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    Clinical Trial Results:
    Identification of tissue biomarkers related to late toxicity in Head and Neck Cancer Patients treated with chemoradiotherapy or bioradiotherapy

    Summary
    EudraCT number
    		 2015-003012-21
    Trial protocol
    		 ES  
    Global end of trial date
    04 Mar 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    16 Oct 2024
    First version publication date
    16 Oct 2024
    Other versions
    Summary report(s)
    		 Scientific manuscript

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    TOX-TTCC-2015-01
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Grupo Español de Tratamiento de Tumores de Cabeza y Cuello
    Sponsor organisation address
    Velazquez St, 7-3o, Madrid, Spain, 28001
    Public contact
    Secretaria, Grupo Español de Tratamiento de Tumores de Cabeza y Cuello (TTCC), 0034 676154172, cmontalban@ttccgrupo.com
    Scientific contact
    Secretaria, Grupo Español de Tratamiento de Tumores de Cabeza y Cuello (TTCC), 0034 676154172, cmontalban@ttccgrupo.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    30 May 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    04 Mar 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    04 Mar 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To explore the differences in healthy tissue caused by bioradiotherapy and chemoradiotherapy
    Protection of trial subjects
    This study was performed in line with the principles of the Declaration of Helsinki. The entire study was approved by Hospital Universitari de Bellvitge Ethics Committee under the approval number AC112/15. All the participants provided written informed consent prior to their inclusion in the study.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Dec 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 33
    Worldwide total number of subjects
    33
    EEA total number of subjects
    33
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    33
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 -

    Pre-assignment period milestones
    Number of subjects started
    		 33
    Number of subjects completed
    		 31

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Consent withdrawn by subject: 1
    Reason: Number of subjects
    		 Not meeting inclusion criteria: 1
    Period 1
    Period 1 title
    Overall study period (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 CRT treatment
    Arm description
    		 Radiotherapy (RT) with concomitant cisplatin (CRT)
    Arm type
    		 Active comparator

    Investigational medicinal product name
    cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Standard of care (intitutional protocol)

    Investigational medicinal product name
    Carboplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Standard of care (intitutional protocol) Switching from cisplatin to carboplatin was allowed if needed due to toxicity.

    Arm title
    		 ERT treatment
    Arm description
    		 Radiotherapy (RT) with concomitant cetuximab (ERT)
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Cetuximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Standard of Care (Institutional protocols)

    Number of subjects in period 1 [1]
    		CRT treatment ERT treatment
    Started
    12
    19
    Completed
    10
    17
    Not completed
    2
    2
         progression
    1
    1
         rescue surgery
    -
    1
         prolonged admission
    1
    -
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Two patients were considered not eligible (screening failures)

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    CRT treatment
    Reporting group description
    		 Radiotherapy (RT) with concomitant cisplatin (CRT)

    Reporting group title
    ERT treatment
    Reporting group description
    		 Radiotherapy (RT) with concomitant cetuximab (ERT)

    Reporting group values
    		 CRT treatment ERT treatment Total
    Number of subjects
    		 12 19 31
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0
        Newborns (0-27 days)
    		 0
        Infants and toddlers (28 days-23 months)
    		 0
        Children (2-11 years)
    		 0
        Adolescents (12-17 years)
    		 0
        Adults (18-64 years)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        median (full range (min-max))
    		 60.5 (45 to 69) 63 (44 to 76) -
    Gender categorical
    Units: Subjects
        Female
    		 2 1 3
        Male
    		 10 18 28
    ECOG-PS
    Eastern Cooperative Oncology Group Performance Status
    Units: Subjects
        Score 0
    		 0 1 1
        Score 1
    		 12 18 30
    Tobacco consumption
    Units: Subjects
        Non smoker
    		 0 1 1
        Former smoker
    		 3 8 11
        Active smoker
    		 9 10 19
    Alcohol consumption
    Units: Subjects
        Non alcohol use
    		 1 3 4
        Former alcohol use
    		 4 6 10
        Active user
    		 7 10 17
    Pre-treatment PG-SGA
    Patient-Generated Subjective Global Assessment
    Units: Subjects
        A, well-nourished
    		 4 11 15
        B, moderate/suspected malnutrition
    		 5 2 7
        C, severly malnourished
    		 1 2 3
        Unknown
    		 2 4 6
    Tumor location
    Units: Subjects
        Oral cavity
    		 1 2 3
        Oropharynx
    		 3 6 9
        Larynx
    		 3 6 9
        Hypopharynx
    		 4 5 9
        Unknown primary location
    		 1 0 1
    Primary tumor (TNM 7th ed.)
    Units: Subjects
        Tx
    		 1 1 2
        T1
    		 0 1 1
        T2
    		 1 1 2
        T3
    		 3 10 13
        T4
    		 7 6 13
    Lymph nodes (TNM 7th ed.)
    Units: Subjects
        N0
    		 4 8 12
        N1
    		 1 0 1
        N2a
    		 0 1 1
        N2b
    		 3 5 8
        N2c
    		 2 2 4
        N3
    		 2 3 5
    Pre-treatment weight
    Units: kilogram(s)
        arithmetic mean (standard deviation)
    		 71.1 ( 12.8 ) 73.7 ( 20 ) -
    Tumor volumes
    Units: Cubic centimetre
        median (full range (min-max))
    		 42 (3 to 153) 47 (6 to 118) -
    Lymph nodes volumes
    Units: Cubic centimetre
        median (full range (min-max))
    		 300 (221 to 400) 317 (175 to 533) -

    End points

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    End points reporting groups
    Reporting group title
    CRT treatment
    Reporting group description
    		 Radiotherapy (RT) with concomitant cisplatin (CRT)

    Reporting group title
    ERT treatment
    Reporting group description
    		 Radiotherapy (RT) with concomitant cetuximab (ERT)

    Subject analysis set title
    late toxicity low
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    A group of patients has been defined as "late toxicity low," which includes those patients who have experienced between 0 and 2 late adverse effects and none of them higher than or equal to RTOG grade 2, and another group, defined as "late toxicity high," which includes those patients who have experienced 3 or more late adverse events or have experienced at least one late adverse event of an RTOG grade higher than or equal to 2

    Subject analysis set title
    late toxicity high
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    A group of patients has been defined as "late toxicity low," which includes those patients who have experienced between 0 and 2 late adverse effects and none of them higher than or equal to RTOG grade 2, and another group, defined as "late toxicity high," which includes those patients who have experienced 3 or more late adverse events or have experienced at least one late adverse event of an RTOG grade higher than or equal to 2.

    Primary: CD34 expression before-after treatment

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    End point title
    		 CD34 expression before-after treatment
    End point description
    End point type
    Primary
    End point timeframe
    Punch biopsies (4 mm) were carried out before study treatment and 2 months after the last radiotherapy dose in healthy skin from cervical node level II, homolateral to the greatest tumor burden.
    End point values
    		 CRT treatment ERT treatment late toxicity low late toxicity high
    Number of subjects analysed
    10 [1]
    14 [2]
    14 [3]
    6 [4]
    Units: Percentage positive cells
    arithmetic mean (standard deviation)
        CD34 pre
    53.53 ( 0 )
    49.45 ( 0 )
    53.05 ( 0 )
    38.05 ( 0 )
        CD34 post
    59.46 ( 0 )
    53.67 ( 0 )
    57.03 ( 0 )
    50.49 ( 0 )
    Attachments
    		 CD34 expression
    CD34 late toxicity
    Notes
    [1] - 2 patients with values missing pre or post dose
    [2] - 5 patients with values missing pre or post dose
    [3] - 6 missing values
    [4] - 1 missing value
    Statistical analysis title
    		 Paired-T test
    Statistical analysis description
    Comparison pre-treatment and post-treatment
    Comparison groups
    CRT treatment v ERT treatment
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.6162
    Method
    		 t-test, 2-sided
    Confidence interval
    Statistical analysis title
    		 Unpaired-T test
    Statistical analysis description
    Comparison pre-treatment and post-treatment
    Comparison groups
    CRT treatment v ERT treatment
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.5484
    Method
    		 t-test, 2-sided
    Confidence interval
    Statistical analysis title
    		 Unpaired-T test
    Statistical analysis description
    Comparison pre-treatment and post-treatment
    Comparison groups
    ERT treatment v CRT treatment
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.5031
    Method
    		 t-test, 2-sided
    Confidence interval
    Statistical analysis title
    		 Paired-T test
    Statistical analysis description
    Comparison pre-treatment and post-treatment
    Comparison groups
    ERT treatment v CRT treatment
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.116
    Method
    		 t-test, 2-sided
    Confidence interval
    Statistical analysis title
    		 Toxicity low vs high Pre
    Statistical analysis description
    Comparison between late toxicity low and the late toxicity high subgroup in pretreatment. Unpaired-T test
    Comparison groups
    late toxicity low v late toxicity high
    Number of subjects included in analysis
    20
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.1171
    Method
    		 t-test, 2-sided
    Confidence interval
    Statistical analysis title
    		 Toxicity low vs high Post
    Statistical analysis description
    Comparison between late toxicity low and the late toxicity high subgroup in posttreatment. Unpaired-T test
    Comparison groups
    late toxicity low v late toxicity high
    Number of subjects included in analysis
    20
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.5251
    Method
    		 t-test, 2-sided
    Confidence interval

    Primary: CD68 expression before-after treatment

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    End point title
    		 CD68 expression before-after treatment
    End point description
    End point type
    Primary
    End point timeframe
    Punch biopsies (4 mm) were carried out before study treatment and 2 months after the last radiotherapy dose in healthy skin from cervical node level II, homolateral to the greatest tumor burden.
    End point values
    		 CRT treatment ERT treatment late toxicity low late toxicity high
    Number of subjects analysed
    10 [5]
    16 [6]
    14 [7]
    6 [8]
    Units: Percentage of positive cells
    arithmetic mean (standard deviation)
        CD68 pre
    3.538 ( 0 )
    3.231 ( 0 )
    3.628 ( 0 )
    1.818 ( 0 )
        CD68 post
    11.70 ( 0 )
    7.443 ( 0 )
    8.026 ( 0 )
    5.901 ( 0 )
    Attachments
    		 A CD68 expression
    CD68 late toxicity
    Notes
    [5] - 2 patients with values missing pre or post dose
    [6] - 3 patients with values missing pre or post dose
    [7] - 6 missing
    [8] - 1 missing
    Statistical analysis title
    		 Paired-T test
    Statistical analysis description
    Comparison pre-treatment and post-treatment
    Comparison groups
    CRT treatment v ERT treatment
    Number of subjects included in analysis
    26
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.3063
    Method
    		 t-test, 2-sided
    Confidence interval
    Statistical analysis title
    		 Paired-T test
    Statistical analysis description
    Comparison pre-treatment and post-treatment
    Comparison groups
    ERT treatment v CRT treatment
    Number of subjects included in analysis
    26
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.0535
    Method
    		 t-test, 2-sided
    Confidence interval
    Statistical analysis title
    		 Unpaired-T test
    Statistical analysis description
    Comparison pre-treatment and post-treatment
    Comparison groups
    CRT treatment v ERT treatment
    Number of subjects included in analysis
    26
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.1161
    Method
    		 t-test, 2-sided
    Confidence interval
    Statistical analysis title
    		 Unpaired-T test
    Statistical analysis description
    Comparison pre-treatment and post-treatment
    Comparison groups
    ERT treatment v CRT treatment
    Number of subjects included in analysis
    26
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.0117
    Method
    		 t-test, 2-sided
    Confidence interval
    Statistical analysis title
    		 Toxicity low vs high Pre
    Statistical analysis description
    "Comparison between late toxicity low and the late toxicity high subgroup in pretreatment Unpaired-T test"
    Comparison groups
    late toxicity low v late toxicity high
    Number of subjects included in analysis
    20
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.044
    Method
    		 t-test, 2-sided
    Confidence interval
    Statistical analysis title
    		 Copy of Toxicity low vs high Post
    Statistical analysis description
    "Comparison between late toxicity low and the late toxicity high subgroup in posttreatment Unpaired-T test"
    Comparison groups
    late toxicity low v late toxicity high
    Number of subjects included in analysis
    20
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.3289
    Method
    		 t-test, 2-sided
    Confidence interval

    Primary: CD163 expression before-after treatment

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    End point title
    		 CD163 expression before-after treatment
    End point description
    End point type
    Primary
    End point timeframe
    Punch biopsies (4 mm) were carried out before study treatment and 2 months after the last radiotherapy dose in healthy skin from cervical node level II, homolateral to the greatest tumor burden.
    End point values
    		 CRT treatment ERT treatment late toxicity low late toxicity high
    Number of subjects analysed
    10 [9]
    14 [10]
    14 [11]
    6 [12]
    Units: Percentage of positive cells
    arithmetic mean (standard deviation)
        CD163 pre
    9.722 ( 0 )
    9.938 ( 0 )
    10.98 ( 0 )
    6.806 ( 0 )
        CD163 post
    21.20 ( 0 )
    16.12 ( 0 )
    17.42 ( 0 )
    14.45 ( 0 )
    Attachments
    		 CD163 expression
    CD163 late toxicity
    Notes
    [9] - 2 patients with values missing pre or post dose
    [10] - 5 patients with values missing pre or post dose
    [11] - 6 missing
    [12] - 1 missing
    Statistical analysis title
    		 Paired-T test
    Statistical analysis description
    Comparison pre-treatment and post-treatment
    Comparison groups
    CRT treatment v ERT treatment
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.0655
    Method
    		 t-test, 2-sided
    Confidence interval
    Statistical analysis title
    		 Paired-T test
    Statistical analysis description
    Comparison pre-treatment and post-treatment
    Comparison groups
    ERT treatment v CRT treatment
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.0993
    Method
    		 t-test, 2-sided
    Confidence interval
    Statistical analysis title
    		 Unpaired-T test
    Statistical analysis description
    Comparison pre-treatment and post-treatment
    Comparison groups
    CRT treatment v ERT treatment
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.0431
    Method
    		 t-test, 2-sided
    Confidence interval
    Statistical analysis title
    		 Unpaired-T test
    Statistical analysis description
    Comparison pre-treatment and post-treatment
    Comparison groups
    ERT treatment v CRT treatment
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.0181
    Method
    		 t-test, 2-sided
    Confidence interval
    Statistical analysis title
    		 Toxicity low vs high Pre
    Statistical analysis description
    "Comparison between late toxicity low and the late toxicity high subgroup in pretreatment Unpaired-T test"
    Comparison groups
    late toxicity low v late toxicity high
    Number of subjects included in analysis
    20
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.1066
    Method
    		 t-test, 2-sided
    Confidence interval
    Statistical analysis title
    		 Toxicity low vs high Post
    Statistical analysis description
    "Comparison between late toxicity low and the late toxicity high subgroup in posttreatment Unpaired-T test"
    Comparison groups
    late toxicity low v late toxicity high
    Number of subjects included in analysis
    20
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.613
    Method
    		 t-test, 2-sided
    Confidence interval

    Primary: CD163/CD68 Ratio

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    End point title
    		 CD163/CD68 Ratio
    End point description
    End point type
    Primary
    End point timeframe
    Punch biopsies (4 mm) were carried out before study treatment and 2 months after the last radiotherapy dose in healthy skin from cervical node level II, homolateral to the greatest tumor burden.
    End point values
    		 CRT treatment ERT treatment
    Number of subjects analysed
    10 [13]
    14 [14]
    Units: Percentage
    arithmetic mean (standard deviation)
        CD163/CD68 pre
    3.768 ( 0 )
    2.996 ( 0 )
        CD163/CD68 post
    2.427 ( 0 )
    2.760 ( 0 )
    Notes
    [13] - 2 patients with values missing pre or post dose
    [14] - 5 patients with values missing pre or post dose
    Statistical analysis title
    		 Mann Whitney test
    Statistical analysis description
    Comparison pre-treatment and post-treatment
    Comparison groups
    CRT treatment v ERT treatment
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.0221
    Method
    		 Mann Whitney test
    Confidence interval
    Statistical analysis title
    		 Mann Whitney test
    Statistical analysis description
    Comparison pre-treatment and post-treatment
    Comparison groups
    ERT treatment v CRT treatment
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.7938
    Method
    		 Mann Whitney test
    Confidence interval

    Primary: Masson Trichrome pre-treatment and post-treatment

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    End point title
    		 Masson Trichrome pre-treatment and post-treatment
    End point description
    End point type
    Primary
    End point timeframe
    Punch biopsies (4 mm) were carried out before study treatment and 2 months after the last radiotherapy dose in healthy skin from cervical node level II, homolateral to the greatest tumor burden.
    End point values
    		 CRT treatment ERT treatment late toxicity low late toxicity high
    Number of subjects analysed
    10 [15]
    16 [16]
    14 [17]
    6 [18]
    Units: Percentage stained cells
    arithmetic mean (standard deviation)
        Masson Trichrome Pre
    48.47 ( 0 )
    43.7 ( 0 )
    44 ( 0 )
    49.27 ( 0 )
        Masson Trichrome post
    38.80 ( 0 )
    37.23 ( 0 )
    40.08 ( 0 )
    36.61 ( 0 )
    Attachments
    		 Collagen deposition & Mason
    Collagen late toxicity
    Notes
    [15] - 2 patients with values missing pre or post dose
    [16] - 3 patients with values missing pre or post dose
    [17] - 6 missing
    [18] - 1 missing
    Statistical analysis title
    		 Paired-T test
    Statistical analysis description
    Comparison pre-treatment and post-treatment
    Comparison groups
    CRT treatment v ERT treatment
    Number of subjects included in analysis
    26
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.0905
    Method
    		 t-test, 2-sided
    Confidence interval
    Statistical analysis title
    		 Paired-T test
    Statistical analysis description
    Comparison pre-treatment and post-treatment
    Comparison groups
    ERT treatment v CRT treatment
    Number of subjects included in analysis
    26
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.8908
    Method
    		 t-test, 2-sided
    Confidence interval
    Statistical analysis title
    		 Unpaired-T test
    Statistical analysis description
    Comparison pre-treatment and post-treatment
    Comparison groups
    CRT treatment v ERT treatment
    Number of subjects included in analysis
    26
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.1953
    Method
    		 t-test, 2-sided
    Confidence interval
    Statistical analysis title
    		 Unpaired-T test
    Statistical analysis description
    Comparison pre-treatment and post-treatment
    Comparison groups
    ERT treatment v CRT treatment
    Number of subjects included in analysis
    26
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.3386
    Method
    		 t-test, 2-sided
    Confidence interval
    Statistical analysis title
    		 Toxicity low vs high Pre
    Statistical analysis description
    "Comparison between late toxicity low and the late toxicity high subgroup in pretreatment Unpaired-T test"
    Comparison groups
    late toxicity low v late toxicity high
    Number of subjects included in analysis
    20
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.5402
    Method
    		 t-test, 2-sided
    Confidence interval
    Statistical analysis title
    		 Toxicity low vs high post
    Statistical analysis description
    "Comparison between late toxicity low and the late toxicity high subgroup in posttreatment Unpaired-T test"
    Comparison groups
    late toxicity low v late toxicity high
    Number of subjects included in analysis
    20
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.6917
    Method
    		 t-test, 2-sided
    Confidence interval

    Primary: Frequency of patients with late toxicities

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    End point title
    		 Frequency of patients with late toxicities [19]
    End point description
    One year after the end of radiation treatment
    End point type
    Primary
    End point timeframe
    Late toxicity was defined as per RTOG/EORTC late radiation morbidity scoring system as adverse events that were still experienced by the patients 90 days after the end of radiation treatment and collected one year after the end of radiation treatment.
    Notes
    [19] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No formal comparison was done between rates of patients experiencing late toxicities. The trial describes the type of toxicities experienced in adverse events section
    End point values
    		 CRT treatment ERT treatment
    Number of subjects analysed
    10 [20]
    17 [21]
    Units: Patients
        late toxicities high
    4
    3
        late toxicities low
    6
    14
    Notes
    [20] - 2 missing: 1 started further chemotherapy and 1 operated on one year after radiotherapy
    [21] - 2 missing: 1 died after 4.6 months and 1 admitted for a long time because of surgical complications
    No statistical analyses for this end point

    Secondary: Lymph node dissection

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    End point title
    		 Lymph node dissection
    End point description
    End point type
    Secondary
    End point timeframe
    Throughout the study period
    End point values
    		 CRT treatment ERT treatment
    Number of subjects analysed
    12
    19
    Units: patients
        underwent Lymph node dissection
    3
    4
        Did not undergo Lymph node dissection
    9
    15
    No statistical analyses for this end point

    Secondary: Relapse frequency

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    End point title
    		 Relapse frequency
    End point description
    End point type
    Secondary
    End point timeframe
    Throughout the study period
    End point values
    		 CRT treatment ERT treatment
    Number of subjects analysed
    12
    19
    Units: Patients
        Relapsed
    3
    3
        Did not relapse
    9
    16
    No statistical analyses for this end point

    Secondary: Requirement of nasogastric feeding tube

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    End point title
    		 Requirement of nasogastric feeding tube
    End point description
    End point type
    Secondary
    End point timeframe
    Throughout the study period
    End point values
    		 CRT treatment ERT treatment
    Number of subjects analysed
    11 [22]
    19
    Units: Patients
        Required
    2
    8
        Not required
    9
    11
    Notes
    [22] - 1 patient was missing
    No statistical analyses for this end point

    Secondary: Gastrostomy

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    End point title
    		 Gastrostomy
    End point description
    End point type
    Secondary
    End point timeframe
    Throughout the study period
    End point values
    		 CRT treatment ERT treatment
    Number of subjects analysed
    12
    19
    Units: Patients
        Performed
    0
    3
        Not performed
    12
    16
    No statistical analyses for this end point

    Secondary: Tracheostomy

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    End point title
    		 Tracheostomy
    End point description
    End point type
    Secondary
    End point timeframe
    Throughout the study period
    End point values
    		 CRT treatment ERT treatment
    Number of subjects analysed
    12
    19
    Units: Patients
        Performed
    0
    1
        Not performed
    12
    18
    No statistical analyses for this end point

    Secondary: Overall survival

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    End point title
    		 Overall survival
    End point description
    Number of patients who died from any cause
    End point type
    Secondary
    End point timeframe
    Throughout the study period
    End point values
    		 CRT treatment ERT treatment
    Number of subjects analysed
    12
    19
    Units: Patients
        Alive
    12
    15
        Dead
    0
    4
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were reported throughout the study from baseline to 1 year after the end of radiation treatment.
    Adverse event reporting additional description
    Late toxicity was defined as per RTOG/EORTC late radiation morbidity scoring system as adverse events that were still experienced by the patients 90 days after the end of radiation treatment and collected one year after the end of radiation treatment.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22
    Reporting groups
    Reporting group title
    CRT treatment
    Reporting group description
    		 Radiotherapy (RT) with concomitant cisplatin (CRT)

    Reporting group title
    ERT treatment
    Reporting group description
    		 Radiotherapy (RT) with concomitant cetuximab (ERT)

    Serious adverse events
    		 CRT treatment ERT treatment
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 12 (16.67%)
    3 / 19 (15.79%)
         number of deaths (all causes)
    0
    4
         number of deaths resulting from adverse events
    0
    0
    Blood and lymphatic system disorders
    Neutropenia
    Additional description: one G3 and one G4 events
         subjects affected / exposed
    2 / 12 (16.67%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia
    Additional description: Grade 1
         subjects affected / exposed
    2 / 12 (16.67%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Fever
    Additional description: Grade 3
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Oral mucositis
         subjects affected / exposed
    0 / 12 (0.00%)
    2 / 19 (10.53%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cheilitis
    Additional description: Grade 3
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash
    Additional description: Grade 3
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
    Additional description: Grade 2
         subjects affected / exposed
    2 / 12 (16.67%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Conjunctivitis
    Additional description: Grade 3
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
    Additional description: Grade 4
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyperpotassemia
    Additional description: Grade 1
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 CRT treatment ERT treatment
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    12 / 12 (100.00%)
    19 / 19 (100.00%)
    Nervous system disorders
    Dysphonia G1
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    Dysgeusia G1
         subjects affected / exposed
    1 / 12 (8.33%)
    5 / 19 (26.32%)
         occurrences all number
    1
    5
    Dysgeusia G2
         subjects affected / exposed
    6 / 12 (50.00%)
    10 / 19 (52.63%)
         occurrences all number
    6
    10
    Dysgeusia G3
         subjects affected / exposed
    3 / 12 (25.00%)
    0 / 19 (0.00%)
         occurrences all number
    3
    0
    Neurotoxicity G1
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    Neurotoxicity G2
         subjects affected / exposed
    2 / 12 (16.67%)
    0 / 19 (0.00%)
         occurrences all number
    2
    0
    General disorders and administration site conditions
    Asthenia G1
         subjects affected / exposed
    6 / 12 (50.00%)
    5 / 19 (26.32%)
         occurrences all number
    6
    5
    Asthenia G2
         subjects affected / exposed
    6 / 12 (50.00%)
    10 / 19 (52.63%)
         occurrences all number
    6
    10
    Blood and lymphatic system disorders
    Febrile neutropenia G3
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Dysphagia G1
         subjects affected / exposed
    1 / 12 (8.33%)
    3 / 19 (15.79%)
         occurrences all number
    1
    3
    Dysphagia G2
         subjects affected / exposed
    2 / 12 (16.67%)
    8 / 19 (42.11%)
         occurrences all number
    2
    8
    Dysphagia G3
         subjects affected / exposed
    0 / 12 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    2
    Oral mucositis G1
         subjects affected / exposed
    4 / 12 (33.33%)
    3 / 19 (15.79%)
         occurrences all number
    4
    3
    Oral mucositis G2
         subjects affected / exposed
    4 / 12 (33.33%)
    6 / 19 (31.58%)
         occurrences all number
    4
    6
    Oral mucositis G3
         subjects affected / exposed
    2 / 12 (16.67%)
    8 / 19 (42.11%)
         occurrences all number
    2
    8
    Nausea/vomiting G1
         subjects affected / exposed
    4 / 12 (33.33%)
    0 / 19 (0.00%)
         occurrences all number
    4
    0
    Nausea/vomiting G3
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    Odynophagia G1
         subjects affected / exposed
    4 / 12 (33.33%)
    4 / 19 (21.05%)
         occurrences all number
    4
    4
    Odynophagia G2
         subjects affected / exposed
    4 / 12 (33.33%)
    8 / 19 (42.11%)
         occurrences all number
    4
    8
    Odynophagia G3
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    Liver toxicity G1
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Xerostomia G1
         subjects affected / exposed
    6 / 12 (50.00%)
    4 / 19 (21.05%)
         occurrences all number
    6
    4
    Xerostomia G2
         subjects affected / exposed
    4 / 12 (33.33%)
    11 / 19 (57.89%)
         occurrences all number
    4
    11
    Xerostomia G3
         subjects affected / exposed
    2 / 12 (16.67%)
    0 / 19 (0.00%)
         occurrences all number
    2
    0
    Skin and subcutaneous tissue disorders
    Radiodermatitis G1
         subjects affected / exposed
    5 / 12 (41.67%)
    7 / 19 (36.84%)
         occurrences all number
    5
    7
    Radiodematitis G2
         subjects affected / exposed
    3 / 12 (25.00%)
    7 / 19 (36.84%)
         occurrences all number
    3
    7
    Radiodermatitis G3
         subjects affected / exposed
    1 / 12 (8.33%)
    2 / 19 (10.53%)
         occurrences all number
    1
    2
    Rash G1
         subjects affected / exposed
    0 / 12 (0.00%)
    8 / 19 (42.11%)
         occurrences all number
    0
    8
    Rash G2
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Renal and urinary disorders
    Renal impairment G1
         subjects affected / exposed
    2 / 12 (16.67%)
    0 / 19 (0.00%)
         occurrences all number
    2
    0
    Renal impairment G3
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    Trismus G1
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1
    Metabolism and nutrition disorders
    Anorexia G1
         subjects affected / exposed
    5 / 12 (41.67%)
    5 / 19 (26.32%)
         occurrences all number
    5
    5
    Anorexia G2
         subjects affected / exposed
    4 / 12 (33.33%)
    4 / 19 (21.05%)
         occurrences all number
    4
    4
    Anorexia G3
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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