Regional chemotherapy for liver tumors

Overview

The liver is a unique organ with a rich dual blood supply (see Chapter 2 ) and serves as a target organ for many tumor metastases. As the portal vein drains the gastrointestinal (GI) tract, malignancies arising from these organs frequently give rise to hematogenous liver metastases. Because colorectal cancer most frequently results in distant metastatic spread to the liver, most hepatic arterial infusion (HAI) chemotherapy studies address outcomes related to colorectal liver metastases (see Chapter 90 ). Data supporting the use of HAI therapy are presented in this chapter, with a special focus on technical issues related to device placement and drug delivery to the liver.

Systemic chemotherapy

Responses to systemic therapy (SYS) vary with the type of tumor. For example, patients with liver metastases from a breast primary may have high response rates with SYS, in contrast to metastases from a gastric or pancreatic primary tumor. Many chemotherapy trials do not differentiate patients with liver-only metastases to show how this subgroup of 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. In patients with colorectal cancer, the liver is the most common site of tumor dissemination, and liver metastases develop in 60% of patients during the course of their disease (see Chapter 90 ).

Outcomes related to the use of SYS have improved significantly with the addition of more modern chemotherapeutic agents such as irinotecan and oxaliplatin ^, (see Chapter 98 ) There has since been a positive correlation between the number of cytotoxic drugs used and overall survival (OS), leading to common chemotherapeutic regimens that are now well established. Dual chemotherapeutic regimens are frequently used and incorporate 5-fluorouracil (5-FU) with either irinotecan-based (FOLFIRI) or oxaliplatin-based regimens (FOLFOX), with little difference in efficacy between the two regimens. The choice depends on toxicity, drug availability, and patient preference. Median survival is generally in the 20-month range, with response rates ranging between 30% and 40%. Interestingly, triple-therapy combinations, which include 5-FU, oxaliplatin, and irinotecan (FOLFOXIRI), have been investigated in phase III studies with mixed results when compared with those with FOLFIRI. ^, Owing to additional toxicity, this particular combination is not routinely used.

Improved outcomes have been demonstrated with the addition of biologic agents in first-line and subsequent regimens, including drugs targeting vascular endothelial growth factor pathways (bevacizumab) or epidermal growth factor receptor (EGFR) pathways (cetuximab). ^, Furthermore, the introduction of molecular tumor biomarker analysis, including KRAS and BRAF, has allowed further tailoring of SYS therapy to underlying tumor genotype. For example, KRAS gene mutations that arise in codons 12 and 13 render patients resistant to EGFR monoclonal antibody therapy. As such, only wild-type KRAS tumors have been treated with cetuximab, with improved response rates versus nonbiologic agents alone in those patients. Similarly, quadruple therapy (addition of a biologic agent to FOLFOXIRI) regimens are being explored, with recent data suggesting benefit for use of FOLFOXIRI plus bevacizumab, particularly, in patients with BRAF mutations. Median survival with the addition of biologic agents is improved to approximately 24 months, and response rates are increased to nearly 60%.

In terms of second-line therapy, patients generally alternate between oxaliplatin or irinotecan, depending on which agent was initially administered before progression. Although outcomes are equivalent with second-line therapies compared with first-line regimens, responses occur less frequently and with shorter progression-free survival (PFS). Biologic agents are also used in second-line therapy, based on treatment intent, molecular profile, patient factors, and drug factors, with several studies currently underway to evaluate the role of biologic agents as second-line therapies in the treatment of metastatic colorectal cancer. ^,

Rationale for hepatic arterial chemotherapy

The rationale for HAI is based on anatomic and pharmacologic principles.

1.
Liver metastases are perfused almost exclusively by the hepatic artery, whereas normal hepatocytes derive their blood supply from both portal venous and hepatic arterial flow. After injection of floxuridine (FUDR) into either the hepatic artery or the portal vein, mean liver concentrations of the drug do not differ based on the route of injection; however, mean tumor FUDR levels are significantly increased (15-fold) when the drug is injected via the hepatic artery.

The use of drugs that are largely extracted by the liver during first-pass metabolism results in high local concentrations of drug with minimal systemic toxicity. Ensminger et al. showed that 94% to 99% of FUDR is extracted by the liver during the first pass compared with 19% to 55% of 5-fluorouracil (5-FU). FUDR is therefore an ideal drug for HAI, with a 400-fold increase in hepatic exposure with FUDR. The pharmacologic advantage of various chemotherapeutic agents for HAI is summarized in Table 97.1 .

TABLE 97.1

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

From Ensminger WD, Gyves JW. Clinical pharmacology of hepatic arterial chemotherapy. Semin Oncol. 1983;10:176–182.

ESTIMATED INCREASE BY DRUG	HALF-LIFE (min)	HEPATIC ARTERIAL EXPOSURE
Fluorouracil	10	5- to 10-fold
Floxuridine	10	100- to 400-fold
Bis-chloroethyl-nitrosourea	5	6- to 7-fold
Mitomycin C	10	6- to 8-fold
Cisplatin	20–30	4- to 7-fold
Doxorubicin	60	2-fold
Dichloromethotrexate	—	6- to 8-fold

3.
Drugs with a steep dose-response curve are more useful when given by the intrahepatic route because small increases in the concentration of administered drug result in a large improvement in response. FUDR follows linear kinetics without response saturation at high doses.
4.
Drugs with a high total-body clearance are more useful for hepatic infusion. The area under the concentration-versus-time curve is a function not only of drug clearance but also of hepatic arterial blood flow. Because hepatic arterial flow has a high regional exchange rate (100–1500 mL/min), drugs with a high clearance rate are required. If a drug is not cleared rapidly, recirculation through the systemic circulation mitigates the advantage of intraarterial therapy versus SYS.
5.
Another rationale for hepatic arterial chemotherapy, especially for patients with metastatic colorectal cancer, is the concept of a stepwise pattern of metastatic progression. ^, This theory states that hematogenous spread occurs first via the portal vein to the liver, then from the liver to the lungs, and then to other organs. Aggressive treatment, either resection or hepatic infusion, of metastases confined to the liver yields prolonged survival for some patients.

The development of an implantable infusion pump allowed the safe administration of hepatic arterial chemotherapy in the outpatient setting. Early trials with an implantable pump and continuous FUDR therapy produced a median response rate of 47% and a median survival of 17 months. To further demonstrate that HAI possessed a therapeutic benefit, several randomized studies were subsequently conducted and are reviewed in detail later.

Surgical technique and operative considerations

Hepatic artery pump placement

The arterial anatomy of the liver varies ( Table 97.2 ), with conventional anatomy present in only approximately two thirds of patients (see Chapter 2 ). Before consideration of pump placement, it is imperative to carefully review available images, including the arteriogram, with the radiologist and formulate a plan for the management of aberrant anatomy. In the past, direct arteriography was required (see Chapter 21 ), but now excellent definition can be ascertained from computed tomography (CT) angiography. In most cases, a pump with a single catheter can adequately provide access to the entire hepatic arterial inflow. It is best not to place the catheter directly into the hepatic artery, which risks thrombosis of the vessel. Instead, the catheter should ideally be placed into an accessible side branch. The gastroduodenal artery (GDA) is the preferred conduit and provides the most reliable method of catheter implantation. As previously mentioned, cholecystectomy should be performed to prevent chemotherapy-induced cholecystitis. Different surgical incisions have been used for this operation with success, including an upper midline incision, right subcostal incision, or limited right subcostal hockey-stick incision. Perioperative intravenous antibiotic administration before incision and adherence to other surgical care improvement project protocols are recommended.

TABLE 97.2

Summary of Reported Prevalence (%) of Hepatic Arterial Anatomic Variants

From Allen PJ, Stojadinovic A, Ben-Porat L, et al: The management of variant arterial anatomy during hepatic arterial infusion pump placement. Ann Surg Oncol 9:875–880, 2001.

	DALY et al., 1984	MICHELS, 1966	KEMENY et al., 1986b	CURLEY et al., 1993	ALLEN et al., 2002
	( n = 200)	( n = 200)	( n = 100)	( n = 180)	( n = 265)
Anatomy
Normal	70	55	50	63	63
Variant gastroduodenal artery	6	—	9	9	11
Accessory right hepatic artery	4	7	4	1	1
Replaced right hepatic artery	6	12	16	12	6
Accessory left hepatic artery	3.5	8	1	2	10
Replaced left hepatic artery	4	10	16	11	4
Other	5	2.5	1	2	5

For patients with unresectable disease, a staging laparoscopy is advisable to rule out occult extrahepatic disease, which, in past experience, was seen in approximately one third of patients, but this figure has certainly declined more recently (see Chapter 24 ). A thorough examination of the abdomen is performed at laparoscopy and at laparotomy to look for extrahepatic disease. The most common sites of extrahepatic metastases are the peritoneum and portal lymph nodes. A biopsy should be performed if the lymph nodes appear suspicious because nodal involvement precludes use of the pump. The extent of liver involvement should be assessed by using intraoperative ultrasonography. Any radiographically occult hepatic tumors should be noted, and the potential for future resection should be specifically addressed in the operative note.

Conventional hepatic arterial anatomy (see Chapter 2 )

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 extrahepatic perfusion of the pancreas, stomach, or duodenum. The common hepatic artery is mobilized 1 cm proximally, and the proper hepatic artery is mobilized approximately 2 cm distally from the origin of the GDA. Branches to the retroperitoneum from the right or left hepatic artery commonly exist and should be ligated. Review of preoperative imaging to detect these branches is important. 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. 97.1 ). The GDA should be temporarily occluded with palpation of the proper hepatic artery to rule out critical retrograde flow to the liver through the GDA secondary to celiac artery disease or stenosis. No attempt to dissect the common bile duct is necessary, which would risk devascularization and ischemic stricturing.

FIGURE 97.1, The common hepatic, proper hepatic, and gastroduodenal arteries are completely mobilized. All branches to the stomach, duodenum, or pancreas are identified and ligated (see Chapter 2 ).

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, placement of the pump over the ribs should be considered because this may help with postoperative pump access. The pump and catheter should be handled carefully and contact with the patient’s skin should be avoided. 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 (see Chapter 127F ).

A transverse arteriotomy is made in the distal GDA, and the catheter is inserted up to, but not beyond, the junction with the hepatic artery ( Fig. 97.2 ). If the catheter protrudes into the common hepatic artery, turbulence of blood flow can lead to thrombosis of the vessel. Conversely, failure to pass the catheter up to that 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 Wood’s 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 lavage (bacitracin solution) of the subcutaneous pocket is recommended. There are no data to support continued postoperative administration of antibiotic therapy. Pump infection, however, is a serious complication, and any sign of erythema indicates a wound infection postoperatively that should be treated immediately and aggressively (see Chapter 127F ).

FIGURE 97.2, 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.

Aberrant hepatic arterial anatomy (see Chapter 2 )

As discussed earlier, aberrant hepatic arterial anatomy is common, and numerous variations occur. Each anatomic situation is specifically addressed here, but first, general principles in managing variant anatomy are discussed. In analyses of our extensive experience with this operation, the factor most consistently associated with catheter-related complications and decreased durability of the catheter is cannulation of a vessel other than the GDA. The overall preferred technique is placement of the catheter in the GDA with ligation of the isolated variant vessel. This method relies on intrahepatic collateral development and cross-perfusion to the liver fed by the ligated vessel (see Chapter 5 ). Although concerns have been raised over incomplete hepatic perfusion with this technique, this rarely occurs. In our published experience with this operation for variant anatomy, incomplete hepatic perfusion occurred once in 52 cases. Cross-perfusion may take as long as 4 weeks to occur, and early perfusion scans may be abnormal initially. However, these should be rechecked after a few weeks to assess for complete cross-perfusion because most normalize. ^, The only exception to this rule may be patients with central tumors so large that they impede cross-collateralization. Lastly, although cross-perfusion after ligation of aberrant vessels is highly reliable, it has not been proven that this results in equal blood flow for chemotherapy delivery.

Aberrant origin of the gastroduodenal artery

The GDA can arise from the right or left hepatic artery, or there can be a trifurcation in which the GDA, right hepatic artery, and left hepatic artery all arise simultaneously from the common hepatic artery. This anomaly occurs 6% to 11% of the time. In general, it is preferable to place the catheter into the GDA and ligate vessels that are not receiving catheter-directed flow because this is the technique associated with the lowest rate of catheter-related complications. ^, In the case of a trifurcation, the catheter should be placed in the GDA, and perfusion should be tested with fluorescein or methylene blue. If bilobar perfusion is adequate, ligation of vessels is unnecessary. If no perfusion to one lobe of the liver is seen at testing, the hepatic artery to that lobe should be ligated, most commonly the left hepatic artery, thereby relying on cross-perfusion of the left liver.

The hepatic arterial tree also may be accessed through the splenic artery just to the left of the celiac axis. The catheter is placed in the splenic artery and maneuvered across the celiac axis to lie freely in the hepatic artery, ending proximal to the bifurcation. The GDA and the right gastric artery are ligated, and the catheter is secured in the splenic artery. This technique is technically difficult because it requires extensive dissection of the celiac axis and manipulation of the catheter across the celiac artery branches. It is also associated with more complications, including thrombosis and extrahepatic perfusion and is therefore rarely used. Another option is retrograde cannulation of the common hepatic artery through the GDA with an attached short, stiff, small-gauge catheter. This technique, however, is also associated with a higher rate of complications, including arterial dissection and thrombosis, and it should be used rarely, if ever.

Accessory left hepatic artery (see Chapter 2 )

An accessory left hepatic artery arises from the left gastric artery, crosses the gastrohepatic ligament, enters the liver at the base of the umbilical fissure, and typically supplies segments II and III. The native left hepatic artery, which arises from the proper hepatic artery, also supplies the left liver, typically segment IV in this situation. This abnormality is present in 2% to 10% of cases. The simplest, safest, and most reliable option is to ligate the accessory left hepatic artery and place the pump catheter in the GDA because cross-perfusion is highly reliable. Another option is to use two catheters (or pumps), one in the GDA and one in the accessory left hepatic artery, although this technique is cumbersome and is generally not necessary.

Accessory right hepatic artery (see Chapter 2 )

Accessory right hepatic arteries arise from the superior mesenteric artery and run in the portacaval space to supply a portion of the right lobe of the liver. This abnormality is present in 1% to 7% of patients. Accessory and replaced right hepatic arteries rarely have side branches adequate for cannulation. The preferred technique in this situation is placement of the catheter in the GDA and ligation of the accessory vessel because cross-perfusion is reliable. Placement of a second catheter directly in the accessory vessel is another option but is generally unnecessary and not recommended.

Replaced left hepatic artery (see Chapter 2 )

A replaced left hepatic artery arises from the left gastric artery and supplies the left liver, without a native left hepatic artery. This abnormality exists in 4% to 16% of patients. Once again, the preferred technique is to place the catheter in the GDA and ligate the replaced left hepatic artery. Initial reports on this specific situation suggested rates of incomplete cross-perfusion of 40%. More recent reports, including our experience, show that incomplete cross-perfusion is uncommon in this situation and occurred in only 1 of 10 of our patients at last analysis. ^, Other techniques, such as placement of catheters in the GDA and in a branch of the replaced left hepatic artery can be considered in patients with bulky disease in the left liver or in those with a large central tumor that may impede cross-perfusion.

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