Introduction
Breast cancer (BC) is the second most frequent cause of cancer-related deaths in women worldwide. It is a heterogeneous disease composed of multiple subtypes with distinct pathological features and clinical implications. Although men are affected, to a lesser degree, the most significant risk factors are gender (women) and older age. Other risk factors include obesity, estrogen exposure, alcohol consumption, and a family history. 1 Over the past 2 decades, accumulating evidence, both clinical and experimental, has suggested that BCs with different histopathological and biological features exhibit distinct behaviors that lead to different treatment responses and, therefore, should be given different therapeutic strategies. 2 On this basis, at diagnosis, BC patients are systematically tested for the presence of receptors, including estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), in order to explore tailored treatment options with molecularly targeted therapies. However, for patients who are triple negative (ER-, PR-, and HER2-), those who have innate or acquired resistance to targeted therapies, and patients whose disease has metastasized, traditional treatment options including surgery, radiotherapy, and chemotherapy are favored.
Anthracycline-based chemotherapy with doxorubicin (DOX) is one of the most efficacious anticancer agents for both early- and late-stage BCs. 3 DOX’s mechanism of action ( Figure 1 ) on cancer cells begins with its passive diffusion through the phospholipid bilayer membrane of malignant cells into the cytoplasm, where DOX is converted into a semiquinone and generates reactive oxygen species (ROS), causing free radical formation and oxidative stress. In the cytosol, DOX enters the mitochondria causing DNA damage and energetic stress. As a result, the mitochondria release the cytochrome C protein, triggering the caspase cascade leading to cell death. From the cytosol, DOX translocates into the nucleus where it intercalates between double-stranded DNA helices and inhibits the enzymes topoisomerases I and II. The resulting damage to DNA leads to free radical generation, alkylation, and activation of the p53 pathway, hence inhibiting cell proliferation and inducing apoptosis. DOX can also hyperactivate the nuclear enzyme poly ADP ribose polymerase (PARP)-1, hence depleting the cell’s energy, thereby resulting in autophagy. 4 – 6
However, the potential therapeutic benefits of DOX are limited by the risk of cardiotoxicity, which has been evidently related to its lifetime cumulative dose. 7 – 9 To overcome this hurdle, the liposomal DOX (L-DOX) formulation was developed in order to reduce DOX-associated cardiotoxicity while preserving its antitumor efficacy. 10 The L-DOX formulation encapsulates DOX within a phospholipid bilayer that is coated with methoxypolyethylene glycol ( Figure 2 ). The PEGylation protects the liposomes from recognition by the mononuclear phagocyte system (MPS) and allows a longer circulation time in the bloodstream while reducing the exposure of free DOX circulating in the plasma. Biodistribution studies have shown that L-DOX has the ability to deposit and/or penetrate tumors and release DOX. 11 Although the mechanism of release of DOX from its liposomes is still unknown, a 10-fold higher exposure of L-DOX than DOX is observed in metastatic BC tissue as compared to healthy breast tissue, 12 which is explained by the enhanced permeability retention effect. 13 This indicates that a therapeutic approach with L-DOX is more targeted compared to DOX. A differential pharmacokinetic (PK) characteristic between the two formulations includes a decreased clearance (CL), a smaller volume of distribution, and a longer half-life for L-DOX compared to DOX as a result of the sequestration of liposomes, due to their increased size, in the sinusoidal lumen of the liver, which limits their flow from the fenestrations of the lumen into the hepatocytes as compared to free DOX. This is also believed to contribute to reduced hepatic extraction of L-DOX compared to DOX as a single agent. 14 The latter being primarily metabolized in the liver to the major cytotoxic metabolites: doxorubicinol and cytotoxic aglycones. The PK properties of L-DOX as compared to DOX are summarized in Table 1 .
The use of DOX as a stand-alone treatment has shown effectiveness in overall survival and response rate and time to disease progression. 15 Its limitations are seen in its effect on healthy cells and the resulting adverse effects, with the most significant being cardiotoxicity. The comparison of safety profiles between DOX and L-DOX is summarized in Table 2 with the most common side effect for L-DOX being palmar–plantar erythrodysesthesia, a skin toxicity that can be managed with supportive care, unlike cardiotoxicity, which is significantly more prevalent for DOX. 16 Although the mechanism of DOX-induced cardiotoxicity is not fully understood, its administration is dose limited. It was shown that the risk of DOX-induced cardiotoxicity increases with the increase in its cumulative lifetime dose to becoming irreversible (ie, cardiomyocytes death) when the latter reaches 450–550 mg/m 2 . 17 The other major cardiotoxic effects of DOX are the occurrence of congestive heart failure (CHF) in >20% of the treated patients. 8 Additional but less detrimental adverse reactions include nausea, vomiting, gastrointestinal problems, neurological symptoms, and cutaneous injuries at the site of injection. 4
While L-DOX has proven to be advantageous over DOX as a single agent, it is only indicated in the treatment of metastatic BC in combination with docetaxel, 18 although it is frequently utilized as adjuvant therapy in metastatic BC. 19 The comparative anticancer efficacies of these two drugs in addition to their use in combination with other anticancer agents in BC continue to be investigated. 20 Table 3 summarizes the main findings of trials assessing regimens containing L-DOX. These trials evaluated the efficacy of several combinations in varied patient populations including both locally advanced and metastatic BCs as well as the elderly and in patients with previously treated BCs. Overall, L-DOX was effective and well tolerated in the majority of trials, making it a feasible treatment option when combined with other chemotherapeutics. In the present work, we sought to investigate L-DOX’s efficacy on BC and its potential associated cardiac toxicity when combined with other chemotherapeutic or targeted therapy, with the goal of showcasing the beneficial effect of L-DOX over DOX on BC therapy and cardiac function.
Methods
A literature search was conducted on PubMed, Google Scholar, and ClinicalTrials.gov using the following main keywords: liposomal DOX, Doxil ® and BC, Caelyx ® and BC, and Doxil ® or Caelyx ® and combinations in BC, to obtain relevant publications evaluating the safety and efficacy of L-DOX in the treatment of breast tumors. Additionally, information regarding the PK and safety profiles of L-DOX and conventional DOX was acquired mainly from drug monographs. Publications assessed in this review included Phases II and III clinical trials of patients with BC, ranging from early to metastatic stages. No particular preference was given in regard to BC subtype, and the only criteria that needed to be met for combinations were the use of L-DOX in at least one arm with at least one additional agent.
Results
Tables 1 and 2 highlight the disparity in PK parameters and toxicity profiles between L-DOX and DOX. These can be attributed to differences in the formulation of the two agents, with the encapsulation of free DOX into a phospholipid bilayer and exterior PEGylation of the liposomes providing improvements in terms of increasing the drug’s half-life ( T 1/2 ), decreasing both the volume of distribution ( V d ) and plasma CL, and reducing the severity of toxicity associated with the use of anthracyclines. L-DOX’s decreased CL (~ 0.7 vs 324–809 mL/ min/m 2 for DOX) and increased T 1/2 (55±4.8 vs 20–48 h for DOX) may be attributed to decreased metabolism by the liver and MPS. L-DOX liposomes are ~80–90 nm in diameter, although some references state that the size of the molecule is ≥100 nm, a characteristic that impedes their passage across hepatic sinusoidal epithelial fenestrations and decreases their metabolism by hepatocytes. In addition, PEGylation of liposomes decreases their opsonization by immunoglobulin/ complement proteins and their uptake by phagocytic cells of the MPS (eg, Kupffer cells and splenic macrophages), thus prolonging the agent’s plasma circulation time.
Another advantage of L-DOX is its extremely small volume of distribution in comparison to that of DOX (2.72±0.12 vs 809–1,214 L/m 2 ). While DOX’s large V d indicates that it can effectively distribute into all compartments of the body, its lack of selectivity for tumors means that it can cause a wide range of toxicities. In contrast, the small volume of distribution of L-DOX indicates that the drug is mostly confined into the vascular space, with little free DOX available, as the drug is contained within the liposomes and does not distribute freely to healthy tissues. The small size of L-DOX allows it to extravasate more selectively across fenestrations in the epithelium of blood vessels supplying tumors, where it releases DOX, meaning that generally the use of L-DOX is associated with milder side effects. 5 , 14 The classic adverse effect associated with DOX use is cardiotoxicity that can range in severity from an acute form that develops shortly after exposure to DOX to a more severe late form where patients may experience decreases in left ventricular ejection fraction (LVEF) and a subsequent diagnosis of DOX induced CHF. Furthermore, the use of DOX is limited by a cumulative lifetime dose limit of up to 550 or 450 mg/m 2 if a patient received previous mediastinal radiation. In contrast, the more common toxicities from L-DOX use include palmar–plantar erythrodysesthesia, nausea, and alopecia. 16 , 21 – 25
Since DOX is considered one of the most effective chemotherapy drugs available, it is often added to regimens for localized or metastatic BC as first- or second-line therapy, as a part of a neoadjuvant therapy prior to surgery or as a salvage therapy. Although it is an effective agent, the risks of cardiotoxicity, particularly when combined with other medications associated with the development of CHF, such as trastuzumab and cyclophosphamide, can limit its use. 26 In the case of L-DOX, the decreased rates of cardiotoxicity due to the formulation/PK differences described in the preceding paragraph allows its inclusion in regimens where free DOX would have a high risk of cardiotoxicity. Table 3 summarizes several trials where L-DOX has been combined with other chemotherapeutics or targeted therapies. Of note, a study combining L-DOX, trastuzumab, and cyclophosphamide was one of the most effective, with an overall survival of 34.2 months and the progression-free survival (PFS) of 12 months. 27 In terms of toxicity, eight of the 48 included patients experienced asymptomatic decreases in LVEF and all but one recovered; of the affected patients, six patients had prior exposure to anthracyclines. As for the other trials included in Table 3 , a majority did not find any significant changes to LVEF or high incidences of clinically relevant cardiotoxicity; however, in several instances where mild-to-moderate cardiotoxicity was reported, it was often in patients who either had prior anthracycline exposure or were concurrently being treated with trastuzumab. 27 – 31
Discussion
The decreased risk for the cardiotoxicity of L-DOX combined with its comparable efficacy to DOX in the treatment of BC has made it a suitable alternative therapy in treatment regimens that traditionally utilized conventional DOX. 16 In the in vivo setting, the prolonged systemic circulation of L-DOX due to its relatively long half-life, 32 along with its selective delivery to the tumor site due to its extravasation through leaky tumor vasculature, 33 results in a higher tumor accumulation as compared to normal tissues. In addition, circulating free-drug concentrations in plasma are reduced due to the highly stable L-DOX formulation, leading to lower cardiac tissue exposure of free-DOX, as compared to tumor tissue. Thus, the use of L-DOX would not only be able to alleviate cardiotoxicity but also to retain significant cytotoxic activity against target tumor cells, due to differences in exposure as well as relative potency of DOX in both tissue types. This is in agreement with results from a Phase III study, 16 where L-DOX was shown to be as efficacious as DOX, with significantly reduced cardiotoxicity and other adverse events, in patients with metastatic BC.
Table 3 summarizes all clinical trials for combinatorial effects of L-DOX with other chemotherapeutics and targeted agents. It is noted that practically all trials are Phase II, and the cardiotoxic events observed were either very low or not existent. In most cases where patients experienced mild-to-moderate cardiotoxicity, they were reported to have received prior anthracycline therapy or were on regimens that included trastuzumab, which is known to augment cardiotoxicity caused due to DOX. 34 Nevertheless, the cardiotoxicity observed in the case of L-DOX was significantly lower than that observed with DOX, thus establishing the cardiac safety of this formulation and supporting its clinical use.
In this work, we sought to discuss the therapeutic use of L-DOX in BC. A review of available Phase II and III trials in BC patients has demonstrated that the use of L-DOX generally causes very little cardiotoxicity, while retaining efficacy when used in combination with other chemotherapeutics. Together, this information suggests that L-DOX should continue to be evaluated in further Phase II and III trials in BC, as it remains an effective agent when combined with other chemotherapeutics and is a reasonable agent to substitute in the place of conventional DOX, particularly in patients who are at higher risk for cardiotoxicity.
Disclosure
The authors report no conflicts of interest in this work.
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