Failure to administer multimodality therapy leads to sub-optimal outcomes for patients with node-positive biliary tract cancers in the United States
Introduction
Biliary tract cancers are rare but aggressive malignancies with a dismal prognosis. Overall five-year survival typically ranges from 5 to 15% [1,2]. Complete surgical resection is the only curative therapy for these cancers, which include intrahepatic and extrahepatic cholangiocarcinoma, Klatskin tumor or hilar cholangiocarcinoma, and gallbladder cancer. For patients who do undergo surgical resection, five-year survival rates are 8–40% [2]. However, less than 35% of patients present at an early stage when surgical resection is feasible [1].
Early lymph node metastases are a characteristic feature of biliary tract cancers, with lymph node metastases present in 30–50% of patients who undergo surgery [[3], [4], [5], [6], [7]]. For those with lymph node-positive disease, five-year survival is less than 15% [8]. Current National Comprehensive Cancer Network (NCCN) guidelines recommend multimodality therapy for all patients diagnosed with node-positive cholangiocarcinoma, including surgical resection and systemic chemotherapy with or without radiation [9].
The optimal adjuvant therapy for biliary tract cancers remains uncertain. Until the recent BILCAP study from the United Kingdom, which compared observation versus capecitabine chemotherapy in patients who underwent biliary tract cancer resection, there were no phase 3 clinical trials to suggest a survival benefit from adjuvant chemotherapy [10,11]. Despite this, adjuvant chemotherapy is recommended for all biliary tract cancer patients with lymph node-positive disease [9]. This guideline is supported by a meta-analysis of nine studies including 230 patients, which found a significant survival benefit with adjuvant therapy in node-positive disease [1]. Secondary analyses of the BILCAP study found that both node-positive and node-negative patients benefited from adjuvant capecitabine, though node-positive patients had decreased overall survival in general. Previous reports have noted that outcomes for patients with locally advanced or node positive disease are particularly poor, and perhaps systemic chemotherapy should be considered prior to surgical resection in these high-risk cases [12]. Given the uncertainty of optimal treatment for node-positive biliary tract cancers, we sought to evaluate the impact of treatment modality on survival in this specific sub-group of patients, and the frequency with which patients receive guideline-recommended care.
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Data source and patients
An augmented version of the National Cancer Institute's Surveillence, Epidemiology, and End Results (SEER) program database was used to identify patients with biliary tract cancers (intrahepatic and extrahepatic cholangiocarcinoma, Klatskin tumors, and gallbladder adenocarcinoma) from 2000 to 2014 [13]. SEER registries represent about 28% of the United States population over 18 geographic areas. Both patient and tumor characteristics are collected, including age at diagnosis, sex, race, primary
Patient population
A total of 3226 patients with node-positive biliary tract cancers were identified (Table 1). The median age of these patients was 67 years. Fifty-seven percent of patients were female and 79% of patients were white. Most tumors were grade III (52%), T3 based on TNM staging criteria (36%), and were 2–5 cm in size (77%). Of these patients, 379 (11.8%) had intrahepatic cholangiocarcinoma, 1250 (38.7%) had extrahepatic cholangiocarcinoma, 51 (1.6%) had Klatskin tumors, and 1546 (47.9%) had
Discussion
In this analysis of patients with node-positive biliary tract cancers, we found that multimodality therapy including surgery and chemotherapy was associated with improved median OS compared to patients who underwent either surgery alone or chemotherapy alone. Furthermore, the addition of radiation seems to be associated with additional survival benefit. This trend was consistent for gallbladder cancers, intrahepatic cholangiocarcinoma, and extrahepatic cholangiocarcinoma. According to National
Conclusions
Patients with clinically node-positive biliary tract cancers of all subtypes have extremely poor outcomes. Our data show a persistent association between receipt of adjuvant chemotherapy and median survival in patients with node-positive biliary tract cancers after adjustment for patient and tumor factors, in agreement with previous studies. There may be an additional benefit with adjuvant chemoradiation for selected patients. In reality, only 51% of patients who undergo up front surgery
Grant support
Ariella Altman is in part supported by the Institute of Basic and Applied Research in Surgery and the VFW grant at the University of Minnesota.
CRediT authorship contribution statement
Adam C. Sheka: Conceptualization, Formal analysis, Investigation, Methodology, Writing - original draft. Ariella Altman: Formal analysis, Investigation, Methodology, Writing - review & editing. Schelomo Marmor: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Visualization, Writing - review & editing. Jane Y.C. Hui: Investigation, Methodology, Writing - review & editing. Jason W. Denbo: Conceptualization, Investigation, Writing - review & editing. Jacob S. Ankeny:
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