Protocol compliance in a multicentric phase III trial investigating scheduled adaptive radiotherapy and dose painting in head and neck cancer.

Purpose: To report on quality assurance (QA) and protocol adherence (PA) in a multicentre phase III trial for head and neck cancer, evaluate patterns of protocol deviations and investigate the effect of PA on study outcomes.
Methods: All 221 patients from the ARTFORCE trial (NCT01504815) were included in this study. Pre- and per-treatment QA measures included protocol guidelines, a dummy run, early case reviews and trial meetings. FDG-PET-guided dose painting and scheduled adaptive radiotherapy were reviewed in patients in the experimental arm (eRT). Patient and disease characteristics, as well as institutes' accrual rate and timing were examined for correlation with PA. Cox regression was used to determine the impact of PA on outcome.
Results: The dummy run was completed in all nine institutes and early case reviews were completed in five out of nine institutes that contributed 190 out of 221 patients. Among all patients randomized to eRT, 64 % had at least one deviation of the experimental trial components. Protocol deviations were significantly correlated with the institute patients were treated at (Cramer'sV 0.34-0.48). Despite early identification of institute-specific deviations in QA, these continued during the trial. No significant associations were seen between deviations and accrual timing or rate (P ≥ 0.26). Within eRT, no significant relation was observed between experimental PA and locoregional control (LRC), the primary endpoint of the trial (P≥.15).
Conclusions: Despite QA, protocol deviations persisted during the trial, which were mostly institute-specific. However, deviations of the experimental treatment strategy did not significantly impact LRC and therefore the trial conclusion.
Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [Anna Liza M.P. de Leeuw; PhD-student at the Antoni van Leeuwenhoek hospital. Jordi Giralt; Radiation oncologist at the Vall d'Hebron Unniversity Hospital. Yungan Tao; Radiation oncologist at the Institut Gustave roussy. Sergi Benavente; Radiation oncologist at the Vall d'Hebron Unniversity Hospital. Thanh-Vân France Nguyen; Radiation oncologist at the Institut Gustave roussy. Frank J.P. Hoebers; Radiation oncologist at the Maastro Center. Ann Hoeben; Clinical oncologist at the Maastro Center. Chris H.J. Terhaard; retired radiation oncologist at the University Medical Center Utrecht. Lip Wai Lee; Radiation oncologist at the Christie NHS Foundation Trust. Signe Friesland; Radiation oncologist at the Karolinska Comprehensive Cancer Center. Roel J.H.M. Steenbakkers; Radiation oncologist at the University Medical Center Groningen. Lisa Tans; Radiation oncologist at the Erasmus Medical Center. Simon R. van Kranen; Postdoc at the Antoni van Leeuwenhoek hospital. Jeroen B van de Kamer; Medical physicist at the Antoni van Leeuwenhoek hospital. Harry Bartelink; retired radiation oncologist at the Antoni van Leeuwenhoek hospital. Coen R.N. Rasch; Professor at Leiden University; Radiation oncologist at the Leiden University Medical Center; Jan-Jakob Sonke; Professor by special appointment at University of Amsterdam; senior group leader at Antoni van Leeuwenhoek hospital; ownership of patent/license fees/copyright at Elekta AB; member of the international advisory board at Physics, medicine and biology; editorial board member of Physics & Imaging in Radiation Oncology. Olga Hamming-Vrieze; Radiation oncologist at Antoni van Leeuwenhoek hospital].
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