Combining metastases-directed stereotactic radiotherapy (SRT) with modern biological cancer therapies is associated with a low risk of severe adverse events, even when systemic treatment is continued, a large registry study has shown.

As biological cancer therapies become increasingly central to the management of metastatic cancer, metastases-directed SRT is more frequently used to control oligoprogressive disease.

To address gaps in the evidence base regarding the safety of concurrent treatment, investigators from the Toxicity and Efficacy of Combined Stereotactic Radiotherapy and Systemic Targeted or Immune Therapy (TOaSTT) consortium undertook a prospective study to assess adverse events associated with concurrent treatment.

Stereotactic radiotherapy and biological cancer therapies

The TOaSTT study was a prospective, multicentre, non-interventional registry conducted at 27 centres between July 2017 and August 2019, with follow-up extending to 24 months. Patients with metastatic or oligometastatic cancer who received metastases-directed SRT concurrently with biological cancer therapies – defined as systemic therapy given within 30 days before or after SRT – were eligible.

In total, 514 SRT treatments were delivered to 433 patients. The median age was 62 years (interquartile range 54–70), and 63.5% were male. The most common primary tumours were malignant melanoma (37.0%) and non–small cell lung cancer (35.8%). Most patients had good performance status, with an Eastern Cooperative Oncology Group Performance Status of 0–1 in 89.6%, but a substantial comorbidity burden, with 57.7% having an age-adjusted Charlson Comorbidity Index score of at least 3.

Of the SRT procedures, 271 targeted intracranial metastases and 243 extracranial lesions. Immune checkpoint inhibitors were used in 61.3% of treatments, small-molecule drugs in 29.2%, and monoclonal antibodies in 9.5%.

In 83.7% of cases, biological cancer therapies had been initiated before SRT, while 18.1% of patients temporarily interrupted systemic therapy during radiotherapy.

No significant increase in severe adverse events

Severe adverse events were uncommon. Grade 3 or higher acute adverse events occurred in 5.3% of treatments, while severe late adverse events were observed in 6.3% of patients. Grade 5 events were rare, occurring in 1.2% of patients overall and confined to those treated for intracranial metastases.

Importantly, continuing biological cancer therapies during SRT was not associated with a statistically significant increase in either acute or late severe adverse events (odds ratio 2.32; 95% CI 0.87–6.22). Univariate analyses showed no significant association between uninterrupted biological cancer therapies and severe toxicity, regardless of treatment site or drug class.

Overall survival outcomes were also examined. Median overall survival was 24 months (95% CI 21–27). Although patients who continued biological cancer therapies during SRT had longer unadjusted survival than those who paused or delayed treatment (31 months (95% CI, 22–not reached) vs 20 months (95% CI 15–26; p= 0.046)), this difference was no longer statistically significant after adjustment for performance status, comorbidity and tumour type (adjusted hazard ratio 0.81; 95% CI, 0.61–1.09; p=0.17).

Considering the evidence, the authors suggested that the favourable safety profile of metastases-directed SRT is largely preserved when combined with contemporary biological cancer therapies, but they noted certain limitations.

As an observational registry, it relied on clinician discretion in treatment decisions, including radiotherapy dose, fractionation and interruptions to biological cancer therapies, introducing heterogeneity. Adverse events were clinician-reported rather than patient-reported, and melanoma was over-represented relative to the general metastatic cancer population, reflecting current patterns of biological cancer therapies use, they said.

The study data were exploratory, and the authors said that further prospective research is therefore needed to refine safety profiles for specific drug–radiotherapy combinations and anatomical sites. However, the current findings can provide reassurance for clinicians considering combined modality treatment and may help inform individualised decisions about whether to maintain or interrupt systemic therapy during SRT, they concluded.

Reference
Looman E et al. Adverse Events After Metastases-Directed Stereotactic Radiotherapy and Biological Cancer Therapy. JAMA Netw Open 2026;9(1):e2553809.