Recent radiotherapy could reduce heart-related death in patients with esophageal cancer: SEER database analysis

Abstract

Background

There have been several reports showing that heart-related deaths are common in long-term survivors of esophageal cancer after radiation therapy; however, radiotherapy technology is evolving year by year. This study was carried out using the SEER database to determine whether the frequency of mortality from heart disease after radiotherapy has improved over time in patients with esophageal cancer.

Methods

SEER*Stat statistical software version 8.3.9.2 (National Cancer Institute) was used to perform case listing and data extraction. We reviewed causes of death in 8,297 patients who were treated by radiotherapy without surgery between 2004 and 2015 (radiotherapy group). For comparison with this group, we also reviewed causes of death in 5,149 patients who were treated by surgery without radiotherapy (surgery group).

Results

In the radiotherapy group, the cumulative heart-related death rate in patients with carcinoma in the middle to abdominal esophagus, for which it was considered that the heart was irradiated with a higher dose, was significantly higher than that in patients with carcinoma in the cervical to upper thoracic esophagus (p = 0.017). However, in the surgery group, the cumulative heart-related death rate in patients with carcinoma in the middle to abdominal esophagus tended to be lower than that in patients with carcinoma in the cervical to upper thoracic esophagus (p = 0.063). The cumulative heart-related death rate in patients treated in 2010–2015 was significantly lower than that in patients treated in 2004–2009 in the radiotherapy group (p = 0.011), although the cumulative heart-related death rate was not significantly different between patients treated in 2010–2015 and patients treated in 2004–2009 in the surgery group (p = 0.90).

Conclusions

The results suggest that recent advances in radiotherapy have enabled a reduction in radiation-induced heart disease in patients with esophageal cancer.

Background

Esophageal cancer was the eighth most common cancer in the world in 2020. There were 604,100 new cases of esophageal cancer and 544,076 deaths due to esophageal cancer worldwide in 2017. Esophageal cancer is the fifth most common cause of cancer-related death worldwide for men and the eighth most common cause of cancer-related death worldwide for women [1]. Based on the results of randomized studies, neoadjuvant chemoradiotherapy or chemotherapy followed by esophagectomy has become the standard treatment strategy for esophageal cancer [2, 3]; however, radiotherapy or chemoradiotherapy without surgery is still performed in many patients who have refused surgery or who have contraindications for surgery. Recently, advances in radiotherapy technology and chemotherapy have improved treatment results for many malignant tumors, and there have been many long-term survivors. Over the past 20 years, there have been several reports showing that heart-related deaths are common in long-term survivors of esophageal cancer after radiation therapy. Gyenes et al. analyzed mortality from ischemic heart disease according to estimated heart dose-volume and found that the cumulative mortality rate after 20 years was significantly higher in patients in a high-dose-volume subgroup than in patients who received no radiotherapy (14% vs. 5%) [4]. Radiotherapy technology is evolving year by year, and intensity-modulated radiotherapy (IMRT) and proton beams are being used to reduce the radiation dose to the heart and have the potential to decrease cardiac toxicity and decrease morbidity [5, 6] compared with the results of three-dimensional conformal radiotherapy (3D-CRT). A survey conducted in the United States (US) in 2010 showed that more cases were treated with IMRT and proton beams than with 3D-CRT [7]. Based on these findings, we hypothesized that heart-related deaths may have decreased since 2010, during which time the number of cases treated with irradiation using the latest treatment technology has increased, and we decided to conduct an analysis using open data from the US. The Surveillance, Epidemiology and End Results Registry (SEER) Program is an authoritative source of information on cancer incidence and survival in the US that collects data from 18 separate cancer registries representing approximately 28% of the US population.

The purpose of this study was to evaluate by using data from the SEER database whether the frequency of mortality from heart disease after radiotherapy has improved over time in patients with esophageal cancer.

Methods

A total of more than 30,000 patients in an open database, SEER, who had esophageal cancer between January 1, 2004 and December 31, 2015 and who had been treated by radiotherapy were initially enrolled. The cutoff date of this database was December 31, 2020. The exclusion criteria were as follows: (1) cases that did not receive radiotherapy or received radiotherapy methods other than beam radiation, (2) cases that received surgery or unknown, (3) cases without American Joint Commission on Cancer (AJCC) 6th staging, (4) cases in which the pathological type was not squamous cell carcinoma or adenocarcinoma, (5) cases in which the location of the tumor was overlapped or unknown, (6) cases less than 60 years of age, and (7) cases with absence or zero survival time. The causes of death in 8,297 patients who were treated by radiotherapy without surgery (radiotherapy group) between 2004 and 2015 were reviewed. For comparison, we also reviewed causes of death in 5,149 patients who were treated by surgery without radiotherapy (surgery group) after excluding patients according to above exclusion criterion except for criteria 1) and 2). The flow for the inclusion of data for patients with esophageal cancer is shown in Fig. 1.

Fig. 1

Eligibility criteria for the inclusion of data for patients with esophageal cancer from the SEER database

Statistical analysis

SEER*Stat statistical software version 8.3.9.2 (National Cancer Institute) was used to perform case listing and data extraction. “Diseases of the heart” according to “COD to site rec KM” was defined as heart-related death in this study. The rate of mortality from heart disease after treatment was calculated using the Kaplan-Meier method, and differences were evaluated by the log-rank test. Cox’s regression hazard analysis using a backward stepwise selection model was used for multivariate analysis. A p value of less than 0.05 was considered significant. All analyses were performed using SPSS 29.0 (IBM, Armonk, NY, USA). SEER data are publicly available, deidentified, and exempt from institutional review board approval and informed consent, per the SEER guidelines.

Results

The characteristics of the patients are shown in Table 1. Heart-related death after treatment occurred in 368 patients (4.4%) in the radiotherapy group and 211 patients (4.1%) in the surgery group. The cumulative heart-related death rate in the radiotherapy group was significantly higher than that in the surgery group (p = 0.022) (Fig. 2). In the radiotherapy group, the cumulative heart-related death rate in patients with carcinoma in the middle to abdominal esophagus, for which it was considered that the heart was irradiated with a higher dose, was significantly higher than that in patients with carcinoma in the cervical to upper thoracic esophagus (p = 0.017) (Fig. 3a). Conversely, in the surgery group, the cumulative heart-related death rate in patients with carcinoma in the middle to abdominal esophagus tended to be lower than that in patients with carcinoma in the cervical to upper thoracic esophagus, but the difference was not significant (p = 0.063) (Fig. 3b). For patients with carcinoma in the middle to abdominal esophagus, the cumulative heart-related death rate in the radiotherapy group was significantly higher than that in the surgery group (p = 0.003), although the cumulative heart-related death rate in the radiotherapy group was conversely significantly lower than that in the surgery group for patients with carcinoma in the cervical to upper thoracic esophagus (p = 0.016) (Fig. 4). The cumulative heart-related death rate in patients treated in 2010–2015 was significantly lower than that in patients treated in 2004–2009 in the radiotherapy group (p = 0.011), although the cumulative heart-related death rate was not significantly different between patients treated in 2010–2015 and patients treated in 2004–2009 in the surgery group (p = 0.90) (Fig. 5). In the radiotherapy group, the median follow-up periods of patients who survived after receiving treatment in 2004–2009 and 2010–2015 were 132.0 months and 58.5 months, respectively. In the radiotherapy group, although the cumulative heart-related death rate in patients with carcinoma in the middle thoracic to abdominal esophagus was significantly higher than that in patients with carcinoma in the cervical to upper thoracic esophagus who were treated in 2004–2009 (p = 0.043), there was no significant difference between the cumulative heart-related death rates in those patients treated in 2010–2014 (p = 0.183). The cumulative heart-related death rate was higher in elderly patients in both the radiotherapy group and surgery group. However, there was no significant gender difference in the cumulative heart-related death rate in either the radiotherapy group or surgery group. In multivariate analysis, male gender, advanced age, treatment period of 2004–2009 and carcinoma in the middle thoracic to abdominal esophagus were selected as risk factors for death from heart disease in the radiotherapy group (hazard ratio (HR): 1.40 (95% confidence interval (CI): 1.081–1.823), HR: 1.47 (95% CI: 1.373–1.576), HR: 1.31 (95% CI: 1.053–1.619 and HR: 1.73 (95% CI: 1.117–2.664), respectively) (Table 2). Only age was selected as a risk factor for death from heart disease in the surgery group (HR: 1.51 (95% CI: 1.379–1.655)).

Table 1 Patients’ characteristics

Fig. 2

Cumulative heart-related death rates in patients treated by radiotherapy without surgery and in patients treated by surgery without radiotherapy (Kaplan-Meier method)

Fig. 3

(a) Cumulative heart-related death rates in patients with carcinoma in the middle to abdominal esophagus and in the cervical to upper thoracic esophagus in the radiotherapy group, (b) Cumulative heart-related death rates in patients with carcinoma in the middle to abdominal esophagus and in the cervical to upper thoracic esophagus in the surgery group (Kaplan-Meier method)

Fig. 4

(a) Cumulative heart-related death rates in patients with carcinoma in the middle to abdominal esophagus in the radiotherapy group and in the surgery group, (b) Cumulative heart-related death rates in patients with carcinoma in the cervical to upper thoracic esophagus in the radiotherapy group and in the surgery group (Kaplan-Meier method)

Fig. 5

(a) Cumulative heart-related death rates in patients treated in 2010–2015 and in patients treated in 2004–2009 in the radiotherapy group, (b) Cumulative heart-related death rates in patients treated in 2010–2015 and patients treated in 2004–2009 in the surgery group (Kaplan-Meier method)

Table 2 Log-rank test/multivariate analysis for heart-related death in the radiotherapy group

Discussion

It has been reported that radiation has various effects on the heart [8]. For patients with esophageal cancer, it is no longer uncommon for patients who have undergone radiotherapy to survive for a long time, but the adverse effects of radiation on the heart have become a problem and improvements are being hoped for. In the radiotherapy group, the cumulative heart-related death rate was significantly lower in patients treated in 2010–2015 than in patients treated in 2004–2009. This may be partially due to the short observation period for the group treated in 2010–2015. Although there was a significant difference in the cumulative heart-related death rate in 2004–2009 between patients with carcinoma in the middle thoracic to abdominal esophagus and patients with carcinoma in the cervical to upper thoracic esophagus, there was no longer a significant difference in 2010–2015. It is possible that recent advances in radiation techniques have resulted in the prevention of radiation-induced heart disease. Although heart-related deaths after surgery have not decreased in the new era, the fact that heart-related deaths after radiation therapy have decreased indicates that the effects of radiation on the heart have decreased. In fact, Sakar et al. reported that patients receiving IMRT had a 68% decreased risk of having a late cardiovascular event compared to the risk in patients receiving conventional radiation [9]. However, in our previous prospective cohort study in which patients were treated for esophageal cancer by 3D-CRT between 2013 and 2015, the 5-year and 7-year cumulative incidences of grade 3 or 4 cardiac events were 14.7% and 22.4%, respectively [10]. Serious radiation-induced heart diseases occurred in some patient in that study, and although IMRT has recently been used for treatment of esophageal cancer also at our institution, it has not yet been determined whether IMRT can reduce the incidence of heart disease. A past report suggested that a volume of the left ventricle receiving greater than or equal to 15 Gy (V15) of less than 1% appeared to confer a decreased risk of major adverse cardiac events among patients with coronary heart disease [11]. The Quantitative Analysis of Normal Tissue Effects in the Clinic (QUANTEC) recommended that V30 of the heart should be kept below 46% with a mean heart dose of less than 15 Gy [12]. Unfortunately, although grade 3 or higher cardiac events occurred in 19.8% of patients who were treated by IMRT or proton beam therapy in MD Anderson Cancer Center [13], it seems not to be significantly lower than the rate with 3D-CRT in our institution [10].

In the US, the standard strategy is preoperative chemoradiotherapy followed by surgery, so this analysis only included patients who did not receive the standard strategy. In the surgery group, in which patients who had undergone radiotherapy were excluded, it is expected that there would be many cases with some kind of complication. However, in patients with carcinoma in the middle thoracic to abdominal esophagus, which is thought to result in greater radiation exposure to the heart, the rate of cardiac death in the radiotherapy group was significantly higher than that in the surgery group, which seems to indicate effects of radiation on the heart. It is known that there are risks of cardiac complications, such as advanced age, obesity, drinking alcohol or smoking, in many patients with esophageal cancer, suggesting that special attention should be paid to radiation exposure to the heart. In fact, there are reports showing that reducing the radiation dose to the heart reduces the frequency of serious heart problems in patients in high-risk groups [13].

Our analysis of data in the SEER database showed differences in heart-related deaths among races in patients treated by postoperative radiotherapy for early breast cancer. That analysis showed that Asians or Pacific Islanders and Native Americans had fewer heart-related deaths after radiotherapy. However, there were no differences between races in the present study. It is unclear whether this is due to differences in the backgrounds of breast cancer and esophageal cancer patients, differences in radiation doses for the heart between breast cancer and esophageal cancer, or both [14].

As a limitation of this study, the SEER database does not have information on irradiation dose for the heart or complications, and the results of this study therefore provide only indirect evidence of radiation effects on the heart. Furthermore, disease of the heart as causes of death are not classified in the SEER database; therefore, the specific nature of the fatal heart disease is unknown.

Conclusion

Analysis of data in a large database showed that the mortality rate from heart disease in patients treated by radiotherapy, especially those with carcinoma in the middle to lower thoracic esophagus, was relatively high. However, since 2010, there has been no significant difference in the mortality rate from heart disease between patients with middle to abdominal esophageal cancer and patients with cervical to upper thoracic esophageal cancer, probably due to recent improvements in radiation therapy technology.