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A multicentric randomized controlled phase III trial of adaptive and 18F-FDG-PET-guided dose-redistribution in locally advanced head and neck squamous cell carcinoma (ARTFORCE)

de Leeuw ALMP, Giralt J, Tao Y, Benavente S, France Nguyen TV, Hoebers FJP, Hoeben A, Terhaard CHJ, Wai Lee L, Friesland S, Steenbakkers RJHM, Tans L, Heukelom J, Kayembe MT, van Kranen SR, Bartelink H, Rasch CRN, Sonke JJ, Hamming-Vrieze O. Radiother Oncol. 2024 Jul;196:110281

Radiother Oncol. 2024 Jul:196:110281.

 doi: 10.1016/j.radonc.2024.110281. 
 

Highlights

  • This multicenter phase 3 trial compared adaptive & FDG-PET-guided radiotherapy (rRT) to conventional radiotherapy in LAHNSCC.
  • FDG-PET-guided dose escalation did not significantly improve locoregional control, progression-free or overall survival.
  • Dose escalation was successfully delivered with comparable toxicity using adaptive and dose redistribution strategies.
  • rRT improved locoregional control in patients with oropharynx (HPV+/-) and N0-1 disease, which warrants further evaluation.

 

Abstract

Background and purpose

This multicenter randomized phase III trial evaluated whether locoregional control of patients with LAHNSCC could be improved by fluorodeoxyglucose-positron emission tomography (FDG-PET)-guided dose-escalation while minimizing the risk of increasing toxicity using a dose-redistribution and scheduled adaptation strategy.

Materials and methods

Patients with T3-4-N0-3-M0 LAHNSCC were randomly assigned (1:1) to either receive a dose distribution ranging from 64-84 Gy/35 fractions with adaptation at the 10th fraction (rRT) or conventional 70 Gy/35 fractions (cRT). Both arms received concurrent three-cycle 100 mg/m2 cisplatin. Primary endpoints were 2-year locoregional control (LRC) and toxicity. Primary analysis was based on the intention-to-treat principle.

Results

Due to slow accrual, the study was prematurely closed (at 84 %) after randomizing 221 eligible patients between 2012 and 2019 to receive rRT (N = 109) or cRT (N = 112). The 2-year LRC estimate difference of 81 % (95 %CI 74–89 %) vs. 74 % (66–83 %) in the rRT and cRT arm, respectively, was not found statistically significant (HR 0.75, 95 %CI 0.43–1.31, P=.31). Toxicity prevalence and incidence rates were similar between trial arms, with exception for a significant increased grade ≥ 3 pharyngolaryngeal stenoses incidence rate in the rRT arm (0 versus 4 %, P=.05). In post-hoc subgroup analyses, rRT improved LRC for patients with N0-1 disease (HR 0.21, 95 %CI 0.05–0.93) and oropharyngeal cancer (0.31, 0.10–0.95), regardless of HPV.

Conclusion

 Adaptive and dose redistributed radiotherapy enabled dose-escalation with similar toxicity rates compared to conventional radiotherapy. While FDG-PET-guided dose-escalation did overall not lead to significant tumor control or survival improvements, post-hoc results showed improved locoregional control for patients with N0-1 disease or oropharyngeal cancer treated with rRT.