Natl. J. Physiol. Pharm. Pharmacol. (2025), Vol. 15(1): 80–85

Research Article

10.5455/NJPPP.2025.v15.i1.14

Cardiotoxic profile of CHOP/R-CHOP regimen in patients with non-Hodgkin Lymphoma

Aswathi Thettummal^1*, Annapurna Yadavalli² and Abdul Majeed Kuruvadangal³

¹Department of Pharmacology, MES Medical College, Perinthalmanna, India

²Department of Pharmacology, Government Medical College, Thiruvananthapuram, India

³Department of General Medicine, I/C of Medical Oncology and Haematology, Government Medical College, Kozhikode, India

*Corresponding Author: Aswathi Thettummal. Department of Pharmacology, MES Medical College, Perinthalmanna, India. Email: pallavi [at] mitmimer.com

Submitted: 05/08/2024 Accepted: 27/12/2024 Published: 31/01/2025

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ABSTRACT

Introduction: Non-Hodgkin lymphoma is the most common hematological malignant tumor, and its prevalence is increasing worldwide. It usually presents with enlarged lymph node along with other symptoms such as weight loss, night sweats, and fever collectively known as B symptoms. Medical history, physical examination, biopsy, computed tomography, magnetic resonance imaging, and positron emission tomography scan all form the basis of diagnosis.

Chemotherapy, radiotherapy, immunotherapy, surgery, and stem cell transplantation are the various treatment options available for non-Hodgkin lymphoma. Among the different chemotherapeutic regimens available, the CHOP or R-CHOP regimen is the gold-standard first-line therapy for non-Hodgkin Lymphoma. It includes cyclophosphamide, doxorubicin, vincristine, and prednisolone for the CHOP regimen and rituximab in addition to the R-CHOP regimen. Cardiotoxicity caused predominantly by doxorubicin and cyclophosphamide is the major adverse effect of this regimen, which can manifest as heart failure. Early identification of cardiotoxicity can improve patient outcomes.

Aim: This study aimed to determine the cardiotoxic profile of the CHOP/R-CHOP regimen in patients with non-Hodgkin Lymphoma (NHL) in a tertiary care center in northern Kerala and to study the risk factors associated with the development of cardiotoxicity.

Methods: This prospective observational study was conducted in patients attending the Department of Medical Oncology and Hematology, in collaboration with the Departments of Pharmacology and Cardiology, Government Medical College, Kozhikode, with a diagnosis of non-Hodgkin Lymphoma who received CHOP/R-CHOP chemotherapy regimen for the same. A total of 55 patients were enrolled in the study according to the inclusion criteria and after obtaining informed consent. All the patients needed 6 cycles of chemotherapy, which was given 3 weekly. Follow-up evaluation is performed with history, physical examination, blood investigation [random blood sugar and renal function test], electrocardiography, and echocardiography after completing the third and sixth cycles of chemotherapy. Reduction in ejection fraction 10% from baseline along with other symptoms and signs of heart failure and ECG changes were evaluated during follow-up.

Results: The analysis was performed after completing the third and sixth cycles with a total of 55 participants. Only one patient (1.82%) experienced a reduction in ejection fraction ≥10% from baseline without any signs, symptoms, or ECG changes. Thus, it was subclinical cardiotoxicity. Various risk factors for the development of cardiotoxicity with the CHOP/R-CHOP regimen were also analyzed using Fisher’s exact test. None of the risk factors had a statistical association with cardiotoxicity (p-value > 0.05).

Conclusion: The cardiotoxicity of the CHOP/R-CHOP regimen in patients with NHL was low, and there were no proven associations with risk factors and cardiotoxicity.

Keywords: Non-Hodgkin lymphoma, CHOP/R-CHOP, Doxorubicin, Cardiotoxicity, Ejection fraction.

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Introduction

Lymphomas are solid tumors of the immune system, of which 90% are non-Hodgkin Lymphoma (NHL) and the remaining 10% are Hodgkin’s lymphoma (Shankland et al., 2012; Armitage et al., 2017). NHL is the most common hematological malignancy worldwide (Limat et al., 2014). Multiple painless lymph node enlargement that may spread to noncontiguous nodes is the most common presentation in patients (Singh et al., 2020). The treatment options for NHL include chemotherapy, radiation therapy, immunotherapy, and targeted therapy. The histological type and stage of NHL, possible adverse effects of various treatment options, patient’s preferences, and overall health of the patient are the factors that determine the treatment option (Lymphoma - Non-Hodgkin Types of Treatment 2012).

Different chemotherapy regimens available for NHL include CHOP, R-CHOP, R-maxi CHOP, R-COMP, CHOEP, hyper-CVAD, and R-CVP, among which the CHOP/R-CHOP regimen is the gold standard first-line therapy (Limat et al., 2014, 2012; Limat et al., 2003). In patients with B-cell lymphoma, the addition of an anti-CD20 monoclonal antibody, such as rituximab against CHOP (R-CHOP regimen), works better (2012).

In the CHOP regimen, the drugs are given as follows: cyclophosphamide 750 mg/m², doxorubicin 50 mg/m², and vincristine 1.4 mg/m² (up to a maximum of 2 mg) intravenously on day 1 and prednisolone 100 mg given orally for days 1–5 (Epelbaum et al., 1995). In the R-CHOP regimen, intravenous rituximab at a dose of 375 mg/m² is added on day 1 (Cunningham et al., 2013). The cycle is repeated 3 times weekly for a total of 6–10 cycles (Khattry et al., 2009).

Common adverse effects of these regimens include myelosuppression (leukopenia, thrombocytopenia, and anemia), nausea, vomiting, diarrhea, stomatitis, mucositis, alopecia, fatigue, neurological manifestations, and local allergic reactions at the site of injection (Brunton and Knollmann 2023).

Cardiotoxicity, mainly caused by doxorubicin, is the long-term adverse effect of these regimens. Cardiotoxicity can be acute or chronic (Limat et al., 2014; Brunton and Knollmann 2023). Acute cardiac complications include ECG changes, arrhythmia, increased plasma troponin levels, acute reversible reduction in ejection fraction, and acute myocardial damage (Brunton and Knollmann 2023; Bansal et al., 2017). Chronic cardiac complications are cumulative and dose-related. It is in the form of cardiomyopathy, which usually manifests as congestive heart failure, where there is a reduction in left ventricular ejection fraction (Brunton and Knollmann 2023; Ganz et al., 1996). Cardiotoxicity can be clinical or subclinical. Subclinical cardiac dysfunction is defined as a ≥10% reduction in ejection fraction from baseline on follow-up echocardiography.^[10] In clinical cardiotoxicity, signs and symptoms of heart failure, including dyspnea, orthopnea, paroxysmal nocturnal dyspnea, chest pain, pedal edema, basal crepitation, and S3 gallop, will also appear (Chatterjee et al., 2010; Swain et al., 2003). Cyclophosphamide can also cause cardiotoxicity in the form of hemorrhagic myocardial necrosis (Dhesi et al., 2013).

Patients may experience cardiac events at a cumulative doxorubicin dose of 150 mg/m², the incidence increases as the cumulative dose increases, and clinically significant congestive heart failure (CHF) can develop at a cumulative dose of ≥400 mg/m² (Swain et al., 2003). The maximum tolerated dose (cumulative) of cyclophosphamide is 7,000 mg/m², above which it can also cause cardiotoxicity (Brunton and Knollmann 2023; Bansal et al., 2017).

History and clinical examination to diagnose cardiotoxicity lack specificity and can miss 50% of early and reversible cardiac dysfunction. Noninvasive echocardiography and electrocardiography along with history and clinical examination form the basic tools for evaluation of cardiac toxicity (Ganz et al., 1996; Singal and Iliskovic 1998). According to the American College of Cardiology, normal left ventricular ejection fraction can vary between 50% and 70% (midpoint 60%) (Kosaraju et al., 2023).

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Methods and Materials

This study was conducted in the Department of Medical Oncology and Hematology in collaboration with the Departments of Cardiology and Pharmacology, Government Medical College, Kozhikode, over a period of 18 months from 6th December 2019 to 5th June 2021. The study was initiated after obtaining the Institutional Research and Ethics Committee approval (Ref. No. GMCKKD/RP 2019/IE/ 271). A total of 55 newly diagnosed cases of non-Hodgkin Lymphoma who fulfilled the inclusion criteria with normal electrocardiography and baseline ejection fraction ≥55% on echocardiography were enrolled in the study. Patients with a previous history of treatment with cardiotoxic drugs, a previous history of irradiation over the mediastinum, a history of cardiovascular events such as stroke and acute coronary syndrome, patients with evidence of presence of cardiovascular disease, symptomatic ischemic heart disease , heart failure, arrhythmia, and patients with a family history of cardiomyopathy or any other malignancy were excluded.

A detailed history was obtained, and clinical examination and blood investigations required [random blood sugar (RBS) and renal function test (RFT)] were done. All patients enrolled in this study received 6 cycles of chemotherapy with the CHOP/R-CHOP regimen. Follow-up was performed after completing the third cycle and after completing the sixth cycle. During each follow-up visit, patients were assessed by clinical history, physical examination, laboratory investigation, electrocardiography, and echocardiography.

Cardiotoxicity was assessed by the presence of signs and symptoms such as dyspnea on exertion, orthopnea, paroxysmal nocturnal dyspnea, chest pain, pedal edema, basal crepitation, and S₃ gallop; ECG findings include ST segment changes, flattening of T wave, prolongation of QT interval and arrhythmia, and reduction in ejection fraction in echocardiography. Echocardiography findings of a decline in resting left ventricular ejection fraction (LVEF) to <50% or a decline in LVEF of ≥10% from baseline were considered significant. Cardiotoxicity was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0.

Statistical analysis was performed using the Statistical Package for Social Sciences (SPSS) software. Patients who had completed 6 cycles of chemotherapy were included in the statistical analysis. The incidence of cardiotoxicity was expressed as percentage. Fisher’s exact test was used to determine the association of cardiotoxicity with gender, age, obesity, diabetes, hypertension, smoking, and renal dysfunction. p-value < 0.05 was considered statistically significant.

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Results

Fifty-five patients who satisfied the inclusion criteria were included in the study. The characteristics are summarized in Table 1.

There were no significant changes in ECG after the third cycle and after the sixth cycle. Blood investigations (RBS and RFT) were also within a normal range after completing the third and sixth cycles.

All patients in this study undergone 6 cycles of chemotherapy, with doxorubicin administered at a dose of 50 mg/m². At the end of third cycle, they received a cumulative dose of doxorubicin of 150 mg/m², and after completing all 6 cycles, they received a cumulative dose of doxorubicin of 300 mg/m². Cyclophosphamide was given at a dose of 750 mg/m². The maximum tolerated cumulative dose of cyclophosphamide is 7,000 mg/m², and all patients received a cumulative dose of cyclophosphamide below this level.

Table 1. Patient characteristics.

Table 2. Prevalence of risk factors and statistical significance.

In this study, none of the patients experienced cardiotoxicity after completing three cycles of chemotherapy. After completing all six cycles with a cumulative dose of doxorubicin of 300 mg/m², one patient (1.82%) experienced subclinical cardiotoxicity. No interventions were performed for this patient.

Statistical analysis was performed using the SPSS software. Fisher’s exact test was used to determine the association of cardiotoxicity with gender, age, obesity, diabetes, hypertension, smoking, and renal dysfunction. None of the risk factors had a statistically significant association with the development of cardiotoxicity (p-value > 0.05).

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Discussion

Non-Hodgkin Lymphoma is a common malignant tumor worldwide with a wide range of histological appearances and clinical features (Shankland et al., 2012; Limat et al., 2014). Symptomatic enlargement of lymph nodes with or without B symptoms (temperature >38°C, night sweats, and weight loss of >10% of body weight in the 6 months preceding admission) is the most common complaint (Zinzani 2005). Laboratory investigations and diagnostic imaging techniques form the basis of diagnosis (Yakubu et al., 2015). Chemotherapy, radiotherapy, immunotherapy, stem cell transplantation, and surgery are the various treatment options available (Zinzani 2005).

Chemotherapy is the most commonly preferred treatment option, and CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone) or R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone) regimens are mostly used (Zinzani 2005; Cai et al., 2017). Doxorubicin and cyclophosphamide have the potential to cause cardiotoxicity, but the incidence is more with former (Limat et al., 2014; Khattry et al., 2009; Swain et al., 2003). This can be manifested as acute cardiotoxicity, which is rare, or chronic cardiotoxicity, which is cumulative and dose-related. Chronic cardiotoxicity may manifest as CHF caused by a reduction in ejection fraction. Chronic cardiotoxicity can be clinical or subclinical (Florescu et al., 2013). Subclinical cardiac dysfunction is defined as a fall in ejection fraction >10% on follow-up echocardiography (Khattry et al., 2009) without signs and symptoms.

According to Thandra et al. (2021) NHL is more frequent in males (39%) and in those aged >65 years (57%).(Thandra et al., 2021) Nair et al. (2016) reported that the incidence of NHL was higher in males with a male:female ratio of 2, and the median age of presentation is 54 years (Nair et al., 2016). In this study, 60% of the participants were male, and 9.09% were 65 years of age or older.

Hershman et al. (2008) stated that age 65 or older is a risk factor for doxorubicin-based chemotherapy-induced cardiotoxicity (Hershman et al., 2008). Lipshultz et al. (1995) found that female sex is a risk factor for cardiotoxicity caused by doxorubicin-based chemotherapy (p < 0.001) (Lipshultz et al., 1995). This study not finds a statistically significant association between age 65 or more and cardiotoxicity (p-value: 0.909) and female sex and cardiotoxicity (p-value: 0.600).

Qiu et al. (2021) found that obesity is a risk factor for anthracycline-induced cardiotoxicity (OR: 1.72; 95% CI: 1.13–2.61; p=0.010; I²=73%) (Qiu et al., 2021); Kabore et al. (2019) found that obesity is associated with anthracycline-based chemotherapy-induced cardiotoxicity (odds ratio [OR] 3.02; 95% CI 1.10–8.25; p=0.03) (Kaboré et al., 2019). In this study, statistical significance is not proven between obesity and cardiotoxicity (p-value: 0.836)

According to Qiu et al. (2021) diabetes and hypertension are also important risk factors for developing anthracycline-based chemotherapy-induced cardiotoxicity. Their finding is as follows: diabetes: OR: 1.74; 95% CI: 1.11–2.74; p < 0.001; and hypertension: OR: 1.99; 95% CI: 1.43–2.76; p < 0.001. (Qiu et al., 2021) According to Cardinale et al. (2015) 16% of current or past smokers developed cardiotoxicity. (Cardinale et al., 2015) There were no statistically significant associations between diabetes and cardiotoxicity (p-value: 0.818), hypertension and cardiotoxicity (p-value: 0.218), and smoking and cardiotoxicity (p-value: 0.909) in this study.

Van Nimwegmen et al. (2015) found that there is a 16.9% incidence of cardiotoxicity in patients who have received mediastinal radiotherapy. (van Nimwege et al., 2015) Szmit et al. (2014) reported that preexisting cardiac diseases were associated with the development of R-CHOP chemotherapy (OR, 5.4; 95% CI, 1.19–24.5; p=0.03). (Szmit et al., 2014) Prior/concurrent treatment with cardiotoxic drugs (traztuzumab, paclitaxel, and so on) is also an important risk factor for cardiotoxicity, and according to Russel et al. (2010) the incidence of symptomatic heart failure events is 2.0% in patients treated with adjuvant traztuzumab. (Russell et al., 2010) Russo et al. (2012) stated that renal dysfunction increases the risk of myocardial insult due to anthracycline-based chemotherapy. (Russo et al., 2012)

In this study, risk factors, such as radiation exposure, pre-existing cardiac disease, and previous cardiotoxic drug treatment, were not examined. Renal dysfunction was assessed using renal function tests, and none of the patients had deranged renal function.

In the CHOP/R-CHOP regimen, both cyclophosphamide and doxorubicin are administered. Concomitant use is also an important risk factor for cardiotoxicity. The maximum tolerated dose (cumulative) of cyclophosphamide is 7,000 mg/m², above which it can also cause cardiotoxicity; however, in this study, after completing six cycles of chemotherapy, the cumulative dose of cyclophosphamide did not exceed the said value. Therefore, it does not pose a significant risk to cardiotoxicity.

The patient may experience cardiac events at a cumulative doxorubicin dose of 150 mg/m². Incidence increases as cumulative dose increases, and clinically significant congestive heart failure can develop at a cumulative dose of ≥400 mg/m². For a cumulative dose of 450–550 mg/m², there is a steep increase in incidence. Therefore, the cumulative dose of doxorubicin limited to 550 mg/m² mostly.

Nousiainen et al. (2002). reported that 7% of patients developed clinical heart failure after a cumulative dose of doxorubicin of 500 mg/m² and declined in left ventricular ejection fraction more than 10% in 36% of patients. Khattry et al. (2009) conducted a study on 30 patients who were on doxorubicin-based chemotherapy and found that one patient (3%) developed congestive cardiac failure at a cumulative dose of doxorubicin of 450 mg/m², while 27% of patients developed subclinical cardiac dysfunction at a cumulative dose of 300 mg/m² (four patients) or 400–450 mg/m² (four patients).^[10] In a study conducted by Hequet et al. (2004) 0.71% of patients had CHF and 27.6% of the patients developed subclinical cardiotoxicity at a cumulative dose of doxorubicin of 300 mg/m². (Hequet et al., 2004)

This study found that one patient (1.82%) developed subclinical cardiotoxicity (percentage reduction in ejection fraction from baseline on follow-up echocardiography) without any signs or symptoms and normal ECG findings at a cumulative dose of doxorubicin of 300 mg/m². No clinical cardiotoxicity was observed in this study.

“Earlier the better” strategy is applied if cardiotoxicity occurs. In symptomatic patients with LVD, an ACE-I or ARB and a beta-blocker can be administered, and if symptoms persist, an MRA can be administered. Angiotensin receptor–neprilysin inhibitor (sacubitril/valsartan) should also be considered. Ivabradine can be administered to symptomatic patients with sinus rhythm and a heart rate above 70 beats/minute. In cases of congestion or risk, diuretics should be considered.

Timely monitoring of patients is necessary because the CHOP/R-CHOP regimen can cause cardiotoxicity, which may lead to significant mortality and morbidity.

Limitations of the study

This study included a smaller sample size. Patients were followed up for a short duration of 6 months. Long-term effects on cardiac profile are not known. These limitations of the study can be rectified by using a larger sample size and by following up with the patients for a slightly longer duration (can be up to 5 years as per literature).

Follow-up with serial Trop: I was not conducted in this study due to the financial burden on patients. The COVID-19 pandemic has affected the smooth conduct and follow-up of the study.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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