‘Cardiac toxicity is associated, to some degree, with most of the therapeutic modalities we offer patients,” pronounced William J. Gradishar, MD, of Northwestern University Feinberg School of Medicine, a member of the Breast Cancer Guidelines Panel. With breast cancer survivors living longer, emerging long-term side effects may assume greater significance, he continued, especially with some of the systemic therapies used, such as the anthracyclines and the targeted agent trastuzumab (Herceptin).
In terms of systemic treatment of breast cancer, particularly chemotherapy, “the anthracyclines [doxorubicin and epirubicin] are the biggest culprit of cardiac toxicity,” Dr. Gradishar stated. A lowered left ventricular ejection fraction (LVEF) and congestive heart failure (CHF) are two major concerns with the use of these drugs. In one of the first seminal reports of cardiac side effects related to chemotherapy (Von Hoff DD et al. Ann Intern Med 1979;91:710–717), an increase in the cumulative dose of exposure to doxorubicin was associated with an increased risk of developing CHF.
The authors of a more recent study (Swain SM et al.
Cancer 2003;97:2869–2879) reached the same conclusion: Increasing the
cumulative dose of an anthracycline (in the range above 300 mg/m2)
increases the risk of developing problems such as CHF and pump action. They
also found that reductions in LVEF may be asymptomatic and that evidence of
cardiac dysfunction can appear at much lower drug exposures than the benchmark
level of 300–400 mg/m2 of doxorubicin. “So I think we have to
recognize that it’s not only CHF that’s the issue,” he added. Although
anthracycline-induced cardiac toxicity does not resolve spontaneously, Dr.
Gradishar discussed, “for many of these patients, there is improvement in
cardiac outcome with good medical treatment, such as use of
angiotensin-converting enzyme inhibitors.”
One drug used to try to prevent or treat anthracycline-induced cardiac dysfunction and failure in breast cancer is dexrazoxane, an iron chelator. Results of most trials evaluating this drug in patients receiving anthracycline-based therapy for breast cancer show that “there is clear indication of a cardioprotective effect,” Dr. Gradishar indicated. However, a critical review of these trials also provided evidence to suggest that dexrazoxane attenuated the antitumor effects of the anthracycline, he said. According to the actual indication, dexrazoxane is used to reduce the incidence and severity of cardiomyopathy associated with doxorubicin administration in women with metastatic breast cancer who have received a cumulative dose of 300 mg/m2 and are considered to be candidates for potential benefit from continued anthracycline therapy. It is not recommended for use with the initiation of doxorubicin therapy.
The newer agent trastuzumab, targeted to the human epidermal growth factor receptor 2 (HER2), also has an impact on cardiac function. Improvements in both progression-free and overall survival in women with metastatic breast cancer have been well documented with trastuzumab (Slamon DJ et al. N Engl J Med 2001;344:783–792). However, this benefit has been achieved at the cost of excess cardiotoxicity.
According to an independent cardiac review and evaluation committee (Seidman A et al. J Clin Oncol 2002;20:1215–1221), a significant fraction of patients with metastatic disease (27%), particularly those who received concurrent trastuzumab plus anthracycline-based chemotherapy, experienced cardiac dysfunction. This complication rate was much higher than that observed in patients who received anthracycline chemotherapy alone and that seen in those who received trastuzumab in conjunction with paclitaxel (13%). “When we use [trastuzumab], based on the data we have available now, it should not be concurrently administered with doxorubicin,” Dr. Gradishar cautioned. Because of the severity of disease in patients with metastatic breast cancer, however, the committee concluded that the risk of cardiac dysfunction with trastuzumab might be justified in this group of patients, given the 25% improvement in overall survival.
In the adjuvant setting, in which patients may be potentially cured of their disease, the thinking is clearly different. Here, “we have to carefully weigh how we use [trastuzumab],” because in many cases, the cure may actually cause another disease, Dr. Gradishar warned. He highlighted the findings of adjuvant trastuzumab in four major trials: NSABP (National Surgical Adjuvant Breast and Bowel Project) B-31, BCIRG (Breast Cancer International Research Group) 006, NCCTG (North Central Cancer Treatment Group) 9831, and HERA (Herceptin Adjuvant). Regardless of the chemotherapy used, the addition of trastuzumab had a significant impact on reducing the risk of recurrence, which to date has translated into an improvement in overall survival in most of the trials, he added. However, according to Dr. Gradishar, “you do buy more in the way of side effects, particularly cardiac side effects, and you have to balance that against the improvement in disease-free survival.”
Dr. Gradishar offered a few caveats regarding the interpretation of these findings. First, most of these cardiac events occurred early on, around the time of therapy, rather than years after. Second, the definition of cardiotoxicity and the methodology used to assess cardiac side effects must be considered, as they varied significantly across the different trials. “You have to keep that in mind and be rigorous about how you interpret the data,” reminded Dr. Gradishar.
The cardiac side effects of radiation therapy (RT) were demonstrated in an overview of randomized clinical trials of RT in the treatment of breast cancer by the Early Breast Cancer Trialists’ Collaborative Group (Clarke M et al. Lancet 2005;366:2087–2106). These side effects were “slight during the first 5 years, but continued after year 15,” said Dr. Gradishar, who emphasized that there is a small, but real, risk of cardiac side effects related to RT for breast cancer, particularly when RT is left-sided.
An investigation of the toxicity associated with adding RT to chemotherapy was performed using data from the phase III NCCTG 9831 trial (Halyard MY et al. J Clin Oncol 2006;24[18S]:523), Dr. Gradishar stated. Chemotherapy included an anthracycline, with or without the use of trastuzumab. After a median follow-up of 1.5 years, there was no apparent increase in the frequency of cardiac side effects with radiation added, he said. “I think this speaks to the issue of better treatment planning today, as opposed to 10–20 years ago,” Dr. Gradishar asserted, although additional follow-up will be needed to assess whether late side effects develop.
Brief mention was made of the newest dual-kinase inhibitor lapatinib (Tykerb), which has been approved by the US Food and Drug Administration for use in conjunction with capecitabine (Xeloda) in patients with HER2-positive advanced or metastatic breast cancer who have had prior treatment with an anthracycline, a taxane, and trastuzumab (Geyer CE et al. N Engl J Med 2006;355:2733–2743). As with trastuzumab, rigorous cardiac evaluation of patients receiving lapatinib has been performed. Based on the cumulative experience of more than 3,000 patients receiving this agent (Perez EA et al. J Clin Oncol 2006;24[18S]:583), only 0.1% of patients experienced a symptomatic drop in LVEF and 1.2% of patients had an asymptomatic fall in LVEF.
Comparisons between trastuzumab and lapatinib with respect to cardiac toxicity are not possible because of a current lack of data, Dr. Gradishar explained. Currently under way is the large ALLTO (The Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization) trial comparing patients with early-stage breast cancer randomized to receive trastuzumab or lapatinib, trastuzumab followed by lapatinib, or the combination of the two agents.
Identifying patients at high risk of developing cardiac problems is essential in guiding therapeutic decisions. Factors that have been associated with an increased risk of cardiotoxicity include older age; a history of mediastinal RT; preexisting conditions such as hypertension, diabetes, coronary artery disease, and peripheral vascular disease; and drugs that may have a synergistic cardiotoxic effect, reported Dr. Gradishar. “We have to be sensitive to clinical signs that there may be problems with the heart, not just gross CHF,” he suggested.
How best to assess cardiotoxicity in breast cancer treatment is a challenge, Dr. Gradishar said. “Symptoms are not necessarily the most sensitive way of detecting or predicting who is going to have a problem, nor are electrocardiographic changes,” Dr. Gradishar admitted. Although changes in cardiac structure and function may be detected as a trend on an echocardiogram or a MUGA (multiple-gated acquisition) scan, he mentioned, “a patient may be fine one day and then with the next cycle of therapy may have a precipitous drop [in LVEF].” Newer biomarkers, such as troponin and BNP (brain natriuretic peptide) levels, appear to be predictive but are not yet viewed as standard of care. In an attempt to discover better tools, several centers are evaluating a number of different strategies for cardiac monitoring, Dr. Gradishar stated. “Until we have better tools, we will still end up using echocardiogram[s] and MUGA,” he concluded.