The role of radiotherapy in the treatment of oligometastatic non-small cell lung cancer

Abstract

In the recent years, the clinical stage where the cancer has spread beyond the primary site, but has not yet metastasised extensively, and which is known as oligometastatic disease (OMD), has become an object of interest to radiation oncologists. OMD is a kind of an “umbrella term” for a variety of clinical situations.

This review focuses on the role of radiotherapy (RT) in the treatment of oligometastatic non-small cell lung cancer (OM-NSCLC). Currently, a wide range of techniques and fractionation regimens are used to treat OM-NSCLC and, unfortunately, it is not yet possible to determine which approach is the most effective. Therefore, more than ever, we should use the concept of risk-adapted RT and consider many factors when choosing the fractionation regimen and total dose applied. For different clinical scenarios, we set different treatment goals and derive different RT techniques and fractionations.

Oligoprogression (OP) is a specific type of OMD that is increasingly encountered in clinical situations, probably due to the increased use of targeted therapy and the subsequent acquired resistance of a certain subpopulation of tumour cells. OP is the progression of a limited number of metastases after an initial response to systemic therapy. The rationale for using RT in areas of progression is to overcome tumour resistance in these progressive lesions.

A number of trials are currently underway to find the optimal RT techniques for the most appropriate patients at a precise clinical stage.

Introduction

Lung cancer is the most commonly diagnosed cancer in the world. In 2022, 2.48 million people worldwide will be diagnosed with the disease. Lung cancer is also the leading cause of cancer death, accounting for 1.8 million deaths in 2022 [1].

Lung cancer is generally divided into two main types — non-small cell lung cancer (NSCLC), which accounts for 80–85% of lung cancers, and small cell lung cancer (SCLC), which accounts for the remaining 15–20%. The two types differ in their biological behaviour, prognosis and treatment strategy. The NSCLC group includes adenocarcinoma, squamous cell carcinoma, large cell carcinoma, adenosquamous carcinoma and lung carcinoid [2].

Radiotherapy (RT) may be indicated in the treatment algorithm for lung cancer at any stage of the disease with different therapeutic goals. In recent years, the clinical stage where the cancer has spread beyond the primary site, but has not yet metastasised extensively, has become of interest to radiation oncologists. This is known as oligometastatic disease (OMD).

Oligometastatic disease

Definition and classification

The term OMD was first described and defined in 1995 by Hellman and Weichselbaum [3] and encompasses the entire spectrum from early progressive tumours with a limited number and locations of metastases to patients with extensive metastases, most of which have been eradicated by systemic therapy, with chemotherapy (ChT) failing to eradicate the remaining metastases due to the large number of tumour cells, the presence of drug-resistant cells or the location of tumour lesions in some pharmacologically difficult to reach sites. These are different clinical scenarios with different total tumour loads, different prognoses, different treatment strategies and approaches, and different RT techniques and doses.

The hypothesis of the oligometastatic (OM) paradigm is also that patients with a limited number of metastatic lesions can achieve long-term disease control if all lesions can be ablated [4]. However, the situation in clinical practice is somewhat more complex and complicated. OMD is a kind of “umbrella term” for a variety of clinical situations and it is desirable to separate them from each other.

The diagnosis of OMD is currently based solely on imaging studies [5], so the classification of patients into this clinical stage is highly dependent on the sensitivity and specificity of the imaging method. However, given the current lack of biomarkers, imaging is still the most appropriate diagnostic method for defining OMD [6].

For these reasons, the European SocieTy for Radiotherapy and Oncology (ESTRO) and the European Organisation for Research and Treatment of Cancer (EORTC) have developed a classification and characterisation of the following individual clinical situations [5]. The division into oligorecurrence, oligoprogression and oligoperistance depends on whether OMD is diagnosed during the treatment-free period (oligorecurrence) or during active systemic treatment (oligoprogression, oligoperistance). A few growing or new metastases are called oligoprogression, and a few persistent metastases are called oligoperistance. OMD can be further subdivided into genuine OMD (no history of polymetastatic disease) and induced OMD (history of polymetastatic disease). Genuine OMD can be further subdivided into de novo (no history of OMD) and recurrent (history of OMD). Finally, de-novo genuine OMD can be further subdivided into synchronous and metachronous according to the time of onset. A period of 6 months between the diagnosis of the primary tumour and the diagnosis of OMD has been reported as the borderline between synchronous and metachronous OMD, but there is no consensus in the literature. Metachronous oligoprogression refers to patients undergoing active systemic therapy. Induced oligoprogression refers to patients in whom systemic therapy for polymetastatic disease has achieved a good therapeutic response, but some metastases have developed resistance and progressed. Metachronous, recurrent or induced oligorecurrence are terms used for patients who do not undergo active systemic therapy (the tumour has responded well to systemic or local therapy, or both, and allowed a period of no treatment, and then recurred in small numbers) [5].

To complicate matters further, we have to work with the concept of a dynamic model of OMD, i.e. we know that the clinical stage of OMD changes, even repeatedly, during the course of treatment and disease evolution.

To illustrate how heterogeneous this group is, we can quote the 5-year overall survival (OS) of patients with OM (as an umbrella term) NSCLC (OM-NSCLC), which ranges from 8.3% to 86% [7], roughly corresponding to the OS range between stage I and IV NSCLC [8].

Oligometastatic disease and radiotherapy

Although surgery was historically the first treatment modality used to remove metastases, new and less invasive modalities are now available, such as SABR (stereotactic ablative radiotherapy) or SBRT (stereotactic body radiotherapy) [4]. Terminologically, these are similar terms and are often used interchangeably. In the following, we will stick to the terms used in the cited studies. If the term is not clearly implied by the study or used in a general way, the term SBRT will be used. However, SABR/SBRT are not the only RT techniques that can be used to treat OMD. As will be discussed later, normofractionated or hypofractionated RT can also be used for different clinical stages and situations.

The first randomised trial to demonstrate the effect of any ablative treatment on OS in patients with OMD of various cancers is the SABR-COMET trial, which was first published in 2019 [9], followed by repeated updates in 2020 and 2022 [4, 10]. This is an international randomised phase 2 trial that recruited patients between 2012 and 2016. The trial enrolled 99 patients who received either standard of care (SOC) or SOC plus SABR. The number of OM lesions was limited to 5 (maximum 3 lesions per organ), with the majority having a maximum of 3, and verified control of the primary tumour was required before RT was indicated. According to the ESTRO-EORTC classification, patients had metachronous oligorecurrence. With a median follow-up of 51 months, median OS was 28 months vs. 50 months in favour of the SABR arm. The 5-year OS was 17.7% vs. 42.3% [4]. Current 8-year OS and progression-free survival (PFS) rates show a continuing trend of −13.6% vs. 27.2% and 0% vs. 21.3%, respectively [10]. The most commonly used fractionation regimens were 5 × 7 Gy, 8 × 7.5 Gy and 3 × 18 Gy. SABR was generally well tolerated; however, higher toxicity (grade ≥ 2 in 9% vs. 29% of patients) and 3 (4.5%) treatment-related deaths were reported. Interestingly, there were significant differences in local control (LC) based on lesion location (adrenal 100%, bone 72%, lung 51%, liver 50%).

Radiotherapy and oligometastatic NSCLC

Evidence

Two recent randomised phase 2 trials in patients with OM-NSCLC have shown an almost threefold increase in PFS with ablative techniques.

In 2016, Gomez et al published a paper [11], which was updated in 2019 [12], investigating the use of local consolidation therapy, i.e. not only RT but also surgery, in the management of patients with NSCLC only after initial ChT without disease progression. However, there were only 49 patients in the study and the method and technique of RT was highly heterogeneous (SBRT/hypofractionation — 12 patients, combination of surgery and RT — 6 patients, chemoradiotherapy — 2 patients). Patients could have ≤ 3 lesions (including primary tumour and nodal areas).

The study designed by Iyengar et al. in 2018 [13] included even fewer patients (29) between 2014 and 2016. The median follow-up was 9.6 months. This was exclusively consolidation RT for stage IV NSCLC without progression after first-line ChT. The maximum number of lesions was 6, including the primary tumour. RT was delivered with either SBRT (1–5 fractions) or hypofractionated RT (15 × 3 Gy).

In the area of randomised phase 3 trials, we can draw on the results of the SINDAS trial, published in 2023 [14], which included patients with EGFR (epidermal growth factor receptor) mutated de novo synchronous OM-NSCLC treated with a tyrosine kinase inhibitor (TKI) with or without RT. A total of 133 patients were enrolled, of whom 631 were screened for entry into the study. The number of metastatic sites was limited to ≤ 5, and only two sites could be in a single organ. RT was administered as SBRT in 5 fractions (total dose 25–40 Gy) to metastases, primary tumour and nodal metastases. Median PFS was 12.5 months vs. 20.2 months and median OS was 17.4 months vs. 25.5 months, always in favour of the combination of TKI plus RT.

At the American Society for Clinical Oncology (ASCO) conference in 2024, the results of the NRG-LU002 trial [15], the largest randomized phase 2/3 trial of local consolidative therapy (LCT) in OM-NSCLC, were presented, enrolling 215 patients with ≤ 3 extracranial lesions at restaging after 4 cycles of first-line therapy. Patients were randomised 1:2 to maintenance systemic therapy or LCT (RT or surgery) followed by maintenance systemic therapy until progression, death or intolerable toxicity. Stratification was based on histology and use of immunotherapy. Estimated 1- and 2-year PFS were 48% and 36% in the systemic maintenance arm and 52% and 40% in the LCT plus systemic maintenance arm. 1- and 2-year PFS and OS were not statistically different between arms. For adverse events reported as definitely, probably or possibly related to treatment, more patients receiving LCT plus maintenance systemic therapy had grade ≥ 2 overall toxicity (73% vs. 84%) and grade ≥ 3 pneumonitis (1% vs. 10%). It is very important to emphasise that more than 90% of patients in this study were receiving systemic immunotherapy-based treatment, which distinguishes this work from previous studies. The surprising conclusions of the paper support the theory that LCT is of insufficient benefit in the group of patients treated with immunotherapy, which may reduce the effect of LCT due to the unique biology of residual disease. These results may suggest that LCT should not be routinely offered to all patients, but should be an informed multidisciplinary decision taken on an individual basis. The risks of toxicity of the treatment under consideration should be carefully weighed against the risks of possible disease progression (Tab. 1).

Table 1.

Trials related to radiotherapy and oligometastatic non-small cell lung cancer (NSCLC)

Trial	Description	Outcomes
Gomez et al. [11,12]; phase 2	OM-NSCLC after ChT without progression 49 patients LCT (RT or surgery) vs. MT/O	Median PFS 14.2 months vs. 4.4 months Median OS 41.2 months vs. 17.0 months Both in favor LCT
Iyengar et al. [13]; phase 2	Stage IV OM-NSCLC without progression after ChT 29 patients Consolidation SBRT/hypofractionated RT + MT ChT vs. MT ChT	Median PFS 9.7 months vs. 3.5 months in favor consolidation SBRT/hypofractionated RT + MT ChT
SINDAS [14]; phase 3	EGFR mutated de novo synchronous OM-NSCLC 133 patients TKI vs. TKI+RT	Median PFS 12.5 months vs. 20.2 months Median OS 17.4 months vs. 22.5 months Both in favor TKI + RT
NRG-LU002 [15]; phase 2/3	OM-NSCLC 215 patients MT systemic therapy or LCT (RT or surgery) followed by MT systemic therapy	1- and 2-year PFS and OS were not statistically different between arms
CURB [20]; phase 2	OP-NSCLC (59 patients) and breast cancer (47 patients); SABR + SOC vs. SOC	Median PFS for patients with OP-NSCLC 10.0 months vs. 2.2 months in favor SABR + SOC
STOP [21]; phase 2	OP disease of various tumours (44% lung) 90 patients SABR + SOC vs. SOC	No statistically significant difference in PFS and OS Better lesion control (70% vs. 38 %)

OM-NSCLC — oligometastatic non-small cell lung cancer; LCT — local consolidative therapy; RT — radiotherapy; ChT — chemotherapy; MT/O — maintenance or observation; PFS — progression-free survival; OS — overall survival; SBRT — stereotactic body radiotherapy; SABR — stereotactic ablative radiotherapy; EGFR — epidermal growth factor receptor; TKI — tyrosine kinase inhibitor; OP — oligoprogressive; SOC — standard of care

Radiotherapy techniques and fractionation regimens

Currently, a wide range of techniques and fractionation regimens are used to treat OMD and, unfortunately, it is not yet possible to determine which approach is the most effective. Doses ranged from BED (biologically effective dose) 39 Gy (10 × 3 Gy to 30 Gy) to BED 151 Gy (3 × 18 Gy to 54 Gy) for α/β ratio 10 (Fig. 1 and 2).

Figure 1.

68-year-old patient with adenocarcinoma of the left lung T3N2M1b, after first line of chemoimmunotherapy with partial remission. Persistent sclerotic metastatic lesion in the left lower arm of the pubic bone (red arrow) indicated for stereotactic body radiotherapy (SBRT)

Figure 2.

Dose distribution plan for the patient from Figure 1. Stereotactic body radiotherapy (SBRT) 40 Gy in 5 fractions. Volumetric-modulated arc therapy (VMAT), 6 MV, flattening filter-free (FFF). Dark green line — gros tumour volume (GTV), brown line — clinical target volume (CTV), red line – planning target volume (PTV), light green area — prescribed dose (70% isodose)

In general, the ideal dose should balance both the benefit of tumour control probability (TCP) and the risk of toxicity, taking into account the localisation of the lesions, their size, the potential number of subsequent RT courses, and with safety as the absolute priority. It is, therefore, a complex interplay between dose, volume and primary tumour. The localisation and size of the lesions influence the dose, which, in turn, influences the TCP. Of course, different local control can be expected for different metastatic sites. In trials, local control has been reported to be in the range of 63–100%. However, it has not been clearly shown that higher doses result in better control. The evidence comes from different primary tumours with different sensitivities and different approaches to systemic therapy. All of this adds layers of complexity. Another unresolved issue is whether we can use the maximum tolerated dose to treat OMD, where we can expect the need for RT to other sites in the future, as we know that the higher the dose, the higher the risk of toxicity. Therefore, more than ever, we should use the concept of risk-adapted RT and consider all of the above factors when choosing the fractionation regimen and total dose applied. However, the risk will never be zero anyway.

In addition to the fact that it is generally difficult to compare different local methods (hypofractionated RT, SBRT, surgery, radiofrequency ablation) because we only have retrospective data from which the benefit of one method over another is not clear, we also have to deal with a large variability of studies on RT. This is especially true with regard to maximum lesion volume, lesion activity (new, stable, progressive), setting (synchronous, metachronous, induced), context of systemic therapy, and inclusion or non-inclusion of regional metastases. Patients with intracranial metastases are also often studied separately, although the trend is to include them in the total number of OM lesions in future studies.

For example, if we look at the aforementioned studies by Gomez [11] and Iyengar [13], we see that these are very heterogeneous groups of patients. Firstly, there were patients with genuine OMD who were resistant to ChT or targeted therapy, and secondly, there were patients with induced oligopersistant in whom systemic treatment of polymetastatic disease achieved a complete response except for a few resistant metastases. A different approach seems to be the local treatment of induced OMD, where patients with initially polymetastatic disease who have progressed to the stage of induced OMD by partial effect of systemic treatment. Thus, local treatment complements systemic treatment rather than the other way around as in genuine OMD where local treatment has the potential for long-term disease control. There is emerging evidence that treating all disease sites with ablative treatments such as surgery or SBRT can improve patient outcomes, including OS and PFS.

SBRT is generally limited to ≤ 8 fractions of RT. Multiple fraction (MF) RT is administered to reduce the burden of a single fraction (SF), which may reduce late toxicity. However, SF RT may be more cost-effective and may also reduce patient treatment time. The phase 2 SAFRON II trial [16] evaluated 90 patients with ≤ 3 lung metastases from non-haematological malignancies. 1 × 28 Gy vs. 4 × 12 Gy fractionation regimens were compared. The study showed no difference between SF and MF RT in the primary endpoint of severe toxicity and similar local control, survival, efficacy and quality of life between treatment arms.

For different clinical scenarios, we set different treatment goals and derive different RT techniques and fractionations. For example, in patients with induced oligoprogression, the goal of radical local treatment is to restore overall sensitivity to systemic therapy by eradicating oligometastases that are resistant to the current line of systemic therapy. And in patients with induced oligopersistence, the goal of radical local therapy is to achieve an overall deeper response to systemic therapy by eradicating oligometastases with reduced sensitivity to the current line of systemic therapy.

Radiotherapy for oligoprogressive disease

Oligoprogression (OP) is a specific type of OMD that deserves its own commentary as it is increasingly encountered in clinical situations, probably due to the increased use of targeted therapy and the subsequent acquired resistance of a certain subpopulation of tumour cells. OP is the progression of a limited number of metastases after an initial response to systemic therapy. Unlike genuine OMD, OP can include any number of metastases, as long as they were under control at some point. OP can be metachronous, recurrent or induced according to the ESTRO-EORTC classification [5].

The rationale for using RT in areas of progression is to overcome tumour resistance in these progressive lesions, prevent the development of more extensive resistant disease and allow the continuation or delay of systemic therapy, thereby prolonging survival [17] (Fig. 3, 4).

Figure 3.

69-year-old patient with squamous cell carcinoma of the right lung T2bN3M1c with a oligoprogressive tumour nodule in the ventrocaudal region of the right hilum after immunotherapy with pembrolizumab. Oligoprogressive nodule was indicated for stereotactic body radiotherapy (SBRT). Left: pre-treatment, right: post-treatment. The red arrows show the original lesion (left) and a small mottled residue with streaky rays into the surrounding area (right)

Figure 4.

Dose distribution plan for the patient from Figure 3. Stereotactic body radiotherapy (SBRT) 55 Gy in 5 fractions. Volumetric-modulated arc therapy (VMAT), 6 MV, flattening filter-free (FFF). Green line — internal target volume (ITV), red line — planning target volume (PTV), light green area — prescribed dose (68% isodose)

The combination of immunotherapy and SBRT in the treatment of OP using Cyber Knife was retrospectively evaluated by Wang et al. [18]. They analysed 24 patients with advanced NSCLC who received SBRT for OP lesions after acquired resistance to checkpoint inhibitors (CPI). SBRT was delivered to a total dose of 30 to 50 Gy over 2 to 6 days. The dose and fractionation schedules were developed based on the patient’s performance status, tumour size, and location. Fifteen (62.5%) were diagnosed with adenocarcinoma and 20 (83.3%) with stage IV disease. Prior to surgery, 16 (66.7%) patients received immunotherapy as first-line treatment. After combining SBRT with CPI, median PFS and OS after OP were 11 months and 34 months, respectively. One- and two-year LC rates were 100% and 81.8%, respectively. Patients with adenocarcinoma and positive programmed death cell ligand 1 (PD-L1) expression tended to have favourable survival outcomes.

In 2024, the first meta-analysis on the use of SABR in OP was published [19]. Published studies are mostly retrospective and often include small numbers of patients and different tumour types, histologies and indications. A total of 25 studies were included [the following primary tumours: prostate — 8 (32%), kidney — 6 (24%), colorectal — 4 (16%), breast — 3 (12%), lung — 2 (8%), mixed 3 (12%)]. The most common localisation of SABR: lung, bone, nodes. The median reported SABR dose was 30–60 Gy. The 1-year PFS for lung cancer was 62%.

The first randomised trial to report the use of SABR plus SOC versus SOC in patients with OP NSCLC and breast cancer was the CURB trial [20], which reported a significant benefit in PFS only in patients with NSCLC, but not in those with breast cancer.

Another relatively large randomised trial investigating the use of SABR in the treatment of OP following systemic therapy was the STOP trial [21]. This study investigated whether patients with ≤ 5 OP lesions would benefit from the addition of SABR to SOC. The study enrolled 90 patients with 127 OP metastases, with 59 patients randomised to SABR and 31 to SOC. The most common primary sites were lung (44%), genitourinary (23%) and breast (13%). Unfortunately, compliance in the SOC arm was suboptimal, with 11 patients (35%) either receiving ablative therapy (against the study protocol) or withdrawing from the study. The median follow-up was 31 months. There was no statistically significant difference in PFS and OS between the arms. Median PFS and OS between SABR and SOC were 8.4 months vs. 4.3 months and 31.2 months vs. 27.4 months, respectively. SABR was well tolerated and resulted in better lesion control (70% vs. 38%), but did not improve PFS or OS. Recruitment was difficult in that trial and results may have been influenced by reluctance to forgo ablative treatment in the SOC arm (Tab. 1).

There are several important issues in the design and conduct of trials in the surgical stages of different cancers. The optimal intervention in the control arm of these trials is unclear. In general, in the SBRT arm, patients stay on their current drug and receive SBRT, whereas in the standard arm, patients can either switch drugs or stay on the same drug. If patients in the standard arm switch drugs, the comparison is between the new drug and the old drug (which may be losing efficacy) plus SBRT. The second important issue is the dissatisfaction of some patients and oncologists with their inclusion in the standard arm, as shown in the STOP trial mentioned above, where a significant number of patients in the standard arm withdrew or received ablative treatment immediately after randomisation [21].

Ongoing trials

A number of trials are currently underway to find the optimal RT techniques for the most appropriate patients at a precise clinical stage. At the same time, the optimal timing with different types of systemic treatment is being determined.

In general, it is worth mentioning the joint project of two European societies, The European Organisation for Research and Treatment of Cancer (EORTC) — The European Society for Radiotherapy and Oncology (ESTRO) OligoCare [22], which is a pragmatic observational cohort study focused on the evaluation of radical RT in patients with OMD. The main objective is to identify patient, tumour, diagnostic and treatment characteristics that influence OS. The OligoCare project was established to collect prospective data from ‘real world’ patients treated with RT.

Several trials are currently underway that are derived from and build on the SABR-COMET trial [9, 10] and focus on diagnoses other than lung cancer. The SABR-COMET-3 [23] and SABR-COMET-10 [24] trials aim to assess the impact of SABR vs. SOC on OS, cost-effectiveness and quality of life in patients with controlled primary tumours and 1–3 and 4–10 metastatic lesions, respectively. The size limit for lesions is ≤ 6 cm outside the brain and ≤ 3 cm for brain metastases. There are clear recommendations for fractionation for different sites. Samples are also collected to assess circulating biomarkers, including circulating tumour DNA and circulating tumour cells.

Multi-organ sites are also addressed in the CORE trial [25], a phase 2/3 trial designed to demonstrate the feasibility of recruiting patients in a multicentre setting in the first phase and to determine the efficacy of SBRT based on PFS. Between 2016 and 2019, 245 patients from United Kingdom (UK) and Australian centres with primary breast (40), prostate (180) or NSCLC (25) cancer and ≤ 3 meta-chronous lesions of OMD who had not previously received systemic treatment for metastatic disease were randomised in a 1:1 ratio to receive either SOC alone or SOC plus SBRT (dose and fractionation dependent on OMD site). The first results were presented at the ESTRO conference in Vienna in 2023 [26]. The median PFS was 25 months for SBRT plus SOC versus 19.9 months for SOC. Thus, the study met its phase 2 objectives, justifying the transition to a larger randomised phase 3 trial in parallel site-specific trials.

Given the concern that the use of SF SABR may have higher toxicity rates than MF SABR and the lack of evidence, a phase 3 SIMPLIFY-SABR-COMET trial [27] was designed to compare the toxicity, efficacy and cost-effectiveness of SF and MF SABR at similar biologically effective doses in a larger sample and across all tumour sites. The objective of this study is to assess non-inferiority grade ≥ 3 toxicity, LC rates, PFS, cost-effectiveness and OS in patients with 1–5 OM or OP lesions treated with SF SABR compared to patients treated with MF SABR.

The SARON trial [28] is a large, randomised, multicentre phase 3 trial in patients with OM-NSCLC with negative EGFR (epidermal growth factor receptor), ALK (anaplastic lymphoma kinase) and ROS1 (c-ros oncogene 1) mutations (1–3 synchronous metastatic lesions, one of which must be extracranial). They were randomised to receive either standard ChT with platinum doublet alone (control arm) or standard ChT followed by radical RT/SABR to the primary tumour and then SABR to all other metastatic sites (study arm). The primary endpoint is OS.

The planned OMEGA trial [29] will enrol patients with synchronous or metachronous OM-NSCLC (1–3 metastatic lesions) who will be randomised to local ablative therapy plus standard treatment (lung resection if primary tumour is present plus local ablative treatment of all metastatic lesions plus standard medical therapy; patients may be enrolled either before any systemic treatment or after 3 months of progression-free treatment, as decided by the local coordinator) vs. standard therapy (platinum doublet according to local protocols or targeted therapy according to EGFR/ALK/ROS-1 mutation status or immunotherapy according to PD-L1 expression). Patients will be stratified according to synchronous versus metachronous presentation, number of oligometastases, nodal status or PD-L1 expression. The primary endpoint will be OS from randomisation.

The ongoing phase 2 SUPPRESS NSCLC trial [17] is expected to enrol 68 patients with OP-NSCLC, defined as 1–5 progressive extracranial lesions ≤ 5 cm in size involving ≤ 3 organs. Patients receiving active systemic therapy (ChT, immunotherapy, targeted therapy or combination) will be randomised 1:1 to either continuation of current systemic therapy in combination with SABR of all lesions (recommended fractionation regimens based on different lesion locations 1–8 fractions up to 16–60 Gy) or SOC (cross-over to next line, continuation of the same treatment or observation). Primary endpoints are PFS and OS and secondary endpoints are time to next systemic treatment, patient-rated quality of life and cost-effectiveness (Tab. 2).

Table 2.

Ongoing trials

Trial	Description	Endpoints
EORTC-ESTRO OligoCare [22]	OMD of various tumours Radical RT	Patients, tumour, diagnostic and treatment characteristics influencing OS
SABR-COMET-3 [23]; phase 3	Various tumours and 1–3 OMD lesions SABR vs. SOC	OS, cost-effectiveness, quality of life
SABR-COMET-10 [24]; phase 3	Various tumours and 4–10 OMD lesions SABR vs. SOC	OS, cost-effectiveness, quality of life
CORE [25]; phase 2/3	Various tumours and = 3 metachronous OMD lesions SOC vs. SOC + SBRT
SIMPLIFY-SABR-COMET [27]; phase 3	all tumour sites, 1–5 OM or OP lesions SF vs. MF SABR	Non-inferiority grade = 3 toxicity, LC rates, PFS, cost-effectiveness and OS
SARON [28]; phase 3	OM-NSCLC (1–3 lesions), EGFR, ALK, ROS1 negative ChT with platinum dublet vs. ChT followed by radical RT/SABR to the primary tumour and then SABR to metastatic sites	OS
OMEGA [29]; phase 3	Synchronous or metachronous OM-NSCLC (1–3 lesions); LAT plus standard systemic therapy vs. standard systemic therapy	OS
SUPPRESS NSCLC [17]; phase 2	OP-NSCLC (1–5 progressive extracranial lesions) Systemic therapy + SABR vs. SOC	PFS, OS, time to next systemic treatment, quality of life, cost-effectiveness

OMD — oligometastatic disease; RT — radiotherapy; OS — overall survival; SABR — stereotactic ablative radiotherapy; SOC — standard of care; SBRT — stereotactic body radiotherapy; OM-NSCLC — oligometastatic non-small cell lung cancer; OP — oligoprogressive; SF — single fraction; MF — multi fraction; LC — local control; PFS — progression-free survival; EGFR — epidermal growth factor receptor; ALK — anaplastic lymphoma kinase; ROS1 — c-ros oncogene 1; LAT — local ablative therapy; ChT — chemotherapy

Conclusion

Although we have strong evidence for the efficacy and benefit of RT in OM- and OP-NSCLC, it should not be routinely offered to all patients, but should be an informed multidisciplinary decision taken on an individual basis. Because we still don’t know the ideal candidates. The risks of toxicity of the treatment under consideration should be carefully weighed against the risks of possible disease progression. And when we decide, together with the patients, to use RT, we should use the concept of risk-adapted RT and consider all possible factors when choosing the fractionation regimen and total dose applied. However, a number of trials are currently underway to find the optimal RT techniques for the most appropriate patients at a precise clinical stage. At the same time, the optimal timing with different types of systemic treatment is being determined.