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Chemoradiotherapy Is Superior to Radiotherapy Alone in Esophageal Cancer Patients Older Than 65 Years: A Propensity Score-Matched Analysis of the SEER Database

Introduction Radiotherapy (RT) is the main treatment for unoperated esophageal cancer (EC) patients. It is controversial whether adding chemotherapy (CT) to RT is beneficial for elderly EC patients. The purpose of our study was to compare the efficacy of chemoradiotherapy (CRT) with RT alone for non-surgical elderly esophageal cancer patients. Methods A total of 7,101 eligible EC patients older than 65 years diagnosed between 2000 and 2018 were collected from the Surveillance, Epidemiology, and End Results (SEER) database. All the samples were divided into the radiotherapy group and the chemoradiotherapy group. After being matched by propensity score matching (PSM) at a 1:1 ratio, 3,020 patients were included in our analysis. The Kaplan–Meier method and log-rank test were applied to compare overall survival (OS) and cancer-specific survival (CSS). Results After PSM, the clinical characteristics of patients between the RT and CRT groups were comparable. For EC patients older than 65 years, the 3-year OS and CSS in the CRT group were 21.8% and 27.4%, and the 5-year OS and CSS in the CRT group were 12.7% and 19.8%, respectively. The 3-year OS and CSS in the RT group were 6.4% and 10.4%, and the 5-year OS and CSS in the RT group were 3.5% and 7.2%, respectively. Next, these patients were divided into five subgroups based on the age stratification (ages 65–69; 70–74; 75–79; 80–84; ≥85). In each subgroup analysis, the 3- and 5-year OS and CSS showed significant benefits in the CRT group rather than in the RT group (all p < 0.05). We were unable to assess toxicities between the two groups due to a lack of correlated information. Conclusions CRT could improve OS and CSS for non-surgical EC patients older than 65 years. Adding chemotherapy to radiation showed a significant prognostic advantage for elderly esophageal cancer patients.


INTRODUCTION
Esophageal cancer is the second tumor of the digestive system besides gastric cancer (1). Esophageal squamous cell carcinoma (ESCC) is the major histology reported in Asian countries; adenocarcinoma in Western countries (2). Even though we have made great progress in esophageal cancer treatment, the prognosis of locally advanced tumors is still poor with a 5-year survival rate ranging from 15% to 25% (3). Most patients with esophageal cancer are not diagnosed until the disease is advanced, and only about 20% of the advanced esophageal cancers can be surgically removed (4). Esophagectomy remains the main treatment for esophageal cancer, but the overall 5-year survival rate with surgery alone is estimated at 16%-33% (5). Definite chemoradiotherapy (CRT) is a satisfactory treatment for esophageal cancer patients who are rejected or not suitable for surgery. JCOG9906, a phase II study of CRT for stage II/III ESCC, showed a promising outcome with a 5-year survival rate of 36.8% (6). Even for stage IV patients, chemoradiotherapy was an effective palliative treatment (7).
In the USA, 44% of EC patients are over 60 years. Moreover, approximately 69.8% of EC patients in males of China are older than 60 years (8,9). Global aging and improved life expectancy indicate that cancer in older patients is becoming an increasingly common social issue. Many elderly patients are not candidates for surgical resection due to medical comorbidities and poorer physiologic status (10). Radical radiation therapy is usually their primary treatment. Because the side effects of radiotherapy combined with chemotherapy are more serious than radiotherapy alone (11), whether radiotherapy combined with chemotherapy is a better choice for elderly esophageal cancer patients has not yet been unified. We thus evaluated the effectiveness of CRT compared with RT alone in EC patients older than 65 years based on a propensity score-matched (PSM) analysis of the SEER database. Furthermore, we performed agestratified analyses to explore survival differences between the two groups, respectively.

Study Population
The Surveillance, Epidemiology, and End Results (SEER) database (http://seer.cancer.gov/) includes clinical information on about 30% of cancer patients in the USA. We enrolled patients aged 65 or older and diagnosed with EC between January 2000 and December 2018. The following are the exclusion criteria: (I) cases that did not receive radiotherapy or receive other radiotherapy methods other than beam radiation; (II) surgical or unknown cases; (III) without AJCC 6th staging; (IV) the pathological type is non-squamous cell carcinoma or adenocarcinoma; (V) cases where the location of the tumor is unknown; and (VI) cases with absence or zero survival time. Information was extracted for age, sex, ethnicity, tumor size, pathological type, stage, radiotherapy, chemotherapy, and month of survival.

Statistical Analysis
We used Pearson chi-square analysis to determine variables between the two groups. To balance the covariance and reduce the bias of efficacy evaluation, we performed a 1:1 propensity score matching between the chemoradiotherapy group and the radiotherapy group alone. Then, we divided these patients into five subgroups based on the age stratification (ages 65-69; 70-74; 75-79; 80-84; ≥85). The Kaplan-Meier method and log-rank test were used to compare the overall survival (OS) and cancerspecific survival (CSS) of the two groups in IBM SPSS Statistics for Windows, Version 26.0 (IBM, Armonk, NY, USA); p < 0.05 indicated that the difference was statistically significant.

Patients' Survival
A total of 44,373 EC patients older than 65 years diagnosed between 2000 and 2018 of the SEER database were initially enrolled, and 37,272 patients were excluded based on exclusion criteria. All characteristics between the RT and CRT groups in the 7,101 eligible patients are shown in Table S1. After six characteristics being matched by PSM at a 1:1 ratio, 3,020 patients were included in our analysis ( Table 1). AS shown in Figure 1, The 3-and 5-year OS of the whole patients were 14.1% and 8.1%, respectively. The 3-and 5-year CSS of the whole group were 19.2% and 13.8%, respectively. The median OS and CSS of the whole group were 9 and 10 months, respectively. After propensity score matching (PSM), there were 1,510 patients in the radiotherapy (RT) alone group and the radiochemotherapy (CRT) group, respectively. In the RT alone group, the 3-and 5year OS were 6.4% and 3.5%, and the 3-and 5-year CSS were 10.4% and 7.2%, respectively. In the CRT group, the 3-and 5year OS and CSS rates were 21.8% and 12.7% and 27.4% and 19.8%, respectively. In EC patients older than 65 years, the survival rate was significantly better in the CRT group than in the RT alone group.

Patients' Characteristics
After PSM, 3,020 well-balanced elderly EC patients were available in the RT alone group and CRT group (1,510 patients in each group

DISCUSSION
ESCC is the leading type worldwide due to the highest rates occurring in Asia. Esophageal adenocarcinoma (EAC) is more popular than ESCC in the Western world in the last half-century (12). The morbidity and mortality of esophageal cancer in developing countries account for more than 80% worldwide (13), and the new cases in China account for about 50% of the world (14,15). The incidence of esophageal cancer rose rapidly after 45 years. According to China's estimated data in 2015, patients over the age of 75 accounted for about 20% in the distribution of EC morbidity and also had upper mortality by 31.1% (8). With the development of aging, cancer in older adults is turning into an increasingly common social problem. However, there is no consensus on the treatment of esophageal cancer in the elderly.
Patients over 70 years have poorer tolerance in esophagectomy than younger patients. Multiple retrospective analyses (16,17) found that EC patients over 70 years old have significantly increased postoperative complications and perioperative mortality. Clinically, definite chemoradiotherapy is the standard therapy for non-surgical esophageal cancer patients.  However, some elderly patients refused chemotherapy and received radiotherapy alone due to treatment complications or economic or psychological reasons. Is chemoradiotherapy better than radiotherapy alone for elderly patients? There are few random studies or bulk data case analysis targeting elderly patients with esophageal cancer at present. In our study, we included a total of 7,101 EC patients over 65 years old diagnosed between 2000 and 2018 in the SEER database. The results of this research indicated that chemoradiotherapy can be used successfully to treat patients older than 65 years. After PSM, 3,020 patients were included for further analysis, the 3-and 5-year OS and CSS in the CRT group were longer than those in the RT-alone group in five subgroup analyses stratified by age (ages 65-69; 70-74; 75-79; 80-84; ≥85, respectively). The 5-year survival rate of elderly cancer patients undergoing radical radiotherapy or radiochemotherapy is 9.7% 30.1% (18,19).   (26). A study including 184 EC patients aged ≥70 years who received oral single-agent CCRT (sCCRT) or double-agent CCRT (dCCRT) or RT alone at a single institution in China demonstrated that CCRT had significant survival benefits compared to RT alone, especially in the oral singleagent group (11). We need prospective clinical trials to search for the best combination of radiotherapy and chemotherapy. In summary, our study findings suggested that adding chemotherapy to radiation for elderly patients with esophageal cancer should be implemented as much as possible, even in patients aged 80 years or older. Furthermore, we need to find the optimal combination of radiotherapy and chemotherapy to maximize the survival benefit of elderly EC patients. Further prospective studies are warranted to verify our results.

DATA AVAILABILITY STATEMENT
The original contributions presented in the study are included in the article/Supplementary Material. Further inquiries can be directed to the corresponding authors.