Critical Reviews in Oncology/Hematology 37 (2001) 115 120 www.elsevier.

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Caelyx (stealth liposomal doxorubicin) in the treatment of advanced breast cancer

M.R. Ranson a,*, S. Cheeseman a, S. White a, J. Margison b
a

Department of Medical Oncology, Cancer Research Campaign, Christie Hospital NHS Trust, Wilmslow Road, Manchester, M20 4BX, UK b Department of Clinical Pharmacology, Christie Hospital NHS Trust, Manchester, UK Accepted 24 July 2000

Contents
1. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Rationale for testing Caelyx in breast cancer. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. Clinical studies with Caelyx. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4. Combination chemotherapy with Caelyx in breast cancer . . . . . . . . . . . . . . . . . . . . . 5. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Reviewers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Biography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115 116 117 118 118 118 119 120

Abstract Anthracyclines are amongst the most active drugs in the treatment of breast cancer. Stealth liposomal doxorubicin (Caelyx, Doxil, Alza Pharmaceuticals Inc.) is a promising new agent under investigation for the treatment of breast cancer and other solid tumours. The liposomal encapsulation alters drug pharmacokinetics and leads to a marked change in toxicity prole compared to non-liposomal doxorubicin. The results of recently completed and ongoing clinical trials in breast cancer are reviewed. 2001 Elsevier Science Ireland Ltd. All rights reserved.
Keywords: Caelyx; Doxil; Doxorubicin; Liposome; Breast cancer

1. Introduction The spectrum of antitumour activity of the anthracyclines has set lasting landmarks in the treatment, not just of breast cancer, but also of leukaemia, lymphomas and sarcomas. Nearly three decades have elapsed since
* Corresponding author. Tel.: + 44-161-4463743; fax: + 44-1614463299. E -mail address: malcolm.ranson@man.ac.uk (M.R. Ranson).

the introduction of anthracyclines for the treatment of breast cancer and this class of cytotoxic drug remains at the forefront of treatment for this malignancy. However, anthracycline use, particularly in the elderly, has been hampered because of toxicity considerations. The development of anticancer agents that have reduced toxicity represents one of the principle requirements for improving chemotherapeutic treatment. In the future, greater target specicity of anticancer agents constitutes an important therapeutic objective. However, it is possible to exploit drug delivery systems to confer altered

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biodistribution and drug release properties, in order to improve the therapeutic index of relatively non-specic cytotoxic drugs. Liposomes represent an attractive drug delivery vehicle for cytotoxic agents and this is based upon three pharmacologic parameters. Firstly, liposomes can provide for a slow release of drug, thereby reducing high free peak concentrations. Secondly, liposomes are able to alter the biodistribution of the encapsulated drug so that there is the potential for site avoidance and reduced toxicity. Thirdly, in certain circumstances liposomes act to enhance drug accumulation within tumours. A potential disadvantage may be that liposomes delay the drug becoming bio-available and this may limit the rapid achievement of high tumour drug levels. The pharmacologic principles that underpin liposomal anthracyclines were developed \ 20 years ago. Indeed, the development of liposomal anthracyclines provides an important perspective of the eld of liposomal drug delivery [1]. The rst liposomal formulations of anthracyclines to be tested in humans were based upon negatively charged lipids (phosphatidylglycerol, cardiolipin) and the liposomes were relatively large at : 300 500 nm diameter. The rationale for these formulations was to reduce the uptake of doxorubicin by the heart and to enhance uptake by the reticuloendothelial system (RES). It was reasoned that this might increase the efcacy of anthracyclines in hepatic tumours. However, in early imaging studies, although there was rapid drug uptake into the RES of liver and spleen, anthracycline uptake into the tumour was disappointing [2]. The requirement for liposomes with longer circulation times and improved avoidance of RES capture became appreciated and this has culminated in the development of Stealth or sterically stabilised liposomes for cytotoxic drug delivery. In the case of stealth liposomal doxorubicin (Caelyx in Europe, Doxil in US, Alza Pharmaceuticals Inc., USA) the liposomes are small ( : 100 nm diameter) and contain a small proportion of phospholipid derivatized with the hydrophilic polymer, methoxypolyethylene glycol (MPEG). The linear MPEG groups extend from the liposome surface to create a hydrophilic layer that reduces interactions between liposome and plasma components. Other liposomal anthracyclines have been developed for clinical use. DaunoXome developed by NeXstar Pharmaceuticals Inc. (Boulder, CO) is a formulation of daunorubicin in small (35 65 nm diameter) unilamellar conventional liposomes, composed of disteroylphosphatidylcholine and cholesterol. TLC D-99 (Evacet) is a formulation of doxorubicin in conventional liposomes (150 nm diameter) composed of egg phosphatidylcholine and cholesterol and under clinical development by The Liposome Company Inc. (Princeton, NJ). Both DaunoXome and Evaset, which utilise non-pegylated

liposomes have signicant pharmacological and pharmacokinetic differences from Caelyx. The interested reader is referred to several recent reviews on their pharmacology [35]. The plasma pharmacokinetics of Caelyx are markedly different from conventional doxorubicin. Gabizon determined the pharmacokinetics of pegylated liposomal doxorubicin compared to free doxorubicin [6]. Seven patients with advanced cancer received a single course of conventional doxorubicin and then received the same dose of pegylated liposomal doxorubicin. Nine additional patients received pegylated liposomal doxorubicin alone. The apparent volume of distribution following intravenous administration was small compared to conventional doxorubicin (2.35 vs. 149 l/m2) [6], and virtually all the doxorubicin detectable was accounted for by encapsulated drug [6]. Clearance was bi-exponential with a short initial halflife of : 2 h and a prolonged terminal half-life of : 45 h. Similar results have been reported during studies in patients with AIDS-related Kaposis sarcoma [7] and solid tumours. The pharmacokinetic data from multiple studies has recently been reviewed [5]. It should be noted that the pharmacokinetics of liposomal drugs are substantially determined by the structure and physicochemical properties of the liposome. The long plasma half-life of Caelyx reects the relative efcacy of the membrane modication, in minimising early liposome disruption in plasma and capture by the RES. In pre-clinical models, some workers have reported that there is a correlation between increasing circulation half-life and the antitumour efcacy of liposome encapsulated cytotoxic drugs [8,9]. It is well recognised that solid tumours are characterised by a requirement for new blood vessel development and tumour angiogenesis results in the formation of immature and relatively permeable blood vessels. These tumour blood vessels may facilitate the exit of liposomes and allow the development of sustained drug accumulation within experimental animal tumours [5,10 12]. The altered pharmacokinetic and biodistribution properties of Caelyx, compared to free doxorubicin, results in a substantial change in the toxicity prole which is discussed below.

2. Rationale for testing Caelyx in breast cancer Caelyx is currently being evaluated in phases II and III studies in breast cancer. In dose escalation phase I trials of Caelyx, responses were recorded in patients with breast cancer, prostate cancer, non-small cell lung cancer, renal carcinoma and head and neck and ovarian carcinoma [13]. The main rationale for the development of Caelyx in patients with breast cancer stems from the fact that anthracyclines are among the most active

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agents in this malignancy. Unfortunately, anthracycline use, particularly in the elderly, is limited by its toxicity. The main acute toxicities of conventional anthracyclines comprise myelosuppression, mucositis, alopecia and nausea and vomiting. In addition, this class of cytotoxic agent is associated with a risk of cumulative cardiotoxicity [14,15]. High cumulative doses of conventional doxorubicin are associated with an increasing incidence of clinical cardiac failure [16]. Cardiac toxicity limits the total anthracycline dose that may be administered and has led to particular caution in the elderly. Although anthracyclines continue to be the mainstay of adjuvant treatment for younger women with breast cancer, there remains a need to minimise the potential risks of devastating cardiac damage from anthracycline use in this curative setting. In patients with metastatic breast cancer, response rates to single agent doxorubicin (50 75 mg/m2 every 3 weeks) range from 25 to 58% and are heavily inuenced by patient characteristics, such as prior chemotherapy, performance status and the extent and sites of disease [17 23]. Intensied dosing of doxorubicin by increasing the dose and by shortening of the cycle interval has been examined for conventional doxorubicin [24]. Whilst this dose dense approach led to responses in almost all patients treated, it was attended by severe mucosal and skin toxicity and the response duration appeared comparable to those achieved with standard dosing [24]. Treatment for patients with advanced breast cancer remains palliative and the most desirable regimen would be one that produced minimal toxicity with the maximal achievable benet in terms of survival and quality of life. The limited success of highly intensive cytotoxic regimens in advanced breast cancer has reinforced the need for developing regimens that are better tolerated.

3. Clinical studies with Caelyx There has been extensive evaluation of Caelyx in patients with AIDS-related Kaposis sarcoma and the agent is licensed in Europe and the US for this indication. The doses of Caelyx used in patients with Kaposis sarcoma are lower than those under investigation in patients with breast cancer and solid tumours. Interested readers are referred to a number of recent reviews that provide a detailed appraisal of Caelyx use in AIDS KS patients [5,25 30]. Phases II and III clinical studies, to assess the safety and efcacy of Caelyx in the treatment of breast cancer, are now in progress. The rst indications of the efcacy and safety prole of Caelyx in advanced breast cancer were gleaned during phase I studies [13]. Of the 56 patients with solid tumours, six had metastatic breast cancer and among

these there were two partial responses and one minor response. The most common dose limiting toxicities observed during the phase I trials were stomatitis, palmar plantar erythrodysthesia and myelosuppression The most comprehensive data to date comes from a multicentre phase II trial of Caelyx in the UK [31]. The efcacy and toxicity prole of Caelyx was dened at three different dose levels. Patients were required to have measurable metastatic breast cancer and were allowed to have received one prior non-anthracycline chemotherapeutic regimen. The three dose levels evaluated were 60 mg/m2 every 3 weeks, 45 mg/m2 every 3 weeks and 45 mg/m2 every 4 weeks. A maximum of six cycles of treatment was permitted. Dose reductions of 25% were required for grade 3 or worse toxicities excepting nausea, vomiting or alopecia. Seventy-one patients entered the trial and all had metastatic disease and a median Karnofsky performance status of 80 (range: 60100), a median age of 57 years (range: 3378). Eighty percent of patients had received prior hormonal agents and 28% of patients had received prior chemotherapy. The patient population was predominantly patients with high tumour burden and visceral tumour involvement. Almost three-quarters of the patients had multiple organ involvement and liver, lung and bone metastasis was the dominant site in 89% of the patients entered. Eight of the entered patients received only one cycle of Caelyx and were not considered assessable for response. The response rate in the 64 assessable patients was 31% and the response rate in those patients who had received prior chemotherapy was 32%. Taking into account the patient characteristics in this trial, the response rate to Caelyx appears comparable to that seen in other multicentre trials with conventional single agent doxorubicin in advanced breast cancer patients with similar pre-treatment characteristics [17 22]. Unlike conventional doxorubicin, nausea, vomiting and alopecia were notably absent or mild with Caelyx. In addition, myelosuppression was mild and its severity was dose related. At doses recommended by the authors for further study (45 50 mg/m2 every 4 weeks) grade 3 or 4 neutropenia occurred in just 7% of cycles. The incidence of mucositis was dose related with grade 3 or 4 mucositis occurring in 20% of cycles at 60 mg/m2 and in 9% of cycles at 45 mg/m2 every 4 weeks. The most important dose limiting toxicity of Caelyx is plantar palmer erythrodysthesia and this was severe at 60 mg/m2 of Caelyx every 3 weeks where seven of the 13 patients developed grade 3 or 4 skin toxicity. It is worth noting that similar skin toxicity is seen with conventional doxorubicin during infusional therapy [32 34] or with dose intensive treatment [24]. Skin toxicity was rarely seen following the rst cycle of Caelyx, implying that it occurred as a result of a cumulative but reversible effect. In view of the pro-

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longed plasma circulation time of stealth liposomes, it is conceivable that a slow release of doxorubicin takes place which mimics the protracted infusion of conventional doxorubicin and that repeated administration at relatively short intervals leads to overt skin toxicity when drug levels persist above a notional threshold. Though the skin toxicity is seen over the palms of the hands and soles of the feet, it may also occur in exure areas and over pressure areas. This pattern of localisation may reect relatively higher rates of keratinocyte turnover, although it is also conceivable that this localisation occurs because of the altered biodistribution of stealth liposomes. As with all liposomal drug delivery systems, occasional instances of hypersensitivity reaction were seen and in two of the 71 patients, this prompted withdrawal of Caelyx. The UK trial was not designed to address the issue of cardiac safety since the median cumulative dose of doxorubicin was 179 mg/m2 (range: 45 399 mg/m2). Larger scale clinical studies and matched case-controlled studies are required to address the cardiac safety of stealth liposomal doxorubicin. However, there is extensive pre-clinical data [35 38] and some limited case-control data which support the view that liposomal formulations of doxorubicin are associated with a signicant reduction in the propensity for cardiac toxicity [5,39]. In pre-clinical studies, liposomal doxorubicin has been reported to have activity in some but not all anthracycline resistant models [40,41]. This has prompted clinical studies in the setting of anthracycline resistance. A small-scale phase II trial to evaluate Caelyx in the setting of anthracycline resistant advanced breast cancer has been reported [42]. In 13 patients with anthracycline resistant tumours, treated at a low dose of 30 mg/m2 every 3 weeks, there were no responses although stable disease was recorded in four patients. In a preliminary study in the neo-adjuvant treatment of locally advanced breast cancer, the efcacy of single agent stealth liposomal doxorubicin appears to be lower than that of standard combination chemotherapy [43]. Caelyx is not ideally suited for use in neo-adjuvant treatment since its formulation produces delayed tumour bioavailability.

nine patients were reported [44]. Similar high response rates have been reported by others using this combination [45]. The rationale for developing taxane liposomal anthracycline regimens as an alternative to those based on conventional anthracyclines is based upon an expectation of reduced myelosuppression and cardiac toxicity. Small dose-ranging phase I studies in combination with docetaxel have been reported [46 48] and further results in this area are awaited with keen interest. Combination regimens with particular interest for elderly patients with breast cancer or for patients requiring low toxicity have included stealth liposomal doxorubicin in combination with either cyclophosphamide or vinorelbine. The combination of Caelyx with oral cyclophosphamide has been explored in pilot studies [49]. Patients received Caelyx 50 mg/m2 i.v. on day 1 and oral cyclophosphamide 100 mg/m2 on days 114. Objective response was seen in ve of seven patients and toxicity was mild. In combination with vinorelbine [50], pilot scheduling studies suggested that Caelyx on day 1 with vinorelbine on days 1 and 15 constitutes a well-tolerated schedule suitable for phase II development. However, results of a phase II trial of Caelyx 40 mg/m2 every 4 weeks with vinorelbine 20 mg/m2 i.v. on days 1 and 8 of each cycle produced a disappointing response rate of just 18% (95% condence interval 234%) [51]. The authors did not dene the reasons for this result.

5. Conclusions Whilst it has taken almost 30 years from Banghams rst description of a liposome [52], the clinical development and licensing of liposomal drugs has shown that this technology has now come of age. Stealth liposomes represent an important milestone in the history of liposome technology. It is anticipated that further improvements will be made in the future based upon membrane modication. The unique pharmacologic properties and favourable toxicity prole of Caelyx may enable oncologists to improve the tolerability of therapy for breast cancer patients. The results of these early studies with Caelyx should be seen as an important foundation for the development of other drugs based on this technology. Reviewers Dr David B. Smith, Consultant in Medical Oncology, Clatterbridge Centre for Oncology, Clatterbridge Road, Bebington, Merseyside, L63 4JY, UK Dr John Whittaker, Alza International Inc., Prole West, 950 Great West Road, Brentford, Middlesex, TW8 9ES, UK

4. Combination chemotherapy with Caelyx in breast cancer Given the comparable antitumour activity and mild myelosuppression in single agent studies, combinations with other agents such as taxanes, vinorelbine and cyclophosphamide are being actively pursued. In a preliminary study of stealth liposomal doxorubicin with paclitaxel, a total of seven partial responses in

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Biography Dr Ranson is a Senior Lecturer in the Cancer Research Campaign Department of Medical Oncology at the Christie Hospital National Health Service Trust in Manchester, UK. After qualifying in Pharmacology he completed his medical training in Manchester. After completing his PhD in 1990, he worked in Clinical Pharmacology at the National Cancer Institute, Bethesda, USA. He runs an active phase I and early phase II clinical pharmacology programme, with particular emphasis on drug delivery systems and novel anticancer agents.