Clinical trial NCT00537823: Pre- and Post-operative FOLFOX Based Therapy for Patients With Colorectal Cancer With Liver Involvement
Official title: Effect of Short-duration Preoperative Neoadjuvant Therapy With FOLFOX Based Therapy on Morbidity After Liver Resection for Colorectal Cancer Metastases
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Colorectal Cancer
Metastases
Keywords: Colorectal Cancer
Metastasis
Neoadjuvant Therapy
Lead sponsor: Washington University School of Medicine
Sponsor class: OTHER
First posted: 2007-10-01
Enrollment: 9
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

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 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)

Primary outcomes:
measure: Postoperative Complication Rate
timeFrame: 30 days following surgery
measure: Major Postoperative Complication Rate
timeFrame: 30 days following surgery
measure: All-cause Mortality
timeFrame: 30 days following surgery
Secondary outcomes:
measure: Postoperative Recurrence Patterns
timeFrame: Up to 5 years
measure: Histologic Hepatic Toxicity at Surgery
timeFrame: Time of surgery (approximately 11-16 weeks)
measure: Nonalcoholic Steatohepatitis Score (0-3)
timeFrame: Time of surgery (approximately 11-16 weeks)
measure: Liver Injury Scale Score (0-27)
timeFrame: Time of surgery (approximately 11-16 weeks)
measure: Effect of Preoperative Chemotherapy on Tumor Size
timeFrame: Upon completion of neoadjuvant chemotherapy (approximately 2 months)
measure: Change in Tumor Size From Pretreatment to Preoperative CT Scan
timeFrame: Completion of neoadjuvant therapy (approximately 8 weeks)
Other outcomes:
Locations:
city: St. Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
Study officials:
affiliation: Washington University School of Medicine
name: David Linehan, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: Adam R, Avisar E, Ariche A, Giachetti S, Azoulay D, Castaing D, Kunstlinger F, Levi F, Bismuth F. Five-year survival following hepatic resection after neoadjuvant therapy for nonresectable colorectal. Ann Surg Oncol. 2001 May;8(4):347-53. doi: 10.1007/s10434-001-0347-3.
citation: Alberts SR, Horvath WL, Sternfeld WC, Goldberg RM, Mahoney MR, Dakhil SR, Levitt R, Rowland K, Nair S, Sargent DJ, Donohue JH. Oxaliplatin, fluorouracil, and leucovorin for patients with unresectable liver-only metastases from colorectal cancer: a North Central Cancer Treatment Group phase II study. J Clin Oncol. 2005 Dec 20;23(36):9243-9. doi: 10.1200/JCO.2005.07.740. Epub 2005 Oct 17.
citation: Andre T, Boni C, Mounedji-Boudiaf L, Navarro M, Tabernero J, Hickish T, Topham C, Zaninelli M, Clingan P, Bridgewater J, Tabah-Fisch I, de Gramont A; Multicenter International Study of Oxaliplatin/5-Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer (MOSAIC) Investigators. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med. 2004 Jun 3;350(23):2343-51. doi: 10.1056/NEJMoa032709.
citation: 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.
citation: Bilchik AJ, Poston G, Curley SA, Strasberg S, Saltz L, Adam R, Nordlinger B, Rougier P, Rosen LS. Neoadjuvant chemotherapy for metastatic colon cancer: a cautionary note. J Clin Oncol. 2005 Dec 20;23(36):9073-8. doi: 10.1200/JCO.2005.03.2334. No abstract available.
citation: Capussotti L, Muratore A, Ferrero A, Massucco P, Ribero D, Polastri R. Randomized clinical trial of liver resection with and without hepatic pedicle clamping. Br J Surg. 2006 Jun;93(6):685-9. doi: 10.1002/bjs.5301.
citation: Clavien PA, Sanabria JR, Strasberg SM. Proposed classification of complications of surgery with examples of utility in cholecystectomy. Surgery. 1992 May;111(5):518-26.
citation: 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.
citation: Cunningham D, Humblet Y, Siena S, Khayat D, Bleiberg H, Santoro A, Bets D, Mueser M, Harstrick A, Verslype C, Chau I, Van Cutsem E. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med. 2004 Jul 22;351(4):337-45. doi: 10.1056/NEJMoa033025.
citation: 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
citation: D'Angelica M, Maddineni S, Fong Y, Martin RC, Cohen MS, Ben-Porat L, Gonen M, DeMatteo RP, Blumgart LH, Jarnagin WR. Optimal abdominal incision for partial hepatectomy: increased late complications with Mercedes-type incisions compared to extended right subcostal incisions. World J Surg. 2006 Mar;30(3):410-8. doi: 10.1007/s00268-005-0183-x.
citation: Delaunoit T, Alberts SR, Sargent DJ, Green E, Goldberg RM, Krook J, Fuchs C, Ramanathan RK, Williamson SK, Morton RF, Findlay BP. Chemotherapy permits resection of metastatic colorectal cancer: experience from Intergroup N9741. Ann Oncol. 2005 Mar;16(3):425-9. doi: 10.1093/annonc/mdi092. Epub 2005 Jan 27.
citation: 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.
citation: Dindo D, Demartines N, Clavien PA. Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg. 2004 Aug;240(2):205-13. doi: 10.1097/01.sla.0000133083.54934.ae.
citation: Ellis LM, Curley SA, Grothey A. Surgical resection after downsizing of colorectal liver metastasis in the era of bevacizumab. J Clin Oncol. 2005 Aug 1;23(22):4853-5. doi: 10.1200/JCO.2005.23.754. No abstract available.
citation: Fausto N, Campbell JS, Riehle KJ. Liver regeneration. Hepatology. 2006 Feb;43(2 Suppl 1):S45-53. doi: 10.1002/hep.20969.
citation: Fernandez FG, Drebin JA, Linehan DC, Dehdashti F, Siegel BA, Strasberg SM. Five-year survival after resection of hepatic metastases from colorectal cancer in patients screened by positron emission tomography with F-18 fluorodeoxyglucose (FDG-PET). Ann Surg. 2004 Sep;240(3):438-47; discussion 447-50. doi: 10.1097/01.sla.0000138076.72547.b1.
citation: Fernandez FG, Ritter J, Goodwin JW, Linehan DC, Hawkins WG, Strasberg SM. Effect of steatohepatitis associated with irinotecan or oxaliplatin pretreatment on resectability of hepatic colorectal metastases. J Am Coll Surg. 2005 Jun;200(6):845-53. doi: 10.1016/j.jamcollsurg.2005.01.024.
citation: Finkelstein SE, Fernandez FG, Dehdashti F, Siegel BA, Hawkins WG, Linehan DC, Strasberg SM. Unique site- and time-specific patterns of recurrence following resection of colorectal carcinoma hepatic metastases in patients staged by FDG-PET. J Hepatobiliary Pancreat Surg. 2008;15(5):483-7. doi: 10.1007/s00534-007-1237-2. Epub 2008 Oct 4.
citation: 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.
citation: Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, Berlin J, Baron A, Griffing S, Holmgren E, Ferrara N, Fyfe G, Rogers B, Ross R, Kabbinavar F. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004 Jun 3;350(23):2335-42. doi: 10.1056/NEJMoa032691.
citation: Ibrahim S, Chen CL, Wang CC, Wang SH, Lin CC, Liu YW, Yang CH, Yong CC, Concejero A, Cheng YF. Liver regeneration and splenic enlargement in donors after living-donor liver transplantation. World J Surg. 2005 Dec;29(12):1658-66. doi: 10.1007/s00268-005-0101-2.
citation: 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
citation: Karoui M, Penna C, Amin-Hashem M, Mitry E, Benoist S, Franc B, Rougier P, Nordlinger B. Influence of preoperative chemotherapy on the risk of major hepatectomy for colorectal liver metastases. Ann Surg. 2006 Jan;243(1):1-7. doi: 10.1097/01.sla.0000193603.26265.c3.
citation: Koniaris LG, McKillop IH, Schwartz SI, Zimmers TA. Liver regeneration. J Am Coll Surg. 2003 Oct;197(4):634-59. doi: 10.1016/S1072-7515(03)00374-0. No abstract available.
citation: Lorenz M, Staib-Sebler E, Gog C, Proschek D, Jauch KW, Ridwelski K, Hohenberger W, Gassel HJ, Lehmann U, Vestweber KH, Padberg W, Zamzow K, Muller HH. Prospective pilot study of neoadjuvant chemotherapy with 5-fluorouracil, folinic acid and oxaliplatin in resectable liver metastases of colorectal cancer. Analysis of 42 neoadjuvant chemotherapies. Zentralbl Chir. 2003 Feb;128(2):87-94. doi: 10.1055/s-2003-37760.
citation: Moertel CG, Fleming TR, Macdonald JS, Haller DG, Laurie JA, Goodman PJ, Ungerleider JS, Emerson WA, Tormey DC, Glick JH, et al. Levamisole and fluorouracil for adjuvant therapy of resected colon carcinoma. N Engl J Med. 1990 Feb 8;322(6):352-8. doi: 10.1056/NEJM199002083220602.
citation: 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.
citation: 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).
citation: Reddy GK. The addition of bevacizumab to FOLFOX4 prolongs survival in relapsed colorectal cancer: interim data from the ECOG 3200 trial. Clin Colorectal Cancer. 2005 Jan;4(5):300-1. doi: 10.1016/s1533-0028(11)70131-1. No abstract available.
citation: Scappaticci FA, Fehrenbacher L, Cartwright T, Hainsworth JD, Heim W, Berlin J, Kabbinavar F, Novotny W, Sarkar S, Hurwitz H. Surgical wound healing complications in metastatic colorectal cancer patients treated with bevacizumab. J Surg Oncol. 2005 Sep 1;91(3):173-80. doi: 10.1002/jso.20301.
citation: Schemmer P, Friess H, Hinz U, Mehrabi A, Kraus TW, Z'graggen K, Schmidt J, Uhl W, Buchler MW. Stapler hepatectomy is a safe dissection technique: analysis of 300 patients. World J Surg. 2006 Mar;30(3):419-30. doi: 10.1007/s00268-005-0192-9.
citation: Shah SA, Haddad R, Al-Sukhni W, Kim RD, Greig PD, Grant DR, Taylor BR, Langer B, Gallinger S, Wei AC. Surgical resection of hepatic and pulmonary metastases from colorectal carcinoma. J Am Coll Surg. 2006 Mar;202(3):468-75. doi: 10.1016/j.jamcollsurg.2005.11.008. Epub 2006 Jan 18.
citation: 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.
citation: Taieb J, Artru P, Paye F, Louvet C, Perez N, Andre T, Gayet B, Hebbar M, Goebel FM, Tournigand C, Parc R, de Gramont A. Intensive systemic chemotherapy combined with surgery for metastatic colorectal cancer: results of a phase II study. J Clin Oncol. 2005 Jan 20;23(3):502-9. doi: 10.1200/JCO.2005.05.082.
citation: Tanaka K, Adam R, Shimada H, Azoulay D, Levi F, Bismuth H. Role of neoadjuvant chemotherapy in the treatment of multiple colorectal metastases to the liver. Br J Surg. 2003 Aug;90(8):963-9. doi: 10.1002/bjs.4160.
citation: Vauthey JN, Pawlik TM, Ribero D, Wu TT, Zorzi D, Hoff PM, Xiong HQ, Eng C, Lauwers GY, Mino-Kenudson M, Risio M, Muratore A, Capussotti L, Curley SA, Abdalla EK. Chemotherapy regimen predicts steatohepatitis and an increase in 90-day mortality after surgery for hepatic colorectal metastases. J Clin Oncol. 2006 May 1;24(13):2065-72. doi: 10.1200/JCO.2005.05.3074.
citation: 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.
citation: Wei AC, Greig PD, Grant D, Taylor B, Langer B, Gallinger S. Survival after hepatic resection for colorectal metastases: a 10-year experience. Ann Surg Oncol. 2006 May;13(5):668-76. doi: 10.1245/ASO.2006.05.039. Epub 2006 Mar 10.
citation: Wolmark N, Wieand S, Kuebler JP, Colangelo L, and Smith RE. A phase III trial comparing FULV to FULV + oxaliplatin in stage II or III carcinoma of the colon: Results of NSABP Protocol C-07. ASCO Meeting Abstracts 2005 23.
citation: Yedibela S, Elad L, Wein A, Dimmler A, Merkel S, Hohenberger W, Meyer T. Neoadjuvant chemotherapy does not increase postoperative complication rate after resection of colorectal liver metastases. Eur J Surg Oncol. 2005 Mar;31(2):141-6. doi: 10.1016/j.ejso.2004.07.030.