Neoadjuvante Therapieverfahren bei Lebermetastasen gastrointestinaler Tumoren

Zusammenfassung

Die R0-Resektion von Lebermetastasen des kolorektalen Karzinomes stellt nach wie vor die einzige kurative Therapieoption dar. Sie kann heutzutage aufgrund moderner chirurgischer Techniken und konsequenter intensivmedizinischer Betreuung mit geringer Morbidität und Mortalität durchgeführt werden. Da nur ein geringer Prozentsatz der erkrankten Patienten primär resektabel ist, hat die neoadjuvante Therapie eine zentrale Rolle in der interdisziplinären Therapie von Lebermetastasen eingenommen. Neben Verfahren zur Induktion einer Hypertrophie des nach Resektion verbleibenden Leberrestes (z. B. durch portale Embolisation / zweizeitige Hepatektomie) steht die Chemotherapie zur präoperativen Reduktion der Tumorlast im Mittelpunkt der Bemühungen. Hier haben sich moderne Schemata mit Dreierkombinationen (5-FU, Oxaliplatin, Irinotecan) und / oder Antikörpern (Bevacizumab / Cetuximab) aufgrund ihrer hoher Effektivität und daraus resultierenden hohen Raten von sekundärer Resektabilität bewährt. Dies führt jedoch zu einer erhöhten postoperativen Morbidität, ohne Erhöhung der Mortalität. Weitere prospektive randomisierte Multizenterstudien sind nötig, um den Effekt der neoadjuvanten Therapie nachhaltiger zu belegen.

Abstract

Surgical resection is still the only curative option in hepatic metastases of colorectal carcinoma. Hepatic resection can be provided with low morbidity and mortality these days. However, most patients are not resectable at the timepoint of primary diagnosis. Therefore, neoadjuvant therapy is a well established concept to achieve secondary resectability. On the one hand, portal vein embolization or two stage hepatectomy allow an extended surgical approach by induction of hypertrophy of the future liver remnant. On the other hand, preoperative chemotherapy is effective in downsizing hepatic lesions leading to secondary resectability of extended hepatic masses. These days, mainly combinations of 5-FU, oxaliplatin and irinotecan are widespread used. A combination with antibodies such as bevacizumab or cetuximab is a further option. While neoadjuvant chemotherapy results in a higher rate of postoperative complications, postoperative mortality rate does not change. Further prospective randomized trials will be necessary to further elucidate the role of neoadjuvant treatment in colorectal liver metastasis.

Schlüsselwörter

Lebermetastasen - kolorektales Karzinom - Antikörper - Chemotherapie

Key words

Liver metastasis - colorectal cancer - antibodies - chemotherapy

Literatur

• 1 Woodington G, Waugh J. Results of resection of metastatic tumors of the liver.  A J Surg. 1963;  105 24-29
• 2 Silen W. Hepatic resection for metastases from colorectal carcinoma is of dubious value.  Arch Surg. 1989;  124 1021-1022
• 3 Belli G, D'Agostino A, Ciciliano F. et al . Liver resection for hepatic metastases:15 years of experience.  J Hepatobiliary Pancreat Surg. 2002;  9 607-613
• 4 Scheele J, Altendorf-Hofmann A. Resection of colorectal liver metastasis.  Langenbeck's Arch Surg. 1999;  384 313-327
• 5 Charnsangavej C, Clary B, Fong Y, Grothey A, Pawlik T, Chonti M. Selection of patients for resection of hepatic colorectal metastases: expert consensus statement.  Ann Surg Oncol. 2006;  13 1261-1268
• 6 Adam R, Delvart V, Pascal G. et al . Rescue surgery for unresectable colorectal liver metastasis downstaged by chemotherapy: a model to predict long term survival.  Ann Surg Oncol. 2004;  240 (4) 644-657
• 7 Leporrier J, Maurel J, Chicche L. et al . A population based study of the incidence, management and prognosis of hepatic metastases from colorectal cancer.  Br J Surg. 2006;  93 465-474
• 8 Biasco G, Derenzini E, Grazi G. et al . Treatment of hepatic metastasis from colorectal cancer; many doubts, some certainties.  Cancer Treat Rev. 2006;  32 214-228
• 9 Poston G. Surgical strategies for colorectal liver metastasis.  Surg Oncol. 2004;  13 125-136
• 10 Nordlinger B, Guiguet M, Vaillant J. et al . Surgical resection of colorectal carcinoma metastasis to the liver. A prognostic scoring system to improve case selection, based on 1 568 patients.  Cancer. 1996;  77 1254-1262
• 11 Fong Y, Cohen A, Fortner J. et al . Liver resection for colorectal metastasis.  J Clin Oncol. 1997;  15 938-946
• 12 Fong Y, Fortner J, Sun R, Brennan M, Blumgart L. et al . Clinical score predicting recurrence after hepatic resection for metastatic colorectal cancer: analysis of 1 001 consecutive cases.  Ann Surg. 1999;  230 309-318
• 13 Iwatsuki S, Dvorchik I, Madariaga J. et al . Hepatic resection for metastasis of colorectal adenocarcinoma: a proposal of a prognostic scoring system.  J Am Coll Surg. 1999;  189 291-299
• 14 Poston G, Adam R, Alberts S. et al . OncoSurge: A strategy improving resectability with curative intent in metastatic colorectal cancer.  J Clin Oncol. 2005;  23 7125-7134
• 15 Adam R, Avisar E, Ariche A. et al . Five year survival following hepatic resection after neoadjuvant therapy for nonresectable colorectal metastases.  Ann Surg Oncol. 2001;  8 347-353
• 16 Lorenz M, Staib-Sebler E, Gog C. et al . Prospective pilot study of neoadjuvant chemotherapy with 5-floururacil, folinic acid and oxaliplatin in resectable liver metastasis of colorectal cancer. Analyses of 42 neoadjuvant chemotherapies.  Zentralbl Chir. 2003;  128 87-94
• 17 Nordlinger B, Sorbye H, Collette L. et al . Final results of the EORTC intergroup randomized phase III study 40983 (EPOC) evaluating the benefit of peri-operative FOLFOX4 chemotherapy for patients with potentially resectable colorectal cancer liver metastases.  J Clin Oncol. 2007;  25 LBA 5-LBA5
• 18 Nordlinger B, Sorbye H, Debois M. et al . Feasibility and risks of pre-operative chemotherapy (CT) with FOLFOX4 and surgery for resectable colorectal cancer liver metastases (LM). Interim results of the EORTC intergroup randomized phase III study 40983.  J Clin Oncol. 2005;  23 3528
• 19 Bismuth H, Adam R, Levi F. et al . Resection of nonresectable liver metastases from colorectal cancer after neoadjuvant chemotherapy.  Ann Surg. 1996;  22 509-522
• 20 Folprecht G, Grothey A, Alberts S, Raab H, Köhne C. et al . Neoadjuvant treatment of unresectable colorectal liver metastasis: correlation between tumor response and resection rates.  Ann Ocol. 2005;  16 1311-1319
• 21 Falcone A, Andreuccetti M, Brunetti I. et al . Updated results, multivariate and subgroup analysis confirm improved activity and efficacy for FOLFOXIRI versus FOLFIRI in the G.O.N.O randomized phase III study in metastatic colorectal cancer.  J Clin Oncol. 2007;  25 4026
• 22 VanCutsem E, Nowacki M, Lang I. et al . Randomized phase III study of irinotecan and 5-FU / FA with or without cetuximab in the first line treatment of patients with metastatic colorectal cancer (mCRC): the CRYSTAL trial.  J Clin Oncol. 2007;  25 4000
• 23 Watkins D, Jackson C, Chua Y. et al . A prospective study of oxaliplatin and capecitabine (CapOx) in metastatic colorectal cancer (mCRC) with baseline stratification according to resectability status.  J Clin Oncol. 2007;  25 4024
• 24 Aloia T, Levi F, Wicherts D. et al . Hepatic resection following rescue cetuximab treatment for colorectal liver metastases previously refractory to conventional systemic therapy.  J Clin Oncol. 2007;  25 4061
• 25 Kretzschmar A, Van Custem E, Michael M. et al . Preliminary efficacy of bevacizumab with first-line FOLFOX, XELOX, FOLFIRI and monotherapy for mCRC: First BEATrial.  J Clin Oncol. 2007;  25 4072
• 26 Gruenberger T, Tamandl D, Puhalla H, Scheithauer W, Zielinski C, Gruenberger B. Bevacicumab plus XELOX as neoadjuvant therapy for patients with potentially curable metastatic colorectal cancer.  J Clin Oncol. 2007;  25 4064
• 27 Nuzzo G, Giuliante F, Ardito F. et al . Liver resection for primarily unresectable colorectal metastases downsized by chemotherapy.  J Gastrointest Surg. 2007;  11 318-324
• 28 Benoist S, Brouquet A, Penna C. et al . Complete response of colorectal liver metastasis after chemotherapy: does it mean cure?.  J Clin Oncol. 2006;  24 3939-3945
• 29 Taylor R, White R, Kemeny N. et al . Prediction of true complete response in colorectal liver metastases that disappear radiologically following chemotherapy.  J Clin Oncol. 2007;  25 179
• 30 Wicherts D, Haas R, Levi F. et al . Complete pathological response of colorectal liver metastases after neoadjuvant chemotherapy: myth or reality.  J Clin Oncol. 2007;  25 179
• 31 Bilchik A, Postone G, Curley S. et al . Neoadjuvant chemotherapy for metastatic colon cancer: A cautionary note.  J Clin Oncol. 2005;  23 9073-9078
• 32 Karoui M, Penna C, Amin-Hashem M. et al . Influence of preoperative chemotherapy on the risk of major hepatectomy for colorectal liver metastasis.  Ann Surg. 2006;  243 1-7
• 33 Aloia T, Sebagh M, Plasse M. et al . Liver histology and surgical outcomes after preoperative chemotherapy with flourouracil plus oxaliplatin in colorectal cancer liver metastasis.  J Clin Oncol. 2006;  24 4983-4990
• 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 Kooby D, Fong Y, Suriawinata A. et al . Impact of steatosis on perioperative outcome following hepatic resection.  J Gastrointest Surg. 2003;  7 1034-1044
• 36 Fernandez F, Ritter J, Goodwin J. et al . Effect of steatohepatitis associated with irinotecan or oxaliplatin pretreatment on resectability of hepatic colorectal metastasis.  J Am Coll Surg. 2005;  200 845-853
• 37 Parikh A, Gentner B, Wu T. et al . Perioperative complications in patients undergoing major liver resection with or without neoadjuvant chemotherapy.  J Gastrointest Surg. 2003;  7 1082-1088
• 38 Welsh F, Tilney H, Tekkis P, John T, Rees M. et al . Safe liver resection following chemotherapy for colorectal metastases in matter of timing.  Br J Cancer. 2007;  96 1037-1042
• 39 Vauthey J, Pawlik T, 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
• 40 Scappaticci F, Fehrenbacher L, Cartwright T. et al . Surgical wound healing complications in metastatic colorectal cancer patients treated with bevacizumab.  J Surg Oncol. 2005;  91 173-180
• 41 Ellis L, Curley S, Grothey A. et al . Surgical resection after downsizing of colorectal liver metastasis in the era of bevacizumab.  J Clin Oncol. 2005;  23 4853-4855
• 42 Gordon M, Margolin K, Talpaz M. et al . Phase I safety and pharmacokinetic study of recombinant human anti-vascular endothelial growth factor in patients with advanced cancer.  J Clin Oncol. 2001;  19 843-850
• 43 Broering D, Hillert C, Krupski G, Rogiers X. et al . Portal vein embolization vs. portal vein ligation for induction of hypertrophy of the future liver remnant.  J Gastrointest Surg. 2002;  6 905-913
• 44 Fusai G, Davidson B. Strategies to increase the resectability of liver metastases from colorectal cancer.  Dig Surg. 2003;  20 481-496
• 45 Elias D, Ouellet J, DeBaere T, Lasser P, Roche A. Preoperative selective portal vein embolization before hepatectomy for liver metastasis: long-term results and impact on survival.  Surgery. 2002;  131 249-299
• 46 Farges O, Belgithi J, Kianmanesh R. et al . Portal vein embolization before right hepatectomy: prospective clinical trial.  Ann Surg. 2003;  237 208-217