EXPERTS’ OPINION

Sebastian Szmit1, Krzysztof J. Filipiak2, Maria Litwiniuk3, Grzegorz Opolski2, Piotr Wysocki4, Beata Zaborska5, Maciej Krzakowski6

1Department of Pulmonary Circulation and Thromboembolic Diseases, Centre of Postgraduate Medical Education, Otwock, Poland

2First Chair and Department of Cardiology, Medical University of Warsaw, Warsaw, Poland

3Department of Oncology, Poznan University of Medical Sciences, Greater Poland Cancer Centre, Poznań, Poland

4Department of Oncology, Jagiellonian University Medical College, Cracow, Poland

5Department of Cardiology, Centre of Postgraduate Medical Education, Warsaw, Poland

6Department of Lung and Thoracic Tumors, The Maria Skłodowska-Curie Memorial Cancer Center & Institute of Oncology, Warsaw, Poland

Liposomal doxorubicin in patients with breast cancer and concomitant cardiovascular diseases — an interdisciplinary expert opinion

The article has been published simultaneously in "Kardiologia Polska" — the Official Journal of the Polish Cardiac Society

ABSTRACT

The use of liposomal doxorubicin in place of conventional form can significantly reduce the risk of clinically important cardiovascular complications of chemotherapy. The use of liposomal doxorubicin-containing regimen seems to be the most justified in treatment of breast cancer patients with coexisting cardiovascular diseases. The document defines the possible clinical scenarios for the use of chemotherapy with liposomal doxorubicin and presents the optimal cardiac monitoring of this therapy.

Key words: breast cancer, liposomal doxorubicin, cardiovascular diseases, cardiotoxicity

Oncol Clin Pract 2016; 12, 3: 92–96

Indications for anthracyclines

Licensed indications for conventional doxorubicin, a member of the anthracycline class of drugs, are very wide and include adjuvant and/or neoadjuvant and palliative treatment of multiple malignancies including breast cancer, ovarian cancer, small-cell lung cancer, bladder cancer, soft tissue and bone sarcomas, lymphomas, and leukemias.

Pegylated liposomal doxorubicin has been licensed for: (a) monotherapy of metastatic breast cancer in patients at an increased risk of cardiac complications; (b) treatment of advanced ovarian cancer following failed first line treatment with platinum compounds; (c) treatment (in combination with bortezomibe) in patients with progressing multiple myeloma who already received at least one treatment course and underwent bone marrow transplantation or are not candidates for the latter treatment; and (d) treatment of Kaposi’s sarcoma in patients with acquired immune deficiency syndrome.

Nonpegylated liposomal doxorubicin has been licensed only for combination treatment with cyclophosphamide as the first line therapy in women with metastatic breast cancer.

Doxorubin therapy in view of everyday clinical problems

Anthracyclines are the mainstay of breast cancer chemotherapy [1]. Anthracyclines, most commonly doxorubicin (DOX) and less frequently epirubicin (EPI), are often used in breast cancer patients within multi-drug chemotherapy regimens in combination with other cytotoxic drugs including fluorouracil (FU), cyclophosphamide (CTX), and docetaxel (DXL). The most commonly used regimens include:

— AC — DOX 60 mg/m2 IV on Day 1, CTX 600 mg/m2 IV on Day 1 (cycle: 21 days);

— TAC — DXL 75 mg/m2 IV on Day 1, DOX 50 mg/m2 IV on Day 1, CTX 500 mg/m2 IV on Day 1 (cycle: 21 days);

— FAC — FU 500 mg/m2 IV on Day 1, DOX 50 mg/m2 IV on Day 1, CTX 500 mg/m2 IV on Day 1 (cycle: 21 days);

— FEC — FU 500 mg/m2 IV on Day 1, EPI 75 mg/m2 IV on Day 1, CTX 500 mg/m2 IV on Day 1 (cycle: 21 days).

The major clinical problem during anthracycline treatment are cardiovascular complications that occur mostly in patients with significant risk factors for the development of heart failure [2, 3].

Recent data indicate an increasing rate of cardiovascular complications following adjuvant treatment in breast cancer patients, with the highest risk in those treated with anthracyclines and trastuzumab [4–6]. Polish study findings confirm that a history of neoadjuvant and adjuvant chemotherapy with anthracyclines and a history of a coronary event are the most important risk factors for systolic left ventricular dysfunction and heart failure in women with metastatic breast cancer [7].

When initiating adjuvant therapy, oncologists need to consider potentially favorable long-term outcomes in these patients. Experts indicate that an anthracycline-free drug regimen may reduce the risk of long-term cardiotoxicity [8]. The CMF regimen (cyclophosphamide, methotrexate, and fluorouracil) is a cardiologically safer adjuvant therapy but shows lower anti-cancer efficacy, with a higher risk of disease recurrence and mortality compared to anthracycline-based regimens [9]. Use of the CMF regimen as adjuvant therapy may increase the risk of cardiovascular complications in case of later anthracycline use due to cancer spread [10].

In few studies, palliative chemotherapy using anthracyclines was not particularly effective [11]. It is believed, however, that anthracycline-based regimens have a higher effect on long-term outcomes, with significantly longer disease progression-free and overall survival time [12, 13]. However, these findings were reported for patients who did not receive neoadjuvant chemotherapy. More recent studies showed that lower efficacy of anthracyclines as palliative therapy was associated, among others, with previous use of adjuvant chemotherapy, shorter disease-free period, worse patient functioning, and localization of metastases [14].

Due to its structure and pharmacokinetics, liposomal doxorubicin may be expected to result in significantly fewer cardiovascular complications compared to its conventional form [15–17]. Liposomes allow slow release of the active substance, the high peak concentrations of doxorubicin in plasma is not noted, while the peak plasma concentration of doxorubicinol, the major cardiotoxic metabolite, occurs later and in lower level in the case of liposomal doxorubicin in comparison with the conventional form [18, 19]. Placement of doxorubicin in liposomes makes that practically the drug has no possibility to penetrate the wall of properly functioning capillaries in normal tissue. Liposomal doxorubicin penetrates the vessel wall damaged by inflammatory or neoplastic infiltration, and penetration into the myocardial tissue is significantly lower [20, 21].

Batist et al. showed that particular benefits from liposomal doxorubicin therapy were seen in patients with at least one risk factor for the development of heart failure [22]. With comparable anti-cancer efficacy, overall survival was nonsignificantly longer (23 vs. 15 months) in patients receiving liposomal doxorubicin therapy, while the risk of cardiovascular adverse effects was reduced several fold. A retrospective analysis showed that even in patients who had received adjuvant therapy using conventional doxorubicin (median dose 240 mg/m2), use of liposomal doxorubicin was associated with a significantly higher response rate (31% vs. 11%; P = 0.04), significantly longer time to treatment failure [hazard ratio (HR) 2.06, P = 0.01], and a five-fold lower risk of cardiovascular complications (HR 5.4; P = 0.001) compared to conventional doxorubicin treatment [23]. Overall survival was not prolonged but the liposomal doxorubicin group included more patients with steroid hormone receptor-negative cancers, which was considered a negative prognostic factor by the authors.

Taking into account available clinical data, we believe that an attempt should be made to define optimal cardiac criteria for using liposomal doxorubicin instead of conventional doxorubicin treatment.

Absolute cardiac contraindications to liposomal doxorubicin

A contraindication for the use of both forms of doxorubicin, conventional and liposomal, is an advanced cardiovascular disease defined as [24]:

— symptomatic New York Heart Association (NYHA) class III or IV heart failure;

— left ventricular systolic dysfunction with the ejection fraction (EF) of < 40%;

— recent myocardial infarction (within 4 weeks);

— a history of documented sustained ventricular tachycardia or ventricular fibrillation;

— uncontrolled hypertension;

— unstable angina [Canadian Cardiovascular Society (CCS) class III or IV].

Proposed detailed cardiac indications for liposomal doxorubicin — clinical scenarios

Clinical scenario #1

The use of liposomal doxorubicin seems to be justified in patients previously treated with conventional doxorubicin at a dose of at least 200 mg/m2. Experts agree that conventional doxorubicin dose above 200 mg/m2 should be considered as a significant risk factor for the development of iatrogenic heart failure [25].

It seems reasonable to delay liposomal doxorubicin treatment for at least 12 months since the end of adjuvant therapy with conventional doxorubicin. In case of such sequential treatment with various forms of doxorubicin, the overall lifetime dose is the sum of conventional and liposomal doxorubicin doses.

If other first or second generation anthracyclines are used, equivalent doses should be added to the overall lifetime dose (e.g., for epirubicin which is frequently used in breast cancer: epirubicin dose = at least 1.5 × conventional doxorubicin dose) [26].

An equivalent of the radiotherapy dose should also be added, with 1 Gy believed to be equal to 10 mg of doxorubicin [27].

Clinical scenario #2

It is possible to use liposomal doxorubicin in patients with a history of conventional doxorubicin treatment due to another cancers. All the above considerations as given under the clinical scenario #1 should apply.

Clinical scenario #3

Established cardiovascular disease — of prognostic importance in terms of morbidity and mortality — is a classic indication for liposomal doxorubicin therapy.

Before initiation of anti-cancer therapy using anthracyclines, each patient with a history of a cardiovascular event or previously treated cardiac disease should undergo a cardiology consultation including echocardiography and evaluation of exercise tolerance. Suitable candidates for substituting liposomal for conventional doxorubicin treatment include patients with the diagnosis of:

— mild left ventricular systolic dysfunction confirmed by echocardiography if EF is greater than 40% and the patient has only mildly limited exercise tolerance (not exceeding NYHA class II);

— any structural cardiac disease (cardiomyopathy, acquired valvular heart disease, congenital heart disease, diastolic dysfunction) confirmed by echocardiography if the patient has only mildly limited exercise tolerance (not exceeding NYHA class II);

— hypertensive target organ damage (left ventricular hypertrophy, diastolic dysfunction, retinopathy, nephropathy) and only mildly limited exercise tolerance (not exceeding NYHA class II).

Clinical scenario #4

Established stable coronary artery disease is a justified indication for liposomal doxorubicin therapy.

Liposomal doxorubicin can be used instead of conventional in each patient with coronary artery disease objectively confirmed by angiography and in all patients with a history of coronary revascularization (percutaneous coronary intervention, coronary artery bypass grafting), and patients with previous acute coronary syndrome or myocardial infarction.

As diabetes is a strong risk factor for coronary artery disease, each diabetic patient should undergo a cardiology consultation prior to initiation of chemotherapy, even if there is no previous diagnosis of ischemic heart disease. If concomitant coronary artery disease is confirmed, chemotherapy using liposomal doxorubicin is justified.

Clinical scenario #5

In patients with a history of symptomatic supraventricular arrhythmia (particularly atrial fibrillation, atrial flutter, and supraventricular tachycardia), or a history of ventricular arrhythmia except for symptomatic ventricular tachycardia, liposomal doxorubicin therapy should be preferred over conventional doxorubicin when considering anthracycline-based chemotherapy.

Clinical scenario #6

In patients with borderline left ventricular systolic function (EF 50–55%) in whom trastuzumab treatment is planned following chemotherapy, an anthracycline-free chemotherapy regimen should be considered, but chemotherapy using liposomal doxorubicin may also be considered. The expected EF reduction below 50% during conventional doxorubicin therapy may render it impossible to use trastuzumab under a breast cancer drug treatment program [28].

Treatment monitoring

1. Follow-up echocardiographic examinations in patients under clinical scenarios #1–6 should be performed at least every 2 chemotherapy cycles, and every cycle if the overall dose exceeds 200 mg/m2 [29, 30].

2. Treatment should be discontinued in case of symptomatic cardiotoxicity, i.e. EF reduction by at least 10 percentage points from the baseline to values below 53% and development of symptoms of exacerbated heart failure (NYHA class III/IV dyspnea, lower limb edema, evidence of pulmonary congestion by auscultation or chest radiography).

3. Asymptomatic EF reduction by less than 10 percentage points is not an indication to discontinue treatment as it may reflect a measurement error [31].

4. If modern cardiac imaging techniques are available in the center [speckle tracing echocardiography — evaluation of left ventricular global longitudinal strain (GLS)], evidence of cardiotoxicity should be an indication for cardiooncology consultation (joint evaluation by a cardiologist and an oncologist) to evaluate the justification and feasibility to continue chemotherapy using liposomal doxorubicin [29]. The risk of symptomatic heart failure and overall survival probability may be predicted based on GLS in patients treated with anthracyclines [32]. The estimated sensitivity, specificity, positive and negative predictive values for GLS as a predictor of cardiotoxicity make this parameter useful for daily clinical practice [33].

5. If troponin or natriuretic peptide [B-type natriuretic peptide (BNP), N-terminal B-type natriuretic propeptide (NT-proBNP)] assays are available in the center, measurement of both these markers (and particularly troponin) may be useful for the identification of patients with cardiotoxicity during chemotherapy using liposomal doxorubicin [34]. In such a situation, a joint cardiology and oncology consultation is definitely needed to evaluate the benefits and risks of continuing anti-cancer therapy.

6. If cardiotoxicity is established, standard management of left ventricular systolic heart failure should be instituted, followed by repeat echocardiography after 2–3 weeks to evaluate the dynamics of the disease process. It has been shown that in patients with anthracyclines induced cardiotoxicity (defined as LVEF ≤ 45%) treatment administered according to the guidelines improves left ventricular systolic function and reduces mortality [35]. The combination of ACE inhibitor (eg. enalapril) with beta-bloker (eg. carvedilol), seems to be most effective in primary and secondary cardiac prevention in this group of patients [36, 37]. At this moment there are no studies comparing the different drugs within the class within head-to-head trails. The key for the sufficient treatment efficacy is the early detection of cardiac damage [38]. Recently new evidence has been published on the effectiveness of candesartan for primary prevention [39].

Final remarks

Long-term palliative treatment with liposomal doxorubicin in patients with breast cancer is justified if objective benefits are confirmed (a positive treatment response or at least disease stabilization), no significant EF reduction (by at least 10 percentage points) is seen at follow-up echocardiographic investigations, and no clinical evidence of exacerbated heart failure is seen.

In a phase III trial comparing an AC regimen (conventional doxorubicin) and an MC regimen (liposomal doxorubicin) in patients with metastatic breast cancer, similar anti-cancer activity of both regimens was seen with a clearly different potential for cardiotoxicity (clinically significant cardiac events due to cardiotoxicity occurred with significantly lower overall lifetime doses of conventional doxorubicin compared to liposomal doxorubicin) [22].

If the oncologist considers the current liposomal doxorubicin regimen most optimal for a patient with an advanced breast cancer, the treatment should not be deferred only due to the need to wait for a scheduled follow-up echocardiographic examination. In special situations, when there is no clinical evidence suggesting cardiotoxicity, the treatment may be continued and the follow-up echocardiographic examination may be performed while waiting for the next chemotherapy cycle.

Treatment with liposomal doxorubicin should be definitely discontinued if cancer progression or a clinically significant cardiotoxicity is found.

Address for correspondence:

Dr hab. n. med. Sebastian Szmit

Klinika Krążenia Płucnego i Chorób

Zakrzepowo-Zatorowych CMKP

ul. Borowa 14/18, 05–400 Otwock

e-mail: s.szmit@gmail.com

Translation: dr n. med. Piotr Jędrusik

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