Uniform FDG-PET guided GRAdient Dose prEscription to reduce late Radiation Toxicity (UPGRADE-RT): study protocol for a randomized clinical trial with dose reduction to the elective neck in head and neck squamous cell carcinoma.
In definitive radiation therapy for head and neck cancer, clinically uninvolved cervical lymph nodes are irradiated with a so-called 'elective dose' in order to achieve control of clinically occult metastases. As a consequence of high-resolution diagnostic imaging, occult tumor volume has significantly decreased in the last decades. Since the elective dose is dependent on occult tumor volume, the currently used elective dose may be higher than necessary. Because bilateral irradiation of the neck contributes to dysphagia, xerostomia and hypothyroidism in a dose dependent way, dose de-escalation to these regions can open a window of opportunity to reduce toxicity and improve quality of life after treatment.



UPGRADE-RT is a multicenter, phase III, single-blinded, randomized controlled trial. Patients to be treated with definitive radiation therapy for a newly diagnosed stage T2-4N0-2M0squamous cell carcinoma of the oropharynx, hypopharynx or larynx are eligible. Exclusion criteria are recurrent disease, oncologic surgery to the head and neck area, concomitant chemotherapy or epidermal growth factor receptor inhibitors. In total, 300 patients will be randomized in a 2:1 ratio to a treatment arm with or without de-escalation of the elective radiation dose and introduction of an intermediate dose-level for selected lymph nodes. Radiation therapy planning FDG-PET/CT-scans will be acquired to guide risk assessment of borderline-sized cervical nodes that can be treated with the intermediate dose level. Treatment will be given with intensity-modulated radiation therapy or volumetric arc therapy with simultaneous-integrated boost using an accelerated fractionation schedule, 33 fractions in 5 weeks. The primary endpoint is 'normalcy of diet' at 1 year after treatment (toxicity). The secondary endpoint is the actuarial rate of recurrence in electively irradiated lymph nodes at 2 years after treatment (safety).



The objective of the UPGRADE-RT trial is to investigate whether de-escalation of elective radiation dose and the introduction of an intermediate dose-level for borderline sized lymph nodes in the treatment of head and neck cancer will result in less radiation sequelae and improved quality of life after treatment without compromising the recurrence rate in the electively treated neck.



ClinicalTrials.gov Identifier: NCT02442375 .
Department of radiation oncology, Radboud University Medical Center, huispost 874, P.O. Box 9101, Nijmegen, 6500, HB, The Netherlands. sven.vandenbosch@radboudumc.nl.
Sven
S
van den Bosch
Department of radiation oncology, Radboud University Medical Center, huispost 874, P.O. Box 9101, Nijmegen, 6500, HB, The Netherlands.
Tim
T
Dijkema
Department of radiation oncology, Radboud University Medical Center, huispost 874, P.O. Box 9101, Nijmegen, 6500, HB, The Netherlands.
Martina C
MC
Kunze-Busch
Department of radiation oncology, University Medical Center Utrecht, Utrecht, The Netherlands.
Chris H J
CH
Terhaard
Department of radiation oncology, University Medical Center Utrecht, Utrecht, The Netherlands.
Cornelis P J
CP
Raaijmakers
Department of radiation oncology, University Medical Center Utrecht, Utrecht, The Netherlands.
Patricia A H
PA
Doornaert
Department of radiation oncology (MAASTRO), Research Institute GROW, Maastricht University, Maastricht, The Netherlands.
Frank J P
FJ
Hoebers
Department of radiation oncology, VU University Medical Center, Amsterdam, The Netherlands.
Marije R
MR
Vergeer
Department of radiation oncology, Radiotherapiegroep, Arnhem, The Netherlands.
Bas
B
Kreike
Department of radiation oncology, Radiotherapeutisch Instituut Friesland, Leeuwarden, The Netherlands.
Oda B
OB
Wijers
Department of nuclear medicine, Radboud University Medical Center, Nijmegen, The Netherlands.|The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London, UK.
Wim J G
WJ
Oyen
Department of radiation oncology, Radboud University Medical Center, huispost 874, P.O. Box 9101, Nijmegen, 6500, HB, The Netherlands.
Johannes H A M
JH
Kaanders
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002294:Carcinoma, Squamous Cell / Q000000981:diagnostic imaging / Q000532:radiotherapy*; D005260:Female; D019788:Fluorodeoxyglucose F18; D006258:Head and Neck Neoplasms / Q000000981:diagnostic imaging / Q000532:radiotherapy*; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D049268:Positron-Emission Tomography / Q000379:methods*; D011788:Quality of Life; D011832:Radiation Injuries / Q000517:prevention & control; D011879:Radiotherapy Dosage; D011880:Radiotherapy Planning, Computer-Assisted / Q000379:methods; D016037:Single-Blind Method
D019788:Fluorodeoxyglucose F18
Accelerated radiation therapy; Dose de-escalation; Dose reduction; Elective nodes; Euality of life; FDG-PET; Head and neck cancer; Squamous cell carcinoma