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Assessment of treatment responses in children and adolescents with Ewing sarcoma with metabolic tumor parameters derived from 18F-FDG-PET/CT and circulating tumor DNA

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A Correction to this article was published on 13 February 2020

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Abstract

Purpose

The purpose of this study was to perform a prospective integrated analysis of 18F-fluorodeoxyglucose (18F-FDG)-positron emission tomography (PET)/computed tomography (CT) and circulating tumor DNA (ctDNA) to assess responses to multimodal chemotherapy in children and adolescents suffering from Ewing sarcoma (EwS).

Methods

A total of 20 patients with histologically confirmed EwS underwent multiple 18F-FDG-PET/CT, performed at the time of each patient’s initial diagnosis and after the second and fifth induction chemotherapy block (EWING2008 treatment protocol, NCT00987636). Additional PET examinations were performed as clinically indicated in some patients, e.g., in patients suspected of having progressive or relapsing disease. All 263 18F-FDG-positive lesions in the field of view suggestive of tumor tissue were assessed quantitatively to calculate PET-derived parameters, including whole-body metabolic tumor volume (wb-MTV) and whole-body total lesion glycolysis (wb-TLG), as well as the following data: standardized uptake value (SUV)max and SUVmean. Tumor-specific ctDNA in patient plasma samples was quantified using digital droplet PCR (ddPCR), and the correlations between ctDNA levels and PET-derived parameters were analyzed. Metabolic responses to multimodal chemotherapy as assessed with PET-parameters were compared to biochemical responses as assessed with changes in ctDNA levels.

Results

Twenty patients underwent a total of 87 18F-FDG-PET/CT scans, which detected 263 FDG-positive tumor lesions. Significant correlations between SUVmax, SUVmean, wb-MTV and wb-TLG values, and ctDNA levels were observed (all p < 0.0001). All patients suffering from EwS, with histology serving as gold standard, also presented with a positive corresponding ctDNA sample and a positive 18F-FDG-PET/CT examination before initiation of therapy. There were no false-negative results. Evaluation of treatment response after the fifth block of induction chemotherapy showed that the agreement between the metabolic response and biochemical response was 90%, which was statistically significant (Cohen κ = 0.62; p < 0.05). Non-detectable ctDNA after the second block of induction chemotherapy was associated with complete biochemical and metabolic responses after the fifth block of induction chemotherapy in 16/17 patients (94%). During a median follow-up period of 36 months (range: 8–104 months), four patients had tumor relapses, which, in all cases, were accompanied by an increase in plasma ctDNA levels and a positive 18F-FDG-PET/CT. No false-negative results were observed in the study cohort. Complete biochemical and metabolic responses after the fifth block of induction chemotherapy had a high positive predictive value for disease remission during the follow-up period; specifically, the positive predictive value was 88%.

Conclusion

The combination of 18F-FDG-PET/CT and ctDNA quantification is a very promising noninvasive tool for assessing treatment responses and detecting tumor relapses in children and young adolescents suffering from EwS who are undergoing multimodal chemotherapy.

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Change history

  • 13 February 2020

    The author names and family names of the originally published article was inversed. Correct presentation is presented here.

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Acknowledgments

The authors would like to thank Sabine Semper for providing excellent technical assistance.

Funding

This work was funded by the Interdisziplinäres Zentrum für Klinsiche Forschung (IZKF) of Friedrich-Alexander University Erlangen-Nürnberg (FAU) (grant to CS), the Barbara und Hubertus Trettner Stiftung, project number T0355/31554/2018/sm (grant to UD and MM) and a research grant from “Schornsteinfeger helfen krebskranken Kindern,” Germany (grant to MK and MM). The German Cancer Aid grant 108128 to UD. ERA-Net-TRANSCAN consortium, project number 01KT1310 to UD, and Euro Ewing Consortium EEC, project number EU-FP7 602856 to UD and MM), both funded under the European Commission Seventh Framework Program FP7-HEALTH (http://cordis.europa.eu/) (to UD).

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Authors and Affiliations

  1. Department of Nuclear Medicine, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen, Germany

    Christian Schmidkonz, Armin Atzinger, Michael Cordes, Theresa Ida Goetz, Olaf Prante, Philipp Ritt & Torsten Kuwert

  2. Department of Pediatrics and Adolescent Medicine, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen, Germany

    Manuela Krumbholz & Markus Metzler

  3. Pediatrics III, West German Cancer Centre, University Hospital of Essen, Essen, Germany

    Christiane Schaefer & Uta Dirksen

  4. Institute of Pathology, University Hospital, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen, Germany

    Abbas Agaimy

  5. Division of Translational Pathology, Gerhard-Domagk Institute of Pathology, University Hospital of Münster, Münster, Germany

    Wolfgang Hartmann

  6. Department of Pediatric Hematology and Oncology, University Children’s Hospital Münster, Münster, Germany

    Claudia Rössig & Birgit Fröhlich

  7. Institute of Radiology Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen, Germany

    Tobias Bäuerle

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  1. Christian Schmidkonz
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Contributions

Designed the study: Schmidkonz C, Krumbholz M, and Metzler M

Acquired the data: Schmidkonz C, Krumbholz M, Metzler M, Cordes M, Atzinger A, and Dirksen U

Analyzed/interpreted the data: Schmidkonz C, Krumbholz M, Metzler M, Cordes M, Bäuerle T, Goetz Th I, Ritt P, and Kuwert T

Contributed reagents/materials/analysis tools: Schmidkonz C, Krumbholz M, Prante O, Metzler M, Agaimy A, Hartmann W, Rössig C, Fröhlich B, Dirksen U, Schaefer C, and Goetz Th I

Drafted the manuscript: Schmidkonz C, Krumbholz M, Metzler M, and Kuwert T

Revised the manuscript: Schmidkonz C, Krumbholz M, Metzler M, Kuwert T, Cordes M, Prante O, Bäuerle T, Ritt P, Atzinger A, Goetz Th I, Rössig C, Fröhlich B, and Dirksen U

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Correspondence to Christian Schmidkonz.

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All procedures involving human participants were performed in accordance with the ethical standards of the institutional and/or national research committee and the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.

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The original version of this article was revised due to author names and family names being inversed.

This article is part of the Topical Collection on Oncology – Muskoskeletal

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Schmidkonz, C., Krumbholz, M., Atzinger, A. et al. Assessment of treatment responses in children and adolescents with Ewing sarcoma with metabolic tumor parameters derived from 18F-FDG-PET/CT and circulating tumor DNA. Eur J Nucl Med Mol Imaging 47, 1564–1575 (2020). https://doi.org/10.1007/s00259-019-04649-1

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