Subscribe to RSS
DOI: 10.1055/s-0029-1245715
© Georg Thieme Verlag KG Stuttgart · New York
Resektable Lebermetastasen beim kolorektalen Karzinom: pro neoadjuvante Therapie – contra neoadjuvante Therapie
Resectable Colorectal Liver Metastases: Pro Neoadjuvant Therapy – Contra Neoadjuvant TherapyPublication History
Manuskript eingetroffen: 19.1.2010
Manuskript akzeptiert: 20.8.2010
Publication Date:
01 December 2010 (online)
![](https://www.thieme-connect.de/media/zfg/201012/lookinside/thumbnails/10.1055-s-0029-1245715-1.jpg)
Zusammenfassung
Bei ungefähr einem Drittel der Patienten mit kolorektalem Karzinom (KRK) stellt die Leber den alleinigen Metastasierungsort dar. Bei ca. 15 % dieser Patienten sind die Metastasen primär resektabel. Die 5-Jahres-Überlebensrate nach Resektion beträgt 25 – 40 %. Die EORTC-Studie von Nordlinger et al. hat den Stellenwert einer neoadjuvanten bzw. perioperativen Chemotherapie bei resektablen Lebermetastasen untersucht und für die Subgruppe der tatsächlich resezierten Patienten eine signifikante Verbesserung des progressionsfreien Überlebens durch die perioperative Therapie gefunden. In der Intent-to-treat-Population waren die Ergebnisse nicht signifikant. Für eine neoadjuvante Therapie bei resektablen Lebermetastasen spricht das Modell der frühen Eradikation möglicher disseminierter Tumorzellen, die präoperative Identifzierung der Tumorbiologie (Ausschluss primär progredienter Patienten), die höhere Dosisdichte, die präoperativ erreicht werden kann, sowie die höhere Wahrscheinlichkeit für eine tatsächlich stattfindende R 0-Resektion. Gegen eine präoperative Therapie bei resektablen Metastasen spricht die Hepatotoxizität der Chemotherapie mit einer – wenn auch moderaten – Erhöhung der perioperativen Morbidität, die Gefahr einer kompletten Remission, die dann das Auffinden der Metastase intraoperativ schwierig macht, und die unklare optimale Dauer einer neoadjuvanten Therapie. Vor allem seitens der Viszeralchirurgie in Deutschland wird die neoadjuvante Therapie bei resektablen Lebermetastasen nicht als Standardbehandlung angesehen. Die zusammenfassende Wertung spricht sich bei fehlender Evidenz der Stärke 1 zur neoadjuvanten Therapie für eine intensive interdisziplinäre Zusammenarbeit von Viszeralchirurgen, Gastroenterologen und internistischen Onkologen bei der Behandlung dieser Patienten aus. Möglicherweise wird die Publikation der Gesamtüberlebensdaten der EORTC-Studie, die für den Herbst 2010 geplant ist, die Evidenzlage ändern.
Abstract
Approximately one third of patients with colorectal cancer (CRC) present with metastases confined to the liver only. In 15 % of these patients the metastases are primarily resectable. After resection of colorectal liver metastases the 5-year survival rate is 25 – 40 %. The EORTC trial of Nordlinger et al. has examined the role of perioperative/neoadjuvant chemotherapy of resectable liver metastases and found in the subgroup of resected patients a significant improvement in disease-free survival through chemotherapy. The results were not significant in the intent-to-treat population. Possible arguments pro neoadjuvant therapy of resectable liver metastases are the early eradication of disseminated tumour cells, the identification of a worse prognosis tumour biology in the individual patient and the higher dose density which can be achieved preoperatively versus postoperatively. Arguments against preoperative chemotherapy are the chemotherapy-induced hepatotoxicity and related increase in perioperative morbidity, the risk of achieving a complete remission of lesions which then cannot be detected intraoperatively and the uncertain optimal duration of chemotherapy. Especially surgical oncologists in Germany do not consider the neoadjuvant treatment of resectable liver metastases as a standard of care. In summary, because of the lack of level 1 evidence, patients with resectable liver metastases of colorectal cancer should be discussed within interdisciplinary tumour boards together with surgeons, gastroenterologists and medical oncologists. Potentially, overall survival data of the EORTC trial which is expected for late 2010 could change the level of evidence.
Schlüsselwörter
kolorektales Karzinom - Lebermetastasen - neoadjuvante Therapie
Key words
colorectal cancer - liver metastases - neoadjuvant therapy
Literatur
- 1 Nordlinger B et al. Perioperative chemotherapy with FOLFOX4 and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC Intergroup trial 40 983): a randomised controlled trial. Lancet. 2008; 371 (9617) 1007-1016
- 2 Tomlinson J S et al. Actual 10-year survival after resection of colorectal liver metastases defines cure. J Clin Oncol. 2007; 25 (29) 4575-4580
- 3 Allen P J et al. Importance of response to neoadjuvant chemotherapy in patients undergoing resection of synchronous colorectal liver metastases. J Gastrointest Surg. 2003; 7 (1) 109-115 ; discussion 116 – 117
- 4 Adam R et al. Tumor progression while on chemotherapy: a contraindication to liver resection for multiple colorectal metastases?. Ann Surg. 2004; 240 (6) 1052-1061 ; discussion 1061 – 1064
- 5 Parikh A A et al. Perioperative complications in patients undergoing major liver resection with or without neoadjuvant chemotherapy. J Gastrointest Surg. 2003; 7 (8) 1082-1088
- 6 Weber J C et al. New technique for liver resection using heat coagulative necrosis. Ann Surg. 2002; 236 (5) 560-563
- 7 Are C et al. The impact of margins on outcome after hepatic resection for colorectal metastasis. Ann Surg. 2007; 246 (2) 295-300
- 8 Figueras J et al. Effect of subcentimeter nonpositive resection margin on hepatic recurrence in patients undergoing hepatectomy for colorectal liver metastases. Evidences from 663 liver resections. Ann Oncol. 2007; 18 (7) 1190-1195
- 9 Scaife C L et al. Accuracy of preoperative imaging of hepatic tumors with helical computed tomography. Ann Surg Oncol. 2006; 13 (4) 542-546
- 10 Fong Y et al. Liver resection for colorectal metastases. J Clin Oncol. 1997; 15 (3) 938-946
- 11 Vauthey J N et al. Chemotherapy regimen predicts steatohepatitis and an increase in 90-day mortality after surgery for hepatic colorectal metastases. J Clin Oncol. 2006; 24 (13) 2065-2072
- 12 Pawlik T M et al. Preoperative chemotherapy for colorectal liver metastases: impact on hepatic histology and postoperative outcome. J Gastrointest Surg. 2007; 11 (7) 860-868
- 13 Portier G 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 (31) 4976-4982
- 14 Langer B et al. Fluorouracil plus leucovorin versus observation after potentially curative resection of liver or lung metastases from colorectal cancer (CRC): results of the ENG (EORTC/NCIC CTC/GIVIO) randomized trial in Proc. ASCO Annual Meeting. abstr. 592. 2002
- 15 Mitry E 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 (30) 4906-4911
- 16 Ychou M et al. Randomized phase III trial comparing infused 5-fluorouracil/folinic acid (LV5FU) versus LV 5FU + irinotecan (LV5FU + IRI) as adjuvant treatment after complete resection of liver metastases from colorectal cancer (LMCRC). (CPT-GMA-301). Proc. ASCO Annual Meeting; 2008
- 17 Steele Jr G, Ravikumar T S. Resection of hepatic metastases from colorectal cancer. Biologic perspective. Ann Surg. 1989; 210 127-138
- 18 Nordlinger B, De Sena G, Szawlowski A et al. Surgical resection of hepatic metastases of cancers of the colon and rectum. Gastroenterol Clin Biol. 1983; 7 240-243
- 19 Scheele J, Stang R, Altendorf-Hofmann A et al. Resection of colorectal liver metastases. World J Surg. 1995; 19 59-71
- 20 Wei A C, Greig P D, Grant D et al. Survival after hepatic resection for colorectal metastases: a 10-year experience. Ann Surg Oncol. 2006; 13 668-676
- 21 Donadon M, Vauthey J N, Loyer E M et al. Portal thrombosis and steatosis after preoperative chemotherapy with FOLFIRI-bevacizumab for colorectal liver metastases. World J Gastroenterol. 2006; 12 6556-6558
- 22 Hurwitz H, Fehrenbacher L, Novotny W et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004; 350 2335-2342
- 23 Rees M, Tekkis P P, Welsh F K et al. Evaluation of long-term survival after hepatic resection for metastatic colorectal cancer: a multifactorial model of 929 patients. Ann Surg. 2008; 247 125-135
- 24 Lordan J T, Karanjia N D, Quiney N et al. A 10-year study of outcome following hepatic resection for colorectal liver metastases – The effect of evaluation in a multidisciplinary team setting. Eur J Surg Oncol. 2008; 35(3) 302-306
- 25 Fong Y, Fortner J, Sun R L 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 ; discussion 318 – 321
- 26 Iwatsuki S, Dvorchik I, Madariaga J R et al. Hepatic resection for metastatic colorectal adenocarcinoma: a proposal of a prognostic scoring system. J Am Coll Surg. 1999; 189 291-299
- 27 Nordlinger B, Guiguet M, Vaillant J C et al. Surgical resection of colorectal carcinoma metastases to the liver. A prognostic scoring system to improve case selection, based on 1568 patients. Association Francaise de Chirurgie. Cancer. 1996; 77 1254-1262
- 28 Ueno H, Mochizuki H, Hatsuse K et al. Indicators for treatment strategies of colorectal liver metastases. Ann Surg. 2000; 231 59-66
- 29 Taylor I. Adjuvant chemotherapy after resection of liver metastases from colorectal cancer. Eur J Cancer. 2008; 44 1198-1201
- 30 Adam R, Avisar E, Ariche A et al. Five-year survival following hepatic resection after neoadjuvant therapy for nonresectable colorectal. Ann Surg Oncol. 2001; 8 347-353
- 31 Leonard G D, Brenner B, Kemeny N E. Neoadjuvant chemotherapy before liver resection for patients with unresectable liver metastases from colorectal carcinoma. J Clin Oncol. 2005; 23 2038-2048
- 32 Kesmodel S B, Ellis L M, Lin E et al. Preoperative bevacizumab does not significantly increase postoperative complication rates in patients undergoing hepatic surgery for colorectal cancer liver metastases. J Clin Oncol. 2008; 26 5254-5260
- 33 Morris-Stiff G, Tan Y M, Vauthey J N. Hepatic complications following preoperative chemotherapy with oxaliplatin or irinotecan for hepatic colorectal metastases. Eur J Surg Oncol. 2008; 34 609-614
- 34 Rubbia-Brandt L, Audard V, Sartoretti P et al. Severe hepatic sinusoidal obstruction associated with oxaliplatin-based chemotherapy in patients with metastatic colorectal cancer. Ann Oncol. 2004; 15 460-466
- 35 Tannapfel A, Reinacher-Schick A. Chemotherapy associated hepatotoxicity in the treatment of advanced colorectal cancer (CRC). Z Gastroenterol. 2008; 46 435-440
- 36 Vauthey J N, Pawlik T M, Ribero D et al. Chemotherapy regimen predicts steatohepatitis and an increase in 90-day mortality after surgery for hepatic colorectal metastases. J Clin Oncol. 2006; 24 2065-2072
- 37 Zorzi D, Laurent A, Pawlik T M et al. Chemotherapy-associated hepatotoxicity and surgery for colorectal liver metastases. Br J Surg. 2007; 94 274-286
- 38 Gruenberger B, Tamandl D, Schueller J et al. Bevacizumab, capecitabine, and oxaliplatin as neoadjuvant therapy for patients with potentially curable metastatic colorectal cancer. J Clin Oncol. 2008; 26 1830-1835
- 39 Benoist S, Brouquet A, Penna C et al. Complete response of colorectal liver metastases after chemotherapy: does it mean cure?. J Clin Oncol. 2006; 24 3939-3945
- 40 Schmiegel W. Update S 3-guideline „colorectal cancer” 2008. Z Gastroenterol. 2008; 46 799-840
- 41 Du Prel J B et al. Konfidenzintervall oder p-Wert? Bewertung wissenschaftlicher Publikationen. DÄB. 2009; 106 335
- 42 Rödel C et al. Prognostic significance of tumor regression after preoperative chemoradiotherapy for rectal cancer. J Clin Oncol. 2005; 23 8688-8696
- 43 Blazer D G et al. Pathologic response to preoperative chemotherapy: a new outcome end point after resection of hepatic colorectal metastases. J Clin Oncol. 2008; 26 5344-5351
- 44 Adam R et al. Patients with initialy unresectable colorectal liver metastases: is there a possibility of cure?. J Clin Oncol. 2009; 27 1829
- 45 Nordlinger B et al. Combination of surgery and chemotherapy and the role of targeted agents in the treatment of patients with colorectal liver metastases: recommendations from an expert panel. Annals of Oncology; 19.January.2009
- 46 Brouquet A et al. Risk factors for chemotherapy-associated liver injuries: A multivariate analysis of a group of 146 patients with colorectal metastases. Surgery. 2009; 145 362-371
- 47 Zorzi D et al. Effect of extended preoperative chemotherapy on pathologic response and postoperative liver insufficiency after hepatic resection for colorectal liver metastases. ASCO Gastrointestinal Cancers Symposium; 2009
- 48 Tsai M S et al. Clinicopathological Features and Prognosis in Resectable Synchronous and Metachronous Colorectal Liver Metastasis. Annals of Surgical Oncology. 2007; 14 786-794
- 49 Tournigand C 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
- 50 Fahy B N et al. Synchronous Hepatic Metastases from Colon Cancer: Changing Treatment Strategies and Results of Surgical Intervention. Ann Surg Oncol. 2009; 16 361-370
Prof. Dr. Dirk Arnold
Hubertus-Wald-Tumorzentrum, Universitäres Cancer Center Hamburg, Universitätsklinikum Eppendorf
Martinistr. 52
20246 Hamburg
Phone: ++ 49/40/74 10-5 54 50
Email: d.arnold@uke.de