Abstract

Stephanie Kroeze¹, Matea Pavic², Karin Stellamans³, Yolande Lievens⁴, Carlotta Becherini⁵, Marta Scorsetti⁶, Filippo Alongi⁷, Umberto Ricardi⁸, Barbara Jereczek⁹, Paulien Westhoff¹⁰, Jasna But-Hadzic¹¹, Joachim Widder¹², Xavier Geets¹³, Samuel Bral¹⁴, Maarten Lambrecht¹⁵, Charlotte Billiet¹⁶, Igor Sirak¹⁷, Sara Ramella¹⁸, Ivaldi Giovanni Battista¹⁹, Sergi Benavente²⁰, Almudena Zapatero²¹, Fabiolo Romero²², Thomas Zilli²³, Kaouthar Khanfir²⁴, Hossein Hemmatazad²⁵, Berardino De Bari²⁶, Desiree Klass²⁷, Shaukat Adnan²⁸, Heike Peulen²⁹, Juan Salinas Ramos³⁰, Michiel Strijbos³¹, Sanjay Popat³², Piet Ost³³, Matthias Guckenberger²

¹Kantonsspital Aarau, Radiation Oncology, Aarau, Switzerland; ²University Hospital Zürich, Radiation Oncology, Zürich, Switzerland; ³AZ Groeninge Kortrijk , Radiation Oncology, Kortrijk, Belgium; ⁴Ghent University Hospital and Ghent University, Radiation Oncology, Ghent, Belgium; ⁵Careggi University Hospital, Radiation Oncology, Florence, Italy; ⁶IRCCS Humanitas Research Hospital, Radiation Oncology, Milan, Italy; ⁷IRCCS Sacro Cuore don Calabria Hospital, Radiation Oncology, Negrar-Verona, Italy; ⁸University of Turin, Radiation Oncology, Turin, Italy; ⁹IRCCS IEO European Institute of Oncology, Radiation Oncology, Milan, Italy; ¹⁰Radboud University Medical Center Nijmegen, Radiation Oncology, Nijmegen, The Netherlands; ¹¹Institute of Oncology, Radiation Oncology, Ljubljana, Slovenia; ¹²Medical University of Vienna, Radiation Oncology, Vienna, Austria; ¹³Cliniques universitaires Saint-Luc, Radiation Oncology, Saint-Luc, Belgium; ¹⁴Onze-Lieve-Vrouwziekenhuis, Radiation Oncology, Aalst, Belgium; ¹⁵UZ Leuven, Radiation Oncology, Leuven, Belgium; ¹⁶Iridium Netwerk, Wilrijk, Radiation Oncology, Antwerp, Belgium; ¹⁷University Hospital Hradec Kralove, Radiation Oncology, Hradec Kralove, Czech Republic; ¹⁸Campus Bio-Medico University, Radiation Oncology, Rome, Italy; ¹⁹Istituti Clinici Scientifici Maugeri, IRCCS, Radiation Oncology, Pavia, Italy; ²⁰Vall d'Hebron University Hospital, Radiation Oncology, Barcelona, Spain; ²¹Hospital Universitario de La Princesa, Radiation Oncology, Madrid, Spain; ²²Hospital Universitario Reina Sofia, Radiation Oncology, Cordoba, Spain; ²³Istituto Oncologico della Svizzera Italiana, Radiation Oncology, Bellinzona, Switzerland; ²⁴Hôpital Valais, Radiation Oncology, Sion, Switzerland; ²⁵University Hospital and University of Bern, Radiation Oncology, Bern, Switzerland; ²⁶Service Radio-Oncologie Neuchâtel Hôpital Network, Radiation Oncology, La Chaux-de-Fonds, Switzerland; ²⁷Cantonal Hospital Graubünden, Radiation Oncology, Chur, Switzerland; ²⁸Aberdeen Royal Infirmary, Radiation Oncology, Aberdeen, United Kingdom; ²⁹Catharina Hospital, Radiation Oncology, Eindhoven, The Netherlands; ³⁰Santa Lucia General University Hospital, Radiation Oncology, Cartagena, Spain; ³¹GasthuisZusters Antwerpen, Medical Oncology, Antwerpen, Belgium; ³²The Royal Marsden, Medical Oncology, London, United Kingdom; ³³Iridium Network, GZA Ziekenhuizen, Radiation Oncology, Antwerp, Belgium

SBRT for patients with (oligo-)metastatic cancer receiving targeted- or immunotherapy (TT/IT) has become a frequently practiced and guideline-supported treatment strategy. Our systematic review and consequential consensus process aimed at providing guidance for safe practice of SBRT concurrent with TT/IT patients with metastatic cancer.

A systematic literature review was performed to identify the toxicity profiles of combined SBRT and TT/IT. These results served as the basis for an international Delphi consensus process among 28 interdisciplinary experts, who are members of the European Society for Radiotherapy and Oncology (ESTRO) and European Organisation for Research and Treatment of Cancer (EORTC) OligoCare consortium. Consensus was searched on risk mitigation strategies, the potential need and length of interrupting TT/IT around SBRT delivery, and potential adaptations of radiation dose and fractionation when metastases-directed SBRT is combined with TT/IT.

The systematic review identified most evidence for immune checkpoint inhibitors (43%), multikinase inhibitors (23%) and EGFR-inhibitors (19%), whereas no evidence was available for almost all other small molecules (SMs) and Her2 antibodies in combination with SBRT. The following combinations were identified to be associated with a clinically relevant risk of grade ≥3 toxicity: ipilimumab and intra-thoracic (12%) and intra-abdominal SBRT (10%), nivolumab & ipilimumab and intra-thoracic SBRT (26%), multikinase inhibitors (22%) or bevacizumab (12%) and intra-abdominal SBRT, and cetuximab and cervical SBRT (15%).

The Delphi process resulted in a consensus (≥75% agreement) of 50% of the drug categories on whether to administer TT/IT on the same days as SBRT delivery. Consensus was reached to not administer anti-VEGF-antibodies, anti-EGFR-antibodies, nivolumab/ipilimumab, BRAF-/MEK-inhibitors and mTKIs on the same days of metastases-directed SBRT delivery; consensus was also reached that trastuzumab and pertuzumab can be administered on the same days as SBRT delivery. Further consensus was reached that multikinase inhibitors and BRAF/MEK-inhibitors be interrupted for a maximum of two weeks and anti-EGFR- and VEGF- antibodies and ipilimumab/nivolumab for minimum one week before/after SBRT. A consensus not to reduce radiation doses and not to change radiotherapy fractionation was reached for all TT/IT groups, irrespective of the anatomical location of SBRT.

Results of this systematic review and consensus process compile best available evidence for safe combination of SBRT and TT/IT for patients with oligometastatic cancer and aim to guide today’s clinical practice and future clinical trial design. In the presence of a paucity of high-level evidence, large international registry trials are recommended to timely generate prospective real-world data on patients receiving combination treatment.