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Recent Postoperative Radiotherapy for Left-sided Breast Cancer Does Not Increase Mortality of Heart Disease in Asians or Pacific Islanders: SEER Database Analysis

KEIICHI JINGU, REI UMEZAWA, TAKAYA YAMAMOTO, NORIYOSHI TAKAHASHI, YU SUZUKI, KEITA KISHIDA, SO OMATA, HIROAKI OGAWA, YUTA SATO, HINAKO HARADA and YASUHIRO SEKI
Anticancer Research August 2023, 43 (8) 3571-3577; DOI: https://doi.org/10.21873/anticanres.16535

Abstract

Background/Aim: The purpose of this study was to evaluate the impact of recent radiotherapy on mortality from heart disease in Asians or Pacific islanders with breast cancer using the Surveillance, Epidemiology, and End Results (SEER) database. Patients and Methods: Asians or Pacific islanders with stage 0 or I (AJCC 6th) breast cancer between 2000 and 2015 were analyzed. The impact of radiotherapy for mortality from heart disease after treatment was evaluated by comparing patients who received radiotherapy for left-sided breast cancer, patients who received radiotherapy for right-sided breast cancer and patients who did not receive radiotherapy. Results: In 25,684 Asians or Pacific islanders, the incidence of cardiac death was higher in patients who did not receive radiotherapy than in patients who received radiotherapy. Among patients who received external beam irradiation, the incidence of cardiac death was 2.00% for patients with left-sided breast cancer and 1.69% for patients with right-sided breast cancer, with no significant difference (chi-square test, p=0.427). In the period from 2000 to 2008, there was no significant difference between the cumulative heart-related death rates in patients who received radiotherapy and in patients who did not receive radiotherapy (Tarone-Ware test, p=0.406); however, in 2009-2015, the cumulative heart-related death rate in patients who did not receive radiotherapy was significantly higher than that in patients who received radiotherapy (log-rank test, p<0.001). Conclusion: Heart-related death after treatment for breast cancer is relatively rare in Asians or Pacific islanders. Since at least 2000, the cardiac impact of postoperative radiotherapy has not been significant.

Key Words:

Postoperative radiotherapy for patients with breast cancer reduces the incidence of local recurrence and breast cancer-related mortality (1). It is included as a standard treatment strategy for patients with early breast cancer. The effect of postoperative radiotherapy for local control has also been demonstrated in Japanese patients (2). Radiation-induced heart damage has recently attracted attention, and serious heart damage due to radiation has been reported in patients with breast cancer (3-5). In patients with breast cancer, the exposure dose to the apex of the heart and coronary arteries can be significantly reduced by the tangential line by deep inhalation breath-holding, and this method has begun to be used for the purpose of reducing future cardiac events. However, in our experience, there have not been many cardiac events in patients with breast cancer after postoperative radiotherapy, and we therefore evaluated the impact of radiotherapy in Asian patients with breast cancer by analysis of data in the Surveillance, Epidemiology, and End Results (SEER) database.

Patients and Methods

Patients. SEER*Stat statistical software version 8.3.9.2 (National Cancer Institute) was used to perform case listing and data extraction. Three hundred thirty-six thousand thirty-one patients with stage 0 or I [according to American Joint Committee on Cancer (AJCC) 6th] breast cancer in the SEER database during the period from 2000 to 2015 were analyzed. The impact of radiotherapy on cumulative mortality from heart disease after treatment was evaluated by comparing patients with left-sided breast cancer who received radiotherapy, patients with right-sided breast cancer who received radiotherapy and patients who did not receive radiotherapy or have no record of radiotherapy. The effect of radiotherapy on cumulative mortality for heart disease after treatment was evaluated in 25,684 Asian or Pacific islander patients in the database. Causes of death were obtained using the SEER Cause of Death Recode, which has been based on the International Statistical Classification of Diseases and Related Health Problems, 10th Revision (World Health Organization).

Statistical analysis. Cumulative heart-related death rate after treatment was calculated using the Kaplan-Meier method, and differences were evaluated by the log-rank test. If the survival curves crossed, the Tarone-Ware test was used to evaluate the difference. A p-value of less than 0.01 (two-sided tests) was considered significant. Cox’s regression hazard analysis using a backward stepwise selection model was used for multivariate analysis. All analyses were performed using SPSS 26.0 (IBM, Armonk, NY, USA).

Results

Analysis of heart-related death in all patients. The median observation period for all of the patients was 103 months. The actual incidence of cardiac death was 7,127 (4.30%) in patients with left-sided breast cancer and 7,376 (4.33%) in patients with right-sided breast cancer. A chi-square test showed no significant difference (p=0.440). Among patients treated with external irradiation, the actual incidence of cardiac death was 2,822 (3.22%) in patients with left-sided breast cancer and 2,838 (3.29%) in patients with right-sided breast cancer, with no significant difference (chi-square test, p=0.60). The cumulative heart-related death rate was significantly higher in patients who did not receive radiotherapy on either the right or left side than in those who received radiotherapy (log-rank test, p<0.001) (Figure 1a). The cumulative heart-related death rate was significantly higher in patients who did not receive radiotherapy than in patients who received radiotherapy for left-sided breast cancer and patients who received radiotherapy for right-sided breast cancer (log-rank test, p<0.001 for both). Among races, black people had the highest cumulative heart-related death rate (10-year rate=5.0%), followed by white people (10-year rate=4.5%), and the cumulative heart-related death rate in Asian or Pacific islander patients (10-year rate=1.9%) was significantly lower than the death rates in black people and white people (log-rank test, p<0.001 for both) (Figure 2). Regarding the treatment period (2000-2008 vs. 2009-2015), the cumulative heart-related death rate in the early period was significantly higher than that in the later period (log-rank test, p<0.001) (Figure 3a). There was no significant difference in the cumulative heart-related death rate between left-sided patients and right-sided patients in either 2000-2008 or 2009-2015 (log-rank test, p=0.715 and 0.443, respectively). Even in patients who only received radiotherapy, there was no significant difference in the cumulative heart-related death rate between left-sided and right-sided patients in either 2000-2008 or 2009-2015 (log-rank test, p=0.598 and 0.942, respectively) (Figure 4).

Figure 1.
Figure 1.

Cumulative heart-related death rates in (a) all patients who received radiotherapy (blue line) and those who did not (red line); (b) Asians or Pacific islanders who received radiotherapy (blue line) and those who did not (red line). p≤0.001 using the log-rank test or the Tanore-Ware test.

Figure 2.
Figure 2.

Cumulative heart-related death rates in patients with breast cancer by race: black people (red line), white people (orange line), Indians (green line) and Asians or Pacific islanders (blue line) are shown.

Figure 3.
Figure 3.

Cumulative heart-related death rates in all patients (a) and in Asians or Pacific islanders (b) by era. p-Values were calculated using the log-rank and Tanore-Ware test.

Figure 4.
Figure 4.

Cumulative heart-related death rates in left-sided (blue line) and right-sided patients (red line) between (a) 2000 and 2008, and (b) 2009 and 2015, in all patients who received radiotherapy. p-Values were calculated using the log-rank test.

Analysis of heart-related death in Asian or Pacific islander patients. Patients’ characteristics are shown in Table I. The median observation period was 100 months. The incidence of cardiac death was 256 (1.97%) in patients with left-sided breast cancer and 238 (1.87%) in patients with right-sided breast cancer. A chi-square test showed no significant difference (p=0.808). Among patients treated with external beam irradiation, the actual incidence of cardiac death was 129 (2.00%) in patients with left-sided breast cancer and 108 (1.69%) in patients with right-sided breast cancer, with no significant difference (chi-square test, p=0.427). There was a significant difference in cumulative heart-related death rate between patients who did not receive radiotherapy and patients who received radiotherapy for either right-sided or left-sided breast cancer (Tarone-Ware test, p=0.001) (Figure 1b). For patients with left-sided breast cancer, there was no significant difference in the cumulative heart-related death rate between patients who did not receive radiotherapy and patients who received radiotherapy (Tarone-Ware test, p=0.121). On the other hand, for patients with right-sided breast cancer, there was a significant difference in the cumulative heart-related death rate between patients who did not receive radiotherapy and patients who did (Tarone-Ware test, p=0.001).

View this table:
Table I.

Patient characteristics.

The cumulative heart-related death rates increased with age (Figure 5). Regarding the treatment period (2000-2008 vs. 2009-2015), the cumulative heart-related death rate in the early period was higher than that in the later period, but there was no significant difference (Tarone-Ware test, p=0.083) (Figure 3b). In 2000-2008, there was no significant difference in the cumulative heart-related death rate between patients who received radiotherapy and patients who did not receive radiotherapy (Tarone-Ware test, p=0.406) (Figure 6a); however, in 2009-2015, there was a significant difference in the cumulative heart-related death rate between patients who did not receive radiotherapy and patients who did (log-rank test, p<0.001) (Figure 6b). There was no significant difference in the cumulative heart-related death rate between left-sided patients and right-sided patients in either 2000-2008 or 2009-2015 (log-rank test, p=0.544 and 0.788, respectively). Even in only patients who received radiotherapy, there was no significant difference in the cumulative heart-related death rate between left-sided patients and right-sided patients in either 2000-2008 or 2009-2015 (log-rank test, p=0.233 and 0.833, respectively) (Figure 7). In multivariate analysis, only advanced age [hazard ratio (HR)=1.136, 99% confidence interval (CI)=1.122-1.149), p<0.001] was a significant risk factor for cardiac death, and radiotherapy, chemotherapy era (2000-2008 or 2009-2015) and laterality of the primary site were not significant risk factors. There was no multicollinearity among those factors based on Spearman correlation coefficient (r=−0.288 to 0.036).

Figure 5.
Figure 5.

Cumulative heart-related death rates in Asians or Pacific islanders by age.

Figure 6.
Figure 6.

Cumulative heart-related death rates in Asians or Pacific islanders who received radiotherapy (blue line) and who did not (red line) between (a) 2000 and 2008, and (b) 2009 and 2015. p-Values were calculated using the log-rank and Tarone-Ware tests.

Figure 7.
Figure 7.

Cumulative heart-related death rates in left-sided patients (blue line) and right-sided patients (red line) between (a) 2000 and 2008, and (b) 2009 and 2015 in Asians or Pacific islanders who received radiotherapy. p-Values were calculated using the log-rank test.

Discussion

In an analysis of 308,861 registered cases from 1973 to 2001, it was shown that the incidence of cardiac death was significantly increased in patients who received radiotherapy and that the incidence of cardiac death was significantly higher in patients with left-sided breast cancer than those with right-sided breast cancer. For patients treated during the period from 1973 to 1982, the cardiac mortality ratios (left vs. right tumor laterality) were 1.20 less than 10 years after radiotherapy, 1.42 at 10-14 years after radiotherapy, and 1.58 at 15 years or more after radiotherapy. However, it was reported that cardiac mortality has not been appreciably high since the early 1980s. It was reported that improvements in radiotherapy planning might have reduced the risks of cardiac mortality (6). Since our results were obtained from analysis of data for patients in a later period, it is not surprising that cardiac-related deaths have not increased with radiotherapy. Our results for Asian or Pacific islander patients are supported by results of recent studies in which tumor laterality was used as a surrogate of heart-irradiated dose, showing no significantly increased risk for cardiac late effects for more recent treatment periods (7).

In this study, we divided the patients into two groups, one group up to 2008 and another group from 2009 onwards and found that the incidence of heart-related death tended to be decreased in the latter group. It is thought that the reason is not improvement of radiotherapy technology but improvement of health consciousness and management of lifestyle-related diseases among black and white people. A similar trend was generally observed in Asians or Pacific islanders, but since heart-related deaths in Asians or Pacific islanders were originally rare, the effect of the era after 2000 was considered to be minor. However, in the early era, the frequency of cardiac-related deaths in patients who received radiotherapy increased sharply at around 150 months, catching up with that in patients who did not receive radiotherapy. In the later era, the frequency of heart-related deaths was significantly lower in patients who received radiotherapy than in patients who did not, possibly because of the short observation period or the improvement of radiotherapy technology. In the future, it will be necessary to pay close attention to the occurrence of cardiac-related deaths in the patients who received radiotherapy in the later era.

A study in which the latest epidemiological data for ischemic heart disease in all countries and regions were analyzed showed that the numbers of people with heart disease per 100,000 people were 2,470 in the United States and 3,771 in Europe, whereas the number in Japan, which is known to have a generally low rate of heart disease, was only 1,427 (8). The present study using patients with breast cancer also showed that the incidence of heart-related death in Asians was significantly lower than the incidences in black and white people, and cumulative heart-related death rates in patients who did not receive radiotherapy were significantly higher than those in patients who received radiotherapy in races other than Asian or Pacific islander. The background difference between those who received radiotherapy and those who did not seems to be responsible for the increased cumulative heart-related death rates.

Our study suggested that radiotherapy for early-stage breast cancer did not affect cardiac death at least after 2000. Breast irradiation by deep inhalation breath-holding was reported by Sixel et al. (9), and it has been reported that the cardiac exposure dose is significantly reduced. Recently, it has been practiced in many facilities. In Japan, it is covered by national insurance. In addition, attempts are being made to further reduce cardiac exposure by using intensity-modulated radiation therapy (IMRT) (10, 11), although, to our knowledge, there has been no evidence that IMRT and deep inhalation breath-holding reduce heart-related deaths. It may not be meaningful to reduce the cardiac exposure dose further by using deep inhalation breath-holding or IMRT. However, caution may be needed in patients with multiple risk factors for cardiac-related events (12-14).

As a limitation of this study, the database used does not have information on comorbidities and details of chemotherapy, and the irradiation dose to the heart was predicted only by information about laterality of the primary site and whether radiation therapy had been performed or not. For breast cancer, a chemotherapy regimen with cardiac toxicity is often used (15). In multivariate analysis, chemotherapy was not selected as a risk factor of cardiac-related death, possibly because patients with early-stage cancer might have been enrolled in this study. Also, we evaluated the impact of radiation on the heart by only heart-related death and did not consider heart events (e.g., coronary events and heart failure). Lastly, the observation period might have been too short to evaluate the impact of radiotherapy on cardiac-related death, because Darby et al. reported that cardiac deaths increase from a few years after to at least 20 years after treatment (3). In patients who were treated in the early era, with the median observation period of 153 months, there was no significant difference in the cumulative cardiac-related death rate between left-sided and right-sided patients. However, we might have to evaluate data with a longer observation period.

Conclusion

Analysis of data in the SEER database showed that cardiac-related deaths after breast cancer treatment are relatively rare in Asians or Pacific islanders and that the cardiac impact of postoperative radiotherapy has not been significant since at least 2000. It was very different from the past reports in patients treated with old radiotherapy techniques. However, we might have to evaluate data with a longer observation period especially in aged patients.

Footnotes

  • Authors’ Contributions

    Conception and design or analysis and interpretation of data: Keiichi Jingu, So Omata, Hiroaki Ogawa, Yuta Sato, Hinako Harada, and Yasuhiro Seki. Drafting of the manuscript or revising it for important intellectual content: Keiichi Jingu, Rei Umezawa, Takaya Yamamoto, Noriyoshi Takahashi, Yu Suzuki, and Keita Kishida. Final approval of the version to be published: Keiichi Jingu, Rei Umezawa, Takaya Yamamoto, Noriyoshi Takahashi, Yu Suzuki, and Keita Kishida.

  • Conflicts of Interest

    The Authors declare that they have no competing interests.

  • Received May 15, 2023.
  • Revision received June 8, 2023.
  • Accepted June 13, 2023.

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).

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Recent Postoperative Radiotherapy for Left-sided Breast Cancer Does Not Increase Mortality of Heart Disease in Asians or Pacific Islanders: SEER Database Analysis
KEIICHI JINGU, REI UMEZAWA, TAKAYA YAMAMOTO, NORIYOSHI TAKAHASHI, YU SUZUKI, KEITA KISHIDA, SO OMATA, HIROAKI OGAWA, YUTA SATO, HINAKO HARADA, YASUHIRO SEKI
Anticancer Research Aug 2023, 43 (8) 3571-3577; DOI: 10.21873/anticanres.16535
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