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

Abstract

BackgroundIn 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.MethodsUPGRADE-RT is a multicenter, phase III, single-blinded, randomized controlled trial.Patients to be treated with definitive radiation therapy for a newly diagnosed stage T2-4 N0-2 M0 squamous 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).DiscussionThe 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.Trial registrationClinicalTrials.gov Identifier: NCT02442375.

Predictive value of quantitative 18F-FDG-PET radiomics analysis in patients with head and neck squamous cell carcinoma

“…4 ROC curves in the training and validation set per patient outcome prediction. Area under the incident receiver operating characteristic curve (ROC) for each final model in the training set as well as in the validation set for the prediction of recurrence, metastasis, and death within 2 years of follow-up after end of treatment patients could be candidates for treatment de-escalation studies [51,52], whereas high-risk patients could benefit from treatment escalation [53], immunotherapy [54], or surgical treatment. This optimization of treatment efficacy might also result in a beneficial reduction of costs.…”

Implications of improved diagnostic imaging of small nodal metastases in head and neck cancer: Radiotherapy target volume transformation and dose de-escalation

“…To date, there is only one ongoing multi center randomized controlled trial that investigates the safety and long-term morbidity of a gradient dose prescription with the introduction of an intermediate dose level and de-escalation of the elective dose in the treatment of oropharyngeal, laryngeal and hypopharyngeal squamous cell carcinoma (NCT02442375) [42]. In this study, named the UGPRADE-RT trail, 300 patients will be accrued in 6 head and neck cancer centers in the Netherlands and will be randomized (ratio 2:1) to gradient dose prescription or to traditional binary dose prescription [42]. Treatment arms will be balanced for tumor site, human papillomavirus (HPV)-status (in case of oropharyngeal cancers) and stage using minimization with a random element.…”

“…Currently, there are few ongoing trials investigating the safety and toxicity of de-escalation of the elective dose. The previously mentioned UPGRADE-RT trial investigates a 35 Gy (EQD2) versus 45 (EQD2) elective dose level (NCT02442375) [42]. Another prospective single-arm trial investigates de-escalation of the elective dose to 40 Gy (NCT03067610).…”

18F-FDG-PET/CT-based treatment planning for definitive (chemo)radiotherapy in patients with head and neck squamous cell carcinoma improves regional control and survival

“…Currently, there is one ongoing multicenter randomized controlled trial that investigates the safety and long-term toxicity of this graded dose prescription concept [25]. In the UPGRADE-RT trial (NCT02442375), 300 patients with stage II-IV oropharyngeal, laryngeal and hypopharyngeal SCC will be randomized (ratio 2:1) to gradient dose prescription or to traditional dose prescription, irrespective of HPV-status.…”