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Management of Postembolization Syndrome Following Hepatic Transarterial Chemoembolization for Primary or Metastatic Liver Cancer

Blackburn, Helen MN, RN; West, Sandra PhD, BSc, RN, RM

doi: 10.1097/NCC.0000000000000302
ARTICLES: ONLINE ONLY
Free

Background: Transarterial chemoembolization (TACE) is an established treatment in managing liver primary neoplasms or liver metastases. Postembolization syndrome (PES) is a common adverse event defined as fever without associated sepsis, pain in the right upper quadrant, and nausea and/or vomiting.

Objective: This integrative review aims to identify effective management strategies for PES or one of its characterizing symptoms (fever, pain, and nausea and/or vomiting).

Methods: Searches of electronic databases MEDLINE, EMBASE, and CINAHL were conducted. Fifteen articles were identified for inclusion. Seven addressed all symptoms of PES, and 8 studies focused on individual symptoms of PES.

Results: Interventions identified are intra-arterial lidocaine, oral and intravenous analgesics, steroids, wrist-ankle acupuncture, antibiotics, and 5-HT3 receptor antagonists. Findings are explicated according to individual symptoms of PES. Intra-arterial lidocaine, steroids, and a 5-HT3 receptor antagonist are found to offer potential benefit in the management of PES symptoms.

Conclusion: A number of interventions have shown potential benefit in the management of PES. A systemic approach using combination therapy is necessary to effectively manage characterizing symptoms. Further research is needed to determine the impact of primary disease site, TACE technique, and chemotherapeutic agent on PES.

Implications for Practice: Oncology nurses are uniquely placed to undertake thorough patient assessment after TACE and implement early intervention to effectively manage PES.

Author Affiliations: North Shore Private Hospital (Ms Blackburn) and Sydney Nursing School, University of Sydney (Ms Blackburn and Dr West), New South Wales, Australia.

The authors have no funding or conflicts of interest to disclose.

Correspondence: Helen Blackburn, MN, RN, North Shore Private Hospital, Level 4 North, Westborne St, St Leonards, Sydney, New South Wales, Australia 2065 (blackburnh@ramsayhealth.com.au).

Accepted for publication July 22, 2015.

Transarterial chemoembolization (TACE) is a minimally invasive intervention that was first used to manage intrahepatic tumor growth in the 1980s and today is an established procedure for managing unresectable hepatocellular carcinoma. Transarterial chemoembolization is now a prominent and standard palliative treatment option for nonresectable liver metastases from primary colorectal cancer, other liver primary neoplasms (cholangiocarcinoma), neuroendocrine tumors, ocular melanoma, and breast cancer,1,2 achieving demonstrated improvement in quality of life (QOL) through symptom management and overall survival time.3 The high safety profile and clinical effectiveness of TACE have therefore meant that it is a viable treatment option for patients with incurable disease.3 Transarterial chemoembolization is also referred to as hepatic artery chemoembolization and hepatic arterial infusion chemotherapy, but in this review, the term TACE will be used for all of these procedures.

Transarterial chemoembolization is a 2-step procedure that involves first the selective injection of 1 or more chemotherapeutic agents and second the insertion of embolic material into the feeding arteries of the tumor. It is possible to use intra-arterial (IA) therapies such as TACE for hepatic disease because of the dual blood supply of the normal liver (portal vein supplies approximately 75% and the hepatic artery 25%) and the knowledge that liver tumors receive 80% to 90% of their blood supply from the hepatic artery.2,3 The selective injection of chemotherapeutic agents, followed by embolization, results in exposure of the tumor to a higher concentration of chemotherapeutic agent and subsequent tumor infarction and necrosis due to vascular occlusion.1,4 Embolization of the feeding arteries decreases arterial inflow and reduces washout of the chemotherapeutic agent, which importantly decreases systemic exposure.1 The conventional (traditional) technique used to perform TACE (known as cTACE) involves the emulsification of the chemotherapeutic agents in a viscous carrier (Lipiodol; Guerbet, France) that delivers the drug closer to the tumor and subsequent embolization with permanent or temporary materials (gel foam or gelatin sponge particles).1,2 Drug-eluting bead TACE (known as DEB-TACE) is a newer technique that uses microspheres loaded with chemotherapeutic agents, which are injected into the tumor feeding artery with or without further embolization.1 Severe complications such as intraperitoneal hemorrhage, liver failure, liver abscess, and cholecystitis are uncommon, with only 7% of patients reported as experiencing such major complications.2,5,6

Post-TACE postembolization syndrome (PES), which is characterized by nausea, vomiting, pain in the right upper quadrant (RUQP), and fever, is, however, the most frequently reported adverse event.2,4,5,7 While undergoing TACE is generally understood to require hospital admission and at least a 1-night inpatient stay,8 PES remains the primary indication for acute inpatient management9 during standard admissions and is primarily responsible for increasing both the patient’s TACE-related length of stay (LoS) and recurrent hospital admissions.5 Although PES is not fully understood, it is believed to be caused by the tissue ischemia induced by the chemoembolization and the consequent cytokine release and inflammatory response.4 Although PES is considered by some to be a self-limiting event that occurs only within the first 24 hours after TACE, some studies4,5 report 80% to 90% of TACE patients experience PES. Durations of PES of up to 2 weeks have also been reported.10 Consequently, Basile et al1 have now proposed considering PES to be an expected outcome of TACE.

Over the last 25 years, considerable TACE-related research has been undertaken; however, the primary end points of many of these studies is either survival time or tumor response. Although PES is recognized within the TACE literature as a common adverse event that impacts on patients’ QOL6,11 and contributes to increases in postprocedure hospital LoS, the management of PES is overlooked perhaps in the understanding that it is an inevitable and expected outcome for patients.1,2 There is little research that seeks to identify strategies to better manage post-TACE PES and thus improve patient QOL and potentially other adverse outcomes of treatment, and no existing reviews have been identified on this topic. While treatment protocols and guidelines exist to manage the individual characterizing symptoms of PES (fever, RUQP, and nausea and/or vomiting) in the chemotherapy or postsurgical oncology patient, the current literature offers no such guidelines on the management and/or prevention of these symptoms in the TACE patient, and interventions appear to be dependent on the technique used (cTACE or DEB-TACE) and/or primary disease site.1,2 The purpose of this review is therefore to gain a better understanding of post-TACE PES and the strategies used to manage patients who experience 1 or more of its characterizing symptoms.

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Methods

The integrative review framework as described by Whittemore and Knafl12 was used as it offers a structured, rigorous, and systematic 5-stage review process while also allowing for the inclusion of research using diverse methodologies to facilitate a more comprehensive understanding of a problem.

This integrative review therefore aims to identify and synthesize what is currently known about effective management strategies for PES and/or its characterizing symptoms (fever, RUQP, and nausea and/or vomiting).

The following inclusion criteria guided both the identification of the search terms and the screening of identified articles:

  • primary research studies reporting on patients undergoing hepatic chemoembolization (TACE) for primary or metastatic liver cancer (all liver dominant metastatic cancers were included with no distinction being made to tumor type or between chemotherapy agents used during the TACE procedure);
  • use of clearly identified pharmacological or nonpharmacological intervention to manage PES or one of its characterizing symptoms; and
  • use of the toxicity grading scale or other recognized means of symptom assessment to report relief or elimination of PES or one of its characterizing symptoms (toxicity grading scales provide standard criteria for measuring oncology treatment–related adverse events and side effects13; although PES is not listed as a syndrome within these toxicity grading scales, criteria exist for the assessment and measurement of the individual characterizing symptoms [Table 1], and these will be used [where appropriate] within this review).
Table 1

Table 1

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Search Strategy

All searches were conducted using MEDLINE, EMBASE, and CINAHL between February and April 2014. Following a preliminary literature survey, 3 primary search terms (hepatic chemoembolisation, postembolisation syndrome, and clinical management) were identified. Keywords comprising each term (Table 2) were then used to search without mapping terms to subject headings in order to explore the subject as widely as possible. Search outcomes for each primary search term were then combined with “AND.” No limit was applied for date of publication; however, searches were limited to published studies with full text availability in English.

Table 2

Table 2

The initial search located 534 records, with 484 then removed following screening of the titles and abstracts. The full texts of the 80 articles retained were then screened against the inclusion criteria by 2 researchers, with further 65 articles then excluded (Figure).

Figure

Figure

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Quality Appraisal

The quality of the remaining 16 articles was then appraised using (as appropriate) the Critical Appraisal Skills Programme Checklist for Randomised Controlled Trials (2013), the Cohort Study Checklist (2010), and the Transparent Reporting of Evaluations with Non-Randomised Designs (TREND) checklist v1.0,14 resulting in the elimination of 1 study because of a methodologically inconsistent small sample size. The remaining 15 articles were then reviewed (Table 3).

Table 3

Table 3

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Results

Of the 15 studies identified, 7 address all symptoms of PES. The remaining 8 studies focused on individual characterizing symptoms, with 6 reviewing RUQP, 1 reviewing nausea and vomiting, and 1 fever. The characterizing symptoms of PES have been used to structure this report of results, including Table 3, which provides an analytical summary of the studies, and Table 4, which provides a summary of the studies’ conclusions. Studies directly addressing PES frequently reported multiple interventions, and the findings of these studies have been separated to allow analysis related to each characterizing symptom.

Table 4

Table 4

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Pain (RUQP)

Twelve studies (Tables 3 and 4: studies 8–10, 15–23) reported interventions to manage postembolization RUQP. Six articles considered PES,8–10,15–17 and 6 focused only on RUQP.19–24 Four pharmacological therapeutic interventions (IA lidocaine, oral [PO] or intravenous [IV] analgesics, steroids) and 1 nonpharmacological intervention (wrist-ankle acupuncture [WAA]) were identified and will structure the following section.

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Intra-arterial Lidocaine

Six studies (Tables 3 and 4: studies 15–17, 19–21) investigated using IA lidocaine to provide analgesia for TACE patients and reported improving RUQP and reducing analgesic requirements. All studies used a similar dose of IA lidocaine (Table 3), which was administered immediately before TACE. Only Lee et al20 offered a comparison of administration time but concluded that optimal analgesic benefit was seen when IA lidocaine was administered immediately prior to TACE (P = .005). Four studies19–22 reported statistically significant decreases in frequency and dose for both procedural and postprocedural analgesia requirements when using IA lidocaine.

Two studies19,22 also examined LoS, and both reported RUQP-related increases in admission time (LoS) in the nonlidocaine group. Hartnell et al19 reported a statistically significant decrease in admission time (P < .05) (67.5 hours in the control group to 53.5 hours in the IA lidocaine group), and Romano et al22 report an intervention group 0.7-day decrease in LoS. Fiorentini et al15 and Narayanan et al17 did not support these findings, reporting median LoS of 3 and 2 days, respectively. However, both studies reported low incidences of grades 2 and 3 RUQP after TACE, and although IA lidocaine was included in the preprocedure medication regimen and may have contributed to RUQP management, these findings must be interpreted with caution as multiple interventions were implemented, and neither study attributes their findings to pre-TACE IA lidocaine alone. It must also be noted that only 3 studies20–22 used a visual analog scale as a subjective measurement of pain. Two of these studies20,22 reported lower pain scores both during and after TACE in patients who received IA lidocaine. The third study21 reported a pain score of 0 following cTACE for 29% (n = 45) of patients receiving IA lidocaine but was re unable to make a direct comparison with the nonlidocaine group as data for this group were collected retrospectively, and patients had not been asked to score their RUQP.

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Intravenous or Oral Analgesia

Five studies (Tables 3 and 4: studies 8, 15, 20, 22, and 23) examined the use of IV or PO analgesics at varying times and intervals throughout preprocedure and postprocedure care, with all studies reporting benefit from analgesia administration (Table 4). The analgesics used were IV morphine8,15,17 and PO oxycodone8,24 (PO morphine sulfate was used as a control).23

Studies using PO oxycodone8,24 after TACE reported an adequate analgesic effect, as defined within these studies. The only available placebo-controlled randomized controlled trial (RCT)24 reported superior pain control in groups receiving PO controlled-release oxycodone (CRO). The intervention groups also demonstrated lower pain scores but an increased incidence of mild to moderate RUQP and a shorter LoS.24 A CRO dosage–related difference (10 mg/20 mg CRO) was only seen during the first 12 hours after TACE (P < .001) with no significant difference evident from 12 to 48 hours after the procedure. These findings were substantiated by Prajapati et al,8 who reported the successful management of grades 1 and 2 abdominal RUQP with PO oxycodone. Zeng et al23 used PO morphine sulfate as the control agent and observed moderate analgesic benefit in the control group (equivalent pain relief to the intervention arm). The duration of pain relief for the control group was 4 hours after TACE beyond which the intervention group reported superior analgesic effect.23

In the 2 DEB-TACE–related studies,15,17 IV morphine was administered 30 minutes before procedure and 6 hours after the procedure. Grades 2 and 3 RUQP was reported in both studies, and Narayanan et al17 report modification of the pain protocol to include IV hydromorphone at increments throughout the procedure. Fewer incidents of grades 2 and 3 RUQP and an increase in grade 1 RUQP were subsequently seen, but caution should be exercised when considering the benefit of this intervention because of multiple management strategies used.

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Steroids

The potential benefit of steroids for RUQP was examined in 5 studies (Tables 3 and 4: studies 10, 9, 15, 18, and 20). Four studies9,15–17 used dexamethasone as a single agent, and 1 study10 used it in combination with ginsenosides. This double-blind RCT randomized patients to receive dexamethasone with or without ginsenosides versus placebo and reported statistically significant decreases in the incidence of RUQP in groups receiving dexamethasone versus ginsenosides alone.10

Interestingly, Kogut and colleagues’9 study of the benefit of steroid prophylaxis failed to reveal any significant differences between steroids and analgesic-based pain management. No analgesic agents were required in similar numbers of patients, regardless of the timing of the intervention, and the dose level and frequency of analgesic agent doses did not significantly differ between patient groups. It was concluded that a single prophylactic dose of dexamethasone had no significant effect on post-TACE analgesics. However, the retrospective design of this study is a limitation that may affect the reliability of the findings.

Studies that included dexamethasone in their DEB-TACE supportive care protocol15–17 reported RUQP (although mostly limited to grade 1 on the toxicity scale) in the majority of participants. Fiorentini et al15 used a regimen of 8 mg twice daily commencing at day −1 before the procedure and continuing to day 5 after the procedure, but saw higher incidences of grades 2 and 3 RUQP compared with Narayanan et al17 and Malagari et al,16 who administered lower doses over a shorter period. Fiorentini et al15 and Narayanan et al17 both implemented and reviewed multiple strategies to manage post-TACE RUQP, which must be considered when interpreting their findings as this could offer explanation for the reported differences in response to dexamethasone.

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Wrist-Ankle Acupuncture

Only 1 study (Tables 3 and 4: study 22) examined the therapeutic benefit of WAA, reporting similar levels of RUQP relief from WAA to control subjects receiving PO morphine sulfate for the first 4 hours after TACE. However, the WAA group reported superior RUQP relief 4 to 6 hours after TACE. These findings show the analgesic benefit of WAA for post-TACE RUQP, but further research is required because the present study was limited by small sample size and the lack of an effective (sham acupuncture) control.23

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Nausea and Vomiting

Eight studies (Tables 3 and 4: studies 8–10, 15, 18, 20, 24, and 25) reported interventions to manage post-TACE nausea and vomiting. Seven studies (Tables 3 and 4: studies 8–10, 15, 18, 20, 24) considered PES, and 1 study (Tables 3 and 4: study 25) directly focused on nausea. Three therapeutic interventions (5-HT3 receptor antagonists; dexamethasone + ginsenosides; dexamethasone + an anticholinergic [Scopolamine patches]) were identified and will structure the following section.

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5-HT3 Receptor Antagonists

Three studies (Tables 3 and 4: studies 8, 24, 25) used the 5-HT3 receptor antagonist ondansetron (dose range, 4–16 mg) for TACE-induced nausea and vomiting. Levels of nausea were determined in 2 studies8,18 by using grading criteria such as the toxicity assessment tool, and the third study25 used patient diaries and a 5-point food intake scale. All studies reported a positive association between the use of ondansetron and post-TACE nausea and vomiting.

De Baere et al18 reported vomiting in 1 subject only and nausea in 61% (n = 24) of subjects, but 40% of these occurrences were assessed as grade 1 only, with the remaining 21% at grade 2 level with symptoms lasting 2 to 4 days for all except 1 subject whose nausea persisted beyond day 7 after TACE.18 Subjects in Prajapati and colleagues’8 study received ondansetron before and after the procedure, and nausea and vomiting was reported by only 12% (n = 110). Sohara et al25 gave ondansetron at subsequent TACE procedures to subjects who had experienced nausea and/or vomiting during the first treatment. Forty-six percent (n = 59) of subjects experienced symptoms, but only 5 received the intervention at the following TACE. While nausea and vomiting was successfully prevented following ondansetron administration, the small sample receiving the intervention limits the generalizability of these findings.

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Steroids

Two studies (Tables 3 and 4: studies 9 and 10) used dexamethasone, and both reported a decrease in levels of nausea and vomiting. Yinglu et al10 reported a statistically significant difference between groups who received dexamethasone, either as a single agent or combined with ginsenosides and groups receiving either placebo alone or ginsenoside plus placebo. Kogut et al9 demonstrated similar findings and reporting a trend toward less doses of antiemetic agent when dexamethasone was administered before procedure when compared with no dexamethasone. This group also reported no significant effect when a single dose of dexamethasone was used as an antiemetic; however, a statistically significant effect on antiemetic agent requirements was reported for multiple doses of dexamethasone. Those patients who were administered a Scopolamine patch trended toward more antiemetic agent doses9; however, the retrospective design of Kogut and colleagues’ study may affect the reliability of these findings.

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5-HT3 Receptor Antagonist + Steroids + H2 Receptor Antagonist

Three studies (Tables 3 and 4: studies 15, 18, and 20) implemented a 5-HT3 receptor antagonist, dexamethasone, and an H2 receptor antagonist within supportive care regimens for DEB-TACE patients. Ranitidine was the H2 receptor antagonist used in all studies, with ondansetron the 5-HT3 in 2 studies16,17 and tropisetron in 1 study.15 All schedules were similar, consisting of dexamethasone and ondansetron or tropisetron before the procedure and ranitidine incorporated into the IV hydration regimen 6 hours after the procedure.

Two studies (Tables 3 and 4: studies 15 and 20) reported high incidences of PES, specifically nausea and vomiting. Narayanan et al17 reported grade 1 level nausea and vomiting in the majority of subjects, whereas Fiorentini et al15 reported grade 2 toxicity in all subjects and consequently only modest benefit for the intervention. Malagari et al16 reported a high incidence of PES (86.5% [n = 205]) assessed as grade 1 in 75% and grade 2 or more in 25% of subjects; however, as this study did not clearly differentiate the characterizing symptoms of PES, it is difficult to determine the reliability of these results with respect to nausea and vomiting specifically.

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Fever

Seven studies Tables 3 and 4: studies 8, 10, 15, 18, 20 24, and 26) reported interventions to manage postembolization fever. Six studies reported on fever with other symptoms of PES, and 1 study directly focused on fever. Interventions included antibiotics in 6 studies8,15–18,26 and dexamethasone in 4 studies.10,15–17 Two therapeutic interventions (antibiotics, dexamethasone) were identified and will structure the following section.

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Antibiotics

Six studies (Tables 3 and 4: studies 8, 15, 18, 20, 24, and 26) administered antibiotics as part of the supportive care regimen and reported fever of 38°C or greater without associated sepsis. Castells et al26 reported fever greater than 38°C in 34% (n = 13) and 32% (n = 37) of subjects in the placebo and antibiotic intervention groups respectively, with mean duration and maximal value not significantly different between groups. De Baere et al18 and Fiorentini et al15 both gave single-agent antibiotic therapy before and after DEB-TACE. De Baere et al18 identified fever in 36% (n = 12) of subjects, but 28% of these were limited to grade 1 level only, whereas Fiorentini et al15 reported grade 2 fever in all patients.

The remaining 3 studies Tables 3 and 4: studies 9, 19, 21) administered antibiotics as part of post–DEB-TACE combination therapy. Prajapati et al8 only reported that no patients required overnight admission due to prolonged fevers. Narayanan et al17 reported fever in 2 patients over 5 procedures, but this was limited to grade 1 level in 4 of these cases. In similar findings, Malagari et al16 reported PES in 86.5% of patients but stated that 57.81% to 75% of the toxicity was grade 1 level only. Again, however, the failure of Malagari et al16 to differentiate their results means that these findings must be interpreted with caution.

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Steroids

Yinglu and colleagues’10 double-blind RCT (Tables 3 and 4: study 10) investigated steroid use in fever management and randomized subjects into 4 groups receiving placebo (group A), placebo and dexamethasone (group B), ginsenosides and placebo (group C), or a combination of dexamethasone and ginsenosides (group D). Whereas grade 2 or less levels of fever occurred in only 20% (B) to 27% (D) of subjects receiving dexamethasone, a 70% occurrence was reported for group A (placebo), and no significant difference was determined between groups B, C, and D.

The results of the 3 remaining studies (Tables 3 and 4: studies 15, 18, and 20) that implemented steroids and reported on PES-related fever failed to demonstrate a strong effect of dexamethasone. Fiorentini et al15 reported grade 2 fever in all patients. Narayanan et al17 and Malagari et al16 reported only grade 1 level fever, and Malagari et al16 concluded that fever was associated with more extensive embolization.

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Discussion

There is a myriad of TACE studies using tumor response and survival time as the primary end points and which increasingly focus on the safety profile of newly adopted TACE techniques. Such studies (see, eg, Aliberti et al,27 Fiorentini et al4) also frequently report occurrences of post-TACE PES, but there is only a small volume of literature addressing the management of PES or its characterizing symptoms when encountered in association with TACE. Hence, the availability of empirical evidence on treatment strategies is limited and no reviews (systematic or integrated) to date. There are, however, some studies that look at either post-TACE PES or RUQP associated with post-TACE PES and a very few studies addressing the management of postembolization fever or nausea. This review has therefore investigated available primary research investigating the management of post-TACE PES.

The pathogenesis of PES is complicated and unclear. It involves multiple mechanisms, with the main ones being the toxicities of chemotherapy agents and embolization-induced ischemia, necrosis, and hypoxia in normal (in this case, hepatic) cells with the consequent release of inflammatory factors and activation of the body’s stress response.8,28 Postembolization syndrome therefore needs to be considered as a systemic complication of TACE, and the complex and multifactorial nature of the condition necessitates a systemic approach in order to effectively manage it.8,28

The findings of this review indicate that the pharmacological agents selected for use in the management of post-TACE PES (IA lidocaine; PO and IV analgesia; steroids; 5-HT3 receptor antagonist) largely reflect the outcomes of other studies that look to manage PES following ablation of renal angiomyolipomas, embolization of polycystic kidneys, and uterine fibroid embolization.29–31 The potential for the metabolic/cellular functions of hepatic cells to further complicate this response and to necessitate the use of other agents does not at this time appear to have been explored.

All studies that implemented IA lidocaine reported some or all of the following positive clinical outcomes: reducing analgesic requirements, reducing length of hospital stay, or decreasing pain scores (Table 4: studies 15–17, 19–21). Comparative analyses of the effect of IA lidocaine were impeded by the inclusion of retrospective data in 2 studies (Tables 3 and 4: studies 16 and 19); however, the available RCTs (Tables 3 and 4: studies 17 and 21) substantiate these findings and confirm the efficacy of the intervention for post-TACE PES. While the dose of IA lignocaine used and administration timing were similar across the located studies, only Lee et al20 tested the hypotheses relating specifically to administration time, concluding that optimal timing for IA lidocaine administration was immediately before TACE. In order to substantiate these findings, further research on the administration time of lidocaine would be encouraged.

Oral analgesics were found to be effective in managing grades 1 and 2 post-cTACE RUQP (Tables 3 and 4: studies 8, 22, and 23). Fiorentini et al15 and Narayanan et al17 used only IV analgesic in their study of post–DEB-TACE PES. However, Prajapati et al8 also studying PES occurring after DEB-TACE reported positive effects from PO analgesics used for grades 1 and 2 RUQP and used only IV analgesia to manage RUQP of grade 3 or greater. Further well-designed studies allowing investigation of both route of analgesia and effects related to TACE type are clearly required to determine efficacy here. Zeng et al23 also offered promising data regarding the use of WAA in managing post-TACE RUQP, and this approach appears to warrant further study also.

Although steroids were administered in several studies (Tables 3 and 4: studies 9, 10, 15, 18, and 20), they were reported as assisting in the management of pain specifically in only 1 study (Table 4: study 10). The analgesic effect of steroid administration in several studies (Table 4: studies 15, 18, and 20) is, however, difficult to determine because of methodological issues relating to the use of multiple interventions and analytical difficulties in separating results relating to RUQP relief. Kogut et al9 also failed to demonstrate the benefit of steroids on pain; however, the retrospective data collection used here might also compromise the reliability of these findings.

The administration of steroids (dexamethasone) was found to be effective in the management of post-TACE nausea (Tables 3 and 4: studies 9 and 10). This finding supports those of Bissler et al29 and Cornelis et al,30 who identified a positive effect from steroids in the management of PES following renal embolization.

Efficacy was also demonstrated with the use of a 5-HT3 receptor antagonist, when given as a single agent for nausea (Tables 3 and 4: studies 8, 24, and 25). However, where a 5-HT3 receptor antagonist was combined with dexamethasone (a strategy that reflects standard approaches used in IV chemotherapy administration32), high incidences of postembolization nausea and vomiting were seen (Tables 3 and 4: studies 15, 18, and 20). Kogut et al9 suggest that the applicability of these protocols for use in TACE patients may be limited. This cannot be assumed, however, as the reported findings from studies using different TACE techniques may also be influencing the findings here. It may well be worthwhile to delay drawing a definitive conclusion here until further studies identifying the benefit of this combination therapy can be done, particularly in light of both their known efficacy in highly emetic systemic chemotherapy protocols32 and the promising data reported from single-agent use in arterial chemoembolization.

Analysis of those studies that addressed the use of prophylactic antibiotics found that antibiotics offered no benefit in preventing or treating postembolization fever. Other studies that reviewed post-TACE fever support this view with Li et al33 and Jun et al,28 concluding that antibiotic therapy is not necessary following embolization procedures. Infection is rare owing to the standard antiseptic procedures associated with TACE,28,33 and fever at this time correlates with tumor necrosis and is a positive prognostic sign of local response to treatment16,26,33 and not sepsis. Jun et al28 also propose the Lipiodol dose as a trigger for postembolization fever as they demonstrate that the incidence of fever correlates with doses equal to or greater than 7 mL. However, this finding was not explored by the studies reviewed here.

This review sought to identify effective treatment strategies for PES and has identified several gaps in current research. First, further research is needed to determine the impact on PES of the primary disease site, TACE technique, and chemotherapeutic agent used. Second, further studies would be warranted in order to confirm the efficacy of WAA and steroids on post-TACE pain, the combined use of steroids and a 5-HT3 receptor antagonist on TACE-associated nausea and vomiting, and the administration time of IA lidocaine. Finally, the findings of this review indicate that a supportive regimen, which offers a combination of therapies in order to manage all presenting symptoms, is necessary to successfully treat post-TACE PES. However, the synergistic effect of treatments needs to be considered when deciding on such a schedule of supportive therapy to ensure that the efficacy of individual agents is also determined.

The findings of this review highlight the diversity and variance of methodological quality in studies investigating post-TACE PES and/or its characterizing symptoms. As Table 4 describes, analysis was impeded by limitations in the study designs such as observational designs, small sample size, and the use of retrospective data. In addition, the lack of consistent independent variables such as disease site, TACE technique, and chemotherapeutic agent administered within the identified studies limited the possibilities for analysis. The failure of some studies to differentiate between the characterizing symptoms of PES within their findings, the weak analysis of implemented interventions, and the lack of a robust measurement or use of established grading tools also contributed to the complexity of this review. However, the findings of those studies with design limitations are in most cases substantiated by higher-quality research, and the studies discussed here reflect the developmental stage of the PES literature both in this clinical population and in others where therapeutic embolization is used.

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Conclusion

Transarterial chemoembolization is an established treatment option for patients with incurable hepatic disease where the primary end point of treatment is extended survival and tolerable QOL. Within postchemotherapy and surgical settings, protocols to manage the characterizing symptoms of PES have long been established and are continually evolving as new and improved therapies become available. Approaches to managing PES in the post-TACE patient, however, at best mirror interventions used in other clinical settings, but as yet no guidelines exist for its management within this unique patient population. The almost inevitable occurrence of post-TACE PES or at least some of its characterizing symptoms and the documented impact of PES on the patient’s QOL and their hospital LoS make this adverse effect of TACE a significant problem and one that from the patient’s perspective it is important to manage efficiently and effectively.

The role of the specialist oncology nurse is pivotal in the management of patients who have undergone TACE as nurses are uniquely placed to undertake thorough patient assessment to facilitate the early recognition of the adverse effects of TACE (including PES) and to instigate effective management.2,34 As the management of complications following treatment increasingly falls into the domain of nursing practice, nurses need extensive knowledge of TACE and its associated adverse effects so they may advocate for effective management and resolution of symptoms.32

The aim of this integrative review was to identify effective management strategies for PES or any of its characterizing symptoms occurring within the TACE patient population, and although not exhaustive, the review has identified and synthesized the current literature for this purpose. A number of interventions have shown potential benefit in the management of post-TACE PES, and the findings of the review highlight the potential value of combination therapy and support the need for consideration of a systemic approach to effectively manage all of the characterizing symptoms of PES. Although findings offer promising data on a number of interventions, more well-designed studies are needed to address the gaps identified here to enable a comprehensive approach to the management of this phenomenon.

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References

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Keywords:

Fever; Nausea; Pain; Postembolization syndrome; Transarterial chemoembolization

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