The impact of adjuvant chemotherapy on overall survival and cancer-specific survival in patients with extrahepatic cholangiocarcinoma across different age groups: a population-based study

Introduction

Cholangiocarcinoma (CCA) is an aggressive malignant tumor originating from bile duct epithelial cells. Based on anatomical location, it is classified into extrahepatic cholangiocarcinoma (ECC) and intrahepatic CCA, with ECC accounting for 70–90% of all CCA cases (1,2). In recent years, the incidence of ECC has increased in Western countries, while mortality rates have remained stable (3,4). Although some ECC patients can be treated by surgical resection, the postoperative recurrence rate is significantly high, resulting in poor prognosis of ECC patients (5). Therefore, various postoperative adjuvant therapies are proposed to improve the prognosis of patients (6).

However, the benefit of postoperative adjuvant therapy (including chemotherapy) for ECC patients is not clear (7). A National Cancer Database analysis report said that there was no difference in the survival rate between patients receiving adjuvant chemotherapy (AC) and patients receiving only surgical treatment (8). Another study on hilar CCA found that, compared with patients without AC, patients with AC had longer overall survival (OS) [hazard ratio (HR) =0.58, P=0.01], especially in patients with positive lymph nodes (9). Most other studies focus on CCA rather than ECC subtypes (10,11). Therefore, although AC is increasingly used in clinical practice, its prognostic impact is still uncertain.

This retrospective study used the Surveillance, Epidemiology, and End Results (SEER) database to compare the prognosis of AC recipients and non-recipients by age groups. The OS and cancer-specific survival (CSS) of each age group were evaluated, and the age group with the greatest benefit from AC was identified, in order to help ECC patients develop more personalized treatment strategies. We present this article in accordance with the STROBE reporting checklist (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2026-0342/rc).

Methods

Data sources

This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. Data were obtained from the SEER database, which contains public and unidentified, population-based monitoring data. According to the Helsinki Declaration and institutional ethical guidelines, this study does not require ethical approval and informed consent (12).

Study population

This study analyzed data from patients diagnosed with ECC between 2010 and 2020, during which the 7th and 8th American Joint Committee on Cancer (AJCC) staging system was implemented. The 7th and 8th AJCC staging systems were unified and integrated to minimize staging heterogeneity, and SEER data were complete. The inclusion criteria were defined as a confirmed diagnosis of ECC (ICD-O-3: primary site codes C24.0), including distal cholangiocarcinoma (dCCA, histology code 8160/3, 8040/3 and 8163/3) and perihilar cholangiocarcinoma (pCCA, histology code 8162/3), with the diagnostic time ranging from 2010 to 2020. The exclusion criteria comprised patients with ECC who received no surgical treatment and those aged outside the 18–85 years range. Data on chemotherapy, radiotherapy, neoadjuvant chemotherapy, surgery, lymph node surgery, anatomical site, liver metastasis, tumor-node-metastasis (TNM) stage, histological grade, marital status, race, and gender were extracted from the SEER database. After applying the aforementioned inclusion and exclusion criteria, 2,189 eligible patients were identified and stratified into four age groups: 18–55, 56–65, 66–75, and 76–85 years. Additional details regarding the patient selection process were presented in Figure 1.

Figure 1 Detailed data collection procedures. ECC, extrahepatic cholangiocarcinoma; SEER, Surveillance, Epidemiology, and End Results.

Statistical analysis

Categorical variables were presented as percentage counts, and Pearson Chi-squared tests were used to compare the groups. The outcome variables are OS and CSS, which are respectively defined as self-diagnosis to death from any cause or ECC death (13). For each age group, the survival curves of OS and CSS were generated by Kaplan-Meier (KM) method, and the differences were evaluated by log rank test. Univariate and multivariate Cox proportional hazards regression models were constructed to evaluate the association between age groups and OS/CSS. Variables with P<0.05 in univariate Cox analysis were enrolled into the multivariate model to screen independent prognostic factors, and adjusted HRs with 95% confidence intervals (CIs) were calculated. The proportional hazard assumption was tested to ensure the validity of the Cox model; 1:1 propensity score matching (PSM) was performed to reduce selection bias among the four age groups (14), and nearest neighbor matching with a caliper width of 0.2 standard deviations of the logit of the propensity score was adopted to balance intergroup covariates. Sensitivity analysis was conducted to assess the robustness of the results. All statistical analyses were performed using R software (version 4.5.0), and a two-tailed P value <0.05 was considered statistically significant. Post-hoc statistical power analysis was performed to validate the rationality of the current sample size. With a two-tailed α of 0.05, our enrolled sample achieved adequate statistical power to detect meaningful prognostic differences and stable regression results, which further guaranteed the reliability and credibility of all statistical conclusions in this study.

Results

Patients’ baseline characteristics

The baseline clinical characteristics of all 2,189 enrolled patients were stratified and summarized in Table 1, according to four age subgroups (18–55, 56–65, 66–75, and 76–85 years). Notably, the proportion of patients receiving radiotherapy and chemotherapy exhibited a gradual decrease with increasing age.

Survival analysis of ECC patients treated and untreated with AC

The KM survival curve was employed to assess OS and CSS in ECC patients who received or did not receive AC (Figures 2,3). Overall, patients who underwent AC achieved superior OS and CSS compared with those who did not (OS: P<0.001; CSS: P=0.03) (Figure 2A and Figure 3A). In subgroup survival analyses stratified by the four age groups, no statistically significant differences in OS or CSS were observed between the 18–55 and 56–65 years age groups (18–55 years: OS: P=0.74, CSS: P=0.92; 56–65 years: OS: P=0.38, CSS: P=0.77). In contrast, a statistically significant difference in both OS and CSS was noted between patients with and without AC in the 66–75 years age group (OS: P=0.002; CSS: P=0.04). For the 76–85 years age group, a statistically significant difference was detected in OS (P=0.04), whereas no statistical significance was observed in CSS (P=0.18). Detailed information on survival analysis results was shown in Figure 2B-2E and Figure 3B-3E.

Figure 2 Kaplan-Meier curves for overall survival of extrahepatic cholangiocarcinoma patients in different age strata stratified by adjuvant chemotherapy status. (A) Overall, (B) 18–55 years, (C) 56–65 years, (D) 66–75 years, (E) 76–85 years. AC, adjuvant chemotherapy; OS, overall survival.

Figure 3 Kaplan-Meier curves for cancer-specific survival of extrahepatic cholangiocarcinoma patients in different age strata stratified by adjuvant chemotherapy status. (A) Overall, (B) 18–55 years, (C) 56–65 years, (D) 66–75 years, (E) 76–85 years. AC, adjuvant chemotherapy; CSS, cancer-specific survival.

Univariate and multivariate COX regression analyses

Since ECC patients in different age groups exhibit different demographic and clinicopathological characteristics, univariate and multivariate Cox regression models were used to evaluate the impact of variables in four different age groups. After adjusting for confounding factors (Table 2 and table available at https://cdn.amegroups.cn/static/public/jgo-2026-0342-1.pdf), chemotherapy was identified as a protective factor for OS in patients aged 66–75 years (HR =0.70, 95% CI: 0.59–0.83, P<0.001) and 76–85 years (HR =0.73, 95% CI: 0.60–0.90, P=0.003). For CSS, chemotherapy remained a protective factor in the 66–75 age group (HR =0.81, 95% CI: 0.68–0.95, P=0.045), whereas no significant survival benefit from AC was observed in patients aged 76–85 years (HR =0.84, 95% CI: 0.65–1.08, P=0.18). The two younger age groups, 18–55 and 56–65 years, were not found to benefit from AC (18–55 years group: OS HR =1.06, 95% CI: 0.77–1.46, P=0.73; CSS HR =1.02, 95% CI: 0.71–1.46, P=0.91; 56–65 years group: OS HR =0.91, 95% CI: 0.74–1.12, P=0.39; CSS HR =0.97, 95% CI: 0.76–1.23, P=0.78).

Survival analysis of ECC patients after PSM

To reduce selection bias across the four age groups and minimize confounding from other variables, 1:1 PSM was conducted between patients who received AC and those who did not (Figures 4,5). After PSM, 13 variables were included, including neoadjuvant chemotherapy, radiotherapy, surgery, anatomical site, lymph node surgery, liver metastasis, T stage, N stage, M stage, histological grade, marital status, race, and gender (table available at https://cdn.amegroups.cn/static/public/jgo-2026-0342-2.pdf). After PSM, survival analysis of the four age groups showed that among patients with and without AC, the differences in OS and CSS remained statistically non-significant in the 18–55 and 56–65 years age groups (18–55 years: OS P=0.91, CSS P=0.81; 56–65 years: OS P=0.2, CSS P=0.33) (Figure 4A,4B and Figure 5A,5B). This finding was consistent with the results prior to PSM. In contrast, statistically significant differences in OS and CSS were observed in the 66–75 and 76–85 years age groups (66–75 years: OS P<0.001, CSS P=0.006; 76–85 years: OS P=0.01, CSS P=0.008) (Figure 4C,4D and Figure 5C,5D).

Figure 4 Kaplan-Meier overall survival estimates for 1:1 matched extrahepatic cholangiocarcinoma cohorts: without vs. with adjuvant chemotherapy, stratified by age group. (A) 18–55 years, (B) 56–65 years, (C) 66–75 years, (D) 76–85 years. AC, adjuvant chemotherapy; OS, overall survival; PSM, propensity score matching.

Figure 5 Kaplan-Meier cancer-specific survival estimates for 1:1 matched extrahepatic cholangiocarcinoma cohorts: without vs. with adjuvant chemotherapy, stratified by age group. (A) 18–55 years, (B) 56–65 years, (C) 66–75 years, (D) 76–85 years. AC, adjuvant chemotherapy; CSS, cancer-specific survival; PSM, propensity score matching.

Sensitivity analyses

In order to determine the robustness of age heterogeneity effect, we selected the alternative cut-off value for sensitivity analysis (≥65 vs. <65 years) (Figure 6). Survival analysis revealed no statistically significant differences in OS and CSS between the chemotherapy and non-chemotherapy groups among individuals younger than 65 years (OS P=0.51, CSS P=0.88) (Figure 6A,6B). Conversely, statistically significant differences in both OS and CSS were observed between the chemotherapy and non-chemotherapy groups among those aged 65 years or older (OS P<0.001, CSS P=0.01) (Figure 6C,6D).

Figure 6 Kaplan-Meier curves for overall survival and cancer-specific survival of extrahepatic cholangiocarcinoma patients in different age strata stratified by adjuvant chemotherapy status. (A) OS <65 years, (B) CSS <65 years, (C) OS ≥65 years, (D) CSS ≥65 years. AC, adjuvant chemotherapy; CSS, cancer-specific survival; OS, overall survival.

Discussion

In this study, stratified analyses were performed based on the age of 2,189 patients with ECC. KM survival curves (with PSM for baseline correction) and Cox regression analysis confirmed significant age-related heterogeneity in the benefits of AC on OS and CSS in ECC patients. This finding provides real-world evidence of high quality for individualized decision-making regarding AC in ECC patients, addressing the limitations of previous studies that neglected age stratification and directly assessed the overall efficacy of chemotherapy. Of note, biliary tract cancer (BTC) comprises heterogeneous subtypes with distinct biological behaviors, and the present study strictly focused on ECC to avoid the confounding effect of intrahepatic disease.

Patients with ECC were divided into four subgroups by age: 18–55, 56–65, 66–75, and 76–85 years. The proportion of AC administration in the younger group was higher, a finding consistent with previous research reports (8). KM curves showed no significant differences in OS and CSS between the 18–55 and 56–65 years groups, both before and after PSM. Cox proportional hazards regression analysis confirmed that chemotherapy was not an independent protective factor, indicating that the incremental benefit of chemotherapy was limited. These two subgroups consisted of relatively young patients, belonging to the young and middle-aged population. Most prior studies on solid tumors had demonstrated that younger patients exhibited better tolerance to chemotherapy and were more prone to derive benefits from AC (15,16). This finding was inconsistent with the results of the present study. This discrepancy was presumably attributed to the more aggressive biological behavior of tumors in young patients with ECC. Existing evidence indicated that in young patients with biliary tract tumors, the incidence of high-risk pathological features. Reddy et al. found that patients with early CCA were diagnosed with stage IV disease in a higher proportion (51%, typical CCA 44%, P<0.001), and the proportion of positive lymphatic vessel invasion was higher (45%, typical CCA 38%, P=0.001) (17). Postoperative AC often fails to sufficiently inhibit tumor recurrence and metastasis, a likely key reason for its absent survival benefit in some groups. Current AC regimens are derived primarily from clinical trials involving middle-aged and elderly populations. Young patients may have specific gene mutations, such as BRAF, ASXL1 and KMT2C mutations (18,19). Recently, Maruki et al. found that the younger age of patients with CCA was significantly correlated with the positive expression of FGFR2 (34.5±3.17 vs. 62.69±1.04 vs. 34.5±3.17; P=0.0003) (20). These characteristics may reduce the efficacy of traditional drugs by driving proliferation and enhancing DNA repair. There is no information about molecular subtypes and chemotherapy regimens in SEER database. Therefore, the possibility of adverse reactions caused by incompatible regimens cannot be ruled out. Additionally, young patients may have decreased treatment compliance due to factors such as work or lifestyle, which could be another confounding factor (21).

KM analysis showed that, before and after PSM, patients with AC had higher OS and CSS than patients with non-AC. Cox regression analysis confirmed that AC was an independent protective factor in this age group. Therefore, AC is clearly most beneficial for patients in this age group. Currently, evidence regarding the benefits of postoperative chemotherapy for elderly patients with ECC is limited. While existing studies have shown that the benefits of AC for elderly patients with CCA are controversial, most fail to divide the population into more specific age subgroups, such as those aged 66–75 and over 75 years old (22). This study specifically highlights the survival advantages of the 66–75 years age group and supports the active use of AC for this group of ECC patients. Compared with younger patients (aged 18–65 years), those aged 66–75 years have lower biological invasiveness (17), and postoperative residual lesions may be more sensitive to chemotherapy. Compared with patients aged 76 years or over, this group usually has enough physical reserves to tolerate a normal chemotherapy dose, achieving more effective tumor control. Therefore, the benefit to this age group may be due to their good physical reserves and response to chemotherapy.

Before PSM, the OS of patients in the 76–85 years age group in the two treatment groups was statistically different, but CSS was not. There were statistical differences between the two groups after PSM. PSM has effectively controlled for some confounding factors, thereby rendering the differences in CSS more pronounced; however, this result still warrants careful consideration. CSS refers to the time from the beginning of treatment to death due to ECC. OS refers to the time from the beginning of treatment to death due to any cause and is affected by cancer factors and non-cancer factors, including cardiovascular and cerebrovascular diseases, infections, and other factors. Elderly patients over 76 years old usually have a variety of underlying diseases (23), and the risk of death from non-cancer factors is significantly higher, which affects the statistical results of OS and CSS. Multiple Cox regression analysis revealed that AC was a protective factor for OS but not for CSS. The underlying cause of this discrepancy remains unclear and may involve multiple factors, including the competing risk of non-cancer mortality, potential misclassification of causes of death, and variations in frailty or comorbidity burden. Further research utilizing the competitive risk model is needed to clarify the efficacy of AC in this elderly population.

The heterogeneity of chemotherapy benefits observed in different age groups in this study is essentially caused by differences in tumor biology, treatment tolerance, and baseline confounding factors between age groups. Young and middle-aged patients showed weak clinical benefits, which may be attributed to high-risk tumor characteristics, gene mutations or poor treatment compliance. Chemotherapy demonstrated complete anti-tumor efficacy in patients aged 66–75 years, with this group exhibiting balanced tolerance to the treatment and tumor biology. In contrast, elderly patients typically have more comorbidities and lower treatment tolerance. For this group, the direct anti-tumor effect of chemotherapy is limited.

Notably, the randomized phase III BILCAP trial established adjuvant capecitabine as the standard of care for resected BTC (24). However, as a SEER-based retrospective analysis, our study lacked detailed records of specific postoperative chemotherapy protocols, making its trial conclusions inapplicable to direct interpretation of our findings. Still, this evidence emphasizes the necessity of postoperative systemic treatment, reinforcing the clinical rationale for our age-stratified individualized analysis. The results of this study on age heterogeneity provide an important reference for individualized decision-making regarding AC for ECC patients. For patients aged 66–75 years, postoperative AC is recommended to maximize survival benefits. For patients aged 76–85 years, an individualized assessment should be performed based on the patient’s physical status and complications. For patients aged 18–65 years, the traditional AC regimen may not be optimal, so targeted research should explore treatment strategies for this group. Additionally, research on the biological characteristics of young and middle-aged patients with ECC should be strengthened to clarify the molecular mechanism of chemotherapy insensitivity.

There are several limitations in this study. Firstly, as a retrospective study, there may be unmeasured confounding factors. Secondly, the SEER database does not provide data on specific variables, such as tumor markers, chemotherapy regimens, time to chemotherapy initiation, chemotherapy compliance, ECOG performance status, postoperative complications, margin status, recurrence patterns, and performance status. Despite using PSM to balance baseline characteristics and conducting multiple Cox regressions to adjust for known confounding factors and reduce bias, some key interfering factors remain in this study. Future studies with more comprehensive clinicopathological and treatment data are needed to clarify the true therapeutic effect of AC.

Conclusions

In conclusion, this study demonstrates that the long-term prognosis of ECC patients undergoing AC varies according to age. Patients in the 66–75 years age group benefited most, while those in the 18–65 years age group did not benefit significantly. Patients over 75 years experienced outcome-specific benefits. These results provide an evidence-based foundation for individualized AC decisions in ECC, supporting the optimization of treatment strategies to balance efficacy and safety for improved patient prognosis. Future prospective studies are needed to further validate these findings.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2026-0342/rc

Peer Review File: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2026-0342/prf

Funding: This study was supported by National Natural Science Foundation of China (Nos. 82402695, 82402683, 82372313, 82272390, 82102482 and 82072371), Program of Shanghai Academic/Technology Research Leader (No. 23XD1404900), Shanghai Healthcare Commission Young Talent Program (No. 2022YQ056), and Shanghai Science and Technology Committee under Grant (No. 21ZR1478200).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2026-0342/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Rimini M, Puzzoni M, Pedica F, et al. Cholangiocarcinoma: new perspectives for new horizons. Expert Rev Gastroenterol Hepatol 2021;15:1367-83. [Crossref] [PubMed]
2. Razumilava N, Gores GJ. Cholangiocarcinoma. Lancet 2014;383:2168-79. [Crossref] [PubMed]
3. Vithayathil M, Khan SA. Current epidemiology of cholangiocarcinoma in Western countries. J Hepatol 2022;77:1690-8. [Crossref] [PubMed]
4. Khan SA, Tavolari S, Brandi G. Cholangiocarcinoma: Epidemiology and risk factors. Liver Int 2019;39:19-31. [Crossref] [PubMed]
5. Yoo C, Jeong H, Jeong JH, et al. Circulating tumor DNA status and dynamics predict recurrence in patients with resected extrahepatic cholangiocarcinoma. J Hepatol 2025;82:861-70. [Crossref] [PubMed]
6. Wang G, Wang Q, Fan X, et al. The Significance of Adjuvant Therapy for Extrahepatic Cholangiocarcinoma After Surgery. Cancer Manag Res 2019;11:10871-82. [Crossref] [PubMed]
7. Benson AB 3rd, D'Angelica MI, Abrams T, et al. Biliary Tract Cancers, Version 2.2025, NCCN Clinical Practice Guidelines In Oncology. J Natl Compr Canc Netw 2025;23:403-18. [Crossref] [PubMed]
8. Hoehn RS, Wima K, Ertel AE, et al. Adjuvant Chemotherapy and Radiation Therapy is Associated with Improved Survival for Patients with Extrahepatic Cholangiocarcinoma. Ann Surg Oncol 2015;22:S1133-9. [Crossref] [PubMed]
9. Krasnick BA, Jin LX, Davidson JT 4th, et al. Adjuvant therapy is associated with improved survival after curative resection for hilar cholangiocarcinoma: A multi-institution analysis from the U.S. extrahepatic biliary malignancy consortium. J Surg Oncol 2018;117:363-71.
10. Luvira V, Satitkarnmanee E, Pugkhem A, et al. Postoperative adjuvant chemotherapy for resectable cholangiocarcinoma. Cochrane Database Syst Rev 2021;9:CD012814. [Crossref] [PubMed]
11. Wang ML, Ke ZY, Yin S, et al. The effect of adjuvant chemotherapy in resectable cholangiocarcinoma: A meta-analysis and systematic review. Hepatobiliary Pancreat Dis Int 2019;18:110-6. [Crossref] [PubMed]
12. Ma W, Wu W, Fu R, et al. Coincident Patterns of Suicide Risk Among Adult Patients with a Primary Solid Tumor: A Large-Scale Population Study. Int J Gen Med 2021;14:1107-19. [Crossref] [PubMed]
13. Zhang Y, Zhang Y, Cheng X, et al. The Prognostic Impact of Lymph Node Dissection on Primary Tumor Resection for Stage IV Non-Small Cell Lung Cancer: A Population-Based Study. Front Oncol 2022;12:853257. [Crossref] [PubMed]
14. Li Y, Ma FH, Xue LY, et al. Neoadjuvant chemotherapy vs upfront surgery for gastric signet ring cell carcinoma: A retrospective, propensity score-matched study. World J Gastroenterol 2020;26:818-27. [Crossref] [PubMed]
15. Zhou P, Recht A. Young age and outcome for women with early-stage invasive breast carcinoma. Cancer 2004;101:1264-74. [Crossref] [PubMed]
16. Son IT, Kang JH, Kim BC, et al. A Retrospective Multicenter Study of the Clinicopathological Characteristics and Prognosis of Young Adult Patients with Colorectal Cancer: Effects of Chemotherapy on Prognosis. J Clin Med 2023;12:3634. [Crossref] [PubMed]
17. Reddy S, Goksu SY, Sanford NN, et al. Characteristics and clinical outcomes in young-onset cholangiocarcinoma. Cancer Med 2023;12:14094-103. [Crossref] [PubMed]
18. Wang J, Shi Y, Chen J, et al. Genomic profiling, prognosis, and potential interventional targets in young and old patients with cholangiocarcinoma. Cancer Biol Ther 2023;24:2223375. [Crossref] [PubMed]
19. Feng H, Tong H, Yan J, et al. Genomic Features and Clinical Characteristics of Adolescents and Young Adults With Cholangiocarcinoma. Front Oncol 2019;9:1439. [Crossref] [PubMed]
20. Maruki Y, Yatabe Y, Mizoguchi C, et al. FGFR2 Fusions or Rearrangements in Young Intrahepatic and Perihilar Cholangiocarcinoma Patients: Key Genetic Insights From a Pan-Asian Study. Hepatol Res 2026;56:78-88. [Crossref] [PubMed]
21. Zeng XL, Heneghan MB, Badawy SM. Adherence to Oral Chemotherapy in Acute Lymphoblastic Leukemia during Maintenance Therapy in Children, Adolescents, and Young Adults: A Systematic Review. Curr Oncol 2023;30:720-48. [Crossref] [PubMed]
22. Cereda S, Belli C, Reni M. Adjuvant treatment in biliary tract cancer: to treat or not to treat? World J Gastroenterol 2012;18:2591-6. [Crossref] [PubMed]
23. Szturz P, Vermorken JB. Treatment of Elderly Patients with Squamous Cell Carcinoma of the Head and Neck. Front Oncol 2016;6:199. [Crossref] [PubMed]
24. Bridgewater J, Fletcher P, Palmer DH, et al. Long-Term Outcomes and Exploratory Analyses of the Randomized Phase III BILCAP Study. J Clin Oncol 2022;40:2048-57. [Crossref] [PubMed]