Introduction
Esophageal cancer is the sixth leading global cause of cancer-related deaths.1 The median age at diagnosis is 68 years, and more than 40% of the patients are aged 70 years or older.2 In practice, there is still controversy on choice of treatment method for esophageal squamous cell carcinoma (ESCC) patients over 80 years old. There is limited research on the local treatment modalities or outcomes of esophageal cancer in this population, and most of it is based on the experience of small, single institutions. In this case, the use of surgery in the elderly is low and may increase postoperative complications, and older people also rarely consider definitive chemoradiotherapy, but the treatment seems to be well tolerated and the efficacy is comparable to that of younger patients.3–6
Several researches suggest that histological type is associated with the efficacy of RT. One population-based study7 showed that potentially curable esophageal adenocarcinoma cancer (EAC) (≥75 years old) had different OS between both definitive chemoradiotherapy (dCRT) or neoadjuvant chemoradiotherapy (nCRT) plus surgery, but not in ESCC (age ≥ 75 years). These differences in treatment response between patients with EAC and ESCC may be associated with tumor aggressiveness and different carcinogenesis.8 However, studies have also shown that in elderly ESCC patients, surgery has a better OS rate than RT.9 A meta-analysis showed that it is difficult to conclude the less efficacy of RT in elderly patients with ESCC.10
Most studies reporting the efficacy of local treatment for EC are focused on patients younger than 80 years old and do not differentiate between adenocarcinoma and squamous cell carcinoma based on pathological types.5,6,9,10 Unfortunately, it is difficult to draw conclusions on local treatments in esophageal squamous cell carcinoma patients over 80 years old from previous studies. Because the lack of randomized trials, available data from small single-institution studies led to no consensus on local treatment for more than 80 years old patients with ESCC. Therefore, the most effective local treatment strategies still need to be further explored. In this regard, we used the data from the Surveillance Epidemiology and End Results (SEER) database to investigate the difference between Surgery and Radiotherapy. Furthermore, we discovered significant differences in the baseline characteristic of the studies. Thus, in this study, we performed propensity-score matched (PSM) analyses to adjust for biases from baseline characteristics of the two treatment groups.
Materials and Methods
Patient Selection in the SEER Database
Patient data were obtained from the latest version of the SEER database as released in Nov 2023 (covering 8 registries, 1973–2021), by using SEER* Stat version 8.4.3. The inclusion criteria of this study were as follows: (1) patients with esophageal squamous cell cancer were clearly diagnosed; (2) age ≥ 80 years old; (3) treatment includes chemoradiotherapy, radiotherapy alone, Surgery alone, Surgery with chemotherapy or unknown. Exclusion criteria in this study were: (1) survival time was 0 or missing; (2) patients with more than one primary tumor. The following covariates were collected from the database: age, race, marital status, primary site, grade, size and Local treatment modalities. Relevant treatment-related data included cancer-directed surgery and Radiotherapy. Duration of follow-up, and cause of death described as due to cancer-specific survival (CSS) and overall survival (OS) were also included. As the SEER database contains public data, informed consent from relevant patients for the use of the SEER database for research purposes was not required, nor was the ethical approval. This study was approved by the Hebei General Hospital Ethics Committee (Approval ID: 2025-LW-0150). This study complies with the Declaration of Helsinki. Our request for access to the SEER data was approved by the National Cancer Institute, USA (reference number 19238-Nov2021).
Statistical Analysis
The chi-squared test (or Fisher’s exact test, if appropriate) was used to analyze the differences between patients grouped by categorical variables. Clinical outcomes were compared between patients treated with cancer-directed surgery (CDS) group and Radiotherapy (RT) group. Survival curves were generated using Kaplan-Meier methods, and compared by Log rank test. Univariate and multivariate Cox regression analyses were used to analyze the independent risk factors for CSS and OS. Only variables with statistical significance (P < 0.05) in univariate analysis were incorporated into multivariate analysis. Hazard ratios (HR) were calculated based on multivariable Cox proportional hazards models to estimate predictors of CSS and OS. All CIs were stated at the 95% confidence level. Statistical significance was set at P < 0.05. To adjust for differences and to minimize possible confounding effects of selection bias between CDS group and RT group for patients, we performed two PSM analyses using logistic regression at a 1:2 ratio accomplished using the nearest neighbor matching method with a caliper width equal to 0.20 standard deviation of logit of propensity score. The PSM model was based upon age, race, marital status, primary site, grade, size and surgery. The difference of each variable was considered significant if two-sided p-values less than 0.05. Statistical analyses were performed using SPSS 26.0 (SPSS Inc., Chicago, IL) and R software (version 3.5.1).
Results
Baseline Characteristics in the Entire Population
In the unmatched database, a total of 1588 patients met our inclusion criteria and were included in our final analysis. The median follow-up time was 147.0 months (range: 103.8–190.2 months) in CDS Group and 169.0 months (range: 90.5–247.5 months) in RT Group. Table 1 summarizes the characteristics of the study population. A total of 165 (10.4%) patients underwent CDS and 1423 (89.6%) patients received RT treatment. Significant differences between two treatment groups were recorded regarding patient characteristics. As shown in Table 1, it was investigated that significant differences were found among the Age, Grade, Stage, Tumor Size and Chemotherapy. All of them had statistical difference (P < 0.05) except Sex, Race, Location and marital status (P>0.05).
Table 1 Characteristics of Patients
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Analysis of Prognostic Factors
In the dataset, univariate analysis showed that age, sex, tumor size, grade, stage, chemotherapy and local treatment modalities were prognostic factors that affected OS and CSS (P < 0.05; Tables 2 and 3). Marital status and race were not associated with OS (P > 0.05; Table 2). Location affected CSS (P < 0.05; Table 3), but not OS (P > 0.05; Table 2).
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Table 2 Univariate and Multivariate Analysis of Overall Survival
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Table 3 Univariate and Multivariate Analysis of Cause-Specific Survival
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Multivariate analysis showed that age, sex, tumor size, stage, chemotherapy and local treatment modalities were prognostic factors that affected OS and CSS (P < 0.05; Tables 2 and 3). Grade affected OS (P < 0.05; Table 2), but not CSS (P > 0.05; Table 3). Patients who received CDS treatment had better OS (HR = 0.717; 95% CI: 0.595–0.863; P < 0.05; Table 2) and CSS (HR = 0.674; 95% CI: 0.544–0.836; P < 0.05; Table 3).
Impact of Local Treatment Modalities on Survival
In the original cohort, according to the survival curve, the median OS of CDS was 11.0 months (95% CI:8.2–13.8 months), which was significantly better than that of RT group (8.0 months) (95% CI: 7.4–8.6 months) (P < 0.05) (Figure 1a). The median CSS of CDS was 16.0 months (95% CI:12.3–19.7 months), which was significantly better than that of RT (10.0 months) (95% CI:9.3–10.7months) (P < 0.05) (Figure 1b). Because there were both significant differences in the baseline characteristic of two groups, we performed PSM analyses at a 1:2 ratio to erase significant difference of each variable, respectively (Table 4). The 1:2 matching for CDS versus RT resulted in a sample size of 379 patients. In the matched dataset, we obtained similar results: the median OS of CDS was 10.0 months, which was significantly better than that of RT group (8.0 months) (P < 0.05) (Figure 1c). The median CSS of CDS was 13.0 months, which was significantly better than that of RT (10.0 months) (P < 0.05) (Figure 1d).According to subgroup analysis, as shown in Tables 5 and 6, CDS was associated with better OS and CSS in In the 80–84 age group (P < 0.05) (Figure 2a–c respectively); nevertheless, no differences were observed in OS and CSS according to different local treatment modalities in over 85 years old group (P>0.05) (Figure 2b–d, respectively).
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Table 4 Characteristics of PSM Cohorts for Patients
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Table 5 Overall Survival of Subgroups Analysis for Local Treatment Modalities
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Table 6 Cause-Specific Survival of Subgroups Analysis for Local Treatment Modalities
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Figure 1 Overall survival and Cancer-specific survival of esophageal squamous cancer patients with ≥80 years older before and after PSM. OS before PSM (a), CSS before PSM (b), OS after PSM (c) and CSS after PSM (d) with different local treatment modalities.
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Figure 2 Overall survival and Cancer-specific survival of esophageal squamous cancer patients with 80–84 years and ≥85 years older after PSM. OS with 80–84 years (a) and ≥85 years older (b), CSS with 80–84 years (c) and ≥85 years older(d) with different local treatment modalities.
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Discussion
In the modern elderly patient population with esophageal squamous cell cancer, our research results indicate significant differences in treatment utilization and related outcomes based on demographic and tumor characteristics. Treatment outcomes are significantly influenced by age, gender, tumor size, stage, grade. Local treatment modalities and chemotherapy also affect utilization rates in specific situations. As the aggressiveness of treatment increases from definitive radiotherapy to surgical treatment of the disease, survival rates gradually improve.
In the elderly population, age is one of the strongest predictors of treatment utilization and survival. More than 80 years old patients are more likely to not receive treatment in non-definitive therapy, while the likelihood of receiving triple therapy and individual esophagectomy in definitive therapy is much lower. These differences may be a combination of patient related factors, physician bias, and clinical reality. In theory, as age increases, the comorbidity rate should increase and physiological reserves should decrease, leading to a decrease in tolerance to aggressive treatment with age. Towards older adults, stem cell reserves and the presence of comorbidities that affect drug absorption and/or metabolism. In addition, esophagectomy is associated with a higher perioperative mortality rate in elderly people. In a large retrospective study evaluating the safety of esophagectomy in elderly patients, the surgical mortality rate significantly increased with age (8.8% for 65–69 years old, 13.4% for 70–79 years old, and 19.9% for those over 80 years old).11 In our analysis, surgery significantly prolonged OS and CSS compared to RT in ≥ 80 years age group. Although baseline characteristic of patients may affect these findings, we do see consistent improvement in matching cohorts with more aggressive treatment. However, surgery was not associated with a better OS in age ≥85 years groups compared to RT in subgroup analysis. However, in properly selected individuals, the incidence rate and mortality of esophagectomy are comparable to those of patients in their 80s.12,13
Endoscopy is used for staging esophageal cancer patients, especially T staging, and can be performed noninvasively. However, elderly patients have more preexisting comorbidities, which are contraindications for this surgery. Therefore, in this study, we used tumor Size and SEER staging instead of TNM staging. Before using endoscopic staging in EC, tumor Size (1–3cm,4–6cm,7–9cm, ≥10cm), is used to predict patient prognosis.14 Several studies have identified that tumor Size is an important prognostic factor for esophageal cancer (EC) in different treatment strategies for young patients.15–17 Similarly, our research findings indicate that tumor size is also a prognostic factor for elderly patients.
Gender is also a predictive factor for the utilization rate and survival rate of esophageal cancer treatment. The results also described esophageal cancer, in which male patients had lower long-term survival rates after surgery.18–20 A nationwide study in Sweden reported a prognostic advantage for female patients with esophageal squamous cell carcinoma (ESCC) both after either curative surgery or dCRT, while no such difference was observed for adenocarcinoma (AC).21 Another study, including patients from a variety of European and North-American centers, highlights that survival was improved for women in the AC group, whereas this difference was not confirmed in squamous cell cancer.22 In the current analysis, the predominant subtype of SCC in women has improved survival rates. Although differences in mortality caused by concurrent diseases may be a contributing factor, gender differences in disease progression and treatment response are an unexplored possibility. A possible biological mechanism for a sex difference is estrogenic influence, which could inhibit cancer cell growth.23,24 Healthcare-seeking patterns, socioeconomic and lifestyle factors might also differ between the sexes, with women more readily and more often using health resources available to them, compared with men. Further research is needed to delve deeper into this hypothesis.
Univariate and multivariate analysis showed that chemotherapy (CT) associated with good prognosis. However, subgroup analysis suggested that CDS for patients did not improve the OS and CSS over RT in CT group. Although the chemotherapy and radiotherapy regimen not recorded in this study, we should note that elderly patients with combined therapy do not tend to improve OS compared to younger patients. Jingu et al reported that concurrent chemotherapy with radiotherapy did not have significant OS benefit over radiotherapy alone for esophageal cancer in patients aged 80 years or older, and the chemotherapeutic regimens were platinum based dual drugs (n=62), and single chemotherapy drug (n=17).25 Ji et al reported that CRT with S-1 (≥80 years: 37 (24.8%)) provided significant benefits over radiotherapy alone (≥80 years: 39 (26.2%)) in older patients with EC in a Phase III randomized clinical trial.26 The chemotherapy regimen and combined with CDS/RT can be considered in the future to improve the OS of elderly patients with EC.
There were some limitations to our study. First, In practical clinical treatment, ≥80 years patients with ESCC who were assessed as not tolerating chemotherapy or unwilling to undergo chemotherapy.27,28 It should be noted that, due to the lack of medical information in the SEER database, we were unable to obtain details of chemotherapy. Potential chemotherapy may influence survival, which lead to biased results. Second, in our study, patients received different doses of radiotherapy, which may have led to some deviations in the survival and safety of patients. In addition, we did not comprehensively assess the health status and quality of life after treatment in elderly patients, which may be a key factor in influencing whether patients can complete treatment, and can better assess the safety of local treatment Local treatment modalities. We were unable to evaluate toxicities, because of lack of information in the registry.
Conclusion
In conclusion, our study provided creditable evidence for characteristics and outcome for ESCC patients aged ≥ 80 years old based on large, population-based registry. Our study suggested that ESCC patients aged ≥ 80 years old benefit from CDS only if the cancer is in localized/regional stage, but not in ≥85 years older in subgroup analysis. However, the limitations of this study must be acknowledged; therefore, more large-scale prospective randomized clinical trials are warranted to investigate the effect of local treatment on over 80 years old patients with ESCC.
Statement of Ethics
This study was approved by the Hebei General Hospital Ethics Committee (Approval ID: 2025-LW-0150). All procedures were performed in accordance with the Declaration of Helsinki.
Acknowledgments
We would like to sincerely thank the original SEER and the related consortiums for sharing and managing the summary statistics. The authors wish to thank all hands and minds involved in this study.
Author Contributions
All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.
Funding
This work was supported by Medical Science Research Project Plan of Hebei Provincial Health Commission (20220920).
Disclosure
The author(s) report(s) no conflicts of interest in this work.
References
1. Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209–249. doi:10.3322/caac.21660
2. Vlacich G, Samson PP, Perkins SM, et al. Treatment utilization and outcomes in elderly patients with locally advanced esophageal carcinoma: a review of the national Cancer Database. Cancer Med. 2017;6(12):2886–2896. doi:10.1002/cam4.1250
3. Sabel MS, Smith JL, Nava HR, et al. Esophageal resection for carcinoma in patients older than 70 years. Ann Surg Oncol. 2002;9(2):210–214. doi:10.1007/BF02557376
4. Cijs TM, Verhoef C, Steyerberg EW, et al. Outcome of esophagectomy for cancer in elderly patients. Ann Thorac Surg. 2010;90(3):900–907. doi:10.1016/j.athoracsur.2010.05.039
5. Ji Y, Qiu G, Sheng L, et al. A Phase I dose escalation study of S‐1 with concurrent radiotherapy in elderly patients with esophageal cancer. J Thorac Dis. 2016;8(3):451–458. doi:10.21037/jtd.2016.02.70
6. Semrau R, Herzog SL, Vallböhmer D, et al. Radiotherapy in elderly patients with inoperable esophageal cancer. Is there a benefit? Strahlenther Onkol. 2012;188(3):226–232. doi:10.1007/s00066-011-0039-2
7. Faiz Z, van Putten M, Verhoeven RHA, et al. Impact of age and comorbidity on choice and outcome of two different treatment options for patients with potentially curable esophageal cancer. Ann Surg Oncol. 2019;26(4):986–995. doi:10.1245/s10434-019-07181-6
8. Tougeron D, Scotté M, Hamidou H, et al. Definitive chemoradiotherapy in patients with esophageal adenocarcinoma: an alternative to surgery? J Surg Oncol. 2012;105(8):761–766. doi:10.1002/jso.22157
9. Bostel T, Akbaba S, Wollschläger D, et al. Chemoradiotherapy in geriatric patients with squamous cell carcinoma of the esophagus: multi-center analysis on the value of standard treatment in the elderly. Front Oncol. 2023;13:1063670. doi:10.3389/fonc.2023.1063670
10. Yao J, Zhao X, Chen J, et al. Treatment strategies for elderly patients with locally advanced esophageal cancer: a systematic review and meta-analysis. BMC Cancer. 2024;24(1):1101. doi:10.1186/s12885-024-12853-y
11. Finlayson E, Fan Z, Birkmeyer JD. Outcomes in octogenarians undergoing high-risk cancer operation: a national study. J Am Coll Surg. 2007;205(6):729–734. doi:10.1016/j.jamcollsurg.2007.06.307
12. Internullo E, Moons J, Nafteux P, et al. Outcome after esophagectomy for cancer of the esophagus and GEJ in patients aged over 75 years. Eur J Cardiothorac Surg. 2008;33(6):1096–1104. doi:10.1016/j.ejcts.2008.03.004
13. Morita M, Egashira A, Yoshida R, et al. Esophagectomy in patients 80 years of age and older with carcinoma of the thoracic esophagus. J Gastroenterol. 2008;43(5):345–351. doi:10.1007/s00535-008-2171-z
14. Thompson WM. Esophageal cancer. Int J Radiat Oncol Biol Phys. 1983;9(10):1533–1565. doi:10.1016/0360-3016(83)90329-2
15. Wang BY, Goan YG, Hsu PK, et al. Tumor length as a prognostic factor in esophageal squamous cell carcinoma. Ann Thorac Surg. 2011;91(3):887–893. doi:10.1016/j.athoracsur.2010.11.011
16. Yendamuri S, Swisher SG, Correa AM, et al. Esophageal tumor length is independently associated with long-term survival. Cancer. 2009;115(3):508–516. doi:10.1002/cncr.24062
17. Griffiths EA, Brummell Z, Gorthi G, et al. Tumor length as a prognostic factor in esophageal malignancy: univariate and multivariate survival analyses. J Surg Oncol. 2006;93(4):258–267. doi:10.1002/jso.20449
18. Hidaka H, Hotokezaka M, Nakashima S, et al. Sex difference in survival of patients treated by surgical resection for esophageal cancer. World J Surg. 2007;31(10):1982–1987. doi:10.1007/s00268-007-9193-1
19. Kauppila JH, Wahlin K, Lagergren P, et al. Sex differences in the prognosis after surgery for esophageal squamous cell carcinoma and adenocarcinoma. Int, J, Cancer. 2019;144(6):1284–1291. doi:10.1002/ijc.31840
20. Su XD, Zhang X, Xie HJ, et al. Younger women have a better prognosis among patients with esophageal squamous cell carcinoma after esophagectomy. J Thorac Dis. 2016;8(5):872–879. doi:10.21037/jtd.2016.03.49
21. Kauppila JH, Mattsson F, Brusselaers N, et al. Prognosis of oesophageal adenocarcinoma and squamous cell carcinoma following surgery and no surgery in a nationwide Swedish cohort study. BMJ Open. 2018;8(5):e021495. doi:10.1136/bmjopen-2018-021495
22. Mantziari S, Elliott JA, Markar SR, et al. Sex-related differences in oncologic outcomes, operative complications and health-related quality of life after curative-intent oesophageal cancer treatment: multicentre retrospective analysis. BJS Open. 2024;8(2):zrae026. doi:10.1093/bjsopen/zrae026
23. Ueo H, Matsuoka H, Sugimachi K, et al. Inhibitory effects of estrogen on the growth of a human esophageal carcinoma cell line. Cancer Res. 1990;50(22):7212–7215.
24. Nozoe T, Oyama T, Takenoyama M, et al. Significance of immunohistochemical expression of estrogen receptors alpha and beta in squamous cell carcinoma of the esophagus. Clin Cancer Res. 2007;13(14):4046–4050. doi:10.1158/1078-0432.CCR-07-0449
25. Jingu K, Takahashi N, Murakami Y, et al. Is concurrent chemotherapy with radiotherapy for esophageal cancer beneficial in patients aged 80 years or older? Anticancer Res. 2019;39(8):4279–4283. doi:10.21873/anticanres.13592
26. Ji Y, Du X, Zhu W, et al. Efficacy of concurrent chemoradiotherapy with S-1 vs radiotherapy alone for older patients with esophageal cancer: a multicenter randomized phase 3 clinical trial. JAMA Oncol. 2021;7(10):1459–1466. doi:10.1001/jamaoncol.2021.2705
27. Hurria A, Togawa K, Mohile SG, et al. Predicting chemotherapy toxicity in older adults with cancer: a prospective multicenter study. J Clin Oncol. 2011;29(25):3457–3465. doi:10.1200/JCO.2011.34.7625
28. Hurria A, Wong FL, Villaluna D, et al. Role of age and health in treatment recommendations for older adults with breast cancer: the perspective of oncologists and primary care providers. J Clin Oncol. 2008;26(33):5386–5392. doi:10.1200/JCO.2008.17.6891