Introduction
Cardio-oncology (C-O) is a new specialty that has developed exponentially in the last decade (Figure 1). Non-existent 20 years ago, it now has dedicated international meetings1, 2, guidelines3, 4, medical journals5, 6 and training programs7, 8.
Enlarge this image.Figure 1 Number of publications on cardio-oncology on PubMed, by year. In 2023 there were 768 papers published where the words cardio-oncology or cardiooncology were present. PubMed search performed by one of the authors (AI) on 26/01/2023.
We reflect on our experience, over the past ten years, of setting up a minimalist C-O service in one of the tertiary cardiac centers in Wales. We try to provide a practical template for the establishment of such a service and place our experience in the perspective of international guidelines and experience within this new field.
1.. Cardio-oncology: A ‘new kid on the block’
Cardio-oncology deals with the prevention and management of heart disease in patients with cancer. Cardiologists have known for many decades that some of the drugs used by oncologists are cardiotoxic: the first report of anthracycline cardiotoxicity dates from 1967, about 10 years after the advent of this drug class.9 As the number of antineoplastic agents increased, so did the survival of most types of cancer; thus, the number of patients at risk for, and experiencing, cardiotoxicity also increased; in addition, the massive development of cardiac imaging, with ever more complex and accurate ways of assessing cardiac function, led to refined criteria and thresholds for evaluating cardiac performance and dysfunction.
Cardio-oncology developed naturally at the confluence of increased cardiac diagnostic accuracy and the substantial rise in the population at risk of cardiac side effects. Conventional cardiovascular risk factors are also risk factors for cancers: smoking, obesity, physical inactivity and deconditioning. Recently, there has also been increasing appreciation of the complex and subtle interplay between cardiac disease and cancer: clonal hematopoiesis of indeterminate potential (CHIP) has emerged as a potent cardiovascular risk factor10, while heart failure predisposes to cancer.11 It is therefore likely that cardio-oncology will continue to develop and expand, and that the interaction between the two specialties will become deeper and more meaningful in the future.
2.. Cardio-oncology guidelines: An evidence-free zone
There is a surprising disconnect between the amount of self-congratulatory ‘noise’ in the cardio-oncology ‘space’ (to use a fashionable idiom) and the lack of high-quality evidence underpinning practice guidelines. The ESC cardio-oncology guidelines, which span 133 pages and summarize 837 references, are a joint effort from the ESC and several international oncology associations. Detailed guidance is given on a wide variety of topics. However, more than two-thirds of the 272 recommendations in the current 2022 ESC guidelines on cardio-oncology are based on evidence of the poorest quality level (LOE C).12 Only 5 (3%) of the Class I recommendations are backed up by the highest quality evidence (LOE A), and all 5 refer to general cardiology topics (DVT management, QTc interval monitoring, and CMR for diagnosing and monitoring of amyloidosis).
3.. Cardio-oncology in West Wales
Morriston Cardiac Centre is an academic tertiary center serving a population of approximately 1.2 million. South West Wales Cancer Centre, based in Singleton Hospital, Swansea, is a tertiary cancer service serving a population of 907,000 (29% of the population of Wales). The Cancer Service catered to around 3,105 new referrals in 2023, increasing from 2,734 new referrals in 2022.
In 2012, one of the authors (AI), inspired by the cardio-oncology service in one of the London teaching hospitals that he had the opportunity to observe during a 3-month educational sabbatical, approached Dr. G Bertelli, one of the Swansea oncologists. Together, they set up a basic CO Service.
The first step was to create a SharePoint-based online referral form. Oncologists were given access to the form and could refer patients by filling it in and by pressing the ‘Submit’ button. The form required demographic data, information about the cardiovascular risk factor profile of the patient, a summary of the available cardiac investigations and a description of the clinical problem that prompted the referral. Its submission generated an automated email for the cardiologist involved (AI).
Initially, the referrals were few and far between, and they were discussed once a month during an ad-hoc video conference between the 2 specialists. After the first few years the oncologist moved to a different hospital and there was a hiatus during which no further formal referrals for a cardiology opinion were received. Around 2018-19 there was renewed interest for the service among the oncologists, following a series of educational talks about cardio-oncology delivered by one of the authors (AI) to the Oncology department, and now we receive approximately 1-5 referrals/month.
4.. Infrastructure and personnel
At present, there is no dedicated infrastructure, sessional allocation or staff dedicated to the CO Service. All the cardiology input is provided by a single cardiologist, and the activity is not reflected in their job plan.
5.. Cardiology clinical scenarios
The vast majority (~90%) of requests for cardiology opinions (approx. 20-30/year) are related to LV function and either anthracycline or trastuzumab cardiotoxicity. According to the data from South West Wales Cancer Centre there were 396 doses of anthracycline authorized in 2023. There are 2 common scenarios:
- A patient currently on one of these drugs has a surveillance TTE which reports a drop in LVEF, and the oncologists are asking whether it is safe to continue the anti-neoplastic agent.
- A patient scheduled to start one of these drugs has an imaging test, and this reports a subnormal LVEF; the oncologists are asking whether it is safe to start the anti-neoplastic agent.
For either of the above questions, the first step is to review all the imaging involved. Not infrequently, the initial (normal) LVEF assessment is performed by MUGA, while the subsequent, sequential LVEF assessments are performed by TTE. Whereas MUGA is highly reproducible and – generally – not affected by patient factors such as body habitus of emphysema, echo is highly operator-dependent and has significant limitations in certain subgroups (the obese, patients with hyper-inflated lungs), which ensures that, even under the best conditions, there is an intrinsic variation of test/retest paired LVEF measurements of around 6 EF units.13 This can be reduced by the use of trans-pulmonary intravenous contrast agents (Sonovue, in the UK), which enhance endocardial border definition in patients with poor echo ‘windows’ by using automated, AI-based 3D LVEF algorithms (e.g. the Dynamic Heart Model, Philips) that have excellent reproducibility, provided good quality images are available, or by using global longitudinal strain (GLS) to characterize LV systolic performance, as this is a more robust and reproducible index than LVEF. In about 50-60% of cases, a simple review of the imaging resolves the query – often by allowing a recalculation of the LVEF, which is compatible with the continuation or initiation of the cardiotoxic agent.
In the remainder of the cases, our practice is to perform dobutamine stress echo (DSE). In common with the vast majority of CO practices, this is not based on evidence but on biological plausibility, local expertise and availability.
In all cases with reduced LVEF at rest or with globally reduced contractile reserve, we initiate treatment with Ramipril and Bisoprolol. If the LVEF is <40%, we refer the patient to the community heart failure service for formal initiation of the ‘4 pillars’ of HeFREF treatment, and we advise cessation or non-initiation of potentially cardiotoxic chemotherapy, with reassessment of LVEF in 6-8/52. We document 3D LVEF by DHM whenever possible, as well as GLS, but we rely primarily on LVEF for decision-making about initiation or continuation of potentially cardiotoxic chemotherapy, a position supported by the recent SUCCOUR RCT14, where GLS monitoring was not superior to LVEF monitoring in terms of prevention of adverse clinical outcomes.
In the vast majority of cases, the cardiac consult reinstates or initiates chemotherapy rather than discontinues it. Thus, the main role of the cardiologist is to adjudicate in cases where the dichotomous approach to LVEF might have denied a cancer patient potentially life-saving or at least life-prolonging treatment.
Other clinical scenarios, in our experience, are rare and have included:
- Questions about the management of AF and of Ves.
- The occurrence of chest pain +/- cTnT release in patients receiving 5-FU infusions.
- It is noteworthy that we have had very few cases where the reason for requesting a cardiology opinion was an elevated cTnT in a patient receiving treatment c. check-point inhibitors (3 cases only). Such patients have a TTE requested by the oncologist, and in all cases LVEF was normal; CMR ensued, and in none of the cases was there CMR evidence of myocarditis. All patients continued to receive immunotherapy successfully.
6.. Discussion: The ideal CO Service, and how to get it – but is it worth the effort?
It is clear from the description above that our service is rather minimalist. An indicator of this state of affairs is the low number of referrals to the service (</=30/year, albeit slowly increasing). Cardiology input should ideally be sought before the initiation of potentially cardiotoxic treatments, but of course in our setting, this would be untenable at present due to under-resourcing.
Contemporary, full-blown cardio-oncology services rely heavily on nurses and nurse practitioners; however, we have no dedicated nursing personnel in our service. We have been trying to obtain funding for training at least one oncology specialist nurse in basic administration of medications for HeFREF, but so far, we have been unsuccessful. Locally, we were fortunate to have witnessed a massive, recent expansion of heart failure community services, with the establishment of a dedicated community HF hub and the appointment of a large number of specialist nurses; at the current levels of demand, the HF service has been able to accommodate our requests for initiation of treatment for LV dysfunction in oncology patients. If the demand increases, this may no longer be the case.
Our use of DSE in this context is perhaps controversial, but DSE has several features that recommend it as an ideal first test for the measurement of LVEF, prognostic stratification and guidance of further investigations:
- It is widely available, and logistically easy to perform and to repeat, without any significant side-effects.
- Because we use Sonovue in >90% of DSEs, it represents an opportunity for accurate LVEF assessment.
- A normal response to Dobutamine, with normal contractile reserve (progressive increase in the amplitude and speed of myocardial contraction in all myocardial segments and reduction in LV volumes) and the absence of evidence of myocardial ischemia, are well-validated indices of good cardiac prognosis, and, even in the presence of mild LV dysfunction at rest, they reassure us that cardiotoxic, but life-saving, chemotherapy can be initiated or continued safely.
- An abnormal global response, with absence, or with a blunted increase in the amplitude and speed of segmental myocardial contraction, would suggest a DCM-like phenotype, and in our practice, it would lead to the performance of a CMR, for gold-standard LVEF measurement and for the identification and semi-quantitative assessment of fibrosis and of myocardial edema.
- An abnormal segmental response confined to a coronary distribution is suggestive of CAD and would prompt us to perform invasive coronary angiography.
It is important to appreciate that the whole paradigm of inducible myocardial ischemia is shifting rapidly and massively15, and that extrapolating from non-oncology patients to our patients is fraught with major difficulties. Nevertheless, myocardial ischemia remains a significant problem in these patients, who should not be denied PCI when indicated.16
As natural ‘medical conservatives’17, we have observed the recent hype around CO with a degree of skepticism. In spite of the rapid and extensive mushrooming of recommendations and guidelines, we are acutely aware that almost none of the major practices endorsed by them rely on RCT-level evidence. In such a situation, is it really necessary to develop an intricate, expensive service in order to deliver ‘eminence-based’ interventions16, as opposed to evidencebased ones? This is obviously a judgment call, but we should not underestimate the pressure and influence of trends and bandwagons in the adoption of medical practices.17
Our message is that if we accept there is a complex and expanding interface between cardiology and oncology, then cooperation and exchange between the specialties is certainly necessary, but that meaningful impact on clinical outcomes is not yet obvious for such a collaboration and may be difficult to prove.
While waiting for the evidence of the impact of CO services on clinical outcomes to accrue, we would propose that the main task of the cardiologist interacting with oncology services is to prevent the interruption, or the denial, of life-prolonging chemotherapy to patients with cardiac diagnoses. In our experience, avoiding unnecessary interruption of cardiotoxic chemotherapy in patients with abnormal LVEF is the most common clinical scenario. In the absence of good-quality data about ‘best tests’ in this setting or easy access to stress perfusion CMR, we find that DSE works well as a ‘rough and ready’ screening test. Ultimately, if we can ensure lifeprolonging treatment is not discontinued unnecessarily, the bulk of our mission is accomplished, regardless of how subtle our approach might be.
Conflict of interests
none to declare.
Consent
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