13th February 2023, Dr Chee L Khoo
Survival rates amongst our cancer patients have improved dramatically over the years with the advent of better chemotherapy regimen. This is particularly the case in breast cancer and the different lymphomas. One of the adverse effects is cardiotoxicity in patients exposed to anthracyclines which can be life-threatening and can occur immediately or in the longer term. Long-term monitoring of heart function in cancer survivors is controversial among international guidelines. The problem with longer term adverse effects is that patients are no longer under the care of the oncologists. These patients are now under the care of their GPs and it is up to us to have a high index of suspicion when patients present with symptoms of heart failure which is often non-specific.
How common is cardiotoxicity from chemotherapy?
Anthracyclines are a class of chemotherapeutic agents used for many types of cancer, particularly in the frontline for breast cancer and lymphoma. They are associated with dose-dependent cardiac toxic effects including congestive cardiac failure (CHF) (1-10). In a 2013 meta-analysis, 16 clinical cardiac toxic effects were reported in 6%of patients treated with an anthracycline after a median follow-up of 9 years, and subclinical cardiac toxic effects were described in 18% of patients (11).
In a nationwide, retrospective study was conducted with the Korean National Health Information Database, Jihyoun Lee et al reported that young breast cancer survivors have a greater risk of late CHF than the young population without cancer (12). A total of 91,227 cases and 273,681 controls were evaluated between January 2007 and December 2013. The risks of late CHF were higher in cases than controls with a hazard ratio [HR] of 1.396. Survivors ≤ 50 years old showed an even higher risk of late CHF than their younger counterparts with a HR of 2.903. Although older age was a risk factor for late CHF, older survivors (age ≥ 66 years) showed no difference in the risk of late CHF in comparison with their counterparts.
Contrary to previous studies that investigated the time of occurrence of CHF, which showed that most cardiotoxicities occurred within the first year after an anthracycline chemotherapeutic regimen, the rates of CHF continued to increase throughout this study.4 The authors postulate that this might be caused by the difference in the anthracycline dose amongst the studies. The Korean study did not capture the dose exposure of the patients.
Carolyn Larsen et al compared the long-term cumulative incidence of CHF in patients with breast cancer or lymphoma treated with anthracycline therapy compared with healthy controls from the same community in Olmsted County, Minnesota, diagnosed with breast cancer or lymphoma from January 1985 through December 2010 (13). The main outcome was new-onset CHF, as defined by the modified Framingham criteria. They compared the risk of CHF in participants with cancer vs controls, adjusted for age, sex, diabetes, hypertension, hyperlipidaemia, coronary artery disease, obesity, and smoking history.
In 2196 individuals (812 patients with cancer and 1384 participants without cancer), patients with cancer had higher risk of CHF compared with the control cohort even after adjusting for age, sex, diabetes, hypertension, coronary artery disease, hyperlipidaemia, obesity, and smoking status (HR, 2.86 [95%CI, 1.90-4.32]; P < .001). After adjusting for the same variables, CHF risk was greater for patients with cancer receiving anthracycline (HR, 3.25 [95%CI, 2.11-5.00]; P < .001).
This risk started from the first year (12 participants with incident CHF) and persisted over time even when excluding the first-year eventsHigher cumulative incidence for patients treated with anthracyclines vs comparator cohort was observed at 1 year (1.81% vs 0.09%), 5 years (2.91%vs 0.79%), 10 years (5.36%vs 1.74%), 15 years (7.42%vs 3.18%), and 20 years (10.75%vs 4.98%) (P < .001).
There was an increased risk of CHF for patients with breast cancer (HR 3.52 [95%CI, 1.78-6.93]; P < .001) or non-Hodgkin lymphoma (HR 1.99 [95%CI, 1.12-3.51]; P = .02). There were only 4 events in the Hodgkin lymphoma group, so we were unable to model this subgroup specifically. At diagnosis, age was an independent risk factor associated with CHF (HR per 10 years, 2.77 [95%CI, 1.99-3.86]; P < .001). Other comorbidities were not independently associated with an increased risk of developing CHF.
Radiation therapy to the chest and mediastinum did not emerge as an independent risk factor for CHF.
Guidelines
The (Korean) National Comprehensive Cancer Network guidelines suggest that clinical screening for CHF should be conducted within 1 year after the completion of anthracycline therapy (14). The American Society of Clinical Oncology guidelines also indicate that echocardiography should be performed 6 to 12 months after cancer-directed treatment in high-risk asymptomatic cancer survivors (15). However, guidelines from the European Society for Medical Oncology, the Canadian Cardiovascular Society, and the American Society of Echocardiography propose long-term cardiac monitoring in cancer survivors (16). There are no definite guidelines about monitoring or managing other cardiac toxicity such as myocardial infarction or myocarditis.
The Heart Failure Association (HFA), the European Association of Cardiovascular Imaging (EACVI) and the Cardio-Oncology Council of the European Society of Cardiology (ESC) include echocardiography surveillance always at baseline, followed by echocardiographic examination after completing a cumulative dose of 250mg/m2 of doxorubicin or equivalent and 12 months after treatment completion.
In patients with high risk, an echocardiographic examination is recommended every 2 cycles and 3 months after treatment, as a class I indication. If higher doses of anthracyclines are administered, an echocardiographic Importantly expert guidelines suggest a 5-year re-evaluation in patients with low or medium risk, and in high-risk groups, re-evaluation should occur annually for 2 or 3 years after the 12-month follow-up, then in 3- to 5-year intervals.
In summary, there is increasing evidence that the incidence of heart failure should be looked for in patients exposed to anthracyclines in the management of breast cancer or lymphoma. Heart failure may appear as early as within 12 months of receiving anthracyclines and the incidence continues to grow over time. It is important that GPs are on a look out of symptoms of HF. It is important that we aggressively manage the traditional cardiovascular risk factors as well especially in those with high cardiovascular risks. Clinically the most important anthracyclines are doxorubicin, daunorubicin, epirubicin and idarubicin
References:
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