General information
There was thirty-seven referred individuals with a total of 62 clinic attendances. Of the 37 individuals seen 33 consented to their data being collected as part of the ACOR.
Twenty-two individuals (59.5%) were male and fifteen (40.5%) were female. Age at first clinic presentation and primary diagnosis are outlined in Table 2. Twenty-four (64.8%) individuals were receiving active oncology treatment at the time of referral (‘on treatment’). Thirteen (35%) individuals were ‘off treatment’. Nineteen (54%) individuals had a documented cardiovascular toxicity or pre-existing risk factor prior to referral including hypertension (1, 2.7%), Left Ventricular (LV) dysfunction (12, 32.4% of which one had a fascio-cutaneous skeletal syndrome with hypertrophic cardiomyopathy), new murmur (1, 2.7%), pericardial effusion (1, 2.7%), elevated troponin I (1, 2.7% ) and tachycardia (1, 2.7%), genetic channelopathy (1, 2.7%), and (1, 2.7%) with x-linked intellectual disability syndrome (Alpha-thalassemia mental retardation (ATRX) syndrome) with a large atrial septal defect. A family history of cardiovascular disease was found, although this was not the reason for referral, in 9 (24.3%) individuals. Of note, one individual had a familial gene mutation causing a sodium channel dysfunction (SCN5A) known to be associated with cardiac conduction dysfunction, dilated cardiomyopathy, Brugada syndrome and prolonged QT syndrome(7). Another family had a history of a bicuspid aortic valve (father of referred individual) not previously recorded in the EMR. This triggered cascade testing in the family.
Indication for Referral to Clinic
The most common reasons for referral to the clinic was previous exposure to a cumulative doxorubicin equivalent anthracycline dose ≥ 250mg/m2 (n=9 (24.3%) with 6 individuals off treatment, 3 on treatment) and left ventricular dysfunction (LVD) often in individuals who had a background exposure of ≥ 250mg/m2 anthracycline (n=12 (32.4%), 9 on treatment, 3 off treatment). The distribution of cumulative doxorubicin equivalent anthracycline dose exposure is shown in the box plot (Figure 1) with a median cumulative doxorubicin equivalent anthracycline dose exposure of 150mg/m2. Five of these individuals had evidence of prior cardiac dysfunction that had recovered on serial 2-dimensional echocardiography imaging.
Molecular inhibitors (monotherapy or in combination with chemotherapy) were another common reason for referral (n=6, 16.2%) including tyrosine kinase inhibitor use (in combination with other referral indications) (n=4, 10.8%) or BRAF inhibitor use (n=2, 5.4%). Seven (18.9%) individuals had a history of radiation although it was only listed as primary reason for referral in 1 individual (2.7%). Less frequent referral indications included family history of genetic heart disease (n=1, 2.7%) and genetic syndrome with congenital heart disease diagnosis (n=1, 2.7%).
Several referrals were made for indications outside of guidelines(3). Individuals were referred for (i) previously elevated biomarkers (n=1, 2.7%); (ii) tachycardia (n=1, 2.7%); pericardial effusion (n=1, 2.7%); (iii) hypertension without metabolic syndrome (n=1, 2.7%); (iv) newly identified murmur (n=1, 1.7%); (vi) risk of QTc prolongation as a result of arsenic trioxide exposure (n=2, 5.4%).
CTCAE Graded Cardiovascular Toxicities documented during clinic attendance
The referral indication and graded cardiovascular toxicities are shown in Figure 2.
Left Ventricle (LV) dysfunction (LVD)
Twelve (32.4%) individuals were referred for a prior history of LVD demonstrated on echocardiography, nine (75%) of which occurred during active therapy and three occurred off therapy (25%). Of the twelve individuals with LVD, three (25%) had CTCAE grade III-IV dysfunction while three individuals (25%) had a previous drop in ejection fraction (EF) (CTCAE grade I-II) that had resolved at the time of clinic appointment.
One individual with grade III-IV LVD had received a cumulative doxorubicin equivalent anthracycline dose of 237mg/m2. On referral, they had a fractional shortening (FS) of 22.4% and EF (Teichholz) 45.5% (Simpson biplane LV EF unable to be performed due to technical issues). The individual had been referred at the end of therapy and cardiac function measurements during cardio-oncology clinic confirmed CTCAE grade I heart failure and CTCAE grade III for LVD. An Angiotensin Converting Enzyme Inhibitor (ACEI) was commenced, and the individual remains on surveillance.
A second individual was referred with a history of LVD (CTCAE grade III) initially found while on active treatment, that required commencement of an ACEI for heart failure (CTCAE grade I). The individual’s echocardiogram prior to commencement of an ACEI demonstrated a FS of 22.9%, EF(Teichholz) 46.1% and a Simpson biplane LV EF 47%. The individual had a history of Acute Myeloid Leukaemia (AML) with a secondary myelodysplastic syndrome requiring an allogeneic transplant. The individual had a cumulative doxorubicin equivalent anthracycline dose of 840mg/m2. Magnetic resonance imaging confirmed abnormal LV function and abnormal epicardial and mid-wall myocardial fibrosis of the basal LV wall affecting 5% of the total LV myocardium. This individual remains clinically stable on an ACEI with ongoing surveillance.
One individual had been referred with known grade III LVD on a background of Noonan-Costello syndrome associated with hypertrophic cardiomyopathy. The individual was being treated with imatinib on referral and remained stable on surveillance.
Of the remaining individuals, three (9%) demonstrated a CTCAE grade II decrease in EF resulting in the multi-disciplinary team recommending the commencement of dexrazoxane with all future doses of anthracycline and early follow-up examination. One individual who was post stem cell transplant on sorafenib had a history of grade II decrease in EF however was discharged from clinic back to their primary oncologist for ongoing routine surveillance once they completed their sorafenib therapy. A further two (6%) individuals were identified as not having had a true decline in EF or indeed LVD on review of their initial echocardiogram. The first was referred with an EF 46% and due to their body habitus limiting echocardiographic views, subsequently underwent a cardiac MRI to confirm their cardiac function (body mass index 32, weight 99th centile). The cardiac MRI demonstrated normal cardiac function with no signs of myocardial fibrosis or oedema and the individual was discharged back to their primary oncologist. The second individual was referred for concerns regarding early diastolic dysfunction on initial echocardiogram imaging prior to anthracycline exposure (EF 48%) however, review of the individual’s previous echocardiograms as well as repeated echocardiogram imaging in clinic, did not confirm initial findings and the individual was discharged back to their oncologist for routine surveillance.
Hypertension
Hypertension was screened for in all individuals as part of the clinic assessment. Screening assessments found ten (27.0%) individuals had blood pressures between the 90th and 95th percentile for age, sex and height (CTCAE grade I). Of note, whilst blood pressures were recorded automatically in the medical notes, further screening recommendations for CTCAE grade I hypertension were not documented in the EMR.
Two further individuals (5.4%) were found to have blood pressures between the 95th and 99th percentile (CTCAE grade II) within clinic, not previously noted in the referral or on EMR. Only 1 of the 2 individuals demonstrated persistent grade 2 hypertension. The individual with grade 2 hypertension had a background diagnosis of Acute Lymphoblastic Leukaemia (ALL). At the time of hypertension documentation, the individual was receiving corticosteroids. The hypertension was successfully managed with a calcium channel blocker. Their cardiac function and ECG assessments performed during clinic were within normal limits and hypertension was the individuals only identified cardiovascular toxicity. The second individual was referred for hypertension and already on an anti-hypertensive agent with normal blood pressure documented in the cardio-oncology clinic. Of the remaining 10 individuals, hypertension was presumed to be secondary to molecular inhibitor use in 3 (8.1%) individuals.
Prolonged QTc measurement or arrhythmias
Evaluation for QTc prolongation was performed in all individuals. QTc prolongation was only demonstrated in two (5.4%) individuals and was documented as CTCAE grade I. One individual was on maintenance tyrosine kinase inhibitor therapy post bone marrow transplant with stable QTc. The second was an individual diagnosed with medulloblastoma. The underlying cause of the individuals prolonged QTc was uncertain with no medication precipitants identified. However, the individual also had a background diagnosis of Fanconi syndrome that was thought to be contributory.
The referring teams for individuals at risk of QTc prolongation were provided with individual specific multidisciplinary written information on how to best minimise the risk of prolonged QTc and surveillance guidance.
Metabolic disease screening
Individuals were screened for metabolic syndrome during their cardio-oncology clinic. Metabolic syndrome was screened by recording height, weight, body mass index, triglyceride level, HbA1c and blood pressure. One individual met criteria for metabolic syndrome. The individual had completed treatment for T-cell ALL and was referred to clinic for LVD. The individual had a long history of morbid obesity and many multiple failed attempts to reduce weight. The individual was counselled on modifiable lifestyle factors and was referred to our institute’s obesity clinic for management. Although only one individual met criteria for metabolic syndrome, all individuals were counselled on the importance of modifiable lifestyle factors with respect to cardiovascular disease.
Interventions undertaken in cardio-oncology clinic
Of the 37 individuals referred to clinic during the year, 23 (62.1%) remain on ongoing surveillance in the cardio-oncology clinic (Figure 3). The interventions undertaken in clinic were many and varied. For the individuals remaining in surveillance in the cardio-oncology clinic (n=23) interventions and advice included addition of dexrazoxane (n=4, 17.4%), Holter monitoring (n=1, 4.3%), hypertension monitoring (n=6, 28.5%), cascade testing for familial valvular disease (n=2, 8.6%), QTc monitoring (n=6, 26%) and lifestyle advice (n=23, 100%).
For the individuals who were discharged from clinic (n= 14) the interventions and advice included QTc monitoring (n=1, 7.1%), hypertension monitoring (n=3, 21.4%), referral to weight management clinic (n=1, 7.1%), and further lifestyle advice on modifiable cardiovascular risk factors (n=14, 100%). Overall, 27 individuals (72.9%) seen within this multidisciplinary clinic had interventions or monitoring recommendations not previously made in their routine oncology care.
Referral indications grouped according to whether the individual met criteria for referral based on the current Australian and New Zealand Pediatric Cardio-oncology guidelines
Of the individuals referred to clinic, 31 met the cardio-oncology clinic referral criteria according to the current Australian and New Zealand Pediatric Cardio-Oncology guidelines(3) (Figure 4). An additional six individuals were referred for exhibiting symptoms or signs that potentially could indicate a cardiovascular toxicity but are not included in the current guidelines in isolation and included palpitations, tachycardia, prolonged QTc in the absence of being on a molecular targeted agent. Of these individuals, 3 (50%) continue to need ongoing review in the cardio-oncology clinic with interventions including hypertension monitoring (n=1), QTc monitoring (n=1) and Holter monitoring (n=1). Therefore of 37 referrals to the clinic, 3 were outside the referral guideline but benefited from review in the clinic for a proportion of 0.081 with a 95% confidence (interval of 0.017 to 0.22).