The survival rate of cancer patients has increased in the last 25 years. In the United States, the five-year relative survival rate of patients diagnosed with cancer between 1975 and 1977 was 50 percent, but it has increased to 68 percent for patients diagnosed between 1999 and 2005. The introduction of more successful anti-cancer treatments has contributed to improved survival. Currently, there are more than 12 million cancer survivors in the United States alone. However, with longer survival, the long-term adverse treatment effects have become increasingly important.
"Cardiotoxicity is a common adverse effect of many treatments, and it may affect patient survival and quality of life independent of the oncological prognosis," according to Farouk Mookadam, M.B., B.Ch., a cardiologist at Mayo Clinic in Arizona. "Given the prevalence of cancer and heart disease, it is common for cardiovascular comorbidities to influence the choice of cancer treatment."
Virtually all anti-cancer drugs that target tumor cell death may result in collateral injury to other healthy tissues. Bone marrow suppression and gastrointestinal toxicities associated with chemotherapy are well recognized and accepted side effects for the benefits that may accrue from the chemotherapy. "Much less appreciated, however, are the cardiotoxic effects of cancer treatment," says Donald W. Northfelt, M.D., a medical oncologist at Mayo Clinic in Arizona. These adverse effects can include:
Furthermore, radiation therapy without adequate cardiac shielding may result in coronary artery disease, valvular heart disease, pericardial injury and myocardial disease from fibrotic changes that occur post-radiation. It is not uncommon for chemotherapy to follow radiation treatment, and in some organs such as the heart, this dual and serial insult can result in a higher likelihood of cardiotoxicity.
Generally, chemotherapeutic cardiac toxicity is classified into two types:
Anthracyclines such as doxorubicin or epirubicin have been key components of many cytotoxic regimens since their introduction in the 1960s. Anthracyclines cause inhibition of DNA polymerases and DNA fragmentation. Cardiotoxic effects of anthracyclines are believed to be related to myocyte injury by oxygen free radicals and lipid peroxidation, resulting in left ventricular dysfunction and congestive heart failure (CHF).
"The occurrence of CHF is dose and schedule dependent, increases in incidence over time, and occurs in up to 20 percent of patients in some reports," says Joerg Herrmann, M.D., a cardiologist at Mayo Clinic in Rochester, Minn. "In the past, the risk was believed to increase significantly with a cumulative doxorubicin dosage of 550 mg/m2, but there is solid evidence that this threshold may be lower or even nonexistent."
The cardiotoxic effects of anthracycline therapy appear to be increased in patients with pre-existing heart disease or advanced age. Late-onset anthracycline cardiotoxicity, presenting as left ventricular dysfunction a year or more after chemotherapy, is increasingly recognized. The risk of cardiotoxicity may also be increased when anthracyclines are used in combination with other potentially cardiotoxic chemotherapeutic agents, such as kinase inhibitors (the dual-hit theory).
Protein kinases in healthy cells may act as tumor suppressors under normal circumstances. Dysfunctional signaling of various kinases is linked to tumorigenesis and tumor angiogenesis.
Kinase inhibitors have been specifically developed by rational drug design. The goal of targeted therapy is to improve anti-tumor activity with a lower risk of adverse effects than traditional anti-cancer therapies. Kinases are also present in cardiac myocytes and are responsible for phosphorylating the amino acids threonine, serine and tyrosine.
Cardiac toxicity from the kinase inhibitors may be the result of either of two mechanisms interfering with myocyte kinase activity: on-target toxicity resulting when the tyrosine kinase also serves an important role in normal cardiomyocyte function, and off-target toxicity occurring when an agent inhibits a kinase not intended to be a drug target.
Tyrosine kinase inhibitors are common anti-neoplastic agents and are of two types: small molecule kinase inhibitors, which target both receptor and nonreceptor kinases, and monoclonal antibodies, which typically target growth factor receptor tyrosine kinases. For example, imatinib (Gleevec) is a small molecule tyrosine kinase inhibitor used in the treatment of chronic myelogenous leukemia.
Many of the small molecule kinase inhibitors induce hypertension in a significant proportion of patients. The development of hypertension can be acute and severe, resulting in mitigation of the chemotherapy either by dose reduction or schedule change — or even cessation, with obvious consequences.
Trastuzumab (Herceptin) is a monoclonal antibody targeting human epidermal growth factor receptor 2 (HER2, also known as ErbB-2). It has led to a significant breakthrough in the treatment of breast cancers that overexpress HER2 receptors (up to 30 percent of all breast cancer cases), a variant of the disease traditionally associated with a poor prognosis.
"Unlike anthracyclines, cardiotoxicity associated with trastuzumab is not dose dependent, and ultrastructural changes typical of anthracycline toxicity are not seen on cardiac biopsy specimens," says Carrie A. Thompson, M.D., a medical oncologist at Mayo Clinic in Rochester. "The clinical outcome of patients with trastuzumab-induced cardiotoxicity is more favorable than that associated with anthracyclines; cardiac function usually recovers after drug withdrawal and initiation of CHF therapy."
Data from randomized controlled trials in women with HER2-positive disease provide clear evidence of disease-free survival and overall survival benefits when trastuzumab is added to standard anthracycline chemotherapy in the adjuvant setting. Mortality is reduced by approximately one-third, but the risk of heart toxicity is five times more likely for women receiving trastuzumab than for women receiving standard therapy alone. Furthermore, concurrent anthracycline-trastuzumab chemotherapy strategies consistently lead to higher adverse event rates compared with sequential treatment strategies.
Cardiotoxicity is a particularly important issue given the large number of women with breast cancer receiving combination anthracycline-trastuzumab therapy in the adjuvant setting. On average, 17 percent of patients receiving this treatment for the most aggressive forms of breast cancer have to stop therapy due to cardiac complications. Cardiotoxicity is reversible in the majority of patients if the treatment is stopped immediately.
Several strategies to reduce anthracycline-trastuzumab-induced cardiotoxicity have been proposed (but are yet unstudied in controlled clinical trials), with key elements including:
In clinical oncology practice, an asymptomatic decrease in LVEF is the most commonly encountered form of cardiotoxicity. However, echocardiographic LVEF assessment has shown low diagnostic sensitivity and low predictive power in detecting subclinical myocardial injury.
Newer tests of systolic function, such as myocardial strain and strain rate, are sensitive measures of tissue deformation that have been shown to be useful in detecting subclinical disease in a number of disease settings. Strain rate imaging is a noninvasive technique that can quantitatively analyze myocardial mechanics by detecting speckles from the myocardium with 2-D echocardiography.
Directional motion is analyzed in an angle-independent manner, unlike tissue Doppler imaging. In general, a reduction of longitudinal strain greater than 10 percent from baseline after three months may be able to predict future cardiac injury with a sensitivity of about 79 percent and a specificity of about 79 percent.
The objectives of an interdisciplinary and integrative management approach to cancer patients with cardiovascular risks or who develop cardiovascular injury are:
The risk of delayed toxicity may be less relevant for patients with advanced disease and a limited life span. However, in the setting of neoadjuvant and adjuvant treatment, the laudable goal should be that a cancer survivor of today does not become the heart failure patient of tomorrow.
To that end, Mayo Clinic has developed specialty cardio-oncology clinics to provide collaborative evaluation and care of these patients. The objectives of these clinics are to provide expert advice and guidance for patients who will undergo cancer treatment and aid in the prevention, monitoring and management of cardiovascular toxicities.
"With the proliferation of new anti-neoplastic agents, the development of new combination therapy protocols, longer patient survival and the large population of cancer patients with pre-existing heart disease, formal specialty collaboration is increasingly recognized as the optimal practice model to deliver integrated care to this population of patients," says Dr. Herrmann. Furthermore, this collaborative effort will facilitate basic, translational and clinical research efforts in the attempt to optimize clinical outcomes.