patients who did not cross over (n = 13) and was 17 months for patients who crossed over to receive SABR at oligoprogression (n = 2). No HRs for OS were reported and the authors reported their study was not powered to show a statistical difference in survival.⁶⁹ Both RCTs^32,58,69 had patients who had been previously treated for their metastases.

Progression-Free Survival

In 2 RCTs,^32,58,69 either at high risk of bias or with some concerns of bias overall, there is some early evidence to suggest that SABR plus systemic therapy may be more effective than systemic therapy alone for PFS^32,58,69 (Table 7). Both RCTs^32,58,69 included patients with multiple metastatic sites and a maximum of 5 oligometastases.

One RCT (SABR-COMET) with 2 publications^32,58 reported a significant advantage in PFS for patients with multiple primary tumour locations who received SABR plus systemic therapy compared with systemic therapy alone. The initial findings from the SABR-COMET RCT³² found a significant PFS benefit for SABR plus systemic therapy compared with systemic therapy alone (unadjusted HR was 0.47; 95% CI, 0.30 to 0.76; P = 0.0012; median follow-up was 26 months [IQR, 23 to 37 months] for SABR plus systemic therapy; and 25 months [IQR, 19 to 54] for systemic therapy alone). A longer surveillance period (median follow-up for both arms was 51 months; IQR, 46 to 58 months) revealed similar PFS benefits in favour of SABR plus systemic therapy (unadjusted HR was 0.48; 95% CI, 0.31 to 0.76; P = 0.001).⁵⁸ Another RCT by Iyengar et al.⁶⁹ of patients with primary lung cancer also reported a significant PFS benefit for SABR plus maintenance chemotherapy compared with maintenance chemotherapy alone (unadjusted HR was 0.304; 95% CI, 0.113 to 0.815; P = 0.01). Both RCTs^32,58,69 had patients whose primary tumour and metastases had been previously treated.

Freedom From Progression

None of the included studies explored freedom from progression. Consequently, no summary of evidence has been conducted.

Health-Related QoL

One RCT with 3 publications^32,58,59 with an overall high risk of bias reported no significant differences between SABR plus systemic therapy and systemic therapy in health-related QoL outcomes (Table 8). The SABR-COMET study reported no significant differences between the 2 groups at 6 months in the patient-reported FACT-G outcome measure used to assess health-related QoL (FACT-G total, mean [standard deviation] for SABR plus systemic therapy: 82.6 [16.6] versus systemic therapy: 82.5 [16.4]; P = 0.99).³² There were also no significant differences between the 2 groups when examining subscales of the FACT-G tool at 6 months (i.e., physical, social, emotional, functional: P > 0.40 for all).³² The SABR-COMET trial also examined the same QoL outcome measures over 42 months and over 5 years.⁵⁹ At both time points, no significant differences were found between the 2 groups (P values ranged from 0.17 to 0.98).^58,59 Thus, the SABR-COMET study concluded SABR plus systemic therapy was not associated with a QoL detriment.^32,58,59 This RCT^32,58,59 included patients with multiple primary tumour locations and multiple metastatic sites with up to 5 oligometastases. Patients had been previously treated for their primary tumour and metastases.

Lesional Control

Limited data from 1 RCT^32,58 with an overall high risk of bias provided inconclusive evidence about LC to assess whether SABR plus SOC is more effective than SOC alone (Table 9).

The SABR-COMET RCT^32,58 found improved crude LC rates for SABR plus systemic therapy compared with systemic therapy alone during initial follow-up (75% versus 49%; P = 0.0010; median follow-up: 26 [IQR, 23 to 37] months for SABR plus systemic therapy; 25 [IQR, 19 to 54] months for systemic therapy)³² and after longer surveillance (63% versus 46%; P = 0.039; median follow-up for both arms 51 [IQR, 46 to 58] months).⁵⁸ HRs were not calculated for this outcome.^32,58 This RCT^32,58 included patients with multiple primary tumour locations and multiple metastatic sites with up to 5 oligometastases. Patients had been previously treated for their primary tumour and metastases.

Systemic Therapy Use

None of the included studies explored systemic therapy use after treatment with SABR. Consequently, no summary of evidence has been conducted.

SABR Versus SOC

Overall Survival

Five nonrandomized studies^{60,61,64,65,67,68} at either high risk of bias or with some concerns of bias overall provided inconclusive evidence about OS to determine whether SABR is more effective than SOC (Table 10); 4 studies did not report any significant differences between SABR and SOC for OS measures reported (i.e., OS rates, unadjusted HRs, adjusted HRs),^{60,61,65,67,68} and 1 study found an OS benefit for SABR when compared with 3DCRT.⁶⁴ None of the studies reported whether they performed a sample size calculation to obtain enough power to determine a statistical difference between groups for OS.

Hurmuz et al.⁶⁵ found no OS benefit for SABR with or without hormonotherapy (n = 129) at 2 years compared with conventional fractionation radiotherapy with or without hormonotherapy (n = 47) in patients with controlled primary prostate cancer with multiple metastatic sites and a maximum of 5 oligometastases. As patients from both arms optionally received hormonotherapy, the comparison in this study was considered to be SABR versus conventional fractionation radiotherapy. The 2-year OS rate was 87.7% (95% CI not reported) for the SABR group compared with 87.3% (95% CI not reported) for the conventional fractionation radiotherapy group (P = 0.91; median follow-up for both arms was 22.9 [IQR, 3.3 to 77.8] months). No HRs were provided by this study.⁶⁵

Filippi et al.⁶⁸ compared SABR (n = 28) with surgery (n = 142) for lung oligometastases (up to 5 lesions) from previously controlled colorectal cancer and found no significant differences in OS between groups according to the unadjusted HR of 1.7 (95% CI, 0.84 to 3.43), and adjusted HR of 1.71 (95% CI, 0.82 to 3.54). This study was highly imbalanced in terms of numbers of patients in each cohort (i.e., n = 28 in the SABR group versus n = 142 in the surgery group), which was exacerbated by a higher proportion of patients who died (i.e., 36% versus 26%) and more patients lost to follow-up at 30 months (i.e., 7 versus 1) in the SABR group compared with the surgery group. That imbalance might have led to the large difference in median follow-up between the 2 groups (i.e., SABR: 27 [IQR, 16.1 to 71.7] months versus surgery: 45.8 [IQR, 13.6 to 107.1] months) and potentially to the large uncertainty in the HR estimates.

Furthermore, another nonrandomized study compared OS outcomes at both short- and long-term follow-up time points with SABR (n = 42) versus surgery (n = 68) in patients with multiple primary tumour locations that metastasized to the lung with up to 5 oligometastases.^60,61 All patients had been previously treated for their primary tumour. The median short-term follow-up was 43 (IQR, 36 to 60) months⁶⁰ and the median long-term follow-up was 91.2 (IQR, 69.6 to 117.6) months.⁶¹ Regardless of length of follow-up, no significant differences were found in OS between groups: the unadjusted HR for short-term follow-up was 0.79 (95% CI, 0.43 to 1.42); the adjusted HR for short-term follow-up was not reported. The unadjusted HR for long-term follow-up was 1.11 (0.70 to 1.75), and the adjusted HR for long-term follow-up was 0.76 (95% CI, 0.38 to 1.54).^60,61

He et al.⁶⁷ compared SABR (n = 11) with 3DCRT (n = 15) in patients with primary colorectal cancer that metastasized to the liver with up to 3 oligometastases. All patients had been previously treated for their primary tumour. With a median follow-up of 13 months across groups, the study⁶⁷ did not find an OS benefit for SABR when compared with 3DCRT (unadjusted HR: 0.61; 95% CI, 0.23 to 1.65). No other results with statistical testing were reported.⁶⁷

Van de ven and colleagues⁶⁴ found an OS benefit for the SABR group (n = 65) compared with the 3DCRT group (n = 66; unadjusted HR: 0.44; 95% CI, 0.21 to 0.81) in patients with multiple primary tumour locations that metastasized to the bone and other locations with up to 5 oligometastases, despite a significantly shorter time of follow-up in the SABR group (i.e., patients in the SABR group had a median follow-up of 25 [IQR, 5 to 52] months, and patients in the 3DCRT group had a median follow-up 46 [IQR, 9 to 55] months).

Progression-Free Survival

Five studies (1 RCT,⁶³ 4 nonrandomized studies^{60,61,64,65,68}) at either high risk of bias or with some concerns of bias overall explored PFS for patients receiving SABR or SOC to treat their oligometastatic cancer (Table 11). Overall, the results were mixed: 3 studies suggested SABR provides a PFS benefit compared with SOC,^63-65 1 study reported SABR provides a worse prognosis in terms of PFS compared with SOC,⁶⁸ and 1 study did not provide any statistical comparison between groups.^60,61

One RCT compared SABR with observation in patients with previously controlled primary prostate cancer that metastasized to multiple sites (bone or soft tissue) with up to 3 oligometastases, and found a PFS benefit for the SABR group.⁶³ The unadjusted HR was 0.3 (95% CI, 0.11 to 0.81; P = 0.002), with a median follow-up for both arms of 18.8 (IQR, 5.8 to 35.0) months.⁶³

The nonrandomized study by Hurmuz et al.⁶⁵ found a PFS benefit of SABR with or without hormonotherapy compared with conventional fractionation radiotherapy with or without hormonotherapy (adjusted HR: 0.26; 95% CI, 0.13 to 0.55; P < 0.001; median total follow-up: 22.9; 95% CI, 3.3 to 77.8 months) in patients with previously controlled primary prostate cancer that metastasized to multiple sites (bone or lymph node or both) with up to 5 oligometastases.

The nonrandomized study by van de Ven and colleagues⁶⁴ reported a PFS benefit for SABR compared with 3DCRT in patients with multiple primary tumour locations and multiple metastatic sites with up to 5 oligometastases. The unadjusted HR was 0.63 (95% CI, 0.41 to 0.95), with a median follow-up of 25 (IQR, 5 to 52) months for the SABR group and 46 (IQR, 9 to 55) months for the 3DCRT group.⁶⁴

One nonrandomized study reported SABR provides a worse prognosis in terms of PFS compared with surgery (adjusted HR: 2.78; 95% CI, 1.67 to 4.62; P < 0.001) in patients with previously controlled primary colorectal cancer that metastasized to the lung with up to 5 oligometastases.⁶⁸ However, it should be noted that the study authors stated their PFS results were unreliable because different follow-up protocols were applied in the 2 cohorts.⁶⁸

Finally, another nonrandomized study compared PFS outcomes at both short- (median follow-up 43 [IQR, 36 to 60] months)⁶⁰ and long-term (91.2 [IQR, 69.6 to 117.6] months)⁶¹ follow-up time points for SABR (n = 42) versus surgery (n = 68) in patients with multiple primary tumour locations that metastasized to the lung with up to 5 oligometastases. The primary tumour in all patients had been previously treated. PFS rates provided for both groups in 1-year increments from 1 to 8 years suggested lower rates with SABR compared with surgery for metastases in the lung; however, without any statistical comparison, a conclusion could not be drawn.^60,61 HRs were not calculated for any length of follow-up to determine the effect of SABR on PFS.^60,61

Freedom From Progression

None of the included studies explored freedom from progression. Consequently, no summary of evidence has been conducted.

Health-Related QoL

Two studies (1 RCT,⁶³ 1 nonrandomized study⁶⁴) with an overall high risk of bias reported no significant differences between SABR versus SOC groups in the majority of health-related QoL outcomes (Table 12).

With no quantitative data reported, the RCT by Phillips and colleagues⁶³ concluded there were no differences in Brief Pain Inventory (Short Form) scores between groups (i.e., SABR versus observation) in patients with previously controlled primary prostate cancer that metastasized to bone or soft tissue with up to 3 oligometastases.

The nonrandomized study by van de Ven et al.⁶⁴ compared SABR with 3DCRT in patients with multiple primary tumour locations and multiple metastatic sites with up to 5 oligometastases and did not find any significant differences in pain response between treatment groups. The nonrandomized study authors also assessed additional pain variables, including complete response, partial response, pain progression, responders, median duration of pain response, ongoing pain response, and re-irradiation for pain recurrence or progression. At all assessed time points (3, 6, and 12 months), no significant differences were observed between the 2 groups with the exception of responders at 12 months (i.e., complete or partial response was achieved on at least 1 of the follow-up time points: SABR: 80%, n = 8; 3DCRT: 50%, n = 13; P = 0.04) and re-irradiation for pain recurrence or progression, where significantly more patients required re-irradiation for pain recurrence or progression after 3DCRT radiation therapy compared with SABR (SABR: 5%, n = 3; 3DCRT: 33.3%, n = 22; P < 0.05). It should be noted, however, the authors of this nonrandomized study excluded all patients with no pain at baseline for the assessment of pain response, which limited the number of patients for analysis and may have amplified the effect. Moreover, no significant differences between groups were found at follow-up for any QoL subscales. The physical functioning subscale appeared to be in favour of the SABR group (52-week follow-up: P = 0.04). However, the study considered P values of less than 0.01 to be statistically significant for mixed models in the QoL analyses.⁶⁴ The median follow-up in the SABR group was 25 months (IQR, 5 to 52 months), which was notably shorter than the median follow-up of 46 months in the 3DCRT group (IQR, 9 to 55 months).⁶⁴

Lesional Control

One nonrandomized study (from 2 publications)^60,61 with an overall high risk of bias explored LC outcomes (Table 13). The study compared LC outcomes at both short- and long-term follow-up time points between SABR (n = 42) and surgery (n = 68) in patients with multiple primary tumour locations that metastasized to the lung with up to 5 oligometastases. The primary tumour in all patients had been previously treated. The median short-term follow-up was 43 (IQR, 36 to 60) months⁶⁰ and the median long-term follow-up was 91.2 (IQR, 69.6 to 117.6) months.⁶¹ LC rates in 1-year increments from 1 to 8 years were numerically comparable between groups, without any statistical comparison. An unadjusted HR was calculated at long-term follow-up, which found no significant differences between groups; the unadjusted HR was 0.8 (95% CI, 0.24 to 2.65).⁶¹

Systemic Therapy Use

None of the included studies explored systemic therapy use after treatment with SABR; consequently, no summary of evidence has been conducted.

Question 2: Safety

SABR With SOC Versus SOC

Adverse Events

Two RCTs (from 3 publications)^32,58,69 at either high risk of bias or with some concerns of bias overall monitored toxicity for patients who received either SABR plus SOC or SOC alone to treat their oligometastatic cancer (Table 14). Both studies used the CTCAE version 4.0 tool to assess AEs.^32,58,69 Overall, it is unclear if there is a difference in AE incidence when comparing SABR with SOC to SOC alone.

Iyengar et al.⁶⁹ compared SABR plus maintenance chemotherapy to maintenance chemotherapy alone in patients with a controlled primary lung tumour that metastasized to multiple locations with up to 5 oligometastases. This study provided AE frequencies for each group, separated according to AE grade, but did not report statistical findings. Despite this, the study authors concluded there were no differences in toxic effects between groups.⁶⁹

The SABR-COMET RCT in 2 publications^32,58 compared SABR plus systemic therapy to systemic therapy alone in patients with controlled primary tumours in multiple locations that metastasized to multiple sites with up to 5 oligometastases. Various toxicity comparisons were presented, including AEs (grade 2 or greater), treatment-related AEs (grade 2 or greater), death (grade 5), fatigue (grade 2 and grade 3), dyspnea (grade 2 and grade 3), and pain (grade 2 [any type, including muscle, bone, and other] and grade 3 [any type]). Results from SABR-COMET^32,58 revealed that SABR plus systemic therapy was associated with a significantly higher rate of related AEs of grade 2 or greater compared with systemic therapy alone (29% versus 9%; P = 0.026), with an absolute increase of 20% (95% CI, 5 to 34). For all other AE comparisons, no significant differences between groups were found.^32,58

AE = adverse event; CI = confidence interval; CTCAE = Common Terminology Criteria for Adverse Events; F/U = follow-up; IQR = interquartile range; met = metastasis; mets = metastases; NR = not reported; RCT = randomized controlled trial; SABR = stereotactic ablative radiotherapy; SOC = standard of care; tx = treatment; vs. = versus .

SABR Versus SOC

Adverse Events

Four studies (1 RCT,⁶³ 3 nonrandomized studies^66-68) at a high risk of bias or with some concerns of bias overall monitored toxicity for patients who received either SABR or SOC to treat their oligometastatic cancer (Table 15). The majority of studies used the CTCAE^63,66-68 or RTOG grading system^66,67 to assess AEs. Overall, it is unclear if there is a difference in AE incidence when comparing SABR with SOC.

One RCT by Phillips et al. reported a larger number of grade 1 and 2 AEs at both 90-day and 180-day time points for the SABR group versus observation.⁶³ Patients in this trial had controlled primary prostate cancer that metastasized to the bone or soft tissue with up to 3 oligometastases.

One nonrandomized study by De Bleser et al.⁶⁶ compared SABR with or without ADT to ENRT with or without ADT in patients with controlled primary prostate cancer that metastasized to pelvic and extra-pelvic lymph nodes with up to 5 oligometastases. Three toxicity comparisons were presented, including early toxicity (all grades), late toxicity (all grades), and early and late toxicity (grade 3 or higher).⁶⁶ Compared with ENRT, SABR was associated with a lower rate of AEs for all 3 comparisons (P < 0.05; median follow-up for both arms: 18.8 months; IQR, 5.8 to 35.0 months).⁶⁶

One nonrandomized study by He et al.⁶⁷ compared SABR with 3DCRT in patients with controlled primary colorectal cancer that metastasized to the liver with up to 3 oligometastases. The study found no differences between groups for the hepatic toxicity–inducing rate, though specific rates per group were not reported (P = 0.674). Between-group differences were descriptively reported for liver toxicity: the SABR group had 1 patient with a grade 1 or 2 AE and 1 patient with a grade 3 AE, and the 3DCRT group had 3 patients with a grade 1 or 2 AE and 2 patients with a grade 3 AE.⁶⁷

One nonrandomized study by Filippi et al.⁶⁸ did not conduct statistical testing to evaluate AEs with SABR compared with SOC. The study reported specific AEs with the number and proportion of patients in each grade, which precludes suitable comparison between groups; however, the study authors reported the SABR group had multiple grade 1 to 3 AEs and the surgery group reported 1 death. Patients in this study had primary colorectal cancer that metastasized to the lung with up to 5 oligometastases.

Patient Engagement

A patient collaborator was involved in the development of this project, from discussing the research question and outcomes in the protocol, to commenting on the draft findings, to being invited to provide feedback on the baseline clinical review.

The involvement of a patient collaborator enabled the research team to consider the evidence along with the wider experiences of patients and families when preparing the assessment. A deep discussion of clinical outcomes, particularly OS, PFS, and health-related QoL, revealed the goals of treatment with SABR. In CADTH’s conversations with the patient collaborator, the outcome that was discussed most by the patient was health-related QoL, including pain and fatigue, indicating the importance of remaining active and being able to return to work after treatment. The patient compared and contrasted the experience of having chemotherapy to treat the primary tumour versus SABR to treat the metastatic site and highlighted that SABR provided improved health-related QoL outcomes. A description of the patient collaborator’s rural location and distance to travel for treatment was noted. Patient group stakeholders (Canadian Partnership Against Cancer and Canadian Cancer Survivors Network) were invited to provide feedback on the clarity and relevance of the draft of the baseline clinical review.

Patient involvement was guided by the GRIPP2-SF reporting checklist and is reported in Table 25.⁵⁵

Summary of Results

Three RCTs (from 5 publications^{32,58,59,62,63}) and 6 nonrandomized studies (from 7 publications^60,61,64-68) were identified that compared SABR alone or in combination with other SOC therapies with SOC alone for the treatment of patients with oligometastatic cancer. All 9 studies reported on clinical effectiveness. Three RCTs and 3 nonrandomized studies reported on AEs. For the included studies, SOC interventions comprised surgery, conventional radiotherapy, systemic therapy (i.e., chemotherapy, hormonotherapy, ADT), or no therapy (i.e., observation). The studies were grouped into 2 main comparisons (i.e., SABR with SOC versus SOC alone and SABR versus SOC). Key findings were narratively synthesized; no meta-analyses were conducted.

Regarding the clinical effectiveness of SABR plus SOC versus SOC alone, 2 RCTs (from 3 publications)^32,58,69 provided some evidence that SABR plus SOC might be associated with OS and PFS benefits compared with SOC alone. The overall risk of bias of these studies was either high or with some concerns. Results from SABR-COMET^32,58 showed longer median OS and lower HRs for OS in the SABR plus systemic therapy group, compared with systemic therapy alone, in both short- and long-term follow-ups. Likewise, the results from the Iyengar et al. RCT⁶⁹ also suggested longer median OS in the SABR plus maintenance chemotherapy group compared with the maintenance chemotherapy alone group. Consistently, the available PFS data from 2 RCTs^58,69,71 suggest that SABR plus SOC provides a significant PFS benefit compared with SOC alone. Considering patients with oligometastases have already had progression of their cancer via metastases, benefits in PFS may be of particular importance to this population; CADTH’s patient collaborator agreed with this suggestion. In terms of health-related QoL, 1 RCT found no significant differences between SABR plus systemic therapy versus systemic therapy alone in the overall mean of the FACT-G scores, or in any of the physical, social, functional, or emotional subscales.^58,59 In terms of LC, 1 RCT^32,58 found improved crude rates for SABR plus systemic therapy compared with systemic therapy alone in both the shorter- and longer-term follow-ups. The paucity of available evidence for health-related QoL and LC makes it difficult to provide definitive conclusions for those outcomes. None of the included studies explored freedom-from-progression outcomes or subsequent systemic therapy use.

Seven studies, comprising 1 RCT⁶³ and 6 nonrandomized studies (from 7 publications),^60,61,64-68 explored the clinical effectiveness of SABR versus SOC. The overall risk of bias of these studies was either high or with some concerns. The SOC comparator varied widely between studies and was dependent on the type of cancer being treated. SOC comparators included observation,⁶³ 3DCRT,^64,65,67 conventional fractionation radiotherapy with or without hormonotherapy,⁶⁵ ENRT with or without ADT,⁶⁶ and surgery (various resections, pulmonary metastasectomy).^60,61,68 Consideration for these differences in the comparator is warranted when interpreting the following narrative findings.

Five nonrandomized studies^{60,61,64,65,67,68} provided evidence suggesting that SABR may not be more effective than SOC for OS. Specifically, 1 nonrandomized study⁶⁴ found that SABR was associated with a significantly longer median OS than 3DCRT, despite the shorter follow-up in the SABR group; however, the study authors attributed the OS benefit largely to selection bias demonstrated by imbalances in baseline characteristics between the 2 groups. The remaining 4 nonrandomized studies^{60,61,65,67,68} did not find significant differences in OS between SABR and SOC. Most of the nonrandomized studies likely had several limitations, such as incomplete control for confounding factors, immaturity in data, selection of patients as shown by differences in baseline characteristics between treatment groups, lack of power, and imbalances in sample sizes and differences in follow-up protocols between treatment groups. These preliminary findings from nonrandomized studies with potential limitations precluded a definitive conclusion regarding the clinical benefit of SABR alone compared with SOC alone in improving OS for patients with oligometastatic cancer.

In terms of PFS, 5 studies (1 RCT⁶³ and 4 nonrandomized studies^{60,61,64,65,68}) provided mixed results when comparing SABR with SOC. Three studies (1 RCT⁶³ and 2 nonrandomized studies^64,65) suggested SABR provided a PFS benefit compared with SOC alone (i.e., observation, hormonotherapy, or radiotherapy), 1 nonrandomized study⁶⁸ suggested that SABR provided a worse prognosis in terms of PFS compared with surgery, and 1 nonrandomized study^60,61 did not find any significant differences between SABR and surgery. Several of the limitations for OS in the nonrandomized studies indicated previously might also apply to PFS and, since PFS data do not always correlate with OS,⁷² the overall findings of PFS in the comparison of SABR versus SOC should be interpreted with caution. One RCT⁶³ and 1 nonrandomized study⁶⁴ explored health-related QoL outcomes and found no significant differences between groups (i.e., SABR versus observation,⁶³ SABR versus 3DCRT⁶⁴) in the majority of health-related QoL outcomes. One nonrandomized study (from 2 publications)^60,61 investigated LC and found no differences in LC rates between SABR and pulmonary metastasectomy surgery at both short- and long-term follow-ups.^60,61 None of the included studies explored outcomes related to freedom from progression or systemic therapy use.

The second clinical research question for this review aimed to determine the safety of SABR alone or in combination with other therapies for the treatment of patients with oligometastatic cancer compared with SOC alone. Results were narratively summarized by comparison (i.e., SABR plus SOC versus SOC alone, SABR versus SOC).

Two RCTs (from 3 publications)^32,58,69 explored AEs for patients who received SABR plus systemic therapy or systemic therapy alone. For the SABR-COMET trial,^32,58 SABR plus systemic therapy was associated with a significantly higher rate of treatment-related AEs of grade 2 or greater, without any significant differences for all other AE comparisons. The trial by Iyengar and colleagues⁶⁹ did not statistically compare the AEs experienced by patients, but the study authors concluded there were no differences in toxic effects between SABR plus maintenance chemotherapy and maintenance chemotherapy alone.

Four studies (1 RCT,⁶³ 3 nonrandomized studies^66-68) provided unclear evidence on whether SABR reduces AE incidence compared with SOC (i.e., observation, radiotherapy, or surgery). Two studies^60,63,68 did not conduct statistical testing to determine whether rates of AEs were different between SABR and SOC groups. The nonrandomized study that explored SABR with or without ADT versus ENRT with or without ADT⁶⁶ found that SABR was associated with a lower rate of AEs compared with ENRT. Finally, the nonrandomized study that compared SABR with 3DCRT⁶⁷ did not find significant differences in hepatic toxicity–inducing rates between groups.

Discussion

Generalizability of Findings

This clinical review explores the clinical effectiveness and safety of SABR for any patients with oligometastatic cancer. There is currently no standardized definition of the oligometastatic state; therefore, CADTH used a definition for oligometastatic cancer informed by clinical experts and solicited stakeholder feedback on the included studies list for this review. For the purposes of this review, the population of interest was patients with oligometastatic cancer, described by study authors as having limited metastatic lesions using terminology such as “oligo,” “limited,” or “few,” including identification of de novo or repeat oligometastatic disease at any time during the patient’s course of treatment, irrespective of the status of the primary tumour. However, this definition may have excluded studies that other research groups may have deemed to involve oligometastatic cancer that did not meet our definition, and the results of this review may not be applicable to every interpretation of “oligometastatic cancer.” On the other hand, the other inclusion criteria were quite broad and allowed for the inclusion of diverse patient populations within the oligometastatic disease spectrum; comparative studies examining SABR for patients with oligometastatic cancer were included regardless of the location of primary tumour, location of metastases, number of metastases, or number of metastatic sites. This review excluded studies involving patients who had a history of widespread metastatic disease (i.e., induced oligometastatic disease); however, it is possible that a study included “oligometastatic” patients without additional information regarding previous widespread disease. For this review, it was assumed that patients had no history of widespread metastatic disease if this was not explicitly described in the study; in those cases, the studies may have included patients with a history of widespread metastatic disease that were unknowingly included in this review.

Oligometastatic disease is an umbrella term in the sense that patients can have different types of primary and metastatic location combinations and may have different clinical profiles. Different primary cancer types have different disease prognoses, making it difficult to assess transferability of findings between patient populations. This review did not identify any subgroup analysis for the subgroups of interest. Nevertheless, some of the findings were specific to primary lung cancer⁶⁹ or primary prostate cancer,^65,66 including up to 3 metastases,^63,67 multiple metastatic sites^{32,58,59,63-66,69} or a single metastatic site such as lung^60,61,68 or liver,⁶⁷ patients with previous treatment of a primary tumour,^{32,58-61,63,65-68} or patients with previous treatment of metastases.^{32,58-61,64,66-69} In addition, while patients of any age were of interest for this review, all included studies evaluated adult patients, with a median age above 60 years in all treatment groups. Therefore, the results may not be applicable to pediatric patients or to younger adults with oligometastatic cancer.

For this review, 1 RCT (from 3 publications)^32,58,59 was conducted at multiple institutions across Canada, the Netherlands, UK, and Australia. The remaining 8 studies^60-68 were conducted outside of Canada. However, the majority of the evidence was from developed countries and, therefore, may be generalizable to the Canadian context.

CADTH engaged 1 patient with lived experience of oligometastatic cancer to inform the selection of important clinical outcomes and to provide the reviewers with some context for interpretation of the findings. The purpose of patient engagement is not to be representative of all Canadians, recognizing that individual patients have a diversity of experiences and perceptions related to oligometastatic cancer and its treatment. Comments and perspectives from our patient collaborator were not analyzed; rather, CADTH drew on patient perspectives and impressions to help better inform the work and help interpret the clinical evidence. Of note, the topic and research questions were already determined before engaging the patient collaborator. Possible limitations of this patient engagement were that our collaborator and other patient stakeholders were invited to participate within a set time frame and with a deadline for providing feedback. People need access to reliable technology and phone and internet service to participate; lack of such access could possibly exclude some voices.

Limitations

There are certain limitations to consider when reviewing the report, which are described subsequently.

Evidence Gaps

There were a number of gaps in the evidence identified for this review. Namely, there were relatively few studies identified for each intervention and comparator combination; 3 studies (2 RCTs^32,58,59,69) evaluated SABR plus SOC versus SOC alone, and 8 studies (1 RCT⁶³ and 7 nonrandomized studies^{60,61,64-68,70}) evaluated SABR versus SOC. Within those comparison categories, the outcomes of interest for this review were often not reported by all of the included studies, further reducing the available evidence for comparison. Evidence for the AE outcomes in particular was very limited due to how the data were recorded (e.g., treatment-related versus non–treatment-related AEs, event data versus patient data, only selective grades reported). No data were identified from any study to report on freedom from progression and subsequent use of systemic therapy. In addition, subgroup analyses within studies were lacking; instead, studies were described with relevant patient characteristics only when presenting overall study results. There was no evidence identified to comment on the effectiveness or safety of SABR based on patient age, sex, or gender.

To be comprehensive, this review used broad inclusion criteria for SOC for metastatic cancer, which varies according to the type of primary cancer and metastatic site. This variety is reflected in the wide range of SOC comparators described in the included studies, which were narratively synthesized in the same manner without discerning the efficacy of 1 comparator over another (e.g., surgery versus observation). In addition, several studies broadly included patients with oligometastatic cancer that included multiple types of primary cancers and locations of oligometastases without presenting subgroup analyses of results by primary tumour or oligometastatic location. While results in the present work compare SABR with any type of SOC deemed appropriate for patients of a certain variation of oligometastatic cancer, there was not enough evidence identified in this review to truly discern whether certain cancer types or intervention combinations may benefit from SABR more than others. Similarly, the dose used when administering SABR was study-dependent and varied based on the protocol used in consideration of the location(s) of the targeted metastatic site(s), the frequency and number of fractions per lesion per patient, and complication risks to nearby normal tissue. Clinical experts engaged by CADTH have suggested that this is consistent with their experience in practice. Furthermore, the relationship between the size of the lesion(s) and dose may affect patient outcomes. For example, treating larger lesions may be associated with higher toxicities from treatment, and lower LC rates may be observed in situations where lower-dose prescriptions are used for patient safety. CADTH is unable to provide details on the optimal SABR regimen or dose, given the variation in the included studies. As SABR dose is dependent on many factors, it may be challenging to identify optimal SABR regimens or standardized doses that could be applicable across all oligometastatic cancers or patients.

Taken together, the limited amount of evidence identified combined with the variation in patient characteristics and outcome reporting across and within the included studies affected the ability to quantitatively synthesize findings and reflects a high degree of uncertainty in the findings to date. For this review, 9 studies (from 12 publications) were included. A 2019 paper identified 64 ongoing studies examining SABR for oligometastatic cancer.³³ CADTH’s detailed scoping exercise and additional grey literature searches also identified a number of ongoing clinical trials.¹ Thus, there is undoubtedly more evidence coming down the research pipeline in the near future that will likely add to our current evidence base to inform whether SABR should be used for patients with oligometastatic cancer and under what conditions (e.g., patient characteristics, dose). Regular updates of this baseline review are planned to capture additional and relevant studies in the form of a LSR.

Heterogeneity

There was substantial clinical, methodological, and statistical heterogeneity among the included studies preventing meta-analyses of the data. Specifically, sources of heterogeneity included differences in study design (i.e., RCT, nonrandomized study), data unavailability (e.g., 2 relevant studies for the comparison of interest, but HRs reported for 1 study), data variability (e.g., AE results included different AE grades reported, treatment-related versus non–treatment-related AEs, or event data versus patient data), and discordant results (i.e., large variability in the direction, magnitude, and statistical significance of the results). As discussed previously, there was variation in the patient characteristics within and across included studies (e.g., type of primary tumour, location of oligometastases) and types of treatment comprising SOC that contributed to the heterogeneity, which is also reflected by the inconsistent results in the narrative synthesis for some comparisons and outcomes.

Quality of Evidence

The included studies comprised both RCTs and nonrandomized studies (with the majority using a retrospective cohort study design). The risk of bias of the included studies ranged from high risk of bias to some concerns. All included RCTs were phase II trials with limitations in the randomization process and with relatively small sample sizes, although power calculations were performed. All of the included nonrandomized studies were susceptible to the risk of selection bias, reporting bias, and lack of power calculations. For feasibility reasons, only studies published in English were eligible for inclusion. It is acknowledged that there is a potential for language bias when language restrictions are used; however, there is also evidence for minimal impact of including studies published in other languages.^73,74

Directions for Future Research

To facilitate decisions around appropriate patient selection and the optimal SABR regimen or dose, additional studies examining the clinical effectiveness and safety of SABR with detailed reporting of criteria for patient selection and dosing are required. Additional studies examining any clinical outcomes outlined in this review may also enable future meta-analyses of the data to provide more robust findings, as several of the comparisons could not be pooled due to the lack of available evidence (i.e., no HRs to pool). Specifically, the patient partner emphasized QoL as 1 of the central outcomes of interest, including breathing issues, fatigue, impact on physical activity, and being able to return to work after treatment. Some evidence was available regarding QoL (3 studies), mainly focusing on pain and less on physical functioning. Additional research regarding the interventions’ impact on QoL is warranted. Moreover, the patient collaborator described the distance to travel for treatment and the costs associated with travel, highlighting some practical considerations related to accessing SABR treatment. As SABR for the treatment of oligometastatic cancer is an active field of research, additional studies are expected to be identified upon updates of this baseline review during the LSR phase. Such updates may provide an opportunity to fill in gaps in the clinical evidence and strengthen the conclusions of this review.

Conclusions and Implications for Decision-Making

To CADTH’s knowledge, this is the first systematic review exploring the clinical effectiveness and safety of SABR for any patients with oligometastatic cancer (i.e., no restrictions on primary or metastatic locations). Key outcomes of interest included OS, PFS, and AEs, consistent with the opinions of our clinical experts and patient partner. Findings from the included studies suggested there may be OS and PFS benefits associated with SABR plus SOC compared with SOC alone. Findings from the included studies on OS and PFS for SABR alone versus SOC were mixed and deemed inconclusive, as the studies were generally limited by unadjusted baseline imbalances associated with the retrospective cohort study design and had small sample sizes and uncertainty around whether the survival data were mature. Few studies statistically compared AE data, making it unclear if SABR, with or without SOC, is more or less harmful than SOC alternatives for patients with oligometastases. There was a lack of literature identified to inform conclusions for other outcomes of interest, including freedom from progression, health-related QoL, LC, and use of systemic therapy after treatment, and for subgroups of interest (i.e., age, sex, gender, location of primary tumour site, number of metastases sites, number of metastases, location of metastases, previous treatment of primary tumour, and previous treatment of metastases). More comparative studies using rigorous methods, such as high-quality randomized trials with sufficient sample sizes and mature OS data, are required to reduce this uncertainty. Future research on the effectiveness of SABR in patients with different characteristics would clarify who might benefit most from this treatment, which would inform patient selection criteria. In addition, evidence on the optimal regimen or dose of SABR for treatment of oligometastases is still needed. Additional studies are expected to be identified during the LSR phase of this project, which will see routine monitoring for newly published literature and regular updating of this baseline review. Finally, this clinical review represents 1 component among many that decision-makers will consider when making the decision about the expanded use of SABR in Canada.

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Appendix 1: Analytical Framework

Figure 1: Analytical Framework

FFP = freedom from progression; LC = lesional control; OS = overall survival; PFS = progression-free survival; QoL = quality of life; SABR = stereotactic ablative radiotherapy.

Appendix 2: Literature Search Methods

Clinical Literature Search

Overview

Interface: Ovid

Databases: MEDLINE All (1946-present), Embase (1974-present), Cochrane Central Register of Controlled Trials (CCTR)

Note: Subject headings have been customized for each database. Duplicates between databases were removed in Ovid.

Date of search: March 20, 2020

Alerts: Monthly search updates until project completion. After completion search alerts will occur every 3 months.

Study types: No publication type filters will be applied.

Limits: Publication date limit: 1990-present

Language limit: none

Conference abstracts: excluded

Syntax Guide

/ = At the end of a phrase, searches the phrase as a subject heading

MeSH = Medical Subject Heading

.fs = Floating subheading

Exp = Explode a subject heading

* = Before a word, indicates that the marked subject heading is a primary topic; or, after a word, a truncation symbol (wildcard) to retrieve plurals or varying endings

? = Truncation symbol for 1 or no characters only

adj# = Requires terms to be adjacent to each other within # number of words (in any order)

.ti = Title

.ab = Abstract

.kf = Author keyword heading word (MEDLINE)

.kw = Author keyword (Embase); keyword (CCTR)

.dq = Candidate term word (Embase)

.pt = Publication type

.my = Device index terms word (Embase)

.dv = Device trade name (Embase)

.dm = Device manufacturer (Embase)

freq = # = Requires terms to occur # number of times in the specified fields

medal = Ovid database code: MEDLINE All, 1946 to present, updated daily

oemezd = Ovid database code; Embase, 1974 to present, updated daily

cctr = Ovid database code; Cochrane Central Register of Controlled Trials

Multi-Database Strategy (Line Number and Search Strategy)

1. (exp radiotherapy/ or radiotherapy.fs.) and (stereo?ta* or stereo ta*).ti,ab,kf,kw.

2. ((stereo?ta* or stereo ta*) adj5 (ablat* or body or lung* or liver* or spin*) adj5 (radiat* or radio therap* or radio?therap* or radio surg* or radiosur* or radio frequen* or radiofrequen* or proton* or photon*)).ti,ab,kf,kw.

3. ((stereo?ta* or stereo ta* or intensity modulat* or linear accelerat*) adj4 (radiat* or radio therap* or radio?therap* or radio surg* or radiosur* or irradiation* or radio frequen* or radiofrequen* or proton* or photon*)).ti,ab,kf,kw.

4. ((fraction* or ultra hypofraction* or ultrahypofraction* or hypofraction* or hyperfraction*) adj4 (radio therap* or radio?therap* or radio surg* or radiosur* or irradiation* or radio frequen* or radiofrequen* or proton* or photon*)).ti,ab,kf,kw.

5. ((dynamic* or volumetric modulat*) adj5 (ARC or wave ARC* or waveARC*)).ti,ab,kf,kw.

6. (precision* adj5 deliver* adj5 system*).ti,ab,kf,kw.

7. (fraction* adj5 (stereo ta* or stereota*)).ti,ab,kf,kw.

8. (SRS* or SABR* or SBRT* or mdSBRT* or FSR or FSRT or LINAC* or DCA or VMAT or IMRS or IMPT or stereo tacic RT* or stereotacic RT* or stereo taxic RT* or stereotaxic RT* or systemSRBT*).ti,ab,kf,kw.

9. (xknife* or infinity* or novalis* or trilogy* or clinac* or accuray* or radixac* or cyberknife* or cyber knife* or synergy* or gammaknife* or gamma knife* or exactrac* or exac trac* or truebeam* or true beam* or MRLinac* or MR Linac* or eclipse* or rapid ARC* or rapidARC* or prefexion* or vero* or model u*2 or modellu* or modellc* or model c*2).ti,ab,kf,kw.

10. (integra or elekta* or varian or brainlab* or brain lab* or Mitsubishi Heavy*).ti,ab,kf,kw.

11. (versa*3 or precise*3 or edge*3).ti,kf,kw.

12. or/1-11

13. exp Neoplasm Metastasis/ and oligo*.ti,ab,kf,kw.

14. (oligomet* or oligoprogress* or oligorecur* or oligopersist* or oligofraction* or oligoclonal* or oligosynchron*).ti,ab,kf,kw.

15. (oligo* adj5 (meta* or progress* or recur* or persist* or fraction* or clonal* or synchron*)).ti,ab,kf,kw.

16. ((tumour* or tumour* or cancer* or neoplasm* or carcinoma*) adj3 (migration* or spread*)).ti,ab,kf,kw.

17. ((few* or limited* or advanced* or number*) adj2 (tumour* or tumour* or site* or metastases or spread or micrometastas*)).ti,ab,kf,kw.

18. ((transitional or intermediate) adj5 (metasta* or micrometastas*)).ti,ab,kf,kw.

19. Limited Metastatic.ti,ab,kf,kw.

20. (secondary adj5 (tumour* or tumour* or lesion* or metastases or micrometastas*)).ti,ab,kf,kw.

21. or/13-20

22. 12 and 21

23. 22 use medall

24. 22 use cctr

25. (exp radiosurgery/ or exp radiotherapy equipment/ or exp radiotherapy/ or radiotherapy.fs.) and (stereo?ta* or stereo ta*).ti,ab,kw,dq.

26. ((stereo?ta* or stereo ta*) adj5 (ablat* or body or lung* or liver* or spin*) adj5 (radiat* or radio therap* or radio?therap* or radio surg* or radiosur* or radio frequen* or radiofrequen* or proton* or photon*)).ti,ab,kw,dq.

27. ((stereo?ta* or stereo ta* or intensity modulat* or linear accelerat*) adj4 (radiat* or radio therap* or radio?therap* or radio surg* or radiosur* or irradiation* or radio frequen* or radiofrequen* or proton* or photon*)).ti,ab,kw,dq.

28. ((fraction* or ultra hypofraction* or ultrahypofraction* or hypofraction* or hyperfraction*) adj4 (radio therap* or radio?therap* or radio surg* or radiosur* or irradiation* or radio frequen* or radiofrequen* or proton* or photon*)).ti,ab,kw,dq.

29. ((dynamic* or volumetric modulat*) adj5 (ARC or wave ARC* or waveARC*)).ti,ab,kw,dq.

30. (precision* adj5 deliver* adj5 system*).ti,ab,kw,dq.

31. (fraction* adj5 (stereo ta* or stereota*)).ti,ab,kw,dq.

32. (SRS* or SABR* or SBRT* or mdSBRT* or FSR or FSRT or LINAC* or DCA or VMAT or IMRS or IMPT or stereo tacic RT* or stereotacic RT* or stereo taxic RT* or stereotaxic RT* or systemSBRT*).ti,ab,kw,dq.

33. (xknife* or infinity* or novalis* or trilogy* or clinac* or accuray* or radixac* or cyberknife* or cyber knife* or synergy* or gammaknife* or gamma knife* or exactrac* or exac trac* or truebeam* or true beam* or MRLinac* or MR Linac* or eclipse* or rapid ARC* or rapidARC* or prefexion* or vero* or model u*2 or modellu*or modellc* or model c*2).ti,ab,kw,dq,my,dv,dm.

34. (integra or elekta* or varian or brainlab* or brain lab* or Mitsubishi Heavy*).ti,ab,kw,dq,dv,dm.

35. (versa*3 or precise*3 or edge*3).ti,kw,dq,my,dv,dm.

36. or/25-35

37. exp metastasis/ and oligo*.ti,ab,kw,dq.

38. (oligomet* or oligoprogress* or oligorecur* or oligopersist* or oligofraction* or oligoclonal* or oligosynchron*).ti,ab,kw,dq.

39. (oligo* adj5 (meta* or progress* or recur* or persist* or fraction* or clonal* or synchron*)).ti,ab,kw,dq.

40. ((tumour* or tumour* or cancer* or neoplasm* or carcinoma*) adj3 (migration* or spread*)).ti,ab,kw,dq.

41. ((few* or limited* or advanced* or number*) adj2 (tumour* or tumour* or site* or metastases or spread or micrometastas*)).ti,ab,kw,dq.

42. ((transitional or intermediate) adj5 (metasta* or micrometastas*)).ti,ab,kw,dq.

43. Limited Metastatic.ti,ab,kw,dq.

44. (secondary adj5 (tumour* or tumour* or lesion* or metastases or micrometastas*)).ti,ab,kw,dq.

45. or/37-44

46. 36 and 45

47. 46 use oemezd

48. 47 not conference abstract.pt.

49. 23 or 24 or 48

50. limit 49 to yr = 1990-current

51. remove duplicates from 50

Clinical Trial Registries

ClinicalTrials.gov

• Produced by the US National Library of Medicine. Targeted search used to capture registered clinical trials.

• [Search terms will include - Stereotactic Ablative Radiotherapy (SABR) OR Stereotactic Radiosurgery (SRS) OR stereotactic body radiation therapy (SBRT) OR fractionated stereotactic radiotherapy (FSRT) OR LINAC OR XKnife OR Versa OR Infinity OR Precise OR Novalis Tx OR Trilogy OR Clinac OR Accuray Tomotherapy OR Radixac OR CyberKnife OR Synergy OR Gamma Knife Icon OR ExacTrac OR TrueBeam OR Edge OR Eclipse RapidArc OR Gamma Knife Model U OR Gamma Knife Model C OR Gamma Knife Prefexion]

Health Canada. Clinical Trials Database

• Produced by Health Canada. Targeted search used to capture registered clinical trials.

• [Search terms will include - Stereotactic Ablative Radiotherapy (SABR) OR Stereotactic Radiosurgery (SRS) OR stereotactic body radiation therapy (SBRT) OR fractionated stereotactic radiotherapy (FSRT) OR LINAC OR XKnife OR Versa OR Infinity OR Precise OR Novalis Tx OR Trilogy OR Clinac OR Accuray Tomotherapy OR Radixac OR CyberKnife OR Synergy OR Gamma Knife Icon OR ExacTrac OR TrueBeam OR Edge OR Eclipse RapidArc OR Gamma Knife Model U OR Gamma Knife Model C OR Gamma Knife Prefexion]

Canadian Cancer Trials

• Produced by the Canadian Partnership Against Cancer Corporation. Targeted search used to capture registered clinical trials.

• [Search terms will include - Stereotactic Ablative Radiotherapy (SABR) OR Stereotactic Radiosurgery (SRS) OR stereotactic body radiation therapy (SBRT) OR fractionated stereotactic radiotherapy (FSRT) OR LINAC OR XKnife OR Versa OR Infinity OR Precise OR Novalis Tx OR Trilogy OR Clinac OR Accuray Tomotherapy OR Radixac OR CyberKnife OR Synergy OR Gamma Knife Icon OR ExacTrac OR TrueBeam OR Edge OR Eclipse RapidArc OR Gamma Knife Model U OR Gamma Knife Model C OR Gamma Knife Prefexion]

Grey Literature

Dates for Search: April 27, 2020 to May 07, 2020

Keywords: Stereotactic Ablative Radiotherapy (SABR) OR Stereotactic Radiosurgery (SRS) OR stereotactic body radiation therapy (SBRT) OR fractionated stereotactic radiotherapy (FSRT) OR LINAC OR XKnife OR Versa OR Infinity OR Precise OR Novalis Tx OR Trilogy OR Clinac OR Accuray Tomotherapy OR Radixac OR CyberKnife OR Synergy OR Gamma Knife Icon OR ExacTrac OR TrueBeam OR Edge OR Eclipse RapidArc OR Gamma Knife Model U OR Gamma Knife Model C OR Gamma Knife Prefexion

Limits: Publication years: 1990-present

Relevant websites from the following sections of the CADTH grey literature checklist Grey Matters: A Practical Tool For Searching Health-Related Grey Literature (https://www.cadth.ca/grey-matters) were searched:

• Health Technology Assessment Agencies

• Health Economics

• Clinical Practice Guidelines

• Drug and Device Regulatory Approvals

• Advisories and Warnings

• Drug Class Reviews

• Clinical Trial Registries

• Databases (free)

• Health Statistics

• Internet Search

• Open Access Journals

Appendix 3: PRISMA Flow Chart of Selected Reports

Figure 2: PRISMA Flow Chart of Selected Reports

Appendix 4: List of Included Studies

1.Hurmuz P, Onal C, Ozyigit G, et al. Treatment outcomes of metastasis-directed treatment using (68)Ga-PSMA-PET/CT for oligometastatic or oligorecurrent prostate cancer: Turkish Society for Radiation Oncology group study (TROD 09-002). Strahlenther Onkol. 2020;196(11):1034-1043. PubMed

2.Palma DA, Olson R, Harrow S, et al. Stereotactic Ablative Radiotherapy for the Comprehensive Treatment of Oligometastatic Cancers: Long-Term Results of the SABR-COMET Phase II Randomized Trial. J Clin Oncol. 2020;38(25):2830-2838. PubMed

3.Phillips R, Shi WY, Deek M, et al. Outcomes of Observation vs Stereotactic Ablative Radiation for Oligometastatic Prostate Cancer: The ORIOLE Phase 2 Randomized Clinical Trial. JAMA Oncol. 2020;6(5):650-659. PubMed

4.van de Ven S, van den Bongard D, Pielkenrood B, et al. Patient-Reported Outcomes of Oligometastatic Patients After Conventional or Stereotactic Radiation Therapy to Bone Metastases: An Analysis of the PRESENT Cohort. Int J Radiat Oncol Biol Phys. 2020;107(1):39-47. PubMed

5.De Bleser E, Jereczek-Fossa BA, Pasquier D, et al. Metastasis-directed Therapy in Treating Nodal Oligorecurrent Prostate Cancer: A Multi-institutional Analysis Comparing the Outcome and Toxicity of Stereotactic Body Radiotherapy and Elective Nodal Radiotherapy. Eur Urol. 2019;76(6):732-739. PubMed

6.Olson R, Senan S, Harrow S, et al. Quality of Life Outcomes After Stereotactic Ablative Radiation Therapy (SABR) Versus Standard of Care Treatments in the Oligometastatic Setting: A Secondary Analysis of the SABR-COMET Randomized Trial. Int J Radiat Oncol Biol Phys. 2019;105(5):943-947. PubMed

7.Palma DA, Olson R, Harrow S, et al. Stereotactic ablative radiotherapy versus standard of care palliative treatment in patients with oligometastatic cancers (SABR-COMET): a randomised, phase 2, open-label trial. Lancet. 2019;393(10185):2051-2058. PubMed

8.He Z, Chen G, Ouyang B, et al. Conformal radiation therapy or stereotactic body radiation therapy: Institutional experience in the management of colorectal liver metastases by radiation therapy. Technol Cancer Res Treat. 2018;17.

9.Iyengar P, Wardak Z, Gerber DE, et al. Consolidative Radiotherapy for Limited Metastatic Non-Small-Cell Lung Cancer: A Phase 2 Randomized Clinical Trial. JAMA Oncol. 2018;4(1):e173501. PubMed

10.Lodeweges JE, Klinkenberg TJ, Ubbels JF, Groen HJM, Langendijk JA, Widder J. Long-term Outcome of Surgery or Stereotactic Radiotherapy for Lung Oligometastases. J Thorac Oncol. 2017;12(9):1442-1445. PubMed

11.Filippi AR, Guerrera F, Badellino S, et al. Exploratory Analysis on Overall Survival after Either Surgery or Stereotactic Radiotherapy for Lung Oligometastases from Colorectal Cancer. Clin Oncol (R Coll Radiol). 2016;28(8):505-512. PubMed

12.Widder J, Klinkenberg TJ, Ubbels JF, Wiegman EM, Groen HJ, Langendijk JA. Pulmonary oligometastases: metastasectomy or stereotactic ablative radiotherapy? Radiother Oncol. 2013;107(3):409-413. PubMed

Appendix 5: List of Excluded Studies and Reasons for Exclusion

Duplicate Report (n = 3)

1.McDonald F, Hanna GG. Oligoprogressive Oncogene-addicted Lung Tumours: Does Stereotactic Body Radiotherapy Have a Role? Introducing the HALT Trial. Clin Oncol (R Coll Radiol). 2018;30(1):1-4. PubMed

2.Trovo M, Furlan C, Polesel J, et al. Radical radiation therapy for oligometastatic breast cancer: Results of a prospective phase II trial. Radiother Oncol. 2018;126(1):177-180. PubMed

3.Kao J, Timmins J, Ozao-Choy J, Packer S. Effects of combined sunitinib and extracranial stereotactic radiotherapy on bone marrow hematopoiesis. Oncol Lett. 2016;12(3):2139-2144. PubMed

Irrelevant Population (n = 20)

1.Deek MP, Taparra K, Phillips R, et al. Metastasis-directed Therapy Prolongs Efficacy of Systemic Therapy and Improves Clinical Outcomes in Oligoprogressive Castration-resistant Prostate Cancer. Eur Urol Oncol. 2020. PubMed

2.Papadopoulos KP, Johnson ML, Lockhart AC, et al. First-In-Human Study of Cemiplimab Alone or In Combination with Radiotherapy and/or Low-dose Cyclophosphamide in Patients with Advanced Malignancies. Clin Cancer Res. 2020;26(5):1025-1033. PubMed

3.Schullian P, Putzer D, Laimer G, Levy E, Bale R. Feasibility, safety, and long-term efficacy of stereotactic radiofrequency ablation for tumors adjacent to the diaphragm in the hepatic dome: a case-control study. Eur Radiol. 2020;30(2):950-960. PubMed

4.Schullian P, Putzer D, Silva MA, Laimer G, Kolbitsch C, Bale R. Stereotactic Radiofrequency Ablation of Liver Tumors in Octogenarians. Front Oncol. 2019;9:929. PubMed

5.Shen PC, Chang WC, Lo CH, et al. Comparison of Stereotactic Body Radiation Therapy and Transarterial Chemoembolization for Unresectable Medium-Sized Hepatocellular Carcinoma. Int J Radiat Oncol Biol Phys. 2019;105(2):307-318. PubMed

6.Franzese C, Comito T, Clerici E, et al. Liver metastases from colorectal cancer: propensity score-based comparison of stereotactic body radiation therapy vs. microwave ablation. J Cancer Res Clin Oncol. 2018;144(9):1777-1783. PubMed

7.Ost P, Reynders D, Decaestecker K, et al. Surveillance or Metastasis-Directed Therapy for Oligometastatic Prostate Cancer Recurrence: A Prospective, Randomized, Multicenter Phase II Trial. J Clin Oncol. 2018;36(5):446-453. PubMed

8.Sapir E, Tao Y, Schipper MJ, et al. Stereotactic Body Radiation Therapy as an Alternative to Transarterial Chemoembolization for Hepatocellular Carcinoma. Int J Radiat Oncol Biol Phys. 2018;100(1):122-130. PubMed

9.Schulz D, Wirth M, Piontek G, et al. Improved overall survival in head and neck cancer patients after specific therapy of distant metastases. Eur Arch Otorhinolaryngol. 2018;275(5):1239-1247. PubMed

10.Sprave T, Verma V, Forster R, et al. Quality of Life Following Stereotactic Body Radiotherapy Versus Three-Dimensional Conformal Radiotherapy for Vertebral Metastases: Secondary Analysis of an Exploratory Phase II Randomized Trial. Anticancer Res. 2018;38(8):4961-4968. PubMed

11.Stenman M, Sinclair G, Paavola P, Wersall P, Harmenberg U, Lindskog M. Overall survival after stereotactic radiotherapy or surgical metastasectomy in oligometastatic renal cell carcinoma patients treated at 2 Swedish centres 2005-2014. Radiother Oncol. 2018;127(3):501-506. PubMed

12.Fleming C, Rimner A, Foster A, Woo KM, Zhang Z, Wu AJ. Palliative efficacy and local control of conventional radiotherapy for lung metastases. Ann. 2017;6(Suppl 1):S21-S27. PubMed

13.Moon SH, Cho KH, Lee CG, et al. IMRT vs. 2D-radiotherapy or 3D-conformal radiotherapy of nasopharyngeal carcinoma: Survival outcome in a Korean multi-institutional retrospective study (KROG 11-06). Strahlenther Onkol. 2016;192(6):377-385. PubMed

14.Reijneveld JC, Taphoorn MJB, Coens C, et al. Health-related quality of life in patients with high-risk low-grade glioma (EORTC 22033-26033): a randomised, open-label, phase 3 intergroup study. Lancet Oncol. 2016;17(11):1533-1542. PubMed

15.Jacob R, Turley F, Redden DT, et al. Adjuvant stereotactic body radiotherapy following transarterial chemoembolization in patients with non-resectable hepatocellular carcinoma tumours of >/= 3 cm. HPB (Oxford). 2015;17(2):140-149. PubMed

16.Langendijk H, Kaanders JH, Doornaert P, et al. POPART vs CPORT in squamous cell head and neck cancer: Results of a multicenter randomised study of the Dutch head and neck Study Group. Radiother Oncol. 2015;114:9-10.

17.Jiang Z, Wang Q, Yang G, et al. Optimized treatment with RF thermotherapy and immunotherapy combined with CyberKnife for advanced high-risk tumors: A clinical trial report. Biomed Rep. 2014;2(2):245-249. PubMed

18.Yu W, Tang L, Lin F, et al. Stereotactic radiosurgery, a potential alternative treatment for pulmonary metastases from osteosarcoma. Int J Oncol. 2014;44(4):1091-1098. PubMed

19.Choi BO, Choi IB, Jang HS, et al. Stereotactic body radiation therapy with or without transarterial chemoembolization for patients with primary hepatocellular carcinoma: preliminary analysis. BMC Cancer. 2008;8:351. PubMed

20.Guo J, Sun XN, Huang M. Evaluation of the efficacy for alternated treatment on primary liver cancer by interventional therapy in combination with fractionated stereotactic conformal radiotherapy. Chin J Clin Oncol. 2005;32(24):1418-1420.

Irrelevant Intervention (n = 5)

1.Chan OSH, Lam KC, Li JYC, et al. ATOM: A phase II study to assess efficacy of preemptive local ablative therapy to residual oligometastases of NSCLC after EGFR TKI. Lung Cancer. 2020;142:41-46. PubMed

2.Gomez DR, Tang C, Zhang J, et al. Local Consolidative Therapy Vs. Maintenance Therapy or Observation for Patients With Oligometastatic Non-Small-Cell Lung Cancer: Long-Term Results of a Multi-Institutional, Phase II, Randomized Study. J Clin Oncol. 2019;37(18):1558-1565. PubMed

3.Steuber T, Jilg C, Tennstedt P, et al. Standard of Care Versus Metastases-directed Therapy for PET-detected Nodal Oligorecurrent Prostate Cancer Following Multimodality Treatment: A Multi-institutional Case-control Study. Eur Urol Focus. 2019;5(6):1007-1013. PubMed

4.Chan OSH, Lee VHF, Mok TSK, Mo F, Chang ATY, Yeung RMW. The Role of Radiotherapy in Epidermal Growth Factor Receptor Mutation-positive Patients with Oligoprogression: A Matched-cohort Analysis. Clin Oncol (R Coll Radiol). 2017;29(9):568-575. PubMed

5.Roos DE, Turner SL, O'Brien PC, et al. Randomized trial of 8 Gy in 1 versus 20 Gy in 5 fractions of radiotherapy for neuropathic pain due to bone metastases (Trans-Tasman Radiation Oncology Group, TROG 96.05). Radiother Oncol. 2005;75(1):54-63. PubMed

Irrelevant Comparator (n = 13)

1.Franzese C, Comito T, Vigano L, et al. Liver Metastases-directed Therapy in the Management of Oligometastatic Breast Cancer. Clin Breast Cancer. 2020;20(6):480-486. PubMed

2.Kalinauskaite GG, Tinhofer, II, Kufeld MM, et al. Radiosurgery and fractionated stereotactic body radiotherapy for patients with lung oligometastases. BMC Cancer. 2020;20(1):404. PubMed

3.Desideri I, Francolini G, Scotti V, et al. Benefit of ablative versus palliative-only radiotherapy in combination with nivolumab in patients affected by metastatic kidney and lung cancer. Clin Transl Oncol. 2019;21(7):933-938. PubMed

4.Lepinoy A, Silva YE, Martin E, et al. Salvage extended field or involved field nodal irradiation in (18)F-fluorocholine PET/CT oligorecurrent nodal failures from prostate cancer. Eur J Nucl Med Mol Imaging. 2019;46(1):40-48. PubMed

5.Fanetti G, Marvaso G, Ciardo D, et al. Stereotactic body radiotherapy for castration-sensitive prostate cancer bone oligometastases. Med Oncol. 2018;35(5):75. PubMed

6.Frost N, Tessmer A, Schmittel A, et al. Local ablative treatment for synchronous single organ oligometastatic lung cancer-A propensity score analysis of 180 patients. Lung Cancer. 2018;125:164-173. PubMed

7.Katoh N, Onishi H, Uchinami Y, et al. Real-Time Tumor-Tracking Radiotherapy and General Stereotactic Body Radiotherapy for Adrenal Metastasis in Patients with Oligometastasis. Technol Cancer Res Treat. 2018;17:1533033818809983. PubMed

8.Mazzola R, Tebano U, Aiello D, et al. Increased efficacy of stereotactic ablative radiation therapy after bevacizumab in lung oligometastases from colon cancer. Tumori. 2018;104(6):423-428. PubMed

9.Sundahl N, Rottey S, Decaestecker K, et al. Phase 1 trial of pembrolizumab with SBRT in metastatic urothelial carcinoma. Radiother Oncol. 2018;127:S357-S358.

10.Sundahl N, De Wolf K, Rottey S, et al. A phase I/II trial of fixed-dose stereotactic body radiotherapy with sequential or concurrent pembrolizumab in metastatic urothelial carcinoma: evaluation of safety and clinical and immunologic response. J Transl Med. 2017;15(1):150. PubMed

11.Fleckenstein J, Petroff A, Schafers HJ, Wehler T, Schope J, Rube C. Long-term outcomes in radically treated synchronous vs. metachronous oligometastatic non-small-cell lung cancer. BMC Cancer. 2016;16:348. PubMed

12.Siva S, Kron T, Bressel M, et al. A randomised phase II trial of Stereotactic Ablative Fractionated radiotherapy versus Radiosurgery for Oligometastatic Neoplasia to the lung (TROG 13.01 SAFRON II). BMC Cancer. 2016;16:183. PubMed

13.Wang YS, Yang G, Wang YY, Yang JL, Yang K. Early efficacy of stereotactic body radiation therapy combined with adoptive immunotherapy for advanced malignancies. Mol Clin Oncol. 2013;1(5):925-929. PubMed

Irrelevant Outcome (n = 3)

1.Xue P, Wu Z, Wang K, Gao G, Zhuang M, Yan M. Oncological outcome of combining cytoreductive prostatectomy and metastasis-directed radiotherapy in patients with prostate cancer and bone oligometastases: A retrospective cohort study. Cancer Manag Res. 2020;12:8867-8873. PubMed

2.Bouman-Wammes EW, van Dodewaard-De Jong JM, Dahele M, et al. Benefits of Using Stereotactic Body Radiotherapy in Patients With Metachronous Oligometastases of Hormone-Sensitive Prostate Cancer Detected by [18F]fluoromethylcholine PET/CT. Clin Genitourin Cancer. 2017;15(5):e773-e782. PubMed

3.Youland RS, Blanchard ML, Dronca R, et al. Role of radiotherapy in extracranial metastatic malignant melanoma in the modern era. Clin Transl Radiat Oncol. 2017;6:25-30. PubMed

Inappropriate Study Design (n = 82)

1.Burkon P, Oberreiterova S, Kazda T, et al. Stereotactic Body Radiotherapy of Lymph Node Oligometastases. Klin Onkol. 2020;33(2):114-122. PubMed

2.Guo T, Ni J, Yang X, et al. Pattern of Recurrence Analysis in Metastatic EGFR-Mutant NSCLC Treated with Osimertinib: Implications for Consolidative Stereotactic Body Radiation Therapy. Int J Radiat Oncol Biol Phys. 2020;107(1):62-71. PubMed

3.Higa J, Wilenius K, Savino S, Larsen C, Scholz M, Vogelzang N. Real World Experience With Pembrolizumab in Recurrent or Advanced Prostate Cancer. Clin Genitourin Cancer. 2020;18(4):e397-e401. PubMed

4.Kim DW, Lee G, Lee H, et al. Stereotactic Body Radiation Therapy to a Splenic Metastasis in Oligoprogressive Non-small Cell Lung Cancer. Adv Radiat Oncol. 2020;5(3):516-521. PubMed

5.Marzec J, Becker J, Paulsen F, et al. (68)Ga-PSMA-PET/CT-directed IGRT/SBRT for oligometastases of recurrent prostate cancer after initial surgery. Acta Oncol. 2020;59(2):149-156. PubMed

6.Nikitas J, Roach M, Robinson C, et al. Treatment of oligometastatic lung cancer with brain metastases using stereotactic radiosurgery (SRS) and stereotactic body radiation therapy (SBRT). Clin Transl Radiat Oncol. 2020;21:32-35. PubMed

7.Pei S, Chen K, Yang Y, Chen L, Zhu X. A retrospective cohort study of low-dose intensity-modulated radiotherapy for unresectable liver metastases. J Int Med Res. 2020;48(4):300060519892382. PubMed

8.Thomas T. SABR improves outcomes in men with recurrent oligometastatic prostate cancer. Nat Rev Urol. 2020;17(5):256. PubMed

9.Agolli L. Stereotactic body radiation therapy could improve disease control in oligometastatic patients with renal cell carcinoma: do we need more evidence? Ann. 2019;7(Suppl 3):S105. PubMed

10.Augugliaro M, Marvaso G, Ciardo D, et al. Recurrent oligometastatic transitional cell bladder carcinoma: is there room for radiotherapy? Neoplasma. 2019;66(1):160-165. PubMed

11.Aujla KS, Katz AW, Singh DP, Okunieff P, Milano MT. Hypofractionated Stereotactic Radiotherapy for Non-breast or Prostate Cancer Oligometastases: A Tail of Survival Beyond 10 Years. Front Oncol. 2019;9:111. PubMed