DAHANCA 35: Proton Versus Photon Therapy for Head-neck Cancer

Study Overview
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Brief Summary
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Patients with squamous cell carcinoma of the pharynx or larynx and an anticipated benefit of proton radiotherapy in reducing the risk of late dysphagia or xerostomia are randomized to proton or photon radiotherapy (2:1)

Detailed Description
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DAHANCA 35 is two parallel conducted, but separate randomized studies, within the same trial (DAHANCA 35D and DAHANCA 35X) by the Danish Head-Neck Cancer Study Group (DAHANCA). In patients with squamous cell carcinoma of the pharynx or larynx planned for primary radiotherapy a proton and a photon doseplan is prepared. If proton radiotherapy reduces the anticipated absolute risk of dysphagia >= grade 2 (DAHANCA scale, DAHANCA 35D) or severe xerostomia >= grade 4 (EORTC Head-Neck 35, DAHANCA 35X) more than 5%, the patient is randomised to either proton therapy or photon therapy, 2:1. The anticipated risk of xerostomia and dysphagia is estimated using Normal-Tissue Complication Models (NTCP). Patient are analysed according to the primary endpoint (dysphagia and/or xerostomia) after which they were enrolled. DAHANCA 35D is expected to enroll 360 patients and DAHANCA 35X 240 patients (in total 600 patients).

Official Title
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DAHANCA 35: A Randomized Trial of Proton Versus Photon Radiotherapy for the Treatment of Head-neck Cancer

Conditions
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Head-and-neck Cancer

Intervention / Treatment
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* Radiation: Proton radiotherapy
* Radiation: Photon radiotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with histologically proven squamous cell carcinoma of the pharynx or larynx planned for primary radiotherapy with curative intent A predicted clinical significant reduction in the risk of any of the two primary endpoints (>= grade 2 observer-rated dysphagia or grade 4 patient-reported xerostomia) after proton therapy compared to photon therapy based on comparison of the individual patient dose plans No current or earlier malignancies, which may influence treatment, evaluation or outcome of the head-neck cancer Informed consent as required by law Above 18 years of age Exclusion Criteria: Patient with cancers of the glottic larynx (stage I/II), skull base, sino-nasal area, unknown primary tumor and prior malignancies. Patients with contraindications for proton therapy. Per October 2020, this includes pacemakers, implanted defibrillators and tracheostomy Inability to attend full course of radiotherapy or follow-up visits in the outpatient clinic Distant metastasis Previous radiotherapy of the head and neck Previous surgery for the primary cancer with curative intent

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomized clinical trial
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Proton radiotherapy<br>Proton radiotherapy according to the guidelines defined by the Danish Head-Neck Cancer Group (DAHANCA). Treatment: 66-68 Gy/ 33-34 fx/ 6/W, with cisplatin 40 mg/m2/W and nimorazole to suitable patients | Radiation: Proton radiotherapy<br>* Proton radiotherapy<br>|
| Active Comparator: Photon radiotherapy<br>Photon radiotherapy according to the guidelines defined by the Danish Head-Neck Cancer Group (DAHANCA). Treatment: 66-68 Gy/ 33-34 fx/ 6/W, with cisplatin 40 mg/m2/W and nimorazole to suitable patients | Radiation: Photon radiotherapy<br>* Photon radiotherapy<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dysphagia >= grade 2 | The rate of observer-reported dysphagia >= grade 2 measured by the DAHANCA late toxicity score (grade 0-4, with 0 being best) | Six months after end of radiotherapy | 
| Xerostomia = grade 4 | The rate of patient-reported xerostomia measured by the EORTC Quality of life questionnaire (QLQ) Head-Neck (HN) 35 (grade 1-4, with 1 being best) | Six months after end of radiotherapy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Loco-regional tumor control | Time to event of local-regional failure, from date of randomization to the date of first documented loco-regional failure. Rates are estimated by the Kaplan-Meier method. Interim analyses after 100, 200 and 300 patients. Will not be reported before the primary endpoint. | Up to five years after end of radiotherapy | 
| Overall survival | From date of randomisation to date of death | Up to five years after end of radiotherapy | 
| Number of participants with disease-free survival | From date of randomization to date of death (all causes), loco-regional failure or distant failure, whichever comes first | Up to five years after end of radiotherapy | 
| Disease-specific survival | From date of randomization to date of death (by loco-regional or distant failure) | Up to five years after end of radiotherapy | 
| Acute toxicity | DAHANCA acute toxicity score (grade 0-4, 0 being best) | From the beginning of and up to two months after end of radiotherapy | 
| Late toxicity | DAHANCA late toxicity score (grade 0-4, 0 being best) | From two months to five years after end of radiotherapy | 
| EORTC QLQ-Head-Neck 35 | Swallowing and social-eating scale and specific HN35 items related to eating and pain (grade 1-4, 1 being best) | Up to ten years after end of radiotherapy | 
| EORTC C30 | Specific C30 items related to fatigue, nausea and vomiting (grade 1-4, 1 being best) | Up to ten years after end of radiotherapy | 
| MD Anderson Dysphagia Index | MD Anderson Dysphagia Index (MDADI) (grade 1-5, 1 being best) | Up to ten years after end of radiotherapy | 
| EuroQol Five Dimension Scale (EQ-5D) | Quality-adjusted life-years | Up to ten years after end of radiotherapy | 
| Composite time corrected toxicity score (CTCT) | The sum of the time corrected dysphagia score and the time corrected xerostomia score normalised to maximum score across all days using EORTC QLQ-Head-Neck 35. The measure is unit-less. | Up to five years after end of radiotherapy | 
| Modified barium swallowing | Functional swallowing test - DIGEST scale (grade 0-4, 0 being best) | One year after end of radiotherapy | 
| Stimulated whole-mouth salivary flow | Stimulated whole-mouth salivary flow | Up to five years after end of radiotherapy | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Proton radiotherapy, DAHANCA