Original Article
18F-FDG-PET guided vs whole tumour radiotherapy dose escalation in patients with locally advanced non-small cell lung cancer (PET-Boost): Results from a randomised clinical trial

https://doi.org/10.1016/j.radonc.2023.109492Get rights and content

Highlights

  • Multi-center trial testing two personalised radiotherapy dose-escalation strategies.

  • 107 patients with stage II/III disease and a large primary tumour were randomised.

  • 24 fractions escalated dose to the whole primary tumour or the PET-subvolume.

  • Freedom from local failure rates were high (1-year > 90 %) in both arms.

  • Unexpected increased rates of grade 5 events were seen in both arms.

Abstract

Background and purpose

We aimed to assess if radiation dose escalation to either the whole primary tumour, or to an 18F-FDG-PET defined subvolume within the primary tumour known to be at high risk of local relapse, could improve local control in patients with locally advanced non-small-cell lung cancer.

Materials and methods

Patients with inoperable, stage II-III NSCLC were randomised (1:1) to receive dose-escalated radiotherapy to the whole primary tumour or a PET-defined subvolume, in 24 fractions.

The primary endpoint was freedom from local failure (FFLF), assessed by central review of CT-imaging. A phase II ‘pick-the-winner’ design (alpha = 0.05; beta = 0.80) was applied to detect a 15 % increase in FFLF at 1-year. ClinicalTrials.gov:NCT01024829.

Results

150 patients were enrolled. 54 patients were randomised to the whole tumour group and 53 to the PET-subvolume group. The trial was closed early due to slow accrual. Median dose/fraction to the boosted volume was 3.30 Gy in the whole tumour group, and 3.50 Gy in the PET-subvolume group. The 1-year FFLF rate was 97 % (95 %CI 91–100) in whole tumour group, and 91 % (95 %CI 82–100) in the PET-subvolume group. Acute grade ≥ 3 adverse events occurred in 23 (43 %) and 20 (38 %) patients, and late grade ≥ 3 in 12 (22 %) and 17 (32 %), respectively. Grade 5 events occurred in 19 (18 %) patients in total, of which before disease progression in 4 (7 %) in the whole tumour group, and 5 (9 %) in the PET-subvolume group.

Conclusion

Both strategies met the primary objective to improve local control with 1-year rates. However, both strategies led to unexpected high rates of grade 5 toxicity. Dose differentiation, improved patient selection and better sparing of central structures are proposed to improve dose-escalation strategies.

Section snippets

Materials and methods

This phase 2, open-label, randomised, investigator-initiated clinical trial was part of the European ARTFORCE consortium, and conducted at seven sites in five countries. The trial protocol, with all in- and exclusion criteria, is provided in Appendix A.

In summary, inclusion criteria were age ≥ 18 years, inoperable stage II-III pathologically confirmed NSCLC, a primary tumour ≥ 4 cm in diameter with no satellite lesions and a SUVmax ≥ 5 on the pre-treatment 18F-FDG-PET scan (to allow targeting

Results

Hundred-fifty patients were enrolled between April 23, 2010 and September 15, 2017 from five European institutions (Fig. 2, Appendix Table B.2). As a result of slower accrual than anticipated, the trial management group decided to close the trial early. Of 150 patients included, 107 were eligible for dose escalation and were subsequently randomised: 54 to receive escalated-dose to the whole tumour, and 53 to the PET-subvolume. Here we publish analysis of data reported as of April 29, 2021. The

Discussion

Local control is an important outcome associated with survival after radiotherapy for LA-NSCLC.[18], [19] In addition to homogeneously increasing radiation dose, it was hypothesised that increasing the radiation dose to areas at high risk of local relapse defined by 18F-FDG-PET subvolumes could improve the cure rate. We investigated the efficacy and safety of a personalised, integrated escalation of radiotherapy dose delivered either to the primary tumour as a whole or to the PET-subvolume. In

Role of the funder/sponsor

The EC and KWF had no role in the design and conduct of the study; collection, management, analysis and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgments

We are grateful for funding by the European Commission’s Seventh Framework Programme (ARTFORCE, grant agreement no 257144) and the Dutch Cancer Society (KWF) (project no 2010-4675).

The content of this report is the sole responsibility of the authors and does not necessarily reflect the official views of the EC or KWF.

Professor Sonke is supported by a grant from Elekta AB.

Professor Faivre-Finn is supported by a grant from the NIHR Manchester Biomedical Research Centre.

We thank the patients and

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