Een subgroep van patiënten met gemetastaseerde ziekte bestaat uit de patiënten met oligometastasen. De definitie hiervan verschilt in de literatuur, maar in het algemeen wordt hiervoor -zowel in inclusiecriteria voor studies als de klinische praktijk- een aantal van maximaal 3 tot 5 metastasen aangehouden.

Patiënten met oligometastasen hebben vaak een langere overleving dan patiënten met uitgebreidere metastasen, waarbij mogelijk zelfs naar curatie gestreefd kan worden. In die gedachte valt het te verdedigen om de metastasen lokaal agressief te behandelen, bijvoorbeeld middels chirurgie of hoge dosis radiotherapie. Hierover is binnen de oncologie nog veel discussie, temeer omdat de meerwaarde van lokale agressieve behandelingen niet in alle settings is aangetoond. Momenteel is de praktijkvariatie van behandeling binnen deze patiëntengroep groot. Daar komt bij dat hier (potentieel) grotere morbiditeit tegenover staat, die wel moet opwegen tegen het oncologisch voordeel.

Conclusions could be drawn for stereotactic ablative radiotherapy, but not for other treatment modalities, such as surgery or ablative techniques, for oligometastatic disease. Only narrative literature was available that underlines the importance of an oncological surgical approach towards oligometastatic disease.

Stereotactic ablative radiotherapy (SABR) versus palliative standard-of-care (SOC) treatments

Description of systematic reviews focusing on treatment type, not focusing on a specific primary tumor

Stereotactic ablative radiotherapy (SABR) vs Standard of care (SOC)

Tran (2022) systematically reviewed clinical evidence to synthesize and critically appraise the current evidence of the clinical effectiveness and safety of stereotactic ablative radiotherapy (SABR) for the treatment of patients with oligometastatic cancer, as part of a health technology assessment. They compared the following outcomes between SABR and standard of care (SOC): OS, PFS, Freedom from progression, Health related quality of life, Local Control (LC), use of Systemic therapy, and Adverse Events (AE). The last literature search covered the period January 1, 1990 to December 30, 2021. Besides, the most recent search for clinical trial registries was conducted on January 21, 2022 and for grey literature between January 10, 2022, and January 24, 2022. In this systematic review, twelve studies, published between 2013 and 2021, were included of which three randomised controlled trials (RCTs). These RCTs can be found in table 1. For more details about the included studies, we refer to Tran (2022).

Lehrer (2021) was included in this summary of the literature for their assessment of safety and survival rates for patients with oligometastatic cancer. They searched PubMed/MEDLINE, Embase, Cochrane Database of Systematic Reviews, and CINAHL up to December 23, 2019. They included 21 prospective trials (including the 3 RCTs also included by Tran, 2022) comprising 943 patients who underwent SABR for the treatment of 1290 oligometastases. The most frequently treated lesions by SABR site were bone and/or spine (44.8%).

Table 1. Study characteristics of RCTs included in Tran 2022

SABR: stereotactic ablative radiotherapy; SOC: Standard of care; OS: Overall Survival; PFS: Progression free survival; LC: Local control; QoL: Quality of Life.

Description of studies focusing on a specific tumor type

Breast cancer

Viani (2021) systematically reviewed the literature from 1990 up to December 2020 to assess the effectiveness and safety of SABR for oligometastatic breast cancer patients. In the analysis 10 studies were included, with one trial examined twice because it included two separate trial arms stratified on metastatic site (bone versus visceral sites). These 10 studies included 467 patients in 7 retrospective and 3 prospective trials. Treatment consisted of SABR with any fractionation or technique (including 3D conformal treatment, Intensity modulated radiotherapy (IMRT) or volumetric arc radiotherapy (VMAT)). Viani (2021) analysed the following outcomes: overall survival (OS), local control (LC), progression free survival (PFS), and grade 2 toxicity. Limitations of the included studies are the limited number of patients and study designs (retrospective and prospective single-arm studies). For more details about the included studies, we refer to Viani 2021. The systematic review by Viani (2021) did not perform risk of bias assessments and suffered from heterogeneity in doses used based on treatment site which may impact observed outcomes.

Lung cancer

No systematic reviews describing oligometastatic lung cancer were identified. Tran (2022) identified one single-institution randomized phase 2 study comparing maintenance chemotherapy alone (n=15) vs non-invasive SABR prior to maintenance chemotherapy (n=14) in patients with non–progressive limited metastatic NSCLC after induction therapy (Iyengar, 2017). For the characteristics of this study see Table 1).

Prostate cancer

SABR versus Standard of care (SOC)

Tran (2022) identified one prospective randomised controlled trial (phase II) that studied treatment for oligometastatic prostate cancer (Phillips, 2020, see table 1).

Surgery or SABR vs Standard of care (SOC)

Rogowski (2021) systematically reviewed the literature to provide an overview of the evidence to date for metastasis-directed therapy (MDT) in oligometastatic prostate cancer. Inclusion criteria for MDT was radiotherapy. Exclusion criteria were: case series that comprised fewer than five cases, studies in which not all metastases were treated or just palliative radiotherapy was conducted, and studies without sufficient clinical survival data. Rogowski (2021) searched up to November 2020 and included 56 studies of which four clinical trials and two RCTs (Phillips, 2020 and Ost, 2017. The characteristics of Phillips (2021) (also identified by Tran, 2022) and Ost (2017) can be found in table 2.

Table 2. Study characteristics of the RCT’s included in the systematic review by Rogowski (2021)

SABR: stereotactic ablative radiotherapy/SBRT: Stereotactic Body Radiation Therapy; ADT: androgen deprivation therapy; SOC: Standard of care; OS: Overall Survival; PFS: Progression free survival; LC: Local control; QoL: Quality of Life.

Renal cell cancer

There was no systematic review that specifically reviewed RCTs comparing treatment of oligometastatic renal cell cancer available. A systematic review of the literature until Sept 30, 2013 included studies with metastatic renal cell carcinoma (Dabestani, 2014). Another review discusses more recent data on this topic (Dabestani, 2016). In this review one retrospective study described oligometastatic renal cell carcinoma in 96 patients with regards to complete metastasectomy, incomplete metastasectomy and no metastasectomy in a setting where 75% of the patients received targeted therapies (Yu, 2022).

Results for studies not focusing on a specific tumor type:

Stereotactic ablative radiotherapy (SABR) versus palliative standard-of-care treatments

The systematic review by Tran (2022) identified some evidence that SABR in addition to SOC may offer a benefit in terms of OS and PFS. However, these findings are just based on two RCTs and one retrospective cohort study of which the overall risk of bias was either high or with some concerns. Tran (2022) also identified a prospective cohort study and five retrospective cohort studies suggesting that SABR alone may not be more effective than SOC for OS.

Lehrer (2021) analysed 15 studies that provided rates of OS at 1 year after SABR. Rates of 1-year OS ranged from 66% to 100%.

The systematic review by Tran identified six studies (one RCT and five nonrandomized studies) that provided mixed results when comparing SABR alone with SOC with regard to PFS.

In terms of AEs, Tran (2022) identified four studies (including two RCTs) that explored AEs for patients who received SABR plus systemic therapy or systemic therapy alone. Furthermore, five studies were identified (1 RCT, 4 nonrandomized studies) which studied whether SABR reduces AE incidence compared with SOC (i.e. observation, radiotherapy, or surgery). Tran (2022) concludes that it is unclear if SABR, with or without SOC, is associated with more or fewer AEs than SOC alternatives for patients with oligometastases.

Lehrer (2021) analysed 12 studies that reported grade 3 to 5 toxic effects after SABR. Rates of acute grade 3 to 5 toxic effects ranged from 0% to 20%. Rates of late toxic effects ranged from 0% to 10%.

Tran (2022) did not find enough evidence to draw conclusions for other outcomes of interest like LC and QoL.

In the SABR-COMET study (n = 99) Palma (2019) initially demonstrated a 13-month improvement in median OS in patients with controlled primary tumors and one to five oligometastases treated with SABR. Furthermore, they found a doubling of PFS, at the cost of increased risk of toxicity, including a 4∙5% risk of grade 5 toxicity. The analysis of extended outcomes of the trial >40 months after completion of accrual showed a 22-month improvement in median OS in patients who received SABR compared with a standard-of-care approach alone (Palma, 2020). This corresponds to an absolute survival benefit of 25% at 5 years (17.7% vs 42.3%, p=.006). At 5 years of follow-up, the 5-year PFS was not reached in the SABR-arm, versus 17.3% in the SOC-arm (p=.001). There were no new safety signals detected and no differences in total QOL scores or subscale scores, between arms over time observed. These results support the hypothesis that patients with a limited number of metastases might be amenable to curative-intent treatment strategies, with improved long-term outcomes. Methodological limitations of this study (high risk of bias) are related to the unblinded, open-label study design. Another concern is that the majority of patients with prostate cancer were assigned to the intervention arm. However, the authors mention that a sensitivity analysis was performed, which did not suggest that the results are merely due to the allocation of patients.

Results for studies focusing on a specific tumor type:

Breast cancer

The meta-analysis of Viani (2021) analyzed the effect of SABR treatment of oligometastatic breast cancer (OMBC). Nine of the included studies reported the local control rate at 1 year and ten at 2 years. The meta-analysis showed that SABR treatment results 1- and 2-year LC rates of 97% (95% CI 95–99%), and 90% (95% CI 84–94%), respectively. Ten studies reported on OS. The 1-year and 2-year OS was 93% (95% CI 89–96%) and 81% (95% CI 72–88%). Six studies, reported on PFS. The 1-year and 2-year PFS was 63% (CI95% 50–75%) and 46% (CI95% 29–62%), respectively. The six studies reported on toxicity. Grade 2 or 3 toxicity was reported in 4.1 % (95% CI 0.1–5%), and 0.7% (0–1%), respectively. The authors conclude that SABR for OMBC is safe (with low rate of grade ≥2 toxicity) and associated with high rates of LC and OS. The authors noted that the study designs of the included studies (retrospective and prospective single arm) limit the interpretation of their meta-analysis.

Lung cancer

The trial by Iyengar (2018) was stopped to accrual early, after a significant improvement in PFS (from 3.5 to 9.7 months) was found with the addition of consolidative radiotherapy to maintenance chemotherapy for patients with limited metastatic NSCLC. Furthermore, they found that toxic effects were similar in both arms. There we no local failures observed in the SABR-plus-maintenance chemotherapy arm, compared to 7 in the maintenance chemotherapy–alone arm at sites of original gross disease. Remarkably, for patients with a limited metastatic burden the PFS was similar to those patients with a greater metastatic burden. The data of this trial suggest there might be a beneficial treatment effect with the addition of SABR to maintenance chemotherapy for patients with oligometastatic NSCLC. This small RCT suffers from some concerns for risk of bias.

Prostate cancer

The systematic review by Rogowski (2021) concludes that radiotherapy as metastasis-directed therapy for prostate cancer resulted in low morbidity and high local control rates, with a considerable proportion of patients (22–83%) that remained progression-free for 2-years. However, in this study treatment regimens varied widely in radiation dose and field size.

The ORIOLE study (Phillips 2020) showed that treatment with SABR for oligometastatic prostate cancer improved outcomes. They observed progression at 6 months in 7/36 patients (19%) receiving SABR versus 11/18 patients (61%) in the observation arm (P = 0.005). Median PFS was significantly improved in the SABR group (not reached vs 5.8 months; HR, 0.30; 95%CI, 0.11-0.81; P = .002). High LC rates were observed after 6 months (98.9%) in the SABR arm. A note of caution is due here, since Tran (2022) judged that the study by Philipps (2020) is at high risk of bias arising from the randomization process. There are also concerns with regard to bias due to deviations from intended interventions and bias in measurement of the outcome (for more information see Tran 2022).

The phase II study by Ost (2018) included patients treated with surgery or SBRT, but unfortunately the results were not reported for these treatments separately. The study showed a median ADT-free survival of 13 months for the surveillance group, compared to 21 months for the MDT group (HR, 0.60 [80% CI, 0.40 to 0.90]; log-rank P = 0.11) after a median follow-up time of 3 years. In patients treated with MDT, no symptomatic or local progression was observed, compared with three symptomatic and six local occurrences in the surveillance group. Ost reported a grade 1 toxicity for 6/36 (17%) patients treated with MDT, and no patients with a toxicity grade ≥2. Ost (2017) did not observe clinically relevant differences in HRQOL scores between the MTD and surveillance group. The authors concluded that ADT-free survival is improved among oligorecurrent prostate cancer patients treated with MDT compared to those with surveillance alone. This study is prone to bias, since there was no allocation concealment (both the patient and the provider were aware of the random assignment) and no blinding of datamanagers and analysts.

Renal cell cancer

In the retrospective study of Yu (2022) comparing 96 patients, a significant difference was observed in OS time between complete resection and no surgery groups (HR = 0.43, P = 0.009). However, these findings should be interpreted with caution, since these are limited by the retrospective study design and small number of patients analyzed.

Level of evidence of the literature

We did not assess the certainty of the evidence for each outcome separately based on the individual studies by using GRADE, but instead adopted the GRADE from the systematic review authors when available (Tran 2020) or described the main limitations of the systematic reviews or the studies included in the systematic reviews to provide an indication of the overall certainty of the evidence.

Conclusions

Conclusions could be drawn for stereotactic ablative radiotherapy, but not for other treatment modalities, such as surgery or ablative techniques, for oligometastatic disease. Only narrative literature was available that underlines the importance of an oncological surgical approach towards oligometastatic disease.

A systematic review of the literature was performed to answer the following question:

What are the (un)favorable effects of treatment with curative intent (surgery or radiotherapy) on local control (radiologic progression, skeletal related events), survival, and quality of life compared to standard treatment in patients with oligometastases?

P: Patients with oligometastases or oligoprogression

I: Treatment with curative intent (surgery or high dose radiotherapy e.g. stereotactic radiotherapy)

C: Standard care (watchful waiting or palliative radiotherapy)

O: Local control (radiologic progression, skeletal related events), survival, quality of life, toxicity, complications

Relevant outcome measures

The guideline development group considered overall survival and progression free survival (if overall survival data is not available) as critical outcome measures for decision making; and local control (radiologic progression, skeletal related events), quality of life, toxicity, and complications as important outcome measures for decision making.

The working group did not define clinically (patient) important differences. When deciding about the balance between desirable and undesirable outcomes ("trade-offs") the guideline working group considered:

1. best estimates of the magnitude of desirable effects and the undesirable effects;

2. importance of outcomes – typical values that patients or a population apply to those outcomes (“weight” of outcomes).

Search and select (Methods)

The databases Medline (via OVID) and Embase (via Embase.com) were searched with relevant search terms for systematic reviews, RCTs and observational studies about treatment of oligometastatic disease in the bone with curative intent until 23^rd of June 2022. The systematic literature search resulted in 362 unique hits. The detailed search strategy is depicted under the tab Methods.

Studies were selected based on the following criteria:

• Systematic review;
• Includes patients with oligometastases or oligoprogression;
• Intervention is treatment with curative intent (surgery or high dose radiotherapy (e.g. stereotactic radiotherapy));
• Comparator is standard care (watchful waiting or palliative radiotherapy);
• Outcomes are local control (radiologic progression, skeletal related events), survival, quality of life, toxicity, complications.

Ten studies were initially selected based on title and abstract screening. After reading the full text of those articles, the working group decided to limit the literature summary for this guideline module to the systematic reviews with 1) a unique contribution in answering the research question, 2) the most recent search strategy, 3) better quality. A total of five systematic reviews were included and five were excluded (see the table with reasons for exclusion under the tab Methods).

Results

Five systematic reviews (Dabestani, 2016; Lehrer, 2021; Viani, 2021; Rogowski, 2021; Tran 2022) were included in the analysis of the literature. Important study characteristics, results and the assessment of the risk of bias were derived from the systematic review and if necessary from the original studies.