title: Toxicity of concurrent stereotactic radiotherapy and targeted therapy or immunotherapy: A systematic review.
abstract: OBJECTIVE
  Both stereotactic radiotherapy (SRT) and immune- or targeted therapy play an increasingly important role in personalized treatment of metastatic disease. Concurrent application of both therapies is rapidly expanding in daily clinical practice. In this systematic review we summarize severe toxicity observed after concurrent treatment.
  
  
  METHODS
  PubMed and EMBASE databases were searched for English literature published up to April 2016 using keywords "radiosurgery", "local ablative therapy", "gamma knife" and "stereotactic", combined with "bevacizumab", "cetuximab", "crizotinib", "erlotinib", "gefitinib", "ipilimumab", "lapatinib", "sorafenib", "sunitinib", "trastuzumab", "vemurafenib", "PLX4032", "panitumumab", "nivolumab", "pembrolizumab", "alectinib", "ceritinib", "dabrafenib", "trametinib", "BRAF", "TKI", "MEK", "PD1", "EGFR", "CTLA-4" or "ALK". Studies performing SRT during or within 30days of targeted/immunotherapy, reporting severe (⩾Grade 3) toxicity were included.
  
  
  RESULTS
  Concurrent treatment is mostly well tolerated in cranial SRT, but high rates of severe toxicity were observed for the combination with BRAF-inhibitors. The relatively scarce literature on extra-cranial SRT shows a potential risk of increased toxicity when SRT is combined with EGFR-targeting tyrosine kinase inhibitors and bevacizumab, which was not observed for cranial SRT.
  
  
  CONCLUSIONS
  This review gives a best-possible overview of current knowledge and its limitations and underlines the need for a timely generation of stronger evidence in this rapidly expanding field.
authors.affiliation: Department of Radiation Oncology, University Hospital Zurich, Rämistrasse 100, 8091 Zurich, Switzerland. Electronic address: Stephanie.kroeze@usz.ch.
authors.forename: Stephanie G C
authors.initials: SG
authors.lastname: Kroeze
authors.affiliation: Department of Radiation Oncology, University Hospital Zurich, Rämistrasse 100, 8091 Zurich, Switzerland.
authors.forename: Corinna
authors.initials: C
authors.lastname: Fritz
authors.affiliation: Danish Center for Particle Therapy, Aarhus University, Palle Juul-Jensens Boulevard, 8200 Aarhus, Denmark.
authors.forename: Morten
authors.initials: M
authors.lastname: Hoyer
authors.affiliation: Department of Radiation Oncology, University of Washington School of Medicine, 1959 N.E. Pacific Street, Box 356043, Seattle, USA.
authors.forename: Simon S
authors.initials: SS
authors.lastname: Lo
authors.affiliation: Department of Oncology, University of Turin, Regione Gonzole 10, 10043 Orbassano, Italy.
authors.forename: Umberto
authors.initials: U
authors.lastname: Ricardi
authors.affiliation: Department of Radiation Oncology, University of Toronto, 27 King's College Circle Toronto, Ontario M5S 1A1, Canada.
authors.forename: Arjun
authors.initials: A
authors.lastname: Sahgal
authors.affiliation: Department of Oncology, University Hospital Zurich, Rämistrasse 100, 8091 Zurich, Switzerland.
authors.forename: Rolf
authors.initials: R
authors.lastname: Stahel
authors.affiliation: Department of Oncology, University Hospital Zurich, Rämistrasse 100, 8091 Zurich, Switzerland.
authors.forename: Roger
authors.initials: R
authors.lastname: Stupp
authors.affiliation: Department of Radiation Oncology, University Hospital Zurich, Rämistrasse 100, 8091 Zurich, Switzerland.
authors.forename: Matthias
authors.initials: M
authors.lastname: Guckenberger
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects; D000068258:Bevacizumab / Q000008:administration & dosage / Q000009:adverse effects; D060908:CTLA-4 Antigen / Q000037:antagonists & inhibitors; D000068818:Cetuximab / Q000008:administration & dosage / Q000009:adverse effects; D006801:Humans; D007167:Immunotherapy / Q000009:adverse effects*; D058990:Molecular Targeted Therapy / Q000009:adverse effects* / Q000379:methods; D009369:Neoplasms / Q000628:therapy*; D009536:Niacinamide / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D010671:Phenylurea Compounds / Q000008:administration & dosage / Q000009:adverse effects; D016634:Radiosurgery / Q000009:adverse effects*; D000077157:Sorafenib
chemical_list: D060908:CTLA-4 Antigen; D010671:Phenylurea Compounds; D009536:Niacinamide; D000068258:Bevacizumab; D000077157:Sorafenib; D000068818:Cetuximab
keywords: Concurrent; Immunotherapy; Stereotactic radiotherapy; Targeted therapy; Toxicity