Skip to main content
Download PDF

Stereotactic body radiotherapy as metastasis-directed therapy in oligometastatic prostate cancer: a systematic review and meta-analysis of randomized controlled trials

Radiation Oncology volume 19, Article number: 173 (2024) Cite this article

Abstract

Background

The use of stereotactic body radiotherapy (SBRT) to definitively treat oligometastases in prostate cancer has drawn large clinical and research interests within radiation oncology. However, the evidence is considered in its early stages and there is currently no systematic review of randomized controlled trials (RCTs) in this field. We aimed to evaluate the efficacy and safety of SBRT as metastasis-directed therapy (MDT) in oligometastatic prostate cancer (OMPC) compared to no MDT reported in RCTs.

Methods

MEDLINE, Embase, CINAHL Complete, and Cochrane Library were searched on October 28, 2023. Eligible studies were RCTs comparing SBRT as MDT with no MDT in extracranial OMPC, without restrictions on follow-up time, publication status, language, or year. Participant subsets fulfilling the eligibility criteria were included. Critical outcomes were overall survival and grade ≥ 3 toxicity, and additional important outcomes were progression-free survival (PFS), local control, grade 5 toxicity, health-related quality of life, and systemic therapy-free survival. Meta-analyses were planned. Risk of bias was assessed using the Cochrane risk-of-bias tool version 2, and the quality of evidence using the Grading of Recommendations Assessment, Development, and Evaluation.

Results

In total, 1825 unique study reports were identified and seven phase II RCTs with 559 eligible participants were included. Four trials included multiple types of primary cancer. Outcome definitions were heterogeneous except for overall survival and toxicity. For overall survival, only one study reported events in both arms. Meta-analysis of the grade ≥ 3 toxicity results from two trials showed no difference (pooled risk ratio 0.78, 95% confidence interval 0.37–1.65, p = 0.52). Four trials reported significantly longer PFS, with a pooled hazard ratio of 0.31 (95% confidence interval 0.21–0.45, p < 0.00001). Risk of bias was of some concerns or high. Quality of evidence was low or moderate.

Conclusions

Phase II trials have shown promising improvements in PFS for several OMPC states without excess toxicity. Overall survival comparisons are immature. In future confirmatory phase III trials, adequately large sample sizes, blinding of outcome assessors, and/or increased adherence to assigned intervention could improve the quality of evidence.

PROSPERO registration number: CRD42021230131.

Background

Comprehensive treatment of a few metastases, or oligometastases, using metastasis-directed therapy (MDT) has several theoretical benefits. It may prevent or delay metastasis-related complications, postpone the need for systemic therapy or a change of therapy by treating isolated nonresponding metastases [1], interfere with metastatic seeding [2], and be curative if all visible lesions represent the total tumor burden [3].

Stereotactic body radiotherapy (SBRT) is an appealing MDT by being noninvasive and delivered on an outpatient basis [4], and by potentially enhancing the anticancer immune response [5]. SBRT has shown encouraging safety and early efficacy across multiple primary cancer types, with one-year local control rates at approximately 95% [6].

There have been significant efforts in the radiation oncology community during the last years in conducting clinical trials on SBRT as MDT [7], as well as in harmonizing the nomenclature and differentiating clinical scenarios where oligometastatic disease (OMD) is encountered. In 2019, the International Commission on Radiation Units and Measurements (ICRU) published its report [8] on stereotactic radiotherapy (RT). In 2020, the European Society for Radiotherapy and Oncology (ESTRO)–European Organization for Research and Treatment of Cancer (EORTC) consensus recommendation [9] charted OMD states and was shortly followed by the ESTRO–American Society for Radiation Oncology (ASTRO) consensus document [10] specifying prioritized outcomes applicable to SBRT as MDT.

Parallel to these efforts, understanding if SBRT as MDT is beneficial in a particular primary cancer type, and if so, determining its place in the current treatment armamentarium, are essential [11]. Prostate cancer (PCa) is one of the most studied primary cancer types [6, 7]. MDT with SBRT is increasingly offered for oligometastatic prostate cancer (OMPC) in routine clinical practice [12, 13], although the evidence is considered weak so far [14]. In response, ESTRO recently published recommendations [15] on patient selection, imaging, and SBRT delivery for clinical practice and acknowledged the lack of level I evidence.

Several systematic reviews have covered MDT in OMPC, including both retrospective and prospective [16,17,18,19,20,21,22,23] and exclusively prospective [24,25,26,27] studies. Among the systematic reviews of prospective studies, some covered multiple types of MDT (i.e., also surgery) [24, 26] and SBRT alone [25, 27].

However, to our knowledge, there is not yet a systematic review on SBRT in OMPC limited to randomized controlled trials (RCTs), which provides the highest level of evidence [28]. Therefore, we conducted a systematic review of RCTs investigating the efficacy and safety of SBRT as MDT in OMPC. The main hypothesis was that this intervention would improve overall survival without increasing grade ≥ 3 toxicity compared to a control group (CG) receiving standard of care or no treatment.

Methods

The protocol was developed according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines [29] and pre-registered in PROSPERO (CRD42021230131) [30]. The following report is written according to the PRISMA 2009 guidelines [31].

Eligibility criteria

We included RCTs that investigated SBRT as MDT for extracranial OMPC. The participants were adults with OMPC diagnosed through biopsy of the primary tumor or metastasis and positron emission tomography (PET)-computed tomography (CT) or whole body magnetic resonance imaging (MRI) [32], or according to the study authors. Studies that included only patients with regional nodal metastases were ineligible. However, participant subsets fulfilling the eligibility criteria were included, such as those from a study that investigated several primary cancer types.

All metastases, or all uncontrolled metastases as a minimum in oligoprogressive disease, had to be treated with SBRT without other concomitant MDTs in the intervention group (IG). SBRT could be referred to using related terms (e.g., stereotactic ablative RT or radiosurgery), with the reservation of dose per fraction being > 2 Gy according to the ICRU definition [8], and could be one of several investigated treatments.

The CG was receiving standard of care (SOC), placebo, no treatment, or RT with lower intensity than the IG as part of the study design. Lower intensity RT was defined as standard palliative RT or equivalent dose in 2-Gy fractions (EQD2) of up to 50 Gy (α/β = 3 Gy) to any metastasis. Higher doses were allowed at the physicians’ discretion during follow-up.

Each study report had to report at least one of the review outcomes (see Outcomes). There were no restrictions on follow-up time and publication status, language, or year of publication. Original study reports and other publication formats (e.g., editorials, comments, and letters) were eligible. Studies with insufficient data for qualitative or quantitative analysis were excluded.

Outcomes

The review outcomes were clinical outcomes from the ESTRO–ASTRO consensus document on metastasis-directed RT in OMD [10] and were grouped into critical, additional important, and other relevant outcomes. Critical outcomes were: overall survival, defined as time from randomization to death from any cause, or according to the study authors; and incidence proportion of grade ≥ 3 toxicity, defined as the proportion of participants with at least one event of grade ≥ 3 on the Radiation Therapy Oncology Group/EORTC toxicity scale [33] or Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 [34] after start of SBRT, or according to the study authors, at 5 years or longest follow-up.

Additional important outcomes were progression-free survival (PFS), defined as time from randomization to disease progression according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (i.e., ≥ 20% increase in the lesions’ baseline sum diameter with a minimum absolute increase of 5 mm for measurable disease and unequivocal progression or progression warranting a change in therapy for nonmeasurable disease) [35], or according to the study authors; local control, defined as the proportion of participants without locally progressive disease according to RECIST 1.1 or according to the study authors, at 5 years or longest follow-up; incidence proportion of grade 5 toxicity, or lethality ascribed to treatment, after start of SBRT or as defined by the study authors, at 5 years or longest follow-up; health-related quality of life (HRQoL), assessed by the EuroQol Group’s EQ-5D-5L index value [36], 36-Item Short Form Health Survey (SF-36) physical or mental component summary [37], EORTC Quality of Life Questionnaire-Core 30 (QLQ-C30) version 3 summary score [38, 39] with or without the complementary module Quality of Life Questionnaire-Prostate 25 (QLQ-PR25) [40], Functional Assessment of Cancer Therapy-General (FACT-G) version 4 total score [41], Functional Assessment of Cancer Therapy-Prostate (FACT-P) version 4 total score [42], or according to the study authors, at 3 months; HRQoL at 5 years or longest follow-up; and systemic therapy-free survival, defined as time from randomization to initiation of any systemic anticancer therapy or death from any cause, or according to the study authors. Five-year follow-up was used if reported for the outcomes defined at these timepoints; otherwise, the longest follow-up was reported. Timepoints of 1–6 months were eligible for HRQoL at 3 months.

Other relevant outcomes were local PFS, defined as time from randomization to progression of metastases present at baseline according to RECIST 1.1 or according to the study authors; and distant PFS, defined as time from randomization to occurrence of a new metastatic lesion according to RECIST 1.1 or according to the study authors.

Search strategy

MEDLINE (through PubMed), Embase (through Embase.com), Cumulative Index to Nursing and Allied Health Literature (CINAHL) Complete (through EBSCOhost), and Cochrane Central Register of Controlled Trials (CENTRAL) were searched for study reports. Additionally, the ClinicalTrials.gov and International Clinical Trials Registry Platform (ICTRP) were searched for protocols to identify ongoing studies.

Other sources were also screened for study reports: reference lists of relevant systematic reviews, abstract collections, backward and forward citations searching on included study reports using Web of Science, authors of the included studies, and selected vendor companies. Relevant systematic reviews were identified by applying systematic review filters in the database searches, except for CENTRAL where Cochrane Database of Systematic Reviews was searched instead.

The first searches covered the period from inception until January 24, 2021, and were rerun on October 28, 2023, when also previously identified ongoing studies were checked for completion. The full search strategy is provided in Additional file 1.

Study selection

The identified study reports were imported into EndNote [43] where duplicates were removed according to the deduplication strategy described in Additional file 2. AEP and AG independently screened unblinded titles and/or abstracts in duplicate in Covidence [44] for potentially eligible study reports. Disagreements were resolved through discussion; otherwise, HT made the final decision. AEP screened other sources.

Study reports were collated at the study level, and a main report was chosen. AH and LBL independently assessed unblinded full texts in duplicate for inclusion and decided the main reason for exclusion based on the order of importance listed in Additional file 3. Disagreements were resolved by discussion; otherwise, AG was consulted and could make the final decision. Study reports and duplicates could be included or excluded until manuscript submission.

The study authors were contacted for clarification of the eligibility criteria, if needed. If no clarification could be obtained, the main report was used in case of conflicting information and if information was missing, the study was excluded. Ongoing and seemingly eligible studies without any reported outcome data were to be described in separate tables.

Data collection

Data were collected from unblinded study reports using Google Forms [45]. We used full reports, their supplements, and abstracts, as well as protocols when relevant for study definitions, and examined the latest protocol in the case of multiple versions. If results were reported only in figures, data were extracted using Engauge Digitizer [46]. AEP collected data on study characteristics, while AH and LBL collected outcome data using forms piloted on one included study. Discrepancies were resolved by discussion; otherwise, AG was consulted and could make the final decision. The study authors were contacted for missing or additional data.

The critical and important outcomes were assessed for risk of bias using the Cochrane risk-of-bias tool version 2 (RoB 2) [47] that considers five domains: randomization process, deviations from intended interventions, missing outcome data, measurement of the outcome, and selection of reported result, on the study and outcome level. AH and LBL independently performed the unblinded assessments in duplicate. Disagreements were resolved by discussion; otherwise, with AEP, HT, and AG until consensus was reached. The assessments were reported in a traffic light plot according to the Robvis tool [48].

The quality of evidence for the critical and important outcomes was assessed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) [49] by applying the same process described above for risk of bias. The assessments were to be reported in the Summary of findings table generated in GRADEpro Guideline Development Tool [50].

Data items

We extracted data on publication details (e.g., publication year and corresponding author), study details (e.g., design and phase, enrollment regions and country/countries, enrollment period, screening procedures, follow-up period and time, funding, and inclusion and exclusion criteria), diagnostic details (e.g., imaging modalities and OMD criteria), participant details (e.g., age, performance status, baseline prostate-specific antigen [PSA], controlled primary tumor, states of OMD, previous use and type of systemic treatment, previous use and type of MDT, and sites and number of treated metastases), intervention details (e.g., content, timing, methods of delivery, doses, number of and time between treatments, length of intervention, and intervention integrity), and outcomes.

During the review process, we added data on randomization procedures and ratio, follow-up procedures, castration-resistant disease, PSA doubling time, and number of progressing metastases in the CG in case of oligoprogressive disease.

Data analysis

The hazard ratio (HR) was the effect measure for time-to-event outcomes (overall survival, PFS, systemic therapy-free survival, and local and distant PFS), the risk ratio (RR) for dichotomous outcomes (toxicity and local control), and the mean difference or standardized mean difference for continuous outcomes (HRQoL). Outcome data reported as intention-to-treat were used.

Overall survival and incidence proportion of grade ≥ 3 toxicity at 5 years or longest follow-up were going to be analyzed in meta-analysis using Review Manager 5.4.1 [51] and presented in forest plots. The random-effects model was chosen because of the expected large clinical heterogeneity among studies. If a study reported no events in neither the IG nor the CG, it was excluded from the meta-analysis. A meta-analysis would not be performed if the clinical or statistical heterogeneity were too high.

For overall survival, a pooled HR with a 95% confidence interval (CI) was going to be estimated using the generic inverse-variance method based on the natural logarithm (ln) of the HR and the variance of the ln(HR) [52]. In case these statistics were not reported, they were estimated using direct or indirect methods described by Tierney et al. [53]. For incidence proportion of grade ≥ 3 toxicity at 5 years or longest follow-up, a pooled RR with a 95% CI was going to be estimated using the DerSimonian and Laird inverse-variance method. The pooled effect estimates were to be tested for an overall effect using the Z-test with a significance level of 0.05.

Statistical heterogeneity was to be assessed using the Chi2 test with a significance level of 0.10. The proportion of observed variation in effects between studies reflecting real statistical heterogeneity was to be estimated using I2 with a 95% CI and quantified using Tau2, the variance in true effects between studies, with a 95% CI. I2 of ≥ 50% was considered to represent substantial heterogeneity. Prediction intervals were to be calculated in case ≥ 10 studies were included in a meta-analysis [52]. Sensitivity analyses excluding studies with high risk of bias were planned.

Formal assessment of publication bias was planned if ≥ 10 studies were included in the meta-analyses by generating funnel plots and testing for asymmetry using Egger’s test with a significance level of 0.10 [54].

All outcome data were reported narratively and in tables. The additional important outcomes were also to be reported using pooled effect estimates.

Results

Study selection

We identified 5286 records from the database searches. After removing duplicates, protocols, systematic reviews, abstract collections, and book chapters, 1815 titles and/or abstracts were screened. After adding 10 records identified from other sources, 39 full texts were assessed for inclusion. Seven RCTs reported in 17 study reports were included. Three of the reports were identified from other sources: two by personal knowledge of the review authors and one by tracking a later report of a pilot study. The flow diagram of the study selection process is shown in Fig. 1.

Fig. 1
figure 1

Modified PRISMA 2009 flow diagram. Flow diagram of study reports during study selection. CENTRAL Cochrane Central Register of Controlled Trials, CINAHL Cumulative Index to Nursing and Allied Health Literature, ICTRP International Clinical Trials Registry Platform. aPotentially eligible study reports from reference lists of relevant systematic reviews, abstract collections, backward and forward citations searching on included study reports, authors of included studies, and selected vendor companies bTwelve additional protocols were identified from other sources cReported in 17 study reports

Full size image

Studies excluded during full-text assessment are shown in Table 1. Eighteen relevant ongoing studies were identified and are described in Additional file 4.

Table 1 Characteristics of excluded studies after full-text assessment
Full size table

Study characteristics

The included trials were STOMP [77,78,79], SABR-COMET [80,81,82,83], ORIOLE [79, 84], ARTO [85,86,87,88,89,90], EXTEND [91], CORE [92], and STOP [93], which were published between 2017 and 2023. The trials included 559 participants with OMPC fulfilling our eligibility criteria: 200 in the IGs, 179 in the CGs, and an additional 180 participants in both groups in CORE. All were phase II multicenter trials conducted in high-income Western countries. Their characteristics are listed in Table 2 and further details are provided in Additional file 5. After contacting the authors of all included studies, we were able to receive supplementary data from the ARTO team.

Table 2 Characteristics of included studies
Full size table

STOMP, ORIOLE, and ARTO included only participants with PCa, whereas SABR-COMET, EXTEND, CORE, and STOP included several primary cancer types. In the included EXTEND study report, the PCa basket receiving intermittent hormone therapy was reported separately. In STOMP, ORIOLE, and CORE, only patients with metachronous oligorecurrence were included, and in STOP, patients with oligoprogression.

OMD was defined as 1–5 (progressing) metastases detected using CT and/or bone scan, MRI, or PET-CT with choline, fluciclovine, or PSMA tracers, with some variations in restrictions on metastatic sites and the number of metastases per organ. It was uncertain if the participants had brain metastases in SABR-COMET, EXTEND, and STOP, but it was considered unlikely per personal correspondence with the study author for SABR-COMET and by the review authors for EXTEND and STOP. Only participants with castration-resistant disease were studied in ARTO and were eligible for enrollment in SABR-COMET, EXTEND, CORE, and STOP.

STOMP investigated either SBRT or surgery as MDT, while the remaining trials investigated SBRT. There was some uncertainty as to whether some participants in EXTEND had received only conventionally fractionated RT, e.g., due to regional nodal disease; however, the proportion of participants with regional nodal disease (7%) was balanced between the arms. The fractionation schedules that were or could be used varied between total doses of 12–70 Gy, with fraction doses of 2.3–27 Gy in 1–28 fractions (EQD23 range 17–227 Gy).

SBRT was delivered without systemic therapy in STOMP and ORIOLE, while the other trials either investigated or allowed systemic therapy in both arms: abiraterone acetate, prednisone, and androgen deprivation therapy (ADT) was added in ARTO; intermittent hormone therapy (ADT with or without a second-generation androgen receptor inhibitor for ≥ 6 months with planned break 4–8 months after enrollment) in EXTEND; and SOC in SABR-COMET, CORE, and STOP.

Results of individual studies

The outcomes fulfilling the review criteria and the corresponding data are listed in Table 3. In one study [84], crossover to the intervention arm was allowed at progression or 6 months, that is, the timepoint of the trial’s primary outcome. Therefore, we only included follow-up until 6 months in the analysis of this trial.

Table 3 Outcome data presented as effect estimates (95% confidence intervals), medians (95% confidence intervals), № (%)
Full size table

Outcomes were measured from either date of informed consent, enrollment, randomization, or start of (systemic) treatment as reported in the study reports or protocols. Overall survival and toxicity were homogenously defined as time to death and by applying CTCAE version 4, respectively. The studies used different clinical, biochemical, and/or radiographic definitions of PFS and local control and HRQoL instruments. One study [77, 78] reported systemic therapy-free survival as time to start of ADT. No study has compared the local PFS. Four studies [79, 82, 91] reported distant PFS as time to new metastasis.

Data were published exclusively as figures for overall survival and PFS until 6 months in ORIOLE [79, 84] and for HRQoL at 3 months in STOMP [77], and were carefully estimated from the respective figures. ORIOLE also reported distant PFS exclusively as a figure [79]; however, we refrained from extracting the data owing to uncertainties in estimation around the 6-month mark.

EXTEND [91] reported overall survival exclusively as a figure with a log-rank test. The study authors described that “Overall survival data were immature, […] similar between arms,” with no events in the IG and two events in the CG, with a log-rank p of 0.21.

Synthesis of results

A meta-analysis for overall survival was not possible because only one out of three trials reported events in both arms. The trial [90] showed no significant differences between the arms (HR 0.65, 95% CI 0.28–1.49, p = 0.302). The pooled results for incidence proportion of grade ≥ 3 toxicity from two trials [90, 91] with events in both arms showed no difference between groups (pooled RR 0.78, 95% CI 0.37–1.65, Z = 0.65, p = 0.52, Fig. 2). Statistical heterogeneity was not detected.

Fig. 2
figure 2

Meta-analysis for incidence proportion of grade ≥ 3 toxicity at 5 years or longest follow-up. Pooled results for critical outcome incidence proportion of grade ≥ 3 toxicity at 5 years or longest follow-up. CI confidence interval df degrees of freedom, IV inverse-variance, M-H Mantel–Haenszel method, SBRT stereotactic body radiotherapy

Full size image

The pooled results from four trials [79, 83, 90, 91] showed significantly longer PFS after SBRT, with an HR of 0.31 (95% CI 0.21–0.45, Z = 6.21, p < 0.00001, Fig. 3). There was no evident statistical heterogeneity. A sensitivity analysis excluding trials with a high risk of bias was not performed because it was not detected in the trials for this outcome (see below).

Fig. 3
figure 3

Meta-analysis for progression-free survival. Pooled results for additional important outcome PFS. The SABR-COMET trial results were for the prostate cancer subset. CI confidence interval, df degrees of freedom, IV inverse-variance, PFS progression-free survival, SBRT stereotactic body radiotherapy

Full size image

The critical and additional important outcomes are summarized in Table 4.

Table 4 Summary of findings
Full size table

Risk of bias and quality of evidence

The risk-of-bias assessment on the study, domain, and outcome levels are shown in Fig. 4, with further comments in Additional file 5.

Fig. 4
figure 4

Risk-of-bias assessment for collated outcomes and per reported outcome. According to the Cochrane risk-of-bias tool version 2, for A Collated outcomes, B Overall survival, C Toxicity, D PFS, E Local control, F HRQoL, G Systemic therapy-free survival, and H Distant PFS. High risk of bias was considered due to the following: bias due to deviations from intended intervention—In STOMP and STOP, a part of the CG received the intervention treatment. In CORE, completion of SOC differed between the IG and CG; bias due to missing outcome data—In ARTO and EXTEND, HRQoL assessments were only available for a part of the participants, at 3 months in ARTO and at baseline in EXTEND; and bias due to measurement of the outcome—In EXTEND, HRQoL assessments were optional for participants and willingness to respond may have differed between the arms. CG control group, D domain, HRQoL health-related quality of life, IG intervention group, PFS progression-free survival, SOC standard of care

Full size image

Overall, the risk of bias arising from the randomization process was low. One trial had some concerns due to no information on allocation concealment; however, only an abstract and trial registry entries were available at that time. Deviations from the intended interventions that could have affected outcomes were observed in three trials. Missing outcome data were considered a risk of bias in two trials, but only for HRQoL outcomes, owing to available data for only some of the trial participants. Bias in measurements of the outcomes was overall of some concerns, except for overall survival, because knowledge of the received intervention could have influenced assessment. However, this was considered unlikely except for HRQoL in one trial where the assessments were optional for the participants and the willingness to respond could have differed between arms.

The quality of evidence assessment is shown in Table 4. The effect estimate for overall survival was considered to have moderate certainty after downgrading by one level for imprecision due to being based on a single study. Toxicity and PFS were considered to have a low certainty and were downgraded by one level each for risk of bias and imprecision. Risk of bias was considered because knowledge of the received intervention could have influenced assessments, and imprecision due to few included participants and events per the GRADE optimal information size criterion [94].

Discussion

Summary of evidence

This is, to our knowledge, the first systematic review approaching studies with high-quality designs using randomization and focusing solely on SBRT as MDT in OMPC. We identified seven randomized phase II trials, of which four investigated PCa among several primary cancer types and one investigated SBRT as one of two MDTs (together with surgery).

The results from four studies, one with reported PCa participant subset data, show promising improvements in PFS in several OMD states with a pooled HR of 0.31 (95% CI 0.21–0.45). No excess toxicities or treatment-related deaths were observed. Overall survival comparisons were immature, as only one of the three trials reported events in both arms.

Our findings are in line with those of previous systematic reviews of prospective trials on OMPC that also found favorable disease control and low toxicity [24,25,26,27]. All of these systematic reviews included STOMP and ORIOLE, being two early RCTs in this field.

Strengths and limitations

To summarize the current evidence, we applied generous eligibility criteria allowing participant subsets and various definitions of OMD and SBRT, and performed a comprehensive search of bibliographic databases and other sources. By including eligible participant subsets and updating our searches in the end of 2023, we identified five additional trials with data on OMPC that were not included in previous systematic reviews (i.e., SABR-COMET, ARTO, EXTEND, CORE, and STOP). Reflecting the rapid development in this field, four of these trials were published in the preceding year.

An important outcome of the review is the presentation of the backdrop against which the current evidence in OMPC is generated. The included studies addressed varying patient groups, treatment approaches (e.g., fractionation schedules and co-administered systemic therapies), and control treatments, which limit the conclusions that can be drawn from pooled effect estimates. The use of ADT and other systemic therapies varied between the trials, which need to be considered when interpreting the results. As more RCTs are published, future systematic reviews may be able to give a more granular picture of the treatment’s efficacy by restricting to individual OMD states and by sensitivity to hormonal therapy, a minimally required EQD2, or certain SOC comparators.

Our results are also limited by aspects encountered in emerging fields, that is, evidence being so far generated in small exploratory phase II trials and heterogeneous outcome definitions. Combining studies in a meta-analysis is a strategy to overcome small sample sizes by increasing the statistical power [52]. However, small RCTs, even when pooled, present limitations. When small studies show positive results, they are more likely to exaggerate differences compared with larger trials owing to statistical imprecision [95]. Furthermore, balancing of prognostic factors between the trial arms from randomization can only be assumed if the sample sizes are sufficiently large. It may not be possible to discern if impressive results are due to a prognostic imbalance or a real treatment effect. Therefore, a pooled estimate would be equally uncertain [94, 96]. This was reflected in our quality of evidence assessment by downgrading for imprecision as the GRADE optimal information size criterion calls for meta-analyses of approximately 250 or more events [94].

The outcome definitions were heterogeneous except for overall survival and toxicity. The definitions of PFS included different event criteria and assessment approaches (e.g., different use of PSA, clinical, and radiographic criteria, imaging modalities, and instructions for repeated imaging), which limit comparability across trials. Our pooled effect estimate from the meta-analysis may have differed had one approach been applied in all studies.

Furthermore, our quality of evidence assessment identified two additional challenges in RCTs: blinding of outcome assessors and adherence to assigned intervention. Blinding in trials of radiotherapeutic interventions is inherently difficult and could be considered for radiologists and data analysts. Issues of intervention adherence and crossover have become central as MDT is increasingly being offered in clinical practice. In two of the included studies [77, 93], parts of the CGs eventually received SBRT, and in one study [84], crossover was allowed after the primary endpoint at 6 months, precluding interpretation of most long-term outcomes in this review. Furthermore, one study [92] reported significantly lower completion of SOC in the IG, which could have underestimated the benefit of SBRT.

Crossover to a yet unestablished treatment should be interpreted with caution because it may compete with other treatments. This could prolong systemic therapy-free survival, favoring the CG, or delay effective treatment, favoring the IG, and therefore cloud the comparison in the intention-to-treat population [97]. While the identified toxicity in the literature was low, there are known rare, severe toxicities that may be life-threatening. It is important to introduce these risks only after confirmatory trials have laid the foundation for risk–benefit assessments in comparison with other established palliative treatments. Currently, there is no evidence that MDT is curative for metastatic PCa, thereby necessitating a cautious approach.

Future research

We identified eight registered and ongoing confirmatory phase III trials that include patients with OMPC (ClinicalTrials.gov registration numbers NCT03143322 [98], NCT03721341 [99], NCT03862911 [100], NCT04115007 [101], NCT04983095 [102], NCT05209243 [103], NCT05717166 [104], and NCT06320067 [105]). One trial including multiple primary cancer types (SABR-COMET-10 [99]) has finalized recruitment, whereas all trials investigating only OMPC are currently recruiting. Of them, the largest is the multi-arm STAMPEDE2 platform [105] with a recruitment target of almost 2500 participants for the comparison of SBRT as MDT added to SOC vs SOC.

SBRT as MDT has several important theoretical benefits (e.g., delaying the start of or a change in systemic therapy and enhancing of the anticancer immune response) that need confirmation through an overall survival impact and cannot be fully captured by other outcomes. Such improvements, together with disease control, could benefit patients by minimizing adverse effects, prolonging the usefulness of systemic therapy, and consequently improving HRQoL and optimizing the use of healthcare resources.

Furthermore, the comparator or concomitant treatments become increasingly important in phase III trials for assessing benefits compared with other established treatments. There are several efficacious systemic therapy options for metastatic PCa at different stages of the disease (e.g., ADT, second-generation androgen receptor inhibitors, chemotherapy, poly-ADP ribose polymerase [PARP] inhibitors, and lutetium-177-PSMA-617 [106, 107]), some of which have only been introduced in the past few years, and is also a field of intense research [108]. Similarly, the participants’ previous treatment histories will become equally important to understand the clinical setting in which MDT is investigated. The differences in outcomes between oligometastatic hormone-sensitive and castration-resistant PCa was illustrated in a prospective phase II trial recruiting before the establishment of second-generation androgen receptor inhibitors [109]. After SBRT as MDT and at least two years of ADT, the three-year metastasis progressions-free survival was 67% (95% CI 53–77) in the cohort with hormone-sensitive disease and 26% (95% CI 7–51) in the cohort with castration-resistant disease.

One way to address outcome heterogeneity is core outcome sets (COS), which are standardized sets of outcomes to be minimally measured and reported in trials for a certain health condition [110]. In the database of Core Outcome Measures in Effectiveness Trials (COMET) [111], an initiative promoting and facilitating the use of COS, three sets for research in advanced PCa are available: one with patient-reported symptoms [112], one for metastatic disease in general [113] (published after the start of this review), and one for castration-resistant disease [114]. However, they are not specific to OMD or MDT.

There is a general agreement on important outcome domains, and the ESTRO–ASTRO consensus document [10] specifying outcomes for RT as MDT (used for outcome selection in this review) is a landmark step towards an OMD- and MDT-specific COS. In the future, harmonizing outcome definitions, measurements, and timing could clarify the interpretation of the results and improve trial comparability. Some of these measurements could include qualitative evaluations such as pain and toxicity and would benefit from involving patients, relatives, and healthcare providers during the development process.

Fractionation schedules and EQD23 varied significantly within and between the included studies, introducing another aspect of heterogeneity. Our review highlights the need for careful consideration of the methods for SBRT planning and delivery, including reporting of dose prescription along with relevant dose-volume metrics for targets and organs at risk [8], in future assessments of ongoing research to ensure reproducibility in clinical practice.

Conclusions

Phase II trials have shown promising improvements in PFS for several OMD states in PCa without excess toxicity. Comparisons for overall survival are currently immature. Outcome definitions were heterogeneous, and harmonization of definitions, measurements, and timing will be essential to the interpretation of results and comparability across trials. The use of outcome measurements as defined in consensus documents is recommended. In future confirmatory phase III trials, adequately large sample sizes, blinding of outcome assessors, and/or adherence to assigned intervention could improve the quality of evidence.

The PRISMA 2009 Checklist is found in Additional file 6.

Availability of data and materials

Datasets analyzed in this study will be available upon reasonable request to the corresponding author.

Abbreviations

ADT:

Androgen deprivation therapy

ASTRO:

American Society for Radiation Oncology

CENTRAL:

Cochrane Central Register of Controlled Trials

CG:

Control group

CI:

Confidence interval

CINAHL:

Cumulative Index to Nursing and Allied Health Literature

COMET:

Core Outcome Measures in Effectiveness Trials

COS:

Core outcome set

CT:

Computed tomography

CTCAE:

Common Terminology Criteria for Adverse Events

EORTC:

European Organization for Research and Treatment of Cancer

EQD2:

Equivalent dose in 2-Gy fractions

ESTRO:

European Society for Radiotherapy and Oncology

FACT-G:

Functional Assessment of Cancer Therapy-General

FACT-P:

Functional Assessment of Cancer Therapy-Prostate

GRADE:

Grading of Recommendations Assessment, Development, and Evaluation

HR:

Hazard ratio

HRQoL:

Health-related quality of life

ICRU:

International Commission on Radiation Units and Measurements

ICTRP:

International Clinical Trials Registry Platform

IG:

Intervention group

ln:

Natural logarithm

MDT:

Metastasis-directed therapy

MRI:

Magnetic resonance imaging

OMD:

Oligometastatic disease

OMPC:

Oligometastatic prostate cancer

PARP:

Poly-ADP ribose polymerase

PCa:

Prostate cancer

PET:

Positron emission tomography

PFS:

Progression-free survival

PRISMA:

Preferred Reporting Items for Systematic Reviews and Meta-analyses

PSA:

Prostate-specific antigen

QLQ-C30:

Quality of Life Questionnaire-Core 30

QLQ-PR25:

Quality of Life Questionnaire-Prostate 25

RCT:

Randomized controlled trial

RECIST:

Response Evaluation Criteria in Solid Tumors

RoB 2:

Cochrane risk-of-bias tool version 2

RR:

Risk ratio

RT:

Radiotherapy

SBRT:

Stereotactic body radiotherapy

SF-36:

36-Item Short Form Health Survey

SOC:

Standard of care

References

  1. Beckham TH, Yang TJ, Gomez D, Tsai CJ. Metastasis-directed therapy for oligometastasis and beyond. Br J Cancer. 2021;124:136–41.

    Article  PubMed  Google Scholar 

  2. Gundem G, Van Loo P, Kremeyer B, Alexandrov LB, Tubio JMC, Papaemmanuil E, et al. The evolutionary history of lethal metastatic prostate cancer. Nature. 2015;520:353–7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. Weichselbaum RR, Hellman S. Oligometastases revisited. Nat Rev Clin Oncol. 2011;8:378–82.

    Article  PubMed  CAS  Google Scholar 

  4. Timmerman RD, Herman J, Cho LC. Emergence of stereotactic body radiation therapy and its impact on current and future clinical practice. J Clin Oncol. 2014;32:2847–54.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Formenti SC, Demaria S. Systemic effects of local radiotherapy. Lancet Oncol. 2009;10:718–26.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Lehrer EJ, Singh R, Wang M, Chinchilli VM, Trifiletti DM, Ost P, et al. Safety and survival rates associated with ablative stereotactic radiotherapy for patients with oligometastatic cancer: a systematic review and meta-analysis. JAMA Oncol. 2021;7:92–106.

    Article  PubMed  Google Scholar 

  7. Marvaso G, Mastroleo F, Corrao G, Zaffaroni M, Vincini MG, Borghetti P, et al. A bibliometric analysis of the oligometastatic state over the last two decades: a shifting paradigm for oncology? An AIRO oligometastatic study group. Cancers (Basel). 2023;15:3902.

    Article  PubMed  Google Scholar 

  8. International Commission on Radiation Units Measurements. ICRU report 91: prescribing, recording, and reporting of stereotactic treatments with small photon beams. J ICRU. 2017;14:1–145.

    Google Scholar 

  9. Guckenberger M, Lievens Y, Bouma AB, Collette L, Dekker A, deSouza NM, et al. Characterisation and classification of oligometastatic disease: a European Society for Radiotherapy and Oncology and European Organisation for Research and Treatment of Cancer consensus recommendation. Lancet Oncol. 2020;21:e18–28.

    Article  PubMed  Google Scholar 

  10. Lievens Y, Guckenberger M, Gomez D, Hoyer M, Iyengar P, Kindts I, et al. Defining oligometastatic disease from a radiation oncology perspective: an ESTRO-ASTRO consensus document. Radiother Oncol. 2020;148:157–66.

    Article  PubMed  Google Scholar 

  11. Kamran SC, Zietman AL. Curing metastatic disease with ablative radiation therapy: separating truth from wish. Int J Radiat Oncol Biol Phys. 2020;107:433–6.

    Article  PubMed  Google Scholar 

  12. Jereczek-Fossa BA, Bortolato B, Gerardi MA, Dicuonzo S, Arienti VM, Berlinghieri S, et al. Radiotherapy for oligometastatic cancer: a survey among radiation oncologists of Lombardy (AIRO-Lombardy). Italy Radiol Med. 2019;124:315–22.

    Article  PubMed  Google Scholar 

  13. Rogowski P, Trapp C, von Bestenbostel R, Konnerth D, Marschner S, Schmidt Hegemann N-S, et al. Radiotherapy in oligometastatic prostate cancer—a pattern of care survey among members of the German Society for Radiation Oncology (DEGRO). Strahlenther Onkol. 2022;198:727–34.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Gillessen S, Bossi A, Davis ID, de Bono J, Fizazi K, James ND, et al. Management of patients with advanced prostate cancer—metastatic and/or castration-resistant prostate cancer: report of the Advanced Prostate Cancer Consensus Conference (APCCC) 2022. Eur J Cancer. 2023;185:178–215.

    Article  PubMed  Google Scholar 

  15. Zilli T, Achard V, Dal Pra A, Schmidt-Hegemann N, Jereczek-Fossa BA, Lancia A, et al. Recommendations for radiation therapy in oligometastatic prostate cancer: an ESTRO-ACROP Delphi consensus. Radiother Oncol. 2022;176:199–207.

    Article  PubMed  Google Scholar 

  16. Yao HH, Hong M, Corcoran NM, Siva S, Foroudi F. Advances in local and ablative treatment of oligometastasis in prostate cancer. Asia Pac J Clin Oncol. 2014;10:308–21.

    Article  PubMed  Google Scholar 

  17. Ost P, Bossi A, Decaestecker K, De Meerleer G, Giannarini G, Karnes RJ, et al. Metastasis-directed therapy of regional and distant recurrences after curative treatment of prostate cancer: a systematic review of the literature. Eur Urol. 2015;67:852–63.

    Article  PubMed  Google Scholar 

  18. Bibault JE. [Stereotactic body radiation therapy for oligometastatic prostate cancer]. Bull Cancer. 2018;105:120–5.

    Article  PubMed  Google Scholar 

  19. Vilela RA, Navarro NF, Faria ET, Ferreira EB, Ruzza RZ, Gadia R, et al. Use of stereotactic body radiation therapy for oligometastatic recurrent prostate cancer: a systematic review. J Med Imaging Radiat Oncol. 2018;62:692–706.

    Article  PubMed  Google Scholar 

  20. Slaoui A, Albisinni S, Aoun F, Assenmacher G, Al Hajj Obeid W, Diamand R, et al. A systematic review of contemporary management of oligometastatic prostate cancer: fighting a challenge or tilting at windmills? World J Urol. 2019;37:2343–53.

    Article  PubMed  Google Scholar 

  21. Albisinni S, Van Damme J, Aoun F, Bou Kheir G, Roumeguère T, De Nunzio C. A systematic review of imaging-guided metastasis-directed therapy for oligorecurrent prostate cancer: revolution or devolution? Minerva Urol Nefrol. 2020;72:279–91.

    Article  PubMed  Google Scholar 

  22. Miura N, Pradere B, Mori K, Mostafaei H, Quhal F, Misrai V, et al. Metastasis-directed therapy and prostate-targeted therapy in oligometastatic prostate cancer: a systematic review. Minerva Urol Nefrol. 2020;72:531–42.

    Article  PubMed  Google Scholar 

  23. Rogowski P, Roach M 3rd, Schmidt-Hegemann NS, Trapp C, von Bestenbostel R, Shi R, et al. Radiotherapy of oligometastatic prostate cancer: a systematic review. Radiat Oncol. 2021;16:50.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Connor MJ, Smith A, Miah S, Shah TT, Winkler M, Khoo V, Ahmed HU. Targeting oligometastasis with stereotactic ablative radiation therapy or surgery in metastatic hormone-sensitive prostate cancer: a systematic review of prospective clinical trials. Eur Urol Oncol. 2020;3:582–93.

    Article  PubMed  Google Scholar 

  25. Marvaso G, Volpe S, Pepa M, Augugliaro M, Corrao G, Biffi A, et al. Oligorecurrent prostate cancer and stereotactic body radiotherapy: where are we now? A systematic review and meta-analysis of prospective studies. Eur Urol Open Sci. 2021;27:19–28.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Miszczyk M, Rajwa P, Yanagisawa T, Nowicka Z, Shim SR, Laukhtina E, et al. The efficacy and safety of metastasis-directed therapy in patients with prostate cancer: a systematic review and meta-analysis of prospective studies. Eur Urol. 2024;85:125–38.

    Article  PubMed  CAS  Google Scholar 

  27. Yan M, Moideen N, Bratti VF, Moraes FY. Stereotactic body radiotherapy (SBRT) in metachronous oligometastatic prostate cancer: a systematic review and meta-analysis on the current prospective evidence. Br J Radiol. 2020;93:20200496.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Burns PB, Rohrich RJ, Chung KC. The levels of evidence and their role in evidence-based medicine. Plast Reconstr Surg. 2011;128:305–10.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Shamseer L, Moher D, Clarke M, Ghersi D, Liberati A, Petticrew M, et al. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015: elaboration and explanation. BMJ. 2015;349:g7647.

    Article  Google Scholar 

  30. PROSPERO: Stereotactic body radiotherapy as metastasis-directed therapy for oligometastatic prostate cancer: a systematic review and meta-analysis of randomized trials (CRD42021230131). https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021230131 (2021). Accessed 27 Mar 2023.

  31. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. BMJ. 2009;339:b2535.

    Article  PubMed  PubMed Central  Google Scholar 

  32. deSouza NM, Liu Y, Chiti A, Oprea-Lager D, Gebhart G, Van Beers BE, et al. Strategies and technical challenges for imaging oligometastatic disease: recommendations from the European Organisation for Research and Treatment of Cancer imaging group. Eur J Cancer. 2018;91:153–63.

    Article  PubMed  Google Scholar 

  33. Cox JD, Stetz J, Pajak TF. Toxicity criteria of the Radiation Therapy Oncology Group (RTOG) and the European Organization for Research and Treatment of Cancer (EORTC). Int J Radiat Oncol Biol Phys. 1995;31:1341–6.

    Article  PubMed  CAS  Google Scholar 

  34. National Cancer Institute: Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. http://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_Reference_8.5x11.pdf (2017). Accessed 22 Aug 2023.

  35. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45:228–47.

    Article  PubMed  CAS  Google Scholar 

  36. Herdman M, Gudex C, Lloyd A, Janssen M, Kind P, Parkin D, et al. Development and preliminary testing of the new five-level version of EQ-5D (EQ-5D-5L). Qual Life Res. 2011;20:1727–36.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Hays RD. The Medical Outcomes Study (MOS) measures of patient adherence. https://www.rand.org/content/dam/rand/www/external/health/surveys_tools/mos/mos_adherence_survey.pdf (1994). Accessed 22 Aug 2023.

  38. Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ, et al. The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst. 1993;85:365–76.

    Article  PubMed  CAS  Google Scholar 

  39. Giesinger JM, Kieffer JM, Fayers PM, Groenvold M, Petersen MA, Scott NW, et al. Replication and validation of higher order models demonstrated that a summary score for the EORTC QLQ-C30 is robust. J Clin Epidemiol. 2016;69:79–88.

    Article  PubMed  Google Scholar 

  40. van Andel G, Bottomley A, Fosså SD, Efficace F, Coens C, Guerif S, et al. An international field study of the EORTC QLQ-PR25: a questionnaire for assessing the health-related quality of life of patients with prostate cancer. Eur J Cancer. 2008;44:2418–24.

    Article  PubMed  Google Scholar 

  41. Cella DF, Tulsky DS, Gray G, Sarafian B, Linn E, Bonomi A, et al. The functional assessment of cancer therapy scale: development and validation of the general measure. J Clin Oncol. 1993;11:570–9.

    Article  PubMed  CAS  Google Scholar 

  42. Esper P, Mo F, Chodak G, Sinner M, Cella D, Pienta KJ. Measuring quality of life in men with prostate cancer using the Functional Assessment of Cancer Therapy-prostate instrument. Urology. 1997;50:920–8.

    Article  PubMed  CAS  Google Scholar 

  43. The Endnote Team: EndNote 21. https://endnote.com/ (2013).

  44. Veritas Health Innovation: Covidence systematic review software. http://www.covidence.org (2023).

  45. Google: Google Forms. https://www.google.com/forms/about/ (2024).

  46. Mitchell M, Muftakhidinov B, Winchen T, et al.: Engauge Digitizer Software version 12.1. http://markummitchell.github.io/engauge-digitizer (2019).

  47. Sterne JAC, Savović J, Page MJ, Elbers RG, Blencowe NS, Boutron I, et al. RoB 2: A revised tool for assessing risk of bias in randomised trials. BMJ. 2019;366:l4898.

    Article  PubMed  Google Scholar 

  48. McGuinness LA, Higgins JPT. Risk-of-bias VISualization (robvis): an R package and Shiny web app for visualizing risk-of-bias assessments. Res Synth Methods. 2020;12:55–61.

    Article  PubMed  Google Scholar 

  49. Schünemann H BJ, Guyatt G, Oxman A, editors. GRADE handbook for grading quality of evidence and strength of recommendations. The GRADE Working Group. 2013. http://www.guidelinedevelopment.org/handbook. Accessed 8 Jan 2021.

  50. McMaster University and Evidence Prime: GRADEpro GDT: GRADEpro Guideline Development Tool. http://www.gradepro.org (2024).

  51. The Cochrane Collaboration: Review Manager (RevMan) version 5.4.1. https://training.cochrane.org/online-learning/core-software-cochrane-reviews/revman (2020).

  52. Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, et al. Chapter 10: Analysing data and undertaking meta-analyses. In: Deeks JJ, Higgins JPT, Altman DG, editors. Cochrane Handbook for Systematic Reviews of Interventions version 6.1. Copenhagen: The Cochrane Collaboration; 2020. https://training.cochrane.org/handbook/archive/v6.1. Accessed 8 Jan 2021.

  53. Tierney JF, Stewart LA, Ghersi D, Burdett S, Sydes MR. Practical methods for incorporating summary time-to-event data into meta-analysis. Trials. 2007;8:16.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Egger M, Smith GD, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315:629.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  55. Bazyar S, Sutera P, Phillips R, Deek MP, Radwan N, Marshall CH, et al. Prognostic impact of circulating tumor cells in oligometastatic hormone-sensitive prostate cancer following metastasis-directed therapy. J Clin Oncol. 2023;41:199.

    Article  Google Scholar 

  56. Bowden P, See AW, Frydenberg M, Haxhimolla H, Costello AJ, Moon D, et al. Fractionated stereotactic body radiotherapy for up to five prostate cancer oligometastases: interim outcomes of a prospective clinical trial. Int J Cancer. 2020;146:161–8.

    Article  PubMed  CAS  Google Scholar 

  57. Broomfield JA, Greenspoon JN, Swaminath A. Utilization of stereotactic ablative radiotherapy in the management of oligometastatic disease. Curr Oncol. 2014;21:115–7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  58. De Bleser E, Willems R, Decaestecker K, Annemans L, De Bruycker A, Fonteyne V, et al. A trial-based cost-utility analysis of metastasis-directed therapy for oligorecurrent prostate cancer. Cancers (Basel). 2020;12:132.

    Article  PubMed  Google Scholar 

  59. Dunst J, Baumann R. [Local metastasis treatment in oligometastatic disease: also relevant for prostate cancer]. Strahlenther Onkol. 2018;194:465–7.

    Article  PubMed  Google Scholar 

  60. Dunst J. [Curative radiotherapy of oligometastatic cancer: long-term results of the SABR-COMET phase II trial]. Strahlenther Onkol. 2021;197:365–7.

    Article  PubMed  PubMed Central  Google Scholar 

  61. Gupta A, Pugh TJ, Lam E, Sheridan AD, Nath S. The role of primary tumor treatment and metastasis-directed therapy in oligometastatic prostate cancer. Oncology (Williston Park). 2019;33:187–91.

    PubMed  Google Scholar 

  62. Hemmatazad H, Mathier E, Aebersold DM, Shelan M. [Single dose of 24 Gy or 3-fraction SBRT regimen in the treatment of oligometastatic cancer? A phase III multi-center trial]. Strahlenther Onkol. 2021;197:859–61.

    Article  PubMed  Google Scholar 

  63. Hermann R-M, Christiansen H, Bremer M. [Influence of fractionation (single dose 24Gy vs. 3 fractions of 9Gy) on oncological end points in SBRT of oligometastases]. Strahlenther Onkol. 2021;197:661–3.

    Article  PubMed  Google Scholar 

  64. Horjeti E, Kim Y, Arafa A, Sutera P, Phillips R, Song D, et al. PSMA-positive extracellular vesicles predict disease recurrence in oligometastatic castration-sensitive prostate cancer treated with stereotactic ablative radiotherapy: analysis of the ORIOLE trial. Int J Radiat Oncol Biol Phys. 2023;117(Suppl):S36.

    Article  Google Scholar 

  65. Hrinivich WT, Phillips R, Da Silva AJ, Radwan N, Gorin MA, Rowe SP, et al. Online prostate-specific membrane antigen and positron emission tomography–guided radiation therapy for oligometastatic prostate cancer. Adv Radiat Oncol. 2020;5:260–8.

    Article  PubMed  Google Scholar 

  66. Kumar A, Straka C, Courtney PT, Vitzthum L, Riviere P, Murphy JD. Cost-effectiveness analysis of stereotactic ablative radiation therapy in patients with oligometastatic cancer. Int J Radiat Oncol Biol Phys. 2021;109:1185–94.

    Article  PubMed  Google Scholar 

  67. Nguyen Q-N, Chun SG, Chow E, Komaki R, Liao Z, Zacharia R, et al. Single-fraction stereotactic vs conventional multifraction radiotherapy for pain relief in patients with predominantly nonspine bone metastases: a randomized phase 2 component of a phase 2/3 trial. JAMA Oncol. 2019;5:872–8.

    Article  PubMed  PubMed Central  Google Scholar 

  68. Qu XM, Chen Y, Zaric GS, Senan S, Olson RA, Harrow S, et al. Is SABR cost-effective in oligometastatic cancer? An economic analysis of the SABR-COMET randomized trial. Int J Radiat Oncol Biol Phys. 2020;109:1176–84.

    Article  PubMed  Google Scholar 

  69. Qu M, Chen Y, Zaric G, Senan S, Olson R, Harrow S, et al. Cost-effectiveness of SABR in oligometastatic cancer: an economic analysis based on long-term results of the SABR-COMET randomized trial. Radiother Oncol. 2021;163(Suppl 1):S13.

    Article  Google Scholar 

  70. Raymakers AJN, Cameron D, Tyldesley S, Regier DA. Cost-effectiveness analysis of stereotactic ablative body radiotherapy for the treatment of oligometastatic tumors versus standard of care. Curr Oncol. 2021;28:1857–66.

    Article  PubMed  PubMed Central  Google Scholar 

  71. Ryu S, Deshmukh S, Timmerman RD, Movsas B, Gerszten PC, Yin FF, et al. Radiosurgery compared to external beam radiotherapy for localized spine metastasis: phase III results of NRG Oncology/RTOG 0631. Int J Radiat Oncol Biol Phys. 2019;105(Suppl):S2–3.

    Article  Google Scholar 

  72. Siva S, Bressel M, Kron T, Mai T, Le HV, Montgomery R, et al. Stereotactic ablative fractionated radiotherapy versus radiosurgery for oligometastatic neoplasia to the lung: a randomized phase II trial. Int J Radiat Oncol Biol Phys. 2020;108(Suppl):S3–4.

    Article  Google Scholar 

  73. Sprave T, Förster R, Schlampp I, Hees K, Bruckner T, Bostel T, et al. Pain response after high dose single-fraction IMRT for patients with spinal bone metastases—a randomized controlled trial. Strahlenther Onkol. 2018;194(Suppl 1):S66.

    Google Scholar 

  74. Sridharan S, Steigler A, Spry NA, Joseph D, Lamb DS, Matthews JH, et al. Oligometastatic bone disease in prostate cancer patients treated on the TROG 0304 RADAR trial. Radiother Oncol. 2016;121:98–102.

    Article  PubMed  Google Scholar 

  75. van de Ven S, van den Bongard D, Pielkenrood B, Kasperts N, Eppinga W, Peters M, 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;107:39–47.

    Article  PubMed  Google Scholar 

  76. Zelefsky MJ, Yamada Y, Greco C, Lis E, Schöder H, Lobaugh S, et al. Phase III multi-center, prospective, randomized trial comparing single dose 24 Gy radiotherapy to a 3-fraction SBRT regimen in the treatment of oligometastatic cancer. Int J Radiat Oncol Biol Phys. 2021;110:672–9.

    Article  PubMed  PubMed Central  Google Scholar 

  77. Ost P, Reynders D, Decaestecker K, Fonteyne V, Lumen N, DeBruycker A, et al. Surveillance or metastasis-directed therapy for oligometastatic prostate cancer recurrence: a prospective, randomized, multicenter phase II trial. J Clin Oncol. 2018;36:446–53.

    Article  PubMed  CAS  Google Scholar 

  78. Ost P, Reynders D, Decaestecker K, Fonteyne V, Lumen N, Bruycker AD, et al. Surveillance or metastasis-directed therapy for oligometastatic prostate cancer recurrence (STOMP): five-year results of a randomized phase II trial. J Clin Oncol. 2020;38:10.

    Article  Google Scholar 

  79. Deek MP, Van der Eecken K, Sutera P, Deek RA, Fonteyne V, Mendes AA, et al. Long-term outcomes and genetic predictors of response to metastasis-directed therapy versus observation in oligometastatic prostate cancer: analysis of STOMP and ORIOLE trials. J Clin Oncol. 2022;40:3377–82.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  80. Palma DA, Olson R, Harrow S, Gaede S, Louie AV, Haasbeek C, 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;393:2051–8.

    Article  PubMed  Google Scholar 

  81. Olson R, Senan S, Harrow S, Gaede S, Louie A, Haasbeek C, 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;105:943–7.

    Article  PubMed  Google Scholar 

  82. Palma DA, Olson R, Harrow S, Gaede S, Louie AV, Haasbeek C, 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;38:2830–8.

    Article  PubMed  PubMed Central  Google Scholar 

  83. Harrow S, Palma DA, Olson R, Gaede S, Louie AV, Haasbeek C, et al. Stereotactic radiation for the comprehensive treatment of oligometastases (SABR-COMET): extended long-term outcomes. Int J Radiat Oncol Biol Phys. 2022;114:611–6.

    Article  PubMed  Google Scholar 

  84. Phillips R, Shi WY, Deek M, Radwan N, Lim SJ, Antonarakis ES, et al. Outcomes of observation vs stereotactic ablative radiation for oligometastatic prostate cancer: the ORIOLE phase 2 randomized clinical trial. JAMA Oncol. 2020;6:650–9.

    Article  PubMed  PubMed Central  Google Scholar 

  85. Francolini G, Garlatti P, Detti B, Bruni A, Mantini G, Pergolizzi S, et al. Early results from a phase II randomized trial testing stereotactic body radiation therapy in patients with oligometastatic castration resistant prostate cancer undergoing I line treatment with abiraterone acetate (ARTO trial-NCT03449719). Eur Urol Open Sci. 2020;21(Suppl 3):S150.

    Article  Google Scholar 

  86. Francolini G, Garlatti P, Loi M, Detti B, Aquilano M, Allegra A, et al. ARTO trial (NCT03449719), a randomized phase II trial enrolling oligometastatic castration-resistant prostate cancer patients treated with first-line abiraterone acetate with or without stereotactic body radiation therapy: preliminary results comprehensive of biochemical outcomes and circulating tumor cells analysis. J Clin Oncol. 2021;39:118.

    Article  Google Scholar 

  87. Francolini G, Detti B, Di Cataldo V, Caini S, Alitto AR, Parisi S, et al. Early outcomes of a randomized trial of SBRT and abiraterore in mCPRC: ARTO trial NCT03449719. Radiother Oncol. 2022;170(Suppl 1):S530–1.

    Article  Google Scholar 

  88. Francolini G, Detti B, Di Cataldo V, Caini S, Alitto AR, Parisi S, et al. Biochemical outcomes from ARTO trial (NCT03449719) a phase II randomized trial testing association between abiraterone acetate and stereotactic body radiation therapy in castrate-resistant prostate cancer patients. Ann Oncol. 2022;33(Suppl 7):S1167–8.

    Article  Google Scholar 

  89. Francolini G, Allegra AG, Caini S, Detti B, Di Cataldo V, Alitto A, et al. Early outcomes from a phase II randomized trial testing stereotactic body radiation therapy in patients undergoing I line treatment with abiraterone acetate for oligometastatic castration resistant prostate cancer (ARTO trial-NCT03449719). Eur Urol. 2023;83(Suppl 1):S1716–7.

    Article  Google Scholar 

  90. Francolini G, Gaetano Allegra A, Detti B, Di Cataldo V, Caini S, Bruni A, et al. Stereotactic body radiation therapy and abiraterone acetate for patients affected by oligometastatic castrate-resistant prostate cancer: a randomized phase II trial (ARTO). J Clin Oncol. 2023;41:5561–8.

    Article  PubMed  CAS  Google Scholar 

  91. Tang C, Sherry AD, Haymaker C, Bathala T, Liu S, Fellman B, et al. Addition of metastasis-directed therapy to intermittent hormone therapy for oligometastatic prostate cancer: the EXTEND phase 2 randomized clinical trial. JAMA Oncol. 2023;9:825–34.

    Article  PubMed  PubMed Central  Google Scholar 

  92. Khoo V, Kirby A, Ahmed M, Dewan M, Van As N, Franks K, et al. CORE - standard of care +/- stereotactic body radiotherapy for oligometastases - primary results. Radiother Oncol. 2023;182(Suppl 1):S627.

    Article  Google Scholar 

  93. Schellenberg D, Gabos Z, Duimering A, Debenham BJ, Fairchild A, Huang F, et al. Stereotactic ablative radiotherapy for oligo-progressive cancers: results of the randomized phase II STOP trial. Int J Radiat Oncol Biol Phys. 2023;117(Suppl):S58.

    Article  Google Scholar 

  94. Guyatt GH, Oxman AD, Kunz R, Brozek J, Alonso-Coello P, Rind D, et al. GRADE guidelines 6. Rating the quality of evidence—imprecision. J Clin Epidemiol. 2011;64:1283–93.

    Article  PubMed  Google Scholar 

  95. Bentzen SM. Radiobiological considerations in the design of clinical trials. Radiother Oncol. 1994;32:1–11.

    Article  PubMed  CAS  Google Scholar 

  96. Sterne JA, Gavaghan D, Egger M. Publication and related bias in meta-analysis: power of statistical tests and prevalence in the literature. J Clin Epidemiol. 2000;53:1119–29.

    Article  PubMed  CAS  Google Scholar 

  97. Haslam A, Prasad V. When is crossover desirable in cancer drug trials and when is it problematic? Ann Oncol. 2018;29:1079–81.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  98. ClinicalTrials.gov: Standard treatment +/- SBRT in solid tumors patients with between 1 and 3 bone-only metastases (STEREO-OS) (NCT03143322). https://clinicaltrials.gov/show/NCT03143322 (2017). Accessed 29 Mar 2024.

  99. ClinicalTrials.gov: Stereotactic ablative radiotherapy for comprehensive treatment of 4-10 oligometastatic tumors (SABR-COMET-10) (NCT03721341). https://clinicaltrials.gov/show/NCT03721341 (2018). Accessed 26 Mar 2024.

  100. ClinicalTrials.gov: Phase III randomized controlled trial and economic evaluation of stereotactic ablative radiotherapy for comprehensive treatment of oligometastatic (1-3 metastases) cancer (SABR-COMET-3) (NCT03862911). https://clinicaltrials.gov/show/NCT03862911 (2019). Accessed 25 Mar 2024.

  101. ClinicalTrials.gov: Prostate-cancer treatment using stereotactic radiotherapy for oligometastases ablation in hormone-sensitive patients - a GETUG-AFU phase III randomized controlled trial (PRESTO) (NCT04115007). https://clinicaltrials.gov/show/NCT04115007 (2019). Accessed 25 Mar 2024.

  102. ClinicalTrials.gov: Metastasis directed stereotactic body radiotherapy for oligo metastatic hormone sensitive prostate cancer (METRO) (NCT04983095). https://clinicaltrials.gov/study/NCT04983095 (2021). Accessed 26 Mar 2024.

  103. ClinicalTrials.gov: Phase III study of stereotactic body radiation therapy (SBRT) plus standard of care in castration sensitive oligometastatic prostate cancer patients (START-MET) (NCT05209243). https://clinicaltrials.gov/study/NCT05209243 (2022). Accessed 29 Mar 2024.

  104. ClinicalTrials.gov: A randomized phase III trial of stereotactic ablative radiotherapy for patients with up to 10 oligometastases and a synchronous primary tumor (SABR-SYNC) (NCT05717166). https://clinicaltrials.gov/study/NCT05717166 (2023). Accessed 31 Mar 2024.

  105. ClinicalTrials.gov: Studying treatments in patients receiving androgen deprivation therapy (ADT) and androgen receptor signalling inhibitors (ARSI) for metastatic prostate cancer: evaluation of drug and radiation efficacy: a 2nd multi-arm multi-stage randomised controlled trial (STAMPEDE2) (NCT06320067). https://clinicaltrials.gov/study/NCT06320067 (2024). Accessed 23 Mar 2024.

  106. Cronford P, Tilki D, van den Bergh RCN, Briers E, Patient Advocate (European Prostate Cancer Coalition/Europa UOMO), Eberli D, et al.: EAU-EANM-ESTRO-ESUR-ISUP-SIOG guidelines on prostate cancer. https://uroweb.org/guidelines/prostate-cancer (2024). Accessed 26 Apr 2024.

  107. Schaeffer EM, Srinivas S, Adra N, An Y, Barocas D, Bitting R, et al. Prostate cancer, version 4.2023, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2023;21:1067–96.

    Article  PubMed  CAS  Google Scholar 

  108. Posdzich P, Darr C, Hilser T, Wahl M, Herrmann K, Hadaschik B, Grünwald V. Metastatic prostate cancer—a review of current treatment options and promising new approaches. Cancers (Basel). 2023;15:461.

    Article  PubMed  CAS  Google Scholar 

  109. Conde-Moreno AJ, López-Campos F, Hervás A, Morillo V, Méndez A, Puertas MDM, et al. A phase II trial of stereotactic body radiation therapy and androgen deprivation for oligometastases in prostate cancer (SBRT-SG 05). Pract Radiat Oncol. 2024;14:e344–52.

    Article  PubMed  Google Scholar 

  110. Williamson PR, Altman DG, Blazeby JM, Clarke M, Devane D, Gargon E, Tugwell P. Developing core outcome sets for clinical trials: issues to consider. Trials. 2012;13:132.

    Article  PubMed  PubMed Central  Google Scholar 

  111. COMET Initiative: Core outcome measures in effectiveness trials. https://www.comet-initiative.org/ (2024). Accessed 18 Apr 2024.

  112. Chen RC, Chang P, Vetter RJ, Lukka H, Stokes WA, Sanda MG, et al. Recommended patient-reported core set of symptoms to measure in prostate cancer treatment trials. J Natl Cancer Inst. 2014;106:dju132.

    Article  PubMed  PubMed Central  Google Scholar 

  113. Beyer K, Moris L, Lardas M, Omar MI, Healey J, Tripathee S, et al. Updating and integrating core outcome sets for localised, locally advanced, metastatic, and nonmetastatic castration-resistant prostate cancer: an update from the PIONEER Consortium. Eur Urol. 2022;81:503–14.

    Article  PubMed  Google Scholar 

  114. Scher HI, Halabi S, Tannock I, Morris M, Sternberg CN, Carducci MA, et al. Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: recommendations of the Prostate Cancer Clinical Trials Working Group. J Clin Oncol. 2008;26:1148–59.

    Article  PubMed  Google Scholar 

  115. The Institute of Cancer Research: CORE: a randomised trial of conventional care versus radioablation (stereotactic body radiotherapy) for extracranial oligometastases. https://www.icr.ac.uk/our-research/centres-and-collaborations/centres-at-the-icr/clinical-trials-and-statistics-unit/our-research/clinical-trials/core (2024). Accessed 25 Mar 2024.

  116. ClinicalTrials.gov: Stereotactic radiotherapy for oligo-progressive metastatic cancer: a randomized phase II trial (STOP) (NCT02756793). https://clinicaltrials.gov/study/NCT02756793 (2016). Accessed 17 Feb 2024.

  117. ClinicalTrials.gov: Conventional care versus radioablation (stereotactic body radiotherapy) for extracranial oligometastases (CORE) (NCT02759783). https://clinicaltrials.gov/show/NCT02759783 (2016). Accessed 31 Mar 2024.

  118. Costelloe CM, Chuang HH, Madewell JE, Ueno NT. Cancer response criteria and bone metastases: RECIST 1.1 MDA and PERCIST. J Cancer. 2010;1:80–92.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank Professor Robin Christensen (Biostatistics and Clinical Epidemiology at the Section for Biostatistics and Evidence-Based Research, The Parker Institute, Copenhagen, Denmark) for his guidance in relation to data analysis of randomized crossover trials, and Dr Giulio Francolini (Radiation Oncology Unit, Oncology Department, Careggi University Hospital, Florence, Italy) for providing supplementary data.

Funding

Open access funding provided by Lund University. This research was funded by the Region Skåne’s Research and Development Foundation, Research Funds of Skåne University Hospital, and Swedish Governmental Funding of Clinical Research (ALF). The Parker Institute is supported by a core grant from the Oak Foundation (OCAY-13–309).

Author information

Author notes

  1. Andreas Hallqvist and Louise Bjørn Larsen contributed equally to this work.

Authors and Affiliations

  1. Division of Oncology, Department of Clinical Sciences, Faculty of Medicine, Lund University, Lund, Sweden

    Astrid E. Persson, Per Nilsson & Adalsteinn Gunnlaugsson

  2. Department of Hematology, Oncology, and Radiation Physics, Skåne University Hospital, Lund, Sweden

    Astrid E. Persson, Jonas Scherman, Per Nilsson & Adalsteinn Gunnlaugsson

  3. Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden

    Andreas Hallqvist

  4. Department of Oncology, Sahlgrenska University Hospital, Gothenburg, Sweden

    Andreas Hallqvist

  5. Department of Oncology, Herlev Hospital, Copenhagen University Hospitals, Herlev, Denmark

    Louise Bjørn Larsen

  6. National Institute of Public Health, University of Southern Denmark, Copenhagen, Denmark

    Mette Rasmussen

  7. Clinical Health Promotion Centre, Department of Health Sciences, Lund University, Lund, Sweden

    Mette Rasmussen & Hanne Tønnesen

  8. Clinical Health Promotion Centre, WHO Collaborating Centre, The Parker Institute, Bispebjerg and Frederiksberg Hospital, Copenhagen University, Copenhagen, Frederiksberg, Denmark

    Hanne Tønnesen

Authors
  1. Astrid E. Persson
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Andreas Hallqvist
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. Louise Bjørn Larsen
    View author publications

    You can also search for this author inPubMed Google Scholar

  4. Mette Rasmussen
    View author publications

    You can also search for this author inPubMed Google Scholar

  5. Jonas Scherman
    View author publications

    You can also search for this author inPubMed Google Scholar

  6. Per Nilsson
    View author publications

    You can also search for this author inPubMed Google Scholar

  7. Hanne Tønnesen
    View author publications

    You can also search for this author inPubMed Google Scholar

  8. Adalsteinn Gunnlaugsson
    View author publications

    You can also search for this author inPubMed Google Scholar

Contributions

AEP, JS, PN, HT, and AG contributed to the conceptualization of the systematic review and all authors to the development of the protocol. AEP performed the literature searches. AEP, AH, LBL, HT, and AG partook in study selection. AEP, AH, and LBL collected data and MR performed the meta-analyses. AH and LBL performed the risk-of-bias and quality of evidence assessments. HT and AG supervised the project. AEP wrote the first manuscript draft. All authors contributed to its revision and approved the final manuscript.

Corresponding author

Correspondence to Astrid E. Persson.

Ethics declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

AEP: None. AH: None. LBL: Receipt of a travelling grant from MSD. MR: None. JS: None. PN: None. HT: None. AG: Receipt of honoraria for a lecture from Janssen-Cilag.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Persson, A.E., Hallqvist, A., Bjørn Larsen, L. et al. Stereotactic body radiotherapy as metastasis-directed therapy in oligometastatic prostate cancer: a systematic review and meta-analysis of randomized controlled trials. Radiat Oncol 19, 173 (2024). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s13014-024-02559-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s13014-024-02559-7

Keywords

Radiation Oncology

ISSN: 1748-717X

Contact us