PDF herunterladen
Gastroenterologie up2date 2010; 6(1): 41-62
DOI: 10.1055/s-0029-1243961
Darm/Anorektum

© Georg Thieme Verlag KG Stuttgart · New York

Medikamentöse Therapie des kolorektalen Karzinoms

Michael  Pohl, Anke  Reinacher-Schick, Wolff  Schmiegel
Weitere Informationen

Publikationsverlauf

Publikationsdatum:
22. März 2010 (online)

Auch verfügbar auf
    Lizenzen und Reprints Alle Artikel dieser Rubrik

Kernaussagen

Adjuvante Therapie

  • Im Stadium II sollten Patienten bei Hochrisikokonstellation eine adjuvante Therapie mit einem Fluoropyrimidin erhalten. Bei Patienten ohne Risikofaktoren kann eine adjuvante Therapie mit einem Fluoropyrimidin erfolgen.

  • Eine FOLFOX-Therapie über 6 Monate ist therapeutischer Standard im Stadium III (mit Lymphknotenbefall).

  • Patienten über 70 Jahre sollten Kombinationstherapien zurückhaltend erhalten.

  • Bei Kontraindikationen für eine Kombinationschemotherapie mit Oxaliplatin sollte Capecitabin gegeben werden.

  • Irinotecan und monoklonale Antikörper haben keinen Stellenwert in der adjuvanten Therapie.

Therapie im Stadium IV

  • Patienten mit Lebermetastasierung (potenziell kurative Therapie) werden nach klinischem Status unterschieden von nicht resektablen Patienten (palliative Therapie).

  • Der k-ras-Mutationsstatus ist ein negativer prädiktiver Faktor für eine Anti-EGFR-Antikörpertherapie. Bei Patienten im Stadium IV mit der Möglichkeit einer Kombinationstherapie sollte der k-ras-Mutationsstatus untersucht werden.

Gruppe 1: Patienten mit primär resektabler Lebermetastasierung:

  • Bei primär resektabler Lebermetastasierung kann eine perioperative Chemotherapie durchgeführt werden (prä- und postoperative oder postoperative Therapie).

Gruppe 2.1: Patienten mit primär nicht resektablen Lebermetastasen, bei denen nach intensiver Kombinationstherapie die Möglichkeit für eine Resektion besteht:

  • Eine intensive Kombinationstherapie aus drei Substanzen sollte eingesetzt werden (Konversionstherapie).

  • Sobald die Erkrankung resektabel erscheint, sollte der Patient operiert werden. Die Hepatotoxizität durch eine präoperative Therapie ist zu berücksichtigen.

Gruppe 2.2: Patienten ohne Möglichkeit einer Resektion mit tumorbedingten Symptomen, Organkomplikationen oder raschem Progress:

  • Bei Erstdiagnose ist eine möglichst intensive Kombinationstherapie indiziert.

  • Eine Kombinationschemotherapie mit monoklonalen Antikörpern verbessert das Überleben, steigert jedoch auch die Kosten und vergrößert den Überlebensvorteil nur moderat.

  • Therapiedeeskalation und Erhaltungstherapien sind bei gleicher Wirksamkeit und verbesserter Lebensqualität durch Reduktion von Toxizitäten möglich.

  • Eine optimale Therapiesequenz gibt es nicht. Entscheidend ist der Einsatz aller wirksamen Substanzen im Erkrankungsverlauf.

Gruppe 3: Patienten mit multiplen Metastasen ohne Option für eine Resektion nach Metastasenrückbildung, ohne tumorbezogene Symptome oder Organkomplikationen und/oder mit schwerer Komorbidität:

  • Eine Monotherapie kann mit 5-FU begonnen werden und ggf. mit Bevacizumab kombiniert werden.

Literatur

  • 1 Robert Koch-Institut .Krebs in Deutschland 2008. http://www.rki.de/
    PubMedGoogle Scholar
  • 2 O’Connell J B, Maggard M A, Ko C Y. Colon cancer survival rates with the new American Joint Committee on Cancer sixth edition staging.  J Natl Cancer Inst. 2004;  96 1420-1427
    PubMedGoogle Scholar
  • 3 Arkenau H, Arnold D, Cassidy J. et al . Efficacy of oxaliplatin plus capecitabine or infusional fluorouracil/leucovorin in patients with metastatic colorectal cancer: a pooled analysis of randomized trials.  J Clin Oncol. 2008;  26 5910-5917
    CrossrefPubMedGoogle Scholar
  • 4 Cassidy J, Clarke S, Diaz-Rubio E. et al . Randomized phase III study of capecitabine plus oxaliplatin compared with fluorouracil/folinic acid plus oxaliplatin as first-line therapy for metastatic colorectal cancer.  J Clin Oncol. 2008;  26 2006-2012
    CrossrefPubMedGoogle Scholar
  • 5 Porschen R, Arkenau H T, Kubicka S. et al . Phase III study of capecitabine plus oxaliplatin compared with fluorouracil and leucovorin plus oxaliplatin in metastatic colorectal cancer: a final report of the AIO Colorectal Study Group.  J Clin Oncol. 2007;  25 4217-4223
    CrossrefPubMedGoogle Scholar
  • 6 Schmiegel W H, Reinacher-Schick A, Freier W. et al . Comparable safety and response rate with bevacizumab in combination with capecitabine/oxaliplatin (CapOx/Bev) versus capecitabine/irinotecan (CapIri/Bev) in advanced CRC (mCRC): A randomized phase II study of the AIO GI Tumor Study Group.  ASCO Annual Meeting Proceedings J Clin Oncol. 2007;  25 18S (Abstr 4034)
    PubMedGoogle Scholar
  • 7 Reinacher-Schick A C, Kubicka S, Freier W. et al . Activity of the combination of bevacizumab (Bev) with capecitabine/irinotecan (CapIri/Bev) or capecitabine/oxaliplatin (CapOx/Bev) in advanced colorectal cancer (ACRC): A randomized phase II study of the AIO Colorectal Study Group (AIO trial 0604).  ASCO Annual Meeting Proceedings J Clin Oncol. 2008;  26 15S (Abstr 4030)
    PubMedGoogle Scholar
  • 8 Hurwitz H, Fehrenbacher L, Novotny W. et al . Bevacizumab plus irinotecan, fluorouracil and leucovorin for metastatic colorectal cancer.  N Engl J Med. 2004;  23 2335-2342
    PubMedGoogle Scholar
  • 9 Van Cutsem E, Köhne C H, Hitre E. et al . Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer.  N Engl J Med. 2009;  360 1408-1417
    CrossrefPubMedGoogle Scholar
  • 10 Schmiegel W, Reinacher-Schick A, Arnold D. et al . S3-Leitlinie „Kolorektales Karzinom” – Aktualisierung 2008.  Z Gastroenterol. 2008;  46 799-840
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 11 Tannapfel A, Reinacher-Schick A. Chemotherapy associated hepatotoxicity in the treatment of advanced colorectal cancer (CRC).  Z Gastroenterol. 2008;  46 435-440
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 12 Mitchell E P, Lacouture M, Shearer H. et al . Final STEPP results of prophylactic versus reactive skin toxicity (ST) treatment (tx) for panitumumab (pmab)-related ST in patients (pts) with metastatic colorectal cancer (mCRC).  J Clin Oncol. 2009;  27 18S (Abstr CRA4027)
    PubMedGoogle Scholar
  • 13 Reinacher-Schick A C, Bechstein W O. Kolorektale Leberfiliae. Neoadjuvante Chemotherapie aus internistischer und chirurgischer Sicht.  Internist. 2007;  48 51-58
    CrossrefPubMedGoogle Scholar
  • 14 Gill S, Loprinzi C L, Sargent D J. et al . Pooled analysis of fluorouracil-based adjuvant therapy for stage II and III colon cancer: who benefits and by how much?.  J Clin Oncol. 2004;  22 1797-1806
    CrossrefPubMedGoogle Scholar
  • 15 Andre T, Boni C, Mounedji-Boudiaf L. et al . Oxaliplatin, Fluorouracil and Leucovorin as adjuvant treatment for colon cancer.  N Engl J Med. 2004;  350 2343-2351
    CrossrefPubMedGoogle Scholar
  • 16 André T, Boni C, Navarro M. et al . Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial.  J Clin Oncol. 2009;  27 3109-3116
    CrossrefPubMedGoogle Scholar
  • 17 Haller D, Tabernero J, Maroun J. et al . 5LBA First efficacy findings from a randomized phase III trial of capecitabine + oxaliplatin vs. bolus 5-FU/LV for stage III colon cancer (NO16968/XELOXA study).  Eur J Cancer Suppl. 2009;  7 4
    PubMedGoogle Scholar
  • 18 Twelves C. et al . Capecitabine as adjuvant treatment for stage III colon cancer.  N Engl J Med. 2005;  352 2696-2704
    CrossrefPubMedGoogle Scholar
  • 19 Goldberg R M, Tabah-Fisch I, Bleiberg H. et al . A pooled safety and efficacy analysis of the FOLFOX4 regimen (bi-monthly oxaliplatin plus fluorouracil/leucovorin) in elderly compared to younger patients with colorectal cancer.  J Clin Oncol. 2006;  24 4085-4091
    CrossrefPubMedGoogle Scholar
  • 20 Sargent D J, Goldberg R M, Jacobson S O. et al . A pooled analysis of adjuvant chemotherapy for resected colon cancer in elderly patients.  N Engl J Med. 2001;  345 1091-1097
    CrossrefPubMedGoogle Scholar
  • 21 Schmiegel W, Pox C, Arnold D. et al . Kolorektales Karzinom: Polypenmanagement, (neo)adjuvante Therapie, Therapie im metastasierten Stadium.  Dtsch Arztebl Int. 2009;  106 843-848
    PubMedGoogle Scholar
  • 22 Allegra C J, Yothers G, O’Connell M J. et al . Initial safety report of NSABP C-08: a randomized phase III study of modified FOLFOX6 with or without bevacizumab for the adjuvant treatment of patients with stage II or III colon cancer.  J Clin Oncol. 2009;  27 3385-3390
    CrossrefPubMedGoogle Scholar
  • 23 Jackson M cCleary, Meyerhardt J, Green E. et al . Impact of older age on the efficacy of newer adjuvant therapies in > 12 500 patients (pts) with stage II/III colon cancer: Findings from the ACCENT Database.  J Clin Oncol. 2009;  27 15S (Abstr 4010)
    PubMedGoogle Scholar
  • 24 Van Cutsem E, Labianca R, Bodoky G. et al . Randomized phase III trial comparing biweekly infusional fluorouracil/leucovorin alone or with irinotecan in the adjuvant treatment of stage III colon cancer: PETACC-3.  J Clin Oncol. 2009;  27 3117-3125
    CrossrefPubMedGoogle Scholar
  • 25 Wolmark N, Yothers G, O’Connell M J. et al . A phase III trial comparing mFOLFOX6 to mFOLFOX6 plus bevacizumab in stage II or III carcinoma of the colon: Results of NSABP Protocol C-08.  J Clin Oncol. 2009;  27 18S
    CrossrefPubMedGoogle Scholar
  • 26 Sargent D J, Marsoni S, Thibodeau S N. et al . Confirmation of deficient mismatch repair (dMMR) as a predictive marker for lack of benefit from 5-FU based chemotherapy in stage II and III colon cancer (CC): A pooled molecular reanalysis of randomized chemotherapy trials.  J Clin Oncol. 2008;  26 15S (Abstr 4008)
    PubMedGoogle Scholar
  • 27 Tejpar S, Bosman F, Delorenzi M. et al . Microsatellite instability (MSI) in stage II and III colon cancer treated with 5FU-LV or 5FU-LV and irinotecan (PETACC 3-EORTC 40 993-SAKK 60/00 trial).  J Clin Oncol. 2009;  27 15S (Abstr 4001)
    PubMedGoogle Scholar
  • 28 Benson A B, Schrag D, Somerfield M R. et al . American Society of Clinical Oncology recommendations on adjuvant chemotherapy for stage II colon cancer.  J Clin Oncol. 2004;  22 3408-3419
    CrossrefPubMedGoogle Scholar
  • 29 VanCutsem E, D’Haens G. et al . KRAS status and efficacy in the first-line treatment of patients with metastatic colorectal cancer (mCRC) treated with FOLFIRI with or without cetuximab: The CRYSTAL experience. ASCO Ann Meet Proc.  J Clin Oncol. 2008;  26 18S (Abstr 2)
    PubMedGoogle Scholar
  • 30 Amado R G, Wolf M, Peeters M. et al . Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer.  J Clin Oncol. 2008;  26 1626-1634
    CrossrefPubMedGoogle Scholar
  • 31 Van Cutsem E, Peeters M. et al . Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer.  J Clin Oncol. 2007;  25 1658-1664
    CrossrefPubMedGoogle Scholar
  • 32 Bokemeyer C, Bondarenko I, Makhson A. et al . Fluorouracil, leucovorin and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer.  J Clin Oncol. 2009;  27 663-671
    CrossrefPubMedGoogle Scholar
  • 33 Fong Y, Sun R L, Brennan M F. et al . Clinical score for predicting recurrence after hepatic resection for metastatic colorectal cancer: analysis of 1001 consecutive cases.  Ann Surg. 1999;  230 309-318
    CrossrefPubMedGoogle Scholar
  • 34 Nordlinger B, Sorbye H, Glimelius B. et al . Perioperative chemotherapy with FOLFOX4 and surgery vs surgery alone for resectable liver metastases from colorectal cancer (EORTC Intergroup trial 40 983): a randomised controlled trial.  Lancet. 2008;  371 1007-1016
    CrossrefPubMedGoogle Scholar
  • 35 Portier G, Elias D, Bouche O. et al . Multicenter randomized trial of adjuvant fluorouracil and folinic acid compared with surgery alone after resection of colorectal liver metastases: FFCD ACHBTH AURC 9002 trial.  J Clin Oncol. 2006;  24 4976-4982
    CrossrefPubMedGoogle Scholar
  • 36 Mitry E, Fields A L, Bleiberg H. et al . Adjuvant chemotherapy after potentially curative resection of metastases from colorectal cancer: a pooled analysis of two randomized trials.  J Clin Oncol. 2008;  26 4906-4911
    CrossrefPubMedGoogle Scholar
  • 37 Parks R, Gonen M, Kemeny N. et al . Adjuvant chemotherapy improves survival after resection of hepatic colorectal metastases: analysis of data from two continents.  J Am Coll Surg. 2007;  204 753-761
    CrossrefPubMedGoogle Scholar
  • 38 Ychou M, Hohenberger W, Thezenas S. Randomized phase III trial comparing infused 5-fluorouracil/folinic acid (LV5-FU) versus LV5-FU+irinotecan (LV5-FU+IRI) as adjuvant treatment after complete resection of liver metastases from colorectal cancer (LMCRC). (CPT-GMA-301).  J Clin Oncol. 2008;  26 15S (Abstr LBA4013)
    PubMedGoogle Scholar
  • 39 Folprecht G, Grothey A, Alberts S. et al . Neoadjuvant treatment of unresectable colorectal liver metastases: correlation between tumour response and resection rates.  Ann Oncol. 2005;  16 1311-1319
    CrossrefPubMedGoogle Scholar
  • 40 Masi G, Allegrini G, Cupini S. et al . First-line treatment of metastatic colorectal cancer with irinotecan, oxaliplatin and 5-fluorouracil/leucovorin (FOLFOXIRI): results of a phase II study with a simplified biweekly schedule.  Ann Oncol. 2004;  12 1766-1772
    PubMedGoogle Scholar
  • 41 Van Cutsem E, Rougier P, Köhne C H. et al . A meta-analysis of the CRYSTAL and OPUS studies combining cetuximab with chemotherapy (CT) as 1st-line treatment for patients (pts) with metastatic colorectal cancer (mCRC): Results according to KRAS and BRAF mutation status.  Eur J Cancer. 2009;  7 (Suppl) 345 (Abstract 6077)
    PubMedGoogle Scholar
  • 42 Bokemeyer C, Bondarenko I, Hartmann J T. et al . Overall survival of patients with KRAS wild-type tumors treated with FOLFOX4 ± cetuximab as 1st-line treatment for metastatic colorectal cancer: The OPUS study.  Eur J Cancer. 2009;  7 (Suppl) 345 (Abstract: 6079)
    PubMedGoogle Scholar
  • 43 Folprecht G, Gruenberger T, Hartmann J T. et al . Cetuximab plus FOLFOX6 or cetuximab plus FOLFIRI as neoadjuvant treatment of nonresectable colorectal liver metastases: A randomized multicenter study (CELIM-study).  ASCO Gastrointestinal Cancer Symposium. 2009;  (Abstr 296)
    PubMedGoogle Scholar
  • 44 Saltz L B, Clarke S, Diaz-Rubio E. et al . Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study.  J Clin Oncol. 2008;  26 2013-2019
    CrossrefPubMedGoogle Scholar
  • 45 Zorzi D, Kishi Y, Maru D M. et al . Effect of extended preoperative chemotherapy on pathologic response and postoperative liver insufficiency after hepatic resection for colorectal liver metastases.  ASCO Gastrointestinal Cancer Symposium. 2009;  (Abstr 295)
    PubMedGoogle Scholar
  • 46 Aloia T, Sebagh M, Plasse M. et al . Liver histology and surgical outcomes after preoperative chemotherapy with fluorouracil plus oxaliplatin in colorectal cancer liver metastases.  J Clin Oncol. 2006;  24 4983-4990
    CrossrefPubMedGoogle Scholar
  • 47 Douillard J Y, Cunningham D, Roth A D. et al . Irinotecan combined with fluorouracil compared with fluorouracil alone as first line treatment for metastatic colorectal cancer: a multicenter randomized trial.  Lancet. 2000;  355 1041-1047
    CrossrefPubMedGoogle Scholar
  • 48 Saltz L B, Cox J V, Blanke C. et al . Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer.  N Engl J Med. 2000;  343 905-914
    CrossrefPubMedGoogle Scholar
  • 49 Falcone A, Ricci S, Brunetti I. et al . Phase III trial of infusional fluorouracil, leucovorin, oxaliplatin and irinotecan (FOLFOXIRI) compared with infusional fluorouracil, leucovorin and irinotecan (FOLFIRI) as first-line treatment for metastatic colorectal cancer: the Gruppo Oncologico Nord Ovest.  J Clin Oncol. 2007;  25 1670-1676
    CrossrefPubMedGoogle Scholar
  • 50 Goldberg R M, Sargent D J, Morton R F. et al . A randomized controlled trial of fluorouracil plus leucovorin, irinotecan and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer.  J Clin Oncol. 2004;  22 23-30
    CrossrefPubMedGoogle Scholar
  • 51 Maughan T. et al . Addition of cetuximab to oxaliplatin-based combination chemotherapy (CT) in patients with KRAS wild-type advanced colorectal cancer (ACRC): a randomized superiorit trial (MRC COIN).  Eur J Cancer Suppl. 2009;  7 4
    PubMedGoogle Scholar
  • 52 Douillard J. et al . Randomized Phase 3 study of pantinumumab with FOLFOX4 compared to FOLFOX4 alone as 1st-line treatment (tx) for metastatic colorectal cancer (mCRC): the PRIME trial.  Eur J Cancer Suppl. 2009;  7 6
    PubMedGoogle Scholar
  • 53 Koopman M, Antonini N F, Douma J. et al . Sequential versus combination chemotherapy with capecitabine, irinotecan, and oxaliplatin in advanced colorectal cancer (CAIRO): a phase III randomised controlled trial.  Lancet. 2007;  370 135-142
    CrossrefPubMedGoogle Scholar
  • 54 Seymour M T, Maughan T S, Ledermann J A. et al . Different strategies of sequential and combination chemotherapy for patients with poor prognosis advanced colorectal cancer (MRC FOCUS): a randomised controlled trial.  Lancet. 2007;  370 143-152
    CrossrefPubMedGoogle Scholar
  • 55 Kabbinavar F F, Hambleton J, Mass R D. et al . Combined analysis of efficacy: the addition of bevacizumab to fluorouracil/leucovorin improves survival for patients with metastatic colorectal cancer.  J Clin Oncol. 2005;  23 3706-3712
    CrossrefPubMedGoogle Scholar
  • 56 Maindrault-Goebel F, Lledo G, Chibaudel B. et al . Final results of OPTIMOX2, a large randomized phase II study of maintenance therapy or chemotherapy-free intervals (CFI) after FOLFOX in patients with metastatic colorectal cancer (MRC): A GERCOR study.  J Clin Oncol. 2007;  25 18S (Abstr 4013)
    PubMedGoogle Scholar
  • 57 Tournigand C, Cervantes A, Figer A. et al . OPTIMOX1: a randomized study of FOLFOX4 or FOLFOX7 with oxaliplatin in a stop-and-go fashion in advanced colorectal cancer – a GERCOR study.  J Clin Oncol. 2006;  24 394-400
    CrossrefPubMedGoogle Scholar
  • 58 Grothey A, Hart L L, Rowland K M. et al . Intermittent oxaliplatin administration and time-to-treatment-failure in metastatic colorectal cancer: Final results of the phase III CONcePT trial.  J Clin Oncol. 2008;  26 18S (Abstr 4010)
    PubMedGoogle Scholar
  • 59 Labianca R IF, Cortesi E. et al . Italian Group for the Study of Digestive Tract Can, Alternating versus continuous „FOLFIR” in advanced colorectal cancer (ACC): A randomized „GISCA” trial. ASCO Annual Meeting Proceedings.  J Clin Oncol. 2006;  24 18S (Abstr 3505)
    PubMedGoogle Scholar
  • 60 Tournigand C, Andre T, Achille E. et al . FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study.  J Clin Oncol. 2004;  22 229-237
    CrossrefPubMedGoogle Scholar
  • 61 Grothey A, Sargent D, Goldberg R M. et al . Survival of patients with advanced colorectal cancer improves with the availability of fluorouracil-leucovorin, irinotecan, and oxaliplatin in the course of treatment.  J Clin Oncol. 2004;  22 1209-1214
    CrossrefPubMedGoogle Scholar
  • 62 Cunningham D, Humblet Y, Siena S. et al . Cetuximab monotherapy and cetuximab plus irinotecan in irinotecanrefractory metastatic colorectal cancer.  N Engl J Med. 2004;  351 337-345
    CrossrefPubMedGoogle Scholar
  • 63 Giantonio B J, Catalano P J. et al . Bevacizumab in combination with oxaliplatin, fluorouracil and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200.  J Clin Oncol. 2007;  25 1539-1544
    CrossrefPubMedGoogle Scholar
  • 64 Peeters M, Price T, Hotko Y. et al . Randomized phase III study of panitumumab with FOLFIRI vs. FOLFIRI alone as second line treatment (tx) in patients (pts) with metastatic colorectal cancer.  Eur J Cancer. 2009;  7 10 (Abstr 14LBA)
    PubMedGoogle Scholar

Prof. Dr. Wolff Schmiegel

Medizinische Universitätsklinik
Knappschaftskrankenhaus Bochum

In der Schornau 23 – 25
44892 Bochum

eMail: meduni-kkh@rub.de

      >