There are growing concerns about an unfortunate but often-unavoidable scenario in modern medicine. Although the latest generation of drugs has improved patient survival for a vast array of diseases, the prolongation of life is often accompanied by a sharp increase in the probability of adverse effects of medication. Treatment of one disease can provoke or complicate another.
Clinicians, of course, focus on the more urgent and life-threatening condition. However, the choice is neither always straightforward or easy. In certain cases, there are both short-term complications and long-term consequences.
One major area of attention in recent years is cardio-oncology (or onco-cardiology). This concerns the development of heart problems in patients treated for cancer. In cancer survivors, years or even decades could elapse after chemotherapy or radiation, before the emergence and detection of problems.
Origins in anthracycline side effects
The origins of ‘cardio-oncology’ date back to the late 1960s/early 1970s, when the use of anthracycline anti-cancer medication began to be associated with cardiac dysfunction – a major side effect.
Anthracyclines like doxorubicin are commonly used in the treatment of solid tumours (e.g. breast cancer, osteosarcoma) and hematologic malignancies (acute lymphoblastic leukemia, Hodgkin- and non-Hodgkin lymphoma etc.)
A variety of studies beginning from the late 1990s through to the late-2000s found the risk of congestive heart failure (CHF) with high cumulative dose of anthracyclines ranging from 3-5% with 400 mg/m2, 7-26% at 550 mg/m2, and 18-48% at 700 mg/m2. Since then, better management of total anthracycline dose has seen CHF reduced significantly.
However, given two demographic factors (growing incidence and survival rates of cancer patients in a high-risk ageing population), the number of patients with cardiac complications remains elevated and is likely to grow further in the coming years.
Cardio-toxicity near-universal for anti-cancer drugs
Though breakthroughs in cancer research have led to therapies selectively targeting malignant cells, many new treatments too continue to cause problems with the heart. In reality, virtually all anti-cancer agents are associated with a significant degree of cardio-toxicity These range from direct cytotoxic effects and cardiac systolic dysfunction, to ischemia, arrhythmias, pericarditis and repolarization abnormalities.
The tyrosine kinase inhibitor, Trastuzumab, for example, also affects cardiac function. Indeed, the HER2/ErbB2 protein in certain breast cancer cells targeted by trastuzumab plays a major role in the myocardium, and it was the occurrence of severe cardiac side effects with trastuzumab which led to the recent revival of serious interest in cardio-oncology.
Other challenges are also seen with newer cardiac agents such as imatinib and bevacizumab. The first contributes to cardiac decompensation by altering preload through fluid retention, while the latter achieves the same effect by alteration afterload through hypertension. Ifosfamide is associated with arrhythmias, while 5-cisoplatin and the anti-metabolite 5-fluourouracil cause cerebrovascular disease.
Type I and II cardio-toxicity
Since 2005, physicians have been using a classification model to define and distinguish between two types of cardio-toxicity.
Type I results in the direct and irreversible damage to the cardiomyocyte, principally in a dose-dependent manner. Anthracyclines are a good example of Type I cardio-toxicity.
Conversely, Type II cardio-toxicity entails cardiac dysfunction with less prominent structural injury or irreversible cell damage. Crucially, it does not exhibit dose dependency, is usually transient and carries a better prognosis. Trastuzumab is associated with Type II cardio-toxicity .
No rest for the heart
Overall, the heart is especially vulnerable to cancer treatments. Cardiac cells are incapable of division or regeneration. They lack sufficient ability to heal if damaged, especially if active – an especially poignant issue since the heart in a living person never rests totally/stops beating. Cardiac cells are also highly sensitive to stress. Disruptions can impact the heart in a negative fashion and do so significantly. Such stress and disruption can be caused by medications, not least against cancer.
An understanding of onco-cardiology will therefore be critical for effective, long-term care of cancer patients, and there is growing recognition that cardiologists should be involved or consulted when cancer drugs are given to patients.
There already are some promising results due to such involvement. Cardio-toxic effects of chemotherapy seem to be decreased by the concurrent use of angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers, or beta-blockers. Anti-platelet or anticoagulation therapy offer improvements in outlook for cancer patients with a potential hyper-coagulable status, associated with chemotherapy.
Cardiac risks of radiation therapy
Medication is however not the only problem.
Radiation therapy too is associated with all-inclusive involvement of the heart (myocardium, pericardium, valves and coronary arteries) and leads to accelerated atherosclerosis in the great vessels and fibrotic changes to the valves, pericardium and myocardium. However, reduction in left ventricular ejection fraction (LVEF) and development of congestive heart failure (CHF) is considered to be one of the most serious problems and has consequently drawn maximum attention. Confounding the problem is one of lead-lag. For most patients, such effects can appear only after a decade or more following radiotherapy.
Once again, new cardio-oncological approaches are seeking to improve longer-term outcomes by reducing the dose of radiation to the heart in cancer patients. Included here are techniques such as intensity-modulated radiation therapy, proton beam therapy, breath-hold techniques and prone positioning, as well as 3-D treatment planning with dose-volume histograms to precisely calculate both heart volume and dose.
The so-called normal tissue complication probability (NTCP) model takes account of the dose and the volume of normal tissues subject to radiation exposure and can be used to make a correlation between a given dose and the risk of cardiac mortality, over a period of 15 years.
Cardiac disease as a therapeutic barrier to cancer
Given the growing connection between today’s cancer survivor and tomorrow’s heart disease patient, many hospitals have begun to dedicate multidisciplinary programmes focused on cardio-oncology. Their aim is to proactively, and sometimes aggressively, balance benefits of cancer treatments against the risks of adverse cardiovascular effects. Though the immediate goal is to improve outcomes for cancer patients with cardiac challenges, eventually, cardio-oncology seeks to eliminate cardiac disease as a barrier to effective cancer therapy.
Some cardio-oncology programmes emphasize the need to consider cardiovascular health in the shortest possible interval of time after a cancer diagnosis. The objective is to not just manage complications as they arise, but assessing and mitigate cardiovascular risks, in both acute and chronic terms, to optimize long-term outcomes.
On their part, cardiologists are expected to stay abreast of all current and emerging cancer therapies – in terms of their cardio-toxic effects. This will allow them to recommend concurrent heart-protective interventions and establish a tailored approach to cardiac therapies for cancer patients.
Detecting cardio-toxicity with echocardiography
There are currently several approaches for the detection of cardio-toxicity and cardiac function. The most commonly used is 2-dimensional echocardiography (2-D echo), to identify anthracycline-induced cardiomyopathy based on left ventricular ejection fraction (LVEF) parameters. One recent study at the European Institute of Oncology in Milan, on a mainly breast cancer population treated with anthracyclines, used standard 2-D echo for prospective and close monitoring of LVEF over the first 12 months after completion of chemotherapy. The technique provided early detection of almost all cases of cardio-toxicity (98%), and prompt treatment led to normalization of cardiac function in most cases (82%). In other words, LVEF at the end of chemotherapy was an independent predictor of further development of cardio-toxicity.
However, only 11% of patients made complete recovery (with LVEF at least equal to the value before initiation of chemotherapy initiation). The researchers concluded that approaches to prevent development of left ventricular dysfunction (LVD) appear more effective than therapy interventions aimed at countering existing damage which can be progressive and irreversible in many cases.
Indeed, some research suggests that diastolic dysfunction precedes LVEF reduction in patients with chemotherapy-induced cardio-toxicity. However, to date, no diastolic parameters have been proven to definitively predict cardio-toxicity, and the role of diastolic dysfunction in cardio-toxicity screening remains controversial.
Newer technology promising improved accuracy in calculating LVEF is strain-echocardiography, which measures myocardial deformation. One common metric, peak systolic longitudinal strain rate, is increasingly accepted as a tool to identify most early-stage variation in myocardial deformation during anticancer therapy.
However, long-term data on large populations confirming the clinical significance of this is not yet available. There are also several other limitations such as the need for offline, time-consuming, analysis and variability between echo machines and software packages.
There is fast-growing enthusiasm about the use of biochemical markers, in particular cardiac troponins, for early real-time identification and monitoring of antitumour drug-induced cardio-toxicity Cardiac troponins are proteins within the myocardium, released within hours of damage to the myocyte. Studies show troponins detect cardio-toxicity at a preclinical phase, long before any reduction in LVEF in patients who have been treated with anticancer drugs.
Such an approach would annul the variability reported with imaging between ultrasound observations. However, there is still more research needed to determine the precise timing of biomarker measurement.
The most promising (and potentially useful) research priorities are allocated to prediction of the severity of future LVD, given that peak troponin value after chemotherapy closely correlates to LVEF reduction. Some researchers also seek to stratify cardiac risk after chemotherapy, in order to personalize the post-chemotherapy process, excluding patients who are not at risk from prolonged monitoring