Trends and Current Status in Anticancer Therapy for Older Patients with Non-Small Cell Lung Cancer in Japan, 2016–2021

Trends and Current Status in Anticancer Therapy for Older Patients with Non-Small Cell Lung Cancer in Japan, 2016–2021 | 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 Trends and Current Status in Anticancer Therapy for Older Patients with Non-Small Cell Lung Cancer in Japan, 2016–2021 Tamaki Kakuwa, Go Naka, Tomone Watanabe, Taisuke Ishii, Yuichi Ichinose, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7927085/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 07 Apr, 2026 Read the published version in International Journal of Clinical Oncology → Version 1 posted 4 You are reading this latest preprint version Abstract Introduction: Anticancer therapy for non-small cell lung cancer in patients ≥ 75 years has evolved with accumulating evidence. Recent guidelines recommend that treatment decisions be based on functional status rather than age alone. However, disparities in treatment rates persist between those above and below 75 years. This study examined whether evidence supporting treatment in older patients influences implementation, comparing trends over time by age groups. Methods: A hospital-based cancer registry covering designated cancer centers was linked with a Diagnosis Procedure Combination database, which records all medical interventions at each facility, capturing approximately 50% of lung cancer cases in Japan. For patients ≥ 75 years with good performance status, the implementation rates of standard anticancer therapy were analyzed by disease stage in 2021 and trends from 2016 to 2021. Results: In 2021, all standard treatments, except oral molecular-targeted therapies for patients with unresectable cancer, were administered less frequently to those ≥ 75 years. Treatments with evidence established before 2016 were stable throughout the study period. Oral molecular-targeted therapies demonstrated no age-related differences, and adjuvant cytotoxic chemotherapy was less frequently administered to patients ≥ 75 years. In contrast, treatments validated in patients ≥ 75 years after 2016 demonstrated a significant trend towards higher implementation, approaching that in younger patients. However, immune checkpoint inhibitors, for which safety and efficacy in older patients remain uncertain, exhibited increasing divergence in implementation rates between age groups over time. Conclusion: Evidence supporting the efficacy and safety of therapies in individuals ≥ 75 years may influence treatment selection over time. Drug therapy Guideline Adherence Health Care Non-small cell lung cancer Older patients Process Assessment Figures Figure 1 Figure 2 Figure 3 1. Introduction Cancer is a leading cause of death worldwide; however, treatment advances have increased the number of individuals who have been cured or are living in remission. This trend is also evident in older adults, for whom rising comorbidities accompany aging. Cancer increasingly serves as both a comorbidity and cause of death in older adults. Globally, as of 2022, lung cancer had the highest incidence and mortality rates, at 12.4% (2,480,675/19,976,499) and 18.7% (1,817,469/9,743,832), respectively [ 1 ]. In Japan, during 2022, lung cancer ranked second in incidence after colorectal cancer, accounting for 13.6% (136,723/1,005,157) of cancer cases; it also had the highest mortality rate, at 19.5% (83,243/426,278) [ 2 ]. The age distribution of patients with lung cancer peaks between 70 and 79 years, indicating its prevalence among older adults. High-quality evidence specific to older patients remains limited. Given the adverse events associated with anticancer agents, many clinical trials had conventionally set an upper age limit—typically 70 or 75 years—as part of their inclusion criteria. However, with growing recognition that performance status, rather than chronological age, is a more relevant factor, recent trials on adjuvant therapy have increasingly included older adults aged ≥ 75 years [ 3 – 5 ]. In advanced-stage lung cancer, some trials have focused exclusively on elderly populations [ 6 – 9 ]. Nonetheless, the majority of studies included patients across all age groups, with outcomes in older adults typically assessed through subgroup analyses. Among previous studies on the implementation rates of standard treatments for lung cancer by stage, a retrospective observational study conducted in Japan by Okuyama et al. examined patients with NSCLC aged ≥ 45 years (in 2012–2015), stratified by 10-year age groups [ 10 ]. A significant gap existed in treatment rates between those < 75 years / ≥ 75 years, with the latter group receiving surgery (stages I and II in Union for International Cancer Control [UICC] Tumor-Node-Metastasis [TNM] 7th ed.), concurrent chemoradiotherapy (stage III), and chemotherapy (stage IV) less frequently. Similarly, in Sweden, Willén et al. (in 2002–2016) demonstrated a decrease in treatment rates with increasing age [ 11 ]. In Austria, Driessen et al. (in 2010–2014) found lower treatment rates and reduced treatment intensity for patients > 70 years with advanced-stage disease, contributing to poorer outcomes [ 12 ]. However, in these previous studies, the correlation between disease stage and treatment was rough, and the treatment did not fully correspond to the guidelines. A 2021 recommendation from the National Comprehensive Cancer Network suggested that patients of older age should undergo comprehensive functional assessments and, if deemed fit, receive standard treatments regardless of age [ 13 ]. To better understand treatment patterns in older populations, it is crucial to evaluate the implementation rates of standard therapies according to cancer stage. In older patients, standard treatments have been assessed for efficacy and safety after validation in all age groups. This study explored whether the establishment of evidence for treatments in patients ≥ 75 years promotes treatment implementation. We examined changes in chemotherapy implementation rates by age over time and their relationship to when supporting evidence was established. 2. Patients and Methods 2.1 Study design This cross-sectional observational study used the latest available data from 2021. Additionally, trends in implementation rates from 2016 to 2021 were examined in a subsequent repeated cross-sectional study. 2.2 Data source This study presents a secondary analysis of existing data by merging hospital-based cancer registry (HBCR) data with Diagnosis Procedure Combination (DPC) data. The HBCR data were sourced from approximately 850 facilities, including primarily cancer care collaboration hospitals, encompassing approximately 70% of all cancer patients in Japan [ 14 ]. The HBCR records patient demographics and clinical cancer information, such as clinical and pathological stages, UICC TNM classification, tumor location, and histopathological findings, based on the International Classification of Diseases Oncology (ICD-O) third edition. DPC data were generated by coding medical procedures, including surgical procedures, radiation therapy, medication, and laboratory and imaging tests, in accordance with the medical reimbursement point system. The combined HBCR and DPC dataset was collected as part of a project on developing a clinical information database to support equitable dissemination of cancer care in Japan. Linkage was performed in the respective hospitals using patient record numbers, and then submitted to the National Cancer Center after deleting identifiers. Data were collected only from facilities voluntarily participating in the HBCR, covering approximately 70% of HBCR-registered patients, corresponding to 50% of all cancer patients in Japan. 2.3 Study participants Patients with NSCLC whose treatment facility was registered continuously in the HBCR from January 1, 2016, to December 31, 2021, were examined. NSCLC was defined by ICD-O morphology (C53.0–53.9) and various histological types (Supplemental Table 1). Stages were defined based on the eighth UICC edition, which was applied to HBCR in 2018. For patients registered before 2018, the stages were translated to the eighth UICC edition. Eligible patients had a Barthel Index (BI) score of 100 and Charlson Comorbidity Index (CCI) score of ≤ 4 for stages I–III and ≤ 8 for stage IV. Exclusion criteria included patients where initial treatment was conducted outside the data registration facilities and patients where diagnosis or treatment facility could not be identified. 2.4 Explanatory variables, outcomes, and analytical items The explanatory variable in this study was age, with patients < 75 years classified into the non-exposed group and those aged 75–84 classified into the exposed group. The outcome measured was the implementation rate of standard chemotherapy for each cancer stage. First, the gap between groups was examined in 2021, followed by an analysis of the gap trend over time from 2016 to 2021. Eight items were set according to disease stage (Table 1 ). For Item #5, evidence supporting the safety and efficacy of concurrent chemoradiotherapy in patients ≥ 75 years had been reported by 2014. In 2017, durvalumab was introduced as consolidation therapy following chemoradiotherapy, and a 2021 retrospective study reported its safety and survival benefit in patients ≥ 70. Given its influence on the implementation rates, Item #5 was classified as post-2016. Evidence sources are listed in Supplementary Table 2. Table 1 Analytical Items Evidence published Items Target population Target therapy Before 2015 #1 Tegafur/uracil for adenocarcinoma after complete resection Stage ⅠA3-ⅡA adenocarcinoma with complete resection Tegafur/uracil after surgery #2 Tegafur/uracil for squamous cell carcinoma after complete resection Stage ⅠA3-ⅡA squamous cell carcinoma with complete resection Tegafur/uracil after surgery #3 Cisplatin combination regimen after complete resection Stage ⅡB/ ⅢA with complete resection Cisplatin combination regimen after surgery #4 Oral molecular-targeted therapy Incurable stage Ⅲ/ stage Ⅳ Oral molecular-targeted therapy After 2016 #5 Concurrent chemoradiotherapy Unresectable stage Ⅲ with radical radiation therapy Chemotherapy during radiation therapy #6 Platinum combination therapy for adenocarcinoma Incurable stage Ⅲ/ stage Ⅳ adenocarcinoma without administration of molecular therapy or immune checkpoint inhibitor Platinum combination regimen #7 Platinum combination therapy for squamous cell carcinoma Incurable stage Ⅲ/ stage Ⅳ squamous cell carcinoma without administration of molecular therapy or immune checkpoint inhibitor Platinum combination regimen #8 Immune checkpoint inhibitors Incurable stage Ⅲ/ stage Ⅳ Immune checkpoint inhibitors 2.5 Analysis Bar graphs illustrate group differences for the most recently available data from 2021, and line graphs depict trends from 2016 to 2021. To compare the implementation rates, the gap between age groups for 2021 was examined using a logistic regression model. The trends in the gap in implementation rates from 2016 to 2021 were investigated using a linear probability model. A binary variable indicating whether the patients were < 75 years / ≥ 75 years was included as an explanatory variable in a model based solely on age and case year, along with an interaction term comprising the case year and binary variable. Analyses were performed using Stata MP/17.0 (Stata Corp LP, College Station, TX, USA), STROBE guidelines were followed, and the study protocol was approved by the Institutional Review Board of the National Cancer Center, Japan (approval no. 2013-081). Patients were provided with the opportunity to opt out of the research through information posted on the institutional websites. 3. Results 3.1 Patient selection and demographics Overall, 369,850 patients were identified, following the application of the selection criteria, 224,869 were included in the analysis (Fig. 1 ). Patients aged 65–74 years accounted for 44.8%, and those aged 75–84 accounted for 33.8%. Histologically, adenocarcinoma constituted 58.3% of the patients, with stages I (40.1%) and IV (28.8%) being the most prevalent (Table 2 ). Table 2 Patient characteristics Total < 75 years ≥ 75 years Number 224,869 148,969 75,900 Mean age, y (SD) 70.1 (8.8) 65.7 (7.6) 78.6 (2.7) < 45, N (%) 3,030 (1.4) 45–54, N (%) 10,889 (4.8) 55–64, N (%) 34,237 (15.2) 65–74, N (%) 100,813 (44.8) 75–84, N (%) 75,900 (33.8) Sex Male (%) 152,799 (68.0) 101,231 (68.0) 51,568 (67.9) Histology Adenocarcinoma, N (%) 131,132 (58.3) 89,771 (60.3) 41,361 (54.5) Squamous cell carcinoma, N (%) 46,102 (20.5) 28,092 (18.7) 18,010 (23.7) Others, N (%) 47,635 (21.2) 31,106 (20.9) 16,529 (21.8) Stage Ⅰ, N (%) 90,126 (40.1) 57,708 (38.7) 32,418 (42.7) Ⅱ, N (%) 23,109 (10.3) 14,421 (9.7) 8,688 (11.5) Ⅲ, N (%) 45,743 (20.3) 31,560 (21.2) 14,183 (18.7) Ⅳ, N (%) 64,712 (28.8) 44,716 (30.0) 19,996 (26.4) Unknown, N (%) 1,179 (0.5) 564 (0.4) 615 (0.8) Year diagnosed 2016, N (%) 37,736 (16.8) 26,371 (17.7) 11,365 (15.0) 2017, N (%) 33,233 (14.8) 22,384 (15.0) 10,849 (14.3) 2018, N (%) 38,893 (17.3) 25,968 (17.4) 12,925 (17.0) 2019, N (%) 39,158 (17.4) 25,416 (17.1) 13,742 (18.1) 2020, N (%) 37,003 (16.5) 23,766 (16.0) 13,237 (17.4) 2021, N (%) 38,864 (17.3) 25,046 (16.8) 13,782 (18.2) Major comorbidities Myocardial infarction/chronic heart failure, N (%) 2,619 (1.2) 1,413 (1.0) 1,206 (1.6) Cerebrovascular diseases, N (%) 212 (0.1) 108 (0.1) 104 (0.1) Dementia, N (%) 1,309 (0.6) 440 (0.3) 869 (1.1) Diabetes without complications, N (%) 36,965 (16.4) 23,324 (15.7) 13,651 (18.0) Diabetes with complications, N (%) 13,099 (5.8) 8,171 (5.5) 4,928 (6.5) Chronic renal disease/hemodialysis, N (%) 1,621 (0.7) 1,005 (0.7) 616 (0.8) 3.2 Treatment implementation rates for 2021 Figure 2 shows the age-specific implementation rates of treatments in 2021. Implementation rates were low for patients ≥ 75 years across all treatments, except for oral molecular-targeted therapy (Fig. 2 d). This trend remained unchanged following multivariate analysis (Supplementary Table 3). 3.3 Trends in implementation rates from 2016 to 2021 by age Trends in treatment implementation rates classified by age group from 2016 to 2021 are displayed in Fig. 3 . Moreover, Table 3 presents the linear probability model results. For treatments published before 2015, the implementation rate of adjuvant chemotherapy for stage IA3-IIA using tegafur/uracil was consistently approximately 20% lower in patients aged ≥ 75 years than that in those < 75 (Fig. 3 a, 3 b). For adjuvant chemotherapy using CDDP-containing regimens in stage IIB-IIIA, the rate in those aged ≥ 75 gradually decreased from 4.3% to 2.8%, whereas in those < 75, it increased from 26.0% to 29.6% (Fig. 3 c). In contrast, the implementation rate of oral molecular-targeted therapy was consistently higher in patients aged ≥ 75 years (Fig. 3 d). Among them, a significant widening in implementation rate was observed for the CDDP-based regimen following complete resection in patients with stage IIB-IIIA (p = 0.02). Table 3 Analysis of gap in treatment implementation between age using linear probability models (age-year models) Items Slope of each linear probability model (per year) (95% CI) p value of interaction term coefficiency < 75 years ≥ 75 years Interaction term #1 Tegafur/uracil for adenocarcinoma after complete resection 0.01 (0.009–0.02) 0.01 (0.004–0.02) -0.003 (-0.01–0.004) 0.41 #2 Tegafur/uracil for squamous cell carcinoma after complete resection -0.01 (-0.02–0.006) -0.004 (-0.01–0.003) 0.01 (0.00001–0.02) 0.05 #3 Cisplatin combination regimen after complete resection 0.008 (0.0004–0.01) -0.002 (-0.007–0.002) -0.01 (-0.02–-0.001) 0.02 #4 Oral molecular-targeted therapy 0.002 (-0.0005–0.005) -0.001 (-0.006–0.003) -0.004 (-0.009–0.002) 0.18 #5 Concurrent chemoradiotherapy 0.006 (0.003–0.009) 0.06 (0.05–0.07) 0.06 (0.05–0.06) < 0.001 #6 Platinum combination therapy for adenocarcinoma 0.02 (0.01–0.02) 0.05 (0.04–0.06) 0.04 (0.03–0.04) < 0.001 #7 Platinum combination therapy for squamous cell carcinoma 0.01 (0.009–0.02) 0.03 (0.02–0.04) 0.02 (0.008–0.03) < 0.001 #8 Immune checkpoint inhibitor 0.11 (0.11–0.12) 0.09 (0.08–0.09) -0.03 (-0.03–-0.02) < 0.001 CI: confidential interval For treatments published after 2016, the implementation rate of concurrent chemoradiotherapy for unresectable locally advanced patients consistently exceeded 90% in those < 75 years throughout the study period, whereas it increased from 52% to 76% in those ≥ 75 years (Fig. 3 e). For platinum-based combination regimens in advanced patients, the implementation rate remained consistently at approximately 90% in patients aged < 75 years for both histological types (Fig. 3 f, 3 g). In patients aged ≥ 75 years, the rate increased from 55.4% to 78.5% and 65.2% to 78.4% for adenocarcinoma and squamous cell carcinoma, respectively. A significant narrowing of gaps was observed for concurrent chemoradiotherapy (6% per year, p < 0.001) and platinum-based regimens for advanced patients (4% per year for adenocarcinoma, p < 0.001; 2% per year for squamous cell carcinoma, p < 0.001). The implementation rate of ICIs for unresectable patients increased across all age groups until 2018. From 2019, while both groups showed a rising trend, the rate of increase differed between groups (Fig. 3 h). The gap between groups significantly widened (-3% per year, p < 0.001). These trends remained unchanged even after covariates were included (Supplementary Table 4). 4. Discussion In 2021, the implementation rate of chemotherapy for patients aged ≥ 75 years remained statistically lower than that for patients aged < 75, excluding oral molecular-targeted therapies. The gap in implementation rates for adjuvant chemotherapy and oral molecular-targeted therapies, both with evidence established before 2015, remained stable after 2016, except for the CDDP-based regimen used for NSCLC stages IIB–IIIA. Treatments established since 2016 have demonstrated both a narrowing and widening trend. Chemoradiotherapy for locally advanced NSCLC and platinum-based regimens for unresectable disease helped narrow the gap; however, the introduction of ICIs for advanced NSCLC has since widened it. 4.1 Relationship between age and chemotherapy implementation A gap in implementation rates between patients < 75 years / ≥ 75 years was observed for adjuvant chemotherapy using cytotoxic agents, concurrent chemoradiotherapy, platinum-based regimens for unresectable cases, and ICIs. In contrast, no significant difference was observed in the implementation of oral molecular-targeted therapies, for which efficacy and safety have been long-established for older patients. Cytotoxic agents affect both normal and cancer cells, causing various adverse events and inducing a great physical burden on patients. Considering the age-related decline in baseline physical function and increase in comorbidities [ 15 ], including cardiovascular and renal impairments, the use of cytotoxic agents becomes increasingly difficult in older adults, especially those aged ≥ 75 years [ 16 ]. Therefore, in clinical practice, the administration rate of regimens containing cytotoxic agents inevitably decreases in older patients. ICIs cause more diverse adverse events than cytotoxic agents, resulting in greater restrictions on administration, particularly in patients with comorbidities. As comorbidities increase with age, patients with more comorbidities experience more adverse events and a poorer prognosis [ 17 ], requiring early detection of symptoms during regular outpatient visits following chemotherapy administration. Therefore, patients and their families must be well-informed to recognize and report symptoms promptly and seek timely medical attention outside of regular outpatient visits. Hence, clinicians may have to be more cautious about the administration of these agents when treating older patients. 4.2 Relation between the establishment of key chemotherapy evidence and implementation rates For treatments wherein evidence was established before 2016, the differences between each age group remained almost stable between 2016 and 2021, excluding CDDP adjuvant therapy due to its toxicity in older patients. Treatments established after 2016 included platinum-based regimens for unresectable tumors, concurrent chemoradiotherapy for locally advanced unresectable tumors, and ICIs for unresectable tumors. Among these, treatments with established safety for patients aged ≥ 75 years include platinum-based regimens for unresectable cases [ 8 , 9 ]). Also, the safety of durvalumab after concurrent chemoradiotherapy for locally advanced unresectable cases in patients aged ≥ 70 years is reported by retrospective study [ 18 ]. Intergroup differences in their implementation rates narrowed during the study period. For ICIs, pembrolizumab monotherapy was established for all age groups in 2016 [ 19 ], for atezolizumab monotherapy and combinations of pembrolizumab or atezolizumab with cytotoxic agents in 2018 [ 20 – 22 ], and for the combination of nivolumab and ipilimumab in 2020 [ 23 ]. Chemotherapy-ICI combination therapy established in 2018, which could be administered regardless of programmed cell death ligand1 expression, expanded the pool of eligible patients, leading to a more aggressive use of ICI in young patients. In contrast, Tsukita et al. reported that a combination of ICI and cytotoxic agents showed no significant survival benefit and worse occurrence of adverse events in patients aged ≥ 75 years [ 24 ]. In addition, administering ICI to older patients can raise safety concerns as mentioned in 4.1. Regarding combination regimens which cause implementation rates to increase more sharply in patients aged < 75 years, intergroup difference might become greater. 4.3 Factors for withholding treatment The World Health Organization defines the categories for withholding treatment as: condition-, therapy-, patient-, socioeconomic-, and healthcare team/health system-related factors [ 25 ]. Condition- and therapy-related factors pertain to a patient’s overall physical condition. Our results suggest that evidence of both safety and efficacy increases treatment adoption in older adults over time. Patient-related reasons are influenced by personal factors such as fear of treatment and personal beliefs. For instance, a common perception among patients is that cytotoxic chemotherapy causes various adverse events, contributing to treatment reluctance. The time commitment for intravenous administration every 3–5 weeks also imposes a burden. Age-related factors exacerbate the frequency of adverse events, necessitating additional outpatient visits beyond the treatment days for management, particularly in older patients. These conditions result in treatment-centered lifestyles. The higher uptake of molecular targeted therapies among patients ≥ 75 years may reflect the lower toxicity and minimal daily life disruptions these therapies offer. In addition, the cost of chemotherapy, exemplified by molecular-targeted therapies or ICIs, remains high. For patients with advanced and incurable diseases, the decision to allocate resources to treatment is personal. Some patients, particularly those ≥ 75-years, may prioritize leaving assets to their families rather than investing in their treatments. Socioeconomic and healthcare team/health system-related factors include financial aspects and accessibility to specialized cancer treatment facilities. The rising cost of anticancer drugs is a burden, and their anticipated survival benefits may offer limited tangible returns. Financial considerations may also influence the treatment decisions of healthcare providers. As the development of various ICIs continues to expand, technological advancements to lower production costs could potentially mitigate these barriers. However, the availability of cancer care facilities is limited. Of the 4,196 general hospitals in Japan with > 100 beds as of 2021, excluding psychiatric hospitals [ 26 ], only 451 appear to aggressively deal with cancer care [ 27 ]. Older patients with cancer may be less able or willing to seek treatment at distant facilities, thus limiting their treatment options. Generally, patients living far from treatment facilities are less likely to receive therapy, particularly adjuvant chemotherapy or radiation therapy, regardless of age [28.29]. Addressing barriers to appropriate evidence-based care, except for cases of patient preference, is a priority to ensure optimal patient outcomes. 4.4 Limitations This study had several limitations. Those inherent to the database include the lack of data covering treatments administered at other institutions and limited collection of DPC data linked to HBCR of 1.25–2.75 years after diagnosis, restricting the tracking of treatments beyond that period. In addition, the absence of linkages between treatments and diagnoses prevents a clear differentiation of treatments, specifically for NSCLC. Additionally, performance status was not collected, necessitating the use of substitute markers such as BIs and CCIs in the DPC data. There may be hidden vulnerabilities in older adults that are not fully captured by the BI, CCI, or age cap of 85 years, leaving uncertainty regarding the comparability of the overall health status between patients aged and < 75 years / ≥ 75 years. Specific limitations associated with each treatment type were also identified. The absence of genetic mutation data may have led to an underestimation of the absolute values of the implementation rate in oral molecular-targeted therapies. Patients who received ICI or gefitinib with platinum-based combination regimens in unresectable cases were excluded. Finally, caution should be exercised when considering result applicability on a nationwide scale, as the data were primarily collected from high-volume centers experienced in cancer treatment, therefore findings may differ in other healthcare institutions. 4.5 Conclusions Among patients with favorable overall health, the implementation rate of oral molecular-targeted therapies showed no difference between those < 75 years / ≥ 75 years. However, for adjuvant cytotoxic chemotherapy, age-based differences in implementation rates were consistently observed. For treatment methods established after 2016, implementation rates for therapies validated in individuals ≥ 75 years showed a significant trend of convergence toward rates observed in younger patients. However, the implementation rate of ICIs, for which safety and efficacy have not been confirmed for those ≥ 75 years, significantly diverged from that of younger patients over time. This suggests that evidence supporting the efficacy and safety of therapies in individuals ≥ 75 years may influence treatment selection over time. Declarations Author Contributions Conceptualization: Tamaki Kakuwa, Go Naka, Tomone Watanabe, Takahiro Higashi; Data curation: Tamaki Kakuwa, Yuichi Ichinose, Tomone Watanabe, Takahiro Higashi; Formal analysis: Tamaki Kakuwa; Funding acquisition: Takahiro Higashi; Investigation: Tamaki Kakuwa; Methodology: Tamaki Kakuwa, Go Naka, Taisuke Ishii, Takahiro Higashi; Project administration: Tamaki Kakuwa, Takahiro Higashi; Resources: Tamaki Kakuwa, Yuichi Ichinose, Tomone Watanabe, Takahiro Higashi; Software: Takahiro Higashi; Supervision: Go Naka, Takahiro Higashi; Validation: Tamaki Kakuwa, Go Naka, Takahiro Higashi; Visualization: Tamaki Kakuwa; Writing - original draft: Tamaki Kakuwa; Writing - review & editing: Go Naka, Taisuke Ishii, Tomone Watanabe, Yuichi Ichinose, Takahiro Higashi Acknowledgments We express our gratitude to the participating facilities and practitioners who contributed to quality indicator project. We are also grateful to Mrs. Yuriko Nishikawa for supporting us in clerical work throughout completion of this manuscript. We are also grateful to Ms. Kaho Shinozaki and Editage for English language editing. We will allocate the research funds to expenses for English editing and publication in academic journals. Conflicts of Interest Go Naka reports a relationship with AstraZeneca that includes speaking and lecture fees. Takahiro Higashi is a member of the Journal of Gynecologic Oncology editorial board. All other authors declare no conflicts of interest. Funding This work was supported by the National Cancer Center Research and Development Fund (2022-A-23). Data Availability Statement The data gathered for this study may result in patient identification; thus, they are not publicly available. References World cancer research fund, Worldwide cancer data. https://www.wcrf.org/cancer-trends/worldwide-cancer-data/, 2022 (accessed 11 October 2024). 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Oncol. 33: 3177–3185. https://doi.org/10.1200/JCO.2015.61.1558. G.B. Rocque, C.P. Williams, H.D. Miller, A. Azuero, S.B. Wheeler, M. Pisu, O. Hull, R.P. Rocconi, K.M. Kenzik (2019) Impact of travel time on health care costs and resource use by phase of care for older patients with cancer, J. Clin. Oncol. 37: 1935–1945. https://doi.org/10.1200/JCO.19.00175. Supplementary Files Supplemental20251016.docx Cite Share Download PDF Status: Published Journal Publication published 07 Apr, 2026 Read the published version in International Journal of Clinical Oncology → Version 1 posted Reviewers agreed at journal 01 Nov, 2025 Reviewers invited by journal 28 Oct, 2025 Editor assigned by journal 23 Oct, 2025 First submitted to journal 22 Oct, 2025 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. 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1","display":"","copyAsset":false,"role":"figure","size":90245,"visible":true,"origin":"","legend":"\u003cp\u003ePatient selection\u003c/p\u003e\n\u003cp\u003eNSCLC: non-small cell lung cancer\u003c/p\u003e\n\u003cp\u003eHBCR: hospital-based cancer registry\u003c/p\u003e\n\u003cp\u003eADL: activities of daily living\u003c/p\u003e\n\u003cp\u003eCCI: Charlson comorbidity index\u003c/p\u003e\n\u003cp\u003eBI: Barthel index\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-7927085/v1/466e83f0cf630edd8d79b885.png"},{"id":94824976,"identity":"51bef5b6-5cba-4060-b9e7-5fd799cf0646","added_by":"auto","created_at":"2025-10-31 06:49:39","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":134834,"visible":true,"origin":"","legend":"\u003cp\u003eTreatment implementation rates in each age group for 2021\u003c/p\u003e\n\u003cp\u003eBlue bars show the implementation rates for those aged \u0026lt; 75 years, and orange bars show the implementation rates for those aged ≥75. a: #1, tegafur/uracil for adenocarcinoma following complete resection; b: #2, tegafur/uracil for squamous cell carcinoma after complete resection; c: #3, cisplatin combination regimen after complete resection; d: #4, oral molecular-targeted therapy; e: #5, concurrent chemoradiotherapy; f: #6, platinum combination therapy for adenocarcinoma; g: #7, platinum combination therapy for squamous cell carcinoma; and h: #8, immune checkpoint inhibitor.\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-7927085/v1/3becfb9ecf317594b59ae454.png"},{"id":94824459,"identity":"11538b04-38f2-441f-bec7-f2d2f6eed76f","added_by":"auto","created_at":"2025-10-31 06:49:01","extension":"jpeg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":1029568,"visible":true,"origin":"","legend":"\u003cp\u003eTrends in treatment implementation rates in each age group from 2016 to 2021\u003c/p\u003e\n\u003cp\u003eBlue lines show the implementation rates for those aged \u0026lt;75 years old, and orange lines show the implementation rates for those aged ≥75. a: #1, tegafur/uracil for adenocarcinoma after complete resection(gap change: −0.3%/year, p = 0.37); b: #2, tegafur/uracil for squamous cell carcinoma after complete resection (gap change: 1%/year, p = 0.06); c: #3, cisplatin combination regimen after complete resection (gap change: −1%/year, p = 0.02); d: #4, oral molecular-targeted therapy (gap change: −0.3%/year, p = 0.16); e: #5, concurrent chemoradiotherapy (gap change: 6%/year, p \u0026lt;0.001); f: #6, platinum combination therapy for adenocarcinoma (gap change: 4%/year, p \u0026lt;0.001); g: #7, platinum combination therapy for squamous cell carcinoma (2%/year, p \u0026lt;0.001); and h: #8, immune checkpoint inhibitor (gap change: −3%/year, p \u0026lt;0.001).\u003c/p\u003e","description":"","filename":"floatimage3.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7927085/v1/7a0da6118b40846940d0bb28.jpeg"},{"id":106809333,"identity":"5af5e2cc-f52e-4a09-926b-4ef1cc325951","added_by":"auto","created_at":"2026-04-13 16:09:34","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2018487,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7927085/v1/7488ad85-38c4-4ffa-a80d-72fcb3f1939e.pdf"},{"id":94762482,"identity":"584caa10-e4e8-4797-ae64-39f0f5fd0dd4","added_by":"auto","created_at":"2025-10-30 12:11:35","extension":"docx","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":52545,"visible":true,"origin":"","legend":"","description":"","filename":"Supplemental20251016.docx","url":"https://assets-eu.researchsquare.com/files/rs-7927085/v1/df56914dff5d165963c372b0.docx"}],"financialInterests":"","formattedTitle":"Trends and Current Status in Anticancer Therapy for Older Patients with Non-Small Cell Lung Cancer in Japan, 2016–2021","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eCancer is a leading cause of death worldwide; however, treatment advances have increased the number of individuals who have been cured or are living in remission. This trend is also evident in older adults, for whom rising comorbidities accompany aging. Cancer increasingly serves as both a comorbidity and cause of death in older adults. Globally, as of 2022, lung cancer had the highest incidence and mortality rates, at 12.4% (2,480,675/19,976,499) and 18.7% (1,817,469/9,743,832), respectively [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. In Japan, during 2022, lung cancer ranked second in incidence after colorectal cancer, accounting for 13.6% (136,723/1,005,157) of cancer cases; it also had the highest mortality rate, at 19.5% (83,243/426,278) [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. The age distribution of patients with lung cancer peaks between 70 and 79 years, indicating its prevalence among older adults.\u003c/p\u003e\u003cp\u003eHigh-quality evidence specific to older patients remains limited. Given the adverse events associated with anticancer agents, many clinical trials had conventionally set an upper age limit\u0026mdash;typically 70 or 75 years\u0026mdash;as part of their inclusion criteria. However, with growing recognition that performance status, rather than chronological age, is a more relevant factor, recent trials on adjuvant therapy have increasingly included older adults aged\u0026thinsp;\u0026ge;\u0026thinsp;75 years [\u003cspan additionalcitationids=\"CR4\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. In advanced-stage lung cancer, some trials have focused exclusively on elderly populations [\u003cspan additionalcitationids=\"CR7 CR8\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Nonetheless, the majority of studies included patients across all age groups, with outcomes in older adults typically assessed through subgroup analyses.\u003c/p\u003e\u003cp\u003eAmong previous studies on the implementation rates of standard treatments for lung cancer by stage, a retrospective observational study conducted in Japan by Okuyama et al. examined patients with NSCLC aged\u0026thinsp;\u0026ge;\u0026thinsp;45 years (in 2012\u0026ndash;2015), stratified by 10-year age groups [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. A significant gap existed in treatment rates between those\u0026thinsp;\u0026lt;\u0026thinsp;75 years / \u0026ge; 75 years, with the latter group receiving surgery (stages I and II in Union for International Cancer Control [UICC] Tumor-Node-Metastasis [TNM] 7th ed.), concurrent chemoradiotherapy (stage III), and chemotherapy (stage IV) less frequently. Similarly, in Sweden, Will\u0026eacute;n et al. (in 2002\u0026ndash;2016) demonstrated a decrease in treatment rates with increasing age [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. In Austria, Driessen et al. (in 2010\u0026ndash;2014) found lower treatment rates and reduced treatment intensity for patients\u0026thinsp;\u0026gt;\u0026thinsp;70 years with advanced-stage disease, contributing to poorer outcomes [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. However, in these previous studies, the correlation between disease stage and treatment was rough, and the treatment did not fully correspond to the guidelines. A 2021 recommendation from the National Comprehensive Cancer Network suggested that patients of older age should undergo comprehensive functional assessments and, if deemed fit, receive standard treatments regardless of age [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. To better understand treatment patterns in older populations, it is crucial to evaluate the implementation rates of standard therapies according to cancer stage. In older patients, standard treatments have been assessed for efficacy and safety after validation in all age groups. This study explored whether the establishment of evidence for treatments in patients\u0026thinsp;\u0026ge;\u0026thinsp;75 years promotes treatment implementation. We examined changes in chemotherapy implementation rates by age over time and their relationship to when supporting evidence was established.\u003c/p\u003e"},{"header":"2. Patients and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003e2.1 Study design\u003c/h2\u003e\u003cp\u003eThis cross-sectional observational study used the latest available data from 2021. Additionally, trends in implementation rates from 2016 to 2021 were examined in a subsequent repeated cross-sectional study.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\u003ch2\u003e2.2 Data source\u003c/h2\u003e\u003cp\u003eThis study presents a secondary analysis of existing data by merging hospital-based cancer registry (HBCR) data with Diagnosis Procedure Combination (DPC) data. The HBCR data were sourced from approximately 850 facilities, including primarily cancer care collaboration hospitals, encompassing approximately 70% of all cancer patients in Japan [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. The HBCR records patient demographics and clinical cancer information, such as clinical and pathological stages, UICC TNM classification, tumor location, and histopathological findings, based on the International Classification of Diseases Oncology (ICD-O) third edition. DPC data were generated by coding medical procedures, including surgical procedures, radiation therapy, medication, and laboratory and imaging tests, in accordance with the medical reimbursement point system. The combined HBCR and DPC dataset was collected as part of a project on developing a clinical information database to support equitable dissemination of cancer care in Japan. Linkage was performed in the respective hospitals using patient record numbers, and then submitted to the National Cancer Center after deleting identifiers. Data were collected only from facilities voluntarily participating in the HBCR, covering approximately 70% of HBCR-registered patients, corresponding to 50% of all cancer patients in Japan.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\u003ch2\u003e2.3 Study participants\u003c/h2\u003e\u003cp\u003ePatients with NSCLC whose treatment facility was registered continuously in the HBCR from January 1, 2016, to December 31, 2021, were examined. NSCLC was defined by ICD-O morphology (C53.0\u0026ndash;53.9) and various histological types (Supplemental Table\u0026nbsp;1). Stages were defined based on the eighth UICC edition, which was applied to HBCR in 2018. For patients registered before 2018, the stages were translated to the eighth UICC edition. Eligible patients had a Barthel Index (BI) score of 100 and Charlson Comorbidity Index (CCI) score of \u0026le;\u0026thinsp;4 for stages I\u0026ndash;III and \u0026le;\u0026thinsp;8 for stage IV. Exclusion criteria included patients where initial treatment was conducted outside the data registration facilities and patients where diagnosis or treatment facility could not be identified.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\u003ch2\u003e2.4 Explanatory variables, outcomes, and analytical items\u003c/h2\u003e\u003cp\u003eThe explanatory variable in this study was age, with patients\u0026thinsp;\u0026lt;\u0026thinsp;75 years classified into the non-exposed group and those aged 75\u0026ndash;84 classified into the exposed group. The outcome measured was the implementation rate of standard chemotherapy for each cancer stage. First, the gap between groups was examined in 2021, followed by an analysis of the gap trend over time from 2016 to 2021. Eight items were set according to disease stage (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). For Item #5, evidence supporting the safety and efficacy of concurrent chemoradiotherapy in patients\u0026thinsp;\u0026ge;\u0026thinsp;75 years had been reported by 2014. In 2017, durvalumab was introduced as consolidation therapy following chemoradiotherapy, and a 2021 retrospective study reported its safety and survival benefit in patients\u0026thinsp;\u0026ge;\u0026thinsp;70. Given its influence on the implementation rates, Item #5 was classified as post-2016. Evidence sources are listed in Supplementary Table\u0026nbsp;2.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eAnalytical Items\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"5\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eEvidence published\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eItems\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eTarget population\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eTarget therapy\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"3\" rowspan=\"4\"\u003e\u003cp\u003eBefore 2015\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e#1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eTegafur/uracil for adenocarcinoma after complete resection\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eStage ⅠA3-ⅡA adenocarcinoma with complete resection\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eTegafur/uracil after surgery\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e#2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eTegafur/uracil for squamous cell carcinoma after complete resection\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eStage ⅠA3-ⅡA squamous cell carcinoma with complete resection\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eTegafur/uracil after surgery\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e#3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eCisplatin combination regimen after complete resection\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eStage ⅡB/ ⅢA with complete resection\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eCisplatin combination regimen after surgery\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e#4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eOral molecular-targeted therapy\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eIncurable stage Ⅲ/ stage Ⅳ\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eOral molecular-targeted therapy\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"3\" rowspan=\"4\"\u003e\u003cp\u003eAfter 2016\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e#5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eConcurrent chemoradiotherapy\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eUnresectable stage Ⅲ with radical radiation therapy\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eChemotherapy during radiation therapy\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e#6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003ePlatinum combination therapy for adenocarcinoma\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eIncurable stage Ⅲ/ stage Ⅳ adenocarcinoma without administration of molecular therapy or immune checkpoint inhibitor\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003ePlatinum combination regimen\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e#7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003ePlatinum combination therapy for squamous cell carcinoma\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eIncurable stage Ⅲ/ stage Ⅳ squamous cell carcinoma without administration of molecular therapy or immune checkpoint inhibitor\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003ePlatinum combination regimen\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e#8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eImmune checkpoint inhibitors\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eIncurable stage Ⅲ/ stage Ⅳ\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eImmune checkpoint inhibitors\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\u003ch2\u003e2.5 Analysis\u003c/h2\u003e\u003cp\u003eBar graphs illustrate group differences for the most recently available data from 2021, and line graphs depict trends from 2016 to 2021. To compare the implementation rates, the gap between age groups for 2021 was examined using a logistic regression model. The trends in the gap in implementation rates from 2016 to 2021 were investigated using a linear probability model. A binary variable indicating whether the patients were \u0026lt;\u0026thinsp;75 years / \u0026ge; 75 years was included as an explanatory variable in a model based solely on age and case year, along with an interaction term comprising the case year and binary variable.\u003c/p\u003e\u003cp\u003e Analyses were performed using Stata MP/17.0 (Stata Corp LP, College Station, TX, USA), STROBE guidelines were followed, and the study protocol was approved by the Institutional Review Board of the National Cancer Center, Japan (approval no. 2013-081). Patients were provided with the opportunity to opt out of the research through information posted on the institutional websites.\u003c/p\u003e\u003c/div\u003e"},{"header":"3. Results","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e\u003ch2\u003e3.1 Patient selection and demographics\u003c/h2\u003e\u003cp\u003eOverall, 369,850 patients were identified, following the application of the selection criteria, 224,869 were included in the analysis (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Patients aged 65\u0026ndash;74 years accounted for 44.8%, and those aged 75\u0026ndash;84 accounted for 33.8%. Histologically, adenocarcinoma constituted 58.3% of the patients, with stages I (40.1%) and IV (28.8%) being the most prevalent (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003ePatient characteristics\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"4\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eTotal\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;75 years\u003c/p\u003e \u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u0026ge;\u0026thinsp;75 years\u003c/p\u003e \u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNumber\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e224,869\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e148,969\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e75,900\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMean age, y (SD)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e70.1 (8.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e65.7 (7.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e78.6 (2.7)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u0026lt; 45, N (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3,030 (1.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e45\u0026ndash;54, N (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e10,889 (4.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e55\u0026ndash;64, N (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e34,237 (15.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e65\u0026ndash;74, N (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e100,813 (44.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e75\u0026ndash;84, N (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e75,900 (33.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSex\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMale (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e152,799 (68.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e101,231 (68.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e51,568 (67.9)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHistology\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAdenocarcinoma, N (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e131,132 (58.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e89,771 (60.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e41,361 (54.5)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSquamous cell carcinoma, N (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e46,102 (20.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e28,092 (18.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e18,010 (23.7)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOthers, N (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e47,635 (21.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e31,106 (20.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e16,529 (21.8)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eStage\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eⅠ, N (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e90,126 (40.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e57,708 (38.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e32,418 (42.7)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eⅡ, N (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e23,109 (10.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e14,421 (9.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e8,688 (11.5)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eⅢ, N (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e45,743 (20.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e31,560 (21.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e14,183 (18.7)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eⅣ, N (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e64,712 (28.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e44,716 (30.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e19,996 (26.4)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eUnknown, N (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1,179 (0.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e564 (0.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e615 (0.8)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eYear diagnosed\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2016, N (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e37,736 (16.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e26,371 (17.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e11,365 (15.0)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2017, N (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e33,233 (14.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e22,384 (15.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e10,849 (14.3)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2018, N (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e38,893 (17.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e25,968 (17.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e12,925 (17.0)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2019, N (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e39,158 (17.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e25,416 (17.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e13,742 (18.1)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2020, N (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e37,003 (16.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e23,766 (16.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e13,237 (17.4)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2021, N (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e38,864 (17.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e25,046 (16.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e13,782 (18.2)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMajor comorbidities\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMyocardial infarction/chronic heart failure, N (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2,619 (1.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1,413 (1.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1,206 (1.6)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCerebrovascular diseases, N (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e212 (0.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e108 (0.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e104 (0.1)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDementia, N (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1,309 (0.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e440 (0.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e869 (1.1)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDiabetes without complications, N (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e36,965 (16.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e23,324 (15.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e13,651 (18.0)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDiabetes with complications, N (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e13,099 (5.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e8,171 (5.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e4,928 (6.5)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eChronic renal disease/hemodialysis, N (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1,621 (0.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1,005 (0.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e616 (0.8)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e\u003ch2\u003e3.2 Treatment implementation rates for 2021\u003c/h2\u003e\u003cp\u003eFigure \u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e2\u003c/span\u003e shows the age-specific implementation rates of treatments in 2021. Implementation rates were low for patients\u0026thinsp;\u0026ge;\u0026thinsp;75 years across all treatments, except for oral molecular-targeted therapy (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e2\u003c/span\u003ed). This trend remained unchanged following multivariate analysis (Supplementary Table\u0026nbsp;3).\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\u003ch2\u003e3.3 Trends in implementation rates from 2016 to 2021 by age\u003c/h2\u003e\u003cp\u003eTrends in treatment implementation rates classified by age group from 2016 to 2021 are displayed in Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e3\u003c/span\u003e. Moreover, Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e presents the linear probability model results. For treatments published before 2015, the implementation rate of adjuvant chemotherapy for stage IA3-IIA using tegafur/uracil was consistently approximately 20% lower in patients aged\u0026thinsp;\u0026ge;\u0026thinsp;75 years than that in those\u0026thinsp;\u0026lt;\u0026thinsp;75 (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e3\u003c/span\u003ea, \u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e3\u003c/span\u003eb). For adjuvant chemotherapy using CDDP-containing regimens in stage IIB-IIIA, the rate in those aged\u0026thinsp;\u0026ge;\u0026thinsp;75 gradually decreased from 4.3% to 2.8%, whereas in those\u0026thinsp;\u0026lt;\u0026thinsp;75, it increased from 26.0% to 29.6% (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e3\u003c/span\u003ec). In contrast, the implementation rate of oral molecular-targeted therapy was consistently higher in patients aged\u0026thinsp;\u0026ge;\u0026thinsp;75 years (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e3\u003c/span\u003ed). Among them, a significant widening in implementation rate was observed for the CDDP-based regimen following complete resection in patients with stage IIB-IIIA (p\u0026thinsp;=\u0026thinsp;0.02).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eAnalysis of gap in treatment implementation between age using linear probability models (age-year models)\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"6\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eItems\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"3\" nameend=\"c5\" namest=\"c3\"\u003e\u003cp\u003eSlope of each linear probability model (per year)\u003c/p\u003e\u003cp\u003e(95% CI)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003ep value of interaction term coefficiency\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;75 years\u003c/p\u003e \u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u0026ge;\u0026thinsp;75 years\u003c/p\u003e \u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eInteraction term\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e#1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eTegafur/uracil for adenocarcinoma after complete resection\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.01\u003c/p\u003e\u003cp\u003e(0.009\u0026ndash;0.02)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.01\u003c/p\u003e\u003cp\u003e(0.004\u0026ndash;0.02)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e-0.003\u003c/p\u003e\u003cp\u003e(-0.01\u0026ndash;0.004)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.41\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e#2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eTegafur/uracil for squamous cell carcinoma after complete resection\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-0.01\u003c/p\u003e\u003cp\u003e(-0.02\u0026ndash;0.006)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-0.004\u003c/p\u003e \u003cp\u003e(-0.01\u0026ndash;0.003)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.01\u003c/p\u003e\u003cp\u003e(0.00001\u0026ndash;0.02)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.05\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e#3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCisplatin combination regimen after complete resection\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.008\u003c/p\u003e\u003cp\u003e(0.0004\u0026ndash;0.01)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-0.002\u003c/p\u003e\u003cp\u003e(-0.007\u0026ndash;0.002)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e-0.01\u003c/p\u003e\u003cp\u003e(-0.02\u0026ndash;-0.001)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.02\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e#4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eOral molecular-targeted therapy\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.002\u003c/p\u003e\u003cp\u003e(-0.0005\u0026ndash;0.005)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-0.001\u003c/p\u003e\u003cp\u003e(-0.006\u0026ndash;0.003)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e-0.004\u003c/p\u003e\u003cp\u003e(-0.009\u0026ndash;0.002)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e0.18\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e#5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eConcurrent chemoradiotherapy\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.006\u003c/p\u003e\u003cp\u003e(0.003\u0026ndash;0.009)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.06\u003c/p\u003e\u003cp\u003e(0.05\u0026ndash;0.07)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.06\u003c/p\u003e\u003cp\u003e(0.05\u0026ndash;0.06)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e#6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePlatinum combination therapy for adenocarcinoma\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.02\u003c/p\u003e\u003cp\u003e(0.01\u0026ndash;0.02)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.05\u003c/p\u003e\u003cp\u003e(0.04\u0026ndash;0.06)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.04\u003c/p\u003e\u003cp\u003e(0.03\u0026ndash;0.04)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e#7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePlatinum combination therapy for squamous cell carcinoma\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.01\u003c/p\u003e\u003cp\u003e(0.009\u0026ndash;0.02)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.03\u003c/p\u003e\u003cp\u003e(0.02\u0026ndash;0.04)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.02\u003c/p\u003e\u003cp\u003e(0.008\u0026ndash;0.03)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e#8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eImmune checkpoint inhibitor\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.11\u003c/p\u003e\u003cp\u003e(0.11\u0026ndash;0.12)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.09\u003c/p\u003e\u003cp\u003e(0.08\u0026ndash;0.09)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e-0.03\u003c/p\u003e\u003cp\u003e(-0.03\u0026ndash;-0.02)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"6\"\u003eCI: confidential interval\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eFor treatments published after 2016, the implementation rate of concurrent chemoradiotherapy for unresectable locally advanced patients consistently exceeded 90% in those\u0026thinsp;\u0026lt;\u0026thinsp;75 years throughout the study period, whereas it increased from 52% to 76% in those\u0026thinsp;\u0026ge;\u0026thinsp;75 years (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e3\u003c/span\u003ee). For platinum-based combination regimens in advanced patients, the implementation rate remained consistently at approximately 90% in patients aged\u0026thinsp;\u0026lt;\u0026thinsp;75 years for both histological types (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e3\u003c/span\u003ef, \u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e3\u003c/span\u003eg). In patients aged\u0026thinsp;\u0026ge;\u0026thinsp;75 years, the rate increased from 55.4% to 78.5% and 65.2% to 78.4% for adenocarcinoma and squamous cell carcinoma, respectively. A significant narrowing of gaps was observed for concurrent chemoradiotherapy (6% per year, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and platinum-based regimens for advanced patients (4% per year for adenocarcinoma, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001; 2% per year for squamous cell carcinoma, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). The implementation rate of ICIs for unresectable patients increased across all age groups until 2018. From 2019, while both groups showed a rising trend, the rate of increase differed between groups (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e3\u003c/span\u003eh). The gap between groups significantly widened (-3% per year, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). These trends remained unchanged even after covariates were included (Supplementary Table\u0026nbsp;4).\u003c/p\u003e\u003c/div\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eIn 2021, the implementation rate of chemotherapy for patients aged\u0026thinsp;\u0026ge;\u0026thinsp;75 years remained statistically lower than that for patients aged\u0026thinsp;\u0026lt;\u0026thinsp;75, excluding oral molecular-targeted therapies. The gap in implementation rates for adjuvant chemotherapy and oral molecular-targeted therapies, both with evidence established before 2015, remained stable after 2016, except for the CDDP-based regimen used for NSCLC stages IIB\u0026ndash;IIIA. Treatments established since 2016 have demonstrated both a narrowing and widening trend. Chemoradiotherapy for locally advanced NSCLC and platinum-based regimens for unresectable disease helped narrow the gap; however, the introduction of ICIs for advanced NSCLC has since widened it.\u003c/p\u003e\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\u003ch2\u003e4.1 Relationship between age and chemotherapy implementation\u003c/h2\u003e\u003cp\u003eA gap in implementation rates between patients\u0026thinsp;\u0026lt;\u0026thinsp;75 years / \u0026ge; 75 years was observed for adjuvant chemotherapy using cytotoxic agents, concurrent chemoradiotherapy, platinum-based regimens for unresectable cases, and ICIs. In contrast, no significant difference was observed in the implementation of oral molecular-targeted therapies, for which efficacy and safety have been long-established for older patients. Cytotoxic agents affect both normal and cancer cells, causing various adverse events and inducing a great physical burden on patients. Considering the age-related decline in baseline physical function and increase in comorbidities [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e], including cardiovascular and renal impairments, the use of cytotoxic agents becomes increasingly difficult in older adults, especially those aged\u0026thinsp;\u0026ge;\u0026thinsp;75 years [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Therefore, in clinical practice, the administration rate of regimens containing cytotoxic agents inevitably decreases in older patients.\u003c/p\u003e\u003cp\u003eICIs cause more diverse adverse events than cytotoxic agents, resulting in greater restrictions on administration, particularly in patients with comorbidities. As comorbidities increase with age, patients with more comorbidities experience more adverse events and a poorer prognosis [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e], requiring early detection of symptoms during regular outpatient visits following chemotherapy administration. Therefore, patients and their families must be well-informed to recognize and report symptoms promptly and seek timely medical attention outside of regular outpatient visits. Hence, clinicians may have to be more cautious about the administration of these agents when treating older patients.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e\u003ch2\u003e4.2 Relation between the establishment of key chemotherapy evidence and implementation rates\u003c/h2\u003e\u003cp\u003eFor treatments wherein evidence was established before 2016, the differences between each age group remained almost stable between 2016 and 2021, excluding CDDP adjuvant therapy due to its toxicity in older patients. Treatments established after 2016 included platinum-based regimens for unresectable tumors, concurrent chemoradiotherapy for locally advanced unresectable tumors, and ICIs for unresectable tumors. Among these, treatments with established safety for patients aged\u0026thinsp;\u0026ge;\u0026thinsp;75 years include platinum-based regimens for unresectable cases [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]). Also, the safety of durvalumab after concurrent chemoradiotherapy for locally advanced unresectable cases in patients aged\u0026thinsp;\u0026ge;\u0026thinsp;70 years is reported by retrospective study [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Intergroup differences in their implementation rates narrowed during the study period. For ICIs, pembrolizumab monotherapy was established for all age groups in 2016 [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e], for atezolizumab monotherapy and combinations of pembrolizumab or atezolizumab with cytotoxic agents in 2018 [\u003cspan additionalcitationids=\"CR21\" citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e], and for the combination of nivolumab and ipilimumab in 2020 [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Chemotherapy-ICI combination therapy established in 2018, which could be administered regardless of programmed cell death ligand1 expression, expanded the pool of eligible patients, leading to a more aggressive use of ICI in young patients. In contrast, Tsukita et al. reported that a combination of ICI and cytotoxic agents showed no significant survival benefit and worse occurrence of adverse events in patients aged\u0026thinsp;\u0026ge;\u0026thinsp;75 years [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. In addition, administering ICI to older patients can raise safety concerns as mentioned in 4.1. Regarding combination regimens which cause implementation rates to increase more sharply in patients aged\u0026thinsp;\u0026lt;\u0026thinsp;75 years, intergroup difference might become greater.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec15\" class=\"Section2\"\u003e\u003ch2\u003e4.3 Factors for withholding treatment\u003c/h2\u003e\u003cp\u003eThe World Health Organization defines the categories for withholding treatment as: condition-, therapy-, patient-, socioeconomic-, and healthcare team/health system-related factors [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Condition- and therapy-related factors pertain to a patient\u0026rsquo;s overall physical condition. Our results suggest that evidence of both safety and efficacy increases treatment adoption in older adults over time.\u003c/p\u003e\u003cp\u003ePatient-related reasons are influenced by personal factors such as fear of treatment and personal beliefs. For instance, a common perception among patients is that cytotoxic chemotherapy causes various adverse events, contributing to treatment reluctance. The time commitment for intravenous administration every 3\u0026ndash;5 weeks also imposes a burden. Age-related factors exacerbate the frequency of adverse events, necessitating additional outpatient visits beyond the treatment days for management, particularly in older patients. These conditions result in treatment-centered lifestyles. The higher uptake of molecular targeted therapies among patients\u0026thinsp;\u0026ge;\u0026thinsp;75 years may reflect the lower toxicity and minimal daily life disruptions these therapies offer. In addition, the cost of chemotherapy, exemplified by molecular-targeted therapies or ICIs, remains high. For patients with advanced and incurable diseases, the decision to allocate resources to treatment is personal. Some patients, particularly those\u0026thinsp;\u0026ge;\u0026thinsp;75-years, may prioritize leaving assets to their families rather than investing in their treatments.\u003c/p\u003e\u003cp\u003eSocioeconomic and healthcare team/health system-related factors include financial aspects and accessibility to specialized cancer treatment facilities. The rising cost of anticancer drugs is a burden, and their anticipated survival benefits may offer limited tangible returns. Financial considerations may also influence the treatment decisions of healthcare providers. As the development of various ICIs continues to expand, technological advancements to lower production costs could potentially mitigate these barriers. However, the availability of cancer care facilities is limited. Of the 4,196 general hospitals in Japan with \u0026gt;\u0026thinsp;100 beds as of 2021, excluding psychiatric hospitals [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e], only 451 appear to aggressively deal with cancer care [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. Older patients with cancer may be less able or willing to seek treatment at distant facilities, thus limiting their treatment options. Generally, patients living far from treatment facilities are less likely to receive therapy, particularly adjuvant chemotherapy or radiation therapy, regardless of age [28.29]. Addressing barriers to appropriate evidence-based care, except for cases of patient preference, is a priority to ensure optimal patient outcomes.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec16\" class=\"Section2\"\u003e\u003ch2\u003e4.4 Limitations\u003c/h2\u003e\u003cp\u003eThis study had several limitations. Those inherent to the database include the lack of data covering treatments administered at other institutions and limited collection of DPC data linked to HBCR of 1.25\u0026ndash;2.75 years after diagnosis, restricting the tracking of treatments beyond that period. In addition, the absence of linkages between treatments and diagnoses prevents a clear differentiation of treatments, specifically for NSCLC. Additionally, performance status was not collected, necessitating the use of substitute markers such as BIs and CCIs in the DPC data. There may be hidden vulnerabilities in older adults that are not fully captured by the BI, CCI, or age cap of 85 years, leaving uncertainty regarding the comparability of the overall health status between patients aged and \u0026lt;\u0026thinsp;75 years / \u0026ge; 75 years. Specific limitations associated with each treatment type were also identified. The absence of genetic mutation data may have led to an underestimation of the absolute values of the implementation rate in oral molecular-targeted therapies. Patients who received ICI or gefitinib with platinum-based combination regimens in unresectable cases were excluded. Finally, caution should be exercised when considering result applicability on a nationwide scale, as the data were primarily collected from high-volume centers experienced in cancer treatment, therefore findings may differ in other healthcare institutions.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec17\" class=\"Section2\"\u003e\u003ch2\u003e4.5 Conclusions\u003c/h2\u003e\u003cp\u003eAmong patients with favorable overall health, the implementation rate of oral molecular-targeted therapies showed no difference between those\u0026thinsp;\u0026lt;\u0026thinsp;75 years / \u0026ge; 75 years. However, for adjuvant cytotoxic chemotherapy, age-based differences in implementation rates were consistently observed. For treatment methods established after 2016, implementation rates for therapies validated in individuals\u0026thinsp;\u0026ge;\u0026thinsp;75 years showed a significant trend of convergence toward rates observed in younger patients. However, the implementation rate of ICIs, for which safety and efficacy have not been confirmed for those\u0026thinsp;\u0026ge;\u0026thinsp;75 years, significantly diverged from that of younger patients over time. This suggests that evidence supporting the efficacy and safety of therapies in individuals\u0026thinsp;\u0026ge;\u0026thinsp;75 years may influence treatment selection over time.\u003c/p\u003e\u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003eAuthor Contributions\u003c/p\u003e\n\u003cp\u003eConceptualization: Tamaki Kakuwa, Go Naka, Tomone Watanabe, Takahiro Higashi; Data curation: Tamaki Kakuwa, Yuichi Ichinose, Tomone Watanabe, Takahiro Higashi; Formal analysis: Tamaki Kakuwa; Funding acquisition: Takahiro Higashi; Investigation: Tamaki Kakuwa; Methodology: Tamaki Kakuwa, Go Naka, Taisuke Ishii, Takahiro Higashi; Project administration: Tamaki Kakuwa, Takahiro Higashi; Resources: Tamaki Kakuwa, Yuichi Ichinose, Tomone Watanabe, Takahiro Higashi; Software: Takahiro Higashi; Supervision: Go Naka, Takahiro Higashi; Validation: Tamaki Kakuwa, Go Naka, Takahiro Higashi; Visualization: Tamaki Kakuwa; Writing - original draft: Tamaki Kakuwa; Writing - review \u0026amp; editing: Go Naka, Taisuke Ishii, Tomone Watanabe, Yuichi Ichinose, Takahiro Higashi\u003c/p\u003e\n\u003cp\u003eAcknowledgments\u003c/p\u003e\n\u003cp\u003eWe express our gratitude to the participating facilities and practitioners who contributed to quality indicator project. We are also grateful to Mrs. Yuriko Nishikawa for supporting us in clerical work throughout completion of this manuscript. We are also grateful to Ms. Kaho Shinozaki and Editage for English language editing. We will allocate the research funds to expenses for English editing and publication in academic journals.\u003c/p\u003e\n\u003cp\u003eConflicts of Interest\u003c/p\u003e\n\u003cp\u003eGo Naka reports a relationship with AstraZeneca that includes speaking and lecture fees. Takahiro Higashi is a member of the Journal of Gynecologic Oncology editorial board. All other authors declare no conflicts of interest.\u003c/p\u003e\n\u003cp\u003eFunding\u003c/p\u003e\n\u003cp\u003eThis work was supported by the National Cancer Center Research and Development Fund (2022-A-23).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eData Availability Statement\u003c/p\u003e\n\u003cp\u003eThe data gathered for this study may result in patient identification; thus, they are not publicly available.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eWorld cancer research fund, Worldwide cancer data. https://www.wcrf.org/cancer-trends/worldwide-cancer-data/, 2022 (accessed 11 October 2024).\u003c/li\u003e\n\u003cli\u003eCancer and disease control division, Ministry of health, labour and welfare. Cancer incidence of Japan 2020. https://www.mhlw.go.jp/content/10900000/001231386.pdf, 2020 (accessed 11 October 2024).\u003c/li\u003e\n\u003cli\u003eY.L. Wu, M. Tsuboi, J. He, T. John, C. Grohe, M. Majem, J.W. Goldman, K. Laktionov, S.W. Kim, T. 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Oncol. 37: 1935\u0026ndash;1945. https://doi.org/10.1200/JCO.19.00175.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":true,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"international-journal-of-clinical-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ijco","sideBox":"Learn more about [International Journal of Clinical Oncology](http://link.springer.com/journal/10147)","snPcode":"10147","submissionUrl":"https://www.editorialmanager.com/ijco/default2.aspx","title":"International Journal of Clinical Oncology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Drug therapy, Guideline Adherence, Health Care, Non-small cell lung cancer, Older patients, Process Assessment","lastPublishedDoi":"10.21203/rs.3.rs-7927085/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7927085/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eIntroduction: Anticancer therapy for non-small cell lung cancer in patients\u0026thinsp;\u0026ge;\u0026thinsp;75 years has evolved with accumulating evidence. Recent guidelines recommend that treatment decisions be based on functional status rather than age alone. However, disparities in treatment rates persist between those above and below 75 years. This study examined whether evidence supporting treatment in older patients influences implementation, comparing trends over time by age groups.\u003c/p\u003e\u003cp\u003eMethods: A hospital-based cancer registry covering designated cancer centers was linked with a Diagnosis Procedure Combination database, which records all medical interventions at each facility, capturing approximately 50% of lung cancer cases in Japan. For patients\u0026thinsp;\u0026ge;\u0026thinsp;75 years with good performance status, the implementation rates of standard anticancer therapy were analyzed by disease stage in 2021 and trends from 2016 to 2021.\u003c/p\u003e\u003cp\u003eResults: In 2021, all standard treatments, except oral molecular-targeted therapies for patients with unresectable cancer, were administered less frequently to those\u0026thinsp;\u0026ge;\u0026thinsp;75 years. Treatments with evidence established before 2016 were stable throughout the study period. Oral molecular-targeted therapies demonstrated no age-related differences, and adjuvant cytotoxic chemotherapy was less frequently administered to patients\u0026thinsp;\u0026ge;\u0026thinsp;75 years. In contrast, treatments validated in patients\u0026thinsp;\u0026ge;\u0026thinsp;75 years after 2016 demonstrated a significant trend towards higher implementation, approaching that in younger patients. However, immune checkpoint inhibitors, for which safety and efficacy in older patients remain uncertain, exhibited increasing divergence in implementation rates between age groups over time.\u003c/p\u003e\u003cp\u003eConclusion: Evidence supporting the efficacy and safety of therapies in individuals\u0026thinsp;\u0026ge;\u0026thinsp;75 years may influence treatment selection over time.\u003c/p\u003e","manuscriptTitle":"Trends and Current Status in Anticancer Therapy for Older Patients with Non-Small Cell Lung Cancer in Japan, 2016–2021","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-10-30 12:11:30","doi":"10.21203/rs.3.rs-7927085/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"","date":"2025-11-01T09:02:38+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-10-28T05:52:45+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-10-23T16:27:24+00:00","index":"","fulltext":""},{"type":"submitted","content":"International Journal of Clinical Oncology","date":"2025-10-22T20:51:38+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"international-journal-of-clinical-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ijco","sideBox":"Learn more about [International Journal of Clinical Oncology](http://link.springer.com/journal/10147)","snPcode":"10147","submissionUrl":"https://www.editorialmanager.com/ijco/default2.aspx","title":"International Journal of Clinical Oncology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"0dd05dae-eaca-4189-8e09-cfb8c2f9003e","owner":[],"postedDate":"October 30th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-04-13T16:06:59+00:00","versionOfRecord":{"articleIdentity":"rs-7927085","link":"https://doi.org/10.1007/s10147-026-03025-y","journal":{"identity":"international-journal-of-clinical-oncology","isVorOnly":false,"title":"International Journal of Clinical Oncology"},"publishedOn":"2026-04-07 15:57:12","publishedOnDateReadable":"April 7th, 2026"},"versionCreatedAt":"2025-10-30 12:11:30","video":"","vorDoi":"10.1007/s10147-026-03025-y","vorDoiUrl":"https://doi.org/10.1007/s10147-026-03025-y","workflowStages":[]},"version":"v1","identity":"rs-7927085","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7927085","identity":"rs-7927085","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}