Non-Hodgkin’s lymphoma (NHL) is a lymphoid malignancy with a variety of biological and clinical behaviors, usually involving lymphatic and hematopoietic tissues but also other organs (Ganapathi, Brown, Prakash, & Bhargava, 2021). Most patients usually have persistent painless lymphadenopathy, but some patients also develop systemic symptoms such as night sweats, persistent fever, and unexplained weight loss (Bowzyk Al-Naeeb, Ajithkumar, Behan, & Hodson, 2018). NHL is the most common hematological malignancy worldwide, accounting for nearly 3% of all cancer diagnoses, and its average age of diagnosis is 67 years (Thandra et al., 2021). Patients with NHL are generally elderly, and they often have cardiovascular risk factors or a history of heart disease, making them more susceptible to cardiotoxicity caused by chemotherapeutic drugs (Abuamsha, Kadri, & Hernandez, 2019). In addition to being a reason for treatment discontinuation, severe cardiotoxicity may be a reason for serious or even life-threatening events.

The (R)-CHOP (rituximab, cyclophosphamide, vincristine, doxorubicin, and prednisone) regimen, an anthracycline-based regimen, is often the first-line treatment for NHL, particularly for diffuse large B-cell lymphoma (Sehn & Salles, 2021). Cardiotoxicity is a particular complication of anthracyclines. The cumulative dose of anthracyclines has been reported consistently as an important factor causing cardiotoxicity. Swain SM et al. found that if the dosage of anthracyclines was greater than 550 mg/m², it would cause relevant cardiomyopathy in 26% of patients (Swain, Whaley, & Ewer, 2003). At present, the main measure to prevent related cardiotoxicity is to reduce the cumulative dose to less than 450 mg/m², but this also limits efficacy and cannot prevent all cardiovascular adverse events (Jones et al., 2021). Due to the uncertainty of the predictors of cardiotoxicity, the optimal monitoring strategy has not been agreed upon. Therefore, the individual management of chemotherapy drugs is still challenging. Doxorubicin liposome is a nanoparticle-based anti-tumor drug approved by the FDA and has been widely used to treat a variety of tumors (Herrmann et al., 2022). However, their clinical application has been limited by their structural instability, drug leakage, short shelf life, and poor tissue targeting. Pegylated liposomal doxorubicin (PLD) is a new type of liposome, in which macromolecular polyethylene glycol (PEG) is coated with doxorubicin on the surface, which makes the release rate of doxorubicin from the heart much lower than that from other tissues, effectively reducing the cardiotoxicity of doxorubicin (O'Brien et al., 2004; Theodoulou & Hudis, 2004). PLD is increasingly used to treat elderly patients with NHL, providing a new strategy for elderly patients. Despite the good safety of PLD and the widespread use of (R)-CDOP in the population, it is unknown whether the use of multiple drugs increases the risk of cardiotoxicity compared with that of PLD alone.

To obtain better scientific evidence, we conducted a meta-analysis to assess the risk of cardiovascular adverse events associated with the (R)-CDOP regimen. Furthermore, we explored the cardiovascular adverse event risk and efficacy of the (R)-CDOP regimen compared with the (R)-CHOP regimen.

In total, 2,601 studies were retrieved (PubMed, n = 30; Embase, n = 599; Cochrane Library, n = 1,535; CNKI, n = 181; WanFang Database, n = 181; and VIP, n = 75). Through literature screening, 30 studies were evaluated for eligibility. The specific literature screening process is presented in Figure 1.

This study investigated the rate of cardiovascular adverse events with the (R)-CDOP regimen in patients with NHL. The study revealed that the (R)-CDOP combination carried a lower risk of cardiovascular adverse events than the (R)-CHOP regimen, indicating the cardiovascular safety of (R)-CDOP. In addition, the (R)-CDOP regimen might improve the prognosis compared with the (R)-CHOP regimen, providing more options for patients in the future.

Anthracyclines apply to the treatment of various types of cancers alone or in combination with other anti-tumor drugs. Mitochondrial dysfunction (Varricchi et al., 2018), disruption of calcium homeostasis (Tscheschner et al., 2019), and apoptosis-related protein production (Merten, Jiang, Feng, & Kang, 2006; Saleme et al., 2019) are important mechanisms of the cardiotoxic effects of anthracyclines. The cardiotoxicity caused by cumulative doses of these drugs is a major limiting factor in their application (Martins-Teixeira & Carvalho, 2020). A study showed that the incidence of left ventricular dysfunction was 10%, 16%, 32%, and 65% at the cumulative doses of doxorubicin of 250, 300, 400, and 550 mg/m², respectively (Bernstein, 2018). According to the guidelines of the American Society of Clinical Oncology (ASCO), the cumulative dose of doxorubicin ≥ 250 mg/m² is considered a high dose (Armenian et al., 2017). To mitigate this cardiotoxicity, novel anthracyclines are increasingly used in the treatment of cancer. Although the long-term cardiotoxicity of these drugs is unclear, studies revealed that anthracycline liposomes, particularly PLD, demonstrated cardiac safety for patients (X. R. Li, Cheng, Zhang, Wang, & Huang, 2022). Yamaguchi et al. revealed that doxorubicin liposomes were less cardiotoxic than conventional doxorubicin in a meta-analysis (Yamaguchi et al., 2015). L Ansari et al. also showed lower cardiotoxicity than traditional doxorubicin in women with metastatic breast cancer treated with pegylated liposomal doxorubicin alone (Ansari et al., 2017). The rate of cardiovascular adverse events in patients who received PLD-based combination therapy for NHL has not been studied adequately. The majority of people in this study were older than 60 years. The overall cardiovascular adverse event rate was 7.45%, indicating the safety of the (R)-CDOP regimen in the elderly population.

In the clinical use of chemotherapeutic agents, potentially lethal toxicity can lead to serious cardiovascular adverse events such as myocardial infarction, heart failure, cardiac arrest, and cardiogenic death. Therefore, we need to further investigate the severity of cardiovascular adverse events associated with (R)-CDOP (Caspani et al., 2021). Due to the differences in the incidence and severity of cardiotoxicity, a general tool is required to assess their severity, which includes the World Health Organization (WHO) and the Common Terminology Criteria for Adverse Events (CTCAE). Grade 3 and higher cardiovascular events often require immediate treatment (Atkinson et al., 2016). We classified cardiovascular events of grade 3 or higher, treatment discontinuation attributable to cardiovascular events, and death caused by cardiovascular events as serious cardiovascular adverse events. We found that the serious adverse cardiovascular event rate was 0.67%, including a heart failure rate of 0.55%, indicating that serious cardiovascular events are not likely to occur in clinical practice. Our study further found that the (R)-CDOP regimen had a 0.02% rate of treatment interruption attributable to left ventricular dysfunction or heart failure, and no deaths attributable to cardiovascular events occurred. This suggests that the (R)-CDOP regimen can significantly prolong patient survival by avoiding treatment interruption or death attributable to cardiotoxicity, thus providing greater benefit to patients.

The (R)-CDOP regimen is often used as an alternative to the (R)-CHOP regimen. However, the cardiac safety of the former regimen is unclear in the overall NHL treatment population. Further studies are still needed to determine whether the multidrug combinations increase cardiotoxicity. This study revealed that (R)-CDOP carried lower risks of total (OR = 0.161) and non-serious cardiovascular adverse events (OR = 0.171) than the (R)-CHOP group, implying a reduced risk of non-fatal cardiotoxicities, such as ECG abnormalities that do not require treatment, asymptomatic cardiac insufficiency, and minor abnormal cardiac laboratory results, for (R)-CDOP. Serious cardiovascular adverse events such as refractory heart failure or other difficult-to-control cardiac symptoms place a large burden on families and the entire healthcare system, which requires us to further explore the severity of cardiovascular adverse events. This study recorded lower risks of serious cardiovascular adverse events (OR = 0.252) and heart failure (OR = 0.294) for (R)-CDOP, providing evidence of its cardiovascular safety in the treatment of NHL. In addition, the meta-analysis of the efficacy suggested that R-CDOP might provide another option for patients with NHL.

To mitigate the occurrence of serious cardiovascular adverse events, cardioprotective agents have been used in combination with anthracyclines. Dexrazoxane is the only drug approved by the FDA for the prevention of cardiotoxicity (Yu et al., 2020). Some clinical trials are currently investigating cardioprotective agents for anthracycline-induced cardiotoxicities, such as beta-blockers and angiotensin-converting enzyme inhibitors. Caspani et al. noted that RAAS blockers, beta-blockers, and aldosterone antagonists provided a statistically significant benefit in the prevention of reduced left ventricular ejection fraction, but this positive effect remains to be confirmed (Caspani et al., 2021). The OVERCOME trial showed that patients with hematological tumors who took enalapril or carvedilol had a lower frequency of heart failure, LVEF <45%, or sudden cardiac death compared with the placebo group (Bosch et al., 2013). Therefore, the use of combination chemotherapy and prevention of chemotherapy-related cardiotoxicity will require a concerted effort by cardiologists and hematologists.

This meta-analysis provided evidence for the cardiac safety of (R)-CDOP combination for NHL, but several limitations must be noted. First, the definition of cardiovascular adverse events was not uniform in some of the studies, which may have affected the incidence of the reported adverse events. Second, single-arm studies include some heterogeneity, which may have affected the accuracy of the results. Finally, some of the included studies had small sample sizes, and the studies did not provide detailed classifications of cardiovascular adverse events.

The (R)-CDOP regimen had a lower cardiovascular risk and was no less efficacious than (R)-CHOP in the treatment of NHL. This analysis suggested that (R)-CDOP therapy is useful in clinical practice and clinical reference. Due to the limitations regarding the number and quality of the included studies, these findings must be validated by additional high-quality studies.