Pegylated liposomal doxorubicin: a review of its use in metastatic breast cancer, ovarian cancer, multiple myeloma and AIDS-related Kaposi's sarcoma

Pegylated liposomal doxorubicin (Caelyx?, Doxil?) represents an improved formulation of conventional doxorubicin, with reduced cardiotoxicity and an improved pharmacokinetic profile. This article reviews the efficacy and tolerability of pegylated liposomal doxorubicin in metastatic breast cancer, progressive ovarian cancer, relapsed or refractory multiple myeloma and AIDS-related Kaposi's sarcoma, as well as summarizing its pharmacological properties. In three randomized, open-label, multicentre trials, monotherapy with pegylated liposomal doxorubicin was as effective as doxorubicin or capecitabine in the first-line treatment of metastatic breast cancer, and as effective as vinorelbine or combination mitomycin plus vinblastine in taxane-refractory metastatic breast cancer. Pegylated liposomal doxorubicin alone was as effective as topotecan or gemcitabine alone in patients with progressive ovarian cancer resistant or refractory to platinum- or paclitaxel-based therapy, according to the results of three randomized multicentre trials. In addition, in patients with progressive ovarian cancer who had received prior platinum-based therapy, progression-free survival was significantly longer with pegylated liposomal doxorubicin plus carboplatin than with paclitaxel plus carboplatin, according to the results of a randomized, open-label multicentre trial. Combination therapy with pegylated liposomal doxorubicin plus bortezomib was more effective than bortezomib alone in patients with relapsed or refractory multiple myeloma, according to the results of a randomized, open-label, multinational trial. Randomized multinational trials also demonstrated the efficacy of pegylated liposomal doxorubicin in patients with advanced AIDS-related Kaposi's sarcoma. Pegylated liposomal doxorubicin exhibited a relatively favourable safety profile compared with conventional doxorubicin and other available chemotherapy agents. The most common treatment-related adverse events included myelosuppression, palmar-plantar erythrodysesthesia and stomatitis, although these are manageable with appropriate supportive measures. To conclude, pegylated liposomal doxorubicin is a useful option in the treatment of various malignancies, including metastatic breast cancer, ovarian cancer, multiple myeloma and AIDS-related Kaposi's sarcoma.     

Liposomal encapsulated anti-cancer drugs

Among several drug delivery systems, liposomal encapsulated anti-cancer agents represent an advanced and versatile technology. Several formulations of liposomal anthracyclines are approved, e.g. for the treatment of metastatic breast cancer (pegylated and non-pegylated liposomal doxorubicin) or AIDS-related Kaposi's sarcoma (pegylated liposomal doxorubicin and liposomal daunorubicin). Meanwhile, virtually all anti-cancer drugs have been encapsulated in liposomes using different technologies. This review will summarize preclinical and clinical data of approved and exemplary emerging liposomal anti-cancer agents.     

Liposomal doxorubicin in breast cancer: new preparation. Much ado about nothing

(1) There is no reference first-line cytotoxic chemotherapy protocol for metastatic breast cancer, but anthracycline combinations are commonly used. In addition to their myelotoxicity, anthracyclines can cause heart failure, both problems during and after treatment. (2) A liposomal formulation of doxorubicin, an anthracycline, has been developed with the aim of reducing this cardiotoxicity. The marketing terms specify that it must be used in combination with cyclophosphamide, in the first-line treatment of metastatic breast cancer. (3) According to the current evaluation file, which chiefly includes data from three comparative trials, liposomal doxorubicin is no more effective, in terms of the duration or quality of survival, than standard doxorubicin or epirubicin. (4) During comparative trials of liposomal doxorubicin, alone or in combination with cyclophosphamide, signs of cardiotoxicity, as measured by ultrasound, were slightly less frequent than with standard doxorubicin but no less frequent than with epirubicin. Given the possibility of late cardiac events, which were not studied in these trials, there is no evidence that liposomal doxorubicin is really less cardiotoxic than either standard doxorubicin or epirubicin. As regards other adverse effects, liposomal doxorubicin has no advantages over standard doxorubicin or epirubicin. (5) Liposomal doxorubicin is far more difficult to prepare than standard doxorubicin. (6) In France, liposomal doxorubicin is about 15 times more expensive than standard doxorubicin and 4 times more expensive than epirubicin. (7) In practice, standard doxorubicin can still be used, at doses appropriate for the individual patient and with cardiac monitoring.     

Pegylated liposomal doxorubicin in the treatment of cancers of the breast and ovary

Peglyated liposomal doxorubicin was developed to maintain or enhance the demonstrated antineoplastic effects of doxorubicin, while improving the toxicity profile associated with this important cytotoxic agent. Accumulating clinical data have confirmed the activity of pegylated liposomal doxorubicin in cancers of the breast and ovary. Furthermore, Phase II and III trial experience has revealed that the drug produces objective responses comparable in rate and duration to doxorubicin and other single agents employed in metastatic breast cancer. In recurrent and platinum-resistant ovarian cancer, single-agent pegylated liposomal doxorubicin has assumed an important role in routine patient management.     

Pegylated liposomal doxorubicin in the treatment of cancers of the breast and ovary

Peglyated liposomal doxorubicin was developed to maintain or enhance the demonstrated antineoplastic effects of doxorubicin, while improving the toxicity profile associated with this important cytotoxic agent. Accumulating clinical data have confirmed the activity of pegylated liposomal doxorubicin in cancers of the breast and ovary. Furthermore, Phase II and III trial experience has revealed that the drug produces objective responses comparable in rate and duration to doxorubicin and other single agents employed in metastatic breast cancer. In recurrent and platinum-resistant ovarian cancer, single-agent pegylated liposomal doxorubicin has assumed an important role in routine patient management.     

Liposomal doxorubicin and weekly paclitaxel in the treatment of metastatic breast cancer

The combination of paclitaxel and doxorubicin or epirubicin is highly active against metastatic breast cancer, yet may produce congestive heart failure. Liposome-encapsulated doxorubicin is a new formulation of doxorubicin with no dose-limiting cardiac toxicity. Twenty-one patients with metastatic breast cancer were treated with pegylated liposomal doxorubicin (20 mg/m2, day 1) and paclitaxel (100 mg/m2, days 1 and 8) for six cycles every 2 weeks. All patients had had relapse or progression on one to five previous chemotherapies. We observed two patients with complete and eight patients with partial remissions (48% response rate). Eight of the 10 responders had had previous therapy with epirubicin, doxorubicin or mitoxantrone. The mean remission duration was 5 months. Disease progression due to brain metastasis occurred in five cases. Severe side effects (grade 3 WHO) were alopecia (100%), skin toxicity in 29%, neuropathy in 24% and mucositis in 13%. Leukopenia (grade 4 WHO) was observed in 48%, but there was no cardiac toxicity, no death and no hospitalization. The combination of weekly paclitaxel and liposomal doxorubicin every 2 weeks is highly effective in previously treated patients. Based on the doses we administered, we recommend 15 mg/m2 liposomal doxorubicin every 2 weeks and 80 mg/m2 paclitaxel weekly.     

聚乙二醇多柔比星脂质体及表柔比星在乳腺癌新辅助化疗中的应用比较

目的 比较聚乙二醇多柔比星脂质体及表柔比星在乳腺癌新辅助化疗中的疗效及不良反应。方法 回顾性分析2015年1月-12月行乳腺癌AC-T或EC-T新辅助化疗的146例患者,其中应用聚乙二醇多柔比星脂质体86例,应用表柔比星60例,分析其临床病理特征、化疗效果及不良反应,并应用Logistic回归分析影响新辅助化疗疗效的因素。结果 聚乙二醇多柔比星脂质体组与表柔比星组临床病理特征一致,无统计学差异。2组新辅助化疗的疗效无统计学差异。HER-2状态是影响新辅助化疗疗效的主要因素。聚乙二醇多柔比星脂质体组的白细胞降低、消化道反应、脱发及心电图异常等不良反应较表柔比星组明显减少,而手足综合征则明显增多,具有统计学差异。结论 聚乙二醇多柔比星脂质体与传统的表柔比星在乳腺癌新辅助化疗中疗效一致。     

Doxetaxel: new indication. Prostate cancer: a few more weeks

(1) The standard treatment for metastatic prostate cancer is hormone therapy, based on medical castration (with an LH-RH agonist) or surgical castration (pulpectomy), possibly combined with an androgen antagonist. For patients with hormone-resistant disease the only cytotoxic agents approved in France, estramustine and mitoxantrone, have no proven impact on survival. (2) Docetaxel is now approved in Europe for the treatment of hormone-resistant metastatic prostate cancer, in combination with a steroid. (3) In an open-label comparative trial involving 1006 patients, docetaxel infusion at a dose of 75 mg/m2 every 3 weeks, in combination with prednisone (or prednisolone), significantly extended the median survival time by about 2.5 months as compared with a mitoxantrone-prednisone combination (18.9 versus 16.5 months). In another open-label comparative trial involving 674 patients, a combination of docetaxel + estramustine was significantly more effective than a mitoxantrone + prednisone combination in extending median survival time (17.5 versus 15.6 months). (4) The adverse effects of docetaxel + prednisone were the same as those seen with other indications (hair loss, nausea and vomiting, diarrhea, neutropenia, nail disorders, neuropathies), and were severe in 25% of patients. (5) In France the cost of docetaxel therapy for hormone-resistant metastatic prostate cancer is more than 1000 euros every three weeks. (6) In practice, docetaxel is the first cytotoxic agent shown to prolong survival in men with hormone-resistant metastatic prostate cancer. The benefit is limited, however, especially given the potentially severe adverse effects of docetaxel, which must be disclosed to patients.     

A pegylated liposomal platform: pharmacokinetics, pharmacodynamics, and toxicity in mice using doxorubicin as a model drug

Aims were to observe pharmacokinetics, pharmacodynamics, and toxicity for constructing a Sino-pegylated liposomal platform. Human hepatocarcinoma cells (Bel7402) and murine hepatocarcinoma cells (H(22)) were used for the cytotoxicity assay and the in vivo solid xenograft tumor model in mice, respectively. Pharmacokinetic results in mice showed that the pegylated liposomal doxorubicin markedly prolonged the blood circulation of doxorubicin. Elimination half-time (T(1/2,gamma)) of pegylated, regular liposomal doxorubicin and free doxorubicin were 46.09 +/- 14.44, 26.04 +/- 3.34, and 23.72 +/- 5.13 h, respectively. The area under the concentration-time curves (AUC(0- infinity )) (h. microg/g) of the pegylated and regular liposomal doxorubicin were 6.8- and 2.6-fold higher than that of free doxorubicin, respectively. Cytotoxicity and antitumor activity in vivo indicated that activity of the pegylated liposomal doxorubicin was higher than that of the regular or the free one, respectively. After two weeks of tail intravenous injection of the pegylated liposomal doxorubicin at a single dose of 10 mg/kg, no significant damage was observed in gastric, intestinal mucosa, and heart muscle, but pronounced damages were found in the control group after dosing free doxorubicin. The results demonstrate that the pegylated liposomes improve the efficacy of toxics and reduce the toxicity, therefore providing favorable evidence for building a pegylated liposomal platform.     

Pharmacokinetics of pegylated liposomal Doxorubicin: review of animal and human studies

Pegylated liposomal doxorubicin (doxorubicin HCl liposome injection; Doxil or Caelyx) is a liposomal formulation of doxorubicin, reducing uptake by the reticulo-endothelial system due to the attachment of polyethylene glycol polymers to a lipid anchor and stably retaining drug as a result of liposomal entrapment via an ammonium sulfate chemical gradient. These features result in a pharmacokinetic profile characterised by an extended circulation time and a reduced volume of distribution, thereby promoting tumour uptake. Preclinical studies demonstrated one- or two-phase plasma concentration-time profiles. Most of the drug is cleared with an elimination half-life of 20-30 hours. The volume of distribution is close to the blood volume, and the area under the concentration-time curve (AUC) is increased at least 60-fold compared with free doxorubicin. Studies of tissue distribution indicated preferential accumulation into various implanted tumours and human tumour xenografts, with an enhancement of drug concentrations in the tumour when compared with free drug. Clinical studies of pegylated liposomal doxorubicin in humans have included patients with AIDS-related Kaposi's sarcoma (ARKS) and with a variety of solid tumours, including ovarian, breast and prostate carcinomas. The pharmacokinetic profile in humans at doses between 10 and 80 mg/m(2) is similar to that in animals, with one or two distribution phases: an initial phase with a half-life of 1-3 hours and a second phase with a half-life of 30-90 hours. The AUC after a dose of 50 mg/m(2) is approximately 300-fold greater than that with free drug. Clearance and volume of distribution are drastically reduced (at least 250-fold and 60-fold, respectively). Preliminary observations indicate that utilising the distinct pharmacokinetic parameters of pegylated liposomal doxorubicin in dose scheduling is an attractive possibility. In agreement with the preclinical findings, the ability of pegylated liposomes to extravasate through the leaky vasculature of tumours, as well as their extended circulation time, results in enhanced delivery of liposomal drug and/or radiotracers to the tumour site in cancer patients. There is evidence of selective tumour uptake in malignant effusions, ARKS skin lesions and a variety of solid tumours. The toxicity profile of pegylated liposomal doxorubicin is characterised by dose-limiting mucosal and cutaneous toxicities, mild myelosuppression, decreased cardiotoxicity compared with free doxorubicin and minimal alopecia. The mucocutaneous toxicities are dose-limiting per injection; however, the reduced cardiotoxicity allows a larger cumulative dose than that acceptable for free doxorubicin. Thus, pegylated liposomal doxorubicin represents a new class of chemotherapy delivery system that may significantly improve the therapeutic index of doxorubicin.     

Caspofungin: new indication. No progress in invasive candidiasis

(1) The reference treatment for invasive candidiasis in patients without neutropenia is standard amphotericin B. If this treatment fails or is too nephrotoxic, second-line alternatives are liposomal amphotericin B and fluconazole. Voriconazole is a third-line option. (2) Caspofungin, an antifungal drug belonging to the echinocandin class, is now approved for use in this indication in France. (3) The clinical evaluation dossier contains no data from comparative trials with fluconazole or voriconazole. It only gives the results of a double-blind trial in 239 patients, designed to show simply that caspofungin was not inferior to standard amphotericin B. Most of the patients did not have neutropenia. About one-third of the patients died. There was no difference in mortality between the two groups. No data are available from trials versus other forms of amphotericin B. (4) In this trial, caspofungin had fewer adverse effects (especially nephrotoxicity) than standard amphotericin B. However, in other trials in other indications, caspofungin had more adverse effects than fluconazole. (5) In France, caspofungin costs nearly 100 times more than standard amphotericin B. (6) In practice, caspofungin has no proven advantages over existing options for the treatment of invasive candidiasis in patients without neutropenia.     

聚乙二醇多柔比星脂质体联合化疗治疗晚期恶性肿瘤临床观察

目的探讨以聚乙二醇多柔比星脂质体为主联合化疗治疗晚期恶性肿瘤的临床疗效和不良反应。方法收集2007年1月—2009年11月以聚乙二醇多柔比星脂质体为主的联合化疗治疗晚期恶性肿瘤患者的治疗信息、临床情况,并对患者进行跟踪随访至2010年4月30日。结果 33例恶性肿瘤患者共计完成化疗106周期,中位3周期（1~8周期）,可评价疗效28例,其中完全缓解4例,占14.3%;部分缓解11例,占39.3%;稳定11例,占39.3%;进展2例,占7.1%;客观有效率为53.6%,临床受益率为92.9%。随访周期6~39个月,中位随访时间16个月,总生存时间4~39个月,中位生存时间16个月,无疾病进展时间2~39个月,中位无疾病进展时间为10个月,1和2年生存率分别为69.2%和34.2%,3例生存3年以上。不良反应主要为骨髓抑制、脱发和胃肠道反应,另外乏力、手足综合症常见,心脏毒性轻微。结论以聚乙二醇多柔比星脂质体为主联合化疗治疗晚期恶性肿瘤是有效的,患者可以良好耐受。     

Docetaxel: new preparation. No first-line use in metastatic breast cancer

(1) For the treatment of metastatic breast cancer, the reference first-line cytotoxic chemotherapy is an anthracycline-based combination such as doxorubicin + cyclophosphamide. (2) The clinical file on docetaxel in this indication mainly comprises data from a comparative trial of doxorubicin + docetaxel versus doxorubicin + cyclophosphamide in 429 patients. (3) In this trial the doxorubicin + docetaxel combination failed to increase the duration or quality of survival relative to the doxorubicin + cyclophosphamide combination, whereas its adverse effect profile was somewhat poorer (notably with a risk of severe neutropenia). (4) Docetaxel currently has no place in this setting.     

Epirubicin: a review of its efficacy as adjuvant therapy and in the treatment of metastatic disease in breast cancer

Epirubicin is a semisynthetic derivative of doxorubicin which has been extensively evaluated in patients with breast cancer. It is effective in the management of metastatic disease and as adjuvant therapy in patients with early breast cancer. In the adjuvant setting, epirubicin-based therapy appears to have efficacy at least equivalent to that of the standard therapy cyclophosphamide, methotrexate and fluorouracil (CMF), with the most recent trials, predominantly in premenopausal patients, reporting significant gains in relapse-free survival and overall survival for epirubicin-based vs CMF therapy. In a single trial, the 5-year relapse-free survival of postmenopausal patients receiving long term hormonal therapy (tamoxifen) was significantly increased when epirubicin was added as single-agent chemotherapy and compared with tamoxifen alone. In patients with metastatic disease, epirubicin- and doxorubicin-containing regimens (with cyclophosphamide and fluorouracil; FEC and FAC) are therapeutically equivalent. Increasing the dose of epirubicin appears to improve response rates in patients with either metastatic or early disease but, with the exception of 1 adjuvant study, improved overall survival has not been demonstrated. Quality of life (QOL) has yet to be adequately evaluated with epirubicin. The major adverse effects of epirubicin are acute dose-limiting haematotoxicity and cumulative dose-related cardiotoxicity. Other important adverse effects include mucositis, nausea and vomiting, reversible alopecia and local cutaneous reactions. However, the tolerability of epirubicin is better than that of doxorubicin at equimolar doses. CONCLUSION: Epirubicin has been extensively investigated in patients with breast cancer and has been found to be a highly effective agent, both for the treatment of patients with metastatic disease and as an adjuvant therapy. Recent trials have confirmed that, in selected patients requiring adjuvant therapy, FEC therapy is at least as effective as CMF, a standard treatment. FEC is also therapeutically equivalent to FAC in patients with metastatic breast cancer, and because the therapeutic index appears to be better the opportunity exists to increase dose intensity in an effort to improve efficacy. Such trials, and those of combinations of epirubicin with newer or alternative agents, should result in the introduction of more effective and better tolerated epirubicin-based protocols for adjuvant therapy and the management of patients with advanced breast cancer. In the meantime there is sufficient evidence to justify consideration of epirubicin for inclusion in first-line therapies for patients with early or metastatic breast cancer.     

Docetaxel: a review of its use in metastatic breast cancer

Docetaxel (Taxotere), a cytotoxic taxane, is an antimicrotubule agent effective in the treatment of patients with breast cancer. The clinical profile of docetaxel as an effective cytotoxic agent in the treatment of metastatic breast cancer is well established. As yet, no single standard regimen has been identified as optimal for the treatment of patients with metastatic breast cancer after failure of prior chemotherapy. However, the efficacy of docetaxel monotherapy administered every 3 weeks as a 1-hour infusion is similar to or better than that of doxorubicin, paclitaxel and fluorouracil plus vinorelbine, and better than that of methotrexate plus fluorouracil or mitomycin plus vinblastine. Although docetaxel is associated with neutropenia and other adverse events, its overall tolerability profile is generally acceptable in the majority of patients. Docetaxel, therefore, is an effective option in the treatment of patients with metastatic breast cancer after failure of prior chemotherapy.     

Role of pegylated liposomal doxorubicin (Caelyx) in the treatment of relapsing ovarian cancer

The most significant factor predicting response to second-line chemotherapy is the time interval elapsed from the end of chemotherapy to relapse occurrence. Two types of situations may be considered: patients with platinum-sensitive relapse (relapse-free interval longer than 6 months) and patients with platinum-refractory relapse (progression during treatment or relapse-free interval under 6 months). Pegylated liposomal doxorubicin is a doxorubicin formulation. Encapsulation in liposomes confers it different pharmacokinetic characteristics and a more favorable toxicity profile. The following review examines the efficacy and safety of pegylated liposomal doxorubicin for the treatment of relapsing epithelial ovarian cancer.     

Role of pegylated lyposomal doxorubicin (PLD) in systemic Kaposi's sarcoma: a systematic review

Kaposi's sarcoma (KS) is a form of skin cancer that can involve internal organs. It is often found in patients with acquired immunodeficiency syndrome (AIDS) and can be fatal. Kaposi's sarcoma produces pink, purple or brown tumors on the skin, mucous membranes or internal organs. Treatment goals for KS are simple: to reduce the severity of the symptoms, shrink tumors and prevent disease progression. Unfortunately, there is no single best treatment-plan that can achieve all these goals. With widespread KS lesions over the body surface or evidence of spreading to other parts of the body, the physicians need to treat the patients with systemic chemotherapy. A new class of drugs, called liposomal anthracyclines, appears to produce good results with fewer toxic side effects than more conventional cytotoxic drugs. One of these drugs, pegylated liposomal doxorubicin (PLD) has become the treatment of choice. This article summarizes all the studies with PLD in systemic Kaposi's sarcoma.     

Polyethylene glycol-liposomal doxorubicin: a review of its use in the management of solid and haematological malignancies and AIDS-related Kaposi's sarcoma

Polyethylene glycol (PEG)-liposomal doxorubicin is a formulation of the anthracycline doxorubicin in which the drug is encapsulated in PEG-coated liposomes. This alters the pharmacokinetic properties of doxorubicin, prolonging circulation time and enhancing localisation to tumours. In a large randomised trial, intravenous PEG-liposomal doxorubicin was at least as effective as topotecan in patients with ovarian cancer refractory or sensitive to first-line platinum-based chemotherapy. Overall response rates of patients with ovarian cancer refractory to platinum- and paclitaxel-based chemotherapy who received the drug ranged from 18.3 to 27.6% in noncomparative clinical trials. PEG-liposomal doxorubicin also has antitumour activity in patients with metastatic breast cancer pretreated with other chemotherapeutic agents. Overall response rates were similar in patients with pretreated metastatic breast cancer who had received PEG-liposomal doxorubicin or two comparator salvage chemotherapy regimens (vinorelbine or mitomycin C plus vinblastine) in an interim analysis of a large randomised study. In patients with advanced AIDS-related Kaposi's sarcoma, PEG-liposomal doxorubicin monotherapy produced overall response rates ranging from 46 to 77% in randomised trials. The drug was significantly more effective than bleomycin plus vincristine alone or in combination with standard doxorubicin, as measured by tumour response. As a replacement for standard doxorubicin in commonly used combination therapies, PEG-liposomal doxorubicin has shown activity in multiple myeloma and aggressive non-Hodgkin's lymphoma in small, preliminary trials. The most common adverse events associated with PEG-liposomal doxorubicin are myelosuppression, palmar-plantar erythrodysaesthesia, stomatitis and nausea. These can be managed by delaying or reducing dosages. Although preliminary trials are promising, the relative cardiotoxicity of PEG-liposomal doxorubicin compared with the standard formulation has not been clearly established. CONCLUSIONS: Monotherapy with PEG-liposomal doxorubicin is effective as a second-line chemotherapy in patients with platinum-refractory ovarian cancer and in patients with metastatic breast cancer. However, as with all chemotherapeutic agents, the benefits of treatment need to be weighed against the agent's tolerability profile. Strong comparative data have helped to establish PEG-liposomal doxorubicin as the first-line treatment option in patients with advanced Kaposi's sarcoma. Anticancer activity has also been observed in studies conducted in small numbers of patients with multiple myeloma or non-Hodgkin's lymphoma receiving PEG-liposomal doxorubicin instead of standard doxorubicin in combination regimens, although further data are needed to confirm the clinical relevance of these findings.     

Liposomal daunorubicin: new preparation. Kaposi's sarcoma: occasional remission

Liposomal daunorubicin rarely leads to complete remission of the unsightly mucocutaneous lesions Kaposi's sarcoma. One trial comparing liposomal daunorubicin with the ABV protocol (doxorubicin + bleomycin + vincristine) showed no statistically significant difference between the treatments in terms of efficacy or overall tolerability. Liposomal daunorubicin caused less hair loss and neuropathy, both of which can affect these patients' quality of survival, but it was more likely to cause neutropenia, sometimes requiring the use of haematopoeitic growth factors. There is some evidence that the liposomal formulation reduces the cardiotoxicity of daunorubicin, but this has to be confirmed, especially in the long term. It is not known whether increasing the dose of daunorubicin leads to better clinical efficacy. However, patients who relapse when liposomal daunorubicin is withdrawn may receive the drug again, without observing a cumulative dose limit, provided that cardiac function remains normal on the basis of tests recommended in the approved summary of product characteristics.     

Improved anti-tumor response rate with decreased cardiotoxicity of non-pegylated liposomal doxorubicin compared with conventional doxorubicin in first-line treatment of metastatic breast cancer in patients who had received prior adjuvant doxorubicin: results of a retrospective analysis

Our objectives were to ascertain the safety (cardiotoxicity) and efficacy of non-pegylated liposomal doxorubicin [Myocet (M)] compared with conventional doxorubicin (A) in patients with metastatic breast cancer (MBC) who had received adjuvant anthracycline treatment and were at high risk of developing iatrogenic cardiomyopathy. This retrospective analysis is based on data pooled from two prospective phase III comparative randomized clinical trials comparing Myocet versus conventional doxorubicin in combination with cyclophosphamide and as single agents, respectively, for the treatment of MBC. The outcome measures reviewed in this analysis were overall response, time to treatment failure, time to disease progression, overall survival and cardiotoxicity. The analysis was carried out by strata according to patients' previous exposure to adjuvant anthracyclines. Kaplan-Meier, log-rank chi-test, Cox proportional-hazards and Cochran-Mantel-Haenszel statistics were used for the analysis. Sixty-eight patients were included in this analysis: 29 and 39 patients from Studies 1 and 2, respectively, had received adjuvant anthracycline treatment. Study 1, with n=297, compared M 60 mg/m (M60) plus cyclophosphamide (C) 600 mg/m (C600) versus A 60 mg/m (A60) plus C600 as first-line treatment for MBC. Twenty-nine patients had received prior adjuvant doxorubicin, of whom, after randomization, 14 received M60+C600 and 15 received A60+C600 for the treatment of MBC. Study 2, with n=224, compared M 75 mg/m (M75) with A 75 mg/m (A75) as first-line treatment for MBC disease. Thirty-nine patients had received prior adjuvant doxorubicin, of whom, after randomization, 18 received M75 and 21 received A75 for their MBC. Hence, 32 patients received M-containing regimens and 36 received A-containing regimens for the treatment of MBC. Median age in both groups was 54 years. The groups were well balanced in terms of demographic characteristics. Overall response rates were 31% and 11% for M-treated patients and A-treated patients, respectively (Cochran-Mantel-Haenszel P=0.04, odds ratio=4.0). Median time to progression was 4.5 versus 3.4 months [log-rank P=0.66, hazard ratio (HR)=1.14], median time to treatment failure was 4.2 versus 2.1 months (log-rank P=0.01, HR=2.06) and median survival time was 16 versus 15 months (log-rank P=0.71, HR=1.12). Cardiac events occurred in 22% of M-treated patients [one congestive heart failure (CHF)] versus 39% of A-treated patients (three CHFs) (log-rank, P=0.001). Median lifetime dose at onset of cardiotoxicity was 780 mg/m for M versus 580 mg/m for A (log-rank P=0.001, HR=4.8). This retrospective analysis shows that treatment based on non-pegylated liposomal doxorubicin (Myocet) significantly reduced the risk of cardiotoxicity in patients with MBC who had received prior adjuvant doxorubicin. Furthermore, anti-tumor activity and time to treatment failure were significantly improved compared with patients who received treatment based on conventional doxorubicin for their MBC. This analysis revisits the therapeutic option of including doxorubicin in the treatment of MBC patients who have had prior adjuvant anthracycline exposure.