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Combination Chemotherapy and Cetuximab in Treating Patients With Metastatic Esophageal Cancer or Gastroesophageal Junction Cancer

Sponsor
Alliance for Clinical Trials in Oncology (Other)
Overall Status
Completed
CT.gov ID
NCT00381706
Collaborator
National Cancer Institute (NCI) (NIH), Eastern Cooperative Oncology Group (Other), Bristol-Myers Squibb (Industry), Sanofi (Industry), Pfizer (Industry)
245
Enrollment
227
Locations
3
Arms
97
Actual Duration (Months)
1.1
Patients Per Site
0
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

RATIONALE: Drugs used in chemotherapy work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as cetuximab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Giving more than one chemotherapy drug (combination chemotherapy) together with cetuximab may kill more tumor cells.

PURPOSE: This randomized phase II trial is studying three different combination chemotherapy regimens to compare how well they work when given together with cetuximab in treating patients with metastatic esophageal cancer or gastroesophageal junction cancer.

Condition or Disease Intervention/Treatment Phase
Phase 2

Detailed Description

OUTLINE: This is a randomized, multicenter study. Patients are stratified according to histology (squamous cell carcinoma vs adenocarcinoma) and Eastern Cooperative Oncology Group (ECOG) performance status (0 or 1 vs 2). Patients are randomized to 1 of 3 treatment arms. For more information please see the "Arms" section which includes a detailed description of the treatment regimens.

The primary objective of the study is evaluate the tumor response rate (RR) for each of the regimens in this trial and to select the most promising regimen based on RR for further testing in patients with metastatic esophageal or GE junction adenocarcinoma. The secondary objectives are:

  1. To evaluate overall survival (OS) for each of the regimens in this trial in patients with metastatic esophageal or GE junction adenocarcinoma.

  2. To evaluate progression-free survival (PFS) for each of the regimens in this trial in patients with metastatic esophageal or GE junction adenocarcinoma.

  3. To evaluate time to treatment failure (TTF) for each of the regimens in this trial in patients with metastatic esophageal or GE junction adenocarcinoma.

  4. To determine the type and severity of toxicities associated with each of these regimens in the multi-institutional phase II setting.

  5. Quantitative immunohistochemistry results will be correlated with objective response rate, overall survival and time to progression.

  6. To evaluate the cellular damage (apoptosis) as a result of oxaliplatin.

  7. To determine if germline EGFR variants correlate with skin rash in patients treated with cetuximab.

  8. To evaluate if a correlation exists between germline EGFR variants and tumor EFGR expression as measured by immunohistochemistry.

All subjects must be premedicated with diphenhydramine hydrochloride 50 mg IV (or a similar agent) prior to the first dose of cetuximab in an effort to minimize infusion and hypersensitivity reactions. Premedication is recommended prior to subsequent doses, but the dose of diphenhydramine (or similar agent) may be reduced at the investigator's discretion. More information is detailed in the protocol including a description of the premedication requirements. Patients were closely monitored for treatment-related adverse events. After completion of study treatment, patients are followed periodically for up to 2 years.

Study Design

Study Type:
Interventional
Actual Enrollment :
245 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
Randomized Phase II Study of ECF-C, IC-C, or FOLFOX-C in Metastatic Esophageal and GE Junction Cancer
Actual Study Start Date :
Sep 15, 2006
Actual Primary Completion Date :
Apr 1, 2011
Actual Study Completion Date :
Oct 15, 2014

Arms and Interventions

Arm Intervention/Treatment
Experimental: Arm A (ECF + cetuximab)

Patients receive cetuximab 400 mg/m^2 IV over 120 minutes on day 1 of the first cycle, then 250 mg/m^2 IV over 60 minutes thereafter. Patients receive cetuximab IV on days 1, 8 and 15. Patients receive epirubicin 50 mg/m^2 IV after cetuximab on day 1 followed by cisplatin 60 mg/m^2 IV over 60 minutes. On days 1-21, patients receive 5-fluorouracil 200 mg/m^2/day continuous IV infusion. Treatment repeats every 21 days in the absence of disease progression and unacceptable toxicity.

Biological: cetuximab
given IV
Other Names:
  • C225

    • Drug: ECF
    epirubicin and 5-fluorouracil given IV
    Other Names:
  • Ellence (epirubicin) and 5-fluorouracil (5-FU)

    		•
    Experimental: Arm B (IC + cetuximab)

    Patients receive cetuximab 400 mg/m^2 IV over 120 minutes on day 1 of the first cycle, then 250 mg/m^2 IV over 60 minutes thereafter. Patients receive cetuximab on days 1, 8 and 15. Patients receive cisplatin 30 mg/m^2 IV over 30 minutes on days 1 and 8 after cetuximab. Patients also receive irinotecan 65 mg/m^2 IV over 90 minutes on days 1 and 8 after receiving cisplatin.Treatment repeats every 21 days in the absence of disease progression and unacceptable toxicity.

    Biological: cetuximab
    given IV
    Other Names:
  • C225

    • Drug: IC
    cisplatin and irinotecan given IV
    Other Names:
  • Platinol-AQ (cisplatin), CPT-11 (irinotecan)

    		•
    Experimental: ARM C (FOLFOX + cetuximab)

    Patients receive cetuximab 400 mg/m^2 IV over 120 minutes on day 1 of the first cycle, then 250 mg/m^2 IV over 60 minutes thereafter. Patients receive cetuximab on days 1 and 8. On Day 1, patients also receive oxaliplatin 85 mg/m^2 IV over 120 minutes and leucovorin 400 mg/m^2 IV over 120 minutes either concurrently with oxaliplatin via a separate infusion line or post oxaliplatin administration. Following leucovorin, patients will receive 5-fluorouracil 400 mg/m^2 IV bolus injection, then 5-fluorouracil 2400 mg/m^2 IV infusion over 46-48 hours. Treatment repeats every 14 days in the absence of disease progression or unacceptable toxicity.

    Biological: cetuximab
    given IV
    Other Names:
  • C225

    • Drug: FOLFOX
    oxaliplatin , leucovorin and 5-fluorouracil IV
    Other Names:
  • Eloxatin (oxaliplatin), folinic acid (leucovorin), and 5-fluorouracil (5-FU)

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Response Rate (Complete and Partial) in Patients With Measurable Esophageal or GE Junction Adenocarcinoma [Up to 2 years post-treatment]

      Response was defined using Response Evaluation Criteria In Solid Tumors (RECIST) criteria: Complete Response (CR): disappearance of all target lesions; Partial Response (PR) 30% decrease in sum of longest diameter of target lesions; Progressive Disease (PD): 20% increase in sum of longest diameter of target lesions; Stable Disease (SD): small changes that do not meet above criteria. Overall tumor response is the total number of CR and PRs in participants with adenocarcinoma who have received at least one cycle of therapy.

    Secondary Outcome Measures

    1. Tumor Response Rate (Complete and Partial) in Patients With Squamous Cell Carcinoma [Up to 2 years post-treatment]

      Response was defined using Response Evaluation Criteria In Solid Tumors (RECIST) criteria: Complete Response (CR): disappearance of all target lesions; Partial Response (PR) 30% decrease in sum of longest diameter of target lesions; Progressive Disease (PD): 20% increase in sum of longest diameter of target lesions; Stable Disease (SD): small changes that do not meet above criteria. Overall tumor response is the total number of CR and PRs in participants with squamous cell carcinoma who have received at least one cycle of therapy.

    2. Overall Survival in Patients With Adenocarcinoma [Up to 2 years post-treatment]

      Overall survival (OS) was defined as the time from study entry to death of any cause. The median OS with 95% CI was estimated using the Kaplan Meier method.

    3. Progression-free Survival in Patients With Adenocarcinoma [Up to 2 years post-treatment]

      Progression free survival (PFS) was defined as the time from study entry to progression or death of any cause. The median PFS with 95% CI was estimated using the Kaplan Meier method.

    4. Time to Treatment Failure in Patients With Adenocarcinoma [Up to 2 years post-treatment]

      Time to treatment failure (TTF) was measured from study entry until documented progression, death resulting from any cause, or end of protocol therapy because of unacceptable toxicity. The median TTF with 95% CI was estimated using the Kaplan Meier method.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No

    1. Metastatic disease of the esophagus or gastroesophageal junction

    2. Histologic, cytologic or radiologic documentation of metastatic squamous cell carcinoma or adenocarcinoma of the esophagus or gastroesophageal junction. Radiologic, endoscopic, histologic or cytologic evidence of locally recurrent or locally residual (post-resection) disease is also permitted.

    3. For the purposes of this study, undifferentiated adenocarcinomas and adenosquamous tumors will be considered as adenocarcinomas. In addition, tumors involving the gastroesophageal junction will be defined by the Siewert classification.

    4. Patients with gastroesophageal junction tumors who are eligible:

    • AEG Type I: Adenocarcinoma of the distal esophagus which usually arises from an area with specialized intestinal metaplasia of the esophagus (eg, Barrett's esophagus, and may infiltrate the esophagogastric junction from above).

    • AEG Type II: True carcinoma of the cardia arising from the cardiac epithelium or short segments with intestinal metaplasia at the esophagogastric junction.

    1. Patients with gastroesophageal junction tumors who are NOT eligible:
    • AEG Type III: Subcardial gastric carcinoma which infiltrates the esophagogastric junction and distal esophagus from below.

    1. Patients must have at least one paraffin block available (or at least 15 unstained slides for analysis of tumor EGFR status.

    2. Patients with a history of esophageal and GE junction carcinoma treated by surgical resection who develop radiological or clinical evidence of metastatic cancer do not require separate histological or cytological confirmation of metastatic disease unless an interval of greater than five years has elapsed between the primary surgery and the development of metastatic disease OR the primary cancer was stage I.

    3. Clinicians should consider biopsy of lesions to establish the diagnosis of metastatic esophageal or GE junction carcinoma if there is substantial clinical ambiguity regarding the nature or source of apparent metastases.

    4. Patients with Measurable Disease - Lesions that can be accurately measured in at least one dimension (longest diameter to be recorded) as ≥ 20 mm with conventional techniques or as ≥ 10 mm with spiral CT scan.

    5. Prior Treatment:

    6. No prior chemotherapy or radiotherapy. No prior therapy which specifically and directly targets the EGF(R) pathway.

    7. No prior allergic reaction to chimerized or murine monoclonal antibody therapy or documented presence of human anti-mouse antibodies (HAMA).

    8. Patients must have completed any major surgery ≥ 4 weeks or any minor surgery ≥ 2 weeks before registration. Patients must have fully recovered from the procedure. Insertion of a vascular access device is not considered major or minor surgery.

    9. No concurrent use of investigational agents is allowed while participating in this study.

    10. Patient Characteristics:

    11. ECOG Performance Status of 0-2

    12. ≥ 18 years of age

    13. Patients must be documented to have a stable weight (or less than one pound weight loss) for at least one week prior to registration.

    14. Non-pregnant and not breast-feeding. The effects of cetuximab, cisplatin, epirubicin, fluorouracil, leucovorin, irinotecan, and oxaliplatin on a developing human fetus are not well-known. Because the risk of toxicity in nursing infants secondary to cetuximab, cisplatin, epirubicin, fluorouracil, irinotecan, and oxaliplatin treatment of the mother is unknown but may be harmful, breastfeeding must be discontinued.

    15. No myocardial infarction < 6 months prior to registration or New York Heart Association classification III or IV.

    16. No ≥ grade 2 diarrhea within 7 days prior to registration.

    17. Patients may not concurrently have any of the following conditions:

    18. Known central nervous system metastases or carcinomatous meningitis

    19. Interstitial pneumonia or symptomatic interstitial fibrosis of the lung

    20. Seizure disorder or active neurological disease requiring anti-epileptic medication

    21. ≥ grade 2 peripheral neuropathy

    22. No evidence of Gilbert's Syndrome - Patients with Gilbert's Syndrome may have a greater risk of irinotecan toxicity due to the abnormal glucuronidation of SN-38, the active metabolite of irinotecan. Evidence of Gilbert's Syndrome would include documentation of elevation of indirect bilirubin at any time in the patient's medical history.

    23. Required Initial Laboratory Data:

    24. Granulocytes ≥ 1500/µl

    25. Platelet count ≥ 100,000/µl

    26. Creatinine ≤ 1.5 mg/dL

    27. AST (SGOT) ≤ 5.0 x Upper limits of normal

    28. Total bilirubin ≤ 1.5 mg/dL

    29. Albumin ≥ 2.5 grams/dL

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Norwalk Hospital Norwalk Connecticut United States 06856
    2 Tunnell Cancer Center at Beebe Medical Center Lewes Delaware United States 19958
    3 CCOP - Christiana Care Health Services Newark Delaware United States 19713
    4 Lombardi Comprehensive Cancer Center at Georgetown University Medical Center Washington District of Columbia United States 20007
    5 Rush-Copley Cancer Care Center Aurora Illinois United States 60504
    6 St. Joseph Medical Center Bloomington Illinois United States 61701
    7 Graham Hospital Canton Illinois United States 61520
    8 Memorial Hospital Carthage Illinois United States 62321
    9 University of Chicago Cancer Research Center Chicago Illinois United States 60637-1470
    10 Decatur Memorial Hospital Cancer Care Institute Decatur Illinois United States 62526
    11 Eureka Community Hospital Eureka Illinois United States 61530
    12 Evanston Hospital Evanston Illinois United States 60201-1781
    13 Galesburg Clinic, PC Galesburg Illinois United States 61401
    14 Galesburg Cottage Hospital Galesburg Illinois United States 61401
    15 Ingalls Cancer Care Center at Ingalls Memorial Hospital Harvey Illinois United States 60426
    16 Mason District Hospital Havana Illinois United States 62644
    17 Hopedale Medical Complex Hopedale Illinois United States 61747
    18 Joliet Oncology-Hematology Associates, Limited - West Joliet Illinois United States 60435
    19 McDonough District Hospital Macomb Illinois United States 61455
    20 BroMenn Regional Medical Center Normal Illinois United States 61761
    21 Community Cancer Center Normal Illinois United States 61761
    22 Community Hospital of Ottawa Ottawa Illinois United States 61350
    23 Oncology Hematology Associates of Central Illinois, PC - Ottawa Ottawa Illinois United States 61350
    24 Cancer Treatment Center at Pekin Hospital Pekin Illinois United States 61554
    25 Proctor Hospital Peoria Illinois United States 61614
    26 CCOP - Illinois Oncology Research Association Peoria Illinois United States 61615
    27 Oncology Hematology Associates of Central Illinois, PC - Peoria Peoria Illinois United States 61615
    28 Methodist Medical Center of Illinois Peoria Illinois United States 61636
    29 OSF St. Francis Medical Center Peoria Illinois United States 61637
    30 Illinois Valley Community Hospital Peru Illinois United States 61354
    31 Perry Memorial Hospital Princeton Illinois United States 61356
    32 Swedish-American Regional Cancer Center Rockford Illinois United States 61104-2315
    33 St. Margaret's Hospital Spring Valley Illinois United States 61362
    34 Regional Cancer Center at Memorial Medical Center Springfield Illinois United States 62781-0001
    35 Carle Cancer Center at Carle Foundation Hospital Urbana Illinois United States 61801
    36 CCOP - Carle Cancer Center Urbana Illinois United States 61801
    37 Elkhart General Hospital Elkhart Indiana United States 46515
    38 Fort Wayne Medical Oncology and Hematology Fort Wayne Indiana United States 46845
    39 Indiana University Melvin and Bren Simon Cancer Center Indianapolis Indiana United States 46202-5289
    40 William N. Wishard Memorial Hospital Indianapolis Indiana United States 46202
    41 Howard Community Hospital Kokomo Indiana United States 46904
    42 Center for Cancer Therapy at LaPorte Hospital and Health Services La Porte Indiana United States 46350
    43 Saint Anthony Memorial Health Centers Michigan City Indiana United States 46360
    44 CCOP - Northern Indiana CR Consortium South Bend Indiana United States 46601
    45 Memorial Hospital of South Bend South Bend Indiana United States 46601
    46 Saint Joseph Regional Medical Center South Bend Indiana United States 46617
    47 South Bend Clinic South Bend Indiana United States 46617
    48 McFarland Clinic, PC Ames Iowa United States 50010
    49 Hematology Oncology Associates of the Quad Cities Bettendorf Iowa United States 52722
    50 Cedar Rapids Oncology Associates Cedar Rapids Iowa United States 52403
    51 Mercy Regional Cancer Center at Mercy Medical Center Cedar Rapids Iowa United States 52403
    52 Mercy Capitol Hospital Des Moines Iowa United States 50307
    53 CCOP - Iowa Oncology Research Association Des Moines Iowa United States 50309
    54 John Stoddard Cancer Center at Iowa Methodist Medical Center Des Moines Iowa United States 50309
    55 Medical Oncology and Hematology Associates at John Stoddard Cancer Center Des Moines Iowa United States 50309
    56 Medical Oncology and Hematology Associates at Mercy Cancer Center Des Moines Iowa United States 50314
    57 Mercy Cancer Center at Mercy Medical Center - Des Moines Des Moines Iowa United States 50314
    58 John Stoddard Cancer Center at Iowa Lutheran Hospital Des Moines Iowa United States 50316
    59 Holden Comprehensive Cancer Center at University of Iowa Iowa City Iowa United States 52242-1002
    60 Mercy Cancer Center at Mercy Medical Center - North Iowa Mason City Iowa United States 50401
    61 McCreery Cancer Center at Ottumwa Regional Ottumwa Iowa United States 52501
    62 Siouxland Hematology-Oncology Associates, LLP Sioux City Iowa United States 51101
    63 Mercy Medical Center - Sioux City Sioux City Iowa United States 51104
    64 St. Luke's Regional Medical Center Sioux City Iowa United States 51104
    65 Medical Oncology and Hematology Associates - West Des Moines West Des Moines Iowa United States 50266
    66 Hospital District Sixth of Harper County Anthony Kansas United States 67003
    67 Cancer Center of Kansas, PA - Chanute Chanute Kansas United States 66720
    68 Cancer Center of Kansas, PA - Dodge City Dodge City Kansas United States 67801
    69 Cancer Center of Kansas, PA - El Dorado El Dorado Kansas United States 67042
    70 Cancer Center of Kansas - Fort Scott Fort Scott Kansas United States 66701
    71 Cancer Center of Kansas-Independence Independence Kansas United States 67301
    72 Cancer Center of Kansas, PA - Kingman Kingman Kansas United States 67068
    73 Lawrence Memorial Hospital Lawrence Kansas United States 66044
    74 Southwest Medical Center Liberal Kansas United States 67901
    75 Cancer Center of Kansas, PA - Newton Newton Kansas United States 67114
    76 Menorah Medical Center Overland Park Kansas United States 66209
    77 Cancer Center of Kansas, PA - Parsons Parsons Kansas United States 67357
    78 Cancer Center of Kansas, PA - Pratt Pratt Kansas United States 67124
    79 Cancer Center of Kansas, PA - Salina Salina Kansas United States 67042
    80 Shawnee Mission Medical Center Shawnee Mission Kansas United States 66204
    81 Cancer Center of Kansas, PA - Wellington Wellington Kansas United States 67152
    82 Associates in Womens Health, PA - North Review Wichita Kansas United States 67208
    83 Cancer Center of Kansas, PA - Medical Arts Tower Wichita Kansas United States 67208
    84 Cancer Center of Kansas, PA - Wichita Wichita Kansas United States 67214
    85 CCOP - Wichita Wichita Kansas United States 67214
    86 Via Christi Cancer Center at Via Christi Regional Medical Center Wichita Kansas United States 67214
    87 Cancer Center of Kansas, PA - Winfield Winfield Kansas United States 67156
    88 CancerCare of Maine at Eastern Maine Medical Center Bangor Maine United States 04401
    89 Harry and Jeanette Weinberg Cancer Institute at Franklin Square Hospital Center Baltimore Maryland United States 21237
    90 Shore Regional Cancer Center at Memorial Hospital - Easton Easton Maryland United States 21601
    91 Union Hospital of Cecil County Elkton Maryland United States 21921
    92 Massachusetts General Hospital Boston Massachusetts United States 02114
    93 Dana-Farber/Brigham and Women's Cancer Center Boston Massachusetts United States 02115
    94 Dana-Farber/Harvard Cancer Center at Dana-Farber Cancer Institute Boston Massachusetts United States 02115
    95 Lahey Clinic Medical Center - Burlington Burlington Massachusetts United States 01805
    96 South Shore Hospital South Weymouth Massachusetts United States 02190
    97 Baystate Regional Cancer Program at D'Amour Center for Cancer Care Springfield Massachusetts United States 01199
    98 Saint Joseph Mercy Cancer Center Ann Arbor Michigan United States 48106-0995
    99 CCOP - Michigan Cancer Research Consortium Ann Arbor Michigan United States 48106
    100 Oakwood Cancer Center at Oakwood Hospital and Medical Center Dearborn Michigan United States 48123-2500
    101 Green Bay Oncology, Limited - Escanaba Escanaba Michigan United States 49431
    102 Genesys Hurley Cancer Institute Flint Michigan United States 48503
    103 Hurley Medical Center Flint Michigan United States 48503
    104 Van Elslander Cancer Center at St. John Hospital and Medical Center Grosse Pointe Woods Michigan United States 48236
    105 Dickinson County Healthcare System Iron Mountain Michigan United States 49801
    106 Foote Memorial Hospital Jackson Michigan United States 49201
    107 Borgess Medical Center Kalamazoo Michigan United States 49001
    108 West Michigan Cancer Center Kalamazoo Michigan United States 49007-3731
    109 Bronson Methodist Hospital Kalamazoo Michigan United States 49007
    110 Sparrow Regional Cancer Center Lansing Michigan United States 48912-1811
    111 St. Mary Mercy Hospital Livonia Michigan United States 48154
    112 St. Joseph Mercy Oakland Pontiac Michigan United States 48341-2985
    113 Mercy Regional Cancer Center at Mercy Hospital Port Huron Michigan United States 48060
    114 Seton Cancer Institute at Saint Mary's - Saginaw Saginaw Michigan United States 48601
    115 Lakeland Regional Cancer Care Center - St. Joseph Saint Joseph Michigan United States 49085
    116 Oncology Care Associates, PLLC Saint Joseph Michigan United States 49085
    117 St. John Macomb Hospital Warren Michigan United States 48093
    118 Fairview Ridges Hospital Burnsville Minnesota United States 55337
    119 Mercy and Unity Cancer Center at Mercy Hospital Coon Rapids Minnesota United States 55433
    120 Essentia Health - Duluth Clinic Duluth Minnesota United States 55805-1983
    121 CCOP - Duluth Duluth Minnesota United States 55805
    122 Miller - Dwan Medical Center Duluth Minnesota United States 55805
    123 Fairview Southdale Hospital Edina Minnesota United States 55435
    124 Mercy and Unity Cancer Center at Unity Hospital Fridley Minnesota United States 55432
    125 Hutchinson Area Health Care Hutchinson Minnesota United States 55350
    126 Meeker County Memorial Hospital Litchfield Minnesota United States 55355
    127 HealthEast Cancer Care at St. John's Hospital Maplewood Minnesota United States 55109
    128 Minnesota Oncology - Maplewood Maplewood Minnesota United States 55109
    129 Virginia Piper Cancer Institute at Abbott - Northwestern Hospital Minneapolis Minnesota United States 55407
    130 Hennepin County Medical Center - Minneapolis Minneapolis Minnesota United States 55415
    131 Veterans Affairs Medical Center - Minneapolis Minneapolis Minnesota United States 55417
    132 Humphrey Cancer Center at North Memorial Outpatient Center Robbinsdale Minnesota United States 55422-2900
    133 CCOP - Metro-Minnesota Saint Louis Park Minnesota United States 55416
    134 Park Nicollet Cancer Center Saint Louis Park Minnesota United States 55416
    135 Regions Hospital Cancer Care Center Saint Paul Minnesota United States 55101
    136 United Hospital Saint Paul Minnesota United States 55102
    137 St. Francis Cancer Center at St. Francis Medical Center Shakopee Minnesota United States 55379
    138 Ridgeview Medical Center Waconia Minnesota United States 55387
    139 Minnesota Oncology - Woodbury Woodbury Minnesota United States 55125
    140 Independence Regional Health Center Independence Missouri United States 64050
    141 Truman Medical Center - Hospital Hill Kansas City Missouri United States 64108
    142 Saint Luke's Cancer Institute at Saint Luke's Hospital Kansas City Missouri United States 64111
    143 St. Joseph Medical Center Kansas City Missouri United States 64114
    144 North Kansas City Hospital Kansas City Missouri United States 64116
    145 Parvin Radiation Oncology Kansas City Missouri United States 64116
    146 CCOP - Kansas City Kansas City Missouri United States 64131
    147 Research Medical Center Kansas City Missouri United States 64132
    148 Liberty Hospital Liberty Missouri United States 64068
    149 Heartland Regional Medical Center Saint Joseph Missouri United States 64506
    150 Missouri Baptist Cancer Center Saint Louis Missouri United States 63131
    151 Arch Medical Services, Incorporated at Center for Cancer Care and Research Saint Louis Missouri United States 63141
    152 CCOP - Missouri Valley Cancer Consortium Omaha Nebraska United States 68106
    153 Methodist Estabrook Cancer Center Omaha Nebraska United States 68114
    154 Immanuel Medical Center Omaha Nebraska United States 68122
    155 Alegant Health Cancer Center at Bergan Mercy Medical Center Omaha Nebraska United States 68124
    156 Creighton University Medical Center Omaha Nebraska United States 68131-2197
    157 University Medical Center of Southern Nevada Las Vegas Nevada United States 89102
    158 CCOP - Nevada Cancer Research Foundation Las Vegas Nevada United States 89106
    159 Norris Cotton Cancer Center at Dartmouth-Hitchcock Medical Center Lebanon New Hampshire United States 03756-0002
    160 Fox Chase Virtua Health Cancer Program at Virtua Memorial Hospital Marlton Marlton New Jersey United States 08053
    161 Newark Beth Israel Medical Center Newark New Jersey United States 07112
    162 Frederick R. and Betty M. Smith Cancer Treatment Center Sparta New Jersey United States 07871
    163 Cancer Institute of New Jersey at Cooper - Voorhees Voorhees New Jersey United States 08043
    164 Fox Chase Virtua Health Cancer Program at Virtua West Jersey Voorhees New Jersey United States 08043
    165 Our Lady of Mercy Medical Center Comprehensive Cancer Center Bronx New York United States 10466
    166 Veterans Affairs Medical Center - Buffalo Buffalo New York United States 14215
    167 CCOP - Hematology-Oncology Associates of Central New York East Syracuse New York United States 13057
    168 Charles R. Wood Cancer Center at Glens Falls Hospital Glens Falls New York United States 12801
    169 Ralph Lauren Center for Cancer Care and Prevention New York New York United States 10035
    170 Memorial Sloan-Kettering Cancer Center New York New York United States 10065
    171 Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel Hill Chapel Hill North Carolina United States 27599-7295
    172 Blumenthal Cancer Center at Carolinas Medical Center Charlotte North Carolina United States 28232-2861
    173 Wayne Memorial Hospital, Incorporated Goldsboro North Carolina United States 27534
    174 Pardee Memorial Hospital Hendersonville North Carolina United States 28791
    175 Kinston Medical Specialists Kinston North Carolina United States 28501
    176 Summa Center for Cancer Care at Akron City Hospital Akron Ohio United States 44309-2090
    177 Aultman Cancer Center at Aultman Hospital Canton Ohio United States 44710-1799
    178 MetroHealth Cancer Care Center at MetroHealth Medical Center Cleveland Ohio United States 44109
    179 Arthur G. James Cancer Hospital and Richard J. Solove Research Institute at Ohio State University Comprehensive Cancer Center Columbus Ohio United States 43210-1240
    180 St. Rita's Medical Center Lima Ohio United States 45801
    181 Morgan Cancer Center at Lehigh Valley Hospital - Cedar Crest Allentown Pennsylvania United States 18105
    182 St. Luke's Cancer Network at St. Luke's Hospital Bethlehem Pennsylvania United States 18015
    183 Geisinger Cancer Institute at Geisinger Health Danville Pennsylvania United States 17822-0001
    184 Dale and Frances Hughes Cancer Center at Pocono Medical Center East Stroudsburg Pennsylvania United States 18301
    185 Geisinger Hazleton Cancer Center Hazleton Pennsylvania United States 18201
    186 Penn State Hershey Cancer Institute at Milton S. Hershey Medical Center Hershey Pennsylvania United States 17033-0850
    187 Lewistown Hospital Lewistown Pennsylvania United States 17044
    188 Abramson Cancer Center of the University of Pennsylvania Philadelphia Pennsylvania United States 19104-4283
    189 Kimmel Cancer Center at Thomas Jefferson University - Philadelphia Philadelphia Pennsylvania United States 19107-5541
    190 Joan Karnell Cancer Center at Pennsylvania Hospital Philadelphia Pennsylvania United States 19107
    191 Fox Chase Cancer Center - Philadelphia Philadelphia Pennsylvania United States 19111-2497
    192 Frankford Hospital Cancer Center - Torresdale Campus Philadelphia Pennsylvania United States 19114
    193 Hematology and Oncology Associates of Northeastern Pennsylvania Scranton Pennsylvania United States 18508
    194 Geisinger Medical Group - Scenery Park State College Pennsylvania United States 16801
    195 Mount Nittany Medical Center State College Pennsylvania United States 16803
    196 Frank M. and Dorothea Henry Cancer Center at Geisinger Wyoming Valley Medical Center Wilkes-Barre Pennsylvania United States 18711
    197 Mercy Hospital at Wilkes-Barre Wilkes-Barre Pennsylvania United States 18765
    198 Susquehanna Cancer Center at Divine Providence Hospital Williamsport Pennsylvania United States 17701
    199 McLeod Regional Medical Center Florence South Carolina United States 29501
    200 Avera Cancer Institute Sioux Falls South Dakota United States 57105
    201 Medical X-Ray Center, PC Sioux Falls South Dakota United States 57105
    202 Sanford Cancer Center at Sanford USD Medical Center Sioux Falls South Dakota United States 57117-5039
    203 Christine LaGuardia Phillips Cancer Center at Wellmont Holston Valley Medical Center Kingsport Tennessee United States 37662
    204 CCOP - Scott and White Hospital Temple Texas United States 76508
    205 Mountainview Medical Berlin Vermont United States 05602
    206 Fletcher Allen Health Care - University Health Center Campus Burlington Vermont United States 05401
    207 Danville Regional Medical Center Danville Virginia United States 24541
    208 Southwest Virginia Regional Cancer Center at Wellmonth Health Norton Virginia United States 24273
    209 Center for Cancer Treatment & Prevention at Sacred Heart Hospital Eau Claire Wisconsin United States 54701
    210 Marshfield Clinic Cancer Care at Regional Cancer Center Eau Claire Wisconsin United States 54701
    211 Green Bay Oncology, Limited at St. Vincent Hospital Regional Cancer Center Green Bay Wisconsin United States 54301-3526
    212 Green Bay Oncology, Limited at St. Mary's Hospital Green Bay Wisconsin United States 54303
    213 St. Mary's Hospital Medical Center - Green Bay Green Bay Wisconsin United States 54303
    214 St. Vincent Hospital Regional Cancer Center Green Bay Wisconsin United States 54307-3508
    215 Bay Area Cancer Care Center at Bay Area Medical Center Marinette Wisconsin United States 54143
    216 Saint Joseph's Hospital Marshfield Wisconsin United States 54449
    217 Medical Consultants, Limited Milwaukee Wisconsin United States 53215
    218 Marshfield Clinic - Lakeland Center Minocqua Wisconsin United States 54548
    219 Green Bay Oncology, Limited - Oconto Falls Oconto Falls Wisconsin United States 54154
    220 Ministry Medical Group at Saint Mary's Hospital Rhinelander Wisconsin United States 54501
    221 Marshfield Clinic - Indianhead Center Rice Lake Wisconsin United States 54868
    222 Saint Michael's Hospital Cancer Center Stevens Point Wisconsin United States 54481
    223 Green Bay Oncology, Limited - Sturgeon Bay Sturgeon Bay Wisconsin United States 54235
    224 Marshfield Clinic - Wausau Center Wausau Wisconsin United States 54401
    225 University of Wisconcin Cancer Center at Aspirus Wausau Hospital Wausau Wisconsin United States 54401
    226 Marshfield Clinic - Weston Center Weston Wisconsin United States 54476
    227 Marshfield Clinic - Wisconsin Rapids Center Wisconsin Rapids Wisconsin United States 54494

    Sponsors and Collaborators

    • Alliance for Clinical Trials in Oncology
    • National Cancer Institute (NCI)
    • Eastern Cooperative Oncology Group
    • Bristol-Myers Squibb
    • Sanofi
    • Pfizer

    Investigators

    • Study Chair: Peter Enzinger, MD, Dana-Farber Cancer Institute

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Alliance for Clinical Trials in Oncology
    ClinicalTrials.gov Identifier:
    NCT00381706
    Other Study ID Numbers:
    • CALGB-80403
    • ECOG-E1206
    • CDR0000505535
    • NCI-2009-00492
    First Posted:
    Sep 28, 2006
    Last Update Posted:
    Sep 29, 2021
    Last Verified:
    Sep 1, 2021
    Keywords provided by Alliance for Clinical Trials in Oncology
    squamous cell carcinoma of the esophagus
    adenocarcinoma of the esophagus
    stage IV esophageal cancer
    recurrent esophageal cancer
    Additional relevant MeSH terms:
    Esophageal Neoplasms
    Leucovorin
    Cisplatin
    Fluorouracil
    Oxaliplatin
    Irinotecan
    Cetuximab
    Epirubicin

    Study Results

    Participant Flow

    Recruitment Details Between September 2006 and May 2009, 245 participants were enrolled and randomized.
    Pre-assignment Detail Twenty three (23) participants had squamous cell carcinoma were excluded from the analysis.
    Arm/Group Title Arm A (ECF + Cetuximab) Arm B (IC + Cetuximab) ARM C (FOLFOX + Cetuximab)
    Arm/Group Description Patients receive cetuximab 400 mg/m^2 IV over 120 minutes on day 1 of the first cycle, then 250 mg/m^2 IV over 60 minutes thereafter. Patients receive cetuximab IV on days 1, 8 and 15. Patients receive epirubicin 50 mg/m^2 IV after cetuximab on day 1 followed by cisplatin 60 mg/m^2 IV over 60 minutes. On days 1-21, patients receive 5-fluorouracil 200 mg/m^2/day continuous IV infusion. Treatment repeats every 21 days in the absence of disease progression and unacceptable toxicity. Patients receive cetuximab 400 mg/m^2 IV over 120 minutes on day 1 of the first cycle, then 250 mg/m^2 IV over 60 minutes thereafter. Patients receive cetuximab on days 1, 8 and 15. Patients receive cisplatin 30 mg/m^2 IV over 30 minutes on days 1 and 8 after cetuximab. Patients also receive irinotecan 65 mg/m^2 IV over 90 minutes on days 1 and 8 after receiving cisplatin.Treatment repeats every 21 days in the absence of disease progression and unacceptable toxicity. Patients receive cetuximab 400 mg/m^2 IV over 120 minutes on day 1 of the first cycle, then 250 mg/m^2 IV over 60 minutes thereafter. Patients receive cetuximab on days 1 and 8. On Day 1, patients also receive oxaliplatin 85 mg/m^2 IV over 120 minutes and leucovorin 400 mg/m^2 IV over 120 minutes either concurrently with oxaliplatin via a separate infusion line or post oxaliplatin administration. Following leucovorin, patients will receive 5-fluorouracil 400 mg/m^2 IV bolus injection, then 5-fluorouracil 2400 mg/m^2 IV infusion over 46-48 hours. Treatment repeats every 14 days in the absence of disease progression or unacceptable toxicity.
    Period Title: Overall Study
    STARTED 82 83 80
    COMPLETED 75 81 79
    NOT COMPLETED 7 2 1

    Baseline Characteristics

    Arm/Group Title Arm A: Adenocarcinoma (ECF + Cetuximab) Arm B: Adenocarcinoma (IC + Cetuximab) Arm C: Adenocarcinoma (FOLFOX + Cetuximab) Arm A: Squamous Cell Carcinoma (ECF + Cetuximab) Arm B: Squamous Cell Carcinoma (IC + Cetuximab) Arm C: Squamous Cell Carcinoma (FOLFOX + Cetuximab) Total
    Arm/Group Description Patients receive cetuximab 400 mg/m^2 IV over 120 minutes on day 1 of the first cycle, then 250 mg/m^2 IV over 60 minutes thereafter. Patients receive cetuximab IV on days 1, 8 and 15. Patients receive epirubicin 50 mg/m^2 IV after cetuximab on day 1 followed by cisplatin 60 mg/m^2 IV over 60 minutes. On days 1-21, patients receive 5-fluorouracil 200 mg/m^2/day continuous IV infusion. Treatment repeats every 21 days in the absence of disease progression and unacceptable toxicity. Patients receive cetuximab 400 mg/m^2 IV over 120 minutes on day 1 of the first cycle, then 250 mg/m^2 IV over 60 minutes thereafter. Patients receive cetuximab on days 1, 8 and 15. Patients receive cisplatin 30 mg/m^2 IV over 30 minutes on days 1 and 8 after cetuximab. Patients also receive irinotecan 65 mg/m^2 IV over 90 minutes on days 1 and 8 after receiving cisplatin.Treatment repeats every 21 days in the absence of disease progression and unacceptable toxicity. Patients receive cetuximab 400 mg/m^2 IV over 120 minutes on day 1 of the first cycle, then 250 mg/m^2 IV over 60 minutes thereafter. Patients receive cetuximab on days 1 and 8. On Day 1, patients also receive oxaliplatin 85 mg/m^2 IV over 120 minutes and leucovorin 400 mg/m^2 IV over 120 minutes either concurrently with oxaliplatin via a separate infusion line or post oxaliplatin administration. Following leucovorin, patients will receive 5-fluorouracil 400 mg/m^2 IV bolus injection, then 5-fluorouracil 2400 mg/m^2 IV infusion over 46-48 hours. Treatment repeats every 14 days in the absence of disease progression or unacceptable toxicity. Patients receive cetuximab 400 mg/m^2 IV over 120 minutes on day 1 of the first cycle, then 250 mg/m^2 IV over 60 minutes thereafter. Patients receive cetuximab IV on days 1, 8 and 15. Patients receive epirubicin 50 mg/m^2 IV after cetuximab on day 1 followed by cisplatin 60 mg/m^2 IV over 60 minutes. On days 1-21, patients receive 5-fluorouracil 200 mg/m^2/day continuous IV infusion. Treatment repeats every 21 days in the absence of disease progression and unacceptable toxicity. Patients receive cetuximab 400 mg/m^2 IV over 120 minutes on day 1 of the first cycle, then 250 mg/m^2 IV over 60 minutes thereafter. Patients receive cetuximab on days 1, 8 and 15. Patients receive cisplatin 30 mg/m^2 IV over 30 minutes on days 1 and 8 after cetuximab. Patients also receive irinotecan 65 mg/m^2 IV over 90 minutes on days 1 and 8 after receiving cisplatin.Treatment repeats every 21 days in the absence of disease progression and unacceptable toxicity. Patients receive cetuximab 400 mg/m^2 IV over 120 minutes on day 1 of the first cycle, then 250 mg/m^2 IV over 60 minutes thereafter. Patients receive cetuximab on days 1 and 8. On Day 1, patients also receive oxaliplatin 85 mg/m^2 IV over 120 minutes and leucovorin 400 mg/m^2 IV over 120 minutes either concurrently with oxaliplatin via a separate infusion line or post oxaliplatin administration. Following leucovorin, patients will receive 5-fluorouracil 400 mg/m^2 IV bolus injection, then 5-fluorouracil 2400 mg/m^2 IV infusion over 46-48 hours. Treatment repeats every 14 days in the absence of disease progression or unacceptable toxicity. Total of all reporting groups
    Overall Participants 67 73 73 8 8 6 235
    Age (years) [Median (Full Range) ]
    Median (Full Range) [years]
    57.7
    60.3
    59.2
    61.6
    61.8
    61.2
    59.3
    Sex: Female, Male (Count of Participants)
    Female
    8
    11.9%
    13
    17.8%
    5
    6.8%
    2
    25%
    3
    37.5%
    1
    16.7%
    32
    13.6%
    Male
    59
    88.1%
    60
    82.2%
    68
    93.2%
    6
    75%
    5
    62.5%
    5
    83.3%
    203
    86.4%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Asian
    0
    0%
    1
    1.4%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    0.4%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Black or African American
    1
    1.5%
    2
    2.7%
    2
    2.7%
    2
    25%
    2
    25%
    0
    0%
    9
    3.8%
    White
    65
    97%
    69
    94.5%
    71
    97.3%
    6
    75%
    6
    75%
    6
    100%
    223
    94.9%
    More than one race
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    Unknown or Not Reported
    1
    1.5%
    1
    1.4%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    2
    0.9%
    Region of Enrollment (participants) [Number]
    United States
    67
    100%
    73
    100%
    73
    100%
    8
    100%
    8
    100%
    6
    100%
    235
    100%

    Outcome Measures

    1. Primary Outcome
    Title Response Rate (Complete and Partial) in Patients With Measurable Esophageal or GE Junction Adenocarcinoma
    Description Response was defined using Response Evaluation Criteria In Solid Tumors (RECIST) criteria: Complete Response (CR): disappearance of all target lesions; Partial Response (PR) 30% decrease in sum of longest diameter of target lesions; Progressive Disease (PD): 20% increase in sum of longest diameter of target lesions; Stable Disease (SD): small changes that do not meet above criteria. Overall tumor response is the total number of CR and PRs in participants with adenocarcinoma who have received at least one cycle of therapy.
    Time Frame Up to 2 years post-treatment

    Outcome Measure Data

    Analysis Population Description
    13 participants did not meet the protocol defined requirements to be evaluated for response (measurable adencarcinoma receiving at least 1 cycle of chemotherapy).
    Arm/Group Title Arm A: Adenocarcinoma (ECF + Cetuximab) Arm B: Adenocarcinoma (IC + Cetuximab) Arm C: Adenocarcinoma (FOLFOX + Cetuximab)
    Arm/Group Description Patients receive cetuximab 400 mg/m^2 IV over 120 minutes on day 1 of the first cycle, then 250 mg/m^2 IV over 60 minutes thereafter. Patients receive cetuximab IV on days 1, 8 and 15. Patients receive epirubicin 50 mg/m^2 IV after cetuximab on day 1 followed by cisplatin 60 mg/m^2 IV over 60 minutes. On days 1-21, patients receive 5-fluorouracil 200 mg/m^2/day continuous IV infusion. Treatment repeats every 21 days in the absence of disease progression and unacceptable toxicity. Patients receive cetuximab 400 mg/m^2 IV over 120 minutes on day 1 of the first cycle, then 250 mg/m^2 IV over 60 minutes thereafter. Patients receive cetuximab on days 1, 8 and 15. Patients receive cisplatin 30 mg/m^2 IV over 30 minutes on days 1 and 8 after cetuximab. Patients also receive irinotecan 65 mg/m^2 IV over 90 minutes on days 1 and 8 after receiving cisplatin.Treatment repeats every 21 days in the absence of disease progression and unacceptable toxicity. Patients receive cetuximab 400 mg/m^2 IV over 120 minutes on day 1 of the first cycle, then 250 mg/m^2 IV over 60 minutes thereafter. Patients receive cetuximab on days 1 and 8. On Day 1, patients also receive oxaliplatin 85 mg/m^2 IV over 120 minutes and leucovorin 400 mg/m^2 IV over 120 minutes either concurrently with oxaliplatin via a separate infusion line or post oxaliplatin administration. Following leucovorin, patients will receive 5-fluorouracil 400 mg/m^2 IV bolus injection, then 5-fluorouracil 2400 mg/m^2 IV infusion over 46-48 hours. Treatment repeats every 14 days in the absence of disease progression or unacceptable toxicity.
    Measure Participants 63 71 66
    Number (95% Confidence Interval) [percentage of participants]
    61
    91%
    45
    61.6%
    54
    74%
    2. Secondary Outcome
    Title Tumor Response Rate (Complete and Partial) in Patients With Squamous Cell Carcinoma
    Description Response was defined using Response Evaluation Criteria In Solid Tumors (RECIST) criteria: Complete Response (CR): disappearance of all target lesions; Partial Response (PR) 30% decrease in sum of longest diameter of target lesions; Progressive Disease (PD): 20% increase in sum of longest diameter of target lesions; Stable Disease (SD): small changes that do not meet above criteria. Overall tumor response is the total number of CR and PRs in participants with squamous cell carcinoma who have received at least one cycle of therapy.
    Time Frame Up to 2 years post-treatment

    Outcome Measure Data

    Analysis Population Description
    4 participants did not meet the protocol defined requirements to be evaluated for response (measurable squamous cell carcinoma receiving at least 1 cycle of chemotherapy).
    Arm/Group Title Arm A: Squamous Cell Carcinoma (ECF + Cetuximab) Arm B: Squamous Cell Carcinoma (IC + Cetuximab) Arm C: Squamous Cell Carcinoma (FOLFOX + Cetuximab)
    Arm/Group Description Patients receive cetuximab 400 mg/m^2 IV over 120 minutes on day 1 of the first cycle, then 250 mg/m^2 IV over 60 minutes thereafter. Patients receive cetuximab IV on days 1, 8 and 15. Patients receive epirubicin 50 mg/m^2 IV after cetuximab on day 1 followed by cisplatin 60 mg/m^2 IV over 60 minutes. On days 1-21, patients receive 5-fluorouracil 200 mg/m^2/day continuous IV infusion. Treatment repeats every 21 days in the absence of disease progression and unacceptable toxicity. Patients receive cetuximab 400 mg/m^2 IV over 120 minutes on day 1 of the first cycle, then 250 mg/m^2 IV over 60 minutes thereafter. Patients receive cetuximab on days 1, 8 and 15. Patients receive cisplatin 30 mg/m^2 IV over 30 minutes on days 1 and 8 after cetuximab. Patients also receive irinotecan 65 mg/m^2 IV over 90 minutes on days 1 and 8 after receiving cisplatin.Treatment repeats every 21 days in the absence of disease progression and unacceptable toxicity. Patients receive cetuximab 400 mg/m^2 IV over 120 minutes on day 1 of the first cycle, then 250 mg/m^2 IV over 60 minutes thereafter. Patients receive cetuximab on days 1 and 8. On Day 1, patients also receive oxaliplatin 85 mg/m^2 IV over 120 minutes and leucovorin 400 mg/m^2 IV over 120 minutes either concurrently with oxaliplatin via a separate infusion line or post oxaliplatin administration. Following leucovorin, patients will receive 5-fluorouracil 400 mg/m^2 IV bolus injection, then 5-fluorouracil 2400 mg/m^2 IV infusion over 46-48 hours. Treatment repeats every 14 days in the absence of disease progression or unacceptable toxicity.
    Measure Participants 6 8 5
    Number [percentage of participants]
    67
    100%
    13
    17.8%
    60
    82.2%
    3. Secondary Outcome
    Title Overall Survival in Patients With Adenocarcinoma
    Description Overall survival (OS) was defined as the time from study entry to death of any cause. The median OS with 95% CI was estimated using the Kaplan Meier method.
    Time Frame Up to 2 years post-treatment

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Arm A: Adenocarcinoma (ECF + Cetuximab) Arm B: Adenocarcinoma (IC + Cetuximab) Arm C: Adenocarcinoma (FOLFOX + Cetuximab)
    Arm/Group Description Patients receive cetuximab 400 mg/m^2 IV over 120 minutes on day 1 of the first cycle, then 250 mg/m^2 IV over 60 minutes thereafter. Patients receive cetuximab IV on days 1, 8 and 15. Patients receive epirubicin 50 mg/m^2 IV after cetuximab on day 1 followed by cisplatin 60 mg/m^2 IV over 60 minutes. On days 1-21, patients receive 5-fluorouracil 200 mg/m^2/day continuous IV infusion. Treatment repeats every 21 days in the absence of disease progression and unacceptable toxicity. Patients receive cetuximab 400 mg/m^2 IV over 120 minutes on day 1 of the first cycle, then 250 mg/m^2 IV over 60 minutes thereafter. Patients receive cetuximab on days 1, 8 and 15. Patients receive cisplatin 30 mg/m^2 IV over 30 minutes on days 1 and 8 after cetuximab. Patients also receive irinotecan 65 mg/m^2 IV over 90 minutes on days 1 and 8 after receiving cisplatin.Treatment repeats every 21 days in the absence of disease progression and unacceptable toxicity. Patients receive cetuximab 400 mg/m^2 IV over 120 minutes on day 1 of the first cycle, then 250 mg/m^2 IV over 60 minutes thereafter. Patients receive cetuximab on days 1 and 8. On Day 1, patients also receive oxaliplatin 85 mg/m^2 IV over 120 minutes and leucovorin 400 mg/m^2 IV over 120 minutes either concurrently with oxaliplatin via a separate infusion line or post oxaliplatin administration. Following leucovorin, patients will receive 5-fluorouracil 400 mg/m^2 IV bolus injection, then 5-fluorouracil 2400 mg/m^2 IV infusion over 46-48 hours. Treatment repeats every 14 days in the absence of disease progression or unacceptable toxicity.
    Measure Participants 67 73 73
    Median (95% Confidence Interval) [months]
    11.6
    8.6
    11.8
    4. Secondary Outcome
    Title Progression-free Survival in Patients With Adenocarcinoma
    Description Progression free survival (PFS) was defined as the time from study entry to progression or death of any cause. The median PFS with 95% CI was estimated using the Kaplan Meier method.
    Time Frame Up to 2 years post-treatment

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Arm A: Adenocarcinoma (ECF + Cetuximab) Arm B: Adenocarcinoma (IC + Cetuximab) Arm C: Adenocarcinoma (FOLFOX + Cetuximab)
    Arm/Group Description Patients receive cetuximab 400 mg/m^2 IV over 120 minutes on day 1 of the first cycle, then 250 mg/m^2 IV over 60 minutes thereafter. Patients receive cetuximab IV on days 1, 8 and 15. Patients receive epirubicin 50 mg/m^2 IV after cetuximab on day 1 followed by cisplatin 60 mg/m^2 IV over 60 minutes. On days 1-21, patients receive 5-fluorouracil 200 mg/m^2/day continuous IV infusion. Treatment repeats every 21 days in the absence of disease progression and unacceptable toxicity. Patients receive cetuximab 400 mg/m^2 IV over 120 minutes on day 1 of the first cycle, then 250 mg/m^2 IV over 60 minutes thereafter. Patients receive cetuximab on days 1, 8 and 15. Patients receive cisplatin 30 mg/m^2 IV over 30 minutes on days 1 and 8 after cetuximab. Patients also receive irinotecan 65 mg/m^2 IV over 90 minutes on days 1 and 8 after receiving cisplatin.Treatment repeats every 21 days in the absence of disease progression and unacceptable toxicity. Patients receive cetuximab 400 mg/m^2 IV over 120 minutes on day 1 of the first cycle, then 250 mg/m^2 IV over 60 minutes thereafter. Patients receive cetuximab on days 1 and 8. On Day 1, patients also receive oxaliplatin 85 mg/m^2 IV over 120 minutes and leucovorin 400 mg/m^2 IV over 120 minutes either concurrently with oxaliplatin via a separate infusion line or post oxaliplatin administration. Following leucovorin, patients will receive 5-fluorouracil 400 mg/m^2 IV bolus injection, then 5-fluorouracil 2400 mg/m^2 IV infusion over 46-48 hours. Treatment repeats every 14 days in the absence of disease progression or unacceptable toxicity.
    Measure Participants 67 73 73
    Median (95% Confidence Interval) [months]
    7.1
    4.9
    6.8
    5. Secondary Outcome
    Title Time to Treatment Failure in Patients With Adenocarcinoma
    Description Time to treatment failure (TTF) was measured from study entry until documented progression, death resulting from any cause, or end of protocol therapy because of unacceptable toxicity. The median TTF with 95% CI was estimated using the Kaplan Meier method.
    Time Frame Up to 2 years post-treatment

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Arm A: Adenocarcinoma (ECF + Cetuximab) Arm B: Adenocarcinoma (IC + Cetuximab) Arm C: Adenocarcinoma (FOLFOX + Cetuximab)
    Arm/Group Description Patients receive cetuximab 400 mg/m^2 IV over 120 minutes on day 1 of the first cycle, then 250 mg/m^2 IV over 60 minutes thereafter. Patients receive cetuximab IV on days 1, 8 and 15. Patients receive epirubicin 50 mg/m^2 IV after cetuximab on day 1 followed by cisplatin 60 mg/m^2 IV over 60 minutes. On days 1-21, patients receive 5-fluorouracil 200 mg/m^2/day continuous IV infusion. Treatment repeats every 21 days in the absence of disease progression and unacceptable toxicity. Patients receive cetuximab 400 mg/m^2 IV over 120 minutes on day 1 of the first cycle, then 250 mg/m^2 IV over 60 minutes thereafter. Patients receive cetuximab on days 1, 8 and 15. Patients receive cisplatin 30 mg/m^2 IV over 30 minutes on days 1 and 8 after cetuximab. Patients also receive irinotecan 65 mg/m^2 IV over 90 minutes on days 1 and 8 after receiving cisplatin.Treatment repeats every 21 days in the absence of disease progression and unacceptable toxicity. Patients receive cetuximab 400 mg/m^2 IV over 120 minutes on day 1 of the first cycle, then 250 mg/m^2 IV over 60 minutes thereafter. Patients receive cetuximab on days 1 and 8. On Day 1, patients also receive oxaliplatin 85 mg/m^2 IV over 120 minutes and leucovorin 400 mg/m^2 IV over 120 minutes either concurrently with oxaliplatin via a separate infusion line or post oxaliplatin administration. Following leucovorin, patients will receive 5-fluorouracil 400 mg/m^2 IV bolus injection, then 5-fluorouracil 2400 mg/m^2 IV infusion over 46-48 hours. Treatment repeats every 14 days in the absence of disease progression or unacceptable toxicity.
    Measure Participants 67 73 73
    Median (95% Confidence Interval) [months]
    5.6
    4.3
    6.7

    Adverse Events

    Time Frame
    Adverse Event Reporting Description
    Arm/Group Title Arm A: Adenocarcinoma (ECF + Cetuximab) Arm B: Adenocarcinoma (IC + Cetuximab) Arm C: Adenocarcinoma (FOLFOX + Cetuximab) Arm A: Squamous Cell Carcinoma (ECF + Cetuximab) Arm B: Squamous Cell Carcinoma (IC + Cetuximab) Arm C: Squamous Cell Carcinoma (FOLFOX + Cetuximab)
    Arm/Group Description Patients receive cetuximab 400 mg/m^2 IV over 120 minutes on day 1 of the first cycle, then 250 mg/m^2 IV over 60 minutes thereafter. Patients receive cetuximab IV on days 1, 8 and 15. Patients receive epirubicin 50 mg/m^2 IV after cetuximab on day 1 followed by cisplatin 60 mg/m^2 IV over 60 minutes. On days 1-21, patients receive 5-fluorouracil 200 mg/m^2/day continuous IV infusion. Treatment repeats every 21 days in the absence of disease progression and unacceptable toxicity. Patients receive cetuximab 400 mg/m^2 IV over 120 minutes on day 1 of the first cycle, then 250 mg/m^2 IV over 60 minutes thereafter. Patients receive cetuximab on days 1, 8 and 15. Patients receive cisplatin 30 mg/m^2 IV over 30 minutes on days 1 and 8 after cetuximab. Patients also receive irinotecan 65 mg/m^2 IV over 90 minutes on days 1 and 8 after receiving cisplatin.Treatment repeats every 21 days in the absence of disease progression and unacceptable toxicity. Patients receive cetuximab 400 mg/m^2 IV over 120 minutes on day 1 of the first cycle, then 250 mg/m^2 IV over 60 minutes thereafter. Patients receive cetuximab on days 1 and 8. On Day 1, patients also receive oxaliplatin 85 mg/m^2 IV over 120 minutes and leucovorin 400 mg/m^2 IV over 120 minutes either concurrently with oxaliplatin via a separate infusion line or post oxaliplatin administration. Following leucovorin, patients will receive 5-fluorouracil 400 mg/m^2 IV bolus injection, then 5-fluorouracil 2400 mg/m^2 IV infusion over 46-48 hours. Treatment repeats every 14 days in the absence of disease progression or unacceptable toxicity. Patients receive cetuximab 400 mg/m^2 IV over 120 minutes on day 1 of the first cycle, then 250 mg/m^2 IV over 60 minutes thereafter. Patients receive cetuximab IV on days 1, 8 and 15. Patients receive epirubicin 50 mg/m^2 IV after cetuximab on day 1 followed by cisplatin 60 mg/m^2 IV over 60 minutes. On days 1-21, patients receive 5-fluorouracil 200 mg/m^2/day continuous IV infusion. Treatment repeats every 21 days in the absence of disease progression and unacceptable toxicity. Patients receive cetuximab 400 mg/m^2 IV over 120 minutes on day 1 of the first cycle, then 250 mg/m^2 IV over 60 minutes thereafter. Patients receive cetuximab on days 1, 8 and 15. Patients receive cisplatin 30 mg/m^2 IV over 30 minutes on days 1 and 8 after cetuximab. Patients also receive irinotecan 65 mg/m^2 IV over 90 minutes on days 1 and 8 after receiving cisplatin.Treatment repeats every 21 days in the absence of disease progression and unacceptable toxicity. Patients receive cetuximab 400 mg/m^2 IV over 120 minutes on day 1 of the first cycle, then 250 mg/m^2 IV over 60 minutes thereafter. Patients receive cetuximab on days 1 and 8. On Day 1, patients also receive oxaliplatin 85 mg/m^2 IV over 120 minutes and leucovorin 400 mg/m^2 IV over 120 minutes either concurrently with oxaliplatin via a separate infusion line or post oxaliplatin administration. Following leucovorin, patients will receive 5-fluorouracil 400 mg/m^2 IV bolus injection, then 5-fluorouracil 2400 mg/m^2 IV infusion over 46-48 hours. Treatment repeats every 14 days in the absence of disease progression or unacceptable toxicity.
    All Cause Mortality
    Arm A: Adenocarcinoma (ECF + Cetuximab) Arm B: Adenocarcinoma (IC + Cetuximab) Arm C: Adenocarcinoma (FOLFOX + Cetuximab) Arm A: Squamous Cell Carcinoma (ECF + Cetuximab) Arm B: Squamous Cell Carcinoma (IC + Cetuximab) Arm C: Squamous Cell Carcinoma (FOLFOX + Cetuximab)
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total / (NaN) / (NaN) / (NaN) / (NaN) / (NaN) / (NaN)
    Serious Adverse Events
    Arm A: Adenocarcinoma (ECF + Cetuximab) Arm B: Adenocarcinoma (IC + Cetuximab) Arm C: Adenocarcinoma (FOLFOX + Cetuximab) Arm A: Squamous Cell Carcinoma (ECF + Cetuximab) Arm B: Squamous Cell Carcinoma (IC + Cetuximab) Arm C: Squamous Cell Carcinoma (FOLFOX + Cetuximab)
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 15/67 (22.4%) 23/73 (31.5%) 22/73 (30.1%) 2/8 (25%) 2/8 (25%) 1/6 (16.7%)
    Blood and lymphatic system disorders
    Blood disorder 1/67 (1.5%) 1 0/73 (0%) 0 1/73 (1.4%) 1 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Febrile neutropenia 1/67 (1.5%) 1 3/73 (4.1%) 3 1/73 (1.4%) 1 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Hemoglobin decreased 7/67 (10.4%) 11 12/73 (16.4%) 12 9/73 (12.3%) 10 2/8 (25%) 4 1/8 (12.5%) 1 1/6 (16.7%) 2
    Hemolysis 0/67 (0%) 0 1/73 (1.4%) 1 1/73 (1.4%) 1 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Cardiac disorders
    Atrial fibrillation 1/67 (1.5%) 1 0/73 (0%) 0 0/73 (0%) 0 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Edema 0/67 (0%) 0 1/73 (1.4%) 1 0/73 (0%) 0 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Left ventricular dysfunction 0/67 (0%) 0 0/73 (0%) 0 1/73 (1.4%) 1 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Myocardial ischemia 0/67 (0%) 0 0/73 (0%) 0 1/73 (1.4%) 1 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Sinus tachycardia 0/67 (0%) 0 0/73 (0%) 0 1/73 (1.4%) 1 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Ventricular tachycardia 0/67 (0%) 0 0/73 (0%) 0 1/73 (1.4%) 1 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Ear and labyrinth disorders
    Tinnitus 1/67 (1.5%) 1 0/73 (0%) 0 0/73 (0%) 0 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Eye disorders
    Eye disorder 0/67 (0%) 0 1/73 (1.4%) 1 0/73 (0%) 0 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Gastrointestinal disorders
    Abdominal pain 1/67 (1.5%) 1 2/73 (2.7%) 2 4/73 (5.5%) 4 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Ascites 1/67 (1.5%) 1 0/73 (0%) 0 0/73 (0%) 0 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Colitis 0/67 (0%) 0 2/73 (2.7%) 3 0/73 (0%) 0 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Constipation 3/67 (4.5%) 3 3/73 (4.1%) 4 1/73 (1.4%) 1 2/8 (25%) 2 2/8 (25%) 2 1/6 (16.7%) 1
    Diarrhea 3/67 (4.5%) 3 15/73 (20.5%) 17 8/73 (11%) 8 2/8 (25%) 3 1/8 (12.5%) 1 1/6 (16.7%) 2
    Dyspepsia 0/67 (0%) 0 1/73 (1.4%) 1 1/73 (1.4%) 1 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Dysphagia 0/67 (0%) 0 0/73 (0%) 0 3/73 (4.1%) 3 1/8 (12.5%) 2 1/8 (12.5%) 1 0/6 (0%) 0
    Ear, nose and throat examination abnormal 2/67 (3%) 2 2/73 (2.7%) 2 1/73 (1.4%) 1 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Esophageal hemorrhage 1/67 (1.5%) 2 0/73 (0%) 0 1/73 (1.4%) 1 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Esophageal obstruction 0/67 (0%) 0 0/73 (0%) 0 0/73 (0%) 0 0/8 (0%) 0 1/8 (12.5%) 1 0/6 (0%) 0
    Esophageal ulcer 0/67 (0%) 0 0/73 (0%) 0 0/73 (0%) 0 0/8 (0%) 0 0/8 (0%) 0 1/6 (16.7%) 1
    Esophagitis 0/67 (0%) 0 0/73 (0%) 0 0/73 (0%) 0 0/8 (0%) 0 1/8 (12.5%) 1 0/6 (0%) 0
    Gastritis 0/67 (0%) 0 0/73 (0%) 0 1/73 (1.4%) 1 0/8 (0%) 0 0/8 (0%) 0 1/6 (16.7%) 1
    Gastrointestinal disorder 0/67 (0%) 0 1/73 (1.4%) 2 0/73 (0%) 0 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Hematemesis 0/67 (0%) 0 1/73 (1.4%) 1 0/73 (0%) 0 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Hemorrhoids 1/67 (1.5%) 1 0/73 (0%) 0 0/73 (0%) 0 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Mucositis oral 3/67 (4.5%) 3 1/73 (1.4%) 1 5/73 (6.8%) 5 0/8 (0%) 0 1/8 (12.5%) 1 0/6 (0%) 0
    Nausea 5/67 (7.5%) 6 8/73 (11%) 9 4/73 (5.5%) 4 1/8 (12.5%) 1 2/8 (25%) 2 1/6 (16.7%) 1
    Oral pain 0/67 (0%) 0 1/73 (1.4%) 1 0/73 (0%) 0 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Pancreatitis 0/67 (0%) 0 0/73 (0%) 0 1/73 (1.4%) 1 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Rectal hemorrhage 0/67 (0%) 0 0/73 (0%) 0 1/73 (1.4%) 1 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Small intestinal obstruction 0/67 (0%) 0 1/73 (1.4%) 1 0/73 (0%) 0 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Stomach pain 1/67 (1.5%) 1 0/73 (0%) 0 0/73 (0%) 0 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Toothache 1/67 (1.5%) 1 0/73 (0%) 0 0/73 (0%) 0 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Upper gastrointestinal hemorrhage 0/67 (0%) 0 0/73 (0%) 0 0/73 (0%) 0 0/8 (0%) 0 0/8 (0%) 0 1/6 (16.7%) 2
    Vomiting 6/67 (9%) 6 8/73 (11%) 10 9/73 (12.3%) 9 1/8 (12.5%) 1 2/8 (25%) 2 1/6 (16.7%) 3
    General disorders
    Chest pain 0/67 (0%) 0 1/73 (1.4%) 1 1/73 (1.4%) 1 0/8 (0%) 0 1/8 (12.5%) 1 1/6 (16.7%) 1
    Chills 1/67 (1.5%) 2 3/73 (4.1%) 3 3/73 (4.1%) 3 1/8 (12.5%) 1 0/8 (0%) 0 0/6 (0%) 0
    Disease progression 1/67 (1.5%) 1 1/73 (1.4%) 1 0/73 (0%) 0 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Edema limbs 1/67 (1.5%) 1 3/73 (4.1%) 3 2/73 (2.7%) 2 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Fatigue 9/67 (13.4%) 12 19/73 (26%) 21 15/73 (20.5%) 18 2/8 (25%) 4 2/8 (25%) 2 1/6 (16.7%) 1
    Fever 1/67 (1.5%) 2 1/73 (1.4%) 1 0/73 (0%) 0 1/8 (12.5%) 1 0/8 (0%) 0 1/6 (16.7%) 1
    Pain 2/67 (3%) 2 0/73 (0%) 0 1/73 (1.4%) 1 0/8 (0%) 0 0/8 (0%) 0 1/6 (16.7%) 2
    Sudden death 2/67 (3%) 2 1/73 (1.4%) 1 0/73 (0%) 0 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Immune system disorders
    Cytokine release syndrome 0/67 (0%) 0 0/73 (0%) 0 1/73 (1.4%) 1 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Hypersensitivity 2/67 (3%) 2 0/73 (0%) 0 0/73 (0%) 0 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Infections and infestations
    Catheter related infection 2/67 (3%) 2 1/73 (1.4%) 1 0/73 (0%) 0 1/8 (12.5%) 1 0/8 (0%) 0 0/6 (0%) 0
    Hepatic infection 0/67 (0%) 0 0/73 (0%) 0 1/73 (1.4%) 1 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Infectious colitis 0/67 (0%) 0 0/73 (0%) 0 0/73 (0%) 0 0/8 (0%) 0 0/8 (0%) 0 1/6 (16.7%) 1
    Jejunal infection 0/67 (0%) 0 0/73 (0%) 0 0/73 (0%) 0 0/8 (0%) 0 0/8 (0%) 0 1/6 (16.7%) 1
    Opportunistic infection 0/67 (0%) 0 1/73 (1.4%) 1 0/73 (0%) 0 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Viral hepatitis 0/67 (0%) 0 0/73 (0%) 0 1/73 (1.4%) 1 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Injury, poisoning and procedural complications
    Vascular access complication 1/67 (1.5%) 1 1/73 (1.4%) 1 0/73 (0%) 0 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Investigations
    Activated partial thromboplastin time prolonged 0/67 (0%) 0 1/73 (1.4%) 1 1/73 (1.4%) 1 1/8 (12.5%) 1 1/8 (12.5%) 1 0/6 (0%) 0
    Alanine aminotransferase increased 0/67 (0%) 0 3/73 (4.1%) 3 1/73 (1.4%) 1 1/8 (12.5%) 1 0/8 (0%) 0 0/6 (0%) 0
    Alkaline phosphatase increased 1/67 (1.5%) 1 4/73 (5.5%) 4 3/73 (4.1%) 3 0/8 (0%) 0 1/8 (12.5%) 1 1/6 (16.7%) 1
    Amylase increased 1/67 (1.5%) 1 0/73 (0%) 0 0/73 (0%) 0 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Aspartate aminotransferase increased 0/67 (0%) 0 2/73 (2.7%) 2 4/73 (5.5%) 4 1/8 (12.5%) 1 0/8 (0%) 0 1/6 (16.7%) 2
    Blood bilirubin increased 0/67 (0%) 0 4/73 (5.5%) 4 2/73 (2.7%) 2 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Cardiac troponin I increased 0/67 (0%) 0 0/73 (0%) 0 1/73 (1.4%) 1 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Coagulopathy 0/67 (0%) 0 0/73 (0%) 0 1/73 (1.4%) 1 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Creatinine increased 3/67 (4.5%) 4 3/73 (4.1%) 3 4/73 (5.5%) 4 1/8 (12.5%) 2 0/8 (0%) 0 0/6 (0%) 0
    Fibrinogen decreased 0/67 (0%) 0 0/73 (0%) 0 1/73 (1.4%) 1 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    INR increased 0/67 (0%) 0 2/73 (2.7%) 2 1/73 (1.4%) 1 1/8 (12.5%) 1 0/8 (0%) 0 0/6 (0%) 0
    Laboratory test abnormal 1/67 (1.5%) 1 0/73 (0%) 0 2/73 (2.7%) 2 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Leukocyte count decreased 6/67 (9%) 7 8/73 (11%) 8 5/73 (6.8%) 5 2/8 (25%) 2 1/8 (12.5%) 1 1/6 (16.7%) 1
    Lipase increased 0/67 (0%) 0 0/73 (0%) 0 2/73 (2.7%) 2 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Lymphocyte count decreased 2/67 (3%) 3 5/73 (6.8%) 5 4/73 (5.5%) 5 1/8 (12.5%) 2 0/8 (0%) 0 1/6 (16.7%) 2
    Neutrophil count decreased 10/67 (14.9%) 12 14/73 (19.2%) 16 7/73 (9.6%) 7 2/8 (25%) 3 1/8 (12.5%) 1 1/6 (16.7%) 2
    Platelet count decreased 4/67 (6%) 5 7/73 (9.6%) 7 7/73 (9.6%) 8 1/8 (12.5%) 2 0/8 (0%) 0 0/6 (0%) 0
    Weight loss 2/67 (3%) 2 2/73 (2.7%) 2 1/73 (1.4%) 1 0/8 (0%) 0 1/8 (12.5%) 1 1/6 (16.7%) 2
    Metabolism and nutrition disorders
    Anorexia 4/67 (6%) 5 7/73 (9.6%) 8 6/73 (8.2%) 6 2/8 (25%) 2 1/8 (12.5%) 1 1/6 (16.7%) 1
    Blood bicarbonate decreased 1/67 (1.5%) 1 0/73 (0%) 0 1/73 (1.4%) 1 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Blood glucose increased 4/67 (6%) 4 8/73 (11%) 9 6/73 (8.2%) 7 1/8 (12.5%) 2 1/8 (12.5%) 1 1/6 (16.7%) 2
    Dehydration 4/67 (6%) 4 5/73 (6.8%) 5 0/73 (0%) 0 0/8 (0%) 0 1/8 (12.5%) 1 1/6 (16.7%) 1
    Serum albumin decreased 4/67 (6%) 5 11/73 (15.1%) 12 11/73 (15.1%) 11 1/8 (12.5%) 1 2/8 (25%) 2 1/6 (16.7%) 2
    Serum calcium decreased 4/67 (6%) 4 7/73 (9.6%) 7 7/73 (9.6%) 8 1/8 (12.5%) 3 0/8 (0%) 0 1/6 (16.7%) 2
    Serum calcium increased 0/67 (0%) 0 0/73 (0%) 0 0/73 (0%) 0 1/8 (12.5%) 1 0/8 (0%) 0 0/6 (0%) 0
    Serum glucose decreased 1/67 (1.5%) 1 0/73 (0%) 0 0/73 (0%) 0 0/8 (0%) 0 0/8 (0%) 0 1/6 (16.7%) 1
    Serum magnesium decreased 4/67 (6%) 5 12/73 (16.4%) 13 9/73 (12.3%) 10 2/8 (25%) 4 1/8 (12.5%) 1 1/6 (16.7%) 3
    Serum magnesium increased 0/67 (0%) 0 1/73 (1.4%) 1 0/73 (0%) 0 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Serum phosphate decreased 1/67 (1.5%) 1 4/73 (5.5%) 4 2/73 (2.7%) 2 1/8 (12.5%) 1 0/8 (0%) 0 1/6 (16.7%) 1
    Serum potassium decreased 4/67 (6%) 4 7/73 (9.6%) 8 7/73 (9.6%) 7 1/8 (12.5%) 1 2/8 (25%) 2 1/6 (16.7%) 1
    Serum potassium increased 0/67 (0%) 0 2/73 (2.7%) 2 0/73 (0%) 0 1/8 (12.5%) 1 0/8 (0%) 0 1/6 (16.7%) 1
    Serum sodium decreased 1/67 (1.5%) 2 9/73 (12.3%) 9 5/73 (6.8%) 6 0/8 (0%) 0 1/8 (12.5%) 1 1/6 (16.7%) 2
    Musculoskeletal and connective tissue disorders
    Back pain 0/67 (0%) 0 1/73 (1.4%) 1 1/73 (1.4%) 1 0/8 (0%) 0 0/8 (0%) 0 1/6 (16.7%) 1
    Bone pain 0/67 (0%) 0 1/73 (1.4%) 1 0/73 (0%) 0 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Buttock pain 0/67 (0%) 0 0/73 (0%) 0 0/73 (0%) 0 0/8 (0%) 0 0/8 (0%) 0 1/6 (16.7%) 1
    Chest wall pain 1/67 (1.5%) 1 0/73 (0%) 0 0/73 (0%) 0 1/8 (12.5%) 1 0/8 (0%) 0 0/6 (0%) 0
    Muscle weakness 1/67 (1.5%) 1 1/73 (1.4%) 1 1/73 (1.4%) 1 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Muscle weakness lower limb 1/67 (1.5%) 1 0/73 (0%) 0 0/73 (0%) 0 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Myalgia 0/67 (0%) 0 1/73 (1.4%) 1 1/73 (1.4%) 1 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Neck pain 0/67 (0%) 0 0/73 (0%) 0 0/73 (0%) 0 0/8 (0%) 0 0/8 (0%) 0 1/6 (16.7%) 1
    Pain in extremity 0/67 (0%) 0 1/73 (1.4%) 1 1/73 (1.4%) 1 0/8 (0%) 0 0/8 (0%) 0 1/6 (16.7%) 1
    Nervous system disorders
    Ataxia 0/67 (0%) 0 1/73 (1.4%) 1 0/73 (0%) 0 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Dizziness 2/67 (3%) 3 0/73 (0%) 0 0/73 (0%) 0 0/8 (0%) 0 1/8 (12.5%) 1 0/6 (0%) 0
    Dysgeusia 0/67 (0%) 0 2/73 (2.7%) 2 1/73 (1.4%) 1 1/8 (12.5%) 1 0/8 (0%) 0 0/6 (0%) 0
    Headache 1/67 (1.5%) 1 0/73 (0%) 0 0/73 (0%) 0 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Peripheral sensory neuropathy 3/67 (4.5%) 4 3/73 (4.1%) 4 9/73 (12.3%) 10 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Syncope 1/67 (1.5%) 1 3/73 (4.1%) 3 1/73 (1.4%) 1 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Syncope vasovagal 1/67 (1.5%) 1 0/73 (0%) 0 0/73 (0%) 0 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Tremor 0/67 (0%) 0 1/73 (1.4%) 1 0/73 (0%) 0 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Psychiatric disorders
    Anxiety 0/67 (0%) 0 0/73 (0%) 0 1/73 (1.4%) 1 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Confusion 0/67 (0%) 0 2/73 (2.7%) 2 1/73 (1.4%) 1 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Depression 2/67 (3%) 2 0/73 (0%) 0 1/73 (1.4%) 1 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Insomnia 1/67 (1.5%) 1 1/73 (1.4%) 1 3/73 (4.1%) 3 0/8 (0%) 0 0/8 (0%) 0 1/6 (16.7%) 1
    Renal and urinary disorders
    Glomerular filtration rate decreased 0/67 (0%) 0 0/73 (0%) 0 0/73 (0%) 0 1/8 (12.5%) 2 0/8 (0%) 0 0/6 (0%) 0
    Hemoglobin urine positive 0/67 (0%) 0 1/73 (1.4%) 1 0/73 (0%) 0 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Proteinuria 1/67 (1.5%) 1 1/73 (1.4%) 1 0/73 (0%) 0 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Renal failure 0/67 (0%) 0 0/73 (0%) 0 1/73 (1.4%) 1 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Respiratory, thoracic and mediastinal disorders
    Adult respiratory distress syndrome 0/67 (0%) 0 0/73 (0%) 0 1/73 (1.4%) 1 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Allergic rhinitis 0/67 (0%) 0 1/73 (1.4%) 1 0/73 (0%) 0 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Aspiration 0/67 (0%) 0 1/73 (1.4%) 1 1/73 (1.4%) 1 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Cough 2/67 (3%) 2 0/73 (0%) 0 1/73 (1.4%) 1 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Dyspnea 3/67 (4.5%) 3 5/73 (6.8%) 5 6/73 (8.2%) 6 1/8 (12.5%) 1 0/8 (0%) 0 0/6 (0%) 0
    Dyspnea (shortness of breath) 0/67 (0%) 0 1/73 (1.4%) 1 0/73 (0%) 0 0/8 (0%) 0 1/8 (12.5%) 1 0/6 (0%) 0
    Epistaxis 0/67 (0%) 0 0/73 (0%) 0 1/73 (1.4%) 1 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Hemoptysis 0/67 (0%) 0 0/73 (0%) 0 0/73 (0%) 0 0/8 (0%) 0 1/8 (12.5%) 1 0/6 (0%) 0
    Hiccups 0/67 (0%) 0 1/73 (1.4%) 1 0/73 (0%) 0 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Hypoxia 0/67 (0%) 0 0/73 (0%) 0 1/73 (1.4%) 1 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Pharyngolaryngeal pain 0/67 (0%) 0 0/73 (0%) 0 0/73 (0%) 0 1/8 (12.5%) 1 0/8 (0%) 0 0/6 (0%) 0
    Pleural effusion 1/67 (1.5%) 1 0/73 (0%) 0 0/73 (0%) 0 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Pleuritic pain 0/67 (0%) 0 0/73 (0%) 0 1/73 (1.4%) 1 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Pneumonitis 0/67 (0%) 0 1/73 (1.4%) 1 0/73 (0%) 0 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Skin and subcutaneous tissue disorders
    Alopecia 3/67 (4.5%) 3 3/73 (4.1%) 3 1/73 (1.4%) 1 1/8 (12.5%) 2 0/8 (0%) 0 0/6 (0%) 0
    Dry skin 1/67 (1.5%) 2 3/73 (4.1%) 4 0/73 (0%) 0 1/8 (12.5%) 2 0/8 (0%) 0 0/6 (0%) 0
    Erythema multiforme 0/67 (0%) 0 0/73 (0%) 0 1/73 (1.4%) 1 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Hand-and-foot syndrome 2/67 (3%) 3 1/73 (1.4%) 1 2/73 (2.7%) 2 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Nail disorder 1/67 (1.5%) 1 0/73 (0%) 0 1/73 (1.4%) 1 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Pruritus 0/67 (0%) 0 2/73 (2.7%) 3 1/73 (1.4%) 1 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Rash acneiform 4/67 (6%) 4 9/73 (12.3%) 9 8/73 (11%) 10 0/8 (0%) 0 1/8 (12.5%) 1 0/6 (0%) 0
    Rash desquamating 1/67 (1.5%) 2 3/73 (4.1%) 3 0/73 (0%) 0 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Skin hyperpigmentation 1/67 (1.5%) 1 0/73 (0%) 0 0/73 (0%) 0 1/8 (12.5%) 1 0/8 (0%) 0 0/6 (0%) 0
    Vascular disorders
    Hemorrhage/bleeding without grade 3 or 4 thrombocytopenia 0/67 (0%) 0 0/73 (0%) 0 0/73 (0%) 0 0/8 (0%) 0 1/8 (12.5%) 1 0/6 (0%) 0
    Hypotension 2/67 (3%) 2 4/73 (5.5%) 4 2/73 (2.7%) 2 0/8 (0%) 0 0/8 (0%) 0 1/6 (16.7%) 1
    Thrombosis 3/67 (4.5%) 3 8/73 (11%) 8 7/73 (9.6%) 8 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Other (Not Including Serious) Adverse Events
    Arm A: Adenocarcinoma (ECF + Cetuximab) Arm B: Adenocarcinoma (IC + Cetuximab) Arm C: Adenocarcinoma (FOLFOX + Cetuximab) Arm A: Squamous Cell Carcinoma (ECF + Cetuximab) Arm B: Squamous Cell Carcinoma (IC + Cetuximab) Arm C: Squamous Cell Carcinoma (FOLFOX + Cetuximab)
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 65/67 (97%) 68/73 (93.2%) 71/73 (97.3%) 8/8 (100%) 8/8 (100%) 6/6 (100%)
    Blood and lymphatic system disorders
    Blood disorder 2/67 (3%) 36 1/73 (1.4%) 3 2/73 (2.7%) 21 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Febrile neutropenia 3/67 (4.5%) 3 1/73 (1.4%) 1 2/73 (2.7%) 2 1/8 (12.5%) 1 0/8 (0%) 0 0/6 (0%) 0
    Hemoglobin decreased 47/67 (70.1%) 264 56/73 (76.7%) 312 49/73 (67.1%) 326 5/8 (62.5%) 25 4/8 (50%) 16 4/6 (66.7%) 35
    Hemolysis 2/67 (3%) 3 4/73 (5.5%) 10 2/73 (2.7%) 13 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Cardiac disorders
    Atrial fibrillation 0/67 (0%) 0 1/73 (1.4%) 2 1/73 (1.4%) 1 0/8 (0%) 0 0/8 (0%) 0 1/6 (16.7%) 1
    Atrial tachycardia 0/67 (0%) 0 1/73 (1.4%) 3 0/73 (0%) 0 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Cardiac pain 0/67 (0%) 0 1/73 (1.4%) 1 0/73 (0%) 0 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Conduction disorder 1/67 (1.5%) 1 1/73 (1.4%) 1 1/73 (1.4%) 1 1/8 (12.5%) 1 0/8 (0%) 0 0/6 (0%) 0
    Edema 0/67 (0%) 0 0/73 (0%) 0 1/73 (1.4%) 1 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Left ventricular dysfunction 2/67 (3%) 5 1/73 (1.4%) 1 1/73 (1.4%) 1 1/8 (12.5%) 1 0/8 (0%) 0 0/6 (0%) 0
    Left ventricular failure 1/67 (1.5%) 1 0/73 (0%) 0 0/73 (0%) 0 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Myocardial ischemia 0/67 (0%) 0 0/73 (0%) 0 0/73 (0%) 0 1/8 (12.5%) 1 0/8 (0%) 0 0/6 (0%) 0
    Palpitations 0/67 (0%) 0 0/73 (0%) 0 3/73 (4.1%) 3 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Sinus tachycardia 2/67 (3%) 4 0/73 (0%) 0 2/73 (2.7%) 5 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Supraventricular tachycardia 1/67 (1.5%) 1 1/73 (1.4%) 2 0/73 (0%) 0 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Ventricular arrhythmia 0/67 (0%) 0 0/73 (0%) 0 1/73 (1.4%) 1 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Ear and labyrinth disorders
    Ear disorder 1/67 (1.5%) 3 1/73 (1.4%) 1 0/73 (0%) 0 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    External ear pain 0/67 (0%) 0 0/73 (0%) 0 1/73 (1.4%) 1 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Hearing impaired 2/67 (3%) 15 7/73 (9.6%) 10 0/73 (0%) 0 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Tinnitus 6/67 (9%) 8 5/73 (6.8%) 17 0/73 (0%) 0 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Endocrine disorders
    Endocrine disorder 0/67 (0%) 0 0/73 (0%) 0 1/73 (1.4%) 3 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Hypothyroidism 0/67 (0%) 0 1/73 (1.4%) 12 0/73 (0%) 0 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Eye disorders
    Conjunctivitis 1/67 (1.5%) 2 0/73 (0%) 0 1/73 (1.4%) 4 1/8 (12.5%) 1 0/8 (0%) 0 0/6 (0%) 0
    Diplopia 1/67 (1.5%) 1 0/73 (0%) 0 0/73 (0%) 0 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Dry eye syndrome 2/67 (3%) 4 0/73 (0%) 0 0/73 (0%) 0 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Extraocular muscle paresis 0/67 (0%) 0 0/73 (0%) 0 1/73 (1.4%) 1 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Eye disorder 3/67 (4.5%) 6 0/73 (0%) 0 3/73 (4.1%) 4 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Eyelid function disorder 1/67 (1.5%) 2 0/73 (0%) 0 0/73 (0%) 0 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Flashing vision 0/67 (0%) 0 1/73 (1.4%) 2 0/73 (0%) 0 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Photophobia 1/67 (1.5%) 1 0/73 (0%) 0 0/73 (0%) 0 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Vision blurred 1/67 (1.5%) 1 3/73 (4.1%) 3 2/73 (2.7%) 3 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Watering eyes 3/67 (4.5%) 7 0/73 (0%) 0 0/73 (0%) 0 1/8 (12.5%) 6 0/8 (0%) 0 0/6 (0%) 0
    Gastrointestinal disorders
    Abdominal distension 2/67 (3%) 2 4/73 (5.5%) 4 3/73 (4.1%) 4 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Abdominal pain 14/67 (20.9%) 30 26/73 (35.6%) 66 14/73 (19.2%) 27 2/8 (25%) 3 3/8 (37.5%) 3 1/6 (16.7%) 1
    Anal pain 0/67 (0%) 0 0/73 (0%) 0 1/73 (1.4%) 1 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Cheilitis 0/67 (0%) 0 1/73 (1.4%) 2 2/73 (2.7%) 3 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Constipation 38/67 (56.7%) 102 39/73 (53.4%) 94 38/73 (52.1%) 137 5/8 (62.5%) 6 2/8 (25%) 3 2/6 (33.3%) 6
    Diarrhea 35/67 (52.2%) 85 54/73 (74%) 175 45/73 (61.6%) 162 5/8 (62.5%) 9 5/8 (62.5%) 6 4/6 (66.7%) 9
    Dry mouth 4/67 (6%) 11 1/73 (1.4%) 1 2/73 (2.7%) 8 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Dyspepsia 10/67 (14.9%) 15 7/73 (9.6%) 12 11/73 (15.1%) 23 1/8 (12.5%) 1 1/8 (12.5%) 1 0/6 (0%) 0
    Dysphagia 22/67 (32.8%) 47 18/73 (24.7%) 45 14/73 (19.2%) 51 3/8 (37.5%) 8 2/8 (25%) 2 1/6 (16.7%) 4
    Ear, nose and throat examination abnormal 30/67 (44.8%) 82 12/73 (16.4%) 26 18/73 (24.7%) 54 4/8 (50%) 11 0/8 (0%) 0 2/6 (33.3%) 13
    Enteritis 0/67 (0%) 0 0/73 (0%) 0 1/73 (1.4%) 2 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Esophageal hemorrhage 0/67 (0%) 0 0/73 (0%) 0 1/73 (1.4%) 1 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Esophageal mucositis 1/67 (1.5%) 2 0/73 (0%) 0 0/73 (0%) 0 1/8 (12.5%) 1 0/8 (0%) 0 0/6 (0%) 0
    Esophageal pain 0/67 (0%) 0 3/73 (4.1%) 4 1/73 (1.4%) 6 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Esophageal stenosis 0/67 (0%) 0 0/73 (0%) 0 1/73 (1.4%) 1 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Esophageal varices hemorrhage 0/67 (0%) 0 1/73 (1.4%) 1 0/73 (0%) 0 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Esophagitis 8/67 (11.9%) 13 3/73 (4.1%) 4 2/73 (2.7%) 3 0/8 (0%) 0 1/8 (12.5%) 1 1/6 (16.7%) 3
    Flatulence 3/67 (4.5%) 3 0/73 (0%) 0 2/73 (2.7%) 14 0/8 (0%) 0 0/8 (0%) 0 1/6 (16.7%) 1
    Gastric hemorrhage 1/67 (1.5%) 1 0/73 (0%) 0 0/73 (0%) 0 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Gastric ulcer 1/67 (1.5%) 4 1/73 (1.4%) 1 0/73 (0%) 0 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Gastritis 1/67 (1.5%) 1 1/73 (1.4%) 3 1/73 (1.4%) 5 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Gastrointestinal disorder 2/67 (3%) 2 4/73 (5.5%) 6 4/73 (5.5%) 5 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Gastrointestinal pain 0/67 (0%) 0 0/73 (0%) 0 1/73 (1.4%) 2 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Hemorrhoids 1/67 (1.5%) 1 2/73 (2.7%) 2 1/73 (1.4%) 1 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Ileus 0/67 (0%) 0 0/73 (0%) 0 0/73 (0%) 0 0/8 (0%) 0 1/8 (12.5%) 1 0/6 (0%) 0
    Intra-abdominal hemorrhage 0/67 (0%) 0 0/73 (0%) 0 1/73 (1.4%) 1 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Lower gastrointestinal hemorrhage 1/67 (1.5%) 1 0/73 (0%) 0 0/73 (0%) 0 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Malabsorption 0/67 (0%) 0 1/73 (1.4%) 1 0/73 (0%) 0 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Mucositis oral 30/67 (44.8%) 81 12/73 (16.4%) 25 29/73 (39.7%) 94 2/8 (25%) 8 1/8 (12.5%) 1 2/6 (33.3%) 8
    Nausea 48/67 (71.6%) 164 54/73 (74%) 151 42/73 (57.5%) 175 7/8 (87.5%) 17 3/8 (37.5%) 6 5/6 (83.3%) 16
    Oesophagoscopy abnormal 2/67 (3%) 3 0/73 (0%) 0 0/73 (0%) 0 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Oral hemorrhage 1/67 (1.5%) 3 0/73 (0%) 0 0/73 (0%) 0 0/8 (0%) 0 1/8 (12.5%) 1 0/6 (0%) 0
    Oral pain 2/67 (3%) 5 1/73 (1.4%) 1 1/73 (1.4%) 1 0/8 (0%) 0 1/8 (12.5%) 1 0/6 (0%) 0
    Proctitis 0/67 (0%) 0 0/73 (0%) 0 1/73 (1.4%) 3 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Proctoscopy abnormal 1/67 (1.5%) 1 0/73 (0%) 0 0/73 (0%) 0 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Rectal hemorrhage 2/67 (3%) 2 3/73 (4.1%) 5 2/73 (2.7%) 3 0/8 (0%) 0 1/8 (12.5%) 1 0/6 (0%) 0
    Rectal pain 1/67 (1.5%) 1 0/73 (0%) 0 0/73 (0%) 0 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Stomach pain 1/67 (1.5%) 2 4/73 (5.5%) 6 7/73 (9.6%) 12 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Tooth disorder 1/67 (1.5%) 1 0/73 (0%) 0 1/73 (1.4%) 1 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Toothache 2/67 (3%) 2 0/73 (0%) 0 0/73 (0%) 0 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Upper gastrointestinal hemorrhage 0/67 (0%) 0 1/73 (1.4%) 1 0/73 (0%) 0 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Vomiting 29/67 (43.3%) 65 34/73 (46.6%) 84 33/73 (45.2%) 61 4/8 (50%) 10 4/8 (50%) 4 4/6 (66.7%) 10
    General disorders
    Chest pain 8/67 (11.9%) 9 4/73 (5.5%) 4 7/73 (9.6%) 23 1/8 (12.5%) 2 1/8 (12.5%) 1 0/6 (0%) 0
    Chills 8/67 (11.9%) 12 12/73 (16.4%) 21 14/73 (19.2%) 27 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Edema limbs 7/67 (10.4%) 10 14/73 (19.2%) 24 9/73 (12.3%) 17 0/8 (0%) 0 0/8 (0%) 0 1/6 (16.7%) 1
    Facial pain 1/67 (1.5%) 1 0/73 (0%) 0 1/73 (1.4%) 1 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Fatigue 63/67 (94%) 318 65/73 (89%) 330 61/73 (83.6%) 558 8/8 (100%) 44 6/8 (75%) 8 5/6 (83.3%) 23
    Fever 4/67 (6%) 6 5/73 (6.8%) 6 11/73 (15.1%) 12 0/8 (0%) 0 0/8 (0%) 0 2/6 (33.3%) 2
    Flu-like symptoms 0/67 (0%) 0 0/73 (0%) 0 1/73 (1.4%) 2 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    General symptom 0/67 (0%) 0 0/73 (0%) 0 1/73 (1.4%) 1 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Ill-defined disorder 0/67 (0%) 0 0/73 (0%) 0 2/73 (2.7%) 2 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Injection site reaction 1/67 (1.5%) 1 0/73 (0%) 0 1/73 (1.4%) 7 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Localized edema 1/67 (1.5%) 2 3/73 (4.1%) 5 1/73 (1.4%) 1 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Pain 12/67 (17.9%) 19 6/73 (8.2%) 10 6/73 (8.2%) 17 0/8 (0%) 0 1/8 (12.5%) 1 2/6 (33.3%) 5
    Visceral edema 0/67 (0%) 0 0/73 (0%) 0 1/73 (1.4%) 1 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Hepatobiliary disorders
    Hepatic failure 0/67 (0%) 0 1/73 (1.4%) 1 0/73 (0%) 0 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Immune system disorders
    Cytokine release syndrome 0/67 (0%) 0 0/73 (0%) 0 1/73 (1.4%) 1 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Hypersensitivity 8/67 (11.9%) 9 5/73 (6.8%) 7 7/73 (9.6%) 7 0/8 (0%) 0 1/8 (12.5%) 1 1/6 (16.7%) 1
    Infections and infestations
    Abdominal infection 0/67 (0%) 0 0/73 (0%) 0 1/73 (1.4%) 1 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Bronchitis 1/67 (1.5%) 1 0/73 (0%) 0 0/73 (0%) 0 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Catheter related infection 6/67 (9%) 7 2/73 (2.7%) 4 1/73 (1.4%) 3 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Conjunctivitis infective 1/67 (1.5%) 1 0/73 (0%) 0 1/73 (1.4%) 2 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Corneal infection 0/67 (0%) 0 0/73 (0%) 0 1/73 (1.4%) 1 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Device related infection 0/67 (0%) 0 1/73 (1.4%) 1 1/73 (1.4%) 2 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Eye infection 1/67 (1.5%) 1 0/73 (0%) 0 0/73 (0%) 0 1/8 (12.5%) 1 0/8 (0%) 0 0/6 (0%) 0
    Gingival infection 1/67 (1.5%) 1 0/73 (0%) 0 1/73 (1.4%) 1 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Infection 5/67 (7.5%) 7 0/73 (0%) 0 3/73 (4.1%) 4 0/8 (0%) 0 0/8 (0%) 0 1/6 (16.7%) 1
    Infection with unknown ANC 1/67 (1.5%) 1 0/73 (0%) 0 0/73 (0%) 0 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Infection without neutropenia 1/67 (1.5%) 1 1/73 (1.4%) 4 0/73 (0%) 0 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Lip infection 2/67 (3%) 2 0/73 (0%) 0 0/73 (0%) 0 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Mucosal infection 0/67 (0%) 0 2/73 (2.7%) 2 0/73 (0%) 0 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Nail infection 5/67 (7.5%) 10 3/73 (4.1%) 4 1/73 (1.4%) 1 0/8 (0%) 0 0/8 (0%) 0 1/6 (16.7%) 13
    Opportunistic infection 0/67 (0%) 0 1/73 (1.4%) 1 1/73 (1.4%) 1 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Otitis externa 0/67 (0%) 0 0/73 (0%) 0 1/73 (1.4%) 2 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Otitis media 0/67 (0%) 0 0/73 (0%) 0 1/73 (1.4%) 2 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Pneumonia 0/67 (0%) 0 1/73 (1.4%) 1 3/73 (4.1%) 3 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Scrotal infection 0/67 (0%) 0 0/73 (0%) 0 1/73 (1.4%) 1 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Sepsis 0/67 (0%) 0 0/73 (0%) 0 1/73 (1.4%) 1 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Sinusitis 3/67 (4.5%) 4 0/73 (0%) 0 2/73 (2.7%) 2 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Skin infection 5/67 (7.5%) 6 4/73 (5.5%) 6 3/73 (4.1%) 3 1/8 (12.5%) 1 0/8 (0%) 0 0/6 (0%) 0
    Upper aerodigestive tract infection 0/67 (0%) 0 1/73 (1.4%) 1 0/73 (0%) 0 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Upper respiratory infection 1/67 (1.5%) 2 4/73 (5.5%) 5 2/73 (2.7%) 2 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Urinary tract infection 1/67 (1.5%) 1 0/73 (0%) 0 2/73 (2.7%) 3 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Wound infection 0/67 (0%) 0 0/73 (0%) 0 1/73 (1.4%) 2 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Injury, poisoning and procedural complications
    Bruising 0/67 (0%) 0 0/73 (0%) 0 1/73 (1.4%) 1 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Fracture 0/67 (0%) 0 0/73 (0%) 0 1/73 (1.4%) 5 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Radiation recall reaction (dermatologic) 1/67 (1.5%) 1 0/73 (0%) 0 1/73 (1.4%) 4 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Thermal burn 0/67 (0%) 0 1/73 (1.4%) 1 0/73 (0%) 0 1/8 (12.5%) 1 0/8 (0%) 0 0/6 (0%) 0
    Vascular access complication 3/67 (4.5%) 4 2/73 (2.7%) 2 1/73 (1.4%) 1 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Wound dehiscence 1/67 (1.5%) 2 1/73 (1.4%) 1 2/73 (2.7%) 2 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Investigations
    Activated partial thromboplastin time prolonged 0/67 (0%) 0 0/73 (0%) 0 2/73 (2.7%) 4 0/8 (0%) 0 1/8 (12.5%) 1 0/6 (0%) 0
    Alanine aminotransferase increased 9/67 (13.4%) 17 23/73 (31.5%) 47 17/73 (23.3%) 59 2/8 (25%) 2 1/8 (12.5%) 1 0/6 (0%) 0
    Alkaline phosphatase 1/67 (1.5%) 4 0/73 (0%) 0 0/73 (0%) 0 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Alkaline phosphatase increased 15/67 (22.4%) 36 24/73 (32.9%) 62 24/73 (32.9%) 92 2/8 (25%) 2 2/8 (25%) 7 2/6 (33.3%) 3
    Aspartate aminotransferase increased 14/67 (20.9%) 19 21/73 (28.8%) 34 27/73 (37%) 91 2/8 (25%) 2 2/8 (25%) 3 1/6 (16.7%) 3
    Blood bilirubin increased 1/67 (1.5%) 2 6/73 (8.2%) 8 4/73 (5.5%) 26 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    CD4 lymphocytes decreased 0/67 (0%) 0 1/73 (1.4%) 1 0/73 (0%) 0 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Creatinine increased 18/67 (26.9%) 57 11/73 (15.1%) 32 3/73 (4.1%) 3 2/8 (25%) 4 0/8 (0%) 0 0/6 (0%) 0
    INR increased 2/67 (3%) 6 2/73 (2.7%) 3 4/73 (5.5%) 40 0/8 (0%) 0 2/8 (25%) 2 1/6 (16.7%) 2
    Laboratory test abnormal 5/67 (7.5%) 43 1/73 (1.4%) 1 3/73 (4.1%) 3 0/8 (0%) 0 1/8 (12.5%) 1 0/6 (0%) 0
    Leukocyte count decreased 38/67 (56.7%) 158 39/73 (53.4%) 165 33/73 (45.2%) 228 2/8 (25%) 2 2/8 (25%) 10 3/6 (50%) 8
    Lipase increased 0/67 (0%) 0 0/73 (0%) 0 1/73 (1.4%) 1 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Lymphocyte count decreased 9/67 (13.4%) 47 13/73 (17.8%) 54 11/73 (15.1%) 107 2/8 (25%) 2 1/8 (12.5%) 5 1/6 (16.7%) 5
    Lymphopenia for pediatric BMT studies 0/67 (0%) 0 0/73 (0%) 0 1/73 (1.4%) 5 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Neutrophil count decreased 51/67 (76.1%) 228 46/73 (63%) 192 40/73 (54.8%) 198 7/8 (87.5%) 33 5/8 (62.5%) 16 4/6 (66.7%) 6
    Platelet count decreased 25/67 (37.3%) 74 29/73 (39.7%) 115 32/73 (43.8%) 239 3/8 (37.5%) 14 3/8 (37.5%) 6 2/6 (33.3%) 7
    Serum cholesterol increased 0/67 (0%) 0 0/73 (0%) 0 4/73 (5.5%) 10 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Weight gain 2/67 (3%) 2 2/73 (2.7%) 2 3/73 (4.1%) 5 1/8 (12.5%) 1 0/8 (0%) 0 0/6 (0%) 0
    Weight loss 15/67 (22.4%) 27 24/73 (32.9%) 53 18/73 (24.7%) 64 2/8 (25%) 2 3/8 (37.5%) 12 2/6 (33.3%) 6
    Metabolism and nutrition disorders
    Anorexia 33/67 (49.3%) 102 34/73 (46.6%) 88 35/73 (47.9%) 130 4/8 (50%) 7 3/8 (37.5%) 3 2/6 (33.3%) 6
    Blood bicarbonate decreased 1/67 (1.5%) 1 2/73 (2.7%) 4 3/73 (4.1%) 5 1/8 (12.5%) 1 0/8 (0%) 0 0/6 (0%) 0
    Blood glucose increased 31/67 (46.3%) 145 38/73 (52.1%) 154 31/73 (42.5%) 225 3/8 (37.5%) 16 2/8 (25%) 2 3/6 (50%) 24
    Dehydration 17/67 (25.4%) 39 28/73 (38.4%) 61 14/73 (19.2%) 34 3/8 (37.5%) 3 3/8 (37.5%) 3 2/6 (33.3%) 2
    Serum albumin decreased 18/67 (26.9%) 59 35/73 (47.9%) 136 31/73 (42.5%) 145 1/8 (12.5%) 13 5/8 (62.5%) 11 3/6 (50%) 33
    Serum calcium decreased 22/67 (32.8%) 53 27/73 (37%) 78 18/73 (24.7%) 69 1/8 (12.5%) 1 3/8 (37.5%) 11 3/6 (50%) 4
    Serum calcium increased 2/67 (3%) 2 1/73 (1.4%) 1 6/73 (8.2%) 12 1/8 (12.5%) 1 1/8 (12.5%) 1 0/6 (0%) 0
    Serum glucose decreased 1/67 (1.5%) 1 5/73 (6.8%) 5 7/73 (9.6%) 11 1/8 (12.5%) 1 1/8 (12.5%) 1 1/6 (16.7%) 1
    Serum magnesium decreased 40/67 (59.7%) 180 51/73 (69.9%) 255 38/73 (52.1%) 238 5/8 (62.5%) 34 4/8 (50%) 15 3/6 (50%) 10
    Serum magnesium increased 0/67 (0%) 0 1/73 (1.4%) 2 0/73 (0%) 0 0/8 (0%) 0 1/8 (12.5%) 1 0/6 (0%) 0
    Serum phosphate decreased 3/67 (4.5%) 3 5/73 (6.8%) 9 3/73 (4.1%) 3 1/8 (12.5%) 1 0/8 (0%) 0 0/6 (0%) 0
    Serum potassium decreased 22/67 (32.8%) 61 29/73 (39.7%) 77 31/73 (42.5%) 91 1/8 (12.5%) 4 2/8 (25%) 7 3/6 (50%) 10
    Serum potassium increased 3/67 (4.5%) 5 6/73 (8.2%) 9 7/73 (9.6%) 13 3/8 (37.5%) 6 0/8 (0%) 0 0/6 (0%) 0
    Serum sodium decreased 26/67 (38.8%) 62 34/73 (46.6%) 79 26/73 (35.6%) 60 0/8 (0%) 0 3/8 (37.5%) 7 3/6 (50%) 6
    Serum sodium increased 1/67 (1.5%) 1 0/73 (0%) 0 0/73 (0%) 0 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Musculoskeletal and connective tissue disorders
    Arthralgia 7/67 (10.4%) 12 5/73 (6.8%) 18 3/73 (4.1%) 29 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Arthritis 0/67 (0%) 0 1/73 (1.4%) 1 0/73 (0%) 0 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Back pain 7/67 (10.4%) 13 12/73 (16.4%) 22 12/73 (16.4%) 27 1/8 (12.5%) 1 0/8 (0%) 0 0/6 (0%) 0
    Bone pain 1/67 (1.5%) 3 2/73 (2.7%) 6 4/73 (5.5%) 7 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Buttock pain 0/67 (0%) 0 0/73 (0%) 0 2/73 (2.7%) 2 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Chest wall pain 4/67 (6%) 7 5/73 (6.8%) 8 1/73 (1.4%) 2 2/8 (25%) 9 0/8 (0%) 0 0/6 (0%) 0
    Joint disorder 0/67 (0%) 0 1/73 (1.4%) 1 0/73 (0%) 0 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Muscle weakness 4/67 (6%) 5 6/73 (8.2%) 11 4/73 (5.5%) 8 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Muscle weakness lower limb 3/67 (4.5%) 3 2/73 (2.7%) 2 2/73 (2.7%) 3 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Musculoskeletal disorder 0/67 (0%) 0 3/73 (4.1%) 4 0/73 (0%) 0 0/8 (0%) 0 0/8 (0%) 0 1/6 (16.7%) 1
    Myalgia 4/67 (6%) 10 6/73 (8.2%) 11 4/73 (5.5%) 8 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Neck pain 4/67 (6%) 7 2/73 (2.7%) 5 1/73 (1.4%) 1 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Pain in extremity 5/67 (7.5%) 13 5/73 (6.8%) 8 7/73 (9.6%) 51 0/8 (0%) 0 1/8 (12.5%) 3 0/6 (0%) 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumor pain 3/67 (4.5%) 7 1/73 (1.4%) 2 4/73 (5.5%) 4 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Tumor pain (onset or exacerbation of tumor pain due to treatment) 0/67 (0%) 0 0/73 (0%) 0 1/73 (1.4%) 1 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Nervous system disorders
    Ataxia 1/67 (1.5%) 1 1/73 (1.4%) 2 2/73 (2.7%) 4 1/8 (12.5%) 1 0/8 (0%) 0 0/6 (0%) 0
    Dizziness 11/67 (16.4%) 24 13/73 (17.8%) 26 13/73 (17.8%) 18 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Dysgeusia 13/67 (19.4%) 26 11/73 (15.1%) 31 19/73 (26%) 111 3/8 (37.5%) 4 0/8 (0%) 0 0/6 (0%) 0
    Extrapyramidal disorder 0/67 (0%) 0 1/73 (1.4%) 1 0/73 (0%) 0 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Headache 6/67 (9%) 9 2/73 (2.7%) 4 5/73 (6.8%) 9 1/8 (12.5%) 2 0/8 (0%) 0 1/6 (16.7%) 1
    Memory impairment 2/67 (3%) 2 0/73 (0%) 0 1/73 (1.4%) 1 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Neurological disorder NOS 1/67 (1.5%) 1 1/73 (1.4%) 2 2/73 (2.7%) 2 1/8 (12.5%) 7 0/8 (0%) 0 0/6 (0%) 0
    Nystagmus 0/67 (0%) 0 0/73 (0%) 0 1/73 (1.4%) 1 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Oculomotor nerve disorder 1/67 (1.5%) 1 0/73 (0%) 0 0/73 (0%) 0 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Peripheral motor neuropathy 2/67 (3%) 5 1/73 (1.4%) 4 4/73 (5.5%) 13 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Peripheral sensory neuropathy 28/67 (41.8%) 117 30/73 (41.1%) 108 60/73 (82.2%) 515 6/8 (75%) 14 1/8 (12.5%) 3 1/6 (16.7%) 22
    Seizure 0/67 (0%) 0 0/73 (0%) 0 1/73 (1.4%) 1 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Speech disorder 1/67 (1.5%) 1 0/73 (0%) 0 0/73 (0%) 0 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Syncope 2/67 (3%) 3 1/73 (1.4%) 1 1/73 (1.4%) 1 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Syncope vasovagal 1/67 (1.5%) 1 0/73 (0%) 0 0/73 (0%) 0 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Tremor 2/67 (3%) 2 2/73 (2.7%) 9 2/73 (2.7%) 7 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Psychiatric disorders
    Agitation 0/67 (0%) 0 0/73 (0%) 0 1/73 (1.4%) 1 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Anxiety 6/67 (9%) 15 4/73 (5.5%) 7 7/73 (9.6%) 31 1/8 (12.5%) 1 0/8 (0%) 0 1/6 (16.7%) 2
    Confusion 1/67 (1.5%) 2 1/73 (1.4%) 1 2/73 (2.7%) 2 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Depression 10/67 (14.9%) 17 5/73 (6.8%) 7 8/73 (11%) 19 1/8 (12.5%) 4 0/8 (0%) 0 1/6 (16.7%) 2
    Insomnia 10/67 (14.9%) 22 13/73 (17.8%) 33 15/73 (20.5%) 49 0/8 (0%) 0 0/8 (0%) 0 3/6 (50%) 4
    Libido decreased 0/67 (0%) 0 0/73 (0%) 0 1/73 (1.4%) 6 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Psychosis 0/67 (0%) 0 0/73 (0%) 0 0/73 (0%) 0 1/8 (12.5%) 2 0/8 (0%) 0 0/6 (0%) 0
    Renal and urinary disorders
    Bladder pain 0/67 (0%) 0 0/73 (0%) 0 0/73 (0%) 0 1/8 (12.5%) 1 0/8 (0%) 0 0/6 (0%) 0
    Cystitis 0/67 (0%) 0 0/73 (0%) 0 1/73 (1.4%) 2 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Dysuria (painful urination) 0/67 (0%) 0 1/73 (1.4%) 1 0/73 (0%) 0 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Glomerular filtration rate decreased 1/67 (1.5%) 1 2/73 (2.7%) 2 0/73 (0%) 0 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Hematuria (absence of vaginal bleeding) 0/67 (0%) 0 1/73 (1.4%) 2 0/73 (0%) 0 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Hemoglobin urine positive 0/67 (0%) 0 1/73 (1.4%) 1 0/73 (0%) 0 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Hemorrhage urinary tract 0/67 (0%) 0 0/73 (0%) 0 1/73 (1.4%) 1 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Kidney pain 2/67 (3%) 4 0/73 (0%) 0 0/73 (0%) 0 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Proteinuria 2/67 (3%) 2 1/73 (1.4%) 1 0/73 (0%) 0 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Renal failure 1/67 (1.5%) 1 1/73 (1.4%) 1 0/73 (0%) 0 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Renal hemorrhage 1/67 (1.5%) 3 0/73 (0%) 0 0/73 (0%) 0 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Ureteric obstruction 1/67 (1.5%) 1 0/73 (0%) 0 0/73 (0%) 0 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Urethral pain 0/67 (0%) 0 0/73 (0%) 0 1/73 (1.4%) 1 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Urinary frequency 2/67 (3%) 12 1/73 (1.4%) 1 2/73 (2.7%) 11 1/8 (12.5%) 1 0/8 (0%) 0 1/6 (16.7%) 2
    Urinary incontinence 1/67 (1.5%) 1 0/73 (0%) 0 0/73 (0%) 0 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Urinary retention 0/67 (0%) 0 0/73 (0%) 0 1/73 (1.4%) 2 0/8 (0%) 0 0/8 (0%) 0 1/6 (16.7%) 1
    Urogenital disorder 1/67 (1.5%) 1 1/73 (1.4%) 2 0/73 (0%) 0 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Reproductive system and breast disorders
    Reproductive tract disorder 1/67 (1.5%) 1 0/73 (0%) 0 1/73 (1.4%) 1 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Respiratory, thoracic and mediastinal disorders
    Allergic rhinitis 4/67 (6%) 6 6/73 (8.2%) 18 4/73 (5.5%) 6 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Atelectasis 0/67 (0%) 0 0/73 (0%) 0 1/73 (1.4%) 1 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Bronchopulmonary hemorrhage 0/67 (0%) 0 1/73 (1.4%) 1 0/73 (0%) 0 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Bronchospasm 0/67 (0%) 0 1/73 (1.4%) 1 0/73 (0%) 0 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Chylothorax 1/67 (1.5%) 3 0/73 (0%) 0 0/73 (0%) 0 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Cough 13/67 (19.4%) 36 15/73 (20.5%) 31 15/73 (20.5%) 45 2/8 (25%) 2 0/8 (0%) 0 1/6 (16.7%) 1
    Dyspnea 18/67 (26.9%) 38 20/73 (27.4%) 49 18/73 (24.7%) 75 2/8 (25%) 5 0/8 (0%) 0 1/6 (16.7%) 4
    Dyspnea (shortness of breath) 0/67 (0%) 0 3/73 (4.1%) 4 0/73 (0%) 0 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Epistaxis 8/67 (11.9%) 12 4/73 (5.5%) 4 11/73 (15.1%) 40 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Hiccups 3/67 (4.5%) 3 3/73 (4.1%) 4 4/73 (5.5%) 12 0/8 (0%) 0 0/8 (0%) 0 1/6 (16.7%) 1
    Hypoxia 1/67 (1.5%) 1 1/73 (1.4%) 1 1/73 (1.4%) 1 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Nasal congestion 1/67 (1.5%) 3 3/73 (4.1%) 5 0/73 (0%) 0 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Pharyngeal examination abnormal 2/67 (3%) 3 0/73 (0%) 0 1/73 (1.4%) 2 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Pharyngolaryngeal pain 3/67 (4.5%) 5 2/73 (2.7%) 2 1/73 (1.4%) 1 0/8 (0%) 0 1/8 (12.5%) 1 0/6 (0%) 0
    Pleural effusion 1/67 (1.5%) 3 2/73 (2.7%) 2 0/73 (0%) 0 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Pleuritic pain 1/67 (1.5%) 1 0/73 (0%) 0 1/73 (1.4%) 2 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Pneumonitis 0/67 (0%) 0 0/73 (0%) 0 2/73 (2.7%) 2 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Voice alteration 6/67 (9%) 19 2/73 (2.7%) 3 2/73 (2.7%) 5 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Skin and subcutaneous tissue disorders
    Alopecia 36/67 (53.7%) 129 25/73 (34.2%) 92 24/73 (32.9%) 117 7/8 (87.5%) 19 0/8 (0%) 0 0/6 (0%) 0
    Decubitus ulcer 1/67 (1.5%) 1 0/73 (0%) 0 2/73 (2.7%) 3 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Dry skin 22/67 (32.8%) 58 16/73 (21.9%) 40 17/73 (23.3%) 75 3/8 (37.5%) 18 0/8 (0%) 0 0/6 (0%) 0
    Erythema multiforme 0/67 (0%) 0 1/73 (1.4%) 1 2/73 (2.7%) 8 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Hand-and-foot syndrome 21/67 (31.3%) 53 11/73 (15.1%) 21 19/73 (26%) 113 3/8 (37.5%) 9 0/8 (0%) 0 0/6 (0%) 0
    Nail disorder 13/67 (19.4%) 26 8/73 (11%) 18 12/73 (16.4%) 63 1/8 (12.5%) 3 0/8 (0%) 0 1/6 (16.7%) 1
    Pain of skin 0/67 (0%) 0 1/73 (1.4%) 1 2/73 (2.7%) 3 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Petechiae 0/67 (0%) 0 1/73 (1.4%) 2 1/73 (1.4%) 1 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Pruritus 6/67 (9%) 11 6/73 (8.2%) 11 16/73 (21.9%) 89 1/8 (12.5%) 8 0/8 (0%) 0 1/6 (16.7%) 2
    Rash acneiform 42/67 (62.7%) 201 49/73 (67.1%) 219 49/73 (67.1%) 530 5/8 (62.5%) 35 4/8 (50%) 5 3/6 (50%) 28
    Rash desquamating 21/67 (31.3%) 84 16/73 (21.9%) 59 25/73 (34.2%) 147 1/8 (12.5%) 1 0/8 (0%) 0 2/6 (33.3%) 11
    Skin disorder 7/67 (10.4%) 11 6/73 (8.2%) 9 8/73 (11%) 26 1/8 (12.5%) 7 0/8 (0%) 0 1/6 (16.7%) 1
    Skin hyperpigmentation 2/67 (3%) 5 1/73 (1.4%) 1 0/73 (0%) 0 1/8 (12.5%) 1 0/8 (0%) 0 0/6 (0%) 0
    Skin ulceration 0/67 (0%) 0 0/73 (0%) 0 1/73 (1.4%) 1 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Sweating 2/67 (3%) 2 3/73 (4.1%) 3 2/73 (2.7%) 2 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Vascular disorders
    Hematoma 0/67 (0%) 0 0/73 (0%) 0 1/73 (1.4%) 1 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Hemorrhage 1/67 (1.5%) 2 1/73 (1.4%) 1 0/73 (0%) 0 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Hot flashes 1/67 (1.5%) 3 1/73 (1.4%) 2 0/73 (0%) 0 1/8 (12.5%) 1 0/8 (0%) 0 0/6 (0%) 0
    Hypertension 1/67 (1.5%) 2 2/73 (2.7%) 2 1/73 (1.4%) 1 1/8 (12.5%) 1 0/8 (0%) 0 0/6 (0%) 0
    Hypotension 6/67 (9%) 6 11/73 (15.1%) 25 4/73 (5.5%) 12 0/8 (0%) 0 1/8 (12.5%) 1 2/6 (33.3%) 7
    Phlebitis 1/67 (1.5%) 1 0/73 (0%) 0 0/73 (0%) 0 0/8 (0%) 0 0/8 (0%) 0 0/6 (0%) 0
    Thrombosis 5/67 (7.5%) 5 10/73 (13.7%) 12 7/73 (9.6%) 18 1/8 (12.5%) 3 1/8 (12.5%) 1 0/6 (0%) 0

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.

    Results Point of Contact

    Name/Title Peter Enzinger, M.D.
    Organization Dana Farber Cancer Institute
    Phone
    Email peter_enzinger@dfci.harvard.edu
    Responsible Party:
    Alliance for Clinical Trials in Oncology
    ClinicalTrials.gov Identifier:
    NCT00381706
    Other Study ID Numbers:
    • CALGB-80403
    • ECOG-E1206
    • CDR0000505535
    • NCI-2009-00492
    First Posted:
    Sep 28, 2006
    Last Update Posted:
    Sep 29, 2021
    Last Verified:
    Sep 1, 2021