Flag of the European Union EU Clinical Trials Register Help

Clinical trials

The European Union Clinical Trials Register   allows you to search for protocol and results information on:
  • interventional clinical trials that were approved in the European Union (EU)/European Economic Area (EEA) under the Clinical Trials Directive 2001/20/EC
  • clinical trials conducted outside the EU/EEA that are linked to European paediatric-medicine development

    • EU/EEA interventional clinical trials approved under or transitioned to the Clinical Trial Regulation 536/2014 are publicly accessible through the
    Clinical Trials Information System (CTIS).

    The EU Clinical Trials Register currently displays   43873   clinical trials with a EudraCT protocol, of which   7292   are clinical trials conducted with subjects less than 18 years old.   The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).

    Phase 1 trials conducted solely on adults and that are not part of an agreed paediatric investigation plan (PIP) are not publicly available (see Frequently Asked Questions ).  
     
    Examples: Cancer AND drug name. Pneumonia AND sponsor name.
    How to search [pdf]
    Search Tips: Under advanced search you can use filters for Country, Age Group, Gender, Trial Phase, Trial Status, Date Range, Rare Diseases and Orphan Designation. For these items you should use the filters and not add them to your search terms in the text field.
    Advanced Search: Search tools
     

    < Back to search results

    Download PDF

    Clinical Trial Results:
    Neo-AEGIS (NEOadjuvant trial in Adenocarcinoma of the oEsophagus and oesophagoGastric Junction International Study): Randomised Clinical Trial of neoadjuvant and adjuvant chemotherapy (Investigator’s choice Modified MAGIC or FLOT regimen) vs. neoadjuvant chemoradiation (CROSS protocol) in adenocarcinoma of the oesophagus and oesophago-gastric junction

    Summary
    EudraCT number
    		 2011-001858-28
    Trial protocol
    		 IE   DK   GB   FR   SE  
    Global end of trial date
    04 Aug 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    16 Dec 2023
    First version publication date
    16 Dec 2023
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CTRIAL-IE (ICORG) 10-14
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01726452
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Cancer Trials Ireland
    Sponsor organisation address
    RCSI House, Dublin, Ireland, D02 H903
    Public contact
    Head of Clinical Operations, Cancer Trials Ireland, 00353 16677211, info@cancertrials.ie
    Scientific contact
    Head of Clinical Operations, Cancer Trials Ireland, 00353 16677211, info@cancertrials.ie
    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
    19 Oct 2023
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    04 Aug 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    04 Aug 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate one, two and three year survival of patients treated with resection plus neoadjuvant and adjuvant chemotherapy versus resection plus neoadjuvant chemo radiotherapy.
    Protection of trial subjects
    This clinical study was conducted in accordance with the EU Directive 2001/20/EC and International Conference on Harmonization (ICH) Harmonized Tripartite Guidelines for Good Clinical Practice (GCP) and the appropriate regulatory requirements. The trial was also conducted in accordance with ethical principles founded in the Declaration of Helsinki.
    Background therapy
    		 N/A
    Evidence for comparator
    		 The primary objective is to compare neoadjuvant and adjuvant chemotherapy (ARM A: Investigator's choice modified MAGIC or FLOT regimen) versus neoadjuvant chemoradiation (ARM B: CROSS Protocol) in adenocarcinoma of the oesophagus and oesophago-gastric junction.
    Actual start date of recruitment
    24 Jan 2013
    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
    Sweden: 2
    Country: Number of subjects enrolled
    United Kingdom: 199
    Country: Number of subjects enrolled
    Denmark: 38
    Country: Number of subjects enrolled
    France: 4
    Country: Number of subjects enrolled
    Ireland: 134
    Worldwide total number of subjects
    377
    EEA total number of subjects
    178
    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)
    194
    From 65 to 84 years
    183
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 377 patients were recruited across 24 sites between 24-Jan-2013 and 23-Dec-2020

    Pre-assignment
    Screening details
    		 Patients presenting with newly diagnosed cancer of the oesophagus or oesophago-gastric junction, pre-treatment stage cT2-3, N0-3, M0 who fulfill all of the inclusion criteria and none of the exclusion criteria.

    Period 1
    Period 1 title
    Overall Trial
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm A: neoadjuvant and adjuvant chemotherapy
    Arm description
    		 Arm A consists of chemotherapy pre-surgery and chemotherapy post-surgery. The chemotherapy regimens included in Neo-Aegis are included as accepted standards of care. Decisions about which chemotherapy regimen to use, i.e. modified MAGIC (ECF/ECX or EOF/EOX) or FLOT, are to be made by the treating clinician.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Epirubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    MAGIC Regimen: 50 mg/m2

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    PA0822-199-001
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for infusion
    Routes of administration
    Concentrate for solution for infusion , Infusion
    Dosage and administration details
    MAGIC Regimen: 60 mg/m2

    Investigational medicinal product name
    5-fluorouracil
    Investigational medicinal product code
    PA2315-091-001
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    MAGIC regimen: 200 mg/m2/Day FLOT: 2600 mg/m2

    Investigational medicinal product name
    Docetaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    FLOT Regimen: 50 mg/m²

    Investigational medicinal product name
    Oxaliplatin
    Investigational medicinal product code
    Other name
    Eloxatin
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Magic Regimen: 130 mg/m² FLOT Regimen: 85 mg/m²

    Investigational medicinal product name
    Leucovorin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    FLOT Regimen: 200 mg/m²

    Investigational medicinal product name
    Capecitabine
    Investigational medicinal product code
    Other name
    Xeloda
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    MAGIC Regimen: 625 mg/m2 twice daily

    Arm title
    		 Arm B - neoadjuvant chemoradiation
    Arm description
    		 Arm B consists of the multimodal CROSS arm, which includes a combination of chemotherapy and radiotherapy prior to surgery. The patient will receive four and a half (4.5) weeks of radiation therapy (41.4 Gy/23 fractions), and 5 weekly cycles of chemotherapy. The chemotherapy and radiotherapy will run concurrently over a 4 and a half-week period. Chemotherapy is given by intravenous infusion on days 1, 8, 15, 22 and 29. The radiation will generally commence on the 1st day of treatment and will run for 4 and a half weeks as follows: days 1-5, days 8-12, days 15-19, days 22-26 and days 29-31 inclusive.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    PA2315-091-001
    Other name
    Pharmaceutical forms
    Concentrate for dispersion for infusion
    Routes of administration
    Infusion
    Dosage and administration details
    50 mg/ m2

    Investigational medicinal product name
    Carboplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Infusion
    Dosage and administration details
    The absolute dose of carboplatin will be calculated for the target Area Under the Curve (AUC)=2 according to the Calvert formula with a maximum weekly dose of Carboplatin of 300mg.

    Number of subjects in period 1
    		Arm A: neoadjuvant and adjuvant chemotherapy Arm B - neoadjuvant chemoradiation
    Started
    189
    188
    Completed
    184
    178
    Not completed
    5
    10
         Ineligible
    2
    3
         Patient decision
    3
    4
         Adverse event
    -
    1
         Investigator decision
    -
    2
    Period 2
    Period 2 title
    Intention to treat IITT)
    Is this the baseline period?
    		 Yes [1]
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm A: neoadjuvant and adjuvant chemotherapy
    Arm description
    		 Arm A consists of chemotherapy pre-surgery and chemotherapy post-surgery. The chemotherapy regimens included in Neo-Aegis are included as accepted standards of care. Decisions about which chemotherapy regimen to use, i.e. modified MAGIC (ECF/ECX or EOF/EOX) or FLOT, are to be made by the treating clinician.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Epirubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    MAGIC Regimen: 50 mg/m2

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    PA0822-199-001
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Concentrate for solution for infusion , Infusion
    Dosage and administration details
    MAGIC Regimen: 60 mg/m2

    Investigational medicinal product name
    5-fluorouracil
    Investigational medicinal product code
    PA2315-091-001
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    MAGIC regimen: 200 mg/m2/Day FLOT: 2600 mg/m2

    Investigational medicinal product name
    Docetaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    FLOT Regimen: 50 mg/m²

    Investigational medicinal product name
    Oxaliplatin
    Investigational medicinal product code
    Other name
    Eloxatin
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Magic Regimen: 130 mg/m² FLOT Regimen: 85 mg/m²

    Investigational medicinal product name
    Leucovorin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    FLOT Regimen: 200 mg/m²

    Investigational medicinal product name
    Capecitabine
    Investigational medicinal product code
    Other name
    Xeloda
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    MAGIC Regimen: 625 mg/m2 twice daily

    Arm title
    		 Arm B: neoadjuvant chemoradiation
    Arm description
    		 Arm B consists of the multimodal CROSS arm, which includes a combination of chemotherapy and radiotherapy prior to surgery. The patient will receive four and a half (4.5) weeks of radiation therapy (41.4 Gy/23 fractions), and 5 weekly cycles of chemotherapy. The chemotherapy and radiotherapy will run concurrently over a 4 and a half-week period. Chemotherapy is given by intravenous infusion on days 1, 8, 15, 22 and 29. The radiation will generally commence on the 1st day of treatment and will run for 4 and a half weeks as follows: days 1-5, days 8-12, days 15-19, days 22-26 and days 29-31 inclusive.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    PA2315-091-001
    Other name
    Pharmaceutical forms
    Concentrate for dispersion for infusion
    Routes of administration
    Infusion
    Dosage and administration details
    50 mg/ m2

    Investigational medicinal product name
    Carboplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Infusion
    Dosage and administration details
    The absolute dose of carboplatin will be calculated for the target Area Under the Curve (AUC)=2 according to the Calvert formula with a maximum weekly dose of Carboplatin of 300mg.

    Notes
    [1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: The primary and secondary analysis were performed on an intention to treat (ITT) basis. There were 362 participants in this set.
    Number of subjects in period 2 [2]
    		Arm A: neoadjuvant and adjuvant chemotherapy Arm B: neoadjuvant chemoradiation
    Started
    184
    178
    Completed
    183
    178
    Not completed
    1
    0
         Adverse event, non-fatal
    1
    -
    Notes
    [2] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: The primary and secondary analysis were performed on an intention to treat (ITT) basis. There were 362 participants in this set.
    Period 3
    Period 3 title
    Safety Set
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm A: neoadjuvant and adjuvant chemotherapy
    Arm description
    		 Arm A consists of chemotherapy pre-surgery and chemotherapy post-surgery. The chemotherapy regimens included in Neo-Aegis are included as accepted standards of care. Decisions about which chemotherapy regimen to use, i.e. modified MAGIC (ECF/ECX or EOF/EOX) or FLOT, are to be made by the treating clinician.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Epirubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    MAGIC Regimen: 50 mg/m2

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    PA0822-199-001
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Concentrate for solution for infusion
    Dosage and administration details
    MAGIC Regimen: 60 mg/m2

    Investigational medicinal product name
    5-fluorouracil
    Investigational medicinal product code
    PA2315-091-001
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    MAGIC regimen: 200 mg/m2/Day FLOT: 2600 mg/m2

    Investigational medicinal product name
    Docetaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    FLOT Regimen: 50 mg/m²

    Investigational medicinal product name
    Oxaliplatin
    Investigational medicinal product code
    Other name
    Eloxatin
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Magic Regimen: 130 mg/m² FLOT Regimen: 85 mg/m²

    Investigational medicinal product name
    Leucovorin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    FLOT Regimen: 200 mg/m²

    Investigational medicinal product name
    Capecitabine
    Investigational medicinal product code
    Other name
    Xeloda
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    MAGIC Regimen: 625 mg/m2 twice daily

    Arm title
    		 Arm B: neoadjuvant chemoradiation
    Arm description
    		 Arm B consists of the multimodal CROSS arm, which includes a combination of chemotherapy and radiotherapy prior to surgery. The patient will receive four and a half (4.5) weeks of radiation therapy (41.4 Gy/23 fractions), and 5 weekly cycles of chemotherapy. The chemotherapy and radiotherapy will run concurrently over a 4 and a half-week period. Chemotherapy is given by intravenous infusion on days 1, 8, 15, 22 and 29. The radiation will generally commence on the 1st day of treatment and will run for 4 and a half weeks as follows: days 1-5, days 8-12, days 15-19, days 22-26 and days 29-31 inclusive.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    PA2315-091-001
    Other name
    Pharmaceutical forms
    Concentrate for dispersion for infusion
    Routes of administration
    Infusion
    Dosage and administration details
    50 mg/ m2

    Investigational medicinal product name
    Carboplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Infusion
    Dosage and administration details
    The absolute dose of carboplatin will be calculated for the target Area Under the Curve (AUC)=2 according to the Calvert formula with a maximum weekly dose of Carboplatin of 300mg.

    Number of subjects in period 3
    		Arm A: neoadjuvant and adjuvant chemotherapy Arm B: neoadjuvant chemoradiation
    Started
    183
    178
    Completed
    183
    178

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Arm A: neoadjuvant and adjuvant chemotherapy
    Reporting group description
    		 Arm A consists of chemotherapy pre-surgery and chemotherapy post-surgery. The chemotherapy regimens included in Neo-Aegis are included as accepted standards of care. Decisions about which chemotherapy regimen to use, i.e. modified MAGIC (ECF/ECX or EOF/EOX) or FLOT, are to be made by the treating clinician.

    Reporting group title
    Arm B: neoadjuvant chemoradiation
    Reporting group description
    		 Arm B consists of the multimodal CROSS arm, which includes a combination of chemotherapy and radiotherapy prior to surgery. The patient will receive four and a half (4.5) weeks of radiation therapy (41.4 Gy/23 fractions), and 5 weekly cycles of chemotherapy. The chemotherapy and radiotherapy will run concurrently over a 4 and a half-week period. Chemotherapy is given by intravenous infusion on days 1, 8, 15, 22 and 29. The radiation will generally commence on the 1st day of treatment and will run for 4 and a half weeks as follows: days 1-5, days 8-12, days 15-19, days 22-26 and days 29-31 inclusive.

    Reporting group values
    		 Arm A: neoadjuvant and adjuvant chemotherapy Arm B: neoadjuvant chemoradiation Total
    Number of subjects
    		 184 178 362
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 93 92 185
        From 65-84 years
    		 91 86 177
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 63.8 ± 8.8 63.8 ± 7.9 -
    Gender categorical
    Units: Subjects
        Female
    		 15 20 35
        Male
    		 169 158 327
    Ethnic Origin
    Units: Subjects
        Caucasian
    		 183 177 360
        Asian
    		 1 1 2
    Smoking status at baseline
    Units: Subjects
        Never
    		 58 52 110
        Past Smoker
    		 101 106 207
        Current Smoker
    		 23 20 43
        Missing value
    		 2 0 2
    ECOG at baseline
    Units: Subjects
        Grade 0
    		 155 148 303
        Grade 1
    		 27 28 55
        Grade 2
    		 2 2 4
    American Society of Anaesthesiologists (ASA) at baseline
    Units: Subjects
        ASA I
    		 86 92 178
        ASA II
    		 94 85 179
        Missing value
    		 4 1 5
    Tumour location
    Units: Subjects
        Lower Oesophagus or AEG Type I
    		 123 126 249
        AEG Type II
    		 46 38 84
        AEG Type III
    		 15 14 29
    Tumour stage (Primary tumour)
    Units: Subjects
        T2
    		 29 28 57
        T3
    		 155 150 305
    Tumour stage (Regional Lymph Nodes)
    Units: Subjects
        N0
    		 73 78 151
        N1
    		 83 73 156
        N2
    		 23 27 50
        N3
    		 5 0 5
    Tumour stage (Distant Metastases)
    Units: Subjects
        M0
    		 184 178 362
    Overall Staging
    Units: Subjects
        Stage 0
    		 1 0 1
        Stage IB
    		 8 10 18
        Stage IIA
    		 26 32 58
        Stage IIB
    		 55 40 95
        Stage IIIA
    		 66 74 140
        Stage IIIB
    		 20 21 41
        Stage IIIC
    		 4 1 5
        Stage IV
    		 1 0 1
        Missing value
    		 3 0 3
    Node positivity at baseline
    Units: Subjects
        Positive
    		 57 53 110
        Negative
    		 112 109 221
        Missing value
    		 15 16 31
    BMI at baseline
    Units: Number
        median (full range (min-max))
    		 27.2 (18 to 41) 26.7 (18 to 43) -
    Subject analysis sets

    Subject analysis set title
    Intention to treat (ITT)
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All patients randomised into the trial, regardless of what study drug they received, as long as they recieved at least one dose of study drug.

    Subject analysis set title
    Safety Analysis Set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Includes All patients who have taken at least one dose of study drug. There is one less patient in this set compared to the ITT set due to one patient proceeding straight to surgery following an SAE that led to hospitilization after signing of informed consent.

    Subject analysis set title
    Pre Surgery
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Treatment group after neoadjuvant treatment

    Subject analysis set title
    1 year Post Surgery
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Treatment group 1 year post surgery

    Subject analysis set title
    3 Year Post Surgery
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Treatment group 3 years past surgery

    Subject analysis sets values
    		 Intention to treat (ITT) Safety Analysis Set Pre Surgery 1 year Post Surgery 3 Year Post Surgery
    Number of subjects
    362
    361
    332
    191
    89
    Age categorical
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
        Newborns (0-27 days)
    0
        Infants and toddlers (28 days-23 months)
    0
        Children (2-11 years)
    0
        Adolescents (12-17 years)
    0
        Adults (18-64 years)
    185
        From 65-84 years
    177
        85 years and over
    0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    63.8 ± 8.4
    63.8 ± 8.4
    ±
    ±
    ±
    Gender categorical
    Units: Subjects
        Female
    35
    35
        Male
    327
    326
    Ethnic Origin
    Units: Subjects
        Caucasian
    360
    359
        Asian
    2
    2
    Smoking status at baseline
    Units: Subjects
        Never
    110
    109
        Past Smoker
    207
    207
        Current Smoker
    43
    43
        Missing value
    2
    2
    ECOG at baseline
    Units: Subjects
        Grade 0
    303
    302
        Grade 1
    55
    55
        Grade 2
    4
    4
    American Society of Anaesthesiologists (ASA) at baseline
    Units: Subjects
        ASA I
    178
    177
        ASA II
    179
    179
        Missing value
    5
    5
    Tumour location
    Units: Subjects
        Lower Oesophagus or AEG Type I
    249
    248
        AEG Type II
    84
    84
        AEG Type III
    29
    29
    Tumour stage (Primary tumour)
    Units: Subjects
        T2
    57
    57
        T3
    305
    304
    Tumour stage (Regional Lymph Nodes)
    Units: Subjects
        N0
    151
    151
        N1
    156
    155
        N2
    50
    50
        N3
    5
    5
    Tumour stage (Distant Metastases)
    Units: Subjects
        M0
    362
    361
    Overall Staging
    Units: Subjects
        Stage 0
    1
    1
        Stage IB
    18
    18
        Stage IIA
    58
    58
        Stage IIB
    95
    95
        Stage IIIA
    140
    139
        Stage IIIB
    41
    41
        Stage IIIC
    5
    5
        Stage IV
    1
    1
        Missing value
    3
    3
    Node positivity at baseline
    Units: Subjects
        Positive
    110
    109
        Negative
    221
    221
        Missing value
    31
    31
    BMI at baseline
    Units: Number
        median (full range (min-max))
    27.0 (18 to 43)
    27.0 (18 to 43)

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    Arm A: neoadjuvant and adjuvant chemotherapy
    Reporting group description
    		 Arm A consists of chemotherapy pre-surgery and chemotherapy post-surgery. The chemotherapy regimens included in Neo-Aegis are included as accepted standards of care. Decisions about which chemotherapy regimen to use, i.e. modified MAGIC (ECF/ECX or EOF/EOX) or FLOT, are to be made by the treating clinician.

    Reporting group title
    Arm B - neoadjuvant chemoradiation
    Reporting group description
    		 Arm B consists of the multimodal CROSS arm, which includes a combination of chemotherapy and radiotherapy prior to surgery. The patient will receive four and a half (4.5) weeks of radiation therapy (41.4 Gy/23 fractions), and 5 weekly cycles of chemotherapy. The chemotherapy and radiotherapy will run concurrently over a 4 and a half-week period. Chemotherapy is given by intravenous infusion on days 1, 8, 15, 22 and 29. The radiation will generally commence on the 1st day of treatment and will run for 4 and a half weeks as follows: days 1-5, days 8-12, days 15-19, days 22-26 and days 29-31 inclusive.
    Reporting group title
    Arm A: neoadjuvant and adjuvant chemotherapy
    Reporting group description
    		 Arm A consists of chemotherapy pre-surgery and chemotherapy post-surgery. The chemotherapy regimens included in Neo-Aegis are included as accepted standards of care. Decisions about which chemotherapy regimen to use, i.e. modified MAGIC (ECF/ECX or EOF/EOX) or FLOT, are to be made by the treating clinician.

    Reporting group title
    Arm B: neoadjuvant chemoradiation
    Reporting group description
    		 Arm B consists of the multimodal CROSS arm, which includes a combination of chemotherapy and radiotherapy prior to surgery. The patient will receive four and a half (4.5) weeks of radiation therapy (41.4 Gy/23 fractions), and 5 weekly cycles of chemotherapy. The chemotherapy and radiotherapy will run concurrently over a 4 and a half-week period. Chemotherapy is given by intravenous infusion on days 1, 8, 15, 22 and 29. The radiation will generally commence on the 1st day of treatment and will run for 4 and a half weeks as follows: days 1-5, days 8-12, days 15-19, days 22-26 and days 29-31 inclusive.
    Reporting group title
    Arm A: neoadjuvant and adjuvant chemotherapy
    Reporting group description
    		 Arm A consists of chemotherapy pre-surgery and chemotherapy post-surgery. The chemotherapy regimens included in Neo-Aegis are included as accepted standards of care. Decisions about which chemotherapy regimen to use, i.e. modified MAGIC (ECF/ECX or EOF/EOX) or FLOT, are to be made by the treating clinician.

    Reporting group title
    Arm B: neoadjuvant chemoradiation
    Reporting group description
    		 Arm B consists of the multimodal CROSS arm, which includes a combination of chemotherapy and radiotherapy prior to surgery. The patient will receive four and a half (4.5) weeks of radiation therapy (41.4 Gy/23 fractions), and 5 weekly cycles of chemotherapy. The chemotherapy and radiotherapy will run concurrently over a 4 and a half-week period. Chemotherapy is given by intravenous infusion on days 1, 8, 15, 22 and 29. The radiation will generally commence on the 1st day of treatment and will run for 4 and a half weeks as follows: days 1-5, days 8-12, days 15-19, days 22-26 and days 29-31 inclusive.

    Subject analysis set title
    Intention to treat (ITT)
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All patients randomised into the trial, regardless of what study drug they received, as long as they recieved at least one dose of study drug.

    Subject analysis set title
    Safety Analysis Set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Includes All patients who have taken at least one dose of study drug. There is one less patient in this set compared to the ITT set due to one patient proceeding straight to surgery following an SAE that led to hospitilization after signing of informed consent.

    Subject analysis set title
    Pre Surgery
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Treatment group after neoadjuvant treatment

    Subject analysis set title
    1 year Post Surgery
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Treatment group 1 year post surgery

    Subject analysis set title
    3 Year Post Surgery
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Treatment group 3 years past surgery

    Primary: Overall Survival

    		 Close Top of page
    End point title
    		 Overall Survival
    End point description
    End point type
    Primary
    End point timeframe
    Overall survival was calculated from the time of randomisation to death from any cause.
    End point values
    		 Arm A: neoadjuvant and adjuvant chemotherapy Arm B: neoadjuvant chemoradiation
    Number of subjects analysed
    184
    178
    Units: Months
        median (confidence interval 95%)
    48.5 (33.1 to 65)
    49.6 (34.6 to 74.3)
    Statistical analysis title
    		 Hazard Ratio (Overall Survival)
    Comparison groups
    Arm A: neoadjuvant and adjuvant chemotherapy v Arm B: neoadjuvant chemoradiation
    Number of subjects included in analysis
    362
    Analysis specification
    Post-hoc
    Analysis type
    		 non-inferiority [1]
    P-value
    		 = 0.824
    Method
    		 Kaplan-Meier
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.77
         upper limit
    		 1.38
    Notes
    [1] - The non-inferiority limit of 1.16 is included in the interval and therefore results are inconclusive with no statistical evidence to declare neoadjuvant and adjuvant chemotherapy arm (Arm A) non-inferior to the neoadjuvant chemoradiation arm (Arm B)
    Statistical analysis title
    		 Adjusted hazard ration (Age)
    Statistical analysis description
    A subgroup analysis was also performed to explore differences in the treatment effect for subsets of participants defined by demographics and baseline characteristics.
    Comparison groups
    Arm A: neoadjuvant and adjuvant chemotherapy v Arm B: neoadjuvant chemoradiation
    Number of subjects included in analysis
    362
    Analysis specification
    Post-hoc
    Analysis type
    		 non-inferiority [2]
    P-value
    		 = 0.068
    Method
    		 Multivariate Cox ph model
    Parameter type
    		 Cox proportional hazard
    Point estimate
    1.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1
         upper limit
    		 1.04
    Notes
    [2] - Age
    Statistical analysis title
    		 Adjusted hazard ration (Gender: Female vs Male)
    Statistical analysis description
    Gender: Female vs Male - A subgroup analysis was also performed to explore differences in the treatment effect for subsets of participants defined by demographics and baseline characteristics.
    Comparison groups
    Arm A: neoadjuvant and adjuvant chemotherapy v Arm B: neoadjuvant chemoradiation
    Number of subjects included in analysis
    362
    Analysis specification
    Post-hoc
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.481
    Method
    		 Multivariate Cox ph model
    Parameter type
    		 Cox proportional hazard
    Point estimate
    0.83
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.5
         upper limit
    		 1.39
    Statistical analysis title
    		 Adjusted hazard ration (Primary tumour: T3 vs T2)
    Comparison groups
    Arm A: neoadjuvant and adjuvant chemotherapy v Arm B: neoadjuvant chemoradiation
    Number of subjects included in analysis
    362
    Analysis specification
    Post-hoc
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.022
    Method
    		 Multivariate Cox ph model
    Parameter type
    		 Cox proportional hazard
    Point estimate
    1.68
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.08
         upper limit
    		 2.62

    Secondary: Disease Free Survival

    		 Close Top of page
    End point title
    		 Disease Free Survival
    End point description
    End point type
    Secondary
    End point timeframe
    Disease free survival was calculated from randomisation to the first event (i.e local recurrence or progression, distant recurrence, or death from any cause)
    End point values
    		 Arm A: neoadjuvant and adjuvant chemotherapy Arm B: neoadjuvant chemoradiation
    Number of subjects analysed
    184
    178
    Units: Months
        median (confidence interval 95%)
    32.1 (22.9 to 65.0)
    24.2 (17.5 to 40.3)
    Statistical analysis title
    		 Hazard Ratio (Disease free Survival)
    Comparison groups
    Arm A: neoadjuvant and adjuvant chemotherapy v Arm B: neoadjuvant chemoradiation
    Number of subjects included in analysis
    362
    Analysis specification
    Post-hoc
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.405
    Method
    		 Kaplan-Meier
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.89
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.68
         upper limit
    		 1.17
    Statistical analysis title
    		 Adjusted hazard ratio (Age)
    Comparison groups
    Arm A: neoadjuvant and adjuvant chemotherapy v Arm B: neoadjuvant chemoradiation
    Number of subjects included in analysis
    362
    Analysis specification
    Post-hoc
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.256
    Method
    		 Multivariate Cox ph model
    Parameter type
    		 Cox proportional hazard
    Point estimate
    1.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.99
         upper limit
    		 1.03
    Statistical analysis title
    		 Adjusted hazard ratio (Gender: Female vs Male)
    Comparison groups
    Arm A: neoadjuvant and adjuvant chemotherapy v Arm B: neoadjuvant chemoradiation
    Number of subjects included in analysis
    362
    Analysis specification
    Post-hoc
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.346
    Method
    		 Multivariate Cox ph model
    Parameter type
    		 Cox proportional hazard
    Point estimate
    0.79
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.48
         upper limit
    		 1.29
    Statistical analysis title
    		 Adjusted hazard ratio (Primary tumour: T3 vs T2)
    Comparison groups
    Arm A: neoadjuvant and adjuvant chemotherapy v Arm B: neoadjuvant chemoradiation
    Number of subjects included in analysis
    362
    Analysis specification
    Post-hoc
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.009
    Method
    		 Multivariate Cox ph model
    Parameter type
    		 Cox proportional hazard
    Point estimate
    1.76
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.15
         upper limit
    		 2.69

    Secondary: Quality of Life - QLQ-C30 Global Health status

    		 Close Top of page
    End point title
    		 Quality of Life - QLQ-C30 Global Health status
    End point description
    The functional derived scores were calculated using the standard EORTC recommended methods. Differences from baseline were compared between arms of the study using independent sample t-tests.
    End point type
    Secondary
    End point timeframe
    The functional and symptomatic scales of the HRQOL questionnaires were examined by calculating the differences in measurements from baseline at specific timepoints.
    End point values
    		 Arm A: neoadjuvant and adjuvant chemotherapy Arm B: neoadjuvant chemoradiation
    Number of subjects analysed
    175
    171
    Units: Number
    arithmetic mean (confidence interval 95%)
        Global health Status/QoL
    78 (75 to 81)
    80 (77 to 82)
    No statistical analyses for this end point

    Secondary: Quality of Life - QLQ-C30 Functional Scales

    		 Close Top of page
    End point title
    		 Quality of Life - QLQ-C30 Functional Scales
    End point description
    The functional derived scores were calculated using the standard EORTC recommended methods.
    End point type
    Secondary
    End point timeframe
    The functional scales of the HRQOL questionnaires were examined by calculating the differences in measurements from baseline at specific time points.
    End point values
    		 Arm A: neoadjuvant and adjuvant chemotherapy Arm B: neoadjuvant chemoradiation
    Number of subjects analysed
    175
    171
    Units: Number
    arithmetic mean (confidence interval 95%)
        Physical functioning
    95 (94 to 97)
    95 (94 to 97)
        Role functioning
    89 (86 to 92)
    92 (89 to 94)
        Emotional functioning
    82 (80 to 85)
    82 (79 to 85)
        Cognitive functioning
    93 (91 to 95)
    93 (91 to 95)
        Social functioning
    86 (83 to 90)
    88 (85 to 91)
    No statistical analyses for this end point

    Secondary: Quality of Life - QLQ-C30 Symptom Scales

    		 Close Top of page
    End point title
    		 Quality of Life - QLQ-C30 Symptom Scales
    End point description
    The symptomatic derived scores were calculated using the standard EORTC recommended method.
    End point type
    Secondary
    End point timeframe
    The symptomatic scales of the HRQOL questionnaires were examined by calculating the differences in measurements from baseline at specific time points.
    End point values
    		 Arm A: neoadjuvant and adjuvant chemotherapy Arm B: neoadjuvant chemoradiation
    Number of subjects analysed
    175
    171
    Units: Number
    arithmetic mean (confidence interval 95%)
        Fatigue
    15 (12 to 17)
    15 (13 to 18)
        Nausea and vomiting
    9 (6 to 11)
    8 (5 to 10)
        Pain
    15 (12 to 17)
    12 (9 to 14)
        Dyspnoea
    3 (2 to 5)
    5 (3 to 7)
        Insomnia
    21 (17 to 24)
    22 (18 to 26)
        Appetite loss
    22 (18 to 27)
    18 (14 to 22)
        Constipation
    15 (11 to 19)
    14 (10 to 17)
        Diarrhoea
    5 (3 to 7)
    6 (3 to 8)
        Financial difficulties
    14 (10 to 19)
    9 (6 to 13)
    No statistical analyses for this end point

    Secondary: Quality of Life - OES-18 Symptom Scales

    		 Close Top of page
    End point title
    		 Quality of Life - OES-18 Symptom Scales
    End point description
    The symptomatic derived scores were calculated using the standard EORTC recommended method.
    End point type
    Secondary
    End point timeframe
    The symptomatic scales of the HRQOL questionnaires were examined by calculating the differences in measurements from baseline at specific time points.
    End point values
    		 Arm A: neoadjuvant and adjuvant chemotherapy Arm B: neoadjuvant chemoradiation
    Number of subjects analysed
    175
    171
    Units: Number
    arithmetic mean (confidence interval 95%)
        Eating
    32 (28 to 36)
    26 (23 to 30)
        Reflux
    15 (12 to 18)
    12 (9 to 15)
        Pain
    17 (14 to 20)
    17 (14 to 21)
        Trouble swallowing saliva
    12 (8 to 16)
    11 (7 to 15)
        Dry mouth
    20 (16 to 24)
    18 (13 to 22)
        Trouble with taste
    8 (5 to 11)
    7 (4 to 10)
        Trouble with coughing
    8 (5 to 11)
    9 (6 to 11)
        Trouble talking
    2 (0 to 3)
    2 (1 to 4)
        Choked when swallowing
    10 (7 to 13)
    10 (7 to 13)
    No statistical analyses for this end point

    Secondary: Quality of Life - OES-18 Functional Scales

    		 Close Top of page
    End point title
    		 Quality of Life - OES-18 Functional Scales
    End point description
    The functional derived scores were calculated using the standard EORTC recommended methods.
    End point type
    Secondary
    End point timeframe
    The functional scales of the HRQOL questionnaires were examined by calculating the differences in measurements from baseline at specific time points.
    End point values
    		 Arm A: neoadjuvant and adjuvant chemotherapy Arm B: neoadjuvant chemoradiation
    Number of subjects analysed
    175
    171
    Units: Number
    arithmetic mean (confidence interval 95%)
        Dysphagia
    79 (76 to 82)
    77 (73 to 81)
    No statistical analyses for this end point

    Secondary: Mean Differences in Quality of Life scores - QLQ-C30 Global Health status

    		 Close Top of page
    End point title
    		 Mean Differences in Quality of Life scores - QLQ-C30 Global Health status
    End point description
    The mean difference (MD) from Baseline to different timepoints are adjusted by Baseline scores in a linear model. Differences are calculated as Arm B - Arm A.
    End point type
    Secondary
    End point timeframe
    From baseline to different time points (Pre-surgery, 1 year post surgery and 3 years post surgery)
    End point values
    		 Pre Surgery 1 year Post Surgery 3 Year Post Surgery
    Number of subjects analysed
    332
    191
    89
    Units: Mean Difference
    number (confidence interval 95%)
        Global Health Status/QoL
    -8 (-12 to -3)
    -2 (-8 to 4)
    -1 (-9 to 7)
    No statistical analyses for this end point

    Secondary: Mean Differences in Quality of Life scores - QLQ-C30 Functional Scales

    		 Close Top of page
    End point title
    		 Mean Differences in Quality of Life scores - QLQ-C30 Functional Scales
    End point description
    The mean difference (MD) from Baseline to different timepoints are adjusted by Baseline scores in a linear model. Differences are calculated as Arm B - Arm A.
    End point type
    Secondary
    End point timeframe
    From baseline to different time points (Pre-surgery, 1 year post surgery and 3 years post surgery)
    End point values
    		 Pre Surgery 1 year Post Surgery 3 Year Post Surgery
    Number of subjects analysed
    332
    191
    89
    Units: Mean Difference
    number (confidence interval 95%)
        Physical functioning
    -5 (-8 to -2)
    -3 (-8 to 2)
    2 (-6 to 11)
        Role functioning
    -6 (-12 to 1)
    -3 (-11 to 6)
    -4 (-15 to 7)
        Emotional functioning
    -5 (-9 to -1)
    -7 (-13 to -1)
    -1 (-10 to 9)
        Cognitive functioning
    -1 (-5 to 3)
    2 (-4 to 8)
    0 (-9 to 9)
        Social functioning
    -4 (-9 to 2)
    0 (-8 to 8)
    2 (-9 to 13)
    No statistical analyses for this end point

    Secondary: Mean Differences in Quality of Life scores- QLQ-C30 Symptom Scales

    		 Close Top of page
    End point title
    		 Mean Differences in Quality of Life scores- QLQ-C30 Symptom Scales
    End point description
    The mean difference (MD) from Baseline to different timepoints are adjusted by Baseline scores in a linear model. Differences are calculated as Arm B - Arm A.
    End point type
    Secondary
    End point timeframe
    From baseline to different time points (Pre-surgery, 1 year post surgery and 3 years post surgery)
    End point values
    		 Pre Surgery 1 year Post Surgery 3 Year Post Surgery
    Number of subjects analysed
    332
    191
    89
    Units: Mean Difference
    number (confidence interval 95%)
        Fatique
    8 (3 to 13)
    -1 (-8 to 6)
    -2 (-13 to 9)
        Nausea and vomiting
    2 (-2 to 5)
    2 (-3 to 7)
    -2 (-10 to 6)
        Pain
    8 (3 to 12)
    8 (0 to 16)
    1 (-10 to 11)
        Dyspnoea
    2 (-2 to 7)
    6 (-2 to 13)
    -1 (-13 to 11)
        Insomnia
    -3 (-9 to 3)
    -3 (-12 to 13)
    -5 (-17 to 7)
        Appetite loss
    9 (3 to 15)
    1 (-7 to 10)
    -1 (-12 to 10)
        Constipation
    6 (1 to 10)
    2 (-4 to 8)
    2 (-6 to 10)
        Diarrhoea
    2 (-2 to 5)
    -5 (-12 to 2)
    -3 (-12 to 6)
        Financial Difficulties
    3 (-3 to 8)
    2 (-6 to 10)
    0 (-11 to 11)
    No statistical analyses for this end point

    Secondary: Mean Differences in Quality of Life scores - OES-18 Symptom Scales

    		 Close Top of page
    End point title
    		 Mean Differences in Quality of Life scores - OES-18 Symptom Scales
    End point description
    The mean difference (MD) from Baseline to different timepoints are adjusted by Baseline scores in a linear model. Differences are calculated as Arm B - Arm A.
    End point type
    Secondary
    End point timeframe
    From baseline to different time points (Pre-surgery, 1 year post surgery and 3 years post surgery)
    End point values
    		 Pre Surgery 1 year Post Surgery 3 Year Post Surgery
    Number of subjects analysed
    332
    191
    89
    Units: Mean Difference
    number (confidence interval 95%)
        Eating
    2 (-3 to 7)
    5 (-2 to 12)
    6 (-4 to 16)
        Reflux
    -1 (-6 to 3)
    -4 (-12 to 4)
    3 (-10 to 15)
        Pain
    4 (1 to 8)
    4 (-2 to 10)
    2 (-8 to 12)
        Trouble swallowing saliva
    -2 (-8 to 3)
    -2 (-8 to 4)
    2 (-6 to 10)
        Choked when swallowing
    -1 (-7 to 6)
    -2 (-7 to 3)
    4 (-4 to 11)
        Dry mouth
    -1 (-7 to 6)
    -5 (-13 to 3)
    -3 (-16 to 10)
        Trouble with taste
    0 (-7 to 7)
    -1 (-8 to 6)
    3 (-8 to 14)
        Trouble with coughing
    6 (1 to 11)
    8 (1 to 16)
    10 (-1 to 21)
        Trouble talking
    0 (-2 to 3)
    4 (-2 to 10)
    8 (0 to 15)
    No statistical analyses for this end point

    Secondary: Mean Differences in Quality of Life scores- OES-18 Functional Scales

    		 Close Top of page
    End point title
    		 Mean Differences in Quality of Life scores- OES-18 Functional Scales
    End point description
    The mean difference (MD) from Baseline to different timepoints are adjusted by Baseline scores in a linear model. Differences are calculated as Arm B - Arm A.
    End point type
    Secondary
    End point timeframe
    From baseline to different time points (Pre-surgery, 1 year post surgery and 3 years post surgery)
    End point values
    		 Pre Surgery 1 year Post Surgery 3 Year Post Surgery
    Number of subjects analysed
    332
    191
    89
    Units: Mean Difference
    number (confidence interval 95%)
        Dysphagia
    -1 (-6 to 4)
    -1 (-8 to 5)
    -6 (-15 to 3)
    No statistical analyses for this end point

    Secondary: Adjusted mean differences in Quality of Life scores - QLQ-C30 Global Health Status

    		 Close Top of page
    End point title
    		 Adjusted mean differences in Quality of Life scores - QLQ-C30 Global Health Status
    End point description
    Mean difference (MD) after adjusting by demographics and relevant prognostic factors (age, gender, smoking status and tumour staging)
    End point type
    Secondary
    End point timeframe
    The mean difference (MD) from Baseline to different timepoints (Pre Surgery, 1 year Post Surgery and 3 years Post surgery)
    End point values
    		 Pre Surgery 1 year Post Surgery 3 Year Post Surgery
    Number of subjects analysed
    332
    191
    89
    Units: Mean difference
    number (confidence interval 95%)
        Global health status/QoL
    -7 (-12 to -3)
    -2 (-8 to 4)
    -2 (-11 to 7)
    No statistical analyses for this end point

    Secondary: Adjusted mean differences in Quality of Life scores - QLQ-C30 Functional scales

    		 Close Top of page
    End point title
    		 Adjusted mean differences in Quality of Life scores - QLQ-C30 Functional scales
    End point description
    Mean difference (MD) after adjusting by demographics and relevant prognostic factors (age, gender, smoking status and tumour staging)
    End point type
    Secondary
    End point timeframe
    The mean difference (MD) from Baseline to different timepoints (Pre Surgery, 1 year Post Surgery and 3 years Post surgery)
    End point values
    		 Pre Surgery 1 year Post Surgery 3 Year Post Surgery
    Number of subjects analysed
    332
    191
    89
    Units: Mean difference
    number (confidence interval 95%)
        Physical functioning
    -4 (-8 to -1)
    -4 (-9 to 1)
    2 (-7 to 11)
        Role functioning
    -5 (-12 to 2)
    -3 (-12 to 5)
    -4 (-16 to 8)
        Emotional functioning
    -4 (-8 to 0)
    -6 (-12 to 5)
    -1 (-11 to 9)
        Cognitive functioning
    0 (-4 to 4)
    2 (-5 to 8)
    2 (-8 to 12)
        Social functioning
    -3 (-9 to 3)
    0 (-8 to 8)
    3 (-8 to 15)
    No statistical analyses for this end point

    Secondary: Adjusted mean differences in Quality of Life scores - QLQ-C30 Symptom scales

    		 Close Top of page
    End point title
    		 Adjusted mean differences in Quality of Life scores - QLQ-C30 Symptom scales
    End point description
    Mean difference (MD) after adjusting by demographics and relevant prognostic factors (age, gender, smoking status and tumour staging)
    End point type
    Secondary
    End point timeframe
    The mean difference (MD) from Baseline to different timepoints (Pre Surgery, 1 year Post Surgery and 3 years Post surgery)
    End point values
    		 Pre Surgery 1 year Post Surgery 3 Year Post Surgery
    Number of subjects analysed
    332
    191
    89
    Units: Mean difference
    number (confidence interval 95%)
        Fatigue
    8 (2 to 13)
    -1 (-9 to 6)
    -1 (-13 to 11)
        Nausea and vomiting
    1 (-2 to 5)
    1 (-4 to 6)
    0 (-7 to 8)
        Pain
    7 (3 to 12)
    9 (1 to 17)
    3 (-9 to 14)
        Dyspnoea
    7 (3 to 12)
    6 (-2 to 14)
    2 (-11 to 15)
        Insomnia
    -3 (-9 to 3)
    -3 (-13 to 6)
    -4 (-17 to 9)
        Appetite loss
    9 (3 to 15)
    3 (-5 to 11)
    2 (-9 to 13)
        Constipation
    5 (0 to 10)
    2 (-4 to 8)
    5 (-4 to 13)
        Diarrhoea
    1 (-2 to 5)
    -5 (-12 to 2)
    -3 (-13 to 6)
        Financial difficulties
    2 (-4 to 8)
    1 (-7 to 9)
    1 (-11 to 13)
    No statistical analyses for this end point

    Secondary: Adjusted mean differences in Quality of Life scores - OES Symptom scales

    		 Close Top of page
    End point title
    		 Adjusted mean differences in Quality of Life scores - OES Symptom scales
    End point description
    Mean difference (MD) after adjusting by demographics and relevant prognostic factors (age, gender, smoking status and tumour staging)
    End point type
    Secondary
    End point timeframe
    The mean difference (MD) from Baseline to different timepoints (Pre Surgery, 1 year Post Surgery and 3 years Post surgery)
    End point values
    		 Pre Surgery 1 year Post Surgery 3 Year Post Surgery
    Number of subjects analysed
    332
    191
    89
    Units: Mean difference
    number (confidence interval 95%)
        Eating
    2 (-3 to 7)
    6 (-1 to 13)
    5 (-6 to 16)
        Reflux
    -2 (-6 to 3)
    -4 (-13 to 4)
    6 (-7 to 20)
        Pain
    4 (0 to 7)
    6 (0 to 12)
    3 (-8 to 13)
        Trouble swallowing saliva
    -3 (-8 to 2)
    -3 (-9 to 3)
    1 (-8 to 10)
        Choked when swallowing
    -1 (-5 to 3)
    -2 (-7 to 3)
    5 (-3 to 13)
        Dry mouth
    -1 (-8 to 5)
    -7 (-15 to 2)
    -5 (-19 to 9)
        Trouble with taste
    0 (-8 to 7)
    -1 (-9 to 7)
    1 (-10 to 13)
        Trouble with coughing
    7 (2 to 12)
    8 (1 to 16)
    11 (-2 to 23)
        Trouble talking
    0 (-2 to 3)
    4 (-2 to 11)
    6 (-2 to 14)
    No statistical analyses for this end point

    Secondary: Adjusted mean differences in Quality of Life scores - OES-18 Functional scales

    		 Close Top of page
    End point title
    		 Adjusted mean differences in Quality of Life scores - OES-18 Functional scales
    End point description
    Mean difference (MD) after adjusting by demographics and relevant prognostic factors (age, gender, smoking status and tumour staging)
    End point type
    Secondary
    End point timeframe
    The mean difference (MD) from Baseline to different timepoints (Pre Surgery, 1 year Post Surgery and 3 years Post surgery)
    End point values
    		 Pre Surgery 1 year Post Surgery 3 Year Post Surgery
    Number of subjects analysed
    332
    191
    89
    Units: Mean difference
    number (confidence interval 95%)
        Dysphagia
    0 (-6 to 5)
    -1 (-8 to 6)
    -6 (-15 to 3)
    No statistical analyses for this end point

    Secondary: Time to Treatment Failure (TTF)

    		 Close Top of page
    End point title
    		 Time to Treatment Failure (TTF)
    End point description
    *Due to the differences with respect to the length and nature of the treatments, it was expected that different times to treatment failure would be observed between treatment arms. The analysis presented for OS and DFS provide the key relevant TTF metrics.
    End point type
    Secondary
    End point timeframe
    Time to treatment failure was calculated from randomization to the first of the following events: Discontinuation of therapy, addition of new anti-cancer therapy or recurrence/progression.
    End point values
    		 Arm A: neoadjuvant and adjuvant chemotherapy Arm B: neoadjuvant chemoradiation
    Number of subjects analysed
    184
    178
    Units: months
        median (confidence interval 95%)
    7.3 (6.8 to 8.2)
    22.3 (15.7 to 40.3)
    Statistical analysis title
    		 Hazard Ratio (Time to treatment failure)
    Comparison groups
    Arm A: neoadjuvant and adjuvant chemotherapy v Arm B: neoadjuvant chemoradiation
    Number of subjects included in analysis
    362
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.001
    Method
    		 Kaplan-Meier
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.81
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.4
         upper limit
    		 2.35

    Secondary: Pathological Response

    		 Close Top of page
    End point title
    		 Pathological Response
    End point description
    Complete pathological response pCR is defined as (y)pT0 or (y)pN0 in pathological staging.
    End point type
    Secondary
    End point timeframe
    From randomization to the first of the following events: Discontinuation of therapy, addition of new anti-cancer therapy or recurrence/progression.
    End point values
    		 Arm A: neoadjuvant and adjuvant chemotherapy Arm B: neoadjuvant chemoradiation
    Number of subjects analysed
    162
    167
    Units: Subjects
    7
    20
    Statistical analysis title
    		 Complete Pathological response
    Comparison groups
    Arm A: neoadjuvant and adjuvant chemotherapy v Arm B: neoadjuvant chemoradiation
    Number of subjects included in analysis
    329
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.012
    Method
    		 Kaplan-Meier
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.33
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.14
         upper limit
    		 0.81

    Secondary: Complete pathological response adjusted by baseline clinical T and N staging

    		 Close Top of page
    End point title
    		 Complete pathological response adjusted by baseline clinical T and N staging
    End point description
    Multivariate logistic model with pathological complete respoonse (YpT=T0 & pN=N0) adjusted by treatment arm and baseline clinical T and N staging (note that N2 and N3 staging had to be grouped together)
    End point type
    Secondary
    End point timeframe
    From randomization to the first of the following events: Discontinuation of therapy, addition of new anti-cancer therapy or recurrence/progression.
    End point values
    		 Intention to treat (ITT)
    Number of subjects analysed
    362
    Units: Odds Ration
    number (confidence interval 95%)
        Regime: Arm A vs Arm B
    0.34 (0.13 to 0.79)
        Primary Tumour: T3 vs T2
    0.69 (0.27 to 1.98)
        Regional Lymph Nodes: N1 vs N0
    0.65 (0.26 to 1.56)
        Regional Lymph Nodes: N2 or N3 vs N0
    0.79 (0.21 to 2.39)
    No statistical analyses for this end point

    Secondary: Major pathological response

    		 Close Top of page
    End point title
    		 Major pathological response
    End point description
    From randomization to the first of the following events: Discontinuation of therapy, addition of new anti-cancer therapy or recurrence/progression. Comprising TRG 1 (complete regression) and TRG 2 (isolated vital residual single tumour cells surrounded by fibrosis) combined.
    End point type
    Secondary
    End point timeframe
    From randomization to the first of the following events: Discontinuation of therapy, addition of new anti-cancer therapy or recurrence/progression.
    End point values
    		 Arm A: neoadjuvant and adjuvant chemotherapy Arm B: neoadjuvant chemoradiation
    Number of subjects analysed
    157
    163
    Units: Subjects
        Major Pathological Response (TRG 1 or TRG 2)
    19
    64
        No Pathological Response (TRG 4 or TRG 5)
    100
    46
    No statistical analyses for this end point

    Secondary: Tumour Regression Grade (TRG)

    		 Close Top of page
    End point title
    		 Tumour Regression Grade (TRG)
    End point description
    End point type
    Secondary
    End point timeframe
    From randomization to the first of the following events: Discontinuation of therapy, addition of new anti-cancer therapy or recurrence/progression.
    End point values
    		 Arm A: neoadjuvant and adjuvant chemotherapy Arm B: neoadjuvant chemoradiation
    Number of subjects analysed
    157
    163
    Units: Subjects
        TRG 1
    8
    23
        TRG 2
    11
    41
        TRG 3
    38
    53
        TRG 4
    65
    39
        TRG 5
    35
    7
    No statistical analyses for this end point

    Secondary: Site of Treatment Failure

    		 Close Top of page
    End point title
    		 Site of Treatment Failure
    End point description
    Only Local Regional - Anastomosis, oesophagus, stomach, regional nodes Only Systemic - Liver, lung, bone, brain, extraregional nodes Systemic and Local Regional combined
    End point type
    Secondary
    End point timeframe
    Time to treatment failure was calculated from randomization to the first of the following events: Discontinuation of therapy, addition of new anti-cancer therapy or recurrence/progression.
    End point values
    		 Arm A: neoadjuvant and adjuvant chemotherapy Arm B: neoadjuvant chemoradiation
    Number of subjects analysed
    184
    178
    Units: Subjects
        Only Local Regional
    18
    16
        Only Systemic
    39
    41
        Systemic and Local Regional combined
    15
    24
    No statistical analyses for this end point

    Secondary: Pattern of recurrence: Surgical Patients

    		 Close Top of page
    End point title
    		 Pattern of recurrence: Surgical Patients
    End point description
    Pattern of recurrence for surgical patients only
    End point type
    Secondary
    End point timeframe
    Time to treatment failure was calculated from randomization to recurrence
    End point values
    		 Arm A: neoadjuvant and adjuvant chemotherapy Arm B: neoadjuvant chemoradiation
    Number of subjects analysed
    162
    167
    Units: Subjects
        Systemic
    44
    58
        Local Regional
    22
    28
        Systemic and Local Regional
    7
    14
    No statistical analyses for this end point

    Secondary: Response to therapy (endoscopy)

    		 Close Top of page
    End point title
    		 Response to therapy (endoscopy)
    End point description
    Response to therapy as determined by endoscopy
    End point type
    Secondary
    End point timeframe
    From randomization to the first of the following events: Discontinuation of therapy, addition of new anti-cancer therapy or recurrence/progression.
    End point values
    		 Arm A: neoadjuvant and adjuvant chemotherapy Arm B: neoadjuvant chemoradiation
    Number of subjects analysed
    130
    138
    Units: Subjects
        Complete response
    23
    28
        Partial response
    62
    83
        No response
    45
    27
    No statistical analyses for this end point

    Adverse events

    		 Close Top of page
    Adverse events information
    Timeframe for reporting adverse events
    From the time of informed consent up to 30 days after the the last dose of trial drug has been received.
    Adverse event reporting additional description
    AEs graded using National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI CTCAE)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    4.03
    Reporting groups
    Reporting group title
    Arm A: neoadjuvant and adjuvant chemotherapy
    Reporting group description
    		 Arm A consists of chemotherapy pre-surgery and chemotherapy post-surgery. The chemotherapy regimens included in Neo-Aegis are included as accepted standards of care. Decisions about which chemotherapy regimen to use, i.e. modified MAGIC (ECF/ECX or EOF/EOX) or FLOT, are to be made by the treating clinician.

    Reporting group title
    Arm B: neoadjuvant chemoradiation
    Reporting group description
    		 Arm B consists of the multimodal CROSS arm, which includes a combination of chemotherapy and radiotherapy prior to surgery. The patient will receive four and a half (4.5) weeks of radiation therapy (41.4 Gy/23 fractions), and 5 weekly cycles of chemotherapy. The chemotherapy and radiotherapy will run concurrently over a 4 and a half-week period. Chemotherapy is given by intravenous infusion on days 1, 8, 15, 22 and 29. The radiation will generally commence on the 1st day of treatment and will run for 4 and a half weeks as follows: days 1-5, days 8-12, days 15-19, days 22-26 and days 29-31 inclusive.

    Serious adverse events
    		 Arm A: neoadjuvant and adjuvant chemotherapy Arm B: neoadjuvant chemoradiation
    Total subjects affected by serious adverse events
         subjects affected / exposed
    91 / 183 (49.73%)
    74 / 178 (41.57%)
         number of deaths (all causes)
    97
    94
         number of deaths resulting from adverse events
    10
    9
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Lymphangiosis carcinomatosa
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to central nervous system
         subjects affected / exposed
    0 / 183 (0.00%)
    2 / 178 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Vascular disorders
    Cyanosis
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Embolism
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Flushing
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 183 (0.00%)
    2 / 178 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphatic fistula
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Orthostatic hypotension
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral ischaemia
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombosis
         subjects affected / exposed
    2 / 183 (1.09%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    3 / 183 (1.64%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chills
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Complication associated with device
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    7 / 183 (3.83%)
    3 / 178 (1.69%)
         occurrences causally related to treatment / all
    6 / 9
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Medical device site necrosis
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucosal inflammation
         subjects affected / exposed
    3 / 183 (1.64%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Performance status decreased
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    5 / 183 (2.73%)
    10 / 178 (5.62%)
         occurrences causally related to treatment / all
    3 / 5
    6 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ulcer haemorrhage
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypersensitivity
         subjects affected / exposed
    0 / 183 (0.00%)
    2 / 178 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Chylothorax
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    2 / 183 (1.09%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphonia
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    6 / 183 (3.28%)
    2 / 178 (1.12%)
         occurrences causally related to treatment / all
    1 / 6
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hiccups
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mediastinal effusion
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oropharyngeal pain
         subjects affected / exposed
    2 / 183 (1.09%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    4 / 183 (2.19%)
    2 / 178 (1.12%)
         occurrences causally related to treatment / all
    0 / 4
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    3 / 183 (1.64%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Productive cough
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    10 / 183 (5.46%)
    10 / 178 (5.62%)
         occurrences causally related to treatment / all
    6 / 10
    10 / 12
         deaths causally related to treatment / all
    0 / 1
    1 / 1
    Pulmonary oedema
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Respiratory failure
         subjects affected / exposed
    5 / 183 (2.73%)
    6 / 178 (3.37%)
         occurrences causally related to treatment / all
    0 / 5
    1 / 6
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Psychiatric disorders
    Aggression
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Confusional state
         subjects affected / exposed
    3 / 183 (1.64%)
    2 / 178 (1.12%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Product issues
    Device leakage
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device occlusion
         subjects affected / exposed
    0 / 183 (0.00%)
    2 / 178 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Blood phosphorus increased
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood urea increased
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoglobin decreased
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Human metapneumovirus test positive
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutrophil count decreased
         subjects affected / exposed
    5 / 183 (2.73%)
    3 / 178 (1.69%)
         occurrences causally related to treatment / all
    6 / 6
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    1 / 183 (0.55%)
    3 / 178 (1.69%)
         occurrences causally related to treatment / all
    1 / 1
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Weight decreased
         subjects affected / exposed
    5 / 183 (2.73%)
    6 / 178 (3.37%)
         occurrences causally related to treatment / all
    1 / 5
    3 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    White blood cell count decreased
         subjects affected / exposed
    3 / 183 (1.64%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Anastomotic leak
         subjects affected / exposed
    4 / 183 (2.19%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Chemical peritonitis
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (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
         subjects affected / exposed
    2 / 183 (1.09%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    0 / 183 (0.00%)
    2 / 178 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Procedural pain
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radiation mucositis
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radiation oesophagitis
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Tracheo-oesophageal fistula
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 183 (0.55%)
    5 / 178 (2.81%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericarditis
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Right ventricular dysfunction
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    1 / 183 (0.55%)
    2 / 178 (1.12%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus tachycardia
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Autonomic neuropathy
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 183 (0.55%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysarthria
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lethargy
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radiculitis brachial
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radiculopathy
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    2 / 183 (1.09%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 183 (0.55%)
    2 / 178 (1.12%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    6 / 183 (3.28%)
    6 / 178 (3.37%)
         occurrences causally related to treatment / all
    6 / 6
    6 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    3 / 183 (1.64%)
    4 / 178 (2.25%)
         occurrences causally related to treatment / all
    3 / 3
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Visual impairment
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    4 / 183 (2.19%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    1 / 183 (0.55%)
    4 / 178 (2.25%)
         occurrences causally related to treatment / all
    1 / 1
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal haemorrhage
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    4 / 183 (2.19%)
    2 / 178 (1.12%)
         occurrences causally related to treatment / all
    2 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diaphragmatic hernia
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    17 / 183 (9.29%)
    3 / 178 (1.69%)
         occurrences causally related to treatment / all
    17 / 19
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    11 / 183 (6.01%)
    9 / 178 (5.06%)
         occurrences causally related to treatment / all
    0 / 14
    5 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric fistula
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric haemorrhage
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal necrosis
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    0 / 183 (0.00%)
    2 / 178 (1.12%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Hiatus hernia
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Impaired gastric emptying
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal infarction
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Nausea
         subjects affected / exposed
    11 / 183 (6.01%)
    11 / 178 (6.18%)
         occurrences causally related to treatment / all
    10 / 13
    10 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Odynophagia
         subjects affected / exposed
    8 / 183 (4.37%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    9 / 9
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal fistula
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal food impaction
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal pain
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    0 / 183 (0.00%)
    9 / 178 (5.06%)
         occurrences causally related to treatment / all
    0 / 0
    11 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Regurgitation
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    21 / 183 (11.48%)
    6 / 178 (3.37%)
         occurrences causally related to treatment / all
    18 / 22
    5 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash erythematous
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash maculo-papular
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 178 (0.56%)
         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
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    1 / 183 (0.55%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Bone pain
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    2 / 183 (1.09%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    3 / 183 (1.64%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia infection
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Extradural abscess
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    3 / 183 (1.64%)
    2 / 178 (1.12%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral discitis
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    4 / 183 (2.19%)
    2 / 178 (1.12%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucosal infection
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    4 / 183 (2.19%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    4 / 4
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oral candidiasis
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    4 / 183 (2.19%)
    5 / 178 (2.81%)
         occurrences causally related to treatment / all
    0 / 4
    3 / 5
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    2 / 183 (1.09%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Sepsis
         subjects affected / exposed
    3 / 183 (1.64%)
    3 / 178 (1.69%)
         occurrences causally related to treatment / all
    1 / 4
    1 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Stoma site infection
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suspected COVID-19
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 183 (0.00%)
    3 / 178 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral pharyngitis
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Cachexia
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Decreased appetite
         subjects affected / exposed
    5 / 183 (2.73%)
    5 / 178 (2.81%)
         occurrences causally related to treatment / all
    3 / 5
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    6 / 183 (3.28%)
    11 / 178 (6.18%)
         occurrences causally related to treatment / all
    6 / 6
    8 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Electrolyte imbalance
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fluid retention
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gout
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoalbuminaemia
         subjects affected / exposed
    1 / 183 (0.55%)
    1 / 178 (0.56%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    3 / 183 (1.64%)
    2 / 178 (1.12%)
         occurrences causally related to treatment / all
    2 / 3
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypomagnesaemia
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypophosphataemia
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Arm A: neoadjuvant and adjuvant chemotherapy Arm B: neoadjuvant chemoradiation
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    182 / 183 (99.45%)
    177 / 178 (99.44%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Malignant melanoma
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences all number
    1
    0
    Tumour pain
         subjects affected / exposed
    1 / 183 (0.55%)
    1 / 178 (0.56%)
         occurrences all number
    1
    1
    Vascular disorders
    Aortic stenosis
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences all number
    1
    0
    Deep vein thrombosis
         subjects affected / exposed
    1 / 183 (0.55%)
    2 / 178 (1.12%)
         occurrences all number
    1
    2
    Embolism
         subjects affected / exposed
    2 / 183 (1.09%)
    0 / 178 (0.00%)
         occurrences all number
    2
    0
    Flushing
         subjects affected / exposed
    1 / 183 (0.55%)
    3 / 178 (1.69%)
         occurrences all number
    1
    3
    Hot flush
         subjects affected / exposed
    1 / 183 (0.55%)
    2 / 178 (1.12%)
         occurrences all number
    1
    2
    Hypertension
         subjects affected / exposed
    9 / 183 (4.92%)
    3 / 178 (1.69%)
         occurrences all number
    9
    4
    Hypotension
         subjects affected / exposed
    5 / 183 (2.73%)
    11 / 178 (6.18%)
         occurrences all number
    6
    12
    Orthostatic hypotension
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences all number
    1
    0
    Phlebitis
         subjects affected / exposed
    5 / 183 (2.73%)
    0 / 178 (0.00%)
         occurrences all number
    5
    0
    Thrombophlebitis
         subjects affected / exposed
    5 / 183 (2.73%)
    2 / 178 (1.12%)
         occurrences all number
    6
    2
    Thrombosis
         subjects affected / exposed
    1 / 183 (0.55%)
    1 / 178 (0.56%)
         occurrences all number
    1
    1
    Vascular pain
         subjects affected / exposed
    4 / 183 (2.19%)
    0 / 178 (0.00%)
         occurrences all number
    4
    0
    General disorders and administration site conditions
    Administration site extravasation
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    0
    1
    Administration site inflammation
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences all number
    1
    0
    Administration site pain
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences all number
    1
    0
    Asthenia
         subjects affected / exposed
    7 / 183 (3.83%)
    3 / 178 (1.69%)
         occurrences all number
    11
    4
    Catheter site pain
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences all number
    1
    0
    Chest discomfort
         subjects affected / exposed
    1 / 183 (0.55%)
    3 / 178 (1.69%)
         occurrences all number
    1
    3
    Chest pain
         subjects affected / exposed
    12 / 183 (6.56%)
    9 / 178 (5.06%)
         occurrences all number
    13
    14
    Chills
         subjects affected / exposed
    2 / 183 (1.09%)
    2 / 178 (1.12%)
         occurrences all number
    3
    2
    Complication associated with device
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences all number
    2
    0
    Extravasation
         subjects affected / exposed
    2 / 183 (1.09%)
    1 / 178 (0.56%)
         occurrences all number
    2
    1
    Fatigue
         subjects affected / exposed
    117 / 183 (63.93%)
    103 / 178 (57.87%)
         occurrences all number
    215
    155
    Feeling hot
         subjects affected / exposed
    2 / 183 (1.09%)
    0 / 178 (0.00%)
         occurrences all number
    2
    0
    Hernia
         subjects affected / exposed
    1 / 183 (0.55%)
    1 / 178 (0.56%)
         occurrences all number
    1
    1
    Induration
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences all number
    1
    0
    Influenza like illness
         subjects affected / exposed
    0 / 183 (0.00%)
    3 / 178 (1.69%)
         occurrences all number
    0
    3
    Malaise
         subjects affected / exposed
    2 / 183 (1.09%)
    1 / 178 (0.56%)
         occurrences all number
    2
    2
    Mucosal dryness
         subjects affected / exposed
    3 / 183 (1.64%)
    0 / 178 (0.00%)
         occurrences all number
    3
    0
    Mucosal inflammation
         subjects affected / exposed
    27 / 183 (14.75%)
    15 / 178 (8.43%)
         occurrences all number
    43
    17
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 183 (0.55%)
    4 / 178 (2.25%)
         occurrences all number
    1
    4
    Oedema peripheral
         subjects affected / exposed
    6 / 183 (3.28%)
    2 / 178 (1.12%)
         occurrences all number
    8
    2
    Pain
         subjects affected / exposed
    1 / 183 (0.55%)
    1 / 178 (0.56%)
         occurrences all number
    1
    1
    Peripheral swelling
         subjects affected / exposed
    5 / 183 (2.73%)
    1 / 178 (0.56%)
         occurrences all number
    5
    2
    Pyrexia
         subjects affected / exposed
    8 / 183 (4.37%)
    18 / 178 (10.11%)
         occurrences all number
    8
    20
    Secretion discharge
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences all number
    1
    0
    Sensation of foreign body
         subjects affected / exposed
    1 / 183 (0.55%)
    1 / 178 (0.56%)
         occurrences all number
    1
    1
    Swelling
         subjects affected / exposed
    2 / 183 (1.09%)
    0 / 178 (0.00%)
         occurrences all number
    2
    0
    Temperature intolerance
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences all number
    1
    0
    Ulcer haemorrhage
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    0
    1
    Immune system disorders
    Cytokine release syndrome
         subjects affected / exposed
    0 / 183 (0.00%)
    2 / 178 (1.12%)
         occurrences all number
    0
    5
    Drug hypersensitivity
         subjects affected / exposed
    2 / 183 (1.09%)
    5 / 178 (2.81%)
         occurrences all number
    2
    6
    Hypersensitivity
         subjects affected / exposed
    1 / 183 (0.55%)
    8 / 178 (4.49%)
         occurrences all number
    1
    10
    Seasonal allergy
         subjects affected / exposed
    1 / 183 (0.55%)
    1 / 178 (0.56%)
         occurrences all number
    1
    1
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    0
    1
    Breast pain
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    0
    1
    Pelvic pain
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences all number
    1
    0
    Penile pain
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Aspiration
         subjects affected / exposed
    1 / 183 (0.55%)
    1 / 178 (0.56%)
         occurrences all number
    1
    1
    Atelectasis
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences all number
    1
    0
    Cough
         subjects affected / exposed
    36 / 183 (19.67%)
    48 / 178 (26.97%)
         occurrences all number
    39
    58
    Dysaesthesia pharynx
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences all number
    1
    0
    Dysphonia
         subjects affected / exposed
    3 / 183 (1.64%)
    2 / 178 (1.12%)
         occurrences all number
    3
    2
    Dyspnoea
         subjects affected / exposed
    27 / 183 (14.75%)
    26 / 178 (14.61%)
         occurrences all number
    35
    32
    Dyspnoea exertional
         subjects affected / exposed
    2 / 183 (1.09%)
    2 / 178 (1.12%)
         occurrences all number
    2
    2
    Epistaxis
         subjects affected / exposed
    8 / 183 (4.37%)
    14 / 178 (7.87%)
         occurrences all number
    8
    15
    Haemoptysis
         subjects affected / exposed
    1 / 183 (0.55%)
    2 / 178 (1.12%)
         occurrences all number
    1
    2
    Hiccups
         subjects affected / exposed
    12 / 183 (6.56%)
    10 / 178 (5.62%)
         occurrences all number
    20
    17
    Hypoxia
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    0
    1
    Increased viscosity of upper respiratory secretion
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    0
    1
    Laryngospasm
         subjects affected / exposed
    2 / 183 (1.09%)
    0 / 178 (0.00%)
         occurrences all number
    3
    0
    Nasal congestion
         subjects affected / exposed
    2 / 183 (1.09%)
    1 / 178 (0.56%)
         occurrences all number
    2
    1
    Nasal discomfort
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences all number
    1
    0
    Oropharyngeal pain
         subjects affected / exposed
    9 / 183 (4.92%)
    6 / 178 (3.37%)
         occurrences all number
    10
    7
    Oropharyngeal spasm
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences all number
    1
    0
    Pleural effusion
         subjects affected / exposed
    3 / 183 (1.64%)
    2 / 178 (1.12%)
         occurrences all number
    3
    2
    Pleuritic pain
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    0
    1
    Pneumonitis
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    0
    1
    Pneumothorax
         subjects affected / exposed
    3 / 183 (1.64%)
    0 / 178 (0.00%)
         occurrences all number
    3
    0
    Productive cough
         subjects affected / exposed
    8 / 183 (4.37%)
    5 / 178 (2.81%)
         occurrences all number
    8
    5
    Pulmonary embolism
         subjects affected / exposed
    3 / 183 (1.64%)
    2 / 178 (1.12%)
         occurrences all number
    3
    2
    Pulmonary fibrosis
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    0
    1
    Respiratory failure
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    0
    1
    Rhinorrhoea
         subjects affected / exposed
    4 / 183 (2.19%)
    0 / 178 (0.00%)
         occurrences all number
    4
    0
    Sinus pain
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences all number
    1
    0
    Tachypnoea
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences all number
    1
    0
    Throat irritation
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences all number
    1
    0
    Upper-airway cough syndrome
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences all number
    1
    0
    Wheezing
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    0
    1
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    1 / 183 (0.55%)
    1 / 178 (0.56%)
         occurrences all number
    1
    2
    Anger
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences all number
    1
    0
    Anxiety
         subjects affected / exposed
    6 / 183 (3.28%)
    2 / 178 (1.12%)
         occurrences all number
    6
    3
    Confusional state
         subjects affected / exposed
    2 / 183 (1.09%)
    0 / 178 (0.00%)
         occurrences all number
    2
    0
    Depressed mood
         subjects affected / exposed
    2 / 183 (1.09%)
    3 / 178 (1.69%)
         occurrences all number
    2
    3
    Depression
         subjects affected / exposed
    1 / 183 (0.55%)
    2 / 178 (1.12%)
         occurrences all number
    1
    2
    Hallucination
         subjects affected / exposed
    1 / 183 (0.55%)
    1 / 178 (0.56%)
         occurrences all number
    1
    1
    Insomnia
         subjects affected / exposed
    13 / 183 (7.10%)
    21 / 178 (11.80%)
         occurrences all number
    13
    26
    Suicidal ideation
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences all number
    1
    0
    Investigations
    Activated partial thromboplastin time prolonged
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences all number
    1
    0
    Alanine aminotransferase increased
         subjects affected / exposed
    15 / 183 (8.20%)
    4 / 178 (2.25%)
         occurrences all number
    18
    4
    Amylase increased
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences all number
    1
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    9 / 183 (4.92%)
    5 / 178 (2.81%)
         occurrences all number
    9
    6
    Blood albumin decreased
         subjects affected / exposed
    3 / 183 (1.64%)
    2 / 178 (1.12%)
         occurrences all number
    4
    4
    Blood alkaline phosphatase decreased
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    0
    1
    Blood alkaline phosphatase increased
         subjects affected / exposed
    11 / 183 (6.01%)
    0 / 178 (0.00%)
         occurrences all number
    13
    0
    Blood bicarbonate decreased
         subjects affected / exposed
    1 / 183 (0.55%)
    6 / 178 (3.37%)
         occurrences all number
    1
    6
    Blood bicarbonate increased
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    0
    1
    Blood bilirubin increased
         subjects affected / exposed
    3 / 183 (1.64%)
    5 / 178 (2.81%)
         occurrences all number
    3
    7
    Blood calcium decreased
         subjects affected / exposed
    1 / 183 (0.55%)
    3 / 178 (1.69%)
         occurrences all number
    1
    3
    Blood calcium increased
         subjects affected / exposed
    0 / 183 (0.00%)
    2 / 178 (1.12%)
         occurrences all number
    0
    3
    Blood chloride decreased
         subjects affected / exposed
    0 / 183 (0.00%)
    3 / 178 (1.69%)
         occurrences all number
    0
    3
    Blood chloride increased
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences all number
    1
    0
    Blood cholesterol increased
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences all number
    1
    0
    Blood creatinine decreased
         subjects affected / exposed
    1 / 183 (0.55%)
    3 / 178 (1.69%)
         occurrences all number
    1
    5
    Blood creatine increased
         subjects affected / exposed
    6 / 183 (3.28%)
    4 / 178 (2.25%)
         occurrences all number
    9
    6
    Blood folate decreased
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    0
    1
    Blood glucose decreased
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    0
    1
    Blood glucagon increased
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences all number
    1
    0
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    5 / 183 (2.73%)
    3 / 178 (1.69%)
         occurrences all number
    6
    3
    Blood magnesium decreased
         subjects affected / exposed
    5 / 183 (2.73%)
    4 / 178 (2.25%)
         occurrences all number
    6
    5
    Blood parathyroid hormone increased
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    0
    1
    Blood phosphorus decreased
         subjects affected / exposed
    10 / 183 (5.46%)
    0 / 178 (0.00%)
         occurrences all number
    11
    0
    Blood potassium decreased
         subjects affected / exposed
    4 / 183 (2.19%)
    3 / 178 (1.69%)
         occurrences all number
    4
    3
    Blood potassium increased
         subjects affected / exposed
    0 / 183 (0.00%)
    3 / 178 (1.69%)
         occurrences all number
    0
    3
    Blood sodium decreased
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences all number
    1
    0
    Blood urea increased
         subjects affected / exposed
    3 / 183 (1.64%)
    5 / 178 (2.81%)
         occurrences all number
    3
    5
    Blood uric acid decreased
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    0
    1
    Blood uric acid increased
         subjects affected / exposed
    2 / 183 (1.09%)
    0 / 178 (0.00%)
         occurrences all number
    2
    0
    Body temperature increased
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    0
    2
    C-reactive protein increased
         subjects affected / exposed
    2 / 183 (1.09%)
    1 / 178 (0.56%)
         occurrences all number
    4
    1
    Creatinine renal clearance decreased
         subjects affected / exposed
    3 / 183 (1.64%)
    0 / 178 (0.00%)
         occurrences all number
    3
    0
    Electrocardiogram QT prolonged
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences all number
    1
    0
    Full blood count abnormal
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    0
    1
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 183 (0.55%)
    4 / 178 (2.25%)
         occurrences all number
    1
    6
    Glycosylated haemoglobin increased
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    0
    1
    Haemoglobin decreased
         subjects affected / exposed
    26 / 183 (14.21%)
    5 / 178 (2.81%)
         occurrences all number
    62
    8
    Heart rate irregular
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    0
    1
    International normalised ratio increased
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences all number
    1
    0
    Liver function test abnormal
         subjects affected / exposed
    1 / 183 (0.55%)
    1 / 178 (0.56%)
         occurrences all number
    1
    1
    Lymphocyte count decreased
         subjects affected / exposed
    0 / 183 (0.00%)
    8 / 178 (4.49%)
         occurrences all number
    0
    28
    Neutrophil count decreased
         subjects affected / exposed
    66 / 183 (36.07%)
    15 / 178 (8.43%)
         occurrences all number
    150
    23
    Neutrophil count increased
         subjects affected / exposed
    4 / 183 (2.19%)
    3 / 178 (1.69%)
         occurrences all number
    4
    3
    Oxygen saturation decreased
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences all number
    1
    0
    Platelet count decreased
         subjects affected / exposed
    16 / 183 (8.74%)
    17 / 178 (9.55%)
         occurrences all number
    25
    20
    Prothrombin time prolonged
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences all number
    1
    0
    Serum ferritin decreased
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences all number
    1
    0
    Weight decreased
         subjects affected / exposed
    59 / 183 (32.24%)
    30 / 178 (16.85%)
         occurrences all number
    75
    36
    White blood cell count decreased
         subjects affected / exposed
    28 / 183 (15.30%)
    19 / 178 (10.67%)
         occurrences all number
    62
    31
    White blood cell count increased
         subjects affected / exposed
    4 / 183 (2.19%)
    3 / 178 (1.69%)
         occurrences all number
    4
    3
    White blood cells urine
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    0
    1
    Injury, poisoning and procedural complications
    Anastomotic leak
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences all number
    1
    0
    Contusion
         subjects affected / exposed
    2 / 183 (1.09%)
    1 / 178 (0.56%)
         occurrences all number
    2
    1
    Fall
         subjects affected / exposed
    2 / 183 (1.09%)
    1 / 178 (0.56%)
         occurrences all number
    2
    1
    Foot fracture
         subjects affected / exposed
    1 / 183 (0.55%)
    1 / 178 (0.56%)
         occurrences all number
    1
    1
    Gastrointestinal anastomotic stenosis
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    0
    1
    Head injury
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences all number
    1
    0
    Incisional hernia
         subjects affected / exposed
    2 / 183 (1.09%)
    1 / 178 (0.56%)
         occurrences all number
    2
    1
    Nerve injury
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    0
    1
    Post procedural erythema
         subjects affected / exposed
    1 / 183 (0.55%)
    1 / 178 (0.56%)
         occurrences all number
    1
    1
    Postoperative wound complication
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences all number
    1
    0
    Procedural pain
         subjects affected / exposed
    9 / 183 (4.92%)
    4 / 178 (2.25%)
         occurrences all number
    11
    5
    Radiation mucositis
         subjects affected / exposed
    0 / 183 (0.00%)
    2 / 178 (1.12%)
         occurrences all number
    0
    2
    Radiation oesophagitis
         subjects affected / exposed
    0 / 183 (0.00%)
    2 / 178 (1.12%)
         occurrences all number
    0
    3
    Radiation skin injury
         subjects affected / exposed
    0 / 183 (0.00%)
    5 / 178 (2.81%)
         occurrences all number
    0
    5
    Rib fracture
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    0
    1
    Splenic rupture
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    0
    1
    Stoma site erythema
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    0
    1
    Superficial injury of eye
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences all number
    1
    0
    Wound complication
         subjects affected / exposed
    3 / 183 (1.64%)
    0 / 178 (0.00%)
         occurrences all number
    3
    0
    Wrist fracture
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences all number
    1
    0
    Cardiac disorders
    Arteriospasm coronary
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences all number
    1
    0
    Atrial fibrillation
         subjects affected / exposed
    5 / 183 (2.73%)
    1 / 178 (0.56%)
         occurrences all number
    5
    1
    Atrial flutter
         subjects affected / exposed
    2 / 183 (1.09%)
    0 / 178 (0.00%)
         occurrences all number
    2
    0
    Atrioventricular block first degree
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    0
    1
    Cardiac disorder
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences all number
    1
    0
    Cardio-respiratory arrest
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    0
    1
    Myocardial infarction
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    0
    1
    Palpitations
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    0
    2
    Pericarditis
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    0
    1
    Sinus bradycardia
         subjects affected / exposed
    2 / 183 (1.09%)
    0 / 178 (0.00%)
         occurrences all number
    2
    0
    Sinus tachycardia
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences all number
    1
    0
    Tachycardia
         subjects affected / exposed
    3 / 183 (1.64%)
    5 / 178 (2.81%)
         occurrences all number
    3
    5
    Ventricular extrasystoles
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Ageusia
         subjects affected / exposed
    3 / 183 (1.64%)
    3 / 178 (1.69%)
         occurrences all number
    3
    3
    Akathisia
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    0
    1
    Anaesthesia
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences all number
    1
    0
    Aphasia
         subjects affected / exposed
    0 / 183 (0.00%)
    2 / 178 (1.12%)
         occurrences all number
    0
    2
    Cognitive disorder
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    0
    1
    Cold dysaesthesia
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences all number
    1
    0
    Disturbance in attention
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences all number
    1
    0
    Dizziness
         subjects affected / exposed
    17 / 183 (9.29%)
    11 / 178 (6.18%)
         occurrences all number
    18
    11
    Dysaesthesia
         subjects affected / exposed
    2 / 183 (1.09%)
    0 / 178 (0.00%)
         occurrences all number
    3
    0
    Dysgeusia
         subjects affected / exposed
    8 / 183 (4.37%)
    8 / 178 (4.49%)
         occurrences all number
    11
    8
    Dyspraxia
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences all number
    1
    0
    Headache
         subjects affected / exposed
    10 / 183 (5.46%)
    14 / 178 (7.87%)
         occurrences all number
    12
    18
    Hypoaesthesia
         subjects affected / exposed
    3 / 183 (1.64%)
    2 / 178 (1.12%)
         occurrences all number
    3
    2
    Lethargy
         subjects affected / exposed
    8 / 183 (4.37%)
    5 / 178 (2.81%)
         occurrences all number
    10
    5
    Nerve compression
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences all number
    1
    0
    Neuralgia
         subjects affected / exposed
    2 / 183 (1.09%)
    2 / 178 (1.12%)
         occurrences all number
    2
    2
    Neuropathy peripheral
         subjects affected / exposed
    69 / 183 (37.70%)
    13 / 178 (7.30%)
         occurrences all number
    115
    15
    Paraesthesia
         subjects affected / exposed
    9 / 183 (4.92%)
    3 / 178 (1.69%)
         occurrences all number
    11
    3
    Parosmia
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences all number
    1
    0
    Peripheral motor neuropathy
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences all number
    1
    0
    Peripheral sensory neuropathy
         subjects affected / exposed
    13 / 183 (7.10%)
    0 / 178 (0.00%)
         occurrences all number
    26
    0
    Peroneal nerve palsy
         subjects affected / exposed
    1 / 183 (0.55%)
    1 / 178 (0.56%)
         occurrences all number
    1
    1
    Presyncope
         subjects affected / exposed
    4 / 183 (2.19%)
    2 / 178 (1.12%)
         occurrences all number
    4
    2
    Radiculitis brachial
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    0
    1
    Restless legs syndrome
         subjects affected / exposed
    0 / 183 (0.00%)
    2 / 178 (1.12%)
         occurrences all number
    0
    2
    Syncope
         subjects affected / exposed
    6 / 183 (3.28%)
    2 / 178 (1.12%)
         occurrences all number
    6
    3
    Taste disorder
         subjects affected / exposed
    13 / 183 (7.10%)
    6 / 178 (3.37%)
         occurrences all number
    13
    7
    Tremor
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences all number
    1
    0
    Vocal cord paralysis
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences all number
    1
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    25 / 183 (13.66%)
    8 / 178 (4.49%)
         occurrences all number
    35
    9
    Febrile neutropenia
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences all number
    1
    0
    Leukopenia
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences all number
    1
    0
    Lymphopenia
         subjects affected / exposed
    0 / 183 (0.00%)
    3 / 178 (1.69%)
         occurrences all number
    0
    3
    Myelosuppression
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    0
    1
    Neutropenia
         subjects affected / exposed
    43 / 183 (23.50%)
    13 / 178 (7.30%)
         occurrences all number
    65
    18
    Thrombocytopenia
         subjects affected / exposed
    3 / 183 (1.64%)
    1 / 178 (0.56%)
         occurrences all number
    5
    1
    Ear and labyrinth disorders
    Ear discomfort
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    0
    1
    Ear pain
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    0
    1
    Hypoacusis
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences all number
    1
    0
    Tinnitus
         subjects affected / exposed
    6 / 183 (3.28%)
    1 / 178 (0.56%)
         occurrences all number
    8
    1
    Eye disorders
    Cataract
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences all number
    1
    0
    Conjunctival haemorrhage
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    0
    1
    Dry eye
         subjects affected / exposed
    6 / 183 (3.28%)
    0 / 178 (0.00%)
         occurrences all number
    6
    0
    Eye discharge
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences all number
    1
    0
    Foreign body sensation in eyes
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences all number
    1
    0
    Lacrimation increased
         subjects affected / exposed
    6 / 183 (3.28%)
    0 / 178 (0.00%)
         occurrences all number
    7
    0
    Ocular hyperaemia
         subjects affected / exposed
    2 / 183 (1.09%)
    0 / 178 (0.00%)
         occurrences all number
    2
    0
    Vision blurred
         subjects affected / exposed
    3 / 183 (1.64%)
    1 / 178 (0.56%)
         occurrences all number
    6
    1
    Visual impairment
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    2 / 183 (1.09%)
    3 / 178 (1.69%)
         occurrences all number
    2
    3
    Abdominal distension
         subjects affected / exposed
    1 / 183 (0.55%)
    6 / 178 (3.37%)
         occurrences all number
    1
    8
    Abdominal pain
         subjects affected / exposed
    29 / 183 (15.85%)
    9 / 178 (5.06%)
         occurrences all number
    39
    10
    Abdominal pain lower
         subjects affected / exposed
    2 / 183 (1.09%)
    0 / 178 (0.00%)
         occurrences all number
    2
    0
    Abdominal pain upper
         subjects affected / exposed
    11 / 183 (6.01%)
    19 / 178 (10.67%)
         occurrences all number
    15
    25
    Abdominal rigidity
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    0
    1
    Abdominal tenderness
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences all number
    1
    0
    Anal fissure
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences all number
    1
    0
    Anal haemorrhage
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences all number
    1
    0
    Aphthous ulcer
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences all number
    1
    0
    Colitis
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences all number
    1
    0
    Constipation
         subjects affected / exposed
    71 / 183 (38.80%)
    78 / 178 (43.82%)
         occurrences all number
    103
    102
    Diaphragmatic hernia
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences all number
    1
    0
    Diarrhoea
         subjects affected / exposed
    93 / 183 (50.82%)
    43 / 178 (24.16%)
         occurrences all number
    176
    60
    Dry mouth
         subjects affected / exposed
    5 / 183 (2.73%)
    6 / 178 (3.37%)
         occurrences all number
    10
    6
    Dumping syndrome
         subjects affected / exposed
    8 / 183 (4.37%)
    3 / 178 (1.69%)
         occurrences all number
    8
    3
    Dyspepsia
         subjects affected / exposed
    16 / 183 (8.74%)
    16 / 178 (8.99%)
         occurrences all number
    22
    19
    Dysphagia
         subjects affected / exposed
    35 / 183 (19.13%)
    44 / 178 (24.72%)
         occurrences all number
    44
    55
    Enterocolitis
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    0
    1
    Epigastric discomfort
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences all number
    1
    0
    Eructation
         subjects affected / exposed
    1 / 183 (0.55%)
    3 / 178 (1.69%)
         occurrences all number
    1
    5
    Faecaloma
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences all number
    1
    0
    Faeces soft
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences all number
    1
    0
    Flatulence
         subjects affected / exposed
    2 / 183 (1.09%)
    3 / 178 (1.69%)
         occurrences all number
    2
    3
    Gastritis
         subjects affected / exposed
    0 / 183 (0.00%)
    6 / 178 (3.37%)
         occurrences all number
    0
    10
    Gastrooesophageal reflux disease
         subjects affected / exposed
    20 / 183 (10.93%)
    29 / 178 (16.29%)
         occurrences all number
    24
    33
    Glossitis
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences all number
    1
    0
    Haematemesis
         subjects affected / exposed
    3 / 183 (1.64%)
    0 / 178 (0.00%)
         occurrences all number
    3
    0
    Haemorrhoids
         subjects affected / exposed
    3 / 183 (1.64%)
    3 / 178 (1.69%)
         occurrences all number
    3
    3
    Intestinal obstruction
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    0
    1
    Lip pain
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences all number
    1
    0
    Melaena
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences all number
    1
    0
    Mouth ulceration
         subjects affected / exposed
    6 / 183 (3.28%)
    0 / 178 (0.00%)
         occurrences all number
    7
    0
    Nausea
         subjects affected / exposed
    110 / 183 (60.11%)
    101 / 178 (56.74%)
         occurrences all number
    210
    143
    Obstruction gastric
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences all number
    1
    0
    Odynophagia
         subjects affected / exposed
    5 / 183 (2.73%)
    38 / 178 (21.35%)
         occurrences all number
    5
    44
    Oesophageal food impaction
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences all number
    1
    0
    Oesophageal hypomotility
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    0
    1
    Oesophageal pain
         subjects affected / exposed
    1 / 183 (0.55%)
    11 / 178 (6.18%)
         occurrences all number
    1
    14
    Oesophageal perforation
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    0
    1
    Oesophageal stenosis
         subjects affected / exposed
    1 / 183 (0.55%)
    2 / 178 (1.12%)
         occurrences all number
    1
    2
    Oesophagitis
         subjects affected / exposed
    6 / 183 (3.28%)
    56 / 178 (31.46%)
         occurrences all number
    7
    72
    Oral dysaesthesia
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences all number
    1
    0
    Oral pain
         subjects affected / exposed
    5 / 183 (2.73%)
    2 / 178 (1.12%)
         occurrences all number
    5
    2
    Overflow diarrhoea
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences all number
    1
    0
    Pancreatic failure
         subjects affected / exposed
    1 / 183 (0.55%)
    1 / 178 (0.56%)
         occurrences all number
    1
    1
    Peptic ulcer
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    0
    1
    Rectal haemorrhage
         subjects affected / exposed
    2 / 183 (1.09%)
    0 / 178 (0.00%)
         occurrences all number
    2
    0
    Regurgitation
         subjects affected / exposed
    3 / 183 (1.64%)
    1 / 178 (0.56%)
         occurrences all number
    3
    1
    Retching
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences all number
    1
    0
    Salivary hypersecretion
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    0
    1
    Steatorrhoea
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences all number
    1
    0
    Stomatitis
         subjects affected / exposed
    7 / 183 (3.83%)
    7 / 178 (3.93%)
         occurrences all number
    10
    7
    Tongue blistering
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    0
    1
    Toothache
         subjects affected / exposed
    1 / 183 (0.55%)
    2 / 178 (1.12%)
         occurrences all number
    1
    2
    Upper gastrointestinal perforation
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    0
    1
    Vomiting
         subjects affected / exposed
    52 / 183 (28.42%)
    35 / 178 (19.66%)
         occurrences all number
    79
    46
    Hepatobiliary disorders
    Hepatic cirrhosis
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences all number
    1
    0
    Hepatic function abnormal
         subjects affected / exposed
    1 / 183 (0.55%)
    1 / 178 (0.56%)
         occurrences all number
    3
    1
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    47 / 183 (25.68%)
    15 / 178 (8.43%)
         occurrences all number
    57
    15
    Blister
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences all number
    1
    0
    Cold sweat
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences all number
    1
    0
    Dermatitis
         subjects affected / exposed
    1 / 183 (0.55%)
    5 / 178 (2.81%)
         occurrences all number
    1
    5
    Dermatitis acneiform
         subjects affected / exposed
    0 / 183 (0.00%)
    3 / 178 (1.69%)
         occurrences all number
    0
    5
    Dry skin
         subjects affected / exposed
    6 / 183 (3.28%)
    2 / 178 (1.12%)
         occurrences all number
    8
    2
    Eczema
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    0
    1
    Erythema
         subjects affected / exposed
    2 / 183 (1.09%)
    5 / 178 (2.81%)
         occurrences all number
    2
    5
    Hyperhidrosis
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    0
    1
    Nail disorder
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences all number
    1
    0
    Nail toxicity
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences all number
    1
    0
    Night sweats
         subjects affected / exposed
    3 / 183 (1.64%)
    0 / 178 (0.00%)
         occurrences all number
    4
    0
    Palmar erythema
         subjects affected / exposed
    2 / 183 (1.09%)
    0 / 178 (0.00%)
         occurrences all number
    3
    0
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    25 / 183 (13.66%)
    3 / 178 (1.69%)
         occurrences all number
    31
    3
    Pigmentation disorder
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    0
    1
    Pruritus
         subjects affected / exposed
    1 / 183 (0.55%)
    3 / 178 (1.69%)
         occurrences all number
    1
    4
    Rash
         subjects affected / exposed
    10 / 183 (5.46%)
    10 / 178 (5.62%)
         occurrences all number
    12
    11
    Rash maculo-papular
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    0
    1
    Rash papular
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences all number
    1
    0
    Rosacea
         subjects affected / exposed
    1 / 183 (0.55%)
    1 / 178 (0.56%)
         occurrences all number
    1
    1
    Scar pain
         subjects affected / exposed
    7 / 183 (3.83%)
    1 / 178 (0.56%)
         occurrences all number
    8
    1
    Skin disorder
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    0
    1
    Skin exfoliation
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences all number
    1
    0
    Skin fissures
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences all number
    1
    0
    Skin reaction
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    0
    1
    Skin texture abnormal
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences all number
    1
    0
    Skin ulcer
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences all number
    2
    0
    Subcutaneous emphysema
         subjects affected / exposed
    1 / 183 (0.55%)
    1 / 178 (0.56%)
         occurrences all number
    1
    1
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 183 (0.55%)
    1 / 178 (0.56%)
         occurrences all number
    1
    1
    Dysuria
         subjects affected / exposed
    3 / 183 (1.64%)
    3 / 178 (1.69%)
         occurrences all number
    3
    3
    Haematuria
         subjects affected / exposed
    0 / 183 (0.00%)
    2 / 178 (1.12%)
         occurrences all number
    0
    2
    Nocturia
         subjects affected / exposed
    2 / 183 (1.09%)
    0 / 178 (0.00%)
         occurrences all number
    2
    0
    Pollakiuria
         subjects affected / exposed
    3 / 183 (1.64%)
    4 / 178 (2.25%)
         occurrences all number
    3
    4
    Renal vein thrombosis
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences all number
    1
    0
    Urinary hesitation
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences all number
    1
    0
    Urinary incontinence
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    0
    1
    Urinary retention
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    11 / 183 (6.01%)
    7 / 178 (3.93%)
         occurrences all number
    11
    8
    Arthritis
         subjects affected / exposed
    2 / 183 (1.09%)
    1 / 178 (0.56%)
         occurrences all number
    2
    1
    Back pain
         subjects affected / exposed
    9 / 183 (4.92%)
    8 / 178 (4.49%)
         occurrences all number
    9
    9
    Flank pain
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences all number
    1
    0
    Groin pain
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences all number
    1
    0
    Joint swelling
         subjects affected / exposed
    2 / 183 (1.09%)
    0 / 178 (0.00%)
         occurrences all number
    2
    0
    Muscle spasms
         subjects affected / exposed
    6 / 183 (3.28%)
    2 / 178 (1.12%)
         occurrences all number
    6
    2
    Muscular weakness
         subjects affected / exposed
    3 / 183 (1.64%)
    2 / 178 (1.12%)
         occurrences all number
    3
    2
    Musculoskeletal chest pain
         subjects affected / exposed
    4 / 183 (2.19%)
    3 / 178 (1.69%)
         occurrences all number
    4
    4
    Musculoskeletal discomfort
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    0
    1
    Musculoskeletal pain
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    0
    1
    Musculoskeletal stiffness
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    0
    1
    Myalgia
         subjects affected / exposed
    3 / 183 (1.64%)
    1 / 178 (0.56%)
         occurrences all number
    3
    1
    Neck pain
         subjects affected / exposed
    1 / 183 (0.55%)
    2 / 178 (1.12%)
         occurrences all number
    1
    2
    Osteopenia
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    0
    1
    Pain in extremity
         subjects affected / exposed
    13 / 183 (7.10%)
    2 / 178 (1.12%)
         occurrences all number
    14
    4
    Pain in jaw
         subjects affected / exposed
    3 / 183 (1.64%)
    0 / 178 (0.00%)
         occurrences all number
    4
    0
    Rhabdomyolysis
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    0
    1
    Spinal osteoarthritis
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    0
    1
    Trismus
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences all number
    2
    0
    Infections and infestations
    Bacterial infection
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences all number
    1
    0
    Candida infection
         subjects affected / exposed
    2 / 183 (1.09%)
    1 / 178 (0.56%)
         occurrences all number
    2
    1
    Cellulitis
         subjects affected / exposed
    2 / 183 (1.09%)
    2 / 178 (1.12%)
         occurrences all number
    2
    2
    Conjunctivitis
         subjects affected / exposed
    2 / 183 (1.09%)
    0 / 178 (0.00%)
         occurrences all number
    2
    0
    Cystitis
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    0
    1
    Diverticulitis
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences all number
    1
    0
    Erysipelas
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences all number
    1
    0
    Escherichia urinary tract infection
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    0
    1
    Folliculitis
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    0
    1
    Fungal infection
         subjects affected / exposed
    1 / 183 (0.55%)
    1 / 178 (0.56%)
         occurrences all number
    1
    1
    Haemophilus infection
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    0
    1
    Herpes simplex
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    0
    1
    Herpes zoster
         subjects affected / exposed
    2 / 183 (1.09%)
    3 / 178 (1.69%)
         occurrences all number
    2
    3
    Infected dermal cyst
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    0
    1
    Infection
         subjects affected / exposed
    2 / 183 (1.09%)
    3 / 178 (1.69%)
         occurrences all number
    2
    3
    Influenza
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    0
    1
    Lip infection
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    0
    1
    Localised infection
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences all number
    1
    0
    Lower respiratory tract infection
         subjects affected / exposed
    6 / 183 (3.28%)
    7 / 178 (3.93%)
         occurrences all number
    6
    7
    Mucosal infection
         subjects affected / exposed
    2 / 183 (1.09%)
    0 / 178 (0.00%)
         occurrences all number
    2
    0
    Nail infection
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    0
    1
    Nasopharyngitis
         subjects affected / exposed
    1 / 183 (0.55%)
    1 / 178 (0.56%)
         occurrences all number
    1
    1
    Oral candidiasis
         subjects affected / exposed
    6 / 183 (3.28%)
    13 / 178 (7.30%)
         occurrences all number
    6
    14
    Oral herpes
         subjects affected / exposed
    2 / 183 (1.09%)
    1 / 178 (0.56%)
         occurrences all number
    2
    1
    Oral infection
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    0
    1
    Pharyngitis
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    0
    1
    Pneumonia
         subjects affected / exposed
    2 / 183 (1.09%)
    3 / 178 (1.69%)
         occurrences all number
    2
    4
    Pneumonia aspiration
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences all number
    1
    0
    Post procedural infection
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences all number
    1
    0
    Postoperative wound infection
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences all number
    1
    0
    Respiratory tract infection
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences all number
    1
    0
    Rhinitis
         subjects affected / exposed
    2 / 183 (1.09%)
    1 / 178 (0.56%)
         occurrences all number
    2
    1
    Sepsis
         subjects affected / exposed
    2 / 183 (1.09%)
    1 / 178 (0.56%)
         occurrences all number
    2
    1
    Sinusitis
         subjects affected / exposed
    1 / 183 (0.55%)
    1 / 178 (0.56%)
         occurrences all number
    1
    1
    Skin infection
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences all number
    1
    0
    Staphylococcal infection
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    0
    1
    Stoma site infection
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    0
    1
    Tooth abscess
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences all number
    2
    0
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 183 (1.09%)
    2 / 178 (1.12%)
         occurrences all number
    2
    3
    Urinary tract infection
         subjects affected / exposed
    5 / 183 (2.73%)
    5 / 178 (2.81%)
         occurrences all number
    6
    6
    Viral infection
         subjects affected / exposed
    1 / 183 (0.55%)
    1 / 178 (0.56%)
         occurrences all number
    1
    1
    Vulvovaginal candidiasis
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences all number
    1
    0
    Wound infection
         subjects affected / exposed
    3 / 183 (1.64%)
    1 / 178 (0.56%)
         occurrences all number
    3
    1
    Metabolism and nutrition disorders
    Appetite disorder
         subjects affected / exposed
    2 / 183 (1.09%)
    1 / 178 (0.56%)
         occurrences all number
    2
    1
    Decreased appetite
         subjects affected / exposed
    54 / 183 (29.51%)
    53 / 178 (29.78%)
         occurrences all number
    72
    70
    Dehydration
         subjects affected / exposed
    3 / 183 (1.64%)
    0 / 178 (0.00%)
         occurrences all number
    3
    0
    Electrolyte imbalance
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    0
    1
    Gout
         subjects affected / exposed
    3 / 183 (1.64%)
    2 / 178 (1.12%)
         occurrences all number
    4
    3
    Hypercalcaemia
         subjects affected / exposed
    6 / 183 (3.28%)
    0 / 178 (0.00%)
         occurrences all number
    7
    0
    Hyperglycaemia
         subjects affected / exposed
    4 / 183 (2.19%)
    1 / 178 (0.56%)
         occurrences all number
    4
    1
    Hyperkalaemia
         subjects affected / exposed
    1 / 183 (0.55%)
    1 / 178 (0.56%)
         occurrences all number
    1
    3
    Hypermagnesaemia
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences all number
    1
    0
    Hypernatraemia
         subjects affected / exposed
    2 / 183 (1.09%)
    0 / 178 (0.00%)
         occurrences all number
    6
    0
    Hyperphosphataemia
         subjects affected / exposed
    1 / 183 (0.55%)
    1 / 178 (0.56%)
         occurrences all number
    1
    1
    Hypoalbuminaemia
         subjects affected / exposed
    16 / 183 (8.74%)
    2 / 178 (1.12%)
         occurrences all number
    34
    5
    Hypocalcaemia
         subjects affected / exposed
    15 / 183 (8.20%)
    3 / 178 (1.69%)
         occurrences all number
    27
    4
    Hypoglycaemia
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    0
    1
    Hypokalaemia
         subjects affected / exposed
    21 / 183 (11.48%)
    7 / 178 (3.93%)
         occurrences all number
    32
    10
    Hypomagnesaemia
         subjects affected / exposed
    17 / 183 (9.29%)
    6 / 178 (3.37%)
         occurrences all number
    28
    8
    Hyponatraemia
         subjects affected / exposed
    10 / 183 (5.46%)
    4 / 178 (2.25%)
         occurrences all number
    13
    4
    Hypophosphataemia
         subjects affected / exposed
    19 / 183 (10.38%)
    12 / 178 (6.74%)
         occurrences all number
    40
    16
    Iron deficiency
         subjects affected / exposed
    1 / 183 (0.55%)
    0 / 178 (0.00%)
         occurrences all number
    1
    0
    Malnutrition
         subjects affected / exposed
    0 / 183 (0.00%)
    1 / 178 (0.56%)
         occurrences all number
    0
    1

    More information

    		 Close Top of page

    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    10 Aug 2011
    Protocol Amendment to Protocol v2 included editorial and admin changes as well as Therapy changes. Update to patient information leaflet also included.
    19 Jun 2012
    Update to Protocol version 3 and updates to patient information leaflets.
    21 Jan 2014
    Update to Protocol v 4, included updates to Study assessments and procedures. Also included updates to Patient information leaflets and schedule of treatments.
    27 Jan 2015
    Update to Protocol version 5 included updates to sample size, recruitment period, eligibility criteria, therapy changes and administrative changes.
    10 Mar 2015
    Update to protocol to version 6 included update requested by the MHRA in UK. Version 6 was applicable to UK only
    26 Feb 2016
    Update to Protocol version 8, included updated guidance on live vaccinations, inclusion criteria and contraceptive requirements.
    28 Apr 2017
    Update to Protocol version 9 included updates to inclusion and exclusion criteria, adverse event guidance and timeframes for screening and treatment assessments.
    22 May 2018
    Update to Protocol version 10.2 included update to therapy by permitting the addition of FLOT regimen as an alternative to MAGIC regimen for neoadjuvant and adjuvant chemotherapy in the study. Other updates to therapy and exclusion criteria also included.
    11 Jun 2019
    Update to Protocol 11 included updates to therapy, sample size, statistical considerations and study assessments and procedures.
    27 Oct 2020
    Update to Protocol version 12 included update to duration of follow-up period, safety information, the translational sub-study and other administrative changes.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    26 Mar 2020
    Temporary Halt to recruitment due to the COVID-19 pandemic
    13 Aug 2020

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Study was under powered due to early termination (70% of planned patients). At 2nd futility analysis (50% of deaths) DSMB assessed, that futility was not evident but data was unlikely to change with increased numbers and longer-term follow up.
    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.

    European Medicines Agency © 1995-Tue May 07 04:26:07 CEST 2024 | Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands
    EMA HMA