Adverse Events After Metastases-Directed Stereotactic Radiotherapy and Biological Cancer Therapy

Esmée L Looman; Stephanie G C Kroeze; Jana Schaule; Mathieu Spaas; Klaus Henning Kahl; Joost J C Verhoeff; Famke L Schneiders; Oliver Blanck; Fabian Lohaus; Susanne Rogers; David Kaul; Sergi Benavente; Stephanie E Combs; Georgios Skazikis; Kynann P Aninditha; Ilinca Popp; Friederike L A Koppe; Hans Geinitz; Katrien de Jaeger; Shankar Siva; Susanne Stera; Andrea Wittig; Victor Lewitzki; Franziska Eckert; Markus M Schymalla; Matthias Guckenberger

doi:10.1001/jamanetworkopen.2025.53809

Adverse Events After Metastases-Directed Stereotactic Radiotherapy and Biological Cancer Therapy

Esmée L Looman
, Stephanie G C Kroeze
, Jana Schaule
, Mathieu Spaas
, Klaus Henning Kahl
, Joost J C Verhoeff
, Famke L Schneiders
, Oliver Blanck
, Fabian Lohaus
, Susanne Rogers
, David Kaul
, Sergi Benavente
, Stephanie E Combs
, Georgios Skazikis
, Kynann P Aninditha
, Ilinca Popp
, Friederike L A Koppe
, Hans Geinitz
, Katrien de Jaeger
, Shankar Siva

Susanne Stera, Andrea Wittig, Victor Lewitzki, Franziska Eckert, Markus M Schymalla, Matthias Guckenberger^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

IMPORTANCE: Metastases-directed stereotactic radiotherapy (SRT) is increasingly performed in patients with metastatic or oligometastatic cancer treated with immune checkpoint inhibitors (ICIs), monoclonal antibodies (mAbs), and small-molecule drugs (SMs). However, little is known about potential interactions between SRT and biological cancer therapy (BCT).

OBJECTIVE: To prospectively investigate adverse events associated with SRT combined with concurrent BCT.

DESIGN, SETTING, AND PARTICIPANTS: This international, prospective, multicenter, noninterventional registry cohort study (Toxicity and Efficacy of Combined Stereotactic Radiotherapy and Systemic Targeted or Immune Therapy [TOaSTT]) was conducted between July 2017 and August 2019 with a 24-month follow-up. Patients from 27 centers whose cancer was treated with metastases-directed SRT concurrently with BCT were eligible. Analyses were performed in January 2025.

EXPOSURE: Patients treated with SRT for intracranial or extracranial metastases and concurrent (within ≤30 days) BCT. Indication for treatment, decision on the radiotherapy dose and fractionation, as well as interruption of BCT, were left to the discretion of the treating clinician.

MAIN OUTCOMES AND MEASURES: The primary outcome was severe (at least grade 3) adverse events of combined modality treatment, as graded by the treating physician. Overall survival (OS) and progression-free survival (PFS) were secondary end points.

RESULTS: In total, 514 SRTs (271 cranial and 243 extracranial) concurrent with BCT were performed in 433 patients (median [IQR] age, 62 [54-70 years; 275 male [63.5%]). In 315 SRTs (61.3%) patients received ICIs, whereas in 150 SRTs (29.2%), patients received SMs and in 49 SRTs (9.5%) patients received mAbs. In 430 SRTs (83.7%), BCT had been initiated in patients before SRT, while 71 of 392 patients (18.1%) paused BCT during SRT. Severe (≥grade 3) acute adverse events were observed in 27 of 506 treatments (5.3%; 3 patients with grade 5 events), and severe late adverse events were observed in 29 of 459 patients (6.3%; 2 patients with grade 5 events). SRT with uninterrupted BCT was not associated with increased severe acute or late adverse events (odds ratio, 2.32; 95% CI, 0.87-6.22). Interruption of BCT during SRT was not associated with worse PFS and OS after correction for performance status and histologic type (hazard ratio, 0.81; 95% CI, 0.61-1.09; P = .17).

CONCLUSIONS AND RELEVANCE: In this cohort study of 433 patients, severe adverse events after SRT and concurrent BCT were uncommon (<10%), continuing BCT during SRT was not associated with increased risk of severe adverse events, and interrupting BCT was not associated with worse OS when correcting for patients' performance status. These findings suggest a favorable safety profile of metastases-directed SBRT in combined modality treatment settings.

Original language	English
Article number	e2553809
Number of pages	14
Journal	JAMA network open
Volume	9
Issue number	1
DOIs	https://doi.org/10.1001/jamanetworkopen.2025.53809
Publication status	Published - Jan 2026

Keywords

Aged
Aged, 80 and over
Combined Modality Therapy/adverse effects
Female
Humans
Immune Checkpoint Inhibitors/therapeutic use
Male
Middle Aged
Neoplasm Metastasis/radiotherapy
Neoplasms/therapy
Prospective Studies
Radiosurgery/adverse effects
Registries

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Adverse Events After Metastases-Directed Stereotactic Radiotherapy and Biological Cancer TherapyFinal published version, 1.08 MBLicence: CC BY

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Looman, E. L., Kroeze, S. G. C., Schaule, J., Spaas, M., Kahl, K. H., Verhoeff, J. J. C., Schneiders, F. L., Blanck, O., Lohaus, F., Rogers, S., Kaul, D., Benavente, S., Combs, S. E., Skazikis, G., Aninditha, K. P., Popp, I., Koppe, F. L. A., Geinitz, H., de Jaeger, K., ... Guckenberger, M. (2026). Adverse Events After Metastases-Directed Stereotactic Radiotherapy and Biological Cancer Therapy. JAMA network open, 9(1), Article e2553809. https://doi.org/10.1001/jamanetworkopen.2025.53809

@article{9d8d73f33b9b46388d534c3b22969c0a,

title = "Adverse Events After Metastases-Directed Stereotactic Radiotherapy and Biological Cancer Therapy",

abstract = "IMPORTANCE: Metastases-directed stereotactic radiotherapy (SRT) is increasingly performed in patients with metastatic or oligometastatic cancer treated with immune checkpoint inhibitors (ICIs), monoclonal antibodies (mAbs), and small-molecule drugs (SMs). However, little is known about potential interactions between SRT and biological cancer therapy (BCT).OBJECTIVE: To prospectively investigate adverse events associated with SRT combined with concurrent BCT.DESIGN, SETTING, AND PARTICIPANTS: This international, prospective, multicenter, noninterventional registry cohort study (Toxicity and Efficacy of Combined Stereotactic Radiotherapy and Systemic Targeted or Immune Therapy [TOaSTT]) was conducted between July 2017 and August 2019 with a 24-month follow-up. Patients from 27 centers whose cancer was treated with metastases-directed SRT concurrently with BCT were eligible. Analyses were performed in January 2025.EXPOSURE: Patients treated with SRT for intracranial or extracranial metastases and concurrent (within ≤30 days) BCT. Indication for treatment, decision on the radiotherapy dose and fractionation, as well as interruption of BCT, were left to the discretion of the treating clinician.MAIN OUTCOMES AND MEASURES: The primary outcome was severe (at least grade 3) adverse events of combined modality treatment, as graded by the treating physician. Overall survival (OS) and progression-free survival (PFS) were secondary end points.RESULTS: In total, 514 SRTs (271 cranial and 243 extracranial) concurrent with BCT were performed in 433 patients (median [IQR] age, 62 [54-70 years; 275 male [63.5\%]). In 315 SRTs (61.3\%) patients received ICIs, whereas in 150 SRTs (29.2\%), patients received SMs and in 49 SRTs (9.5\%) patients received mAbs. In 430 SRTs (83.7\%), BCT had been initiated in patients before SRT, while 71 of 392 patients (18.1\%) paused BCT during SRT. Severe (≥grade 3) acute adverse events were observed in 27 of 506 treatments (5.3\%; 3 patients with grade 5 events), and severe late adverse events were observed in 29 of 459 patients (6.3\%; 2 patients with grade 5 events). SRT with uninterrupted BCT was not associated with increased severe acute or late adverse events (odds ratio, 2.32; 95\% CI, 0.87-6.22). Interruption of BCT during SRT was not associated with worse PFS and OS after correction for performance status and histologic type (hazard ratio, 0.81; 95\% CI, 0.61-1.09; P = .17).CONCLUSIONS AND RELEVANCE: In this cohort study of 433 patients, severe adverse events after SRT and concurrent BCT were uncommon (<10\%), continuing BCT during SRT was not associated with increased risk of severe adverse events, and interrupting BCT was not associated with worse OS when correcting for patients' performance status. These findings suggest a favorable safety profile of metastases-directed SBRT in combined modality treatment settings.",

keywords = "Aged, Aged, 80 and over, Combined Modality Therapy/adverse effects, Female, Humans, Immune Checkpoint Inhibitors/therapeutic use, Male, Middle Aged, Neoplasm Metastasis/radiotherapy, Neoplasms/therapy, Prospective Studies, Radiosurgery/adverse effects, Registries",

author = "Looman, \{Esm{\'e}e L\} and Kroeze, \{Stephanie G C\} and Jana Schaule and Mathieu Spaas and Kahl, \{Klaus Henning\} and Verhoeff, \{Joost J C\} and Schneiders, \{Famke L\} and Oliver Blanck and Fabian Lohaus and Susanne Rogers and David Kaul and Sergi Benavente and Combs, \{Stephanie E\} and Georgios Skazikis and Aninditha, \{Kynann P\} and Ilinca Popp and Koppe, \{Friederike L A\} and Hans Geinitz and \{de Jaeger\}, Katrien and Shankar Siva and Susanne Stera and Andrea Wittig and Victor Lewitzki and Franziska Eckert and Schymalla, \{Markus M\} and Matthias Guckenberger",

note = "Publisher Copyright: {\textcopyright} 2026 Looman EL et al.",

year = "2026",

month = jan,

doi = "10.1001/jamanetworkopen.2025.53809",

language = "English",

volume = "9",

journal = "JAMA network open",

issn = "2574-3805",

publisher = "American Medical Association",

number = "1",

}

Looman, EL, Kroeze, SGC, Schaule, J, Spaas, M, Kahl, KH, Verhoeff, JJC, Schneiders, FL, Blanck, O, Lohaus, F, Rogers, S, Kaul, D, Benavente, S, Combs, SE, Skazikis, G, Aninditha, KP, Popp, I, Koppe, FLA, Geinitz, H, de Jaeger, K, Siva, S, Stera, S, Wittig, A, Lewitzki, V, Eckert, F, Schymalla, MM & Guckenberger, M 2026, 'Adverse Events After Metastases-Directed Stereotactic Radiotherapy and Biological Cancer Therapy', JAMA network open, vol. 9, no. 1, e2553809. https://doi.org/10.1001/jamanetworkopen.2025.53809

TY - JOUR

T1 - Adverse Events After Metastases-Directed Stereotactic Radiotherapy and Biological Cancer Therapy

AU - Looman, Esmée L

AU - Kroeze, Stephanie G C

AU - Schaule, Jana

AU - Spaas, Mathieu

AU - Kahl, Klaus Henning

AU - Verhoeff, Joost J C

AU - Schneiders, Famke L

AU - Blanck, Oliver

AU - Lohaus, Fabian

AU - Rogers, Susanne

AU - Kaul, David

AU - Benavente, Sergi

AU - Combs, Stephanie E

AU - Skazikis, Georgios

AU - Aninditha, Kynann P

AU - Popp, Ilinca

AU - Koppe, Friederike L A

AU - Geinitz, Hans

AU - de Jaeger, Katrien

AU - Siva, Shankar

AU - Stera, Susanne

AU - Wittig, Andrea

AU - Lewitzki, Victor

AU - Eckert, Franziska

AU - Schymalla, Markus M

AU - Guckenberger, Matthias

PY - 2026/1

Y1 - 2026/1

N2 - IMPORTANCE: Metastases-directed stereotactic radiotherapy (SRT) is increasingly performed in patients with metastatic or oligometastatic cancer treated with immune checkpoint inhibitors (ICIs), monoclonal antibodies (mAbs), and small-molecule drugs (SMs). However, little is known about potential interactions between SRT and biological cancer therapy (BCT).OBJECTIVE: To prospectively investigate adverse events associated with SRT combined with concurrent BCT.DESIGN, SETTING, AND PARTICIPANTS: This international, prospective, multicenter, noninterventional registry cohort study (Toxicity and Efficacy of Combined Stereotactic Radiotherapy and Systemic Targeted or Immune Therapy [TOaSTT]) was conducted between July 2017 and August 2019 with a 24-month follow-up. Patients from 27 centers whose cancer was treated with metastases-directed SRT concurrently with BCT were eligible. Analyses were performed in January 2025.EXPOSURE: Patients treated with SRT for intracranial or extracranial metastases and concurrent (within ≤30 days) BCT. Indication for treatment, decision on the radiotherapy dose and fractionation, as well as interruption of BCT, were left to the discretion of the treating clinician.MAIN OUTCOMES AND MEASURES: The primary outcome was severe (at least grade 3) adverse events of combined modality treatment, as graded by the treating physician. Overall survival (OS) and progression-free survival (PFS) were secondary end points.RESULTS: In total, 514 SRTs (271 cranial and 243 extracranial) concurrent with BCT were performed in 433 patients (median [IQR] age, 62 [54-70 years; 275 male [63.5%]). In 315 SRTs (61.3%) patients received ICIs, whereas in 150 SRTs (29.2%), patients received SMs and in 49 SRTs (9.5%) patients received mAbs. In 430 SRTs (83.7%), BCT had been initiated in patients before SRT, while 71 of 392 patients (18.1%) paused BCT during SRT. Severe (≥grade 3) acute adverse events were observed in 27 of 506 treatments (5.3%; 3 patients with grade 5 events), and severe late adverse events were observed in 29 of 459 patients (6.3%; 2 patients with grade 5 events). SRT with uninterrupted BCT was not associated with increased severe acute or late adverse events (odds ratio, 2.32; 95% CI, 0.87-6.22). Interruption of BCT during SRT was not associated with worse PFS and OS after correction for performance status and histologic type (hazard ratio, 0.81; 95% CI, 0.61-1.09; P = .17).CONCLUSIONS AND RELEVANCE: In this cohort study of 433 patients, severe adverse events after SRT and concurrent BCT were uncommon (<10%), continuing BCT during SRT was not associated with increased risk of severe adverse events, and interrupting BCT was not associated with worse OS when correcting for patients' performance status. These findings suggest a favorable safety profile of metastases-directed SBRT in combined modality treatment settings.

AB - IMPORTANCE: Metastases-directed stereotactic radiotherapy (SRT) is increasingly performed in patients with metastatic or oligometastatic cancer treated with immune checkpoint inhibitors (ICIs), monoclonal antibodies (mAbs), and small-molecule drugs (SMs). However, little is known about potential interactions between SRT and biological cancer therapy (BCT).OBJECTIVE: To prospectively investigate adverse events associated with SRT combined with concurrent BCT.DESIGN, SETTING, AND PARTICIPANTS: This international, prospective, multicenter, noninterventional registry cohort study (Toxicity and Efficacy of Combined Stereotactic Radiotherapy and Systemic Targeted or Immune Therapy [TOaSTT]) was conducted between July 2017 and August 2019 with a 24-month follow-up. Patients from 27 centers whose cancer was treated with metastases-directed SRT concurrently with BCT were eligible. Analyses were performed in January 2025.EXPOSURE: Patients treated with SRT for intracranial or extracranial metastases and concurrent (within ≤30 days) BCT. Indication for treatment, decision on the radiotherapy dose and fractionation, as well as interruption of BCT, were left to the discretion of the treating clinician.MAIN OUTCOMES AND MEASURES: The primary outcome was severe (at least grade 3) adverse events of combined modality treatment, as graded by the treating physician. Overall survival (OS) and progression-free survival (PFS) were secondary end points.RESULTS: In total, 514 SRTs (271 cranial and 243 extracranial) concurrent with BCT were performed in 433 patients (median [IQR] age, 62 [54-70 years; 275 male [63.5%]). In 315 SRTs (61.3%) patients received ICIs, whereas in 150 SRTs (29.2%), patients received SMs and in 49 SRTs (9.5%) patients received mAbs. In 430 SRTs (83.7%), BCT had been initiated in patients before SRT, while 71 of 392 patients (18.1%) paused BCT during SRT. Severe (≥grade 3) acute adverse events were observed in 27 of 506 treatments (5.3%; 3 patients with grade 5 events), and severe late adverse events were observed in 29 of 459 patients (6.3%; 2 patients with grade 5 events). SRT with uninterrupted BCT was not associated with increased severe acute or late adverse events (odds ratio, 2.32; 95% CI, 0.87-6.22). Interruption of BCT during SRT was not associated with worse PFS and OS after correction for performance status and histologic type (hazard ratio, 0.81; 95% CI, 0.61-1.09; P = .17).CONCLUSIONS AND RELEVANCE: In this cohort study of 433 patients, severe adverse events after SRT and concurrent BCT were uncommon (<10%), continuing BCT during SRT was not associated with increased risk of severe adverse events, and interrupting BCT was not associated with worse OS when correcting for patients' performance status. These findings suggest a favorable safety profile of metastases-directed SBRT in combined modality treatment settings.

KW - Aged

KW - Aged, 80 and over

KW - Combined Modality Therapy/adverse effects

KW - Female

KW - Humans

KW - Immune Checkpoint Inhibitors/therapeutic use

KW - Male

KW - Middle Aged

KW - Neoplasm Metastasis/radiotherapy

KW - Neoplasms/therapy

KW - Prospective Studies

KW - Radiosurgery/adverse effects

KW - Registries

U2 - 10.1001/jamanetworkopen.2025.53809

DO - 10.1001/jamanetworkopen.2025.53809

M3 - Article

C2 - 41533377

SN - 2574-3805

VL - 9

JO - JAMA network open

JF - JAMA network open

IS - 1

M1 - e2553809

ER -

Adverse Events After Metastases-Directed Stereotactic Radiotherapy and Biological Cancer Therapy

Abstract

Keywords

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