Endoscopic ultrasound-guided gallbladder drainage for bilirubin normalization in distal malignant biliary obstruction: A focused review

Abstract

Endoscopic transpapillary biliary drainage is currently recommended as the gold standard treatment modality for distal malignant biliary obstruction (DMBO) with endoscopic ultrasound (EUS)-guided biliary drainage being advocated in cases of endoscopic retrograde cholangiopancreatography failure. EUS-guided gallbladder drainage (GBD) has recently been proposed as a promising “rescue” and first-line alternative tool for managing DMBO. Indeed, high rates of both technical and clinical success along with a favorable safety profile have been reported. However, evidence regarding the capability of EUS-GBD to normalize total bilirubin in patients with DMBO is still lacking. Notably, bilirubin normalization is regarded as mandatory before starting chemotherapy, thus representing a crucial outcome of any biliary drainage method for DMBO. Our study aimed to summarize and discuss the current evidence concerning the effectiveness of EUS-GBD for bilirubin normalization in DMBO.

Key Words: Endoscopic ultrasound-guided gallbladder drainage; Distal malignant biliary obstruction; Biliary drainage; Endoscopic ultrasound-guided biliary drainage; Endoscopic retrograde cholangiopancreatography

Core Tip: Endoscopic ultrasound (EUS)-guided gallbladder drainage (GBD) has recently been proposed as a promising “rescue” and first-line option for managing distal malignant biliary obstruction (DMBO). Indeed, high rates of both technical and clinical success along with low adverse events rates have been reported. However, evidence concerning the effectiveness of EUS-GBD for bilirubin normalization in DMBO is currently still lacking. Our study aimed to review the current evidence about the efficacy of EUS-GBD for bilirubin normalization in patients with DMBO.

INTRODUCTION

Endoscopic retrograde cholangiopancreatography (ERCP) is currently recommended as the first-line treatment modality for distal malignant biliary obstruction (DMBO)[1,2]. In cases of ERCP failure, percutaneous transhepatic biliary drainage (PTBD) and more recently endoscopic ultrasound (EUS)-guided biliary drainage have been advocated as second-line modalities[1-4]. Given its capability to provide a rapid and sustained bilirubin normalization[5,6], transpapillary biliary stenting through ERCP is currently regarded as the gold standard technique for DMBO[1,2]. In fact, due to the higher risk of drug toxicity, a total bilirubin level < 1.5 times the upper limit of normal (ULN) is considered mandatory before starting standard neoadjuvant or palliative chemotherapy and for its continuation[7-9]. In cases of total bilirubin < 5 ULN, a dose reduction and/or a less toxic regimen may be considered. Conversely, in the presence of total bilirubin > 5 ULN, systemic anticancer treatment is generally not recommended[10,11].

Following its growing application in patients with acute cholecystitis who are unfit for surgery[4,12,13], EUS-guided gallbladder drainage (GBD) has recently been suggested as a promising alternative modality, either as a “rescue” or a first-line approach for managing patients with DMBO without previous cholecystectomy and with clear patency of the cystic duct[14-17]. However, despite its engaging technical simplicity compared with ERCP, evidence regarding the efficacy of EUS-GBD for bilirubin normalization in DMBO is still lacking[18,19]. Notably, the clinical success was defined by bilirubin reduction of > 50% within 2-4 weeks in most of the currently available studies[14-17]. Our review aimed to summarize and discuss the current available evidence with regard to the effectiveness of EUS-GBD for bilirubin normalization in DMBO.

LITERATURE SEARCH

A comprehensive search of PubMed/MEDLINE, EMBASE, and Google Scholar databases were performed through August 2025 in order to identify relevant studies evaluating the effectiveness of EUS-GBD for bilirubin normalization in DMBO, either as a “rescue” or a first-line approach. Studies omitting data on the bilirubin normalization rate were excluded. The search terms included (“endoscopic ultrasound-guided gallbladder drainage” OR “EUS-GBD”) AND (“distal malignant biliary obstruction” OR “DMBO”). The search was restricted to English-language articles. Abstracts, case reports/series (< 5 cases), reviews, position papers, editorials, and book chapters were excluded. References from the included studies and pertinent reviews were carefully screened for potential inclusion.

EFFICACY OF EUS-GBD FOR BILIRUBIN NORMALIZATION IN DMBO

Evidence

A total of three studies reported data on the bilirubin normalization rate and were included in our final analysis[20-22]. All of them were retrospective in nature[20-22]. In all of the included studies, an electrocautery-enhanced lumen-apposing metal stent was used for the creation of an anastomosis between the gallbladder and the gastric/duodenal wall[20-22]. The main features of the included studies are illustrated in Table 1.

Table 1 Summary of studies reporting on the effectiveness of endoscopic ultrasound-guided gallbladder drainage for bilirubin normalization in distal malignant biliary obstruction.

	Study type and period	Number	EUS-GBD intention	Bilirubin normalization (%)	Bilirubin normalization definition	Time to bilirubin normalization (days)	TS (%)	CS (%)	CS definition	CTX administration (%)	AEs (%)	Median follow-up (days)
Debourdeau et al[20]	RMC; 2018-2022	41	After ERCP failure		Total bilirubin at day 28 (< 2.8 mg/dL)		100	87.8	> 50% decrease in total bilirubin at day 7 or normalization at day 28	47.4	9.8	158
Martínez-Moreno et al[21]	RMC; 2016-2024	96	After ERCP and/or EUS-BD failure	65.6	Total bilirubin (< 3 mg/dL)	15 (7-27)	99	78.1	≥ 50% decrease in total; bilirubin at day 14	57.1	26.3	72
Chieng et al[22]	RMC; 2017-2023	26	After ERCP and/or EUS-BD failure	19.2	Full bilirubin normalization over the follow-up		100	100	Improvement in bilirubin and/or jaundice within 72 h of the procedure	87.5	50.0	103

RMC: Retrospective multicenter cohort; EUS: Endoscopic ultrasound; GBD: Gallbladder drainage; ERCP: Endoscopic retrograde cholangiopancreatography; BD: Biliary drainage; TS: Technical success; CS: Clinical success; CTX: Chemotherapy; AE: Adverse event.

Bilirubin outcomes

The GALLBLADEUS multicenter study by Debourdeau et al[20] compared retrospectively the efficacy and safety of EUS-guided choledochoduodenostomy (EUS-CDS) (37 patients) and EUS-GBD (41 patients) in DMBO following ERCP failure. The observed technical and clinical success for EUS-GBD was 100% and 87.8%, respectively, with no significant differences compared with EUS-CDS. Although the clinical success was broadly defined by a > 50% decrease in total bilirubin levels at day 7 or normalization at day 28 (< 2.8 mg/dL), no data on the bilirubin normalization rate were specifically provided by the authors. Nevertheless, a significantly slower speed of bilirubin reduction following EUS-GBD was detected with a bilirubin lowering rate at day 30 of 68.4% in the EUS-GBD group vs 81.7% in the EUS-CDS group (P = 0.07)[20]. Subsequently, Martínez-Moreno et al[21], in their retrospective multicentric study, observed bilirubin normalization, defined by post-drainage bilirubin reduction below 3 mg/dL, in 66.3% of the included patients within a median time of 15 days[21]. Finally, Chieng et al[22] reported retrospectively that despite 100% technical and clinical success “rescue” EUS-GBD was able to fully normalize bilirubin over the follow-up period in 5 of 26 included patients (19.2%). Of note, the follow-up lasted from the time of intervention until the patient’s death with a reported median survival of 103 (38-192) days. Conversely, bilirubin normalization at 2-4 weeks post-drainage was omitted[22].

Chemotherapy initiation

Although no significant differences in terms of chemotherapy administration were reported between the two groups in the GALLBLADEUS study, 47.37% of the eligible patients in the EUS-GBD group were finally able to initiate chemotherapy post-drainage compared with 58.33% following EUS-CDS (P = 0.477)[20]. Martínez-Moreno et al[21] reported that 57.1% of the eligible patients for adjuvant therapy were finally allowed to start chemotherapy. In contrast, in the retrospective study from Chieng et al[22], 7/8 (87.5%) patients who were potentially eligible for chemotherapy were allowed to receive systemic anticancer treatment post-procedure. However, it is unknown if these patients obtained bilirubin normalization. Nevertheless, the need for chemotherapy dose adjustments and/or regimen switch and the time to chemotherapy initiation were also not reported by the authors.

DISCUSSION

From a strict oncological point of view, a key outcome of biliary drainage in DMBO is a rapid and sustained bilirubin normalization, which is mandatory before starting the full-dose standard chemotherapy regimen and for its continuation[7-11]. Moreover, bilirubin normalization is associated with an improved chemotherapy tolerance, jaundice-related symptoms, quality of life, performance status, and overall survival[22-25].

The efficacy of ERCP and more recently of EUS-CDS in terms of bilirubin normalization has been widely reported and appreciated in real-life routine clinical practice[5,6,26,27]. In recent years EUS-GBD has been suggested as a promising rescue and even a first-line therapeutic tool for patients affected by DMBO without previous cholecystectomy and with a clear patency of the cystic duct[14-17]. Importantly, it has been associated with high rates of both technical and clinical success along with a low adverse events rate[14-17]. However, clinical success is not synonymous with bilirubin normalization. Indeed, the standard definition adopted in most of the currently available studies for clinical success is a bilirubin reduction to below 50% of baseline at 14 days. In many cases this may not be sufficient to initiate full-dose standard chemotherapy[14-17]. Nevertheless, several concerns still exist about the effectiveness of EUS-GDS for bilirubin normalization[18,19].

As opposed to the European Society of Gastrointestinal Endoscopy guidelines, which define clinical success by a reduction in total bilirubin of 50%-75% within 2-4 weeks[4], a ≥ 50% reduction or normalization of total bilirubin within 2 weeks is suggested by the latest Tokyo criteria[28]. Furthermore, it is worth noting that the Japanese criteria suggest reporting additional items to evaluate the overall clinical outcomes of endoscopic biliary drainage in DMBO, such as the rate of administration/delay/discontinuation of anticancer treatment and its type[28].

Despite the accumulating literature, likely driven by the technical simplicity of EUS-GBD compared with other modalities, we have found that only three studies have reported data on the bilirubin normalization rate and were thus eligible for inclusion in our review[21,22]. Moreover, one of the included studies broadly defined the clinical success by a > 50% decrease in total bilirubin at day 7 or normalization at day 28 (< 2.8 mg/dL) without specifically providing data on the bilirubin normalization rate. Nevertheless, a bilirubin reduction rate at day 30 of only 68.4% was detected. This was significantly lower than that observed following EUS-CDS (81.7%; P = 0.07) with only less than half (47.37%) of the patients allowed to initiate chemotherapy post-drainage[20]. Furthermore, a suboptimal bilirubin normalization rate was reported by the remnant two included studies, which specifically addressed this outcome[21,22].

Notably, Chieng et al[22] reported a bilirubin normalization rate of 19.2% only following “rescue” EUS-GBD despite the very long time for achieving this outcome (median follow-up, 103 days; interquartile range, 38-192 days). Regardless of this very low bilirubin normalization rate, a majority of the eligible candidates (7 out of 8) were able to commence chemotherapy post-drainage[22]. However, the authors did not clarify whether these patients were those who achieved bilirubin normalization or whether chemotherapy dose adjustments and/or administration of a less toxic regimen were needed. Finally, a suboptimal bilirubin normalization (< 3 mg/dL) rate of 66.3% was also reported by Martínez-Moreno et al[21]. Importantly, only 57.1% of the eligible candidates were finally able to start chemotherapy following EUS-GBD. Normalized bilirubin was found to be significantly associated with the possibility of chemotherapy initiation[21]. It is worth mentioning that the chemotherapy administration rate reported by Debourdeau et al[20] and Martínez-Moreno et al[21] is relatively low even when compared to rates previously reported for second-line or third-line modalities, such as PTBD[29].

The bilirubin normalization rate along with the time to normalization rate, the rate of chemotherapy administration among eligible candidates, the time to its initiation, and the type of chemotherapy administered (i.e., dosage and regimen) are clinically crucial outcomes and essential to fully understand the therapeutic potential and the oncological benefit of EUS-GBD in this setting and its proper allocation in the management algorithm[27-31]. In addition, to our knowledge no data exist regarding EUS-GBD in the setting of DMBO complicated with cholangitis.

According to the currently available evidence, caution is warranted when proposing EUS-GBD as a first-line option in the management of DMBO. Until more evidence regarding the bilirubin normalization rate and the previously discussed oncological outcomes is available, EUS-GBD should probably be considered as a “rescue” tool for patients with DMBO who are ineligible for chemotherapy and candidates for the best supportive care. In addition, it could also be a salvage option for the preoperative biliary drainage of patients with severe hyperbilirubinemia who are planned to undergo delayed (> 2 weeks) surgery and do not require neoadjuvant treatment.

CONCLUSION

Large prospective randomized trials in high-volume referral centers comparing EUS-GBD with the reference standard biliary drainage techniques for DMBO, such as ERCP, EUS-CDS, and PTBD, are strongly needed. Future trials should be designed to specifically address the bilirubin normalization rate and the above-discussed chemotherapy-related outcomes in a strictly standardized fashion in order to better define the oncological benefits of EUS-GBD and its proper allocation in the therapeutic algorithm for DMBO.

ACKNOWLEDGEMENTS

We are grateful to Velia De Magistris for English editing.