Cardio-oncology: in search of the right balance

KEYWORDS:

• Heart failure with reduced ejection fraction
• heart failure with preserved ejection fraction
• hospitalizations
• readmissions
• health costs
• morbidity and mortality

The introduction of newer and more sophisticated anti-cancer treatment agents has significantly changed the landscape for a large number of cancer patients that are now surviving or even living with cancer for longer periods of time. In 2014, the American Cancer Society reported that over 14 million cancer survivors were alive in the USA [1]. A number that is projected to reach approximately 19 million by the year 2024 [1].

As a direct consequence of this revolutionized management success, many of these surviving patients face yet another challenge, not related to progression or recurrence of their primary malignancy nor occurrence of a second malignancies, but rather due to an increased risk of cardiovascular diseases (CVD). The latter is now being recognized as the leading cause of both morbidity and mortality among most cancer survivors [2–5].

Since more than 60% of cancer survivors are alive at 5 years after their diagnosis while 40% remain alive more than 10 years [6]; it appears that prompt and efficient identification of cancer survivors at risk of developing CVD it is now a clinical priority [7].

When properly viewed in its right perspective, the origins of cardio oncology can be traced back to the late 1960s when anthracylines were widely introduced as a treatment for many cancers [8–10]. Eventual identification of dose-dependent cardiotoxic effects not only led to significant modifications of anthracycline-based regimens due to cumulative dose limits causing cardiotoxicity [11], but also prompted the interest of gaining a better understanding of diagnosing and preventing these cardiac toxic effects.

It would then be appropriate to accurately try to define cardiotoxicity. Although this term, as proposed by The National Cancer Institute and the National Heart, Lung, and Blood Institute in 2013 is known to encompass an extensive wide array of CVD manifestations lying beyond the scope of this Editorial [12]; it would be sufficient at this time to highlight the fact that both cardiomyopathy and heart failure have received much of the attention until now, but is crucial to understand that cardiac toxic effects extend well beyond these boundaries [13].

Specifically, hypertension, endothelial dysfunction, accelerated atherosclerosis with coronary artery disease, ischemia, valvular disease, pericardial disease, conduction abnormalities a different array of both supra and ventricular arrhythmias, arterial and venous thromboembolism as well as vascular disorders are some of the many untoward side effects of present-day cancer therapy [14,15].

In the beginning, the use of anthracyclines led to the initial categorization of cardiac injury that became the prototype of what we now recognize as Type-I cancer therapy-related cardiac dysfunction [14]. A largely irreversible and dose-dependence cardiac muscle necrosis that contrasts to Type II cardiac dysfunction associated with molecularly targeted cancer therapeutics whose effects are not dose-related, there is no cardiac necrosis and the abnormalities are often reversible [16,17]. This distinction, first proposed in 2005 [18], has significantly evolved. Most recently Witteles suggested that at least nine different classes of currently used chemotherapeutic agents are responsible for very distinct patterns of cardiac injury [19]. Obviously, this is a moving target as several other pathways and mechanisms would undoubtedly become obvious once we begin to better understand the biologic response to the ongoing introduction on new and emerging immunomodulators.

Though not altogether a main concern of cardio oncology; it is, however, important to make the distinction between cardiotoxicity and hypersensitivity reactions [20]. The latter has been described in approximately 5% of parenterally administered chemotherapeutic agents [20]. Though hypersensitive reactions are mainly the result of a heightened immune response, some cases are the result of an exaggerated histamine or cytokines release. The use of L-asparaginase, taxanes, platinum compounds, and epipodophyllotoxins have been most commonly associated with hypersensitive reactions. Although uncommon, hypersensitivity reactions could be life-threatening [21].

In terms of cardiotoxicity, the most important short- and long-term complications of cancer therapy relates to their adverse impact on both CVD morbidity and mortality. Most of these deleterious CVD side effects are largely attributed to the use of anthracycline-based chemotherapy, tyrosine kinase inhibitors, and thoracic radiation therapy. Specifically, the use of anthracycline-based chemotherapy and tyrosine kinase inhibitors affect left ventricular systolic function resulting in heart failure. In contrast, thoracic radiation therapy not only has been linked to accelerated atherosclerosis and calcification causing significant life-threatening proximal coronary artery disease involvement and valvular damage, respectively; but also, results in clinically relevant and difficult to manage pericardial constriction and restrictive cardiomyopathy even after the field of radiation exposure has been adjusted for quite some time now.

As a result of these and many other concerns, cardio oncology came to fruition. This rapidly growing field not only is intended to maximize survival of cancer patients but also identify those cancer survivors at risk of cardiotoxicity to minimize their impact on morbidity and mortality.

Following this initiative some programs across the United States, mainly located at tertiary/quaternary referral centers, have pioneered the creation of cardio oncology programs. Unfortunately, these programs have formed in isolation without a coordinated effort to guide and bridge their development. [7]

To complicate matters even further, the contribution of multiple organizations when formulating recommendations and guidelines regarding identification of cardiotoxicity among cancer survivors rather than simplifying our jobs has made it somewhat confusing and more difficult as most recommendations are simply based on our previous experience using anthracyclines without a comprehensive understanding on how each other established chemotherapeutic agent or new immunomodulator drug will impact CVD manifestations as well as long term outcome of cancer survivors [22–26].

Survivorship is another term in need of a standardized definition. According to The European Organization of Research and Treatment of Cancer Survivorship Task Force, it has been defined as patients that have completed their primary treatment [27]. It is now recognized that aside from the well-described CVD side effects, many cancer survivors also may endure potentially disabling neurological deficits, secondary malignancies and social discrimination

Certainly, until a more standardized and cohesive approach is not reached, cardio oncology would neither be considered as an optimal strategy to accurately predict each individual patient’s cardiotoxicity risk nor a sound cost-effective proposition. Furthermore, prospective hard-core scientific and epidemiologic data not only showing clinical improvement in CVD outcomes but also substantial reductions in health-care costs are definitively needed to solidify cardio oncology’s claims as a sound discipline for treating cancer patients.

While the financial and economic impact of long-term cardiotoxicity remains largely unknown; significant upfront capital and resource investments would be required from each participant institutions in the creation of cardio oncology programs. Certainly, the programs would not be limited to the day-to-day clinical enterprise but encompass a basic as well as translational research components, participation in a clinical trial that will foster collaborative efforts and creation of a multidisciplinary patient approach. An ideal multidisciplinary survivorship program not only would include oncologists, oncological surgeons, radiation oncologists, pathologists, and cardiologists but also internal medicine subspecialists, general practitioners, general surgeons, palliative care specialists, and psychiatrists [28].

In the end, the once parallel universes of cancer and CVD have inexplicable aligned themselves into common clinical entities affecting a significant number of cancer survivors. Unfortunately, this fast-growing field with its intricate complexities has caught most cardiologists off guard with little training or clinical experience and certainly unfamiliar with regards to chemotherapies and their potential side effects on the CVD system. The newly created field of cardio-oncology not only represents a serious attempt to standardize screening, monitoring, prevention, and management of various CVD toxicities of cancer patients but also, a venue to generate useful guidelines and much-needed recommendations that will narrow so many gaps in our knowledge regarding this fascinating field. Which newly introduced cancer therapies would have which CVD side effect; which imaging tool is best for which patient and how often this has to be repeated; which laboratory marker best compliments patient follow-up, etc. Certainly, many gaps can be found along the way and given the paucity of data and the limited number of high-volume cancer centers, international collaboration appears to be the only logical solution. Finally, this field needs to integrate general practitioners and other health professionals treating recently diagnosed cancer patients or those treated in the past as it is necessary to never lose track that cardiotoxicity sure be in the forefront at the time of diagnosis but has to be kept in mind for those survivors that might have late cardiac manifestations such as coronary artery, valvular and pericardial involvement.

Declaration of interest

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. Peer reviewers on this manuscript have no relevant financial relationships to disclose.

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Funding

This manuscript is not funded.