Dexamethasone and N-acetylcysteine before transarterial chemoembolization in hepatocellular carcinoma: A Western perspective

Abstract

Post-embolization syndrome (PES) is the most common complication in patients with hepatocellular carcinoma treated with transarterial chemoembolization. Many strategies have been evaluated to reduce the incidence of PES, but no standard prevention guidelines currently exist. In a single-center, placebo-controlled trial, Simasingha et al evaluated the prophylactic administration of a combination of dexamethasone and N-acetylcysteine and documented a significant reduction in the incidence of PES (from 80% to 6%), of post-procedural liver decompensation (from 14% to 0%), and a shorter hospital stay (4 days vs 6 days), alongside an acceptable safety profile. The results of this study raise several controversial points regarding their applicability in the Western world. In the West, there is a greater and increasing prevalence of metabolic and alcoholic etiologies of liver cirrhosis, so a not negligible number of patients with type II diabetes or hypertension would be excluded from high-dosage dexamethasone prophylaxis. Furthermore, in the West, there is a preferred use of drug-eluting beads loaded with doxorubicin, which are associated with a lower incidence of PES. A study on prophylaxis with dexamethasone and/or N-acetylcysteine in a Western population is hopefully awaited.

Key Words: Chemotherapeutic drugs, Lipiodol, Post-embolization syndrome, Prevention, Prophylaxis

Core Tip: Post-embolization syndrome is the most common complication of transarterial chemoembolization, which represents the most widespread treatment of hepatocellular carcinoma. In a single-center, placebo-controlled trial, Simasingha et al documented the efficacy and safety of the prophylactic administration of dexamethasone and N-Acetylcysteine in the prevention of post-embolization syndrome in these patients. The applicability of this prophylaxis in the Western world presents some concerns. In the West, there are important differences in the disease etiology, the drug used, and the use of microspheres, compared to the Eastern scenario. Furthermore, the use of dexamethasone presents risks that must be carefully evaluated in this population.

INTRODUCTION

Hepatocellular carcinoma (HCC) is the sixth most common cancer and the third leading cause of cancer-related deaths worldwide[1]. Transarterial chemoembolization (TACE) consists of hepatic angiography with intra-tumoral selective delivery of chemotherapeutic agents and embolization of the artery feeding the tumor. Conventional TACE (cTACE) is performed using a combination of ethiodized oil, an embolizing agent, and a chemotherapeutic drug. In contrast, TACE with drug-eluting beads (DEB-TACE) uses microspheres with the dual function of embolizing agent and carrier for the anticancer drug. According to an international, multi-regional study, TACE is the most widely employed treatment approach in patients with intermediate-stage HCC and the second most used therapy in patients in the early stage[2]. TACE is poorly affected by the degree of liver function, portal hypertension, or the location of the lesion in patients with compensated or slightly decompensated liver disease; this partially explains its greater applicability in clinical practice compared to resective or ablative treatments[3]. Furthermore, TACE has relatively few contraindications and is easily reproducible, even in patients with multiple comorbidities.

POST-EMBOLIZATION SYNDROME

The most common adverse event associated with TACE is post-embolization syndrome (PES), with poorly understood pathogenesis mechanisms, including ischemic-hypoxic injury, systemic release of inflammatory mediators (such as interleukin-6), and direct toxic effects of chemotherapeutic agents[4]. PES symptoms usually occur 24–72 h after the procedure and include non-infectious fever, abdominal pain, and, according to some definitions, anorexia, nausea, and vomiting in the context of liver enzyme elevation. The reported incidence of PES varies widely, with a range of 36%-80% in clinical studies, which can be attributed to unavoidable biases arising from the heterogeneity of the patients and treatment protocols, different definitions of PES, and inadequate follow-up. Although PES is transitory and self-limiting, it significantly impacts patient comfort, may require additional diagnostic testing, can prolong hospital stays, and may impact compliance with subsequent treatments[5,6]. Many strategies have been evaluated to reduce the incidence of PES, including dexamethasone (DEXA) and N-acetylcysteine (NAC); however, no standard prevention guidelines currently exist for PES.

DEXAMETHASONE BEFORE TRANSARTERIAL CHEMOEMBOLIZATION

Four randomized controlled single-center trials evaluated the efficacy of DEXA in preventing PES in patients with HCC who underwent TACE. In a Chinese study, Yinglu et al[7] showed that oral DEXA (cumulative dose 27 mg) reduced the incidence of fever, nausea/vomiting, and abdominal pain in patients treated with cTACE (5-fluorouracil, epirubicin, and hydroxy-camptothecin as chemotherapeutic agents). In a Korean study of 88 patients, Yang et al[8] showed a lower incidence of PES and a shorter hospital stay in patients receiving an intravenous single dose of DEXA 12 mg before cTACE with doxorubicin. In a Japanese study of 120 patients treated with cTACE (miriplatin), intravenous DEXA (cumulative dose 36 mg) reduced the incidence of fever, anorexia, and nausea/vomiting within 5 days from the procedure[9]; this was the only double-blind study conducted in this setting. Finally, in a study performed in Thailand including 100 patients, Sainamthip et al[10] showed a lower incidence of fever in patients who received an intravenous single dose of DEXA 8 mg before cTACE with doxorubicin or mitomycin-c. However, the use of DEXA in patients with cirrhosis has raised some concerns[11]. Patients with actively replicating hepatitis B virus infection were excluded from trials, as well as patients with uncontrolled diabetes. However, most patients with controlled diabetes or impaired glucose tolerance who received DEXA exhibited hyperglycemia during the follow-up period; a higher incidence of hypertension, ascites, and pleural effusion was also recorded in a previously cited study by Ogasawara et al[9]. Another issue is the risk of corticosteroid treatment-associated negative effect on tumor response to TACE[11]. For these reasons, pre-TACE prophylaxis with DEXA is rarely used in clinical practice. According to a recent Korean survey, only 18% of hepatologists considered the use of prophylactic steroids. Regarding their reluctance to use preemptive steroids, 56.3% of the respondents worried about steroids-related adverse events[3].

N-ACETYLCYSTEINE BEFORE TRANSARTERIAL CHEMOEMBOLIZATION

NAC, a glutathione precursor with antioxidant activity, is used in the treatment protocol for acetaminophen and non-acetaminophen-related acute liver failure[12]. Similarly, it has been tested for severe alcoholic hepatitis[13]. Since NAC proved effective in improving ischemic liver injury in animal models, Siramolpiwat et al[14], in a randomized controlled single-center study involving 111 patients with HCC treated with cTACE, evaluated the efficacy of NAC administered the day before and for 2 days after the procedure in preventing PES. The study showed a lower incidence of PES, but not of post-TACE liver decompensation, in the NAC group compared to the placebo group. Few mild allergic skin reactions were reported in the NAC group.

DEXAMETHASONE AND N-ACETYLCYSTEINE BEFORE TRANSARTERIAL CHEMOEMBOLIZATION

Simasingha et al[15] evaluated the efficacy and safety of prophylactic DEXA and NAC in preventing PES. In their single-center, single-blind, and placebo-controlled trial, they enrolled 100 cirrhotic patients with HCC stratified by Child class A or B treated with cTACE (mitomycin). The patients were randomized to receive intravenous DEXA (cumulative dose 36 mg) and continuous infusion of N-Acetylcysteine starting 24 hours before cTACE and continuing up to 48 hours post-procedure. The placebo group received a continuous 5% glucose infusion. Unfortunately, the study did not include a single DEXA or NAC control group; thus, the synergistic effectiveness of the two drugs could not be demonstrated. The incidence of PES, defined as the presence of fever, nausea, vomiting, and/or abdominal pain within 48 hours post-procedure with a calculated sum score of more than two points according to the South West Oncology Group toxicity code[16], was 80% in the placebo group and 6% in the DEXA and NAC group. The secondary outcome was the development of post-TACE liver decompensation, defined as an increase in Child-Pugh score of more than two points or newly developed decompensating events, such as ascites, hepatic encephalopathy, or serum total bilirubin > 2 mg/dL. The authors observed a significant reduction in post-TACE liver decompensation (from 14% to 0%) in the DEXA and NAC group, associated with a shorter hospital stay (4 days vs 6 days). Concerning safety, only minor allergic skin reactions and hyperglycemia were reported, but no secondary bacterial infection. However, patients with poorly controlled diabetes mellitus or uncontrolled hypertension were excluded from the study, and details on antiviral treatment in patients with chronic hepatitis B were not provided.

DISCUSSION

The results of this study, and those of other studies that have tested pre-TACE prophylaxis using DEXA or NAC, all performed in Eastern countries (Table 1), raise some controversial points regarding their applicability in the Western world. In the West, a greater and increasing prevalence of metabolic and alcoholic etiologies of liver cirrhosis exists compared to viral etiologies. Consequently, a substantial number of patients might be excluded from pre-TACE prophylactic protocols, including high-dosage DEXA, due to type II diabetes or hypertension. Furthermore, in Western countries, a lower number of TACE procedures per patient is usually performed, doxorubicin is preferred as the chemotherapy drug (less emetogenic than platinum derivates), and, above all, DEB-TACE is more frequently applied than cTACE. Indeed, prospective studies have shown a significantly lower incidence of PES in patients treated with DEB-TACE compared to those who underwent cTACE[17,18]. Therefore, the incidence of PES in a hypothetical placebo arm of a Western study on pre-TACE prophylaxis is likely to be significantly lower than the 48%-97% reported in the placebo arms of six randomized controlled Eastern studies (7-10,14,15). In the systematic review by Lencioni et al[19], which included 217 studies and 15351 patients with HCC treated with cTACE in both Eastern and Western countries, the overall incidence of PES was 47.7%. Finally, as previously mentioned, the use of DEXA in patients with HCC undergoing TACE presents some concern as DEXA could dampen the inflammatory-mediated tumor response; moreover, DEXA-related hyperglycemia could be associated with an increased level of insulin growth factor 1, which shows a mitogenic and antiapoptotic effect, negatively affecting the tumor response to TACE[11,20]. This issue requires further research with longer follow-up.

Table 1 Randomized trials evaluating dexamethasone and/or N-Acetylcysteine in the prevention of post-embolization syndrome in patients with hepatocellular carcinoma.

Country	Number of patients	Chemoterapy drug employed	Prophylactic strategy	PES incidence in the active arm, %	PES incidence in the placebo arm, %	Follow-up duration (days)	Ref.
China	60	5-fluorouracil, epirubicin, and hydroxy-camptothecin	DEXA 27 mg (oral)	20-40	70-80	7	[7]
Korea	88	Doxorubicin	DEXA 12 mg (i.v.)	78	97.5	2	[8]
Japan	120	Miriplatin	DEXA 36 mg (i.v.)	52.5	89.8	5	[9]
Thailand	100	Doxorubicin or mitomycin-c	DEXA 8 mg (i.v.)	36.7	70.6	2	[10]
Thailand	111	5-fluorouracil and mitomycin	NAC (i.v.)	24.6	48.2	2	[14]
Thailand	100	mitomycin	DEXA 36 mg (i.v.) plus NAC (i.v.)	6	80	2	[15]

DEXA: Dexamethasone; NAC: N-Acetylcysteine; PES: Post-embolization syndrome; i.v.: Intravenous.

CONCLUSION

For these reasons, we think that the results of the study by Simasingha et al[15] cannot be immediately transferred to Western patients with HCC treated with cTACE. A study on pre-TACE prophylaxis with DEXA and/or NAC in a Western population treated with superselective DEB-TACE is hopefully awaited.