The aim for the present study named RAREST (RAdiotherapy RElated Skin Toxicity) is to compare the new dressing with the standard skin care. 168 patients receiving radiotherapy alone or radiochemotherapy for locally advanced head-and-neck cancer will be included. The primary aim is to investigate the rate of patients experiencing severe, stressful radiation dermatitis. The skin status will daily be inspected and assessed by specially trained doctors and nursing staff.

It is expected that the new self-adhesive dressing is superior to standard care with respect to prevention of grade ≥2 radiation dermatitis in patients receiving radiotherapy or radio(chemo)therapy for a head-and-neck tumor. Thus, the dressing would be well qualified to become a new standard procedure at the skin care of patients with a head-neck tumor.

The primary goal of this randomized trial is to demonstrate that Mepitel® Film is superior to Standard Care with respect to prevent grade ≥2 radiation dermatitis (RD) in patients receiving radio(chemo)therapy up to 50 Gy for locally advanced squamous cell carcinoma of the head-and-neck (SCCHN).

The primary aim of this randomized multinational multicenter trial is to investigate the rate of patients experiencing grade ≥2 RD (CTCAE v4.03) until 50 Gy of radiotherapy (RT).

Evaluation until 50 Gy of RT is the primary endpoint, since up to 50 Gy, the irradiated volume includes the primary tumor and the bilateral cervical and supraclavicular lymph nodes, and, therefore, is almost identical in all patients. After 50 Gy, the irradiated volume is much more individual, depending on location and size of the primary tumor, involvement of lymph nodes, and the treatment approach (definitive vs. adjuvant).

This is a randomized, active-controlled, parallel-group trial, comparing the following treatments of radiation related skin toxicity in patients with head-and-neck cancer:

Mepitel® Film (Arm A) vs. Standard Care (Arm B). About 4 contributing centers are planned to include an average of 21 patients/year. The recruitment duration of 168 patients = 24 months. The follow-up period will be 3 weeks. The total running time = 25 months.

Stratification by prognostic factors:

1. Tumor site: oropharynx/oral cavity vs. hypopharynx/larynx
2. Treatment approach: radiochemotherapy vs. RT alone
3. Participating site In case of very small groups due to uneven distribution of stratification groups, strata might be connected for Analysis (before data base lock and final analysis of the data).

This trial is for patients receiving definitive or adjuvant radio(chemo)therapy for locally advanced (SCCHN).

Radiotherapy RT is administered using conventional fractionation (5 x 2.0 Gy per week). In all patients, the initial target volume includes the region of the primary tumor plus bilateral cervical and supraclavicular lymph nodes up to 50 Gy.

Patients treated with adjuvant RT following complete resection of the primary tumor and the involved lymph nodes (R0-resection) receive a radiation boost of 10 Gy (5 x 2.0 Gy per week) to the regions of the primary tumor and the involved lymph nodes.

In case of a microscopically incomplete resection (R1-resection), the boost dose to the primary tumor region is 16 Gy.

In case of extra-capsular spread (ECS) of lymph nodes, the lymph nodes showing ECS receive an additional boost of 6 Gy (i.e. a cumulative boost dose of 16 Gy).

Patients receiving definitive RT, receive a boost of 10 Gy (5 x 2.0 Gy/week) to the primary tumor, the involved lymph nodes, and the lymph node levels adjacent to the involved lymph nodes. An additional boost of another 10 Gy (5 x 2.0 Gy/week) is administered to the primary tumor and the involved lymph nodes.

Treatment should be performed as either intensity-modulated RT (IMRT) or volumetric modulated arc therapy (VMAT) RT.

The rate of patients experiencing grade ≥2 RD (CTCAE v4.03) until the 5. week of therapy (50 Gy) is in focus of this clinical study. Additionally another 2 weeks of RT (up to 70 Gy) might be performed. This further treatment will be conducted in accordance with common treatment guidelines. The treatment of the patients > 50 Gy will not be analyzed within this study. The occurrence of adverse events (AEs) and serious adverse events (SAEs) will be documented for the duration of RT. The final dose of RT will be documented in the Case Report Form (CRF).

Concomitant Chemotherapy In patients who receive definitive RT, concomitant chemotherapy with cisplatin or carboplatin is administered. The cumulative cisplatin or carboplatin dose at the end of the 5. week of RT (50 Gy) should be 200 mg/m2. This cumulative dose may either be achieved with 20 mg/m2 given with RT fractions 1-5 and 21-25, 25 mg/m2 given with RT fractions 1-4 and 21-24, or weekly doses of 40 mg/m2.

Cisplatin or carboplatin will be administered after saline hydration as intravenous bolus infusion. The saline hyper-hydration will be given according to the investigational centre's routine. All patients treated with cisplatin or carboplatin in addition to RT must receive adequate anti-emetic therapy prior to the administration of cisplatin or carboplatin. It is recommended that a 5-Hydroxytryptamine type 3 (5HT3) antagonist (e.g. granisetron) and dexamethasone 8 mg i.v. are administered prior to each cycle of treatment.

Quality assurance plan:

Monitoring: The Center for Clinical Studies (ZKS) Lübeck will conduct clinical on-site monitoring at the German sites according to common guidelines and regulations.

According to SOPs, all trial specific monitoring activities will be defined before starting the trial and documented in writing (monitoring manual).

Patient registration and randomization The patients will be assigned two code numbers: the number of the contributing center plus a patient identification (ID) number, continuously ascending, starting with 001.

After registration, patients will be randomized in a 1:1 ratio to receive either Mepitel® Film (Arm A) or Standard Care (Arm B) for treatment of radiation related skin toxicity.

A stratified randomization will be performed in blocks. The stratification will be conducted for about 4 centers, 2 treatment approaches, 2 tumor sites.

The randomization will be performed centrally at the ZKS via fax. The proceeding is based on standard operating procedures (SOPs) of the ZKS. .

Sample size calculation The primary goal of this randomized trial is to demonstrate that Mepitel® Film is superior to Standard Care with respect to prevent grade ≥2 RD in patients receiving radio(chemo)therapy up to 50 Gy for locally advanced SCCHN.

The null hypothesis of equal rates of grade ≥2 skin toxicity is tested against the two-sided alternative hypothesis of different rates. Based on this hypothesis system, the sample size required for this trial is calculated taking into account the following assumptions:

• A Chi-square Test will be applied
• The two-sided significance level is set to 5%
• In patients treated with radio(chemo)therapy for locally advanced SCCHN, previous studies have suggested rates of grade ≥2 skin toxicity of 86-92% if standard skin care was administered.
• Based on these data, a rate of grade ≥2 skin toxicity of 85% can be assumed in the reference group ("worst-case"), i.e. in patients receiving standard care for skin toxicity.
• Administration of Mepitel® Film will be considered to be clinically relevant, if the rate of grade ≥2 skin toxicity can be reduced to 65%.
• The power to yield statistical significance if the the difference in rates is in fact 20 percentage points is set to 80%.

Based on these assumptions, 80 patients are required per study arm within the Full Analysis Set (FAS). Taking into account that 5% of patients will not qualify for FAS, a total of 168 patients should be randomized.

Statistical analysis General Considerations All data recorded in the CRFs describing the study population, toxicity and quality of life (QoL) will be analyzed descriptively. Categorical data will be presented in contingency tables with frequencies and percentages. Continuous data will be summarized with at least: frequency (n), median, quartiles, mean, SD, min and max. Number of patients with protocol deviations and listings describing the deviations will be provided.

In general, chi-square tests will be used to compare percentages in a two-by-two contingency table, replaced by Fisher´s exact test if the expected frequency in at least one cell of the associated table is less than 5. Stratified two-by-two contingency tables will be analyzed using Cochran-Mantel-Haenszel tests. Logistic regression models serve as multivariable methods for binary endpoint data. Comparison of ordinal variables between treatment arms will be performed using the asymptotic Wilcoxon-Mann-Whitney test, replaced by its exact version in case of ordinal categories with small number of categories and/or sparse data within categories. Any shift in location of quantitative variables between study groups will be performed with Wilcoxon-Mann-Whitney tests as well.

Time-to-event data will be analyzed by Kaplan-Meier methods, when merely non-informative censoring occurs. For statistical comparison, the logrank-test will be provided supplemented by multivariate Cox proportional hazards models.

The data analysis will be performed according to the statistical analysis plan (SAP), finalised prior to database lock and prior to statistical analysis.

Primary Endpoint The rates of patients experiencing grade ≥2 RD in patients receiving radio(chemo)therapy up to 50 Gy will be statistically compared using the Cochran-Mantel-Haenszel Chi-square test on a two-sided significance level of 5%. This test is the natural non-parametric extension of the Chi-square test for testing the treatment effect, while adjusting for the effects of the stratification variables used for randomization. For further assessment of the robustness of the results, a logistic regression model for grade ≥2 RD will be applied including the parameters used for stratification. In addition, a model including also additional patient characteristics will be fitted.

The confirmatory evaluation will be performed within the FAS, the Per Protocol Set serves for further sensitivity analyses.

Secondary endpoints Time to grade 2 RD until 50 Gy of RT is defined as the time from start of RT to at least grade 2 RD. Patients without grade 2 RD will be censored after the date of receiving a total dose of 50 Gy.

The distribution of the time to grade 2 RD until administration of 50 Gy will be described using Kaplan-Meier methods. These analyses will be stratified by treatment arm and prognostic risk groups used for randomization. Estimates of median time to grade 2 RD and estimates of rates for specific time points will be extracted from the Kaplan-Meier analyses together with the associated 95% confidence limits. The treatment differences will be tested using a stratified log-rank test, stratified by stratification factors. Furthermore, Cox proportional hazards models will be applied to yield adjusted estimates of the associated hazard ratios.

All other AEs as reported according to CTCAE v4.03 will also be subjected to statistical analysis. AE tables will present the total number of patients reporting at least one specific event and the maximum CTCAE grade. Patients reporting more than one episode of the same event will be counted only once by the worst CTCAE grade per patient. Special tables will be given for CTCAE Grade III/IV/V AEs. Analysis will be restricted to treatment related AEs and treatment related CTCAE Grade III/IV/V events.

QoL will be evaluated using the validated EORTC quality of life questionnaire (QLQ)-C30 and EORTC QLQ-H&N35 questionnaires. Data will be scored according to the algorithm described in the respective scoring manuals. For all QoL domains and items, descriptive analyses will be presented stratified by visit and treatment arm.

For descriptive statistical analysis, summary tables will be provided showing measures of location and dispersion (min, quartiles, median, max, mean, SD) stratified by visit, treatment arm. Individual score items will be subjected to statistical analysis. Absolute changes of QoL-scores from baseline will be tabulated stratified by treatment group and visit. For graphical illustrations, Box-Whisker diagrams will be presented across visits for each treatment group. Nonparametric (exact) Wilcoxon-Mann-Whitney tests will be applied for exploratory comparison purposes. Additional details of the QoL analysis will be described in the SAP.

Inclusion Criteria:

• Histologically proven locally advanced squamous cell carcinoma of the head-and-neck (SCCHN)
• Conventionally fractionated (5x2 Gy per week) definitive or adjuvant radio(chemo)therapy
• Age ≥18 years
• Written informed consent
• Capacity of the patient to contract

Exclusion Criteria:

• N3 stage (lymph nodes >6 cm)
• Distant metastases (M1)
• Pregnancy, Lactation
• Treatment with epidermal growth factor receptor (EGFR)-antibodies (either given or planned)
• Expected non-compliance

up to 10 weeks following the start of radiotherapy