Cardiac Safety with High Cumulative Dose of Pegylated Liposomal Doxorubicin in Patients with Metastatic Breast Cancer Previously Treated with Conventional Anthracyclines

Introduction: The treatment of metastatic breast cancer (MBC) is still challenging. Many 
studies documented the efficacy of pegylated 
liposomal doxorubicin (PLD) in patients with MBC, but there is a limited data 
about the cardiac safety with high cumulative dose (HCD) of PLD. Aim of the 
work: We conducted this trial to outline the cardiac 
safety of HCD of PLD in patients with 
MBC who previously received conventional anthracyclines. Methods: During the period of nine years (January 2011 to 
December 2019). We extracted the data of the patients with MBC receiving 
PLD at Medical Oncology Department, South Egypt Cancer Institute, Assiut 
University. These included patients’ demographics and therapeutic data 
including the full data of PLD, prior conventional anthracyclines, prior 
trastuzumab, and prior radiotherapy. Also, data about comorbidities as well as 
cardiac and other toxicities of PLD were obtained. The data was analysed using 
SPSS v. 21. Results: For all 81 eligible patients, the mean age was 43.9 
years (±standard deviation (SD) 13.2). The mean cumulative dose of PLD was 
378.4 mg/m2 (± SD of 250.2) and a range of 100 - 1200 
mg/m2. About thirty-one (38.3%) patients received high cumulative dose (400 mg/m2 or more), 
while the remaining 50 patients did not. The decline in left 
ventricular ejection fraction (LVEF) was relatively rare; and of low grade. Grade 2 decline in LVEF occurred in only two patients who 
received high cumulative dose of PLD, and only one patient who did not reach 
HCD (p = 0.555). Grade 3 or 4 decline in LVEF did not occur in patients either with 
or without HCD. Regarding other toxicities, there was a significant increase in 
incidence of all grades palmar plantar erythrodysesthesia (PPE) in patients who received HCD of PLD when compared to those who did not reach the HCD (38.7% versus 16% respectively; p = 0.021). Conclusion: Our study concluded that the use of 
PLD seems to be a justified agent in the treatment of MBC who previously 
treated by conventional anthracyclines in the adjuvant, metastatic or both settings, 
even in patients reaching the cumulative dose of conventional anthracycline.


Introduction
Globally, breast cancer is the most common cancer diagnosed in women [1]. At initial presentation, about 17% have advanced stage [2]. The treatment of this advanced stage is still challenging [3]. The primary goal of that treatment is finding a tool with higher, or at least equal efficacy and lower toxicity [3].
There is no standard of care for management of the metastatic breast cancer (MBC). However, chemotherapy is a treatment option for many patients with MBC [4]. Anthracyclines and taxanes are the most effective cytotoxic agents in treatment of MBC [4]. The use of the anthracyclines is limited by their cumulative doses regarding the cardiac toxicity [5] [6] [7]. This problem is greatly resolved by invention of pegylated liposomal doxorubicin (PLD) by capsulation of doxorubicin with polyethylene glycol-coated liposome [8] [9]. By this modification, PLD has limited penetration into cardiac muscle, resulting in lesser cardiac toxicity when compared with conventional anthracyclines [8] [9].
Although many studies documented the efficacy of PLD in patients with MBC, there is a limited data about the cardiac safety with high cumulative dose (HCD) of PLD [6] [7] [8] [10] [11]. Kesterson et al. published a retrospective chart review showing that the cumulative doses of PLD ≥ 400 mg/m 2 are not associated with clinically evident cardiac toxicity in patients with gynecologic malignancies. However, they assessed the cardiac toxicity in patients without prior exposure to anthracyclines [12].
We conducted this trial to outline the cardiac safety of HCD of PLD in patients with MBC who previously received conventional anthracyclines.

Study Design
The data were extracted from the medical hospital records of patients with evidence of MBC during the period of nine years (January 2011 to December 2019) treated at Medical Oncology Department, South Egypt Cancer Institute, Assiut University. The inclusion criteria included the evidence of MBC, received PLD, age of 18 years old or more, no evidence of heart failure before treatment, frequent assessments by echocardiography were present. These data included the

Grades of the Decline in LVEF According to CTCAE 4.03 [13]
Grade 1: not applicable;

Grades of the Heart Failure According to CTCAE 4.03 [13]
Grade 1: Asymptomatic with cardiac imaging abnormalities; Grade 2: Symptoms with mild to moderate activity or exertion; Grade 3: Severe with symptoms at rest or with minimal activity or exertion; intervention indicated; Grade 4: Life-threatening consequences; urgent intervention indicated (e.g., continuous IV therapy or mechanical hemodynamic support); Grade 5: Death.

Treatment Plan and Assessment of Cardiac Function
PLD was given as 50 mg/m 2 as a 30-or 60-minute intravenous infusion on day 1, Advances in Breast Cancer Research repeated every 28 days. The medical history and clinical examination were taken every visit specially cardiac symptoms and signs suggesting cardiac failure and other toxicity. Baseline echocardiography was done, then every 3 -4 courses of PLD. Treatment was continued until maximum response, unacceptable toxicity, or patient refusal to continue.

Statistical Analysis
The primary endpoint was PLD-related cardiotoxicity though outlining the grades of the decline of LVEF and grades of heart failure. This assessment is based

Patients' Demographics and Disease Characteristics
On initial statistical assessment, we found that our sample was normally distributed (Shapiro-Wilk test is not significant, p = 0.076).    Table 2 shows that the decline in LVEF was relatively rare; and of low grade. Grade 2 decline in LVEF occurred in two patients who received HCD of PLD, and only one patient who did not reach HCD (p = 0.555). Grade 3 or 4 decline in LVEF did not occur in patients either with or without HCD. Also, there were no reported grade 3/4 congestive heart failure in both groups.

Dose-Related Other Toxicities of PLD
Regarding other non-hematological toxicities, there was a significant increase in incidence of all grades palmar plantar erythrodysesthesia (PPE) in patients received HCD of PLD when compared to those did not reach the HCD (38.7% versus 16% respectively; p = 0.021). Also, the grades 3/4 PPE significantly increased with HCD (16.1% for patients with HCD versus 2.0% for those without HCD; P = 0.028) ( Table 2). In addition to previous findings, patients who received HCD of PLD experienced higher incidences of grades 3/4 stomatitis (p = 0.039), all grades constipation (p = 0.049), all grades anorexia (p = 0.004), grades 3/4 anorexia (0.028), and all grades fatigue (p = 0.007) when compared to those Advances in Breast Cancer Research  who not reaching the HCD. From data about hematological toxicities, HCD was associated with a significant increase in the incidence of allgrades leukopenia (p = 0.026) and grades 3/4 neutropenia (p = 0.019) ( Table 2). Regarding the other toxicities, there was no statistical difference between patients who received HCD of PLD and those who did not (Table 2). There was no treatment-related death.

Discussion
This study on a group of MBC patients who were pretreated with an anthracycline to evaluates the toxicity of anthracycline rechallenge using PLD. All patients had received conventional anthracyclines. Therefore, most patients in this study were in an advanced and palliative course of their disease when they received PLD.
Our data suggest safety profile of PLD. Results from this study showed the decline in LVEF was relatively rare. Grade 2 decline in LVEF occurred in two patients who received HCD of PLD, and only one patient who did not reach HCD (p = 0.555). Grade 3 or 4 decline in LVEF did not occur in patients either with or Advances in Breast Cancer Research without HCD. Also, there were no reported grade 3/4 congestive heart failure in both groups.
Similar to our results, a Phase III study [15] was proposed in which 301 patients with metastatic breast cancer progressing on taxanes (<6 months) were randomized to receive one of the following three alternatives: PLD 50 mg/m 2 every 4 weeks; vinorelbine 30 mg/m 2 every week; or mitomycin-C 10 mg/m 2 , on days, on 1 and 28 plus vinblastine 5 mg/m 2 on days 1, 14, 28, and 42 every 6 -8 weeks. 83% of patients had received prior anthracyclines. No patient treated with PLD showed clinical symptoms of cardiotoxicity.
In another study [16], 129 patients with metastatic breast cancer treated with PLD were analyzed. Seventy percent of patients had 2 or more cardiovascular risk factors. Despite this, only 4% of patients had some degree of cardiotoxicity and only 2 cases of clinical heart failure were reported.
Results from this study showed increase in incidence of PPE in patients received PLD, the grades 3/4 PPE significantly increased with HCD (16.1% for patients with HCD versus 2.0% for those without HCD; p = 0.028). Our finding appears to be keeping with results published by Fiegl et al. [16], which demonstrated that PPE was significantly more prevalent in patients who received > 3 cycles PLD compared to patients receiving only 1 -3 cycles (22% vs 8%, p = 0.043).
In our study, in spite of thirty-one patients received HCD of PLD, the frequencies of other toxicities induced by PLD were within the range of previously published studies [17] [18] [19] [20] [21]. The typical side effects of PLD therapy (Table 2) appeared to be of minor relevance, probably due to the intensified management of these toxicities according to the manufacturer's recommendations and published guidelines [22].
The main limitation of this study is the retrospective nature of study. Also, there is lack of measurement of cardiac biomarker i.e. troponin. We would to conduct this trial prospectively with large sample size and biomarker measurement.

Conclusion
Our study concluded that the use of PLD even with HCD seems to be a justified agent in the treatment of MBC who previously treated by conventional anthracyclines in the adjuvant, metastatic or both settings, even in patients reaching the cumulative dose of conventional anthracycline.

Ethical Approval
This article does not contain any studies with animals performed by any of the authors. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.