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.
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