Pre- and Post-operative FOLFOX Based Therapy for Patients With Colorectal Cancer With Liver Involvement

This study has been terminated.
(Poor accrual.)
Sponsor:
Information provided by (Responsible Party):
Washington University School of Medicine
ClinicalTrials.gov Identifier:
NCT00537823
First received: September 27, 2007
Last updated: July 22, 2013
Last verified: July 2013
  Purpose

The purpose of this study is to determine the effect of short-duration pre-operative FOLFOX based therapy on postoperative problems after liver surgery for patients with metastatic colorectal cancer.


Condition Intervention Phase
Colorectal Cancer
Metastases
Drug: Cetuximab
Drug: Bevacizumab
Drug: Leucovorin
Drug: Oxaliplatin
Drug: Fluorouracil
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Effect of Short-duration Preoperative Neoadjuvant Therapy With FOLFOX Based Therapy on Morbidity After Liver Resection for Colorectal Cancer Metastases

Resource links provided by NLM:


Further study details as provided by Washington University School of Medicine:

Primary Outcome Measures:
  • Total postoperative complication rate (Fraction of patients with any grade of complication I-V) [ Time Frame: 30 days following surgery ] [ Designated as safety issue: Yes ]
  • Major postoperative complication rate (Fraction of patients with any complication grades IV and V) [ Time Frame: 30 days following surgery ] [ Designated as safety issue: Yes ]
  • All-cause mortality postoperatively [ Time Frame: 30 days following surgery ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Study postoperative recurrence patters (liver only vs distant disease) [ Time Frame: 1, 3, 5 years ] [ Designated as safety issue: No ]
  • Calculate liver recurrence-free survival at one, three, and five years [ Time Frame: 1, 3, 5 years ] [ Designated as safety issue: No ]
  • Document the histologic hepatic toxicity at operation [ Time Frame: Time of surgery (approximately 11-16 weeks) ] [ Designated as safety issue: Yes ]
  • Provide the nonalcoholic steatohepatitis score (0-3) [ Time Frame: Time of surgery (approximately 11-16 weeks) ] [ Designated as safety issue: No ]
  • Provide the liver injury scale score (0-27) [ Time Frame: Time of surgery (approximately 11-16 weeks) ] [ Designated as safety issue: Yes ]
  • Describe the effect of preoperative chemotherapy on tumor size [ Time Frame: Upon completion of neoadjuvant chemotherapy (approximately 2 months) ] [ Designated as safety issue: No ]
  • Calculate change in tumor size from pretreatment to preoperative CT scan [ Time Frame: Completion of neoadjuvant therapy (approximately 8 weeks) ] [ Designated as safety issue: No ]

Enrollment: 9
Study Start Date: June 2007
Study Completion Date: July 2011
Primary Completion Date: December 2009 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm 1 - Wildtype

Neoadjuvant therapy

Week 1

  • Leucovorin 400 mg/m2 IV
  • Oxaliplatin 85 mg/m2 IV Cetuximab 400 mg/m2 IV
  • 5FU bolus 400 mg/m2
  • 5FU CIVI 1200 mg/m2/day over 46 hours

Weeks 2, 4, 6, 8 *Cetuximab 250 mg/m2 IV weekly

Weeks 3, 5, 7

  • Leucovorin 400 mg/m2 IV
  • Oxaliplatin 85 mg/m2 IV Cetuximab 400 mg/m2 IV
  • 5FU bolus 400 mg/m2
  • 5FU CIVI 1200 mg/m2/day over 46 hours

Wait 3-8 weeks after completion of therapy

Liver resection

Wait 4 weeks or until clinical status allows

Adjuvant Therapy

Week 1, 3, 5, 7, 9, 11, 13, 15

  • Leucovorin 400 mg/m2 IV
  • Oxaliplatin 85 mg/m2 IV Cetuximab 400 mg/m2 IV
  • 5FU bolus 400 mg/m2
  • 5FU CIVI 1200 mg/m2/day over 46 hours

Weeks 2, 4, 6, 8, 10, 12, 16

*Cetuximab 250 mg/m2 IV weekly

Drug: Cetuximab
Other Name: Erbitux
Drug: Leucovorin Drug: Oxaliplatin Drug: Fluorouracil
Experimental: Arm 2 K-Ras 12/13 codon mutation

Neoadjuvant Therapy

Weeks 1, 3, 5

  • Leucovorin 400 mg/m2 IV
  • Oxaliplatin 85 mg/m2 IV
  • Bevacizumab 5 mg/kg IV
  • 5FU bolus 400 mg/m2
  • 5FU CIVI 1200 mg/m2

Week 7

  • Leucovorin 400 mg/m2 IV
  • Oxaliplatin 85 mg/m2 IV
  • 5FU bolus 400 mg/m2
  • 5FU CIVI 1200 mg/m2

Wait 3-8 weeks after completion of therapy

Liver resection

Wait 4 weeks or until clinical status allows

Adjuvant Therapy

Weeks 1, 3, 5, 9, 11, 13

  • Leucovorin 400 mg/m2 IV
  • Oxaliplatin 85 mg/m2 IV
  • Bevacizumab 5 mg/kg IV
  • 5FU bolus 400 mg/m2
  • 5FU CIVI 1200 mg/m2

Week 7, 15

  • Leucovorin 400 mg/m2 IV
  • Oxaliplatin 85 mg/m2 IV
  • 5FU bolus 400 mg/m2
  • 5FU CIVI 1200 mg/m2
Drug: Bevacizumab
Other Name: Avastin
Drug: Leucovorin Drug: Oxaliplatin Drug: Fluorouracil

Detailed Description:

Although early stage, localized colon and rectal cancers are associated with 5 year survival rates of nearly 90%, only a minority of patients present with localized disease. Unfortunately, at the time of their initial presentation, approximately 35% of patients with colon or rectal cancer have metastatic disease. Nearly two thirds of these patients with stage IV disease have evidence of extrahepatic spread and have a median overall survival rate of 8-10 months in the absence of further treatment. Even with the most intensive chemotherapeutic regimens, the median overall survival for these patients ranges from 12 months to 20 months. However, a small subset of patients with stage IV disease has isolated hepatic metastatic disease and can undergo resection. The patients with completely resected liver metastases enjoy a significantly higher overall five-year survival, which is as high as 58% in carefully selected patients. Ten-year overall survival has been reported in 22% of patients. Despite this improvement, the five-year disease-free survival for these patients is at best 35%, with hepatic recurrences occurring in 46%.

The fact that adjuvant chemotherapy improves the three-year survival rate for stage II disease and five-year survival rates for stage III disease implies that it can treat micrometastatic disease in some fraction of patients. Because micrometastatic disease is likely the cause of the high recurrence rate in patients who undergo liver resection, there is a clear biologic rationale for using postoperative adjuvant chemotherapy after liver resection. Although this strategy is a common practice in many centers, no convincing data that this improves survival have been reported. A large randomized phase III trial (EORTC 40983) examining this question is currently ongoing and effect on survival has not yet been reported. Given that systemic chemotherapy after liver resection remains of unproven benefit at the present time, many have wondered if preoperative treatment might have more promise in improving recurrence rates.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Synchronous or metachronous colorectal metastases
  • Technically resectable liver metastases

    • Four or fewer metastases
    • No tumors in porta hepatis
    • Resection of no more than 70% of liver needed
  • Medically suitable candidate for major liver resection
  • FDG-PET scan without metastatic disease outside the liver

Exclusion Criteria:

  • Near-obstructing or obstructing colon lesions in patients in whom combined resection is planned (as delay for preoperative chemotherapy would be medially impossible)
  • Treatment with FOLFOX or cetuximab within 12 months
  • Treatment with irinotecan within 12 months
  • Abnormal liver function (ALT or AST > 5x ULN, bilirubin > 3x ULN)
  • Body mass index >/= 35 kg/m² (as the risk for steatohepatitis is increased)
  • Renal insufficiency (Cr > 2.5mg/dL)
  • Interstitial lung disease (because cetuximab has been rarely associated with development of interstitial lung disease)
  • ECOG performance score >/= 3
  • Patients unable to give informed consent
  • Pregnant patient (as cetuximab is a Class C drug)
  • Peripheral neuropathy >/= grade II (as oxaliplatin causes neuropathy to worsen)
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00537823

Locations
United States, Missouri
Washington University School of Medicine
St. Louis, Missouri, United States, 63110
Sponsors and Collaborators
Washington University School of Medicine
Investigators
Principal Investigator: David Linehan, MD Washington University School of Medicine
  More Information

Additional Information:
Publications:
Adam R, Aloia T, Figueras J, Capussotti L, Poston G, Mentha G, Selzner M, and the LiverMetSurvey Scientific Committee. LiverMetSurvey: Analysis of clinicopathologic factors associated with the efficacy of preoperative chemotherapy in 2,122 patients with colorectal liver metastases. Journal of Clinical Oncology, 2006 ASCO Annual Meeting Proceedings Part I. Vol 24, No. 18S (June 20 Supplement), 2006: 3521.
Badarinath S, Mitchell EP, Jennis A, Graham CD, Hansen VL, Henderson CA, Chen TT, Langer C. Cetuximab plus FOLFOX for colorectal cancer (EXPLORE): Preliminary safety analysis of a randomized phase III trial. Journal of Clinical Oncology, 2004 ASCO Annual Meeting Proceedings (Post-Meeting Edition). Vol 22, No 14S (July 15 Supplement), 2004: 3531.
Colucci G, Giuliani F, Mattioli R, Garufi C, Mallamaci R, Pezzella G, Lopez M, Maiello E. FOLFOX-4 + cetuximab in untreated patients with advanced colorectal cancer. A phase II study of the Gruppo Oncologico dell'Italia Meridionale . Journal of Clinical Oncology, 2006 ASCO Annual Meeting Proceedings Part I. Vol 24, No. 18S (June 20 Supplement), 2006: 3559.
Dakhil S, Cosgriff T, Headley D, Badarinath S, International Oncology Network, R. V. Boccia. Cetuximab + FOLFOX6 as first line therapy for metastatic colorectal cancer. Journal of Clinical Oncology, 2006 ASCO Annual Meeting Proceedings Part I. Vol 24, No. 18S, 2006: 3557
Díaz Rubio E, JTabernero J, van Cutsem E, Cervantes A, André T, Humblet Y, Soulié P, Corretgé S, Kisker O,de Gramont A. Cetuximab in combination with oxaliplatin/5-fluorouracil (5-FU)/folinic acid (FA) (FOLFOX-4) in the first-line treatment of patients with epidermal growth factor receptor (EGFR)-expressing metastatic colorectal cancer: An international phase II study. Journal of Clinical Oncology, 2005 ASCO Annual Meeting Proceedings. Vol 23, No. 16S, Part I of II (June 1 Supplement), 2005: 3535.
Fausta N, Campbell J, Riehle K. Liver regeneration. Hepatology 2006;43:S45-53.
Finkelstein SE, Fernandez FG, Dehdashti F, Siegel A, Hawkins WG, Linehan DC, Strasberg SM. Unique site and time specific patterns of failure following curative resection of colorectal carcinoma hepatic metastases in patients screened by FDG-PET. ASCO 2006 Gastrointestinal Cancers Symposium (abstr).
Fausto N. Campbell JS. Riehle KJ. Liver regeneration.. Hepatology (2006); 43(2 Suppl 1):S45-53.
Gruenberger T, Sorbye H, Debois M, Bethe U, Primrose J, Rougier P, Jaeck D, Finch-Jones M, Van Cutsem E, Nordlinger B. Tumor response to pre-operative chemotherapy (CT) with FOLFOX-4 for resectable colorectal cancer liver metastases (LM). Interim results of EORTC Intergroup randomized phase III study 40983. Journal of Clinical Oncology, 2006 ASCO Annual Meeting Proceedings Part I. Vol 24, No. 18S (June 20 Supplement), 2006: 3500.
Jennis A , J. Polikoff, E. Mitchell, S. Badarinath, C. Graham, T. Chen, T. Gustafson, C. Langer Erbitux (Cetuximab) Plus FOLFOX for Colorectal Cancer (EXPLORE): Preliminary efficacy analysis of a randomized phase III trial. Journal of Clinical Oncology, 2005 ASCO Annual Meeting Proceedings. Vol 23, No. 16S, Part I of II (June 1 Supplement), 2005: 3574
Koniaris LG. McKillop IH. Schwartz SI. Zimmers TA. Liver regeneration. Journal of the American College of Surgeons (2003);197(4):634-59.
Nordlinger B, Sorbye H, Debois M, Praet M, Glimelius B, Poston GJ, P. Schlag M, Walpole ET, Bechstein W, Gruenberger T. Feasibility and risks of pre-operati ve chemotherapy (CT) with Folfox 4 and surgery for resectable colorectal cancer liver metastases (LM). Interim results of the EORTC Intergroup randomized phase III study 40983. Journal of Clinical Oncology, 2005 ASCO Annual Meeting Proceedings. Vol 23, No. 16S, Part I of II (June 1 Supplement), 2005: 3528.
Portier G, Rougier P, Milan C et al. Adjuvant systemic chemotherapy using 5-fluorouracil and folinic acid after resection of liver metastases from colorectal origin. Results of an intergroup phase III study (trial FFCD-ACHBTH-AURC 9002). Proc Am Soc Clin Oncol (2002); 20:528 (abstr).
Tabernero JM, Van Cutsem E, Sastre J, Cervantes A, Van Laethem JL, Humblet Y, Soulié P, Corretgé S, Mueser M, De Gramont A; Vall d'Hebron. An international phase II study of cetuximab in combination with oxaliplatin/5-fluorouracil (5-FU)/folinic acid (FA) (FOLFOX-4) in the first-line treatment of patients with metastatic colorectal cancer (CRC) expressing Epidermal Growth Factor Receptor (EGFR). Preliminary results. Journal of Clinical Oncology, 2004 ASCO Annual Meeting Proceedings (Post-Meeting Edition). Vol 22, No 14S (July 15 Supplement), 2004: 3512.
Venook A, Niedzwiecki D, Hollis D, Sutherland S, Goldberg R, Alberts S, Benson A, Wade J, Schilsky R, Mayer R. Phase III study of irinotecan/5FU/LV (FOLFIRI) or oxaliplatin/5FU/LV (FOLFOX) ± cetuximab for patients with untreated metastatic adenocarcinoma of the colon or rectum (MCRC): CALGB 80203 preliminary results. Journal of Clinical Oncology, 2006 ASCO Annual Meeting Proceedings Part I. Vol 24, No. 18S (June 20 Supplement), 2006: 3509.

Responsible Party: Washington University School of Medicine
ClinicalTrials.gov Identifier: NCT00537823     History of Changes
Other Study ID Numbers: 07-0182
Study First Received: September 27, 2007
Last Updated: July 22, 2013
Health Authority: United States: Institutional Review Board

Keywords provided by Washington University School of Medicine:
Colorectal Cancer
Metastasis
Neoadjuvant Therapy

Additional relevant MeSH terms:
Neoplasm Metastasis
Colorectal Neoplasms
Neoplastic Processes
Neoplasms
Pathologic Processes
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Bevacizumab
Cetuximab
Oxaliplatin
Fluorouracil
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs
Pharmacologic Actions
Growth Inhibitors
Antineoplastic Agents
Therapeutic Uses
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antimetabolites, Antineoplastic
Immunosuppressive Agents

ClinicalTrials.gov processed this record on September 16, 2014