The curative potential of stereotactic radiotherapy in oligometastatic colorectal cancer: a narrative review

Introduction

Colorectal cancer (CRC) is the fourth deadliest cancer globally and accounts for 10% of all cancers diagnosed annually (1-3). Oligometastatic CRC represents an intermediate stage of cancer progression, characterised by a limited number of metastatic lesions (commonly up to five) that are potentially amenable to localised, curative-intent treatments (4,5). Historically, metastatic CRC has been managed with palliative intent, focusing on extending survival and alleviating symptoms rather than achieving a cure (6,7). Conventional strategies such as systemic chemotherapy and surgical resection have shown survival benefits but rarely result in complete remission (8). Furthermore, many patients are unsuitable for surgery due to the location, volume of metastases, or overall health status, leaving them with limited treatment options (9). Other modalities, such as aggressive local radiofrequency ablation, have shown significant improvements in overall survival (OS) in patients with unresectable colorectal liver metastases (10,11).

The advent of stereotactic ablative radiotherapy (SABR), also referred to as stereotactic body radiotherapy (SBRT), has revolutionised the treatment of oligometastatic CRC (12). The SABR consortium defines SABR as the precise irradiation of an image-defined extra-cranial lesion with the use of high radiation dose in a small number of fractions (13), using advanced imaging and planning techniques to minimise damage to surrounding healthy tissues (14). Initially developed for inoperable cancers, SABR has gained traction in treating oligometastatic disease, where its precision, high local control (LC) rates, and low toxicity offer a compelling alternative or complement to surgery and systemic therapy (15-17). This modality provides a unique opportunity to shift the treatment approach for a subset of patients from palliative to potentially curative intent.

SABR’s efficacy in oligometastatic CRC has been supported by emerging evidence from trials like SABR-COMET, SABR-5 and ORCHESTRA, which demonstrated significant improvements in OS and progression-free survival (PFS) when SABR was added to standard care (18-21). These findings underscore the potential of SABR to achieve durable disease control, especially in patients with fewer and slower-growing metastases. However, the effectiveness of SABR varies by metastatic site; pulmonary metastases typically respond better than liver metastases, likely due to differences in the radiosensitivity of the tissue (22,23). Moreover, SABR’s ability to delay systemic therapy, enhance quality of life, and achieve LC further supports its role as a versatile tool in both palliative and curative settings.

The eligibility for SABR, however, is nuanced. While younger, healthier patients may tolerate curative doses, older or frail patients might struggle with high-dose regimens. Typically, curative-intent doses range from 45 to 80 Gy, whereas palliative doses are lower, between 7 and 35 Gy (24). However, current reporting on whether SABR studies are treating with palliative or curative intent is vague. Careful patient selection based on age, performance status, and tumour characteristics becomes pivotal in deciding whether SABR is suitable as a curative approach (25).

This review aims to explore the role of SABR in oligometastatic CRC, focusing on its curative potential, clinical outcomes, and safety profile. It will also address the limitations of current evidence, compare SABR with traditional treatment modalities, and highlight future research directions. As SABR continues to integrate into multidisciplinary care, it holds the potential to redefine the management and prognosis of oligometastatic CRC, offering new hope to patients previously limited to palliative care. We present this article in accordance with the Narrative Review reporting checklist (available at https://apm.amegroups.com/article/view/10.21037/apm-24-170/rc).

Methods

A literature search was conducted and is described in Table 1. Images of metastatic CRC SABR plans were provided by Royal Surrey County Hospital NHS Foundation Trust.

The current outlook regarding the use of SABR in the radical versus the palliative context is highly complex. This paper aims to investigate the published data regarding SABR in both the palliative and curative contexts. With advancements in systemic therapies and cancer care, the distinction between curative and palliative treatment has become increasingly blurred (27). Therefore, when assessing if a paper was palliative or radical, we considered the study intentions and characteristics of the patient populations rather than just dosage alone. Dosage can be highly variable based on the patient, tumour size, metastasis number, and location and proximity to vital organs (28). For example, for liver metastases from CRC primaries, the SABR consortium recommends doses varying from 30 to 60 Gy, based on the volume of the liver which is irradiated during treatment (13). Different fractionation regimens are recommended once again based on the size of the tumour. Other studies quote different values for palliative dosage, such as Lindberg et al., which suggests a BED10 of below 95 Gy for palliative care (26).

Current outlook

SABR has become an increasingly integral component in the treatment of oligometastatic CRC in both palliative and curative settings. Its precision, adaptability, and potential to deliver high doses of radiation while sparing healthy tissue have made it particularly suitable for patients with limited metastases. For instance, SABR treatment plans for oligometastatic CRC to the liver (Figure 1), lung (Figure 2), and right common iliac lymph node (Figure 3) illustrate how treatment can be tailored to specific metastatic sites, optimising outcomes and minimising risks. These examples highlight the adaptability of SABR across diverse clinical scenarios, where precise targeting enables effective control while sparing surrounding healthy tissues. Overall, the evidence in the literature for SABR as a potentially curative treatment in oligometastatic cancer is gradually improving, although stronger evidence in the form of Phase III trials is still required (29,30). Despite the limited number of randomised controlled clinical trials investigating SABR in the context of CRC, there are single-arm, prospective, and observational studies that provide insight into SABR use in various populations. This section will give an overview of the current outlook of this data in both the palliative and radical context.

Figure 1 SABR treatment plan for metastatic CRC to the liver (50 Gy in 5 fractions). CRC, colorectal cancer; SABR, stereotactic ablative radiotherapy.

Figure 2 SABR treatment plan for metastatic CRC to the lung (30 Gy in 5 fractions). CRC, colorectal cancer; SABR, stereotactic ablative radiotherapy.

Figure 3 SABR treatment plan for metastatic CRC to the right common iliac lymph node (60 Gy in 8 fractions). CRC, colorectal cancer; SABR, stereotactic ablative radiotherapy.

Investigations into palliative doses can be inferred in populations where tumours are inoperable when patients are elderly or have multiple co-morbidities. SABR can be used palliatively in these contexts to slightly extend lifespan while mainly focusing on managing symptoms rather than with a curative treatment intent. Palliative SABR has also shown promise in the management of pain symptoms. Wang et al. investigated the use of palliative SABR in patients with spinal metastases (1 or 2 spinal lesions), administering a dose of 27–30 Gy over three fractions [biologically effective dose (BED) not reported] (31). The study found that patients reported significant pain reduction within 6 months after SABR treatment based on the MD Anderson Symptom Inventory (MDASI) pain reduction scale. Additionally, there was also a considerable reduction in MDASI symptom interference with daily life. Although only a small proportion of patients had a CRC primary (n=6), this study provides a proof of concept for the use of palliative SABR in symptom management. Ji et al. corroborate these findings in their ‘local control of the dominant tumour’ study group, which includes tumours causing severe morbidity, pain, and obstruction—an emerging indication for SABR (32). In this cohort (n=17), 50% met the definition for oligometastatic CRC and showed significant benefit from low-dose palliative SABR, with an average BED10 as low as 68.4 Gy. Notably, pain relief was achieved in 100% of patients, highlighting the potential role of SABR in symptom management for these cases. In this context, SABR may be an effective option with a minimal adverse effect on patient quality of life and alleviating pain symptoms.

However, in some contexts, palliation using SABR has proved ineffective. Ito et al. investigated the impact of SABR on CRC-derived bone metastases in a cohort of 385 patients (33). Spinal metastases were treated with 24 Gy in two fractions, while non-spinal metastases received 35 Gy in five fractions. Local failure rates at one year were high at 44%. Initially, pain reduction was significant, with 84% of patients experiencing symptom relief at one month. However, by six months, this had decreased to only 50%. Overall, outcomes were unfavourable, possibly due to insufficient dosing to sustain pain relief and maintain LC. This study underscores the need for clinical trials to optimise SABR dosing in palliative care, ensuring maximal patient response and quality of life.

A recent systematic review evaluated the effectiveness of SABR therapy on oligoprogressive disease, focussing on studies where SABR was used as a non-radical treatment (34). In terms of outcomes, the systematic review assessed whether SABR established stable disease and prolonged the time to the next systemic therapy. Delay to the subsequent systemic therapy is an essential aim in the context of SABR, given that in some cases, the next line of treatment may be significantly more toxic, options for treatment may be limited or it may have an adverse impact on the quality of life of patients (32). This outcome is reported in the context of both colorectal and non-small cell lung cancer (NSCLC) (22). SABR delayed the transition to systemic therapy by a median of 4.9 months in the oligoprogressive CRC cohort using doses varying from 24–60 Gy in 2–5 fractions, though other primary cancers (e.g., rectal, NSCLC) showed a better response (34). A recent systematic review supported this finding, reporting a 5.2-month delay (35). Furthermore, in the CRC patient population, PFS was reported as between 2.9 and 6.8 months and OS between 19.6 and 26.1 months (34), which is comparable to other studies treating oligoprogressive disease such as Pembroke et al. who reported a 6.4 month PFS in the oligoprogressive cohort (over 30% with colorectal primaries) (36). This study employed a variable dosage regimen, with some patients receiving lower BEDs and others receiving higher BEDs, indicating a varied approach between curative and palliative treatment (lung; BED10 72–150 Gy, liver; BED10 48–106 Gy, lymph node; BED10 48–100 Gy).

Palliative SABR is often used to control tumours and metastases, including in patients who may not be eligible for surgical resection (37). For example, in a study on patients with oligometastatic CRC, which has metastasised to the lung and has a poor prognosis, SABR displayed no worse outcomes in the inoperable cohort as compared to the surgical outcomes in the operable cohort (8,38). Additionally, in patients with spinal metastases where standard of care was palliative radiotherapy, SABR allowed for a higher BED while sparing healthy tissues and maintaining high levels of pain control and LC in comparison to palliative radiotherapy (37). SABR is now used in clinical practice in this context (8,39). However, the evidence supporting the use of SABR for palliative care is still weak, and dose fractionations as well as target populations, are not well defined in the literature (Table 2). Further studies are required to elucidate the most effective dose regimens for maximal pain and symptom control, while maintaining acceptable levels of LC and survival.

In treatment with curative intent, a higher BED tends to be used, to expose the tumour to as much radiation as possible whilst sparing healthy tissues. Several papers show when lower dose SABR is used, which could be interpreted as palliative or adjuvant intent (to systemic therapy), there are worse outcomes in terms of LC when compared to a more radical approach. For example, McPartlin et al. reported a strong dose-response relationship for LC in patients with hepatic CRC oligometastases, using a varying dose, but consistent treatment schedule of 6 fractions (41). With BED10 >75 Gy, LC at one year was 65% and 49% at two years. At lower doses, these values were only 44% and 23%. BED10 >117 Gy was required to achieve 90% LC rate at one year. A second study validates these findings, Joo et al., who reported a 2-year LC rate of just 52% in the BED10 <80 Gy group compared to 89% in the >132 Gy group, using a fractionation schedule of 45–60 Gy in 3 to 4 fractions (42). Although these studies show higher levels of LC with higher doses, these papers fail to consider patient quality of life and cost factors, which could be central to improving patient experience with these end-of-life conditions (22,43).

Radical SABR aims to cure patients by delivering high BED to target tissue and this is beneficial in patients with few slower-growing lesions such as oligometastatic cancer (44). However, there is evidence in the literature that pulmonary metastases from oligometastatic CRC is associated with radioresistance, and therefore, in large studies which collect data for oligometastatic CRC, as well as other types of cancer, CRC tends to have worse outcomes in terms of LC and OS (43,45). A comparative meta-analysis between patients with CRC and non-colorectal pulmonary metastases showed a significantly lower LC rate in the colorectal group, suggesting that higher BED may be required to maintain the same levels of LC and PFS (45). Despite this fact, Cao et al. reported that patients with oligometastatic CRC had unacceptable OS, with a three-year OS rate of 53%, which may improve with an increased BED (45). Similarly, Sharma et al. reported a two-year OS rate of 63% in patients with inoperable pulmonary metastases, a favourable outcome in patients who are not eligible for surgery (29). Lehrer et al. reported SABR was safe and well tolerated in the oligometastatic cancer population, with estimated incidences of acute and late grade 3–5 toxic effects at 1.2% and 1.7%, respectively (46).

Radical SABR has seen positive outcomes in terms of controlled oligometastatic CRC in the contexts of both liver metastases and lung metastases (45,47). A systematic review analysing liver metastasis has shown that SABR is an effective option for patients with advanced oligometastatic CRC, with a median PFS of 11.5 months, OS of 31.5 months and at one year, an acceptable LC rate of 67% (47). Other studies have supported this notion with lung metastases, with a systematic review mentioned earlier demonstrating even higher LC rates of 81% at one year and a large prospective study showing low levels of local failure (a relapsing metastasis) of 23.6% at 24 months (43,45,48). Liver metastasis from CRC tend to have worse outcomes than lung metastasis. However, with radical SABR, one study of both liver and lung metastases suggests better outcomes at 5 years than with curative-intent surgery (12). An NHS-sanctioned study showed high rates of OS and LC rates of 72% at 2 years, which suggests SABR allows the body to maintain good control of the cancer (49). In oligometastatic CRC with lymph node metastases, SABR demonstrated superior outcomes in lymph nodes compared to lung and liver metastases despite using a lower dosage. Lung and liver metastases were irradiated with 50–60 Gy in 3 fractions (BED 100–151.2 Gy), whereas lymph node metastases received 30–40 Gy in three fractions (BED 60–93.3 Gy). Despite this, median PFS was 9 vs. 19 months, and median OS was 32 months, with the median not yet reached in the lymph node group. This suggests that lymph node metastases may be more sensitive to SABR than visceral metastases (50).

Overall, SABR represents an additional treatment option in the repertoire against cancer that can be explored in both the palliative and curative contexts, helping to extend OS and maintain LC. In conjunction with other treatments, such as systemic chemotherapy and surgery, it could form a strong weapon, particularly once we fully understand its abscopal effects (Table 3). However, the evidence base is currently weak, with few large, randomised control trials comparing SABR to the current gold standard of care (9). This will be necessary to elucidate the ideal doses, treatment regimens and patient groups moving forward and support an evidence-based approach to cancer treatment.

Comparing outcomes: radical vs. palliative SABR in oligometastatic CRC

The role of SABR in treating oligometastatic CRC varies based on the intent—palliative or curative (Table 4). In this section, we compare SABR’s efficacy in palliative versus radical contexts, analysing how it measures against traditional treatments like surgery, chemotherapy, and systemic therapies.

Palliative SABR

Palliative SABR primarily aims to control symptoms and improve quality of life rather than achieve complete remission. The ideal candidates for palliative SABR are often those who are ineligible for surgery due to their health status or the inaccessibility of metastatic sites. Takeda et al. [2014] emphasise the need to refine palliative SABR indications, as studies have shown it can offer LC comparable to surgical resection but with less treatment time and hospital stay, enhancing the quality of life for CRC patients who are often dealing with a high burden of symptoms (8).

A recent study by Li et al. [2022] highlighted SABR’s role in managing lung oligoprogressive metastatic CRC (40). Treating with 5 to 12 fractions and 50–60 Gy total, SABR delayed the need for systemic therapy change by an average of 5.2 months, suggesting it provides a therapeutic window for patients before advancing to more intensive therapies. Patients who received targeted therapy prior to SABR also showed improved PFS, suggesting potential benefits in combining SABR with certain systemic therapies such as chemotherapy or immunotherapy, for longer disease stabilisation.

The Multicentre Phase 2 Trial of SABR for Oligometastatic Cancer by Sutera et al. supports SABR’s role in palliative settings, demonstrating its feasibility and safety for diverse tumour types, including CRC (38). Treating with doses of 41–54 Gy in 3–5 fractions, the study targeted several oligometastatic sites, with the most common being lung, lymph node, bone and liver. Metastases from CRC primaries (22% of patients) reported a median OS of 54.4 months and a distant PFS (DPFS) of 10.4 months, compared to the average 42.3 and 8.7 months across all cancer types, highlighting oligometastatic CRC as a better responder to SABR compared to other primary cancers. The 42% 5-year OS observed in this cohort compares favourably to outcomes reported in surgical studies but can be biased by the small patient numbers. Furthermore, quality-of-life assessments showed no significant decline post-treatment, and patients even reported improved quality of life at six and twelve months. Importantly, SABR’s low rates of grade 3 or higher toxicities in both acute and late stages suggest that it is a tolerable palliative option that can enhance life quality without severely impacting health (44).

The ORCHESTRA trial (Gootjes et al., 2020) supports the use of SABR alongside chemotherapy as a viable approach for managing extensive metastatic CRC (20). In this trial, tumour debulking—including SABR, resection, or thermal ablation—was added to chemotherapy in patients with multiorgan metastasis. The trial found that local treatment did not interfere with systemic therapy, as 89% of patients could resume chemotherapy after debulking. This finding indicates that SABR does not preclude further systemic treatment and may provide additional disease stability.

An interesting finding by Thompson et al. [2020] in their retrospective analysis of extracranial SABR for metastatic CRC, is that the median PFS after a second course of SABR was 8.5 months, closely mirroring the median PFS of 9.9 months observed after the first course of SABR (22). This indicates that, among the 31 patients who underwent “second-line” SABR, their PFS outcomes were comparable to those receiving SABR for the first time. This suggests that repeated courses of SABR could offer cumulative benefits in delaying disease progression for patients, providing an effective strategy for ongoing disease management (22).

Radical (curative) SABR

As previously mentioned, radical SABR aims to achieve long-term disease control and potentially curative outcomes in patients with a limited number of metastases. Evidence from the SABR-COMET trial, a phase II randomised study, supports SABR’s role as a transformative treatment in extending survival for patients with oligometastatic disease. Palma et al. [2019, 2020] demonstrated that adding SABR to standard care improved median OS from 28 months (standard care) to 50 months (with SABR), with a five-year survival rate of 33.1% compared to 16.2% in the control group (18,19). However, adverse events were notably higher in the SABR group, with 29% experiencing grade 2 or worse side effects compared to 9% in the control group. Furthermore, only 18 out of 99 patients in this trial had CRC listed as their primary cancer, of which just 9 of them received SABR treatment. In many cases, patients still develop new metastases, suggesting micrometastases are present before SABR treatment begins, in which repeat SABR is used in these cases. Despite these drawbacks, the survival benefit highlights SABR’s value as a radical approach for long-term disease control in selected patients.

A phase II trial (Scorsetti et al., 2015) exclusively evaluating colorectal liver metastases demonstrated the efficacy of SABR as a curative option for inoperable cases (52). With a median follow-up of 24 months, the study achieved a LC rate of 91% at 2 years and a median OS of 29.2 months. Impressively, patients maintained a 65% OS rate at 24 months, emphasising the potential of high-dose SABR (75 Gy in 3 fractions) to achieve durable disease control in colorectal liver metastases. The absence of grade ≥3 toxicities further highlights SABR’s safety profile in this radical setting. While these outcomes are promising, they are lower than those typically reported for surgical resection, where median OS ranges from 40 to 53 months, with 5-year survival rates between 30–60% (53-55). However, as the majority of patients with colorectal liver metastases are ineligible for surgery due to factors such as tumour burden, anatomical constraints, or comorbidities, SABR offers a viable and effective alternative, particularly for those who would otherwise have limited treatment options (30).

A phase I and II study by McPartlin et al. [2017] evaluated the efficacy of six-fraction SABR for patients with colorectal liver metastases unsuitable for surgical resection (41). The study prescribed a median gross tumour volume (GTV) minimum dose of 37.6 Gy, delivered in six fractions over two weeks. Results showed that LC was significantly associated with the delivered dose, with lesions receiving a GTV minimum dose ≥45 Gy achieving a 4-year LC rate of 49% compared to 14% for lower doses. The study reported a median OS of 16 months, highlighting the potential of SABR as a safe and effective option for durable disease control in a heavily pretreated population with advanced disease. Importantly, no acute or late toxicities beyond grade 2 were observed, emphasising SABR’s tolerability even in challenging clinical scenarios​. However, a randomised trial evaluating the combination of radiofrequency ablation and chemotherapy for treating non-resectable CRC liver metastases reported 3-, 5-, and 8-year OS rates of 56.9%, 43.1%, and 35.9%, respectively (10). Comparable outcomes were observed for CRC lung metastases, indicating that thermal ablation can achieve local tumour control rates similar to those of surgery and radiotherapy for small metastases (56). These findings underscore the fact that while SABR shows promise, it has yet to establish itself as a first-line curative treatment for oligometastatic CRC.

The SABR-5 trial (Baker et al., 2022) reported on a large cohort of 381 patients with up to 5 oligometastases treated with SABR, including 63 patients with CRC primaries (21). The prescribed SABR doses ranged from 24 to 60 Gy delivered in 2 to 8 fractions, with the highest doses correlating with the most favourable LC. Although the paper did not list any specific data for patients with CRC oligometastasis, the study described a median PFS of 15 months, 3-year LC of 87% and 3-year OS of 71%. The 2024 SABR-5 analysis further refined outcomes, focusing on the sequencing of SABR and systemic therapies (57). The results highlighted that delaying systemic treatment after SABR was associated with a median PFS of 19 months, with reduced toxicity.

Takeda et al. [2014] explored dose escalation within SABR for patients with pulmonary and hepatic oligometastasis, revealing that higher doses may approach the outcomes of surgical resection while avoiding the morbidity associated with surgery (8). In cases where SABR is feasible at radical doses, it can achieve LC rates and survival benefits that rival surgery, offering a non-surgical alternative for patients with accessible lesions. Sharma et al. [2019] corroborated these findings, reporting that SABR achieved a two-year OS of 63% and a five-year OS of 30% in patients with pulmonary oligometastases, particularly those with smaller tumour sizes and CRC primaries (median OS of 39.2 months compared to 27.5 months in other primaries) (29). This study emphasised SABR’s efficacy in achieving long-term disease control in CRC patients with limited pulmonary metastasis, thus supporting its role as an effective radical treatment for those unable or unwilling to undergo surgery. Furthermore, SABR results for CRC pulmonary metastasis seem to outperform studies looking at liver metastasis, something which has previously been documented in the literature (22,23). Suggested explanations for this include difficulty finding all liver lesions on scans, the liver microenvironment giving rise to a higher tumour radioresistance, and heterogenous molecular patterns between the sites such as microsatellite instability (58,59). This may be countered by MRI image guidance during treatment, and gating or breath hold techniques.

SABR’s quality-of-life advantages are also significant when compared to surgery. Patients undergoing SABR generally experience shorter recovery times, lower morbidity, and fewer disruptions to their daily lives. Szturz et al. [2020] report that SABR may offer a quality-of-life edge over surgical resection, as it requires fewer sessions and is minimally invasive, making it an attractive option for patients with CRC who prioritise maintaining functionality during treatment (44). Across the various aforementioned trials, SABR seems a valuable approach for the treatment of oligometastatic CRC, reporting promising PFS, OS and LC rates (Table 5).

Dosage

Despite the heterogeneity in dose-fractionation schedules for liver and lung metastasis in CRC, the literature suggests that there is an apparent dose-response effect on LC (13,61). For example, McCammon et al. report in their study that an LC of 89.3% was achieved with a dose of 54–60 Gy compared to an LC of 59% at a dose of 36–53.9 Gy in CRC with liver or lung metastasis, supporting the use of aggressive SABR regiments for tumour control (62). Similarly, Helou et al. report in their study that a dose of 60 Gy given in 4 fractions was associated with a 73% reduction in local failure of CRC with lung metastasis compared to any dose less than 60 Gy, further underscoring the benefit of a higher radical dose (43). Another study found the 1-year LC rates to be 97% in patients treated with 60–75 Gy in 3 fractions compared to 85% in patients treated with 48 Gy in 4 fractions, highlighting the importance of a higher dose for better outcomes (63).

Although there is a strong body of evidence for a dose-response relationship, there is no clear consensus on the minimum required planned target volume (PTV) dose needed to achieve a defined level of LC (64). Indeed, the SABR-5 trial found that undercoverage of the PTV was not associated with recurrence or worse PFS, which supports prioritising the organs at risk (OAR) during treatment planning (65). Secondary analysis of the SABR-COMET trial also confirms this, finding that the prescribed radiation dose for PTV coverage is not significantly associated with lesional control or OS (66). Furthermore, Andratschkeet al. state that as long as a mean BED10 greater than 151.2 Gy10 is maintained for the GTV, a significantly lower PTV BED10 compared to literature is sufficient to achieve a high LC rate (64). This indicates that a high mean GTV dose is more important for LC, although the study acknowledges that a minimum PTV BED10 of 86.1 Gy10 is required even with GTV mean dose optimisation.

Generally, SABR appears to be safe with respect to early and late toxicity, with rarely any toxicities above grade 3 (67). However, Palma et al. reported a grade 5 toxicity rate of 4.5% in their study, which was higher than other reported studies and highlights the need to optimise SABR delivery and dosage to minimise toxicity (19). Rates of liver enzyme derangement can also be low from SABR, with a grade 1/2 elevation of liver enzymes in only 28% of patients, although such increases can be transient (68). Overall, these findings suggest that whilst SABR is a promising treatment option, there is a need for more research to look into optimal dosing and monitoring to ensure patient safety.

Limitations

Clearly, SABR has emerged as a promising treatment for oligometastatic CRC, with some curative potential. However, while this modality offers several potential benefits by targeting a limited number of metastatic lesions with high precision, significant limitations in its application for oligometastatic CRC need to be carefully considered. Firstly, there is a lack of randomised, prospective, long-term data. Many studies evaluating the effectiveness of SABR in this context have been retrospective or involved small patient cohorts, with short timeframes limiting conclusions about long-term disease progression. The SABR-COMET phase II trial was the first randomised controlled trial to test the oligometastatic paradigm in the context of CRC and has so far offered the most reliable data about the use of SABR vs. palliative standard of care in patients with oligometastatic disease (19). However, only 18 of the 99 patients included had CRC, and only half of these patients were in the treatment group despite a 2:1 ratio of patient allocation between the treatment and control groups. Therefore, any insights about the effectiveness of SABR, specifically in oligometastatic CRC, is limited by a small patient cohort and disproportionate representation of these patients in the control group (27% vs. 14%).

Instead, more generalised conclusions were made about the effectiveness of SABR in oligometastatic disease, which means that tumour-specific differences in SABR-susceptibility were not considered. For example, it has been suggested that CRC cells may have greater radio-resistance than other cancer types, meaning SABR may be less effective in this context (69). Therefore, greater representation of breast and prostate cancer patients in the treatment group may have positively impacted the results. However, other studies suggest that oligometastatic CRC is a better responder to SABR compared to other primary cancers, which necessitates further studies to understand whether CRC has greater or worse radio-resistance (38). Importantly, the SABR-COMET trial was not blinded, meaning many sources of bias could have been introduced, including higher quality of life reporting from patients in the experimental group and different approaches to systemic therapy from physicians depending on the patient’s group allocation. Indeed, the lack of high-quality prospective trial data has meant that the benefits associated with the use of SABR in oligometastatic CRC are unclear. The ASCO guidelines, written following a review of the available evidence by an expert panel, suggest that SABR may be recommended for patients with CRC who have oligometastases of the liver and are not candidates for surgical resection (9). However, they deem that the evidence to support this is low, and thus, it is marked as a weak recommendation.

Beyond these studies and evidence-based limitations, there are also some intrinsic limitations of SABR as a curative intervention. A systematic review of the use of SABR as a primary modality for the treatment of CRC liver oligometastases found a poor correlation between the SABR dose and LC, suggesting higher dosages may not necessarily achieve better disease control (47). Therefore, if a curative dose regimen is not possible, then a significant dose reduction to palliative levels may have the same effect. However, the systematic review by Kobiela et al. found that higher doses were associated with improved LC in both liver and lung metastases (12). Clearly, there is uncertainty about the optimal dosing regimen for SABR, and the lack of defined dosing regimens has meant that many studies only use one dose or a seemingly arbitrary range of doses. This increases heterogeneity between studies and makes it difficult to compare outcomes directly, limiting the conclusions that can be made about the general effectiveness of SABR.

Future directions

Moving forward, more high-quality evidence about the effectiveness of SABR in treating oligometastatic CRC is required. This will involve large-scale, appropriately blinded, randomised controlled trials testing the efficacy of SABR against standard of care in a tumour-specific manner. Accordingly, several phase 3 trials are underway, including SABR-COMET-3 (NCT03862911) and SABR-COMET-10 (NCT03721341), aiming to compare the effect of SABR, relative to standard of care alone, on OS for patients with 1–3 metastatic lesions or 4–10 metastatic lesions respectively. Similarly, the Alliance trial (A022101/NRG-GI009) is an ongoing phase III trial focused on determining the efficacy of adding SABR to standard-of-care systematic therapy for improving OS in patients with extrahepatic metastases. The outcomes of these trials will provide important insights into the utility of SABR in treating CRC patients with differing patterns of metastases, providing more robust evidence about the curative potential of these interventions in various indications.

It has been argued that LC is the best metric for determining the curative efficacy of SABR. This is based on the premise that patients eligible for SABR are typically in worse condition, with more comorbidities, higher clinical stage or more complicated localisation of oligometastases, thus making OS a less reliable metric for determining efficacy (12). Accordingly, there is some evidence to suggest that expediting the administration of SABR in patients with oligometastatic disease may enhance its efficacy. Franzese et al. [2019] collected data from a sample of 270 patients with colorectal carcinoma treated with SABR for retrospective analysis (70). They found that the only factor that was predictive of LC of treated metastases was the time from diagnosis of metastases to the administration of SABR, with longer delays being associated with poorer LC. This suggests that early administration of SABR following diagnoses of metastases may enhance its curative potential by improving LC of metastatic disease, thus providing an incentive to streamline the associated clinical pathway.

Recent findings from Hong et al. [2017] highlight the potential of proton-based SABR in managing liver metastases from CRC (60). This phase II study demonstrated a one-year LC rate of 58.8% for colorectal adenocarcinoma, lower than other histologies, whereas PFS and OS times were comparable with the rest of the cohort. Proton-based SABR offers unique advantages over conventional photon-based SABR, including improved dose distribution and reduced exposure to surrounding healthy tissues (by depositing its energy at a defined depth without exit dose). It is particularly beneficial when treating lesions near critical organs such as the liver. The use of risk-adapted dosing with protons allowed for safe treatment of larger tumours (≥6 cm) without grade 3 or higher toxicities, suggesting that dose escalation could address the unique challenges of CRC liver metastases. Additionally, the study found that genetic profiles, particularly KRAS and TP53 mutations, were strong predictors of poor LC, underlining the need for integrating genomic data to refine patient selection and optimise SABR strategies​. Future research should focus on stratifying patients based on genetic markers to develop more tailored SABR regimens. This could include combining radiation with radiosensitisers targeting KRAS-mutant tumours or intensifying treatment for radioresistant subsets (71,72). Furthermore, proton-based SABR’s dosimetric advantages suggest a path forward in improving outcomes for larger tumours and CRC-specific challenges.

Importantly, developments in immunotherapy for the treatment of CRC mean that SABR should also be tested in this context to assess whether it can act synergistically with immunotherapeutic interventions. A recent single-arm phase II trial tested the combination of atezolizumab and SABR in 60 pre-treated advanced CRC patients with unirradiated lesions and eligible for SABR (51). Although the median PFS was only 1.4 months, 5 patients (8%)—two of which were mismatch repair proficient (pMMR)—experienced excellent disease control for more than one year and were termed ‘elite responders’. It is possible that in these patients, SABR may have boosted the efficacy of PD-1 blockade, as checkpoint inhibitors are typically ineffective against pMMR CRC. Therefore, it may be the case that the additional liver-directed radiotherapy can aid in the activation of the systemic anti-tumour immune response. Indeed, comparing the gene expression profiles of tumours from elite responders to non-elite responders found that there was significantly higher expression of genes associated with T cell and B cell trafficking and migration in the former group, suggesting that this combinatorial approach has the potential to alter the immunological landscape of the tumour microenvironment. This is particularly promising in the context of a curative rather than palliative approach. Further work is necessary to determine whether combining these therapeutic modalities can improve outcomes. Additionally, identifying biomarkers that may correlate with improved responses to this combination would be particularly useful for identifying patients who are most likely to be ‘elite responders’.

Conclusions

SABR represents a significant advancement in treating oligometastatic CRC, improving LC, PFS, and OS in both palliative and curative settings. While its efficacy, particularly for pulmonary metastases, is promising, challenges remain regarding optimal dosing, patient selection, and the need for CRC-specific trials. At present, SABR is not definitively curative, and surgery remains a more optimal approach, but it may offer curative potential for selected patients, particularly those with limited oligometastases who are ineligible for surgery. Combining SABR with systemic therapies offers potential, but further evidence is needed. Upcoming phase III trials like SABR-COMET-3 and SABR-COMET-10 will be pivotal in refining its role.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://apm.amegroups.com/article/view/10.21037/apm-24-170/rc

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Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://apm.amegroups.com/article/view/10.21037/apm-24-170/coif). C.M. received consulting fees and honoraria from BAYER AG and Astra-Zeneca. The other authors have 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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