Abstract

Title

Metastases-directed SRT and systemic therapy: EORTC-ESTRO OligoCare delphi consensus recommendations

Authors

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

Authors Affiliations

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

Purpose or Objective

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.

Materials and Methods

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.


Results

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.

Conclusion

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.