MRI - Guided Adaptive RadioTHerapy for Reducing XerostomiA in Head and Neck Cancer (MARTHA-trial)

Study Overview
=================
Brief Summary
-----------------
Radiotherapy is the main treatment for locally advanced squamous cell carcinoma of the head and neck (SCCHN). Many advances regarding tumor control and patient survival have been made over the past decades. However, treatment-induced toxicity remains a crucial problem, leading to reduced quality of life and permanent impairment for many survivors. Xerostomia is up to this day the leading cause of late toxicity for these patients. Toxicity has been reduced by implementation of modern image guided radiotherapy (IGRT) and intensity-modulated radiotherapy (IMRT), but the low soft-tissue contrast of routine x-ray image guidance does not allow exact planning adaptation and daily imaging is associated with high radiation exposure. Furthermore, despite the routinely use of IMRT, rates of clinically relevant xerostomia (i.e. grade 2 or worse) are still common and reported in approximately 38%. Recently developed hybrid machines (MRidian®-CE approval since 2016), consisting of a linear accelerator and an integrated low-field MRI, could allow a) better visualization of tumor and organs at risk, such as parotid glands during patient positioning and daily treatment, b) daily imaging without additional radiation exposure, c) narrowest established safety margins for the treatment volumes, and finally d) repetitive adaptation of target volumes according to changes in patient weight and tumor anatomy during the radiotherapy course. These procedures would facilitate a high-precision treatment and help reduce dose exposure of critical structures.

Official Title
-----------------
MARTHA-trial: MRI - Guided Adaptive RadioTHerapy for Reducing XerostomiA in Head and Neck Cancer Including Longitudinal Evaluation of the Patient's Immune Profile Under Radiotherapy

Conditions
-----------------
Head and Neck Cancer, Xerostomia Due to Radiotherapy

Intervention / Treatment
-----------------
* Other: Pre-defined MR-linac based IGRT and plan adaptation protocol
* Diagnostic Test: salivary flow measurements


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Histologically proven squamous cell carcinoma of the oral cavity oro- or hypopharynx or larynx, Stages II-IVB, requiring definitive or postoperative bilateral neck irradiation Age ≥ 18 years, no upper age limit ECOG-Performance score < 2 The trial is open to both genders History/physical examination within 30 days prior to registration by head and neck surgeon and Radiation Oncologist FDG-PET-CT-scan within 30 days prior to registration Exclusion Criteria: Not adequately controlled hepatitis or HIV disease (HIV-viral load detectable) Second non-controlled malignancy other than basalioma or cervical/genital/anal in situ neoplasia during the last 2 years before enrollment Bilirubin > 2,0 mg/dl, SGOT, SGPT, AP, Gamma-GT >3x norm, GFR < 30 ml/min leucocytes <3,5 x 10^9/l or platelets < 100 x 10^9/l or neutrophiles < 1,5 x 10^9/l Other severe comorbidities or psychic disorders (e.g. myocardial infraction within 6 months prior to registration, permanent cardiac arrhythmia, COPD Gold IV, hepatitis B/C, schizophrenia, ongoing alcohol abuse etc.) Lactating and pregnant women Previous radiotherapy of the neck Contraindications for MRI (e.g. pacemaker/ICD, tattoos, cochlear or other not MR-compatible implants) Pre-existing salivary gland disease (e.g. Sjorgen's-syndrome) or xerostomia-inducing medication (e.g. anticholinergic medication like tricyclic antidepressant) Claustrophobia

Ages Eligible for Study
-----------------
Minimum Age: 18 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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Single Intervention Arm<br>daily imaging for MR-IGRT once weekly offline plan adaptation subjective/objective LENT-SOMA xerostomia-evaluation including flow measurements at baseline, 6 month-, 12 month- and 24 month-follow up EORTC-QoL questionnaires at baseline, 6 month-, 12 month- and 24 month-follow up | Other: Pre-defined MR-linac based IGRT and plan adaptation protocol<br>* daily MR-imaging/MR guided radiotherapy once weekly offline plan adaptation to a total of 6<br>Diagnostic Test: salivary flow measurements<br>* baseline, 6 month-, 12 month- and 24 month-follow up salivary flow measurements and LENT-SOMA subjective/objective evaluation of xerostomia<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of patients with xerostomia of grade 2 or worse | will be evaluated by the LENT-SOMA (Late Effects Normal Tissue Task Force (LENT)-Subjective, Objective, Management, Analytic (SOMA)) side-effect scale: SOM (1)-(4) (higher score represents higher grade xerostomia), A: objective flow measurement (1) 76-95%, (2) 51-75%, (3) 26-50%, (4) 0-25% | 12 month-follow up | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of patients with xerostomia of grade 2 or worse | will be evaluated by the LENT-SOMA (Late Effects Normal Tissue Task Force (LENT)-Subjective, Objective, Management, Analytic (SOMA)) side-effect scale: SOM (1)-(4) (higher score represents higher grade xerostomia), A: objective flow measurement (1) 76-95%, (2) 51-75%, (3) 26-50%, (4) 0-25% | 6- and 24-months follow up | 
| Locoregional control rate as defined from treatment start to histologically confirmed tumor progression, persistence or last follow up | as defined from treatment start to histologically confirmed tumor progression, persistence or last follow up | 2-years | 
| Overall survival | as defined from treatment start to death from any cause or last follow up | 2-years | 
| Description of Quality of life - scoring 6 months after treatment, assessed according to the general EORTC-quality of life core questionnaire QLQ C30 (overall quality of life for cancer patients) | Questionnaire consists of 30 questions with a maximal score of 100. Absolute scores after linear transformation will be reported as descriptive statistics The QLQ-C30 is composed of both multi-item scales and single-item measures. These include five functional scales, three symptom scales, a global health status / QoL scale, and six single items. Each of the multi-item scales includes a different set of items - no item occurs in more than one scale. All of the scales and single-item measures range in score from 0 to 100. A high scale score represents a higher response level. A high score for a functional scale represents a high / healthy level of functioning, a high score for the global health status / QoL represents a high QoL, but a high score for a symptom scale / item represents a high level of symptomatology / problems. See also: https://www.eortc.org/app/uploads/sites/2/2018/02/SCmanual.pdf | 6 months after treatment | 
| Description of Head-Neck cancer related symptoms 6 months after treatment, assessed according to the specific EORT-head and neck quality of life supplementary questionnaire HN35 | total scoring of an additional 35 questions with a similar approach to that of the core questionnaire will be reported as descriptive statistics | 6 months after treatment | 
| Description of Quality of life - scoring 12 months after treatment, assessed according to the general EORTC-quality of life core questionnaire QLQ C30 (overall quality of life for cancer patients) | Questionnaire consists of 30 questions with a maximal score of 100. Absolute scores after linear transformation will be reported as descriptive statistics The QLQ-C30 is composed of both multi-item scales and single-item measures. These include five functional scales, three symptom scales, a global health status / QoL scale, and six single items. Each of the multi-item scales includes a different set of items - no item occurs in more than one scale. All of the scales and single-item measures range in score from 0 to 100. A high scale score represents a higher response level. A high score for a functional scale represents a high / healthy level of functioning, a high score for the global health status / QoL represents a high QoL, but a high score for a symptom scale / item represents a high level of symptomatology / problems. See also: https://www.eortc.org/app/uploads/sites/2/2018/02/SCmanual.pdf | 12 months after treatment | 
| Description of Head-Neck related symptoms 12 months after treatment, assessed according to the specific EORT-head and neck quality of life supplementary questionnaire HN35 | total scoring of an additional 35 questions with a similar approach to that of the core questionnaire will be reported as descriptive statistics | 12 months after treatment | 
| Description of Quality of life - scoring 24 months after treatment, assessed according to the general EORTC-quality of life core questionnaire QLQ C30 (overall quality of life for cancer patients) | Questionnaire consists of 30 questions with a maximal score of 100. Absolute scores after linear transformation will be reported as descriptive statistics The QLQ-C30 is composed of both multi-item scales and single-item measures. These include five functional scales, three symptom scales, a global health status / QoL scale, and six single items. Each of the multi-item scales includes a different set of items - no item occurs in more than one scale. All of the scales and single-item measures range in score from 0 to 100. A high scale score represents a higher response level. A high score for a functional scale represents a high / healthy level of functioning, a high score for the global health status / QoL represents a high QoL, but a high score for a symptom scale / item represents a high level of symptomatology / problems. See also: https://www.eortc.org/app/uploads/sites/2/2018/02/SCmanual.pdf | 24 months after treatment | 
| Description of Head-Neck related symptoms 24 months after treatment, assessed according to the specific EORT-head and neck quality of life supplementary questionnaire HN35 | total scoring of an additional 35 questions with a similar approach to that of the core questionnaire will be reported as descriptive statistics | 24 months after treatment | 
| Toxicity rates | evaluated by the CTCAE v5-questionnaires | weekly during radiotherapy and at 3, 6, 9, 12, 15, 18, 21 and 24 months |