A new horizon in the prevention of the postembolization syndrome after transcatheter arterial chemoembolization for hepatocellular carcinoma
Authors: Fabio Piscaglia, Francesco Tovoli, Patrizia Pini, Veronica Salvatore
Journal: Hepatology (2017)

Potential conflict of interest: Fabio Piscaglia advises and is on the speakers' bureau for Bayer, advises Eisai, is on the speakers' bureau for Bracco, and has received grants from Esaote. See Article On Page 575 Endovascular embolizing treatments, represented mainly by transcatheter arterial chemoembolization (TACE), are widely used in the treatment of hepatocellular carcinoma (HCC). Almost half of patients undergo TACE at some point in their course of disease, making it the most commonly used therapy in HCC. Lencioni et al.1 conducted a systematic review evaluating the safety of lipiodol‐TACE (or conventional TACE). A total of 21,461 adverse events occurred in 15,351 patients who underwent at least 27,497 treatment sessions in the included 217 articles. Among them, almost half (47.7%) were related to postembolization syndrome (PES), a condition that includes noninfectious fever, nausea/vomiting, malaise and asthenia, pain, and enzyme elevation. PES is also observed after either TACE with drug‐eluting beads,2 with rates of 25%‐42% for grade 2 PES, or after radioembolization with Yttrium90, with a metanalysis showing an overall occurrence rate of 18%‐20%, regardless of whether glass or resin embolizing beads were used.3 Symptoms of PES (nausea, fever, and malaise/asthenia) are not specific to TACE, but rather represent a generalized event reported to occur after embolization of other abdominal organs, such as the spleen,4 kidney,5 uterus,6 which only differ in terms of location of the pain. PES is, in fact, reported to be caused by the release of inflammatory cytokines in the bloodstream.7 Strategies to reduce its occurrence are warranted, but no method has yet been established, and most occasional reports dealt more with the treatment after its occurrence, rather than systematic prevention. A small randomized trial testing the addition of local anesthetics to the embolizing mixture showed only the reduction of painkiller drugs in the next few days, but not a reduction in the occurrence of PES.7 Prophylactic use of nonsteroidal antinflammatory drugs has been adopted in some centers to prevent PES after uterine embolization,6 but clearly these drugs are contraindicated in patients who have cirrhosis and HCC. It seems, therefore, that PES is an unavoidable consequence of TACE that is to be tolerated for the major benefit of prolonged survival. However, PES is not only an inconvenience for patients—which occasionally discourages subsequent TACE courses due to the threat of recurrence—but it often prolongs hospital stays, causes diagnostic dilemmas in case of fever and pain leading to additional diagnostic testing, and is therefore a burden for physicians and administrators. Moreover, in a recent study,8 the occurrence of PES was associated with worse survival after TACE.8 Because this study was retrospective and was not designed with adequate stratification, the findings cannot be considered conclusive; nonetheless, this suggestion cannot be ignored given the potential detrimental effects of cytokines released during PES. Hence, a safe and effective prevention of PES occurrence after endovascular treatments for HCC would be of great benefit for the medical community, and most importantly for patients' quality of life. The prophylactic use of corticosteroids and 5‐HT3 receptor antagonists had been already demonstrated as efficacious in reducing nausea and vomiting in various chemotherapeutic regimens for other tumors and are therefore recommended by the American Society of Clinical Oncology in various situations. However, a well‐designed randomized, double‐blind, placebo‐controlled trial in HCC was still missing until the study published by Ogasawara et al. in this issue of Hepatology.9 In this multicenter Japanese study, dexamethasone treatment (20 mg on day 1, in addition to granisetron, in a single session immediately before TACE followed by 8 mg in a single morning session on days 2 and 3) was compared with a control regimen (placebo and granisetron on day 0, followed by placebo on days 2 and 3) in 120 patients undergoing superselective TACE for HCC (using lipiodol plus a chemotherapeutic agent, followed by gelatine sponge particles). The primary endpoint was the cumulative absence of fever, anorexia, and nausea/vomiting and no rescue therapy within 5 days after the procedure, defined as complete response. Interestingly, significantly more patients in the dexamethasone group achieved complete response both in the acute phase (0‐24 hours) and in the delayed phase (24‐120 hours) with respect to patients in the placebo group (approximately 55% versus 15%, respectively, in the delayed phase), with a very good safety profile. Furthermore, it is worth noting that subclinical adrenal insufficiency is a relatively common but often overlooked complication of liver cirrhosis, potentially affecting prognosis.10 In this setting, the supplementation of steroids may compensate the absence of sufficient adrenal response after a stress stimulus such as TACE. The exclusion criteria that added to the usual 3correct indications for TACE were not strict (reasonably, only patients with uncontrolled diabetes showing glycosilated hemoglobin >8.0% or with uncontrolled cardiovascular disease or with actively replicating and untreated hepatitis B virus DNA were excluded), so that the population represented the patients we usually see in our wards. The effects on the nutritional status were evaluated by determining the serum levels of prealbumin and retinol‐binding protein, which worsened in both groups from baseline to days 3 and 7 and later recovered by week 12, with a significantly greater decrease in the placebo group in the first week, indicating that the appetite of patients in the dexamethasone group was better maintained with no deleterious effects on protein metabolism. After such promising findings, a word of caution is necessary and clearly deals with the details of the safety profile. One of the main problems related to steroid use is hyperglycemia, which occurred in almost all (18 out of 19) patients with diabetes mellitus or impaired glucose tolerance in the dexamethasone group at grade ≥3 according to Common Terminology Criteria for Adverse Events version 4.0, namely glycemia between 250 and 500 mg/dL. This deals not only with the diabetic decompensation, but also with the known mitogenic and antiapoptotic effects of insulin growth factor 1, increasing the risk of a negative effect of corticosteroid treatment on tumor response to TACE. The treatment response has been evaluated by Ogasawa et al.9 as a secondary endpoint, avoiding any definitive conclusion about this issue; however, no differences emerged between the dexamethasone group and the control group in the radiological response according to either RECIST or mRECIST criteria at 4 and 12 weeks, but a larger sample size and longer follow‐up appear necessary. Among the other adverse events, a statistical difference between dexamethasone and control groups emerged only for abdominal pain (lower occurrence in the dexamethasone group, corresponding to a benefit for patients) and gamma‐glutamyltransferase increase and hiccup, both with a lower occurrence in the placebo group. A competitive binding of corticosteroids to steroid receptors of the hiccup reflex arc has been suggested, but a switch from dexamethasone to methylprednisolone (which has a different blood–brain barrier permeability) may limit this effect. Future trials are desirable to explore this hypothesis. Regarding the other specific adverse events that seem to be associated with dexamethasone, ascites, pleural effusion, and hypertension showed a trend (though not statistically significant) toward being more frequent in the dexamethasone group than in the placebo group, which is as expected based on the effects of steroids. Furthermore, one patient had a hepatic infection grade of ≥3 and another patient had a heart failure grade of ≥3 in the dexamethasone group, although there were no significant differences in grade ≥3 adverse events between the two treatment groups.9 However, these trends must be verified in larger studies and, most importantly, should be considered with caution from now on if multiple courses of TACE are needed, given that the severity of such events may become more important. Finally, it is worth noting that the benefits of steroids must not be viewed as a tool to avoid the delivery of superselective rather than large arterial bed embolization. In conclusion, PES is a relatively common event in clinical practice after TACE, and every attempt to prevent it must be welcomed from many points of view, particularly in patients who have cirrhosis and HCC. The study by Ogasawara et al.9 is a solid first step, showing the potential benefit of a short course of steroids together with granisetron to prevent PES occurrence after TACE. However, caution must be taken before such a strategy is definitively endorsed (particularly when several courses of TACE are expected) and until certain safety concerns and longer‐term antitumor effects are clarified in larger case series. Furthermore, the extent to which the size of the treated tumors, their location, the degree of liver dysfunction, the possibility of superselective versus selective or nonselective embolization, or other factors influence the rate of incidence and the severity of PES deserve focused investigation, because it will be important to establish whether all or only some patients require prophylaxis for PES.