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INSTITUT FÜR MEDIZINISCHE BIOMETRIE UND INFORMATIK

RUPRECHT-KARLS-UNIVERSITÄT HEIDELBERG

Nr. 62

A Phase III Trial of Postoperative Cisplatin, Interferon Alpha-2b, and 5-FU Combined with External Radiation Treatment (CapRI) versus 5-FU alone for Patients with

Resected Pancreatic Adenocarcinoma

Oktober 2010

Forschungsberichte der Abteilung Medizinische Biometrie, Universität Heidelberg

Nr. 62 A Phase III Trial of Postoperative Cisplatin, Interferon Alpha-2b, and 5-FU Combined with External Radiation Treatment (CapRI) versus 5-FU alone for Patients with

Resected Pancreatic Adenocarcinoma

Abschlussbericht

ULRICH ABEL, JUDITH MUNZINGER, RONALD LIMPRECHT

Institut für Medizinische Biometrie und Informatik (IMBI), Universität Heidelberg

Heidelberg, Oktober 2010

Impressum: Reihentitel: Forschungsberichte der Abteilung Medizinische Biometrie, Universität Heidelberg Herausgeber: Prof. Dr. Meinhard Kieser Anschrift: Im Neuenheimer Feld 305, 69120 Heidelberg Druck: Hausdruckerei der Ruprecht-Karls-Universität Heidelberg Elektronischer Bezug: http://www.biometrie.uni-heidelberg.de ISSN: 1619-5833

Basic Study Information

ISRCTN: 62866759 Principle Investigator: Prof. Dr. Dr. M. Büchler Dept. of Surgery, University Hospital of Heidelberg. Biostatistics: Prof. Dr. Dr. U. Abel NCT Heidelberg und IMBI Heidelberg Prof. Dr. U. Mansmann, IBE Medical School, LMU München Data Management: Sabrina Brucher, Carmen Bauer, Judith Munzinger,

Ronald Limprecht Institut für medizinische Biometrie und Informatik (IMBI), Universität Heidelberg Note: Data contained in Appendix II of the CRF (description of SAEs) remained with the Pancreatic Study Group (NCT/Dept. of Surgery). Further Cooperating Partners and Investigators: Trial Coordinator: Prof. Dr. A. Märten c/o Dept. of Surgery, University Hospital of Heidelberg and NCT Heidelberg Co-Chairman: Prof. Dr. J. Schmidt Dept. of Surgery, University Hospital of Heidelberg Data Monitoring Committee (DMC): Dr. med. Lilienfeld-Toal Dept. of Internal Medicine, Univ. Hospital, Bonn Dr. med. C. Ziske St. Josef-Hospital, Troisdorf Dr. L. Edler DKFZ Heidelberg Randomization: Klinisches Studienzentrum Chirurgie (KSC) Heidelberg Clinical Monitoring: ECRON ACUNOVA GmbH, Frankfurt Sponsor: University Hospital of Heidelberg Participating Centers:

1. University Hospital, Heidelberg 2. St.Joseph-Krankenhaus, Berlin 3. University Hospital, Marburg (this center did not contribute any patients to the trial) 4. University Hospital, Regensburg 5. Städtische Kliniken Bielefeld 6. Dept. of Surgical Oncology, Istituto per la Ricerca e la Cura del Cancro, Caniolo, Torino

Table of Contents

List of Abbreviations ....................................................................................................1

List of Figures..............................................................................................................2

List of Tables ...............................................................................................................6

Data Listings..............................................................................................................11

1. Introduction .........................................................................................................12

1.1. Scope of the Report....................................................................................12

1.2. Study Protocol, Ethics, Organization of the Trial ........................................12

2. Investigational Plan and Trial conduct ................................................................13

2.1. Study Objectives.........................................................................................13

2.2. Study Design - General Aspects.................................................................13

2.3. Sequence of Planned Analyses..................................................................13

2.4. Changes to the Conduct and Analysis of the Trial......................................14

2.5. Study Population ........................................................................................14

2.6. Patient Recruitment ....................................................................................14

2.7. Study Treatment and Treatment Groups ....................................................15

2.8. Study Periods, Visit Window Definitions, and Follow-up.............................15

2.9. Randomization............................................................................................16

2.10. Hypotheses and Decision Rules.................................................................16

2.11. Sample Size ...............................................................................................16

2.12. Protocol Deviations.....................................................................................17

3. Statistical Analysis ..............................................................................................17

3.1. Analysis Populations ..................................................................................17

3.1.1. Study Population ..................................................................................17

3.1.2. Full Analysis Set (FAS) ........................................................................17

3.1.3. Safety Population .................................................................................17

3.2. Treatment Misallocations............................................................................18

3.3. Study Endpoints and Covariates ................................................................18

3.3.1. Efficacy Endpoint(s) .............................................................................18

3.3.2. Safety and Tolerability Endpoints.........................................................19

3.3.3. Quality of Life (QoL) Endpoints ............................................................19

3.3.4. Covariates ............................................................................................20

3.4. Statistical Methodology...............................................................................20

3.4.1. General Remarks .................................................................................20

3.4.2. Adjustments for Covariates ..................................................................21

3.4.3. Multiple Comparisons/Multiplicity .........................................................21

3.4.4. Handling of Dropouts or Missing Data ................................................. 21

3.4.5. Center Pooling Method and Handling Center Effects .......................... 21

3.4.6. Analysis of Demographic and Other Baseline Characteristics............. 21

3.4.7. Analysis of Treatment Compliance and Exposure ............................... 21

3.4.8. Analysis of the Primary Efficacy Variable ............................................ 22

3.4.9. Analysis of the Secondary Efficacy Variable (DFS) ............................. 23

3.4.10. Analysis of Further Endpoints.............................................................. 23

3.4.11. Analysis of the Safety and Tolerability Variables ................................. 24

3.4.12. Analysis of Adverse Events ................................................................. 24

3.4.13. Additional Analyses of Toxicity ............................................................ 24

3.4.14. Clinical Laboratory Evaluation ............................................................. 25

3.4.15. Vital Signs, Physical Findings and Other Observations Related to Safety................................................................................. 25

3.4.16. Changes in the Planned Analyses ....................................................... 25

4. Results ............................................................................................................... 27

4.1. Disposition of Patients, Enrolment ............................................................. 27

4.2. Demographic and Other Baseline Characteristics ..................................... 27

4.3. Treatment Compliance and Exposure........................................................ 27

4.4. Efficacy Analysis ........................................................................................ 27

4.4.1. Analysis of the Primary Efficacy Variable ............................................ 27

4.4.2. Analysis of the Secondary Efficacy Variable (DFS) ............................. 28

4.5. Analysis of Other Endpoints....................................................................... 29

4.5.1. Quality of Life (QoL), Not Adjusted ...................................................... 29

4.5.2. Quality of Life (QoL), Adjusted............................................................. 29

4.5.3. Prognostic Relevance of Baseline Variables ....................................... 29

4.5.4. Time from Relapse to Death................................................................ 29

4.6. Analysis of the Safety and Tolerability Variables ....................................... 29

4.6.1. Analysis of Adverse Events ................................................................. 29

4.6.2. Clinical Laboratory Evaluation ............................................................. 30

4.6.3. Vital signs, Physical Findings and Other Observations Related to Safety................................................................................. 30

5. Appendix: Tables and Figures............................................................................ 31

6. References ....................................................................................................... 172

1

List of Abbreviations

AE Adverse event BP Blood pressure CI Confidence interval CRF Case report form DBP Diastolic blood pressure DMC Data Monitoring Committee FA Folinic acid FAS Full analysis set 5-FU 5-Fluorouracil GCP Good Clinical Practice HR Heart rate ICH International Conference on Harmonisation ITT Intent-to-treat KSC Klinisches Studienzentrum Chirurgie, Heidelberg NCI National Cancer Institute (USA) NCT National Center for Tumor Diseases, Heidelberg QoL Quality of life SAE Serious adverse event SAP Statistical analysis plan SBP Systolic blood pressure SD Standard deviation SR Statistical Report ULN Upper limit normal WHO World Health Organization

2

List of Figures

Figure 5-1: Disposition of patients in the CapRI trial ................................................. 31

Figure 5-2: Cumulative patient enrolment in the CapRI trial ..................................... 32

Figure 5-3: Overall survival (starting point: resection of the primary tumor), FAS..... 58

Figure 5-4: Overall survival (starting point: date of randomization), FAS.................. 59

Figure 5-5: Overall survival (starting point: date of randomization), all patients........ 60

Figure 5-6: DFS (starting point: resection of primary tumor), FAS............................ 61

Figure 5-7: DFS (starting point: randomization), FAS ............................................... 62

Figure 5-8: EORTC QLQ-C30, "physical functioning", group A ................................ 64

Figure 5-9: EORTC QLQ-C30, "role functioning", group A ....................................... 65

Figure 5-10: EORTC QLQ-C30, "emotional functioning", group A............................ 66

Figure 5-11: EORTC QLQ-C30, "cognitive functioning", group A ............................. 67

Figure 5-12: EORTC QLQ-C30, "social functioning", group A .................................. 68

Figure 5-13: EORTC QLQ-C30, "global health status", group A............................... 69

Figure 5-14: EORTC QLQ-C30, "fatigue", group A................................................... 70

Figure 5-15: EORTC QLQ-C30, "nausea / vomiting", group A.................................. 71

Figure 5-16: EORTC QLQ-C30, "pain", group A "..................................................... 72

Figure 5-17: EORTC QLQ-C30, "dyspnea", group A ................................................ 73

Figure 5-18: EORTC QLQ-C30, "insomnia", group A ............................................... 74

Figure 5-19: EORTC QLQ-C30, "appetite loss", group A.......................................... 75

Figure 5-20: EORTC QLQ-C30, "constipation", group A........................................... 76

Figure 5-21: EORTC QLQ-C30, "diarrhea", group A ................................................ 77

Figure 5-22: EORTC QLQ-C30, "financial problems", group A................................. 78

Figure 5-23: EORTC QLQ-C30, "physical functioning", group B .............................. 79

Figure 5-24: EORTC QLQ-C30, "role functioning", group B ..................................... 80

Figure 5-25: EORTC QLQ-C30, "emotional functioning", group B............................ 81

Figure 5-26: EORTC QLQ-C30, "cognitive functioning", group B ............................. 82

Figure 5-27: EORTC QLQ-C30, "social functioning", group B .................................. 83

Figure 5-28: EORTC QLQ-C30, "global health status", group B............................... 84

Figure 5-29: EORTC QLQ-C30, "fatigue", group B................................................... 85

Figure 5-30: EORTC QLQ-C30, "nausea / vomiting", group B.................................. 86

Figure 5-31: EORTC QLQ-C30, "pain", group B....................................................... 87

Figure 5-32: EORTC QLQ-C30, "dyspnea", group B ................................................ 88

Figure 5-33: EORTC QLQ-C30, "insomnia", group B ............................................... 89

Figure 5-34: EORTC QLQ-C30, "appetite loss", group B.......................................... 90

Figure 5-35: EORTC QLQ-C30, "constipation", group B........................................... 91

3

Figure 5-36: EORTC QLQ-C30, "diarrhea", group B .................................................92

Figure 5-37: EORTC QLQ-C30, "financial problems", group B .................................93

Figure 5-38: EORTC QLQ-PAN26, "pancreatic pain", group A .................................96

Figure 5-39: EORTC QLQ-PAN26, "digestive symptoms", group A ..........................97

Figure 5-40: EORTC QLQ-PAN26, "altered bowel habit", group A ...........................98

Figure 5-41: EORTC QLQ-PAN26, "hepatic", group A..............................................99

Figure 5-42: EORTC QLQ-PAN26, "body image", group A.....................................100

Figure 5-43: EORTC QLQ-PAN26, "satisfaction with health care", group A ...........101

Figure 5-44: EORTC QLQ-PAN26, "sexuality", group A .........................................102

Figure 5-45: EORTC QLQ-PAN26, "pancreatic pain", group B ...............................103

Figure 5-46: EORTC QLQ-PAN26, "digestive symptoms", group B ........................104

Figure 5-47: EORTC QLQ-PAN26, "altered bowel habit", group B .........................105

Figure 5-48: EORTC QLQ-PAN26, "hepatic", group B............................................106

Figure 5-49: EORTC QLQ-PAN26, "body image", group B.....................................107

Figure 5-50: EORTC QLQ-PAN26, "satisfaction with health care", group B ...........108

Figure 5-51: EORTC QLQ-PAN26, "sexuality", group B .........................................109

Figure 5-52: CES-D, "total score", group A .............................................................111

Figure 5-53: CES-D, "total score", group B .............................................................112

Figure 5-54: EORTC QLQ-C30, "physical functioning", group A (adj.) ....................113

Figure 5-55: EORTC QLQ-C30, "role functioning", group A (adj.)...........................114

Figure 5-56: EORTC QLQ-C30, "emotional functioning", group A (adj.) .................114

Figure 5-57: EORTC QLQ-C30, "cognitive functioning", group A (adj.)...................115

Figure 5-58: EORTC QLQ-C30, "social functioning", group A (adj.)........................115

Figure 5-59: EORTC QLQ-C30, "global health status", group A (adj.) ....................116

Figure 5-60: EORTC QLQ-C30, "fatigue ", group A (adj.) .......................................116

Figure 5-61: EORTC QLQ-C30, "nausea / vomiting", group A (adj.) .......................117

Figure 5-62: EORTC QLQ-C30, "pain", group A (adj.) ............................................117

Figure 5-63: EORTC QLQ-C30, "dyspnea", group A (adj.)......................................118

Figure 5-64: EORTC QLQ-C30, "insomnia", group A (adj.).....................................118

Figure 5-65: EORTC QLQ-C30, "appetite loss", group A (adj.) ...............................119

Figure 5-66: EORTC QLQ-C30, "constipation", group A (adj.) ................................119

Figure 5-67: EORTC QLQ-C30, "diarrhea", group A (adj.) ......................................120

Figure 5-68: EORTC QLQ-C30, "financial problems", group A (adj.) ......................120

Figure 5-69: EORTC QLQ-C30, "physical functioning", group B (adj.) ....................121

Figure 5-70: EORTC QLQ-C30, "role functioning", group B (adj.)...........................121

Figure 5-71: EORTC QLQ-C30, "emotional functioning", group B (adj.) .................122

Figure 5-72: EORTC QLQ-C30, "cognitive functioning", group B (adj.)...................122

4

Figure 5-73: EORTC QLQ-C30, "social functioning", group B (adj.) ....................... 123

Figure 5-74: EORTC QLQ-C30, "global health status", group B (adj.).................... 123

Figure 5-75: EORTC QLQ-C30, " fatigue", group B (adj.)....................................... 124

Figure 5-76: EORTC QLQ-C30, "nausea / vomiting", group B (adj.) ...................... 124

Figure 5-77: EORTC QLQ-C30, "pain", group B (adj.)............................................ 125

Figure 5-78: EORTC QLQ-C30, "dyspnea", group B (adj.) ..................................... 125

Figure 5-79: EORTC QLQ-C30, "insomnia", group B (adj.) .................................... 126

Figure 5-80: EORTC QLQ-C30, "appetite loss", group B (adj.) .............................. 126

Figure 5-81: EORTC QLQ-C30, "constipation", group B (adj.) ............................... 127

Figure 5-82: EORTC QLQ-C30, "diarrhea", group B (adj.) ..................................... 127

Figure 5-83: EORTC QLQ-C30, "financial problems", group B (adj.)...................... 128

Figure 5-84: EORTC QLQ-PAN26, "pancreatic pain", group A (adj.) ..................... 131

Figure 5-85: EORTC QLQ-PAN26, "digestive symptoms", group A (adj.) .............. 131

Figure 5-86: EORTC QLQ-PAN26, "altered bowel habit", group A (adj.)................ 132

Figure 5-87: EORTC QLQ-PAN26, "hepatic", group A (adj.) .................................. 132

Figure 5-88: EORTC QLQ-PAN26, "body image", group A (adj.) ........................... 133

Figure 5-89: EORTC QLQ-PAN26, "satisfaction with health care", group A (adj.).. 133

Figure 5-90: EORTC QLQ-PAN26, "sexuality", group A (adj.)................................ 134

Figure 5-91: EORTC QLQ-PAN26, "pancreatic pain", group B (adj.) ..................... 134

Figure 5-92: EORTC QLQ-PAN26, "digestive symptoms", group B (adj.) .............. 135

Figure 5-93: EORTC QLQ-PAN26, "altered bowel habit", group B (adj.)................ 135

Figure 5-94: EORTC QLQ-PAN26, "hepatic", group B (adj.) .................................. 136

Figure 5-95: EORTC QLQ-PAN26, "body image", group B (adj.) ........................... 136

Figure 5-96: EORTC QLQ-PAN26, "satisfaction with health care", group B (adj.).. 137

Figure 5-97: EORTC QLQ-PAN26, "sexuality", group B (adj.)................................ 137

Figure 5-98: CES-D, "total score", group A (adj.).................................................... 139

Figure 5-99: CES-D, "total score", group B (adj.).................................................... 139

Figure 5-100: Time from relapse to death............................................................... 140

Figure 5-101: CRP, group A ................................................................................... 155

Figure 5-102: GGT, group A ................................................................................... 155

Figure 5-103: GOT, group A ................................................................................... 156

Figure 5-104: GPT, group A.................................................................................... 156

Figure 5-105: Creatinine, group A........................................................................... 157

Figure 5-106: Glucose, group A.............................................................................. 157

Figure 5-107: CRP, group B ................................................................................... 160

Figure 5-108: GGT, group B ................................................................................... 160

Figure 5-109: GOT, group B ................................................................................... 161

5

Figure 5-110: GPT, group B ....................................................................................161

Figure 5-111: Creatinine, group B ...........................................................................162

Figure 5-112: Glucose, group B ..............................................................................162

Figure 5-113: CA 19-9, group A ..............................................................................164

Figure 5-114: CEA, group A ....................................................................................164

Figure 5-115: CA 19-9, group B ..............................................................................166

Figure 5-116: CEA, group B ....................................................................................166

Figure 5-117: ANA, group A ....................................................................................167

Figure 5-118: Heart rate, group A............................................................................168

Figure 5-119: Systolic blood pressure, group A.......................................................169

Figure 5-120: Diastolic blood pressure, group A .....................................................169

Figure 5-121: Heart rate, group B............................................................................170

Figure 5-122: Systolic blood pressure, group B.......................................................170

Figure 5-123: Diastolic blood pressure, group B .....................................................171

6

List of Tables

Table 5-1: Demographics (all randomized patients) ................................................. 32

Table 5-2: Demographics (FAS) ............................................................................... 33

Table 5-3: Demographics (patients excluded from the FAS) .................................... 34

Table 5-4: Disease-specific medical history (all randomized patients)...................... 35

Table 5-5: Disease-specific medical history (FAS) ................................................... 36

Table 5-6: Disease-specific medical history (patients excluded from the FAS)......... 37

Table 5-7: Further prognostic factors (all randomized patients)................................ 38

Table 5-8: Further prognostic factors (FAS).............................................................. 38

Table 5-9: Further prognostic factors (patients excluded from the FAS)................... 38

Table 5-10: Baseline medications (all randomized patients)..................................... 39

Table 5-11: Baseline medications (FAS)................................................................... 39

Table 5-12: Baseline medical history (all randomized patients) ................................ 40

Table 5-13: Baseline medical history (FAS).............................................................. 41

Table 5-14: Baseline medical history (patients excluded from the FAS)................... 41

Table 5-15: Baseline physical examination (all randomized patients)....................... 41

Table 5-16: Baseline physical examination (FAS) .................................................... 43

Table 5-17: Baseline physical examination (Patients excluded from the FAS) ......... 44

Table 5-18: Treatment cycles per patient, group A ................................................... 45

Table 5-19: Treatment cycles per patient, group B ................................................... 45

Table 5-20: Dose modifications, group A.................................................................. 46

Table 5-21: Dose modifications, group B.................................................................. 47

Table 5-22: Treatment interruption, group A............................................................. 48

Table 5-23: Treatment interruption, group B............................................................. 49

Table 5-24: Completion of treatment as planned ...................................................... 49

Table 5-25: Cumulative dose of drugs and radiation, group A.................................. 50

Table 5-26: Cumulative dose of drugs, group B........................................................ 50

Table 5-27: Total dose of drugs and radiation (absolute terms), group A, by treatment cycle.................................................................................. 51

Table 5-28: Total dose of drugs (absolute terms), group B, by treatment cycle.................................................................................. 52

Table 5-29: Total dose of drugs and radiation (percentage of intended dose), group A, by cycle ................................................................................... 53

Table 5-30: Total dose of drugs (percentage of intended dose), group B, by cycle ................................................................................... 54

Table 5-31: Concomitant medication by type of medication, group A ....................... 55

Table 5-32: Concomitant medication by type of medication, group B ....................... 56

7

Table 5-33: Dose modifications, treatment interruptions, dose reductions (any cycle): comparison across treatment groups ..................................57

Table 5-34: Estimated 1- and 2-year survival rates (S(1) and S(2), resp.), see Fig. 5-3 ............................................................................................58



Table 5-37: Adjustment for potential confounding using the Cox Regression Model: Estimated model parameters for the treatment effect after inclusion of covariates ....................................................................60

Table 5-38: Estimated 1- and 2-year DFS rates (DFS(1) and DFS(2), resp.), see Fig. 5-6 ............................................................................................61

Table 5-39: Estimated 1- and 2-year DFS rates (DFS(1) and DFS(2), resp.), see Fig. 5-7 ............................................................................................62

Table 5-40: Site of relapse ........................................................................................63

Table 5-41: Site of second relapse............................................................................63

Table 5-42: Quality of life assessment: Completion of QoL forms (EORTC QLQ-C30, QLQ-PAN26; CES-D). Number of forms completed as proportion (%) of those anticipated ........................63

Table 5-43: EORTC QLQ-C30, "physical functioning", group A ................................64

Table 5-44: EORTC QLQ-C30, "role functioning", group A .......................................65

Table 5-45: EORTC QLQ-C30, "emotional functioning", group A..............................66

Table 5-46: EORTC QLQ-C30, "cognitive functioning", group A ...............................67

Table 5-47: EORTC QLQ-C30, "social functioning", group A....................................68

Table 5-48: EORTC QLQ-C30, "global health status", group A.................................69

Table 5-49: EORTC QLQ-C30, "fatigue", group A.....................................................70

Table 5-50: EORTC QLQ-C30, "nausea / vomiting", group A ...................................71

Table 5-51: EORTC QLQ-C30, "pain", group A.........................................................72

Table 5-52: EORTC QLQ-C30, "dyspnea", group A..................................................73

Table 5-53: EORTC QLQ-C30, "insomnia", group A .................................................74

Table 5-54: EORTC QLQ-C30, "appetite loss", group A ...........................................75

Table 5-55: EORTC QLQ-C30, "constipation", group A ............................................76

Table 5-56: EORTC QLQ-C30, "diarrhea", group A ..................................................77

Table 5-57: EORTC QLQ-C30, "financial problems", group A...................................78

Table 5-58: EORTC QLQ-C30, "physical functioning", group B ................................79

Table 5-59: EORTC QLQ-C30, "role functioning", group B .......................................80

Table 5-60: EORTC QLQ-C30, "emotional functioning", group B..............................81

Table 5-61: EORTC QLQ-C30, "cognitive functioning", group B ...............................82

Table 5-62: EORTC QLQ-C30, "social functioning", group B....................................83

8

Table 5-63: EORTC QLQ-C30, "global health status", group B ................................ 84

Table 5-64: EORTC QLQ-C30, "fatigue", group B .................................................... 85

Table 5-65: EORTC QLQ-C30, "nausea / vomiting", group B................................... 86

Table 5-66: EORTC QLQ-C30, "pain", group B ........................................................ 87

Table 5-67: EORTC QLQ-C30, "dyspnea", group B ................................................. 88

Table 5-68: EORTC QLQ-C30, "insomnia", group B ................................................ 89

Table 5-69: EORTC QLQ-C30, "appetite loss", group B........................................... 90

Table 5-70: EORTC QLQ-C30, "constipation", group B............................................ 91

Table 5-71: EORTC QLQ-C30, "diarrhea", group B.................................................. 92

Table 5-72: EORTC QLQ-C30, "financial problems", group B .................................. 93

Table 5-73: EORTC QLQ-C30, summary statistics for the AUC............................... 94

Table 5-74: EORTC QLQ-PAN26, "pancreatic pain", group A.................................. 96

Table 5-75: EORTC QLQ-PAN26, "digestive symptoms", group A........................... 97

Table 5-76: EORTC QLQ-PAN26, "altered bowel habit", group A ............................ 98

Table 5-77: EORTC QLQ-PAN26, "hepatic", group A .............................................. 99

Table 5-78: EORTC QLQ-PAN26, "body image", group A...................................... 100

Table 5-79: EORTC QLQ-PAN26, "satisfaction with health care", group A ............ 101

Table 5-80: EORTC QLQ-PAN26, "sexuality", group A .......................................... 102

Table 5-81: EORTC QLQ-PAN26, "pancreatic pain", group B................................ 103

Table 5-82: EORTC QLQ-PAN26, "digestive symptoms", group B......................... 104

Table 5-83: EORTC QLQ-PAN26, "altered bowel habit", group B .......................... 105

Table 5-84: EORTC QLQ-PAN26, "hepatic", group B ............................................ 106

Table 5-85: EORTC QLQ-PAN26, "body image", group B...................................... 107

Table 5-86: EORTC QLQ-PAN26, "satisfaction with health care", group B ............ 108

Table 5-87: EORTC QLQ-PAN26, "sexuality", group B .......................................... 109

Table 5-88: EORTC QLQ-PAN26, summary statistics for the AUC ........................ 110

Table 5-89: CES-D, "total score", group A .............................................................. 111

Table 5-90: CES-D, "total score", group B .............................................................. 112

Table 5-91: CES-D, summary statistics for the AUC .............................................. 113

Table 5-92: EORTC QLQ-C30, "physical functioning", group A (adj.) .................... 113

Table 5-93: EORTC QLQ-C30, "role functioning", group A (adj.) ........................... 114

Table 5-94: EORTC QLQ-C30, "emotional functioning", group A (adj.) .................. 114

Table 5-95: EORTC QLQ-C30, "cognitive functioning", group A (adj.) ................... 115

Table 5-96: EORTC QLQ-C30, "social functioning", group A (adj.) ........................ 115

Table 5-97: EORTC QLQ-C30, "global health status", group A (adj.) ..................... 116

Table 5-98: EORTC QLQ-C30, "fatigue", group A (adj.) ......................................... 116

Table 5-99: EORTC QLQ-C30, "nausea / vomiting", group A (adj.)........................ 117

9

Table 5-100: EORTC QLQ-C30, "pain", group A (adj.) ...........................................117

Table 5-101: EORTC QLQ-C30, "dyspnea", group A (adj.).....................................118

Table 5-102: EORTC QLQ-C30, "insomnia", group A (adj.) ....................................118

Table 5-103: EORTC QLQ-C30, "appetite loss", group A (adj.) ..............................119

Table 5-104: EORTC QLQ-C30, "constipation", group A (adj.) ...............................119

Table 5-105: EORTC QLQ-C30, "diarrhea", group A (adj.) .....................................120

Table 5-106: EORTC QLQ-C30, "financial problems", group A (adj.) .....................120

Table 5-107: EORTC QLQ-C30, "physical functioning", group B (adj.) ...................121

Table 5-108: EORTC QLQ-C30, "role functioning", group B (adj.) ..........................121

Table 5-109: EORTC QLQ-C30, "emotional functioning", group B (adj.) ................122

Table 5-110: EORTC QLQ-C30, "cognitive functioning", group B (adj.) ..................122

Table 5-111: EORTC QLQ-C30, "social functioning", group B (adj.) .......................123

Table 5-112: EORTC QLQ-C30, "global health status", group B (adj.) ...................123

Table 5-113: EORTC QLQ-C30, "fatigue", group B (adj.)........................................124

Table 5-114: EORTC QLQ-C30, "nausea / vomiting", group B (adj.) ......................124

Table 5-115: EORTC QLQ-C30, "pain", group B (adj.) ...........................................125

Table 5-116: EORTC QLQ-C30, "dyspnea", group B (adj.).....................................125

Table 5-117: EORTC QLQ-C30, "insomnia", group B (adj.) ....................................126

Table 5-118: EORTC QLQ-C30, "appetite loss", group B (adj.) ..............................126

Table 5-119: EORTC QLQ-C30, "constipation", group B (adj.) ...............................127

Table 5-120: EORTC QLQ-C30, "diarrhea", group B (adj.) .....................................127

Table 5-121: EORTC QLQ-C30, "financial problems", group B (adj.) .....................128

Table 5-122: EORTC QLQ-C30, summary statistics for the AUC (adj.) ..................129

Table 5-123: EORTC QLQ-PAN26, "pancreatic pain", group A (adj.) .....................131

Table 5-124: EORTC QLQ-PAN26, "digestive symptoms", group A (adj.) ..............131

Table 5-125: EORTC QLQ-PAN26, "altered bowel habit", group A (adj.) ...............132

Table 5-126: EORTC QLQ-PAN26, "hepatic", group A (adj.) ..................................132

Table 5-127: EORTC QLQ-PAN26, "body image", group A (adj.) ...........................133

Table 5-128: EORTC QLQ-PAN26, "satisfaction with health care", group A (adj.)..133

Table 5-129: EORTC QLQ-PAN26, "sexuality", group A (adj.)................................134

Table 5-130: EORTC QLQ-PAN26, "pancreatic pain", group B (adj.) .....................134

Table 5-131: EORTC QLQ-PAN26, "digestive symptoms", group B (adj.) ..............135

Table 5-132: EORTC QLQ-PAN26, "altered bowel habit", group B (adj.) ...............135

Table 5-133: EORTC QLQ-PAN26, "hepatic", group B (adj.) ..................................136

Table 5-134: EORTC QLQ-PAN26, "body image", group B (adj.) ...........................136

Table 5-135: EORTC QLQ-PAN26, "satisfaction with health care", group B (adj.)..137

Table 5-136: EORTC QLQ-PAN26, "sexuality", group B (adj.)................................137

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Table 5-137: EORTC QLQ-PAN26, summary statistics for the AUC (adj.) ............. 138

Table 5-138: CES-D, "total score", group A (adj.) ................................................... 139

Table 5-139: CES-D, "total score", group B (adj.) ................................................... 139

Table 5-140: CES-D, summary statistics for the AUC (adj.) ................................... 140

Table 5-141: Results of the Cox regression analysis for baseline variables ........... 140

Table 5-142: Numbers of patients with AEs / SAEs................................................ 141

Table 5-143: Percentages of patients with AEs / SAEs (with 95% confidence intervals).......................................................... 142

Table 5-144: Total numbers of AEs/ SAEs ............................................................. 142

Table 5-145: Total number of AEs, broken down by severity and causal relationship ...................................................................... 142

Table 5-146: Number of AEs per patient................................................................. 143

Table 5-147: Strongest causal relationship to intervention reported in AEs............ 143

Table 5-148: Highest severity level reported in AEs ............................................... 143

Table 5-149: Number of AEs per patient by causality............................................. 144

Table 5-150: Number of AEs per patient by severity .............................................. 145

Table 5-151: Listing of AEs prior to treatment......................................................... 146

Table 5-152: Toxicity (AE), A - Therapy block 1 .................................................... 147

Table 5-153: Toxicity (AE), group A - Therapy block 2 ........................................... 149

Table 5-154: Toxicity (AE), group A - Therapy block 3 ........................................... 150

Table 5-155: Toxicity (AE), group B........................................................................ 150

Table 5-156: Hematotoxicity, group A - Therapy block 1 ........................................ 152



Table 5-159: Hematotoxicity, group B..................................................................... 153

Table 5-160: Toxicity (AE/Hematology), group A - Therapy block 1 ....................... 154



Table 5-163: Toxicity (AE/Hematology), group A - Therapy block1-3 ..................... 154

Table 5-164: Toxicity (AE/Hematology), group B.................................................... 154

Table 5-165: Shift table for laboratory data (group A): clinical chemistry Baseline → end of first treatment cycle (visit 9) ................................. 158

Table 5-166: Shift table for laboratory data (group A): clinical chemistry Baseline → end of second treatment cycle (visit 16) ......................... 159

Table 5-167: Shift table for laboratory data (group A): clinical chemistry Baseline → end of third treatment cycle (visit 23) ............................. 159

Table 5-168: Shift table for laboratory data (group B): clinical chemistry Baseline → end of treatment (visit 8) ................................................. 163

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Table 5-169: Shift table for laboratory data (group A): tumor markers Baseline → begin of second treatment cycle (visit 10) .......................165

Table 5-170: Shift table for laboratory data (group A): tumor markers Baseline → begin of third treatment cycle (visit 17)............................165

Table 5-171: Shift table for laboratory data (group A): tumor markers Baseline → end of third treatment cycle (visit 23) ..............................165

Table 5-172: Shift table for laboratory data (group B): tumor markers Baseline → end of treatment (visit 8)..................................................167

Table 5-173: Shift table for laboratory data (group A): autoantibodies Baseline → end of first treatment cycle (Visit 8) .................................168

Table 5-174: Physical examination, group A, changes with respect to baseline .....171

Table 5-175: Physical examination, group B, changes with respect to baseline .....171

Data Listings

Except for AEs, the listings are stored in data files on a separate CD ROM.

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1. INTRODUCTION

1.1. Scope of the Report The present Statistical Report (SR) describes the results of the final statistical analysis of the CapRI trial.

This randomized multicenter phase III study was conducted to assess the safety and efficacy of the Virginia Mason regimen (CapRI=Cisplatin, Interferon alpha-2b, and 5-FU, combined with external radiation therapy) versus 5-FU+FA for the postoperative treatment of patients with resected pancreatic adenocarcinoma.

The SR is based on the following documents: Clinical Research Protocol, Version 4 and 11, as well as amendments issued

September 29, 2004; February 14, 2005; March 8, 2005; June 7, 2005; November 22, 2005; April 10, 2006, October 16, 2006; March 30, 2007.

Case report forms (CRFs) for the protocol The Statistical Analysis Plan (SAP) for the CapRI trial (final version of Dec. 3, 2007)

Note that, in conformity with the SAP, the SR is restricted in regard to the analysis of secon-dary endpoints; specifically,

the multivariate analysis of groups of potential prognostic markers the cluster analysis of time series [of interesting markers]

mentioned in the study analysis plan (Study Protocol, §17.2; p.22-23) were to be conducted and reported by a different center (Prof. Dr. Ulrich Mansmann, IBE Medical School, LMU München).

Note on the translation of special terms: Baseline or concomitant medication, as well as items describing toxicity, which were coded using a German classification system, were not translated. The same applies to AEs, which were tabulated and summarized as documented.

1.2. Study Protocol, Ethics, Organization of the Trial The study protocol was developed by Prof. Dr. A. Märten in cooperation with Prof. Dr. M. Büchler and Prof. Dr. U. Mansmann, who was responsible for the biometrical design. Prof. Dr. Abel was responsible for the statistical analysis, except for the aspects noted in 1.1.

There were 11 versions of the study protocol. Version 4 was submitted to the Ethics Com-mittee at the University Hospital of Heidelberg, who approved the trial on Feb. 18, 2004. In this SR, version 4 of the protocol will be referred to as the "Study Protocol". Essentially, the subsequent versions were created by including the Amendments.

While the study was originally planned as a single-center trial (University Hospital of Heidel-berg), five additional centers joined the study group at a later time point (Amendments Feb. 14, 2005, and June 7, 2005, as well as protocol version No 7, p.12).

Data management was performed by the data management group at the Institute of Medical Biometry and Informatics, University of Heidelberg.

Randomization was carried out by the Klinisches Studienzentrum (KSC) Heidelberg.

Serious adverse events had to be reported to the Principle Investigator (represented by Prof. A. Märten, NCT Heidelberg and Dept. of Surgery, University Hospital of Heidelberg).

Clinical monitoring was performed by ECRON ACUNOVA GmbH, Frankfurt.

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2. INVESTIGATIONAL PLAN AND TRIAL CONDUCT

2.1. Study Objectives The primary objective of this study was to determine whether the adjuvant treatment with 5-FU, Cisplatin, Interferon alpha-2b, combined with external radiation therapy (=CapRI) im-proves survival compared to treatment with 5-FU plus folinic acid (FA) in patients with re-sected adenocarcinoma of the pancreas. In view of the poor survival of patients with pancreatic cancer, even a modest extension of survival was deemed to be of clinical relevance. The study was motivated by the fact that encouraging results had been obtained for the CapRI regimen in a previous phase-II trial at the Virginia Mason Clinic.

The secondary objectives of the trial were as follows: to evaluate the role and mechanism of interferon alpha-2b in the chemoradiation

regimen to assess toxicity, the disease-free interval, and quality of life (QoL) to examine different factors as potential predictive markers for the treatment effect.

2.2. Study Design - General Aspects This study was an open-label, prospective, randomized, multicenter phase-III trial comparing two treatment groups. Given the complex and very different treatment regimens, blinding was not feasible.

The projected accrual time was 18 months, the duration of the subsequent follow-up was 24 months, resulting in an expected total study duration of 42 months.

2.3. Sequence of Planned Analyses According to the initial planning, one interim analysis was to be conducted one year after the start of patient enrolment. In case of a highly significant advantage (p<0.001) for the CapRI regimen, the treatment in the 5-FU/FA group was to be replaced with a regimen consisting of a radiochemotherapy according to the CapRI regimen, but without the interferon treatment. As described below (see §2.4), the provision regarding the timing of the interim analysis was modified during the course of the trial. The results of this analysis did not warrant any change in the conduct of the trial.

Furthermore, the study included a stopping rule based on a continuous monitoring of treat-ment-related deaths. This rule, which used a Bayesian criterion with non-informative prior, stipulated that the study had to be stopped once the posterior probability that the rate of treatment-related deaths exceeded 5% was higher than 90%.

While not stated in the protocol, it was understood that this criterion was to be applied to each group separately.

Since no treatment-related deaths were reported, the stopping rule was not activated.

According to the protocol, the main analysis was to take place 24 months after the enrolment of the last patient.

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2.4. Changes to the Conduct and Analysis of the Trial Eight Amendments to the Study Protocol were submitted to, and approved by, the Ethics Committee (see above). The following changes specified in the Amendments were of relevance to the statistical analysis:

a) In the amendment of March 8, 2005, it was stated that, different from the Study Protocol, "The data analysis will be performed according to the intention-to-treat principle". In the amendment of April 10, 2006, the analysis population underwent another change. It was now stipulated (see, e.g., protocol version 11) that "The data analysis will be performed pri-marily according to the 'Intention To Treat'-principle. Only subjects who received at least one dose of chemo- and/or radiotherapy will be analyzed. A subject who exits the study prior to start of treatment will be replaced". It should be noted that this specification, first appearing in version 11 of the protocol (dated March 30, 2007), is not reflected in the diagram on page 21 of this protocol version. The aforementioned changes in the analysis population and in the replacement strategy necessitated an increase in the number of patients to be randomized.

b) As regards the interim analysis, biometrical calculations carried out by the first author of this SR and communicated to the DMC revealed that the criterion for early termination of the study lacked practicality due to the fact that the expected number of patients available for the decision was too low. Based on these calculations the provision regarding the interim analy-sis was changed as follows: One interim analysis was to be done after 20 events, but no later than in November 2005 (see the Protocol amendment of March 8, 2005). By November 2005 five patients had died in the study, 2 in treatment group A (CapRI) and 3 in group B (5-FU/FA), yielding a nonsignificant difference between the survival curves. Thus, the criterion for early termination was not fulfilled. In view of the small number of deaths, no detailed interim analysis was carried out (see the amendment of November 22, 2005).

2.5. Study Population The key inclusion/exclusion criteria were as follows (for details see the Study Protocol as well as the amended protocol version 11, section 9-10):

Eligibility criteria Patients with completely resected (R0 or R1) pancreatic adenocarcinoma of the

pancreatic head or uncinate process Protocol treatment must begin within 12 weeks of surgery Karnofsky performance status: ≥70

Ineligibility criteria Residual (clinically or CT definable) metastatic or incompletely resected local disease Age <18 years

2.6. Patient Recruitment The first patient was enrolled on July 29, 2004, the last patient was enrolled on December 18, 2007. The database was closed on February 23, 2010.

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2.7. Study Treatment and Treatment Groups The details of the treatment regimens are described in sections 12.1-12.3 as well as Appen-dix G and H of the Study Protocol.

Briefly, the treatments were as follows (days are counted from the first day of treatment, not from the date of randomization):

Group A (CapRI regimen) 5-FU: 200mg/m2/day by continuous intravenous infusion on days 1-38 Cisplatin: 30mg/m2 (capped at BSA=2m2; maximum single Cisplatin dose: 60mg) via

intravenous infusion over 60 minutes on days 1,8,15,22,29,36 Interferon alpha-2b: 3 million units SQ MWF d1-38 (a total of 17 doses) Radiation therapy of the pancreatic bed, the porta hepatis, origins of the celiac axis

and superior mesenteric artery (50.4 Gy in 28 fractions over 5.5 weeks =1.8 Gy/day). Radiation treatment was to be given concurrently with chemotherapy (i.e., on treat-ment day 1) and to begin no later than 12 weeks after surgery.

Post chemoradiation 5-FU infusions (200mg/m2/day by continuous infusion on days 64-101 and 120-161).

Group B (5-FU/FA) Folinic acid (FA), D-L form: 20mg/m2 intravenous bolus injection followed by 5-FU: 425mg/m2/day in intravenous bolus injection

The combination was given on 5 consecutive days every 28 days for 6 cycles (i.e., 25 weeks)

2.8. Study Periods, Visit Window Definitions, and Follow-up The timing of the treatment is described in section 12.1-12.3 as well as in Appendix G and H of the Study Protocol (see above).

The evaluations during the study are described in section 12.4 as well as Appendix D and E of the Study Protocol (see, however, section 3.4.16 of this SR for deviations from the sched-uled assessment of QoL). Patients who were enrolled in group A received a single low-dose (3 Mio U) injection of in-terferon alpha-2b prior to therapy. Blood was drawn for intensive immunological studies (Appendices M and N of the Study Protocol).

In the post-treatment period patients were seen every 3 months during the first 2 years, every 4 months during the third year, and every 6 months during the 4th and 5th year.

Each study patient was to be followed up until death, but no longer than 24 months after the enrolment of the last patient.

For patients who, two years after the inclusion of the last study patient, were supposedly alive and not known to be lost to follow-up, a verification of the vital status was done in the first two weeks of 2010.

The timing of measurements and data collection followed a complex scheme described in Appendix D and E as well as section 12.4.5 of the Study Protocol. It should be noted that - due to the very different treatment schedules - both the timing of the visits and the examina-tions were different in the two arms of the trial.

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2.9. Randomization Randomization was central. It was carried out by the Klinisches Studienzentrum (KSC) Heidelberg. A separate randomization list (block randomization, 1:1) was prepared for each participating center via computer system. The sealed randomization list was stored in the investigator file and to be opened after the closure of the database. For each enrolled patient one envelope was available.

2.10. Hypotheses and Decision Rules The null and alternative hypotheses regarding the primary objective of this trial were as follows:

H0: The hazard ratio of the treatment groups, as calculated in the Cox Proportional Hazards Model, is equal to 1. H1: The hazard ratio of the treatment groups, as calculated in the Cox Proportional Hazards Model, is unequal to 1.

The significance level to be used in the main analysis was α=0.05 (two-sided testing). Given that the significance level used in the interim analysis was very low (α=0.001), no adjustment of the main evaluation for multiple testing was deemed necessary in the planning of the study.

2.11. Sample Size The sample size calculation outlined in the Study Protocol was based on the assumption (under H1) of a constant monthly hazard rate of 0.044 in group B (5-FU/FA) and a constant monthly hazard rate of 0.021 in group A (CapRI). These hazard values were derived from two-year survival rates of 35% in arm B and 60% in arm A, assuming exponential survival curves. Assuming an accrual period of 18 months and a (total) follow-up of 42 (=18+24) months, testing for the aforementioned difference in hazard rates on a level of α=5% and with a power of 80% yielded a study size of 96 evaluable patients (48 per treatment group). Originally, patients not completing the treatment were planned to be excluded from the analysis. With an anticipated number of 14 patients stopping the treatment prematurely, a total 110 patients were planned to be randomized (see Study Protocol, section 17.1).

As described above, the definition of the primary efficacy analysis population changed sev-eral times during the course of the study. According to the final decision, all patients who did not receive at least one dose of the study treatment were to be excluded and replaced.

In total, 132 patients were randomized. Of these, 110 patients started the study treatment and thus belong to the full analysis set (see section 3.1.2).

17

2.12. Protocol Deviations There were two major protocol deviations during the trial related to study inclusion or exclu-sion criteria and trial conduct:

Some patients entered the study but were found (before treatment start) to have metastases/local tumor.

Some patients withdrew their informed consent after randomization but before treat-ment start.

Both subsets of patients were to be excluded from the primary analysis of efficacy and from the analysis of safety/tolerability endpoints (see section 2.4). They were, however, included in the description of the baseline characteristics of the study patients.

Another deviation from the protocol was related to the QoL assessments. The scheduled timing of the QoL assessments as described in the Study Protocol was somewhat contra-dictory. Thus, section 12.4.3 of the Study Protocol stated that the "three module question-naire" was to be completed "during weeks 3 and 6 (study arm A) or week 3 and week 24 for study arm B (Appendix E)". In contrast to this, according to another specification found in section 12.4.3 of version 11 of the protocol as well as Appendix D of the Study Protocol (but not in section 12.4.3. of the Study Protocol), one of the three modules (the CES-D) was, in fact, to be completed weekly (until week 6) in treatment group A; and (again according to Appendix B), the QoL assessments in arm B were to be performed during week 1 and 25. The timing of the QoL assessments actually performed during the trial differed from the vari-ous schedules outlined in the Study Protocol. In particular, the CES-D was completed at exactly the same dates as the other two questionnaires. The timing of the assessments was as follows:

• Treatment group A: visit 2,5,9,10,17, as well as all follow-up visits • Treatment group B: visit 1,8, as well as all follow-up visits.

3. STATISTICAL ANALYSIS

3.1. Analysis Populations

3.1.1. Study Population In conformity to ICH E9, Section V(B), and ICH E3 (European Medicines Agency, 1996,1998), all randomized patients were included in the analysis of demographic and base-line data.

3.1.2. Full Analysis Set (FAS) According to the protocol, and taking into consideration the amendments described above, the full analysis set used for the primary analysis of efficacy was defined as the subset of patients who received any amount of the planned study medication.

The responsible biostatistician (and first author of this SR) was explicitly directed by his su-perior to exclude patients from the primary analysis who did not receive at least one dose of the study medication.

Except for this restriction to patients having started the study treatment, protocol deviations (e.g., non-compliance with the study treatment) did not affect the full analysis set.

3.1.3. Safety Population The safety population was defined as the set of patients who received any amount of the planned study medication.

18

As an exception to this rule, however, adverse events (if any) were to be documented and listed for those patients who were randomized but not included in the full analysis set.

3.2. Treatment Misallocations As stated above, patients who were randomized but not treated were excluded from the pri-mary efficacy analysis. There were no patients in this study who were randomized but took incorrect treatment.

3.3. Study Endpoints and Covariates A tabular overview of the primary and secondary endpoints is presented in section 17.2 of the Study Protocol. In the following, the endpoints for the statistical analyses described in this SR will be speci-fied. No definitions will be given for endpoints regarding analyses carried out in a different center (see section 1 of this SR).

3.3.1. Efficacy Endpoint(s) Primary endpoint The primary efficacy endpoint was survival time, defined as the time from the resection of the primary tumor to death of any cause, censored by the end of observation.

In a secondary analysis an alternative starting point, namely, the date of randomization, was used for calculating survival time.

Generally, for patients who did not die prematurely, the end of observation was defined as the date of study termination as indicated by the corresponding entry of the CRF. If this date was not documented, the end of observation was defined as the last documented follow-up date.

Secondary endpoint The secondary efficacy endpoint was disease-free survival.

Remark: The Study Protocol (§17.2) contains two different definitions of disease-free survival:

a) Time from day of surgery to either recorded date of relapse or death (whichever occurs first), censored by the end of observation

b) Time from day of the first post-treatment observation of a Karnofsky performance status of >70 to either recorded date of relapse or death (whichever occurs first), cen-sored by the end of observation.

It should be noted, however, that the Karnofsky performance index was not assessed after the start of treatment, and that prior to treatment (i.e., at visit 0 and 1) it was only determined whether the performance index was ≥70. Therefore, definition b) could not be used for the analysis.

19

Relapse was defined as the observation of symptoms clinically related to disease recurrence. The statistical analysis of time to relapse was based on the clinical judgment reflected in the corresponding entries in the CRF. According to the Study Protocol the following clinical crite-ria were to be used for determining disease recurrence:

evidence of radiographically defined local tumor recurrence or distant metastases an increase in serum CA19-9 level (deemed indicative of relapse) ascites or other signs of peritoneal seeding.

As described in the SAP, a further definition of disease-free survival was used, namely, c) Time from randomization to recorded date of relapse (as defined above) or death

(whichever occurs first), censored by the end of observation.

d) It should be noted that for some study visits under therapy the CRF did not provide for a documentation of a relapse date. Also, in cases where therapy was stopped due to relapse, the date of relapse was not documented in the CRF. Consequently, in some of these cases no relapse date was documented; it was then personally com-municated by one of investigators (Prof. Märten) upon inspection of the patient files.

3.3.2. Safety and Tolerability Endpoints e) Toxicity assessment was specified in §15 of the Study Protocol. Except for the WHO

toxicity criteria, no specific safety and tolerability endpoints were mentioned in the Statistical Considerations section (§17) of the protocol.

The following safety and tolerability endpoints were used in the statistical analysis Adverse events (AEs; see ICH E3, section 12.2) Serious adverse events (SAEs; see ICH E3, section 12.3) Extent of exposure (see ICH E3, section 12.1) Abnormal laboratory values (see ICH E3, section 12.4.) Vital signs, physical findings, and other observations related to safety (see ICH E3,

section 12.5) Toxicity graded by the NCI 1998 CTC (see Appendix I of the Study Protocol).

Note: No formal (both necessary and sufficient) criteria for AEs are mentioned in §15 of the Study Protocol. However, it is stated that abnormal values of CRP, AST, ALT, or GGT are considered to be an AE only if they exceed the cut-off values specified in §14 of version 11 of the Study Protocol, i.e., CRP>50mg/L; AST, ALT, GGT>2ULN; Glucose>150mg/dl. By contrast, §15.2 of the Study Protocol introduces the term "unacceptable toxicity", which is defined as "unpredictable, or irreversible Grade 4 toxicity". By definition, this includes the patient's "refusal of therapy due to a specific toxicity" (see §16.1. of the Study Protocol).

3.3.3. Quality of Life (QoL) Endpoints Three QoL instruments were used in this study (see §7 of the Study Protocol):

EORTC QLQ-C30 EORTC QLQ-PAN26 CES-D (=Center for Epidemiologic Studies - Depression), a 20-item instrument.

The endpoints to be included in the analysis of quality of life were the single items of the in-struments, except where aggregate scales are proposed in the User Manuals. Thus, in case of the EORTC QLQ-C30, the scales and single items summarized on p.8 of the Scoring Manual (see also §7 of the Study Protocol) were used as QoL endpoints. For the CES-D, the scoring and treatment of missing values followed the specifications given at http://www.valueoptions.com/providers/Education_Center/Provider_Tools/Depression_Screening.pdf.

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3.3.4. Covariates No covariates were used in the primary efficacy analysis. However, extensive use of clinical baseline covariates was made in secondary efficacy analyses (see section 3.4.8 for a de-tailed description).

3.4. Statistical Methodology

3.4.1. General Remarks The biometrics and data management group at the Institute for Medical Biometry and Infor-matics, Univ. of Heidelberg, performed quality control and validation of programming and statistical analysis.

SAS Version 9.1.3 was used to conduct the analysis.

The statistical analyses planned in the protocol are briefly mentioned in section 17.2 and 17.3 of the Study Protocol.

There was counting of the absolute and relative frequencies (percentages) for categorical variables, with missing values being accounted for in a separate category. Percentages for categorical variables were based on all non-missing values (=100%); they were rounded to one decimal place.

Continuous variables were summarized descriptively. Number of observations (n, nmiss), means, medians, standard deviations, range, as well as the 5th,25th,75th and 95th percen-tiles were determined. Two-sided 95% confidence intervals were constructed as appropriate. Boxplots were created using boxstyle "SCHEMATIC", which means that a whisker is drawn from the upper edge of the box to the largest observed value within the upper fence and from the lower edge of the box to the smallest observed value within the lower fence. The fences are imaginary horizontal lines localized 1.5 x IRQ above 75 th percentile (upper fence) re-spectively 1.5 x IRQ below 25 th percentile (lower fence). Observations lying outside the fences are identified by circle symbols.

Medical history and adverse events were coded according to ICD-10. Baseline and con-comitant medications were coded according to the "Rote Liste" (Anonymous, 2009).

Given that major post-randomization exclusions occurred in this study, the distribution of baseline characteristics of patients in the FAS was compared across the treatment groups using inferential statistics by means of the Wilcoxon rank sum test for at least ordinally scaled variables, and Fisher's exact test or the Chi squared test (the latter being used in case of more than two categories) for categorical variables.

Standard methods for survival analysis were used in the analysis of time-to-event endpoints (Kaplan-Meier estimates of the survivor functions, Greenwood's formula for estimating the standard error of event rates, the Cox Proportional Hazards Model, and the log rank test for comparing two survival curves, see Collett, 1994).

All statistical tests were two-tailed. The significance level was α=5%.

All analyses of secondary objectives were strictly descriptive. This also applies to instances where p-values were calculated.

21

3.4.2. Adjustments for Covariates In addition to the analyses specified in the Study Protocol, a secondary efficacy analysis was done in which the study results with respect to survival were adjusted for potential con-founding due to imbalance in prognostic baseline variables, using multivariable modeling with the Cox Proportional Hazards model. (See section 3.4.8 for a precise description of the model building process).

3.4.3. Multiple Comparisons/Multiplicity No multiple testing occurred in the primary efficacy analysis. All other statistical tests were of a descriptive nature. No adjustment for multiplicity was done.

3.4.4. Handling of Dropouts or Missing Data Generally, missing data were not replaced or imputed. One exception to this rule was the handling of attrition bias in quality of life (QoL) analysis. To minimize this bias, an adjustment score representing the worst possible value on the scale of every item to be analyzed was used to indicate QoL on the day of death and each subsequent day until the end of the assessment period (see Hollen et al., 1997).

3.4.5. Center Pooling Method and Handling Center Effects The numbers of randomized patients by center were as follows:

Heidelberg: 113 Berlin: 2 Turin: 5 Regensburg: 4 Bielefeld: 8

Following the planned analysis in the Study Protocol, and considering that nearly all patients were recruited in one center, no center effects were incorporated in the primary efficacy analysis or in the analysis of secondary or safety endpoints, and no exploratory analysis of treatment-by-center interaction was done.

3.4.6. Analysis of Demographic and Other Baseline Characteristics The baseline characteristics (demographics, disease-specific medical history, further prog-nostic factors, baseline medications - i.e., medication with an onset date prior to the start of study treatment -, baseline medical history, baseline physical examination) were analyzed descriptively, as outlined in section 3.4.1.

3.4.7. Analysis of Treatment Compliance and Exposure The following items were analyzed by treatment group in the FAS:

a) Number of treatment cycles per patient (mean, median, minimum, maximum of the treatment group)

b) Number of patients having 1,2,3,... treatment cycles (frequency distribution) c) Number of patients with dose modifications (overall and by treatment cycle) d) Number of patients with treatment interruptions (overall and by treatment cycle) e) Number of patients definitely withdrawing from treatment (overall, by treatment cycle,

and by reason of withdrawal) f) Number of patients completing the treatment as planned (i.e., without any dose

reductions) g) Summaries (mean, median value, minimum, maximum) of cumulative dose of drugs

and radiation (if applicable)

22

h) Summaries (mean, median value, minimum, maximum) by treatment cycle of total dose of drugs and radiation exposed, both in absolute terms and expressed as per-centages of the intended dose (broken down by drug, except for FA in treatment group B)

i) Number of patients receiving concomitant medications, overall as well as broken down by type of medication.

For items c), d), e), f) the numbers were compared across the treatment groups using Fisher's exact test.

3.4.8. Analysis of the Primary Efficacy Variable a) The primary efficacy analysis was based on the full analysis set (see section 3.1.2) and the primary endpoint survival from the date of surgery. The following coding was used for the treatment group: 1=treatment group A, 0=treatment group B. Using the Cox Proportional Hazards model, the hazard ratio (with 95% confidence interval) for the treatment group effect (group A vs. B=baseline) was calculated. In view of the defini-tions of survival time and censoring, no missing values needed to be accounted for in this analysis. The model was used for statistical testing of the null hypothesis, namely,

H0: βtreatment =0 vs. H1: βtreatment ≠0

where βtreatment is the true value of the model parameter for the treatment effect in the Cox Proportional Hazards Model. The test was based on the Wald statistic of the model parameter as obtained in this analysis (two-tailed test, α=5%). Kaplan-Meier estimates of the survival curve were calculated, along with two-sided 95% con-fidence intervals for the 1-year and 2-year survival rate using Greenwood's formula.

b) A secondary analysis of the primary endpoint was performed employing the same methodology as the primary analysis but using the alternative definition of survival with the date of randomization as the starting point, see section 3.3.1.

c) A third analysis of survival was performed following the same line as the secondary analy-sis, but based on all randomized patients.

d) Given that the full analysis set was subject to post-randomization exclusions from the set of randomized patients, a fourth analysis of survival was performed, in which the study re-sults for survival from the date of randomization were adjusted for potential confounding by imbalance in prognostic baseline variables using multivariable modeling with the Cox Pro-portional Hazards model. The modeling process consisted of two steps: Step 1: Screening for potential confounders This screening process included the following variables:

Time interval [days] from surgery to randomization Age Gender BMI T N G Surgical procedure

23

Any of the variables listed above was selected for multivariable adjustment if and only if the model parameter estimate for the treatment effect changed by at least 10% when the vari-able was included as a second variable in the Cox Regression Model (see Kleinbaum et al, 1988; Hosmer & Lemeshow, 1989, for the rationale underlying this procedure). Step 2: Multivariable modeling: The potential confounders selected in Step 1 were included in a multivariable Cox regression model. Backward selection using the a similar criterion (at most 10% change in the model parameter estimate for the treatment group upon dropping the variable in question from the model) was used to achieve a leaner model. This final model was used for the analysis of the treatment effect (model parameter estima-tion with 95% confidence interval, test of the null hypothesis that the true model parameter equals 0) in the same way as outlined for the primary analysis.

3.4.9. Analysis of the Secondary Efficacy Variable (DFS) An analysis of the DFS was done for both of the definitions a) and c) of DFS given in section 3.3.1. The analysis was based on the full analysis set. It followed the same line as the analy-sis of the primary endpoint (survival). However, analyses c) and d) outlined in 3.4.8 were to be performed if and only if the two analyses planned for the primary endpoint yielded statisti-cally conflicting results using statistical significance of the treatment effect on the 5% level as a criterion.

3.4.10. Analysis of Further Endpoints Quality of life (QoL) endpoints (see section 3.3.3): Generally, all QoL analyses were done in two different ways:

1. Using the data without any adjustment 2. Using the adjustment for attrition bias outlined in section 3.4.4. I.e., each patient who

died within the time interval considered in the analysis was assigned the worst possi-ble score for the day of death and each subsequent day in the time interval.

The following analyses were performed: a) Patient compliance with the QoL assessment, defined as the number of forms com-

pleted as a proportion of those anticipated For all aggregate items (scores) mentioned in section 3.3.3:

b) Box-and Whisker-Plots. The x-axis of these plots was given by the scheduled time of assessment (days from randomization). The mean values of the scores were tabu-lated (see Machin and Weeden, 1998; Table 1).

c) Average Areas Under the Curve (AUC) for a time interval of two years, calculated es-sentially as described in Hollen et al. (1997). Briefly, the average area under the curve was calculated as the total AUC divided by the number of days in the interval. The total AUC was calculated as the area of the quadrilaterals formed by plotting the QoL scores at adjacent visit dates. The number of days in the interval was the num-ber of days from randomization to the last QoL assessment prior to randomization + 2 years. (If the patient died during the interval then, in the analysis adjusted for attrition bias, the number of days was set at 730). Only patients who completed at least three QoL assessment were included in the cal-culation of AUC.

Treatment groups were compared with respect to average AUC using the Wilcoxon rank sum test.

Prognostic relevance of baseline variables The influence of potentially important prognostic factors (age, gender, BMI, N, CEA, CA19-9, surgical procedure, time interval from surgery to randomization) on survival time was investi-gated using the Cox Proportional Hazards Model. Whenever longitudinal measurements of any one of these variables were available then the analysis was restricted to the prognostic influence of the baseline (pre-treatment) values.

24

Time from relapse to death For patients with a documented relapse the time from relapse to death was calculated (Kaplan-Meier estimator) and compared across the treatment groups using the logrank test.

3.4.11. Analysis of the Safety and Tolerability Variables As specified in 3.1.3, the analysis of safety and tolerability was essentially based on all patients who completed one or more doses of trial medication. One particular category of safety and tolerability is the drug exposure the analysis of which is described in section 3.4.7 of this SR. The following further categories were analyzed:

Adverse events (AEs) - AEs and SAEs - any deaths

Clinical laboratory investigations Vital signs, physical findings and other observations related to safety (see ICH E3,

section 12.5) Toxicity graded by the NCI 1998 CTC (see Appendix I of the Study Protocol)

3.4.12. Analysis of Adverse Events The analysis determined the number and percentage of patients in each treatment group in whom at least one of the following events occurred after the start of study treatment:

• AEs (all causalities) • AEs (relation to treatment at least possible) Serious AEs (all causalities, regardless of the relation to treatment).

For each category - defined either by the grading of severity of AEs or the relationship to study treatment - the number of patients whose AEs with maximum severity or strongest causal relationship to study treatment (respectively) falls into this category was determined. Two-sided Clopper-Pearson confidence intervals were calculated for the aforementioned percentages of patients. Fisher's exact test was used to compare the percentages across treatment groups.

In addition, the total numbers of AEs and SAEs per treatment group were determined. The total number of AEs was further broken down by severity and causal relationship to study treatment. For each class of AE, the number of occurrences was tabulated by treatment group. Also, the number of AEs per patient was calculated and compared across treatment groups by means of the Wilcoxon rank sum test.

3.4.13. Additional Analyses of Toxicity According to the Study Protocol (§15.2) toxicity of treatment was graded according to NCI-CTC 1998, which was contained in Appendix I of the protocol. Therefore, in deviation from the specification given in §17.2 of the Study Protocol, the analysis of toxicity had to be based on the NCI CTC criteria, not on the WHO toxicity criteria.

25

For each treatment group, the number of documented grade 3/4 toxicities as well as the number of patients with at least one documented grade 3/4 toxicity under treatment were determined. In group A, these numbers were further broken down by treatment block, i.e. block 1 (visit 1-9), block 2 (visit 10-16), and block 3 (visit 17-23). According to the type of toxicity and the data source, three types of displays were distin-guished:

1. Toxicity data based on either the AE reports or on laboratory values, using the NCI-CTC for the latter. (To avoid double-counting no overall numbers of grade 3/4 toxici-ties were determined.)

2. Toxicity data as reported in the AEs. Here, the display was broken down by type of toxicity.

3. Hematotoxicity (leucocytes, thrombocytes, and Hb) based on the documentation of laboratory values, and using the NCI-CTC.

3.4.14. Clinical Laboratory Evaluation The following laboratory parameters were regularly assessed during the trial:

a) Creatinine, Glucose, GOT, GPT, GGT, CRP, b) CEA, ANA, CA19-9

For each parameter, changes with respect to baseline were analyzed at the end of treatment (for treatment group A: at the end of treatment block 1, 2, and 3); more specifically, the fol-lowing displays were produced:

• boxplots showing mean and median values, as well as quartiles, of the differences with respect to baseline values

• shift tables showing the number of patients who were low, normal, or high at base-line and then at the particular visit. Given that the norm values were heterogeneous across the study centers, this analysis was restricted to patients treated at the Heidelberg study center.

3.4.15. Vital Signs, Physical Findings and Other Observations Related to Safety

Heart rate (HR) and blood pressure (SBP and DBP) were measured at each visit. The de-scription of these parameters was done in a similar manner as that of laboratory measure-ments (using the same timing, but restricted to boxplots).

The results of the physical examinations were analyzed by determining, for each treatment group, the number of patients with at least one change with respect to the first measurement.

3.4.16. Changes in the Planned Analyses (i) The following additions to, or modifications of, the methods mentioned in the protocol should be noted (see the SAP):

• The comparison of the treatment groups with respect to categorical or quantitative variables was done using Fisher's exact test and the Wilcoxon rank sum test, respec-tively.

• Neither within-treatment group comparisons using paired t-tests nor analyses of vari-ance were done for QoL data.

• Additional analyses of the primary endpoint (survival) were done as described in section 3.4.8 (c) and (d) of this SR.

26

(ii) The following differences between the analyses actually performed and those outlined in the SAP should be noted:

• The patients who were excluded after randomization because of a violation of eligi-bility criteria were not broken down by the specific criteria leading to the exclusion. Reason: No specific criteria were mentioned in the CRF.

• No curves representing the cumulative enrolment were produced for any specific center.

• The CONSORT flow diagram was prepared according to the most recent version of the CONSORT statement (Schulz et al. 2010). However, only an abbreviated version of the flow diagram could be produced for this SR because additional information (e.g., regarding assessment for eligibility and detailed reasons for the exclusion of patients) were unavailable to the data management group.

• The adjustment process described in 3.4.8 (d) was restricted to clinical covariates. Reason: The laboratory baseline values were missing for many patients, and, more-over, it was thought unlikely that a differential exclusion of patients based on baseline laboratory parameters might have occurred. While for tumor markers this is not self-evident, baseline values of these parameters were available for only 3 patients (CA19-9) and 2 patients (CEA), respectively, who were excluded from the FAS. In addition, the baseline Karnofksy index was omitted from the adjustment process because its value was coded 1 (i.e., >=70) for all patients but one in the database.

• Given that, out of the 110 patients in the FAS, 104 patients had tumor stage T3, the T stage was omitted both from the analysis of the prognostic relevance of baseline variables and from the adjustment process of the primary efficacy analysis. On the other hand, CEA was added to the baseline variables examined as prognostic factors.

• In conformity with the Study Protocol, the primary efficacy endpoint was survival from the resection of the primary tumor.

• According to the SAP (§5.4.1 (c)) it was planned to extend - in a secondary analysis - the comparison of survival curves to all patients who did not withdraw their consent to participate in the study. However, survival data turned out to be available also for pa-tients who withdrew their consent. In fact, except for two patients in group A, the sur-vival data were complete. Consequently, it was decided to perform a survival analysis based on all randomized patients.

• QoL analysis: a) Adjustment for attrition bias: In agreement with the idea underlying this adjustment, each patient who died within the time interval considered in the analysis was assigned the worst possible score (and not the value zero, as stated in the SAP) for the day of death and each subsequent day in the time interval. b) AUCs were not calculated, unless the baseline value as well as at least two further measurements were available for the item in question. c) Boxplots for QoL values were produced only up and until follow-up visit no. 8.

• Because of the heterogeneity of normal ranges used by the different participating centers, shift tables for laboratory parameters were restricted to patients treated at the Heidelberg study center.

• The number of changes in physical findings were not broken down by organ system. • The changes in vital signs were calculated with respect to measurements at visit 3

(group A) and visit 2 (group B), respectively, because baseline values (visit 2 and 1, respectively) were not assessed.

27

4. RESULTS

In the following, the treatment groups will be denoted as specified in section 2.7, i.e., group A and B, respectively.

4.1. Disposition of Patients, Enrolment Fig. 5-1 shows the disposition of the patients in the CapRI trial. Originally, 64 patients were randomly assigned to study arm A, and 68 were assigned to study arm B. Among the patients constituting the FAS, 53 were in group A, and 57 in group B.

The cumulative enrolment is shown in Fig. 5-2.

4.2. Demographic and Other Baseline Characteristics Tables 5-1 through 5-17 show the summaries of demographic and baseline characteristics for all randomized patients, for the FAS, and for patients excluded after randomization.

As noted in section 3.4.1, p-values (for the FAS ) were calculated using the Wilcoxon rank sum test for continuous variables and Fisher's exact test or the Chi squared Test in case of categorical variables with 2 or >2 categories, respective. No statistical tests were performed for Baseline Medications and Baseline Medical History.

4.3. Treatment Compliance and Exposure Descriptive summaries of treatment compliance and exposure are given in Tables 5-18 to 5-33. It should be noted that in study arm A, the planned treatment consisted of 3 cycles, whereas in group B a complete therapy comprised 6 cycles.

4.4. Efficacy Analysis

4.4.1. Analysis of the Primary Efficacy Variable Median follow-up for the patients in the FAS was 25.9 months (Min=4.7, Max=65.2, 25th per-centile=14.9, 75th percentile=39.1 months). Fig. 5-3 shows the Kaplan-Meier estimates of the survival curves for the patients in the FAS. The Cox Proportional Hazards model yielded a hazard ratio of group A vs. B of 0.85 (95% CI: 0.53 to 1.35), and a p-value of p=0.49. The estimated 1- and 2-year survival rates are given in Table 5-34. Median survival from resec-tion of the primary tumor was 32.1 (95% CI: 22.8 to 42.2) months in group A and 28.5 (95% CI: 19.5 to 38.6) months in group B.

The analogous results which were obtained when using the date of randomization as the starting point for measuring survival time are shown in Fig. 5-4 and Table 5-35. The results of the Proportional Hazards model were all but unchanged, with a hazard ratio of 0.843 (95% CI: 0.53 to 1.34) and a p-value of p=0.47. Median survival from the date of randomization was 29.9 (95% CI: 22.0 to 40.4) months in group A and 26.6 (95% CI: 17.7 to 38.2) months in group B.

28

Median follow-up for all randomized patients was 24.8 months (Min=0.2, Max=65.2, 25th per-centile=12.6, 75th percentile=37.7 months). The survival curves for these patients are shown in Fig. 5-5. The fact that these curves were virtually undistinguishable is reflected in a hazard ratio of 0.999 of group A vs. B (95% CI: 0.66 to1.52), as well as in the p-value (p=0.997). Median survival from the date of randomization was 26.0 (95% CI: 20.8 to 37.7) months in group A and 26.6 (95% CI: 18.9 to 36.7) months in group B. The estimated 1- and 2-year survival rates for this analysis are given in Table 5-36. It is noteworthy that the extension of the analysis population did not change the results for group B, whereas survival in group A was shorter when the excluded patients were taken into account.

The adjustment for confounders (as described in section 3.4.8) using the Cox Regression model yielded the following results (see Table 5-37): The model parameter βtreat for treatment group alone was -0.171. The screening of covari-ables showed potential confounding effects (i.e., a change in βtreat of at least 10% when in-cluding the covariable in the model) for the factors age, nodes (N1 vs. N0) and type of sur-gery, the latter being a variable with three levels which were modeled by means of two dummy variables representing the effects of the ppWhipple and the Whipple procedure, resp., relative to the left resection. None of these potential confounders were eliminated in the backward selection process. The final model yielded a model parameter for the treatment group of β=-0.082, corresponding to a hazard ratio (group A vs. B) of 0.92 (95% CI: 0.57 to 1.49), p=0.78. These results indicate that the slight, nonsignificant survival advantage for group A apparent in the FAS can be explained by confounding due to differential exclusions of patients after randomization. It is noteworthy that, among the three variables determined in the screening process, the type of surgery (more specifically, the Whipple procedure) appeared to be the strongest confounder as measured by the change of the model parameter for the treatment effect when including the variable in the model. Inclusion of type of surgery alone led to a hazard ratio for the treatment effect of 0.989 (95% CI: 0.613-1.595). Also, type of surgery was the only clinical baseline variable which showed a statistically significant prognostic influence in the Cox Proportional Hazards model both alone (p=0.001) and in the final adjustment model mentioned above (p=0.004).

4.4.2. Analysis of the Secondary Efficacy Variable (DFS) Fig. 5-6 shows the Kaplan-Meier estimates of the DFS for the patients in the FAS, using re-section of the primary tumor as the starting point. The hazard ratio of group A vs. B esti-mated from the Cox Proportional Hazards was 0.897 (95% CI: 0.59 to 1.37), p=0.61. The estimated 1- and 2-year survival rates are given in Table 5-38. Median DFS was 15.2 (95% CI: 10.3 to 24.8) months in group A and 11.5 (95% CI: 9.8 to 17.6) months in group B.

The analogous results using the date of randomizations as the starting point for the DFS are shown in Fig. 5-7 and Table 5-39. Here the hazard ratio of group A vs. B was 0.899 (95%-CI: 0.59 to 1.37), p=0.62. Median DFS was 14.2 (95% CI: 8.8 to 23.1) months in group A and 10.6 (95% CI: 8.6 to 15.7) months in group B

In conformity with the SAP, and given that the results for the primary endpoint did not change materially when the data base was extended to all randomized patients or when potential confounder were taken into account, no further analyses of the secondary endpoint DFS were performed.

The sites of first and second relapse (for patients in the FAS) are tabulated in Tables 5-40 and 5-41.

29

4.5. Analysis of Other Endpoints

4.5.1. Quality of Life (QoL), Not Adjusted Table 5-42 gives a summary of the completion of the QoL forms. The results of the QoL analyses of the EORTC QLQ-C30 as laid out in section 3.4.10 are shown in Tables 5-43 through 5-73. Except for Table 5-73, all tables are of the same format, displaying mean val-ues of the subscales in question. Table 5-73 gives the results of the AUC analysis for the various subscales of the QLQ-C30. Box plots for the subscales at the various visits are shown in Fig. 5-8 to 5-37. The following exemplary explanation may help to facilitate the interpretation of Tables 5-43ff: The entry "59.49" to be found in row 4 ("V17") and the column with the heading "V10" of Table 5-43 is the mean value of physical functioning at visit V10, evaluated for patients who had QoL documentation until, but not beyond, visit 17. Tables 5-74 to 5-88 and Fig. 5-38 to 5-51 give the analogous results for the EORTC QLQ-PAN26. The analogous results for the CES-D (Total score) are shown in Tables 5-89 to 5-91 and Fig. 5-52 to 5-53. It should be noted that for the symptom scales of the EORTC QLQ-C30 and EORTC QLQ-PAN26 as well as for the CES-D higher scores imply a worse QoL.

4.5.2. Quality of Life (QoL), Adjusted Tables 5-92 through 5-140, and Fig. 5-54 through 5-99 show the results of QoL analyses based on QoL data that were adjusted for attrition bias, as described in section 3.4.10. The tables and figures are organized in the same way as those in 4.5.1. However, since, by con-struction, no premature termination of the adjusted QoL measurements occurred, only overall mean values could be calculated for each visit.

4.5.3. Prognostic Relevance of Baseline Variables Table 5-141 shows the result of the Cox regression model for baseline variables. Except for the type of surgery, which was modeled as described in the adjustment process for the effi-cacy analysis (see section 4.4.1), each variable was investigated in a separate model with one independent variable only.

4.5.4. Time from Relapse to Death Fig. 5-100 shows the survivor curves for the time from first relapse to death for patients in the FAS. The difference between the curves were not statistically significant (p=0.85, logrank test). Median survival from first relapse was 12.3 (95% CI: 9.3 to 14.4) months in group A and 10.2 (95% CI: 7.6 to 13.0) months in group B

4.6. Analysis of the Safety and Tolerability Variables All analyses presented in this section were carried out on the FAS.

4.6.1. Analysis of Adverse Events The results of the safety analysis (AEs, toxicity) are shown in Tables 5-142 to 5-164. Re-garding overall toxicity (as reported either in the AEs or in the laboratory findings), the num-ber of patients with at least one grade 3/4 toxicity – and, specifically, with grade 4 toxicity – was significantly (p<0.0001, Fisher's exact test) higher in group A (45 and 15, resp.) than in group B (9 and 1, resp.).

30

4.6.2. Clinical Laboratory Evaluation Boxplots for the difference between the laboratory parameters at the end of cycles 1-3 (group A) and cycle 6 (group B), resp., and the baseline values are displayed in Fig. 5-101 to 5-117. This includes tumor markers and autoantibodies, which, however, were measured at different time points. The corresponding shift tables are shown in Tables 5-165 to 5-173. The analysis shown in shift tables was restricted to patients treated in the Heidelberg study center.

4.6.3. Vital signs, Physical Findings and Other Observations Related to Safety

Boxplots for changes in physical findings with respect to the first measurements are shown in Fig. 5-118 to 5-123; shift tables are shown in Tables 5-174 to 5-175.

31

5. APPENDIX: TABLES AND FIGURES

Figure 5-1: Disposition of patients in the CapRI trial

32

Figure 5-2: Cumulative patient enrolment in the CapRI trial

Last patient in: 18/12/2007 Fi rst patient in: 29/07/2004

No. Patients

0

20

40

60

80

100

120

140

Months

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48

Table 5-1: Demographics (all randomized patients)

A

N=64 B

N=68 Total

N=132 age - N 64 68 132 - Mean +/- SD 60.0 +/- 10.0 60.4 +/- 10.8 60.2 +/-10.4 - p5, p25, p75, p95 44.0, 53.0, 68.0, 72.0 39.0, 54.5, 68.0, 72.0 39.0, 53.5, 68.0, 72.0 - Median 62.0 63.5 63.0 - Min, Max 31.0, 74.0 33.0, 77.0 31.0, 77.0 gender - male 40 ( 62.5%) 33 ( 48.5%) 73 ( 55.3%) - female 24 ( 37.5%) 35 ( 51.5%) 59 ( 44.7%) height (cm) - N 55 56 111 - Mean +/- SD 170.7 +/- 8.2 168.4 +/- 9.2 169.5 +/-8.7 - p5, p25, p75, p95 158.0, 164.0, 176.0,

186.0 155.0, 162.0, 173.0,

187.0 156.0, 163.0, 175.0,

186.0 - Median 170.0 168.0 168.0 - Min, Max 156.0, 187.0 151.0, 191.0 151.0, 191.0 weight (kg) - N 55 56 111 - Mean +/- SD 68.1 +/- 14.3 68.0 +/- 11.7 68.0 +/-13.0 - p5, p25, p75, p95 52.0, 58.0, 74.5, 90.0 49.0, 60.1, 74.0, 90.0 50.0, 59.0, 74.0, 90.0 - Median 67.0 69.4 68.0 - Min, Max 41.0, 132.0 44.5, 97.0 41.0, 132.0

33

A

N=64 B

N=68 Total

N=132 BMI (kg/m²) - N 55 56 111 - Mean +/- SD 23.3 +/- 4.0 24.0 +/- 4.0 23.6 +/-4.0 - p5, p25, p75, p95 17.8, 21.1, 25.2, 29.1 18.2, 21.3, 25.8, 30.5 18.2, 21.1, 25.3, 30.5 - Median 22.1 23.7 23.1 - Min, Max 15.1, 41.7 16.5, 37.0 15.1, 41.7

Table 5-2: Demographics (FAS)

A

N=53 B

N=57 Total

N=110 p-value1

age - N 53 57 110 0.9522 - Mean +/- SD 61.1 +/- 9.3 60.3 +/- 11.2 60.7 +/-10.3 - p5, p25, p75, p95 44.0, 57.0, 69.0, 73.0 35.0, 54.0, 69.0, 75.0 39.0, 55.0, 69.0, 73.0 - Median 63.0 63.0 63.0 - Min, Max 37.0, 74.0 33.0, 77.0 33.0, 77.0 gender - male 34 ( 64.2%) 27 ( 47.4%) 61 ( 55.5%) 0.087 - female 19 ( 35.8%) 30 ( 52.6%) 49 ( 44.5%) height (cm) - N 53 56 109 0.1112 - Mean +/- SD 170.9 +/- 8.2 168.4 +/- 9.2 169.6 +/-8.8 - p5, p25, p75, p95 158.0, 164.0, 176.0,

186.0 155.0, 162.0, 173.0,

187.0 156.0, 163.0, 175.0,

186.0

- Median 172.0 168.0 169.0 - Min, Max 156.0, 187.0 151.0, 191.0 151.0, 191.0 weight (kg) - N 53 56 109 0.6515 - Mean +/- SD 68.1 +/- 14.3 68.0 +/- 11.7 68.0 +/-13.0 - p5, p25, p75, p95 52.0, 58.0, 74.0, 90.0 49.0, 60.1, 74.0, 90.0 50.0, 59.2, 74.0, 90.0 - Median 67.0 69.4 68.0 - Min, Max 41.0, 132.0 44.5, 97.0 41.0, 132.0 BMI (kg/m²) - N 53 56 109 0.2312 - Mean +/- SD 23.2 +/- 3.9 24.0 +/- 4.0 23.6 +/-4.0 - p5, p25, p75, p95 17.8, 21.1, 25.0, 29.1 18.2, 21.3, 25.8, 30.5 18.2, 21.1, 25.3, 30.5 - Median 22.1 23.7 23.1 - Min, Max 15.1, 41.7 16.5, 37.0 15.1, 41.7

1see §4.2

34

Table 5-3: Demographics (patients excluded from the FAS)

A

N=11 B

N=11 Total N=22

age - N 11 11 22 - Mean +/- SD 54.8 +/- 12.2 60.7 +/- 8.6 57.8 +/-10.7 - p5, p25, p75, p95 31.0, 45.0, 67.0, 71.0 44.0, 55.0, 67.0, 71.0 44.0, 52.0, 67.0, 71.0 - Median 53.0 65.0 59.5 - Min, Max 31.0, 71.0 44.0, 71.0 31.0, 71.0 gender - male 6 ( 54.5%) 6 ( 54.5%) 12 ( 54.5%) - female 5 ( 45.5%) 5 ( 45.5%) 10 ( 45.5%) height (cm) - N 2 2 - Mean +/- SD 165.0 +/- 0.0 165.0 +/-0.0 - p5, p25, p75, p95 165.0, 165.0, 165.0,

165.0 165.0, 165.0, 165.0,

165.0 - Median 165.0 165.0 - Min, Max 165.0, 165.0 165.0, 165.0 weight (kg) - N 2 2 - Mean +/- SD 67.7 +/- 16.5 67.7 +/-16.5 - p5, p25, p75, p95 56.0, 56.0, 79.3, 79.3 56.0, 56.0, 79.3, 79.3 - Median 67.7 67.7 - Min, Max 56.0, 79.3 56.0, 79.3 BMI (kg/m²) - N 2 2 - Mean +/- SD 24.8 +/- 6.1 24.8 +/-6.1 - p5, p25, p75, p95 20.6, 20.6, 29.1, 29.1 20.6, 20.6, 29.1, 29.1 - Median 24.8 24.8 - Min, Max 20.6, 29.1 20.6, 29.1

35

Table 5-4: Disease-specific medical history (all randomized patients)

A

N=64 B

N=68 Total

N=132 TN classification - T1 N1 1 ( 1.6%) 0 ( 0.0%) 1 ( 0.8%) - T2 N0 1 ( 1.6%) 0 ( 0.0%) 1 ( 0.8%) - T2 N1 1 ( 1.6%) 1 ( 1.5%) 2 ( 1.5%) - T3 N0 10 ( 15.6%) 13 ( 19.1%) 23 ( 17.4%) - T3 N1 50 ( 78.1%) 53 ( 77.9%) 103 ( 78.0%) - T4 N0 1 ( 1.6%) 0 ( 0.0%) 1 ( 0.8%) - T4 N1 0 ( 0.0%) 1 ( 1.5%) 1 ( 0.8%) Tumor resection - R0 30 ( 55.6%) 37 ( 66.1%) 67 ( 60.9%) - R1 24 ( 44.4%) 19 ( 33.9%) 43 ( 39.1%) - missing 10 12 22 Histology - poor 13 ( 20.3%) 17 ( 25.0%) 30 ( 22.7%) - moderate 48 ( 75.0%) 49 ( 72.1%) 97 ( 73.5%) - well 3 ( 4.7%) 2 ( 2.9%) 5 ( 3.8%) Surgical procedure - pp Whipple 42 ( 65.6%) 46 ( 67.6%) 88 ( 66.7%) - Whipple 6 ( 9.4%) 12 ( 17.6%) 18 ( 13.6%) - left resection 16 ( 25.0%) 10 ( 14.7%) 26 ( 19.7%) Preoperative CA 19.91 (U/ml) - N 54 57 111 - Mean +/- SD 882.3 +/- 2362.0 407.8 +/- 596.0 638.7 +/-1710.5 - p5, p25, p75, p95 12.0, 54.3, 584.0,

2732.0 1.0, 87.6, 399.0,

1800.0 2.5, 71.8, 530.6,

1978.0 - Median 257.9 190.0 208.9 - Min, Max 1.0, 15641.0 0.6, 3258.8 0.6, 15641.0

1The following changes in the data entries were done when calculating summary statistics for CA19.9: "<2.5" was replaced with "2.5" (n=4), and "<1" was replaced with "1" (n=1).

36

Table 5-5: Disease-specific medical history (FAS)

A

N=53 B

N=57 Total

N=110 p-value1 TN classification - T1 N1 1 ( 1.9%) 0 ( 0.0%) 1 ( 0.9%) 0.790 - T2 N0 1 ( 1.9%) 0 ( 0.0%) 1 ( 0.9%) - T2 N1 1 ( 1.9%) 1 ( 1.8%) 2 ( 1.8%) - T3 N0 9 ( 17.0%) 12 ( 21.1%) 21 ( 19.1%) - T3 N1 40 ( 75.5%) 43 ( 75.4%) 83 ( 75.5%) - T4 N0 1 ( 1.9%) 0 ( 0.0%) 1 ( 0.9%) - T4 N1 0 ( 0.0%) 1 ( 1.8%) 1 ( 0.9%) Tumor resection - R0 29 ( 54.7%) 37 ( 66.1%) 66 ( 60.6%) 0.245 - R1 24 ( 45.3%) 19 ( 33.9%) 43 ( 39.4%) - missing 0 1 1 Histology - poor 11 ( 20.8%) 12 ( 21.1%) 23 ( 20.9%) 0.927 - moderate 40 ( 75.5%) 44 ( 77.2%) 84 ( 76.4%) - well 2 ( 3.8%) 1 ( 1.8%) 3 ( 2.7%) Surgical procedure - pp Whipple 35 ( 66.0%) 39 ( 68.4%) 74 ( 67.3%) 0.064 - Whipple 4 ( 7.5%) 11 ( 19.3%) 15 ( 13.6%) - left resection 14 ( 26.4%) 7 ( 12.3%) 21 ( 19.1%) Preoperative CA 19.92 (U/ml) - N 45 47 92 0.5845 - Mean +/- SD 990.6 +/- 2574.2 408.7 +/- 613.4 693.3 +/-1865.4 - p5, p25, p75, p95 19.9, 61.1, 643.0,

2732.0 1.0, 92.0, 399.0,

1800.0 2.5, 80.5, 536.6,

2490.0

- Median 208.9 190.0 197.4 - Min, Max 1.0, 15641.0 0.6, 3258.8 0.6, 15641.0 1see §4.2 2 The following changes in the data entries were done when calculating summary statistics for CA19.9: "<2.5" was replaced with "2.5" (n=4), and "<1" was replaced with "1" (n=1).

37

Table 5-6: Disease-specific medical history (patients excluded from the FAS)

A

N=11 B

N=11 Total N=22

TN classification - T3 N0 1 ( 9.1%) 1 ( 9.1%) 2 ( 9.1%) - T3 N1 10 ( 90.9%) 10 ( 90.9%) 20 ( 90.9%) Tumor resection - R0 1 (100.0%) 0 ( 0.0%) 1 (100.0%) - missing 10 11 21 Histology - poor 2 ( 18.2%) 5 ( 45.5%) 7 ( 31.8%) - moderate 8 ( 72.7%) 5 ( 45.5%) 13 ( 59.1%) - well 1 ( 9.1%) 1 ( 9.1%) 2 ( 9.1%) Surgical procedure - pp Whipple 7 ( 63.6%) 7 ( 63.6%) 14 ( 63.6%) - Whipple 2 ( 18.2%) 1 ( 9.1%) 3 ( 13.6%) - left resection 2 ( 18.2%) 3 ( 27.3%) 5 ( 22.7%) Preoperative CA 19.91 (U/ml) - N 9 10 19 - Mean +/- SD 340.9 +/- 345.4 403.4 +/- 535.4 373.8 +/-444.3 - p5, p25, p75, p95 12.0, 18.7, 433.0,

1124.0 1.0, 50.7, 595.1,

1713.0 1.0, 32.7, 436.3,

1713.0 - Median 320.6 189.9 299.9 - Min, Max 12.0, 1124.0 1.0, 1713.0 1.0, 1713.0 1 The following changes in the data entries were done when calculating summary statistics for CA19.9: "<2.5" was replaced with "2.5" (n=4), and "<1" was replaced with "1" (n=1).

38

Table 5-7: Further prognostic factors (all randomized patients)

A

N=64 B

N=68 Total

N=132 Karnofsky Index <= 70 - no 0 ( 0.0%) 1 ( 1.8%) 1 ( 0.9%) - yes 55 (100.0%) 56 ( 98.2%) 111 ( 99.1%) - missing 9 11 20 Time interval from surgery to randomization (days)

- N 64 68 132 - Mean +/- SD 36.5 +/- 19.1 39.3 +/- 18.6 38.0 +/-18.8 - p5, p25, p75, p95 9.0, 20.5, 51.0, 69.0 10.0, 27.0, 53.0, 74.0 9.0, 22.0, 51.5, 70.0 - Median 37.0 38.0 38.0 - Min, Max 8.0, 74.0 7.0, 83.0 7.0, 83.0

Table 5-8: Further prognostic factors (FAS)

A

N=53 B

N=57 Total

N=110 p-value1 Karnofsky Index <= 70 - yes 53 (100.0%) 56 (100.0%) 109 (100.0%) - missing 0 1 1 Time interval from surgery to randomization (days)

- N 53 57 110 0.5964 - Mean +/- SD 37.5 +/- 17.8 40.1 +/- 18.7 38.9 +/-18.2 - p5, p25, p75, p95 9.0, 23.0, 51.0, 69.0 10.0, 27.0, 52.0, 76.0 10.0, 25.0, 51.0, 70.0 - Median 39.0 41.0 39.0 - Min, Max 8.0, 72.0 9.0, 83.0 8.0, 83.0

1see §4.2

Table 5-9: Further prognostic factors (patients excluded from the FAS)

A

N=11 B

N=11 Total N=22

Karnofsky Index <= 70 - no 0 ( 0.0%) 1 (100.0%) 1 ( 33.3%) - yes 2 (100.0%) 0 ( 0.0%) 2 ( 66.7%) - missing 9 10 19 Time interval from surgery to randomization (days)

- N 11 11 22 - Mean +/- SD 31.8 +/- 24.7 35.5 +/- 18.7 33.6 +/-21.5 - p5, p25, p75, p95 8.0, 10.0, 63.0, 74.0 7.0, 21.0, 56.0, 64.0 8.0, 17.0, 56.0, 67.0 - Median 22.0 37.0 31.5 - Min, Max 8.0, 74.0 7.0, 64.0 7.0, 74.0

39

Table 5-10: Baseline medications (all randomized patients)

A

N=64 B

N=68 Total

N=132 Baseline Medication - Analgetika/Antirheumatika 35 ( 15.6%) 42 ( 16.4%) 77 ( 16.0%) - Antianämika 0 ( 0.0%) 1 ( 0.4%) 1 ( 0.2%) - Antibiotika/Antiinfektiva 1 ( 0.4%) 2 ( 0.8%) 3 ( 0.6%) - Antidiabetika 19 ( 8.5%) 25 ( 9.8%) 44 ( 9.2%) - Antiemetika/Antivertiginosa 3 ( 1.3%) 4 ( 1.6%) 7 ( 1.5%) - Antiepileptika 0 ( 0.0%) 2 ( 0.8%) 2 ( 0.4%) - Antihypertonika 1 ( 0.4%) 1 ( 0.4%) 2 ( 0.4%) - Antikoagulantia 6 ( 2.7%) 7 ( 2.7%) 13 ( 2.7%) - Antitussiva/Expektorantia 1 ( 0.4%) 1 ( 0.4%) 2 ( 0.4%) - Betarezeptoren-, Calciumkanalblocker u. Hemmstoffe d. Renin-Angiotensin-Systems

35 ( 15.6%) 36 ( 14.1%) 71 ( 14.8%)

- Broncholytika/Antiasthmatika 2 ( 0.9%) 0 ( 0.0%) 2 ( 0.4%) - Cholagoga u. Gallenwegstherapeutika 0 ( 0.0%) 1 ( 0.4%) 1 ( 0.2%) - Diuretika 7 ( 3.1%) 9 ( 3.5%) 16 ( 3.3%) - Gichtmittel 3 ( 1.3%) 2 ( 0.8%) 5 ( 1.0%) - Infusions- u. Standardinjektionslösungen, Organperfusionslösungen

1 ( 0.4%) 0 ( 0.0%) 1 ( 0.2%)

- Kardiaka 2 ( 0.9%) 0 ( 0.0%) 2 ( 0.4%) - Koronarmittel 0 ( 0.0%) 2 ( 0.8%) 2 ( 0.4%) - Laxantia 5 ( 2.2%) 6 ( 2.3%) 11 ( 2.3%) - Lipidsenker 1 ( 0.4%) 4 ( 1.6%) 5 ( 1.0%) - Magen-Darm-Mittel 78 ( 34.8%) 82 ( 32.0%) 160 ( 33.3%) - Mineralstoffpräparate 9 ( 4.0%) 15 ( 5.9%) 24 ( 5.0%) - Ophthalmika 1 ( 0.4%) 0 ( 0.0%) 1 ( 0.2%) - Psychopharmaka 4 ( 1.8%) 1 ( 0.4%) 5 ( 1.0%) - Roborantia/Tonika 0 ( 0.0%) 2 ( 0.8%) 2 ( 0.4%) - Schilddrüsentherapeutika 3 ( 1.3%) 6 ( 2.3%) 9 ( 1.9%) - Tuberkulosemittel 0 ( 0.0%) 1 ( 0.4%) 1 ( 0.2%) - Urologika 4 ( 1.8%) 2 ( 0.8%) 6 ( 1.3%) - Venentherapeutika 0 ( 0.0%) 1 ( 0.4%) 1 ( 0.2%) - Vitamine 2 ( 0.9%) 1 ( 0.4%) 3 ( 0.6%) - Zytostatika, andere antineoplastische Mittel u. Protektiva

1 ( 0.4%) 0 ( 0.0%) 1 ( 0.2%)

Multiple entries per patient are possible (i.e., the number of medications may exceed the number of patients)

Table 5-11: Baseline medications (FAS)

A

N=53 B

N=57 Total

N=110 Baseline Medication - Analgetika/Antirheumatika 35 ( 15.6%) 42 ( 16.4%) 77 ( 16.0%) - Antianämika 0 ( 0.0%) 1 ( 0.4%) 1 ( 0.2%) - Antibiotika/Antiinfektiva 1 ( 0.4%) 2 ( 0.8%) 3 ( 0.6%) - Antidiabetika 19 ( 8.5%) 25 ( 9.8%) 44 ( 9.2%) - Antiemetika/Antivertiginosa 3 ( 1.3%) 4 ( 1.6%) 7 ( 1.5%) - Antiepileptika 0 ( 0.0%) 2 ( 0.8%) 2 ( 0.4%) - Antihypertonika 1 ( 0.4%) 1 ( 0.4%) 2 ( 0.4%) - Antikoagulantia 6 ( 2.7%) 7 ( 2.7%) 13 ( 2.7%) - Antitussiva/Expektorantia 1 ( 0.4%) 1 ( 0.4%) 2 ( 0.4%) - Betarezeptoren-, Calciumkanalblocker u. Hemmstoffe d. Renin-Angiotensin-Systems

35 ( 15.6%) 36 ( 14.1%) 71 ( 14.8%)

- Broncholytika/Antiasthmatika 2 ( 0.9%) 0 ( 0.0%) 2 ( 0.4%) - Cholagoga u. Gallenwegstherapeutika 0 ( 0.0%) 1 ( 0.4%) 1 ( 0.2%) - Diuretika 7 ( 3.1%) 9 ( 3.5%) 16 ( 3.3%) - Gichtmittel 3 ( 1.3%) 2 ( 0.8%) 5 ( 1.0%) - Infusions- u. Standardinjektionslösungen, Organperfusionslösungen

1 ( 0.4%) 0 ( 0.0%) 1 ( 0.2%)

- Kardiaka 2 ( 0.9%) 0 ( 0.0%) 2 ( 0.4%)

40

A

N=53 B

N=57 Total

N=110 - Koronarmittel 0 ( 0.0%) 2 ( 0.8%) 2 ( 0.4%) - Laxantia 5 ( 2.2%) 6 ( 2.3%) 11 ( 2.3%) - Lipidsenker 1 ( 0.4%) 4 ( 1.6%) 5 ( 1.0%) - Magen-Darm-Mittel 78 ( 34.8%) 82 ( 32.0%) 160 ( 33.3%) - Mineralstoffpräparate 9 ( 4.0%) 15 ( 5.9%) 24 ( 5.0%) - Ophthalmika 1 ( 0.4%) 0 ( 0.0%) 1 ( 0.2%) - Psychopharmaka 4 ( 1.8%) 1 ( 0.4%) 5 ( 1.0%) - Roborantia/Tonika 0 ( 0.0%) 2 ( 0.8%) 2 ( 0.4%) - Schilddrüsentherapeutika 3 ( 1.3%) 6 ( 2.3%) 9 ( 1.9%) - Tuberkulosemittel 0 ( 0.0%) 1 ( 0.4%) 1 ( 0.2%) - Urologika 4 ( 1.8%) 2 ( 0.8%) 6 ( 1.3%) - Venentherapeutika 0 ( 0.0%) 1 ( 0.4%) 1 ( 0.2%) - Vitamine 2 ( 0.9%) 1 ( 0.4%) 3 ( 0.6%) - Zytostatika, andere antineoplastische Mittel u. Protektiva

1 ( 0.4%) 0 ( 0.0%) 1 ( 0.2%)

Multiple entries per patient are possible (i.e., the number of medications may exceed the number of patients)

Table 5-12: Baseline medical history (all randomized patients)

A

N=64 B

N=68 Total

N=132 Medical history - all systems without relevant medical history 1 ( 0.5%) 0 ( 0.0%) 1 ( 0.2%) - eyes,ears,nose,throat 5 ( 2.4%) 5 ( 2.4%) 10 ( 2.4%) - respiratory 9 ( 4.4%) 1 ( 0.5%) 10 ( 2.4%) - cardiovascular 41 ( 19.9%) 50 ( 24.3%) 91 ( 22.1%) - gastrointestinal 38 ( 18.4%) 42 ( 20.4%) 80 ( 19.4%) - musculoskeletal 8 ( 3.9%) 5 ( 2.4%) 13 ( 3.2%) - neurological 7 ( 3.4%) 10 ( 4.9%) 17 ( 4.1%) - endocrine 68 ( 33.0%) 69 ( 33.5%) 137 ( 33.3%) - lymphatic 7 ( 3.4%) 0 ( 0.0%) 7 ( 1.7%) - dermatological 8 ( 3.9%) 5 ( 2.4%) 13 ( 3.2%) - genitourinary 14 ( 6.8%) 19 ( 9.2%) 33 ( 8.0%) - missing 8 11 19

41

Table 5-13: Baseline medical history (FAS)

A

N=53 B

N=57 Total

N=110 Medical history - eyes,ears,nose,throat 5 ( 2.5%) 5 ( 2.5%) 10 ( 2.5%) - respiratory 9 ( 4.5%) 1 ( 0.5%) 10 ( 2.5%) - cardiovascular 40 ( 20.0%) 49 ( 24.1%) 89 ( 22.1%) - gastrointestinal 37 ( 18.5%) 42 ( 20.7%) 79 ( 19.6%) - musculoskeletal 8 ( 4.0%) 5 ( 2.5%) 13 ( 3.2%) - neurological 7 ( 3.5%) 10 ( 4.9%) 17 ( 4.2%) - endocrine 67 ( 33.5%) 68 ( 33.5%) 135 ( 33.5%) - lymphatic 7 ( 3.5%) 0 ( 0.0%) 7 ( 1.7%) - dermatological 7 ( 3.5%) 5 ( 2.5%) 12 ( 3.0%) - genitourinary 13 ( 6.5%) 18 ( 8.9%) 31 ( 7.7%) - missing 0 1 1

Table 5-14: Baseline medical history (patients excluded from the FAS)

A

N=11 B

N=11 Total N=22

Medical history - all systems without relevant medical history 1 ( 16.7%) 0 ( 0.0%) 1 ( 11.1%) - cardiovascular 1 ( 16.7%) 1 ( 33.3%) 2 ( 22.2%) - gastrointestinal 1 ( 16.7%) 0 ( 0.0%) 1 ( 11.1%) - endocrine 1 ( 16.7%) 1 ( 33.3%) 2 ( 22.2%) - dermatological 1 ( 16.7%) 0 ( 0.0%) 1 ( 11.1%) - genitourinary 1 ( 16.7%) 1 ( 33.3%) 2 ( 22.2%) - missing 8 10 18

Table 5-15: Baseline physical examination (all randomized patients)

A

N=64 B

N=68 Total

N=132 General appearance - normal 55 (100.0%) 54 ( 98.2%) 109 ( 99.1%) - abnormal 0 ( 0.0%) 1 ( 1.8%) 1 ( 0.9%) - missing 9 13 22 Head & Neck - normal 55 (100.0%) 55 (100.0%) 110 (100.0%) - missing 9 13 22 Eyes & ears - normal 55 (100.0%) 55 (100.0%) 110 (100.0%) - missing 9 13 22 Nose & throat - normal 55 (100.0%) 55 (100.0%) 110 (100.0%) - missing 9 13 22

42

A

N=64 B

N=68 Total

N=132 Chest - normal 55 (100.0%) 55 (100.0%) 110 (100.0%) - missing 9 13 22 Lungs - normal 55 (100.0%) 55 (100.0%) 110 (100.0%) - missing 9 13 22 Heart - normal 55 (100.0%) 55 (100.0%) 110 (100.0%) - missing 9 13 22 Abdomen - normal 55 (100.0%) 53 ( 96.4%) 108 ( 98.2%) - abnormal 0 ( 0.0%) 2 ( 3.6%) 2 ( 1.8%) - missing 9 13 22 Extremities & joints - normal 55 (100.0%) 55 (100.0%) 110 (100.0%) - missing 9 13 22 Lymph nodes - normal 55 (100.0%) 55 (100.0%) 110 (100.0%) - missing 9 13 22 Skin - normal 54 ( 98.2%) 54 ( 96.4%) 108 ( 97.3%) - abnormal 1 ( 1.8%) 2 ( 3.6%) 3 ( 2.7%) - missing 9 12 21 Neurological - normal 54 ( 98.2%) 55 (100.0%) 109 ( 99.1%) - abnormal 1 ( 1.8%) 0 ( 0.0%) 1 ( 0.9%) - missing 9 13 22

43

Table 5-16: Baseline physical examination (FAS)

Arm A N=53

Arm B N=57

Total N=110 p-value1

General appearance - normal 53 (100.0%) 54 ( 98.2%) 107 ( 99.1%) 1.000 - abnormal 0 ( 0.0%) 1 ( 1.8%) 1 ( 0.9%) - missing 0 2 2 Head & Neck - normal 53 (100.0%) 55 (100.0%) 108 (100.0%) - missing 0 2 2 Eyes & ears - normal 53 (100.0%) 55 (100.0%) 108 (100.0%) - missing 0 2 2 Nose & throat - normal 53 (100.0%) 55 (100.0%) 108 (100.0%) - missing 0 2 2 Chest - normal 53 (100.0%) 55 (100.0%) 108 (100.0%) - missing 0 2 2 Lungs - normal 53 (100.0%) 55 (100.0%) 108 (100.0%) - missing 0 2 2 Heart - normal 53 (100.0%) 55 (100.0%) 108 (100.0%) - missing 0 2 2 Abdomen - normal 53 (100.0%) 53 ( 96.4%) 106 ( 98.1%) 0.496 - abnormal 0 ( 0.0%) 2 ( 3.6%) 2 ( 1.9%) - missing 0 2 2 Extremities & joints - normal 53 (100.0%) 55 (100.0%) 108 (100.0%) - missing 0 2 2 Lymph nodes - normal 53 (100.0%) 55 (100.0%) 108 (100.0%) - missing 0 2 2 Skin - normal 52 ( 98.1%) 54 ( 96.4%) 106 ( 97.2%) 1.000 - abnormal 1 ( 1.9%) 2 ( 3.6%) 3 ( 2.8%) - missing 0 1 1 Neurological - normal 52 ( 98.1%) 55 (100.0%) 107 ( 99.1%) 0.491 - abnormal 1 ( 1.9%) 0 ( 0.0%) 1 ( 0.9%) - missing 0 2 2 1see §4.2

44

Table 5-17: Baseline physical examination (Patients excluded from the FAS)

Arm A N=11

Arm B N=11

Total N=22

General appearance - normal 2 (100.0%) 0 ( 0.0%) 2 (100.0%) - missing 9 11 20 Head & Neck - normal 2 (100.0%) 0 ( 0.0%) 2 (100.0%) - missing 9 11 20 Eyes & ears - normal 2 (100.0%) 0 ( 0.0%) 2 (100.0%) - missing 9 11 20 Nose & throat - normal 2 (100.0%) 0 ( 0.0%) 2 (100.0%) - missing 9 11 20 Chest - normal 2 (100.0%) 0 ( 0.0%) 2 (100.0%) - missing 9 11 20 Lungs - normal 2 (100.0%) 0 ( 0.0%) 2 (100.0%) - missing 9 11 20 Heart - normal 2 (100.0%) 0 ( 0.0%) 2 (100.0%) - missing 9 11 20 Abdomen - normal 2 (100.0%) 0 ( 0.0%) 2 (100.0%) - missing 9 11 20 Extremities & joints - normal 2 (100.0%) 0 ( 0.0%) 2 (100.0%) - missing 9 11 20 Lymph nodes - normal 2 (100.0%) 0 ( 0.0%) 2 (100.0%) - missing 9 11 20 Skin - normal 2 (100.0%) 0 ( 0.0%) 2 (100.0%) - missing 9 11 20 Neurological - normal 2 (100.0%) 0 ( 0.0%) 2 (100.0%) - missing 9 11 20

45

Table 5-18: Treatment cycles per patient, group A N=53 Number of treatment cycles (summary) - N 51 - Mean +/- SD 2.4 +/- 0.8 - Median 3.0 - Min, Max 1.0, 3.0 Number of treatment cycles (frequencies)

- one cycle 9 ( 17.6%) - two cycles 14 ( 27.5%) - three cycles 28 ( 54.9%) - missing 2

Table 5-19: Treatment cycles per patient, group B N=57 Number of treatment cycles (summary) - N 57 - Mean +/- SD 5.3 +/- 1.5 - Median 6.0 - Min, Max 1.0, 6.0 Number of treatment cycles (frequencies)

- one cycle 3 ( 5.3%) - two cycles 2 ( 3.5%) - three cycles 3 ( 5.3%) - four cycles 3 ( 5.3%) - five cycles 2 ( 3.5%) - six cycles 44 ( 77.2%)

A cycle was counted if at least one dose of the planned medication was administered.

46

Table 5-20: Dose modifications, group A N=53 Interferon / first cycle - dose reduction 12 ( 23.5%) - intended dose 39 ( 76.5%) - missing 2 5-FU / first cycle - dose reduction 46 ( 86.8%) - intended dose 1 ( 1.9%) - dose escalation 6 ( 11.3%) Cisplatin / first cycle - dose reduction 41 ( 77.4%) - intended dose 12 ( 22.6%) Radiation / first cycle - dose reduction 6 ( 11.5%) - intended dose 46 ( 88.5%) - missing 1 5-FU / second cycle - dose reduction 39 ( 79.6%) - intended dose 2 ( 4.1%) - dose escalation 8 ( 16.3%) - missing 4 5-FU / third cycle - dose reduction 26 ( 61.9%) - intended dose 16 ( 38.1%) - missing 11 dose modification (any cycle) - dose modification 41 (100.0%) - missing 12

Dose modification= reduction or escalation Dose reduction=administration of less than the intended dose

47

Table 5-21: Dose modifications, group B N=57 5-FU / first cycle - dose reduction 1 ( 1.8%) - intended dose 55 ( 98.2%) - missing 1 5-FU / second cycle - dose reduction 6 ( 11.1%) - intended dose 48 ( 88.9%) - missing 3 5-FU / third cycle - dose reduction 8 ( 15.4%) - intended dose 44 ( 84.6%) - missing 5 5-FU / fourth cycle - dose reduction 11 ( 22.4%) - intended dose 38 ( 77.6%) - missing 8 5-FU / fifth cycle - dose reduction 10 ( 21.7%) - intended dose 36 ( 78.3%) - missing 11 5-FU / sixth cycle - dose reduction 11 ( 23.9%) - intended dose 35 ( 76.1%) - missing 11 dose modification overall - no dose modification 32 ( 69.6%) - dose modification 14 ( 30.4%) - missing 11

Dose modification= reduction or escalation Dose reduction=administration of less than the intended dose

48

Table 5-22: Treatment interruption, group A N=53 Interferon / first cycle - no treatment interruption 38 ( 73.1%) - treatment interruption 14 ( 26.9%) - missing 1 5-FU / first cycle - no treatment interruption 11 ( 23.9%) - treatment interruption 35 ( 76.1%) - missing 7 Cisplatin / first cycle - no treatment interruption 12 ( 26.1%) - treatment interruption 34 ( 73.9%) - missing 7 Radiation / first cycle - no treatment interruption 46 ( 88.5%) - treatment interruption 6 ( 11.5%) - missing 1 5-FU / second cycle - no treatment interruption 35 ( 83.3%) - treatment interruption 7 ( 16.7%) - missing 11 5-FU / third cycle - no treatment interruption 31 ( 88.6%) - treatment interruption 4 ( 11.4%) - missing 18 treatment interruption (any cycle) - no treatment interruption 5 ( 18.5%) - treatment interruption 22 ( 81.5%) - missing 26

49

Table 5-23: Treatment interruption, group B N=57 5-FU / first cycle - no treatment interruption 55 ( 98.2%) - treatment interruption 1 ( 1.8%) - missing 1 5-FU / second cycle - no treatment interruption 54 (100.0%) - missing 3 5-FU / third cycle - no treatment interruption 51 ( 98.1%) - treatment interruption 1 ( 1.9%) - missing 5 5-FU / fourth cycle - no treatment interruption 48 ( 98.0%) - treatment interruption 1 ( 2.0%) - missing 8 5-FU / fifth cycle - no treatment interruption 46 (100.0%) - missing 11 5-FU / sixth cycle - no treatment interruption 44 ( 95.7%) - treatment interruption 2 ( 4.3%) - missing 11 treatment interruption (any cycle) - no treatment interruption 43 ( 93.5%) - treatment interruption 3 ( 6.5%) - missing 11

Table 5-24: Completion of treatment as planned

A

N=53 B

N=57 - total dose applied 1 ( 2.4%) 32 ( 69.6%) - dose reduced (any cycle) 40 ( 97.6%) 14 ( 30.4%) - missing 12 11

"Dose reduction"= administration of less than the intended dose/missing value

50

Table 5-25: Cumulative dose of drugs and radiation, group A N=53 Interferon /intended dose: 51 Mio Units SQ MWF - N 53 - Mean +/- SD 48.4 +/- 6.4 - Median 51.0 - Min, Max 12.0, 51.0 5-FU /intended dose: 23600 mg/m² - N 53 - Mean +/- SD 17391.0 +/- 5815.3 - Median 19300.0 - Min, Max 1400.0, 24400.0 Cisplatin /intended dose: 180 mg/m² - N 53 - Mean +/- SD 134.4 +/- 33.9 - Median 120.0 - Min, Max 30.0, 180.0 Radiation /intended dose: 50.4 Gy - N 52 - Mean +/- SD 49.5 +/- 3.3 - Median 50.4 - Min, Max 30.4, 50.4

Table 5-26: Cumulative dose of drugs, group B N=57 5-FU /intended dose: 12750 mg/m² - N 56 - Mean +/- SD 10944.5 +/- 2971.0 - Median 12750.0 - Min, Max 2125.0, 12750.0

51

Table 5-27: Total dose of drugs and radiation (absolute terms), group A, by treatment cycle

N=53 Interferon / cycle 1 / intended dose: 51 Mio Units SQ MWF - N 53 - Mean +/- SD 48.4 +/- 6.4 - Median 51.0 - Min, Max 12.0, 51.0 5-FU / cycle 1 / intended dose: 7600 mg/m² - N 53 - Mean +/- SD 5469.6 +/- 1714.0 - Median 5200.0 - Min, Max 1400.0, 9400.0 Cisplatin / cycle 1 / intended dose: 180 mg/m² - N 53 - Mean +/- SD 134.4 +/- 33.9 - Median 120.0 - Min, Max 30.0, 180.0 Radiation / cycle 1 / Intended dose: 50.4 Gy - N 52 - Mean +/- SD 49.5 +/- 3.3 - Median 50.4 - Min, Max 30.4, 50.4 5-FU / cycle 2 / intended dose: 7600 mg/m² - N 49 - Mean +/- SD 6785.4 +/- 1712.0 - Median 7400.0 - Min, Max 0.0, 8400.0 5-FU / cycle 3 / intended dose: 8400 mg/m² - N 42 - Mean +/- SD 7127.3 +/- 1886.8 - Median 7900.0 - Min, Max 1400.0, 8400.0

52

Table 5-28: Total dose of drugs (absolute terms), group B, by treatment cycle

N=57 5-FU / cycle 1 / intended dose: 2125 mg/m² - N 56 - Mean +/- SD 2109.8 +/- 113.6 - Median 2125.0 - Min, Max 1275.0, 2125.0 5-FU / cycle 2 / intended dose: 2125 mg/m² - N 54 - Mean +/- SD 2058.1 +/- 203.6 - Median 2125.0 - Min, Max 1062.5, 2125.0 5-FU / cycle 3 / intended dose: 2125 mg/m² - N 52 - Mean +/- SD 2043.0 +/- 194.3 - Median 2125.0 - Min, Max 1576.5, 2125.0 5-FU / cycle 4 / intended dose: 2125 mg/m² - N 49 - Mean +/- SD 1983.7 +/- 335.3 - Median 2125.0 - Min, Max 318.8, 2125.0 5-FU / cycle 5 / intended dose: 2125 mg/m² - N 46 - Mean +/- SD 1999.9 +/- 252.3 - Median 2125.0 - Min, Max 1062.5, 2125.0 5-FU / cycle 6 / intended dose: 2125 mg/m² - N 46 - Mean +/- SD 1916.8 +/- 481.7 - Median 2125.0 - Min, Max 0.0, 2125.0

53

Table 5-29: Total dose of drugs and radiation (percentage of intended dose), group A, by cycle

N=53 Interferon / cycle 1 / intended dose: 51 Mio Units SQ MWF - N 51 - Mean +/- SD 96.3 +/- 7.6 - Median 100.0 - Min, Max 70.6, 100.0 5-FU / cycle 1 / intended dose: 7600 mg/m² - N 53 - Mean +/- SD 72.0 +/- 22.6 - Median 68.4 - Min, Max 18.4, 123.7 Cisplatin / cycle 1 / intended dose: 180 mg/m² - N 53 - Mean +/- SD 74.7 +/- 18.8 - Median 66.7 - Min, Max 16.7, 100.0 Radiation / cycle 1 / intended dose: 50.4 Gy - N 52 - Mean +/- SD 98.3 +/- 6.5 - Median 100.0 - Min, Max 60.3, 100.0 5-FU / cycle 2 / intended dose: 7600 mg/m² - N 49 - Mean +/- SD 89.3 +/- 22.5 - Median 97.4 - Min, Max 0.0, 110.5 5-FU / cycle 3 / intended dose: 8400 mg/m² - N 42 - Mean +/- SD 93.8 +/- 24.8 - Median 103.9 - Min, Max 18.4, 110.5

54

Table 5-30: Total dose of drugs (percentage of intended dose), group B, by cycle

N=57 5-FU / cycle 1 / intended dose: 2125 mg/m² - N 56 - Mean +/- SD 99.3 +/- 5.3 - Median 100.0 - Min, Max 60.0, 100.0 5-FU / cycle 2 / intended dose: 2125 mg/m² - N 54 - Mean +/- SD 96.9 +/- 9.6 - Median 100.0 - Min, Max 50.0, 100.0 5-FU / cycle 3 / intended dose: 2125 mg/m² - N 52 - Mean +/- SD 96.1 +/- 9.1 - Median 100.0 - Min, Max 74.2, 100.0 5-FU / cycle 4 / intended dose: 2125 mg/m² - N 49 - Mean +/- SD 93.4 +/- 15.8 - Median 100.0 - Min, Max 15.0, 100.0 5-FU / cycle 5 / intended dose: 2125 mg/m² - N 46 - Mean +/- SD 94.1 +/- 11.9 - Median 100.0 - Min, Max 50.0, 100.0 5-FU / cycle 6 / intended dose: 2125 mg/m² - N 44 - Mean +/- SD 94.3 +/- 11.9 - Median 100.0 - Min, Max 50.0, 100.0

55

Table 5-31: Concomitant medication by type of medication, group A

N=57 Type of medication - Analgetika/Antirheumatika 73 ( 10.5%) - Antiallergika 1 ( 0.1%) - Antianämika 6 ( 0.9%) - Antibiotika/Antiinfektiva 26 ( 3.8%) - Antidementiva (Nootropika) 1 ( 0.1%) - Antidiabetika 23 ( 3.3%) - Antiemetika/Antivertiginosa 94 ( 13.6%) - Antiepileptika 1 ( 0.1%) - Antihypertonika 1 ( 0.1%) - Antihypotonika 1 ( 0.1%) - Antikoagulantia 12 ( 1.7%) - Antimykotika 4 ( 0.6%) - Antitussiva/Expektorantia 1 ( 0.1%) - Betarezeptoren-, Calciumkanalblocker u. Hemmstoffe d. Renin- Angiotensin-Systems

37 ( 5.3%)

- Broncholytika/Antiasthmatika 3 ( 0.4%) - Corticoide (Interna) 22 ( 3.2%) - Dermatika 6 ( 0.9%) - Diuretika 10 ( 1.4%) - Fibrinolytika 1 ( 0.1%) - Gichtmittel 3 ( 0.4%) - Grippemittel u. Mittel gegen Erkältungskrankheiten

1 ( 0.1%)

- Immunmodulatoren 9 ( 1.3%) - Infusions- u. Standardinjektionslösungen, Organperfusionslösungen

73 ( 10.5%)

- Kardiaka 2 ( 0.3%) - Laxantia 10 ( 1.4%) - Lipidsenker 2 ( 0.3%) - Magen-Darm-Mittel 156 ( 22.5%) - Mineralstoffpräparate 40 ( 5.8%) - Mund- u. Rachentherapeutika 8 ( 1.2%) - Muskelrelaxanzien 1 ( 0.1%) - Ophthalmika 2 ( 0.3%) - Psychopharmaka 26 ( 3.8%) - Roborantia/Tonika 2 ( 0.3%) - Schilddrüsentherapeutika 4 ( 0.6%) - Spasmolytika 10 ( 1.4%) - Urologika 5 ( 0.7%) - Vitamine 9 ( 1.3%) - Wundbehandlungsmittel 6 ( 0.9%) - Zytostatika, andere antineoplastische Mittel u. Protektiva

1 ( 0.1%)

Sum of medications may exceed number of patients. N.B.: All patients in study arm A received some concomitant medication at least once during the study therapy.

56

Table 5-32: Concomitant medication by type of medication, group B

N=57 Type of medication - Analgetika/Antirheumatika 53 ( 11.5%) - Antiallergika 1 ( 0.2%) - Antianämika 3 ( 0.6%) - Antibiotika/Antiinfektiva 12 ( 2.6%) - Antidiabetika 26 ( 5.6%) - Antiemetika/Antivertiginosa 22 ( 4.8%) - Antiepileptika 2 ( 0.4%) - Antihypertonika 1 ( 0.2%) - Antikoagulantia 8 ( 1.7%) - Antimykotika 4 ( 0.9%) - Antitussiva/Expektorantia 3 ( 0.6%) - Betarezeptoren-, Calciumkanalblocker u. Hemmstoffe d. Renin- Angiotensin-Systems

40 ( 8.7%)

- Cholagoga u. Gallenwegstherapeutika

1 ( 0.2%)

- Corticoide (Interna) 8 ( 1.7%) - Dermatika 6 ( 1.3%) - Diuretika 11 ( 2.4%) - Gichtmittel 4 ( 0.9%) - Hypophysen-, Hypothalamushormone, andere regulatorische Peptide u. ihre Hemmstoffe

2 ( 0.4%)

- Infusions- u. Standardinjektionslösungen, Organperfusionslösungen

18 ( 3.9%)

- Koronarmittel 2 ( 0.4%) - Laxantia 8 ( 1.7%) - Lipidsenker 5 ( 1.1%) - Magen-Darm-Mittel 163 ( 35.3%) - Mineralstoffpräparate 22 ( 4.8%) - Mund- u. Rachentherapeutika 12 ( 2.6%) - Psychopharmaka 3 ( 0.6%) - Roborantia/Tonika 2 ( 0.4%) - Schilddrüsentherapeutika 7 ( 1.5%) - Spasmolytika 5 ( 1.1%) - Tuberkulosemittel 1 ( 0.2%) - Urologika 2 ( 0.4%) - Venentherapeutika 1 ( 0.2%) - Vitamine 3 ( 0.6%) - Wundbehandlungsmittel 1 ( 0.2%)

Sum of medications may exceed number of patients. N.B.: All patients in study arm B received some concomitant medication at least once during the study therapy.

57

Table 5-33: Dose modifications, treatment interruptions, dose reductions (any cycle): comparison across treatment groups

A

N=53 B

N=57 Total

N=110 p-value1 Dose modifications - no dose modification 0 ( 0.0%) 32 ( 69.6%) 32 ( 36.8%) <.001 - dose modification 41 (100.0%) 14 ( 30.4%) 55 ( 63.2%) - missing 12 11 23 Treatment interruption - no treatment interruption 5 ( 18.5%) 43 ( 93.5%) 48 ( 65.8%) <.001 - treatment interruption 22 ( 81.5%) 3 ( 6.5%) 25 ( 34.2%) - missing 26 11 37 Dose reduction - total dose applied 1 ( 2.4%) 32 ( 69.6%) 33 ( 37.9%) <.001 - dose reduced 40 ( 97.6%) 14 ( 30.4%) 54 ( 62.1%) - missing 12 11 23

1Fisher's exact test

58

Figure 5-3: Overall survival (starting point: resection of the primary tumor), FAS

Arm A Arm B

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 6 12 18 24 30 36 42 48 54 60 66 72

Arm A Arm B

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 6 12 18 24 30 36 42 48 54 60 66 72

Table 5-34: Estimated 1- and 2-year survival rates (S(1) and S(2), resp.), see Fig. 5-3 Therapy Group S(1) 95% CI S(2) 95% CI

A 0.89 [ 0.77; 0.95] 0.62 [ 0.48; 0.74] B 0.79 [ 0.66; 0.87] 0.52 [ 0.38; 0.64]

59

Figure 5-4: Overall survival (starting point: date of randomization), FAS

Arm A Arm B

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 6 12 18 24 30 36 42 48 54 60 66 72

Arm A Arm B

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 6 12 18 24 30 36 42 48 54 60 66 72


A 0.85 [ 0.72; 0.92] 0.55 [ 0.40; 0.67] B 0.77 [ 0.64; 0.86] 0.52 [ 0.38; 0.64]

60

Figure 5-5: Overall survival (starting point: date of randomization), all patients

Arm A Arm B

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 6 12 18 24 30 36 42 48 54 60 66 72

Arm A Arm B

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 6 12 18 24 30 36 42 48 54 60 66 72


A 0.77 [ 0.64; 0.86] 0.51 [ 0.38; 0.62] B 0.76 [ 0.64; 0.85] 0.52 [ 0.40; 0.64]

Table 5-37: Adjustment for potential confounding using the Cox Regression Model: Estimated model parameters for the treatment effect after inclusion of covariates

Included Covariate model parameter for the treatm. effect Hazard Ratio 95% CI

- -0.171 0.843 0.530 - 1.339

age -0.189 0.828 0.520 - 1.316

BMI -0.180 0.835 0.521 - 1.339

interv* -0.172 0.842 0.530 - 1.338

nodal status -0.196 0.822 0.517 - 1.307

G -0.172 0.842 0.530 - 1.337

type of surgery (ppWhipple, Whipple)**

-0.011 0.989 0.613 - 1.595

age,nodal status,type of surgery

-0.082 0.921 0.568 - 1.492

*time interval from primary surgery to randomization **compared to left resection

61

Figure 5-6: DFS (starting point: resection of primary tumor), FAS

Arm A Arm B

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 6 12 18 24 30 36 42 48 54 60 66 72

Arm A Arm B

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 6 12 18 24 30 36 42 48 54 60 66 72

Table 5-38: Estimated 1- and 2-year DFS rates (DFS(1) and DFS(2), resp.), see Fig. 5-6 Therapy Group DFS(1) 95% CI DFS(2) 95% CI

A 0.51 [ 0.37; 0.63] 0.38 [ 0.25; 0.50] B 0.49 [ 0.36; 0.61] 0.29 [ 0.18; 0.41]

62

Figure 5-7: DFS (starting point: randomization), FAS

Arm A Arm B

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 6 12 18 24 30 36 42 48 54 60 66 72

Arm A Arm B

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 6 12 18 24 30 36 42 48 54 60 66 72

Table 5-39: Estimated 1- and 2-year DFS rates (DFS(1) and DFS(2), resp.), see Fig. 5-7 Therapy Group DFS(1) 95% CI DFS(2) 95% CI

A 0.51 [ 0.37; 0.63] 0.34 [ 0.22; 0.47] B 0.44 [ 0.31; 0.56] 0.29 [ 0.18; 0.41]

63

Table 5-40: Site of relapse

A

N=41 B

N=45 Total N=86

relapse - local 12 ( 29.3%) 25 ( 55.6%) 37 ( 43.0%) - liver 17 ( 41.5%) 10 ( 22.2%) 27 ( 31.4%) - lung 5 ( 12.2%) 2 ( 4.4%) 7 ( 8.1%) - lymph node 1 ( 2.4%) 5 ( 11.1%) 6 ( 7.0%) - peritoneal carcinoma 5 ( 12.2%) 1 ( 2.2%) 6 ( 7.0%) - unknown 1 ( 2.4%) 2 ( 4.4%) 3 ( 3.5%)

Table 5-41: Site of second relapse

A

N=41 B

N=45 Total N=86

second relapse - liver 1 ( 20.0%) 2 ( 20.0%) 3 ( 20.0%) - lung 1 ( 20.0%) 1 ( 10.0%) 2 ( 13.3%) - spleen 1 ( 20.0%) 2 ( 20.0%) 3 ( 20.0%) - lymph node 2 ( 40.0%) 3 ( 30.0%) 5 ( 33.3%) - peritoneal carcinoma 0 ( 0.0%) 2 ( 20.0%) 2 ( 13.3%) - missing 36 35 71

Table 5-42: Quality of life assessment: Completion of QoL forms (EORTC QLQ-C30, QLQ-PAN26; CES-D). Number of forms completed as proportion (%) of those anticipated

Arm A N=53

Arm B N=57

Total N=110

EORTC-C30 - N 53 57 110 - Mean +/- SD 92.1 +/-15.7 82.0 +/-26.1 86.8 +/-22.2 - p25, p75 100.0, 100.0 60.0, 100.0 75.0, 100.0 - Median 100.0 100.0 100.0 - Min, Max 46.2, 100.0 0.0, 100.0 0.0, 100.0 EORTC-PAN26 - N 53 57 110 - Mean +/- SD 91.4 +/-15.8 82.2 +/-25.8 86.6 +/-22.0 - p25, p75 91.7, 100.0 60.0, 100.0 75.0, 100.0 - Median 100.0 100.0 100.0 - Min, Max 46.2, 100.0 0.0, 100.0 0.0, 100.0 CES-D - N 53 57 110 - Mean +/- SD 86.1 +/-23.0 75.3 +/-30.1 80.5 +/-27.4 - p25, p75 77.8, 100.0 55.6, 100.0 60.0, 100.0 - Median 100.0 90.0 100.0 - Min, Max 0.0, 100.0 0.0, 100.0 0.0, 100.0

64

Table 5-43: EORTC QLQ-C30, "physical functioning", group A Questionnaire Assessment

Number of patients V 2 V 5 V 9 V 10 V 17 FU 1 FU 2 FU 3 FU 4 FU 5 FU 6 FU 7 FU 8

V 2 2 60.00 V 9 2 100.00 40.00 40.00 V 10 6 79.72 54.44 48.89 61.11 V 17 13 75.90 56.67 44.10 59.49 71.79 FU 1 6 86.67 73.33 51.11 64.44 82.22 94.44 FU 2 1 80.00 60.00 60.00 66.67 80.00 66.67 80.00 FU 3 3 46.67 27.78 31.11 44.44 64.44 77.78 77.78 84.44 FU 4 2 100.00 73.33 33.33 73.33 75.83 100.00 100.00 93.33 100.00 FU 5 1 66.67 46.67 13.33 46.67 73.33 86.67 73.33 80.00 46.67 66.67 FU 6 5 80.00 69.33 60.00 76.00 81.67 78.33 93.33 92.00 95.00 91.67 93.33 FU 7 1 80.00 66.67 53.33 73.33 80.00 93.33 73.33 86.67 80.00 73.33 80.00 .FU 8 11 77.58 66.67 53.33 71.36 79.39 89.09 88.67 80.67 85.15 83.67 84.24 83.64 84.55All patients n evaluated 51 49 49 49 43 29 23 22 19 16 17 11 11 n missing 2 2 2 0 0 1 1 1 1 2 0 1 0 n total 53 51 51 49 43 30 24 23 20 18 17 12 11 mean overall 76.96 60.41 47.76 64.46 76.43 87.59 87.54 85.15 86.49 83.96 86.67 83.64 84.55

Figure 5-8: EORTC QLQ-C30, "physical functioning", group A

V 2 V 5 V 9 V 10 V 17 FU 1 FU 2 FU 3 FU 4 FU 5 FU 6 FU 7 FU 8

0

25

50

75

100

Phy

sica

l Fun

ctio

ning

Visi t

51 49 49 49 43 29 23 22 19 16 17 11 11N

65

Table 5-44: EORTC QLQ-C30, "role functioning", group A Questionnaire Assessment


V 2 2 58.33 V 9 2 33.33 0.00 0.00 V 10 6 60.00 41.67 19.44 41.67 V 17 13 52.56 42.31 20.51 47.44 57.69 FU 1 6 69.44 44.44 27.78 30.56 66.67 86.11 FU 2 1 50.00 33.33 33.33 66.67 66.67 66.67 66.67 FU 3 3 22.22 27.78 0.00 22.22 44.44 55.56 66.67 88.89 FU 4 2 41.67 41.67 0.00 33.33 41.67 50.00 100.00 91.67 100.00 FU 5 1 0.00 33.33 0.00 16.67 66.67 66.67 50.00 66.67 50.00 66.67 FU 6 5 33.33 30.00 26.67 30.00 56.67 62.50 73.33 93.33 70.83 75.00 73.33FU 7 1 66.67 50.00 50.00 33.33 66.67 100.00 66.67 83.33 66.67 66.67 66.67 .FU 8 11 50.00 43.33 38.33 60.61 72.73 81.67 83.33 71.67 81.82 80.00 75.76 77.27 77.27All patients n evaluated 51 50 49 49 43 28 23 22 19 16 17 11 11 n missing 2 1 2 0 0 2 1 1 1 2 0 1 0 n total 53 51 51 49 43 30 24 23 20 18 17 12 11 mean overall 49.67 38.67 23.47 43.20 61.63 74.40 77.54 81.06 78.95 77.08 74.51 77.27 77.27

Figure 5-9: EORTC QLQ-C30, "role functioning", group A


0

25

50

75

100

Rol

e Fu

nctio

ning

Visi t

51 50 49 49 43 28 23 22 19 16 17 11 11N

66

Table 5-45: EORTC QLQ-C30, "emotional functioning", group A Questionnaire Assessment



Figure 5-10: EORTC QLQ-C30, "emotional functioning", group A


0

25

50

75

100

Em

otio

nal F

unct

ioni

ng

Visi t

52 49 49 48 42 29 22 22 18 16 17 10 11N

67

Table 5-46: EORTC QLQ-C30, "cognitive functioning", group A Questionnaire Assessment



Figure 5-11: EORTC QLQ-C30, "cognitive functioning", group A


0

25

50

75

100

Cog

nitiv

e Fu

nctio

ning

V isi t

52 50 49 48 43 29 23 22 19 16 17 10 11N

68

Table 5-47: EORTC QLQ-C30, "social functioning", group A Questionnaire Assessment



Figure 5-12: EORTC QLQ-C30, "social functioning", group A


0

25

50

75

100

Soc

ial F

unct

ioni

ng

V isi t

52 49 49 48 43 29 23 22 19 16 17 10 10N

69

Table 5-48: EORTC QLQ-C30, "global health status", group A Questionnaire Assessment


V 2 2 50.00 V 9 2 50.00 41.67 37.50 V 10 6 55.56 50.00 50.00 58.33 V 17 13 50.64 37.82 28.21 49.36 62.82 FU 1 6 69.44 43.06 43.06 68.06 73.33 80.00 FU 2 1 33.33 . 50.00 50.00 50.00 66.67 33.33 FU 3 3 33.33 19.44 33.33 55.56 61.11 63.89 58.33 61.11 FU 4 2 62.50 58.33 33.33 70.83 66.67 79.17 54.17 66.67 75.00 FU 5 1 33.33 33.33 16.67 50.00 33.33 75.00 83.33 25.00 50.00 66.67 FU 6 5 41.67 45.00 40.00 55.00 61.67 45.83 56.67 60.00 62.50 66.67 56.67FU 7 1 33.33 50.00 33.33 33.33 . 66.67 83.33 66.67 75.00 75.00 66.67 .FU 8 11 57.58 40.00 33.33 62.12 68.94 73.48 65.00 54.17 65.91 65.83 62.50 76.85 64.39All patients n evaluated 52 49 49 48 41 28 23 22 19 16 16 9 11 n missing 1 2 2 1 2 2 1 1 1 2 1 3 0 n total 53 51 51 49 43 30 24 23 20 18 17 12 11 mean overall 52.40 41.16 36.05 57.12 64.63 69.64 61.59 56.82 65.79 66.67 60.94 76.85 64.39

Figure 5-13: EORTC QLQ-C30, "global health status", group A


0

25

50

75

100

Glo

bal h

ealth

sta

tus

/ QoL

V isi t

52 49 49 48 41 28 23 22 19 16 16 9 11N

70

Table 5-49: EORTC QLQ-C30, "fatigue", group A Questionnaire Assessment



Figure 5-14: EORTC QLQ-C30, "fatigue", group A


0

25

50

75

100

Fatig

ue

Visi t

51 50 49 49 43 29 22 21 19 16 17 11 11N

71

Table 5-50: EORTC QLQ-C30, "nausea / vomiting", group A Questionnaire Assessment



Figure 5-15: EORTC QLQ-C30, "nausea / vomiting", group A


0

25

50

75

100

Nau

sea

/ Vom

iting

Visi t

52 50 49 48 43 29 23 22 19 16 17 11 11N

72

Table 5-51: EORTC QLQ-C30, "pain", group A Questionnaire Assessment



Figure 5-16: EORTC QLQ-C30, "pain", group A "


0

25

50

75

100

Pai

n

Visi t

52 50 49 49 43 29 23 21 19 16 17 11 11N

73

Table 5-52: EORTC QLQ-C30, "dyspnea", group A Questionnaire Assessment


V 2 2 16.67 V 9 2 0.00 33.33 33.33 V 10 6 11.11 16.67 33.33 27.78 V 17 13 17.95 28.21 43.59 41.03 33.33 FU 1 6 11.11 16.67 55.56 38.89 11.11 0.00 FU 2 1 66.67 33.33 33.33 0.00 0.00 66.67 66.67 FU 3 3 22.22 22.22 44.44 33.33 33.33 22.22 22.22 22.22 FU 4 2 33.33 16.67 66.67 33.33 33.33 33.33 0.00 16.67 33.33 FU 5 1 100.00 66.67 66.67 33.33 33.33 33.33 33.33 . 66.67 33.33 FU 6 5 13.33 6.67 20.00 20.00 0.00 8.33 0.00 13.33 8.33 8.33 13.33FU 7 1 0.00 33.33 66.67 66.67 33.33 0.00 33.33 0.00 33.33 33.33 33.33 .FU 8 11 24.24 29.63 46.67 39.39 15.15 13.33 16.67 10.00 12.12 10.00 21.21 12.12 16.67All patients n evaluated 52 49 49 49 43 28 22 21 19 16 17 11 10 n missing 1 2 2 0 0 2 2 2 1 2 0 1 1 n total 53 51 51 49 43 30 24 23 20 18 17 12 11 mean overall 19.87 23.81 42.86 35.37 20.93 14.29 16.67 12.70 17.54 12.50 19.61 12.12 16.67

Figure 5-17: EORTC QLQ-C30, "dyspnea", group A


0

25

50

75

100

Dys

pnea

Visi t

52 49 49 49 43 28 22 21 19 16 17 11 10N

74

Table 5-53: EORTC QLQ-C30, "insomnia", group A Questionnaire Assessment



Figure 5-18: EORTC QLQ-C30, "insomnia", group A


0

25

50

75

100

Inso

mni

a

Visi t

52 50 49 49 43 29 23 21 19 16 17 11 11N

75

Table 5-54: EORTC QLQ-C30, "appetite loss", group A Questionnaire Assessment



Figure 5-19: EORTC QLQ-C30, "appetite loss", group A


0

25

50

75

100

App

etite

loss

Visi t

52 50 49 48 42 29 23 22 19 16 17 11 11N

76

Table 5-55: EORTC QLQ-C30, "constipation", group A Questionnaire Assessment



Figure 5-20: EORTC QLQ-C30, "constipation", group A


0

25

50

75

100

Con

stip

atio

n

Visi t

50 50 49 48 43 29 23 22 19 16 17 10 10N

77

Table 5-56: EORTC QLQ-C30, "diarrhea", group A Questionnaire Assessment



Figure 5-21: EORTC QLQ-C30, "diarrhea", group A


0

25

50

75

100

Dia

rrhea

Visi t

51 50 47 48 42 27 22 20 19 16 16 10 10N

78

Table 5-57: EORTC QLQ-C30, "financial problems", group A Questionnaire Assessment



Figure 5-22: EORTC QLQ-C30, "financial problems", group A


0

25

50

75

100

Fina

ncia

l Pro

blem

s

Visi t

52 50 49 48 43 28 22 21 18 16 17 10 11N

79

Table 5-58: EORTC QLQ-C30, "physical functioning", group B Questionnaire Assessment

Number of patients V 1 V 8 FU 1 FU 2 FU 3 FU 4 FU 5 FU 6 FU 7 FU 8

V 1 11 64.24 V 8 9 68.15 67.96 FU 1 9 78.52 81.48 75.83 FU 2 6 73.33 74.44 84.00 75.56 FU 3 1 . 80.00 73.33 73.33 73.33 FU 4 3 65.56 63.33 86.67 60.00 53.33 60.00 FU 5 2 66.67 86.67 83.33 93.33 86.67 76.67 80.00 FU 6 3 68.89 51.11 51.11 73.33 93.33 76.67 80.00 66.67 FU 7 2 60.00 60.00 70.00 63.33 83.33 86.67 86.67 86.67 83.33 FU 8 10 74.44 74.67 82.00 82.00 85.00 82.67 82.22 80.67 77.59 84.00 All patients n evaluated 54 44 33 25 19 19 14 15 11 10 n missing 2 1 3 2 2 1 3 0 1 0 n total 56 45 36 27 21 20 17 15 12 10 mean overall 70.25 72.54 77.37 77.07 84.04 78.25 82.38 78.67 78.64 84.00

Figure 5-23: EORTC QLQ-C30, "physical functioning", group B

V 1 V 8 FU 1 FU 2 FU 3 FU 4 FU 5 FU 6 FU 7 FU 8

0

25

50

75

100

Phy

sica

l Fun

ctio

ning

V isi t

54 44 33 25 19 19 14 15 11 10N

80

Table 5-59: EORTC QLQ-C30, "role functioning", group B Questionnaire Assessment



Figure 5-24: EORTC QLQ-C30, "role functioning", group B


0

25

50

75

100

Rol

e Fu

nctio

ning

V isi t

50 43 33 25 19 19 14 15 11 10N

81

Table 5-60: EORTC QLQ-C30, "emotional functioning", group B Questionnaire Assessment



Figure 5-25: EORTC QLQ-C30, "emotional functioning", group B


0

25

50

75

100

Em

otio

nal F

unct

ioni

ng

V isi t

54 45 33 25 19 19 14 15 11 10N

82

Table 5-61: EORTC QLQ-C30, "cognitive functioning", group B Questionnaire Assessment



Figure 5-26: EORTC QLQ-C30, "cognitive functioning", group B


0

25

50

75

100

Cog

nitiv

e Fu

nctio

ning

V isi t

54 44 33 25 19 19 14 15 11 10N

83

Table 5-62: EORTC QLQ-C30, "social functioning", group B Questionnaire Assessment



Figure 5-27: EORTC QLQ-C30, "social functioning", group B


0

25

50

75

100

Soc

ial F

unct

ioni

ng

V isi t

52 45 33 25 19 19 14 15 11 10N

84

Table 5-63: EORTC QLQ-C30, "global health status", group B Questionnaire Assessment



Figure 5-28: EORTC QLQ-C30, "global health status", group B


0

25

50

75

100

Glo

bal h

ealth

sta

tus

/ QoL

V isi t

53 42 31 23 18 19 14 15 11 10N

85

Table 5-64: EORTC QLQ-C30, "fatigue", group B Questionnaire Assessment



Figure 5-29: EORTC QLQ-C30, "fatigue", group B


0

25

50

75

100

Fatig

ue

Visi t

54 45 33 25 19 19 14 15 11 10N

86

Table 5-65: EORTC QLQ-C30, "nausea / vomiting", group B Questionnaire Assessment



Figure 5-30: EORTC QLQ-C30, "nausea / vomiting", group B


0

20

40

60

80

100

Nau

sea

/ Vom

iting

Visi t

54 45 33 25 19 19 14 15 11 10N

87

Table 5-66: EORTC QLQ-C30, "pain", group B Questionnaire Assessment



Figure 5-31: EORTC QLQ-C30, "pain", group B


0

25

50

75

100

Pai

n

Visi t

53 45 33 25 19 19 14 15 11 10N

88

Table 5-67: EORTC QLQ-C30, "dyspnea", group B Questionnaire Assessment



Figure 5-32: EORTC QLQ-C30, "dyspnea", group B


0

25

50

75

100

Dys

pnea

Visi t

50 45 33 25 19 19 14 14 11 10N

89

Table 5-68: EORTC QLQ-C30, "insomnia", group B Questionnaire Assessment



Figure 5-33: EORTC QLQ-C30, "insomnia", group B


0

25

50

75

100

Inso

mni

a

Visi t

53 43 33 24 19 19 14 14 11 10N

90

Table 5-69: EORTC QLQ-C30, "appetite loss", group B Questionnaire Assessment



Figure 5-34: EORTC QLQ-C30, "appetite loss", group B


0

25

50

75

100

App

etite

loss

Visi t

54 45 32 24 19 19 13 15 11 10N

91

Table 5-70: EORTC QLQ-C30, "constipation", group B Questionnaire Assessment



Figure 5-35: EORTC QLQ-C30, "constipation", group B


0

25

50

75

100

Con

stip

atio

n

Visi t

54 44 33 24 19 19 14 15 11 10N

92

Table 5-71: EORTC QLQ-C30, "diarrhea", group B Questionnaire Assessment



Figure 5-36: EORTC QLQ-C30, "diarrhea", group B


0

25

50

75

100

Dia

rrhea

Visi t

52 43 33 25 18 19 14 15 11 9N

93

Table 5-72: EORTC QLQ-C30, "financial problems", group B Questionnaire Assessment



Figure 5-37: EORTC QLQ-C30, "financial problems", group B


0

25

50

75

100

Fina

ncia

l Pro

blem

s

Visi t

51 44 33 24 19 19 14 15 11 10N

94

Table 5-73: EORTC QLQ-C30, summary statistics for the AUC

group A

N=53 group B

N=57 Total

N=110 p-value1

Pysical functioning - N 50 36 86 0.633 - Mean +/- SD 72.3 +/-18.4 74.4 +/-17.8 73.1 +/-18.1 - p25, p75 59.7, 88.1 65.1, 87.2 62.4, 88.1 - Median 73.6 77.0 76.1 - Min, Max 31.3, 98.1 13.3, 98.6 13.3, 98.6 Role functioning - N 50 35 85 0.008 - Mean +/- SD 55.6 +/-22.6 69.5 +/-22.5 61.4 +/-23.5 - p25, p75 37.3, 73.6 54.8, 86.9 45.0, 83.2 - Median 55.5 69.3 61.6 - Min, Max 9.0, 97.0 13.4, 100.0 9.0, 100.0 Emotional functioning - N 50 36 86 1.000 - Mean +/- SD 68.3 +/-17.3 67.2 +/-22.3 67.8 +/-19.5 - p25, p75 59.6, 76.9 57.2, 81.7 59.3, 79.5 - Median 68.2 67.1 67.9 - Min, Max 19.9, 100.0 13.4, 100.0 13.4, 100.0 Cognitive functioning - N 50 36 86 0.902 - Mean +/- SD 78.2 +/-17.2 78.0 +/-16.8 78.1 +/-16.9 - p25, p75 66.5, 95.1 69.4, 91.7 67.1, 91.8 - Median 79.5 81.2 80.5 - Min, Max 39.3, 100.0 47.1, 100.0 39.3, 100.0 Social functioning - N 50 35 85 0.061 - Mean +/- SD 64.5 +/-24.0 74.5 +/-19.4 68.6 +/-22.7 - p25, p75 49.5, 84.1 63.6, 89.7 52.9, 86.5 - Median 66.0 76.6 70.7 - Min, Max 11.8, 100.0 30.1, 100.0 11.8, 100.0 Global Health Status - N 50 36 86 0.024 - Mean +/- SD 55.8 +/-16.4 62.8 +/-14.6 58.7 +/-16.0 - p25, p75 46.1, 65.8 56.4, 70.2 50.5, 69.3 - Median 57.2 64.1 59.4 - Min, Max 22.0, 100.0 16.7, 95.4 16.7, 100.0 Fatigue - N 50 36 86 0.360 - Mean +/- SD 43.8 +/-20.0 41.8 +/-19.9 43.0 +/-19.8 - p25, p75 32.9, 58.0 31.4, 53.2 31.9, 54.7 - Median 43.9 39.3 40.8 - Min, Max 3.9, 87.8 0.0, 87.7 0.0, 87.8 Nausea / Vomiting - N 50 36 86 0.001 - Mean +/- SD 15.9 +/-15.1 8.2 +/-13.3 12.7 +/-14.8 - p25, p75 3.6, 25.3 0.0, 8.8 1.6, 18.3 - Median 12.0 3.8 7.2 - Min, Max 0.0, 58.8 0.0, 66.7 0.0, 66.7

95

group A

N=53 group B

N=57 Total

N=110 p-value1

Pain - N 50 36 86 0.351 - Mean +/- SD 25.9 +/-20.8 22.8 +/-21.9 24.6 +/-21.2 - p25, p75 8.3, 38.3 4.3, 32.0 6.3, 37.6 - Median 21.4 17.4 20.0 - Min, Max 0.0, 84.9 0.0, 94.9 0.0, 94.9 Dyspnea - N 50 35 85 0.053 - Mean +/- SD 24.3 +/-19.5 18.2 +/-23.2 21.8 +/-21.2 - p25, p75 8.6, 41.0 0.0, 24.3 3.6, 33.3 - Median 18.6 10.0 16.9 - Min, Max 0.0, 70.1 0.0, 93.4 0.0, 93.4 Insomnia - N 50 36 86 0.913 - Mean +/- SD 27.4 +/-23.6 28.1 +/-26.1 27.7 +/-24.5 - p25, p75 8.7, 42.5 4.7, 46.0 7.8, 44.3 - Median 19.7 16.7 19.0 - Min, Max 0.0, 82.0 0.0, 83.3 0.0, 83.3 Appetite loss - N 50 36 86 0.004 - Mean +/- SD 29.8 +/-21.5 18.2 +/-22.1 25.0 +/-22.4 - p25, p75 10.8, 41.0 0.0, 31.0 5.8, 39.5 - Median 29.2 8.5 17.5 - Min, Max 0.0, 90.5 0.0, 71.3 0.0, 90.5 Constipation - N 50 36 86 0.055 - Mean +/- SD 13.6 +/-18.1 9.2 +/-15.1 11.8 +/-17.0 - p25, p75 0.0, 22.1 0.0, 15.3 0.0, 16.7 - Median 5.8 0.0 2.0 - Min, Max 0.0, 64.9 0.0, 50.0 0.0, 64.9 Diarrhea - N 50 35 85 0.886 - Mean +/- SD 25.7 +/-21.2 28.2 +/-25.7 26.7 +/-23.1 - p25, p75 11.5, 37.2 4.6, 49.7 10.2, 41.0 - Median 23.4 22.4 23.2 - Min, Max 0.0, 89.0 0.0, 100.0 0.0, 100.0 Financial Problems - N 50 35 85 0.231 - Mean +/- SD 29.1 +/-30.9 20.0 +/-24.5 25.3 +/-28.6 - p25, p75 0.0, 41.8 0.0, 33.3 0.0, 39.5 - Median 24.2 15.3 16.7 - Min, Max 0.0, 100.0 0.0, 94.8 0.0, 100.0 1 Wilcoxon rank sum test

96

Table 5-74: EORTC QLQ-PAN26, "pancreatic pain", group A Questionnaire Assessment



Figure 5-38: EORTC QLQ-PAN26, "pancreatic pain", group A


0

25

50

75

100

Pan

crea

tic p

ain

V isi t

52 50 49 48 43 29 23 21 18 16 15 11 10N

97

Table 5-75: EORTC QLQ-PAN26, "digestive symptoms", group A Questionnaire Assessment



Figure 5-39: EORTC QLQ-PAN26, "digestive symptoms", group A


0

25

50

75

100

Dig

estiv

e sy

mpt

oms

V isi t

51 50 49 48 43 29 23 21 18 16 15 11 10N

98

Table 5-76: EORTC QLQ-PAN26, "altered bowel habit", group A Questionnaire Assessment



Figure 5-40: EORTC QLQ-PAN26, "altered bowel habit", group A


0

25

50

75

100

Alte

red

bow

el h

abit

V isi t

51 50 49 48 42 28 22 20 17 16 15 11 10N

99

Table 5-77: EORTC QLQ-PAN26, "hepatic", group A Questionnaire Assessment



Figure 5-41: EORTC QLQ-PAN26, "hepatic", group A


0

25

50

75

100

Hep

atic

V isi t

51 50 49 48 43 29 23 21 18 16 15 11 10N

100

Table 5-78: EORTC QLQ-PAN26, "body image", group A Questionnaire Assessment



Figure 5-42: EORTC QLQ-PAN26, "body image", group A


0

25

50

75

100

Bod

y im

age

V isi t

51 49 49 48 42 29 23 22 19 16 17 11 11N

101

Table 5-79: EORTC QLQ-PAN26, "satisfaction with health care", group A Questionnaire Assessment


V 2 2 83.33 V 9 2 100.00 66.67 100.00 V 10 6 86.67 100.00 100.00 100.00 V 17 13 97.44 96.15 93.59 96.15 96.15 FU 1 6 62.50 83.33 93.33 96.67 100.00 80.56 FU 2 1 100.00 100.00 100.00 100.00 100.00 . 100.00 FU 3 3 83.33 83.33 83.33 83.33 83.33 88.89 44.44 44.44 FU 4 2 50.00 100.00 83.33 91.67 66.67 41.67 66.67 33.33 66.67 FU 5 1 100.00 83.33 100.00 100.00 100.00 33.33 100.00 83.33 100.00 100.00 FU 6 5 66.67 83.33 96.67 86.67 86.67 83.33 93.33 100.00 100.00 100.00 100.00FU 7 1 100.00 100.00 100.00 100.00 100.00 100.00 100.00 100.00 100.00 100.00 100.00 .FU 8 11 87.88 90.00 90.00 87.88 84.85 87.88 90.00 90.00 92.42 98.33 96.30 86.67 87.88All patients n evaluated 49 47 48 46 43 28 23 21 17 15 14 10 11 n missing 4 4 3 3 0 2 1 2 3 3 3 2 0 n total 53 51 51 49 43 30 24 23 20 18 17 12 11 mean overall 85.03 90.78 93.75 92.75 90.70 80.95 84.06 83.33 93.14 98.89 97.62 86.67 87.88

Figure 5-43: EORTC QLQ-PAN26, "satisfaction with health care", group A


0

25

50

75

100

Sat

isfa

ctoo

n w

ith h

ealth

car

e

Visi t

49 47 48 46 43 28 23 21 17 15 14 10 11N

102

Table 5-80: EORTC QLQ-PAN26, "sexuality", group A Questionnaire Assessment


V 2 2 83.33 V 9 2 66.67 50.00 0.00 V 10 6 46.67 40.00 23.33 37.50 V 17 13 48.61 45.00 41.67 48.33 66.67 FU 1 6 50.00 37.50 62.50 45.83 66.67 83.33 FU 2 1 . 33.33 33.33 33.33 66.67 . 66.67 FU 3 3 55.56 44.44 50.00 33.33 83.33 83.33 50.00 83.33 FU 4 2 66.67 50.00 . 66.67 66.67 83.33 33.33 50.00 50.00 FU 5 1 50.00 0.00 33.33 33.33 33.33 100.00 100.00 100.00 100.00 100.00 FU 6 5 33.33 25.00 33.33 56.67 56.67 66.67 43.33 40.00 25.00 38.89 36.67 FU 7 1 33.33 33.33 33.33 33.33 33.33 33.33 33.33 33.33 33.33 33.33 33.33 .FU 8 11 42.42 30.00 18.52 42.59 39.39 46.97 41.67 51.67 43.94 58.33 48.33 46.67 58.33All patients n evaluated 46 42 40 38 36 24 21 20 18 15 16 10 10 n missing 7 9 11 11 7 6 3 3 2 3 1 2 1 n total 53 51 51 49 43 30 24 23 20 18 17 12 11 mean overall 47.83 36.90 32.92 45.18 56.02 62.50 46.03 53.33 42.59 55.56 43.75 46.67 58.33

Figure 5-44: EORTC QLQ-PAN26, "sexuality", group A


0

25

50

75

100

Sex

ualit

y

Visi t

46 42 40 38 36 24 21 20 18 15 16 10 10N

103

Table 5-81: EORTC QLQ-PAN26, "pancreatic pain", group B Questionnaire Assessment



Figure 5-45: EORTC QLQ-PAN26, "pancreatic pain", group B


0

25

50

75

100

Pan

crea

tic p

ain

V isi t

51 45 34 24 19 19 14 15 10 9N

104

Table 5-82: EORTC QLQ-PAN26, "digestive symptoms", group B Questionnaire Assessment



Figure 5-46: EORTC QLQ-PAN26, "digestive symptoms", group B


0

25

50

75

100

Dig

estiv

e sy

mpt

oms

V isi t

50 44 34 24 19 19 14 15 10 9N

105

Table 5-83: EORTC QLQ-PAN26, "altered bowel habit", group B Questionnaire Assessment



Figure 5-47: EORTC QLQ-PAN26, "altered bowel habit", group B


0

25

50

75

100

Alte

red

bow

el h

abit

V isi t

52 45 34 24 19 19 13 15 10 9N

106

Table 5-84: EORTC QLQ-PAN26, "hepatic", group B Questionnaire Assessment



Figure 5-48: EORTC QLQ-PAN26, "hepatic", group B


0

20

40

60

80

100

Hep

atic

V isi t

50 45 34 24 19 19 14 15 10 9N

107

Table 5-85: EORTC QLQ-PAN26, "body image", group B Questionnaire Assessment



Figure 5-49: EORTC QLQ-PAN26, "body image", group B


0

25

50

75

100

Bod

y im

age

V isi t

53 45 34 25 19 19 15 15 11 10N

108

Table 5-86: EORTC QLQ-PAN26, "satisfaction with health care", group B Questionnaire Assessment



Figure 5-50: EORTC QLQ-PAN26, "satisfaction with health care", group B


0

25

50

75

100

Sat

isfa

ctoo

n w

ith h

ealth

car

e

Visi t

51 44 32 20 16 16 14 13 10 8N

109

Table 5-87: EORTC QLQ-PAN26, "sexuality", group B Questionnaire Assessment



Figure 5-51: EORTC QLQ-PAN26, "sexuality", group B


0

25

50

75

100

Sex

ualit

y

Visi t

45 38 25 20 17 16 13 11 9 7N

110

Table 5-88: EORTC QLQ-PAN26, summary statistics for the AUC

Arm A N=53

Arm B N=57


Pancreatic pain - N 50 37 87 0.551 - Mean +/- SD 25.3 +/-18.9 26.3 +/-16.6 25.7 +/-17.9 - p25, p75 8.5, 38.2 15.3, 35.6 12.1, 36.9 - Median 21.4 20.6 20.8 - Min, Max 0.0, 68.1 0.0, 66.7 0.0, 68.1 Digestive symptoms - N 50 36 86 0.272 - Mean +/- SD 40.9 +/-22.4 35.0 +/-21.6 38.5 +/-22.1 - p25, p75 22.3, 55.1 22.5, 48.1 22.3, 53.7 - Median 39.6 33.3 36.5 - Min, Max 3.3, 92.9 0.0, 88.1 0.0, 92.9 Altered bowel habit - N 50 37 87 0.415 - Mean +/- SD 36.5 +/-21.3 40.4 +/-25.6 38.2 +/-23.2 - p25, p75 19.5, 49.0 17.5, 52.4 17.7, 51.7 - Median 36.9 44.2 39.5 - Min, Max 0.0, 76.5 0.0, 100.0 0.0, 100.0 Hepatic - N 50 36 86 0.627 - Mean +/- SD 10.2 +/-13.5 8.6 +/-11.0 9.6 +/-12.4 - p25, p75 0.6, 12.6 0.0, 15.5 0.0, 14.3 - Median 4.9 4.2 4.7 - Min, Max 0.0, 58.3 0.0, 46.8 0.0, 58.3 Body image - N 50 37 87 0.218 - Mean +/- SD 29.9 +/-19.9 27.2 +/-25.7 28.8 +/-22.5 - p25, p75 17.0, 38.4 8.3, 35.0 9.4, 38.2 - Median 27.7 21.0 26.8 - Min, Max 0.0, 77.0 0.0, 91.7 0.0, 91.7 Satisfaction with health care - N 50 37 87 0.062 - Mean +/- SD 90.7 +/-13.9 81.4 +/-20.1 86.8 +/-17.3 - p25, p75 85.1, 100.0 65.1, 100.0 80.2, 100.0 - Median 97.3 90.5 94.2 - Min, Max 40.4, 100.0 38.6, 100.0 38.6, 100.0 Sexuality - N 43 32 75 0.107 - Mean +/- SD 48.5 +/-22.8 57.7 +/-23.0 52.4 +/-23.2 - p25, p75 33.3, 64.9 41.0, 70.7 36.4, 68.5 - Median 50.1 56.7 52.6 - Min, Max 0.0, 96.0 9.5, 100.0 0.0, 100.0

1Wilcoxon rank sum test

111

Table 5-89: CES-D, "total score", group A Questionnaire Assessment


V 2 2 20.00 V 9 2 20.00 24.00 21.50 V 10 6 12.67 12.25 17.33 10.40 V 17 13 15.54 20.00 21.83 13.27 11.08 FU 1 6 12.20 9.75 15.00 11.00 5.67 7.00 FU 2 1 . 10.00 15.00 5.00 3.00 5.00 6.00 FU 3 3 24.33 28.67 28.00 14.67 17.00 13.33 16.67 13.00 FU 4 2 12.00 18.00 . 14.50 12.00 8.00 10.00 8.00 10.00 FU 5 1 26.00 29.00 26.00 17.00 23.00 2.00 5.00 9.00 8.00 5.00 FU 6 5 18.00 22.60 18.00 22.75 11.20 2.00 11.20 8.67 5.75 8.50 6.33FU 7 1 14.00 . 28.00 19.00 19.00 9.00 15.00 14.00 20.00 23.00 19.00 .FU 8 11 15.30 17.13 25.40 14.71 12.45 7.44 9.60 12.80 9.09 10.22 13.40 10.70 13.70All patients n evaluated 46 41 46 39 37 23 22 19 18 15 14 10 10 n missing 7 10 5 10 6 7 2 4 2 3 3 2 1 n total 53 51 51 49 43 30 24 23 20 18 17 12 11 mean overall 15.85 18.66 21.33 14.10 11.73 7.65 10.82 11.79 8.94 10.27 12.29 10.70 13.70

Figure 5-52: CES-D, "total score", group A


0

10

20

30

40

50

scor

e

Visi t

46 41 46 39 37 23 22 19 18 15 14 10 10N

112

Table 5-90: CES-D, "total score", group B Questionnaire Assessment


V 1 11 19.44 V 8 9 12.43 17.43 FU 1 9 16.38 15.63 16.25 FU 2 6 7.75 9.40 7.60 15.20 FU 3 1 . 12.00 4.00 4.00 21.00 FU 4 3 11.00 14.00 11.00 3.00 14.00 23.67 FU 5 2 12.00 16.00 10.00 8.50 9.50 8.50 13.00 FU 6 3 18.33 27.67 26.00 18.00 . 19.00 24.00 25.67 FU 7 2 11.00 9.50 7.50 5.00 7.00 7.00 11.50 8.50 7.00 FU 8 10 10.83 14.90 11.57 11.13 11.71 12.50 12.71 14.75 13.67 10.00 All patients n evaluated 43 41 29 20 12 19 13 13 11 8 n missing 13 4 7 7 9 1 4 2 1 2 n total 56 45 36 27 21 20 17 15 12 10 mean overall 14.23 15.39 12.48 10.85 11.92 13.95 14.31 16.31 12.45 10.00

Figure 5-53: CES-D, "total score", group B


0

10

20

30

40

50

scor

e

Visi t

43 41 29 20 12 19 13 13 11 8N

113

Table 5-91: CES-D, summary statistics for the AUC

group A

N=53 group B

N=57 Total

N=110 p-value1 Total score - N 49 32 81 0.935 - Mean +/- SD 13.6 +/-7.4 13.8 +/-7.6 13.7 +/-7.5 - p25, p75 8.2, 18.2 8.1, 17.7 8.2, 18.2 - Median 12.2 13.2 13.1 - Min, Max 0.4, 35.0 1.8, 33.8 0.4, 35.0 1Wilcoxon rank sum test

Table 5-92: EORTC QLQ-C30, "physical functioning", group A (adj.) V 2 V 5 V 9 V 10 V 17 FU 1 FU 2 FU 3 FU 4 FU 5 FU 6 FU 7 FU 8

All patients n evaluated 51 51 51 53 52 51 46 46 46 44 49 45 47 n missing 2 2 2 0 1 2 7 7 7 9 4 8 6 n total 53 53 53 53 53 53 53 53 53 53 53 53 53 mean overall 76.96 58.04 45.88 59.59 63.21 49.80 43.77 40.72 35.72 30.53 30.07 20.44 19.79

Figure 5-54: EORTC QLQ-C30, "physical functioning", group A (adj.)


0

25

50

75

100

Phy

sica

l Fun

ctio

ning

Visi t

51 51 51 53 52 51 46 46 46 44 49 45 47N

114

Table 5-93: EORTC QLQ-C30, "role functioning", group A (adj.) V 2 V 5 V 9 V 10 V 17 FU 1 FU 2 FU 3 FU 4 FU 5 FU 6 FU 7 FU 8


Figure 5-55: EORTC QLQ-C30, "role functioning", group A (adj.)


0

25

50

75

100

Rol

e Fu

nctio

ning

Visi t

51 52 51 53 52 50 46 46 46 44 49 45 47N

Table 5-94: EORTC QLQ-C30, "emotional functioning", group A (adj.) V 2 V 5 V 9 V 10 V 17 FU 1 FU 2 FU 3 FU 4 FU 5 FU 6 FU 7 FU 8


Figure 5-56: EORTC QLQ-C30, "emotional functioning", group A (adj.)


0

25

50

75

100

Em

otio

nal F

unct

ioni

ng

Visi t

52 51 51 52 51 51 45 46 45 44 49 44 47N

115

Table 5-95: EORTC QLQ-C30, "cognitive functioning", group A (adj.) V 2 V 5 V 9 V 10 V 17 FU 1 FU 2 FU 3 FU 4 FU 5 FU 6 FU 7 FU 8


Figure 5-57: EORTC QLQ-C30, "cognitive functioning", group A (adj.)


0

25

50

75

100

Cog

nitiv

e Fu

nctio

ning

Visi t

52 52 51 52 52 51 46 46 46 44 49 44 47N

Table 5-96: EORTC QLQ-C30, "social functioning", group A (adj.) V 2 V 5 V 9 V 10 V 17 FU 1 FU 2 FU 3 FU 4 FU 5 FU 6 FU 7 FU 8


Figure 5-58: EORTC QLQ-C30, "social functioning", group A (adj.)


0

25

50

75

100

Soc

ial F

unct

ioni

ng

Visi t

52 51 51 52 52 51 46 46 46 44 49 44 46N

116

Table 5-97: EORTC QLQ-C30, "global health status", group A (adj.) V 2 V 5 V 9 V 10 V 17 FU 1 FU 2 FU 3 FU 4 FU 5 FU 6 FU 7 FU 8


Figure 5-59: EORTC QLQ-C30, "global health status", group A (adj.)


0

25

50

75

100

Glo

bal h

ealth

sta

tus

/ QoL

Visi t

52 51 51 52 50 50 46 46 46 44 48 43 47N

Table 5-98: EORTC QLQ-C30, "fatigue", group A (adj.) V 2 V 5 V 9 V 10 V 17 FU 1 FU 2 FU 3 FU 4 FU 5 FU 6 FU 7 FU 8


Figure 5-60: EORTC QLQ-C30, "fatigue ", group A (adj.)


0

25

50

75

100

Fatig

ue

Visi t

51 52 51 53 52 51 45 45 46 44 49 45 47N

117

Table 5-99: EORTC QLQ-C30, "nausea / vomiting", group A (adj.) V 2 V 5 V 9 V 10 V 17 FU 1 FU 2 FU 3 FU 4 FU 5 FU 6 FU 7 FU 8


Figure 5-61: EORTC QLQ-C30, "nausea / vomiting", group A (adj.)


0

25

50

75

100

Nau

sea

/ Vom

iting

Visi t

52 52 51 52 52 51 46 46 46 44 49 45 47N

Table 5-100: EORTC QLQ-C30, "pain", group A (adj.) V 2 V 5 V 9 V 10 V 17 FU 1 FU 2 FU 3 FU 4 FU 5 FU 6 FU 7 FU 8


Figure 5-62: EORTC QLQ-C30, "pain", group A (adj.)


0

25

50

75

100

Pai

n

Visi t

52 52 51 53 52 51 46 45 46 44 49 45 47N

118

Table 5-101: EORTC QLQ-C30, "dyspnea", group A (adj.) V 2 V 5 V 9 V 10 V 17 FU 1 FU 2 FU 3 FU 4 FU 5 FU 6 FU 7 FU 8


Figure 5-63: EORTC QLQ-C30, "dyspnea", group A (adj.)


0

25

50

75

100

Dys

pnea

Visi t

52 51 51 53 52 50 45 45 46 44 49 45 46N

Table 5-102: EORTC QLQ-C30, "insomnia", group A (adj.) V 2 V 5 V 9 V 10 V 17 FU 1 FU 2 FU 3 FU 4 FU 5 FU 6 FU 7 FU 8


Figure 5-64: EORTC QLQ-C30, "insomnia", group A (adj.)


0

25

50

75

100

Inso

mni

a

Visi t

52 52 51 53 52 51 46 45 46 44 49 45 47N

119

Table 5-103: EORTC QLQ-C30, "appetite loss", group A (adj.) V 2 V 5 V 9 V 10 V 17 FU 1 FU 2 FU 3 FU 4 FU 5 FU 6 FU 7 FU 8


Figure 5-65: EORTC QLQ-C30, "appetite loss", group A (adj.)


0

25

50

75

100

App

etite

loss

Visi t

52 52 51 52 51 51 46 46 46 44 49 45 47N

Table 5-104: EORTC QLQ-C30, "constipation", group A (adj.) V 2 V 5 V 9 V 10 V 17 FU 1 FU 2 FU 3 FU 4 FU 5 FU 6 FU 7 FU 8


Figure 5-66: EORTC QLQ-C30, "constipation", group A (adj.)


0

25

50

75

100

Con

stip

atio

n

Visi t

50 52 51 52 52 51 46 46 46 44 49 44 46N

120

Table 5-105: EORTC QLQ-C30, "diarrhea", group A (adj.) V 2 V 5 V 9 V 10 V 17 FU 1 FU 2 FU 3 FU 4 FU 5 FU 6 FU 7 FU 8


Figure 5-67: EORTC QLQ-C30, "diarrhea", group A (adj.)


0

25

50

75

100

Dia

rrhea

Visi t

51 52 49 52 51 49 45 44 46 44 48 44 46N

Table 5-106: EORTC QLQ-C30, "financial problems", group A (adj.) V 2 V 5 V 9 V 10 V 17 FU 1 FU 2 FU 3 FU 4 FU 5 FU 6 FU 7 FU 8


Figure 5-68: EORTC QLQ-C30, "financial problems", group A (adj.)


0

25

50

75

100

Fina

ncia

l Pro

blem

s

Visi t

52 52 51 52 52 50 45 45 45 44 49 44 47N

121

Table 5-107: EORTC QLQ-C30, "physical functioning", group B (adj.) V 1 V 8 FU 1 FU 2 FU 3 FU 4 FU 5 FU 6 FU 7 FU 8

All patients n evaluated 55 55 51 45 42 47 46 48 48 50 n missing 2 2 6 12 15 10 11 9 9 7 n total 57 57 57 57 57 57 57 57 57 57 mean overall 68.97 58.03 50.07 42.81 38.02 31.63 25.07 24.58 18.02 16.80

Figure 5-69: EORTC QLQ-C30, "physical functioning", group B (adj.)


0

25

50

75

100

Phy

sica

l Fun

ctio

ning

Visi t

55 55 51 45 42 47 46 48 48 50N

Table 5-108: EORTC QLQ-C30, "role functioning", group B (adj.) V 1 V 8 FU 1 FU 2 FU 3 FU 4 FU 5 FU 6 FU 7 FU 8


Figure 5-70: EORTC QLQ-C30, "role functioning", group B (adj.)


0

25

50

75

100

Rol

e Fu

nctio

ning

Visi t

51 54 51 45 42 47 46 48 48 50N

122

Table 5-109: EORTC QLQ-C30, "emotional functioning", group B (adj.) V 1 V 8 FU 1 FU 2 FU 3 FU 4 FU 5 FU 6 FU 7 FU 8


Figure 5-71: EORTC QLQ-C30, "emotional functioning", group B (adj.)


0

25

50

75

100

Em

otio

nal F

unct

ioni

ng

Visi t

55 56 51 45 42 47 46 48 48 50N

Table 5-110: EORTC QLQ-C30, "cognitive functioning", group B (adj.) V 1 V 8 FU 1 FU 2 FU 3 FU 4 FU 5 FU 6 FU 7 FU 8


Figure 5-72: EORTC QLQ-C30, "cognitive functioning", group B (adj.)


0

25

50

75

100

Cog

nitiv

e Fu

nctio

ning

Visi t

55 55 51 45 42 47 46 48 48 50N

123

Table 5-111: EORTC QLQ-C30, "social functioning", group B (adj.) V 1 V 8 FU 1 FU 2 FU 3 FU 4 FU 5 FU 6 FU 7 FU 8


Figure 5-73: EORTC QLQ-C30, "social functioning", group B (adj.)


0

25

50

75

100

Soc

ial F

unct

ioni

ng

Visi t

53 56 51 45 42 47 46 48 48 50N

Table 5-112: EORTC QLQ-C30, "global health status", group B (adj.) V 1 V 8 FU 1 FU 2 FU 3 FU 4 FU 5 FU 6 FU 7 FU 8


Figure 5-74: EORTC QLQ-C30, "global health status", group B (adj.)


0

25

50

75

100

Glo

bal h

ealth

sta

tus

/ QoL

Visi t

54 53 49 43 41 47 46 48 48 50N

124

Table 5-113: EORTC QLQ-C30, "fatigue", group B (adj.) V 1 V 8 FU 1 FU 2 FU 3 FU 4 FU 5 FU 6 FU 7 FU 8


Figure 5-75: EORTC QLQ-C30, " fatigue", group B (adj.)


0

25

50

75

100

Fatig

ue

Visi t

55 56 51 45 42 47 46 48 48 50N

Table 5-114: EORTC QLQ-C30, "nausea / vomiting", group B (adj.) V 1 V 8 FU 1 FU 2 FU 3 FU 4 FU 5 FU 6 FU 7 FU 8


Figure 5-76: EORTC QLQ-C30, "nausea / vomiting", group B (adj.)


0

25

50

75

100

Nau

sea

/ Vom

iting

Visi t

55 56 51 45 42 47 46 48 48 50N

125

Table 5-115: EORTC QLQ-C30, "pain", group B (adj.) V 1 V 8 FU 1 FU 2 FU 3 FU 4 FU 5 FU 6 FU 7 FU 8


Figure 5-77: EORTC QLQ-C30, "pain", group B (adj.)


0

25

50

75

100

Pai

n

Visi t

54 56 51 45 42 47 46 48 48 50N

Table 5-116: EORTC QLQ-C30, "dyspnea", group B (adj.) V 1 V 8 FU 1 FU 2 FU 3 FU 4 FU 5 FU 6 FU 7 FU 8


Figure 5-78: EORTC QLQ-C30, "dyspnea", group B (adj.)


0

25

50

75

100

Dys

pnea

Visi t

51 56 51 45 42 47 46 47 48 50N

126

Table 5-117: EORTC QLQ-C30, "insomnia", group B (adj.) V 1 V 8 FU 1 FU 2 FU 3 FU 4 FU 5 FU 6 FU 7 FU 8


Figure 5-79: EORTC QLQ-C30, "insomnia", group B (adj.)


0

25

50

75

100

Inso

mni

a

Visi t

54 54 51 44 42 47 46 47 48 50N

Table 5-118: EORTC QLQ-C30, "appetite loss", group B (adj.) V 1 V 8 FU 1 FU 2 FU 3 FU 4 FU 5 FU 6 FU 7 FU 8


Figure 5-80: EORTC QLQ-C30, "appetite loss", group B (adj.)


0

25

50

75

100

App

etite

loss

Visi t

55 56 50 44 42 47 45 48 48 50N

127

Table 5-119: EORTC QLQ-C30, "constipation", group B (adj.) V 1 V 8 FU 1 FU 2 FU 3 FU 4 FU 5 FU 6 FU 7 FU 8


Figure 5-81: EORTC QLQ-C30, "constipation", group B (adj.)


0

25

50

75

100

Con

stip

atio

n

Visi t

55 55 51 44 42 47 46 48 48 50N

Table 5-120: EORTC QLQ-C30, "diarrhea", group B (adj.) V 1 V 8 FU 1 FU 2 FU 3 FU 4 FU 5 FU 6 FU 7 FU 8


Figure 5-82: EORTC QLQ-C30, "diarrhea", group B (adj.)


0

25

50

75

100

Dia

rrhea

Visi t

53 54 51 45 41 47 46 48 48 49N

128

Table 5-121: EORTC QLQ-C30, "financial problems", group B (adj.) V 1 V 8 FU 1 FU 2 FU 3 FU 4 FU 5 FU 6 FU 7 FU 8


Figure 5-83: EORTC QLQ-C30, "financial problems", group B (adj.)


0

25

50

75

100

Fina

ncia

l Pro

blem

s

Visi t

52 55 51 44 42 47 46 48 48 50N

129

Table 5-122: EORTC QLQ-C30, summary statistics for the AUC (adj.)

group A

N=53 group B

N=57 Total

N=110 p-value1 Pysical functioning - N 53 56 109 0.739 - Mean +/- SD 47.7 +/-34.3 46.3 +/-31.6 47.0 +/-32.8 - p25, p75 15.5, 83.0 18.1, 78.1 15.5, 79.5 - Median 52.7 41.1 43.6 - Min, Max 2.3, 98.1 2.4, 97.6 2.3, 98.1 Role functioning - N 53 56 109 0.685 - Mean +/- SD 38.8 +/-30.5 41.9 +/-31.2 40.4 +/-30.8 - p25, p75 9.1, 63.3 12.6, 64.6 11.6, 64.1 - Median 36.9 42.7 38.3 - Min, Max 0.0, 97.0 0.0, 100.0 0.0, 100.0 Emotional functioning - N 53 56 109 0.723 - Mean +/- SD 42.8 +/-29.8 41.1 +/-29.8 41.9 +/-29.7 - p25, p75 15.5, 67.7 10.6, 64.0 14.8, 64.3 - Median 44.0 42.0 42.2 - Min, Max 2.9, 99.6 0.0, 100.0 0.0, 100.0 Cognitive functioning - N 53 56 109 0.630 - Mean +/- SD 49.4 +/-34.4 47.2 +/-31.1 48.2 +/-32.6 - p25, p75 14.4, 82.4 20.3, 76.0 15.7, 79.1 - Median 49.4 47.5 48.0 - Min, Max 3.3, 100.0 0.0, 100.0 0.0, 100.0 Social functioning - N 53 56 109 0.665 - Mean +/- SD 41.4 +/-31.5 44.8 +/-31.8 43.1 +/-31.6 - p25, p75 12.4, 67.2 14.9, 68.0 13.3, 67.9 - Median 40.3 47.0 41.8 - Min, Max 1.7, 96.8 0.0, 100.0 0.0, 100.0 Global Health Status - N 53 56 109 0.660 - Mean +/- SD 36.2 +/-26.2 38.8 +/-27.3 37.5 +/-26.6 - p25, p75 10.0, 60.4 12.9, 64.6 12.4, 62.1 - Median 41.3 39.8 41.3 - Min, Max 1.7, 88.6 0.0, 91.7 0.0, 91.7 Fatigue - N 53 56 109 0.709 - Mean +/- SD 61.9 +/-29.3 63.6 +/-27.0 62.7 +/-28.1 - p25, p75 38.6, 89.9 39.0, 92.3 38.6, 90.3 - Median 61.2 65.6 62.8 - Min, Max 9.1, 99.8 7.4, 100.0 7.4, 100.0 Nausea / Vomiting - N 53 56 109 0.662 - Mean +/- SD 45.0 +/-36.8 43.5 +/-37.4 44.2 +/-36.9 - p25, p75 7.2, 82.3 5.4, 79.9 6.9, 81.6 - Median 35.0 38.6 35.9 - Min, Max 0.0, 96.2 0.0, 96.4 0.0, 96.4

130

group A

N=53 group B

N=57 Total

N=110 p-value1 Pain - N 53 56 109 0.901 - Mean +/- SD 53.9 +/-32.8 52.4 +/-35.0 53.1 +/-33.8 - p25, p75 21.5, 85.1 18.8, 90.1 20.7, 86.8 - Median 58.2 55.4 56.0 - Min, Max 0.0, 96.7 0.0, 98.8 0.0, 98.8 Dyspnea - N 53 56 109 0.846 - Mean +/- SD 51.5 +/-34.6 49.5 +/-35.9 50.5 +/-35.1 - p25, p75 15.4, 86.7 13.7, 81.7 14.4, 84.5 - Median 52.7 57.3 56.1 - Min, Max 0.0, 96.7 0.0, 100.0 0.0, 100.0 Insomnia - N 53 55 108 0.849 - Mean +/- SD 56.6 +/-31.7 54.9 +/-33.7 55.7 +/-32.6 - p25, p75 25.2, 84.0 22.4, 87.6 23.6, 85.2 - Median 62.8 51.2 60.6 - Min, Max 0.0, 98.3 0.0, 100.0 0.0, 100.0 Appetite loss - N 53 56 109 0.691 - Mean +/- SD 51.2 +/-35.2 49.3 +/-36.9 50.2 +/-36.0 - p25, p75 18.2, 86.5 13.6, 84.7 14.9, 85.5 - Median 41.6 50.2 44.9 - Min, Max 0.0, 100.0 0.0, 100.0 0.0, 100.0 Constipation - N 53 56 109 0.798 - Mean +/- SD 46.2 +/-36.2 44.7 +/-36.8 45.4 +/-36.3 - p25, p75 6.0, 81.0 0.0, 81.1 4.7, 81.0 - Median 49.2 45.8 46.3 - Min, Max 0.0, 95.0 0.0, 95.2 0.0, 95.2 Diarrhea - N 53 56 109 0.709 - Mean +/- SD 54.6 +/-32.2 55.4 +/-33.6 55.0 +/-32.7 - p25, p75 23.9, 83.1 28.5, 90.8 25.7, 84.6 - Median 55.4 53.8 54.3 - Min, Max 0.0, 98.3 0.0, 100.0 0.0, 100.0 Financial Problems - N 53 56 109 0.514 - Mean +/- SD 57.0 +/-34.1 52.5 +/-34.9 54.7 +/-34.5 - p25, p75 32.2, 85.5 17.1, 89.9 19.5, 86.7 - Median 72.2 57.3 60.6 - Min, Max 0.0, 100.0 0.0, 95.2 0.0, 100.0

1 Wilcoxon rank sum test

131

Table 5-123: EORTC QLQ-PAN26, "pancreatic pain", group A (adj.) V 2 V 5 V 9 V 10 V 17 FU 1 FU 2 FU 3 FU 4 FU 5 FU 6 FU 7 FU 8


Figure 5-84: EORTC QLQ-PAN26, "pancreatic pain", group A (adj.)


0

25

50

75

100

Pan

crea

tic p

ain

Visi t

52 52 51 52 52 51 46 45 45 44 47 45 46N

Table 5-124: EORTC QLQ-PAN26, "digestive symptoms", group A (adj.) V 2 V 5 V 9 V 10 V 17 FU 1 FU 2 FU 3 FU 4 FU 5 FU 6 FU 7 FU 8


Figure 5-85: EORTC QLQ-PAN26, "digestive symptoms", group A (adj.)


0

25

50

75

100

Dig

estiv

e sy

mpt

oms

Visi t

51 52 51 52 52 51 46 45 45 44 47 45 46N

132

Table 5-125: EORTC QLQ-PAN26, "altered bowel habit", group A (adj.) V 2 V 5 V 9 V 10 V 17 FU 1 FU 2 FU 3 FU 4 FU 5 FU 6 FU 7 FU 8


Figure 5-86: EORTC QLQ-PAN26, "altered bowel habit", group A (adj.)


0

25

50

75

100

Alte

red

bow

el h

abit

Visi t

51 52 51 52 51 50 45 44 44 44 47 45 46N

Table 5-126: EORTC QLQ-PAN26, "hepatic", group A (adj.) V 2 V 5 V 9 V 10 V 17 FU 1 FU 2 FU 3 FU 4 FU 5 FU 6 FU 7 FU 8


Figure 5-87: EORTC QLQ-PAN26, "hepatic", group A (adj.)


0

25

50

75

100

Hep

atic

Visi t

51 52 51 52 52 51 46 45 45 44 47 45 46N

133

Table 5-127: EORTC QLQ-PAN26, "body image", group A (adj.) V 2 V 5 V 9 V 10 V 17 FU 1 FU 2 FU 3 FU 4 FU 5 FU 6 FU 7 FU 8


Figure 5-88: EORTC QLQ-PAN26, "body image", group A (adj.)


0

25

50

75

100

Bod

y im

age

Visi t

51 51 51 52 51 51 46 46 46 44 49 45 47N

Table 5-128: EORTC QLQ-PAN26, "satisfaction with health care", group A (adj.) V 2 V 5 V 9 V 10 V 17 FU 1 FU 2 FU 3 FU 4 FU 5 FU 6 FU 7 FU 8


Figure 5-89: EORTC QLQ-PAN26, "satisfaction with health care", group A (adj.)


0

25

50

75

100

Sat

isfa

ctoo

n w

ith h

ealth

car

e

Visi t

49 49 50 50 52 50 46 45 44 43 46 44 47N

134

Table 5-129: EORTC QLQ-PAN26, "sexuality", group A (adj.) V 2 V 5 V 9 V 10 V 17 FU 1 FU 2 FU 3 FU 4 FU 5 FU 6 FU 7 FU 8


Figure 5-90: EORTC QLQ-PAN26, "sexuality", group A (adj.)


0

25

50

75

100

Sex

ualit

y

Visi t

46 44 42 42 45 46 44 44 45 43 48 44 46N

Table 5-130: EORTC QLQ-PAN26, "pancreatic pain", group B (adj.) V 1 V 8 FU 1 FU 2 FU 3 FU 4 FU 5 FU 6 FU 7 FU 8


Figure 5-91: EORTC QLQ-PAN26, "pancreatic pain", group B (adj.)


0

25

50

75

100

Pan

crea

tic p

ain

Visi t

52 56 52 44 42 47 46 48 47 49N

135

Table 5-131: EORTC QLQ-PAN26, "digestive symptoms", group B (adj.) V 1 V 8 FU 1 FU 2 FU 3 FU 4 FU 5 FU 6 FU 7 FU 8


Figure 5-92: EORTC QLQ-PAN26, "digestive symptoms", group B (adj.)


0

25

50

75

100

Dig

estiv

e sy

mpt

oms

Visi t

51 55 52 44 42 47 46 48 47 49N

Table 5-132: EORTC QLQ-PAN26, "altered bowel habit", group B (adj.) V 1 V 8 FU 1 FU 2 FU 3 FU 4 FU 5 FU 6 FU 7 FU 8


Figure 5-93: EORTC QLQ-PAN26, "altered bowel habit", group B (adj.)


0

25

50

75

100

Alte

red

bow

el h

abit

Visi t

53 56 52 44 42 47 45 48 47 49N

136

Table 5-133: EORTC QLQ-PAN26, "hepatic", group B (adj.) V 1 V 8 FU 1 FU 2 FU 3 FU 4 FU 5 FU 6 FU 7 FU 8


Figure 5-94: EORTC QLQ-PAN26, "hepatic", group B (adj.)


0

25

50

75

100

Hep

atic

Visi t

51 56 52 44 42 47 46 48 47 49N

Table 5-134: EORTC QLQ-PAN26, "body image", group B (adj.) V 1 V 8 FU 1 FU 2 FU 3 FU 4 FU 5 FU 6 FU 7 FU 8


Figure 5-95: EORTC QLQ-PAN26, "body image", group B (adj.)


0

25

50

75

100

Bod

y im

age

Visi t

54 56 52 45 42 47 47 48 48 50N

137

Table 5-135: EORTC QLQ-PAN26, "satisfaction with health care", group B (adj.) V 1 V 8 FU 1 FU 2 FU 3 FU 4 FU 5 FU 6 FU 7 FU 8


Figure 5-96: EORTC QLQ-PAN26, "satisfaction with health care", group B (adj.)


0

25

50

75

100

Sat

isfa

ctoo

n w

ith h

ealth

car

e

Visi t

52 55 50 40 39 44 46 46 47 48N

Table 5-136: EORTC QLQ-PAN26, "sexuality", group B (adj.) V 1 V 8 FU 1 FU 2 FU 3 FU 4 FU 5 FU 6 FU 7 FU 8


Figure 5-97: EORTC QLQ-PAN26, "sexuality", group B (adj.)


0

25

50

75

100

Sex

ualit

y

Visi t

46 49 43 40 40 44 45 44 46 47N

138

Table 5-137: EORTC QLQ-PAN26, summary statistics for the AUC (adj.)

Arm A N=53

Arm B N=57


Pancreatic pain - N 53 54 107 0.948 - Mean +/- SD 53.8 +/-32.6 53.1 +/-31.6 53.5 +/-31.9 - p25, p75 22.4, 85.7 20.8, 84.3 20.8, 85.5 - Median 57.5 51.6 53.9 - Min, Max 2.8, 96.7 0.0, 97.6 0.0, 97.6 Digestive symptoms - N 53 54 107 0.638 - Mean +/- SD 58.7 +/-31.5 60.1 +/-30.4 59.4 +/-30.8 - p25, p75 25.4, 88.3 36.8, 88.3 33.3, 88.3 - Median 57.3 62.3 59.4 - Min, Max 9.1, 100.0 0.0, 100.0 0.0, 100.0 Altered bowel habit - N 53 55 108 0.980 - Mean +/- SD 63.0 +/-26.2 61.3 +/-30.3 62.1 +/-28.3 - p25, p75 43.8, 84.6 38.7, 88.2 41.5, 85.4 - Median 68.3 68.7 68.5 - Min, Max 2.4, 98.3 0.0, 100.0 0.0, 100.0 Hepatic - N 53 54 107 0.378 - Mean +/- SD 45.3 +/-34.9 41.8 +/-37.0 43.5 +/-35.9 - p25, p75 10.3, 76.8 2.6, 74.8 5.3, 76.6 - Median 44.1 43.4 44.1 - Min, Max 0.0, 95.8 0.0, 98.8 0.0, 98.8 Body image - N 53 56 109 0.755 - Mean +/- SD 57.1 +/-29.4 54.5 +/-34.5 55.8 +/-32.0 - p25, p75 34.4, 82.4 20.3, 89.4 29.2, 85.0 - Median 58.2 58.6 58.2 - Min, Max 3.3, 100.0 0.0, 100.0 0.0, 100.0 Satisfaction with health care - N 53 56 109 0.444 - Mean +/- SD 54.3 +/-35.4 49.3 +/-33.2 51.7 +/-34.2 - p25, p75 23.5, 90.8 21.9, 81.5 23.2, 88.1 - Median 47.7 44.5 45.8 - Min, Max 4.2, 100.0 1.2, 100.0 1.2, 100.0 Sexuality - N 48 50 98 0.320 - Mean +/- SD 30.0 +/-25.1 36.0 +/-28.6 33.1 +/-27.0 - p25, p75 6.8, 50.0 11.7, 55.1 8.3, 51.5 - Median 25.3 28.1 26.7 - Min, Max 0.0, 89.0 0.0, 100.0 0.0, 100.0


139

Table 5-138: CES-D, "total score", group A (adj.) V 2 V 5 V 9 V 10 V 17 FU 1 FU 2 FU 3 FU 4 FU 5 FU 6 FU 7 FU 8


Figure 5-98: CES-D, "total score", group A (adj.)


0

20

40

60

scor

e

Visi t

46 43 48 43 46 45 45 43 45 43 46 44 46N

Table 5-139: CES-D, "total score", group B (adj.) V 1 V 8 FU 1 FU 2 FU 3 FU 4 FU 5 FU 6 FU 7 FU 8


Figure 5-99: CES-D, "total score", group B (adj.)


0

20

40

60

scor

e

Visi t

44 52 47 40 35 47 45 46 48 48N

140

Table 5-140: CES-D, summary statistics for the AUC (adj.)

group A

N=53 group B

N=57 Total

N=110 p-value1 Total score - N 52 53 105 0.766 *2 - Mean +/- SD 30.8 +/-18.8 31.1 +/-19.2 30.9 +/-18.9 - p25, p75 12.6, 49.0 13.3, 49.7 13.2, 49.0 - Median 28.3 30.0 28.4 - Min, Max 1.9, 58.0 4.0, 58.2 1.9, 58.2 1Wilcoxon rank sum test

Table 5-141: Results of the Cox regression analysis for baseline variables Baseline Variable Hazard Ratio 95% CI p-value

sex (f vs m) 1.100 [0.689;.755] 0.69 age 1.011 [0.986;.036] 0.39 BMI 0.981 [0.923;1.043] 0.54

nodes (N1 vs N0) 1.931 [1.035;3.602] 0.039 interv* 1.002 [0.988;1.016] 0.82 CEA 1.002 [0.981;1.024] 0.83

CA19-9 1.008 [1.004;1.012] <0.0001 1.389 [0.701;2.752] 0..35 ppWhipple

Whipple** 3.836 [1.704;8.635] 0.001 *time interval from primary surgery to randomization **compared to left resection

Figure 5-100: Time from relapse to death

Arm A Arm B

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 6 12 18 24 30 36 42 48 54 60

Arm A Arm B

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 6 12 18 24 30 36 42 48 54 60

141

Table 5-142: Numbers of patients with AEs / SAEs

A

N=53 B

N=57 Total

N=110 p-value1 At least one AE - no 0 ( 0.0%) 2 ( 3.5%) 2 ( 1.8%) 0.496 - yes 53 (100.0%) 55 ( 96.5%) 108 ( 98.2%) At least one AE (relation to treatment at least possible)

- no 0 ( 0.0%) 5 ( 8.8%) 5 ( 4.5%) 0.058 - yes 53 (100.0%) 52 ( 91.2%) 105 ( 95.5%) At least one SAE - no 30 ( 56.6%) 48 ( 84.2%) 78 ( 70.9%) 0.002 - yes 23 ( 43.4%) 9 ( 15.8%) 32 ( 29.1%) At least one treatment-related SAE - no 31 ( 58.5%) 49 ( 86.0%) 80 ( 72.7%) 0.001 - yes 22 ( 41.5%) 8 ( 14.0%) 30 ( 27.3%) At least one severe AE - no 22 ( 41.5%) 44 ( 77.2%) 66 ( 60.0%) <.001 - yes 31 ( 58.5%) 13 ( 22.8%) 44 ( 40.0%) At least one AE with definite causality to trial intervention

- no 26 ( 49.1%) 40 ( 70.2%) 66 ( 60.0%) 0.032 - yes 27 ( 50.9%) 17 ( 29.8%) 44 ( 40.0%)

1Fisher's exact test

142

Table 5-143: Percentages of patients with AEs / SAEs (with 95% confidence intervals1)

A B Percent [95% CI] Percent [95% CI] At least one AE 100.0 [93.3, 100.0] 96.5 [89.4, 99.4] At least one AE (relation to treatment at least possible)

100.0 [93.3, 100.0] 91.2 [80.7, 97.1]

At least one SAE 43.4 [29.8, 57.7] 15.8 [7.5, 27.9] At least one treatment-related AE

41.5 [28.1, 55.9] 14.0 [6.3, 25.8]

At least one severe AE 58.5 [44.1, 71.9] 22.8 [12.7, 35.8] At least one AE with definite causality to trial intervention

50.9 [36.8, 64.9] 29.8 [18.4, 43.4]

1exact 95% confidence intervals

Table 5-144: Total numbers of AEs/ SAEs

A

N=53 B

N=57 Total

N=110 Total number of AEs 695 (100.0%) 396 ( 99.5%) 1091 ( 99.8%) Total number of SAEs 62 ( 8.9%) 18 ( 4.5%) 80 ( 7.3%)

Table 5-145: Total number of AEs, broken down by severity and causal relationship

A

N=53 B

N=57 Total

N=110 p-value1 Severity - mild 295 ( 42.5%) 234 ( 59.2%) 529 ( 48.6%) <.001 - moderate 314 ( 45.2%) 131 ( 33.2%) 445 ( 40.9%) - severe 85 ( 12.2%) 30 ( 7.6%) 115 ( 10.6%) - missing 1 3 4 Causality - unrelated 29 ( 4.2%) 40 ( 10.1%) 69 ( 6.3%) <.001 - possible 211 ( 30.4%) 109 ( 27.5%) 320 ( 29.3%) - probable 190 ( 27.3%) 135 ( 34.1%) 325 ( 29.8%) - definite 175 ( 25.2%) 64 ( 16.2%) 239 ( 21.9%) - not assessable 90 ( 12.9%) 48 ( 12.1%) 138 ( 12.6%) - missing 0 2 2

1Chi squared test

143

Table 5-146: Number of AEs per patient

A

N=53 B

N=57 Total

N=110 p-value1 - N 53 57 110 <.001 - Mean +/- SD 13.1 +/-6.3 7.0 +/-4.8 9.9 +/-6.3 - p25, p75 8.0, 17.0 3.0, 10.0 6.0, 13.0 - Median 13.0 6.0 8.5 - Min, Max 1.0, 27.0 1.0, 22.0 1.0, 27.0


Table 5-147: Strongest causal relationship to intervention reported in AEs

group A

N=53 group B

N=57 Total

N=110 p-value1 stronges causal relationship - unrelated 0 ( 0.0%) 2 ( 3.6%) 2 ( 1.9%) 0.087 - possible 3 ( 5.7%) 11 ( 20.0%) 14 ( 13.0%) - probably 5 ( 9.4%) 7 ( 12.7%) 12 ( 11.1%) - definitely 9 ( 17.0%) 7 ( 12.7%) 16 ( 14.8%) - not assessable 36 ( 67.9%) 28 ( 50.9%) 64 ( 59.3%) - missing 0 2 2 1 Chi squared test

Table 5-148: Highest severity level reported in AEs

group A

N=53 group B

N=57 Total

N=110 p-value1

highest severity level - mild 2 ( 3.8%) 12 ( 21.8%) 14 ( 13.0%) <.001 - moderate 20 ( 37.7%) 30 ( 54.5%) 50 ( 46.3%) - severe 31 ( 58.5%) 13 ( 23.6%) 44 ( 40.7%) - missing 0 2 2 1 Chi squared test

144

Table 5-149: Number of AEs per patient by causality

Arm A N=53

Arm B N=57


Causality unrelated - N 16 25 41 0.365 - Mean +/- SD 1.8 +/-1.2 1.6 +/-1.2 1.7 +/-1.1 - p25, p75 1.0, 2.0 1.0, 2.0 1.0, 2.0 - Median 1.5 1.0 1.0 - Min, Max 1.0, 5.0 1.0, 6.0 1.0, 6.0 Causality possible - N 48 37 85 0.031 - Mean +/- SD 4.4 +/-3.5 2.9 +/-2.1 3.8 +/-3.0 - p25, p75 2.0, 6.0 2.0, 4.0 2.0, 5.0 - Median 3.0 2.0 3.0 - Min, Max 1.0, 18.0 1.0, 10.0 1.0, 18.0 Causality probable - N 42 27 69 0.985 - Mean +/- SD 4.5 +/-4.0 5.0 +/-4.8 4.7 +/-4.3 - p25, p75 2.0, 6.0 2.0, 8.0 2.0, 6.0 - Median 3.5 3.0 3.0 - Min, Max 1.0, 20.0 1.0, 18.0 1.0, 20.0 Causality definite - N 27 17 44 0.038 - Mean +/- SD 6.5 +/-4.8 3.8 +/-2.9 5.4 +/-4.3 - p25, p75 3.0, 10.0 2.0, 5.0 2.0, 8.0 - Median 5.0 2.0 4.0 - Min, Max 1.0, 17.0 1.0, 9.0 1.0, 17.0 Causality not assessable - N 36 28 64 0.005 - Mean +/- SD 2.5 +/-1.5 1.7 +/-1.1 2.2 +/-1.4 - p25, p75 2.0, 3.0 1.0, 2.0 1.0, 3.0 - Median 2.0 1.0 2.0 - Min, Max 1.0, 9.0 1.0, 5.0 1.0, 9.0 1Wilcoxon rank sum test

145

Table 5-150: Number of AEs per patient by severity

A

N=53 B

N=57 Total

N=110 p-value1 Severity: mild - N 52 53 105 0.009 - Mean +/- SD 5.7 +/-3.4 4.4 +/-3.8 5.0 +/-3.6 - p25, p75 3.5, 7.5 2.0, 6.0 2.0, 7.0 - Median 5.0 4.0 4.0 - Min, Max 1.0, 17.0 1.0, 19.0 1.0, 19.0 Severity: moderate - N 51 39 90 <.001 - Mean +/- SD 6.2 +/-4.1 3.4 +/-2.1 4.9 +/-3.7 - p25, p75 3.0, 9.0 2.0, 5.0 2.0, 7.0 - Median 5.0 3.0 4.0 - Min, Max 1.0, 19.0 1.0, 10.0 1.0, 19.0 Severity: severe - N 31 13 44 0.302 - Mean +/- SD 2.7 +/-1.9 2.3 +/-2.1 2.6 +/-1.9 - p25, p75 1.0, 4.0 1.0, 3.0 1.0, 4.0 - Median 2.0 1.0 2.0 - Min, Max 1.0, 8.0 1.0, 8.0 1.0, 8.0


146

Table 5-151: Listing of AEs prior to treatment Pat. Ident.*

diagnosis/ symptom ICD 10 SAE? severity start end outcome causality

2/A/f Brechreiz Übelkeit und Erbrechen no mild 14/09/2004

22/12/2004

recovered completely

unrelated

2/A/f Fieber Sonstiges näher bezeichnetes Fieber

no mild 14/09/2004

14/09/2004


definitely

2/A/f Haarverlust Haarausfall ohne Narbenbildung, nicht näher bezeichnet

no mild 14/09/2004

18/02/2005


definitely

4/A/m Appetitlosigkeit Anorexie no moderate 19/08/2004

04/10/2004


probably

4/A/m gain of weight Abnorme Gewichtszunahme

no mild 24/08/2004

30/08/2004


not assessable

7/A/m Neurogener Schmerz Fuss re

Sonstige näher bezeich-nete Polyneuropathien

no moderate 04/11/2004

16/11/2004

recovered with

sequelae

unrelated

10/A/m Pain Schmerz, nicht näher bezeichnet


14/10/2004


unrelated

10/A/m Schuettelfrost Sonstiges näher bezeich-netes Fieber

no mild 12/10/2004

12/10/2004


definitely

11/B/m Steatorrhoea Pankreatogene Steatorrhoe


22/10/2004


unrelated


no mild 23/11/2004

29/11/2004


not assessable

17/A/m fever Sonstiges näher bezeichnetes Fieber


08/02/2005


definitely

26/A/f shivering Sonstiges näher bezeichnetes Fieber

no mild 02/03/2005

02/03/2005


possible


no mild 14/07/2005

18/07/2005


not assessable

66/A/m Hypomagnese-mia

Sonstige Störungen des Wasser- und Elektrolythaushaltes, anderenorts nicht klassifiziert


20/06/2006


possible

158/A/f Gain of Weight Abnorme Gewichtszunahme


22/10/2007


possible

*The treatment groups are indicated in capital letters in the ID numbers.

147

Toxicity data as reported in the AE

Table 5-152: Toxicity (AE), A - Therapy block 1 N=53 Patients with/without at least one grade 3/4 toxicity - no grade 3 or 4 toxicity 17 ( 32.1%) - at least one grade 3 or 4 toxicity 36 ( 67.9%) - at least one grade 4 toxicity 9 ( 17.0%) Number of grade 3/4 toxicities per patient - N 53 - Mean +/- SD 1.8 +/-2.0 - p25, p75 0.0, 2.0 - Median 1.0 - Min, Max 0.0, 8.0 Total number of grade 3/4 toxicities 93 Total number of grade 4 toxicities 11 Type of grade 3/4 toxicities (coded according to ICD10) - Akutes Nierenversagen, nicht näher bezeichnet 1 ( 1.1%) - Anorexie 1 ( 1.1%) - Anämie, nicht näher bezeichnet 3 ( 3.2%) - Essentielle Hypertonie, nicht näher bezeichnet: Ohne Angabe einer hypertensiven Krise 1 ( 1.1%) - Gingivostomatitis herpetica und Pharyngotonsillitis herpetica 1 ( 1.1%) - Hyperglykämie, nicht näher bezeichnet 1 ( 1.1%) - Hypotonie, nicht näher bezeichnet 1 ( 1.1%) - Lokalisierte Hauteruption durch Drogen oder Arzneimittel 3 ( 3.2%) - Neutropenie, nicht näher bezeichnet 52 ( 55.9%) - Nichtinfektiöse Gastroenteritis und Kolitis, nicht näher bezeichnet 4 ( 4.3%) - Sonstige Formen der Stomatitis 1 ( 1.1%) - Sonstige Störungen des Wasser- und Elektrolythaushaltes, anderenorts nicht klassifiziert 8 ( 8.6%) - Sonstiges näher bezeichnetes Fieber 2 ( 2.2%) - Synkope und Kollaps 2 ( 2.2%) - Thrombozytopenie, nicht näher bezeichnet: Nicht als transfusionsrefraktär bezeichnet 2 ( 2.2%) - Unwohlsein und Ermüdung 1 ( 1.1%) - Volumenmangel 1 ( 1.1%) - Übelkeit und Erbrechen 8 ( 8.6%) Type of grade 4 toxicities (coded according to ICD10) - Akutes Nierenversagen, nicht näher bezeichnet 1 ( 9.1%) - Lokalisierte Hauteruption durch Drogen oder Arzneimittel 1 ( 9.1%) - Neutropenie, nicht näher bezeichnet 7 ( 63.6%) - Sonstige Störungen des Wasser- und Elektrolythaushaltes, anderenorts nicht klassifiziert 1 ( 9.1%) - Übelkeit und Erbrechen 1 ( 9.1%) Patients with/without at least one grade 3/4 toxicity of type <Akutes Nierenversagen, nicht näher bezeichnet>

- no grade 3 or 4 toxicity 52 ( 98.1%) - at least one grade 4 toxicity 1 ( 1.9%) Patients with/without at least one grade 3/4 toxicity of type <Anorexie> - no grade 3 or 4 toxicity 52 ( 98.1%) - at least one grade 3 or 4 toxicity 1 ( 1.9%) Patients with/without at least one grade 3/4 toxicity of type <Anämie, nicht näher bezeichnet> - no grade 3 or 4 toxicity 50 ( 94.3%) - at least one grade 3 or 4 toxicity 3 ( 5.7%)

148

N=53 Patients with/without at least one grade 3/4 toxicity of type <Essentielle Hypertonie, nicht näher bezeichnet: Ohne Angabe einer hypertensiven Krise>

- no grade 3 or 4 toxicity 52 ( 98.1%) - at least one grade 3 or 4 toxicity 1 ( 1.9%) Patients with/without at least one grade 3/4 toxicity of type <Gingivostomatitis herpetica und Pharyngotonsillitis herpetica>

- no grade 3 or 4 toxicity 52 ( 98.1%) - at least one grade 3 or 4 toxicity 1 ( 1.9%) Patients with/without at least one grade 3/4 toxicity of type <Hyperglykämie, nicht näher bezeichnet> - no grade 3 or 4 toxicity 52 ( 98.1%) - at least one grade 3 or 4 toxicity 1 ( 1.9%) Patients with/without at least one grade 3/4 toxicity of type <Hypotonie, nicht näher bezeichnet> - no grade 3 or 4 toxicity 52 ( 98.1%) - at least one grade 3 or 4 toxicity 1 ( 1.9%) Patients with/without at least one grade 3/4 toxicity of type <Lokalisierte Hauteruption durch Drogen oder Arzneimittel>

- no grade 3 or 4 toxicity 51 ( 96.2%) - at least one grade 3 or 4 toxicity 2 ( 3.8%) - at least one grade 4 toxicity 1 ( 1.9%) Patients with/without at least one grade 3/4 toxicity of type <Neutropenie, nicht näher bezeichnet> - no grade 3 or 4 toxicity 25 ( 47.2%) - at least one grade 3 or 4 toxicity 28 ( 52.8%) - at least one grade 4 toxicity 6 ( 11.3%) Patients with/without at least one grade 3/4 toxicity of type <Nichtinfektiöse Gastroenteritis und Kolitis, nicht näher bezeichnet>

- no grade 3 or 4 toxicity 50 ( 94.3%) - at least one grade 3 or 4 toxicity 3 ( 5.7%) Patients with/without at least one grade 3/4 toxicity of type <Sonstige Formen der Stomatitis> - no grade 3 or 4 toxicity 52 ( 98.1%) - at least one grade 3 or 4 toxicity 1 ( 1.9%) Patients with/without at least one grade 3/4 toxicity of type <Sonstige Störungen des Wasser, und Elektrolythaushaltes, anderenorts nicht klassifiziert>

- no grade 3 or 4 toxicity 48 ( 90.6%) - at least one grade 3 or 4 toxicity 5 ( 9.4%) - at least one grade 4 toxicity 1 ( 1.9%) Patients with/without at least one grade 3/4 toxicity of type <Sonstiges näher bezeichnetes Fieber> - no grade 3 or 4 toxicity 52 ( 98.1%) - at least one grade 3 or 4 toxicity 1 ( 1.9%) Patients with/without at least one grade 3/4 toxicity of type <Synkope und Kollaps> - no grade 3 or 4 toxicity 51 ( 96.2%) - at least one grade 3 or 4 toxicity 2 ( 3.8%) Patients with/without at least one grade 3/4 toxicity of type <Thrombozytopenie, nicht näher bezeichnet: Nicht als transfusionsrefraktär bezeichnet>

- no grade 3 or 4 toxicity 52 ( 98.1%) - at least one grade 3 or 4 toxicity 1 ( 1.9%) Patients with/without at least one grade 3/4 toxicity of type <Unwohlsein und Ermüdung> - no grade 3 or 4 toxicity 52 ( 98.1%) - at least one grade 3 or 4 toxicity 1 ( 1.9%)

149

N=53 Patients with/without at least one grade 3/4 toxicity of type <Volumenmangel> - no grade 3 or 4 toxicity 52 ( 98.1%) - at least one grade 3 or 4 toxicity 1 ( 1.9%) Patients with/without at least one grade 3/4 toxicity of type <Übelkeit und Erbrechen> - no grade 3 or 4 toxicity 48 ( 90.6%) - at least one grade 3 or 4 toxicity 5 ( 9.4%) - at least one grade 4 toxicity 1 ( 1.9%)

Table 5-153: Toxicity (AE), group A - Therapy block 2 N=51 Patients with/without at least one grade 3/4 toxicity - no grade 3 or 4 toxicity 49 ( 96.1%) - at least one grade 3 or 4 toxicity 2 ( 3.9%) Number of grade 3/4 toxicities per patient - N 51 - Mean +/- SD 0.0 +/-0.2 - p25, p75 0.0, 0.0 - Median 0.0 - Min, Max 0.0, 1.0 Total number of grade 3/4 toxicities 2 Total number of grade 4 toxicities 0 Type of grade 3/4 toxicities (coded according to ICD10) - Neutropenie, nicht näher bezeichnet 2 (100.0%) Patients with/without at least one grade 3/4 toxicity of type <Neutropenie, nicht näher bezeichnet> - no grade 3 or 4 toxicity 49 ( 96.1%) - at least one grade 3 or 4 toxicity 2 ( 3.9%)

150

Table 5-154: Toxicity (AE), group A - Therapy block 3 N=46 Patients with/without at least one grade 3/4 toxicity - no grade 3 or 4 toxicity 44 ( 95.7%) - at least one grade 3 or 4 toxicity 2 ( 4.3%) Number of grade 3/4 toxicities per patient - N 46 - Mean +/- SD 0.0 +/-0.2 - p25, p75 0.0, 0.0 - Median 0.0 - Min, Max 0.0, 1.0 Total number of grade 3/4 toxicities 2 Total number of grade 4 toxicities 0 Type of grade 3/4 toxicities (coded according to ICD10) - Lokalisierte Hauteruption durch Drogen oder Arzneimittel 2 (100.0%) Patients with/without at least one grade 3/4 toxicity of type <Lokalisierte Hauteruption durch Drogen oder Arzneimittel>

- no grade 3 or 4 toxicity 44 ( 95.7%) - at least one grade 3 or 4 toxicity 2 ( 4.3%)

Table 5-155: Toxicity (AE), group B N=57 Patients with/without at least one grade 3/4 toxicity - no grade 3 or 4 toxicity 48 ( 84.2%) - at least one grade 3 or 4 toxicity 9 ( 15.8%) - at least one grade 4 toxicity 1 ( 1.8%) Number of grade 3/4 toxicities per patient - N 57 - Mean +/- SD 0.2 +/-0.6 - p25, p75 0.0, 0.0 - Median 0.0 - Min, Max 0.0, 3.0 Total number of grade 3/4 toxicities 13 Total number of grade 4 toxicities 1 Type of grade 3/4 toxicities (coded according to ICD10) - Diarrhoe und Gastroenteritis, vermutlich infektiösen Ursprungs 1 ( 7.7%) - Haarausfall ohne Narbenbildung, nicht näher bezeichnet 1 ( 7.7%) - Nichtinfektiöse Gastroenteritis und Kolitis, nicht näher bezeichnet 9 ( 69.2%) - Sonstige Störungen des Wasser- und Elektrolythaushaltes, anderenorts nicht klassifiziert 1 ( 7.7%) - Übelkeit und Erbrechen 1 ( 7.7%)

151

N=57 Type of grade 4 toxicities (coded according to ICD10) - Nichtinfektiöse Gastroenteritis und Kolitis, nicht näher bezeichnet 1 (100.0%) Patients with/without at least one grade 3/4 toxicity of type <Diarrhoe und Gastroenteritis, vermutlich infektiösen Ursprungs>

- no grade 3 or 4 toxicity 56 ( 98.2%) - at least one grade 3 or 4 toxicity 1 ( 1.8%) Patients with/without at least one grade 3/4 toxicity of type <Haarausfall ohne Narbenbildung, nicht näher bezeichnet>

- no grade 3 or 4 toxicity 56 ( 98.2%) - at least one grade 3 or 4 toxicity 1 ( 1.8%) Patients with/without at least one grade 3/4 toxicity of type <Nichtinfektiöse Gastroenteritis und Kolitis, nicht näher bezeichnet>

- no grade 3 or 4 toxicity 51 ( 89.5%) - at least one grade 3 or 4 toxicity 6 ( 10.5%) - at least one grade 4 toxicity 1 ( 1.8%) Patients with/without at least one grade 3/4 toxicity of type <Sonstige Störungen des Wasser, und Elektrolythaushaltes, anderenorts nicht klassifiziert>

- no grade 3 or 4 toxicity 56 ( 98.2%) - at least one grade 3 or 4 toxicity 1 ( 1.8%) Patients with/without at least one grade 3/4 toxicity of type <Übelkeit und Erbrechen> - no grade 3 or 4 toxicity 56 ( 98.2%) - at least one grade 3 or 4 toxicity 1 ( 1.8%)

152

Toxicity data as reported in the laboratory data

Table 5-156: Hematotoxicity, group A - Therapy block 1 N=53 Patients with at least one grade 3/4 hematotoxicity - no grade 3 or 4 toxicity 14 ( 26.4%) - at least one grade 3 or 4 toxicity 39 ( 73.6%) - at least one grade 4 toxicity 9 ( 17.0%) Number of grade 3/4 toxicities per patient - N 53 - Mean +/- SD 1.6 +/- 1.3 - p5, p25, p75, p95 0.0, 0.0, 3.0, 4.0 - Median 1.0 - Min, Max 0.0, 4.0 Total number of grade 3/4 toxicities 86 Total number of grade 4 toxicities 11 Leukocytes: Patients with grade 3/4 hematotoxicity - no grade 3 or 4 toxicity 14 ( 26.4%) - at least one grade 3 or 4 toxicity 39 ( 73.6%) - at least one grade 4 toxicity 9 ( 17.0%) Thrombocytes: Patients with grade 3/4 hematotoxicity - no grade 3 or 4 toxicity 50 ( 94.3%) - at least one grade 3 or 4 toxicity 3 ( 5.7%) Hb: Patients with grade 3/4 hematotoxicity - no grade 3 or 4 toxicity 53 (100.0%)

153

Table 5-157: Hematotoxicity, group A - Therapy block 2 N=51 Patients with/without at least one grade 3/4 hematotoxicity - no grade 3 or 4 toxicity 46 ( 90.2%) - at least one grade 3 or 4 toxicity 5 ( 9.8%) Number of grade 3/4 toxicities per patient - N 53 - Mean +/- SD 0.2 +/- 0.5 - p5, p25, p75, p95 0.0, 0.0, 0.0, 1.0 - Median 0.0 - Min, Max 0.0, 3.0 Total number of grade 3/4 toxicities 8 Total number of grade 4 toxicities 0 Leukocytes: Patients with/without grade 3/4 hematotoxicity - no grade 3 or 4 toxicity 50 ( 98.0%) - at least one grade 3 or 4 toxicity 1 ( 2.0%) Thrombocytes: Patients with/without grade 3/4 hematotoxicity - no grade 3 or 4 toxicity 51 (100.0%) Hb: Patients with/without grade 3/4 hematotoxicity - no grade 3 or 4 toxicity 47 ( 92.2%) - at least one grade 3 or 4 toxicity 4 ( 7.8%)

Table 5-158: Hematotoxicity, group A - Therapy block 3 N=46 Patients with/without at least one grade 3/4 hematotoxicity - no grade 3 or 4 toxicity 46 (100.0%)

Table 5-159: Hematotoxicity, group B N=57 Patients with/without at least one grade 3/4 hematotoxicity - no grade 3 or 4 toxicity 57 (100.0%)

154

Toxicity data as reported in AE- and laboratory data

Table 5-160: Toxicity (AE/Hematology), group A - Therapy block 1 N=53 AE/Haematology: Patients with grade 3/4 toxicity - no grade 3 or 4 toxicity 8 ( 15.1%) - at least one grade 3 or 4 toxicity 45 ( 84.9%) - at least one grade 4 toxicity 15 ( 28.3%)

Table 5-161: Toxicity (AE/Hematology), group A - Therapy block 2 N=51 AE/Hematology: Patients with/without grade 3/4 toxicity - no grade 3 or 4 toxicity 45 ( 88.2%) - at least one grade 3 or 4 toxicity 6 ( 11.8%)

Table 5-162: Toxicity (AE/Hematology), group A - Therapy block 3 N=46 AE/Hematology: Patients with/without grade 3/4 toxicity - no grade 3 or 4 toxicity 44 ( 95.7%) - at least one grade 3 or 4 toxicity 2 ( 4.3%)

Table 5-163: Toxicity (AE/Hematology), group A - Therapy block1-3 N=53 AE/Haematology: Patients with grade 3/4 toxicity - no grade 3 or 4 toxicity 8 ( 15.1%) - at least one grade 3 or 4 toxicity 45 ( 84.9%) - at least one grade 4 toxicity 15 ( 28.3%)

Table 5-164: Toxicity (AE/Hematology), group B N=57 AE/Hematology: Patients with/without grade 3/4 toxicity - no grade 3 or 4 toxicity 48 ( 84.2%) - at least one grade 3 or 4 toxicity 9 ( 15.8%) - at least one grade 4 toxicity 1 ( 1.8%)

155

Clinical Laboratory Evaluation

Figure 5-101: CRP, group A

1 2 3

-50

-25

0

25

50

CR

P (m

g/l)

End of treatment cycle

31 14 31N

Figure 5-102: GGT, group A

1 2 3

-600

-400

-200

0

200

400

GG

T (U

/l)


32 14 32N

156

Figure 5-103: GOT, group A

1 2 3

-60

-40

-20

0

20

40

GO

T (U

/l)


32 13 32N

Figure 5-104: GPT, group A

1 2 3

-150

-100

-50

0

50

100

GP

T (U

/l)


32 13 31N

157

Figure 5-105: Creatinine, group A

1 2 3

-0.2

0

0.2

0.4

0.6

0.8C

reat

inin

e (m

g/dl

)


32 14 32N

Figure 5-106: Glucose, group A

1 2 3

-200

-100

0

100

200

Glu

cose

(mg/

dl)


26 9 27N

158

Table 5-165: Shift table for laboratory data (group A): clinical chemistry Baseline → end of first treatment cycle (visit 9)

Variable Baseline Visit Visit 9 N CRP normal missing 2

normal 17 high 2 high missing 1 normal 4 high 4

GGT normal missing 1 normal 10 high 6 high missing 1 normal 3 high 9

GOT normal missing 2 normal 21 high 4 high high 3

GPT missing missing 1 normal missing 1 normal 21 high normal 3 high 4

creatinine normal missing 2 normal 28

glucose missing missing 1 high 4 low high 1 normal missing 3 normal 3 high 4 high normal 1 high 13

159

Table 5-166: Shift table for laboratory data (group A): clinical chemistry Baseline → end of second treatment cycle (visit 16)

Variable Baseline Visit Visit 16 N CRP normal normal 8

high normal 2 high 1

GGT normal normal 4 high 1 high normal 3 high 3

GOT normal missing 1 normal 6 high 3 high normal 1

GPT normal missing 1 normal 4 high 3 high normal 2 high 1

creatinine normal normal 11 glucose missing normal 2

high 2 normal normal 4 high high 3

Table 5-167: Shift table for laboratory data (group A): clinical chemistry Baseline → end of third treatment cycle (visit 23)


normal 18 high 1 high normal 4 high 3

GGT normal normal 15 high 3 high normal 3 high 6

GOT normal normal 21 high 3 high normal 3

GPT missing normal 1 normal normal 18 high 2 high normal 6

creatinine normal normal 27 glucose missing normal 1

high 3 low high 1 normal normal 7 high missing 1 normal 6 high 8

160

Figure 5-107: CRP, group B

6

-40

-20

0

20

40

CR

P (m

g/l)


12N

Figure 5-108: GGT, group B

6

-100

0

100

200

300

GG

T (U

/l)


13N

161

Figure 5-109: GOT, group B

6

-20

-10

0

10

20G

OT

(U/l)


15N

Figure 5-110: GPT, group B

6

-60

-40

-20

0

20

40

GP

T (U

/l)


15N

162

Figure 5-111: Creatinine, group B

6

-0.15

-0.10

-0.05

0

0.05

0.10

0.15

Cre

atin

ine

(mg/

dl)


15N

Figure 5-112: Glucose, group B

6

-100

-50

0

50

100

150

Glu

cose

(mg/

dl)


15N

163

Table 5-168: Shift table for laboratory data (group B): clinical chemistry Baseline → end of treatment (visit 8)


normal 5 high 1 high normal 1 high 2

GGT missing normal 1 normal missing 3 normal 4 high 1 high missing 1 normal 3 high 1

GOT normal missing 3 normal 6 high 3 high missing 1 normal 1

GPT normal missing 2 normal 3 high 3 high missing 2 normal 3 high 1

creatinine normal missing 4 normal 10

glucose missing high 1 normal normal 2 high 1 high missing 3 normal 5 high 2

164

Figure 5-113: CA 19-9, group A

2 3 4

-250

0

250

500

750

1000

CA

19-

9 (U

/ml)

2 = Begin cycle 2, 3 = Begin cycle 3, 4 = End cycle 3

39 36 25N

Figure 5-114: CEA, group A

2 3 4

-100

-75

-50

-25

0

25

50

CE

A (µ

g/l)

2 = Begin cycle 2, 3 = Begin cycle 3, 4 = End cycle 3

25 21 12N

165

Table 5-169: Shift table for laboratory data (group A): tumor markers Baseline → begin of second treatment cycle (visit 10)

Variable Baseline Visit Visit 10 N CA 19-9 missing normal 4

high 1 normal normal 24 high 2 high missing 2 normal 3 high 8

CEA missing missing 16 normal 1 high 1 normal missing 3 normal 11 high 2 high normal 1 high 9

Table 5-170: Shift table for laboratory data (group A): tumor markers Baseline → begin of third treatment cycle (visit 17)


high 1 normal missing 1 normal 19 high 4 high normal 3 high 7

CEA missing missing 13 high 3 normal missing 4 normal 3 high 6 high high 9

Table 5-171: Shift table for laboratory data (group A): tumor markers Baseline → end of third treatment cycle (visit 23)


normal missing 2 normal 12 high 3 high normal 5 high 2

CEA missing missing 9 high 3 normal missing 5 normal 2 high 4 high missing 1 high 3

166

Figure 5-115: CA 19-9, group B

6

-2000

0

2000

4000

6000

8000

CA

19-

9 (U

/ml)


16N

Figure 5-116: CEA, group B

6

0

2

4

6

8

10

CE

A (µ

g/l)


14N

167

Table 5-172: Shift table for laboratory data (group B): tumor markers Baseline → end of treatment (visit 8)

Variable Baseline Visit Visit 8 N CA 19-9 missing missing 2

normal normal 7 high 2 high high 3

CEA missing missing 3 normal missing 1 normal 4 high 4 high high 2

Figure 5-117: ANA, group A

1

-1000

-500

0

500

1000

AN

A


30N

168

Table 5-173: Shift table for laboratory data (group A): autoantibodies Baseline → end of first treatment cycle (Visit 8)

Variable Baseline Visit Visit 8 N ANA normal missing 1

normal 1 high 4 negative 1 high normal 2 high 6 negative missing 8 high 1 negative 15

Vital signs, Physical Findings

Figure 5-118: Heart rate, group A

1 2 3

-40

-20

0

20

40

Hea

rt ra

te (b

pm)


40 25 27N

169

Figure 5-119: Systolic blood pressure, group A

1 2 3

-75

-50

-25

0

25

50S

ysto

lic B

P (m

mH

g)


40 25 27N

Figure 5-120: Diastolic blood pressure, group A

1 2 3

-30

-20

-10

0

10

20

Dia

stol

ic B

P (m

mH

g)


40 25 27N

170

Figure 5-121: Heart rate, group B

6

-30

-20

-10

0

10

20

Hea

rt ra

te (b

pm)


30N

Figure 5-122: Systolic blood pressure, group B

6

-50

-25

0

25

50

Sys

tolic

BP

(mm

Hg)


31N

171

Figure 5-123: Diastolic blood pressure, group B

6

-30

-20

-10

0

10

20D

iast

olic

BP

(mm

Hg)


31N

Table 5-174: Physical examination, group A, changes with respect to baseline

N baseline - end first treatment-cycle - no 20 ( 95.2%) - yes 1 ( 4.8%) - missing 31 baseline - end second treatment-cycle - no 13 ( 86.7%) - yes 2 ( 13.3%) - missing 30 baseline - end third treatment-cycle - no 15 ( 93.8%) - yes 1 ( 6.3%) - missing 21

Table 5-175: Physical examination, group B, changes with respect to baseline

N baseline - end of treatment - no 17 ( 85.0%) - yes 3 ( 15.0%) - missing 21

172

6. REFERENCES

Anonymous (2009): Rote Liste®. Arzneimittelinformationen für Deutschland. Rote Liste Service GmbH, Frankfurt

Collett D (1994): Modelling survival data in medical research. Chapman & Hall, London

European Medicines Agency (1996): ICH Guidelines E3 “Note for Guidance on Structure and Content of Clinical Study Reports”. http://www.emea.europa.eu/pdfs/human/ich/013795en.pdf

European Medicines Agency (1998): ICH Guidelines E9 “Note for Guidance on Statistical Principles for Clinical Trials”. http://www.emea.europa.eu/pdfs/human/ich/036396en.pdf

Hollen PJ, Gralla RJ, Cox C, Eberly SW, Kris MG (1997): A dilemma in analysis: issues in the serial measurement of quality of life in patients with advanced lung cancer. Lung Cancer 18: 119-136

Hosmer DW, Lemeshow S (1989): Applied logistic regression. Wiley, New York

Kleinbaum DG, Kupper LL, Muller KE (1988): Applied regression analysis and other multi-variable methods. 2nd ed. Duxbury Press, Belmont

Machin D, Weeden S (1998): Suggestions for the presentation of quality of life data from clinical trials. Stat. Med. 17:711-724

Schulz KF, Altman DG, Moher D; CONSORT Group (2010): Updated guidelines for reporting parallel group randomized trials. Ann Intern Med 152:726-732

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