Pegylated Liposomal Doxorubicin in the Treatment of Breast Cancer

comprehensive

review

Pegylated Liposomal Doxorubicin in the Treatment of Breast Cancer Joyce A. O’Shaughnessy Abstract Anthracyclines, particularly conventional doxorubicin, play an important role in the treatment of breast cancer, both in the adjuvant and metastatic settings. However, the benefits of conventional doxorubicin in terms of antitumor activity are limited by its therapeutic index. Liposomal formulations were developed to increase the therapeutic index of conventional doxorubicin. Pegylated liposomal doxorubicin, the most widely studied liposomal doxorubicin formulation in breast cancer, has been evaluated in > 20 clinical trials. Pegylated liposomal doxorubicin provides tumor-targeted efficacy without many of the toxicities associated with conventional doxorubicin, including myelosuppression, alopecia, nausea and vomiting, and most importantly, cardiac toxicity. As a single agent, pegylated liposomal doxorubicin has demonstrated similar efficacy to that of conventional doxorubicin in patients with metastatic breast cancer. It has also demonstrated efficacy in combination with other agents or modalities, including cyclophosphamide, paclitaxel, docetaxel, gemcitabine, vinorelbine, and hyperthermia. Response rates in patients with metastatic breast cancer receiving pegylated liposomal doxorubicin either alone or in combination regimens range from 27% to 83%, with median survival estimated at 7-20 months. Small studies also suggest a role for pegylated liposomal doxorubicin in the treatment of locally advanced breast cancer. Preliminary results suggest that pegylated liposomal doxorubicin may be safely administered in combination with docetaxel and trastuzumab in patients with HER2-positive disease. Owing to its comparable efficacy and favorable safety profile, pegylated liposomal doxorubicin may be a useful alternative to conventional doxorubicin, as well as other agents commonly used in the treatment of breast cancer. Clinical Breast Cancer, Vol. 4, No. 5, 318-328, 2003 Key words: Cardiac toxicity, Liposomal anthracyclines, Metastatic breast cancer, Safety

Introduction Breast cancer is the most frequently diagnosed cancer in women, and it is expected to account for 31% of all new cancer cases in the United States in 2002.1 Despite the many advances in breast cancer treatment that have resulted in a decrease in mortality, breast cancer continues to be the most common cause of cancer death for women aged 20-59 years. Median survival ranges from 2 to 3 years in patients diagnosed with metastatic disease.2 Current research efforts are focused on the development of new agents or combination chemotherapy regimens that Charles A. Sammons Cancer Center, US Oncology, Baylor University Medical Center, Dallas, TX Submitted: ??; Revised: ??; Accepted: ?? Address for correspondence: Joyce A. O’Shaughnessy, MD, Codirector, Breast Cancer Research, US Oncology, Baylor Charles A. Sammons Cancer Center, Collins Bldg, 3535 Worth St, Dallas, TX 75246 Fax: 214-370-1055; e-mail: joyce.o’[email protected]

improve efficacy and minimize the toxicities associated with breast cancer treatment. While conventional doxorubicin is considered a mainstay of treatment in breast cancer due to its efficacy, its toxicity profile, particularly cardiac toxicity, limits its clinical use. This article reviews the current treatment options for breast cancer and will focus on the use of pegylated liposomal doxorubicin (PLD), a formulation of conventional doxorubicin that provides tumor-targeted efficacy without many of the toxicities associated with conventional doxorubicin, in the treatment of breast cancer.

Treatment Options for Metastatic Breast Cancer The goals for treating metastatic breast cancer are to extend survival, improve symptoms, and maintain or improve overall quality of life. Chemotherapeutic agents commonly used as first-line agents in metastatic breast cancer include anthracyclines (ie, doxorubicin, epirubicin), taxanes, cy-

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318 • Clinical Breast Cancer December 2003

Figure 1 Plasma Half-Life with Pegylated Liposomal Doxorubicin Versus Conventional Doxorubicin 25.0

Plasma Doxorubicin Concentration (mg/mL)

clophosphamide, fluorouracil, methotrexate, vinorelbine, and capecitabine. Reported objective response rates for these drugs range from 25% to 55% in patients who have received no prior chemotherapy in the metastatic setting.2,3 Patients with hormone receptor-positive tumors and limited to moderate disease generally should also receive hormonal therapy for metastatic disease, due to the established efficacy and limited toxicity associated with these agents. In premenopausal women, tamoxifen alone or in combination with a luteinizing hormone-releasing hormone agonist is the hormonal agent of choice.2,4 In postmenopausal women, the results of several recent trials suggest superior efficacy with aromatase inhibitors versus tamoxifen in women with metastatic breast cancer.5-8 Moreover, aromatase inhibitors (exemestane, letrozole, and anastrozole) have shown superior results versus megestrol acetate in patients with metastatic breast cancer who progressed on adjuvant or metastatic tamoxifen therapy.9-11 Measurement of objective response rates is standard in breast cancer trials; however, the value of these response rates is in their relationship to survival, quality of life, or both.2 Although several agents have demonstrated significant activity in metastatic breast cancer, there have been minimal data demonstrating that treatment produces a survival advantage in these patients. In a recent phase III trial comparing combination therapy with conventional doxorubicin and paclitaxel versus the same drugs given sequentially in patients with metastatic breast cancer, response rates and progression-free survival were improved in patients receiving combination therapy; however, combination therapy did not increase overall survival or quality of life.12 There is evidence, however, that newer chemotherapy regimens, such as paclitaxel- and docetaxel-containing combinations, prolong survival, with an overall range in survival time from 9 to 33 months.3,13-15 Moreover, the combination of docetaxel and capecitabine has been shown to produce a significant survival advantage versus docetaxel alone (P = 0.0126).16 In addition to prolonging survival, maintaining quality of life is an important factor in the metastatic breast cancer setting. Drugs that have a favorable safety profile and convenient dosing schedule are optimal treatment choices for this patient population.

10.0 5.0

Pegylated Liposomal Doxorubicin

2.5 1.0

0.25

Conventional Free Doxorubicin

0.05 0

4

8

12

16

20

24

Time Following Injection (Hours) Plasma clearance of doxorubicin after a single 50-mg/m2 dose of pegylated liposomal doxorubicin is higher when compared with an equal dose of conventional doxorubicin. Pegylated liposomal doxorubicin had a half-life of approximately 45 hours compared with a half-life of only minutes with conventional doxorubicin. Adapted with permission from Gabizon A, et al. Prolonged circulation time and enhanced accumulation in malignant exudates of doxorubicin encapsulated in polyethylene-glycol coated liposomes. Cancer Res 1994; 54:987-992.

include myelosuppression, acute nausea and vomiting, alopecia, stomatitis, and extravasation reactions.21-23 Research over the past several decades has focused on creating anthracycline analogues (eg, daunorubicin, epirubicin, idarubicin) that would maintain the broad activity profile of the class while minimizing the toxicity profile. However, cardiac toxicity has remained the treatment-limiting toxicity of these anthracycline analogues in patients with metastatic breast cancer.24 Recent research efforts have focused on the liposomal encapsulation of anthracyclines. The goal of liposomal encapsulation is to alter the tissue distribution and pharmacokinetics, thereby increasing the therapeutic index of conventional anthracyclines.22,25 There are currently 3 liposomal anthracycline formulations under clinical investigation for the treatment of breast cancer: liposomal daunorubicin, liposomal doxorubicin, and pegylated liposomal doxorubicin. The remainder of this review will focus on the efficacy and safety of PLD, which is commercially available and has been extensively studied in the treatment of breast cancer.

Conventional Doxorubicin in the Treatment of Breast Cancer

Pegylated Liposomal Doxorubicin

Conventional doxorubicin is considered one of the most active agents for the treatment of advanced breast cancer;2,3,17,18 however, the benefits of conventional doxorubicin in terms of antitumor activity are limited by its toxicity profile. Cardiac toxicity is the major dose-limiting toxicity associated with conventional doxorubicin, restricting the recommended cumulative lifetime dose to 450-550 mg/m2.19 A recent analysis of 3 phase III trials suggests that conventional doxorubicin-induced cardiac toxicity may occur at lower cumulative doses (≤ 300 mg/m2) and at a somewhat greater frequency than previously reported.20 Other toxicities associated with conventional doxorubicin

Pegylated liposomal doxorubicin represents a unique formulation of conventional doxorubicin. A polyethylene glycol layer surrounds the doxorubicin-containing liposome as a result of a process termed “pegylation.” Pegylation protects the liposomes from detection by the mononuclear phagocyte system and increases the plasma half-life compared with conventional doxorubicin (Figure 1).26,27 The size of these drug-containing vesicles allows the liposomes to extravasate through leaky tumor vasculature.28,29 This property, combined with its prolonged circulation time, results in drug accumulation in tissues with increased vascular permeability, such as tumor tissue (Figure 2).27,28,30-33 Animal models as

Clinical Breast Cancer December 2003 • 319

Pegylated Liposomal Doxorubicin for Breast Cancer posi sarcoma in patients with disease that has progressed on prior combination therapy or in patients who are intolerant to such therapy.42 Pegylated liposomal doxorubicin is being investigated in a variety of other cancer types, including multiple myeloma, non-Hodgkin’s lymphoma, and gynecologic malignancies. There is also increasing evidence that it demonstrates activity in breast cancer, leading to its recent approval in the European Union and in Canada as monotherapy for metastatic breast cancer in patients who are at increased cardiac risk, as well as its compendial listing in the United States for patients with metastatic breast cancer. While the majority of clinical studies have focused on the use of PLD in metastatic breast cancer, there is also some evidence supporting its use in combination regimens in patients with locally advanced breast cancer.

Figure 2 Proposed Mechanism of Pegylated Liposomal Doxorubicin Tumor Cells Tissue Compartment

2 1

4 3 4

Proposed mechanism depicting the tumor accumulation properties of pegylated liposomal doxorubicin. (1) Doxorubicin-containing liposomes circulate for 2-3 weeks after injection of pegylated liposomal doxorubicin. Drug remains encapsulated. (2) Liposomes extravasate through leaky tumor vasculature into the tissue compartment. (3) Free doxorubicin is released from the liposome. (4) Free doxorubicin penetrates into the tumor, killing tumor cells. Please note: for descriptive purposes, liposomes (approximately 0.1 μm) appear larger in this figure than they should relative to cells (approximately 10 μm). Adapted with permission from Martin F. Clinical pharmacology and anti-tumor efficacy of Doxil (pegylated liposomal doxorubicin). In: Lasic DD, Papahadjopoulos D, eds. Medical applications of liposomes. New York: Elsevier, 1998:638.

Efficacy of Single-Agent Pegylated Liposomal Doxorubicin Several clinical studies have demonstrated the efficacy of PLD as a single agent in the treatment of metastatic breast cancer (Table 1).17,42-44 A phase II study conducted by Ranson and colleagues was, effectively, a dose-finding study for PLD in patients with metastatic breast cancer.17 A total of 71 patients with metastatic breast cancer, most of whom had poor prognostic factors, were enrolled in the study. The initial dose of PLD was 60 mg/m2 every 3 weeks, which was decreased to 45 mg/m2 every 3 weeks, and then adjusted to a final dose of 45 mg/m2 every 4 weeks (as a result of hand-foot syndrome [HFS]). The median cumulative dose was 179 mg/m2 (range, 45-399 mg/m2). Sixty-four patients were evaluable for antitumor response, with 4 complete responses (CRs) and 16 partial responses (PRs), for an overall response rate of 31.3%. In addition, 20 patients maintained stable disease (SD); therefore, clinical benefit was achieved in 40/64 patients (62.5%). Median overall sur-

well as trials using radiation-labeled liposomes support this theory regarding the tumor accumulation properties of PLD.34-39 Tumor localization of these long-circulating liposomes can be considered a passive targeting effect, allowing for accumulation of liposome-encapsulated drug at the tumor location.40 Pegylated liposomal doxorubicin is currently indicated for the treatment of metastatic ovarian cancer in patients with disease refractory to both paclitaxel- and platinumbased chemotherapy regimens.41 It is also indicated for the treatment of autoimmune deficiency syndrome–related Ka-

Table 1 Studies of Single-Agent Pegylated Liposomal Doxorubicin in Metastatic Breast Cancer Study

Trial Design

PLD Dosage

Efficacy

Common Toxicities

Ranson et al17 (N = 71)

Dose-finding (Phase II)

45 mg/m2 every 4 weeks

Response rate, 31.3% (4 CRs, 16 PRs); median survival, 7 months

Mucositis, skin toxicity

Dose- and schedule-finding (Phase II)

35-70 mg/m2 every 3-6 weeks

Response rate, 33.3% (2 CRs, 7 PRs, 6 improvement); median survival, 16 months

Stomatitis, HFS

Wigler et al43 (N = 509)

Comparative vs. conventional doxorubicin (Phase III)

50 mg/m2 every 4 weeks

Response rate, 27%; median survival, 21 months; no significant differences vs. conventional doxorubicin

HFS; decreased cardiac toxicity, myelosuppression, alopecia, and nausea and vomiting vs. conventional doxorubicin

Keller et al44 (N = 301)

Comparative vs. standard salvage chemotherapy* (Phase III)

50 mg/m2 every 4 weeks

Median survival, 10.4 months; no significant differences vs. salvage chemotherapy

HFS, stomatitis

Lyass et al42 (N = 45)

*Vinorelbine or mitomycin C/vinblastine. Abbreviations: HFS = hand-foot syndrome; PLD = pegylated liposomal doxorubicin

320 • Clinical Breast Cancer December 2003

Joyce A. O’Shaughnessy vival was calculated to be 7 months. Ranson and colleagues concluded that a dose of 45 mg/m2 every 4 weeks was effective and well tolerated in this group of patients with metastatic breast cancer. Lyass and colleagues conducted a phase II dose- and schedule-finding study in 45 patients with metastatic breast cancer who were previously treated with chemotherapy.42 Thirty-two patients (71.1%) had received prior anthracycline therapy. Six doses/regimens were studied for a median of 5 cycles: 35 mg/m2 every 3 weeks (n = 11), 45 mg/m2 every 3 weeks (n = 5), 50 mg/m2 every 4 weeks (n = 5), 60 mg/m2 every 4 weeks (n = 6), 65 mg/m2 every 5 weeks (n = 6), and 70 mg/m2 every 6 weeks (n = 12). Fifteen patients (33.3%) demonstrated a positive response, defined as a CR (2 patients), PR (7 patients), or improvement (6 patients; used for patients with nonmeasurable disease to describe clinical improvement, > 50% decrease in tumor markers and no new lesions). Responses were observed in all dose schedule groups. In patients previously treated with anthracyclines (n = 32), there were 5 PRs and 2 improvements. Median survival was estimated to be 16 months, with 1- and 3-year survival estimates of 66% and 38%, respectively. In a recently completed phase III study, Wigler and colleagues compared the efficacy and safety of PLD with that of conventional doxorubicin as first-line therapy in 509 patients with metastatic breast cancer.43 Patients were randomly assigned to receive a standard dose of 60 mg/m2 every 3 weeks of conventional doxorubicin (until disease progression or a cumulative dose of 550 mg/m2) or PLD 50 mg/m2 every 4 weeks (until disease progression or unacceptable toxicity). There was no difference in progressionfree survival between the PLD and conventional doxorubicin groups (6.9 months vs. 7.8 months, respectively; hazard ratio [HR; 95% CI] = 1.00 [0.82-1.22]). Likewise, overall survival was not significantly different between the PLD and conventional doxorubicin groups (21 months vs. 22 months, respectively; HR = 0.94 [0.74-1.19]). Results from this study confirm the similar efficacy of PLD and conventional doxorubicin, a standard agent for the treatment of metastatic breast cancer. Pegylated liposomal doxorubicin has also been compared with standard salvage chemotherapy regimens (vinorelbine or mitomycin C/vinblastine) in a phase III study in patients with refractory advanced breast cancer.44 Progression-free and overall survival were similar in both treatment groups. In summary, clinical trials demonstrate that PLD and conventional doxorubicin exhibit comparable efficacy in patients with metastatic breast cancer. Pegylated liposomal doxorubicin as a single agent may be a useful alternative to conventional doxorubicin for the treatment of metastatic breast cancer, owing to its comparable efficacy and favorable tolerability profile, which is described in detail later in this review.

Combination Therapy with Pegylated Liposomal Doxorubicin Several clinical studies have been conducted to evaluate the efficacy and safety of PLD in combination with other agents in patients with metastatic breast cancer (Table 2).

Pegylated Liposomal Doxorubicin/ Cyclophosphamide Pegylated liposomal doxorubicin in combination with cyclophosphamide was evaluated in a phase Ib, open-label pilot study as first-line treatment for patients recently diagnosed with metastatic breast cancer.45 Based on the activity observed in 10 patients with metastatic breast cancer who received PLD 50 mg/m2 every 28 days and cyclophosphamide 100 mg/m2 orally on days 1-14 of each cycle, 20 patients were enrolled in a second dosing cohort and received PLD 30 mg/m2 plus cyclophosphamide 600 mg/m2 intravenously every 21 days. The most commonly reported toxicities included infusion reactions, neutropenia, HFS, and stomatitis. Objective responses were observed in 7/17 evaluable patients (1 CR, 6 PRs), for an objective response rate of 41.2%. Based on the activity and tolerability of the PLD and cyclophosphamide combination, additional patients were enrolled in a third dosing cohort to receive cyclophosphamide and an increased dose of PLD. The final results of this study are still pending.

Pegylated Liposomal Doxorubicin/Paclitaxel Pegylated liposomal doxorubicin in combination with paclitaxel was evaluated in a phase II trial conducted by Jones and colleagues during which patients with locally advanced or metastatic breast cancer received PLD 45 mg/m2 every 4 weeks and paclitaxel 80 mg/m2 weekly (N = 18).46 Thirteen patients had received previous adjuvant chemotherapy (7 conventional doxorubicin; range, 50-318 mg/m 2), but none had received prior treatment for metastatic disease. Of the 12 patients evaluable for efficacy, there were 2 CRs and 7 PRs, for an objective response rate of 75%. The duration of response has not been determined. In 16 patients evaluable for toxicity, treatment was well tolerated. Grade 3/4 neutropenia was observed in 8 and 3 patients, respectively, and 1 patient required hospitalization for febrile neutropenia. Grade 3/4 mucositis was reported in 5 and 1 patients, respectively. No significant decrease (> 10%) in left ventricular ejection fraction (LVEF) and no clinical heart failure were reported, including in those patients with prior adjuvant doxorubicin exposure. The combination of PLD and paclitaxel has also been studied in 2 additional phase II studies as first-line treatment for patients with advanced breast cancer.47,48 Patients in both studies received PLD 30 mg/m2 and paclitaxel 175 mg/m2 every 21 days. In the first study, a response rate of 73% was observed; median survival has not been reached.47 The most commonly reported grade 3/4 toxicities with the combination were neutropenia and HFS. Reported response rate in the second study was 70%, with a median survival of

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Pegylated Liposomal Doxorubicin for Breast Cancer Table 2 Studies of Combination Pegylated Liposomal Doxorubicin Treatment in Metastatic Breast Cancer Study

Trial Design

Regimen

Efficacy

Common Toxicities

Overmoyer et al45 (N = 20)

Pilot study; first-line metastatic treatment (Phase Ib)

PLD 30 mg/m2 Cyclophosphamide 600 mg/m2 every 3 weeks

RR, 41.2% (1 CR, 6 PRs)

Infusion reaction, neutropenia, HFS, stomatitis

Jones et al46 (N = 18)

First-line metastatic treatment (Phase II)

PLD 45 mg/m2 every 4 weeks Paclitaxel 80 mg/m2 weekly

RR, 75% (2 CRs, 7 PRs)

Neutropenia, mucositis

Vorobiof et al47 (N = 34)

First-line advanced breast cancer (Phase II)

PLD 30 mg/m2 Paclitaxel 175 mg/m2 every 21 days

RR, 73% (7 CRs, 8 PRs)

Neutropenia, HFS

Rigatos et al48 (N = 23)

First-line advanced breast cancer (Phase II)

PLD 30 mg/m2 Paclitaxel 175 mg/m2 every 21 days

RR, 70% (2 CRs, 14 PRs); median survival, 10 months

HFS

Sparano et al49 (N = 41)

Phase I

PLD 30-45 mg/m2 Docetaxel 60-75 mg/m2 every 3 weeks

RR, 55.2% (1 CR, 15 PRs); median survival, 18 months

Neutropenia, hyperglycemia, stomatitis, HFS

Alexopoulos et al51 (N = 32)

First-line metastatic treatment (Phase II)

PLD 30 mg/m2 Docetaxel 75 mg/m2 every 21 days

RR, 83% (6 CRs, 14 PRs)

Neutropenia

Athanassiou et al52 (N = 19)

First-line metastatic treatment (Phase II)

PLD 30 mg/m2 Docetaxel 70 mg/m2 every 21 days

RR, 47% (3 CRs, 6 PRs)

Neutropenia, HFS, alopecia

Rivera et al53 (N = 27)

Phase I

PLD 20 mg/m2 day 1 escalated by 20% every cycle Gemcitabine 800 mg/m2 days 1 and 8 every 3 weeks

RR, 33.3% (2 CRs, 7 PRs)

Neutropenia, thrombocytopenia

Rivera et al54 (N = 49)

First-line metastatic treatment (Phase II)

PLD 24 mg/m2 day 1 Gemcitabine 800 mg/m2 days 1 and 8 every 3 weeks

RR, 52% (3 CRs, 21 PRs); median survival, 16.1 months

Hematologic, nausea and vomiting, fatigue, stomatitis, HFS

Phase I/II

PLD 45 mg/m2 Hyperthermia every 28 days

RR, 60.0% (1 CR, 11 PRs)

HFS, mucositis, neutropenia, thermal burn

Park et al58 (N = 23)

Abbreviations: HFS = hand-foot syndrome; PLD = pegylated liposomal doxorubicin

10 months (range, 4-20 months).48 Hand-foot syndrome occurred in almost one-half of the patient group (48%).

Pegylated Liposomal Doxorubicin/Docetaxel Sparano and colleagues conducted a phase I study of PLD in combination with docetaxel in patients with locally advanced and metastatic breast cancer (N = 41).49 During the initial phase of the trial, when the maximum tolerated dose and dose-limiting toxicity were defined, patients received 30, 40, or 45 mg/m2 of PLD, followed by 60-75 mg/m2 of docetaxel every 3-4 weeks. Dose-limiting toxicity was defined as febrile neutropenia or grade 3/4 nonhematologic toxicity. Of the 41 patients treated, 34% had received adjuvant therapy, 22% had received prior conventional doxorubicin, and 10% had received prior chemotherapy for metastatic disease. The investigators determined that the maximum tolerated dose of PLD was 30 mg/m2 in combination with docetaxel 60 mg/m2 every 3 weeks, without

322 • Clinical Breast Cancer December 2003

concomitant granulocyte colony-stimulating factor. Of the 29 patients with metastatic disease who were evaluable for response, 16 patients (55.2%) demonstrated an objective response (1 CR, 15 PRs). In the 9 patients with stage III disease, 88% had an objective response. Of the 12 patients treated at the recommended dose and schedule (PLD 30 mg/m2; docetaxel 60 mg/m2 every 3 weeks), there was a 42% objective response rate. Median overall survival was 18 months, median response duration was 7 months, and median time to tumor progression was 8 months. Grade 3/4 toxicities (at the recommended doses) included neutropenia (60%), hyperglycemia (20%), stomatitis (13%), and HFS (13%). Only 13% of patients experienced vomiting, which was mild. No patients developed clinical evidence of congestive heart failure, including those patients who received prior conventional doxorubicin treatment. A phase I dose and sequencing study evaluated the combination of PLD and docetaxel in patients (N = 22) with

Joyce A. O’Shaughnessy advanced malignancies, including breast cancer.50 Doselimiting toxicities included grade 3 skin toxicity and thrombocytopenia. The authors recommended phase II study of PLD 20 mg/m2 followed by docetaxel 40 mg/m2 on days 1 and 15 every 28 days in patients with breast cancer to establish the efficacy of this well tolerated regimen. The combination of PLD and docetaxel has been further explored in 2 phase II studies recently presented during the Annual Meeting of the American Society of Clinical Oncology.51,52 In a study conducted by Alexopoulos and colleagues, 32 patients received PLD 30 mg/m2 in combination with docetaxel 75 mg/m2 every 21 days for the first-line treatment of metastatic breast cancer.51 Response rate was 83%, and the most common grade 3/4 toxicity was neutropenia. In the second study, done by Athanassiou and colleagues, patients (N = 19) with metastatic breast cancer were treated with PLD 30 mg/m2 and docetaxel 70 mg/m2 every 21 days.52 Forty-seven percent of patients had an objective response. Grade 3/4 toxicities included neutropenia, HFS, and alopecia.

Pegylated Liposomal Doxorubicin/Gemcitabine The combination of PLD and gemcitabine has also been evaluated in the treatment of metastatic breast cancer. Rivera and colleagues conducted a phase I study to evaluate the safety and efficacy of this combination in patients with metastatic breast cancer (N = 27).53 Patients received a fixed dose of gemcitabine 800 mg/m2 on days 1 and 8. Pegylated liposomal doxorubicin was administered at a starting dose of 20 mg/m2 on day 1 of the 21-day cycle, and the dose was escalated by 20% each cycle until the maximum tolerated dose was reached. Twenty-three of 27 patients (85%) had received prior conventional doxorubicin. The dose-limiting toxicity was myelosuppression. Grade 3/4 nonhematologic toxicities were generally gastrointestinal in nature and not a significant problem, and there was no evidence of cardiac toxicity. Of the 27 evaluable patients, there were 2 CRs (7%), 7 PRs (26%), and 2 minor responses (7%). Eight patients (30%) had SD. Based on this study, the recommended dose for further study was PLD 24 mg/m2 on day 1 and gemcitabine 800 mg/m2 on days 1 and 8 every 21 days. The dose recommended from this phase I study was further evaluated in a phase II trial in patients with metastatic breast cancer (N = 49).54 A total of 27 patients (55%) had received adjuvant chemotherapy: 8 received singleagent anthracycline, 11 received anthracycline/taxane, and 8 received CMF (cyclophosphamide/methotrexate/fluorouracil). No patients had received prior chemotherapy for metastases. Three CRs (6.5%) and 21 PRs (46%) were achieved in 46 evaluable patients for an overall response rate of 52%. Median overall survival was 16.1 months. Median response duration and time to progression were 5.6 and 4.5 months, respectively. The most common grade 3/4 toxicities were hematologic; however, few neutropenic complications resulted. The most frequent nonhematologic toxicities were nausea and vomiting, fatigue, stomatitis, and

HFS. One patient experienced a transient decrease > 20% in LVEF, with cardiac function recovering within 2 months after completion of therapy.

Pegylated Liposomal Doxorubicin/Hyperthermia Another potential combination therapy that is currently being explored is PLD and hyperthermia (HT). Previous preclinical studies have shown that HT can facilitate PLD accumulation in tumors.55-57 These results provided the rationale for the first phase I/II study of HT of the chest wall and PLD combination therapy in patients with metastatic breast cancer (N = 23).58 Patients received HT via 16-element planar array microwave or ultrasound applicators. One hour after HT therapy, patients received PLD 45 mg/m2, with HT/PLD repeated every 28 days. The combination was well tolerated. Toxicities that occurred were expected with either modality. Grade 2 toxicities included HFS, mucositis, neutropenia, and thermal burn. One patient developed grade 3 congestive heart failure. Of the 20 patients evaluable for response, there was 1 CR and 11 PRs, for an objective response rate of 60%. In patients with additional chest wall tumors outside the HT region, there were 6 PRs (35%) caused by PLD alone. It was concluded that HT improved efficacy by increasing PLD uptake in the tumor cells. The efficacy of PLD and HT combination therapy has also been demonstrated in other tumor types, including skin metastases of breast carcinoma59 and advanced hepatocellular carcinoma.60 In summary, PLD has shown efficacy in several combination regimens, including cyclophosphamide,45 paclitaxel,46-48 docetaxel,49-52 gemcitabine,53,54 and HT,58 for the treatment of breast cancer. These combinations are generally tolerable; however, the incidence of myelosuppression may be increased, requiring lower doses of PLD than can be safely used during single-agent therapy. It is noteworthy that cardiac safety was improved compared with conventional doxorubicin when PLD was incorporated into these combination regimens. In addition, results from these studies suggest prior therapy with conventional anthracyclines does not affect subsequent activity and tolerability with PLD.

Pegylated Liposomal Doxorubicin in Locally Advanced Breast Cancer Results from 2 small studies show the efficacy and tolerability of PLD as neoadjuvant therapy for patients with locally advanced breast cancer. In a phase II study, performed by the Hellenic Cooperative Oncology Group, PLD in combination with paclitaxel was effective in the management of locally advanced breast cancer.61 In this trial, 35 women with newly diagnosed advanced breast cancer received PLD 35 mg/m2 plus paclitaxel 175 mg/m2 every 3 weeks. Twenty-five patients (71.4%) had a response, including 6 CRs and 19 PRs. No survival data are available to date. The primary toxicity observed was skin toxicity, with grade 3 HFS observed in 3 patients (9%). Hematologic toxicity included grade 3 leukopenia in 4 patients (11%). Other grade 3 adverse events

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Pegylated Liposomal Doxorubicin for Breast Cancer Table 3 Comparative Safety of Pegylated Liposomal Doxorubicin Versus Conventional Doxorubicin43 Event

Pegylated Liposomal Doxorubicin (n = 254) All Grades

Grade 3

Conventional Doxorubicin (n = 255)

Grade 4

All Grades

Grade 3

Grade 4

Alopecia

51 (20%)

0

0

169 (66%)

0

0

Anemia

12 (5%)

2 (< 1%)

1 (< 1%)

19 (7%)

3 (1%)

1 (< 1%)

Cardiac Toxicity

10 (4%)

NA

NA

48 (19%)

NA

NA

0

0

NA

NA

Erythema

18 (7%)

2 (< 1%)

0

3 (1%)

Infusion Reactions

32 (13%)

NA

NA

8 (3%)

Mucositis

59 (23%)

10 (4%)

0

33 (13%)

5 (2%)

0

Nausea

94 (37%)

8 (3%)

0

136 (53%)

12 (5%)

0

Neutropenia

10 (4%)

3 (1%)

1 (< 1%)

25 (10%)

10 (4%)

9 (4%)

Hand-Foot Syndrome

123 (48%)

42 (17%)

0

5 (2%)

0

0

Rash

25 (10%)

6 (2%)

0

4 (2%)

0

0

Stomatitis

55 (22%)

12 (5%)

0

38 (15%)

4 (2%)

0

2 (< 1%)

0

78 (31%)

11 (4%)

0

Vomiting

48 (19%)

were uncommon, and included alopecia in 29 patients (83%), which the investigators attributed to the paclitaxel component of the regimen. There was no grade 3/4 neurotoxicity. Dose reductions were necessary in 7 patients (6 for skin toxicity and 1 for neutropenia). Pegylated liposomal doxorubicin has also been studied in combination with cyclophosphamide in patients with locally advanced breast cancer (N = 32) in a phase II study by Srimuninnimit and colleagues.62 Patients received PLD 35 mg/m2 plus cyclophosphamide 600 mg/m2 every 3 weeks for 3 cycles. Responding patients underwent modified radical mastectomy and PLD and cyclophosphamide combination therapy for 4 additional cycles, followed by local radiation therapy and tamoxifen for 5 years (patients with hormone receptor-positive tumors only). Objective responses were observed in 73% of patients. Grade 3/4 adverse events included anemia, leukopenia, neutropenia, nausea and vomiting, stomatitis, alopecia, HFS, and infusion-related reactions.

Toxicity Profile of Pegylated Liposomal Doxorubicin The tolerability of PLD has been demonstrated in several clinical trials.17,42-44 Myelosuppression was generally dose dependent, but mild, and nausea and vomiting and alopecia were uncommon.17,42,43 Despite cumulative doses as high as 1500 mg/m2 of PLD and prior adjuvant anthracycline therapy, cardiac toxicity was seldom observed.17,42-44 Mucositis and skin toxicity, such as HFS, were the most notable side effects, which were found to be dose and schedule dependent based on pharmacokinetic analyses.42 The frequency and severity of stomatitis were dose related, with the highest incidence occurring at PLD doses of 60-70 mg/m2. By definition, HFS is characterized by erythema and swelling of the

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palms of the hands and the soles of the feet; however, it may also affect other areas that experience pressure or friction, such as the waistband and under the breasts. Hand-foot syndrome occurred after ≥ 2 cycles of treatment and occurred with greater frequency and severity with shorter dosing intervals.17,42,43 A correlation analysis of dose and pharmacokinetic parameters with PLD toxicities demonstrated that dose and peak plasma concentration were strongly correlated with stomatitis and myelosuppression, and half-life was significantly correlated with HFS.42 The toxicity profile of PLD was compared with that of conventional doxorubicin in a phase III study conducted by Wigler and colleagues (Table 3).43 Baseline and disease characteristics were similar between treatment groups. Thirtyeight patients (15%) in the PLD group and 40 patients (16%) in the conventional doxorubicin group had received prior adjuvant anthracycline therapy. While efficacy was comparable between treatment groups, PLD demonstrated reduced cardiac toxicity, myelosuppression, alopecia, and nausea and vomiting. Moreover, pronounced or total hair loss occurred in 7% of PLD-treated patients compared with 54% of conventional doxorubicin–treated patients. Prior exposure to conventional doxorubicin did not negatively impact tolerability to PLD. Pegylated liposomal doxorubicin demonstrates an improved cardiac toxicity profile compared with that of conventional doxorubicin.43,63-65 In the comparative study conducted by Wigler and colleagues, 10 PLD-treated patients compared with 48 conventional doxorubicin–treated patients developed cardiac toxicity (measured by changes in LVEF).43 The overall risk for developing cardiac toxicity was significantly higher with conventional doxorubicin compared with that of PLD (P < 0.001). Moreover, at doses of > 500-550

Joyce A. O’Shaughnessy mg/m2, there was a 40% risk of developing a cardiac event with conventional doxorubicin compared with an 11% risk with PLD. In subgroups of patients with an increased risk for cardiac toxicity, there was less risk with PLD than with conventional doxorubicin. For example, there was a 7 times greater risk of cardiac toxicity with conventional doxorubicin (n = 11) compared with that of PLD (n = 1) in patients who received prior adjuvant anthracycline therapy (HR, 7.27). In addition, results from several studies presented herein suggest that prior therapy with conventional anthracyclines does not affect subsequent cardiac safety with PLD.43,46,49,54 The relative cardiac safety of PLD is one of the clearest differentiating aspects of PLD compared with conventional doxorubicin.

Management of Common Toxicities Hand-foot syndrome is the most common adverse event associated with PLD, generally developing after 2-3 cycles of therapy. The incidence and severity of HFS appear to be schedule (ie, dose and cycle) dependent.43,66,67 In most cases, HFS is mild and resolves within 1-2 weeks without requiring discontinuation of therapy. To prevent HFS, patients should avoid the following for 24 hours before and 35 days following drug administration: tight clothing and shoes, steam and hot baths/showers, direct sunlight, friction-causing activities, and excessive exercise.68 Early assessment of HFS is key in preventing further complications. Although support for its use is anecdotal, some patients with HFS are treated with oral pyridoxine (100-300 mg/day).69,70 Stomatitis/mucositis is also associated with PLD therapy and appears to be dose related.42 Dose modifications for stomatitis are similar to those for HFS, with dose delays and reductions based upon the severity of the symptoms observed. For patients with grade 1/2 HFS or stomatitis, the recommended guidelines for dose modification suggest extending the dosing interval up to 2 weeks, or until the event has resolved. In the case of grade 3/4 HFS or stomatitis, it is recommended to delay dosing up to 2 weeks or until resolution to grade 0/1, and then decrease the dose by 25% and return to the original dose interval.41 In an effort to reduce the dose- and schedule-dependent adverse events associated with PLD (ie, stomatitis and HFS, respectively), some clinicians empirically reduce the dose of PLD or extend the dosing interval. Results of preliminary studies in patients with metastatic breast cancer suggest that these alternative dosing regimens improve the tolerability of PLD without compromising its antitumor activity.71 A retrospective analysis was performed to test the hypothesis that toxicities can be minimized by administering lower doses of PLD at less frequent intervals. The rationale for this analysis was based on anecdotal experience that a dosage of 40 mg/m2 every 4 weeks was well tolerated. A consecutive series of 40 patients with metastatic breast cancer who had received PLD were identified from a private practice in Florida. The median initial dose of PLD was 42.5 mg/m2, and it was generally administered every 4 weeks. Efficacy was maintained

at the lower doses, with 10 PRs and 7 patients with SD for > 6 months, resulting in a clinical benefit rate of 43%. As anticipated, the toxicity profile was improved over that seen with PLD dosing schedules used in previous studies (50 mg/m2 every 4 weeks).42-44 There was no grade 4 toxicity, and the only grade 3 toxicities were leukopenia (18%), mucositis (3%), and HFS (3%).71 The results of this retrospective analysis, combined with those of Ranson and colleagues,17 suggest that PLD at a dosage of 40-45 mg/m2 every 4 weeks deserves prospective study in patients with metastatic breast cancer. The schedule dependence of HFS also has been confirmed in studies of patients with ovarian cancer.66,67 In addition to HFS and stomatitis, infusion-related reactions may be observed during the first minutes of the initial PLD infusion.68 Although these reactions mimic hypersensitivity reactions in terms of symptom presentation, it is thought that a different mechanism is involved. It has been suggested that complement activation may play a role in these reactions.72 Patients who do not have an infusion-related reaction during the first cycle of PLD generally do not have subsequent reactions. In an attempt to reduce these reactions, some clinicians administer PLD over a 2.5-hour time period (vs. 1-hour infusion time recommended in the prescribing information).42,53,68

Future Direction Trastuzumab has demonstrated antitumor activity as a single agent for the treatment of breast cancer,73-75 and prolongs overall survival when used in combination with established chemotherapy agents in patients with HER2-positive metastatic disease.76 In a phase III trial conducted by Slamon and colleagues, patients with metastatic breast cancer were assigned randomly to receive chemotherapy as a single agent or in combination with trastuzumab.76 A combination of anthracycline, cyclophosphamide, and trastuzumab was the most effective regimen in terms of response rate (56% vs. 17%-42% with other regimens) and survival (26.8 months vs. 18.4-22.1 months). However, this regimen was associated with an unacceptably high incidence of cardiac toxicity (27% of patients in this group had symptomatic or asymptomatic cardiac dysfunction, based on a retrospective analysis by an independent cardiac review and evaluation committee). Investigators are currently evaluating the effects of substituting a liposomal doxorubicin formulation for conventional doxorubicin in this regimen. In a phase I/II study of liposomal doxorubicin in combination with trastuzumab in patients with advanced breast cancer, cardiac safety appeared to be acceptable, with reversible cardiac toxicity seen in 2 of 39 patients.77 An overall response rate of 59% was reported. Based on the positive responses and improved cardiac safety reported with this formulation of liposomal doxorubicin plus trastuzumab and the demonstrated cardiac safety of PLD, PLD in combination with trastuzumab may offer clinical benefit to patients with HER2-positive breast cancer. The Eastern Cooperative Oncology Group is currently

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Pegylated Liposomal Doxorubicin for Breast Cancer evaluating the efficacy and safety of PLD in combination with docetaxel with or without trastuzumab (based on HER2 status) in patients with metastatic breast cancer (E3198). Early results from this study were presented by Wolff and colleagues at the 2003 Annual Meeting of the American Society of Clinical Oncology.78 Treatment includes PLD 30 mg/m2 and docetaxel 60 mg/m2 every 3 weeks in patients with HER2-negative disease, and PLD 30 mg/m2 and docetaxel 60 mg/m2 every 3 weeks combined with trastuzumab, 4 mg/kg initially and 2 mg/kg weekly thereafter, in HER2-positive disease. Preliminary evaluation of cardiac function in 22 patients at baseline and after 4 cycles of therapy with PLD, docetaxel, and trastuzumab showed no significant effect on LVEF (≤ 4%) and no clinical episodes of congestive heart failure. Cardiac safety has also been shown when PLD and trastuzumab are administered sequentially.79 While trastuzumab combined with chemotherapy has been shown to extend survival in patients with HER2-positive metastatic breast cancer compared with chemotherapy alone,76 it may provide even greater benefit in patients with early-stage breast cancer. There are currently several ongoing studies that are examining the use of trastuzumab given sequentially with conventional doxorubicin in the adjuvant setting.80 Pegylated liposomal doxorubicin in combination with trastuzumab may also be a viable treatment option in the adjuvant setting, based on its improved therapeutic index compared with conventional doxorubicin.

Conclusion Clinical studies demonstrate that PLD is as effective as conventional doxorubicin, either alone or in combination with other agents, as front-line or salvage therapy in patients with metastatic breast cancer. Objective response rates range from 27% to 83%, and they compare favorably with those reported in patients with metastatic breast cancer treated with other chemotherapy regimens (25%-55%).2 Pegylated liposomal doxorubicin has also shown efficacy in the neoadjuvant setting in patients with locally advanced breast cancer. In addition, preliminary data support the clinical utility of PLD, docetaxel, and trastuzumab in patients with HER2-positive metastatic breast cancer. Pegylated liposomal doxorubicin provides an improved therapeutic index compared with that of conventional doxorubicin, with a significantly decreased risk of cardiac toxicity and decreased myelosuppression, nausea and vomiting, and alopecia.43 Moreover, cardiac safety is maintained in patients with prior conventional anthracycline exposure. These benefits perhaps make PLD a suitable agent for consideration in the elderly or in patients with preexisting cardiac disease. Pegylated liposomal doxorubicin may also have clinical utility in patients with anthracycline-sensitive breast cancer who reach the maximum lifetime cumulative dose of conventional doxorubicin in the adjuvant setting and cannot continue with therapy due to cardiac toxicity concerns.

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Adverse events associated with PLD, namely HFS and mucositis, are schedule and dose related and typically do not lead to discontinuation of therapy. These events can be successfully managed dose or schedule modifications. The favorable safety profile of PLD combined with its convenient once-monthly dosing schedule may also translate into an improved quality of life for patients with breast cancer, based on its positive effects on quality of life in patients with ovarian cancer.81 Pegylated liposomal doxorubicin, the most widely studied liposomal doxorubicin formulation in breast cancer, has been evaluated in more than 20 clinical trials. Based on the clinical evidence reviewed, it appears that PLD is a viable therapeutic option as a front-line agent in patients with metastatic breast cancer. Small studies also suggest a role for PLD in the neoadjuvant setting in patients with locally advanced breast cancer. Further evaluation of PLD in the adjuvant setting, especially in elderly patients and in patients with cardiac disease, may also be warranted based on its efficacy and safety in patients with locally advanced and metastatic breast cancer.

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