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    Clinical Trial Results:
    Multimodal therapy with and without cetuximab in patients with locally advanced esophageal carcinoma. An open-label phase III trial

    Summary
    EudraCT number
    		 2009-016584-10
    Trial protocol
    		 DE   HU   AT  
    Global end of trial date
    09 Dec 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    01 Apr 2023
    First version publication date
    01 Apr 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    SAKK 75/08
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01107639
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 DRKS-ID: DRKS00003758
    Sponsors
    Sponsor organisation name
    Swiss Group for Clinical Cancer Research (SAKK)
    Sponsor organisation address
    Effingerstrasse 33, Bern, Switzerland, 3008
    Public contact
    Head Regulatory Affairs, Swiss Group for Clinical Cancer, +41 31389 91 91, sakkcc@sakk.ch
    Scientific contact
    Head Regulatory Affairs, Swiss Group for Clinical Cancer, +41 31389 91 91, sakkcc@sakk.ch
    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
    25 Sep 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Dec 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Determine the efficacy of neoadjuvant radiochemotherapy (RCT) combined with immunotherapy followed by adjuvant immunotherapy compared with the same schedule without immunotherapy (neoadjuvant and adjuvant).
    Protection of trial subjects
    Protection of trial subjects was ensured by Safety Monitoring, i.e. assessment of adverse events, serious adverse events, adverse drug reactions, and the continous assessment of laboratory values and vital signs.
    Background therapy
    		 (1) Induction phase comprising two cycles of chemotherapy with docetaxel 75 mg/m2, cisplatin 75 mg/m2, followed by (2) radiochemotherapy (RCT) with 45 Gy, docetaxel 20 mg/m2 and cisplatin 25 mg/m2, weekly for 5 weeks and subsequent (3) surgery.
    Evidence for comparator
    		 Not applicable.
    Actual start date of recruitment
    01 May 2010
    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
    Austria: 37
    Country: Number of subjects enrolled
    France: 13
    Country: Number of subjects enrolled
    Germany: 99
    Country: Number of subjects enrolled
    Switzerland: 151
    Worldwide total number of subjects
    300
    EEA total number of subjects
    149
    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)
    198
    From 65 to 84 years
    102
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 In total, 300 patients were enrolled at 53 centers in four European countries between May 2010 and December 2013.

    Pre-assignment
    Screening details
    		 Eligibility criteria of a patient were checked by the investigator. Once a patient fullfils all inclusion criteria and not any of the exclusion criteria, he/she was enrolled.

    Period 1
    Period 1 title
    Randomization
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Cetuximab
    Arm description
    		 Cetuximab arm at baseline.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Cetuximab
    Investigational medicinal product code
    Other name
    Erbitux®
    Pharmaceutical forms
    Infusion
    Routes of administration
    Infusion
    Dosage and administration details
    Inductionphase with concomitant neoadjuvant cetuximab 250 mg/m2 weekly, followed by chemoradiation and surgery, with subsequent adjuvant cetuximab 500 mg/m2 biweekly for 3 months.

    Arm title
    		 Control
    Arm description
    		 Control arm at baseline.
    Arm type
    		 Control

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    		Cetuximab Control
    Started
    149
    151
    Completed
    149
    151
    Period 2
    Period 2 title
    Induction Phase
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Cetuximab
    Arm description
    		 Cetuximab arm in inductionphase.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Cetuximab
    Investigational medicinal product code
    Other name
    Erbitux®
    Pharmaceutical forms
    Infusion
    Routes of administration
    Infusion
    Dosage and administration details
    Inductionphase with concomitant neoadjuvant cetuximab 250 mg/m2 weekly, followed by chemoradiation and surgery, with subsequent adjuvant cetuximab 500 mg/m2 biweekly for 3 months.

    Arm title
    		 Control
    Arm description
    		 Control arm in inductionphase.
    Arm type
    		 Control

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 2
    		Cetuximab Control
    Started
    149
    151
    Completed
    140
    145
    Not completed
    9
    6
         Consent withdrawn by subject
    3
    1
         Death
    2
    1
         Ineligibility (primary metastatic)
    1
    -
         Unacceptable Toxicity
    3
    3
         Progressive disease
    -
    1
    Period 3
    Period 3 title
    Radiationchemotherapy
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Cetuximab
    Arm description
    		 Cetuximab arm in radiochemotherapy phase.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Cetuximab
    Investigational medicinal product code
    Other name
    Erbitux®
    Pharmaceutical forms
    Infusion
    Routes of administration
    Infusion
    Dosage and administration details
    Inductionphase with concomitant neoadjuvant cetuximab 250 mg/m2 weekly, followed by chemoradiation and surgery, with subsequent adjuvant cetuximab 500 mg/m2 biweekly for 3 months.

    Arm title
    		 Control
    Arm description
    		 Control arm in radiochemotherapy phase.
    Arm type
    		 Control

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 3
    		Cetuximab Control
    Started
    140
    145
    Completed
    132
    130
    Not completed
    8
    15
         Consent withdrawn by subject
    3
    2
         Death
    -
    1
         PO / extend of disease
    3
    5
         Ineligibility (primary metastatic)
    -
    1
         Comorbidities / poor performance status
    2
    6
    Period 4
    Period 4 title
    Surgery
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Cetuximab
    Arm description
    		 Cetuximab arm at surgery.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Cetuximab
    Investigational medicinal product code
    Other name
    Erbitux®
    Pharmaceutical forms
    Infusion
    Routes of administration
    Infusion
    Dosage and administration details
    Inductionphase with concomitant neoadjuvant cetuximab 250 mg/m2 weekly, followed by chemoradiation and surgery, with subsequent adjuvant cetuximab 500 mg/m2 biweekly for 3 months.

    Arm title
    		 Control
    Arm description
    		 Control arm at baseline.
    Arm type
    		 Control

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 4
    		Cetuximab Control
    Started
    132
    130
    Completed
    100
    0
    Not completed
    32
    130
         No adjuvant therapy (Control arm)
    -
    127
         Withdrawal of IC, toxicity during neoadj. therapy
    10
    -
         Complications post surgery, poor general condition
    10
    -
         Death
    8
    -
         PO / extend of disease
    -
    2
         Ineligibility (primary metastatic)
    -
    1
         PO
    2
    -
         Mistake by site
    2
    -
    Period 5
    Period 5 title
    Therapy after surgery
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Cetuximab
    Arm description
    		 Cetuximab arm at baseline.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Cetuximab
    Investigational medicinal product code
    Other name
    Erbitux®
    Pharmaceutical forms
    Infusion
    Routes of administration
    Infusion
    Dosage and administration details
    Inductionphase with concomitant neoadjuvant cetuximab 250 mg/m2 weekly, followed by chemoradiation and surgery, with subsequent adjuvant cetuximab 500 mg/m2 biweekly for 3 months.

    Number of subjects in period 5
    		Cetuximab
    Started
    100
    Completed
    100

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cetuximab
    Reporting group description
    		 Cetuximab arm at baseline.

    Reporting group title
    Control
    Reporting group description
    		 Control arm at baseline.

    Reporting group values
    		 Cetuximab Control Total
    Number of subjects
    		 149 151 300
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 99 99 198
        From 65-84 years
    		 50 52 102
    Gender categorical
    Units: Subjects
        Female
    		 19 18 37
        Male
    		 130 133 263

    End points

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    End points reporting groups
    Reporting group title
    Cetuximab
    Reporting group description
    		 Cetuximab arm at baseline.

    Reporting group title
    Control
    Reporting group description
    		 Control arm at baseline.
    Reporting group title
    Cetuximab
    Reporting group description
    		 Cetuximab arm in inductionphase.

    Reporting group title
    Control
    Reporting group description
    		 Control arm in inductionphase.
    Reporting group title
    Cetuximab
    Reporting group description
    		 Cetuximab arm in radiochemotherapy phase.

    Reporting group title
    Control
    Reporting group description
    		 Control arm in radiochemotherapy phase.
    Reporting group title
    Cetuximab
    Reporting group description
    		 Cetuximab arm at surgery.

    Reporting group title
    Control
    Reporting group description
    		 Control arm at baseline.
    Reporting group title
    Cetuximab
    Reporting group description
    		 Cetuximab arm at baseline.

    Subject analysis set title
    Cetuximab (ITT)
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Cetuximab arm of the full analysis set.

    Subject analysis set title
    Control (ITT)
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Control arm of the full analysis set.

    Primary: PE | Progression free survival (PFS)

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    End point title
    		 PE | Progression free survival (PFS)
    End point description
    Progression-free survival (PFS) was calculated from the date of randomization until one of the following events, whichever came first: (1) Tumor progression at any time (progression of primary tumor or local lymph nodes, appearance of new lesions), (2) Recurrence at local, regional or distant site after surgery, (3) Death from any cause. The primary endpoint PFS was calculated for all patients in the ITT population. 174 (Cetuximab arm: 78 | Control arm: 96) patients (58.6%) experienced an event. *Note: Upper confidence interval of median PFS (for cetuximab arm) not reached. Dummy data ("9999") entered due to database restrictions.
    End point type
    Primary
    End point timeframe
    From randomization until occurence of tumor progression (incl. local/regional occurence after surgery) or death.
    End point values
    		 Cetuximab (ITT) Control (ITT)
    Number of subjects analysed
    148
    149
    Units: PFS (years)
        median (confidence interval 95%)
    3.8 (2.0 to 99999)
    2.0 (1.5 to 2.8)
    Statistical analysis title
    		 PE | Log Rank and Hazard Ratio
    Statistical analysis description
    Log Rank test and Hazard Ratio for PFS
    Comparison groups
    Cetuximab (ITT) v Control (ITT)
    Number of subjects included in analysis
    297
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.072
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.76
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.56
         upper limit
    		 1.03

    Secondary: SE | Overall survivall (OS)

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    End point title
    		 SE | Overall survivall (OS)
    End point description
    OS was calculated from the date of randomization until the date of death from any cause. Patients not experiencing an event were censored at the last date they were known to be alive. OS was calculated for all patients in the ITT population. 156 (Cetuximab arm: 72 | Control arm: 84) patients (52.5%) died. Upper confidence interval of median OS (for cetuximab arm) not reached. Dummy data ("9999") entered due to database restrictions.
    End point type
    Secondary
    End point timeframe
    From randomization until death.
    End point values
    		 Cetuximab (ITT) Control (ITT)
    Number of subjects analysed
    148
    149
    Units: OS (years)
        median (confidence interval 95%)
    5.7 (3.8 to 9999)
    3.0 (2.2 to 5.9)
    Statistical analysis title
    		 OS | Log Rank and Hazard Ratio
    Statistical analysis description
    Log Rank test and Hazard Ratio for OS
    Comparison groups
    Cetuximab (ITT) v Control (ITT)
    Number of subjects included in analysis
    297
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.135
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.79
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.57
         upper limit
    		 1.08

    Secondary: SE |OS rate

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    End point title
    		 SE |OS rate
    End point description
    End point type
    Secondary
    End point timeframe
    At year 1, 2, 3, 4 and 5.
    End point values
    		 Cetuximab (ITT) Control (ITT)
    Number of subjects analysed
    148
    149
    Units: OS rate (%)
    number (confidence interval 95%)
        1 year
    85.3 (78.4 to 90.2)
    78.9 (71.4 to 84.7)
        2 years
    71.3 (63.2 to 78.0)
    63.2 (54.8 to 70.4)
        3 years
    62.2 (53.8 to 69.9)
    51.5 (43.1 to 59.3)
        4 years
    57.3 (48.7 to 64.9)
    45.3 (37.1 to 53.1)
        5 years
    53.6 (45.0 to 61.4)
    44.6 (36.4 to 52.4)
    No statistical analyses for this end point

    Secondary: SE | PFS after surgery (PFS-OP)

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    End point title
    		 SE | PFS after surgery (PFS-OP)
    End point description
    PFS-OP was only calculated for operated patients from date of surgery to an event. 147 (Cetuximab arm: 69 | Control arm: 77) patients (57.0%) experienced an event. Upper confidence interval of median PFS-OP (for cetuximab arm) not reached. Dummy data ("9999") entered due to database restrictions.
    End point type
    Secondary
    End point timeframe
    From date of surgery to an event.
    End point values
    		 Cetuximab (ITT) Control (ITT)
    Number of subjects analysed
    131 [1]
    127 [2]
    Units: PFS-OP (years)
        median (confidence interval 95%)
    3.7 (1.8 to 9999)
    2.1 (1.6 to 5.1)
    Notes
    [1] - Only for operated patients.
    [2] - Only for operated patients.
    Statistical analysis title
    		 PFS-OP | Log Rank and Hazard Ratio
    Statistical analysis description
    Log Rank test and Hazard Ration for PFS of operated patients from date of surgery.
    Comparison groups
    Cetuximab (ITT) v Control (ITT)
    Number of subjects included in analysis
    258
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.351
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.86
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.62
         upper limit
    		 1.19

    Secondary: SE | Time to Progression (TTP)

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    End point title
    		 SE | Time to Progression (TTP)
    End point description
    Time to progression was defined as time from randomization to one of the following events, whichever came first: (1) Tumor progression at any time (progression of primary tumor or local lymph nodes, appearance of new lesions), (2) Recurrence at local, regional or distant site after surgery, (3) Death due to tumor TTP was calculated for all patients in the ITT population. 130 (Cetuximab arm: 58 | Control arm: 72) patients (44.1%) experienced an event. *Note: Median TTP (cetuximab arm) and upper confidence intervals of median TTP (both arms) were not reached. Dummy data ("9999") entered due to database restrictions.
    End point type
    Secondary
    End point timeframe
    From randomization until event.
    End point values
    		 Cetuximab (ITT) Control (ITT)
    Number of subjects analysed
    148
    149
    Units: TTP (years)
        median (confidence interval 95%)
    9999 (3.1 to 9999)
    3.3 (2.0 to 9999)
    Statistical analysis title
    		 TTP | Log Rank and Hazard Ratio
    Comparison groups
    Cetuximab (ITT) v Control (ITT)
    Number of subjects included in analysis
    297
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.106
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.75
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.53
         upper limit
    		 1.06

    Secondary: SE | Time to loco-regional failure after R0-resection

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    End point title
    		 SE | Time to loco-regional failure after R0-resection
    End point description
    This endpoint was only derived for patients with R0-resection. It was calculated from date of surgery to date of first documented loco-regional failure. Loco-regional failure was defined as tumor recurrence within the radiotherapy field. Death caused by tumor was counted as an event. Time to loco-regional failure after R0-resection was calculated for all patients with R0-resection from date of surgery to an event. 60 (Cetuximab arm: 22 | Control arm: 38) patients (24.2%) experienced an event. *Note: Median Time to loco-regional failure and upper and lower confidence intervals not reached (both arms). Dummy data ("9999") entered due to database restrictions.
    End point type
    Secondary
    End point timeframe
    From date of surgery to date of first documented loco-regional failure.
    End point values
    		 Cetuximab (ITT) Control (ITT)
    Number of subjects analysed
    125 [3]
    123 [4]
    Units: Time to loco-regional failure (years)
        median (confidence interval 95%)
    9999 (9999 to 9999)
    9999 (9999 to 9999)
    Notes
    [3] - Only patients with R0-resection.
    [4] - Only patients with R0-resection.
    Statistical analysis title
    		 Time to loco-reg. fail | Log Rank and Hazard Ratio
    Comparison groups
    Cetuximab (ITT) v Control (ITT)
    Number of subjects included in analysis
    248
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.018
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.54
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.32
         upper limit
    		 0.91

    Secondary: SE | Loco-regional failure after R0-resection rate

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    End point title
    		 SE | Loco-regional failure after R0-resection rate
    End point description
    End point type
    Secondary
    End point timeframe
    At year 1, 2, 3, 4 and 5.
    End point values
    		 Cetuximab (ITT) Control (ITT)
    Number of subjects analysed
    125 [5]
    123 [6]
    Units: Loco-regional failure rate (%)
    number (confidence interval 95%)
        1 year
    88.2 (80.5 to 93.0)
    85.6 (77.5 to 90.9)
        2 years
    85.0 (76.6 to 90.5)
    71.2 (61.4 to 79.0)
        3 years
    79.3 (69.9 to 86.0)
    64.1 (53.7 to 72.8)
        4 years
    78.0 (68.3 to 85.0)
    62.9 (52.4 to 71.7)
        5 years
    78.0 (68.3 to 85.0)
    62.9 (52.4 to 71.7)
    Notes
    [5] - Only for patients with R0-resection.
    [6] - Only for patients with R0-resection.
    No statistical analyses for this end point

    Secondary: SE | Time to distant failure after R0-resection

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    End point title
    		 SE | Time to distant failure after R0-resection
    End point description
    This endpoint was only derived for patients with R0-resection. It was calculated from date of surgery to date of first documented distant failure (either distant failure or both loco-regional and distant failure). Death caused by tumor was counted as an event. Time to distant failure after R0-resection was calculated for all patients with R0-resection from date of surgery to an event. 80 (Cetuximab arm: 40 | Control arm: 40) patients (32.3%) experienced an event. *Note: Median Time to loco-regional failure and upper confidence intervals not reached (both arms). Dummy data ("9999") entered due to database restrictions.
    End point type
    Secondary
    End point timeframe
    From date of surgery to date of first documented distant failure.
    End point values
    		 Cetuximab (ITT) Control (ITT)
    Number of subjects analysed
    125 [7]
    123 [8]
    Units: Time to distant failure (years)
        median (confidence interval 95%)
    9999 (6.0 to 9999)
    9999 (5.6 to 9999)
    Notes
    [7] - Only for patients with R0-resection.
    [8] - Only for patients with R0-resection.
    Statistical analysis title
    		 Time to dist. failure | Log Rank and Hazard Ratio
    Comparison groups
    Cetuximab (ITT) v Control (ITT)
    Number of subjects included in analysis
    248
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.838
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.95
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.61
         upper limit
    		 1.48

    Secondary: SE | Distant failure after R0-resection rate

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    End point title
    		 SE | Distant failure after R0-resection rate
    End point description
    End point type
    Secondary
    End point timeframe
    At year 1, 2, 3, 4 and 5.
    End point values
    		 Cetuximab (ITT) Control (ITT)
    Number of subjects analysed
    125 [9]
    123 [10]
    Units: Distant failure rate (%)
    number (confidence interval 95%)
        1 year
    82.9 (74.7 to 88.6)
    83.2 (74.9 to 88.9)
        2 years
    73.4 (64.2 to 80.6)
    69.3 (59.5 to 77.1)
        3 years
    67.6 (57.9 to 75.5)
    67.0 (57.1 to 75.2)
        4 years
    64.4 (54.5 to 72.6)
    65.7 (55.6 to 74.1)
        5 years
    64.4 (54.5 to 72.6)
    63.9 (53.5 to 72.7)
    Notes
    [9] - Only for patients with R0-resection.
    [10] - Only for patients with R0-resection.
    No statistical analyses for this end point

    Secondary: SE | Pathological remission

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    End point title
    		 SE | Pathological remission
    End point description
    Pathological remission was assessed according to the tumor regression model of Mandard. TRG 1 (pCR) was defined as complete regression, absence of histologically identifiable residual cancer and fibrosis extending through the different layers of the esophageal wall, with or without granuloma. | TRG 2 was defined as presence of rare residual cancer cells scattered through the fibrosis. |TRG 3 was defined as increase in the number of residual cancer cells, but fibrosis still predominant. |TRG 4 was defined as residual cancer outgrowing fibrosis. | TRG 5 was defined as absence of regressive changes Pathological remission (=TRG 1+2). It was calculated only for patients who had undergone a surgical resection.
    End point type
    Secondary
    End point timeframe
    After surgery.
    End point values
    		 Cetuximab (ITT) Control (ITT)
    Number of subjects analysed
    131 [11]
    127 [12]
    Units: Patients with TRG1 + 2 (%)
    number (not applicable)
        No
    32.1
    35.4
        Yes
    67.2
    64.6
        Missing
    0.8
    0.0
    Notes
    [11] - Only for patients who had undergone a surgical resection.
    [12] - Only for patients who had undergone a surgical resection.
    Statistical analysis title
    		 Pathological remission | Chi-Square Test
    Comparison groups
    Cetuximab (ITT) v Control (ITT)
    Number of subjects included in analysis
    258
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.6
    Method
    		 Chi-squared
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.15
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.69
         upper limit
    		 1.93

    Secondary: SE | R0-resection

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    End point title
    		 SE | R0-resection
    End point description
    R0-resection was defined as no residual tumor (meaning thus neither microscopic nor macroscopic). It was a macroscopically complete removal by a non-contaminated operation with wide or radical margin. The R0-resection rate was reported only for patients who had undergone a surgical resection.
    End point type
    Secondary
    End point timeframe
    After surgery.
    End point values
    		 Cetuximab (ITT) Control (ITT)
    Number of subjects analysed
    131 [13]
    127 [14]
    Units: Patients (%)
    number (not applicable)
        Resection R0
    95.4
    96.6
        Resection R1
    3.8
    3.1
        Missing
    0.8
    0.0
    Notes
    [13] - Only for patients who had undergone a surgical resection.
    [14] - Only for patients who had undergone a surgical resection.
    Statistical analysis title
    		 R0-resection | Fisher's exact test
    Comparison groups
    Cetuximab (ITT) v Control (ITT)
    Number of subjects included in analysis
    258
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 1
    Method
    		 Fisher exact
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.81
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.21
         upper limit
    		 3.1

    Secondary: SE | Completion of therapy

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    End point title
    		 SE | Completion of therapy
    End point description
    Completion of therapy was defined as: (1) Two cycles of neoadjuvant chemo(immuno)therapy (dose reductions are allowed); (2) At least 39.6 Gy of RT together with at least 75% of the doses of each drug of the concomitant chemo(immuno)therapy; (3) Performed surgery (independent of resection status); (4) Being alive 60 days postoperatively; (5) At least five of the six doses of adjuvant cetuximab therapy (arm A).
    End point type
    Secondary
    End point timeframe
    At particular study milestones.
    End point values
    		 Cetuximab Control
    Number of subjects analysed
    149
    151
    Units: Patients (%)
    number (not applicable)
        Two cycles of neoadjuvant therapy
    96.0
    96.7
        At least 39.6 Gy of RT
    92.6
    92.1
        At least 75% of the doses of each drug of RCT
    85.2
    88.7
        Was surgery performed?
    88.6
    86.1
        Alive 60 days postoperatively
    85.9
    82.1
        At least five doses of adjuvant cetuximab therapy
    53.7
    0
        Completion of therapy
    48.3
    72.8
    No statistical analyses for this end point

    Secondary: SE | In-hospital mortality

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    End point title
    		 SE | In-hospital mortality
    End point description
    In-hospital mortality was defined as any form of death (therapy, cancer or other related) occurring after surgery but while the patient remained in hospital.
    End point type
    Secondary
    End point timeframe
    After surgery.
    End point values
    		 Cetuximab (ITT) Control (ITT)
    Number of subjects analysed
    132 [15]
    130 [16]
    Units: Patients (%)
        number (not applicable)
    6.1
    3.1
    Notes
    [15] - Only for postoperative patients.
    [16] - Only for postoperative patients.
    No statistical analyses for this end point

    Secondary: SE | Compliance with radiotherapy standards

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    End point title
    		 SE | Compliance with radiotherapy standards
    End point description
    The compliance with radiotherapy standards was assessed within the quality assurance program for selected patients. Deviations of radiotherapy were assessed within the quality assurance program. They were divided into major and minor deviations: [A] Major deviations: (i) The 95% isodose does not encompass the complete GTV; (ii) Less than 85% of the PTV are encompassed by the 95% isodose, if normal tissue restrictions are not fully exploited; (iii) Exceeding one or more normal tissue dose restriction by > 15%; (iv) Largely inadequate volumes of interest (GTV, CTV, PTV, normal tissue) or irradiated volumes [B] Minor deviations: (i) Any deviations not fulfilling the criteria of major deviations
    End point type
    Secondary
    End point timeframe
    From randomization.
    End point values
    		 Cetuximab (ITT) Control (ITT)
    Number of subjects analysed
    37 [17]
    41 [18]
    Units: Patients (%)
    number (not applicable)
        Largely inadequate volumes or irradiated volumens
    2.7
    0
        The 95% isodose does not encompass complete GTV
    0
    2.4
        Minor deviations
    43.2
    65.9
    Notes
    [17] - Only selected patients of the assurance program.
    [18] - Only selected patients of the assurance program.
    No statistical analyses for this end point

    Other pre-specified: PE | PFS rate

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    End point title
    		 PE | PFS rate
    End point description
    End point type
    Other pre-specified
    End point timeframe
    At 1, 2, 3, 4 and 5 years.
    End point values
    		 Cetuximab (ITT) Control (ITT)
    Number of subjects analysed
    148
    149
    Units: PFS rate (%)
    number (confidence interval 95%)
        1 year
    74.3 (66.3 to 80.7)
    72.7 (64.7 to 79.1)
        2 years
    58.3 (49.8 to 65.8)
    50.0 (41.7 to 57.8)
        3 years
    51.2 (42.8 to 59.0)
    41.0 (33.0 to 49.8)
        4 years
    49.0 (40.6 to 56.9)
    38.8 (30.9 to 46.7)
        5 years
    47.6 (39.2 to 55.5)
    38.1 (30.2 to 45.9)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From randomization until end of study, i.e. during induction phase, RC(I)T and within 30 days after its end. Late AEs were followed up in the follow-up phase.
    Adverse event reporting additional description
    Patients were instructed by the investigator to report the occurrence of any AE. The investigator assessed and recorded all AEs observed during the study. Late AEs (in the Follow-up phase) were observed until disease progression.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.0
    Reporting groups
    Reporting group title
    Cetuximab
    Reporting group description
    		 Cetuximab arm at baseline.

    Reporting group title
    Control
    Reporting group description
    		 Control arm at baseline.

    Serious adverse events
    		 Cetuximab Control
    Total subjects affected by serious adverse events
         subjects affected / exposed
    111 / 149 (74.50%)
    109 / 151 (72.19%)
         number of deaths (all causes)
    72
    85
         number of deaths resulting from adverse events
    15
    17
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Anal cancer
         subjects affected / exposed
    0 / 149 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder cancer
         subjects affected / exposed
    1 / 149 (0.67%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric cancer
         subjects affected / exposed
    1 / 149 (0.67%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypopharyngeal cancer
    Additional description: One patient in Cetuximab arm: Laryngeal-hypopharyngeal cancer Grade 3.
         subjects affected / exposed
    2 / 149 (1.34%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-small cell lung cancer
         subjects affected / exposed
    0 / 149 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Oropharyngeal cancer
         subjects affected / exposed
    0 / 149 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatic carcinoma
         subjects affected / exposed
    1 / 149 (0.67%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Prostate cancer
         subjects affected / exposed
    1 / 149 (0.67%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestine neuroendocrine tumour
         subjects affected / exposed
    0 / 149 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    1 / 149 (0.67%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thyroid neoplasm
    Additional description: Extrathyroidal manifestation of pre-existing papillary thyroid carcinoma requiring surgery Grade 3.
         subjects affected / exposed
    0 / 149 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transitional cell carcinoma
         subjects affected / exposed
    1 / 149 (0.67%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Arterial haemorrhage
         subjects affected / exposed
    1 / 149 (0.67%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Femoral artery embolism
    Additional description: Peripheral ischemia due to (recurrent) acute arterial femorocrural embolism.
         subjects affected / exposed
    1 / 149 (0.67%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
    Additional description: One patient: Syncope Grade 3 associated with hypotension due to bleeding of tumor and decompensated antihypertensive therapy; one patient: Tachycardia Grade 1 (NOS), hypotension Grade 3, cold sweating.
         subjects affected / exposed
    2 / 149 (1.34%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphorrhoea
         subjects affected / exposed
    0 / 149 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Orthostatic hypotension
    Additional description: Dizziness Grade 3 due to orthostatic hypotension Grade 3 and paroxysmal benign vertigo.
         subjects affected / exposed
    1 / 149 (0.67%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral artery occlusion
    Additional description: Arterial occlusion Grade 3 (A. iliaca) with existing overcross bypass due to chronic peripheral artery occlusion disease requiring thrombectomy.
         subjects affected / exposed
    1 / 149 (0.67%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Venous thrombosis
    Additional description: One patient in Control arm: Venous thrombosis Grade2, diarrhea Grade2, renal insufficiency Grade 2.
         subjects affected / exposed
    3 / 149 (2.01%)
    2 / 151 (1.32%)
         occurrences causally related to treatment / all
    3 / 3
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Jejunostomy closure
         subjects affected / exposed
    0 / 149 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
    Additional description: One patient in Cetuximab arm: Pain Grade 3 (retrosternal) with nausea Grade 2, vomiting Grade 2
         subjects affected / exposed
    2 / 149 (1.34%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chills
    Additional description: One patient in Cetuximab arm: Fever Grade 1, chills Grade2; one patient in Control arm: Fever Grade 1, chills Grade1.
         subjects affected / exposed
    2 / 149 (1.34%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Complication associated with device
    Additional description: One event: Abdominal and peritoneal infection Grade 4 (abscess formation) in context of jejunal feeding tube dysfunction requiring open small intestine resection; other event: Abdominal pain G2 in the context of removal of defective feeding tube
         subjects affected / exposed
    1 / 149 (0.67%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehiscence
    Additional description: Patient in Cetuximab arm: Cervical anastomosis dehiscence with abscess formation (wound infection Grade 3).
         subjects affected / exposed
    1 / 149 (0.67%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
    Additional description: One patient: Fatigue Grade 3 leading to vertigo Grade 3; one patient: Hypotension Grade 2 in context of fatigue Grade 3.
         subjects affected / exposed
    3 / 149 (2.01%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    1 / 149 (0.67%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucosal inflammation
    Additional description: Fever Grade 1 in context of mucositis Grade 3.
         subjects affected / exposed
    1 / 149 (0.67%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 149 (0.67%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    1 / 149 (0.67%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 149 (0.67%)
    2 / 151 (1.32%)
         occurrences causally related to treatment / all
    0 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden death
    Additional description: Sudden death Grade 5 arrhythmia suspected.
         subjects affected / exposed
    1 / 149 (0.67%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    3 / 149 (2.01%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome
    Additional description: One patient in Cetuximab arm: Respiratory insufficiency due to ARDS in the context of pulmonary CMV infection (lung infection).
         subjects affected / exposed
    2 / 149 (1.34%)
    4 / 151 (2.65%)
         occurrences causally related to treatment / all
    2 / 2
    4 / 4
         deaths causally related to treatment / all
    1 / 1
    1 / 1
    Aspiration
         subjects affected / exposed
    1 / 149 (0.67%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atelectasis
         subjects affected / exposed
    1 / 149 (0.67%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chylothorax
         subjects affected / exposed
    3 / 149 (2.01%)
    3 / 151 (1.99%)
         occurrences causally related to treatment / all
    2 / 3
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 149 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epistaxis
    Additional description: Epistaxis Grade 3 (phenprocoumon treatment), bronchial infection Grade 2 (normal Absolute Neutrophil Count).
         subjects affected / exposed
    1 / 149 (0.67%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hiccups
    Additional description: Hiccups Grade 3 in context of dysphagia Grade 2 and vomiting Grade 2.
         subjects affected / exposed
    1 / 149 (0.67%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophagobronchial fistula
         subjects affected / exposed
    1 / 149 (0.67%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
    Additional description: One patient in Cetuximab arm: Pneumothorax Grade 2 after lung biopsy, one patient in Control arm: Pain (periumbilical and epigastral) Grade 3 in context of seropneumothorax.
         subjects affected / exposed
    1 / 149 (0.67%)
    2 / 151 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
    Additional description: One patient in Control arm: Postoperative death due to pulmonary embolism (suspected) Grade 5.
         subjects affected / exposed
    3 / 149 (2.01%)
    2 / 151 (1.32%)
         occurrences causally related to treatment / all
    3 / 3
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Pulmonary mass
    Additional description: Multiple bilateral pulmonary nodules requiring video-assisted thoracoscopic resection (histologically inflammation, no malignancy) Grade 3.
         subjects affected / exposed
    1 / 149 (0.67%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
    Additional description: One patient: Respiratory failure Grade 5 due to chronic bronchitis with recurrent respiratory infections, extreme post-surgical muscular weakness.
         subjects affected / exposed
    0 / 149 (0.00%)
    3 / 151 (1.99%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Tracheal fistula
    Additional description: One patient: Weight loss Grade 2 due to anorexia and adipsia in context of tracheal fistula.
         subjects affected / exposed
    2 / 149 (1.34%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Anxiety
    Additional description: Confusion Grade 1 in context of anxiety attack Grade 1.
         subjects affected / exposed
    1 / 149 (0.67%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Completed suicide
         subjects affected / exposed
    0 / 149 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Drug abuse
         subjects affected / exposed
    0 / 149 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    1 / 149 (0.67%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Product issues
    Device dislocation
    Additional description: One patient: Extravasation with inflammation due to port-a-cath needle dislocation Grade 2; one patient: Vomiting Grade 2 due to dislocated stent requiring stent removal.
         subjects affected / exposed
    2 / 149 (1.34%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    1 / 149 (0.67%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Body temperature increased
         subjects affected / exposed
    1 / 149 (0.67%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    C-reactive protein increased
    Additional description: One patient: Fever Grade 1, elevated CRP; one patient: Fever Grade 1, elevated CRP, suspicion of esophageal fistula.
         subjects affected / exposed
    2 / 149 (1.34%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Weight decreased
         subjects affected / exposed
    1 / 149 (0.67%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    White blood cell count decreased
    Additional description: Two patients in Cetuximab arm: Fever Grade 1, white blood cell decreased Grade 3.
         subjects affected / exposed
    2 / 149 (1.34%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Anastomotic leak
    Additional description: Revision surgery due to persistent thoracic anastomotic leak with persistent broncho-esophageal fistula Grade 4.
         subjects affected / exposed
    0 / 149 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anastomotic stenosis
    Additional description: One patient in Control arm: Dysphagia Grade 1 due to cervical anstomotic stenosis Grade 2; Two patients in Cetuximab arm: Dysphagia Grade 2 due to esophageal anastomotic stenosis (1); Esophag. obstruction Grade 3 (thoracic anastomosis stricture) (2)
         subjects affected / exposed
    2 / 149 (1.34%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anastomotic ulcer
    Additional description: Esophageal pain Grade 2 due to Candida esophagitis and thoracic anastomotic ulcers.
         subjects affected / exposed
    0 / 149 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
    Additional description: Bone fracture (femur) due to fall Grade 3.
         subjects affected / exposed
    1 / 149 (0.67%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal anastomotic leak
    Additional description: Gastrointestinal anastomotic leak in conjunction with various other conditions for 3 patients in Cetuximab arm and 3 patients in Control arm (e.g. fistula, pulmonary disorder/infection, requiring re-surgery).
         subjects affected / exposed
    9 / 149 (6.04%)
    15 / 151 (9.93%)
         occurrences causally related to treatment / all
    9 / 9
    15 / 15
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Gastrointestinal stoma complication
    Additional description: Local skin irritation due to leaking jejunostomy tube (pain Grade 3 skin).
         subjects affected / exposed
    1 / 149 (0.67%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Incisional hernia
    Additional description: Abdominal incisional hernia Grade 3 requiring omentoplasty.
         subjects affected / exposed
    0 / 149 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infusion related reaction
         subjects affected / exposed
    8 / 149 (5.37%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    8 / 8
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower limb fracture
    Additional description: Bone fracture (leg) due to trauma Grade 3.
         subjects affected / exposed
    0 / 149 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radiation oesophagitis
    Additional description: Patient in Cetuximab arm: Weight loss Grade (G)2 due to radiotherapy (RT)-induced esophagitis G3; two patients in Control arm: Dysphagia G3 due to RT induced esophagitis G2 [1] | Nausea G3, vomiting G3, gastritis due to post-RT esophagitis [2]).
         subjects affected / exposed
    1 / 149 (0.67%)
    3 / 151 (1.99%)
         occurrences causally related to treatment / all
    1 / 1
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal fracture
    Additional description: Back pain Grade 3 due to vertebra fracture (Th12 and L3) in context of osteoporosis.
         subjects affected / exposed
    1 / 149 (0.67%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound dehiscence
    Additional description: Wound dehiscence Grade 3 (hiatushernia).
         subjects affected / exposed
    0 / 149 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    2 / 149 (1.34%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Atrial flutter
    Additional description: Syncope Grade 3 in context of atrial flutter.
         subjects affected / exposed
    1 / 149 (0.67%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial tachycardia
         subjects affected / exposed
    0 / 149 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular block complete
    Additional description: Asystole Grade 4 due to AV-Block 3rd degree.
         subjects affected / exposed
    0 / 149 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
    Additional description: One patient in control arm: Cardiac arrest Grade 4 before extubtion after gastric pull-up.
         subjects affected / exposed
    1 / 149 (0.67%)
    2 / 151 (1.32%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorder
         subjects affected / exposed
    1 / 149 (0.67%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
    Additional description: One patient in Cetuximab arm: Cardiac failure Grade 5 with respiratory insufficiency; one patient in Control arm: Heart failure Grade 3 with consecutive dyspnea Grade 2
         subjects affected / exposed
    1 / 149 (0.67%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    1 / 149 (0.67%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Left ventricular dysfunction
    Additional description: Left ventricular systolic dysfunction Grade 4, dyspnea Grade 4.
         subjects affected / exposed
    0 / 149 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    1 / 149 (0.67%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericarditis constrictive
         subjects affected / exposed
    1 / 149 (0.67%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Right ventricular dysfunction
    Additional description: Pericardial effusion Grade 3 with right ventricular dysfunction Grade 3.
         subjects affected / exposed
    0 / 149 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular dysfunction
    Additional description: Acute dyspnea Grade 3 due to left ventricular dysfunction.
         subjects affected / exposed
    1 / 149 (0.67%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular fibrillation
         subjects affected / exposed
    0 / 149 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Nervous system disorders
    Cerebral ischaemia
         subjects affected / exposed
    0 / 149 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depressed level of consciousness
    Additional description: Depressed level of consciousness Grade 3 due to opioide use.
         subjects affected / exposed
    0 / 149 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
    Additional description: Dizziness Grade 3, nausea Grade 2, fatigue Grade 2.
         subjects affected / exposed
    1 / 149 (0.67%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    1 / 149 (0.67%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Laryngeal nerve palsy
         subjects affected / exposed
    1 / 149 (0.67%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post herpetic neuralgia
    Additional description: Fatigue Grade 2 in context of post-zoster neutralgia.
         subjects affected / exposed
    0 / 149 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 149 (0.67%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vocal cord paresis
    Additional description: Aphonia Grade 3 due to vocal cord paresis.
         subjects affected / exposed
    0 / 149 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
    Additional description: One patient in Control arm: Fatigue grade 2 in context of anemia grade 3.
         subjects affected / exposed
    0 / 149 (0.00%)
    3 / 151 (1.99%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
    Additional description: Febrile neutropenia in conjunction with other conditions for 2 patients in Cetuximab arm (i.e. diarrhea/stomatitis [1]| diarrhea/platelet count decreased [2]) and 3 patients in Control arm (i.e. diarrhea [1]| dysphagia [2] | diarrhea/vomiting [3]).
         subjects affected / exposed
    10 / 149 (6.71%)
    10 / 151 (6.62%)
         occurrences causally related to treatment / all
    10 / 10
    11 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
    Additional description: Neutropenia in conjunction with other conditions for 2 patients in Control arm (i.e. colitis [1] | leukocytopenia [2]).
         subjects affected / exposed
    1 / 149 (0.67%)
    2 / 151 (1.32%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 149 (0.67%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Deafness neurosensory
    Additional description: Hearing impaired Grade 3 (labyrinthine hearing loss)
         subjects affected / exposed
    0 / 149 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tinnitus
         subjects affected / exposed
    1 / 149 (0.67%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Dacryostenosis acquired
    Additional description: Docetaxel induced lacrimal duct stenosis (watering eyes Grade 3) requiring surgery.
         subjects affected / exposed
    0 / 149 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 149 (0.67%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
    Additional description: One patient in Cetuximab arm: Diarrhea Grade 3 due to colitis Grade 3; one patient in Control arm: Diarrhea Grade 3 due to pancolitis, urinary tract infection Grade 3
         subjects affected / exposed
    3 / 149 (2.01%)
    2 / 151 (1.32%)
         occurrences causally related to treatment / all
    2 / 3
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
    Additional description: Abdominal pain Grade 2 due to constipation Grade 2.
         subjects affected / exposed
    1 / 149 (0.67%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diaphragmatic hernia
    Additional description: One patient: Small intestinal obstruction Grade 3 due to diaphragmatic herniation; one patient: Subileus Grade 3 due to diaphragmatic hernia requiring surgical intestinal reposition.
         subjects affected / exposed
    4 / 149 (2.68%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    5 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
    Additional description: Diarrhoea in conjunction with other conditions for 3 patients in Cetuximab arm (i.e. dehydration [1]| two events (dehydration +/- hypokalemia) [2] | worsening of general condition [3]) and 2 patients in Control arm (i.e. fatigue[1] | dehydration [2])
         subjects affected / exposed
    5 / 149 (3.36%)
    7 / 151 (4.64%)
         occurrences causally related to treatment / all
    5 / 6
    7 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal obstruction
    Additional description: Duodenal obstruction Grade 3 due to postoperative adhesions followed lung infection Grade 5.
         subjects affected / exposed
    0 / 149 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Duodenal perforation
         subjects affected / exposed
    0 / 149 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer haemorrhage
    Additional description: One patient: Dyspnea Grade 3 and anorexia Grade 3 due to anemia Grade 4 associated with a bleeding ulcer of the duodenal bulbus.
         subjects affected / exposed
    2 / 149 (1.34%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer perforation
    Additional description: Abdominal pain Grade 3 due to peritonitis secondary to perforated duodenal ulcer Grade 3 related to premedication (dexamethasone) and concomitant medication (acetyl salicylic acid).
         subjects affected / exposed
    1 / 149 (0.67%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspepsia
         subjects affected / exposed
    0 / 149 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphagia
    Additional description: Dysphagia in conjunction with various other conditions for 4 patients in Cetuximab arm and 8 patients in Control arm (including aspiration, fever, nausea, vomiting and others).
         subjects affected / exposed
    15 / 149 (10.07%)
    24 / 151 (15.89%)
         occurrences causally related to treatment / all
    15 / 19
    20 / 24
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enteritis
    Additional description: Syncope due to enteritis Grade 2 with dehydration Grade 2.
         subjects affected / exposed
    0 / 149 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric fistula
    Additional description: Cervical abscess, gastric fistula Grade 3
         subjects affected / exposed
    1 / 149 (0.67%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric haemorrhage
    Additional description: One patient: Gastric hemorrhage Grade 3 due to ulcers
         subjects affected / exposed
    2 / 149 (1.34%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric stenosis
         subjects affected / exposed
    1 / 149 (0.67%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
    Additional description: Acute epigastric pain Grade 3 in context of esophagitis Grade 3 and antrum gastritis Grade 3.
         subjects affected / exposed
    0 / 149 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis erosive
    Additional description: Dehydration Grade 1 and nausea Grade 1 associated with erosive antrum gastritis.
         subjects affected / exposed
    1 / 149 (0.67%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    2 / 149 (1.34%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal motility disorder
    Additional description: Patient in Cetuximab arm: Postoperative intestinal motility disturbance Grade 2 with dehydration Grade 2 and weight loss Grade 2; patient in Control arm: Functional passage disturbance of the gastric sleeve Grade 3 with consecutive vomiting Grade 3
         subjects affected / exposed
    1 / 149 (0.67%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal necrosis
    Additional description: Gastric conduit necrosis requiring re-surgery Grade 4.
         subjects affected / exposed
    1 / 149 (0.67%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal pain
    Additional description: Gastrointestinal pain Grade 3 due to nephro-and choledocholithiasis.
         subjects affected / exposed
    0 / 149 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrooesophageal reflux disease
    Additional description: Dysphagia Grade 3 in context of reflux esophagitis.
         subjects affected / exposed
    0 / 149 (0.00%)
    2 / 151 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
    Additional description: Ileus Grade 4 requiring laparotomy and adhesiolysis.
         subjects affected / exposed
    3 / 149 (2.01%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal ischaemia
         subjects affected / exposed
    1 / 149 (0.67%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestine perforation
    Additional description: Colonic perforation Grade 4 after colonoscopy with polypectomy.
         subjects affected / exposed
    0 / 149 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mechanical ileus
    Additional description: Death due to adhesion ileus with ischemic intestinal wall necrosis (Grade 5).
         subjects affected / exposed
    0 / 149 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Mouth haemorrhage
    Additional description: Oral hemorrhage Grade 2 in context of anticoagulation.
         subjects affected / exposed
    1 / 149 (0.67%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
    Additional description: Nausea in conjunction with other conditions for 3 patients in Cetuximab arm (i.e.anorexia/dehydration [1]| abdominal pain [2]| esophageal stent insertion [3]) and 2 patients in Control arm (i.e. anorexia/insomnia [1] | dehydration [2]).
         subjects affected / exposed
    7 / 149 (4.70%)
    3 / 151 (1.99%)
         occurrences causally related to treatment / all
    8 / 9
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal fistula
    Additional description: One patient in Control arm: Esophageal fistula Grade 4 progressing to mediastinitis.
         subjects affected / exposed
    2 / 149 (1.34%)
    2 / 151 (1.32%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Oesophageal motility disorder
    Additional description: One event: Dysphagia Grade 3 in context of functional esophageal hiatus motility disturbance; other event: Vomiting Grade 3 in context of functional esophageal hiatus motility disturbance.
         subjects affected / exposed
    1 / 149 (0.67%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal obstruction
    Additional description: Patient in Cetuximab arm: Dysphagia Grade 3 due to subtotal tumor related esophageal obstruction; patient in Control arm: Dysphagia Grade 3 due to esophageal obstruction with food remainder.
         subjects affected / exposed
    1 / 149 (0.67%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal perforation
         subjects affected / exposed
    0 / 149 (0.00%)
    2 / 151 (1.32%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal stenosis
    Additional description: One patient in Control arm: Dehydration Grade 3 due to esophageal stenosis, gastric tube insertion.
         subjects affected / exposed
    2 / 149 (1.34%)
    2 / 151 (1.32%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal ulcer
    Additional description: Esophageal ulcer Grade 3 with esophageal hemorrhage Grade 2.
         subjects affected / exposed
    0 / 149 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophagitis
    Additional description: Oesophagitis in conjunction with other conditions for 2 patients in Cetuximab arm (anorexia/dehydration/dysphagia [1] | partial ileus [2]) and 3 patients in Control arm (epigastric pain [1] | pain/dysphagia [2], odynophagia/dysphagia/nausea [3]).
         subjects affected / exposed
    6 / 149 (4.03%)
    10 / 151 (6.62%)
         occurrences causally related to treatment / all
    5 / 6
    11 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophagitis haemorrhagic
    Additional description: Fever Grade 3 in context of infection Grade 3 and hemorrhagic esophagitis Grade 3 with persistent nausea.
         subjects affected / exposed
    0 / 149 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophagitis ulcerative
         subjects affected / exposed
    1 / 149 (0.67%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumoperitoneum
    Additional description: Pneumoperitoneum (Grade 3) consecutive to feeding tube insertion.
         subjects affected / exposed
    1 / 149 (0.67%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stomatitis
    Additional description: Patient in Cetuximab arm: Stomatitis/Pharyngitis Grade 3.
         subjects affected / exposed
    1 / 149 (0.67%)
    2 / 151 (1.32%)
         occurrences causally related to treatment / all
    1 / 1
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subileus
    Additional description: Subileus G2 consecutive to laparotomical adhesiolysis before trial treatment start
         subjects affected / exposed
    1 / 149 (0.67%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tooth disorder
    Additional description: Fever Grade 1 in context of odontopathy.
         subjects affected / exposed
    1 / 149 (0.67%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
    Additional description: Vomiting in conjunction with various other conditions for 4 patients in Cetuximab arm and 5 patients in Control arm (including chest pain, nausea, pain, anorexia, dehydration, syncope and others).
         subjects affected / exposed
    4 / 149 (2.68%)
    8 / 151 (5.30%)
         occurrences causally related to treatment / all
    4 / 4
    8 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal adhesions
    Additional description: Abdominal pain due to intestinal adhesions and internal herniation.
         subjects affected / exposed
    1 / 149 (0.67%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct stenosis
    Additional description: Infectious choledochus stenosis Grade 3 due to dislocated choledochus stent.
         subjects affected / exposed
    0 / 149 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cirrhosis alcoholic
    Additional description: Liver cirrhosis (alcohol induced Grade 3) with ascites Grade 2 requiring drain insertion.
         subjects affected / exposed
    1 / 149 (0.67%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Perforation bile duct
    Additional description: Abdominal pain Grade 4 due to biliary peritonitis in context of Ductus choledochus leak requiring revision laparotomy.
         subjects affected / exposed
    0 / 149 (0.00%)
    1 / 151 (0.66%)
         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: Acute kidney injury in conjunction with other conditions for 3 patients in Cetuximab arm (i.e. nausea/diarrhea [1]| edema limbs [2]| requiring hemodialysis [3]) and 1 patient in Control arm (i.e. vomiting).
         subjects affected / exposed
    9 / 149 (6.04%)
    2 / 151 (1.32%)
         occurrences causally related to treatment / all
    8 / 9
    2 / 2
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Nephrolithiasis
    Additional description: Renal colic Grade 3 due to nephrolithiasis, temporary uretral splint insertion.
         subjects affected / exposed
    1 / 149 (0.67%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Bone erosion
    Additional description: Back pain Grade 3 due to progressive Th6 errosion in context of upper mediastinal infection (Staph. aureus).
         subjects affected / exposed
    1 / 149 (0.67%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gouty arthritis
    Additional description: Pseudo-gout and gout-arthritis Grade 3 (knee).
         subjects affected / exposed
    1 / 149 (0.67%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteitis
    Additional description: Osteitis (ventral rib 5) with chronic super-infection (Pseudomonas aeruginosa) in context of wound healing disorder Grade 3 after protocol surgery.
         subjects affected / exposed
    1 / 149 (0.67%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal pain
         subjects affected / exposed
    1 / 149 (0.67%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal infection
    Additional description: Abdominal infection due to dislocated PEG.
         subjects affected / exposed
    1 / 149 (0.67%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal wall abscess
    Additional description: Abdominal pain G3 due to abscess formation (abdominal wall) requiring revision and percutaneous drainage.
         subjects affected / exposed
    1 / 149 (0.67%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal abscess
         subjects affected / exposed
    1 / 149 (0.67%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    1 / 149 (0.67%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Biliary tract infection
         subjects affected / exposed
    0 / 149 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 149 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Catheter site abscess
         subjects affected / exposed
    1 / 149 (0.67%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Catheter site infection
         subjects affected / exposed
    1 / 149 (0.67%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 149 (0.67%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
    Additional description: One patient in Control arm: Port-a-cath infection Grade 3 requiring surgical revision.
         subjects affected / exposed
    2 / 149 (1.34%)
    2 / 151 (1.32%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related sepsis
         subjects affected / exposed
    0 / 149 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Empyema
         subjects affected / exposed
    1 / 149 (0.67%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endophthalmitis
    Additional description: Endophthalmitis Grade 3 with preceding keratitis Grade 3 and consecutive retinal detachment Grade 3.
         subjects affected / exposed
    1 / 149 (0.67%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal infection
    Additional description: Fever Grade 1 due to suspected Gastrointestinal infection, diarrhea Grade 1, vomiting Grade 1.
         subjects affected / exposed
    1 / 149 (0.67%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
    Additional description: One patient in Cetuximab arm: Fever Grade 1 in context of infection of unknown origin.
         subjects affected / exposed
    2 / 149 (1.34%)
    2 / 151 (1.32%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infectious pleural effusion
    Additional description: Cervical esophageal anastomotic leak Grade 3, pleural effusion Grade 3, pleural empyema Grade 3.
         subjects affected / exposed
    0 / 149 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral discitis
    Additional description: Back pain Grade 3 (lumbal spine) due to intervertebral discitis (metastasis unlikely).
         subjects affected / exposed
    1 / 149 (0.67%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Kidney infection
         subjects affected / exposed
    1 / 149 (0.67%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Localised infection
    Additional description: Patient in Cetuximab arm: Clavus infection Grade 3 (big toe) requiring clavus ablation.
         subjects affected / exposed
    1 / 149 (0.67%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal candidiasis
         subjects affected / exposed
    3 / 149 (2.01%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    3 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Penile infection
         subjects affected / exposed
    0 / 149 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural infection
         subjects affected / exposed
    1 / 149 (0.67%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
    Additional description: Pneumonia in conjunction with various other conditions for 5 patients in Cetuximab arm and 3 patients in Control arm (including fever, thromboembolic event, esophageal anastomotic leak, respiratory failure/insufficiency and others).
         subjects affected / exposed
    8 / 149 (5.37%)
    8 / 151 (5.30%)
         occurrences causally related to treatment / all
    7 / 8
    8 / 8
         deaths causally related to treatment / all
    2 / 2
    1 / 1
    Pneumonia aspiration
    Additional description: One patient in Control arm: Respiratory failure Grade 5 in context of aspiration pneumonia.
         subjects affected / exposed
    1 / 149 (0.67%)
    2 / 151 (1.32%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Pseudomonas infection
    Additional description: Pseudomonas aeruginosa infection Grade 3 with fever Grade 2.
         subjects affected / exposed
    1 / 149 (0.67%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
    Additional description: Sepsis in conjunction with various other conditions for 6 patients in Cetuximab arm and 5 patients in Control arm (including pleural empyema, lung infection/respiratory insufficiency, febrile neutropenia, and others).
         subjects affected / exposed
    7 / 149 (4.70%)
    7 / 151 (4.64%)
         occurrences causally related to treatment / all
    5 / 7
    7 / 7
         deaths causally related to treatment / all
    1 / 1
    3 / 3
    Septic shock
    Additional description: Patient in Cetuximab arm: Pulmonary fibrosis leading to pulmonary infection and subsequent septic shock Grade 5.
         subjects affected / exposed
    1 / 149 (0.67%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    1 / 1
    Systemic bacterial infection
    Additional description: Systemic Enterobacter infection Grade 3.
         subjects affected / exposed
    0 / 149 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
    Additional description: Upper respiratory infection with fever Grade 2.
         subjects affected / exposed
    1 / 149 (0.67%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    1 / 149 (0.67%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Cachexia
         subjects affected / exposed
    0 / 149 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Decreased appetite
    Additional description: Decreased appetite in conjunction with other conditions for 4 patients in Cetuximab arm (i.e. dehydration [1]| diarrhea [2]| dysgeusia/diarrhea [3]; dehydration [4]) and 1 patient in Control arm (i.e. fatigue/dehydration/depression).
         subjects affected / exposed
    5 / 149 (3.36%)
    6 / 151 (3.97%)
         occurrences causally related to treatment / all
    5 / 5
    5 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
    Additional description: One patient in Control arm: Dehydration Grade 3 with presyncope Grade 2, nausea Grade 3, dysphagia Grade 2, diarrhea Grade 1.
         subjects affected / exposed
    2 / 149 (1.34%)
    3 / 151 (1.99%)
         occurrences causally related to treatment / all
    2 / 2
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes mellitus
    Additional description: Hyperglycemia Grade 3 in context of diabetes.
         subjects affected / exposed
    0 / 149 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gout
         subjects affected / exposed
    0 / 149 (0.00%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercalcaemia
    Additional description: Hypercalcemia Grade 4 (following calcium substitution for hypocalcemia), creatinine increase Grade 3.
         subjects affected / exposed
    1 / 149 (0.67%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypernatraemia
         subjects affected / exposed
    1 / 149 (0.67%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypocalcaemia
    Additional description: Hypocalcemia Grade 4, acute kidney injury Grade 1, seizure Grade 3, worsening of general condition Grade 3.
         subjects affected / exposed
    1 / 149 (0.67%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
    Additional description: One patient in Cetuximab arm: Hypokalemia Grade 3, nausea Grade 2, vomiting Grade 2, fatigue Grade 2; one patient in Crontrol arm: Hypokalemia Grade 4 due to dysphagia Grade 3.
         subjects affected / exposed
    2 / 149 (1.34%)
    1 / 151 (0.66%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypomagnesaemia
    Additional description: One patient: Hypomagnesemia Grade 4, esophagitis Grade 3, fatigue Grade 3.
         subjects affected / exposed
    2 / 149 (1.34%)
    0 / 151 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    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
    		 Cetuximab Control
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    149 / 149 (100.00%)
    151 / 151 (100.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    17 / 149 (11.41%)
    19 / 151 (12.58%)
         occurrences all number
    27
    30
    Hypotension
         subjects affected / exposed
    18 / 149 (12.08%)
    15 / 151 (9.93%)
         occurrences all number
    20
    16
    Embolism
         subjects affected / exposed
    11 / 149 (7.38%)
    7 / 151 (4.64%)
         occurrences all number
    15
    9
    General disorders and administration site conditions
    Oedema peripheral
         subjects affected / exposed
    11 / 149 (7.38%)
    9 / 151 (5.96%)
         occurrences all number
    14
    12
    Fatigue
         subjects affected / exposed
    108 / 149 (72.48%)
    103 / 151 (68.21%)
         occurrences all number
    217
    179
    Pyrexia
         subjects affected / exposed
    25 / 149 (16.78%)
    17 / 151 (11.26%)
         occurrences all number
    27
    19
    Non-cardiac chest pain
         subjects affected / exposed
    8 / 149 (5.37%)
    14 / 151 (9.27%)
         occurrences all number
    8
    16
    Pain
         subjects affected / exposed
    12 / 149 (8.05%)
    11 / 151 (7.28%)
         occurrences all number
    13
    12
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    13 / 149 (8.72%)
    6 / 151 (3.97%)
         occurrences all number
    13
    7
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    30 / 149 (20.13%)
    28 / 151 (18.54%)
         occurrences all number
    37
    30
    Dyspnoea
         subjects affected / exposed
    34 / 149 (22.82%)
    14 / 151 (9.27%)
         occurrences all number
    44
    18
    Epistaxis
         subjects affected / exposed
    17 / 149 (11.41%)
    12 / 151 (7.95%)
         occurrences all number
    20
    14
    Dysphonia
         subjects affected / exposed
    4 / 149 (2.68%)
    8 / 151 (5.30%)
         occurrences all number
    4
    11
    Psychiatric disorders
    Depression
         subjects affected / exposed
    10 / 149 (6.71%)
    7 / 151 (4.64%)
         occurrences all number
    11
    8
    Insomnia
         subjects affected / exposed
    10 / 149 (6.71%)
    11 / 151 (7.28%)
         occurrences all number
    11
    11
    Investigations
    Blood alkaline phosphatase increased
         subjects affected / exposed
    12 / 149 (8.05%)
    5 / 151 (3.31%)
         occurrences all number
    16
    6
    Aspartate aminotransferase increased
         subjects affected / exposed
    10 / 149 (6.71%)
    3 / 151 (1.99%)
         occurrences all number
    11
    3
    Blood creatinine increased
         subjects affected / exposed
    25 / 149 (16.78%)
    36 / 151 (23.84%)
         occurrences all number
    33
    48
    Neutrophil count decreased
         subjects affected / exposed
    33 / 149 (22.15%)
    36 / 151 (23.84%)
         occurrences all number
    37
    37
    Pancreatic enzymes decreased
         subjects affected / exposed
    12 / 149 (8.05%)
    17 / 151 (11.26%)
         occurrences all number
    13
    17
    Platelet count decreased
         subjects affected / exposed
    95 / 149 (63.76%)
    94 / 151 (62.25%)
         occurrences all number
    102
    97
    Weight decreased
         subjects affected / exposed
    66 / 149 (44.30%)
    57 / 151 (37.75%)
         occurrences all number
    110
    89
    White blood cell count decreased
         subjects affected / exposed
    22 / 149 (14.77%)
    17 / 151 (11.26%)
         occurrences all number
    27
    18
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    18 / 149 (12.08%)
    14 / 151 (9.27%)
         occurrences all number
    23
    18
    Dysaesthesia
         subjects affected / exposed
    8 / 149 (5.37%)
    5 / 151 (3.31%)
         occurrences all number
    9
    5
    Dysgeusia
         subjects affected / exposed
    52 / 149 (34.90%)
    46 / 151 (30.46%)
         occurrences all number
    84
    73
    Paraesthesia
         subjects affected / exposed
    17 / 149 (11.41%)
    17 / 151 (11.26%)
         occurrences all number
    22
    22
    Peripheral sensory neuropathy
         subjects affected / exposed
    21 / 149 (14.09%)
    25 / 151 (16.56%)
         occurrences all number
    33
    35
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    102 / 149 (68.46%)
    112 / 151 (74.17%)
         occurrences all number
    168
    190
    Ear and labyrinth disorders
    Hypoacusis
         subjects affected / exposed
    8 / 149 (5.37%)
    3 / 151 (1.99%)
         occurrences all number
    15
    3
    Tinnitus
         subjects affected / exposed
    10 / 149 (6.71%)
    18 / 151 (11.92%)
         occurrences all number
    14
    24
    Vertigo
         subjects affected / exposed
    13 / 149 (8.72%)
    8 / 151 (5.30%)
         occurrences all number
    17
    9
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    35 / 149 (23.49%)
    25 / 151 (16.56%)
         occurrences all number
    45
    28
    Constipation
         subjects affected / exposed
    47 / 149 (31.54%)
    49 / 151 (32.45%)
         occurrences all number
    55
    57
    Diarrhoea
         subjects affected / exposed
    96 / 149 (64.43%)
    93 / 151 (61.59%)
         occurrences all number
    144
    121
    Dumping syndrome
         subjects affected / exposed
    8 / 149 (5.37%)
    10 / 151 (6.62%)
         occurrences all number
    8
    10
    Dyspepsia
         subjects affected / exposed
    15 / 149 (10.07%)
    25 / 151 (16.56%)
         occurrences all number
    15
    27
    Dysphagia
         subjects affected / exposed
    81 / 149 (54.36%)
    82 / 151 (54.30%)
         occurrences all number
    117
    111
    Oesophageal pain
         subjects affected / exposed
    9 / 149 (6.04%)
    14 / 151 (9.27%)
         occurrences all number
    9
    14
    Oesophageal stenosis
         subjects affected / exposed
    12 / 149 (8.05%)
    16 / 151 (10.60%)
         occurrences all number
    12
    16
    Oesophagitis
         subjects affected / exposed
    16 / 149 (10.74%)
    21 / 151 (13.91%)
         occurrences all number
    16
    23
    Gastrointestinal pain
         subjects affected / exposed
    5 / 149 (3.36%)
    9 / 151 (5.96%)
         occurrences all number
    7
    11
    Stomatitis
         subjects affected / exposed
    62 / 149 (41.61%)
    33 / 151 (21.85%)
         occurrences all number
    82
    39
    Nausea
         subjects affected / exposed
    97 / 149 (65.10%)
    104 / 151 (68.87%)
         occurrences all number
    153
    162
    Abdominal pain upper
         subjects affected / exposed
    8 / 149 (5.37%)
    8 / 151 (5.30%)
         occurrences all number
    8
    8
    Vomiting
         subjects affected / exposed
    64 / 149 (42.95%)
    56 / 151 (37.09%)
         occurrences all number
    85
    72
    Gastrooesophageal reflux disease
         subjects affected / exposed
    28 / 149 (18.79%)
    22 / 151 (14.57%)
         occurrences all number
    31
    26
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    63 / 149 (42.28%)
    66 / 151 (43.71%)
         occurrences all number
    116
    107
    Dry skin
         subjects affected / exposed
    34 / 149 (22.82%)
    6 / 151 (3.97%)
         occurrences all number
    49
    6
    Erythema multiforme
         subjects affected / exposed
    9 / 149 (6.04%)
    1 / 151 (0.66%)
         occurrences all number
    11
    1
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    15 / 149 (10.07%)
    4 / 151 (2.65%)
         occurrences all number
    28
    5
    Pruritus
         subjects affected / exposed
    13 / 149 (8.72%)
    2 / 151 (1.32%)
         occurrences all number
    15
    2
    Dermatitis acneiform
         subjects affected / exposed
    98 / 149 (65.77%)
    4 / 151 (2.65%)
         occurrences all number
    181
    5
    Rash maculo-papular
         subjects affected / exposed
    23 / 149 (15.44%)
    0 / 151 (0.00%)
         occurrences all number
    43
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    17 / 149 (11.41%)
    11 / 151 (7.28%)
         occurrences all number
    19
    15
    Pain in extremity
         subjects affected / exposed
    8 / 149 (5.37%)
    10 / 151 (6.62%)
         occurrences all number
    13
    10
    Infections and infestations
    Mucosal infection
         subjects affected / exposed
    8 / 149 (5.37%)
    5 / 151 (3.31%)
         occurrences all number
    8
    5
    Rash pustular
         subjects affected / exposed
    8 / 149 (5.37%)
    1 / 151 (0.66%)
         occurrences all number
    16
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    81 / 149 (54.36%)
    66 / 151 (43.71%)
         occurrences all number
    138
    100
    Hyperkalaemia
         subjects affected / exposed
    13 / 149 (8.72%)
    18 / 151 (11.92%)
         occurrences all number
    21
    22
    Hypocalcaemia
         subjects affected / exposed
    64 / 149 (42.95%)
    46 / 151 (30.46%)
         occurrences all number
    100
    62
    Hypokalaemia
         subjects affected / exposed
    65 / 149 (43.62%)
    44 / 151 (29.14%)
         occurrences all number
    101
    57
    Hypomagnesaemia
         subjects affected / exposed
    87 / 149 (58.39%)
    59 / 151 (39.07%)
         occurrences all number
    159
    90
    Hyponatraemia
         subjects affected / exposed
    53 / 149 (35.57%)
    47 / 151 (31.13%)
         occurrences all number
    80
    60
    Vitamin D deficiency
         subjects affected / exposed
    5 / 149 (3.36%)
    8 / 151 (5.30%)
         occurrences all number
    5
    8

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Jul 2010
    The protocol was updated to reflect the safety recommendations from Merck and Paul-Ehrlich-Institut.
    01 May 2011
    The protocol was updated to specify some safety issues and to make general clarifications and corrections.
    01 Jun 2012
    The protocol was updated to specify some scientific issues and to implement general clarifications and corrections.

    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.
    Limitations are that (1) the planned event rate for the primary analysis was not reached, (2) the inclusion of both SCC and adenocarcinoma patients, (3) lack of prospectively test for potential biomarkers of EGFR-inhibition.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/32111181
    http://www.ncbi.nlm.nih.gov/pubmed/33055589
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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