Correlation of Equilibrium Radionuclide Ventriculography Scan with Two-Dimensional Transthoracic Echocardiography for Early Evaluation of the Left Ventricular Ejection Fraction after Anthracycline Treatment in Patients with Acute Lymphoid Leukemia

1. Introduction

Acute lymphoblastic leukemia (ALL)/lymphoma represents a family of genetically heterogeneous lymphoid neoplasms derived from B and T lymphoid progenitors, with more than 64 000 cases diagnosed yearly, worldwide (1). Current intensive chemotherapy regimens have achieved overall cure rates of 85% to 90% in children and 40% to 50% in adults, depending on the disease’s genetic subtype and the clinical characteristics at the presentation time (2).

Anthracyclines are prescribed in combination with other drugs to treat ALL. Their use is often limited by associated cardiotoxicity, leading to cardiomyopathy that may progress to heart failure. Cardiotoxicity can occur during or shortly after treatment or late after in long-term survivors. Anthracyclines have the potential to induce non-reversible cardiac damage in a dose-dependent manner.  The cumulative probability of doxorubicin-induced heart failure increases from 3%–5% for 400 mg/m2, up to 18%–48% for 700 mg/m2 (2-4).

Cardiac risk and preexistent cardiac disease assessment is recommended for all patients who are expected to receive chemotherapy. The evaluation includes physical examination, electrocardiogram, cardiac biomarkers (high-sensitive troponin and N-terminal pro-brain natriuretic peptide (NT-proBNP)), and echocardiography, depending on the type of therapy. Further tests are made during treatment and follow-up and adapted to risk factors, clinical signs, and symptoms. Diagnosing cardiac impairment as soon as possible allows the change of the treatment strategy and decreases the risk of heart failure. Left ventricular ejection fraction (LVEF) is the most commonly used parameter to evaluate cardiac dysfunction (3,4). LVEF has to be at least 50% at baseline. Left-ventricular dysfunction was defined by an LVEF decrease of at least 5% to less than 55% with symptoms or an LVEF decline of at least 10% to less than 55% without symptoms. LVEF decrease to less than 50% requires holding anthracycline therapy and reevaluation after 3 weeks, while an LVEF decline to less than 40% requires cessation (3).

A systematic review and meta-analysis of the natural progression of left ventricular function following anthracyclines without cardioprotective therapy concluded that LVEF showed a progressive decline until approximately 6 months, after which there was no significant change. The overall pooled risk of a decline to an LVEF below 50%, or a 10% absolute decline in LVEF from baseline, was 17% (5).

However, cardiac evaluation modalities have different advantages and drawbacks.

Due to low cost and wide availability, two-dimensional transthoracic echocardiography (2D-TTE) is commonly used for serial LVEF assessment in patients with solid or non-solid cancers. However, it has high intra- and interobserver variability, depends on the patient’s anatomical characteristics, and does not have enough accuracy to detect small changes that can be significant for subclinical cardiac toxicity. Contrast-enhanced or 3D-TTE have been shown to have better sensitivity, but their use is still limited. Using other parameters, such as global longitudinal strain combined with cardiac troponins, might overcome some of the current limitations (6-8).

Cardiac magnetic resonance (CMR) imaging is highly accurate and reproducible in evaluating cardiac toxicity and detecting signs of edema and inflammation before left ventricular dysfunction. However, its use is limited by high costs and low availability. Additionally, there are patients who, for various reasons, could not undergo magnetic resonance investigations (6).

The equilibrium radionuclide ventriculography (ERNV), also called Multiple Gated Acquisition scan (MUGA), represents an alternative method to evaluate LVEF. It can be performed serially to assess specific cardiac parameters at rest and/or under stressful stimuli. It can accurately determine ventricular volume and altered synchrony without requiring geometric calculations. ERNV has high intra- and inter-observer repeatability and reproducibility, being useful in patients with a need for precise LVEF quantification (6,9).

Due to the inter-technique variability of LVEF measurements, using the same technique for serial LVEF evaluation is preferred (10,11). Nevertheless, this can be challenging in some situations. This study aimed to compare the LVEF determined in parallel by 2D-TTE and ERNV in patients diagnosed with ALL) who received chemotherapy. We hypothesized that 2D-TTE performed by an experienced professional could produce measurements with similar accuracy to ERNV.

2. Materials and Method

2.1. Patient population

We included patients older than 14 diagnosed with ALL / lymphoma and treated in the Imam Khomeini Hospital hematology department in Tehran between January 2022 and May 2024. Patients with a history of cardiovascular diseases, risk factors for cardiovascular disease, or previous anticancer treatment were not eligible for inclusion.

The diagnosis of ALL was based on the evaluation of bone marrow and blood samples, flow cytometry, and morphology. Patients or their tutors signed informed consent for investigations and treatment. Chemotherapy was performed according to international protocols (prednisolone, vincristine daunorubicin, and cyclophosphamide – HYPER CVAD regimen).

2.2. Evaluation of LVEF

The 2D-TTE was performed by a single experienced cardiologist who evaluated LVEF and pulmonary artery pressure (PAP) before chemotherapy and three months after receiving the first dose of daunorubicin, which represented a cumulative dose of 100 mg/m2 (two cycles).

Regardless of the 2D-TTE results, ERNV was used to evaluate all patients’ LVEF, PFR, and TTPFR index.

ERVN was done after injection of labeled autologous red blood cells (RBC) in the best septal planar view using a dual head gamma camera with cardiac cycle gating (Philips, Forte, ADAC). For labeling the RBC, two ml of patient blood was collected into a vial containing 1 ml ACD and injected into the Sn vial of an ultra-fast RBC labeling kit (Pars-isotope Company, Karaj, Iran). Extra Sn out of RBCs was absorbed employing a buffer containing Na hypochlorite. The Technetium-99m pertechnetate was added into the reaction vial and incubated according to the manufacturer’s instructions. The labeled RBC was re-injected to the patient. The images were reconstructed using the Eurocostum menu software embedded in the camera processing units. LVEF, peak filling rate (PFR), and time to peak filling rate (TTPFR) were collected for the analyses.

The 2D-TTE results were compared with the ERNV scans. In case of differences of ≥ 10% in LVEF values and LVEF<50% in either method, CMR was performed.

2.3. Data Analysis

A paired T-test was used to assess the LVEF, PFR, TTPF, and PAP changes derived from ERNV and 2D-TTE before and after treatment and compare the LVEF between the ERNV and 2D-TTE. The correlation of the LVEF measured by ERNV and 2D-TTE was assessed by calculating the correlation coefficient. The Bland-Altman graph was drawn to assess the agreement of LVEF using two methods. The concordance of the LVEF by cardiac MRI with the other two methods is discussed case by case when performed. SPSS V22 was used for data analysis. P values smaller than 5% were considered significant.

3. Results

Forty-four patients (95.5%) diagnosed with ALL and 2 (4.5%) with T-cell lymphoblastic lymphoma were included in our study. Twenty-four (54.5%) patients were males and 20 (45.4%) were females. Most patients (56.8%) were between 20 and 40 years old. The median age 33, ranging from 15 to 61. The patients had no personal history or risk factors of cardiovascular disease, or history of anticancer treatment. Of 44 patients, only 11 (25%) could be evaluated after two cycles. The reasons for not performing the second evaluations were events which occurred before or during the second cycle of chemotherapy: death (n=16; 36.3%), schedule for transplant (n=4; 9.1%), change of treatment due to lack of response (n=7; 15.9%), change of the treatment center (n=6; 13.6%). A total of 13 patients received transplant (Table 1).

Table 1. Patients’ demographic data (N=44)

*Four patients received transplant before the 2^nd cycle; N= total number of patients

After two cycles of chemotherapy, a slight decrease of LVEF was observed on 2D-TTE (55.2±5.3 to 54.3±4.6; p=0.89) and ERNV (56.5±9.8 to 54.9±8.1; p=0.68). The PAP significantly decreased on 2D-TTE (24.3±5.5 vs 22.2±5.2; p=0.02). The TTPF measured by ERNV increased from 138.3±39.8 to 170±52.9 milliseconds (p=0.004). The PFR decreased but was not statistically significant (2.7±0.8 to 2.4±0.5; p=0.31) (Table 2).

Table 2. Cardiac dysfunction parameters before and after chemotherapy on ERNV and echocardiography

ERNV – equilibrium radionuclide radiotherapy; LVEF – left ventricular ejection fraction; PAP – pulmonary artery pressure; Sig – significance; †before and after; ‡ Between LVEF ERNV and Echocardiography

Baseline LVEF volumes were correlated on 2D-TTE and ERNV (r=0.5; P=0.001). However, after therapy, although the reported LVEF values were similar (54.9±8.1 vs. 54.3±4.6; P=0.552), there was no linear correlation between these measures (r= 0.3; p=0.409) (Figure 1).

Figure 1. The correlation between the values of LVEF measured by ERNV and by echocardiography, respectively, before chemotherapy (above, N=44) and after 2 chemotherapy cycles (below, N=11).

The difference between the LVEF values determined by the two methods before and after treatment were 1.21 (p= 0.353) and 1.5 (p=0.552), respectively. These differences were insignificant on the one sample T-tests, and most of the different values were within the 1.96 standard deviation limit (Figure 2).

Figure 2. The difference between the LVEF values measured by ERNV and echocardiography before chemotherapy (above) and after 2 chemotherapy cycles (below)

In our study, four patients had discordant LVEF values between 2D-TTE and ERNV evaluation. Three of the patients were found before beginning chemotherapy. The 2D-TTE results were close to CMR in their case. One patient had discordant LVEF values after the second dose of daunorubicin. In this case, the ERNV scan result was closer to CMR.

4. Discussion

This unicentric study prospectively evaluated cardiac dysfunction by transthoracic 2D-TTE and ERNV in 44 ALL patients before treatment. Of those, 11 patients had a second assessment after two cycles of anthracycline-based chemotherapy. The reason for the low number of reevaluated patients was non-cardiac mortality, referral for bone marrow transplantation, or discontinuation of treatment.

Most of the patients in our group were young adults, which is in line with the epidemiology of ALL. Eight patients were below 20, the minimal age being 15. The young age was recognized as a risk factor for developing cardiac toxicity. This group’s curability rate is also high, which justifies additional cautions and vigilance to accurately diagnose subclinical cardiac dysfunction and decrease the risk of long-term side effects. A retrospective analysis of 171 patients with acute myeloid leukemia found that daunorubicin doses of ≥ 500 mg/m2 were associated with cardiotoxicity (12). Nevertheless, another study, this time on pediatric patients, concluded that a cumulative dose of ≥120 mg/m2 daunorubicin was a significant risk factor for early cardiomyopathy in childhood ALL (13). In our study, we reassessed the cardiac function after 100 mg/m2 daunorubicin.

The LVEF values were not significantly different between the ERNV and 2D-TTE methods. There was a linear correlation between the results of ERNV and 2D-TTE before therapy. After therapy, the LVEF measures of ERNV and 2D-TTE were not significantly different, but a linear correlation was not observed, which was more likely due to the low sample size. Furthermore, in most patients, the LVEF measured by 2D-TTE showed agreement with those produced using ERNV before and after therapy.

A similar study included pediatric patients with leukemia or solid tumors and compared LVEF determined by 2D-TTE and ERNV before the first chemotherapy course and in the first 3 months of completing chemotherapy. The mean cumulative anthracycline doses were equivalent to 276 +/- 83 mg/m2 doxorubicin. 2D-TTE detected systolic dysfunction in 14% and ERNV in 38%. Additionally, ERNV revealed diastolic dysfunction in 29% of the cases, which was not detected by 2D-TTG (14). Our study focused on evaluating systolic dysfunction but the threshold for diagnosing it was not met. The different results could be explained by differences in the study group (children with a median age of 7 vs. young adults with a median age of 33) or by technology differences (the pediatric study gathered data from 2003 to 2005 and our study from 2022 to 2024).

A comparative study on adult lymphoma patients who received 400-500 mg/m2 of doxorubicin compared the LVEF measured by 2D-TTE, M-mode echography, and ERNV. The correlation coefficient between M-Mode echography and ERNV was 0.615 (P=0.002), and between 2D-TTE and ERNV was only r=0.364 (P=0.096) (15). In another study, the correlation coefficient of left ventricular end-diastolic volume evaluated by 2D-TTE and CMR in breast cancer patients was 0.64 at baseline and 0.69 at 12 months, respectively. 3D-TTE and ERNV were better correlated with CMR in this group of patients (r = 0.91 at baseline; r = 0.90 at 12 months, respectively) (16).  In our study, the correlation coefficient between LVEF determined by 2D-TTE and ERNV was 0.5.

The differences in LVEF and other cardiac toxicity parameters evaluated in our study did not show values that could be interpreted as cardiac dysfunction—neither before nor after therapy. This result can be partially explained by the absence of previous cardiac disease and risk factors for it. Additionally, the cumulative daunorubicin was low, the interval of 3 months could be too short for toxic effects to become visible, and only 11 patients could be reevaluated after therapy.

However, we identified significantly increased TTPFR values after therapy using ERNV, compatible with an early-stage diastolic dysfunction. In a cohort of breast cancer patients receiving anthracyclines and trastuzumab evaluated by ERNV, the diastolic dysfunction preceded systolic dysfunction by 73 days, on average (17).

In this study, 4 out of 44 patients had a difference above 10% in LVEF results (2D-TTE vs. ERNV), so a CMR was performed. Three discordant results were obtained at baseline and one after receiving medication. Of 4 patients, three 2D-TTE LVEF results were confirmed by CMR, and one ERNV LVEF result was closer to CMR.

It is worth mentioning that direct comparisons between different studies cannot be made without a risk of bias. A recently published study showed that ERNV software packages provided significantly different results. When reprocessing 582 scans using two different software, the median LVEF was 56% and 66%, respectively. One classified 11.4% as having cancer therapy-related cardiac dysfunction, while the other identified 26.4% using the same scans (18).

ERNV scan does not involve receiving a high dose of irradiation. However, alternative methods for LVEF calculations have been tested. An interesting one is the contrast-enhanced helical low-dose CT, which was compared to ERNV, having CMR as a reference. This method had 100% sensitivity and 95% specificity for classifying reduced LVEF at a quarter of the irradiation dose, compared to ERNV. Another advantage was that it was possible to combine with chest-abdomen-pelvis CT (19).

Using blood tests such as NTproBNP and troponin increases 2D-TTE’s accuracy in detecting cardiac dysfunction. However, using these biomarkers only to estimate LVEF cannot replace ERNV examinations for anthracycline-induced cardiotoxicity. For a cutoff of 100 pg/ml for BNP, 68% of the patients with an LVEF below 50% would not have been identified (20).

Diagnostic or treatment alternatives’ clinical and economic impact should not be overseen. A retrospective analysis of 227 cancer patients in whom ERNV was used to measure left-ventricular ejection fraction before and during doxorubicin chemotherapy estimated its incremental survival benefit and cost-effectiveness. The use of ERNV for pretreatment screening appears to be more cost-effective for patients older than 40 who received a cumulative doxorubicin dose of a maximum of 350 mg m−2(21).

Our study has several limitations. Firstly, the relatively low number of patients included and the reduced proportion of those who could be reevaluated. Secondly, the 2D-TTE measurements were made by a single evaluator. Especially for an examination prone to subjectivity, it can be a source of bias. Thirdly, the daunorubicin dose or the interval could have been too low or too short, respectively, to allow the development of cardiac dysfunction. The results could not be safely extrapolated to a group of patients with different characteristics (for example, with preexistent cardiovascular disease), receiving a different dose of daunorubicin, or for measurements made at another time point. Nevertheless, our results showed a better correlation between 2D-TTE and ERNV than previously reported, supporting the increased role of 2D-TTE in evaluating cardiac dysfunction. They are also documenting the low risk of developing cardiotoxicity in the short term after 100 mg/m² daunorubicin in teenagers and young healthy adults.

5. Conclusion

In young adults without preexistent cardiac disease diagnosed with ALL who received a cumulative dose of 100 mg/m2 of daunorubicin, pretreatment LVEF values measured by 2D-TTE and ERNV were correlated and were not suggestive for systolic dysfunction. Other cardiac function parameters were similar on 2D-TTE and ERNV before and after treatment. PAP significantly decreased, and TTPFR increased after chemotherapy.

Abbreviations

2D-TTE – two-dimensional transthoracic echocardiography

ALL – acute lymphoid leukemia

CMR – cardiac magnetic resonance

ERNV – equilibrium radionuclide ventriculography

HYPER CVAD – prednisolone, vincristine daunorubicin, and cyclophosphamide

LVEF – left ventricular ejection fraction

MUGA – Multiple Gated Acquisition scan

NT-proBNP – N-terminal pro-brain natriuretic peptide

PAP – pulmonary artery pressure

PFR – peak filling rate

TTPFR – time to peak filling rate

Statements

Authors’ contribution: MS and HRA conceived and planned the analysis. MN coordinated the research project, collected patient information, and gathered data during the study. MA and MRE contributed to the interpretation of the results. AMK took the lead in writing the manuscript. All authors contributed significantly by providing valuable insights and shaping the research, analysis, and manuscript.

Consent for publication: As the corresponding author, I confirm that the manuscript has been read and approved for submission by all named authors.

Conflict of interests: The authors declare no conflict of interest

Funding Sources: None

Statement of Ethics: The study was approved by the Ethics Committee of the Teheran University of Medical Sciences (approval ID – IR.TUMS.IKHC.REC.1400.494)

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