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Breast cancer survivors treated with older irradiation protocols remained at significant risk of treatment-related cardiovascular disease (CVD) for decades afterward, authors of a large retrospective review concluded.

Encompassing a treatment period of almost 40 years beginning in 1970, the review showed that anthracycline-containing chemotherapy plus irradiation of the internal mammary chain (IMC) was associated with a heart failure (CHF) risk nine times greater than that of women in the general population. Anthracycline therapy alone increased heart failure risk four times over that of the general population, according to Flora E. van Leeuwen, PhD, of the Netherlands Cancer Institute in Amsterdam, and colleagues.

IMC irradiation also increased the risk of ischemic heart disease (IHD) and valvular heart disease (VHD), regardless of whether the radiation treatment was on the right or left side. In many instances, the CVD risk did not emerge for 20 years or more after treatment for breast cancer, they reported in the .

"Our results are relevant to a large number of breast cancer survivors treated with older IMC regimens, who may remain at an elevated CVD risk for an extensive period," the authors stated. "Follow-up in our study was too short to detect or reject an IHD risk increase associated with IMC irradiation during 2000 to 2009."

"Recent studies showing improved breast cancer survival after IMC irradiation, still have insufficient follow-up to detect an increased CVD risk, which, as we report, continues into the third decade after treatment," they noted.

An unrelated study showed a dose-dependent association between irradiation for breast cancer and the risk of injury to the left ventricle (LV) and coronary artery segments. Covering a 43-year period beginning in 1958, the data suggested that all coronary segments "are sensitive to radiation and that doses to all segments should be minimized," Carolyn Taylor, PhD, of the University of Oxford in England, and colleagues, wrote in the .

Better Survival, New Risks

Advances in early diagnosis and treatment of breast cancer substantially improved survival over the past several decades. Radiation therapy and anthracycline-based chemotherapy have contributed to improved survival but at a recognized expense of an increased CVD risk, Van Leeuwen's group noted.

Anthracycline-based chemotherapy has a dose-dependent association with cardiomyopathy and heart failure, although the cumulative incidence varied in prior studies. Documented heart effects of radiation therapy include IHD and VHD, and some studies have suggested the effects are dose-dependent.

Initial studies suggested the adverse heart effects of radiation therapy emerged about 10 years after exposure, but more recent analyses have shown that the risk begins to increase within 5 years of exposure, the authors continued.

Given the growing population of breast cancer survivors, investigators sought to quantify the long-term CVD risks following treatment for the disease. The analysis comprised 14,645 Dutch patients age <62, treated for early breast breast cancer during 1970 to 2009, with follow-up to 2012.

Following surgery, 56% of patients received radiation therapy alone, 3% received chemotherapy alone, 30% received both, and 11% received neither. For patients who received radiation to the breast or chest wall but not the IMC, the usual radiation dose to the heart ranged between 4 and 6 Gy until 2000 to 2009, when it decreased to about 1.5 Gy.

When the radiation field included the IMC, the typical dose to the heart ranged from 12 to 22 Gy, except for the subgroup of women who received radiation to the IMC and breast, which was associated with a heart dose of 9 Gy during 2000 to 2009.

When the IMC was not exposed, the CVD rate ratio (RR) for left-versus-right sided beast irradiation was 1.11, which failed to achieve statistical significance (95% CI 0.93-1.32). IMC irradiation at a dose range of 9-16 Gy versus right-sided breast irradiation only significantly increased the risk of total CVD, IHD, VHD, and CHF (RR 1.6-2.4). IHD risk remained elevated for at least 20 years after treatment.

Anthracycline-based chemotherapy significantly increased the risk of CHF versus the general Dutch population of women within 5 years of treatment and remained elevated at least 10 to 15 years after treatment (HR 4.18, 95% CI 3.07-5.69). The combination of IMC irradiation plus anthracycline-based chemotherapy increased CHF risk more than nine-fold versus women exposed to neither treatment (HR 9.23, 95% CI 6.01-14.18).

The study had some limitations including the potential for unreported CVD events.

Higher RT Doses, Higher Risk

Taylor's group analyzed the association between radiation therapy and CVD risk in 456 women who received radiotherapy for breast cancer from 1958 to 2001 and who subsequently had major coronary events. Radiation dose to five LV segments could be estimated for 414 patients. Additionally, radiation dose to six coronary segments was estimated for a subgroup of 133 patients who had documented coronary artery disease associated with ≥70 stenosis.

Of the 414 patients with LV injury, 243 had left-sided breast cancer and 171 had right-sided cancer (RR 1.42, 95% CI 1.17-1.73), reflecting a higher typical LV radiation dose in left-sided cancer, the authors noted.

For the five segments assessed, the ratios for left-versus-right sided radiotherapy were 0.94 for inferior (95% CI 0.70-1.25); 1.42 for lateral (95% CI 1.04-1.95); 2.09 for septal (95% CI 1.37-3.19); 1.85 for anterior (95% CI 1.39-2.46); and 4.64 for apex (95% CI 2.42-8.90). Corresponding radiation dose differences for the five segments were 2.7, 4.9, 7.2, 10.4, and 21.6 Gy (P<0.001 for trend).

For the subgroup of women with coronary artery disease, the ratios for left-versus-right radiotherapy for the six segments evaluated were 0.48 for proximal right coronary artery (95% CI 0.26-0.91); 1.69 for mid/distal right coronary (95% CI 0.85-3.36); 1.46 for proximal circumflex (95% CI 0.72-2.96); 1.11 for distal circumflex (95% CI 0.45-2.73); 1.89 for proximal left anterior descending (95% CI 1.07-3.34); and 2.33 for mid/distal left anterior descending (95% CI 1.19-4.59). The corresponding left-minus-right radiation dose differences were -5.0, -2.5, 1.6, 3.5, 9.5, and 38.8 Gy (P=0.002 for trend).

"For individual LV and coronary artery segments, higher radiation doses were strongly associated with more frequent injury, suggesting that all segments are sensitive to radiation and that doses to all segments should be minimized," the authors concluded.

They noted a study limitation was that "individual CT information was unavailable because the women were irradiated before the era of three-dimensional CT radiotherapy planning. Therefore, it was necessary to estimate cardiac doses retrospectively using a typical CT scan."