The use of stereotactic ablative body radiotherapy (SABR) for oligoprogressive cancers

In chess, facing an opponent who only has a king almost guarantees victory. Conversely, playing against a skilled competitor with a full set of pieces—ready to promote pawns into additional queens—presents a formidable challenge, one that even grandmasters would struggle to overcome. But what if you were up against a king with just a few supporting pieces? This middle ground would represent an entirely different kind of game, requiring a distinct strategic approach. In such a game, if we could utilise an approach to remove even some of the opponent’s pieces, this would give us an upper hand in the overall play.

A similar concept applies in oncology. In 1995, Hellman and Weichselbaum introduced the notion of “oligometastatic” disease—a state that lies between localized cancer and widespread metastatic disease (1). It is characterized by a limited number of metastatic lesions, often defined as fewer than five, which may be suitable for local ablative treatment. Today, the oligometastatic paradigm is well-recognized, and several prospective randomized clinical trials have demonstrated that ablative radiotherapy in such patients can significantly improve both progression-free survival (PFS) and overall survival (OS).

Several studies have previously been conducted to examine the use of stereotactic ablative radiotherapy (SABR) in the oligometastatic setting. For example, the SABR-COMET multi-centre randomized phase II trial found that SABR, when added to standard-of-care (SOC) therapy significantly improved median OS compared to standard therapy alone [50 vs. 28 months, P=0.006; hazard ratio (HR) =0.47; 95% confidence interval (CI): 0.27 to 0.81] (2). With 5-year OS rates of 42.3% (95% CI: 28% to 56%) vs. 17.7% (95% CI: 6% to 34%) in a basket trial of patients with different cancer types. In the specific context of breast cancer, the BOSTON trial (3) showed that SABR is feasible, well-tolerated, and effective in a cohort of patients with bone only metastatic disease, with two-thirds of patients remaining disease-free at 2 years. A meta-analysis of patients with oligometastatic breast cancer (4) confirmed that SABR offers excellent local control with 90% of irradiated lesions controlled at 2 years and with grade 3 or greater toxicity seen in <1% of patients it is a well-tolerated treatment. However, patient survival is heavily influenced by tumour biology, and systemic control of unirradiated disease, with a 2 years OS of 100% and 32% seen for patients with human epidermal growth factor receptor-2-positive (HER2⁺) and triple negative breast cancer respectively.

The success of SABR in treating oligometastatic non-small cell lung cancer (NSCLC) has also shown promising results. A meta-analysis (5) of NSCLC patients compared local consolidative treatment (surgery or radiotherapy) with systemic therapy alone. In the oligometastatic subgroup, the HR for PFS was 0.30 (P<0.001), and for OS, 0.41 (P<0.001), indicating a significant benefit of local therapy in this patient population. In a 2018 study by Iyengar et al. (6), in which patients with oligometastatic NSCLC who had stable disease after treatment with 4–6 cycles of chemotherapy were randomized to receive either SABR plus maintenance chemotherapy or maintenance chemotherapy alone, interim analysis revealed a significant benefit in the SABR group, with a median PFS of 9.6 months compared to 3.5 months in the control group (the trial was closed to accrual early due to these findings). These findings were corroborated by Gomez et al. (7), which similarly demonstrated improved OS in the local consolidative therapy (LCT) arm (inclusive of chemoradiotherapy or resection of all lesions) [median, 41.2 months (95% CI: 18.9 months to not reached) LCT vs. 17.0 months (95% CI: 10.1 to 39.8 months) with systemic therapy alone; P=0.017].

However, more recent randomized phase II studies—NRG-LU002 in NSCLC (8) and NRG-BR002 in breast cancer (9)—investigated the role of local consolidative therapy in patients with limited metastatic disease. Neither study met its primary endpoint or progressed to the phase III component. Both have been critiqued for the inclusion of heterogeneous patient populations, including variability in prior systemic therapies, mixtures of synchronous and metachronous metastatic disease, diverse tumour subtypes, and the enrolment of patients who initially presented with polymetastatic disease but were rendered oligometastatic through treatment (“induced” oligometastatic state). These results highlight the key challenge of identifying patients with truly limited oligometastatic disease, particularly when relying solely on radiological assessment, which may fail to detect subclinical polymetastatic spread.

While there is compelling evidence supporting the use of SABR in oligometastatic disease, evidence for its role in treating oligoprogressive disease (OPD), which is defined as the progression of 1 to 5 metastatic sites in patients who are otherwise responding to ongoing systemic therapy (10), is less convincing. This difference from oligometastatic difference is key—whereas oligometastatic disease describes an initial state of limited spread (<5 metastatic sites), oligoprogression specifically refers to progression within a limited number of sites on a background of both controlled or widespread disease. Oligoprogression arises from tumour heterogeneity, whereby some metastatic lesions remain sensitive to systemic treatment, while others, driven by more drug-resistant subclones continue to grow (10-12).

It is believed that treating sites of progression with metastasis-directed therapy may eliminate resistant clonal populations and help halt further metastatic spread. By reducing tumour heterogeneity, this approach has the potential not only to improve PFS but also to extend the duration of the current systemic therapy. This can help delay the need for less effective or more toxic subsequent treatments, thereby reducing both costs and patient burden, and improving overall quality of life.

In the oligoprogressive setting, the clinical trial data is emerging. The AVATAR trial (13), a multicentre, prospective, single-arm phase II study, demonstrated a potential benefit of SABR in patients with oligoprogressive breast cancer. In contrast, the STOP trial (14), a phase II multi-institutional randomized study, originally designed to only include patients with NSCLC and expanded to encompass all nonhematologic cancers, found no significant improvement in PFS or OS with the addition of SABR compared to SOC systemic therapy alone. The lack of improvement in PFS may be explained by significant crossover between the treatment and control groups. About one third (35%) of patients on the SOC arm either withdrew from the study or received ablative local therapies and 71% of patients on the SOC arm received some form of radiation during the follow-up period. The HALT trial is investigation the role of SABR for patients with actionable genomic alteration driven NSCLC has completed accrual with outcome data awaited (15).

The CURB trial (16) evaluates the benefit of metastatic directed therapy in the form of SABR for 107 patients with oligoprogressive metastatic breast and NSCLC. These patients were randomised to receive SABR to all oligoprogressive sites in combination with SOC systemic therapy, or SOC systemic therapy alone. Oligoprogression was defined as progression at up to five individual extracranial metastatic sites, all of which needed to be amenable to treatment with SABR. The primary endpoint of the trial was PFS.

The trial demonstrated that the addition of SABR in patients with OPD in NSCLC significantly prolonged PFS compared to standard therapy alone, emphasising its efficacy as an ablative treatment for OPD. It also showed that patients receiving SABR were able to remain on their existing systemic therapy regimens for a longer duration, with only modest increases in toxicity. Excellent local control of treated lesions was seen in both patient cohorts but in contrast, no PFS benefit was observed in the breast cancer cohort.

This study was the first open-label, randomized phase II trial which has shown promise in the use of SABR for treating OPD, particularly for NSCLC patients. The authors included 4 stratification factors: (I) number of progressive sites of metastasis (1 vs. 2–5); (II) receptor or driver genetic alteration status [absence/presence of epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), or ROS1 genetic alterations for NSCLC patients or oestrogen receptor (ER) ^+/− for breast cancer patients]; (III) primary site; (IV) type of systemic therapy received thus far (immunotherapy vs. other). In a multivariable Cox model adjusting for the 4 stratification factors and change of systemic therapy at enrolment, the PFS benefit of stereotactic body radiotherapy (SBRT) remained substantial in NSCLC group (HR =0.33; 95% CI: 0.16–0.66; stratified log-rank P=0.002).

In addition, unlike other trials assessing the use of SABR in oligometastatic NSCLC patients, a particular strength of the trial was that 80% of patients had received prior immunotherapy, reflecting more up-to-date clinical practice. The study also highlighted important toxicity considerations regarding the use of SABR. Whilst most patients did not experience serious adverse events, grade 2 or higher adverse events occurred in 41% (21 patients) of the standard care group and 62% (34 patients) of the SBRT group, thus highlighting the importance of considering treatment-related toxicity when using SBRT for OPD.

While the results for patients with NSCLC in the CURB trial are encouraging, the study was not powered to detect an OS benefit and was closed early due to limited accrual. The results may have been further compromised by the fact that over half of the patients in the SOC group received off-protocol SABR after disease progression, potentially diluting the observed treatment effect.

Whilst there is debate as to the definition of oligometastatic disease, it is generally defined as only involving extracranial metastases (10). The CURB trial notably included patients with brain metastases at enrolment—specifically, 12 patients with breast cancer (25.5%) and 9 with NSCLC (15.2%)—all of whom had previously received standard brain-directed treatments such as whole-brain radiotherapy or stereotactic radiosurgery. This however is where the distinction between oligometastatic and OPD is paramount, as oligoprogression refers to the number of progressing lesions rather than the overall number of metastases. Therefore, these patients with intracranial metastases were at a more advanced stage with multimetastatic disease.

During recruitment for the study, although all patients underwent imaging within 28 days prior to randomization, the selection of eligible participants involved different baseline staging modalities, which may have varied in sensitivity for detecting metastatic disease. To minimize this variability, efforts were made to standardize the imaging modality for each patient from baseline through subsequent follow-up visits. However, the use of diverse imaging techniques, including computed tomography (CT), positron emission tomography (PET), and magnetic resonance imaging (MRI) could still have contributed to differences in metastasis detection rates.

There is ongoing debate regarding the definition of oligometastatic disease in terms of disease burden. The historical threshold of ≤5 metastases is largely arbitrary, and emerging data suggest that total metastatic volume may be more clinically relevant. Indeed, this limit is being challenged in ongoing prospective trials such as SABR-SYNC (17) and RISE (18), both of which include patients with up to 10 metastases.

Additionally, the CURB study allowed for different dose fractionation (27–30 Gy/3# and 30–50 Gy/5#) which resulted in differential biologically effective doses (BEDs) assuming an α/β ratio of 10 (BED₁₀ of 51.3–60 and 48–100 respectively). The study protocol recommends doses of BED₁₀ ≥70 Gy, which is in contrast to the ESTRO-ASTRO consensus document which recommends BED₁₀ ≥100 Gy, which may have affected the efficacy of SABR (19). However, it is important to note that this occurs with all studies on oligometastatic disease; SBRT dose and fractionation depend on the tumour type, size, location, and proximity to critical organs, and so the individualisation of SBRT prescription cannot be avoided. Therefore, whilst not a weakness of this study specifically, it does speak overall to the challenges of conducting clinical trials across multiple sites. Unlike in NSCLC, the CURB trial revealed no PFS benefit for patients with oligoprogressive breast cancer.

The differing outcomes between the lung and breast cancer cohorts in the CURB trial are likely multifactorial, reflecting a trial patient population with a more extensive and aggressive disease profile that is less responsive to SABR. For instance, breast cancer patients had a higher metastatic burden at recruitment, with 55% having more than five metastases, compared to 36% of lung cancer patients. We know that tumour clonal evolution of diverse populations of cancer cells during cancer progression contributes to the longitudinal variations of clonal, morphological, anatomical, and molecular heterogeneity of tumours (20) and so the increased metastatic load in breast cancer patients is reflective of greater clonal heterogeneity, higher mutation burden, and increased therapeutic resistance. This suggests that breast cancer patients in the trial were at a more advanced disease stage, limiting their potential benefit from SABR compared to NSCLC patients at an earlier stage of OPD (21).

Additionally, breast cancer patients in the CURB trial had received more systemic therapies—a median of four in the standard therapy group and three in the SABR group—versus only one to two therapies in NSCLC patients. This is reflective of real-world practice, where breast cancer patients have more lines of treatment compared to NSCLC patients, but it is important to recognise that multiple lines of systemic treatment increase resistance and outcomes may differ by prior history of systemic therapy (22). The study lacked sufficient statistical power, specifically the study was not powered to detect the trial protocol specified improvement in PFS from 40% to 45% at 6 months for the overall breast cancer population nor was it adequately powered to assess the subgroup of breast cancer patients treated with SABR after only first- or second-line systemic therapy.

While the trial accounted for the number of metastases, it did not stratify patients by other relevant factors such as metastatic site or lesion size. Evidence suggests that certain metastatic sites respond better to SABR, particularly in breast cancer. For example, the BOSTON trial (10) reported excellent local control with single-fraction SABR in patients with oligometastatic bone-only breast cancer, suggesting SABR may benefit clinically or biologically defined subgroups.

Genomic stratification in the CURB trial was broad, resulting in heterogeneous genomic profiles within each strata. Patients were stratified by ER status, but almost one third of the breast cancer patients were triple-negative—this subtype is associated with fewer systemic treatment options, lower response rates, a higher likelihood of early relapse, and generally poorer outcomes compared to hormone receptor-positive or HER2-positive subtypes (23). Thus, the inclusion of biologically aggressive subtypes with higher-grade tumours may have influenced the limited efficacy of SABR in the breast cancer cohort.

Whilst there are limitations to the CURB trial, these weaknesses, rather than intrinsic to the study design themselves, reflect the difficulties associated with real-world clinical practice as patients with oligoprogression are a heterogenous group. However, it still provides key insights into which patients are more likely to benefit most from SABR in the oligoprogressive setting.

In recent years, several new systemic therapies—often costly and associated with significant side effects—have been approved despite offering only modest survival benefits (24). The potential benefit of SABR extends beyond its impact on PFS—SABR was well tolerated in the CURB trial and gave an additional benefit of allowing patients to remain on their current systemic regimens longer with only modest increases in toxicity. This suggests that, for breast cancer patients, even in the absence of significant survival improvement, SABR could provide meaningful clinical value by reducing toxicity and improving quality of life.

In summary, the CURB trial underscores the potential role of SABR in managing OPD, an area of growing clinical relevance. While the evidence supporting its use in NSCLC is encouraging, the limitations in methodology, most notably the heterogeneity in the cohort and the lack of statistical power, highlight the need for caution before drawing definitive conclusions about its utility in this setting.

The study reinforces the need for further well-powered trials to define which patients with OPD are most likely to benefit from SABR. Importantly, conventional endpoints such as PFS and OS may not fully capture patient-centred outcomes. In this context, the deferral of systemic therapy, particularly if it delays toxicity and preserves quality of life, may represent a more meaningful clinical endpoint. Historically, radiotherapy trials have been held to a higher standard of evidence, often requiring OS benefit or non-inferiority designs, compared to systemic therapy trials (25). Yet, in the setting of SABR for metastasis-directed therapy, where lesion control and safety are consistently excellent, more patient-focused endpoints may be both appropriate and necessary.

Returning to our original chess analogy: in the oligoprogressive setting, SABR serves as a tactical tool to remove specific lesions, akin to capturing key pieces on the board. While it does not guarantee victory, when used strategically against the right opponent, it may help prolong the game and improve patient outcomes.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Translational Cancer Research. The article has undergone external peer review.

Peer Review File: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-1753/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-1753/coif). A.C. reports an Entry Level Scholarship (Wellbeing of Women Society and British Gynaecological Cancer Society) (paid to institution). N.N. reports Consulting fees from Amgen, Astra Zeneca, AXANA, BeiGene, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, EQRx, Fujifilm, Guardant Health, Intuitive, Janssen, Lilly, Merck Sharp & Dohme, Olympus, Roche and Sanofi; honoraria from Astra Zeneca, Bristol Myers Squibb, Fujifilm, Intuitive, Janssen, Lilly, Merck Sharp & Dohme, Olympus, Sanofi and Roche. He reports grants from the Medical Research Council Clinical Academic Research Partnership, CRUK, NIHR, Horizon Europe and UKRI. He reports support for attending meetings and/or travel from Astra Zeneca, Fujifilm, Intuitive, Merck Sharp & Dohme, Olympus. He has a leadership in role Steering committee British Thoracic Oncology Group, Director of UK Lung Cancer Coalition and Senior Clinical Lead of National Lung Cancer Audit. C.T.H. reports a grant from Cancer Research UK, payment/honoraria from Merck for educational events, support for travel to meeting from Genesiscare UK, British Thoracic Oncology Group and the International Association for the Study of Lung Cancer, planned patent for an immunotherapy novel target, participating on a Data Safety Monitoring Board or Advisory Board for the British Thoracic Oncology Group Research Committee, a leadership role at Genesiscare UK and stock/stock options at Genesiscare UK. The other author has no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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