Introduction

Esophageal cancer is the sixth-most common cause of cancer-related deaths worldwide for men and the ninth-most common cause of cancer-related deaths worldwide for women [1, 2]. In recent years, there have been about 4000 patients aged 80 years or older with esophageal cancer in Japan every year. Concurrent chemoradiotherapy has been recognized to be a better treatment method than radiotherapy alone for esophageal cancer. However, most patients aged 80 years or older are unlikely to be able to tolerate chemotherapy. Based on the data from Surveillance, Epidemiology, and End Results (SEER), patients aged 80 years or older with esophageal cancer benefit from radiotherapy alone compared with no radiotherapy if the cancer is in a localized/regional stage [3]. However, there has been no definitive evidence of chemoradiotherapy being superior to radiotherapy alone for patients aged 80 years or older. The Japanese Radiation Oncology Study Group (JROSG) Working Subgroup of Gastrointestinal Cancers showed by propensity score-matched analysis that there was no significant benefit of concurrent chemotherapy with radiotherapy over radiotherapy alone in patients aged 80 or older [4]. We previously reported results of chemoradiotherapy and radiotherapy alone for esophageal cancer using data in the Comprehensive Registry of Esophageal Cancer in Japan between 2009 and 2011 [5]. The purpose of the present study was to evaluate the results of radiotherapy and the results of chemoradiotherapy in patients with esophageal cancer who were aged 80 years or older using data in that database.

Materials and methods

Patient eligibility

The eligibility criteria included (i) histopathologically proven esophageal cancer, (ii) clinical stages 0–IV (the Union for International Cancer Control-Tumor-Node-Metastasis (UICC-TNM) classification, 7th edition) [6], (iii) 80 or more years of age, and iv) patients with data for radiotherapy alone or chemoradiotherapy in the Comprehensive Registry of Esophageal Cancer in Japan by the Japan Esophageal Society for 2015–2017 surveys (patients treated between 2009 and 2011). Patients with cervical/abdominal esophageal cancer were excluded.

Statistics

Survival rates were estimated using the Kaplan–Meier method from the first date of radiotherapy, and differences were evaluated by the log-rank test. Cox’s proportional hazard model was performed for multivariate analysis. A p value of less than 0.05 was considered significant. All analyses were performed using the SAS 9.4 software package (SAS Institute Inc., Cary, NC, USA).

Results

Three hundred and fifty-eight patients aged 80 years or older of 2346 patients treated with radiotherapy alone or chemoradiotherapy in the Comprehensive Registry of Esophageal Cancer in Japan by the Japan Esophageal Society for 2015–2017 surveys were enrolled in this study. The characteristics of the patients are shown in Table 1. The 5-year overall survival (OS) rates in patients with cStages 0–I, cStage II, cStage III and cStage IV were 40.9% [95% confidence interval (CI) = 29.7–51.7%], 24.7% (95% CI = 13.2–38.2%), 12.2% (95% CI = 6.3–20.1%) and 4.9% (95% CI = 3.4–20.0%), respectively (Fig. 1). The OS rates in patients aged 80 years or older with cStages 0–I, cStage II, cStage III and cStage IV were worse than those in patients aged less than 80 years (log-rank test: p = 0.0031, p = 0.0006, p = 0.0535 and p = 0.0141, respectively) (Fig. 2). The 5-year cause-specific survival (CSS) rates in patients aged 80 years or older with cStages 0–I, cStage II, cStage III and cStage IV were 73.5% (95% CI = 59.6–83.3%), 41.4% (95% CI = 24.9–57.2%), 25.3% (95% CI = 15.3–36.5%) and 7.4% (95% CI = 4.9–27.9%), respectively (Fig. 3). Only in cStage II, the CSS rate in patients aged 80 years or older was worse than that in patients aged less than 80 years (log-rank test: p = 0.0119).

Table 1 Characteristics of patients
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Fig. 1
figure 1

Overall survival curves for patients aged 80 years or older cStage 0–I, II, III and IV esophageal cancer (Kaplan–Meier method)

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Fig. 2
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Overall survival curves for patients aged 80 years or older and patients aged less than 80 years with cStage 0–I (a), II (b), III (c) and IV (d) esophageal cancer (Kaplan–Meier method)

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Fig. 3
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Cause-specific survival curves for patients aged 80 years or older and patients aged less than 80 years with cStage 0–I (a), II (b), III (c) and IV (d) esophageal cancer (Kaplan–Meier method)

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One hundred and ninety-six of the 358 patients received concurrent chemoradiotherapy. In patients treated with chemoradiotherapy, the 5-year OS rates for patients with cStage 0–I, II, III and IV diseases were 45.0% (29.2–59.5%), 36.1% (17.6–55.1%), 16.4% (7.6–28.1%) and 7.1% (0.4–27.5%), respectively, which were not significantly different from those in patients aged less than 80 years (log-rank test: p = 0.064, p = 0.16, p = 0.78 and p = 0.17, respectively) (Fig. 4). In patients treated with radiotherapy alone, the 5-year OS rates for patients with cStage 0–I, II, III and IV diseases were 36.5% (21.2–52.0%), 12.0% (2.2–30.8%), 5.4% (1.0–15.7%) and 0%, respectively. A comparison of the OS rates in patients treated with chemoradiotherapy and the OS rates in patients treated with radiotherapy alone showed that there were significant differences for patients with cStages II and III (log-rank test: p = 0.0144 and p = 0.0022, respectively); however, there were no significant differences for patients with cStages 0–I and IV (log-rank test: p = 0.30 and p = 0.24, respectively) (Fig. 5).

Fig. 4
figure 4

Overall survival curves for patients aged 80 years or older and patients aged less than 80 years with cStage 0–I (a), II (b), III (c) and IV (d) esophageal cancer treated by chemoradiotherapy (Kaplan–Meier method)

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Fig. 5
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Overall survival curves for patients aged 80 years or older treated with chemoradiotherapy or radiotherapy alone with cStage 0–I (a), II (b), III (c) and IV (d) esophageal cancer (Kaplan–Meier method)

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In multivariate analysis for OS in patients aged 80 years or older, concurrent chemotherapy, early cStage and squamous cell carcinoma were selected as significantly favorable prognostic factors (Table 2).

Table 2 Results of multivariate Cox’s proportional hazards regression analysis for overall survival in patients aged 80 years or older
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Discussion

Based on the Japanese Cancer Registry, the number of new patients aged 80 years or older with esophageal cancer in 2014 in Japan was 4169, which was significantly increased from 2004 to 2009 [7]. It is very important to show recommended treatment methods for elderly patients in developed countries with a growing proportion of elderly people.

The results of the study by JROSG [4] also showed that the results of chemoradiotherapy were significantly better than those of radiotherapy alone before propensity score matching. Those results are consistent with the results of our study; however, the significant difference between the results of chemoradiotherapy and radiotherapy alone disappeared after propensity score matching. In the present study, concurrent chemotherapy with radiotherapy improved overall survival in patients with cStage II or III. This might suggest that concurrent chemotherapy should be performed actively in patients with an advanced stage that has many potential metastases, even if the patients are aged 80 years or older. Inversely, concurrent chemotherapy might be meaningless in an early stage that could be cured by only control of the primary site. In cStages 0–I, chemoradiotherapy might be an overtreatment for patients aged 80 years or older. Detailed analysis for cStage IV in this study was difficult because the number of enrolled patients was small.

Hamamoto et al. reported that only 21% of institutions selected definitive chemoradiotherapy as a treatment method for patients aged 80 years or older with esophageal cancer [8]. In the present study, 196 of the 358 patients received concurrent chemotherapy, and this higher proportion might be because chemoradiotherapy penetrates deeply in esophageal cancer and because support methods for adverse events caused by chemotherapy have been developed, although the proportion was still very small compared to the proportion of patients aged less than 80 years who received chemoradiotherapy, which was 1762 out of 1988 patients. We were unable to evaluate toxicities, such as aggravation of COPD, radiation pneumonitis and esophageal stenosis, with this database. To what extent those factors might have influenced the analysis remains unclear, thus limiting the generalizability of this study. In the study of JROSG, because more severe late toxicities in patients who received chemoradiotherapy than in patients who received radiotherapy alone were shown, concurrent chemotherapy should be performed with special care for patients aged 80 years or older [4]. Ito et al. reported that older age was found to be a risk factor for late toxicity after definitive chemoradiotherapy for esophageal cancer [9]. Xu et al. also reported that there was a particularly high incidence of pulmonary toxicity in patients aged 80 years or older who received chemoradiotherapy compared with the incidence in younger patients [10]. The use of intensity-modulated radiation therapy or proton radiation therapy might be helpful for chemoradiotherapy to be performed safely in aged patients.

Based on the results of multivariate analysis in this study, total irradiation dose was not related to survival. In Japan, 60 Gy remains the standard dose for esophageal cancer, which is different from the standard dose in the United States. There is also an issue of the irradiation field. Unfortunately, there was no information on the irradiation field in the database we used. Recently, there have been some reports showing that elective nodal irradiation was not needed in esophageal cancer [11, 12]. A prospective study is needed to determine whether elective nodal irradiation or involved-field irradiation is better in elderly patients treated with radiotherapy alone and which is better in elderly patients treated with chemoradiotherapy.

There were some other limitations in this study. Since only cases that were actually treated with radiotherapy alone or chemoradiotherapy were registered in the database, some cases in which radical treatment could not be performed because of a poor general condition might have been excluded. All cases registered in the database might have had a relatively good general condition. It is unclear because the database has no information on performance status or comorbidities. For multivariate analysis, the lack of information on performance status must be a major issue. In the present study, chemoradiotherapy was shown to be better than radiotherapy alone in patients with cStage II or III; it is likely that concurrent chemotherapy with radiotherapy was used for patients with good performance status and a low Charlson Comorbidity Index (CCI) [13]. Thus, concurrent chemotherapy might be overestimated as a prognostic factor. Also, many patients who were treated with chemotherapy alone because of metastases in distant organs were not included in the database.

Conclusion

The results of our study findings suggest that concurrent chemoradiotherapy for esophageal cancer in elderly patients should be performed as much as possible for patients with cStage II or III, even patients aged 80 years or older. However, we need to find the appropriate condition to perform concurrent chemoradiotherapy in patients aged 80 years or older.