Moderate Whole Body Hyperthermia for Patients Undergoing Re-irradiation for Head and Neck Cancer -Influence on the Tumor Microenvironment

Study Overview
=================
Brief Summary
-----------------
The aim of the study is to determine the feasibility and efficacy of moderate weekly whole Body hyperthermia Treatment during radiochemotherapy for pre-irradiated locally or regionally recurrent head and neck squamous cell carcinomas. The Primary aim of the study is feasibility, defined as 80% of patients completing at least four applications of hyperthermia. Secondary endpoints include an increase of Tumor Perfusion by the use of hyperthermia, measured by magnetic resonance Imaging during week two of Treatment and reduction of Tumor hypoxia, measured by hypoxia specific Positron emission tomography.

Detailed Description
-----------------
Previously irradiated patients with loco/ loco-regional recurrent head and neck squamous cell carcinomas usually undergo re-irradiation. However prognosis of these patients is unfavourable, especially for non-human papilloma virus associated cancers. Moderate whole body hyperthermia will be performed by water-filtered IR-A-radiation using a Heckel-HT3000 device. Preclinical data have indicated that moderate whole body hyperthermia decreases intratumoral interstitial fluid pressure and leads to increased perfusion of the tumor. The study investigates if this holds also true in patients and leads to a marked decrease of tumor hypoxia, measured by 18F-Fluoromisonidazole PET. The Primary aim of the study is feasibility, defined as 80% of patients completing at least four applications of hyperthermia. Secondary endpoints include an increase of Tumor Perfusion by the use of hyperthermia, measured by magnetic resonance Imaging during week two of Treatment and reduction of Tumor hypoxia, measured by hypoxia specific Positron emission tomography.

Official Title
-----------------
Gemäßigte Ganzkörperhyperthermie Bei Patienten Mit Rezidivierten Plattenepithelkarzinomen Der Kopf-Hals Region Nach Hochdosierter Vorbestrahlung: Pilotstudie Zur Beeinflussung Des Tumormikromilieus.

Conditions
-----------------
Head and Neck Neoplasms, Recurrence Tumor

Intervention / Treatment
-----------------
* Device: Moderate whole body hyperthermia using water-filtered IR-A-radiation


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: patients with unresectable local, regional or loco-regional recurrent non HPV-associated squamous cell head and neck cancer with prior high-dose radiotherapy of the head and neck region time interval of 6 months to 5 years after completion of last radiotherapy of the head and neck region Completed staging examinations, preferentially 18f-fluorodeoxyglucose (FDG) PET of the whole body general health condition according to ECOG status of 0,1 or 2 age between 18 and 75 years written informed consent Exclusion Criteria: HPV associated primary tumor or recurrent tumor recurrence more than 5 years after end of previous radiotherapy Any medical circumstances impeding the application of radiotherapy, concomitant chemotherapy or whole body hyperthermia

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: Phase I feasibility study
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Single Arm<br>Additional application of weekly moderate whole-body hyperthermia concurrent to re-irradiation plus chemotherapy | Device: Moderate whole body hyperthermia using water-filtered IR-A-radiation<br>* four to six applications of whole Body hyperthermia concomitant to radiochemotherapy. Additional measurement of Perfusion and hypoxia by 18F-FMISO hypoxia PET and magnetic resonance Imaging<br>* Other names: hypoxia imaging using 18f-fluoromisonidazole before radiochemotherapy and during second week of treatment;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| feasibility of whole body hyperthermia as adjunct to radiochemotherapy | feasibility is defined as at least 4 cycles of whole body hyperthermia in 80% of patients | within 6 weeks of treatment with radiochemotherapy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Reduction of positron emission tomography (PET) measured hypoxia | defined as at least 80% reduction of the tumor to background ratio measured at the end of the second week of treatment compared to pre-treatment | 1 year (recruitment) plus additional 2 weeks (evaluation of PET parameter) | 
| magnetic resonance imaging (MRI) measured perfusion changes | measured before treatment and at the end of week 2 | 1 year (recruitment) plus additional 2 weeks (evaluation of MRI parameter) | 
| Patient reported quality of life (head and neck cancer specific quality of life) | measured by questionnaires according to EORTC (H&N35) and Transformation of absolute values to percentual values. | 3 years (i.e. recruitment plus two years of follow-up) | 
| Patient reported quality of life (general quality of life) | measured by questionnaires according to EORTC (C30) and Transformation of absolute values to percentual values. | 3 years (i.e. recruitment plus two years of follow-up) | 
| Local control after 2 years of follow-up | From start of re-irradiation. Analysis will be performed by cox regression and log-rank analyses. | 3 years (1 year recruitment, 2 years follow-up) | 
| Loco-regional control after 2 years of follow-up | From start of re-irradiation. Analysis will be performed by cox regression and log-rank analyses. | 3 years (1 year recruitment, 2 years follow-up) | 
| Overall survival after 2 years of follow-up | From start of re-irradiation. Analysis will be performed by cox regression and log-rank analyses. | 3 years (1 year recruitment, 2 years follow-up) | 
| Freedom from distant metastases after 2 years of follow-up | From start of re-irradiation. Analysis will be performed by cox regression and log-rank analyses. | 3 years (1 year recruitment, 2 years follow-up) | 
| Tumor response | Response of the irradiated tumor 3 months after end of treatment according to recist criteria | 1 year (recruitment) and 3 months (follow-up) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
head and neck squamous cell carcinoma, hyperthermia, hypoxia, 18f-fluoromisonidazole, positron emission tomography, FMISO, PET, whole body hyperthermia, local recurrence, lymph node recurrence, radiochemotherapy