This phase I, single-center study evaluates the safety, tolerability, and recommended phase II dose (RP2D) of mild hyperthermia (thermotherapy) when added to standard-of-care treatment in patients with locally advanced head and neck squamous cell carcinoma (LAHNSCC). Tumor recurrence remains common despite chemoradiotherapy, highlighting the need for treatment intensification. Thermotherapy, which increases tumor temperature to 39-45°C, may enhance the effect of the treatment.
The study consists of two components: (1) a dose-escalation cohort in patients receiving definitive chemoradiotherapy, using a Time-to-Event Bayesian Optimal Interval (TiTE-BOIN) design to determine the RP2D based on dose-limiting toxicities (DLTs) and treatment tolerability; and (2) a parallel cohort of patients receiving radiotherapy alone, in whom thermotherapy is administered at dose levels previously shown to be safe and tolerable in the chemoradiotherapy cohort to evaluate tolerability in this patient population.
Besides the safety and tolerability of the thermotherapy RP2D, the secondary objectives include evaluation of safety in patients receiving radiotherapy alone, as well as exploratory assessment of tumor control and survival outcomes.
This study aims to support the development of safe and feasible thermotherapy-based treatment strategies to improve locoregional control and outcomes in patients with LAHNSCC.
Age ≥ 18 years
WHO 0-1
Maximal mouth opening of ≥ 40 mm for women and ≥ 45 mm for men before treatment
Squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx and larynx proven by cytology/histology
Patients previously treated by radiation on the same target volume.
Any condition or circumstance potentially hampering compliance with the follow-up schedule.
Parallel
Thermotherapy
Other interventionPatients will receive thermotherapy once weekly, adjuvant to standard of care (chemo)radiotherapy.
Radiotherapy
RadiationStandard of care radiotherapy, often 70 Gy in 35 daily fractions, 5 times per week.
Concurrent chemoradiation
RadiationStandard of care chemoradiotherapy, 70 Gy in 35 daily fractions, 5 times per week with concurrent platinum based chemotherapy (cisplatin or carboplatin).
Dose Limiting Toxicity: mild trismus
Trismus is objectively scored by measuring the mouth opening using a caliper according to standardized protocol. When the mouth opening is \<35 mm, the patient is scored with trismus and this will be a dose limiting toxicity (DLT). Using a Time to Event Bayesian Optimal Interval Design, we will determine dose (de)escalation with an incidence threshold of 55% in the primary cohort.
Dose Limiting Toxicities
Upon occurence of the following DLTs, the dose level will be stopped immediately for further inclusion: • Grade III trismus • Grade IV mucositis • Grade IV dermatitis • Grade III or IV osteo- or soft tissue necrosis • Grade IV Burn wound • Grade IV tumor hemorrhage • Grade IV laryngeal edema
Tolerability of thermotherapy dose
Tolerability of the thermotherapy dose is defined as the ability of ≥66% of the patients to successfully complete ≥40% of the planned thermotherapy fractions. If the dose level does not meet these criteria, the dose level is considered intolerable and is eliminated.
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