The liver is a frequent site of metastatic colorectal disease. Over the past 20 years, improvements in systemic chemotherapy and surgical techniques have improved the survival of patients with hepatic metastases. For 4 decades, fluorouracil and leucovorin were the only drugs available to treat metastatic colorectal cancer, but several new drugs and a variety of novel regimens are now available. Further improvements in results have been seen with the delivery of chemotherapy via the hepatic artery. Surgical resection of liver metastases has been encouraged when possible, and recent advances in surgery such as portal vein embolization, have made liver resection a possibility for more patients. This review considers the timing and sequence of chemotherapy and surgery in this setting, as well as the roles of cryoablation, radiofrequency ablation, and radiation therapy.
The liver is a frequent site of metastatic disease, especially for cancers of the gastrointestinal tract. Since venous drainage from the colon and rectum flows via the portal vein to the liver, it is not surprising that patients with colorectal cancer frequently develop liver metastases. Approximately 15% of patients will have liver metastases at the time of diagnosis, and another 60% of patients who develop metastatic disease will have metastases to the liver. For many years, the approach to patients with hepatic metastases was nihilistic. In the past 2 decades, improvements in systemic chemotherapy, in modalities to detect liver metastases, and in surgical techniques for hepatic resection, have improved the survival of these patients.
For 4 decades, fluorouracil (5-FU) plus leucovorin (LV) were the only drugs available to treat metastatic colorectal cancer, yielding a response rate of 20% to 30% and a median survival of 11 to 12 months. A number of new agents are now available, including irinotecan (Camptosar), a topo-isomerase inhibitor, and oxaliplatin (Eloxatin), a platinum compound with in vivo and in vitro activity against colon cancer cell lines and the ability to synergize with 5-FU.[2,3]
Randomized trials using irinotecan with 5-FU/LV vs 5-FU/LV alone[4,5] produced an increase in response rate and survival (Table 1). When irinotecan/5-FU/LV (IFL) was compared to oxaliplatin plus 5-FU/LV (FOLFOX), the response rate was increased from 35% to 45%, and survival was increased from 15 to 19.5 months for the IFL and FOLFOX groups, respectively. That said, 5-FU given by continuous infusion is more effective than bolus 5-FU; therefore, when 5-FU administration was changed to infusion (ie, FOLFIRI rather than IFL), the regimen of irinotecan/5-FU/LV became more effective and produced results similar to those seen with FOLFOX.
In the past few years, targeted agents have become available: bevacizumab (Avastin), a monoclonal antibody to vascular endothelial growth factor, and cetuximab (Erbitux), an antibody to epidermal growth factor receptor. The addition of bevacizumab to IFL increased response rates and survival (35% to 45%, and 15.6 to 19.5 months, for IFL vs bevacizumab/IFL, respectively). For almost 4 decades, the 2-year survival for metastatic colorectal patients treated with 5-FU or 5-FU/LV was 25%; with these new agents, 2-year survival rates have increased to 30%-39%, with a marked improvement in overall survival (Table 1).
In the second-line setting, even with the new agents, results are less impressive. Irinotecan is associated with a response rate of 5% to 14% and a median survival of 9.9 months. FOLFOX administered to irinotecan-refractory patients produces a 9.9% response rate, with a median survival of 9.8 months (Table 2). After progression on irinotecan, cetuximab alone can produce a 10% response rate, which increases to 23% when this agent is combined with irinotecan. Second-line bevacizumab combined with FOLFOX increased survival to 12 months from 10 months for FOLFOX alone (Table 2).
Hepatic Arterial Infusional Chemotherapy
To further improve on results, adding direct liver perfusion with chemotherapy might be useful. The first trials compared hepatic arterial infusion (HAI) alone to systemic chemotherapy. The rationale for HAI is based on the following facts: (1) liver metastases are perfused almost exclusively by the hepatic artery, whereas the normal liver is perfused by the portal vein, (2) certain drugs are largely extracted by the liver during the first pass, allowing for minimal systemic toxicity, and (3) the liver is often the first and only site of metastatic disease. Therefore, aggressive treatment of metastases confined to the liver by resection or hepatic infusion may yield prolonged survival for some patients.
Regional therapy can be delivered using a hepatic arterial port or a totally implantable pump. Early studies with catheters produced clotting and bleeding that did not allow for long-term hepatic infusion with reliable patency. Studies in Europe still use the catheters rather than pumps, perhaps explaining the inferior results in the European trials.
Ten randomized studies have compared HAI to systemic chemotherapy (Table 3).[17-26] Almost all the studies showed an increase in response rate. Only the English trial that used HAI 5-FU failed to increase response rate.
Why did the superior response rates seen with HAI not translate into improved survival in the earlier trials? Most of these trials were too small, and a number of them allowed crossover to HAI at the time of progression on systemic chemotherapy, potentially diluting statistical results that might have demonstrated a survival benefit. Two earlier European studies demonstrated an increase in survival with HAI, but appropriate systemic therapy was not always used.
Two recent European trials did not show an increase in survival—the first being the Medical Research Council and European Organization for Research and Treatment of Cancer (EORTC) study, which randomized patients to HAI 5-FU/LV via a port rather than a pump (using 5-FU rather than floxuridine [FUDR]) vs systemic 5-FU/LV. In this study, 37% of the patients assigned to the HAI arm did not receive treatment and 29% had to stop treatment. No differences were seen in response rate at 12 weeks (22% vs 19%, for HAI and systemic therapy, respectively), and no differences were seen in toxicity, progression-free survival (PFS), or survival. The study was not analyzed to look at the patients who actually received treatment.
A German cooperative group randomized patients to HAI FUDR, HAI 5-FU/LV, or systemic 5-FU/LV. Tumor response rates were 43.2%, 45%, and 19.7%, and development of extrahepatic disease was 40.5%, 12.5%, and 18.3% for the HAI FUDR, HAI 5-FU/LV, and systemic 5-FU/LV groups, respectively. Toxicity data indicated that 5-FU/LV therapy was much more toxic than FUDR. A port was used, rather than a pump, and the FUDR regimen was different from what was used in the American studies in that the dosage was reduced from 0.2 to 0.15 mg/kg/d after three cycles rather than adjusting for patient toxicity. The median survival was 12.7, 18.7, and 17.6 months for the HAI FUDR, HAI 5-FU/LV, and systemic 5-FU/LV groups, respectively. Only 66% of patients randomized to HAI FUDR were treated, but all were included in the survival analysis. Eight patients in the HAI FUDR group died before ever receiving treatment, perhaps explaining the very low survival with HAI FUDR.
The Cancer and Leukemia Group B (CALGB) trial differs from the other HAI studies in that it included the use of dexamethasone in the HAI arm. HAI FUDR, dexamethasone plus LV was compared to systemic bolus 5-FU/LV. No crossover was allowed. The HAI group had a significant increase in survival (24.4 months, vs 20 months in the systemic group, P = .0034). The time to hepatic progression was better in the HAI arm (9.8 vs 7.3 months, P = .034) but the time to extrahepatic progression was better in the systemic arm (14.8 vs 7.7 months in the HAI group, P < .029). The toxicities were as expected, with a significant increase in diarrhea and neutropenia for the systemic arm and a significant increase in biliary toxicity for the HAI arm (18% vs 0%). A quality-of-life assessment was performed as part of the study, and the HAI group experienced improvement in this parameter, as measured at 3 and 6 months.
Differences between the CALGB study and the European studies might explain differences in the outcomes. The CALGB study used pumps instead of ports, and HAI therapy included FUDR with dexamethasone to decrease toxicity. Survival was based on intent to treat in all three studies, and the actual number of patients treated was much lower in the European studies—66% in the German study and 63% in the English study—while it was 86% in the CALGB study. The CALGB study did demonstrate that regional therapy alone can improve survival over systemic 5-FU/LV with a survival similar to that seen with newer agents. Randomized studies of HAI therapy vs the new therapies have not been conducted. In the future, studies comparing HAI or HAI plus new agents vs the new agents alone would be appropriate.
HAI-based therapy in patients refractory to systemic chemotherapy has produced much higher response rates in small single-institution studies (Table 4). A trial using HAI FUDR/LV/dexamethasone in both chemotherapy-naive and previously treated patients produced response rates of 72% and 52%, and median survivals of 23 and 13.5 months for the chemotherapy-naive and previously treated patients, respectively. HAI FUDR/dexamethasone plus mitomycin administered through the pump sideport, produced a 70% response rate in previously treated patients, with a median survival of 19 months from the start of HAI therapy after progression on systemic 5-FU/LV.
A phase I study of HAI FUDR combined with systemic irinotecan in previously treated patients (45% had previously received irinotecan) reported a response rate of 74%, a time to disease progression of 8.1 months, and a median survival of 20 months. A total of 13 of the 16 patients with prior irinotecan exposure responded to this regimen. Systemic oxaliplatin plus 5-FU/LV or oxaliplatin plus irinotecan with concurrent HAI FUDR/dexamethasone in 36 previously treated patients (74% had received prior irinotecan) produced response rates of 86%, with a median survival of 36 months, and a 1-year survival of 80%. These and other small studies (Table 4) suggest that a benefit may be derived from HAI and systemic therapy as second-line therapy, and randomized studies exploring the use of HAI plus systemic therapy vs new agents alone in the second-line setting should be performed.
Toxicity of Hepatic Arterial FUDR Infusion
The most common problems with HAI therapy are hepatic toxicity and gastric ulcerations. Myelosuppression, nausea, vomiting, and diarrhea do not occur with HAI FUDR. If diarrhea does occur, shunting to the bowel should be suspected. Clinically, biliary toxicity is manifested as elevations of aspartate transaminase, alkaline phosphatase, and bilirubin. In early stages of the disease, hepatic enzyme elevations will return to normal when the drug is withdrawn and the patient is given a rest period, whereas in more advanced cases, it does not resolve. Therefore, careful monitoring of liver function tests is necessary to avoid this toxicity. The bile ducts derive their blood supply almost exclusively from the hepatic artery, and thus are also perfused with high doses of chemotherapy during HAI treatment. HAI 5-FU causes fewer biliary problems and more arteritis.
In patients who develop jaundice, an endoscopic retrograde cholangiopancreatogram (ERCP) may demonstrate lesions resembling idiopathic sclerosing cholangitis in 5% to 29% of patients treated. The strictures may be focal and present at the hepatic duct bifurcation, and therefore drainage procedures either by ERCP or by transhepatic cholangiogram may be helpful. Duct obstruction from metastases or bile duct strictures from surgery can also be causes of elevated bilirubin and must be ruled out before concluding that the elevation in liver function tests is due to HAI therapy.
1. Kemeny N, Kemeny MM, Lawrence TS: Liver metastases, in Abeloff MD, Armitage JO, Niederhuber JE, et al (eds): Clinical Oncology, 3rd ed, pp 1141-1178. Philadelphia, Elsevier, 2004.
2. Tashiro T, Kawada Y, Sakurai Y, et al: Antitumor activity of a new platinum complex, oxalato (trans-l-1,2-diaminocyclohexane) platinum (II): New experimental data. Biomed Pharmacother 43:251-260, 1989.
3. Mathe G, Kidani Y, Segiguchi M, et al: Oxalato-platinum or 1-OHP, a third-generation platinum complex: An experimental and clinical appraisal and preliminary comparison with cis-platinum and carboplatinum. Biomed Pharmacother 43:237-250, 1989.
4. Saltz LB, Cox JV, Blanke C, et al: Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. Irinotecan Study Group. N Engl J Med 343:905-914, 2000.
5. Douillard JY, Cunningham D, Roth AD, et al: Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: A multicentre randomised trial. Lancet 355:1041-1047, 2000.
6. Goldberg RM, Sargent DJ, Morton RF, 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 22:23-30, 2004.
7. 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 22:229-237, 2004.
8. Hurwitz H, Fehrenbacher L, Novotny W, et al: Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350:2335-2342, 2004.
9. Rothenberg ML, Cox JV, DeVore RF, et al: A multicenter, phase II trial of weekly irinotecan (CPT-11) in patients with previously treated colorectal carcinoma. Cancer 85:786-795, 1999.
10. Rothenberg ML, Oza AM, Bigelow RH, et al: Superiority of oxaliplatin and fluorouracil-leucovorin compared with either therapy alone in patients with progressive colorectal cancer after irinotecan and fluorouracil-leucovorin: Interim results of a phase III trial. J Clin Oncol 21:2059-2069, 2003.
11. Cunningham D, Humblet Y, Siena S, et al: Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 351:337-345, 2004.
12. Giantonio BJ, Catalano PJ, Meropol NJ, et al: High-dose bevacizumab improves survival when combined with FOLFOX4 in previously treated advanced colorectal cancer: Results from the Eastern Cooperative Oncology Group (ECOG) study E3200 (abstract 2). J Clin Oncol 23(16S):1s, 2005.
13. Breedis C, Young G: The blood supply of neoplasms in the liver. Am J Pathol 30:969-977, 1954.
14. Ensminger W, Niederhuber J, Dakhil S, et al: Totally implanted drug delivery system for hepatic arterial chemotherapy. Cancer Treat Rep 65:393-400, 1981.
15. Weiss L, Grundmann E, Torhorst J, et al: Haematogenous metastatic patterns in colonic carcinoma: An analysis of 1541 necropsies. J Pathol 150:195-203, 1986.
16. Tandon RN, Bunnell IL, Cooper RG: The treatment of metastatic carcinoma of the liver by the percutaneous selective hepatic artery infusion of 5-fluorouracil. Surgery 73:118-121, 1973.
17. Lorenz M, Muller HH: Randomized, multicenter trial of fluorouracil plus leucovorin administered either via hepatic arterial or intravenous infusion vs fluorodeoxyuridine administered via hepatic arterial infusion in patients with nonresectable liver metastases from colorectal carcinoma. J Clin Oncol 18:243-254, 2000.
18. Kemeny NE, Niedzwiecki D, Hollis DR, et al: Hepatic arterial infusion vs systemic therapy for hepatic metastases from colorectal cancer: A randomized trial of efficacy, quality of life, and molecular markers (CALGB 9481). J Clin Oncol 24:1395-1403, 2006.
19. Kemeny N, Daly J, Reichman B, et al: Intrahepatic or systemic infusion of fluorodeoxyuridine in patients with liver metastases from colorectal carcinoma. A randomized trial. Ann Intern Med 107:459-465, 1987.
20. Chang AE, Schneider PD, Sugarbaker PH, et al: A prospective randomized trial of regional vs systemic continuous 5-fluorodeoxyuridine chemotherapy in the treatment of colorectal liver metastases. Ann Surg 206:685-693, 1987.
21. Hohn DC, Stagg RJ, Friedman MA, et al: A randomized trial of continuous intravenous vs hepatic intraarterial floxuridine in patients with colorectal cancer metastatic to the liver: The Northern California Oncology Group trial. J Clin Oncol 7:1646-1654, 1989.
22. Wagman LD, Kemeny MM, Leong L, et al: A prospective, randomized evaluation of the treatment of colorectal cancer metastatic to the liver. J Clin Oncol 8:1885-1893, 1990.
23. Martin JK, Jr., O'Connell MJ, Wieand HS, et al: Intra-arterial floxuridine vs systemic fluorouracil for hepatic metastases from colorectal cancer. A randomized trial. Arch Surg 125:1022-1027, 1990.
24. Rougier P, Laplanche A, Huguier M, et al: Hepatic arterial infusion of floxuridine in patients with liver metastases from colorectal carcinoma: Long-term results of a prospective randomized trial. J Clin Oncol 10:1112-1118, 1992.
25. Allen-Mersh TG, Earlam S, Fordy C, et al: Quality of life and survival with continuous hepatic-artery floxuridine infusion for colorectal liver metastases. Lancet 344:1255-1260, 1994.
26. Kerr DJ, McArdle CS, Ledermann J, et al: Intrahepatic arterial vs intravenous fluorouracil and folinic acid for colorectal cancer liver metastases: A multicentre randomised trial. Lancet 361:368-373, 2003.
27. Kemeny N, Seiter K, Niedzwiecki D, et al: A randomized trial of intrahepatic infusion of fluorodeoxyuridine with dexamethasone vs fluorodeoxyuridine alone in the treatment of metastatic colorectal cancer. Cancer 69:327-334, 1992.
28. Kemeny N, Conti JA, Cohen A, et al: Phase II study of hepatic arterial floxuridine, leucovorin, and dexamethasone for unresectable liver metastases from colorectal carcinoma. J Clin Oncol 12:2288-2295, 1994.
29. Kemeny N, Eid A, Stockman J, et al: Hepatic arterial infusion of floxuridine and dexamethasone plus high-dose mitomycin C for patients with unresectable hepatic metastases from colorectal carcinoma. J Surg Oncol 91:97-101, 2005.
30. Kemeny N, Gonen M, Sullivan D, et al: Phase I study of hepatic arterial infusion of floxuridine and dexamethasone with systemic irinotecan for unresectable hepatic metastases from colorectal cancer. J Clin Oncol 19:2687-2695, 2001.
31. Kemeny N, Jarnagin W, Paty P, et al: Phase I trial of systemic oxaliplatin combination chemotherapy with hepatic arterial infusion in patients with unresectable liver metastases from colorectal cancer. J Clin Oncol 23:4888-4896, 2005.
32. Gluck WL, Akwari OE, Kelvin FM, et al: A reversible enteropathy complicating continuous hepatic artery infusion chemotherapy with 5-fluoro-2-deoxyuridine. Cancer 56:2424-2427, 1985.
33. Northover JM, Terblanche J: A new look at the arterial supply of the bile duct in man and its surgical implications. Br J Surg 66:379-384, 1979.
34. Stagg RJ, Venook AP, Chase JL, et al: Alternating hepatic intra-arterial floxuridine and fluorouracil: A less toxic regimen for treatment of liver metastases from colorectal cancer. J Natl Cancer Inst 83:423-428, 1991.
35. Steele G Jr, Ravikumar TS: Resection of hepatic metastases from colorectal cancer. Biologic perspective. Ann Surg 210:127-138, 1989.
36. Hughes KS, Simon R, Songhorabodi S, et al: Resection of the liver for colorectal carcinoma metastases: A multi-institutional study of patterns of recurrence. Surgery 100:278-284, 1986.
37. Scheele J, Stangl R, Altendorf-Hofmann A: Hepatic metastases from colorectal carcinoma: Impact of surgical resection on the natural history. Br J Surg 77:1241-1246, 1990.
38. Scheele J, Altendorf-Hofmann A: Resection of colorectal liver metastases. Langenbecks Arch Surg 384:313-327, 1999.
39. Ohlsson B, Stenram U, Tranberg KG: Resection of colorectal liver metastases: 25-year experience. World J Surg 22:268-277 (incl discussion), 1998.
40. Minagawa M, Makuuchi M, Torzilli G, et al: Extension of the frontiers of surgical indications in the treatment of liver metastases from colorectal cancer: Long-term results. Ann Surg 231:487-499, 2000.
41. Bolton JS, Fuhrman GM: Survival after resection of multiple bilobar hepatic metastases from colorectal carcinoma. Ann Surg 231:743-751, 2000.
42. Makuuchi M, Thai BL, Takayasu K, et al: Preoperative portal embolization to increase safety of major hepatectomy for hilar bile duct carcinoma: a preliminary report. Surgery 107:521-527, 1990.
43. Makuuchi M, Hasegawa H, Yamazaki S: Ultrasonically guided subsegmentectomy. Surg Gynecol Obstet 161:346-350, 1985.
44. Vajdova K, Heinrich S, Tian Y, et al: Ischemic preconditioning and intermittent clamping improve murine hepatic microcirculation and Kupffer cell function after ischemic injury. Liver Transpl 10:520-528, 2004.
45. Launois B, Jamieson GG: The importance of Glisson's capsule and its sheaths in the intrahepatic approach to resection of the liver. Surg Gynecol Obstet 174:7-10, 1992.
46. Khatri VP, Petrelli NJ, Belghiti J: Extending the frontiers of surgical therapy for hepatic colorectal metastases: Is there a limit? J Clin Oncol 23:8490-8499, 2005.
47. Poston GJ, Adam R, Alberts S, et al: OncoSurge: A strategy for improving resectability with curative intent in metastatic colorectal cancer. J Clin Oncol 23:7125-7134, 2005.
48. Fong Y, Fortner J, Sun RL, et al: Clinical score for predicting recurrence after hepatic resection for metastatic colorectal cancer: Analysis of 1001 consecutive cases. Ann Surg 230:309-321 (incl discussion), 1999.
49. Nordlinger B, Guiguet M, Vaillant JC, 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 77:1254-1262, 1996.
50. Adam R, Aloia T, Figueras J, et al: LiverMetSurvey: Analysis of clinicopathologic factors associated with the efficacy of preoperative chemotherapy in 2,122 patients with colorectal liver metastases (abstract 3521). J Clin Oncol 24(18S):151s, 2006.
51. Bismuth H, Adam R, Levi F, et al: Resection of nonresectable liver metastases from colorectal cancer after neoadjuvant chemotherapy. Ann Surg 224:509-522 (incl discussion), 1996.
52. Giacchetti S, Itzhaki M, Gruia G, et al: Long-term survival of patients with unresectable colorectal cancer liver metastases following infusional chemotherapy with 5-fluorouracil, leucovorin, oxaliplatin and surgery. Ann Oncol 10:663-669, 1999.
53. Adam R, Delvart V, Pascal G, et al: Rescue surgery for unresectable colorectal liver metastases downstaged by chemotherapy: A model to predict long-term survival. Ann Surg 240:644-658 (incl discussion), 2004.
54. Alberts SR, Horvath WL, Sternfeld WC, et al: 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 23:9243-9249, 2005.
55. Pozzo C, Basso M, Quirino M, et al: Long-term follow-up of colorectal cancer (CRC) patients treated with neoadjuvant chemotherapy with irinotecan and fluorouracil plus folinic acid (5-FU/FA) for unresectable liver metastases (abstract 3576). J Clin Oncol 24(18S):164s, 2006.
56. Rougier P, Raoul J-L, Van Laethem J-L, et al: Cetuximab+FOLFIRI as first-line treatment for metastatic colorectal CA (abstract 3513). Proc Am Soc Clin Oncol 23:248, 2004.
57. Noda M, Yanagi H, Yoshikawa R, et al: Second-look hepatectomy after pharmacokinetic modulating chemotherapy (PMC) combination with hepatic arterial 5FU infusion and oral UFT in patients with unresectable hepatic colorectal metastases (abstract 3739). Proc Am Soc Clin Oncol 23:304, 2004.
58. Falcone A, Masi G, Brunetti I, et al: The triplet combination of irinotecan, oxaliplatin and 5FU/leucovorin (FOLFOXIRI) vs the doublet of irinotecan and 5FU/leucovorin (FOLFIRI) as first-line treatment of metastatic colorectal cancer (MCRC): Results of a randomized phase III trial by the Gruppo Oncologico Nord Ovest (G.O.N.O.) (abstract 3513). J Clin Oncol 24(18S):149s, 2006.
59. Nordlinger B, Brouquet A, Penna C, et al: Complete radiological response of colorectal liver metastases (LM) after chemotherapy: Does it mean cure? (abstract 3501). J Clin Oncol 24(18S):146s, 2006.
60. 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 15:460-466, 2004.
61. Kooby DA, Fong Y, Suriawinata A, et al: Impact of steatosis on perioperative outcome following hepatic resection. J Gastrointest Surg 7:1034-1044, 2003.
62. Parikh AA, Gentner B, Wu TT, et al: Perioperative complications in patients undergoing major liver resection with or without neoadjuvant chemotherapy. J Gastrointest Surg 7:1082-1088, 2003.
63. Vauthey JN, Pawlik TM, Ribero D, et al: Chemotherapy regimen predicts steatohepatitis and an increase in 90-day mortality after surgery for hepatic colorectal metastases. J Clin Oncol 24:2065-2072, 2006.
64. Tanaka K, Shimada H, Matsuo K, et al: Outcome after simultaneous colorectal and hepatic resection for colorectal cancer with synchronous metastases. Surgery 136:650-659, 2004.
65. Tanaka K, Adam R, Shimada H, et al: Role of neoadjuvant chemotherapy in the treatment of multiple colorectal metastases to the liver. Br J Surg 90:963-969, 2003.
66. Mentha G, Majno PE, Andres A, et al: Neoadjuvant chemotherapy and resection of advanced synchronous liver metastases before treatment of the colorectal primary. Br J Surg 93:872-878, 2006.
67. Gruenberger T, Sorbye H, Debois M, et al: 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 (abstract 3500). J Clin Oncol 24(18S): 146s, 2006.
68. Kemeny N, Huang Y, Cohen AM, et al: Hepatic arterial infusion of chemotherapy after resection of hepatic metastases from colorectal cancer. N Engl J Med 341:2039-2048, 1999.
69. Kemeny NE, Gonen M: Hepatic arterial infusion after liver resection. N Engl J Med 352:734-735, 2005.
70. Kemeny MM, Adak S, Gray B, et al: Combined-modality treatment for resectable metastatic colorectal carcinoma to the liver: Surgical resection of hepatic metastases in combination with continuous infusion of chemotherapy-an intergroup study. J Clin Oncol 20:1499-1505, 2002.
71. Lorenz M, Muller HH, Schramm H, et al: Randomized trial of surgery vs surgery followed by adjuvant hepatic arterial infusion with 5-fluorouracil and folinic acid for liver metastases of colorectal cancer. German Cooperative on Liver Metastases (Arbeitsgruppe Lebermetastasen). Ann Surg 228:756-762, 1998.
72. Kusunoki M, Yanagi H, Noda M, et al: Results of pharmacokinetic modulating chemotherapy in combination with hepatic arterial 5-fluorouracil infusion and oral UFT after resection of hepatic colorectal metastases. Cancer 89:1228-1235, 2000.
73. Clancy TE, Dixon E, Perlis R, et al: Hepatic arterial infusion after curative resection of colorectal cancer metastases: A meta-analysis of prospective clinical trials. J Gastrointest Surg 9:198-206, 2005.
74. Kemeny N, Jarnagin W, Gonen M, et al: Phase I/II study of hepatic arterial therapy with floxuridine and dexamethasone in combination with intravenous irinotecan as adjuvant treatment after resection of hepatic metastases from colorectal cancer. J Clin Oncol 21:3303-3309, 2003.
75. Kemeny NE, Jarnagin W, Gonen M, et al: Phase I trial of hepatic arterial infusion (HAI) with floxuridine (FUDR) and dexamethasone (DEX) in combination with systemic oxaliplatin (OXAL), fluorouracil (FU) + leucovorin (LV) after resection of hepatic metastases from colorectal cancer (abstract 3579). J Clin Oncol 23(16S):265s, 2005.
76. Alberts SR, Mahoney MR, Donohue JH, et al: Systemic capecitabine and oxaliplatin administered with hepatic arterial infusion (HAI) of floxuridine (FUDR) following complete resection of colorectal metastases (M-CRC) confined to the liver: A North Central Cancer Treatment Group (NCCTG) phase II intergroup trial (abstract 3525). J Clin Oncol 24(18S):152s, 2006.
77. Langer B, Bleiberg H, Labianca R, et al: Fluorouracil (FU) plus l-leucovorin (l-LV) vs observation after potentially curative resection of liver or lung metastases from colorectal cancer (CRC): Results of the ENG (EORTC/NCIC CTG/GIVIO) randomized trial (abstract 592). Proc Am Soc Clin Oncol 21:149a, 2002.
78. Morris DL, Ross WB: Australian experience of cryoablation of liver tumors: metastases. Surg Oncol Clin N Am 5:391-397, 1996.
79. Finlay IG, Seifert JK, Stewart GJ, et al: Resection with cryotherapy of colorectal hepatic metastases has the same survival as hepatic resection alone. Eur J Surg Oncol 26:199-202, 2000.
80. Rivoire M, De Cian F, Meeus P, et al: Combination of neoadjuvant chemotherapy with cryotherapy and surgical resection for the treatment of unresectable liver metastases from colorectal carcinoma. Cancer 95:2283-2292, 2002.
81. Seifert JK, Morris DL: World survey on the complications of hepatic and prostate cryotherapy. World J Surg 23:109-114 (incl discussion), 1999.
82. Lencioni R, Crocetti L, Cioni D, et al: Percutaneous radiofrequency ablation of hepatic colorectal metastases: Technique, indications, results, and new promises. Invest Radiol 39:689-697, 2004.
83. Cheung L, van Sonnenberg E, Morrison P, et al: Radiofrequency ablation therapy. Contemporary Diagnostic Radiology 28(4):1-5, 2005.
84. Elias D, De Baere T, Smayra T, et al: Percutaneous radiofrequency thermoablation as an alternative to surgery for treatment of liver tumour recurrence after hepatectomy. Br J Surg 89:752-756, 2002.
85. Livraghi T, Solbiati L, Meloni F, et al: Percutaneous radiofrequency ablation of liver metastases in potential candidates for resection: The "test-of-time approach." Cancer 97:3027-3035, 2003.
86. Berber E, Pelley R, Siperstein AE: Predictors of survival after radiofrequency thermal ablation of colorectal cancer metastases to the liver: A prospective study. J Clin Oncol 23:1358-1364, 2005.
87. Solbiati L, Livraghi T, Goldberg SN, et al: Percutaneous radio-frequency ablation of hepatic metastases from colorectal cancer: Long-term results in 117 patients. Radiology 221:159-166, 2001.
88. Abdalla EK, Vauthey JN, Ellis LM, et al: Recurrence and outcomes following hepatic resection, radiofrequency ablation, and combined resection/ablation for colorectal liver metastases. Ann Surg 239:818-827 (incl discussion), 2004.
89. Scaife CL, Curley SA, Izzo F, et al: Feasibility of adjuvant hepatic arterial infusion of chemotherapy after radiofrequency ablation with or without resection in patients with hepatic metastases from colorectal cancer. Ann Surg Oncol 10:348-354, 2003.
90. Kainuma O, Asano T, Aoyama H, et al: Combined therapy with radiofrequency thermal ablation and intra-arterial infusion chemotherapy for hepatic metastases from colorectal cancer. Hepatogastroenterology 46:1071-1077, 1999.
91. Martin RC 2nd, Scoggins CR, McMasters KM: A phase II study of radiofrequency ablation of unresectable metastatic colorectal cancer with hepatic arterial infusion pump chemotherapy. J Surg Oncol 93:387-393, 2006.
92. de Baere T, Risse O, Kuoch V, et al: Adverse events during radiofrequency treatment of 582 hepatic tumors. AJR Am J Roentgenol 181:695-700, 2003.
93. Wood BJ, Ramkaransingh JR, Fojo T, et al: Percutaneous tumor ablation with radiofrequency. Cancer 94:443-451, 2002.
94. Ten Haken RK, Lawrence TS, McShan DL, et al: Technical considerations in the use of 3-D beam arrangements in the abdomen. Radiother Oncol 22:19-28, 1991.
95. Lawrence TS, Tesser RJ, ten Haken RK: An application of dose volume histograms to the treatment of intrahepatic malignancies with radiation therapy. Int J Radiat Oncol Biol Phys 19:1041-1047, 1990.
96. Robertson JM, Lawrence TS, Walker S, et al: The treatment of colorectal liver metastases with conformal radiation therapy and regional chemotherapy. Int J Radiat Oncol Biol Phys 32:445-450, 1995.
97. Mohiuddin M, Chen E, Ahmad N: Combined liver radiation and chemotherapy for palliation of hepatic metastases from colorectal cancer. J Clin Oncol 14:722-728, 1996.
98. Ben-Josef E, Normolle D, Ensminger WD, et al: Phase II trial of high-dose conformal radiation therapy with concurrent hepatic artery floxuridine for unresectable intrahepatic malignancies. J Clin Oncol 23:8739-8747, 2005.
99. Blomgren H, Lax I, Naslund I, et al: Stereotactic high dose fraction radiation therapy of extracranial tumors using an accelerator. Clinical experience of the first thirty-one patients. Acta Oncol 34:861-870, 1995.
100. Herfarth KK, Debus J, Lohr F, et al: Stereotactic single-dose radiation therapy of liver tumors: results of a phase I/II trial. J Clin Oncol 19:164-170, 2001.
101. Gray BN, Anderson JE, Burton MA, et al: Regression of liver metastases following treatment with yttrium-90 microspheres. Aust N Z J Surg 62:105-110, 1992.
102. Tian JH, Xu BX, Zhang JM, et al: Ultrasound-guided internal radiotherapy using yttrium-90-glass microspheres for liver malignancies. J Nucl Med 37:958-963, 1996.
103. Stubbs RS, Cannan RJ, Mitchell AW: Selective internal radiation therapy (SIRT) with 90Yttrium microspheres for extensive colorectal liver metastases. Hepatogastroenterology 48:333-337, 2001.
104. Gray B, Van Hazel G, Hope M, et al: Randomised trial of SIR-Spheres plus chemotherapy vs. chemotherapy alone for treating patients with liver metastases from primary large bowel cancer. Ann Oncol 12:1711-1720, 2001.
105. Thomas DS, Nauta RJ, Rodgers JE, et al: Intraoperative high-dose rate interstitial irradiation of hepatic metastases from colorectal carcinoma. Results of a phase I-II trial. Cancer 71:1977-1981, 1993.
106. Byfield JE, Calabro-Jones P, Klisak I, et al: Pharmacologic requirements for obtaining sensitization of human tumor cells in vitro to combined 5-fluorouracil or ftorafur and x rays. Int J Radiat Oncol Biol Phys 8:1923-1933, 1982.
107. Bruso CE, Shewach DS, Lawrence TS: Fluorodeoxyuridine-induced radiosensitization and inhibition of DNA double strand break repair in human colon cancer cells. Int J Radiat Oncol Biol Phys 19:1411-1417, 1990.
108. Heimburger DK, Shewach DS, Lawrence TS: The effect of fluorodeoxyuridine on sublethal damage repair in human colon cancer cells. Int J Radiat Oncol Biol Phys 21:983-987, 1991.
109. Van Hazel G, Blackwell A, Anderson J, et al: Randomised phase 2 trial of SIR-Spheres plus fluorouracil/leucovorin chemotherapy vs fluorouracil/leucovorin chemotherapy alone in advanced colorectal cancer. J Surg Oncol 88:78-85, 2004.
110. Kohne CH, van Cutsem E, Wils J, et al: Phase III study of weekly high-dose infusional fluorouracil plus folinic acid with or without irinotecan in patients with metastatic colorectal cancer: European Organisation for Research and Treatment of Cancer Gastrointestinal Group Study 40986. J Clin Oncol 23:4856-4865, 2005.
111. Grothey A, Deschler B, Kroening H, et al: Phase III study of bolus 5-fluorouracil (5-FU)/ folinic acid (FA) (Mayo) vs weekly high-dose 24h 5-FU infusion/ FA + oxaliplatin (OXA) (FUFOX) in advanced colorectal cancer (ACRC) (abstract 512). Proc Am Soc Clin Oncol 21:129a, 2002.
112. Giacchetti S, Perpoint B, Zidani R, et al: Phase III multicenter randomized trial of oxaliplatin added to chronomodulated fluorouracil-leucovorin as first-line treatment of metastatic colorectal cancer. J Clin Oncol 18:136-147, 2000.
113. de Gramont A, Figer A, Seymour M, et al: Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 18:2938-2947, 2000.
114. Fuchs CS, Marshall JL, Mitchell EP, et al: A randomized trial of first-line irinotecan/fluoropymidine combinations with or without celecoxib in metastatic colorectal cancer (BICC-C) (abstract 3506). J Clin Oncol 24(18S):147s, 2006.
115. Saltz LB, Lenz HJ, Hochster H, et al: Randomized phase II trial of cetuximab/bevacizumab/irinotecan (CBI) vs cetuximab/bevacizumab (CB) in irinotecan-refractory colorectal cancer (abstract 3508). J Clin Oncol 23(16S):248s, 2005.
116. Kemeny NE, Niedzwiecki D, Hollis DR, et al: Hepatic arterial infusion (HAI) vs systemic therapy for hepatic metastases from colorectal cancer; a CALGB randomized trial of efficacy, quality of life (QOL), cost effectiveness, and molecular markers (abstract 1010). Proc Am Soc Clin Oncol 22:252,
117. Kemeny N, Cohen A, Seiter K, et al: Randomized trial of hepatic arterial floxuridine, mitomycin, and carmustine vs floxuridine alone in previously treated patients with liver metastases from colorectal cancer. J Clin Oncol 11:330-335, 1993.
118. Neyns B, Fontaine C, Delvaux G, Di Betta D, et al: Efficacy of sequential hepatic arterial infusion of CPT-11 and MTX modulated 5-fluorouracil for patients with colorectal cancer metastatic to the liver after failure of systemic thymidilate-synthase inhibitor treatment (abstract 2301). Proc Am Soc Clin Oncol 21, 2002.
119. Cyjon A, Neuman-Levin M, Rakowsky E, et al: Liver metastases from colorectal cancer: Regional intra-arterial treatment following failure of systemic chemotherapy. Br J Cancer 85:504-508, 2001.
120. Boige V, Lacombe S, De Baere T, et al: Hepatic arterial infusion oxaliplatin combined with intravenous 5-FU and folinic acid in non resectable liver metastasis of colorectal cancer: A promising option for failures to systemic chemotherapy (abstract 1770). Proc Am Soc Clin Oncol 22:291, 2003.
121. Ducreux M, Ychou M, Laplanche A, et al: Hepatic arterial oxaliplatin infusion plus intravenous chemotherapy in colorectal cancer with inoperable hepatic metastases: A trial of the gastrointestinal group of the Federation Nationale des Centres de Lutte Contre le Cancer. J Clin Oncol 23:4881-4887, 2005.
122. de Gramont A, Cervantes A, Andre T, et al: OPTIMOX study: FOLFOX 7/LV5FU2 compared to FOLFOX 4 in patients with advanced colorectal cancer (abstract 3525). Proc Am Soc Clin Oncol 23:251, 2004.
123. Tabernero JM, Van Cutsem E, Sastre J, et al: 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 (abstract 3512). Proc Am Soc Clin Oncol 23:248, 2004.
124. Delaunoit TP, Krook JE, Sargent DJ, et al: Chemotherapy-allowed resection of metastatic colorectal cancer: A cooperative group experience (abstract 196). Presented at the Gastrointestinal Cancers Symposium, American Society of Clinical Oncology, San Francisco, 2004.
125. Martoni A, Pinto C, Di Fabio F, et al: Phase II randomized trial on protracted 5-fluorouracil infusion plus oxaliplatin (FOX) vs capecitabine plus oxaliplatin (XELOX) as first line treatment in advanced colorectal cancer (ACRC): Preliminary results of the Italian FOCA study (abstract 3617). J Clin Oncol 23(16S):275s, 2005.
126. Wein A, Riedel C, Bruckl W, et al: Neoadjuvant treatment with weekly high-dose 5-fluorouracil as 24-hour infusion, folinic acid and oxaliplatin in patients with primary resectable liver metastases of colorectal cancer. Oncology 64:131-138, 2003.
127. Gaspar EM, Artigas V, Montserrat E, et al: Single centre study of L-OHP/5-FU/LV before liver surgery in patients with NOT optimally resectable colorectal cancer isolated liver metastases (abstract 1416). Proc Am Soc Clin Oncol 22:353, 2003.
128. Quenet F, Nordlinger B, Rivoire M, et al: Resection of previously unresectable liver metastases from colorectal cancer (LMCRC) after chemotherapy (CT) with CPT-11/L-OHP/LV5FU (Folfirinox): A prospective phase II trial (abstract 3613). Proc Am Soc Clin Oncol 23:273, 2004.
129. Abad A, Antón A, Massuti B, et al: Resectability of liver metastases (LM) in patients with advanced colorectal cancer (ACRC) after treatment with the combination of oxaliplatin (OXA), irinotecan (IRI) and 5FU. Final results of a phase II study (abstract 3618). J Clin Oncol 23:16s, 2005.
130. Falcone A, Masi G, Cupini S, et al: Surgical resection of metastases (mts) after biweekly chemotherapy with irinotecan, oxaliplatin and 5-fluorouracil/leucovorin (FOLFOXIRI) in initially unresectable metastatic colorectal cancer (MCRC) (abstract 3553). Proc Am Soc Clin Oncol 23:258, 2004.
131. Ho WM, Ma B, Mok T, et al: Liver resection after irinotecan, 5-fluorouracil, and folinic acid for patients with unresectable colorectal liver metastases: A multicenter phase II study by the Cancer Therapeutic Research Group. Med Oncol 22:303-312, 2005.
132. Masi G, Cupini S, Marcucci L, et al: Treatment with 5-fluorouracil/folinic acid, oxaliplatin, and irinotecan enables surgical resection of metastases in patients with initially unresectable metastatic colorectal cancer. Ann Surg Oncol 13:58-65, 2006.
133. Wein A, Riedel C, Kockerling F, et al: Impact of surgery on survival in palliative patients with metastatic colorectal cancer after first line treatment with weekly 24-hour infusion of high-dose 5-fluorouracil and folinic acid. Ann Oncol 12:1721-1727, 2001.
134. Bouchahda M, Adam R, Giacchetti S, et al: Effective salvage therapy of liver-only colorectal cancer metastases with chronomodulated irinotecan-fluorouracil-oxaliplatin via hepatic artery infusion (abstract 3585). J Clin Oncol 24(18S): 167s, 2006.
135. Kemeny MM: personal communication. New York, 2005.
136. Zelek L, Bugat R, Cherqui D, et al: Multimodal therapy with intravenous biweekly leucovorin, 5-fluorouracil and irinotecan combined with hepatic arterial infusion pirarubicin in nonresectable hepatic metastases from colorectal cancer (a European Association for Research in Oncology trial). Ann Oncol 14:1537-1542, 2003.
137. Clavien PA, Selzner N, Morse M, et al: Downstaging of hepatocellular carcinoma and liver metastases from colorectal cancer by selective intra-arterial chemotherapy. Surgery 131:433-442, 2002.
138. Tono T, Hasuike Y, Ohzato H, et al: Limited but definite efficacy of prophylactic hepatic arterial infusion chemotherapy after curative resection of colorectal liver metastases: A randomized study. Cancer 88:1549-1556, 2000.
139. Lygidakis NJ, Sgourakis G, Vlachos L, et al: Metastatic liver disease of colorectal origin: The value of locoregional immunochemotherapy combined with systemic chemotherapy following liver resection. Results of a prospective randomized study. Hepatogastroenterology 48:1685-1691, 2001.
140. Asahara T, Kikkawa M, Okajima M, et al: Studies of postoperative transarterial infusion chemotherapy for liver metastasis of colorectal carcinoma after hepatectomy. Hepatogastroenterology 45:805-811, 1998.
141. Mitry E, Fields A, Bleiberg H, et al: Adjuvant chemotherapy after potentially curative resection of metastases from colorectal cancer. A meta-analysis of two randomized trials (abstract 3524). J Clin Oncol 24(18S):152s, 2006.
142. Mackay HJ, Billingsley K, Gallinger S, et al: A multicenter phase II study of "adjuvant" irinotecan following resection of colorectal hepatic metastases. Am J Clin Oncol 28:547-554, 2005.
143. Garassino I, Carnaghi C, Rimassa L, et al: Definitive results of hybrid chemotherapy with intravenous oxaliplatin and folinic acid and intra-hepatic infustion of 5-fluorouracil in patients with colorectal liver metastases (abstract 3670). J Clin Oncol 23(16S):288s,