Thermotherapy for Locally Advanced Head and Neck Cancer Patients in Primary Setting - a Phase I Dose-finding Study

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.