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The liver is a common site of metastasis from a variety of primary cancers. The liver is unique in that aggressive removal of certain hepatic metastases can confer an overall survival benefit. As such, various liver-directed therapies have been developed in the treatment of hepatic metastases from colorectal cancer and low-grade neuroendocrine tumors, as well as in the control of primary hepatocellular carcinoma in cases where surgery is not feasible. Some of these methods include radiofrequency ablation, cryoablation, and transarterial embolization (TAE) or transarterial chemoembolization (TACE). These therapies have the advantage of being minimally invasive and generally well tolerated, though responses are often not durable, and they must be used judiciously.
In this report, we describe a patient with metastatic carcinoid tumor who underwent TACE after a Whipple procedure. The therapy in this setting led to the complication of a series of liver abscesses requiring long-term drainage and long-term antibiotics associated with significant morbidity. We performed a review of the literature on hepatic abscesses in TACE and found a paucity of data surrounding rates and prevention of liver abscesses following this procedure. However, we did find strong observational evidence to preclude TACE in patients with unsterile biliary systems secondary to prior bilioenteric anastomosis. We concluded that TACE should not be offered to patients with prior bilioenteric anastomosis except in rare circumstances, wherein aggressive prophylaxis should be considered.
A 39-year-old woman with low-grade neuroendocrine tumor meta-static to the liver was admitted to the hospital of a comprehensive cancer center 2 weeks after undergoing TACE. She had been diagnosed with a well-differentiated pancreatic head neuroendocrine carcinoma and was treated at that time with pancreaticoduodenectomy with reanastomosis of the common bile duct (Whipple’s procedure) and cholecystectomy. Surgical margins were positive, and the patient underwent postoperative radiation therapy to the tumor bed. She did not develop overt carcinoid syndrome, but did develop postoperative diabetes mellitus. A few months thereafter, she was found to have an isolated metastatic lesion in the right lobe of the liver, which was treated with intraoperative radiofrequency ablation followed by radiation treatment to the initial tumor bed with long-term remission achieved. Four years later, however, the patient was found to have two hepatic metastases to the right lobe of the liver on a follow-up computed tomography (CT) scan (Figure 1). The decision was then made to perform TACE for treatment of these lesions.
At the time of TACE, she received 5 days of periprocedure antibiotics with levofloxacin and metronidazole. Chemoembolization was performed in the right lobe using localized cisplatin, doxorubicin, and mitomycin-C, 10 mL of ethiodized oil contrast, and 0.5 mL of Contour® PVA (polyvinyl alcohol) Embolization Particles (Boston Scientific, Natick, MA) selectively into the right hepatic artery.
Two weeks after her procedure she developed high fevers, intractable nausea, vomiting, and right upper quadrant abdominal pain. CT scan revealed two large areas of low attenuation with gas present (Figure 2). CT-guided drain placement into the inferior hepatic lesion was achieved (Figure 3), but no fluid was removable from the superior lesion, and this lesion was thus deemed by the radiologists to represent infarcted noninfected tissue. However, fluid from the drain and biopsy of the inferior lesion grew Klebsiella and Enterococcus species and she was started on vancomycin and ceftazidime.
After only a few days, output from the drain became sluggish. The patient’s nausea and abdominal pain did not resolve, and she was started on total parenteral nutrition (TPN). Soon thereafter, the patient redeveloped leukocytosis, transaminitis, and a rise in alkaline phosphatase. Blood cultures grew Klebsiella and Candida kephyr. She was treated with broad spectrum antibiotics and antifungals for 2 weeks. However, on stopping the antibiotics, clinical sepsis returned with worsening of pain and intractable nausea.
Ultimately, open surgical drainage of the abscess was necessary. Three months after the initial procedure, she continued to have active abscesses (Figure 4). In the 6 months following the initial chemoembolization procedure, the patient was hospitalized for biliary sepsis four times and hepatic drains remained in place. Ultimately, she required right hepatic lobectomy (Figure 5). One year after the procedure, the patient was finally taken off antibiotics and is currently free of any clinical or radiographic signs of infection or tumor recurrence.
Hepatic transarterial chemoembolization is often used as a minimally invasive method to treat hepatic malignancies or metastases. Liver tumors are primarily nourished by the hepatic artery, while normal liver parenchyma receives most nourishment from the portal system.1,2 Intra-arterial infusion, thus, selectively delivers a high concentration of chemotherapy directly to the tumor (Figure 6). Combined with embolization, selective ischemia is produced.1
Two randomized controlled trials in the past decade have shown improvements in overall survival when TACE was used in hepatocellular carcinoma compared to best supportive care. 3,4 In neuroendocrine tumors, TACE has been shown to decrease hormonal symptoms and reduce tumor size.5 Though objective evidence on survival advantage is lacking in these patients, various studies have found survival advantages when compared with historical controls.5–9 While earlier studies generally found overall survival from time of TACE of 24 months,6,8 a more recent study with more stringent selection criteria achieved an overall survival of 3.5 years in patients with unresectable neuroendocrine tumors. 5
Selection criteria remain poorly defined. Generally, the procedure is reserved for patients who are not surgical candidates due to either multiple lesions or inadequate liver reserve.10 The therapeutic effects of embolization appear greatest in small hypervascular lesions, such as occur in hepatocellular carcinoma or neuroendocrine tumors.10,11 Factors such as large tumor size, large amount of liver replaced by tumor, high serum alpha-fetoprotein, severe underlying liver disease, poor health status, and poor response to treatment have in various studies been found to negatively predict survival following TACE.12,13 However, some experts maintain that since these predictors have not been validated in a randomized controlled trial, they should not be used as absolute contraindications for the procedure, but rather as relative contraindications only.2
Side effects of the procedure are well described. A common short-term side effect is the postembolization syndrome which includes fever, nausea/vomiting, and abdominal pain. This is usually short-lived and self-limited and represents necrosis.14 It is neither a predictor of tumor response nor of incipient infection.14,15 Commonly, ultrasound or CT scan performed soon after TACE will reveal small amounts of intrahepatic gas. This too signifies necrosis and not infection. 10 Other potential adverse events include deposition of chemoembolization material outside of the intended site into surrounding organs including lungs, stomach, gallbladder, pancreas, and spleen.10,12 While this often causes only mild symptoms, gallbladder or splenic infarction has been known to occur as a result.10 Severe side effects are usually due to ischemic damage to normal hepatic parenchyma leading to liver failure, but this complication can largely be avoided with proper patient selection.12 Liver abscess and resulting sepsis may also occur.10
The risk of liver abscess after TACE appears related to the extent of liver infarction. While some amount of infarction in the necrotic affected area is probably inevitable, abscess formation is rare.10 When abscess occurs, it is due to colonization of necrotic tumor from either enteric organisms or from bacteria introduced exogenously during the procedure.16,17 Up to 60% of organisms are Gram-positive.16
Different case series have shown different rates and risks of hepatic abscess. In a review of case series involving TACE, Marelli et al found that liver abscesses were only documented in 11 series, involving 1,451 patients. They occurred in a median of 1.3% of patients (range 0%–2.5%).12 Song et al reviewed charts of 2,459 Korean patients who received TACE for hepatic tumors and found only a 0.2% incidence of liver abscess.18 In a retrospective analysis of 397 procedures in 157 patients in the University of Pennsylvania’s health system, Kim et al found that liver abscess occurred seven times, in 2% of procedures, and 4.5% of patients.19
Though the risks of developing hepatic abscess are low in general, certain features appear to predispose patients to abscess development. Song et al found that of the 114 TACE procedures in their study performed for metastatic tumors (rather than for primary hepatocellular carcinoma), liver abscess developed in 3 (2.6%), which was higher than their overall rate of 0.2%. The authors likewise found that of 18 procedures performed for malignant gastrointestinal mucosal lesions, 2 liver abscesses developed (11.1%).18 Kim et al found that 2 of 24 patients in their study who received TACE for neuroendocrine tumors developed liver abscess (12.5%, odds ratio [OR] 4.6, 95% confidence interval [CI] 0.96–22.1).19
In the University of Pennsylvania case series, of the seven patients who developed liver abscess following TACE, all but one (86%) had previously had a bilioenteric anastomosis (Whipple procedure), usually for a primary pancreatic neuroendocrine tumor. Additionally, all but one patient who had previously had a Whipple procedure went on to develop an abscess (86%). Of those patients who had not had a Whipple procedure, only 1 of 150 patients developed abscess (0.7%), a rate closer to that found by Song et al. The OR of developing abscess after Whipple was calculated by the authors in their study at 894 (95% CI 50–16,000), and the authors concluded that previous Whipple procedure is the major determinant of hepatic abscess formation after TACE.19 This high rate of liver abscess related to TACE after biliary reconstructive surgery has been seen in other studies.20 In patients who have undergone biliary reconstruction there is no effective boundary between the biliary tree and the intestine. This leads to decreased sterility of the biliary system and is hypothesized to account for the increase in risk of hepatic abscess after an ischemic insult such as TACE.19,20
The issue of periprocedure antibiotics remains unresolved for TACE. Many studies on TACE have included prophylactic antibiotics. Generally, various broad-spectrum agents are used starting a few hours before the procedure and continuing for 3–7 days. 12 One recent study comparing 15 patients who received antibiotic prophylaxis with ciprofloxacin and metronidazole to 15 patients who received no prophylactic antibiotics showed no differences in hospital stay or side effects. However, the authors note that they did not evaluate any patients with prior biliary reconstruction, and they recommend antibiotic prophylaxis in these patients.21 In the University of Pennsylvania series, all patients received antibiotic prophylaxis, yet patients who had previously undergone Whipple procedures still developed a high rate of subsequent liver abscess.19
Aggressiveness of prophylaxis may contribute to abscess risk following Whipple and TACE. One small study evaluated four patients with prior biliary reconstruction who received prophylactic intravenous cephalexin, and compared them to four patients with prior biliary reconstruction who received prophylactic bowel preparation and piperacillin/tazobactam. All four patients who received cephalexin developed liver abscess, but none of the patients who received piperacillin/tazobactam and bowel preparation developed abscess.20
Clinical presentation is similar to the postembolization syndrome with fever, nausea and vomiting, and abdominal pain. CT scan may show gas in the infarcted tissue. High suspicion is warranted if these symptoms appear or persist after the first 5 days post procedure. Mortality from these abscesses is relatively low.18,19 However, long-term antibiotics and long-term percutaneous catheter drainage are universally required, usually for longer than 1 month.18–20 In our patient, percutaneous drainage did not adequately control the infection, and surgical drainage ultimately followed by hepatic lobectomy was required.
Transarterial chemoembolization is generally a safe and effective procedure for control of primary hepatocellular carcinoma, metastatic colorectal cancer, and low-grade metastatic neuroendocrine tumors to the liver in patients who cannot undergo surgical resection. The patients should be chosen carefully. Liver abscess, while otherwise rare in most patients, is the rule rather than the exception in patients who have an unsterile biliary system due to prior biliary reconstruction, even with prophylactic antibiotics. In these patients, TACE should be avoided, but if it must be performed, very broad-spectrum prophylactic antibiotics and bowel preparation before the procedure should be considered.15
The authors indicated no potential conflicts of interest.