Obstructive Jaundice in Patients Receiving Hepatic Artery Infusional Chemotherapy: Etiology, Treatment Implications, and Complications after Transhepatic Biliary Drainage

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Pancreaticobiliary Intervention

Obstructive Jaundice in Patients Receiving Hepatic Artery Infusional Chemotherapy: Etiology, Treatment Implications, and Complications ~ age' after Transhepatic ~ i l i atrrain Karen T. Brown, MD Nancy Kemeny, MD Manuela F. Berger, MD George I. Getrajdman, MD Tracy Napp, MD Yuman Fong, MD Sean Herman, BS Robert C. Kurtz, MD Jose Botet, MD Leslie H. Blumgart, MD

Index terms: Bile ducts, interventional procedure Bile ducts, stenosis or obstruction Chemotherapy, complications Jaundice Liver neoplasms, chemotherapeutic infusion

JVIR 1997; 8:229-234 Abbreviations: CHD = common hepatic duct, CIBS = chemotherapyinduced biliary sclerosis, FUDR = 5-fluorodeoxyuridine, GDA = gastroduodenal arteries, HA1 = hepatic artery infusional, PBD = percutaneous biliary drainage

From the Departments of Radiology (K.T.B., G.I.G., T.N., S.H., J.B.), Medicine (N.K., M.F.B., R.C.K.), and Surgery (Y.F., L.H.B.), Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021. From the 1996 SCVIR annual meeting. Received March 9, 1996; revision requested May 13; revision received October 9; accepted October 12. Address correspondence to K.T.B. O SCVIR, 1997

PURPOSE: The authors determined the incidence and cause of obstructive jaundice requiring percutaneous biliary drainage (PBD) occurring in patients treated with hepatic artery infusional (HAI) chemotherapy. The radiographic findings in the different causes of obstruction are characterized, and predictors of outcome are identified. MATERIALS AND METHODS: Charts and radiographs were reviewed for 30 patients who developed obstl-uctive jaundice while receiving HAI chemotherapy and who subsequently required biliary drainage. The cause of obstruction, complications related to PBD, and survival from the time of PBD were recorded for each patient. RESULTS: Of 282 patients treated with HAI chemotherapy, 30 (10.6%)developed obstructive jaundice requiring PBD. Obstruction was related to chemotherapy-induced biliary sclerosis in 24 patients (80%).Five patients (17%) had bleeding complications related to PBD. Average survival was 32 weeks after biliary drainage. All four patients who had bilomas at the time of PBD had been treated with high-dose mitomycin, and lived an average of 10 weeks after the procedure. CONCLUSION: Chemotherapy-inducedbiliary sclerosis is the most common cause of obstructive jaundice in patients receiving HAT chemotherapy. These patients have a higher incidence of bleeding complications and may develop pseudoaneurysms remote from the ductal puncture site. Development of intrahepatic bilomas is associated with high-dose mitomycin-C treatment, and the presence of a biloma at the time of PBD is a poor prognostic indicator. UP to 75% of patients with colorectal carcinoma will develop hepatic metastases during the course of their disease (1). Unfortunately, these patients do not readily respond to systemic chemotherapy, with response rates rarely higher than 30% (2) and median survival of 9-12 months. Hepatic artery infusional (HA11 chemotherapy appears to have a higher response rate, and increased median sur-

vival, but may be associated with hepatobiliary toxicity (3). A dreaded finding during HA1 chemotherapy is hyperbilirubinemia. This may herald progression of disease, direct hepatotoxicity requiring dose modification or discontinuance of therapy, or the development of obstruction. Chemotherapy-induced biliary sclerosis (CIBS) has been a recognized cause of hyperbilirubinemia in these patients, reported in

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recent studies by Rougier and Kemeny to occur in 7%-25% of patients (4,5). Both of these studies involved small series of patients in which findings of CIBS were documented with endoscopic retrograde cholangiopancreatography; however, no statement was made as to what percentage of patients required biliary drainage. The purpose of this study is to determine the incidence and cause of obstructive jaundice requiring biliary drainage occurring in patients treated with HA1 chemotherapy, characterize the radiographic findings in the different causes of obstruction, and evaluate the outcome of percutaneous biliary drainage (PBD) in this group of patients.

I MATERIALS AND METHODS A surgical database of all patients having pumps placed for HA1 chemotherapy between November 23, 1990, and November 30, 1995, was crossmatched with a radiology database of all patients undergoing biliary drainage during that period, and a list of patients having had both procedures was retrieved. The research database of all 315 patients identified in the surgical database was then reviewed. Any patient who had a pump placed but did not receive HA1 chemotherapy or received only one or two treatments was identified. In addition, a search was made for any patient who developed obstructive jaundice while receiving therapy but was not treated by means of PBD. Two hundred eighty-two patients were treated with HA1 chemotherapy. Thirteen of the 282 were treated for hepatoma; the rest had metastatic colorectal carcinoma. Thirty patients developed obstructive jaundice requiring biliary drainage. The charts and radiographs of these 30 patients treated with PBD were reviewed. Information retrieved from the patients' chart included patient demographics, type and duration of chemotherapy infusion prior to the onset

of jaundice, and history of other (average age, 69 years), all being interventions. including liver resectreated for metastatic colorectal tion. HA1 chehotheraG was admin- cancer. Indication for drainage istered via Infusaid pump (Infusaid, included progressive hyperbilirubinNorwood, MA) according to previemia despite discontinuance of HA1 ously described methods (3,5),with chemotherapy with development of the exact regimen determined by pruritus andlor sepsis in the setting which ongoing clinical trial the of new or progressive biliary ductal patient qualified for and was dilation. Every patient with biliary entered into. All of the regimens obstruction underwent drainage were 5-fluorodeoxyuridine (FUDR) unless extensive parenchymal rebased, with the addition of mitomy- placement by tumor was believed to cin (low or high dose), levamasole, be the primary cause of the paleucovorin, or carmustine, with or tient's liver failure. without dexamethasone. Overall, 14 Of the 282 patients treated with different ~rotocolswere used. HA1 therapy, 124 patients (43%) ~ e l e v a kimaging studies includ- were treated with mitomycin; 77 ing contrast-enhanced computed patients (27%) received high-dose tomography (CT), ultrasound exmitomycin-C, and 47 patients (16%) aminations, and cholangiography received low-dose mitomycin-C. were reviewed by one interventional Twenty-four of the 30 patients radiologist to determine site of (80%)requiring biliary drainage obstruction, nature of obstruction, had received mitomycin-C as part of and presence, location (central vs their treatment. Sixteen patients peripheral), and extent of liver (53%)were given high-dose (20 metastases. In cases in which the mg/m2) mitomycin-C therapy; 14 of findings were not straightforward, these had findings of CIBS, and the consensus was reached by review other two had intraductal tumor. with another interventional radioloEight patients received low-dose gist. Results of intraductal biopsies and cultures were recorded. Compli- mitomycin-C therapy (10 mg/m2); five had CIBS, two had a central cations related to the PBD were mass, and one had an intraductal noted, as well as the number of tumor causing obstruction. The repeat procedures related to the average duration of HA1 treatment PBD. Follow-up data were obtained was 6 months (range, 1-19 months) from the HA1 research database or direct patient contact, and length of prior to the onset of jaundice. In the entire group, CIBS was survival after drainage was calcuthe cause of obstruction in 21 of 30 lated. patients (70%);a central mass compressing the bile duct was discovered in six (20%)with concomitant findings of sclerosis in three of RESULTS the six. Intraductal tumor was the Etiology of Obstruction cause of obstruction in the remaining three patients (10%). Overall, 24 of 30 patients (80%) requiring Of 315 patients who had pumps drainage had CIBS, and in 21 paplaced, 282 were treated with HA1 tients it was the primary cause of chemotherapy. The other 33 paobstruction. tients had pump-related problems including pocket infection, catheter thrombosis, misperfusion, or disRadiographic Appearance lodgment precluding more than two HA1 chemotherapy treatments. The most common radiographic Thirty of the 282 patients treated finding in CIBS is high-grade ob(10.6%) developed obstructive jaunstruction of the common hepatic dice requiring biliary drainage while undergoing HA1 therapy. This duct (CHD); in 50% of patients this extended to involve the confluence group included 22 men (average of right and left hepatic ducts, age, 61 years) and eight women

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Figure 1. (a) Patient with CIBS. Cholangiogram demonstrates high-grade narrowing involving CHD (arrowhead) and extending to involve right and left hepatic ducts (arrows) as well, similar to that seen with a Klatskin tumor. (b) CIBS with classic obstruction involving junction of CHD and CBD. Note unusual "striated" appearance (arrow), with suggestion of flame shaped filling defect extending into CBD. ( c ) Patient with diffuse CIBS demonstrates multiple regions of narrowing (arrows) and dilation of intrahepatic ductal system.

mimicking a Klatskin tumor (Fig la). Frequently, there is a "striated" appearance to the area of CHD obstruction (Fig lb), giving it a rather "fuzzy," ill-defined appearance, rather than the "smooth appearance of a stricture. Typically, there are multiple areas of narrowing involving the intrahepatic ductal system as well (Fig lc), but these are not always present. Six patients in our study had centrally located metastases from their colorectal carcinoma extending to the liver hilus as a potential cause of obstruction. Three of these six patients also had findings of CIBS. It is likely that both processes contributed to obstruction in these patients. Patients with intraductal tumor had obvious filling defects within the ductal system, which were positive at biopsy for adenocarcinoma metastatic from their primary tumor.

Complications Five of 30 patients (17%)had significant bleeding episodes after biliary drainage; all had CIBS. Two patients did not require treatment other than transfusion, and the bleeding stopped spontaneously. These patients presented with hemobilia 10 days after drainage. One patient did not have angio-

graphic evaluation, and the other patient underwent angiography on two separate occasions without identifying a source of bleeding. Three other patients presented 10-30 days after uneventful biliary drainage procedures with acute onset of hemobilia. All three of these patients underwent emergent angiography without identification of a bleeding site. Two patients had embolizations through the biliary drainage catheter tract, one of an arterial pseudoaneurysm, the other of a hepatic vein; both had repeated episodes of hemobilia. All three patients subsequently had abnormalities demonstrated at repeated angiography. All were remote from the bile duct puncture site but adjacent to the course of the drainage catheter through the hilus of the liver (Fig 2). Two of the patients had undergone resection of one hepatic lobe. All embolizations were successful, and no further episodes of hemobilia occurred.

Outcome Overall, the 30 patients who underwent PBD lived an average of 36 weeks after biliary drainage (range, 1-183 weeks) and underwent an average of seven repeat procedures related to their biliary drainage (range, one to 33). Eight of

the 30 patients were treated with Wallstents (Schneider, Minneapolis, MN) after internavexternal catheter placement, with an average patency of 5.1 months. Three of these patients required repeated drainage at an average of 3.3 months; the other five patients died with patent Wallstents after an average of 6.2 months. The 2 1 patients who never developed bilomas survived an average of 38.5 weeks after drainage. Nine of the 30 patients (30%) either had bilomas at the time of drainage or developed them subsequently. All nine patients had received mitomycin-C as part of their chemotherapeutic regimen, seven received the high-dose mitomycin-C, and all had infected bile at the time the bilomas were first identified. Candida grew from the bile of four of these patients; the other five patients had various bacterial micro-organisms. One patient was successfully treated and lived 111 weeks, the other eight patients died within 14 weeks of developing bilomas. Four patients with bilomas at the time of initial drainage died within an average of 10 weeks. Hemorrhage requiring embolization was not an indicator of poor prognosis because the three patients requiring embolization lived an average of 78 weeks, with one patient still alive at 183 weeks.

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a. b. C. Figure 2. (a) Cholangiogram obtained at the time of biliary drainage in a 66-year-old man with CIBS. The ductal puncture site is indicated by the arrow. (b)Initial arteriogram of patient after left hepatic lobectomy who presented with hemobilia 1 month after PBD demonstrating spasm of right hepatic artery branch (arrowhead).(c) Arteriogram of same patient 3 days later demonstrates pseudoaneurysm (curved arrow) and extravasation into biliary tree (straight arrows) along PBD catheter.

I DISCUSSION The onset of jaundice in patients with liver tumors often reflects extensive hepatic d i s s e ~ i n a t i o nof tumor (6). Obstructive jaundice may develop in these patients as well. Causes of obstruction include intrahepatic centrally located metastases extending to the liver hilus, extrahepatic nodal disease in the region of the porta or distal common bile duct, and intraductal tumor, as well as the occasional development of other co-morbid conditions such as choledocholithiasis. Patients receiving HA1 chemotherapy may experience direct hepatotoxicity from the chemotherapy. However, they may also develop CIBS. The current study demonstrates that CIBS is the most common cause of obstructive jaundice in patients undergoing HA1 chemotherapy. Botet et a1 (7) first described radiologic findings similar to those seen in sclerosing cholangitis in six jaundiced patients receiving HA1 FUDR chemotherapy in 1985. Pien et a1 (8) described a n entity they called "iatrogenic sclerosing cholangitis" in a patient treated with HA1 FUDR. Both authors discussed the potential reversibility of the problem by discontinuing chemotherapy, and stressed that hyperbilirubinemia in this patient group not

be attributed to tumor progression or he~atotoxicitvwithout further investigation. The authors also proposed mechanisms for bile duct injury including direct toxicity, fibrotic encasement, and chronic ischemia. although ', the actual cause of sclerosis remains unclear. We have seen new radiographic findings typical of a hepatic arteritis in patients receiving HA1 chemotherapy who undergo angiography for other reasons. Such a n arteritis involving the small vessels supplying the bile ducts could certainly cause a relative ischemia. The blood supply to the biliary ductal system was evaluated by Northover and Terblanche in 1979 (9). These authors found that the right and left hepatic ducts were supplied by numerous small vessels from the right and left hepatic arteries. The "supraduodenal duct," defined as the CHD and upper common bile duct, is supplied by axial vessels that, in 60% of cases, ran upward from the retroduodenal or gastroduodenal (GDA) arteries, but in 38% of cases these vessels arose from the right hepatic artery. When catheters are placed for HA1 chemotherapy, they are traditionally placed retrograde into the GDA, which is ligated distally. Patients whose primary blood supply to the supraduodenal duct is

from the right hepatic artery might be a t higher risk for developing chemotherapy-induced sclerosis if it is caused by direct toxicity because the relevant portion of the biliary system is exposed to a higher concentration of the chemothera~eutic agent. Similarly, ischemia may occur to a greater degree in these patients if an occlusive arteritis is induced in both the vessels supplying the hilar ducts and supraduodenal duct, a "watershed type phenomenon. It is also conceivable that axial vessels arising from the GDA are interrupted a t the time of pump catheter placement, causing a relative ischemia of the supraduodenal duct. Indeed Kemeny (1)has commented on the higher rate of biliary sclerosis and lower rate of ulcers in patients undergoing more extensive surgery a t the time of pump placement, suggesting that "efficient gastric devascularization" may contribute to the development of CIBS. Pettavel et a1 (10) found gross bile duct damage associated with histologic changes in the blood vessels a t autopsy in four patients who received HA1 chemotherapy with FUDR. In some ~ a t i e n t s . damage extended i n t i the periductal tissues. This extension into periductal tissues was associated with strong bile staining. The presence of extraductal bile is known to

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result in fibrosis. Fibrotic encasement of the small vessels supplying the peribiliary plexus can result in ischemic injury to the duct (11). Some patients treated with HA1 chemotherapy develop the usual causes of bile duct obstruction and should be treated with conventional measures. Patients with intraductal tumor are often managed with internallexternal catheters because the tumor may act as a ball valve to obstruct endoprostheses. A very peripheral puncture is desired, with a maximum number of side holes within the traversed portion of the ductal system. One of our patients had marked decrease in intraductal tumor after brachytherapy and survived for 1year after drainage. Whatever the exact cause of biliary sclerosis, there are several unusual features that interventional radiologists should be aware of when performing biliary drainage on patients receiving HA1 chemotherapy. Because some degree of reversibility has been demonstrated, patients should not undergo drainage unless relentless and significant progression of hy~erbilirubinemiaoff treatment has keen documented, or the patient presents with pruritus or sepsis. One of the patients in our study who met the criteria for drainage ultimately had a plastic endoprosthesis placed that "fell out" 14 months later, unbeknown to patient or physician, but it was noted to be absent on a follow-up CT scan. The patient has remained clinically well for 26 months. Patients with CIBS who undergo percutaneous transhepatic biliary drainage are at increased risk of having bleeding complications related to the drainage. When bleeding occurs it is often delayed, even when associated with arterial injuries. The arterial abnormalities may be subtle and may require repeated episodes of angiography with the biliary drainage catheter removed over a guide wire to be identified. Central bile duct punctures should be avoided because ( a ) arterial injury is more likely with central punctures, ( 6 ) these punctures often do not result in ad-

equate biliary drainage, and ( c ) central punctures do not allow for proper positioning of Wallstents in cases of high bile duct obstruction. All three of the patients in this study with arterial pseudoaneurysms had peripheral bile duct punctures, yet developed pseudoaneurysms centrally. Balloons were not used to dilate the central area of obstruction in any of these patients, nor were any of these patients treated with Wallstents. In all three patients, the pseudoaneurysm was adjacent to the intraductal course of the biliary drainage catheter. Given that fibrosis has been found to involve the entire portal triad, it is conceivable that the shear forces generated by passing dilators at the time of PBD are transmitted to the hepatic artery centrally in the area of obstruction, damaging the arterial wall. If this was the mechanism, one might expect the patients to present with hemobilia in the immediate postdrainage period, rather than 10-30 days later. Another ~ossibleex~lanationis that contrac;ion of the ieriductal space induced by fibrosis causes the hepatic artery to become closely apposed to the catheter, and that the constant movement of the catheter as the patient breathes eventually results in erosion through the arterial wall. It is also conceivable that at the time of drainage, a needle or guide wire resulted in arterial injury, although again one would expect a more immediate onset of hemobilia. In addition, we have not seen this complication in any of our patients undergoing PBD who have not received HA1 chemotherapy. Because the sclerotic process may involve the intrahepatic ductal system, these patients are prone to develop intrahepatic bilomas as strictures extend into segmental and subsegmental ducts. As in the case of patients with primary sclerosing cholangitis, it may be very difficult to provide adequate drainage of all affected segments, and ongoing sepsis may become a problem. All of the patients with bilomas exhibited signs of sepsis at the time of biloma formation. The

presence of an infected biloma seems to be a poor prognostic indicator, as all but one of our nine patients with bilomas died within an average of 14 weeks of exhibiting biloma formation. All of these patients received mitomycin as part of their chemotherapeutic regimen, seven of nine (78%) received the high-dose regimen. The patient who lived the longest (111weeks) developed a single biloma that virtually replaced the lateral segment of the left lobe of the liver, caused by a focal stricture of one of the segment three ducts. After drainage of the biloma, it was possible to demonstrate a fistulous communication to the affected duct. This fistula was cannulated, and an internallexternal catheter was placed through this subsegmental duct, draining both the biloma and the liver. In summary, obstructive jaundice developed in 10.6% of patients receiving HA1 chemotherapy. The most common cause was CIBS. Patients with CIBS present a challenge to the interventional radiologist. They have high obstructions, require peripheral punctures to drain effectively, and yet may develop central pseudoaneurysms as a complication of drainage. When treated with mitomycin, they are also prone to develop infected intrahepatic bilomas, which is a poor prognostic indicator. References 1. Kemeny N. Review of regional therapy of liver metastases in colorectal cancer. Semin Oncol 1992;

19(suppl):155-162. Is hepatic infusion chemotherapy effective treatment for liver metastases? Yes. DeVita V, Hellman S, Rosenberg S (eds). Important advances in oncology. Philadelphia, PA: Lippincott, 1992; 207-229. 3. Kemeny N, Daly J, Oderman P, et al. Hepatic artery pump infusion: toxicity and results in patients with metastatic colorectal carcinoma. J Clin Oncol 1984; 2595-600. 4. Rougier P, Laplanche A, Huguier M, et al. Hepatic arterial infusion of Floxuridine in patients with liver metastases from colorectal carcinoma: long term results of a pro2. Kemeny N.

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spective randomized trial. J Clin Oncol 1992; 10:1112-1118. 5. Kemeny N, Cohen A, Seiter K, et al. Randomized trial of hepatic arterial Floxuridine, Mitomycin, and Carmustine versus Floxuridine alone in previously treated patients with liver metastases from colorectal cancer. J Clin Oncol 1993; 11: 330-335. 6. Jaffe BM, Donegan WL, Watson F, et al. Factors influencing survival in patients with untreated hepatic

metastases. Surg Gynecol Obstet 1968; 127:l-11.7 7. Botet JF, Watson RC, Kemeny N, e t al. Cholangitis complicating intraarterial chemotherapy in liver metastases. Radiology 1985; 156:335337. 8. Pien EH, Zeman RK, Benjamin SB, et al. Iatrogenic sclerosing cholangitis following hepatic arterial chemotherapy infusion. Radiology 1985; 156:329-330. 9. Northover JMA, Terblanche J . A

new look a t the arterial supply of the bile duct in man and its surgical implications. Br J Surg 1979; 66:379-384. 10. Pettavel J , Gardiol D, Bergier N, et al. Necrosis of main bile ducts caused by infusion of 5-fluoro-2deoxyuridine. Reg Cancer Treat 1988; 1:83-92. 11. Terblanche J , Allison HF, Northover JMA. An ischemic basis for biliary strictures. Surgery 1983; 94:52-57.