The epidemiological trends of Biliary tract cancers in United States

doi:10.21203/rs.3.rs-2005610/v1

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The epidemiological trends of Biliary tract cancers in United States

https://doi.org/10.21203/rs.3.rs-2005610/v1

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Background: Biliary tract cancers (BTCs) are a series of heterogeneous malignancies that are broadly grouped based on the anatomical site where they arise into subtypes including intrahepatic cholangiocarcinoma (ICC), extrahepatic cholangiocarcinoma (ECC), gallbladder cancer (GBC), and ampulla of Vater cancer (AVC).

Methods and Results: The present study serves to provide an overview of the epidemiology of various biliary tract cancers (BTCs) based on data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) database from 2000-2018. Differences in both incidence and mortality rates were observed for these distinct BTCs as a function of age, sex, ethnicity, and calendar year. In 2018, BTCs emerged as the 5^th most prevalent form of alimentary tract cancer in US. While increasing trends were observed with respect to ICC incidence and associated mortality, the rates of GBC, ECC, and AVC have remained stable, as have the corresponding mortality rates. The most common and deadliest BTCs in 2018 were ICC and GBC among males and females, respectively. The ethnic groups exhibiting the highest incidence rates of these different BTCs were Black individuals for GBC, Asian and Pacific Islanders for ECC and AVC, and White or Asian and Pacific Islanders for ICC. The incidence of all of these forms of BTC rose with age. There were a few changes among BTCs in staging, locoregional surgical treatments, adjuvant therapies, and prognostic outcomes from 2000-2018.

Conclusions: The epidemiological characteristics, staging, locoregional surgical treatments, adjuvant therapies, and prognostic outcomes were distinct for each of these BTCs.

Biliary tract cancers (BTCs)

intrahepatic cholangiocarcinoma (ICC)

extrahepatic cholangiocarcinoma (ECC)

gallbladder cancer (GBC)

ampulla of Vater cancer (AVC)

Biliary tract cancers (BTCs) are a series of heterogeneous malignancies that are broadly grouped based on the anatomical site where they arise into subtypes including intrahepatic cholangiocarcinoma (ICC), extrahepatic cholangiocarcinoma (ECC), gallbladder cancer (GBC), and ampulla of Vater cancer (AVC) (1, 2). These different forms of BTC exhibit distinct epidemiological, etiological, and molecular characteristics that contribute to differences in their clinical presentation and treatment(3). Overall, BTCs account for ~3% of all gastrointestinal neoplasms and are the 6^th most common cancer of the alimentary tract after colorectal, pancreatic, liver, stomach, and esophageal cancers(4, 5). Although rare, the prognosis for patients affected by BTCs is poor, with a 5-year overall survival (OS) rate of just 10-40% even after surgical tumor resection(6-10).

A growing number of recently published studies have suggested that BTC incidence is rising throughout the globe, with some changes in the prevalence of these tumors and associated mortality rates in recent decades(11, 12). Strikingly, ICC rates have risen substantially, with an average annual increase of 4.36% over the last 10 years(13, 14). Many researchers have also demonstrated that adjuvant therapy is associated with survival benefits in BTC patients(10, 15-17). However, at present there is a lack of publications providing an updated overview of the epidemiological characteristics of BTC and associated patient survival outcomes.

The present study was thus developed as a population-based analysis of data derived from the Surveillance, Epidemiology, and End Results (SEER) database produced by the National Cancer Institute (https://seer.cancer.gov/) Program. Here, the epidemiology, clinical characteristics, and prognostic findings associated with BTCs are surveyed in detail.

The SEER 18 registry serves as a definitive source for cancer-related statistics corresponding to ~28% of the population of the United States. These data were thus used to assess BTC incidence and mortality rates for the period from 2000-2018 using the SEER*Stat software (v 8.4.0), with data being obtained for intrahepatic bile duct [C22.1], extrahepatic bile duct [C24.0], gallbladder [C23.9], ampulla of Vater [C24.1], and other biliary tract cancers [C24.8 and C24.9]. Hematological cancers were excluded from this analysis. Overall alimentary tract cancer incidence rates were also analyzed, as were the demographic, tumor characteristicscharacteristic, treatment, and survival details for all BTC cases diagnosed in the 2000-2018 period. While Klatskin tumors were misclassified as ICC in the ICD-O-2 and as ICC or ECC in ICD-O-3, for the present study liver and intrahepatic Klatskin tumors (histology code 8162/3) were treated as ECC cases given that these tumors are of extrahepatic origin(18). As the BTC staging criteria published by the AJCC changed significantly from 2000 to 2018, the SEER staging system was instead used for the present analysis, with tumors being staged as cases of localized, regional, or distant disease. Cases were grouped based into four categories in accordance with the surgical and adjuvant therapy approaches employed, including no surgery or adjuvant therapy, surgery without adjuvant therapy, adjuvant therapy without surgery, and both surgery and adjuvant therapy,

Statistical Analysis

Categorical data are given as counts with percentages. BTC incidence rates were compared to those of other forms of alimentary tract cancer. Incidence and incidence-based mortality rates for different BTC subtypes are reported as a function of sex, ethnicity, age, and calendar year. The annual percentage change (APC) in BTC incidence and incidence-based mortality was analyzed using Joinpoint (v 4.9.0.0) based on the piecewise log-linear time calendar trends(19). Similarly, the average age-specific percentage change (AAPC) was performed in the trend of age. Estimated 2-year relative survival rates were additionally compared among patients with different subtypes of BTC and across calendar years. SPSS 26.0 was used for all statistical testing, a two-sided P < 0.05 was the threshold of significance.

From 2000 to 2018, 64,666 cases of BTC (14,830 ICC [22.9%], 17,004 ECC [26.3%], 19,187 GBC [29.7%], 9,742 AVC [15.1%], and 3,903 other biliary tract cancer [6.0%]) (Table 1 in the Supplement). In total, 661 Klatskin tumors (18 coded as in the liver, 643 as ICC) were identified and recategorized as ECC for the purposes of this analysis. Of these identified BTC cases, 53.6% (34,691) and 46.4% (29,975) were diagnosed in females and males, respectively.

The mean patient age at time of diagnosis was 70.03 ± 12.96 years, with a median age of 71 years (range: 1-100 years). Of these patients, 98.4% were 40 years of age or older (63,641 cases). Overall, 78.2% (50,589) of patients were white, 9.5% (6,130) were black, 11.1% (7,151) were Asian and Pacific Islanders, 1% (625) were American Indians and Alaskan Natives, and 0.3% (171) were of unknown race. Of the 30,266 BTC cases for which a known grade was available (46.8%), 4,125 (6.4%), 13,558 (21%), 11,909 (18.4%), and 674 (1.0%) were grade I, grade II, grade III, and grade IV, respectively. Of the 56,262 BTC cases for which staging information was available (87.0%), 11,299 (17.5%) were localized, 22,993(35.6%) were regional, and 21,970 (34%) were classified as distant disease when initially diagnosed. With respect to treatment, 25,514 cases (39.5%) did not undergo surgery or adjuvant therapy, while 15,158 (23.4%) underwent surgery alone, 1,350 (20.9%) underwent adjuvant treatment alone, and 10,489 (16.2%) underwent both surgery and adjuvant treatment.

Next, age-adjusted incidence and incidence-based mortality rates (per 100,000 persons) were calculated for these different BTCs based on population data derived from the SEER database with reference to the 2000 US standard population. Overall, BTC incidence rates were 3.5 and 4.4 per 100,000 persons in 2000 and 2018, respectively, with an APC of 1.4 (95% CI, 1.1-1.8) from 2004-2018, ranking as the 6^th and 5^th most common alimentary tract cancers in 2000 and 2018, respectively (Figure 1). Incidence and incidence-based mortality rates for these different forms of BTC among males and females were next compared (Figure 2a andFigure 2b, respectively), revealing that GBC incidence was higher among females, whereas ICC, ECC and AVC incidence was higher among males. In 2018, the highest BTC incidence and mortality rates were for ICC in males and GBC in females. From 2003-2018, significant increases in incidence and incidence-based mortality rates were observed among patients with ICC, with respective incidence APC values of 7.7 (95% CI, 6.9-8.5) and 7.0 (95% CI, 6.0-8.0) for males and females, and corresponding incidence-based mortality rate APC values of 6.4 (95% CI, 4.8-8.1) and 6.3 (95% CI, 5.0-7.6). Overall trends in BTC incidence as a function of ethnicity were also assessed (Figure 3a), revealing that the highest rates of GBC were observed among black individuals, while ECC and AVC incidence rates were highest among Asian and Pacific Islanders, and ICC incidence was highest among white individuals or Asian and Pacific Islanders. From 2003-2018, ICC incidence rates rose among all analyzed ethnic groups other than the American Indian and Alaska Native population (White: APC, 8.1 [95% CI, 7.0-9.2]; Black: APC, 7.7 [95% CI, 6.2-9.2]; Asian and Pacific Islander: APC, 3.5 [95% CI, 2.1-4.9]).

BTC incidence rates were additionally assessed as a function of patient age (≥ 40 years) over the years (Figure 3b), revealing significant increases in the incidence of all analyzed BTCs with age (ICC: AAPC, 7.2 [95% CI, 5.4-9.8]; ECC: AAPC, 9.0 [95% CI, 7.5-10.6]; GBC: AAPC, 8.3 [95% CI, 6.9-9.7]; AVC: AAPC, 7.5 [95% CI, 6.0-9.0]).

Trends in BTC staging and treatment

Trends in BTC patient staging at initial presentation and treatment patterns are summarized in Figure 4a and Figure 4b, respectively. Overall, the percentage of BTC patients diagnosed with distant-stage disease rose with time (ICC: from 36.80% in 2000 to 52.10% in 2018; ECC: from27.60% in 2000 to 37.20% in 2018;GBC: from 31.9% in 2000 to 47.2% in 2018; AVC: from 15.60% in 2000 to 32.30% in 2018), while the percentage of patients diagnosed with localized disease declined with time (ICC: from 30.10% in 2000 to 22.00% in 2017; ECC: from 27.60% in 2000 to 37.20% in 2018; GBC: from 28.4% in 2000 to 11.5% in 2018; AVC: from 22.70% in 2000 to 16.50% in 2018). For patients with AVC and GBC, surgery alone was the most common treatment strategy, while patients with ICC and ECC most commonly underwent neither surgery nor adjuvant therapy. For patients with BTC, the percentage of patients that underwent surgery alone declined with time (ICC: from 8.40% in 2000 to 7.80% in 2018; ECC: from 15.40% in 2000 to 10.2% in 2018; GBC: from 52.70% in 2000 to 33.60% in 2018; AVC: from 42.50% in 2000 to 28.40% in 2018), while the percentage of patients that underwent adjuvant therapy alone or in combination with surgery rose with time (ICC: from 22.9% in 2000 to 53.2% in 2018; ECC: from 25.5% in 2000 to 41.3% in 2018; GBC: from 28.1% in 2000 to 43.1% in 2018; AVC: from 27.9% in 2000 to 48.6% in 2018).

BTC patient survival trends

Lastly, trends in the 2-year survival outcomes for BTC patients from 2000-2015 were assessed (Figure 5). The survival rates for AVC and ECC patients were the highest and lowest among BTC patients, respectively, with corresponding average 2-year survival rates of 44.5% and 17.4%. The 2-year survival rates for ICC and GBC and AVC improved from 2000 to 2015 (GBC: from 23.00% to 27.40%; AVC: from 40.20% to 54.20%; ICC: from 15.90% to 22.70%). ECC patient 2-year survival rates improved from 2000 to 2006 (from 15.4% in 2000 to 20.3% in 2006), changed few from 2006 to 2014 (20.10% in 2014).

The present population-based study leverage data from the SEER registry to conduct the largest analysis of BTC patient data available through 2018. Overall, BTC incidence has continued to rise over the analyzed 19-year period, primarily owing to increases in ICC rates, in line with findings from previous epidemiological studies(13, 14).

ICC is a heterogeneous disease, the development of which is associated with several risk factors including viral hepatitis, liver cirrhosis, and other systemic or gastrointestinal diseases(4, 20). There are also marked geographic differences in ICC incidence throughout the world, and epidemiological differences have been observed even when examining populations exposed to similar risk factors. These differences may thus be attributable to ICC misclassification in at least some cases. Consistently, ICCs have been diagnosed as cases of hepatocellular carcinoma, mixed cancer, or cancer of unknown primary, while Klatskin tumors are sometimes misclassified as ICC cases(4, 18, 21). Definitive ICC diagnosis in the more advanced stages is disease is also challenging. Overall, ICC remains a relatively rare form of cancer such that its misdiagnosis can lead to significant bias regarding overall ICC incidence rates. Clearer diagnostic criteria are thus essential to guide the more accurate diagnosis of this disease. However, it is important to note that no identifiable risk factors are known to be associated with the observed increase in ICC incidence over time.

Over the 2000-2018 period, rates of GBC, AVC, and ECC remained relatively stable in the US, with some increases and decreases in these incidence rates in certain years. Stable or decreasing ECC incidence has also been reported in Europe and Japan(22, 23). One systematic review found that congenital cystic dilatations of the biliary tree were most strongly associated with ECC (OR 34.94, 95% CI, 24.36-50.12), although these dilatations are more common in females than males, in contrast to the observed ECC incidence pattern. Both choledocholithiasis and cholelithiasis are risk factors associated with ECC (OR 18.58, 95% CI 11.07-31.18 and OR 5.92, 95% CI, 3.09-11.32; respectively), although insufficient evidence is available to definitively establish whether alcohol intake, smoking, diabetes, overweight/obesity, or inflammatory bowel disease are also risk factors for this form of BTC(24).

Several known risk factors for GBC include gallstones, infections, gallbladder polyps, and other inflammatory conditions(8, 25). The past study reported that due to Cholecystectomy population at risk of developing GBC decreased (GBC). Given that total cholecystectomy rates have remained largely unchanged since the mid-1990s, there were few changes in GBC incidence over the target study period(11). GBC incidence among females is substantially higher than among males, with these gender-related differences observed in the US being consistent with those observed in other regions of the world. One recent analysis found GBC susceptibility in females to be associated with variants in the prostate stem cell antigen gene(26).

Overall, AVC is a relatively rare form of cancer, accounting for just 15.1% of all BTC cases in the US. One recent study found that AC incidence change less during 1992 and 2009 among whites, while declining among female Asian and Pacific Islanders(11). In the present study, AVC trends remained stable in all ethnic groups over the analyzed period (P ≥ 0.05). AVC-related risk factors have not been definitively established, although one recent study observed increased ABC incidence to be related to smoking but not alcohol intake(27). The higher rates of smoking among males were consistent with the observed higher incidence of AVC among males.

Effectively treating BTC remains a significant clinical challenge, as patients often do not present for diagnosis until the disease is in an advanced stage(28). Rising rates of BTC patients being diagnosed with distant-stage disease in recent years suggest that certain imaging-based diagnostic tools may have led to the detection of metastases that would previously have been overlooked. Rates of adjuvant therapy for BTC patients have also risen over the past 19 years, with several studies having demonstrated a link between such treatment and improved BTC patient survival outcomes. For example, one systematic review and meta-analysis of 20 studies determined that adjuvant chemotherapy and adjuvant chemoradiation (OR, 0.39, 95% CI, 0.23 to 0.66; 0.61, 95% CI 0.38 to 0.99; respectively) yielded greater benefits in BTC patients that underwent surgical tumor resection(29). This is consistent with the 2-year survival rates observed in the present study, suggesting that adjuvant therapy use is contributing to a better prognosis for individuals diagnosed with BTC. The survival rates were low among ECC patients as well as ICC patients, potentially owing to the fact that these two forms of BTC are relatively difficult to resect. Overall, mortality rates among patients with BTC have not declined substantially, suggesting that there has been little improvement in long-term patient prognosis. As the ICC mortality APC was lower than that for incidence, this suggests that the rise in patient 2-year survival may ultimately correspond to prolonged overall survival in this expanding patient population.

There are certain limitations to this analysis. First, the SEER database did not include all BTC cases, the classifications of other biliary tract remained unclear. As a result, the observed incidence rate was lower than the true incidence rate. In addition, data pertaining to patient vital exposure, diabetes status, smoking history, or history of biliary tract disease were not available, precluding any analyses of these risk factors. Despite significant progress in the development of targeted therapies and immunotherapies in recent years, data from the SEER database could not be used to examine the relationship between these therapies and BTC patient survival outcomes(30). One recent study using the SEER database found that treatment with FDA-approved targeted therapies led to significant improvements in lung cancer patient 2-year survival since 2013 with corresponding reductions in mortality(31). However, this was not observed in the present study.

In summary, the results of this analysis of SEER registry data over a 19-year period revealed that ICC incidence and mortality rates have risen with time, while ECC and GBC and AVC incidence and mortality have remained relatively stable. These different forms of BTC exhibited significant differences in their epidemiology, staging at diagnosis, treatment and prognosis. Both surgery and adjuvant therapy remain important approaches to BTC patient treatment, and the average 2-year survival rates for patients with these cancers have continued to improve with time. However, further research is required to determine the efficacy of targeted therapies and immunotherapeutic interventions in patients with BTC.

Acknowledgements Not applicable.

Authors' contributions YJ and LYJ conceived and designed the study. YJ, FYL, QBL and SY collected the data. SHH, YDF, LYJ, XYY, HXL, YJ, and SHL performed the statistical analysis. YJ, LYJ and FYL wrote the manuscript. JC, QBL and JL revised it. All authors read and approved the final manuscript.

Funding This work was fund by the National Natural Science Foundation of China (General Program), No.81770646.

Data availability The data generated in this study are publicly available in the Surveillance, Epidemiology, and End Results (SEER) database produced by the National Cancer Institute (https://seer.cancer.gov/) Program.

Code availability Not applicable

Ethics approval and consent to participate Not applicable

Competing interests The authors have no competing interests to declare that are relevant to the content of this article.

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No competing interests reported.

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The epidemiological trends of Biliary tract cancers in United States

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