Impact of specialized multi-disciplinary approach and an integrated pathway on outcomes in hilar cholangiocarcinoma

doi:10.1016/j.ejso.2013.10.009

European Journal of Surgical Oncology (EJSO)

Volume 40, Issue 1, January 2014, Pages 77-84

https://doi.org/10.1016/j.ejso.2013.10.009 Get rights and content

Abstract

Aims

To assess the outcomes of patients with hilar cholangiocarcinoma following referral to a specialist multi-disciplinary team.

Methods

Over an 11-year period, patients referred with hilar cholangiocarcinoma were identified from a prospectively maintained registry. Collated data included demographics, operative findings and histo-pathological data. Survival differences and prognostic factors were determined.

Results

345 patients were referred with hilar cholangiocarcinoma, of which 57 (16.5%) patients had surgery. Prior to 2008, of 143 patients referred, only 17 (11.9%) patients underwent surgery, compared to 40 (19.8%) of 202 patients referred from 2008 onwards (p = 0.051). In the surgery group, the majority of patients underwent left hemi-hepatectomy (n = 19). In addition, portal vein (n = 5), hepatic artery (n = 2) and inferior vena cava (n = 3) resections were performed. The R0 resection rate was 73.7%. The morbidity and mortality rates were 59.6% and 14.0%, respectively. The median disease-free survival was 16 (4–101) months. The presence of lymph node metastasis (p = 0.002) was the only predictor of poorer disease-free survival. The 5-year overall survival was 39.5% and was significantly better than that of the palliative group (p < 0.001).

Conclusions

Surgery is the optimal treatment option for patients with hilar cholangiocarcinoma and is associated with better overall survival. Prompt referral to tertiary centres with a core team of clinicians to manage this difficult condition may allow more patients to come to potentially curative surgical resections.

Introduction

Biliary malignancies constitute approximately 2% of all cancers found at autopsy, of which hilar or “Klatskin” tumours represent around 50–80% of these cases.1, 2, 3 At present, it is unclear whether there is a true increase in the incidence of hilar cholangiocarcinoma (HC), or additional cases are being identified with more accurate cross-sectional imaging being performed.

The overall 5-year survival rates following hepatic resection of HC varies from 20 to 40%.4, 5, 6, 7 Although surgery remains the only potential curative therapy, it is technically demanding due to the presence of locally advanced disease, proximity of the tumour to hilar vasculature and tumour biology. Various clinico-pathological variables have been shown to influence survival, including margin status, nodal status, tumour differentiation and peri-neural and/or vascular invasion.4, 7, 8, 9 However, the majority of patients with HC are unresectable at either presentation, following staging laparoscopy or during laparotomy. Criteria for unresectable disease include locally advanced tumours involving portal and hepatic vasculature, distant metastases and nodal metastases beyond the hepato-duodenal ligament. In addition, patients must have limited co-morbidities; as most cases require an extended hepatectomy against a background of cholangitis and obstructive jaundice.

The improved treatment of HC over the last decade is not only related to changes in surgical strategy, but also improvement in selection and pre-operative work-up of patients considered for curative resection. With the introduction of specialist multi-disciplinary team (MDT) management, this treatment process may contribute to better outcomes.¹⁰ The aim of this study was to assess the outcomes of patients with HC following such a specialist MDT approach.

Section snippets

Patients and methods

Patients with HC referred during an 11-year period from January 2001 to December 2012 were identified from a prospectively maintained hepatobiliary database and specialist multi-disciplinary recording system.

Patients that had potentially resectable and unresectable HC were included. In addition, intra-hepatic cholangiocarcinoma affecting the portal hilum (often termed peri-hilar cholangiocarcinoma) were included, as the treatment is similar and often difficult to differentiate from true HC.

Pre-operative evaluation

Collated data included patient demographics, surgery, histopathology analysis and outcome. Pre-operative assessment included multi-slice triple phase contrast-enhanced computer tomography (CT) scan of the thorax, abdomen and pelvis, and liver-specific contrast enhanced magnetic resonance imaging (MRI) of the liver (from 2008).

Pre-operative biliary drainage was considered in patients with obstructive jaundice. Biliary drainage of the future liver remnant was achieved endoscopically, percutaneous

Multi-disciplinary approach

All patients were discussed in a specialist MDT meeting that consisted of hepatobiliary surgeons, hepatologist, oncologist, radiologist and pathologist prior to surgery. Since 2008, an integrated care pathway was implemented, and jaundiced patients with a proximal biliary stricture were managed by a specialist MDT.

Surgical and post-operative details

Parenchymal transection was performed using the Cavi-Pulse Ultrasonic Surgical Aspirator (CUSA) or Kellyclasia. Intra-operative ultrasound was performed to confirm the findings of pre-operative imaging. The number of hepatic (Couinaud's) segments¹³ resected was determined by the procedure performed as stated in the Brisbane nomenclature.¹⁴ The type of surgical procedure was dependent on the resection of all macroscopic disease and achieving a clear resection margin, while preserving sufficient

Histo-pathological analysis

The Bismuth–Corlette classification¹¹ was used to pre-operatively define tumour extension along the intra-hepatic bile ducts based on cross-sectional imaging. Intra-operatively, tumour extension and margins were examined by histo-pathological evaluation of frozen sections. The histological staging of the disease was determined according to the TNM classification following the criteria of the American Joint Committee on Cancer (AJCC).¹⁶ Tumour differentiation was graded as well, moderately and

Follow-up protocol

Patients were followed up in specialist hepatobiliary clinics. Following initial post-operative review at one month after discharge, all patients were seen in the outpatient clinic at 3, 6, 12, 18 and 24 months and annually thereafter. At each clinic review, blood tests were drawn for liver function tests and CA 19.9 levels. Patients underwent 6-monthly surveillance CT scan during the first two post-operative years, followed by annual CT scans thereafter.

Overall and disease-free survival data

Statistical analysis

Categorical data were analysed using the Pearson's chi-squared test. The Kaplan–Meier method was used to assess the actuarial survival and disease-free survival. Uni-variate analysis was performed to assess for a significant difference in clinico-pathological characteristics that influenced survival following resection. Statistical analyses were performed using the SPSS for Windows™ version 16.0 (SPSS Inc, Chicago, Ill, USA), and statistical significance was taken at the 5% level.

Results

During the study period, 345 patients with HC were referred and discussed at the unit's specialist MDT meeting, of which 244 patients were deemed unresectable on initial cross-sectional imaging (Fig. 1). One hundred and one patients considered potentially resectable on imaging underwent staging laparoscopy which subsequently excluded 18 (17.8%) patients due to locally advanced tumour or the presence of liver and/or peritoneal metastasis. Eighty-three patients underwent laparotomy, of which 57

Prognostic factors influencing survival outcome

Fourteen patients that underwent potentially curative surgery developed recurrent disease. The median disease-free survival was 16 (4–101) months. The presence of lymph node metastasis (p = 0.002) was the only predictor of poorer disease-free survival on uni-variate analysis [median survival N1 = 10 (5–87) months versus N0 = 21 (5–101) months, Table 3, Fig. 2].

The 1-, 3-, and 5-year overall survival was 73.5%, 49.6% and 39.5%, respectively in the surgical group. In comparison, the 1- and 3-year

Discussion

Due to both tumour proximity to the hilar vasculature and tumour biology, HC remains a surgical challenge. Nevertheless, surgical resection represents the only potentially curative option for these patients and improves long-term outcome. A radical resection with negative margins is the only factor with a demonstrated impact on outcome that can be influenced by the surgeon, and therefore should be the main aim of treatment.³

Whether there is a true increase in the incidence of HC, these patients

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Results from the european survey on preoperative management and optimization protocols for PeriHilar cholangiocarcinoma
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Major surgery, along with preoperative cholestasis-related complications, are responsible for the increased risk of morbidity and mortality in perihilar cholangiocarcinoma (pCCA). The aim of the present survey is to provide a snapshot of current preoperative management and optimization strategies in Europe.
61 European centers, experienced in hepato-biliary surgery completed a 59-questions survey regarding pCCA preoperative management. Centers were stratified according to surgical caseload (<5 and ≥ 5 cases/year) and preoperative management protocols’ application.
The overall case volume consisted of 6333 patients. Multidisciplinary discussion was routinely performed in 91.8% of centers. Most respondents (96.7%) recognized the importance of a well-structured preoperative protocol. The preferred method for biliary drainage was percutaneous transhepatic biliary drainage (60.7%) while portal vein embolization was the preferred technique for liver hypertrophy (90.2%). Differences in preoperative pathologic confirmation of malignancy (35.8% vs 28.7%; p < 0.001), number of mismanaged referred patients (88.2% vs 50.8%; p < 0.001), biliary drainage (65.1% vs 55.6%; p = 0.015) and liver function evaluation (37.2% vs 5.6%; p = 0.001) were found between centers according to groups’ stratification.
The importance of a correct preoperative management is recognized. Nevertheless, the current lack of guidelines leads to wide heterogeneity of behaviors among centers. This survey can provide recommendations to improve pCCA perioperative outcomes.
Radial and longitudinal margins in surgery of perihilar cholangiocarcinoma: When R1 definition is associated with different prognosis
2023, Surgery (United States)
Infiltrated margins of resection (R1) and lymph node invasion are dominant negative predictors of survival in patients with a resectable perihilar cholangiocarcinoma. Less clear is whether survival predictors stratify differently between R0 (tumor-free margins) and R1 patients and whether the prognosis of the latter patients is influenced by the pattern of neoplastic infiltration (ie, radial versus longitudinal infiltration). We retrospectively evaluated a series of reported resected perihilar cholangiocarcinoma to obtain insights on the predictive power of these histologic features.
The study includes 264 patients with perihilar cholangiocarcinoma treated between 2004 and 2019 in our center and followed up for >18 months. There were 176 patients with R0 (66.6%) and 88 patients with R1 (33.3%), 31 with radial infiltration only, 30 with longitudinal infiltration only, and 27 with both infiltration patterns. In all patients, the criteria for resection was the absence of metastatic involvement (ie, distant organ metastases, liver metastases, and lymph node metastases beyond the hepatoduodenal ligament). Histopathologic specimens of the resected tumors were centrally reviewed by a pathologist unaware of the clinical outcomes.
Three- and 5-year long-term survival were significantly better in R0 (respectively) compared to R1 patients (55% and 42% vs 42% and 18%, respectively, P < .05). In R1 patients with radial infiltration only and those with radial + longitudinal infiltration, both disease-free and overall survival were worse than those with longitudinal infiltration only (median disease-free survival of 18 and 23 months, respectively, P < .05, median overall survival of 33 and 39 months, respectively, P < .05). At multivariable analysis, nodal status, side of hepatectomy, grading, and presence of radial margin infiltration were associated with long-term outcome.
Radial infiltration of resection margins enhances the negative prognostic value of R1 margins in perihilar cholangiocarcinoma patients and should specifically be accounted for in the prediction of the outcome of adjuvant therapy.
Long-term morbidity after surgery for perihilar cholangiocarcinoma: A cohort study
2022, Surgical Oncology
Citation Excerpt :
Surgery for pCCA remains a formidable undertaking usually requiring a major liver resection in addition to a radical bile duct resection and complex biliary reconstruction. The magnitude of this surgery is reflected in its operative mortality, reported between 7 and 15% in most Western centres [4,5,9–12]. In addition, almost half of patients will suffer a major complication prior to discharge from hospital [5,9,12].
Surgery for perihilar cholangiocarcinoma (pCCA) offers the only possibility of long-term survival, but remains a formidable undertaking. Traditionally, 90-day post-operative complications and death are used to define operative risk. However, there is concern that this metric may not accurately capture long-term morbidity after such complex surgery.
A retrospective review of a prospective database of patients undergoing surgery for pCCA at a Western centre between January 2009-2020.
Eighty-five patients underwent surgical resection for pCCA with a median overall survival of 36.3 months. Post-op (<90day) morbidity rates were high with 46% of patients developing a major complication (Clavien-Dindo grade 3–4). Post-op mortality rate was 13%. In total 38% (28/74) of patients experienced at least 1 episode of delayed morbidity (>90-days of surgery) resulting in 53 separate admissions with a median LOS of 7 days (IQR 2–15). These episodes were predominately secondary to biliary obstruction with the majority requiring radiological intervention (Clavien-Dindo grade 3). The development of long-term morbidity was associated with increased recurrence rates and correlated with poorer OS (27.6 months vs. 65.7 months HR 2.2 CI 1.63-2.77).
Routinely cited 90-day morbidity and mortality does not accurately capture the patient morbidity experienced following surgery for pCCA. Surgery clearly offers a survival benefit and should be pursued in selected patients, but they must be fully counselled on the potential for long-term morbidity before embarking on this strategy.
Impact of preoperative biliary drainage on postoperative outcomes in hilar cholangiocarcinoma
2022, Asian Journal of Surgery
Complete resection is the most effective treatment of hilar cholangiocarcinoma (HC) but may result in high morbidity and mortality. Most HC patients have jaundice, and preoperative biliary drainage may reduce their risk of obstructive jaundice. ERCP and PTBD have been advocated for this purpose. This retrospective study investigated the influence of ERCP versus PTBD versus their combination on the short-term outcomes of curative HC resection.
Patients having curative HC resection with preoperative biliary drainage in a span of 26 years were reviewed and divided into groups according to drainage modality. Drainage-related and surgical complications and hospital mortality were compared between groups. Intention-to-treat analysis using a separate set of initial drainage data was performed.
Eighty-six patients were divided into: Group A, ERCP only, n = 32 (32/86 = 37.2%); Group B, PTBD only, n = 10 (10/86 = 11.6%); Group C, ERCP + PTBD, n = 44 (44/86 = 51.2%). International normalized ratio was significantly higher in Group B (p = 0.008). The three groups were comparable in operative details, hospital stay, and mortality. Fifty-two patients had postoperative complications. Significantly more patients in Groups A and C had subphrenic abscess (A: 25%, B: 0%, C: 9.1%; p = 0.035) and subsequent radiological drainage. Group A had insignificantly more patients with wound infection (31.3% vs 10% vs 22.7%, p = 0.334), chest infection (28.1% vs 20% vs 11.4%, p = 0.178), and urinary tract infection (6.3% vs 0% vs 0%, p = 0.133). The three groups had similar rates of major complications (p = 0.501). They also had comparable survival outcomes (overall, p = 0.370; disease-free, p = 0.569). Fifteen and 71 patients received PTBD and ERCP respectively as first drainage mode. These two groups were comparable in liver function, preoperative comorbidity, intraoperative details, and postoperative outcomes.
In the preoperative management of HC, the use of ERCP, PTBD or their combination is acceptable and can optimize patients’ condition for curative HC resection.
Italian Clinical Practice Guidelines on Cholangiocarcinoma – Part II: Treatment
2020, Digestive and Liver Disease
Currently, the only curative treatment for cholangiocarcinoma (CCA) is surgical resection, though this treatment is possible in less than 40% of patients. However, recent improvements in preoperative management have led to a higher number of patients who are candidates for this procedure. For unresectable patients, progress is ongoing in terms of locoregional and chemoradiation treatments and target therapies, especially in the definition of patient selection criteria. This is the second part of the Italian CCA guidelines, dealing with CCA treatment, that have been formulated in accordance with Italian National Institute of Health indications and developed according to the GRADE method and related advancements.
Increased multimodality treatment options has improved survival for Hepatocellular carcinoma but poor survival for biliary tract cancers remains unchanged
2019, European Journal of Surgical Oncology
Citation Excerpt :
Surgery is the only effective curative option for cholangiocarcinoma, yielding 5-year survival rates of approximately 40% [12]. Our current resection rate for hilar cholangiocarcinomas of 19% is a modest, yet important advance on our previous figure of 16.5% published 4 years ago [12]. Most series agree that resection rates for cholangiocarcinoma are low but there is heterogeneity in resectability rates, a range of 10–40% of presenting patients being reported by a recent review [13].
Primary hepatobiliary cancer incidence in the UK is rising and survival rates are low. Surgery is the main curative option for these cancers, but multimodality therapies are expanding. The aim of our original study was to determine trends in survival, over an 8-year period, of patients treated for primary hepatobiliary cancers at our tertiary referral Centre.
Patients treated for the most common types of primary hepatobiliary cancers, namely Hepatocellular carcinoma (HCC), Cholangiocarcinoma and Gallbladder cancer between January 2009 and December 2016 were retrospectively analysed from a prospective database linked to UK Hospital Episode Statistics data.
A total of 1536 patients with primary hepatobiliary cancers were assessed and treatment plans formulated at our supra-regional specialist Hepatobiliary MDT. The primary hepatobiliary cancers treated were HCC (n = 836), Cholangiocarcinoma (n = 516), and Gallbladder cancer (n = 184). Survival for all the 3 cancers was significantly better with curative treatment. Overall median survival times were 350, 180, and 150 days respectively for HCC, Cholangiocarcinoma and Gallbladder cancer. Excluding best supportive care patients, the respective survival figures were 900, 600, and 400 days. Survival for HCC patients improved over time and was significantly increased in the final 3 years of the study (p ≤ 0.011 for all). Cholangiocarcinoma and Gallbladder cancer survivals were poor and did not change significantly over time.
HCC outcome has improved in association with expanded multimodal therapies. Survivals for cholangiocarcinoma and gallbladder cancer remain poor in parallel with limited expansion of multimodal therapies highlighting an unmet therapeutic need for biliary tract cancers.

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Impact of specialized multi-disciplinary approach and an integrated pathway on outcomes in hilar cholangiocarcinoma

Abstract

Aims

Methods

Results

Conclusions

Introduction

Section snippets

Patients and methods

Pre-operative evaluation

Multi-disciplinary approach

Surgical and post-operative details

Histo-pathological analysis

Follow-up protocol

Statistical analysis

Results

Prognostic factors influencing survival outcome

Discussion

Lancet

Eur J Surg Oncol

HPB (Oxford)

Eur J Surg Oncol

HPB (Oxford)

HPB (Oxford)

Eur J Surg Oncol

HPB (Oxford)

Increase in mortality rates from intrahepatic cholangiocarcinoma in England and Wales 1968–1998

Gut

Hilar cholangiocarcinoma: current management

Ann Surg

Hilar cholangiocarcinoma: patterns of spread, the importance of hepatic resection for curative operation, and a presurgical clinical staging system

Ann Surg

Staging, resectability, and outcome in 225 patients with hilar cholangiocarcinoma

Ann Surg

Cholangiocarcinoma. A spectrum of intrahepatic, perihilar, and distal tumors

Ann Surg

Surgery for hilar cholangiocarcinoma: an Italian experience

J Hepatobiliary Pancreat Surg

Long-term outcome of extended hemihepatectomy for hilar bile duct cancer with no mortality and high survival rate

Ann Surg

Intrahepatic cholangioenteric anastomosis in carcinoma of the hilus of the liver

Surg Gynecol Obstet

Anatomic principles of left and right regulated hepatectomy: technics

J Chir (Paris)

Nomenclature of hepatic anatomy and resections: a review of the Brisbane 2000 system

J Hepatobiliary Pancreat Surg

The Clavien-Dindo classification of surgical complications: five-year experience

Ann Surg

Extrahepatic bile ducts

Resection of hilar cholangiocarcinoma: concomitant liver resection decreases hepatic recurrence

Ann Surg