Author Affiliations: Division of Hepatobiliary & Pancreatic Surgery and Liver Transplantation, Department of Surgery, The University of Hong Kong, Hong Kong, China (She WH, Chan ACY, Cheung TT, Chok KSH, Chan SC, Poon RTP and Lo CM)

Corresponding Author: Albert CY Chan, MD, Division of Hepatobiliary & Pancreatic Surgery and Liver Transplantation, Department of Surgery, The University of Hong Kong, 102 Pokfulam Road, Hong Kong, China (Tel: +852-22553025; Fax: +852-28165284; Email: acchan@hku.hk)

 

© 2016, Hepatobiliary Pancreat Dis Int. All rights reserved.

doi: 10.1016/S1499-3872(15)60034-0

Published online November 9, 2015.

 

 

Contributors: PRTP proposed the study. SWH and CACY performed the research, analyzed the data and wrote the first draft. All authors contributed to the design and interpretation of the study and to further drafts. CSC, PRTP and LCM are the guarantors.

Funding: None.

Ethical approval: This study was approved by the Ethics Committee of The University of Hong Kong.

Competing interest: No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.

 

 

BACKGROUND: Acute pancreatitis is a relatively rare but potentially lethal complication after transarterial chemotherapy. This study aimed to review the complications such as acute pancreatitis after transarterial chemotherapy with or without embolization for hepatocellular carcinoma.

 

METHODS: A total of 1632 patients with hepatocellular carcinoma who had undergone transarterial chemoembolization from January 2000 to February 2014 in a single-center were reviewed retrospectively. We investigated the potential complications of transarterial chemoembolization, such as acute pancreatitis and acute pancreatitis-related complications.

 

RESULTS: Of the 1632 patients with hepatocellular carcinoma who had undergone 5434 transarterial chemoembolizations, 1328 were male and 304 female. The median age of these patients was 61 years. Most (79.6%) of the patients suffered from HBV-related hepatocellular carcinoma. The median tumor size was 5.2 cm. Of the 1632 patients, 145 patients underwent transarterial chemoembolization with doxorubicin eluting bead, making up a total of 538 episodes. The remaining patients underwent transarterial chemoembolization with cisplatin. Seven (0.4%) patients suffered from acute pancreatitis post-chemoembolization. Six patients had chemoembolization with doxorubicin and one had chemoembolization with cisplatin. Patients who received doxorubicin eluting bead had a higher risk of acute pancreatitis [6/145 (4.1%) vs 1/1487 (0.1%), P<0.0001]. Two patients had anatomical arterial variations. Four patients developed acute pancreatitis-related complications including necrotizing pancreatitis (n=3) and pseudocyst formation (n=1). All of the 4 patients resolved after the use of antibiotics and other conservative treatment. Three patients had further transarterial chemoembolization without any complication.

 

CONCLUSIONS: Acute pancreatitis after transarterial chemoembolization could result in serious complications, especially after treatment with doxorubicin eluting bead. Continuation of current treatment with transarterial chemoembolization after acute pancreatitis is feasible providing the initial attack is completely resolved.

 

KEY WORDS: transarterial chemoembolization; acute pancreatitis; hepatocellular carcinoma

 

Transarterial chemotherapy with or without embolization (TACE) is commonly used in the treatment of primary hepatocellular carcinoma (HCC) or secondary liver cancers.^[1-9] It is also used in neo-adjuvant or adjuvant setting in liver resection, or before liver transplantation to serve as a bridging therapy. It exploits the predominant hepatic artery blood supply of liver tumors to deliver a high dose of cytotoxic agents.^{[10, 11]}

 

Acute pancreatitis (AP) is a rare but certainly well-known complication after TACE, which usually develops within 24 hours of the procedure. It occurs in around 1.7%-2% of all patients after selective and superselective liver embolization.^[12] The potential morbidity and mortality of this iatrogenic AP cannot be overlooked especially in patients who suffer from underlying malignancy. The aim of this study was to review our experience in the management of patients who suffered from AP post-TACE.

 

 

All patients with HCC who had undergone TACE during the period of January 2000 to February 2014 were reviewed retrospectively. The clinical, biochemical and pathological data of the patients were collected from our database.

 

The diagnostic criteria for HCC in our center were as follows: 1) typical image abnormality with arterial enhancement and contrast washout in the portal venous phase in contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI) or combined modalities; and/or 2) elevated serum AFP level >400 ng/mL. Needle biopsy was generally avoided in resectable or transplantable cases so as to avoid the risk of needle tract seeding of tumor cells. In resectable or transplantable cases, the diagnosis of HCC was confirmed histologically.^[13]

 

The inclusion criteria for TACE for patients with HCC were as follows: unresectable HCC due to bilobar involvement or inadequate future liver remnant despite portal vein embolization, adjuvant therapy for unfavorable tumor pathology, high perioperative risk for surgery, recurrent HCC, and patient’s preference. These patients might have undergone one or more episodes of TACE. For those patients who were diagnosed to have main portal vein thrombosis, ascites, poor liver function (Child’s C cirrhosis, serum bilirubin level >50 µmol/L), poor renal function (serum creatinine >150 µmol/L), significant arterioportal venous shunting would be contraindicated for TACE.

 

Patients with incomplete laboratory tests before and after TACE, as well as those who suffered from chronic pancreatitis and recurrent pancreatitis unrelated to TACE were excluded.

 

Diagnosis of AP was made according to the latest Atlanta classification 2012. It included two of the following three features: abdominal pain suggestive strongly of AP, serum amylase and/or lipase activity at least 3 times greater than the upper limit of normal and the characteristic findings of AP on transabdominal ultrasonography or on CT scan.^[14]

 

Post-TACE AP is defined as the onset of AP within 24 hours after TACE and the exclusion of other possible etiologies, such as alcoholism, gallstone disease, hyperlipidemia or hypercalcemia.

 

Patients were fasted at six hours before TACE and adequate hydration was ensured by intravenous fluid. Blood tests including complete blood picture, liver and renal function test, amylase, clotting profile and AFP were taken for pre-procedural assessment. One dose of intravenous amoxicillin-clavulanic acid (1.2 mg) and pantoprazole (40 mg) were given at the time of transferal to the procedure. Vascular access was established via puncture of the femoral artery under local anesthesia. Hepatic and superior mesenteric angiographies were performed to define the size and locations of tumor nodules. The right or left hepatic artery feeding the tumor was superselectively catheterized. An emulsion was prepared by mixing cisplatin (1 mg/mL) with lipiodol in a volume ratio of 1 to 1. Various amounts of the emulsion, up to a maximum of 60 mL (containing 30 mg of cisplatin) were injected slowly under fluoroscopic monitoring according to the size of the tumor and until sluggish arterial flow was evident. For doxorubicin eluting bead (DEB), the usual dosage was 40-60 mg/m² with a maximum dosage of 150 mg for a single session. If the tumor involved both lobes of the liver or if superselective catheterization was not possible, the emulsion was injected into the proper hepatic artery distal to the origin of the gastroduodenal artery. This was followed by embolization with small gelatin-sponge (Spongostan; Ferrosan, Johnson & Johnson Medical Ltd., Skipton, England) pellets of 1 mm diameter mixed with 40 mg of gentamicin. After the procedure, oral amoxicillin-clavulanic acid (375 mg 3 times per day) and pantoprazole (40 mg per day) were administered for 3 days. Discharge from the hospital was decided according to the clinical state. Chemoembolization was repeated every 2 to 3 months and would be withheld or discontinued whenever vascular contraindications, poor liver function (bilirubin >50 µmol/L, presence of ascites), poor renal function (serum creatinine >150 µmol/L), severe adverse effects, or progressive disease developed.

 

Vascular anatomical variant of the celiac trunk was identified if there was presence of the replaced or accessory hepatic artery, common hepatic artery arising from the superior mesenteric artery or an early bifurcation of the celiac trunk.

 

Patients were fasted for at least four hours after the procedure and diet was resumed when tolerated. Abdominal, groin and peripheral vascular examinations were carried out to look for potential complications. Complete blood count, liver and renal function test, amylase and clotting profile were checked. One would be observed overnight for clinical symptoms and blood result, and discharged on the following day. All the patients would receive CT or MRI scan in 2 months’ time after the initial intervention to assess the treatment effect. Further treatment plan would depend on the subsequent clinical and radiological findings.

 

All the results were expressed in median. Simple statistics was used to count the total number of TACE and the number of TACE per patient. Yates’ correction for continuity was used to calculate the incidence of AP in both groups of TACE using cisplatin and DEB. For the statistical tests used among those patients suffered from AP, discrete variables were compared by Fisher’s exact test or Yate’s correction for continuity whenever appropriate and continuous variables were compared by the Mann-Whitney U test in view of small sample size.The Kruskal-Wallis test was employed for comparison of three or more groups.

 

 

During the period of January 2000 to February 2014, there were a total number of 1632 patients undergoing 5434 TACEs, of whom 1328 were male and 304 were female. The median age of the patients was 61 years (Table 1). Of these patients 91.1% underwent TACE with cisplatin, but 8.9% underwent TACE with DEB. Most (79.6%) of the patients suffered from HBV-related HCC. The median size of HCC was 5.2 cm. Complications resulted from TACE are listed in Table 2.

 

There were a total of seven patients who suffered from post-TACE AP that accounted for 0.4% of all the TACE procedures. In these patients, amylase was elevated three times the upper limit within 24 hours after TACE. Only one patient had AP after his first episode for TACE; whereas the remaining six patients had more than one episode of TACE previously. Six patients had TACE with DEB and one had conventional TACE with cisplatin. These 7 patients had a similar baseline characteristic. Those who used DEB as the chemotherapeutic agent had a higher risk of acute pancreatitis [6/145 (4.1%) vs 1/1487 (0.1%), P<0.0001]. Two patients had celiac trunk vascular variation. There was no technical difficulty encountered during the procedures. Four patients suffered from severe pancreatitis leading to necrotizing pancreatitis (n=3) and pseudocyst formation (n=1). All of them resolved with antibiotics and conservative management. One patient had gallstone and underwent endoscopic retrograde cholangiopancreatography (ERCP) to exclude biliary cause, whereas other causes of AP such as alcoholic consumption, hypercalcemia, hypertriglyceridemia were eliminated. Apart from those who suffered from severe pancreatitis, the other three patients had further TACE without any complication (Table 3).

 

 

Biliary, alcohol and ERCP are the three commonest causes of AP. The incidence and mortality of AP vary in different regions and are influenced by the prevalence of biliary disease and alcoholism. The incidence may range from 24.2 per 100 000 in England^[15] to 90 per 100 000 in the United States.^[16] A previous study showed an incidence of post-TACE AP in the range of 1.7%-2% after selective and superselective liver embolization.^[12] However, our study showed that the incidence of AP could be lower with experience of applying TACE for HCC.

 

The clinical presentation of post-TACE AP may mimic post-TACE syndrome which occurs up to 90% of patients after the procedure.^[17] Post-TACE syndrome is postulated to be resulted from a combination of inflammatory response to chemoembolization and tissue ischemia. Symptoms include nausea, right upper quadrant or abdominal pain, and fever, raise the level of liver enzymes without evidence of sepsis and it is a self-limiting condition.^{[17, 18]} The diagnosis of AP followed the modified Atlanta consensus.^[14] This required high index of clinical suspicion, regular blood test and even CT scan of the abdomen in order to confirm the diagnosis. Before this is solely attributed to the TACE induced AP, one should rule out biliary in etiology, as this is readily treatable with ERCP.^[19] In addition to AP, rare but important side effects after TACE such as peptic ulcer disease, cholecystitis, dissection of the artery should also be excluded.

 

Various mechanisms have been proposed to cause post-TACE AP, such as ischemic changes of intra- and extra-pancreatic arteries,^{[20, 21]} drug reflux from the hepatic artery or due to a malposition of the infusion catheter,^[22-24] embolization particles and vascular anomalies e.g. intrahepatic arterioportal fistulas.^[20] The time of the AP could also tell the etiology, i.e. within 24 hours would be ischemia due to the embospheres or several days later due to the effect of chemotherapy.^[25]

 

Doxorubicin has been used as an alternative chemotherapeutic agent in TACE for the treatment of HCC. It has been proven to be safe and effective in the management of HCC as compared with the conventional TACE with cisplatin.^[26-28] Doxorubicin tends to induce more tumor necrosis especially in larger and encapsulated HCC.^[29] The more tumoricidal and irritating effect of doxorubicin, together with the drug eluting beads, may account for a more complete blockage of the gastroduodenal artery, hence higher chance of getting AP post-TACE.

 

Our study illustrated the use of conservative management in our patients who suffered from post-TACE AP. Even those suffered from severe AP, they could still be managed conservatively without subsequent operation. Management of post-TACE AP is similar to the usual management of AP caused by other etiologies. However, rapid clinical deterioration could be expected in patients with immunocompromised state given the underlying malignancy and liver cirrhosis. It remains unclear if patients with severe form of post-TACE AP are more susceptible to develop serious pancreatic complications when compared with severe AP due to other etiologies. A liberal use of CT for interval reassessment is therefore justified once clinical deterioration is developed. From our experience, a course of conservative treatment with parenteral nutrition and antibiotics is usually effective for post-TACE AP. Nonetheless, vascular anatomical variation may be considered a relative contraindication for TACE^[20] if superselective cannulation of the tumor feeding vessels could not be achieved.^[30] Furthermore, continuation of the cancer treatment with TACE is possible once the initial AP attack is completely resolved. This is particularly important for patients with unresectable and non-transplantable HCC as TACE often remains the only choice of effective treatment for their diseases.^[19]

 

In conclusion, post-TACE AP could result in serious complications, especially after treatment with DEB. Continuation of current treatment with TACE after AP is feasible providing the initial attack is completely resolved.

 

 

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