Clinical investigation
Cardiac perfusion changes in patients treated for breast cancer with radiation therapy and doxorubicin: preliminary results

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Abstract

Purpose: To determine the incidence and dose dependence of regional cardiac perfusion abnormalities in patients with left-sided breast cancer treated with radiation therapy (RT) with and without doxorubicin (Dox).

Methods: Twenty patients with left-sided breast cancer underwent cardiac perfusion imaging using single photon emission computed tomography (SPECT) prechemotherapy, pre-RT, and 6 months post-RT. SPECT perfusion images were registered onto 3-dimensional (3D) RT dose distributions. The volume of heart in the RT field was quantified, and the regional RT dose was calculated. A decrease in regional cardiac perfusion was assessed subjectively by visual inspection and objectively using image fusion software. Ten patients received Dox-based chemotherapy (total dose 120–300 mg/m2), and 10 patients had no chemotherapy. RT was delivered by tangent beams in all patients to a total dose of 46–50 Gy.

Results: Overall, 60% of the patients had new visible perfusion defects 6 months post-RT. A dose-dependent perfusion defect was seen at 6 months with minimal defect appreciated at 0–10 Gy, and a 20% decrease in regional perfusion at 41–50 Gy. One of 20 patients had a decrease in left ventricle ejection fraction (LVEF) of greater than 10% at 6 months; 2/20 patients had developed transient pericarditis. No instances of myocardial infarction or congestive heart failure (CHF) have occurred.

Conclusions: RT causes cardiac perfusion defects 6 months post-RT in most patients. Long-term follow-up is needed to assess whether these perfusion changes are transient or permanent and to determine if these findings are associated with changes in overall cardiac function and clinical outcome.

Introduction

Radiation therapy (RT) is widely used to treat patients with breast cancer. Breast-conserving surgery combined with RT to the breast is standard practice in the management of early-stage breast cancer. Mounting evidence suggests that postmastectomy RT provides benefits in local control and overall survival 1, 2. With the increasing use of radiotherapy in the management of primary breast cancer, there has been rising concern about long-term side effects of RT. Some randomized series evaluating patients irradiated postmastectomy report an excess number of cardiovascular deaths in the irradiated group (3). In the overview analysis by Cuzick et al., the reduction in cause-specific deaths from breast cancer afforded by postmastectomy RT was offset by an excess cardiac mortality in the irradiated patients, resulting in no change in overall survival (4). The cardiac complications secondary to RT are thought to be primarily ischemic heart disease with a time of onset of many years following RT (5).

The concern for cardiotoxicity is heightened by the widespread use of adjuvant systemic therapy, in particular, anthracycline-containing drug regimens. Doxorubicin (Dox) is a well-known cardiotoxin, the principal effects being on the myocardium, with an increasing incidence of congestive heart failure (CHF) correlated with increasing doses (6). The time to onset of Dox-induced CHF is typically 1–3 months but has been reported to be as long as 20 years in the pediatric population (7). Radiotherapy to the heart in conjunction with Dox appears to increase the risk of developing cardiac damage 8, 9, 10, 11, 12.

Recent advances in radiation treatment planning and functional cardiac imaging provide an opportunity to quantitatively study changes in regional and global heart function and relate them to radiation dose. New three-dimensional (3D) radiation treatment planning tools can calculate accurate 3D dose distributions throughout the heart (13). Gated cardiac single photon emission computed tomography (SPECT) perfusion imaging provides a noninvasive assessment of myocardial perfusion and function. Herein we report the initial results of a prospective study exploiting these technologies (14), to assess RT-induced changes in cardiac function in 20 patients treated for breast cancer.

Section snippets

Methods and materials

All patients with left-sided breast cancer who planned to undergo RT to either the chest wall or breast with or without regional lymph nodes at Duke University Medical Center and affiliated institutions were eligible. The protocol was approved by the Duke University Medical Center Institutional Review Board. Appropriate informed consent was obtained.

Results

Twelve patients developed new visibly detectable perfusion defects 6 months post-RT (60%). Among patients receiving Dox-based CTx, the incidence was 70% (7/10). Among patients receiving Dox-based CTx with any volume of LV in the RT field, the incidence of new perfusion defects was 100% (7/7). All 10 patients receiving RT alone (without CTx) had some volume of their heart in the RT field, and 5 of the 10 developed new perfusion defects (50%). Figure 2 shows an example of one patient’s pre- and

Discussion

The Stockholm Group was one of the first to attempt to quantify the volume of heart irradiated and dose received and relate this to cardiac damage. In a 1992 report, Rutqvist et al. (3) retrospectively analyzed cardiac toxicity among the 960 patients in the Stockholm randomized trial of postmastectomy RT compared with surgery alone. No patients received adjuvant systemic therapy. Radiation doses to the heart were reconstructed using 3D techniques in four patients. The subset of patients who

Acknowledgements

We wish to thank the Department of Radiation Oncology, University of North Carolina for the use of the 3-D radiation planning system, Plan UNC.

References (26)

  • A. Chakravarthy et al.

    Radiation therapy and 5-Fluorouracil in pancreatic cancer

    Semin Radiat Oncol

    (1997)
  • M. Overgaard et al.

    Postoperative radiotherapy in high-risk premenopausal women with breast cancer who receive adjuvant chemotherapy

    N Engl J Med

    (1997)
  • J. Ragaz et al.

    Adjuvant radiotherapy and chemotherapy in node-positive premenopausal women with breast cancer

    N Engl J Med

    (1997)
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    This study was supported in part by a Department of Defense Breast Cancer Research Grant #BC972695.

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