Head and Neck Cancer, Head and Neck Squamous Cell Carcinoma, Hypopharyngeal Carcinoma, Laryngeal Carcinoma, Locally Advanced Head and Neck Carcinoma, Oral Cavity Carcinoma, Oropharyngeal Carcinoma
Conditions
Keywords
Hyperthermia, Thermotherapy, Phase 1 trial, Chemoradiotherapy, Radiosensitization, Safety, Tolerability, Locoregional Control, Locally advanced cancer
Brief summary
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.
Detailed description
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.
Interventions
OTHERThermotherapy
Patients will receive thermotherapy once weekly, adjuvant to standard of care (chemo)radiotherapy.
RADIATIONRadiotherapy
Standard of care radiotherapy, often 70 Gy in 35 daily fractions, 5 times per week.
RADIATIONConcurrent chemoradiation
Standard of care chemoradiotherapy, 70 Gy in 35 daily fractions, 5 times per week with concurrent platinum based chemotherapy (cisplatin or carboplatin).
Sponsors
Erasmus Medical Center
Dutch Cancer Society
Sensius BV
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
The trial includes two single-arm interventional cohorts. In both groups, patients will recieve the same intervention, being thermotherapy.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
Netherlands
Contacts
CONTACTMichiel Kroesen, MD, Dr.
CONTACTTessa L. Coenraad, MSc
PRINCIPAL_INVESTIGATORMichiel Kroesen, MD, Dr.
Erasmus Medical Center
Outcome results
None listed