Advertisement

Combination of stereotactic radiotherapy and targeted therapy: patterns-of-care survey in German-speaking countries

  • S. G. C. KroezeEmail author
  • C. Fritz
  • L. Basler
  • E. Gkika
  • T. B. Brunner
  • A. L. Grosu
  • M. Guckenberger
Original Article
  • 24 Downloads

Abstract

Introduction

Stereotactic body radiotherapy (SBRT) is increasingly used in metastasized patients receiving targeted/immunotherapy. Information on safety and effectivity of concurrent SBRT and targeted/immunotherapy remains limited, resulting in a lack of consensus on treatment strategies. This study aimed to investigate how SBRT-experienced centers in German-speaking countries combine both therapies.

Materials and methods

Patterns-of-care of combined treatment with SBRT and targeted/immunotherapy were assessed in 27 radiation oncology centers (19 German, 1 Austrian and 7 Swiss centers). A survey was performed to analyze the details of SBRT, SBRT planning and combined modality treatment. Consensus was defined as ≥75% agreement among participants.

Results

Most participants (60%) were university centers. SBRT for oligometastases has been performed since the year 2008 (median, range 1997–2016), since then a median of 140 cases (5–1100) of SBRT have been performed. In all, 67% performed concurrent SBRT and targeted agents. BRAF inhibitors and VEGF/EGFR inhibitors (bevacizumab [90%], erlotinib [11%], sorafenib [19%], lapatinib [4%]) were considered a contraindication. Bevacizumab was never given simultaneously with SBRT; other agents were given concurrently in 7–52% of centers. A majority (59%) paused targeted agents 1 week before/after SBRT. Only 1 center reduced SBRT dose when combined with targeted agents.

Conclusion

Although evidence for safety and efficacy of concurrent SBRT and targeted agents is limited, it is regularly performed outside of clinical trials. The survey showed consensus not to combine SBRT with antiangiogenic agents, especially bevacizumab. Furthermore, SBRT with concurrent BRAF inhibitors should be practiced with caution and BRAF inhibitors should be paused at least 1 week before SBRT.

Keywords

Survey Stereotactic radiotherapy Targeted therapy Concurrent Toxicity 

Kombination von stereotaktischer Strahlentherapie und zielgerichteter Therapie: Patterns-of-Care-Umfrage im deutschsprachigen Raum

Zusammenfassung

Einleitung

Bei Metastasierung erhalten Patienten neben zielgerichteten („targeted therapy“, TT) oder Immuntherapien auch zunehmend Lokaltherapien, wie etwa die SBRT („stereotactic body radiotherapy“). Bisher gibt es nur wenig Informationen zu Wirksamkeit bzw. Sicherheit und daher keinen Konsens bezüglich der Therapiestrategien. Ziel dieser Studie war es, die Behandlungskonzepte erfahrener SBRT-Zentren in deutschsprachigen Ländern zu analysieren.

Methoden

Die Konzepte die Kombination einer SBRT mit einer TT/Immuntherapie wurden in 27 radioonkologischen Zentren in Deutschland (19), Österreich (1) und der Schweiz (7) erfasst. Die Umfrage beinhaltete Details zur durchgeführten SBRT, zur SBRT-Planung zu den kombinierten Therapiemodalitäten. Ein Behandlungskonsens war definiert als ≥75 % Übereinstimmung der an der Umfrage Teilnehmenden.

Ergebnisse

Die Mehrheit der teilnehmenden Zentren (60 %) waren Universitätskliniken. SBRT für Oligometastasen wurde im Median seit 2008 angewandt (1997–2016), im Median wurden seitdem 140 (5–1100) SBRTs durchgeführt. In der klinischen Routine führten 67 % der Zentren gleichzeitig eine SBRT und eine TT durch. BRAF-Inhibitoren (41 %) und Anti-VEGF/EGFR-Medikamente (Bevacizumab [90 %], Erlotinib [11 %], Sorafenib [19 %], Lapatinib [4 %]) wurden als Kontraindikation für eine zeitgleiche Therapie angesehen. Bevacizumab wurde von keinem Zentrum simultan verabreicht, andere zielgerichtete Therapien wurden gleichzeitig mit einer SBRT in 7–52 % der Zentren verabreicht. Die Mehrheit der Zentren (59 %) pausierte die TT eine Woche vor/nach der SBRT. Nur ein Zentrum reduzierte die SBRT-Dosis aufgrund einer kombinierten TT.

Schlussfolgerung

Obwohl nur eine limitierte Evidenz für die Sicherheit und Wirksamkeit einer kombinierten SBRT und TT existiert, wird diese Kombination regelmäßig außerhalb von klinischen Studien angewandt. In unserer Analyse zeigte sich ein Konsens, antiangiogenetische Wirkstoffe (Bevacizumab) nicht mit einer SBRT zu kombinieren. Eine BRAF-Inhibitor-Therapie sollte zumindest eine Woche vor/nach SBRT pausiert werden.

Schlüsselwörter

Umfrage Stereotaktische Radiotherapie Zielgerichtete Therapie Zeitgleich Toxizität 

Notes

Conflict of interest

S.G.C. Kroeze, C. Fritz, L. Basler, E. Gkika, T.B. Brunner, A.L. Grosu and M. Guckenberger declare that they have no competing interests.

References

  1. 1.
    Network NCC (2019) Non-small cell lung cancer. Version 4.2019. https://www.nccn.org. Accessed 2/2019Google Scholar
  2. 2.
    Tan DSW, Yom SS, Tsao MS, Pass HI, Kelly K, Peled N et al (2016) The International Association for the Study of Lung Cancer consensus statement on optimizing management of EGFR mutation-positive non-small cell lung cancer: status in 2016. J Thorac Oncol 11:946–963CrossRefPubMedGoogle Scholar
  3. 3.
    Sprave T, Verma V, Forster R, Schlampp I, Bruckner T, Bostel T et al (2018) Randomized phase II trial evaluating pain response in patients with spinal metastases following stereotactic body radiotherapy versus three-dimensional conformal radiotherapy. Radiother Oncol 128:274–282CrossRefPubMedGoogle Scholar
  4. 4.
    Popp I, Grosu AL, Niedermann G, Duda DG (2016) Immune modulation by hypofractionated stereotactic radiation therapy: therapeutic implications. Radiother Oncol 120:185–194CrossRefPubMedGoogle Scholar
  5. 5.
    Reynders K, Illidge T, Siva S, Chang JY, De Ruysscher D (2015) The abscopal effect of local radiotherapy: using immunotherapy to make a rare event clinically relevant. Cancer Treat Rev 41:503–510CrossRefPubMedGoogle Scholar
  6. 6.
    Zhang X, Niedermann G (2018) Abscopal effects with hypofractionated schedules extending into the effector phase of the tumor-specific T‑cell response. Int J Radiat Oncol Biol Phys 101:63–73CrossRefPubMedGoogle Scholar
  7. 7.
    Aibe N, Yamazaki H, Nakamura S, Tsubokura T, Kobayashi K, Kodani N et al (2014) Outcome and toxicity of stereotactic body radiotherapy with helical tomotherapy for inoperable lung tumor: analysis of grade 5 radiation pneumonitis. J Radiat Res 55:575–582CrossRefPubMedGoogle Scholar
  8. 8.
    Oskan F, Becker G, Bleif M (2017) Specific toxicity after stereotactic body radiation therapy to the central chest: a comprehensive review. Strahlenther Onkol 193:173–184CrossRefPubMedGoogle Scholar
  9. 9.
    Pollom EL, Deng L, Pai RK, Brown JM, Giaccia A, Loo BW Jr. et al (2015) Gastrointestinal toxicities with combined antiangiogenic and stereotactic body radiation therapy. Int J Radiat Oncol Biol Phys 92:568–576CrossRefPubMedGoogle Scholar
  10. 10.
    Zeng J, Baik C, Bhatia S, Mayr N, Rengan R (2014) Combination of stereotactic ablative body radiation with targeted therapies. Lancet Oncol 15:e426–e434CrossRefPubMedGoogle Scholar
  11. 11.
    Anker CJ, Grossmann KF, Atkins MB, Suneja G, Tarhini AA, Kirkwood JM (2016) Avoiding severe toxicity from combined BRAF inhibitor and radiation treatment: consensus guidelines from the Eastern Cooperative Oncology Group (ECOG). Int J Radiat Oncol Biol Phys 95:632–646CrossRefPubMedGoogle Scholar
  12. 12.
    Kroeze SG, Fritz C, Hoyer M, Lo SS, Ricardi U, Sahgal A et al (2017) Toxicity of concurrent stereotactic radiotherapy and targeted therapy or immunotherapy: a systematic review. Cancer Treat Rev 53:25–37CrossRefPubMedGoogle Scholar
  13. 13.
    Tallet AV, Dhermain F, Le Rhun E, Noel G, Kirova YM (2017) Combined irradiation and targeted therapy or immune checkpoint blockade in brain metastases: toxicities and efficacy. Ann Oncol 28:2962–2976CrossRefPubMedGoogle Scholar
  14. 14.
    Vanpouille-Box C, Alard A, Aryankalayil MJ, Sarfraz Y, Diamond JM, Schneider RJ et al (2017) DNA exonuclease Trex1 regulates radiotherapy-induced tumour immunogenicity. Nat Commun 8:15618CrossRefPubMedGoogle Scholar
  15. 15.
    Herrera FG, Bourhis J, Coukos G (2017) Radiotherapy combination opportunities leveraging immunity for the next oncology practice. CA Cancer J Clin 67:65–85CrossRefPubMedGoogle Scholar
  16. 16.
    Magnuson WJ, Lester-Coll NH, Wu AJ, Yang TJ, Lockney NA, Gerber NK et al (2017) Management of brain metastases in tyrosine kinase inhibitor-naive epidermal growth factor receptor-mutant non-small-cell lung cancer: a retrospective multi-institutional analysis. J Clin Oncol 35:1070–1077CrossRefPubMedGoogle Scholar
  17. 17.
  18. 18.
    Gkika E, Hallauer L, Kirste S, Adebahr S, Bartl N, Neeff HP et al (2017) Stereotactic body radiotherapy (SBRT) for locally advanced intrahepatic and extrahepatic cholangiocarcinoma. BMC Cancer 17:781CrossRefPubMedGoogle Scholar
  19. 19.
    Muller AC, van Oorschot B, Micke O, Guckenberger M (2018) German S3 guideline for renal cell carcinoma: presentation and discussion of essential aspects for the radiation oncologist. Strahlenther Onkol 194:1–8CrossRefPubMedGoogle Scholar
  20. 20.
    Jones TL, Baxter MA, Khanduja V (2013) A quick guide to survey research. Ann R Coll Surg Engl 95:5–7CrossRefPubMedGoogle Scholar
  21. 21.
    Diamond IR, Grant RC, Feldman BM, Pencharz PB, Ling SC, Moore AM et al (2014) Defining consensus: a systematic review recommends methodologic criteria for reporting of Delphi studies. J Clin Epidemiol 67:401–409CrossRefPubMedGoogle Scholar
  22. 22.
    Sambade MJ, Peters EC, Thomas NE, Kaufmann WK, Kimple RJ, Shields JM (2011) Melanoma cells show a heterogeneous range of sensitivity to ionizing radiation and are radiosensitized by inhibition of B‑RAF with PLX-4032. Radiother Oncol 98:394–399CrossRefPubMedGoogle Scholar
  23. 23.
    Griffioen AW, Mans LA, de Graaf AMA, Nowak-Sliwinska P, de Hoog C, de Jong TAM et al (2012) Rapid angiogenesis onset after discontinuation of sunitinib treatment of renal cell carcinoma patients. Clin Cancer Res 18:3961–3971CrossRefPubMedGoogle Scholar
  24. 24.
    Michot JM, Bigenwald C, Champiat S, Collins M, Carbonnel F, Postel-Vinay S et al (2016) Immune-related adverse events with immune checkpoint blockade: a comprehensive review. Eur J Cancer 54:139–148CrossRefPubMedGoogle Scholar
  25. 25.
    Aljabab S, Vellayappan B, Vandervoort E, Bahm J, Zohr R, Sinclair J et al (2018) Comparison of four techniques for spine stereotactic body radiotherapy: dosimetric and efficiency analysis. J Appl Clin Med Phys 19:160–167CrossRefPubMedGoogle Scholar
  26. 26.
    Brade AM, Ng S, Brierley J, Kim J, Dinniwell R, Ringash J et al (2016) Phase 1 trial of Sorafenib and stereotactic body radiation therapy for hepatocellular carcinoma. Int J Radiat Oncol Biol Phys 94:580–587CrossRefPubMedGoogle Scholar
  27. 27.
    Schulze B, Meissner M, Wolter M, Rodel C, Weiss C (2014) Unusual acute and delayed skin reactions during and after whole-brain radiotherapy in combination with the BRAF inhibitor vemurafenib. Two case reports. Strahlenther Onkol 190:229–232CrossRefPubMedGoogle Scholar
  28. 28.
    Hecht M, Meier F, Zimmer L, Polat B, Loquai C, Weishaupt C et al (2018) Clinical outcome of concomitant vs interrupted BRAF inhibitor therapy during radiotherapy in melanoma patients. Br J Cancer 118:785–792CrossRefPubMedGoogle Scholar
  29. 29.
    Hapani S, Chu D, Wu S (2009) Risk of gastrointestinal perforation in patients with cancer treated with bevacizumab: a meta-analysis. Lancet Oncol 10:559–568CrossRefPubMedGoogle Scholar
  30. 30.
    Tarnawski AS, Ahluwalia A, Jones MK (2014) Angiogenesis in gastric mucosa: an important component of gastric erosion and ulcer healing and its impairment in aging. J Gastroenterol Hepatol 29(Suppl 4):112–123CrossRefPubMedGoogle Scholar
  31. 31.
    Sturdza A, Hofmann S, Kranawetter M, Polterauer S, Grimm C, Krainer M et al (2017) Increased genitourinary fistula rate after bevacizumab in recurrent cervical cancer patients initially treated with definitive radiochemotherapy and image-guided adaptive brachytherapy. Strahlenther Onkol 193:1056–1065CrossRefPubMedGoogle Scholar
  32. 32.
    Barney BM, Markovic SN, Laack NN, Miller RC, Sarkaria JN, Macdonald OK et al (2013) Increased bowel toxicity in patients treated with a vascular endothelial growth factor inhibitor (VEGFI) after stereotactic body radiation therapy (SBRT). Int J Radiat Oncol Biol Phys 87:73–80CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • S. G. C. Kroeze
    • 1
    Email author
  • C. Fritz
    • 1
  • L. Basler
    • 1
  • E. Gkika
    • 2
    • 3
    • 4
  • T. B. Brunner
    • 5
  • A. L. Grosu
    • 2
    • 3
    • 4
  • M. Guckenberger
    • 1
  1. 1.Department of Radiation OncologyUniversity Hospital ZurichZürichSwitzerland
  2. 2.Department of Radiation Oncology, Medical Center, Faculty of MedicineUniversity of FreiburgFreiburgGermany
  3. 3.German Cancer Consortium (DKTK) Partner Site FreiburgFreiburgGermany
  4. 4.German Cancer Research Center (DKFZ)HeidelbergGermany
  5. 5.Department of Radiation OncologyUniversity Hospital MagdeburgMagdeburgGermany

Personalised recommendations