Colorectal cancer is the third most common cancer in the United States with approximately 140,000 new cases annually.1 At diagnosis, 15% of patients will have colorectal liver metastases (CRLM). For patients that develop metastases during surveillance, the liver is commonly the only, or the dominant, metastatic site.2, 3 Therefore, the treatment of CRLM is a significant determinant in the outcomes and survival of patients with metastatic colorectal cancer. At Memorial Sloan Kettering Cancer Center (MSK) , our team of surgeons, medical oncologists, interventional radiologists, radiation oncologists, and gastroenterologists work together for multi-disciplinary care of patients with CRLM.
For patients with metastatic disease confined to the liver, resection of CRLM is the treatment of choice and associated with long-term survival and approximately 20% cure.4 Our surgeons have performed hepatic resection for selected patients with CRLM for decades and reported the largest surgical series of long-term outcomes and cure regarding this operation.4 Currently, our team performs approximately 300 hepatic resections per year. Due to this experience and volume, our institution has led the development and utilization of additional treatments for CRLM such as hepatic arterial infusion (HAI) chemotherapy.
While systemic chemotherapy is a component of treatment for all patients with metastatic colorectal cancer, HAI is used to deliver chemotherapy directly targeting CRLM. Our institution utilizes an implantable pump that can be accessed percutaneously for chemotherapy delivery (Figure 1 and 2). The rationale for HAI exploits the dual blood supply of the liver and the vascularization pattern of hepatic metastases. These metastases derive their blood supply predominantly from the hepatic artery. In contrast, normal hepatocytes derive their blood supply from the portal vein and hepatic artery.5 Comparison of injection into the hepatic artery with injection into the portal vein has demonstrated that mean tumor floxuridine (FUDR) levels are significantly increased (15-fold) when the drug is delivered via the hepatic artery. Also, the use of drugs that are extracted by the liver largely during the first pass through the arterial circulation, such as FUDR, results in the presence of high local concentrations of the drug at the liver metastases and with minimal systemic toxicity.6
Expert concensus statements recommend HAI therapy in a multidisciplinary program with experience in pump placement, clinical management, and intervention for potential complications.7 At MSK, HAI therapy may be employed in the adjuvant and neoadjuvant setting for treatment of CRLM, and care is provided by our team at all steps of utilization- from the time of pump insertion, treatment, and even potential pump removal.
Although hepatic resection is associated with long-term survival and cure, approximately 70% of patients will have disease recurrence, and about 50% of these recurrences will involve the liver. Therefore, adjuvant HAI represents a treatment strategy to improve outcomes and survival.
At MSK, we performed a randomized trial comparing adjuvant HAI-FUDR/Dex plus systemic fluorouracil/leucovorin (5FU/LV) with systemic 5FU/LV alone.8 With the addition of adjuvant HAI FUDR, two-year overall survival was significantly increased from 72 to 86%. Updated results report 10-year survival rates of 41% and 27% favoring the HAI group, and progression-free survival (PFS) of 31 versus 17 months, also favoring the HAI group.9
Three consecutive phase II trials at our institution have combined systemic irinotecan, FOLFOX, and FOLFOX/FOLFIRI +/- Avastin with HAI FUDR/Dex after liver resection. Results showed an increase in overall survival with 4-year survival rates as high as 85%.10 Dr. Kemeny and Dr. D’Angelica are leading another ongoing, randomized, phase II clinical trial of adjuvant therapy evaluating the addition of panitumumab (EGFR inhibitor) to a combination of systemic therapy and HAI-FUDR/Dex. The study aims to determine if the addition of panitumumab can improve recurrence-free survival after hepatic resection for patients treated with adjuvant HAI and systemic chemotherapy (NCT01312857) (MSKCC IRB #10-137).
Conversion to Resection
At MSK, hepatic resection is pursued when margin-negative clearance is possible with adequate future liver remnant (FLR) for regeneration. However, patients may be unresectable due to the number and location of hepatic metastases. Our group defines unresectable CRLM as disease in which a margin-negative resection requires resection of 3 hepatic veins, both portal veins, or the retrohepatic vena cava or that leaves less than 2 adequately perfused and drained segments. In patients who are not surgical candidates, chemotherapy can be used to convert patients with unresectable disease. HAI plus systemic chemotherapy can be used to downsize CRLM and make potentially curative surgery possible (Figure 3). At MSK, patient selection for neoadjuvant HAI is a multidisciplinary decision that involves medical oncologists and surgeons.
Drs. Kemeny and D’Angelica led both a phase I and phase II trial at MSK to assess the efficacy of HAI in unresectable CRLM. In 2009, they published the results of a phase I trial that combined HAI-FUDR/Dex with systemic oxaliplatin and irinotecan.11 In 49 patients with unresectable liver metastases (53% of whom had already received at least one chemotherapy regimen), 47% were able to undergo subsequent curative resection (57% of chemotherapy-naïve patients and 38% of previously treated patients). Furthermore, a recent phase II study was conducted that combined HAI-FUDR/Dex with systemic chemotherapy.12 Overall response rate was 76% and 47% of patients underwent subsequent hepatic resection (Figure 4). Conversion to resection was associated with improved survival.
In summary, MSK utilizes a combination of hepatic resection and HAI chemotherapy for individualized treatment strategies for patients with CRLM. With these therapies, our team strives to provide unprecedented potential for long-term survival and cure for patients with liver metastases.
Dr. Kemeny speaking on the HAI pump:
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- Manfredi S, Lepage C, Hatem C, et al. Epidemiology and management of liver metastases from colorectal cancer. Ann Surg 2006; 244(2):254-9.
- Pugh SA, Shinkins B, Fuller A, et al. Site and Stage of Colorectal Cancer Influence the Likelihood and Distribution of Disease Recurrence and Postrecurrence Survival: Data From the FACS Randomized Controlled Trial. Ann Surg 2015.
- Tomlinson JS, Jarnagin WR, DeMatteo RP, et al. Actual 10-year survival after resection of colorectal liver metastases defines cure. J Clin Oncol 2007; 25(29):4575-80.
- Ackerman NB. The blood supply of experimental liver metastases. IV. Changes in vascularity with increasing tumor growth. Surgery 1974; 75(4):589-96.
- Ensminger WD, Gyves JW. Clinical pharmacology of hepatic arterial chemotherapy. Semin Oncol 1983; 10(2):176-82.
- Karanicolas PJ, Metrakos P, Chan K, et al. Hepatic arterial infusion pump chemotherapy in the management of colorectal liver metastases: expert consensus statement. Curr Oncol 2014; 21(1):e129-36.
- 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 1999; 341(27):2039-48.
- Kemeny NE, Gonen M. Hepatic arterial infusion after liver resection. N Engl J Med 2005; 352(7):734-5.
- Kemeny NE, Jarnagin WR, Capanu M, et al. Randomized phase II trial of adjuvant hepatic arterial infusion and systemic chemotherapy with or without bevacizumab in patients with resected hepatic metastases from colorectal cancer. J Clin Oncol 2011; 29(7):884-9.
- Kemeny NE, Melendez FD, Capanu M, et al. Conversion to resectability using hepatic artery infusion plus systemic chemotherapy for the treatment of unresectable liver metastases from colorectal carcinoma. J Clin Oncol 2009; 27(21):3465-71.
- D’Angelica MI, Correa-Gallego C, Paty PB, et al. Phase II trial of hepatic artery infusional and systemic chemotherapy for patients with unresectable hepatic metastases from colorectal cancer: conversion to resection and long-term outcomes. Ann Surg 2015; 261(2):353-60.