Epidemiologic Trends in Secondary Malignant Neoplasms of the Liver in the United States: A 25-Year National Study

Epidemiologic Trends in Secondary Malignant Neoplasms of the Liver in the United States: A 25-Year National Study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Epidemiologic Trends in Secondary Malignant Neoplasms of the Liver in the United States: A 25-Year National Study Mahnoor Khan, Daniyal Ali Khan, Kantesh Kumar, Syed Ali Tayyeb Hasan, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7613109/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 07 Jan, 2026 Read the published version in Journal of Gastrointestinal Cancer → Version 1 posted You are reading this latest preprint version Abstract Background Secondary malignant neoplasms of the liver (SMNL) are more common than primary liver cancers but remain understudied. This study provides the first nationwide analysis of SMNL mortality trends and disparities in the US. Methods This study analyzed SMNL-related (ICD-10: C78.7) CDC WONDER mortality data (1999–2023), and US Cancer Statistics incidence data for adults ≥ 45 years, stratified by demographics, geography, and primary site. Age-adjusted mortality and incidence rates (AAMRs, AAIRs) and crude mortality rates (CMRs) were reported per 100,000 population. Temporal trends were analyzed using Joinpoint regression. Results SMNL-related AAMR rose from 23.8 (1999) to 25.1 (2023). Males accounted for 51.3% of the 597,332 deaths and had higher AAMRs than females throughout. Lung (25.6%) and colon (24.6%) cancers were the leading primary sites causing SMNL-related deaths. AAIRs and AAMRs (irrespective of metastasis) declined for most primary cancers. CMRs progressively increased across each successive 10-year age group. Non-Hispanic (NH) Blacks had the highest AAMR but with a declining trend, while NH Whites saw a significant increase. West’s AAMRs showed the biggest increase. Rural areas consistently had higher AAMRs. Conclusions SMNL mortality is rising among older US adults, with disparities. Improved primary cancer survival extends the window for metastatic progression, highlighting the need for better detection and management. Epidemiology Gastroenterology & Hepatology Health Inequities Epidemiology Mortality Liver Neoplasms Neoplasm Metastasis Figures Figure 1 Figure 2 Figure 3 Figure 4 1 Introduction Secondary malignant neoplasm of the liver (SMNL) is often more prevalent than primary liver cancer, yet its mortality trends remain underexplored. 1 This has been represented in a University of Cologne study where liver metastases (611 cases) outnumbered primary hepatocellular carcinoma (380 cases) among 1,357 tumor samples. 2 Liver cancer is the sixth most common cancer worldwide, ranking fifth in men and ninth in women. 3 In 2022, the US had the second-highest liver cancer incidence (43,492 cases) and the third-highest mortality (30,931 deaths). 3 The liver is a common site for organ-specific metastasis due to its unique microvascular circulation. 4 , 5 Gastrointestinal, breast, and prostate cancers, along with neuroendocrine tumors and sarcomas, commonly metastasize to the liver. 6 While some studies have examined the burden of SMNL in the US using the Surveillance, Epidemiology, and End Results (SEER) database, they provide only limited coverage due to incomplete geographic representation and inconsistent registry inclusion over time. 6 , 7 Although primary liver cancer mortality trends have been previously studied, no large-scale analysis has comprehensively examined SMNL mortality across demographic and geographic factors. 8 Liver cancer, often diagnosed at advanced stages, has a poor prognosis due to its rapid progression and the liver’s vulnerability to metastasis, necessitating a nationwide analysis. 9 This study addresses that gap by providing the first nationwide evaluation of SMNL mortality trends, highlighting demographic and geographic disparities and the primary cancers most commonly leading to SMNL-related mortality, offering insights for targeted surveillance and treatment strategies. 2 Materials and Methods 2.1 Study design and population We conducted a population-based cross-sectional study primarily focused on SMNL-related mortality trends. Mortality data from 1999–2023 were obtained from the CDC’s Wide-Ranging Online Data for Epidemiologic Research (CDC WONDER), using the Multiple Cause of Death database. 10,11 Individuals aged ≥ 45 years with SMNL were identified using the International Classification of Diseases, Tenth Revision (ICD-10) code C78.7. To contextualize SMNL-related mortality, we examined both incidence and mortality trends for the primary cancers most associated with SMNL-related deaths. Incidence data from 1999–2021 were obtained from the United States Cancer Statistics (USCS) database, the official federal source for cancer surveillance. USCS is produced by the CDC and the National Cancer Institute (NCI), incorporating data from the National Program of Cancer Registries (NPCR) and the SEER program, covering nearly the entire US population. 12 This study adhered to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines and the Declaration of Helsinki. 13 Since the study used publicly available, deidentified data, informed consent and institutional review board approval were not required. 2.2 Outcome Variables This study primarily analyzed SMNL-related mortality in the US, including (1) trends in overall age-adjusted mortality rates (AAMR); (2) AAMR trends stratified by gender, race, region, urbanization status, primary cancer site, and the three states with the highest and lowest average annual percentage changes (AAPC); (3) trends in crude mortality rates (CMR) across different age groups; (4) trends in the proportion of deaths by place of death; and (5) state-level variation in overall AAMR and AAPC. The secondary objectives were to examine trends in AAIR and AAMR for the top ten primary cancers most frequently associated with SMNL-related mortality, using overall cancer-specific incidence and mortality data irrespective of SMNL contribution. 2.3 Data abstraction Gender was used as a binary variable. Race/ethnicity classifications included non-Hispanic (NH) White, NH Black or African American (NH-BAA), NH Asian or Pacific Islander (NH-A/PI), NH American Indian or Alaska Native (NH-AI/AN), and Hispanic. Age groups were stratified into 45–54, 55–64, 65–74, 75–84, and ≥ 85 years. Places of death were classified as inpatient hospital (IPH), outpatient or emergency room facility (OEF), the decedent's home, hospice facility, and nursing home/long-term care facility. According to the 2013 US Census classification, the population was categorized using the National Center for Health Statistics Urban-Rural Classification Scheme as urban (≥ 50,000) or rural (< 50,000). 14 AAMR by urbanization status was available only for 1999–2020. Regions were classified into Northeast, Midwest, South, and West according to the Census Bureau definitions. Primary cancer sites were identified using concurrent ICD-10 codes with SMNL on death certificates (Supplementary Table 1) . Analyses for prostate and ovarian cancers were restricted to males and females, respectively. Breast cancer analysis focused on females, with a sensitivity analysis combining both genders. Male breast cancer was excluded due to suppressed or negligible AAMRs (< 0.1). To protect confidentiality, CDC WONDER suppresses counts below 10 and flags rates as unreliable for counts under 20. Subgroups with small numbers in our study included such suppressed or unreliable data, indicated by “-” in tables and dotted lines in figures. 2.4 Statistical analysis AAMRs, AAIRs, and CMRs per 100,000 individuals were calculated. The 2000 US population served as the standard for AAMRs and AAIRs. 15 The Joinpoint Regression Program (version 5.3.0) was used to compute annual percent changes (APCs) and AAPC, as well as 95% confidence intervals (CI), using log-linear regression models. Temporal variations were recorded to identify significant shifts in AAMRs and AAIRs. The statistical significance of the APCs that were computed for each segment connecting join points was determined using the Monte Carlo permutation test. A two-tailed t-test (P < 0.05, indicated by an asterisk "*" in data and graphics) was used to assess changes in APC. A significant deviation of the mortality trend slope from zero classified the change as increasing or decreasing. 3 Results Supplementary Fig. 1 provides a central illustration of our study's SMNL-related mortality summary. Detailed results of the study are shown in Figs. 1 – 4 , supplementary tables 1–14 , and supplementary Figs. 2–11. 3.1 Overall Between 1999 and 2023, the study reported 597,332 SMNL-related deaths among adults aged 45 and above (Supplementary Table 2) . For overall SMNL-related mortality, AAMR increased from 23.8 per 100,000 in 1999 to a peak of 25.1 in 2023 (AAPC = 0.22%*, 95% CI: 0.14 to 0.29) ( Fig. 1 ) . The AAMR initially declined significantly from 23.8 in 1999 to 14.9 in 2008 (APC= -5.21%*, 95% CI: -5.49 to -4.94). This was followed by a significant rise, especially from 15.7 in 2013 to 20.1 in 2016 (APC = 8.56%*, 95% CI: 7.07 to 9.36). (Supplementary Table 3) . 3.2 Gender Stratified Of the total SMNL-related deaths, 306,558 (51.3%) were men, with consistently higher AAMR than women from 1999 to 2023 ( Fig. 1 ) . Both genders followed similar mortality trends throughout, with a significant initial decline from 1999 till 2008. During this period, AAMR almost halved from 20.6 to 12.9 for females (APC=-5.04%*, 95% CI: -5.32 to -4.79) and 28.4 to 17.4 for men (APC=-5.42%*, 95% CI: -5.84 to -5.09). Following this period, AAMR kept increasing till 2023 for both genders, with AAMR of females reaching a peak of 22.6 in 2023 but that of males reached 28.2, close to their peak of 28.4 in 1999. The initial rise from 2008 to 2013 was significant only for females (females: APC = 0.91%*, 95% CI: 0.41 to 1.35; males: APC = 1.23%, 95% CI: -0.84 to 2.46). The steepest rise in AAMR was observed by both genders from 2013 to 2017. AAMR for females increased from 13.5 in 2013 to 18.3 in 2017 (APC = 8.26%*, 95% CI: 7.26 to 9.56), and from 18.7 to 23.5 for males (APC = 6.38%*, 95% CI: 5.30 to 7.96). 3.3 Primary cancer site stratified The top five primary cancers associated with the highest SMNL-related mortality were bronchus and lung, colon, breast, pancreas, and prostate ( Fig. 2 ) . Bronchus and lung cancer accounted for the most SMNL-related deaths (104,893), while colon cancer, though second in deaths (100,846), had the highest initial AAMR. All the top five cancers shared an initial significant drop in AAMR till 2008 followed by a rising trend till 2023. Of these, only colon cancer showed an overall significant decline in AAMR, dropping from 5.6 in 1999 to 3.7 in 2023 (AAPC=–1.78%*, 95% CI: − 2.03 to − 1.58). Its most significant drop in AAMR was from 1999 to 2008, reaching 2.6 (APC=-8.27%*, 95% CI: -9.87 to -7.59). Although, it kept a significantly increasing trend after 2013, especially from 2.4 in 2013 to 3.2 in 2016 (APC = 8.96%*, 95% CI: 5.02 to 11.57), it could only reach almost two-thirds of its value in 1999. Bronchus and lung became the leading cause of SMNL-related death in 2010, with an insignificant overall change in AAMR from 4.1 in 1999 to 4.2 in 2023 (AAPC=-0.10%, 95% CI: 0.32 to 0.14). Female breast cancer’s AAMR declined from 3.7 in 1999 to 2.5 in 2008 (APC=-4.32%*, 95% CI: -6.46 to -3.47), then steadily rose, becoming the leading cause of SMNL-related mortality by 2018. Initially third in 1999, its AAMR reached 4.4 in 2023 (AAPC = 0.67%*, 95% CI: 0.39 to 0.92). Pancreatic cancer showed the largest overall rise in AAMR, nearly doubling from 1.8 in 1999 to 3.8 in 2023 (AAPC = 3.12%*, 95% CI: 2.95 to 3.30). It surpassed colon cancer to become the third leading cause of SMNL-related mortality in 2023. Prostate cancer’s AAMR rose by 1.5 times from 1.4 in 1999 to 2.1 in 2023 (AAPC = 1.68%*, 95% CI: 1.30 to 2.21). Other primary cancers contributing to SMNL-related mortality, such as esophageal, stomach, rectal, ovarian, and renal cancers, have been presented in Supplementary Tables 4 and 5 . Between 1999 and 2021, AAIR declined for colon, bronchus and lung, and prostate cancers, while breast and pancreatic cancers showed relative stability or modest increases (Supplementary Fig. 2, Supplementary Tables 6–8) . Colon cancer incidence declined steadily from 113.3 to 65.0, nearly halving over the period (APC=–2.79%*, 95% CI: − 2.98 to − 2.60). Prostate cancer, despite initial fluctuations, showed the sharpest overall decline from 483.5 to 327.8 (AAPC=–1.77%*, 95% CI: − 2.20 to − 1.19), with a significant drop between 2008–2014 (APC=–6.29%*, 95% CI: − 12.6 to − 3.97). Bronchus and lung cancer incidence also decreased significantly (AAPC=–1.70%*, 95% CI: − 1.92 to − 1.46), particularly between 2006–2019. Only pancreatic cancer observed a significant overall rise in AAIR from 30.3 to 36.9 (AAPC = 0.85%*, 95% CI: 0.78 to 0.93). Female breast cancer incidence declined from 336.3 to 298.4 by 2005, but subsequently increased, resulting in a non-significant overall AAPC of − 0.27% (95% CI: − 0.48 to 0.05). Supplementary analysis of breast cancer in both genders showed AAMRs and AAIRs nearly half those of female breast cancer (Supplementary Figs. 3 and 4) . Trends in AAMRs for the top ten primary cancers leading to SMNL-related mortality, excluding SMNL as a contributing cause, showed a significant decline for all cancers except pancreatic cancer. Pancreatic cancer experienced a modest increase in AAMR (APC = 0.35%*, 95% CI: 0.29–0.41) (Supplementary Fig. 5, Supplementary Tables 9 and 10) . AAMR for stomach, colon, bronchus and lung, ovarian, and prostate cancers nearly halved from 1999–2023. 3.4 Age Stratified CMRs increased progressively across each successive 10-year age group, with a nearly 10-fold difference between ages 45–54 and 85+ (Supplementary Fig. 6) . Rates declined across all age groups in the early 2000s, plateaued around 2008, and remained stable until 2013. The 45–54 age group exhibited the highest AAPC (0.69%*, 95% CI: 0.48–0.89), with CMR rising from 6.1 to 7.3. At the other end, the 85 + group reached a peak of 70.7 in 2023 from 62.5 in 1999 (AAPC = 0.47%*, 95% CI: 0.21 to 0.73). The steepest rise occurred in the 55–64 group between 2013–2016 (APC = 11.46%*, 95% CI: 8.56–13.07), from 11.9 to 16.2. Only the 65–74 group showed a significant overall decline in CMR, from 37.6 to 36.5 (AAPC=-0.12%*, 95% CI: -0.20 to -0.04). 3.5 Race stratified Throughout the study period, NH-BAA had the highest AAMR, declining from 31.1 to 27.1 (AAPC=-0.66%*, 95% CI: -0.94 to -0.39) ( Fig. 3 ) . Initially, three-fourths of NH-BAAs' AAMR, NH Whites saw a significant increase from 23.6 in 1999 to 26.6 in 2023 (AAPC = 0.49%*, 95% CI: 0.40 to 0.58), nearing NH-BAAs' rates. Both groups experienced a nearly 40% decline in AAMR until 2008, after which mortality rose again. Although NH-A/PI, NH-AI/AN, and Hispanics initially saw significant declines in mortality, subsequent increases rendered their overall changes insignificant (NH-A/PI AAPC = 0.28%; NH-AI/AN AAPC = 0.44%; Hispanics AAPC = 0.12%). 3.6 Place of death stratified 50.0% of deaths occurred at home, followed by IPH (25.4%), nursing homes (12.2%), hospice facilities (10.9%), and OEF (1.5%) (Supplementary Table 11) . From 1999–2023, IPH deaths more than halved, declining from 38.9% to 19.0%, while home deaths increased from 43.9% to 56.2% (Supplementary Fig. 7) . Hospice deaths increased 31-fold (0.5% in 2003 to 15.5% in 2023), whereas nursing home deaths declined by nearly half (15.4% to 8.2%). 3.7 State stratified States in the upper 90th percentile for overall SMNL-related AAMR (≥ 28.7) included Arkansas (37.7), Indiana (31.8), Vermont (31.1), Mississippi (30.8), Nevada (29.0), and Delaware (28.7) ( Fig. 4 ) . In contrast, states in the 10th percentile (≤ 13.0) were Alabama (13.0), Virginia (12.8), Connecticut (12.3), Massachusetts (11.2), Utah (10.4), and Montana (9.9). AAMR rose the most in Vermont (AAPC = 5.30%*, 95% CI: 3.40–8.09), Oregon (AAPC = 4.90%*, 95% CI: 4.33–5.56), and Hawaii (AAPC = 2.62%*, 95% CI: 1.77–3.54) (Supplementary Figs. 8 and 9; Supplementary Tables 12–14) . The largest declines were seen in the District of Columbia (DC) (AAPC=-5.01%*, 95% CI: -6.55 to 3.25), New Jersey (AAPC=-4.09%*, 95% CI: -4.50 to -3.69), and Rhode Island (-2.92%*, 95% CI: -3.75 to -2.13). 3.8 Region stratified While all US census regions showed an initial decline in SMNL-related mortality, only the Northeast had an overall decrease in AAMR (AAPC=-1.83%*, 95% CI: -2.05 to -1.61), dropping from 24.9 in 1999 to 16.3 in 2023 (Supplementary Fig. 10) . By 2023, the Northeast’s AAMR was approximately two-thirds that of the other regions. In contrast, the West, which began with the lowest AAMR (19.8), saw the largest increase to 25.8 (AAPC = 1.24%*, 95% CI: 0.97 to 1.51). The South also experienced a significant rise (AAPC = 0.47%*, 95% CI: 0.29 to 0.66), while the Midwest showed a non-significant increase (AAPC = 0.17%, 95% CI: -0.02 to 0.34). 3.9 Urbanization status stratified Rural areas consistently had higher mortality rates, with no significant overall change (AAPC = 0.16%, 95% CI: -0.08 to 0.38) (Supplementary Fig. 11) . In contrast, urban areas saw a significant decline from 23.5 in 1999 to 21.9 in 2020 (AAPC=-0.24%*, 95% CI: -0.36 to -0.11). After an initial drop in both settings, AAMRs began to rise, with the steepest increase occurring between 2013 and 2016 (Rural APC = 9.55%*, 95% CI: 6.41 to 11.62; Urban APC = 7.99%*, 95% CI: 6.43 to 8.97). 4 Discussion 4.1 Main findings of this study Our study provides a comprehensive 25-year overview (1999–2023) of SMNL-related AAMRs in US adults aged ≥ 45. While AAMRs declined until 2008, a reversal occurred thereafter, with a particularly sharp increase between 2013 and 2016. This upward trend raises critical questions about the interplay between survivorship, late effects of cancer, and the healthcare system response. Notably, this increase occurred despite a significant decline in both AAIRs and AAMRs for most primary cancers, irrespective of metastasis, that were most frequently linked to SMNL-related mortality in our study. These trends likely reflect improved survival among patients with primary cancers, resulting in a longer window for metastatic progression, especially to the liver. Our study also identified notable disparities with higher mortality rates among males, NH-BAA individuals, older age groups, and those in rural areas. These disparities necessitate focused public health initiatives. 4.2 What is already known on this topic Improved survivorship means that as patients live longer following a primary cancer diagnosis, their risk of developing late metastatic disease correspondingly rises. This is supported by prior studies showing high rates of metastasis among cancer survivors. Out of 150,000 metastatic breast cancer patients, 75% were initially diagnosed with Stage II/III cancer. 16 Moreover, as noted by Mani et al, metastatic disease remains the principal cause of cancer-related mortality. 17 In this context, our findings underscore both the successes and emerging challenges of modern cancer care. Prior literature shows that males face a higher burden of cancers prone to liver metastasis, such as prostate cancer, and are twice as likely as females to present with liver metastases. 18 Similarly, NH-BAA individuals are more often diagnosed at later stages. Akinyemiju et al found higher rates of de novo metastasis in NH-BAA with breast, colorectal, and prostate cancer compared to NH Whites (11% vs 9%). 19 4.3 What this study adds To our knowledge, this is the first study to analyze SMNL-related mortality trends in the US, with important policy implications. Although the rise in AAMRs after 2008 may appear alarming, it likely reflects advances in cancer treatment, screening, and awareness, which have prolonged survival and, in turn, increased opportunities for late metastatic disease. These findings highlight the need for long-term survivorship strategies, including routine monitoring for metastatic spread in high-risk groups. The gender- and race-based disparities observed underscore the need for equity-focused cancer control policies. Males had consistently higher AAMRs, which may be attributable to the higher incidence of male-dominant cancers, such as prostate cancer, that often metastasize to the liver and carry poorer prognoses. The higher AAMRs among NH-BAA likely reflect a combination of delayed cancer diagnosis, more advanced disease at presentation, and systemic inequities in access to timely and effective cancer care. NH Whites were the only group to show a significant increase in AAMRs over time, reaching rates nearly equal to those of NH-BAA. This may reflect longer survival after primary cancer diagnosis, providing more time for metastasis, a pattern also observed in the higher CMRs among older adults in our study. 20 – 22 These racial disparities likely stem from a mix of socioeconomic, access-related, and systemic factors. 23 Although our study did not directly assess these drivers, it highlights persistent inequities in cancer outcomes across the US healthcare system. Targeted resource allocation is essential to improve early detection, timely diagnosis, and access to effective treatment in underserved communities. Integrating stratified risk assessments into survivorship protocols, based on demographic and clinical profiles, may help optimize monitoring and intervention strategies. 4.4 Limitations of this study Our study utilized the CDC WONDER database; as a result, it is subject to misclassification or incomplete reporting, as it is dependent on death certificate documentation. In rare cases with multiple malignancies, it was not possible to determine the primary source of SMNL, as it was based on co-listed ICD-10 codes on death certificates. The cross-sectional design limits causal inference. Urban-rural analysis was restricted to data up to 2020 due to unavailable population estimates and AAMRs thereafter. Additionally, subgroups with fewer than 10 deaths were suppressed, and those with fewer than 20 were considered statistically unreliable, including data from hospice facilities and select states. 5 Conclusion Despite declining mortality from most primary cancers, AAMRs for SMNL have steadily increased in the US since 2008. This pattern likely reflects that the advancements in the early detection and treatment of primary tumor sources have resulted in increased survival, leading to an increased chance of metastatic progression, particularly to the liver. Our study also highlighted several disparities in SMNL-related mortalities by gender, age, and race, with males, older adults, and NH-BAA having the highest mortality rates. These findings support the need for enhanced long-term surveillance after the initial treatment of primary tumors, for the early diagnosis of recurrence, and to prevent metastasis. Declarations CRediT author statement All authors meet the authorship criteria outlined by the International Committee of Medical Journal Editors (ICMJE). * Mahnoor Khan : Conceptualization, Methodology, Project administration, Formal analysis, Validation, Writing - original draft, and Writing - review & editing. * Daniyal Ali Khan : Conceptualization, Methodology, Project administration, Formal analysis, Validation, Writing - original draft, and Writing - review & editing. Kantesh Kumar : Methodology, Writing - original draft, and Writing - review & editing. Syed Ali Tayyeb Hasan : Methodology, Writing - original draft, and Writing - review & editing. Shahzaib Khan : Methodology, Investigation, Data curation, Formal analysis, Visualization, and Writing - review & editing. Fatima Najam : Methodology, Investigation, Data curation, Formal analysis, Visualization, and Writing - review & editing. Munir Mehmood : Methodology, Writing - original draft, and Writing - review & editing. Waqas Nawaz : Methodology, Supervision, and Writing - review & editing. All authors had full access to the data, approved the final manuscript, and accept responsibility for its accuracy and integrity. *These authors contributed equally. Conflict of Interest The authors declare no conflicts of interest. Consent to participate and publish No patient consent was needed for this study, as CDC-WONDER contains anonymized, publicly available data. Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Acknowledgments None. Data availability statement Data were abstracted from the Centers for Disease Control and Prevention’s Wide-Ranging Online Data for Epidemiologic Research (CDC-WONDER) platform. All relevant data are included in the manuscript and supplementary materials. 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Additional Declarations The authors declare no competing interests. Supplementary Files SupplementaryAppendixTablesandFiguresfinal.docx Supplementary Appendix Cite Share Download PDF Status: Published Journal Publication published 07 Jan, 2026 Read the published version in Journal of Gastrointestinal Cancer → Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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Khan","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA5ElEQVRIiWNgGAWjYFACHhjNfPjBByDNxk68FrY0wxkgLczEa+ExkAazCWnRbT977MGHinsMuj0HDIxtfm2T52NmYPzwMQe3FrMzeemGM84UM5idbUh4nNt327CNmYFZcuY2PFoO5JhJ87YlMJidZzhgnNtzmxGohY2ZF5+W829gWhgbpC17btsT1nIDZsvZZgZphh+3E4nQ8sZMcsaZBB6zM8fYDHsbbie3MTM24/fL+RwziQ8VCXJmZ/I/P/jx57bt/Pbmgx8+4tECA5DYYWwDkw2E1SPAH1IUj4JRMApGwUgBAKdNTnufhPj+AAAAAElFTkSuQmCC","orcid":"https://orcid.org/0009-0009-8028-6814","institution":"Shaikh Khalifa Bin Zayed Al Nahyan Medical \u0026 Dental College","correspondingAuthor":true,"prefix":"","firstName":"Mahnoor","middleName":"","lastName":"Khan","suffix":""},{"id":514838639,"identity":"1c1d2c23-3780-4579-b221-530b1b3db63d","order_by":1,"name":"Daniyal Ali Khan","email":"","orcid":"https://orcid.org/0000-0001-9027-570X","institution":"Aga Khan University","correspondingAuthor":false,"prefix":"","firstName":"Daniyal","middleName":"Ali","lastName":"Khan","suffix":""},{"id":514838640,"identity":"d406ee17-30b7-4922-9846-4c0491494250","order_by":2,"name":"Kantesh Kumar","email":"","orcid":"https://orcid.org/0000-0002-2147-4614","institution":"Aga Khan University","correspondingAuthor":false,"prefix":"","firstName":"Kantesh","middleName":"","lastName":"Kumar","suffix":""},{"id":514838641,"identity":"ffc7abfb-215a-48c2-bf5d-ed63a6bd961f","order_by":3,"name":"Syed Ali Tayyeb Hasan","email":"","orcid":"https://orcid.org/0000-0001-6707-3675","institution":"Aga Khan University","correspondingAuthor":false,"prefix":"","firstName":"Syed","middleName":"Ali Tayyeb","lastName":"Hasan","suffix":""},{"id":514838642,"identity":"e782178a-a91c-4aa7-a921-d1ca91304d9c","order_by":4,"name":"Shahzaib Khan","email":"","orcid":"https://orcid.org/0009-0009-0547-9296","institution":"Rutgers Health Community Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Shahzaib","middleName":"","lastName":"Khan","suffix":""},{"id":514838643,"identity":"04f6497e-cc45-4fdc-b309-d9e4aa441ce8","order_by":5,"name":"Fatima Najam","email":"","orcid":"https://orcid.org/0009-0003-7825-4537","institution":"Jefferson Abington Hospital","correspondingAuthor":false,"prefix":"","firstName":"Fatima","middleName":"","lastName":"Najam","suffix":""},{"id":514838644,"identity":"b395d701-2575-4cd0-a7af-eb15d6e90b2f","order_by":6,"name":"Munir Mehmood","email":"","orcid":"https://orcid.org/0000-0002-2969-9551","institution":"Aga Khan University","correspondingAuthor":false,"prefix":"","firstName":"Munir","middleName":"","lastName":"Mehmood","suffix":""},{"id":514838645,"identity":"70ad0e49-86fb-4ac7-8b2e-587b8c763e4d","order_by":7,"name":"Waqas Nawaz","email":"","orcid":"","institution":"Ohio State University Wexner Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Waqas","middleName":"","lastName":"Nawaz","suffix":""}],"badges":[],"createdAt":"2025-09-14 14:13:15","currentVersionCode":1,"declarations":{"humanSubjects":true,"vertebrateSubjects":false,"conflictsOfInterestStatement":false,"humanSubjectEthicalGuidelines":true,"humanSubjectConsent":true,"humanSubjectClinicalTrial":false,"humanSubjectCaseReport":false,"vertebrateSubjectEthicalGuidelines":false},"doi":"10.21203/rs.3.rs-7613109/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7613109/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s12029-025-01391-w","type":"published","date":"2026-01-08T00:00:00+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":91457201,"identity":"0384bde4-0855-4985-9a8d-03e49c39dc25","added_by":"auto","created_at":"2025-09-16 16:33:31","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":552193,"visible":true,"origin":"","legend":"\u003cp\u003eAge-adjusted mortality rates per 100,000 overall and stratified by gender\u003c/p\u003e\n\u003cp\u003eStatistically significant values have been represented by an asterisk “*”.\u003c/p\u003e","description":"","filename":"FIG1.JPEG.OverallGender.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7613109/v1/9388a62c78720ecfd18875e1.jpg"},{"id":91455826,"identity":"ae27988c-0102-4179-91a7-ce2b2326912c","added_by":"auto","created_at":"2025-09-16 16:17:31","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":736290,"visible":true,"origin":"","legend":"\u003cp\u003eAge-adjusted mortality rates per 100,000 stratified by primary cancer sites that led to the highest SMNL-related mortality (with SMNL selected as a contributing cause of death)\u003c/p\u003e\n\u003cp\u003eStatistically significant values have been represented by an asterisk “*”.\u003c/p\u003e","description":"","filename":"FIG2.JPEG.ICD.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7613109/v1/b5a6c0c3ee25b2df4e416b71.jpg"},{"id":91455435,"identity":"6837122d-68eb-4633-bb4a-799e181a882f","added_by":"auto","created_at":"2025-09-16 16:09:31","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":915865,"visible":true,"origin":"","legend":"\u003cp\u003eAge-adjusted mortality rates per 100,000 stratified by race\u003c/p\u003e\n\u003cp\u003eStatistically significant values have been represented by an asterisk “*”.\u003c/p\u003e","description":"","filename":"FIG3.JPEG.Race.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7613109/v1/0cdbcc4bd0da39621284f375.jpg"},{"id":91455447,"identity":"243dd91b-e533-4481-a6d2-2a8d7e25cd1b","added_by":"auto","created_at":"2025-09-16 16:09:31","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":10926415,"visible":true,"origin":"","legend":"\u003cp\u003eOverall age-adjusted mortality rates per 100,000 from 1999-2023 stratified by states\u003c/p\u003e","description":"","filename":"FIG4.JPEG.StatesMap.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7613109/v1/e83b13b50d88e52cf641dbf7.jpg"},{"id":100085824,"identity":"e0b34058-90ad-4369-8b73-219febafdb7b","added_by":"auto","created_at":"2026-01-12 20:44:47","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":6578035,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7613109/v1/e656464c-6b25-4e36-9e83-d68ca5c5a816.pdf"},{"id":91457202,"identity":"dae5c807-452d-4659-90a5-e3fc598245aa","added_by":"auto","created_at":"2025-09-16 16:33:31","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":4792684,"visible":true,"origin":"","legend":"\u003cp\u003eSupplementary Appendix\u003c/p\u003e","description":"","filename":"SupplementaryAppendixTablesandFiguresfinal.docx","url":"https://assets-eu.researchsquare.com/files/rs-7613109/v1/29b897e4d9090aa075efb390.docx"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"\u003cp\u003e\u003cstrong\u003eEpidemiologic Trends in Secondary Malignant Neoplasms of the Liver in the United States: A 25-Year National Study\u003c/strong\u003e\u003c/p\u003e","fulltext":[{"header":"1 Introduction","content":"\u003cp\u003eSecondary malignant neoplasm of the liver (SMNL) is often more prevalent than primary liver cancer, yet its mortality trends remain underexplored.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e This has been represented in a University of Cologne study where liver metastases (611 cases) outnumbered primary hepatocellular carcinoma (380 cases) among 1,357 tumor samples.\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eLiver cancer is the sixth most common cancer worldwide, ranking fifth in men and ninth in women.\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e In 2022, the US had the second-highest liver cancer incidence (43,492 cases) and the third-highest mortality (30,931 deaths).\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e The liver is a common site for organ-specific metastasis due to its unique microvascular circulation.\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e,\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e Gastrointestinal, breast, and prostate cancers, along with neuroendocrine tumors and sarcomas, commonly metastasize to the liver.\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eWhile some studies have examined the burden of SMNL in the US using the Surveillance, Epidemiology, and End Results (SEER) database, they provide only limited coverage due to incomplete geographic representation and inconsistent registry inclusion over time.\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e,\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e Although primary liver cancer mortality trends have been previously studied, no large-scale analysis has comprehensively examined SMNL mortality across demographic and geographic factors.\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e Liver cancer, often diagnosed at advanced stages, has a poor prognosis due to its rapid progression and the liver\u0026rsquo;s vulnerability to metastasis, necessitating a nationwide analysis.\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eThis study addresses that gap by providing the first nationwide evaluation of SMNL mortality trends, highlighting demographic and geographic disparities and the primary cancers most commonly leading to SMNL-related mortality, offering insights for targeted surveillance and treatment strategies.\u003c/p\u003e"},{"header":"2 Materials and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003e2.1 Study design and population\u003c/h2\u003e\u003cp\u003eWe conducted a population-based cross-sectional study primarily focused on SMNL-related mortality trends. Mortality data from 1999\u0026ndash;2023 were obtained from the CDC\u0026rsquo;s Wide-Ranging Online Data for Epidemiologic Research (CDC WONDER), using the Multiple Cause of Death database.\u003csup\u003e10,11\u003c/sup\u003e Individuals aged\u0026thinsp;\u0026ge;\u0026thinsp;45 years with SMNL were identified using the International Classification of Diseases, Tenth Revision (ICD-10) code C78.7.\u003c/p\u003e\u003cp\u003eTo contextualize SMNL-related mortality, we examined both incidence and mortality trends for the primary cancers most associated with SMNL-related deaths. Incidence data from 1999\u0026ndash;2021 were obtained from the United States Cancer Statistics (USCS) database, the official federal source for cancer surveillance. USCS is produced by the CDC and the National Cancer Institute (NCI), incorporating data from the National Program of Cancer Registries (NPCR) and the SEER program, covering nearly the entire US population.\u003csup\u003e12\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eThis study adhered to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines and the Declaration of Helsinki.\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e Since the study used publicly available, deidentified data, informed consent and institutional review board approval were not required.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\u003ch2\u003e2.2 Outcome Variables\u003c/h2\u003e\u003cp\u003eThis study primarily analyzed SMNL-related mortality in the US, including (1) trends in overall age-adjusted mortality rates (AAMR); (2) AAMR trends stratified by gender, race, region, urbanization status, primary cancer site, and the three states with the highest and lowest average annual percentage changes (AAPC); (3) trends in crude mortality rates (CMR) across different age groups; (4) trends in the proportion of deaths by place of death; and (5) state-level variation in overall AAMR and AAPC. The secondary objectives were to examine trends in AAIR and AAMR for the top ten primary cancers most frequently associated with SMNL-related mortality, using overall cancer-specific incidence and mortality data irrespective of SMNL contribution.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\u003ch2\u003e2.3 Data abstraction\u003c/h2\u003e\u003cp\u003eGender was used as a binary variable. Race/ethnicity classifications included non-Hispanic (NH) White, NH Black or African American (NH-BAA), NH Asian or Pacific Islander (NH-A/PI), NH American Indian or Alaska Native (NH-AI/AN), and Hispanic. Age groups were stratified into 45\u0026ndash;54, 55\u0026ndash;64, 65\u0026ndash;74, 75\u0026ndash;84, and \u0026ge;\u0026thinsp;85 years. Places of death were classified as inpatient hospital (IPH), outpatient or emergency room facility (OEF), the decedent's home, hospice facility, and nursing home/long-term care facility. According to the 2013 US Census classification, the population was categorized using the National Center for Health Statistics Urban-Rural Classification Scheme as urban (\u0026ge;\u0026thinsp;50,000) or rural (\u0026lt;\u0026thinsp;50,000).\u003csup\u003e14\u003c/sup\u003e AAMR by urbanization status was available only for 1999\u0026ndash;2020. Regions were classified into Northeast, Midwest, South, and West according to the Census Bureau definitions. Primary cancer sites were identified using concurrent ICD-10 codes with SMNL on death certificates \u003cb\u003e(Supplementary Table\u0026nbsp;1)\u003c/b\u003e. Analyses for prostate and ovarian cancers were restricted to males and females, respectively. Breast cancer analysis focused on females, with a sensitivity analysis combining both genders. Male breast cancer was excluded due to suppressed or negligible AAMRs (\u0026lt;\u0026thinsp;0.1).\u003c/p\u003e\u003cp\u003eTo protect confidentiality, CDC WONDER suppresses counts below 10 and flags rates as unreliable for counts under 20. Subgroups with small numbers in our study included such suppressed or unreliable data, indicated by \u0026ldquo;-\u0026rdquo; in tables and dotted lines in figures.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\u003ch2\u003e2.4 Statistical analysis\u003c/h2\u003e\u003cp\u003eAAMRs, AAIRs, and CMRs per 100,000 individuals were calculated. The 2000 US population served as the standard for AAMRs and AAIRs.\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e The Joinpoint Regression Program (version 5.3.0) was used to compute annual percent changes (APCs) and AAPC, as well as 95% confidence intervals (CI), using log-linear regression models. Temporal variations were recorded to identify significant shifts in AAMRs and AAIRs. The statistical significance of the APCs that were computed for each segment connecting join points was determined using the Monte Carlo permutation test. A two-tailed t-test (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05, indicated by an asterisk \"*\" in data and graphics) was used to assess changes in APC. A significant deviation of the mortality trend slope from zero classified the change as increasing or decreasing.\u003c/p\u003e\u003c/div\u003e"},{"header":"3 Results","content":"\u003cp\u003e\u003cstrong\u003eSupplementary Fig.\u0026nbsp;1\u003c/strong\u003e provides a central illustration of our study\u0026apos;s SMNL-related mortality summary. Detailed results of the study are shown in Figs. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e, \u003cstrong\u003esupplementary tables 1\u0026ndash;14\u003c/strong\u003e, and \u003cstrong\u003esupplementary Figs.\u0026nbsp;2\u0026ndash;11.\u003c/strong\u003e\u003c/p\u003e\n\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\n \u003ch2\u003e3.1 Overall\u003c/h2\u003e\n \u003cp\u003eBetween 1999 and 2023, the study reported 597,332 SMNL-related deaths among adults aged 45 and above \u003cstrong\u003e(Supplementary Table\u0026nbsp;2)\u003c/strong\u003e. For overall SMNL-related mortality, AAMR increased from 23.8 per 100,000 in 1999 to a peak of 25.1 in 2023 (AAPC\u0026thinsp;=\u0026thinsp;0.22%*, 95% CI: 0.14 to 0.29) \u003cstrong\u003e(\u003c/strong\u003eFig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e\u003cstrong\u003e)\u003c/strong\u003e. The AAMR initially declined significantly from 23.8 in 1999 to 14.9 in 2008 (APC= -5.21%*, 95% CI: -5.49 to -4.94). This was followed by a significant rise, especially from 15.7 in 2013 to 20.1 in 2016 (APC\u0026thinsp;=\u0026thinsp;8.56%*, 95% CI: 7.07 to 9.36). \u003cstrong\u003e(Supplementary Table\u0026nbsp;3)\u003c/strong\u003e.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e\n \u003ch2\u003e3.2 Gender Stratified\u003c/h2\u003e\n \u003cp\u003eOf the total SMNL-related deaths, 306,558 (51.3%) were men, with consistently higher AAMR than women from 1999 to 2023 \u003cstrong\u003e(\u003c/strong\u003eFig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e\u003cstrong\u003e)\u003c/strong\u003e. Both genders followed similar mortality trends throughout, with a significant initial decline from 1999 till 2008. During this period, AAMR almost halved from 20.6 to 12.9 for females (APC=-5.04%*, 95% CI: -5.32 to -4.79) and 28.4 to 17.4 for men (APC=-5.42%*, 95% CI: -5.84 to -5.09). Following this period, AAMR kept increasing till 2023 for both genders, with AAMR of females reaching a peak of 22.6 in 2023 but that of males reached 28.2, close to their peak of 28.4 in 1999. The initial rise from 2008 to 2013 was significant only for females (females: APC\u0026thinsp;=\u0026thinsp;0.91%*, 95% CI: 0.41 to 1.35; males: APC\u0026thinsp;=\u0026thinsp;1.23%, 95% CI: -0.84 to 2.46). The steepest rise in AAMR was observed by both genders from 2013 to 2017. AAMR for females increased from 13.5 in 2013 to 18.3 in 2017 (APC\u0026thinsp;=\u0026thinsp;8.26%*, 95% CI: 7.26 to 9.56), and from 18.7 to 23.5 for males (APC\u0026thinsp;=\u0026thinsp;6.38%*, 95% CI: 5.30 to 7.96).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e\n \u003ch2\u003e3.3 Primary cancer site stratified\u003c/h2\u003e\n \u003cp\u003eThe top five primary cancers associated with the highest SMNL-related mortality were bronchus and lung, colon, breast, pancreas, and prostate \u003cstrong\u003e(\u003c/strong\u003eFig. \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e\u003cstrong\u003e)\u003c/strong\u003e. Bronchus and lung cancer accounted for the most SMNL-related deaths (104,893), while colon cancer, though second in deaths (100,846), had the highest initial AAMR. All the top five cancers shared an initial significant\u003c/p\u003e\n \u003cp\u003edrop in AAMR till 2008 followed by a rising trend till 2023. Of these, only colon cancer showed an overall significant decline in AAMR, dropping from 5.6 in 1999 to 3.7 in 2023 (AAPC=\u0026ndash;1.78%*, 95% CI: \u0026minus;\u0026thinsp;2.03 to \u0026minus;\u0026thinsp;1.58). Its most significant drop in AAMR was from 1999 to 2008, reaching 2.6 (APC=-8.27%*, 95% CI: -9.87 to -7.59). Although, it kept a significantly increasing trend after 2013, especially from 2.4 in 2013 to 3.2 in 2016 (APC\u0026thinsp;=\u0026thinsp;8.96%*, 95% CI: 5.02 to 11.57), it could only reach almost two-thirds of its value in 1999. Bronchus and lung became the leading cause of SMNL-related death in 2010, with an insignificant overall change in AAMR from 4.1 in 1999 to 4.2 in 2023 (AAPC=-0.10%, 95% CI: 0.32 to 0.14). Female breast cancer\u0026rsquo;s AAMR declined from 3.7 in 1999 to 2.5 in 2008 (APC=-4.32%*, 95% CI: -6.46 to -3.47), then steadily rose, becoming the leading cause of SMNL-related mortality by 2018. Initially third in 1999, its AAMR reached 4.4 in 2023 (AAPC\u0026thinsp;=\u0026thinsp;0.67%*, 95% CI: 0.39 to 0.92).\u003c/p\u003e\n \u003cp\u003ePancreatic cancer showed the largest overall rise in AAMR, nearly doubling from 1.8 in 1999 to 3.8 in 2023 (AAPC\u0026thinsp;=\u0026thinsp;3.12%*, 95% CI: 2.95 to 3.30). It surpassed colon cancer to become the third leading cause of SMNL-related mortality in 2023. Prostate cancer\u0026rsquo;s AAMR rose by 1.5 times from 1.4 in 1999 to 2.1 in 2023 (AAPC\u0026thinsp;=\u0026thinsp;1.68%*, 95% CI: 1.30 to 2.21). Other primary cancers contributing to SMNL-related mortality, such as esophageal, stomach, rectal, ovarian, and renal cancers, have been presented in \u003cstrong\u003eSupplementary Tables\u0026nbsp;4 and 5\u003c/strong\u003e.\u003c/p\u003e\n \u003cp\u003eBetween 1999 and 2021, AAIR declined for colon, bronchus and lung, and prostate cancers, while breast and pancreatic cancers showed relative stability or modest increases \u003cstrong\u003e(Supplementary Fig.\u0026nbsp;2, Supplementary Tables\u0026nbsp;6\u0026ndash;8)\u003c/strong\u003e. Colon cancer incidence declined steadily from 113.3 to 65.0, nearly halving over the period (APC=\u0026ndash;2.79%*, 95% CI: \u0026minus;\u0026thinsp;2.98 to \u0026minus;\u0026thinsp;2.60). Prostate cancer, despite initial fluctuations, showed the sharpest overall decline from 483.5 to 327.8 (AAPC=\u0026ndash;1.77%*, 95% CI: \u0026minus;\u0026thinsp;2.20 to \u0026minus;\u0026thinsp;1.19), with a significant drop between 2008\u0026ndash;2014 (APC=\u0026ndash;6.29%*, 95% CI: \u0026minus;\u0026thinsp;12.6 to \u0026minus;\u0026thinsp;3.97). Bronchus and lung cancer incidence also decreased significantly (AAPC=\u0026ndash;1.70%*, 95% CI: \u0026minus;\u0026thinsp;1.92 to \u0026minus;\u0026thinsp;1.46), particularly between 2006\u0026ndash;2019. Only pancreatic cancer observed a significant overall rise in AAIR from 30.3 to 36.9 (AAPC\u0026thinsp;=\u0026thinsp;0.85%*, 95% CI: 0.78 to 0.93). Female breast cancer incidence declined from 336.3 to 298.4 by 2005, but subsequently increased, resulting in a non-significant overall AAPC of \u0026minus;\u0026thinsp;0.27% (95% CI: \u0026minus;\u0026thinsp;0.48 to 0.05). Supplementary analysis of breast cancer in both genders showed AAMRs and AAIRs nearly half those of female breast cancer \u003cstrong\u003e(Supplementary Figs.\u0026nbsp;3 and 4)\u003c/strong\u003e.\u003c/p\u003e\n \u003cp\u003eTrends in AAMRs for the top ten primary cancers leading to SMNL-related mortality, excluding SMNL as a contributing cause, showed a significant decline for all cancers except pancreatic cancer. Pancreatic cancer experienced a modest increase in AAMR (APC\u0026thinsp;=\u0026thinsp;0.35%*, 95% CI: 0.29\u0026ndash;0.41) \u003cstrong\u003e(Supplementary Fig.\u0026nbsp;5, Supplementary Tables\u0026nbsp;9 and 10)\u003c/strong\u003e. AAMR for stomach, colon, bronchus and lung, ovarian, and prostate cancers nearly halved from 1999\u0026ndash;2023.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\n \u003ch2\u003e3.4 Age Stratified\u003c/h2\u003e\n \u003cp\u003eCMRs increased progressively across each successive 10-year age group, with a nearly 10-fold difference between ages 45\u0026ndash;54 and 85+ \u003cstrong\u003e(Supplementary Fig.\u0026nbsp;6)\u003c/strong\u003e. Rates declined across all age groups in the early 2000s, plateaued around 2008, and remained stable until 2013. The 45\u0026ndash;54 age group exhibited the highest AAPC (0.69%*, 95% CI: 0.48\u0026ndash;0.89), with CMR rising from 6.1 to 7.3. At the other end, the 85\u0026thinsp;+\u0026thinsp;group reached a peak of 70.7 in 2023 from 62.5 in 1999 (AAPC\u0026thinsp;=\u0026thinsp;0.47%*, 95% CI: 0.21 to 0.73). The steepest rise occurred in the 55\u0026ndash;64 group between 2013\u0026ndash;2016 (APC\u0026thinsp;=\u0026thinsp;11.46%*, 95% CI: 8.56\u0026ndash;13.07), from 11.9 to 16.2. Only the 65\u0026ndash;74 group showed a significant overall decline in CMR, from 37.6 to 36.5 (AAPC=-0.12%*, 95% CI: -0.20 to -0.04).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\n \u003ch2\u003e3.5 Race stratified\u003c/h2\u003e\n \u003cp\u003eThroughout the study period, NH-BAA had the highest AAMR, declining from 31.1 to 27.1 (AAPC=-0.66%*, 95% CI: -0.94 to -0.39) \u003cstrong\u003e(\u003c/strong\u003eFig. \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e\u003cstrong\u003e)\u003c/strong\u003e. Initially, three-fourths of NH-BAAs\u0026apos; AAMR, NH Whites saw a significant increase from 23.6 in 1999 to 26.6 in 2023 (AAPC\u0026thinsp;=\u0026thinsp;0.49%*, 95% CI: 0.40 to 0.58), nearing NH-BAAs\u0026apos; rates. Both groups experienced a nearly 40% decline in AAMR until 2008, after which mortality rose again. Although NH-A/PI, NH-AI/AN, and Hispanics initially saw significant declines in mortality, subsequent increases rendered their overall changes insignificant (NH-A/PI AAPC\u0026thinsp;=\u0026thinsp;0.28%; NH-AI/AN AAPC\u0026thinsp;=\u0026thinsp;0.44%; Hispanics AAPC\u0026thinsp;=\u0026thinsp;0.12%).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\n \u003ch2\u003e3.6 Place of death stratified\u003c/h2\u003e\n \u003cp\u003e50.0% of deaths occurred at home, followed by IPH (25.4%), nursing homes (12.2%), hospice facilities (10.9%), and OEF (1.5%) \u003cstrong\u003e(Supplementary Table\u0026nbsp;11)\u003c/strong\u003e. From 1999\u0026ndash;2023, IPH deaths more than halved, declining from 38.9% to 19.0%, while home deaths increased from 43.9% to 56.2% \u003cstrong\u003e(Supplementary Fig.\u0026nbsp;7)\u003c/strong\u003e. Hospice deaths increased 31-fold (0.5% in 2003 to 15.5% in 2023), whereas nursing home deaths declined by nearly half (15.4% to 8.2%).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e\n \u003ch2\u003e3.7 State stratified\u003c/h2\u003e\n \u003cp\u003eStates in the upper 90th percentile for overall SMNL-related AAMR (\u0026ge;\u0026thinsp;28.7) included Arkansas (37.7), Indiana (31.8), Vermont (31.1), Mississippi (30.8), Nevada (29.0), and Delaware (28.7) \u003cstrong\u003e(\u003c/strong\u003eFig. \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e\u003cstrong\u003e)\u003c/strong\u003e. In contrast, states in the 10th percentile (\u0026le;\u0026thinsp;13.0) were Alabama (13.0), Virginia (12.8), Connecticut (12.3), Massachusetts (11.2), Utah (10.4), and Montana (9.9). AAMR rose the most in Vermont (AAPC\u0026thinsp;=\u0026thinsp;5.30%*, 95% CI: 3.40\u0026ndash;8.09), Oregon (AAPC\u0026thinsp;=\u0026thinsp;4.90%*, 95% CI: 4.33\u0026ndash;5.56), and Hawaii (AAPC\u0026thinsp;=\u0026thinsp;2.62%*, 95% CI: 1.77\u0026ndash;3.54) \u003cstrong\u003e(Supplementary Figs.\u0026nbsp;8 and 9; Supplementary Tables\u0026nbsp;12\u0026ndash;14)\u003c/strong\u003e. The largest declines were seen in the District of Columbia (DC) (AAPC=-5.01%*, 95% CI: -6.55 to 3.25), New Jersey (AAPC=-4.09%*, 95% CI: -4.50 to -3.69), and Rhode Island (-2.92%*, 95% CI: -3.75 to -2.13).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec15\" class=\"Section2\"\u003e\n \u003ch2\u003e3.8 Region stratified\u003c/h2\u003e\n \u003cp\u003eWhile all US census regions showed an initial decline in SMNL-related mortality, only the Northeast had an overall decrease in AAMR (AAPC=-1.83%*, 95% CI: -2.05 to -1.61), dropping from 24.9 in 1999 to 16.3 in 2023 \u003cstrong\u003e(Supplementary Fig.\u0026nbsp;10)\u003c/strong\u003e. By 2023, the Northeast\u0026rsquo;s AAMR was approximately two-thirds that of the other regions. In contrast, the West, which began with the lowest AAMR (19.8), saw the largest increase to 25.8 (AAPC\u0026thinsp;=\u0026thinsp;1.24%*, 95% CI: 0.97 to 1.51). The South also experienced a significant rise (AAPC\u0026thinsp;=\u0026thinsp;0.47%*, 95% CI: 0.29 to 0.66), while the Midwest showed a non-significant increase (AAPC\u0026thinsp;=\u0026thinsp;0.17%, 95% CI: -0.02 to 0.34).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec16\" class=\"Section2\"\u003e\n \u003ch2\u003e3.9 Urbanization status stratified\u003c/h2\u003e\n \u003cp\u003eRural areas consistently had higher mortality rates, with no significant overall change (AAPC\u0026thinsp;=\u0026thinsp;0.16%, 95% CI: -0.08 to 0.38) \u003cstrong\u003e(Supplementary Fig.\u0026nbsp;11)\u003c/strong\u003e. In contrast, urban areas saw a significant decline from 23.5 in 1999 to 21.9 in 2020 (AAPC=-0.24%*, 95% CI: -0.36 to -0.11). After an initial drop in both settings, AAMRs began to rise, with the steepest increase occurring between 2013 and 2016 (Rural APC\u0026thinsp;=\u0026thinsp;9.55%*, 95% CI: 6.41 to 11.62; Urban APC\u0026thinsp;=\u0026thinsp;7.99%*, 95% CI: 6.43 to 8.97).\u003c/p\u003e\n\u003c/div\u003e"},{"header":"4 Discussion","content":"\u003cdiv id=\"Sec18\" class=\"Section2\"\u003e\u003ch2\u003e4.1 Main findings of this study\u003c/h2\u003e\u003cp\u003eOur study provides a comprehensive 25-year overview (1999\u0026ndash;2023) of SMNL-related AAMRs in US adults aged\u0026thinsp;\u0026ge;\u0026thinsp;45. While AAMRs declined until 2008, a reversal occurred thereafter, with a particularly sharp increase between 2013 and 2016. This upward trend raises critical questions about the interplay between survivorship, late effects of cancer, and the healthcare system response. Notably, this increase occurred despite a significant decline in both AAIRs and AAMRs for most primary cancers, irrespective of metastasis, that were most frequently linked to SMNL-related mortality in our study. These trends likely reflect improved survival among patients with primary cancers, resulting in a longer window for metastatic progression, especially to the liver. Our study also identified notable disparities with higher mortality rates among males, NH-BAA individuals, older age groups, and those in rural areas. These disparities necessitate focused public health initiatives.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec19\" class=\"Section2\"\u003e\u003ch2\u003e4.2 What is already known on this topic\u003c/h2\u003e\u003cp\u003eImproved survivorship means that as patients live longer following a primary cancer diagnosis, their risk of developing late metastatic disease correspondingly rises. This is supported by prior studies showing high rates of metastasis among cancer survivors. Out of 150,000 metastatic breast cancer patients, 75% were initially diagnosed with Stage II/III cancer.\u003csup\u003e16\u003c/sup\u003e Moreover, as noted by Mani et al, metastatic disease remains the principal cause of cancer-related mortality.\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e In this context, our findings underscore both the successes and emerging challenges of modern cancer care.\u003c/p\u003e\u003cp\u003ePrior literature shows that males face a higher burden of cancers prone to liver metastasis, such as prostate cancer, and are twice as likely as females to present with liver metastases.\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e Similarly, NH-BAA individuals are more often diagnosed at later stages. Akinyemiju et al found higher rates of de novo metastasis in NH-BAA with breast, colorectal, and prostate cancer compared to NH Whites (11% vs 9%).\u003csup\u003e19\u003c/sup\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec20\" class=\"Section2\"\u003e\u003ch2\u003e4.3 What this study adds\u003c/h2\u003e\u003cp\u003eTo our knowledge, this is the first study to analyze SMNL-related mortality trends in the US, with important policy implications. Although the rise in AAMRs after 2008 may appear alarming, it likely reflects advances in cancer treatment, screening, and awareness, which have prolonged survival and, in turn, increased opportunities for late metastatic disease. These findings highlight the need for long-term survivorship strategies, including routine monitoring for metastatic spread in high-risk groups.\u003c/p\u003e\u003cp\u003eThe gender- and race-based disparities observed underscore the need for equity-focused cancer control policies. Males had consistently higher AAMRs, which may be attributable to the higher incidence of male-dominant cancers, such as prostate cancer, that often metastasize to the liver and carry poorer prognoses. The higher AAMRs among NH-BAA likely reflect a combination of delayed cancer diagnosis, more advanced disease at presentation, and systemic inequities in access to timely and effective cancer care. NH Whites were the only group to show a significant increase in AAMRs over time, reaching rates nearly equal to those of NH-BAA. This may reflect longer survival after primary cancer diagnosis, providing more time for metastasis, a pattern also observed in the higher CMRs among older adults in our study.\u003csup\u003e\u003cspan additionalcitationids=\"CR21\" citationid=\"CR17\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e These racial disparities likely stem from a mix of socioeconomic, access-related, and systemic factors.\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e Although our study did not directly assess these drivers, it highlights persistent inequities in cancer outcomes across the US healthcare system.\u003c/p\u003e\u003cp\u003eTargeted resource allocation is essential to improve early detection, timely diagnosis, and access to effective treatment in underserved communities. Integrating stratified risk assessments into survivorship protocols, based on demographic and clinical profiles, may help optimize monitoring and intervention strategies.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec21\" class=\"Section2\"\u003e\u003ch2\u003e4.4 Limitations of this study\u003c/h2\u003e\u003cp\u003eOur study utilized the CDC WONDER database; as a result, it is subject to misclassification or incomplete reporting, as it is dependent on death certificate documentation. In rare cases with multiple malignancies, it was not possible to determine the primary source of SMNL, as it was based on co-listed ICD-10 codes on death certificates. The cross-sectional design limits causal inference. Urban-rural analysis was restricted to data up to 2020 due to unavailable population estimates and AAMRs thereafter. Additionally, subgroups with fewer than 10 deaths were suppressed, and those with fewer than 20 were considered statistically unreliable, including data from hospice facilities and select states.\u003c/p\u003e\u003c/div\u003e"},{"header":"5 Conclusion","content":"\u003cp\u003eDespite declining mortality from most primary cancers, AAMRs for SMNL have steadily increased in the US since 2008. This pattern likely reflects that the advancements in the early detection and treatment of primary tumor sources have resulted in increased survival, leading to an increased chance of metastatic progression, particularly to the liver. Our study also highlighted several disparities in SMNL-related mortalities by gender, age, and race, with males, older adults, and NH-BAA having the highest mortality rates. These findings support the need for enhanced long-term surveillance after the initial treatment of primary tumors, for the early diagnosis of recurrence, and to prevent metastasis.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cb\u003eCRediT author statement\u003c/b\u003e\u003c/p\u003e\u003cp\u003eAll authors meet the authorship criteria outlined by the International Committee of Medical Journal Editors (ICMJE). *\u003cb\u003eMahnoor Khan\u003c/b\u003e: Conceptualization, Methodology, Project administration, Formal analysis, Validation, Writing - original draft, and Writing - review \u0026amp; editing. *\u003cb\u003eDaniyal Ali Khan\u003c/b\u003e: Conceptualization, Methodology, Project administration, Formal analysis, Validation, Writing - original draft, and Writing - review \u0026amp; editing. \u003cb\u003eKantesh Kumar\u003c/b\u003e: Methodology, Writing - original draft, and Writing - review \u0026amp; editing. \u003cb\u003eSyed Ali Tayyeb Hasan\u003c/b\u003e: Methodology, Writing - original draft, and Writing - review \u0026amp; editing. \u003cb\u003eShahzaib Khan\u003c/b\u003e: Methodology, Investigation, Data curation, Formal analysis, Visualization, and Writing - review \u0026amp; editing. \u003cb\u003eFatima Najam\u003c/b\u003e: Methodology, Investigation, Data curation, Formal analysis, Visualization, and Writing - review \u0026amp; editing. \u003cb\u003eMunir Mehmood\u003c/b\u003e: Methodology, Writing - original draft, and Writing - review \u0026amp; editing. \u003cb\u003eWaqas Nawaz\u003c/b\u003e: Methodology, Supervision, and Writing - review \u0026amp; editing. All authors had full access to the data, approved the final manuscript, and accept responsibility for its accuracy and integrity.\u003c/p\u003e\u003cp\u003e*These authors contributed equally.\u003c/p\u003e\u003ch2\u003eConflict of Interest\u003c/h2\u003e\u003cp\u003eThe authors declare no conflicts of interest.\u003c/p\u003e\u003ch2\u003eConsent to participate and publish\u003c/h2\u003e\u003cp\u003e\u003cb\u003e\u003c/b\u003e No patient consent was needed for this study, as CDC-WONDER contains anonymized, publicly available data.\u003c/p\u003e\u003ch2\u003eFunding\u003c/h2\u003e\u003cp\u003eThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\u003c/p\u003e\u003ch2\u003eAcknowledgments\u003c/h2\u003e\u003cp\u003eNone.\u003c/p\u003e\u003ch2\u003eData availability statement\u003c/h2\u003e\u003cp\u003eData were abstracted from the Centers for Disease Control and Prevention\u0026rsquo;s Wide-Ranging Online Data for Epidemiologic Research (CDC-WONDER) platform. All relevant data are included in the manuscript and supplementary materials.\u003c/p\u003e\u003cp\u003eCDC-WONDER Multiple Cause of Death 1999\u0026ndash;2020: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://wonder.cdc.gov/mcd-icd10.html\u003c/span\u003e\u003cspan address=\"https://wonder.cdc.gov/mcd-icd10.html\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\u003cp\u003eCDC-WONDER Multiple Cause of Death 2018\u0026ndash;2023: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://wonder.cdc.gov/mcd-icd10-expanded.html\u003c/span\u003e\u003cspan address=\"https://wonder.cdc.gov/mcd-icd10-expanded.html\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eAnanthakrishnan A, Gogineni V, Saeian K. 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Racial/ethnic disparities in de novo metastases sites and survival outcomes for patients with primary breast, colorectal, and prostate cancer. \u003cem\u003eCancer Med\u003c/em\u003e 2018; \u003cstrong\u003e7\u003c/strong\u003e(4): 1183-93.\u003c/li\u003e\n \u003cli\u003eAizer AA, Wilhite TJ, Chen MH, et al. Lack of reduction in racial disparities in cancer-specific mortality over a 20-year period. \u003cem\u003eCancer\u003c/em\u003e 2014; \u003cstrong\u003e120\u003c/strong\u003e(10): 1532-9.\u003c/li\u003e\n \u003cli\u003eStenzel AE, Buas MF, Moysich KB. Survival disparities among racial/ethnic groups of women with ovarian cancer: An update on data from the Surveillance, Epidemiology and End Results (SEER) registry. \u003cem\u003eCancer Epidemiol\u003c/em\u003e 2019; \u003cstrong\u003e62\u003c/strong\u003e: 101580.\u003c/li\u003e\n \u003cli\u003eKucera CW, Tian C, Tarney CM, et al. Factors Associated With Survival Disparities Between Non-Hispanic Black and White Patients With Uterine Cancer. \u003cem\u003eJAMA Netw Open\u003c/em\u003e 2023; \u003cstrong\u003e6\u003c/strong\u003e(4): e238437.\u003c/li\u003e\n \u003cli\u003eHaider AH, Scott VK, Rehman KA, et al. Racial disparities in surgical care and outcomes in the United States: a comprehensive review of patient, provider, and systemic factors. \u003cem\u003eJ Am Coll Surg\u003c/em\u003e 2013; \u003cstrong\u003e216\u003c/strong\u003e(3): 482-92.e12.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Health Inequities, Epidemiology, Mortality, Liver Neoplasms, Neoplasm Metastasis","lastPublishedDoi":"10.21203/rs.3.rs-7613109/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7613109/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003eSecondary malignant neoplasms of the liver (SMNL) are more common than primary liver cancers but remain understudied. This study provides the first nationwide analysis of SMNL mortality trends and disparities in the US.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eThis study analyzed SMNL-related (ICD-10: C78.7) CDC WONDER mortality data (1999\u0026ndash;2023), and US Cancer Statistics incidence data for adults\u0026thinsp;\u0026ge;\u0026thinsp;45 years, stratified by demographics, geography, and primary site. Age-adjusted mortality and incidence rates (AAMRs, AAIRs) and crude mortality rates (CMRs) were reported per 100,000 population. Temporal trends were analyzed using Joinpoint regression.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eSMNL-related AAMR rose from 23.8 (1999) to 25.1 (2023). Males accounted for 51.3% of the 597,332 deaths and had higher AAMRs than females throughout. Lung (25.6%) and colon (24.6%) cancers were the leading primary sites causing SMNL-related deaths. AAIRs and AAMRs (irrespective of metastasis) declined for most primary cancers. CMRs progressively increased across each successive 10-year age group. Non-Hispanic (NH) Blacks had the highest AAMR but with a declining trend, while NH Whites saw a significant increase. West\u0026rsquo;s AAMRs showed the biggest increase. Rural areas consistently had higher AAMRs.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e\u003cp\u003eSMNL mortality is rising among older US adults, with disparities. Improved primary cancer survival extends the window for metastatic progression, highlighting the need for better detection and management.\u003c/p\u003e","manuscriptTitle":"Epidemiologic Trends in Secondary Malignant Neoplasms of the Liver in the United States: A 25-Year National Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-16 16:09:26","doi":"10.21203/rs.3.rs-7613109/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"233e8c8f-9cd7-4a3d-9bf1-426d13b492f8","owner":[],"postedDate":"September 16th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":54686787,"name":"Epidemiology"},{"id":54686788,"name":"Gastroenterology \u0026 Hepatology"}],"tags":[],"updatedAt":"2026-01-12T20:44:26+00:00","versionOfRecord":{"articleIdentity":"rs-7613109","link":"https://doi.org/10.1007/s12029-025-01391-w","journal":{"identity":"journal-of-gastrointestinal-cancer","isVorOnly":false,"title":"Journal of Gastrointestinal Cancer"},"publishedOn":"2026-01-08 00:00:00","publishedOnDateReadable":"January 8th, 2026"},"versionCreatedAt":"2025-09-16 16:09:26","video":"","vorDoi":"10.1007/s12029-025-01391-w","vorDoiUrl":"https://doi.org/10.1007/s12029-025-01391-w","workflowStages":[]},"version":"v1","identity":"rs-7613109","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7613109","identity":"rs-7613109","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}