Ursula Nestle1, Tanja Schimek-Jasch2, Stephanie Kremp3, Andrea Schaefer-Schuler4, Michael Mix5, Andreas Küsters6, Marco Tosch7, Thomas Hehr8, Susanne Martina Eschmann9, Yves-Pierre Bultel10, Peter Hass11, Jochen Fleckenstein3, Alexander Thieme12, Marcus Stockinger13, Karin Dieckmann14, Matthias Miederer15, Gabriele Holl16, H Christian Rischke17, Eleni Gkika2, Sonja Adebahr18, Jochem König19, Anca-Ligia Grosu18. 1. Department of Radiation Oncology, Faculty of Medicine, Medical Center, University of Freiburg, Freiburg, Germany; German Cancer Consortium Partner Site Freiburg and German Cancer Research Center, Heidelberg, Germany; Department of Radiation Oncology, Kliniken Maria Hilf, Mönchengladbach, Germany. Electronic address: ursula.nestle@mariahilf.de. 2. Department of Radiation Oncology, Faculty of Medicine, Medical Center, University of Freiburg, Freiburg, Germany. 3. Department of Radiotherapy and Radiation Oncology, Saarland University Medical Center and Faculty of Medicine, Homburg/Saar, Germany. 4. Department of Nuclear Medicine, Saarland University Medical Center and Faculty of Medicine, Homburg/Saar, Germany. 5. Department of Nuclear Medicine, Faculty of Medicine, Medical Center, University of Freiburg, Freiburg, Germany. 6. Department of Radiation Oncology, Kliniken Maria Hilf, Mönchengladbach, Germany. 7. Department of Nuclear Medicine, Helios University Hospital Wuppertal, Wuppertal, Germany; Department of Medicine, Faculty of Health, University of Witten/Herdecke, Witten, Germany. 8. Department of Radiation Oncology, Marienhospital Stuttgart, Stuttgart, Germany. 9. Department of Nuclear Medicine, Marienhospital Stuttgart, Stuttgart, Germany. 10. Department of Radiation Oncology, Klinikum Mutterhaus der Boromäerinnen, Trier, Germany. 11. Department of Radiation Oncology, University Hospital Magdeburg, Magdeburg, Germany. 12. Charité-Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany; Department of Radiation Oncology, Berlin Institute of Health, Berlin, Germany. 13. Department of Radiation Oncology, University Hospital Mainz, Mainz, Germany. 14. Department of Radiotherapy, Medical University of Vienna, Vienna General Hospital, Vienna, Austria. 15. Department of Nuclear Medicine, University Hospital Mainz, Mainz, Germany. 16. Department of Nuclear Medicine, Helios Kliniken Schwerin, Schwerin, Germany. 17. Department of Radiation Oncology, Faculty of Medicine, Medical Center, University of Freiburg, Freiburg, Germany; Department of Nuclear Medicine, Faculty of Medicine, Medical Center, University of Freiburg, Freiburg, Germany. 18. Department of Radiation Oncology, Faculty of Medicine, Medical Center, University of Freiburg, Freiburg, Germany; German Cancer Consortium Partner Site Freiburg and German Cancer Research Center, Heidelberg, Germany. 19. Institute of Medical Biostatistics, Epidemiology and Informatics, University Hospital Mainz, Mainz, Germany.
Abstract
BACKGROUND: With increasingly precise radiotherapy and advanced medical imaging, the concept of radiotherapy target volume planning might be redefined with the aim of improving outcomes. We aimed to investigate whether target volume reduction is feasible and effective compared with conventional planning in the context of radical chemoradiotherapy for patients with locally advanced non-small-cell lung cancer. METHODS: We did a multicentre, open-label, randomised, controlled trial (PET-Plan; ARO-2009-09) in 24 centres in Austria, Germany, and Switzerland. Previously untreated patients (aged older than 18 years) with inoperable locally advanced non-small-cell lung cancer suitable for chemoradiotherapy and an Eastern Cooperative Oncology Group performance status of less than 3 were included. Undergoing 18F-fluorodeoxyglucose (18F-FDG) PET and CT for treatment planning, patients were randomly assigned (1:1) using a random number generator and block sizes between four and six to target volume delineation informed by 18F-FDG PET and CT plus elective nodal irradiation (conventional target group) or target volumes informed by PET alone (18F-FDG PET-based target group). Randomisation was stratified by centre and Union for International Cancer Control stage. In both groups, dose-escalated radiotherapy (60-74 Gy, 2 Gy per fraction) was planned to the respective target volumes and applied with concurrent platinum-based chemotherapy. The primary endpoint was time to locoregional progression from randomisation with the objective to test non-inferiority of 18F-FDG PET-based planning with a prespecified hazard ratio (HR) margin of 1·25. The per-protocol set was included in the primary analysis. The safety set included all patients receiving any study-specific treatment. Patients and study staff were not masked to treatment assignment. This study is registered with ClinicalTrials.gov, NCT00697333. FINDINGS:From May 13, 2009, to Dec 5, 2016, 205 of 311 recruited patients were randomly assigned to the conventional target group (n=99) or the 18F-FDG PET-based target group (n=106; the intention-to-treat set), and 172 patients were treated per protocol (84 patients in the conventional target group and 88 in the 18F-FDG PET-based target group). At a median follow-up of 29 months (IQR 9-54), the risk of locoregional progression in the 18F-FDG PET-based target group was non-inferior to, and in fact lower than, that in the conventional target group in the per-protocol set (14% [95% CI 5-21] vs 29% [17-38] at 1 year; HR 0·57 [95% CI 0·30-1·06]). The risk of locoregional progression in the 18F-FDG PET-based target group was also non-inferior to that in the conventional target group in the intention-to-treat set (17% [95% CI 9-24] vs 30% [20-39] at 1 year; HR 0·64 [95% CI 0·37-1·10]). The most common acute grade 3 or worse toxicity was oesophagitis or dysphagia (16 [16%] of 99 patients in the conventional target group vs 17 [16%] of 105 patients in the 18F-FDG PET-based target group); the most common late toxicities were lung-related (12 [12%] vs 11 [10%]). 20 deaths potentially related to study treatment were reported (seven vs 13). INTERPRETATION: 18F-FDG PET-based planning could potentially improve local control and does not seem to increase toxicity in patients with chemoradiotherapy-treated locally advanced non-small-cell lung cancer. Imaging-based target volume reduction in this setting is, therefore, feasible, and could potentially be considered standard of care. The procedures established might also support imaging-based target volume reduction concepts for other tumours. FUNDING: German Cancer Aid (Deutsche Krebshilfe).
RCT Entities:
BACKGROUND: With increasingly precise radiotherapy and advanced medical imaging, the concept of radiotherapy target volume planning might be redefined with the aim of improving outcomes. We aimed to investigate whether target volume reduction is feasible and effective compared with conventional planning in the context of radical chemoradiotherapy for patients with locally advanced non-small-cell lung cancer. METHODS: We did a multicentre, open-label, randomised, controlled trial (PET-Plan; ARO-2009-09) in 24 centres in Austria, Germany, and Switzerland. Previously untreated patients (aged older than 18 years) with inoperable locally advanced non-small-cell lung cancer suitable for chemoradiotherapy and an Eastern Cooperative Oncology Group performance status of less than 3 were included. Undergoing 18F-fluorodeoxyglucose (18F-FDG) PET and CT for treatment planning, patients were randomly assigned (1:1) using a random number generator and block sizes between four and six to target volume delineation informed by 18F-FDG PET and CT plus elective nodal irradiation (conventional target group) or target volumes informed by PET alone (18F-FDG PET-based target group). Randomisation was stratified by centre and Union for International Cancer Control stage. In both groups, dose-escalated radiotherapy (60-74 Gy, 2 Gy per fraction) was planned to the respective target volumes and applied with concurrent platinum-based chemotherapy. The primary endpoint was time to locoregional progression from randomisation with the objective to test non-inferiority of 18F-FDG PET-based planning with a prespecified hazard ratio (HR) margin of 1·25. The per-protocol set was included in the primary analysis. The safety set included all patients receiving any study-specific treatment. Patients and study staff were not masked to treatment assignment. This study is registered with ClinicalTrials.gov, NCT00697333. FINDINGS: From May 13, 2009, to Dec 5, 2016, 205 of 311 recruited patients were randomly assigned to the conventional target group (n=99) or the 18F-FDG PET-based target group (n=106; the intention-to-treat set), and 172 patients were treated per protocol (84 patients in the conventional target group and 88 in the 18F-FDG PET-based target group). At a median follow-up of 29 months (IQR 9-54), the risk of locoregional progression in the 18F-FDG PET-based target group was non-inferior to, and in fact lower than, that in the conventional target group in the per-protocol set (14% [95% CI 5-21] vs 29% [17-38] at 1 year; HR 0·57 [95% CI 0·30-1·06]). The risk of locoregional progression in the 18F-FDG PET-based target group was also non-inferior to that in the conventional target group in the intention-to-treat set (17% [95% CI 9-24] vs 30% [20-39] at 1 year; HR 0·64 [95% CI 0·37-1·10]). The most common acute grade 3 or worse toxicity was oesophagitis or dysphagia (16 [16%] of 99 patients in the conventional target group vs 17 [16%] of 105 patients in the 18F-FDG PET-based target group); the most common late toxicities were lung-related (12 [12%] vs 11 [10%]). 20 deaths potentially related to study treatment were reported (seven vs 13). INTERPRETATION:18F-FDG PET-based planning could potentially improve local control and does not seem to increase toxicity in patients with chemoradiotherapy-treated locally advanced non-small-cell lung cancer. Imaging-based target volume reduction in this setting is, therefore, feasible, and could potentially be considered standard of care. The procedures established might also support imaging-based target volume reduction concepts for other tumours. FUNDING: German CancerAid (Deutsche Krebshilfe).
Authors: Maja Guberina; Ken Herrmann; Christoph Pöttgen; Nika Guberina; Hubertus Hautzel; Thomas Gauler; Till Ploenes; Lale Umutlu; Axel Wetter; Dirk Theegarten; Clemens Aigner; Wilfried E E Eberhardt; Martin Metzenmacher; Marcel Wiesweg; Martin Schuler; Rüdiger Karpf-Wissel; Alina Santiago Garcia; Kaid Darwiche; Martin Stuschke Journal: Sci Rep Date: 2022-10-20 Impact factor: 4.996
Authors: Maja Guberina; Kaid Darwiche; Hubertus Hautzel; Till Ploenes; Christoph Pöttgen; Nika Guberina; Ken Herrmann; Lale Umutlu; Axel Wetter; Dirk Theegarten; Clemens Aigner; Wilfried Ernst Erich Eberhardt; Martin Schuler; Rüdiger Karpf-Wissel; Martin Stuschke Journal: Eur J Nucl Med Mol Imaging Date: 2021-02-05 Impact factor: 9.236
Authors: Constantin Lapa; Ursula Nestle; Nathalie L Albert; Christian Baues; Ambros Beer; Andreas Buck; Volker Budach; Rebecca Bütof; Stephanie E Combs; Thorsten Derlin; Matthias Eiber; Wolfgang P Fendler; Christian Furth; Cihan Gani; Eleni Gkika; Anca-L Grosu; Christoph Henkenberens; Harun Ilhan; Steffen Löck; Simone Marnitz-Schulze; Matthias Miederer; Michael Mix; Nils H Nicolay; Maximilian Niyazi; Christoph Pöttgen; Claus M Rödel; Imke Schatka; Sarah M Schwarzenboeck; Andrei S Todica; Wolfgang Weber; Simone Wegen; Thomas Wiegel; Constantinos Zamboglou; Daniel Zips; Klaus Zöphel; Sebastian Zschaeck; Daniela Thorwarth; Esther G C Troost Journal: Strahlenther Onkol Date: 2021-07-14 Impact factor: 3.621