Summary
Background
Local therapies can achieve durable disease control in selected patients with oligometastatic colorectal liver metastases. Microwave ablation (MWA) is widely used, whereas stereotactic body radiotherapy (SBRT) is a non-invasive alternative with limited prospective comparative evidence. We aimed to compare freedom from local progression and safety of MWA versus SBRT.
Methods
LAVA-CRLM was a randomised, phase II trial conducted at two centres in Copenhagen, Denmark. Adults with one to three colorectal liver metastases, each ≤4.0 cm, deemed suitable for both MWA and SBRT with curative intent by a multidisciplinary team were randomly assigned (1:1) to MWA or SBRT. The primary endpoint was freedom from local progression in the modified intention-to-treat population. Toxicity was assessed in the safety population. The trial is registered with ClinicalTrials.gov (NCT03654131).
Findings
Between Jan 29, 2019, and Dec 3, 2024, 100 patients were randomly assigned; 92 were included in the modified intention-to-treat population. At a median follow-up of 34.9 months, 1-year freedom from local progression was 77.7% (95% CI 66.5–90.9) with MWA and 83.0% (72.3–95.4) with SBRT (hazard ratio 0.87, 95% CI 0.43–1.74; p = 0.70). Grade 2 or higher treatment-related toxicity occurred in 13 (25%) of 52 patients treated with MWA and one (3%) of 40 treated with SBRT. Grade 3 or higher toxicity occurred only with MWA (four [8%] patients), including one treatment-related death.
Interpretation
SBRT demonstrated a more favourable treatment-related safety profile, with no difference in freedom from local progression detected between SBRT and MWA in this phase II study. These findings support consideration of SBRT as a non-invasive local treatment option for selected patients with oligometastatic colorectal liver metastases.
Funding
Danish Cancer Society.
Keywords: Colorectal cancer, Oligometastatic, Microwave ablation, Stereotactic body radiotherapy, Clinical trials, Prospective, Randomised, Phase II
Research in context.
Evidence before this study
We searched PubMed for clinical trials comparing microwave ablation (MWA) and stereotactic body radiotherapy (SBRT) for liver metastases in patients with oligometastatic colorectal cancer. The search included articles published between Sept 1, 2017, and June 2026, using combinations of the terms “colorectal cancer”, “oligometastatic”, “microwave ablation”, “stereotactic body radiotherapy”, and “clinical trials”, without language restrictions. We identified no prospective randomised studies directly comparing MWA and SBRT. Surgical resection is the standard of care for colorectal liver metastases; however, optimal local treatment strategies with curative intent remain insufficiently defined. MWA is widely used and supported by evidence for durable local control. SBRT is an alternative approach that can be delivered using a conventional linear accelerator with cone-beam CT guidance and fiducial tracking, or without invasive fiducial placement using MR-guided systems, and may be advantageous for lesions that are technically challenging to ablate or associated with a higher risk of ablation-related complications. However, it has been less frequently applied in the absence of prospective comparative data.
Added value of this study
To our knowledge, LAVA-CRLM is the first prospective randomised phase II trial to provide direct comparative evidence on local control following MWA and SBRT in patients with oligometastatic colorectal liver metastases. No evidence of a difference in local control was observed between treatment groups. Grade 2 or higher treatment-related toxicity occurred in 25% of patients treated with MWA and 3% treated with SBRT, while grade 3 or higher treatment-related toxicity occurred only in the MWA group. These findings provide clinically relevant comparative data on local control and treatment-related toxicity to inform selection of local treatment strategies.
Implications of all the available evidence
For patients with oligometastatic colorectal liver metastases measuring 3 cm or less, no difference in local control was detected between SBRT and MWA in this phase II study, whereas fewer severe treatment-related adverse events were observed following SBRT. The ability to deliver SBRT fully non-invasively using MR-guided technology may expand local treatment options and influence multidisciplinary decision-making. Taken together, the available evidence supports consideration of SBRT alongside MWA in local treatment planning. Further comparative studies are needed to confirm these findings and to better define the optimal role of each modality.
Introduction
Management of metastatic colorectal cancer (mCRC) relies on multidisciplinary team assessment, encompassing diagnostic evaluation, assessment of metastatic disease resectability, and selection of treatment strategies for both the primary tumour and metastatic sites.1,2 At diagnosis, approximately 25–30% of patients with colorectal cancer present with distant metastases, and a further 50–60% will develop metastatic disease during the course of their illness, most commonly involving the liver.3, 4, 5 Oligometastatic disease represents an intermediate state between localised and widely disseminated cancer and is characterised by a limited number of metastases and organ sites, typically defined as fewer than five metastases across no more than two anatomical locations and identified primarily through radiographic imaging.6, 7, 8 In mCRC with oligometastatic disease, curative-intent treatment of the primary tumour and metastases can achieve prolonged disease control and long-term survival, highlighting the need for individualised strategies and predictors of benefit from local therapies.9,10 Surgical resection and local ablative approaches, including thermal ablation with radiofrequency ablation (RFA) or microwave ablation (MWA), and stereotactic body radiotherapy (SBRT), are key treatment options for colorectal liver metastases (CRLM). Surgical resection remains the standard of care, with local control rates exceeding 90%, 5-year overall survival (OS) ranging from 35% to 60%, and 10-year survival approaching 24%.11, 12, 13, 14, 15 Outside of surgical resection, thermal ablation is generally preferred when technically feasible because of robust evidence supporting durable local control and long-term outcomes.16, 17, 18 Like surgery, thermal ablation typically requires general anaesthesia but may offer a less invasive alternative.18 MWA is widely used for thermal ablation and achieves high local control rates.19,20 SBRT offers a non-invasive alternative, particularly for lesions that are technically challenging for thermal ablation, including centrally located lesions and appropriately selected larger lesions.14,21 It does not require general anaesthesia and can be delivered with image guidance to enable precise targeting while sparing surrounding organs at risk. Reported 2-year local control rates following SBRT reach up to 91%, with higher biologically effective doses associated with improved local control.14,22,23 Despite increasing use of both modalities, prospective comparative data evaluating MWA and SBRT are lacking.9,10,19,24 This absence of prospective comparative evidence is a key knowledge gap for multidisciplinary teams selecting optimal local treatment strategies for patients with oligometastatic, potentially curable mCRC, while balancing local control and treatment-related toxicity. The LAVA-CRLM (Local Ablation Versus Ablative Radiotherapy in ColoRectal Liver Metastases) trial was designed to provide initial comparative data on freedom from local progression between MWA and SBRT in patients with oligometastatic CRLM deemed suitable by the multidisciplinary team for local therapy. The trial was not designed to establish equivalence or non-inferiority between treatments. Secondary endpoints included treatment-related toxicity and OS; patient-reported health-related quality of life was assessed throughout follow-up.
Methods
Study design and participants
The LAVA-CRLM trial was an investigator-initiated, prospective, randomised, phase II trial conducted at Copenhagen University Hospital, Rigshospitalet, and Herlev Hospital (Denmark). Eligible patients were aged 18 years or older with oligometastatic CRLM (one to three lesions, each ≤4.0 cm). Only patients with Child–Pugh class A liver function were eligible. Patients with limited extrahepatic disease or an untreated primary tumour were eligible if a curative treatment strategy was considered feasible. Patients who had received systemic chemotherapy within the preceding 3 months were eligible. Exclusion criteria included previous liver radiotherapy, a liver volume of less than 700 mL, or another active malignancy within the past 36 months.
All patients were assessed by a hepatopancreatobiliary multidisciplinary team and were included only if deemed suitable for both microwave ablation (MWA) and stereotactic body radiotherapy (SBRT) with curative intent. Eligibility was confirmed using liver ultrasonography and contrast-enhanced magnetic resonance imaging (MRI).
The study was conducted in accordance with the Declaration of Helsinki and International Council for Harmonisation–Good Clinical Practice guidelines. Approval was obtained from institutional review boards and the Regional Committee on Health Research Ethics for the Capital Region of Denmark (H-18000085). Written informed consent was obtained from all participants. Patients who withdrew consent were re-evaluated by the multidisciplinary team and continued to receive standard-of-care treatment. Clinical and patient-reported data were recorded in REDCap in accordance with data protection regulations. The trial was registered at ClinicalTrials.gov (NCT03654131). The trial was reported in accordance with the CONSORT 2025 statement. Patients and members of the public were not involved in the design, conduct, reporting, or dissemination plans of the trial.
Randomisation and masking
After informed consent had been obtained, patients were randomly assigned (1:1) to MWA or SBRT by an independent unit via telephone using a computer-generated randomisation sequence without prespecified stratification factors; molecular characteristics were not systematically available at enrolment. Patients were permitted to receive the alternative treatment modality if the allocated therapy was not feasible. Owing to the nature of the interventions, patients and treating clinicians were not blinded to treatment allocation. Clinical data, including adverse events, were entered into the study database by a dedicated research nurse. Primary endpoint assessment was masked to treatment allocation, whereas treatment-related toxicity assessment was not.
Procedures
At randomisation, patients underwent baseline evaluation, including clinical assessment and blood sampling. Systemic chemotherapy was withheld for at least 2 weeks before the intervention. Surgical procedures were permitted; however, surgery that replaced or precluded the allocated treatment with MWA or SBRT was considered treatment outside the study protocol.
MWA was performed by experienced operators under general anaesthesia, either percutaneously (with local anaesthesia at the entry site) or during open or laparoscopic surgery. Ablations were performed using a microwave ablation system under real-time ultrasound guidance. Energy delivery was tailored to tumour size, with power settings ranging from 40 to 100 W and ablation durations of 4–15 min; track ablation was performed during probe withdrawal.
SBRT was delivered using either an integrated MRI–linear accelerator (MR-linac) or a conventional linear accelerator with cone-beam CT guidance and fiducial tracking.25 During treatment planning, liver MRI was performed to support delineation of the gross tumour volume (GTV). Image guidance and motion management strategies were used to ensure accurate target delineation and treatment delivery while sparing surrounding organs at risk. Renal scintigraphy (renography) was performed when clinically relevant renal radiation exposure was anticipated, and pulmonary function tests were performed when lung irradiation was expected.
The preferred SBRT regimen was 45 Gy delivered in three fractions over 1 week to the planning target volume (PTV), prescribed to the 67% isodose line and normalised to a mean dose of 100% to the gross tumour volume (GTV). The preferred regimen was selected to provide a high biologically effective tumour dose while allowing compliance with predefined organ-at-risk constraints. PTV margins were 10 mm in the craniocaudal direction and 5 mm radially. SBRT was delivered during free breathing or using breath-hold techniques. For patients treated during free breathing, respiratory tumour motion was accounted for in the PTV. Predefined organ-at-risk dose constraints were applied as previously described.26 Target cropping was permitted when required to meet these constraints, and 50 Gy in five fractions over 2 weeks was used when adequate target dosing could not be achieved in three fractions. Daily online adaptation was used for MR-linac treatment. All SBRT regimens delivered a biologically effective dose (BED10) greater than 173 Gy to the GTV.
Follow-up was conducted for 5 years according to standard protocols for colorectal liver metastases, including clinical evaluation and contrast-enhanced CT of the chest, abdomen, and pelvis every 3 months for the first 2 years, every 6 months during year 3, and annually thereafter. MRI was obtained when CT findings were equivocal or additional characterisation of suspected local progression was clinically required.
A specialised radiologist masked to treatment allocation reviewed imaging, and tumour response was assessed using RECIST version 1.1.27 Expected treatment-related imaging changes following MWA and SBRT were considered when assessing local progression.
Health-related quality of life was assessed using the EORTC QLQ-C30 questionnaire at 1 month after treatment and at subsequent follow-up visits. Adverse events were recorded and graded according to the Common Terminology Criteria for Adverse Events (CTCAE), version 5.0.28
Outcomes
Patient characteristics were summarised by treatment group using descriptive statistics. The primary endpoint was freedom from local progression at the patient level, assessed after a minimum follow-up of 1 year and defined as the time from randomisation to progression of a treated lesion. Patients were censored at death or at the end of imaging-based follow-up for liver metastasis control; development of new lesions or progression in untreated intrahepatic or extrahepatic lesions was not considered an event.
Prespecified secondary endpoints included overall survival (OS), treatment-related grade 3 or higher toxicity, and other toxicity outcomes.
OS was defined as the time from randomisation to death from any cause; patients who were alive or lost to follow-up at the time of analysis were censored at the date last known to be alive. Treatment-related grade 3 or higher toxicity was assessed at 1 month after treatment, and grade 2 or higher toxicity was assessed during subsequent follow-up for late adverse events. Missing data and survival status were retrieved from medical records during data cleaning one year after inclusion; complete survival data were obtained from national registries.
Statistical analyses
The primary analysis was conducted in the modified intention-to-treat (mITT) population, excluding screening failures and patients who did not receive protocol-defined local therapy (MWA or SBRT) because of disease progression or patient choice. A secondary per-protocol analysis included patients who received the full study treatment to which they were assigned.
The null hypothesis was that freedom from local progression did not differ between MWA and SBRT in patients with oligometastatic CRLM measuring 4.0 cm or less. In the absence of randomised comparative data at the time of study design, this phase II trial was designed to detect a large difference in local control between treatment groups. A difference of approximately 10 percentage points in 1-year local progression was considered clinically relevant. For the sample-size calculation, 1-year freedom from local progression was assumed to be 94% in one group and 85% in the comparator group, corresponding to a hazard ratio of 0.38. Assuming patient accrual over 3 years with an additional year of follow-up and an exponential hazard function, 35 patients per group provided 80% power to detect this difference at a two-sided significance level of 0.05. To account for competing risks, 50 patients per group were planned.
Kaplan–Meier curves were used to estimate freedom from local progression and OS at 1 and 3 years, with corresponding 95% confidence intervals. Treatment groups were compared using the log-rank test, and hazard ratios with 95% confidence intervals were estimated using Cox proportional hazards regression with treatment group as the sole covariate. Analyses were performed in the mITT population, with secondary analyses in the per-protocol population. Potential follow-up time was estimated using the reverse Kaplan–Meier method. A post-hoc sensitivity analysis in the mITT population compared the cumulative incidence of local progression between treatment groups, with death treated as a competing risk; subdistribution hazard ratios were estimated using Fine–Gray regression. A second post-hoc sensitivity analysis used multivariable Cox regression to evaluate freedom from local progression after adjustment for key baseline prognostic factors (largest lesion size, KRAS status, number of liver lesions, and distant metastases at baseline).
Toxicity analyses were conducted in the safety population, comprising all patients who initiated protocol-defined local therapy (i.e., excluding screening failures and patients who did not initiate treatment), and were analysed according to treatment received. Differences in grade 3 or higher toxicity at 1 month were assessed using Fisher’s exact test. The cumulative incidence of any treatment-related grade 2 or higher toxicity was estimated using the Aalen–Johansen method, with death treated as a competing risk. Fine–Gray regression was used to estimate subdistribution hazard ratios with 95% confidence intervals. Other toxicity outcomes were summarised descriptively without formal between-group statistical testing.
Quality-of-life scores from the EORTC QLQ-C30 questionnaire were transformed into standardised functional and symptom scales according to the EORTC QLQ-C30 scoring manual and analysed longitudinally using mixed-effects linear regression models. Patient was included as a random effect, and treatment group and time from randomisation were included as fixed effects. Time was modelled non-linearly using restricted cubic splines with four knots, and an interaction between treatment group and time was included to allow for different temporal trajectories between groups. Missing questionnaire assessments were not imputed; mixed-effects models were fitted using all available observations.
Statistical analyses were performed using R (version 4.5.3) and RStudio (version 2026.01.2). The prespecified statistical analysis plan, which further specified the analysis populations and statistical methods, was finalised before analysis of the primary endpoint and is provided in the Supplementary material.
Role of the funding source
This was an investigator-initiated study. The funders of the study had no role in study design; data collection, analysis, or interpretation; writing of the report; or the decision to submit for publication.
Results
Between Jan 29, 2019, and Dec 3, 2024, 100 patients with one to three colorectal liver metastases smaller than 4.0 cm, selected for curative-intent local therapy and deemed suitable for both treatment modalities by the multidisciplinary team, were randomly assigned to SBRT (n = 50) or MWA (n = 50).
Eight patients (three assigned to MWA and five to SBRT) did not meet criteria for inclusion in the modified intention-to-treat (mITT) population due to another primary malignancy (n = 1), disease progression (n = 3), or surgical treatment outside the study protocol, including resection of liver metastases (n = 3) or the primary tumour (n = 1). The mITT population consequently comprised the 92 patients undergoing protocol-defined local therapy (SBRT n = 45; MWA n = 47; Fig. 1). In the mITT population, 72 (78%) patients had one metastasis, 16 (17%) had two, and four (4%) had three. Median metastasis size was 1.2 cm (IQR 1.0–1.6). Synchronous metastases, present at diagnosis of the primary tumour, occurred in 16 (34%) patients in the MWA group and 15 (33%) in the SBRT group; all other patients had metachronous metastases. No patients had oligoprogressive disease while receiving systemic therapy. Before protocol-defined local treatment, nine patients (20%) in the SBRT group and 16 patients (34%) in the MWA group had received chemotherapy within the preceding 3 months. KRAS mutations were present in 11 (24%) patients in the SBRT group and 21 (45%) in the MWA group. Baseline demographic and clinical characteristics are shown in Table 1. Imaging follow-up was incomplete for one (1%) of 92 patients in the mITT population; survival follow-up was complete for all patients.
Fig. 1.
Trial profile.
Table 1.
Baseline characteristics of the modified intention-to-treat population.
| Characteristic | MWA N = 47a | SBRT N = 45a |
|---|---|---|
| Sex | ||
| Female | 18 (38%) | 18 (40%) |
| Male | 29 (62%) | 27 (60%) |
| Age [years] | 70 (61, 77) | 72 (62, 81) |
| Number of liver lesions | ||
| 1 | 37 (79%) | 35 (78%) |
| 2 | 8 (17%) | 8 (18%) |
| 3 | 2 (4.3%) | 2 (4.4%) |
| Maximum baseline lesion size [mm] | 13.0 (10.0, 19.0) | 14.0 (10.0, 18.0) |
| Planned MWA treatment method | ||
| Percutaneous | 39 (83%) | 35 (78%) |
| Open | 8 (17%) | 10 (22%) |
| Performance status | ||
| 0 | 27 (57%) | 27 (60%) |
| 1 | 13 (28%) | 13 (29%) |
| 2 | 6 (13%) | 4 (8.9%) |
| 3 | 1 (2.1%) | 1 (2.2%) |
| CEA [ng/mL] | 3 (2, 9) | 2 (1, 6) |
| Unknown | 13 (28%) | 18 (40%) |
| Smoking history | ||
| Never | 18 (38%) | 16 (36%) |
| Former smoker | 26 (55%) | 23 (51%) |
| Current smoker | 3 (6.4%) | 6 (13%) |
| Unknown | 0 (0%) | 0 (0%) |
| Alcohol use | ||
| No | 15 (32%) | 14 (31%) |
| Yes | 32 (68%) | 31 (69%) |
| Unknown | 0 (0%) | 0 (0%) |
| KRAS mutated | ||
| No | 17 (36%) | 26 (58%) |
| Yes | 21 (45%) | 11 (24%) |
| Unknown | 9 (19%) | 8 (18%) |
| TP53 positive | ||
| No | 0 (0%) | 4 (8.9%) |
| Yes | 11 (23%) | 5 (11%) |
| Unknown | 36 (77%) | 36 (80%) |
| Synchronous versus metachronous | ||
| Synchronous | 16 (34%) | 15 (33%) |
| Metachronous | 31 (66%) | 30 (67%) |
| Distant metastases at baseline | ||
| No | 44 (94%) | 37 (82%) |
| Yes | 3 (6.4%) | 8 (18%) |
| Chemotherapy within the last 3 months | ||
| No | 31 (66%) | 36 (80%) |
| Yes | 16 (34%) | 9 (20%) |
n (%); Median (Q1, Q3).
Five patients (5%) randomised to SBRT received MWA because of patient preference (n = 2), inability to perform breath-hold (n = 1), or technical limitations including unmet organ-at-risk dose constraints (n = 2). The safety population therefore comprised 40 patients treated with SBRT and 52 patients treated with MWA; of the latter, 42 underwent percutaneous ablation, eight open surgical ablation, and two laparoscopic ablation.
Of 40 patients treated with SBRT, 35 (88%) were treated on an MR-linac and five (13%) on a conventional linear accelerator. Thirty-two patients received 45 Gy in three fractions and eight received 50 Gy in five fractions. One patient did not complete SBRT as planned because of technical issues and was excluded from the per-protocol population. Consequently, the per-protocol population comprised 86 patients (SBRT n = 39; MWA n = 47), after excluding five patients randomised to SBRT who received MWA and one patient who did not complete SBRT.
In the mITT population, with a median follow-up of 35.0 months (SBRT) and 34.8 months (MWA), local progression occurred in 15 (33%) and 17 (36%) patients, respectively. The estimated 1-year freedom from local progression was 83.0% (95% CI 72.3–95.4) with SBRT and 77.7% (95% CI 66.5–90.9) with MWA, with no evidence of a difference between groups (hazard ratio [HR] 0.87, 95% CI 0.43–1.74; log-rank p = 0.70; Fig. 2A). The subdistribution HR for the cumulative incidence of local progression, with death treated as a competing risk, was 0.86 (95% CI 0.43–1.69). The effect estimate did not change substantially after adjustment for baseline prognostic factors (HR 0.83, 95% CI 0.36–1.92).
Fig. 2.
Local control in the modified intention-to-treat population (A), and the per-protocol population (B).
In the per-protocol population, at a median follow-up of 35.0 months (SBRT) and 34.8 months (MWA), local progression occurred in 12 (31%) and 17 (36%) patients, respectively. The estimated 1-year freedom from local progression was 86.0% (95% CI 75.3–98.2) with SBRT and 77.7% (95% CI 66.5–90.9) with MWA, with no evidence of a difference between groups (HR 0.78, 95% CI 0.37–1.63; log-rank p = 0.50; Fig. 2B).
After a median follow-up of 46.8 months (SBRT) and 45.5 months (MWA), 19 patients in the SBRT group and 20 in the MWA group had died in the mITT population. The estimated 1-year OS was 88.9% (95% CI 80.2–98.6) with SBRT and 95.7% (95% CI 90.1–100) with MWA. The estimated 3-year OS was 71.5% (95% CI 58.3–87.7) and 63.3% (95% CI 49.3–81.2), respectively, with no evidence of a difference between groups (HR 0.91, 95% CI 0.48–1.70; log-rank p = 0.80; Fig. 3A).
Fig. 3.
Overall survival in the modified intention-to-treat population (A), and the per-protocol population (B).
In the per-protocol population, 15 patients in the SBRT group and 20 patients in the MWA group had died, with no evidence of a difference between groups (HR 0.86, 95% CI 0.44–1.69; log-rank p = 0.70; Fig. 3B).
In the safety population (SBRT n = 40; MWA n = 52), any-grade toxicity during treatment or within 1 month after treatment occurred in 15 (38%) patients in the SBRT group and 37 (71%) in the MWA group (Table 2). Grade 2 or higher treatment-related toxicity occurred in one (3%) patient in the SBRT group and 13 (25%) in the MWA group. Grade 3 or higher treatment-related toxicity occurred only in the MWA group (four [8%] patients), including one treatment-related death (Fisher’s exact test p = 0.13). A 74-year-old patient was acutely admitted with abdominal pain two days after percutaneous MWA. Exploratory laparotomy revealed hepatic necrosis with capsular perforation, and the patient died the same day.
Table 2.
Toxicity during treatment and within 1 month thereafter in the safety population.
| Characteristic | SBRT N = 40 | MWA N = 52 |
|---|---|---|
| Maximum toxicity during treatmenta | ||
| 0 | 25 (63%) | 15 (29%) |
| 1 | 14 (35%) | 24 (46%) |
| 2 | 1 (2.5%) | 9 (17%) |
| 3 | 0 (0%) | 2 (3.8%) |
| 4 | 0 (0%) | 1 (1.9%) |
| 5 | 0 (0%) | 1 (1.9%) |
| Fatigue | ||
| 0 | 30 (75%) | 51 (98%) |
| 1 | 9 (23%) | 0 (0%) |
| 2 | 1 (2.5%) | 1 (1.9%) |
| Nausea | ||
| 0 | 39 (98%) | 51 (98%) |
| 1 | 1 (2.5%) | 1 (1.9%) |
| Liver pain | ||
| 0 | 37 (93%) | 16 (31%) |
| 1 | 3 (7.5%) | 25 (48%) |
| 2 | 0 (0%) | 9 (17%) |
| 3 | 0 (0%) | 2 (3.8%) |
| Perforation | ||
| 0 | 40 (100%) | 50 (96%) |
| 4 | 0 (0%) | 2 (3.8%) |
| Hepatic failure | ||
| 0 | 40 (100%) | 51 (98%) |
| 5 | 0 (0%) | 1 (1.9%) |
| Necrosis | ||
| 0 | 40 (100%) | 51 (98%) |
| 4 | 0 (0%) | 1 (1.9%) |
| Skin toxicity | ||
| 0 | 40 (100%) | 50 (96%) |
| 2 | 0 (0%) | 2 (3.8%) |
| Other toxicityb | ||
| 0 | 37 (93%) | 46 (88%) |
| 1 | 3 (7.5%) | 2 (3.8%) |
| 2 | 0 (0%) | 2 (3.8%) |
| 3 | 0 (0%) | 2 (3.8%) |
Maximum toxicity represents the highest CTCAE grade per patient during the specified period. Individual adverse-event categories represent events; patients could contribute more than one event.
Other toxicities included grade 1–2 diarrhoea, grade 1 cough, grade 1 dizziness, and grade 3 post-ablation abscesses.
During follow-up, any-grade toxicity occurred in 23 (58%) patients in the SBRT group and 30 (58%) patients in the MWA group. Grade 3 adverse events during follow-up were observed in one (3%) patient in the SBRT group (associated with disease progression) and three (6%) patients in the MWA group (all related to chemotherapy); none were considered treatment related.
The cumulative incidence of grade 2 or higher toxicity during follow-up is shown in Fig. 4A. The 1-year cumulative incidence was 7.5% (95% CI 1.9–18.4) in the SBRT group and 20.7% (95% CI 10.6–33.1) in the MWA group; the corresponding 3-year cumulative incidences were 24.6% (95% CI 9.8–42.9) and 32.7% (95% CI 18.5–47.6). There was no evidence of a difference between groups (Gray’s test p = 0.13; Fine–Gray HR 0.51, 95% CI 0.21–1.24).
Fig. 4.
Cumulative incidence of grade 2 or higher toxicity during follow-up (A) and EORTC QLQ-C30 Summary Score (B). Lines represent estimated mean score over time, with 95% confidence intervals (shaded area).
Health-related quality-of-life data were available for 89 (98%) patients, comprising 441 completed EORTC QLQ-C30 questionnaires. There was no evidence of a difference between groups in the EORTC QLQ-C30 summary score during follow-up in the safety population (Fig. 4B), or in any of the individual functional or symptom scales (data not shown).
Discussion
LAVA-CRLM is, to our knowledge, the first randomised controlled trial to directly compare MWA and SBRT in patients with oligometastatic CRLM selected for local therapy with curative intent and deemed suitable for both treatment modalities. The trial addresses an important unmet need to support multidisciplinary decision-making in this population.
Local control following both MWA and SBRT was high, with no evidence of a difference between treatment groups in this phase II study. In the per-protocol analysis, 1-year freedom from local progression was 86.0% with SBRT and 77.7% with MWA, corresponding to an absolute difference of 8.3 percentage points. Long-term local control was within the range reported in previous studies, although direct comparison is limited by the predominantly retrospective nature of available evidence and heterogeneous patient populations. For MWA, previous studies have reported local control rates exceeding 90%.19,20 By contrast, reported 1-year local control rates after SBRT range from 50% to 95%,14 likely reflecting heterogeneity in patient populations, tumour biology, lesion size, and prescribed radiation dose. Higher radiation doses have consistently been associated with improved local control following SBRT.
In the present study, SBRT treatment adaptation was required in a small number of patients because of tumour proximity to radiosensitive organs, which may have affected local control. Nevertheless, all patients received biologically effective doses exceeding those previously associated with high local control rates. In a retrospective cohort, Kang and colleagues reported that a biologically effective dose (BED10) greater than 75 Gy independently predicted local control, with a BED10 exceeding 117 Gy required to achieve approximately 90% local control at 1 year.23 Similarly, a large multicentre analysis of 623 liver metastases demonstrated a clear dose–response relationship, with higher BED associated with improved local control.29
Emerging evidence suggests that tumour biology, including molecular characteristics such as KRAS and TP53 alterations, in addition to radiation dose, may influence response to SBRT.30 KRAS and TP53 alterations have been associated with less favourable local outcomes in colorectal liver metastases, particularly when co-occurring. Hong and colleagues reported lower 1-year local control in KRAS-mutant compared with wild-type lesions (43% versus 72%; p = 0.02), with further reduction in KRAS/TP53 co-mutated disease (20%; p = 0.001).31 Similar findings have been reported by Jethwa and colleagues.32 In LAVA-CRLM, KRAS-mutated tumours were numerically more frequent in the MWA group than in the SBRT group, which may have influenced the observed local control estimates. The lack of systematic molecular profiling therefore represents a limitation when interpreting local control outcomes.
Surgical resection remains the standard of care for oligometastatic CRLM. For highly selected patients with unresectable liver-limited colorectal metastases, liver transplantation has also emerged as a potential curative-intent treatment strategy.33 However, recent data suggest that MWA can achieve local control and survival outcomes comparable to surgery for lesions smaller than 3 cm.18 In that study, serious adverse events occurred more frequently after resection than after MWA, supporting the role of ablation as an effective local treatment option in selected patients. Recent international consensus further emphasises procedural standardisation, operator experience, and appropriate patient selection for liver tumour thermal ablation.34
In the present study, grade 3 or higher treatment-related toxicity occurred in 8% of patients in the MWA group, including one treatment-related death, whereas no grade 3 or higher treatment-related toxicity was observed following SBRT. These findings are consistent with previously reported safety profiles for both modalities.14,18,22 The more favourable treatment-related safety profile observed with SBRT may in part reflect its non-invasive delivery. In contrast, MWA requires invasive probe placement and general anaesthesia and may additionally require laparoscopic or open surgical access, introducing procedural risks that are not inherent to SBRT. However, the trial was not powered to formally compare toxicity outcomes.
For SBRT, image guidance, motion management, and, where available, MR-guided adaptive treatment may further reduce treatment-related toxicity by facilitating precise target coverage while limiting dose to surrounding organs at risk. Improved soft-tissue visualisation and real-time tracking may be particularly relevant for lesions located near radiosensitive structures and may facilitate maintenance of therapeutic tumour doses. Most patients receiving SBRT were treated using an MR-linac, and the small number treated using a conventional linear accelerator precluded meaningful platform-specific comparisons. Requiring all lesions to be considered technically suitable for both MWA and SBRT was an important design strength because it preserved clinical equipoise and enabled a valid randomised comparison between treatment modalities. However, this eligibility criterion limits generalisability to lesions for which both modalities are technically feasible.
Several additional limitations should be considered when interpreting these findings. First, this was a phase II trial with a relatively small sample size and was not designed or powered to establish equivalence or non-inferiority between MWA and SBRT. Consequently, the absence of a statistically significant difference in local control should not be interpreted as evidence that the two modalities are equivalent. The wide confidence intervals remain compatible with clinically relevant differences between treatments. Rather, the findings provide prospective comparative data that support the feasibility of both approaches and may inform the design of future phase III confirmatory trials. Second, although patients were enrolled from two hospitals, the study was conducted within a single institutional network, which may limit the generalisability of the findings to other settings with different patient populations, referral patterns, treatment workflows, and levels of technical expertise. Potential differences in the use of systemic therapy after protocol treatment may also have influenced subsequent disease control and overall survival outcomes.
Despite the non-invasive nature of SBRT, some patients may prefer MWA because SBRT generally requires longer planning and treatment times and may involve repeated breath-hold manoeuvres during MR-guided delivery. The development of single-fraction SBRT may mitigate some of these logistical considerations by reducing treatment burden and the number of hospital visits required. Patients with contraindications to MRI or difficulty performing breath-holds may instead be treated with CT-based SBRT using fiducial markers. Although the study allowed inclusion of lesions up to 4.0 cm, all treated metastases were 3.0 cm or smaller. Therefore, evidence for intermediate-sized lesions remains limited. Ongoing trials, including the COLLISION-XL study, are expected to address this gap.35
Health-related quality-of-life outcomes did not differ between treatment groups. This finding likely reflects the influence of disease progression and systemic therapy on long-term quality of life, which may limit the sensitivity of these measures for detecting differences between local treatment modalities.
In summary, the LAVA-CRLM trial provides initial prospective randomised evidence that no difference in freedom from local progression was observed between SBRT and MWA in patients with oligometastatic CRLM measuring 3 cm or smaller, while SBRT demonstrated a more favourable treatment-related safety profile. These findings support consideration of both modalities as local treatment options and highlight the importance of individualised treatment selection based on patient characteristics, tumour location, technical feasibility, and institutional expertise.
Contributors
SLR was the chief investigator of the trial. SLR, LBS, IRV, BN, NAS, MJ, and PNL were involved in conception and study design. SLR, LBS, BN, NAS, LP, MOF, and PNL were involved in the collection and assembly of the data. AA prepared the statistical analysis plan and performed the statistical analysis. SLR, LBS, AA, IRV, BN and PNL were responsible for data analysis and interpretation and had access to and verified all study data; all other authors had access upon request. SLR, LBS, and AA contributed to writing the manuscript, with the main draft prepared by SLR. SLR, LBS, AA, IRV, BN, NAS, LP, MOF and PNL edited and reviewed the manuscript. All authors contributed to and approved the final version.
Data sharing statement
De-identified individual participant data will be made available upon reasonable request to the corresponding author after publication of all analyses of the primary and secondary trial endpoints and following approval by an independent review committee. Data sharing will be conducted in accordance with Danish law on the processing of personal data, regulations of the Danish Data Protection Authority, and applicable health legislation.
Declaration of interests
IRV reports research and teaching contracts with Varian, a Siemens Healthineers company, and Brainlab. All other authors declare no competing interests.
Acknowledgements
This investigator-initiated study was supported by a grant (R302-A17351) from the Danish Cancer Society. Preliminary toxicity results were presented in abstract form at the 2025 Annual Meeting of the American Society of Clinical Oncology. We thank our colleagues at Rigshospitalet and Herlev Hospital for their contributions to the study; our research nurses, Birthe Michaelsen Klarskov, Christina Ditlevsen, and Dorthe Sørensen, for patient screening, patient care, and data monitoring; and all patients for their participation.
Footnotes
Supplementary data related to this article can be found at https://doi.org/10.1016/j.lanepe.2026.101879.
Appendix A. Supplementary data
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