Liver metastases from colorectal cancer are a common problem. Approximately 15 percent of patients with colorectal cancer present with liver metastases at the time of diagnosis and another 50 percent will ultimately develop liver metastases.
While colorectal cancer liver metastases may be accompanied by other sites of metastatic disease, the liver is commonly the only, or the dominant, metastatic site. Therefore, the treatment of liver metastases is a very important determinant of outcome in many patients with metastatic colorectal cancer. At Memorial Sloan Kettering, we have a large team of surgeons, medical oncologists, radiation oncologists, and radiologists who are dedicated to the treatment of liver metastases.
For patients with colorectal cancer metastases limited to the liver, approximately 10 to 20 percent are candidates for hepatic resection at the time of diagnosis. For decades we have performed hepatic resections to treat metastatic colorectal cancer. We have led the way in demonstrating that resection of limited liver metastases is associated with long-term survival, measurable in years, and is potentially curative, with approximately 20 percent of such patients cured by a combination of chemotherapy and surgery.
In our hands, after hepatic resection with or without systemic therapy, 50 percent of patients survive five years, and anywhere from 20 to 40 percent of these patients can survive 10 years. Of great significance is that patients today with limited resectable metastases have cure rates in excess of some primary, non-metastatic liver cancers. (1),(2),(3)
Over the past two decades, Memorial Sloan Kettering has assembled a group of extremely experienced, high-volume hepatic surgeons who now routinely perform approximately 300 hepatic resections annually. Historically, hepatic resection was a dangerous proposition for patients. The procedure was associated with large-volume blood loss and high complication rates, as well as significant perioperative mortality.
The safety of hepatic resection has dramatically improved over the last two decades. Perioperative blood transfusions are rare today because significant intraoperative blood loss has become uncommon. In recent years, complication rates for hepatic resection have dropped dramatically and perioperative mortality has fallen to as low as one percent. 2,4 The improved safety of this operation is a result of better imaging and operative techniques, and greater levels of experience.
For example, the use of new parenchymal-sparing techniques in hepatic resection is a likely contributor to improved perioperative outcomes. One of the strongest predictors of post-hepatectomy complications is the volume of resected liver. In the past, hepatic resections were typically accomplished by removal of an entire lobe or more (ie, lobectomy or trisegmentectomy). We have developed and exploited strategies and techniques that allow resection of smaller liver volumes, such as single-segment or two-segment resections that are associated with improved safety. (5)
These parenchymal-sparing resections, combined with the use of intraoperative ablation, allow us to safely resect multiple bilobar metastases that were previously considered unresectable. Pre-operative procedures, such as percutaneous portal vein embolization, can also help to increase the size of the future liver remnant, and have rendered major lobar resections safer.
In summary, hepatic resection for metastatic colorectal cancer has become safe and effective for treating patients who have limited and even somewhat extensive metastatic disease, and with unprecedented rates of long-term survival.
Hepatic Arterial Infusion Chemotherapy
Another therapy that we use in our treatment of hepatic metastases is hepatic arterial infusion (HAI) chemotherapy. HAI enables the delivery of chemotherapy to the liver through a surgically implanted pump. This method exploits the vascularization pattern of colorectal liver metastases; they obtain their blood supply almost exclusively from the hepatic artery. Normal hepatocytes, in contrast, derive their blood supply from both the portal vein and the hepatic artery.
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 during the first pass through the arterial circulation (eg, FUDR) results in the presence of high local concentrations of the drug in the liver metastases and with minimal systemic toxicity.
Hepatic Arterial Infusion as Adjuvant Therapy
One setting in which HAI should be considered is as adjuvant therapy after hepatic resection. Although hepatic resection is associated with long-term survival and cure, approximately 70 percent of patients will have disease recurrence, and about 50 percent of these recurrences will involve the liver.
At Memorial Sloan Kettering we performed a randomized trial comparing adjuvant HAI-FUDR plus systemic fluorouracil/leucovorin (5FU/LV) with systemic 5FU/LV alone. With the addition of adjuvant HAI-FUDR, two-year overall survival was significantly increased, from 72 percent to 86 percent. Updated results report 10-year survival rates of 41 percent and 27 percent favoring the HAI group, and progression-free survival (PFS) of 31 versus 17 months (also favoring the HAI group). (3)
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 four-year survival rates as high as 88 percent. (6)
In an ongoing, randomized, phase II clinical trial of adjuvant therapy, we are evaluating the addition of panitumumab (EGFR inhibitor) to a combination of systemic therapy and HAI-FUDR/Dex to determine whether or not it can increase recurrence-free survival (NCT01312857) (7) (MSK IRB #10-137). (8)
Hepatic Arterial Infusion as a Second-Line Therapy
A second circumstance in which HAI may be considered is as treatment for unresectable metastases. HAI has shown particular promise as a second-line therapy in patients who have either failed to respond, or plateaued in their response, to standard, first-line systemic chemotherapy. Multiple published studies have demonstrated significant rates of response and survival.
In one study that evaluated HAI-FUDR plus systemic oxaliplatin and irinotecan as second-line therapy, the response rate was 88 percent with a 35-month median survival. Because second-line systemic therapy alone has low response (<20 percent) and low survival rates, HAI therapy should absolutely be considered in patients with metastatic disease that is confined to the liver. According to our analysis, when used as first-line therapy, the response rate was 100 percent (23 of 23 patients) and median survival was 50.8 months. (9),(10),(11),(12),(13)
Conversion to Resection
For selected patients with unresectable disease, HAI combined with systemic therapy should be considered as a means to shrink hepatic metastases and thereby make liver resection possible. Systemic chemotherapy has been used to decrease tumor size and volume, and 15 percent to 20 percent (rarely 30 percent) of patients with unresectable disease who receive systemic chemotherapy can be converted to resectable disease. Given that HAI therapy combined with systemic chemotherapy is associated with a high response rate, it is possible to increase the rate of conversion with this combination.
Results of a phase I trial at Memorial Sloan Kettering that combined HAI-FUDR/Dex with systemic oxaliplatin and irinotecan in 49 patients who had unresectable liver metastases (53 percent of these patients had been previously treated with chemotherapy) revealed that 47 percent were able subsequently to undergo surgery to remove their tumors (57 percent of chemotherapy-naïve patients and 38 percent of previously treated patients). The metastatic burden in these 49 patients was high: 98 percent had bilobar disease (disease in both lobes), 86 percent had more than six segments of the liver involved, and 73 percent had more than five metastatic lesions. (11)
Our recent phase II trial combining HAI-FUDR/Dex with systemic therapy demonstrated that approximately 50 percent of patients with extensive, limited liver metastases (approximately 66 percent for second-line therapy patients) were converted to complete resection. Furthermore, the patients who were able to be resected had survival rates similar to patients with initially resectable disease (unpublished data).
In summary, at Memorial Sloan Kettering, combinations of surgery and HAI chemotherapy are providing unprecedented potential for long-term survival and cure to patients with colorectal cancer liver metastases.