Coronary heart disease after radiotherapy for peptic ulcer disease

doi:10.1016/j.ijrobp.2004.07.708

International Journal of Radiation OncologyBiologyPhysics

Volume 61, Issue 3, 1 March 2005, Pages 842-850

https://doi.org/10.1016/j.ijrobp.2004.07.708 Get rights and content

Purpose

To evaluate the risk of coronary heart disease (CHD) and cerebrovascular disease after radiotherapy (RT) for peptic ulcer disease.

Methods and materials

Peptic ulcer disease patients treated with RT (n = 1859) or by other means (n = 1860) at the University of Chicago Medical Center between 1936 and 1965, were followed through 1997. The observed numbers of cause-specific deaths were compared with the expected numbers from the general population rates. During RT, 5% of the heart was in the treatment field and the remainder of the heart mostly received scattered radiation. A volume-weighted cardiac dose was computed to describe the average tissue dose to the entire organ. We used Cox proportional hazards regression analysis to analyze the CHD and cerebrovascular disease risk associated with RT, adjusting for confounding factors.

Results

Greater than expected CHD mortality was observed among the irradiated patients. The irradiated patients received volume-weighted cardiac doses ranging from 1.6 to 3.9 Gy and the portion of the heart directly in the field received doses of 7.6–18.4 Gy. The CHD risk increased with the cardiac dose (p trend = 0.01). The cerebrovascular disease risk was not associated with the surrogate carotid dose.

Conclusion

The excess CHD risk in patients undergoing RT for peptic ulcer disease decades previously indicates the need for long-term follow-up for cardiovascular disease after chest RT.

Introduction

The adverse cardiac effects of high-dose radiotherapy (RT) were first recognized in the late 1960s, when cases of heart disease were observed among patients treated with RT for Hodgkin's lymphoma and other mediastinal tumors (1). Pericardial disease was initially thought to be the predominant radiation-induced heart damage, but additional follow-up of Hodgkin's lymphoma patients showed a statistically significant increased risk of coronary heart disease (CHD) many years after undergoing megavoltage mantle therapy (2, 3) that yielded a total mediastinal dose of 40–44 Gy. An excess risk of myocardial infarction has also been linked to the adjuvant RT for breast cancer used before 1980 (4, 5, 6, 7). It has not been clear, however, whether relatively low therapeutic doses from modern RT for Hodgkin's lymphoma (3, 8, 9) or early breast cancer (10, 11, 12, 13, 14) have resulted in a statistically significant reduction in the heart disease risk in RT patients.

Recent mortality and morbidity data from studies of the Japanese atomic bomb survivors have demonstrated a statistically significant dose–response relation for mortality from heart disease and stroke at doses of <4–5 Gy (15, 16), suggesting that an excess risk of heart disease can occur after exposure to low-dose RT. The excess risk in the atomic bomb survivors persisted for several decades after the radiation exposure. An excess risk of heart disease after exposure to low doses has also been reported from studies of patients undergoing RT for benign disease (e.g., ankylosing spondylitis [17], metropathia hemorrhagica [18]) and occupationally exposed radiologists and radiologic technologists in the United States (19, 20, 21). No excess heart disease risk was found in studies of fluoroscoped tuberculosis patients (22) or U.K. radiologists (23).

In the 1940–1960s, RT was frequently used to treat patients with peptic ulcer disease (PUD) at the University of Chicago (24, 25). During RT, a small portion (estimated to be about 5%) of the heart volume was in the treatment field and the remaining volume of the heart was mostly exposed to scattered radiation. A cohort comprising irradiated and nonirradiated PUD patients has been studied since 1974, with the latest follow-up mortality data available through 1997. Earlier mortality studies of this cohort focused on cancer (26, 27) and showed greater than expected mortality from diseases of the circulatory system associated with RT, but no dose–response analysis was conducted. In this paper, we discuss the results of a quantitative assessment of the risk of heart disease mortality in relation to the estimated radiation dose, controlling for smoking and other cardiovascular risk factors.

Section snippets

Study population and follow-up

The characteristics of this population and study design have been previously described (27). In brief, the study cohort comprised 3719 subjects (1859 irradiated and 1860 nonirradiated), retrospectively selected from among about 4000 PUD patients treated at the University of Chicago between 1937 and 1965. Because the principal rationale for RT was to reduce gastric secretions, patients selected for RT tended to have a high acid production The irradiated patients also were hospitalized and had

Results

A total of 3719 patients contributed 92,979 person-years, with an average follow-up duration of 22.5 years for irradiated and 27.5 years for nonirradiated patients. By December 31, 1997, 83.6% of the irradiated and 81.1% of the nonirradiated patients had died. In both groups of patients, 2.5% were confirmed alive, and 13.9% of irradiated and 16.5% of nonirradiated patients had been lost to follow-up. Of the 2936 deaths, 2187 were from causes other than cancer, including 1097 from circulatory

Discussion

We found a statistically significant elevated risk of CHD in patients who underwent cardiac RT during treatment of PUD. We estimated that 5% of the cardiac volume (apex) was directly in the radiation field and received mean cumulative absorbed doses of 7.6–18.4 Gy (in-field dose). The remaining 95% of the cardiac volume outside the field received scattered radiation, and, thus, the heart as a whole received volume-weighted doses of 1.6–3.9 Gy. We found the CHD risk to increase significantly

Acknowledgments

The authors wish to thank Prof. Klaus R. Trott, Dr. Norman Coleman and Dr. Steve Simon who reviewed a draft version of this manuscript and provided valuable comments, sharing their insights on radiation dose estimation and radiation-induced heart disease.

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Clinical investigationNormal tissuesCoronary heart disease after radiotherapy for peptic ulcer disease

Purpose

Methods and materials

Results

Conclusion

Introduction

Section snippets

Study population and follow-up

Results

Discussion

Acknowledgments

Crit Rev Oncol Hematol

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Lancet

Semin Radiat Oncol

Am Heart J

Prim Care

Radiother Oncol

Semin Ultrasound CT MR

J Am Coll Cardiol

Radiation-induced heart disease: An update

Prog Cardiovasc Dis

Coronary artery disease mortality in patients treated for Hodgkin's disease

Cancer

Factors affecting late mortality from heart disease after treatment of Hodgkin's disease

JAMA

Cause-specific mortality in long-term survivors of breast cancer who participated in trials of radiotherapy

J Clin Oncol

Favourable and unfavourable effects on long-term survival of radiotherapy for early breast cancer: An overview of the randomised trials

Lancet

Mortality from myocardial infarction after adjuvant radiotherapy for breast cancer in the Surveillance, Epidemiology, and End Results cancer registries

J Clin Oncol

Mortality by laterality of the primary tumour among 55,000 breast cancer patients from the Swedish Cancer Registry

Br J Cancer

Childhood cancer survivorship: Improving care and quality of life

No long-term increase in cardiac-related mortality after breast-conserving surgery and radiation therapy using modern techniques

J Clin Oncol

Assessment of coronary heart disease morbidity and mortality after radiation therapy for early breast cancer

J Clin Oncol

Studies of the mortality of atomic bomb survivorsReport 12, part II. Noncancer mortality: 1950–1990

Radiat Res

Profiles of non-cancer diseases in atomic bomb survivors

World Health Stat Q

Long term mortality after a single treatment course with X-rays in patients treated for ankylosing spondylitis

Br J Cancer

Mortality in a cohort of women given X-ray therapy for metropathia haemorrhagica

Int J Cancer

Mortality from diseases of the circulatory system in radiologic technologists in the United States

Am J Epidemiol

Cancer risks in radiologists and radiation workers

Clinical investigation
Normal tissues
Coronary heart disease after radiotherapy for peptic ulcer disease