Biliary Drainage in Palliative and Curative Intent European Patients with Hilar Cholangiocarcinoma and malignant hilar obstruction: a retrospective single center analysis

doi:10.21203/rs.3.rs-4320025/v1

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Research Article

Biliary Drainage in Palliative and Curative Intent European Patients with Hilar Cholangiocarcinoma and malignant hilar obstruction: a retrospective single center analysis

https://doi.org/10.21203/rs.3.rs-4320025/v1

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published 10 Oct, 2024

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Background and Aims:

Relief of cholestasis in hilar cholangiocarcinoma is commonly undertaken in both curative and palliative treatment concepts. There are numerous open questions with regard to the ideal biliary drainage strategy – including what constitutes clinical success (CS). In the existing data, curative patients and patients from the Western world are underrepresented.

Patients and Methods:

We performed a retrospective analysis of patients with complex malignant hilar obstruction (Bismuth-Corlette II and higher) due to cholangiocarcinoma who underwent biliary drainage at a German referral center between 2010 and 2020. We aimed to define CS and complication rates and directly compare outcomes in curative and palliative patients.

Results

56 curative and 72 palliative patients underwent biliary drainage. In patients with curative intent, CS was achieved significantly more often regardless of what definition of CS was applied (e.g., total serum bilirubin (TSB) < 2 mg/dl: 66.1% vs. 27.8%, p = < 0.001, > 75% reduction of TSB: 57.1% vs. 29.2%, p = 0.003). This observation held true when only subgroups with the same Bismuth-Corlette stage were compared. Moreover, palliative patients experienced a significantly greater percentage of adverse events (33.3% vs 12.5%, p = 0.01). Curative intent treatment and TSB at presentation were predictive factors of CS regardless of what definition of CS was applied. The observed CS rates are comparable to those published series of curative patients, but inferior to reported CS rates in palliative series mostly from Asia.

Conclusions

Biliary drainage in complex malignant hilar obstruction due to cholangiocarcinoma is more likely to be successful and less likely to cause adverse events in curative patients compared to palliative patients.

Drainage

Klatskin Tumor

Cholestasis

Cholangiocarcinoma

Bile Duct Neoplasms

Bilirubin

Among biliary tract cancer (BTC) tumors arising in the hilar region of the biliary tree (perihilar cholangiocarcinoma; pCCA) also known as Klatskin tumors are relatively common [1, 2]. pCCA of Bismuth-Corlette stage II or higher commonly presents with jaundice due to malignant hilar obstruction (MHO). While most patients present with advanced disease and will receive palliative treatment, some are amenable to a curative treatment, i.e., a treatment concept that includes a surgical procedure aimed at R0 resection of the tumor.

Relief of cholestasis, i.e., restoration of bile flow, as evidenced by a reduction in total serum bilirubin (TSB) to near normal levels, is usually attempted both in the curative and in the palliative treatment setting. In the curative setting, there is some evidence that a lower TSB prior to major hepatic resection is associated with reduced postoperative mortality [3]. In the palliative setting, persistent cholestasis with high TSB may limit the range and dose of anti-neoplastic therapies that can be administered. Moreover, cholestasis may cause pruritus and puts patients at risk of cholangitis. Finally, jaundice is perceived as a highly visual stigma of disease and hence should be addressed for reasons of patient comfort.

Currently, guidelines advise an interventional drainage therapy for malignant jaundice in both, curative and palliative patients [4, 5]. Biliary drainage in pCCA causing MHO is challenging since the liver lobes are functionally separated by the tumor and require separate drainage. Moreover, variations in biliary anatomy commonly require individualized approaches. Endoscopic biliary drainage (EBD) by means of endoscopic retrograde cholangiography (ERC), percutaneous transhepatic drainage (PTBD) or a combination of both is most commonly used. In Asian countries nasobiliary drainage catheters are used more commonly than in Western countries and there is some evidence suggesting they may have a more favorable safety profile than EBD [6]. Endoscopic ultrasound-directed interventions provide a good option to drain the left lobe but will do not usually reach the right liver lobe in patients with MHO.

Despite the large body of studies addressing biliary drainage in MHO, there is no clear consensus on the optimal modality of drainage (EBD vs. PTBD), type of stent (plastic vs. metal) or the required extent of drainage (unilateral vs. bilateral or limited vs. complete). Among studies addressing biliary drainage in MHO, there is some overrepresentation of palliative patients and patients from Asia (Supplement 1s). Moreover, studies are almost exclusively retrospective and there is wide variation in the definition of what constitutes clinical success in biliary drainage therapy. The aims of our study were threefold: first, since data from Western countries are limited and there is no comparison of curative and palliative cases, we retrospectively evaluated drainage modalities and outcomes in both curative and palliative patients seen at our center. Second, we evaluated the type, number and associated complications of interventions performed to achieve biliary drainage. Third, we aimed to test the hypothesis that therapy concept (i.e., curative vs. palliative intent), TSB at presentation, bilateral or complete drainage and Bismuth-Corlette stage are predictors of successful biliary drainage in patients with pCCA and MHO.

1. Study design, patients and outcome

In this monocentric study, we conducted a retrospective analysis of all patients treated due to a perihilar cholangiocarcinoma at the Center of Viszeral Medicine (Asklepios Hospital Hamburg Barmbek) between 2010 and 2020.

The decision on therapy concepts (curative versus palliative) was discussed in the hospital’s interdisciplinary tumor board. To be included in this analysis, patients had to be over 18 years of age with proven perihilar cholangiocarcinoma (i.e., histopathologically proven or clinically diagnosed in the cholangiogram by tumor board consensus). We excluded patients who received no interventional treatment to achieve biliary drainage, those who received an endoscopic ultrasound-guided biliary drainage procedure, and those with incomplete clinical data, missing laboratory parameters, anatomically uncertain perihilar localization and Bismuth-Corlette stage I. Baseline characteristics (i.e., sex and age), history of liver disease, laboratory data and peri-interventional data (i.e., number of interventions, localization of biliary drain, endoscopic technique and complications) were assessed from the electronic patient files. At our center, we aim to achieve resolution of jaundice and ideally normal or near normal TSB in both curative and palliative patients as long as their functional status is largely preserved, i.e., patients categorized as Eastern Cooperative of Oncology Group [ECOG] status 0–2 and some ECOG 3 patients. The drainage strategy at our center is similar for curative and palliative patients: we perform EBD first, changing to PTBD if sufficient drainage is not achieved. Throughout the study period when performing EBD, we aimed to place bilateral plastic stents in order to avoid implanting materials that cannot be exchanged during surgery or later endoscopic revisions. This strategy is in line with the German guideline published in 2022 [7] while the European guideline of 2017 recommend the use of uncovered metal stents in palliative patients [5]. Given the European recommendation and accumulating data favouring metal stents in palliative pCCA, we have begun to use bilateral uncovered metal stents in palliative patients with poor functional status and/or poor prognosis; these patients were not included in the analysis. We collected data on all EBD and PTBD interventions performed until near normal TSB was achieved or the patient’s drainage situation was considered not further improvable by two experienced interventional endoscopists. TSB measured before the first intervention performed at our center was defined as pre-therapeutic TSB; the lowest TSB measured within three months after the last intervention included in the analysis, but before any other therapeutic measures that might potentially change the drainage situation (e.g., surgery) was defined as the post-therapeutic TSB.

2. Definitions

We used four alternative definitions of clinical success (CS) that have previously been used in studies addressing biliary drainage in pCCA with MHO:

TSB < 2 mg/dl
TSB < 5 mg/dl
> 50% reduction of pretherapeutic TSB
> 75% reduction of pretherapeutic TSB.

Complications were all adverse events that occurred related to interventional treatment. Cholangitis was diagnosed in accordance with the Tokyo classification for cholangitis and findings from endoscopy [8]. Clinically significant bleeding was defined as any intervention-related bleeding leading to transfusion of blood products or termination of the intervention. Post-endoscopic retrograde cholangiography (ERC)-pancreatitis was defined as abdominal pain plus elevated serum lipase above three times the upper limit of normal. Perforation was diagnosed either through direct intraprocedural visualization of the defect or abdominal pain plus free air on imaging. The classification of adverse events was performed by the novel classification for adverse events in gastrointestinal endoscopy (AGREE) [9].

3. Statistical Analyses

The data were collected in Microsoft Excel and analysed with IBM SPSS Statistics 25 and R Core Team 2022. Categorical data are expressed as count (percentage) and continuous data are expressed as medians (quartiles). Depending on the particular data set, Mann-Whitney test, Wilcoxon rank sum test, or Pearson’s chi-squared test with Yates’ continuity correction was used to test for statistical significance. Binary logistic regression was used to identify predictors of clinical success. The results are presented as odds ratios (OR) and confidence intervals (CI) of 95%.

4. Ethics Board Approval

The study protocol was submitted to the ethics board of the Hamburg chamber of physicians and was approved without a formal vote because of the retrospective nature of the study (reference numbers 2022-300198-WF, WF-078/20). The study was registered in the German Clinical Trials Registry (DRKS) on 7th of August 2023 (DRKS00032372).

Baseline characteristics

We identified 128 patients with a diagnosis of MHO due to pCCA treated at the Center of Visceral Medicine at Asklepios Hospital Hamburg-Barmbek between 2010 and 2020 (Tbl. 1). Of these, 77 (60.2%) were histologically confirmed. Median age was 72 (interquartile range 63–78) years and a non-significant male predominance (57%) was observed. All patients were discussed in our interdisciplinary tumor board: 56 (43.7%) patients were deemed suitable for a curative approach and for 72 (56.3%) patients, palliative therapy was recommended. Patients planned for curative therapy were significantly younger and had lower Bismuth-Corlette stage.

(Insert Table 1 here)

Table 1

**Baseline characteristics** Baseline-characteristics of patients presenting for perihilar Cholangiocarcinoma. Mann-Whitney test or Pearson’s Chi-squared test with Yates’ continuity correction was used to test for statistical significance.
Table 1 Baseline characteristics
	Overall (n = 128)	Curative (n = 56)	Palliative (n = 72)	p
Age
Median (Q1, Q3)	72 (63, 79)	68 (61, 75)	76 (68, 82)	< 0.001*
Mean (SD)	71 (12)	67 (11)	73 (12)
Sex
Male % (n)	57 (73)	57.1 (32)	56.9 (41)	1
Female % (n)	43 (55)	42.9 (24)	43.1 (31)
Bismuth Classification, % (n)
II	10.2 (13)	14.3 (8)	6.9 (5)	0.29
IIIA	28.1 (36)	39.3 (22)	19.5 (14)	0.02*
IIIB	27.3 (35)	33.9 (19)	22.2 (16)	0.2
IV	34.4 (44)	12.5 (7)	51.4 (37)	< 0.001*
Pretherapeutic TSB (mg/dl)
Median (Q1, Q3)	10 (5, 16)	9.6 (3.1, 16.5)	10.6 (7, 16.5)	0.17
Mean (SD)	11.1 (7.2)	10.2 (7.3)	11.7 (7.1)

Interventional data

The median pre-therapeutic TSB was 10 (4.93, 16.5) mg/dl in the overall population and did not differ between palliative and curative patients (9.6 mg/dl vs. 10.6 mg/dl, p = 0.168). To achieve optimal biliary drainage, a total of 335 interventions, i.e., 2.6 interventions per patient on average, were performed (Tbl. 2). These included 260 (77.6%) patients who underwent EBD and 75 (22.4%) who underwent PTBD. 47 patients underwent at least one PTBD procedure. Bilateral drainage, i.e., drainage of both the right and the left lobe, was performed in 55.4% of curative and 47.2% of palliative patients; this difference was not statistically different (p = 0.46). Since variations in biliary anatomy are common, bilateral drainage does not necessarily equate with complete drainage of all liver segments. For the purpose of our retrospective study, complete drainage was defined as the absence of undrained liver segments in a post-therapeutic ultrasound or – if no post-therapeutic ultrasound report was available – bilateral drainage. Complete drainage was achieved in 52% of the overall population and significantly more often in curative patients (66.1% vs. 41.7%, p = 0.01).

(Insert Table 2 here)

Table 2

**Interventional data** Pearson’s Chi-squared test with Yates’ continuity correction was used to test for statistical significance.
Table 2: Interventional data
	Curative(n = 56)		Palliative (n = 72)		p
	n	%	n	%
Number of EBD procedures
0	0	0	1	1.4	1
1	23	41.1	19	26.4	0.16
2	19	33.9	29	40.3	0.58
>=3	14	25	23	31.9	0.51
Number of PTBD procedures
0	35	62.5	46	63.9	1
1	13	23.2	14	19.5	0.76
2	7	12.5	6	8.3	0.63
>=3	1	1.8	6	8.3	0.22
Unilateral drainage	25	44.6	38	52.8	0.46
Bilateral drainage	31	55.4	34	47.2	0.46
Complete drainage	37	66.1	30	41.7	0.01*

Outcomes: Clinical Success

In our study, an average 79% reduction of the initial TSB was achieved, with a significantly greater reduction in curative compared to palliative patients (Fig. 1). Patients in the curative subgroup reached CS significantly more frequently than did those in the palliative subgroup, irrespective of what definition of CS was applied (Tbl. 3): A TSB under 2 mg/dl was attained in 66.1% of curative patients and 27.8% of palliative patients (p < 0.001), as was a TSB under 5 mg/dl (94.6% vs. 59.7%, p < 0.001). Likewise, a decrease of more than 75% of initial TSB was achieved more frequently in curative patients (57.1% vs. 29.2%, p = 0.003) as was a 50% or more decrease (76.8% vs. 51.4%, p = 0.006). When considering only patients with Bismuth-Corlette stage III, CS was more frequently achieved in curative patients, irrespective of CS definition. When comparing patients with Bismuth-Corlette stage IV disease, TSB < 2 mg/dl was achieved significantly more often in curative patients (85.7% vs. 24.3%, p = 0.007). For TSB reduction under 5 mg/dl or reduction under 50%, we observed a sub significant trend towards higher efficacy in curative Patients. The percentage of patients who showed a decrease of more than 75% of the initial TSB did not differ significantly between therapy groups in patients with Bismuth-Corlette stage IV (Supplement 2s).

(Insert Fig. 1 and Table 3 here)

Table 3

**Outcome** Mann-Whitney test or Pearson’s Chi-squared test with Yates’ continuity correction was used to test for statistical significance.
Table 3: Outcome
		Curative (n = 56)	Palliative (n = 72)	p
Pre-therapeutic TSB
	Median (Q1, Q3)	9.6 (3.1,16.5)	10.6 (6, 16.5)	0.17
	Mean (SD)	10.2 (7.3)	11.7 (7.1)
Post-therapeutic TSB
	Median (Q1, Q3)	1.45 (0.83, 2.8)	3.5 (1.7, 8.3)	< 0.001*
	Mean (SD)	1.9 (1.4)	5.5 (5.1)
Delta TSB
	Median (Q1, Q3)	7.8 (1.9, 12.4)	5.2 (1.8, 9.4)	0.11
	Mean (SD)	8.3 (6.8)	6.2 (7.2)
Percent reduction
	Median (Q1, Q3)	79 (62.8, 88.9)	50.4 (25.6, 78.7)	< 0.001*
	Mean (SD)	71.1 (23.2)	38.1 (70.7)
Clinical Success
< 2mg/dl % (n)		66.1 (37)	27.8 (20)	< 0.001*
< 5mg/dl % (n)		94.6 (53)	59.7 (43)	< 0.001*
> 50% TSB reduction % (n)		76.8 (43)	51.4 (37)	0.006*
> 75% TSB reduction % (n)		57.1 (32)	29.2 (21)	0.003*

Outcomes: Adverse events

A total of 24.2% of patients experienced complications, with a significantly greater rate in the palliative compared to the curative subgroup (33.3% vs. 12.5%, p = 0.01) (Tbl. 4). The most frequent adverse events were infectious complications, post-ERC pancreatitis, perforation and clinically relevant bleeding. The majority of complications were Class II or IIIa, only two complications had a complication rated Grade IV or higher. Both occurred in the palliative subgroup (Supplement 3s).

(Insert Table 4 here)

Table 4

**Complications** Pearson’s Chi-squared test with Yates’ continuity correction was used to test for statistical significance.
Table 4 Complications
	All (n = 128)		Palliative (n = 72)		Curative (n = 56)		p
	n	%	n	%	n	%
All complications	31	24.2	24	33.3	7	12.5	0.01*
Pancreatitis	6	4.7	4	5.6	2	3.6	0.92
Perforation	4	3.1	3	4.2	1	1.8	0.8
Pancreatitis + perforation	1	0.8	1	1.4	0	0	1
Infectious	12	9.4	11	15.3	1	1.8	0.02*
Cholangitis	8	6.3	8	11.1	0	0	0.03*
Pyogenic liver abscess	3	2.3	2	2.8	1	1.8	1
Sepsis	1	0.8	1	1.4	0	0	1
Clinically relevant bleeding	3	2.3	2	2.8	1	1.8	1
Bilioma	2	1.6	1	1.4	1	1.8	1
Cardiac arrest	1	0.8	1	1.4	0	0	1
Hemothorax	1	0.8	0	0	1	1.8	0.9
Stent induced cholecystitis	1	0.8	1	1.4	0	0	1

Predictors of CS

To evaluate the hypothesized predictors of clinical success, we conducted binary logistic regression models for all 4 CS cut-off values (Tbl. 5). A curative therapeutic approach was a predictor of CS irrespective of the definition used; the highest OR was observed for TSB reduction under 5 mg/dl. TSB at presentation was also a significant predictor of CS irrespective of the definition used. BC stage IV was identified as a predictor of not achieving TSB reduction under 5 mg/dl and achieving a 75% reduction of TSB at presentation. Bilateral drainage was not a significant predictor of CS in this analysis.

(Insert Table 5 here)

Table 5

Predictors for Clinical Success
CS-Grade	Corrected R2	Predictor	OR	95% CI		p
				Lower	Upper
< 2	0.26	Curative Therapy	5.3	2.21	12.88	< 0.001*
		TSB at presentation	0.92	0.87	1	0.007*
		Bilateral drainage	0.9	0.4	2.04	0.8
		BMC < IV	0.9	0.35	2.28	0.81
< 5	0.43	Curative Therapy	7.28	1.82	29.1	0.005*
		TSB at presentation	0.88	0.81	0.95	0.001*
		Bilateral drainage	2.74	0.96	7.9	0.06
		BMC < IV	3.44	1.18	10.04	0.02*
> 50%	0.36	Curative Therapy	4.12	1.54	11.04	0.005*
		TSB at presentation	1.19	1.1	1.29	< 0.001*
		Bilateral drainage	1.63	0.68	3.99	0.27
		BMC < IV	2.4	0.91	6.34	0.78
> 75%	0.34	Curative Therapy	3.15	1.23	7.84	0.01*
		TSB at presentation	1.14	1.07	1.21	< 0.001*
		Bilateral drainage	2.22	0.95	5.2	0.07
		BMC < IV	3.21	1.18	8.74	0.02*

Table 5.: Predictors for Clinical Success Clinical important variables were included in the binary logistic model to test for predictive factors.

In pCCA patients with MHO, biliary drainage is a critical part of the treatment of patients planned for curative or palliative therapy. While several studies have addressed this topic, there is no clear consensus on the optimal strategy for biliary drainage with regard to several important questions, such as first line drainage procedure, type of stent, extent of drainage and target TSB. Most studies address palliative patients only and patients from the Western world are somewhat underrepresented in the existing literature. This is the first direct comparison of biliary drainage in palliative and curative patients with MHO. We observed that – despite comparable drainage strategies and also when controlling for Bismuth-Corlette stage – interventional biliary drainage in curative patients was robustly associated with better clinical success rates and fewer adverse events.

Current European guidelines advise against routine preoperative biliary drainage in curative patients with pCCA and MHO, but favor of a decision “by a multidisciplinary team based on patient characteristics and institutional experience”. They do not recommend any specific TSB goal [5]. Likewise, a statement from a consensus conference by a global group of surgeons merely noted that some centers favor preoperative biliary drainage aiming for an TSB of 2–3 mg/dl while other centers do not require routine biliary drainage; consensus existed that biliary drainage is indicated under specific circumstances such as cholangitis, planned preoperative anti-neoplastic therapy, preoperative portal vein embolization, hyperbilirubinaemia-induced malnutrition, hepatic insufficiency or renal insufficiency [3, 5]. In a European prospective multicenter study, Farges et al. observed that low preoperative TSB was associated with a favorable outcome (90-day mortality) of right-sided but not left-sided hepatectomy [10].

For palliative patients, the European guidelines recommend drainage of more than 50% of liver volume using uncovered self-expanding metal stents [5]. A large retrospective series from China supports this approach since it revealed a superior CS (TSB below 2 mg/dl in this case) of 99% compared to unilateral stenting of bilateral plastic stents [11]. In contrast, the more recent German guideline recommends multiple plastic stents arguing that metal stents that cannot be removed from the bile ducts make reinterventions more technically difficult [7]. This problem becomes more relevant as palliative CCA patients live longer as novel targeted and immunological treatment options become available. The rationale for treating cholestasis in palliative CCA is (1) relief of jaundice and pruritus, (2) protection from or treatment of cholangitis and (3) enabling anti-neoplastic treatment since gemcitabine, that is part of the current first line regime for CCA, is thought to have increased toxicity in patients with elevated bilirubin [12, 13].

In the absence of conclusive evidence and strong guideline recommendations at our center we pursue a biliary drainage strategy that is comparable in both palliative and curative patients aiming for complete drainage in most cases and utilizing EBD first, followed by PTBD if EBD does not achieve complete drainage. Our analysis indicates that despite the similar approach and even if the extent of hilar tumor growth, i.e., the Bismuth-Corlette stage, biliary drainage is more likely to be successful and adverse events are rarer in curative compared to palliative patients. This information is relevant to manage patient and provider expectations and guide planning of biliary interventions.

Our investigation suggests that TSB decrease to near normal values, i.e., below 2 mg/dl, is challenging in a real world setting; in our patient cohort this was achieved only in 66.1% and 27.8% in curative and palliative patients, respectively. This is in contrast to a recent series from China in which unilateral and bilateral plastic stent placement in palliative patients with MHO resulted in TSB below 2 mg/dl in 65.4% and 71.4%, respectively [11]. This is despite a high percentage of Bismuth-Corlette stage IV individuals in that cohort. However, the patients evaluated were younger and a broad range of tumor entities causing MHO such as hepatocellular carcinoma, gallbladder cancer and metastases of distant primary tumors were included. Similarly, Liang et al. reported CS rates (in this case TSB decrease > 75%) of 50.6% for unilateral and 69.6% for bilateral drainage (EBD or PTBD) in Chinese palliative patients with MHO compared to 29.2% in our cohort [14]. Again, patients were younger and tumor entities other than CCA were included. In a large older palliative cohort from Europe a functional success rate (TSB reduction of 75% or more, intention to treat) of 84.8% was reported (EBD using plastic stents) [15]. However, this group included a majority of Bismuth-Corlette stage I lesions. These patients were excluded from our analysis because in these cases the bile ducts of both liver lobes are still functionally connected and drainage is thus considerably easier. Our results are in line with results of Sanchan et al., who only included palliative patients at a large volume center in Thailand with complex MHO due to pCCA [16].

Overall, differences in included tumor entities and stages, drainage strategy (e.g. EBD vs. PTBD; plastic vs. metal stents; unilateral vs. bilateral drainage), age and comorbidities, and end points (definitions of clinical success; per protocol vs. intention to treat) make comparisons across studies very difficult. Moreover, it is unclear if patient cohorts from different global regions are directly comparable. For instance, patients in Asian cohorts tend to be younger and the percentage with underlying parasitic disease as a key risk factor for CCA is much greater.

Several studies indicate that for EBD in palliative patients metal stents are probably superior to plastic stents in terms of short term clinical success and duration of stent patency [11, 15–19]. However, there is concern that reinterventions will be more difficult with metal stents in situ that cannot be removed [7]. This may be of high relevance in a setting where most palliative patients receive state-of-the-art anti-neoplastic therapy. For this reason, over the course of the study period, we have favored an approach where EBD with plastic stents was performed first and, if this was unsuccessful, PTBD was used. Meanwhile we employ bilateral metal stenting in patients with very limited prognosis due to poor functional status and/or no good medical treatment options.

The situation may be different for curative patients, but data in this group is very limited. Coelen et al. performed a randomized controlled trial comparing EBD and PTBD in patients with potentially resectable pCCA [20]. The trial was stopped prematurely after inclusion of 54 patients due to high all-cause mortality in the PTBD group, although excess mortality was not clearly related to complications of the drainage procedure. Clinical success (TSB reduction by 20% or more and sonographic relief of cholestasis in the future liver remnant) was seen in 63% and 78% in the EBD and PTB group with a high rate of crossover form EBD to PTB. Thus, this study is very comparable to our study both in terms of drainage strategy and clinical success.

To our knowledge, this our analysis presented here is the first one directly comparing success and adverse events of biliary drainage between palliative and curative patients with complex MHO due to CCA. We found a curative intent treatment to be associated with successful biliary drainage in terms of cholestasis relief and a lower rate of adverse events compared to palliative patients. This association held true even though a very similar drainage strategy was applied, a similar number of interventions was performed and was still evident when controlling for Bismuth-Corlette stage. As this study is retrospective, we cannot provide a definitive explanation for these differences, but the most likely explanation is that palliative patients were older, likely had poorer functional status and more advanced tumor stage. Even when comparing subgroups with the same Bismuth-Corlette stage the palliative group may still have had more advanced tumor growth. These same factors may also account to an extent for a higher rate of complications and severe complications in the palliative group. The reported complication rate in palliative patients matches several studies [11, 17, 21–23]. To our surprise, curative patients in our study faced fewer complications than presented in the literature [20, 24]. General health and frailty are typical parameters discussed in tumor boards and therefore, patients in the curative group are likely to be healthier. Thus, patients in the palliative group are likely to be more frail – a known risk factor for adverse events in endoscopy [25]. Another factor contributing to the higher rate of adverse events may be that palliative remain with their stents in situ for a longer period of time and are more likely to suffer cholangitis eventually, while most curative patients eventually undergo surgical resection.

Our work has several limitations. Most importantly, the study is retrospective and there are numerous known and unknown differences between the groups. Moreover, some important factors such as functional status and coexisting liver disease could not reliably be extracted for all patients from available records. Only a negligible number of patients received a therapy with metal stents for the reasons outlined above. Finally, while we could analyze unilateral vs. bilateral drainage there are frequent variations in biliary anatomy so that ultrasound confirmed complete drainage may be the more relevant parameter, but this information was not available in all cases.

In conclusion this retrospective analysis of European patients with complex MHO due to CCA provides a number of insights: (1) compared to curative patients palliative patients have poorer clinical responses when biliary drainage is performed. (2) They are also more likely to suffer adverse events and these tend to be more severe. These findings are potentially important information when planning biliary drainage in palliative patients and may help to manage both patient and provider expectations. (3) Studies on biliary drainage in MHO are extremely heterogeneous. Of note, we found success rates comparable to published series in curative patients, while recent series on mostly Asian palliative patients report better clinical success rates even when trying to control for the drainage technique applied. More data from different global regions and ideally more standardized study designs are needed.

pCCA, perihilar cholangiocarcinoma

EBD, endoscopic biliary drainage

TSB, total serum bilirubin

PTBD, percutaneous transhepatic biliary drainage

Bismuth-Corlette, Bismuth-Corlette

MHBO, malignant hilar biliary obstruction

CS, clinical success

AGREE, adverse events in GI endoscopy

OR, odds ratio

CI, confidence interval

ERC, endoscopic retrograde cholangiography

ESGE, European Society of Gastrointestinal Endoscopy

Jan Drews has no conflicts of interest or financial ties relevant to this study to disclose.

Lea-Catharina Baar has no conflicts of interest or financial ties relevant to this study to disclose.

Theresa Schmeisl has no conflicts of interest or financial ties relevant to this study to disclose.

Torsten Bunde has no conflicts of interest or financial ties relevant to this study to disclose.

Axel Stang has no conflicts of interest or financial ties relevant to this study to disclose.

Tim Reese has no conflicts of interest or financial ties relevant to this study to disclose.

Kim Caroline Wagner has no conflicts of interest or financial ties relevant to this study to disclose.

Karl Jürgen Oldhafer has no conflicts of interest or financial ties relevant to this study to disclose.

Thomas von Hahn has no conflicts of interest or financial ties relevant to this study to disclose.

Human Ethics and Consent to Participate declarations:

Not applicable.

Sources of funding

None.

External funding Sources specific to this paper:

None.

Acknowledgments

The study was registered in the German Clinical Trials Registry (DRKS) on 7^th of August 2023 (DRKS00032372).

Author contributions

Conceptualization: J.D., T.H., K.W., K.O., A.S.; Data curation: J.D., L.B., T.S, T.H., T.R.; Formal Analysis: J.D.; Investigation: T.B., T.H. Supervision: T.V.H.; Visualization: J.D., T.H.; Writing–original draft: J.D.; Writing–review & editing: all authors.

DeOliveira ML, Cunningham SC, Cameron JL, et al. Cholangiocarcinoma: thirty-one-year experience with 564 patients at a single institution. Ann Surg 2007; 245: 755–762. doi:10.1097/01.sla.0000251366.62632.d3
Khan SA, Thomas HC, Davidson BR, et al. Cholangiocarcinoma. Lancet 2005; 366: 1303–1314. doi:10.1016/S0140-6736(05)67530-7
Mansour JC, Aloia TA, Crane CH, et al. Hilar Cholangiocarcinoma: Expert consensus statement. HPB 2015; 17: 691–699. doi:10.1111/hpb.12450
Qumseya BJ, Jamil LH, Elmunzer BJ, et al. ASGE guideline on the role of endoscopy in the management of malignant hilar obstruction. Gastrointest Endosc 2021; 94: 222-234.e22. doi:10.1016/j.gie.2020.12.035
Dumonceau JM, Tringali A, Papanikolaou IS, et al. Endoscopic biliary stenting: Indications, choice of stents, and results: European Society of Gastrointestinal Endoscopy (ESGE) Clinical Guideline - Updated October 2017. Endoscopy 2018; 50: 910–930
Zhang W, Che X. Comparison of effect between nasobiliary drainage and biliary stenting in malignant biliary obstruction: a systematic review and updated meta-analysis. World J Surg Oncol 2020; 18: 71. doi:10.1186/s12957-020-01848-1
Deutsche Gesellschaft für Gastroenterologie VS e. V (DGVS). Leitlinienprogramm Onkologie (Deutsche Krebsgesellschaft, Deutsche Krebshilfe, AWMF): Diagnostik und Therapie des Hepatozellulären Karzinoms und biliärer Karzinome Langversion 3.0, 2022, AWMF-Registernummer: 032/053OL, https://www.leitlinienprogramm-onkologie.de/leitlinien/hcc-und-biliaere-karzinome/; Retrieved 10/03/2023. 2022
Kiriyama S, Kozaka K, Takada T, et al. Tokyo Guidelines 2018: diagnostic criteria and severity grading of acute cholangitis (with videos). J Hepatobiliary Pancreat Sci 2018; 25: 17–30. doi:10.1002/jhbp.512
Nass KJ, Zwager LW, van der Vlugt M, et al. Novel classification for adverse events in GI endoscopy: the AGREE classification. Gastrointest Endosc 2022; 95: 1078-1085.e8. doi:10.1016/j.gie.2021.11.038
Farges O, Regimbeau JM, Fuks D, et al. Multicentre European study of preoperative biliary drainage for hilar cholangiocarcinoma. Br J Surg 2013; 100: 274–283. doi:10.1002/bjs.8950
Xia MX, Cai XB, Pan YL, et al. Optimal stent placement strategy for malignant hilar biliary obstruction: a large multicenter parallel study. Gastrointest Endosc 2020; 91: 1117-1128.e9. doi:10.1016/j.gie.2019.12.023
Venook AP, Egorin MJ, Rosner GL, et al. Phase I and pharmacokinetic trial of gemcitabine in patients with hepatic or renal dysfunction: Cancer and Leukemia Group B 9565. J Clin Oncol 2000; 18: 2780–2787. doi:10.1200/JCO.2000.18.14.2780
Oh D-Y, Ruth He A, Qin S, et al. Durvalumab plus Gemcitabine and Cisplatin in Advanced Biliary Tract Cancer. NEJM Evidence 2022; 1. doi:10.1056/EVIDoa2200015
Liang X-Y, Li W, Liu F, et al. A Retrospective Study of Biliary Drainage Strategies for Patients with Malignant Hilar Biliary Strictures. Cancer Manag Res 2021; 13: 4767–4776. doi:10.2147/CMAR.S308833
Liberato MJA, Canena JMT. Endoscopic stenting for hilar cholangiocarcinoma: efficacy of unilateral and bilateral placement of plastic and metal stents in a retrospective review of 480 patients. BMC Gastroenterol 2012; 12. doi:10.1186/1471-230X-12-103
Sangchan A, Kongkasame W, Pugkhem A, et al. Efficacy of metal and plastic stents in unresectable complex hilar cholangiocarcinoma: a randomized controlled trial. Gastrointest Endosc 2012; 76: 93–99. doi:10.1016/j.gie.2012.02.048
Xia MX, Pan YL, Cai XB, et al. Comparison of endoscopic bilateral metal stent drainage with plastic stents in the palliation of unresectable hilar biliary malignant strictures: Large multicenter study. Digestive Endoscopy 2021; 33: 179–189. doi:10.1111/den.13680
Kim JY, Lee SG, Kang D, et al. The comparison of endoscopic biliary drainage in malignant hilar obstruction by cholangiocarcinoma: Bilateral metal stents versus multiple plastic stents. Gut Liver 2021; 15: 922–929. doi:10.5009/gnl20257
Paik WH, Park YS, Hwang J-H, et al. Palliative treatment with self-expandable metallic stents in patients with advanced type III or IV hilar cholangiocarcinoma: a percutaneous versus endoscopic approach. Gastrointest Endosc 2009; 69: 55–62. doi:10.1016/j.gie.2008.04.005
Coelen RJS, Roos E, Wiggers JK, et al. Endoscopic versus percutaneous biliary drainage in patients with resectable perihilar cholangiocarcinoma: a multicentre, randomised controlled trial. Lancet Gastroenterol Hepatol 2018; 3: 681–690. doi:10.1016/S2468-1253(18)30234-6
Lee TH, Kim TH, Moon JH, et al. Bilateral versus unilateral placement of metal stents for inoperable high-grade malignant hilar biliary strictures: a multicenter, prospective, randomized study (with video). Gastrointest Endosc 2017; 86: 817–827. doi:10.1016/j.gie.2017.04.037
Lee SH, Park JK, Yoon WJ, et al. Optimal biliary drainage for inoperable Klatskin’s tumor based on Bismuth type. World J Gastroenterol 2007; 13: 3948–3955. doi:10.3748/wjg.v13.i29.3948
de Palma GD, Galloro G, Siciliano S, et al. Unilateral versus bilateral endoscopic hepatic duct drainage in patients with malignant hilar biliary obstruction: results of a prospective, randomized, and controlled study. Gastrointest Endosc 2001; 53: 547–553. doi:10.1067/mge.2001.113381
Ba Y, Yue P, Leung JW, et al. Percutaneous transhepatic biliary drainage may be the preferred preoperative drainage method in hilar cholangiocarcinoma. Endosc Int Open 2020; 8: E203–E210. doi:10.1055/a-0990-9114
Acosta CJ, Goldberg D, Amin S. Evaluating the impact of frailty on periprocedural adverse events and mortality among patients with GI bleeding. Gastrointest Endosc 2021; 94: 517-525.e11. doi:10.1016/j.gie.2021.03.021

No competing interests reported.

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published 10 Oct, 2024

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Biliary Drainage in Palliative and Curative Intent European Patients with Hilar Cholangiocarcinoma and malignant hilar obstruction: a retrospective single center analysis

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Abstract

Background and Aims:

Patients and Methods:

Results

Conclusions

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Introduction

Material and Methods

1. Study design, patients and outcome

2. Definitions

3. Statistical Analyses

4. Ethics Board Approval

Results

Baseline characteristics

Interventional data

Outcomes: Clinical Success

Outcomes: Adverse events

Predictors of CS

Discussion

Abbreviations

Declarations

References

Additional Declarations

Supplementary Files

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Journal Publication

Version 1