Impact of adjuvant therapy on outcomes after curative-intent resection for distal cholangiocarcinoma.

BACKGROUND: The benefit of adjuvant therapy (AT) after curative resection of distal cholangiocarcinoma (DCC) remains unclear. The objective of the current study was to investigate the impact of AT on long-term survival of patients who underwent curative-intent resection for DCC. METHODS: Patients who underwent curative-intent resection for DCC between 2000 and 2020 were identified from a multi-institutional database. The primary outcomes included overall (OS) and recurrence-free survival (RFS). RESULTS: Among 245 patients, 150 (61.2%) patients received AT (chemotherapy alone: n = 43; chemo- and radiotherapy: n = 107) after surgical resection, whereas 95 (38.8%) patients underwent surgery only. Patients who received AT were younger, and more likely to have an advanced tumor with the presence of perineural invasion (PNI), lymph node metastasis (LNM), lymph-vascular invasion, and higher T categories (all p < 0.05). Overall, there was no difference in OS (median, surgery + AT 25.5 vs. surgery alone 24.5 months, p = 0.27) or RFS (median, surgery + AT 15.8 vs. surgery alone 18.9 months, p = 0.24) among patients who did versus did not receive AT. In contrast, AT was associated with improved long-term survival among patients with PNI (median OS, surgery + AT 25.9 vs. surgery alone 17.8 months, p = 0.03; median RFS, surgery + AT 15.9 vs. surgery alone 11.9 months, p = 0.04) and LNM (median, surgery + AT 20.0 vs. surgery alone 17.8 months, p = 0.03), but not among patients with no PNI or LNM (all p > 0.1). CONCLUSIONS: AT was commonly utilized among patients with DCC. Patients with more advanced disease, including the presence of PNI or LNM, benefited the most from AT with improved long-term outcomes among this subset of patients.

Identification of patients who may benefit the most from adjuvant chemotherapy following resection of incidental gallbladder carcinoma.

BACKGROUND: To develop a scoring system to identify the subset of patients who may benefit the most from adjuvant chemotherapy following curative-intent resection for incidental gallbladder cancer (IGBC). METHODS: A novel scoring system was utilized to stratify patients relative to overall survival (OS), as well as potential benefit from adjuvant chemotherapy following curative resection for IGBC. RESULTS: Among 266 patients with IGBC, a total of 99 (37.2%) patients received adjuvant chemotherapy. Five risk factors were used to develop an integer-based score to predict OS. Risk of death at 5-years incrementally increased among patients in the low (n = 42, 69.0%), medium (n = 64, 56.3%) and high-risk groups (n = 40, 30.0%) (median OS, 99.4 vs. 33.5 vs. 15.6 months, all p < .001). Use of adjuvant chemotherapy did not provide a survival benefit among patients in the low-risk group (median survival, 99.4 vs. 60.7 months, p = .56). In contrast, utilization of adjuvant chemotherapy was associated with an improvement in survival among medium- (median survival, 21.7 vs. 59.5 months, p = .04) and high-risk patients (median survival, 11.6 vs. 20.1 months, p = .01). CONCLUSIONS: While low-risk patients did not benefit from adjuvant chemotherapy, individuals with medium or high-risk scores had an improved survival with the utilization of adjuvant chemotherapy.

The Impact of Intraoperative Re-Resection of a Positive Bile Duct Margin on Clinical Outcomes for Hilar Cholangiocarcinoma.

BACKGROUND: The impact of re-resection of a positive intraoperative bile duct margin on clinical outcomes for resectable hilar cholangiocarcinoma (HCCA) remains controversial. We sought to define the impact of re-resection of an initially positive frozen-section bile duct margin on outcomes of patients undergoing surgery for HCCA. METHODS: Patients who underwent curative-intent resection for HCCA between 2000 and 2014 were identified at 10 hepatobiliary centers. Short- and long-term outcomes were analyzed among patients stratified by margin status. RESULTS: Among 215 (83.7%) patients who underwent frozen-section evaluation of the bile duct, 80 (37.2%) patients had a positive (R1) ductal margin, 58 (72.5%) underwent re-resection, and 29 ultimately had a secondary negative margin (secondary R0). There was no difference in morbidity, 30-day mortality, and length of stay among patients who had primary R0, secondary R0, and R1 resection (all p > 0.10). Median and 5-year survival were 22.3 months and 23.3%, respectively, among patients who had a primary R0 resection compared with 18.5 months and 7.9%, respectively, for patients with an R1 resection (p = 0.08). In contrast, among patients who had a secondary R0 margin with re-resection of the bile duct margin, median and 5-year survival were 30.6 months and 44.3%, respectively, which was comparable to patients with a primary R0 margin (p = 0.804). On multivariable analysis, R1 margin resection was associated with decreased survival (R1: hazard ratio [HR] 1.3, 95% confidence interval [CI] 1.0-1.7; p = 0.027), but secondary R0 resection was associated with comparable long-term outcomes as primary R0 resection (HR 0.9, 95% CI 0.4-2.3; p = 0.829). CONCLUSIONS: Additional resection of a positive frozen-section ductal margin to achieve R0 resection was associated with improved long-term outcomes following curative-intent resection of HCCA.

Oncologic effects of preoperative biliary drainage in resectable hilar cholangiocarcinoma: Percutaneous biliary drainage has no adverse effects on survival.

BACKGROUND AND OBJECTIVES: The objective of the current study was to define long-term survival of patients with resectable hilar cholangiocarcinoma (HCCA) after preoperative percutaneous transhepatic biliary drainage (PTBD) versus endoscopic biliary drainage (EBD). METHODS: Between 2000 and 2014, 240 patients who underwent curative-intent resection for HCCA were identified at 10 major hepatobiliary centers. Postoperative morbidity and mortality, as well as disease-specific survival (DSS) and recurrence-free survival (RFS) were analyzed among patients. RESULTS: The median decrease in total bilirubin levels after biliary drainage was similar comparing PTBD (n = 104) versus EBD (n = 92) (mg/dL, 4.9 vs 4.9, P = 0.589) before surgery. There was no difference in baseline demographic characteristics, type of surgical procedure performed, final AJCC tumor stage or postoperative morbidity among patients who underwent EBD only versus PTBD (all P > 0.05). Patients who underwent PTBD versus EBD had a comparable long-term DSS (median, 43.7 vs 36.9 months, P = 0.802) and RFS (median, 26.7 vs 24.0 months, P = 0.571). The overall pattern of recurrence relative to regional or distant disease was also the same among patients undergoing PTBD and EBD (P = 0.669) CONCLUSIONS: Oncologic outcomes including DSS and RFS were similar among patients who underwent PTBD versus EBD with no difference in tumor recurrence location.

Defining Early Recurrence of Hilar Cholangiocarcinoma After Curative-intent Surgery: A Multi-institutional Study from the US Extrahepatic Biliary Malignancy Consortium.

BACKGROUND: Time to tumor recurrence may be associated with outcomes following resection of hepatobiliary cancers. The objective of the current study was to investigate risk factors and prognosis among patients with early versus late recurrence of hilar cholangiocarcinoma (HCCA) after curative-intent resection. METHODS: A total of 225 patients who underwent curative-intent resection for HCCA were identified from 10 academic centers in the USA. Data on clinicopathologic characteristics, pre-, intra-, and postoperative details and overall survival (OS) were analyzed. The slope of the curves identified by linear regression was used to categorize recurrences as early versus late. RESULTS: With a median follow-up of 18.0 months, 99 (44.0%) patients experienced a tumor recurrence. According to the slope of the curves identified by linear regression, the functions of the two straight lines were y = -0.465x + 16.99 and y = -0.12x + 7.16. The intercept value of the two lines was 28.5 months, and therefore, 30 months (2.5 years) was defined as the cutoff to differentiate early from late recurrence. Among 99 patients who experienced recurrence, the majority (n = 80, 80.8%) occurred within the first 2.5 years (early recurrence), while 19.2% of recurrences occurred beyond 2.5 years (late recurrence). Early recurrence was more likely present as distant disease (75.1% vs. 31.6%, p = 0.001) and was associated with a worse OS (Median OS, early 21.5 vs. late 50.4 months, p < 0.001). On multivariable analysis, poor tumor differentiation (HR 10.3, p = 0.021), microvascular invasion (HR 3.3, p = 0.037), perineural invasion (HR 3.9, p = 0.029), lymph node metastases (HR 5.0, p = 0.004), and microscopic positive margin (HR 3.5, p = 0.046) were independent risk factors associated with early recurrence. CONCLUSIONS: Early recurrence of HCCA after curative resection was common (~35.6%). Early recurrence was strongly associated with aggressive tumor characteristics, increased risk of distant metastatic recurrence and a worse long-term survival.

Evaluating the American College of Surgeons National Surgical Quality Improvement project risk calculator: results from the U.S. Extrahepatic Biliary Malignancy Consortium.

BACKGROUND: The objective of this study is to evaluate use of the American College of Surgeons (ACS) National Surgical Quality Improvement Program (NSQIP) online risk calculator for estimating common outcomes after operations for gallbladder cancer and extrahepatic cholangiocarcinoma. METHODS: Subjects from the United States Extrahepatic Biliary Malignancy Consortium (USE-BMC) who underwent operation between January 1, 2000 and December 31, 2014 at 10 academic medical centers were included in this study. Calculator estimates of risk were compared to actual outcomes. RESULTS: The majority of patients underwent partial or major hepatectomy, Whipple procedures or extrahepatic bile duct resection. For the entire cohort, c-statistics for surgical site infection (0.635), reoperation (0.680) and readmission (0.565) were less than 0.7. The c-statistic for death was 0.740. For all outcomes the actual proportion of patients experiencing an event was much higher than the median predicted risk of that event. Similarly, the group of patients who experienced an outcome did have higher median predicted risk than those who did not. CONCLUSIONS: The ACS NSQIP risk calculator is easy to use but requires further modifications to more accurately estimate outcomes for some patient populations and operations for which validation studies show suboptimal performance.

Elevated NLR in gallbladder cancer and cholangiocarcinoma - making bad cancers even worse: results from the US Extrahepatic Biliary Malignancy Consortium.

BACKGROUND: Gallbladder and extrahepatic biliary malignancies are aggressive tumors with high risk of recurrence and death. We hypothesize that elevated preoperative Neutrophil-Lymphocyte Ratios (NLR) are associated with poor prognosis among patients undergoing resection of gallbladder or extrahepatic biliary cancers. METHODS: Patients who underwent complete surgical resection between 2000-2014 were identified from 10 academic centers (n=525). Overall (OS) and recurrence-free survival (RFS) were analyzed by stratifying patients with normal (<5) versus elevated (>5) NLR. RESULTS: Overall, 375 patients had NLR <5 while 150 patients had NLR >5. Median OS was 24.5 months among patients with NLR<5 versus 17.0 months among patients with NLR>5 (p<0.001). NLR was also associated with OS in subgroup analysis of patients with gallbladder cancer. In fact, on multivariable analysis, NLR>5, dyspnea and preoperative peak bilirubin were independently associated with OS in patients with gallbladder cancer. Median RFS was 26.8 months in patients with NLR<5 versus 22.7 months among patients with NLR>5 (p=0.030). NLR>5 was independently associated with worse RFS for patients with gallbladder cancer. CONCLUSIONS: Elevated NLR was associated with worse outcomes in patients with gallbladder and extrahepatic biliary cancers after curative-intent resection. NLR is easily measured and may provide important prognostic information.

Impact of Preoperative Jaundice and Biliary Drainage on Short- and Long-term Outcomes among Patients with Gallbladder Cancer.

OBJECTIVES: To characterize the prognostic implication of jaundice and preoperative biliary drainage on postoperative outcomes among patients with gallbladder cancer (GBC) undergoing surgical resection. METHODS: Patients who underwent surgical resection of GBC identified from a multicenter database between January 2000 and December 2019 were retrospectively analyzed. Data on clinical and pathological details, as well as short- and long-term overall survival (OS), were obtained and compared among patients with and without preoperative jaundice and biliary drainage. RESULTS: Among 449 patients with GBC, median and 1-, 3-, and 5-year OS were 17.4 months, 63.7%, 28.4%, and 22.1%, respectively. Patients who presented with preoperative jaundice (n = 100, 22.3%) were more likely to have advanced disease, a lower incidence of R0 resection (29.0% vs. 69.1%, p < 0.001), as well as a higher incidence of postoperative liver failure (4% vs. 0, p = 0.002), and worse long-term survival versus patients without jaundice (median OS, 10.4 vs. 27.1 months, p < 0.001). Preoperative biliary drainage was performed for the majority of jaundiced patients (77.0%) and was associated with decreased risk of postoperative liver failure (1.3% vs. 13.0%, p = 0.041); preoperative biliary drainage failed to improve long-term survival (median OS, 10.2 months vs. 12.0 months, p = 0.679). On multivariable analysis, R0 resection (17.5 vs. 7.6 months, p < 0.001) and adjuvant therapy (15.6 vs. 6.6 months, p = 0.027) were associated with improved long-term survival among jaundiced patients. CONCLUSIONS: While preoperative biliary drainage of jaundiced GBC patients decreased the risk of postoperative liver failure, it did not impact long-term outcomes. Rather, preoperative jaundice was associated with a lower chance at R0 resection and worse long-term survival.

Surgical Strategies for Bismuth Type I and II Hilar Cholangiocarcinoma: Impact on Long-Term Outcomes.

BACKGROUND: The surgical approach to treat Bismuth type I and II hilar cholangiocarcinoma (HCCA) has been a topic of debate. We sought to characterize whether bile duct resection (BDR) with or without concomitant hepatic resection (HR) was associated with R0 margin status, as well as define the impact of HR+BDR versus BDR alone on long-term survival. METHODS: Patients who underwent curative-intent HR+BDR for HCCA between 2000 and 2014 were identified from a multi-institutional database. Perioperative and long-term outcomes were compared among patients who underwent BDR only, BDR+left hepatic resection (LHR), and BDR+right hepatic resection (RHR) for Bismuth type I and II HCCA. RESULTS: Among 257 patients with HCCA, 61 (23.7%) patients had a Bismuth type I (n=25, 41.0%) or II (n=36, 59.0%) lesion. The incidence of R0 resection after BDR only was the same as among patients after LHR and RHR (BDR 70.0% vs. BDR+LHR 71.4% vs. BDR+RHR 76.5%, p=0.891). In contrast, severe complications were more likely after LHR and RHR than BDR only (BDR 21.4% vs. BDR+LHR 60.0% and BDR+RHR 50.0%, p=0.041). Overall (median: BDR 20.9 vs. BDR+LHR 23.2 and BDR+RHR 25.0 months, p=0.213) and recurrence-free (median: BDR 13.4 vs. BDR+LHR 15.3 and BDR+RHR 25.0, p= 0.109) survival were comparable. On multivariable analysis, while CA19-9>37.0U/ml (Ref. CA19-9≤37.0U/ml, HR 3.2, 95% CI 1.1-9.4, p=0.035) and AJCC T3-T4 disease (Ref. T1-T2, HR 4.6, 95% CI 1.5-13.7, p=0.007) were associated with long-term survival, surgical approach was not (BDR+LHR: HR 1.0, 95% CI 0.5-2.2, p=0.937; BDR+RHR: HR 0.6, 95% CI 0.3-1.3, p=0.197). CONCLUSION: R0 resection, overall survival, and recurrence-free survival were comparable among well-selected patients who had BDR versus BDR+HR for Bismuth type I and II HCCA.