Radiosurgery Combined with Targeted Therapy and Immunotherapy: Which Combinations Are Safe, and Which Carry Risks?
In this article
Radiotherapy While on Targeted Therapy or Immunotherapy: What Do the Data From 7,694 Patients Show?
In metastatic cancer, patients are increasingly receiving stereotactic radiotherapy (SRT, radiosurgery) during the same period as targeted therapy or immunotherapy. Whether it is safe to give the two together, however, is often not studied in drug approval trials. The OligoCare group of the European Society for Radiotherapy and Oncology (ESTRO) and the European Organisation for Research and Treatment of Cancer (EORTC) is answering this question with the first "living" systematic review, updated every six months. The study, called LINACS, pooled data from 7,694 patients in 191 studies and was published in September 2026 in the journal Radiotherapy and Oncology. We have previously covered radiation necrosis after T-DM1 and radiosurgery, the combined use of antibody–drug conjugates and radiotherapy, CyberKnife radiosurgery and SBRT in oligometastatic breast cancer.
- The overall picture is reassuring: With immunotherapy (anti-PD-(L)1), multitargeted TKIs, PARP inhibitors, sacituzumab govitecan, and EGFR-targeted TKIs combined with SRT to the lung, no more serious adverse events than expected were seen when the drug was used within the same month as radiotherapy.
- Caution signals: With SRT to the brain, trastuzumab emtansine (31.6%) and BRAF + MEK inhibitors (21%) were associated with high rates of serious adverse events in the irradiated area. With SRT to the liver, the rate of serious overall adverse events was high with immunotherapy (30.3%) and multitargeted TKIs (40.5%).
- Changed results: EGFR-targeted TKIs with SRT to the brain are now a caution signal (they were reassuring in the previous review), while dual immunotherapy (anti-PD-(L)1 + anti-CTLA-4) is now reassuring (previously a caution signal).
- Limitation: Most studies did not report the timing of the drug relative to radiotherapy or whether it was paused. The findings are a descriptive summary; some signals are based on 20–40 patients. Decisions should be made jointly by the oncologist and the radiation oncologist.
Why does this matter?
As survival in metastatic cancer grows longer, situations where the disease is present in a limited number of sites (oligometastatic) or progresses in only a few sites during treatment are becoming more common (what is metastasis). In these patients, stereotactic radiotherapy, which delivers a high dose in a few sessions while largely sparing the surrounding tissue, is often used to improve local control and to allow an effective drug to be continued. In brain metastases, radiosurgery is already one of the standard treatments.
The problem is this: approval trials of new drugs usually do not allow radiotherapy during the same period. As a result, the answer to the question "should we pause your drug?" is often based on limited data. Pausing may seem safer, but it carries the risk of the disease flaring up and of losing systemic control. Because new drugs are approved quickly, conventional systematic reviews can be out of date as soon as they are published. LINACS was therefore designed as a database that is updated every six months.
Is stereotactic radiotherapy safe while on targeted therapy or immunotherapy?
For the large majority, yes. According to the LINACS review, when drugs such as immunotherapy, multitargeted TKIs, PARP inhibitors and sacituzumab govitecan are given within the same month as stereotactic radiotherapy, no more serious adverse events than expected are seen at most target sites. However, trastuzumab emtansine and BRAF + MEK inhibitors call for caution when the brain is irradiated, as do immunotherapy and multitargeted TKIs when the liver is irradiated.
How was the study done?
The researchers searched for studies published since 2000, using search terms based on a list of approved cancer drugs (last search 2 April 2026). A total of 3,784 studies were screened and 191 were included in the review. Case reports, studies that did not clearly report adverse events or treatment timing, and studies at high risk of bias were excluded.
Figure 1 · Scope of the review
Definition of "concurrent": within 30 days before or after radiotherapy
How fast is the evidence growing?
Number of patients treated with stereotactic radiotherapy combined with new drugs, in successive systematic reviews.
The numbers of studies were 49, 108 and 191, respectively. LINACS gathered the most data despite stricter criteria that excluded case reports and included only studies from which a serious adverse event rate could be calculated.
Where the evidence comes from
Percent. Studies and patients included in LINACS, by prospective or retrospective design.
Studies (191)
Patients (7,694)
Retrospective studies often did not report the timing of the drug relative to radiotherapy or whether it was paused.
Figure 2 · Two types of serious adverse events
Calculated separately in the review
Because the rates of serious adverse events with SRT alone and with the drug alone are reported across a very wide range in the literature, the researchers did not use a single numerical threshold. They made a separate assessment for each drug and target site:
Figure 3 · How was a combination assessed?
Simplified decision logic
Results: which combinations are reassuring, and which call for caution?
Figure 4 · LINACS signal map (April 2026 search)
When the drug is given within 30 days before or after radiotherapy
Serious adverse events in the irradiated area, by drug class
Grade 3 or higher RT-related adverse events, percent; all targets. Red bar: caution signal.
For comparison: in the literature, the rate of serious adverse events with stereotactic radiotherapy alone is 1–13%, depending on the target site. Values are pooled from different studies. Comparisons across different studies are indirect; patient populations, prior treatments and follow-up times differ.
The clearest signals for serious adverse events in the irradiated area relate to brain irradiation. Of 19 patients who received trastuzumab emtansine (T-DM1) within the same month as stereotactic radiotherapy to the brain, 6 (31.6%) developed a serious adverse event in the irradiated area; this result is consistent with earlier studies showing increased radiation necrosis after T-DM1 and radiosurgery, and with the ESTRO consensus recommendation not to give T-DM1 during brain irradiation (Kadcyla (T-DM1), brain metastases in breast cancer). No such signal was seen with trastuzumab deruxtecan (22 patients, 4.5%) or sacituzumab govitecan (51 patients, 2%), which belong to the same drug class (sacituzumab govitecan).
Stereotactic radiotherapy to the brain: serious adverse events in the irradiated area
Grade 3 or higher, percent. Red bar: caution signal.
The expected rate of serious adverse events with stereotactic radiotherapy to the brain alone is 2–12%. In the 24 patients who received a BRAF inhibitor alone, the drug had been paused for 2–3 days before and after radiotherapy. Comparisons across different studies are indirect; patient populations, prior treatments and follow-up times differ.
In melanoma, serious adverse events were seen in 8 of 38 patients (21%) who had SRT to the brain while on BRAF + MEK inhibitors; in some patients the drug had been paused and in others it had been continued, but it was not reported which group the patients with adverse events were in (BRAF-mutated melanoma, brain metastases in melanoma). This finding is also consistent with the increased adverse events reported when conventional radiotherapy is combined with BRAF/MEK inhibitors. In contrast, no serious adverse events were seen in 24 patients who received a BRAF inhibitor alone and paused the drug for 2–3 days before and after radiotherapy.
Serious overall adverse events: all targets and the liver
Grade 3 or higher, all adverse events related to the drug or to radiotherapy, percent. Coloured bar: all targets; red bar: caution signal.
Expected rates for comparison: stereotactic radiotherapy to the liver alone 3–10%; anti-PD-(L)1 alone 8–22%; multitargeted TKI alone 15–76%; EGFR-targeted TKI alone 10–40%. About half of the anti-PD-(L)1 patients in the liver group had also undergone transarterial embolisation (TAE); when they were excluded, the rate was 27.7%. The 41 patients in the EGFR-targeted TKI and brain group had also received whole-brain radiotherapy. Comparisons across different studies are indirect; patient populations, prior treatments and follow-up times differ.
- SRT to the liver and immunotherapy: In 175 patients, the rate of serious overall adverse events was 30.3%. However, a large share of these adverse events were abnormal laboratory values, and about half of the patients had also undergone transarterial embolisation (TAE). Data on adverse events in the irradiated area were available for only 15 patients (1 patient, 6.7%). The authors note that this may be an additive effect, since SRT to the liver alone can cause serious adverse events in up to 10% of patients (liver cancer).
- SRT to the liver and multitargeted TKIs: In 138 patients who had SRT to the liver together with lenvatinib or sorafenib, the rate of serious overall adverse events was 40.5%. In an 18-patient study in which sorafenib was given during radiotherapy, 10 patients had serious adverse events. Because these drugs can also cause high rates of adverse events on their own, it is unclear how much additional risk the radiotherapy adds (advanced liver cancer). With SRT to the brain, lung and spine, on the other hand, no more adverse events than expected were seen with multitargeted TKIs (kidney cancer).
- SRT to the brain and EGFR-targeted TKIs: This combination, which was reassuring in the previous review, is now a caution signal. However, the signal rests on a single study of 41 patients who received erlotinib together with whole-brain radiotherapy and SRT (49%); serious adverse event rates of up to 40.8% have also been reported with erlotinib alone. The rate of adverse events in the irradiated area was 8.6% in 81 patients. EGFR-targeted TKIs with SRT to the lung were well tolerated, even though 97.6% of patients continued the drug throughout radiotherapy (osimertinib).
- Head and neck re-irradiation and cetuximab: In 394 patients, the rate of early serious adverse events in the irradiated area was 9.3% and the rate of late serious adverse events was 13.6%, and treatment-related loss of life (for example, carotid artery bleeding) was reported. How much of this was due to the re-irradiation and how much to the drug is unclear (radiotherapy in head and neck cancer).
Reassuring results
- Immunotherapy (anti-PD-(L)1): This group has the most data: 2,166 patients in 69 studies. Serious RT-related adverse events 6.4%, serious overall adverse events 14.2%; no increase with SRT to the brain, lung, pancreas or bone (immunotherapy side effects, bone metastases).
- Dual immunotherapy: With anti-PD-(L)1 + anti-CTLA-4, serious adverse events in 388 patients were 11.6% in the irradiated area and 27.8% overall; with these data, the caution signal from the previous review changed to reassuring. Data for liver SRT are still insufficient.
- PARP inhibitors: In 125 patients, most with ovarian cancer, serious adverse events in the irradiated area were 2.4%. However, 74% of patients had paused the drug for a few days before and after radiotherapy (PARP inhibitors).
- Anti-VEGF antibodies: In 411 patients, mostly receiving bevacizumab with brain SRT, serious adverse event rates were 3–4%.
An important detail: immunotherapy drugs stay in the body for a long time, and their effects on the immune system can persist after the drug is stopped. It is therefore unclear whether a short break from immunotherapy actually lowers the risk of adverse events; instead, a lower radiation dose or a technique that better spares healthy tissue may be considered.
Should the drug be paused?
LINACS cannot give a clear answer to this question: most studies did not report when the drug was given relative to radiotherapy or whether it was paused. In consensus recommendations from ESMO and ESTRO experts, based on older data, "major adaptations" such as pausing the drug, reducing its dose or lowering the radiation dose are recommended for many combinations; however, some of these stem from a lack of data rather than from increased adverse events. The new LINACS data suggest that this caution could be relaxed for some combinations.
Figure 5 · Options in joint planning
Every option has a cost; the decision is tailored to the patient
Limitations
- Missing timing information: The 30-day window groups together patients who continued the drug throughout radiotherapy and patients who started it weeks later; the risk in these two groups is very likely different.
- Descriptive summary: The rates were calculated by adding up the numbers of adverse events in the studies; this is not a true meta-analysis. The figures are exploratory estimates, not exact frequencies.
- Differences in reporting: The studies reported adverse events using different definitions; whether they occurred in the irradiated area, the radiation dose and the number of sessions were often missing. More than 10% of studies were excluded because of a high risk of bias.
- Small groups: Important signals such as T-DM1 (19 patients) and BRAF + MEK (44 patients) rest on small numbers of patients (reading research correctly).
- Safety only: The review does not assess how effective the combinations are (survival, local control).
In Turkey, stereotactic radiotherapy and radiosurgery (such as LINAC-based systems, CyberKnife and Gamma Knife) are widely used in many centres, and most of the drug classes included in the review are also used in the country. The LINACS findings are therefore directly relevant to everyday practice in Turkey as well. Decisions such as whether to pause the drug, the radiation dose and the timing require a joint assessment by the medical oncology and radiation oncology teams; where possible, they should be discussed at a multidisciplinary tumour board. Up-to-date data can be followed in the LINACS online database (in English).
Tips for patients and their families
- Share your medication list: When radiotherapy is being planned, tell your radiation oncologist about all the cancer drugs you are taking, including targeted therapies taken by mouth, and the date of your last dose.
- Do not decide to pause on your own: Whether to pause a drug should be decided jointly by your oncologist and your radiation oncologist.
- Watch for symptoms: In the weeks and months after radiotherapy to the brain, report new symptoms such as headache, vomiting, or difficulty speaking or weakness straight away; after radiotherapy to the liver, report jaundice, abdominal swelling or marked fatigue straight away (which symptoms to call about).
- Follow-up scans: Radiation necrosis in the brain can appear even months later and can look like disease progression on imaging; it should be assessed by an experienced team.
- At the decision stage, do not hesitate to get a second opinion from an experienced centre.
Frequently asked questions
- Can radiosurgery or SBRT be done while on immunotherapy?
- In most cases, yes. In the LINACS review, among 2,166 patients, no more serious adverse events than expected were seen with stereotactic radiotherapy to the brain, lung, bone and pancreas given within the same month as immunotherapy. With radiotherapy to the liver, however, the rate of serious overall adverse events was around 30%, so more careful planning is recommended.
- Which drugs call for caution with radiotherapy to the brain?
- With stereotactic radiotherapy to the brain, serious adverse events in the irradiated area were seen in 31.6% of patients on trastuzumab emtansine (T-DM1) and in 21% of those on BRAF + MEK inhibitors. There is also a caution signal for EGFR-targeted TKIs. These results are based on small numbers of patients; the decision should be made by the team.
- Should the drug be paused during radiotherapy?
- There is no definitive answer to this question. Pausing may seem safer with some combinations, but it carries the risk of disease progression. Because most studies did not report timing, LINACS cannot make a clear recommendation on this. The decision should be made by the oncologist and the radiation oncologist and tailored to the patient.
- What is LINACS?
- LINACS is the first living systematic review of the safety of combining stereotactic radiotherapy with new cancer drugs, prepared by the OligoCare group of ESTRO and EORTC. The data are updated every six months and published at linacs.net; the April 2026 search covers 191 studies and 7,694 patients.
Glossary
- Stereotactic radiotherapy (SRT, SBRT, radiosurgery)
- Radiotherapy in which a high dose is focused on the target in a small number of sessions while largely sparing the surrounding tissue.
- Living systematic review
- A systematic review of the literature that is updated at regular intervals as new studies are published.
- Oligometastatic disease
- A situation in which cancer has spread to a limited number of sites.
- Grade 3 or higher adverse event
- A serious or potentially life-threatening adverse event that requires hospital admission or treatment.
- TKI (tyrosine kinase inhibitor)
- A targeted therapy, usually taken by mouth, that blocks growth signals in cancer cells.
- Radiation necrosis
- Damage that can develop in irradiated tissue months later; in the brain it can cause headache and neurological symptoms.
- Antibody–drug conjugate
- A treatment in which a chemotherapy drug is attached to an antibody that recognises cancer cells.
DROZDOGAN Academy Commentary
LINACS shows, on the basis of evidence, that the reflex of "stop the drug and give radiotherapy" is not always necessary, but that caution is justified for some combinations.
⚡ Why it matters
Pausing a drug carries the risk of losing systemic control, especially in rapidly progressing disease. Knowing which combinations are safe can reduce unnecessary breaks, and for risky combinations it allows precautions to be taken.
✅ Strengths
The largest dataset in the field; a pre-registered (PROSPERO) method; separate assessment of RT-related and overall adverse events; an online database that is updated every six months and open to everyone.
⚠️ Limitations
Information on timing and drug breaks is missing; the rates are descriptive totals. Some of the important caution signals rest on small numbers of patients, and some on confounding factors such as re-irradiation or transarterial embolisation. The review does not assess effectiveness.
🩺 In practice
We plan stereotactic radiotherapy alongside immunotherapy and many targeted therapies on a case-by-case basis, often without a long break from the drug. With T-DM1 and BRAF/MEK inhibitors for the brain, and with immunotherapy and multitargeted TKIs for the liver, however, we plan the timing, dose and monitoring more cautiously together with the radiation oncology team.
❓ Open questions
Does pausing a drug really reduce adverse events, or does it only impair disease control? Are trastuzumab deruxtecan and newer antibody–drug conjugates safe with brain irradiation? Answering these questions will require prospective studies in which adverse events and timing are reported in a standard way.
Bottom line: LINACS is an up-to-date, continuously renewed reference for combining radiotherapy with new drugs. Most combinations are reassuring; a few call for special caution.
- This article was prepared in October 2026.
- The information is taken from the full text of the LINACS review published in Radiotherapy and Oncology (April 2026 search); later updates to the online database may differ. The details in the supplementary file were not accessed.
- The rates in the charts are descriptive values pooled from different studies in the review; comparisons between drug classes are indirect. The expected adverse event ranges are taken from a figure in the paper.
- The study received no external funding; some authors' relationships with drug and device companies are declared in the paper.
- Information on practice in Turkey is general. This article is for general information only and is not personal medical advice. The diagrams are derived from the tables and figures in the paper. The Academy commentary is our own.
References
- Sundahl N, Looman EL, Ollivier L, et al. LINACS: a living systematic review of the safety of concurrent stereotactic radiotherapy and novel systemic therapies by the ESTRO/EORTC OligoCare Consortium. Radiother Oncol 2026;225:111791. doi:10.1016/j.radonc.2026.111791
- LINACS online database. linacs.net
- Kroeze SGC, Pavic M, Stellamans K, et al. Metastases-directed stereotactic body radiotherapy in combination with targeted therapy or immunotherapy: systematic review and consensus recommendations by the EORTC-ESTRO OligoCare consortium. Lancet Oncol 2023;24:e121-e132. doi:10.1016/s1470-2045(22)00752-5
- Kroeze SG, Fritz C, Hoyer M, et al. Toxicity of concurrent stereotactic radiotherapy and targeted therapy or immunotherapy: a systematic review. Cancer Treat Rev 2017;53:25-37. doi:10.1016/j.ctrv.2016.11.013
- Stumpf PK, Cittelly DM, Robin TP, et al. Combination of trastuzumab emtansine and stereotactic radiosurgery results in high rates of clinically significant radionecrosis and dysregulation of aquaporin-4. Clin Cancer Res 2019;25:3946-3953. doi:10.1158/1078-0432.CCR-18-2851
- Looman EL, Kroeze SGC, Schaule J, et al. Adverse events after metastases-directed stereotactic radiotherapy and biological cancer therapy. JAMA Netw Open 2026;9:e2553809. doi:10.1001/jamanetworkopen.2025.53809
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