Download PDF
Zentralbl Chir 2003; 128(2): 87-94
DOI: 10.1055/s-2003-37760
Originalarbeiten und Übersichten

© Georg Thieme Verlag Stuttgart · New York

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*

Prospektive Pilotstudie zur neoadjuvanten Chemotherapie mit 5-Fluorouracil, Folinsäure und Oxaliplatin bei resektablen Lebermetastasen kolorektaler Karzinome. Analyse von 42 neoadjuvanten ChemotherapienM. Lorenz1 , E. Staib-Sebler1 , C. Gog1 , D. Proschek1 , K.-W. Jauch2 , K. Ridwelski3 , W. Hohenberger4 , H.-J. Gassel5 , U. Lehmann 6 , K.-H. Vestweber7 , W. Padberg8 , K. Zamzow9 , H.-H. Müller9
  • 1Dept. of General and Vascular Surgery, Johann-Wolfgang-Goethe-University Frankfurt
  • 2Clinic of Surgery of the University Regensburg
  • 3Clinic of Surgery, Otto-von-Guericke University, Magdeburg
  • 4Clinic of Surgery of the Friedrich-Alexander University, Erlangen
  • 5Clinic of Surgery of the Julius-Maximilians University, Würzburg
  • 6Clinic of General Surgery, St. Georg Hospital, Leipzig
  • 7Clinic of General Surgery, Klinikum Leverkusen, Leverkusen
  • 8Clinic of General Surgery of the Justus-Liebig University, Gießen
  • 9Institute of Medical Biometry and Epidemiology, Philipps University, Marburg
*Herrn Prof. Dr. Albrecht Encke zur Emeritierung gewidmet
Further Information

Publication History

Publication Date:
11 March 2003 (online)

Also available at
    Permissions and Reprints

Abstract

Purpose: Since there are currently no data available from a prospective trial, the primary objective of this prospective study was to investigate whether the rate of R0-liver resections without morbidity would be at least 50 % in patients with neoadjuvant chemotherapy for colorectal liver metastases.

Patients and methods: 42 patients were treated with a biweekly FOLFOX regimen. Chemotherapy consisted of a 2-hour infusion of folinic acid (FOL) 500 mg/m2, followed by a 24-hour infusion of 5- fluorouracil (F) 2 000 mg/m2 daily for two days. Oxaliplatin (OX) 85 mg/m2 was given simultaneously with FOL. Treatment allocation was randomized with either 3 or 6 cycles for the final 30 patients. A liver resection was performed 2 to 5 weeks after the final infusion.

Results: An objective response was observed in 20 of 42 patients (response rate was 27 % higher after 6 cycles). Liver resection (R0) could be performed in 34 patients. Postoperative complications were reported in 14 patients (13 occurring within 30 days after resection) and severe complications in 5 cases (including two deaths after extended resection). Liver failure and persistent biliary fistula were the most frequently documented complications. There was no relevant difference in safety criteria between 3 and 6 applications.

Conclusion: The use of neoadjuvant chemotherapy in resectable liver metastases induced significant remissions without increasing morbidity. The rate of severe complications and cases of no R0-resection in this study was 31 % and was with that significantly lower than 50 % (95 % CI 17.6 %-47.1 %). The risk to the patient is therefore acceptable when undergoing neoadjuvant treatment in a prospective intergroup trial.

Zusammenfassung

Ziel der Untersuchung: Derzeit existieren keine prospektiven Daten zur neoadjuvanten Chemotherapie vor Resektion kolorektaler Lebermetastasen. Primäres Studienziel war es deshalb in dieser prospektiven Studie zu überprüfen, ob bei dieser Therapie eine Rate von mindestens 50 % R0-Resektionen ohne Morbidität erzielt werden kann.

Methodik: 42 Patienten wurden mit einem 14-tägigen FOLFOX-Regime behandelt. Die Chemotherapie beinhaltete eine 2-h-Infusion mit Folinsäure (FOL) 500 mg/m2/d, gefolgt von einer 24-h-Infusion mit 5-Fluorouracil (F) 2 000 mg/m2/d jeweils über zwei Tage. Oxaliplatin (OX) 85 mg/m2 wurde simultan mit FOL am ersten Therapietag verabreicht. Die letzten 30 Patienten wurden in entweder 3 oder 6 Zyklen der Chemotherapie randomisiert. Die Leberresektion wurde 2 bis 5 Wochen nach der letzten Chemotherapie durchgeführt.

Ergebnisse: Ein objektives Ansprechen wurde in 20 von 42 Patienten beobachtet. Bei der Durchführung von 6 Zyklen war die Ansprechrate um 27 % höher. 34 Patienten konnten R0-leberreseziert werden. Über postoperative Komplikationen wurde bei 14 Patienten (13 innerhalb von 30 Tagen nach Resektion) und über schwere Komplikationen in 5 Fällen (inklusive 2 Todesfälle nach erweiterter Resektion) berichtet. Leberversagen und persistierende Gallefisteln wurden am häufigsten dokumentiert. Relevante Unterschiede hinsichtlich der Sicherheitskriterien zwischen 3 und 6 Applikationen ergaben sich nicht.

Diskussion: Eine neoadjuvante Chemotherapie bei resektablen Lebermetastasen führt zu einer signifikanten Remission ohne Anstieg der Morbidität nach Resektion. Die Rate an schweren Komplikationen und R1- oder R2-Resektionen betrug 31 % und war damit signifikant niedriger als 50 % (95 % CI 17,6 %-47,1 %). Das Risiko der Durchführung einer neoadjuvanten Chemotherapie innerhalb einer prospektiven Intergroup-Studie ist somit für den Patienten akzeptabel.

Key words

Neoadjuvant chemotherapy - liver metastases - colorectal

Schlüsselwörter

Neoadjuvante Chemotherapie - Lebermetastasen - Kolorektal

References

  • 1 Adam R, Avisar E, Ariche A. et al . Five year survival following hepatic resection after neoadjuvant therapy of non resectable colorectal liver metastases.  Ann Surg Oncol. 2001;  8 347-353
    CrossrefPubMedSearch in Google Scholar
  • 2 American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference . definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis.  Critical Care Medicine. 1992;  20 864-867
    PubMedSearch in Google Scholar
  • 3 Bismuth H, Adam R, Lévi F, Farabos C, Waechter F, Castaing D, Majno P, Engerran L. Resection of nonresectable liver metastases from colorectal cancer after neoadjuvant chemotherapy.  Ann Surg. 1996;  224 509-522
    CrossrefPubMedSearch in Google Scholar
  • 4 Black R J, Bray F, Ferlay J, Parkin D M. Cancer incidence and mortality in the European Union: cancer registry data and estimates of national incidence for 1990.  Cancer. 1997;  33 1075-1079
    CrossrefPubMedSearch in Google Scholar
  • 5 Bolder U, Brune A, Schmidt S, Tacke J, Jauch K W, Lohlein D. Preoperative assessment of mortality risk in hepatic resection by clinical variables: a multicenter analysis.  Liver Transplantation and Surgery. 1999;  5 227-237
    PubMedSearch in Google Scholar
  • 6 Broadwater R J, Edwards M J, Kuglen C Hortobagyi G N, Ames F C, Balch C M. Mastectomy following preoperative chemotherapy: Strict operative criteria control operative morbidity.  Ann Surg. 1991;  213 126-129
    PubMedSearch in Google Scholar
  • 7 Buzdar A U, Singletary S E, Theriault R L, Booser D J, Valero V, Ibrahim N, Smith T L, Asmar L, Frye D, Manuel N, Kau S W, McNeese M, Strom E, Hunt K, Ames F, Hortobagyi G N. Prospective evaluation of Paclitaxel versus combination chemotherapy with fluorouracil, doxorubicin, and cyclophosphamide as neoadjuvant therapy in patients with operable breast cancer.  J Clin Oncol. 1999;  17 3412-3417
    PubMedSearch in Google Scholar
  • 8 Cady B, Monson D O, Swinton N W. Survival of patients after colonic resection for carcinoma with simultaneous liver metastases.  Surg Gynecol Obstet. 1970;  131 697-700
    PubMedSearch in Google Scholar
  • 9 Cornell K, Waters D J. Impaired wound healing in the cancer patient: effects of cytotherapy and pharmacologic modulation by growth factors.  Vet Clin North Am Small Anim Pract. 1995;  25 111-131
    PubMedSearch in Google Scholar
  • 10 Crohnert T U, Rau H G, Buttler E, Hernandez-Richter T, Sauter G, Reuter C, Schildberg F W. Preoperative risk assessment of hepatic resection for malignant disease.  World J Surg. 1997;  21 396-401
    PubMedSearch in Google Scholar
  • 11 Danforth DN J r, Lippmann M E, McDonald. Bader J, Egan E, Lampert M, Steinberg SM, Swain SM. Effect of preoperative chemotherapy on mastectomy for locally advanced breast cancer.  Am Surg. 1990;  56 6-11
    PubMedSearch in Google Scholar
  • 12 de Gramont A, Tournigand C, Louvet C, Andre T, Molitor J L, Raymond E, Moreau S, Vignoud J, Le Bail N, Krulik M. Oxaliplatine, acide folinique et 5-fluorouracile (folfox) en seconde ligne thérapeutique du cancer colorectal métastasé.  Rev Méd Interne. 1997;  18 (10) 769-775
    PubMedSearch in Google Scholar
  • 13 de Gramont A, Figer A, Seymour M, Homerin M, Hmissi A, Cassidy J, Boni C, Cortes-Funes H, Cervantes A, Freyer G, Papamichael D, Le Bail N, Louvet C, Hendler D, de Braud F, Wilson C, Morvan F, Bonetti A. Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment.  J Clin Oncol. 2000;  18 2938-2947
    CrossrefPubMedSearch in Google Scholar
  • 14 Doci R, Gennari L, Bignami P, Montalto F, Morabito A, Bozzetti F, Bonalumi M G. Morbidity and mortality after hepatic resection of metastases from colorectal cancer.  British Journal of Surgery. 1995;  82 377-381
    PubMedSearch in Google Scholar
  • 15 Edmondson H A, Peters R L. Neoplasms of the liver. In: Schiff L, Schiff EL (eds). Anonymous Disease of the Liver. Philadelphia PA, JB Lippincott 1987; 1103
  • 16 Finn D, Steele G J r, Osteen R T, Wilson A E. Morbidity and mortality after surgery in patients with disseminated or locally advanced cancer receiving systemic chemotherapy.  J Surg Oncol. 1980;  13 237-244
    PubMedSearch in Google Scholar
  • 17 Giachetti S, Itzhaki M, Gruia G, Adam R, Zidani R, Kunstlinger F, Brienza S, Alafaci E, Bertheault-Cvitkovic F, Jasmin C, Reynes M, Bismuth H, Misset J L, Levi F. Long-term survival of patients with unresectable colorectal cancer liver metastases following infusional chemotherapy with 5-fluorouracil, leucovorin, oxaliplatin and surgery.  Annals of Oncology. 1999;  10 663-669
    CrossrefPubMedSearch in Google Scholar
  • 18 Gunduz N, Fisher B, Saffer E A. Effect of surgical removal on the growth and kinetics of residual tumor.  Cancer Res. 1979;  39 3861-3865
    PubMedSearch in Google Scholar
  • 19 Jaeck D, Nordlinger B, Schaal J C. Methods of surgical excision. In: Nordlinger B, Jaeck D (eds). Treatment of hepatic metastases of colorectal cancer. Springer-Verlag, B. France 1992; 87
  • 20 Jarnaging W R, Fong Y, Ky A, Schwartz L H, Paty P B, Cohen A M, Blumgart L H. Liver resection for metastatic colorectal cancer.  J Am Coll Surg. 1999;  188 33-42
    CrossrefPubMedSearch in Google Scholar
  • 21 Jarnagin W R, Conlon K, Bodniewicz J, Dougherty E, DeMatteo R P, Blumgart L H, Fong Y. A clinical scoring system predicts the yield of diagnostic laparoscopy in patients with potentially resectable hepatic colorectal metastases.  Cancer. 2001;  91 1121-1128
    CrossrefPubMedSearch in Google Scholar
  • 22 Kavolius J, Fong Y, Blumgart L H. Surgical resection of metastatic liver tumors.  Surg Oncol Clin N Am. 1996;  5 337-352
    PubMedSearch in Google Scholar
  • 23 Kemeny N, Huang Y, Cohen A M, Shi W, Conti J A, Brennan M F, Bertino J R, Turnbull A D, Sullivan D, Stockman J, Blumgart L H, Fong Y. Hepatic arterial infusion of chemotherapy after resection of hepatic metastases from colorectal cancer.  N Engl J Med. 1999;  341 2039-2048
    CrossrefPubMedSearch in Google Scholar
  • 24 Lambert L A, Colacchio T A, Barth R J. Interval hepatic resection of colorectal metastases improves patient selection.  Arch Surg. 2000;  135 473-479
    CrossrefPubMedSearch in Google Scholar
  • 25 Lawrence W T, Norton J A, Harvey A K, Gorschboth C M, Talbot T L, Grotendorst G R. Doxorubicin-induced impairment of wound healing in rats.  J Natl Cancer Inst. 1986;  76 119-126
    PubMedSearch in Google Scholar
  • 26 Lévi F, Misset J L, Brienza S, Adam R, Metzger G, Itzakhi M, Caussanel J P, Kunstlinger F, Lecouturier S, Descorps-Declere A. A chronopharmacologic phase II clinical trial with 5-fluorouracil, folinic acid and oxaliplatin using an ambulatory multichannel programmable pump: High antitumor effectiveness against metastatic colorectal cancer.  Cancer. 1992;  69 893-900
    PubMedSearch in Google Scholar
  • 27 Lorenz M, Müller H -H, Schramm H, Gassel H J, Rau H G, Ridwelski K, Hauss J, Stieger R, Jauch K W, Bechstein W O, Encke A. Randomized trial of surgery versus surgery followed by adjuvant hepatic arterial infusion with 5-fluorouracil and folinic acid for liver metastases of colorectal cancer.  Ann Surg. 1998;  228 756-762
    CrossrefPubMedSearch in Google Scholar
  • 28 Lorenz M, Hochmuth K, Müller H H. Letter to the Editor. Hepatic arterial infusion of chemotherapy after resection of hepatic metastases from colorectal cancer.  N Engl J Med. 2000;  342 1525-1526
    PubMedSearch in Google Scholar
  • 29 McMasters K M, Hunt K H. Neoadjuvant chemotherapy, locally advanced breast cancer and quality of life.  J Clin Oncol. 1999;  17 441-446
    PubMedSearch in Google Scholar
  • 30 Nagorney D M, van Heerden J A, Ilstrup D M, Doherty D, Ikai I, Yamaoka Y, Regimbeau J M, Belghiti J, Curley S A, Ellis L M, Vauthey J N. Primary hepatic malignancy: surgical management and determinants of survival.  Surgery. 1989;  106 740-749
    PubMedSearch in Google Scholar
  • 31 Nordlinger B, Jaeck D, Guiguet M. Surgical resection of hepatic metastases. Multicentric retrospective study by the French Association of Surgery. In: Nordlinger B, Jaeck D (eds). Treatment of hepatic metastases of colorectal cancer. Springer-Verlag, B. France 1992; 129
  • 32 Nordlinger B, Guiguet M, Vaillant J C, Balladur P, Boudjema K, Bachellier P, Jaeck D. Surgical resection of colorectal carcinoma metastases to the liver. Association Française de Chirurgie.  Cancer. 1996;  77 1254-1262
    CrossrefPubMedSearch in Google Scholar
  • 33 Pace R F, Blenkharn J I, Edwards WJ Orloff M, Blumgart L H, Benjamin I S. Intra-abdominal sepsis after hepatic resection.  Ann Surg. 1989;  209 302-306
    CrossrefPubMedSearch in Google Scholar
  • 34 Parker S L, Tong T, Bolden S, Wingo P A. Cancer Statistics 1997.  CA Cancer J Clin. 1997;  47 5-27
    CrossrefPubMedSearch in Google Scholar
  • 35 Rees M, Plant G, Wells J, Bygrave S. One hundred and fifty hepatic resections: evolution of technique towards bloodless surgery.  Brit J Surgery. 1996;  83 1526-1529
    PubMedSearch in Google Scholar
  • 36 Saltz J B, Cox J V, Blanke C, Rosen L S, Fehrenbacher L, Moore M J, Maroun J A, Ackland S P, Locker P K, Pirotta N, Elfring G L, Miller L L. Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. Irinotecan Study Group.  N Engl J Med. 2000;  34 905-914
    PubMedSearch in Google Scholar
  • 37 Steele G, Bleday R, Mayer R J, Lindblad A, Petrelli N, Weaver D. A prospective evaluation of hepatic resection for colorectal carcinoma metastases to the liver: gastrointestinal tumor study group protocol 6 584.  J Clin Oncol. 1991;  9 2078-2079
    PubMedSearch in Google Scholar
  • 38 Taylor I, Mullee M A, Campbell M J. Prognostic index for the development of liver metastases in patients with colorectal cancer.  Br J Surg. 1990;  77 499-501
    PubMedSearch in Google Scholar
  • 39 Vauthey J N. Liver imaging: a surgeon’s perspective.  Radiol Clin North Am. 1998;  36 63-67
    PubMedSearch in Google Scholar
  • 40 Vetto J T, Hughes K S, Rosenstein R, Sugarbaker P H. Morbidity and mortality of hepatic resection for metastatic colorectal carcinoma.  Dis Colon Rectum. 1990;  33 408-412
    CrossrefPubMedSearch in Google Scholar
  • 41 Weiss L, Grundmann E, Torhorst J, Hartveit F, Moberg I, Eder M, Fenoglio- Preiser C M, Napier J, Horne C H, Lopez M J. Haematogoneous metastatic patterns in colonic carcinoma: an analysis of 1 541 necropsies.  J Pathol. 1986;  150 195-203
    CrossrefPubMedSearch in Google Scholar
  • 42 Weitz J, Koch M, Kienle P, Schrodel A, Willeke F, Benner A, Lehnert T, Herfarth C, von Knebel Doeberitz M. Detection of hematogenic tumor cell dissemination in patients undergoing resection of liver metastases of colorectal cancer.  Ann Surg. 2000;  232 66-72
    CrossrefPubMedSearch in Google Scholar
  • 43 Wiezer M J, Meijer C, Sietses C, Prins H A, Cuesta M A, Beelen R H, Meijer S, van Leeuwen P A. Bactericidal/permeability increasing protein preserves leukocyte functions after major liver resection.  Ann Surg. 2000;  232 208-215
    PubMedSearch in Google Scholar
  • 44 World Health Organization: handbook for reporting results of cancer t reatment. WHO Offset Publication N0.48. Geneva WHO 1979
  • 45 Zadavski K E, Lee Y TM. Liver metastases from colorectal carcinoma: incidence, respectability and survival results.  Ann Surg. 1994;  60 929-932
    PubMedSearch in Google Scholar

Prof. Dr. Matthias Lorenz

Department of General and Vascular Surgery

Johann-Wolfgang-Goethe University

Theodor-Stern-Kai 7

60590 Frankfurt am Main

Phone: 0 69/6 31 43 46

Fax: 0 69/6 31 43 47

Email: gog@em.uni-frankfurt.de