Overview

The liver is an organ with a rich blood supply, therefore it serves as the destination of metastases for many tumors. As the portal vein drains the entire gastrointestinal (GI) tract, malignancies arising from these organs frequently produce liver metastases. Because of the dual blood supply and the large volume of blood flow in the liver, extraabdominal tumors—such as bronchogenic carcinoma, breast cancer, and malignant melanoma—spread hematogenously and also metastasize to the liver with some frequency. This chapter focuses on the use of intraarterial chemotherapy and associated surgical issues for the treatment of liver metastases from colorectal cancer (CRC), which is the third most common malignancy in the United States, with 141,210 new cases and 49,388 deaths in 2009. Additionally, because CRC often presents with or develops isolated spread to the liver, most major studies of hepatic intraarterial chemotherapy address liver metastases deriving from CRC. The use of systemic therapy is discussed briefly to put in perspective the relative response rates and survival with intrahepatic therapy.

Systemic Chemotherapy

Responses to systemic chemotherapy (SYS) vary with the type of tumor; for example, patients with liver metastases from a breast primary may have high response rates with SYS (Harris et al, 1997), in contrast to metastases from a gastric or pancreatic primary tumor. Despite 20% response rates and median survivals less than 1 year, fluoropyrimidines represented the standard of care for metastatic CRC for decades (Thirion et al, 2004). More recently, patients with metastatic colon carcinoma have had response rates greater than 30%. With the development of newer drugs, such as irinotecan and oxaliplatin, response rates have increased to 35% to 40% with median survivals of 15 to 19 months (Goldberg et al, 2002; Saltz et al, 2000). The use of targeted agents, such as bevacizumab and cetuximab (Cunningham et al, 2004), has further improved outcomes, and bevacizumab demonstrated overall survival of 20 months (Hurwitz et al, 2004). Many chemotherapy trials do not differentiate patients with liver-only metastases to show how these patients respond to chemotherapy. In tumors with high response rates, such as breast carcinoma, a reasonable response to SYS is found even in patients with liver metastases, although the response is lower with liver metastases than with soft-tissue metastases (George & Hoogstraten, 1978). In patients with CRC, the liver is the most common site of dissemination, and 60% of patients (Daly & Kemeny, 1986) develop liver metastases during the course of their disease.

Rationale for Hepatic Arterial Chemotherapy

The rationale for hepatic arterial infusion (HAI) is based upon anatomic and pharmacologic principles.

Table 86.1 Estimated Increase in Hepatic Exposure for Drugs Given by Hepatic Arterial Infusion

The development of an implantable infusion pump allowed for the safe administration of hepatic arterial chemotherapy in the outpatient setting (Blackshear et al, 1972). Early trials using an implantable pump and continuous FUDR therapy produced a median response rate of 47% (Johnson & Rivkin, 1985) and a median survival of 17 months (Weiss et al, 1983). To further show that HAI had a therapeutic benefit, several randomized studies were conducted.

First-Line Therapy in Unresectable Liver Metastases

One of the first randomized trials was conducted at Memorial Sloan-Kettering Cancer Center (MSKCC) (Kemeny et al, 1987). Before randomization, patients were stratified for extent of liver involvement by tumor and baseline lactate dehydrogenase level, two factors that have been shown to be important prognostic indicators of survival (Table 86.2; Kemeny & Braun, 1983; Kemeny et al, 1989). This prospective randomized trial compared HAI with SYS using the same chemotherapeutic agent (FUDR), drug schedule (a 14-day continuous infusion), and method of administration (internal pump) in both groups.

Of the 99 evaluable patients, two complete responses and 23 partial responses (53%) were observed in the group receiving HAI, and 10 partial responses (21%) were reported in the SYS group (P = .001). Of the patients randomized to SYS, 31 (60%) crossed over to HAI after tumor progression, and 25% of these patients went on to a partial response after the crossover, and 60% had a decrease in carcinoembryonic antigen (CEA) levels.

Toxicity differed between the two groups. An increase in hepatic enzymes and serum bilirubin levels occurred in the HAI group. In the SYS group, diarrhea occurred in 70% of patients, and 9% required admission for intravenous hydration. Mucositis occurred in 10% of patients receiving SYS.

The median survival for the HAI and SYS groups was 17 and 12 months, respectively (P = .424). The interpretation of survival in this study is difficult because 60% of the patients in the systemic group crossed over. The patients who did not cross over usually had clots of the hepatic arterial system and had a median survival of only 8 months compared with 18 months for the patients who crossed over to hepatic infusion (P = .04). An analysis of baseline characteristics in the crossover and noncrossover groups revealed no significant differences.

Two subsequent European randomized trials using HAI therapy in this setting have been published. The first was conducted by the Medical Research Council (MRC) and European Organization for the Research and Treatment of Cancer (EORTC) groups, which compared HAI 5-FU/leucovorin (LV) with intravenous 5-FU/LV. Crossover from the intravenous to the HAI arm was not allowed. Of 290 patients randomized, only 66% on the HAI arms received treatment. Response rates were 22% for HAI and 19% for intravenous 5-FU/LV. This trial used subcutaneous ports rather than implantable pumps and had significant catheter-related problems (36% of HAI patients) (Kerr et al, 2003). The median survival was 14.7 months and 14.8 months in the HAI and SYS groups, respectively (P = .79).

The second trial was by a German cooperative group that randomized 168 patients with unresectable colorectal liver metastases to HAI of FUDR, HAI of 5-FU/LV, or intravenous 5-FU/LV (Lorenz & Muller, 2000). Response rates were higher in the two HAI arms, with no significant differences in time to progression, the primary end point, or overall survival (OS) between the arms. Only 70% of patients on the HAI arms actually received assigned treatment. The study also used ports instead of pumps.

The Cancer and Leukemia Group B (CALGB) (Kemeny et al, 2006) completed trial 9481, which compared systemic 5-FU/LV via the Mayo Clinic regimen, considered standard of care at the time of trial design, with HAI of FUDR, LV, and dexamethasone, a regimen that had produced high response rates (78%) and lower toxicity (3% biliary sclerosis) in a phase II study (Kemeny et al, 1994). An earlier trial randomized patients to HAI of FUDR with or without dexamethasone, which demonstrated less biliary toxicity and a trend toward median OS (23 months vs. 15 months, respectively, P = .06) in the dexamethasone-containing arm (Kemeny et al, 1992). In CALGB 9481, no crossover was permitted, and a total of 134 patients were randomized. Most patients (70%) had greater than 30% liver involvement, synchronous metastases (78%), and were chemotherapy naive (97%). Response rates were higher in the HAI group (47% vs. 24%; P = .012), although time to progression was not significantly different (5.3 months vs. 6.8 months; P = .8); time to hepatic progression was better in the HAI arm (9.8 months vs. 7.3 months; P =.017) and in the systemic arm (7.7 months vs. 14.8 months; P = .029). Median OS was significantly better in the HAI arm (24.4 months vs. 20 months; P = .0034; Kemeny et al, 2006). Resource use, quality of life, and molecular markers of prognosis, such as thymidylate synthase (TS) and p21 gene expression, were examined prospectively in this study, and final analysis of these factors were presented. At 3- and 6-month follow-up, physical functioning was improved in the HAI group. TS levels correlated with survival in HAI patients (24 months if TS >4, 14 months if TS ≤4), but these differences were not significant (P = .17).

A total of 10 randomized phase III trials have been done, most of which demonstrate a higher response rate with HAI versus SYS in patients with hepatic metastases from CRC (see Table 86.2). Whether this increase in response rate translates into increased survival is controversial. Several factors complicate this issue. Importantly, most of the trials contain relatively few patients; therefore the power to observe differences in survival rates is low. Also, because of early successes with intrahepatic infusion, some of these studies allowed patients in the systemic arm to cross over to intrahepatic therapy after tumor progression on systemic therapy. This crossover may have negated any difference in survival between the two groups. The studies show a survival advantage for those who received subsequent HAI, with a mean 1-year survival of 69% for the patients who had crossed over from SYS to HAI versus 35% for the patients who did not cross over (Table 86.3). Additionally, some trials included patients with extrahepatic disease, complicating survival analyses in the absence of systemic treatment. Other factors to consider are that some patients randomized to HAI did not receive it but were included in the survival analysis, and an absence of modern toxicity-based dose-titration schema may have resulted in fewer cycles of treatment.

The European studies are difficult to interpret, because in the first two studies, the SYS group received SYS only when they became symptomatic. The two new European studies used ports instead of pumps, which resulted in more technical complications.

Two meta-analyses of the original seven trials were conducted and included more than 600 patients. The Meta-Analysis Group in Cancer (MAGIC, 1996) confirmed the increased response rates seen with HAI over SYS (41% vs. 14%); however, survival differences were deemed only statistically significant in the trials that included a control group treated only when symptoms arose. With the statistical methodology used, the authors were unable to include the data from Hohn and colleagues (1989); however, a second meta-analysis published the same year did incorporate the results from that study and found an absolute survival difference of 12.5% at 1 year (P = .002) and 7.5% at 2 years (P = .026) in favor of HAI (Harmantas et al, 1996). The authors omitted the trial by Allen-Mersch and colleagues (1994) given the fact that most patients in the SYS arm of that study received best supportive care only. Furthermore, they analyzed their results to show that, when omitting the data from Rougier and colleagues (1992)—because, like the study from Allen-Mersh and others (1994), only half of the patients in the SYS arm received chemotherapy—survival was only statistically significantly higher at the 1-year time point. Nonetheless, factoring only those six studies without crossover, the survival differences at 1 and 2 years were accentuated, and actually both significantly favor of HAI.

As mentioned above, CALGB 9481 permitted no crossover, and with the incorporation of dexamethasone, it demonstrated survival with HAI that compares well to published results with modern SYS regimens; however, a recent and well-orchestrated third meta-analysis that accounted for the design flaws discussed above examined all 10 randomized trials to date and failed to demonstrate a survival benefit with HAI (Mocellin et al, 2007). This report and the published commentary that followed demonstrated that, although there may be no clear survival benefit in using HAI instead of SYS, combining HAI and SYS has led to high response rates with acceptable toxicity profiles.

Subsequent sections of the chapter discuss how newer management principles, such as the incorporation of dexamethasone for toxicity abrogation and the use of combination HAI and SYS, may improve overall outcomes. This underscores the need to examine response and OS data in the context of modern treatment paradigms.

Toxicity of Intrahepatic Therapy

Table 86.4 summarizes the GI toxicities noted by investigators using the implantable pump. The side effects of SYS are almost never observed with HAI, and myelosuppression does not occur with intrahepatic FUDR (Kemeny et al, 1984). Although intrahepatic mitomycin C or bis-chloroethyl-nitrosourea may depress platelet counts, the absolute depression and frequency of depression are less than with systemic administration. Nausea, vomiting, and diarrhea do not occur with HAI of FUDR. If diarrhea does occur, shunting of the chemotherapeutic agent to the bowel should be suspected (Gluck et al, 1985).

The most common problems with HAI are ulcer disease and hepatic toxicity (Hohn et al, 1985; Kemeny et al, 1984). Severe ulcer disease results from inadvertent perfusion of the stomach and duodenum with drug via small, unligated branches from the hepatic artery, but this can be prevented by meticulous dissection at the time of pump placement (Hohn et al, 1985); however, even without radiologically visible perfusion of the stomach or duodenum, mild gastritis and duodenitis can occur. This toxicity can be reduced by careful dose reductions when any GI symptoms arise. Hepatobiliary toxicity is the most problematic toxicity seen with HAI. Although some evidence of hepatocellular necrosis and cholestasis has been found on liver biopsy specimens (Doria et al, 1986), most studies point to a combined ischemic and inflammatory effect on the bile ducts as the most important cause of this toxicity. The bile ducts are particularly sensitive to HAI; this is because the bile ducts derive their blood supply almost exclusively from the hepatic artery, similar to hepatic tumors (Northover & Terblanche, 1979).

In patients with severe toxicity, endoscopic retrograde cholangiopancreatography (ERCP) shows lesions resembling primary sclerosing cholangitis (Kemeny et al, 1985). Because the ducts are sclerotic and nondilated, ultrasound usually is not helpful. In some patients, the strictures are more focal, and they are usually worse at the bifurcation, and drainage procedures by endoscopic or by percutaneous transhepatic intubation may be helpful. Duct obstruction from metastases should be excluded first by computed tomography (CT) of the liver.

Close monitoring of liver function tests is necessary to avoid biliary sclerosis. If the serum bilirubin becomes elevated, no further treatment should be given until the bilirubin returns to normal, and then treatment should proceed with only a small test dose (0.05 mg/kg/day). In patients who cannot tolerate even a low dose for 2 weeks, it may be possible to continue treatment by giving the FUDR infusion for 1 week rather than the usual 2 weeks. At MSKCC, we modify treatment as outlined in Table 86.5.

In older trials, cholecystitis occurred in 33% of patients receiving HAI (Kemeny et al, 1986a). In more recent series, the gallbladder was removed at the time of catheter placement to prevent this complication and to avoid the confusion of these symptoms with other hepatic side effects of chemotherapy.

Surgical Technique

Standard Hepatic Arterial Anatomy

A standard cholecystectomy is performed, and the hepatic artery and its branches are circumferentially dissected. The common hepatic artery and the GDA are palpable superior to the body of the pancreas and the first portion of the duodenum. The GDA runs parallel to and lies immediately to the left of the common bile duct, and it is advisable to start by dissecting the common hepatic artery to minimize the risk of injuring the bile duct. The right gastric artery is ligated and divided. The distal common hepatic artery, the entire GDA, and the proximal proper hepatic artery are dissected away from their attachments. It is important to mobilize the full length of the extrapancreatic GDA to facilitate insertion of the catheter. Suprapyloric side branches of the GDA are often encountered and must be ligated. Frequently, branches to the pancreas and duodenum arise from many of these dissected vessels, and it is essential to identify and ligate these branches to avoid perfusion of the pancreas, stomach, or duodenum. The common hepatic artery is mobilized 1 cm proximally, and the proper hepatic artery is mobilized about 2 cm distally from the origin of the GDA. Branches to the retroperitoneum from the right or left hepatic artery are common and should be ligated. Review of preoperative angiography to look specifically for these branches is important, because they are often found in retrospect. At this point, a complete circumferential dissection of the common hepatic artery, GDA, and proper hepatic artery should be ensured such that no vessels to the pancreas, stomach, or duodenum remain (Fig. 86.1). The GDA should be temporarily occluded with palpation of the proper hepatic artery to rule out retrograde flow to the liver through the GDA secondary to celiac stenosis. No attempt at dissection of the common bile duct is necessary, because this risks devascularization and ischemic stricturing.

FIGURE 86.1 The common hepatic, proper hepatic, and gastroduodenal arteries are completely mobilized. All branches to the stomach, duodenum, or pancreas are identified and ligated.

The pump pocket should be created in the lower abdomen so that the pump lies below the waist and avoids contact with the iliac spine and the edge of the ribs. In obese patients, placing the pump over the ribs should be considered, because this may help in locating and accessing the pump. The pump and catheter should be handled carefully, avoiding contact with the patient’s skin. The catheter is trimmed at a level just beyond the last tying ring and is tunneled into the abdominal cavity. The pump is secured to the abdominal fascia with nonabsorbable sutures; the catheter should be positioned behind the pump to prevent injury by a needle. The GDA is ligated with a nonabsorbable tie at its most distal point, and vascular control of the common and proper hepatic arteries is achieved with vascular clamps or vessel loops. Isolated vascular control of the GDA at its orifice also can be used to avoid occlusion of the hepatic artery.

An arteriotomy is made in the distal GDA, and the catheter is inserted up to, but not beyond, the junction with the hepatic artery (Fig. 86.2). If the catheter protrudes into the common hepatic artery, turbulence of blood flow can lead to thrombosis of the vessel. Failure to pass the catheter to the junction leaves a short segment of the GDA exposed to full concentrations of FUDR without the diluting effect of blood flow, potentially resulting in sclerosis, thrombosis, or late dislodgment. When positioned, the catheter should be secured two or three times with nonabsorbable ties proximal to the tying rings on the catheter. Perfusion of both lobes of the liver and lack of extrahepatic perfusion is confirmed by infusing 2 to 3 mL of half-strength fluorescein through the pump and visualizing it with a Woods lamp. Half-strength methylene blue injection is an alternative method of ensuring proper perfusion. After the perfusion test, the catheter is flushed with heparinized saline, and the wounds are closed. Antibiotic coverage should be continued for 2 to 3 days postoperatively because of the seriousness of a pump infection. Any sign of erythema indicates a wound infection postoperatively and should be treated immediately and aggressively.

FIGURE 86.2 The infusion pump ideally is placed in the left lower quadrant, away from the liver, to avoid artifacts on subsequent computed tomographic scans. With normal anatomy, the catheter is placed in the gastroduodenal artery and secured with nonabsorbable ties, the right gastric artery is ligated, and the gallbladder is removed.

Pump Placement after Major Hepatectomy

In the event that a pump is being placed for adjuvant therapy after hepatectomy, the specific anatomy to the remnant liver must be considered. In general, the best results are obtained if the catheter is placed in the GDA. In the presence of replaced or accessory vessels to the remnant liver, the surgeon must consider the condition of that remnant (i.e., steatosis, congestion) and the potential risk of ligating the arterial supply or risking thrombosis by directly cannulating the vessel to the remnant. One option that is often available after a hemihepatectomy is to use the stump of the artery to the resected liver as a conduit for the catheter, if the anatomy allows this. If the arterial anatomy is normal, or a trifurcation is present at the GDA, there is generally no issue, and the catheter is placed routinely in the GDA. When a variation of the origin of the GDA is present (i.e., off of the right or left hepatic artery), care must be taken to preserve the origin such that the catheter can be placed. For a remnant right lobe, an accessory right hepatic artery generally can be ligated, unless major concerns about the condition of the remnant are an issue. In the case of a remnant right lobe and a replaced right hepatic artery, it is generally not recommended to place a pump, because it would require direct cannulation of that artery, risking thrombosis, injury, and a higher rate of catheter-related complications in general. For a remnant left lobe, an accessory left artery generally can be ligated. If the remnant left lobe is fed solely by a replaced left hepatic artery, a pump can be placed, but this requires dissection of the left gastric artery and a suitable side branch for the catheter. Special care must be taken to ensure that all branches to the stomach have been properly ligated to prevent extrahepatic perfusion.

Postoperative Assessment

After surgery and before administering chemotherapy, the distribution of arterial perfusion is assessed by a radionuclide pump flow study (see Chapter 15). A baseline technetium 99m (^99mTc)-sulfur colloid scan is obtained to identify the liver contour. Pump perfusion is assessed by infusing ^99mTc-labeled macroaggregated albumin (MAA) through the bolus port of the pump and into the hepatic artery. When the MAA scan produces an image that matches the sulfur colloid liver scan, the pump is perfusing the entire liver as intended. Perfusion of extrahepatic tissues produces ^99mTc signals outside the liver image (Fig. 86.3). Incomplete perfusion of the liver produces an incomplete image on the MAA scan. Misperfusion is discovered in 5% to 7% of cases and often can be corrected by surgical or angiographic intervention to occlude additional hepatic vessels missed at operation (Campbell et al, 1993). If no additional vessels are seen on angiography for embolization, it is worth repeating the scan in a few weeks to allow sufficient time for intrahepatic collaterals and cross-perfusion to develop (Allen et al, 2002).

FIGURE 86.3 The liver-spleen technetium 99m–sulfur colloid scan on the left shows the normal liver. The macroaggregated albumin (MAA) scan on the right shows extrahepatic perfusion to the duodenum and head of the pancreas.

Technical Complications of Hepatic Artery Infusion Pump Placement

Surgical and technical complications of pump placement occur, and the spectrum and frequency of these complications must be understood by the surgeon, the medical oncologist, and the patient before initiating treatment. To assess the risks of insertion and the use of an implantable pump for hepatic artery chemotherapy, we reviewed the charts of all patients who underwent pump insertion for unresectable metastases over a 15-year period (1986 to 2001) at MSKCC (Allen et al, 2005). During this period, 544 infusion pumps were inserted by several different surgeons for HAI of FUDR alone or in combination with other drugs for patients with isolated unresectable colorectal hepatic metastases. Variant arterial anatomy was present in 205 patients (38%), most of which (82%) involved a single vessel. A colectomy was performed in addition to the pump placement in 136 patients (25%).

Operative mortality was low, and five patients died within 30 days of the operation (0.9% mortality rate). Early in this series, two deaths were from hepatic failure secondary to extensive metastatic disease within the liver. We now exclude patients with extensive (>70%) liver replacement from pump placement because of this risk. Generalized operative morbidity unrelated to the pump itself occurred in approximately 25% of patients in our series. The most common complications were prolonged ileus, wound complications, atelectasis, and abscesses.

Pump-related morbidity occurred in 120 patients (22%) and is summarized in Table 86.7. Most of these complications (63%) occurred more than 30 days after pump placement. The most common complications (51%) were related to the hepatic arterial system and included thrombosis, hemorrhage, or perfusion abnormalities. Early (<30 days) pump-related morbidity occurred in only 8% of cases, and all of the catheter-related complications occurred after 30 days. Overall, the pumps were salvaged from these complications 45% of the time; however, salvage was much more common with early complications (70% if <30 days) than with late complications (30% if >30 days). In a multivariate analysis, surgeon experience and the use of any vessel other than the GDA were independently associated with pump-related morbidity and pump survival. Pump failure was generally low—5% at 6 months, 9% at 1 year, 16% at 2 years, and 26% at 3 years—and HAI was discontinued for pump-related complications in only 9% of cases. The performance of a concomitant colorectal resection was not associated with a higher rate of complications.

Extrahepatic Perfusion

Small branches of the hepatic artery to the stomach, duodenum, and pancreas can be missed on preoperative angiography. If small vessels are not divided and ligated, perfusion of the bowel with FUDR produces severe pain and GI ulceration; if the pancreas is perfused, severe pancreatitis will ensue. These complications are potentially lethal, and extrahepatic perfusion should be identified and corrected before starting chemotherapy whenever possible.

If extrahepatic perfusion is seen on the ^99mTc MAA scan, the next step is to perform an angiogram by bolus injection through the pump; the angiogram usually shows the vessel responsible for the extrahepatic perfusion. This occasionally is unsuccessful, and a transfemoral celiac or superior mesenteric artery study is needed to identify the problem (Fig. 86.4). More recently, we have proceeded directly to transfemoral angiograms for assessment of patients in whom the perfusion scan shows obvious extrahepatic perfusion. This approach simplifies the process, because one procedure can diagnose the problem and potentially treat it. In our review of 544 cases, 9 patients (2%) were found to have extrahepatic perfusion on the postoperative scan. The cause was identified arteriographically, and in 7 cases, it was corrected with transarterial embolization or surgical ligation; these patients went on to receive HAI without complication (Allen et al, 2005).

FIGURE 86.4 A transfemoral celiac angiogram shows a vessel arising from the gastroduodenal artery (GDA), which had not been ligated. At operation, this vessel was found to be arising from the posterior aspect of the GDA.

Arterial or Catheter Thrombosis

Complete dissection and thrombosis of the hepatic artery intraoperatively has been described during pump insertion, but this condition is rare. In our series, 13 cases (2%) of acute postoperative arterial thrombosis were noted, but the technical problem leading to thrombosis was uncertain in most of these cases. Of these 13 cases of early thrombosis, 31% were salvaged with anticoagulation or lytic therapy. We also observed that delayed thrombosis of the hepatic artery (20 cases) was more common than acute thrombosis (13 cases). The vasculitis caused by infusional chemotherapy is thought to contribute to late arterial thrombosis. Often, arterial thrombosis manifests as extrahepatic perfusion on ^99mTc MAA scan (Fig. 86.5). Catheter thrombosis was seen only as a late complication, and it occurred in 11 cases (2%) and was more likely to be related to technical errors, such as not filling the pump frequently or allowing back bleeding into the catheter during side-port manipulation.

FIGURE 86.5 A, When hepatic artery thrombosis occurs, the macroaggregated albumin scan (right) shows an absence of perfusion of the liver together with perfusion of the spleen, stomach, and pancreas. B, Arteriogram before operation shows normal patent vessels (left), but postoperative arteriography (right) confirms that the artery is thrombosed. The first sign of hepatic artery thrombosis may be abdominal pain occurring with chemotherapy owing to perfusion of the stomach and pancreas. If severe pain occurs during chemotherapy, the first step should be to empty the pump and replace the chemotherapy with heparinized saline.

Laparoscopic Placement of Hepatic Arterial Infusion Pumps

The necessity of a laparotomy to place HAI pumps has been and remains a hurdle for pump chemotherapy. Because a major operation is mandated, many oncologists and patients have been deterred, and minimally invasive methods of pump implantation are attractive. HAI pump placement requires substantial skill, sophisticated knowledge of upper GI anatomy, and experience, making this operation technically challenging and difficult to perform laparoscopically.

The technique of laparoscopic HAI pump placement should mimic the open operation. Review of the preoperative angiogram is crucial, and management of aberrant anatomy must be planned for in advance. A right subcostal port is placed for retraction of the liver, and a three-port working triangle is created in the left upper quadrant, aiming at the porta hepatis. The dissection and isolation of the vessels is exactly the same as in the open operation. Ultrasonic dissectors are helpful to divide the often dense lymphatics and keep bleeding to a minimum. Branches to the stomach, duodenum, and pancreas can be clipped or divided with the ultrasonic dissector; because controlling torn branches can be difficult, patience is crucial.

When the anatomy is dissected, the pump pocket is made in the right abdominal wall, and the catheter is placed into the peritoneal cavity under laparoscopic visualization. The distal GDA is ligated, and ties are left long for countertraction. Laparoscopic bulldogs are used for vascular isolation; two can be placed on the common hepatic artery and proper hepatic artery each, or a single clamp can be placed just at the orifice of the GDA. A tie is left around the GDA in anticipation of tying the catheter in, and a laparoscopic No. 11 blade is used to create an arteriotomy. Using countertraction on the GDA, the catheter is placed into the GDA, up to the orifice, and tied into place. The clamps are carefully removed, and hemostasis is ensured; this is followed by intraoperative dye injection to confirm bilobar hepatic perfusion and absence of extrahepatic flow.

Published experience with laparoscopic placement of HAI pumps is largely limited to small cases series (Cheng et al, 2003, 2004; Feliciotti et al, 1996; Urbach & Hansen, 2000; Urbach et al, 2001). The largest series to date was published by Cheng and colleagues and describes their experience in 38 patients (Cheng et al, 2004), of whom 24 had additional radiofrequency ablation (RFA), 2 had a laparosopic partial hepatectomy, and 1 was converted to laparotomy. The median time in the operating room was 5.5 hours, and the overall results were excellent: only one postoperative cardiac-related mortality was reported but no pump-related morbidity, and the median hospital stay was 3 days.

When this chapter was submitted for the previous edition of this text, we had attempted laparoscopic pump placement in 13 cases over a 2-year period; of these, five were converted for minor bleeding, severe chronic cholecystitis, bowel injury, dense adhesions, and a small GDA that could not be cannulated at open operation. Eight cases were completed laparoscopically with no significant moribidy, no pump-related complications, and a median hospital stay of 3.5 days (unpublished data). With limited experience, it seems that laparoscopic HAI pump placement is feasible and safe. It is crucial, however, that these cases are attempted by surgeons experienced in laparoscopic surgery and open pump placement.

Nonoperative Placement of Hepatic Arterial Infusion Pumps

HAI pump placement can be done safely by laparotomy with an acceptable morbidity. Poor overall prognosis and the requirement for a laparotomy have deterred many surgeons and oncologists from using this modality, however. Robotic-assisted laparoscopic pump placement has recently been described (Hellan & Pigazzi, 2008) that carries the potential to improve on perioperative outcomes but warrants surgical expertise with new technology. Several groups have worked on alternate placement methods to eliminate the laparotomy “hurdle.”

Percutaneous techniques to catheterize the hepatic artery for delivery of intrahepatic chemotherapy have been developed using a variety of peripheral arteries for access (Table 86.8). Most of these techniques have been abandoned or are used only by a few specialized groups for the following reasons:

Table 86.8 Peripheral Arteries Used for Catheter Placement in the Hepatic Artery

Castaing and colleagues (1998) tried to address these shortfalls by using an intercostal artery as conduit. A cutdown is performed over the tenth left rib. The intercostal artery is catheterized and the catheter is advanced, under fluoroscopic control, across the aorta into the ostium of the celiac axis and ultimately into the proper hepatic artery, just beyond the takeoff of the GDA. The catheter is connected to an implantable port located in the left upper quadrant. The study included 35 patients with metastatic lesions to the liver, mainly from CRC, and 30 patients (86%) underwent a successful placement. Placement was not feasible in five patients because of an unsuitable artery. No procedure-associated deaths were reported, no thrombotic complications in either the aorta or the hepatic artery resulted, and no dislocations or migrations of the catheter occurred. Follow-up was brief because most of these patients died from their disease, although all of the patients had not responded to previous standard treatments and had advanced disease at the time of catheter placement.

This method has clear advantages because of its simplicity and the fact that the catheter is attached to an immobile part of the body, thus preventing catheter motion. Catheter patency was less than 50% at 4 months, likely as a result of a lack of continuous flow. Also, the catheter used in Castaing’s study has not been approved by the FDA for prolonged indwelling use; their method is therefore not applicable in the United States.

Our group modified Castaing’s method to address these points (Saldinger & Sandhu, 2004). A peripherally inserted 3-Fr central catheter was chosen as the indwelling arterial catheter (Arrow International, Reading, PA). We used a 15-mL Codman 3000 constant-flow implantable pump for access and drug delivery (Codman, Raynham, MA). The pump catheter and arterial catheter were connected via a special connector (Arrow International, Walpole, MA; Fig. 86.6). Our method uses largely the same techniques as described by Castaing, but with a few differences:

FIGURE 86.6 The indwelling arterial catheter is tunneled from the insertion site at the eleventh rib to the left upper quadrant, where it is connected to the catheter of the infusion pump via a connector. The pump is placed into a pocket in the subcutaneous tissue.

FIGURE 86.7 Transfemoral celiac arteriogram mapping the hepatic arterial anatomy. GDA, gastroduodenal artery; LHA, left hepatic artery; RHA, right hepatic artery.

FIGURE 86.8 Fluoroscopic control of guidewire placement. Note the course of the wire: its entrance into the aorta and exit into the celiac axis, and finally the hepatic artery, is outlined.

FIGURE 86.9 A 3-Fr catheter secured to the intercostal artery. The inferior border of the eleventh rib has been exposed, allowing exposure of the intercostal artery and vein.

This procedure was performed successfully in four patients with metastatic colon cancer to the liver as part of a feasibility study. All patients had failed at least two chemotherapeutic regimens and were unresectable; no perioperative deaths or complications were reported. The catheters remained patent until the patient’s death from progression of disease at 1, 3, 6, and 7 months. The nonoperative placement of HAI pumps is a safe method and has all the advantages of minimally invasive procedures. Its role in the armamentarium of therapies to treat metastatic CRC to the liver depends largely on the role of intraarterial chemotherapy for liver tumors.

Approaches to Decrease Hepatic Toxicity

New approaches to decrease the hepatic toxicity induced by HAI of FUDR have been studied. Because portal triad inflammation may lead to ischemia and stricturing of the bile ducts, the hepatic arterial administration of dexamethasone decreases biliary toxicity. As previously mentioned, a prospective double-blind randomized study of intrahepatic FUDR with dexamethasone versus FUDR alone was conducted at MSKCC (Kemeny et al, 1992). The response rate in 49 evaluable patients was 71% for those who received FUDR plus dexamethasone versus 40% for those given FUDR alone (P = .03). Survival also favored the FUDR-dexamethasone group: 23 months versus 15 months for FUDR alone (P = .06). In addition, a trend was noted toward decreased bilirubin elevation in patients receiving FUDR plus dexamethasone compared with the group receiving FUDR alone (9% vs. 30%; P = .07).

A second method to decrease hepatic toxicity is the use of circadian modification of hepatic intraarterial FUDR infusion. In a retrospective nonrandomized study (Hrushesky et al, 1990), a comparison of constant (flat) infusion versus circadian-modified HAI of FUDR was conducted in 50 patients. Over nine courses of treatment, the patients with circadian-modified infusion tolerated almost twice the daily dose of FUDR. Circadian-modified infusion resulted in 46% of patients having no hepatic toxicity versus 16% after flat FUDR infusion. The authors did not present information on response rates achieved in both groups.

Another approach to decrease toxicity from HAI is to alternate intraarterial FUDR with intraarterial 5-FU. A weekly intraarterial bolus of 5-FU has similar activity to intraarterial FUDR and does not cause hepatobiliary toxicity; however, it frequently produces treatment-limiting systemic toxicity or arteritis with the pharmacokinetic differences previously discussed. Stagg and colleagues (1991) used an alternating regimen of HAI of FUDR and HAI of 5-FU, with a response rate of 51% and median survival of 22.4 months. In contrast to the experience with single-agent HAI of FUDR, no patient had treatment terminated because of drug toxicity. Another report described 57 CRC patients with unresectable liver metastases treated with an alternating HAI schedule of FUDR and 5-FU (Davidson et al, 1996), of which 2 patients (3.5%) developed biliary sclerosis, and 12 (21.1%) had mild transient liver function abnormalities.

Methods to Increase Response Rate

Based on the fact that systemic combination chemotherapy regimens are more effective than single agents, the potential benefit of multidrug HAI has been evaluated. In an early study using mitomycin C, bis-chloroethyl-nitrosourea, and FUDR, Cohen and associates (1985) produced a 69% partial response rate. In a randomized trial at MSKCC comparing this three-drug regimen with FUDR alone (Kemeny et al, 1993), the response rates were 45% for the three-drug regimen and 32% for FUDR alone in the 67 patients who entered this trial. The median survivals from the initiation of HAI were 18.9 months and 14.9 months. Other trials using FUDR and LV have produced response rates up to 62% (Hohn et al, 1989).

Methods to Treat Extrahepatic Disease: Combined Hepatic Arterial Infusion and Systemic Chemotherapy

Extrahepatic disease develops in 40% to 70% of patients who undergo HAI. Such metastases can occur even when the patient’s hepatic tumors are responding. In many patients, extrahepatic disease is the cause of death. Safi and colleagues (1989) studied whether concomitant SYS reduces the development of extrahepatic metastases in patients who receive HAI. Ninety-five patients were randomized to intraarterial FUDR (0.2 mg/kg/day for 14 of 28 days) or a combination of intraarterial FUDR (0.21 mg/kg/day) and intravenous FUDR (0.09 mg/kg/day) given concurrently for 14 of 28 days (intraarterial/intravenous). The response rates were 60% for both arms of the study; however, the incidence of extrahepatic disease was significantly less in patients who received the intraarterial/intravenous treatment (56%) compared with intraarterial treatment (79%; P < .01). No significant difference in survival was found between the two groups (P = .08). The results of this trial, as well as the development of improved SYS regimens, have underscored the need for further study of combined systemic/intraarterial regimens. Results of some of these studies are presented in Table 86.9, and SYS irinotecan and oxaliplatin are discussed in detail below.

Irinotecan is a topoisomerase I inhibitor with proven efficacy in first-line and second-line treatment of metastatic CRC. The activity of irinotecan is not inhibited by high thymidylate synthase activity (Saltz et al, 1998); combining systemic irinotecan with HAI therapy may therefore result in improved control of extrahepatic disease. In a Phase I study at MSKCC, 46 patients with unresectable liver metastases, 8 of whom underwent cryosurgery, received HAI of FUDR/dexamethasone and systemic irinotecan in escalating doses; all 38 patients who did not undergo cryosurgery were previously treated, and 16 had prior therapy with irinotecan. The regimen was well tolerated, with dose-limiting toxicities of diarrhea and myelosuppression. The response rate was 74%, median time to progression was 8.1 months, and 13 of 16 patients who had previously received irinotecan had partial responses (Kemeny et al, 2001).

Another nonrandomized study used HAI of FUDR with systemic irinotecan as “adjuvant” therapy after cytoreduction (therefore not “true adjuvant”) of unresectable hepatic CRC metastases. The cytoreduction was defined as using cryosurgery, RFA, partial resection, or some combination to treat all identifiable sites of disease. Seventy-one patients received “adjuvant” therapy and were compared with a historic control group that received cytoreduction alone. Time to progression was 19 months versus 10 months, and median survival was 30.6 months versus 20 months, for HAI versus control groups (Bilchik et al, 2000). A Japanese group examined HAI of 5-FU and SYS irinotecan in previously treated patients and demonstrated response rates of 76.5%, with median OS of 20 months (Shiatra et al, 2006).

Oxaliplatin is a cytotoxic agent with a mechanism of action similar to that of other platinum derivatives, but it has a different spectrum of activity and toxicity. When combined with 5-FU/LV, clinical response rates have been greater than 50%, with median survival of 16.2 months in untreated patients with metastatic CRC (de Gramont et al, 2000; Tournigand et al, 2004). Preliminary studies using systemic oxaliplatin-based regimens combined with HAI of FUDR demonstrated the feasibility and safety of this approach and revealed promising early results (Pancera et al, 2002). In a two-grouped MSKCC Phase I study, 36 patients with unresectable hepatic metastases, 89% of whom were previously treated, received HAI of FUDR/dexamethasone and SYS oxaliplatin plus either SYS irinotecan or SYS 5-FU/LV. Both regimens were well tolerated, and response rates for the two groups were 90% and 88% (see Table 86.9; Kemeny et al, 2005a). This high response rate for second-line therapy with HAI plus SYS, as well as conversion to resectability, was demonstrated in a recent MSKCC pooled analysis of phase I data in 49 patients with unresectable liver metastases from CRC (Kemeny et al, 2009a). Patients received HAI of FUDR/dexamethasone, SYS irinotecan, and SYS oxaliplatin, and 98% had bilobar disease, whereas 85% had tumors bordering vasculature. A partial or complete response was reported in 92% (84% partial, 8% complete), and 47% of patients were resectable, three with pathologic complete responses. With a median follow-up of 26 months from time of pump placement, OS was 51 months for untreated patients: all 23 responded to treatment, and 57% had resection. OS was 35 months for previously treated patients: 85% responded to treatment, and 38% had resection. This revealed that even in heavily pretreated patients with significant hepatic metastasis, HAI of FUDR can increase response and resection rates when combined with modern SYS. Future randomized trials are needed to assess the impact that HAI specifically has in these outcomes.

Adjuvant Treatment after Liver Resection of Colorectal Metastases

The rationale for the use of adjuvant chemotherapy after resection of liver metastases from CRC is based on the observation that, although some patients have long-term disease-free survival (DFS) after resection, many patients’ disease recurs. Recurrence may be solely in the liver, it may be extrahepatic and intrahepatic, or it may be solely extrahepatic. An effective adjuvant treatment may have a substantial impact on recurrence and survival. The use of SYS without HAI has been formally tested in this setting, but only to a limited extent, with one randomized study (Portier et al, 2006) that met its primary end point of 5-year DFS—33.5% for the chemotherapy group and 26.7% for the control group (P = .028)—but failed to show a survival benefit with 6 months of adjuvant 5-FU/folinic acid. Because this trial and another Phase III study (EORTC) both closed early because of slow accrual, their results were pooled and reported together (Mitry et al, 2009), demonstrating both a lack of DFS and OS statistical significance for 5-FU adjuvant therapy in this setting. When adjusting for poor characteristics in a multivariate analysis, however, an increase in DFS was reported for the group treated with chemotherapy. In EORTC 40983, reversible complications occurred in 25% of the patients receiving perioperative 5-FU plus leucovorin and oxaliplatin (FOLFOX) compared with 16% in the surgery-alone group (P =.04) (Nordlinger et al, 2008). The Japanese are conducting a multicenter randomized Phase II/III trial of adjuvant modified FOLFOX versus hepatic metastasectomy alone (Kanemitsu et al, 2009).

Because combining HAI and SYS may be useful in decreasing recurrence, four relatively large randomized trials have been conducted in this group of patients (Table 86.10). In the MSKCC study (Kemeny et al, 1999), 156 patients with resected hepatic metastases were randomized to 6 months of systemic 5-FU/LV or systemic 5-FU/LV plus HAI with FUDR. Primary end points were 2-year overall and progression-free survival. Forty percent of patients received prior adjuvant chemotherapy after resection of their primary CRC, and 15% had received prior chemotherapy as treatment for metastatic disease. Randomization was performed intraoperatively after complete resection of metastases, and patients were stratified based on number of metastases and prior treatment history. Of enrolled patients, 92% received treatment as assigned; 2-year survival was 86% in the combined therapy group versus 72% for those who received systemic therapy alone (P = .03), with median survivals of 72.2 months and 59.3 months, respectively. In an updated analysis, 10-year survival was 41% in the HAI plus SYS group, with 27% alive in the SYS-alone group still alive (Fig. 86.10; Kemeny & Gonen, 2005). Two-year hepatic progression-free survival was 90% for the combined group and 60% for the monotherapy group (P < .001). Updated hepatic progression-free survival at 10 years was 70% and 40%, respectively (P = .0001; Fig. 86.11), and overall progression-free survival was 40% and 20%, respectively, at 10 years (P = .001). If patients with poor clinical risk scores are considered (Fong et al, 1999), their survival is still improved with HAI compared with SYS alone (Fig. 86.12).

FIGURE 86.10 Updated overall survival from the Memorial Sloan-Kettering Cancer Center trial comparing adjuvant systemic therapy (SYS) with hepatic arterial infusion (HAI) plus SYS.

FIGURE 86.11 Updated hepatic disease-free survival from the Memorial Sloan-Kettering Cancer Center trial comparing adjuvant systemic therapy (SYS) with hepatic arterial infusion (HAI) plus SYS.

FIGURE 86.12 Survival stratified by clinical risk score. A score ranging from 0 to 5 was calculated by adding 1 point for the following clinical variables: tumor size >5 cm, tumor number >1, serum CEA >200 ng/mL, node-positive primary tumor, and disease-free interval >12 months (Fong et al, 1999). SYS, systemic therapy; HAI, hepatic anterial infusion.

Toxicity was increased in the combined group, and 39% of patients required hospitalization for diarrhea, neutropenia, mucositis, or small bowel obstruction compared with 22% in the monotherapy group (P = .02). Elevated bilirubin was seen in 18% of patients in the combined group. In most patients, the bilirubin returned to normal, but 6% of patients required biliary stents. In the control group, 2% had an elevation in bilirubin, and 2% required biliary stents. No significant difference was found among the groups in therapy-related deaths (one combined, two monotherapy).

The intergroup study (Kemeny et al, 2002) randomized 109 patients to resection alone or resection followed by four cycles of HAI with FUDR and infusional systemic 5-FU, followed by eight more cycles of systemic 5-FU. Patients with more than three liver metastases or extrahepatic disease at laparotomy were taken off the study; only 80 of 109 patients were actually included in the study, which was designed to examine the effect of adjuvant therapy on DFS. When patients were analyzed as treated (n = 75), the 4-year DFS (46% vs. 25%; P = .04) and 4-year hepatic DFS (67% vs. 43%; P = .03) favored HAI over the control groups. Based on an intention-to-treat analysis, no difference was reported in median or 4-year OS between the groups. Currently, the 5-year survival is 55% versus 37.5% favoring adjuvant therapy (Kemeny M, 2005); however, this study was not designed to look at OS.

In the German cooperative multicenter study (Lorenz et al, 1998), 226 patients were randomized to resection alone or resection plus 6 months of HAI with 5-FU/LV given as a 5-day continuous infusion every 28 days. The study was terminated early, because an interim analysis suggested a very low chance of showing a survival benefit with adjuvant therapy. The impact of HAI in this study is difficult to assess because only 74% of patients assigned to HAI received this treatment, and only 30% completed it. No difference in time to progression, time to hepatic progression, and median OS was noted in an intention-to-treat analysis. When patients were analyzed “as treated,” time to hepatic progression (45 months vs. 23 months) and time to progression or death (20 months vs. 12.6 months) were improved in the HAI arm. Grade 3 or 4 toxicity—including stomatitis, nausea, and vomiting—was noted in 63% of patients who received adjuvant therapy. These findings reflect significant systemic absorption of 5-FU when given via HAI.

A study conducted in Greece on 122 patients used mitomycin C, 5-FU, and interleukin (IL)-2 by both HAI and the intravenous (IV) route versus the IV route alone. The 2-year survival was 92% versus 75%, and 5-year survival was 73% versus 60% for the HAI plus SYS group versus the SYS-alone group, respectively. DFS was significantly longer for the HAI plus SYS group: 60% at 5 years versus 20% for the intravenous group (P = .0012); hepatic DFS was 85% versus 50% (P = .0001; Lygidakis et al, 2001).

The two American studies showed a reduction in hepatic and extrahepatic recurrence for combined HAI plus systemic therapy after surgical resection. Of the two European studies, one showed a significant increase in survival and DFS, whereas the other did not. In the MSKCC study, 2-year survival after liver resection was significantly improved with combined therapy: 86% compared with 72% with systemic therapy alone. Historic 2-year survivals (Chang et al, 1987; Fegiz et al, 1991; Jamison et al, 1997; Scheele et al, 1990) for patients treated with resection alone range from 55% to 70%.

Nonrandomized studies of modern chemotherapy regimens combined with HAI of FUDR in the post–liver metastasis resection (adjuvant) setting have been conducted and suggest improved outcomes. Phase I and II trials of adjuvant SYS irinotecan combined with FUDR/dexamethasone in 96 patients showed a 2-year survival of 89% at a median follow-up of 26 months. The dose-limiting toxicities were diarrhea and neutropenia, and all 27 patients treated at the maximum-tolerated dose were alive at publication (Kemeny et al, 2003). A phase I trial of adjuvant HAI of FUDR/dexamethasone with escalating doses of SYS oxaliplatin/5-FU/LV in 35 patients revealed 4-year survival and progression-free survival of 88% and 50%, respectively, at a median follow-up of 43 months. Dose-limiting toxicities of diarrhea and elevated bilirubin were each 8.5% (Kemeny et al, 2009b).

A multivariate analysis performed as a part of a recent review of over 1000 patients showed that post–liver metastasis resection HAI was one of the significant factors to improve survival. Median OS was 50 months in those who did not receive HAI and 68 months in those who did (P = .0001) (Ito et al, 2008). Another MSKCC retrospective review described 612 patients who underwent liver resection from 1985 to 1994. The 10-year OS was 38% for patients who received HAI of FUDR and 15% for those who did not (P < .0001) (Tomlinson et al, 2007). Finally, colleagues at our institution retrospectively compared outcomes from 125 metastatic CRC patients who received postoperative SYS (FOLFOX or 5-FU plus leucovorin and irinotecan [FOLFIRI]) with HAI to 125 similar patients who received only SYS. The 5-year hepatic progression-free survival was 75% in the HAI group and 52% in the SYS group (P = .0005) with a median follow-up of 43 months; OS at 5 years was 72% and 52%, respectively (House et al, 2011). These data underscore the need for randomized studies of modern HAI plus SYS compared with modern SYS alone.

Neoadjuvant Hepatic Arterial Infusion

Neoadjuvant treatment is a strategy increasingly used in solid-tumor oncology, given the multifaceted rationale that it may enable downsizing and subsequent resectability of tumor burden, and more systemic treatment may be tolerated, or given at all, than in postoperative settings, where complications may limit or preclude administration of chemotherapy. In addition, neoadjuvant HAI may prevent unnecessary operations in patients who have clinically and biologically declared themselves to have inoperable metastatic disease. In the context of converting CRC patients with unresectable liver metastases to operable candidates, some neoadjuvant approaches have been discussed above. Combining SYS with HAI agents besides FUDR has been studied in the neoadjuvant setting. Numerous reports have been made that HAI of oxaliplatin, for instance, has shown benefit in response and resectability rates when combined with SYS 5-FU (Boige et al, 2008; Del Freo et al, 2006; Ducreux et al, 2005).

Hepatic Arterial Infusion for Noncolorectal Liver Metastases and Primary Liver Cancer (See Chapters 50A, 80, and 81C)

Although liver metastases from noncolorectal carcinoma are less commonly treated with regional therapy, HAI chemotherapy has been used in cases of breast cancer, HCC, melanoma (Melichar et al, 2009), bronchogenic carcinoma, and pancreas cancer. Studies in breast cancer have employed numerous HAI agents including FUDR, mitomycin/FU/doxorubin, vinblastine/cisplatin, and cyclophosphamide/etoposide. One trial of 15 patients undergoing systemic chemotherapy for refractory metastatic breast cancer tested HAI of FUDR and mitomycin and demonstrated a partial response rate of 53% and OS of 18 months after HAI was begun (Maral et al, 1985). FUDR alone and in combination with various cytotoxic agents has also been evaluated in HCC (see Chapter 80), including treatment with mitomycin/interferon/FUDR (Atiq el al, 1992) and LV/doxorubicin/cisplatin/FUDR (Patt el al, 1994) in 27 patients. In the latter, response rates were 41% to 54%, and median OS was 15 months.

More recent experience with HAI for HCC and intrahepatic cholangiocarcinoma (ICC; see Chapter 50A) at MSKCC was published, and it demonstrates the correlative and predictive utility of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in 34 patients with unresectable disease treated with HAI of FUDR/dexamethasone. Partial responses were seen in 47%, with median OS of 30 months (Jarnagin et al, 2009). One patient in this study responded sufficiently to undergo resection and was found to have had a complete pathologic response. The median duration of response was 1 year, and median time to progression was 7 months. Median follow-up at time of publication was 35 months, and 1- and 2-year survival was 88% and 67%, respectively. Therapy was well tolerated, and DCE-MRI data showed that pretreatment and posttreatment tumor perfusion and permeability parameters correlated with median survival, therefore these may serve as a biomarker of treatment outcome.

Conclusion

HAI offers several advantages. From a pharmacologic standpoint, HAI is more effective than SYS, because higher drug levels are achieved at the sites of metastatic disease. Using agents with high hepatic extraction virtually eliminates the systemic toxicity observed with standard systemic therapy. The 50% to 70% response rate obtained in trials of intrahepatic FUDR therapy has not been matched by any systemic therapy to date. The addition of leucovorin or dexamethasone to FUDR has increased both response rate and survival. Most randomized HAI studies do not clearly evaluate the issue of survival, mainly because a crossover was allowed in some, whereas patients with positive portal nodes were included in the HAI-treated groups in other studies. In addition, severe toxicity may occur with HAI or SYS. Although HAI therapy may produce GI or hepatic toxicity, this is minimized with proper surgical technique during pump placement, with close monitoring of liver function tests, and with HAI of dexamethasone.

Because the liver is often the initial site of metastatic disease in patients with colorectal carcinoma, early intensive therapy with surgical resection, HAI, or both at a time when the tumor burden is small may prevent the progression of metastases to other sites. Although HAI therapy is applicable only to selected patients with hepatic metastases, it may be the best therapy available.