Thermotherapy for Head and Neck Cancer Patients

Locoregionally advanced head and neck cancer (LAHNC) carries a substantial risk of locoregional recurrence despite curative-intent chemoradiotherapy. Most recurrences arise within high-dose radiation regions, suggesting that additional intensification of locoregional therapy may be required. Thermotherapy (mild hyperthermia) is a non-invasive, local regional treatment that can enhance the effect of radiotherapy and chemotherapy by multiple working mechanisms, including improving tissue oxygenation, inhibiting DNA-repair mechanisms, and stimulating immune response. Before thermotherapy can be integrated into curative-intent treatment for LAHNC, its safety and tolerability in combination with (chemo)radiotherapy must be established in a prospective setting.

Previous work at Erasmus MC with the first-generation HyperCollar and the next-generation HyperCollar3D involved patients with recurrent or second-primary HNSCC receiving re-irradiation with thermotherapy. These cohorts suggested a possible dose-dependent relationship between the delivered energy and acute trismus, with fewer events observed after dose reduction. Although these findings were encouraging, the re-irradiation population is not directly representative of patients with primary LAHNC. Consequently, the optimal and safely deliverable thermotherapy dose for primary disease remains unknown, and prospective dose-finding in a chemoradiotherapy setting is needed.

The TANCAP-I trial is a prospective phase I study evaluating the safety, tolerability, and highest safely deliverable thermotherapy dose in LAHNC. The study consists of two single-arm cohorts. The primary cohort includes patients receiving definitive chemoradiotherapy and serves as the dose-escalation cohort. Dose escalation is guided by the Time-to-Event Bayesian Optimal Interval (TITE-BOIN) design, which incorporates the timing of toxicity events and allows for efficient, ethically balanced dose escalation, using mild trismus (mouth opening limited <35 mm) as the guiding DLT. The secondary cohort consists of patients receiving radiotherapy monotherapy for whom chemotherapy is contraindicated. In this group, thermotherapy safety and tolerability will be prospectively recorded without independent dose escalation.

For both groups, thermotherapy will be administered once weekly using the HyperCollar3D device, which enables precise, patient-specific deep heating of the primary tumor and involved lymph nodes. The applied thermotherapy dose is defined by Specific Absorption Rate (W/kg) in 50cc healthy tissues. Optional invasive temperature measurements may be performed in a subset of participants under separate consent.

Safety and tolerability will be assessed at baseline, throughout treatment and up to 6 months following completion. Dose-limiting toxicities (DLTs) include mild trismus and predefined severe grade III-IV toxicities. Tolerability is defined by a participant's ability to complete planned thermotherapy sessions.

Results from the TANCAP-I trial will inform the recommended phase 2 dose (RP2D) and provide the foundation for future studies evaluating whether adjuvant thermotherapy can safely enhance locoregional control and improve outcomes for patients with LAHNC.

• Thermotherapy (Other), also known as Hyperthermia: Patients will receive thermotherapy once weekly, adjuvant to standard of care (chemo)radiotherapy.
• Radiotherapy (Radiation): Standard of care radiotherapy, often 70 Gy in 35 daily fractions, 5 times per week.
• Concurrent chemoradiation (Radiation): Standard of care chemoradiotherapy, 70 Gy in 35 daily fractions, 5 times per week with concurrent platinum based chemotherapy (cisplatin or carboplatin).

Primary outcomes

• Dose Limiting Toxicity: mild trismus [8 months (treatment period + follow-up)]: 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 [8 months (treatment period + follow-up)]: 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 [7 weeks (treatment period)]: 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.

Sex: All, ages: 18 Years to any

For eligibility to participate in this study in the primary cohort, a patient must meet all following criteria:

* 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
* Locally advanced disease (stage III-IV)
* Curative intent treatment with radiotherapy and concurrent platinum based chemotherapy in primary setting
* Ability to understand the requirements of the study and to give written informed consent, as determined by the treating physician
* Written informed consent

For the parallel secondary cohort, the same inclusion criteria must be met, except for the standard of care treatment:

* Curative intent treatment with radiotherapy monotherapy in primary setting

Exclusion criteria for either cohort:

* Patients previously treated by radiation on the same target volume.
* Any condition or circumstance potentially hampering compliance with the follow-up schedule.

• Michiel Kroesen, MD, Dr., Principal investigator, Erasmus Medical Center