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Phase II Study of Pegylated Liposomal Doxorubicin in Combination With Gemcitabine in Patients With Metastatic Breast Cancer

Edgardo Rivera, Vicente Valero, Banu Arun, Melanie Royce, Rosni Adinin, Karen Hoelzer, Ronald Walters, James L. Wade, III, Lajos Pusztai, Gabriel N. Hortobagyi

From The Department of Breast Medical Oncology, Division of Cancer Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, TX; M.D. Anderson Community Clinical Oncology Program, Decatur, IL.

Address reprint requests to Edgardo Rivera, MD, Department of Breast Medical Oncology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Unit 424, Houston, TX 77030-4009; e-mail: erivera{at}mail.mdanderson.org.

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Purpose: We conducted a phase II clinical trial to determine the clinical efficacy and safety of pegylated liposomal doxorubicin in combination with gemcitabine in patients with metastatic breast cancer.

Patients and Methods: Patients were eligible if they had measurable disease, no prior chemotherapy for metastatic disease, and a performance status 2 on the Zubrod scale. Patients received pegylated liposomal doxorubicin 24 mg/m² intravenously on day 1, plus gemcitabine 800 mg/m² intravenously on days 1 and 8 of each 21-day cycle.

Results: Of 49 patients enrolled, 27 had received prior adjuvant chemotherapy (19 with an anthracycline). Prior median cumulative anthracycline dose was 240 mg/m². In total, three complete responses and 21 partial responses were achieved in 46 assessable patients, for an overall response rate of 52% (95% confidence interval, 37% to 67%). Responses were observed in 11 (58%) of 19 patients with previous anthracycline exposure. Median response duration was 5.6 months, time to progression was 4.5 months, and overall survival was 16.1 months. Although the most common grade 3 to 4 toxicities were hematologic, few neutropenic complications resulted. The most frequent nonhematologic toxicities were nausea and vomiting, fatigue, stomatitis, and hand-foot syndrome. One patient previously treated with an anthracycline developed a transient decrease (21%) in the left ventricular ejection fraction, with cardiac function recovering within 2 months.

Conclusion: Pegylated liposomal doxorubicin in combination with gemcitabine is active and well tolerated in patients with metastatic breast cancer. Median overall survival was 16.1 months, and approximately 78% of patients derived clinical benefit from treatment. This regimen represents a therapeutic option for patients receiving front-line therapy for their metastatic breast cancer.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
DOXORUBICIN IS one of the most widely used anticancer drugs for the treatment of solid tumors and hematologic malignancies. It is active against a variety of cancer types, and is used extensively as a single agent and in combination chemotherapy regimens. In addition to its pivotal role in the treatment of breast cancer, doxorubicin has also demonstrated antitumor activity in ovarian, cervical, endometrial, gastric, bladder, and small-cell lung cancer, uterine sarcoma, acute lymphoblastic leukemia, Hodgkin’s and non-Hodgkin’s lymphoma, multiple myeloma, and soft tissue and bone sarcomas. While doxorubicin displays an excellent antitumor activity profile, its use in clinical practice is limited by drug-associated toxicities, particularly myelosuppression and cardiotoxicity.

The goal of liposomal encapsulation of doxorubicin is to alter the tissue distribution and pharmacokinetics of the drug to increase its therapeutic index. Pegylated liposomal doxorubicin (Doxil, Ortho Biotech Products LP, Bridgewater, NJ; CAELYX, Schering Plough, Kenilworth, NJ) is a new formulation of doxorubicin. Pegylation protects the liposomes from detection by the mononuclear phagocyte system and increases circulation time, allowing for more targeted delivery of doxorubicin to the tumor cells.¹

Pegylated liposomal doxorubicin has demonstrated efficacy as a single agent in patients with metastatic or recurrent breast cancer, with objective response rates ranging from 31% to 33%.^2,3 In comparison with conventional doxorubicin, pegylated liposomal doxorubicin has a similar efficacy profile and an improved safety profile, with a significantly reduced incidence of cardiotoxicity and significantly fewer cardiac events, as well as a reduced incidence of myelosuppression, nausea, vomiting, and alopecia.^4–6 Several phase II studies in patients with metastatic breast cancer have reported that pegylated liposomal doxorubicin is effective in combination with other agents or modalities, including cyclophosphamide,⁷ paclitaxel,^8,9 docetaxel,¹⁰ vinorelbine,¹¹ and hyperthermia,¹² with response rates ranging from 35% to 75%. There are minimal survival data relating to the use of pegylated liposomal doxorubicin in combination with other agents to date; however, Sparano et al¹⁰ observed a median overall survival of 18 months in 41 patients with metastatic breast cancer treated with pegylated liposomal doxorubicin in combination with docetaxel.

Gemcitabine (Gemzar; Eli Lilly and Co, Indianapolis, IN) is a nucleoside analog that demonstrates antitumor activity by targeting specific phases of the cell cycle, primarily DNA synthesis (S phase) and the boundary between the G1 and S phases.^13–15 Efficacy and safety of single-agent gemcitabine have been reported in patients with locally advanced or metastatic breast cancer, with response rates ranging from 25% to 37% and overall survival ranging from 12 to 21 months.^16–18 Based on its single-agent activity, modest toxicity, and novel mechanism of action, combination therapy with gemcitabine may provide clinical benefit in patients with metastatic breast cancer.

The development of new, clinically effective combination chemotherapy regimens with improved efficacy, more convenient dosing schedules, better tolerability, and fewer side effects may increase survival and improve quality of life for many patients with advanced breast cancer. The observed antitumor activities of pegylated liposomal doxorubicin and gemcitabine as single agents and their different mechanisms of action and non-overlapping toxicity profiles provide the rationale for evaluating the combination of these two agents in patients with metastatic breast cancer.

In patients with breast cancer, there has been limited clinical experience to date using pegylated liposomal doxorubicin in combination with gemcitabine. A small dose-finding study in which patients with metastatic breast cancer received pegylated liposomal doxorubicin (25 to 30 mg/m²) on day 1 plus gemcitabine (1,000 to 1,200 mg/m²) on days 1 and 8, every 21 days as first-line treatment reported objective responses in four (50%) of eight patients.¹⁹ We studied the combination in a phase I trial to determine the maximum-tolerated dose and toxicity profile of pegylated liposomal doxorubicin plus gemcitabine before initiating the current phase II study. The results of this study were previously published in the Journal of Clinical Oncology.²⁰ Patients (N = 27) received a fixed dose of gemcitabine (800 mg/m²) on days 1 and 8 and a starting dose of pegylated liposomal doxorubicin (20 mg/m²) on day 1 (the dose was escalated by 20% each cycle until the maximum-tolerated dose was reached) every 21 days. It was concluded from this study that pegylated liposomal doxorubicin in combination with gemcitabine is an active regimen (objective response rate, 33%) that is well tolerated and, therefore, warrants further study. The recommended dose based on the phase I data was pegylated liposomal doxorubicin 24 mg/m² on day 1 and gemcitabine 800 mg/m² on days 1 and 8 every 21 days.

This phase II trial was conducted to determine the clinical efficacy and safety of pegylated liposomal doxorubicin 24 mg/m² in combination with gemcitabine 800 mg/m² in patients with metastatic breast cancer, and to evaluate the qualitative and quantitative toxicity and reversibility of toxicity of this combination.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Eligibility Criteria
Patients 18 years of age or older were eligible to participate in the study if they had histologically confirmed metastatic breast cancer, bidimensionally measurable disease, no prior chemotherapy for metastatic disease, and no history of concomitant malignancy, except for nonmelanoma skin cancer, cervical cancer in situ, or other malignancy treated curatively, with no evidence of disease for at least 5 years. Previous surgery and radiotherapy for breast cancer, adjuvant/neoadjuvant chemotherapy, or adjuvant or palliative hormone therapy was permitted. Patients with prior exposure to anthracyclines (as adjuvant therapy) were eligible if their last dose was at least 12 months before initiation of current treatment, and if there was no evidence of anthracycline resistance (ie, development of disease progression while receiving adjuvant therapy or within 6 months after completing adjuvant therapy). Patients previously treated with doxorubicin or mitoxantrone were eligible for inclusion if the total doxorubicin dose was 300 mg/m² by intravenous (IV) bolus or 400 mg/m² by continuous IV infusion, or if the total mitoxantrone dose was 105 mg/m² by IV bolus or 140 mg/m² by continuous IV infusion. Other eligibility criteria included life expectancy 3 months; performance status 2 on the Zubrod scale;²¹ and adequate bone marrow function, defined as a platelet count 100,000/µL, a hemoglobin concentration 8 g/dL, and an absolute granulocyte count 1,500 cells/µL. Patients were required to have adequate renal function, defined as a serum creatinine concentration 2.0 mg/dL; adequate liver function, defined as ALT less than 1.5x the upper limit of normal and a bilirubin concentration 1.2 mg/dL; and left ventricular ejection fraction (LVEF) 50%, determined by multiple-gated acquisition (MUGA) scan. Female patients of childbearing potential were required to practice adequate contraception. Patients with brain metastases treated by surgery or radiotherapy were eligible if their neurologic status was stable 2 weeks after discontinuing dexamethasone.

Patients were not eligible to participate in the study if they had evidence of uncontrolled brain metastases, leptomeningeal disease, or other serious illness or condition, including cardiac disease, congestive heart failure, psychiatric disorder, or active infection. Patients who had chemotherapy or radiotherapy within the last 21 days or who did not recover from prior therapy were excluded. Prior treatment with pegylated liposomal doxorubicin, gemcitabine, or both, or a prior history of high-dose chemotherapy followed by bone marrow transplantation was not allowed. Patients were excluded if they had participated in another investigational study within 21 days of the current study registration.

Treatment Plan and Evaluation
Before study entry, patients underwent a complete medical history and physical examination, including evaluation of performance status, body weight, and vital signs. Radiologic assessments were performed to determine the extent of disease, and a MUGA scan was required within 30 days before study entry to evaluate LVEF. Laboratory data included a complete blood cell count with differential and platelet count, blood chemistry studies, urinalysis, and a serum pregnancy test in females of childbearing potential.

All eligible patients signed a written informed consent form before registering with the M.D. Anderson Cancer Center (Houston, TX) data management office. Based on phase I study results, the recommended dose for phase II study was pegylated liposomal doxorubicin 24 mg/m² IV over 2.5 hours (to minimize infusion-related reactions) on day 1 and gemcitabine 800 mg/m² IV over 30 minutes on days 1 and 8. Each cycle was repeated every 21 days.

Patients were treated until evidence of disease progression was observed or until they experienced unacceptable toxicity. Unacceptable toxicity was defined as: grade 3 nonhematologic toxicity (excluding nausea and vomiting) and grade 4 vomiting, despite the use of antiemetics; grade 2 nonhematologic toxicity, including hand-foot syndrome (palmar-plantar erythrodysesthesia), that does not resolve by day 21; grade 4 neutropenia lasting greater than 7 days, grade 3 or 4 neutropenia at day 21, or grade 4 neutropenia accompanied by either a documented infection or fever (38.3°C) that requires parenteral antibiotics; and grade 4 thrombocytopenia or grade 3 thrombocytopenia associated with bleeding. Toxicities were graded using the National Cancer Institute common toxicity criteria, version 2.0. If unacceptable toxicity was observed, treatment was interrupted until recovery to baseline, and patients were rechallenged at lower dose levels, based on the following two-step dose reduction schema: pegylated liposomal doxorubicin 20 mg/m² plus gemcitabine 800 mg/m², or pegylated liposomal doxorubicin 20 mg/m² plus gemcitabine 640 mg/m². Patients requiring more than two dose reductions were removed from the study.

Patients were followed with weekly complete blood counts with differential and platelet counts (days 1, 8, 15, and 21). Physical examinations, serum chemistry studies, and toxicity assessments were performed every 3 weeks. Appropriate radiologic assessments (computed tomography, magnetic resonance imaging, x-rays, bone scan) were performed after every two courses (6 weeks). After a response was documented, a confirmatory study was obtained after two additional courses (6 weeks). If the patient continued in response status, these studies were repeated after every three courses (9 weeks) unless the clinical situation required an earlier evaluation. A MUGA scan was performed after the patient had received 300 mg/m² of anthracycline (including past therapies), and every 100 mg/m² thereafter.

In terms of response criteria, the size of measurable lesions was determined before each course of therapy and reported as the product of the longest diameter and its perpendicular. Standard response criteria were applied.²² Responses were categorized as follows: complete response (CR), complete disappearance of all measurable and assessable disease lasting at least 4 weeks, no new lesions, no disease-related symptoms; partial response (PR), 50% decrease in the sum of the products of the bidimensional perpendicular diameters of all measurable lesions lasting at least 4 weeks, no progression of assessable disease, no new lesions, no disease-related symptoms; stable disease (SD), did not qualify for CR, PR, or progressive disease; progressive disease (PD), 25% increase using the same techniques as those used at baseline, appearance of any lesion that had disappeared, appearance of any new lesion/site, clear worsening of any assessable disease, or failure to return for evaluation because of death or deteriorating condition (unless clearly unrelated to this cancer). For bone disease, increased uptake on the computed tomography or magnetic resonance imaging scan did not constitute clear worsening. Worsening of existing nonassessable disease did not constitute progression.

Statistical Analysis
The objectives of this phase II study were to evaluate the antitumor activity and toxicity profile of pegylated liposomal doxorubicin in combination with gemcitabine in patients with metastatic breast cancer. The dose of study drugs used was based on the maximum-tolerated dose during the phase I trial.²⁰ It is assumed that the new combination therapy will be of no further interest in patients with breast cancer if the true tumor response rate is less than 30% (H_o). The alternate hypothesis (H_A) assumes that a true response rate of 50% or more would be of considerable interest in patients with the disease. The study took place in two stages; the first stage consisted of 22 patients. If less than eight responses had been seen then the trial would have been terminated, otherwise, accrual was to continue to a total of 46 patients with a 10% rejection error and a power of 90%. If more than 17 responses were observed, we would conclude that the combination therapy is promising unless other considerations indicated otherwise. Patients who died during therapy or who were lost to follow-up were counted as having progressive disease as of the date of death or date of last follow-up, unless there was a definite clinical diagnosis or autopsy of treatment-related death or death as the result of an unrelated cause. Patient survival and progression-free intervals were measured from time of entry into the protocol. Toxicity was assessed through the use of descriptive statistics.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patient Characteristics
A total of 49 patients were entered into the study between November 2000 and November 2001. Demographic and baseline clinical characteristics of all patients are listed in Tables 1 and 2. The median age was 55 years, and the median performance status was 1. A total of 27 patients (55%) had received prior adjuvant chemotherapy (eight single-agent anthracycline, 11 both anthracycline and taxane, eight cyclophosphamide/methotrexate/fluorouracil), 21 (42.9%) had received prior hormonal therapy, and 25 patients (51%) had undergone prior radiation therapy. Two of the patients who received treatment were found later to have had prior therapy with a taxane for metastatic disease. Three patients were not assessable for response. Two patients withdrew consent immediately after deciding not to pursue further therapy, and one patient had an infusion reaction to pegylated liposomal doxorubicin on day 1 and decided not to continue treatment (patient did not receive the total amount of pegylated liposomal doxorubicin and did not receive gemcitabine).

The most common grade 3 to 4 toxicities were hematologic in nature; granulocytopenia, thrombocytopenia, and anemia (Table 5). Neutropenic complications were few, with only one episode of neutropenic fever and one episode of non-neutropenic fever. The patient with neutropenic fever had negative cultures, with no obvious source of infection. The most frequent grade 3 to 4 nonhematologic toxicities were nausea and vomiting, fatigue, stomatitis, and hand-foot syndrome. Pyridoxine was not used in this study to prevent or treat hand-foot syndrome. Two patients developed hemolytic-uremic syndrome more than 1 month after completion of chemotherapy. There were no treatment-related deaths in the study.

Dose Modifications
Twenty-two patients (47%) required dose reductions. Eleven of these 22 patients had one dose reduction, and 11 had two dose reductions. Most dose reductions were related to hematologic toxicity. In 88 courses (28%), there was a 50% dose reduction in the dose of gemcitabine on day 8, and in 39 courses (13%), the day-8 dose of gemcitabine was omitted. However, this did not seem to dramatically affect the dose delivered for each agent. The median dose delivered for liposomal doxorubicin was 23.81 mg/m², and for gemcitabine, (days 1 and 8) 1,548.39 mg/m².

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Based on our previously reported results of a phase I trial of pegylated liposomal doxorubicin in combination with gemcitabine for metastatic breast cancer,²⁰ this phase II study was conducted to further evaluate the activity and tolerability of this regimen. In this trial, more than 50% of patients had received prior adjuvant chemotherapy or radiation therapy, but none had received prior treatment for metastatic disease. The overall objective response rate was 52% (3 CR, 21 PR) in the 46 assessable patients. In addition to the confirmed objective responses (as defined in the study protocol), it is likely that an even greater proportion of patients derived some palliative benefit from this combination therapy. For instance, confirmed clinical benefit (defined as CR, PR, or SD) was observed in 36 (78.2%) of 46 patients. It is also noteworthy that responses were observed in patients with previous anthracycline exposure (response rate, 58%). Median overall survival was 16.1 months, median response duration was 5.6 months, and median time to progression was 4.5 months.

Consistent with the modest toxicity profile reported during the phase I study,²⁰ pegylated liposomal doxorubicin in combination with gemcitabine was well tolerated. Although the most common grade 3 to 4 toxicities were hematologic in nature, few neutropenic complications resulted. There was only one episode of neutropenic fever, with no obvious source of infection. The most frequent nonhematologic adverse events were nausea and vomiting, fatigue, stomatitis, and hand-foot syndrome. Only one patient with predisposing risk factors developed a decrease in LVEF greater than 20% after 236 mg/m² of cumulative pegylated liposomal doxorubicin exposure, with cardiac function returning to normal within 2 months after discontinuing therapy. There were no reports of congestive heart failure among any of the patients. Two patients developed evidence of hemolytic uremic syndrome more than a month after completion of their chemotherapy. In both cases the patients had responded to the treatment. This event was not observed during our initial phase I study. However, since this has been reported in the past with the use of single agent gemcitabine, it was assumed to be therapy-related. One of the patients recovered completely, while the second patient has continued evidence of mild renal dysfunction.

Few studies in the literature report results of the use of pegylated liposomal doxorubicin in combination with gemcitabine in patients with metastatic breast cancer. Results from two phase I studies in this patient population reported similar efficacy to that demonstrated by pegylated liposomal doxorubicin plus gemcitabine combination in other cancer types (response rates, 22% to 52%).^23–26 A small dose-finding study in which patients received pegylated liposomal doxorubicin 25 to 30 mg/m² on day 1 plus gemcitabine 1,000 to 1,200 mg/m² on days 1 and 8 every 21 days reported objective responses in four of eight (50%) patients.¹⁹ In the dose-finding portion of this study, where patients (N = 27) received a fixed dose of gemcitabine 800 mg/m² on days 1 and 8 and a starting dose of pegylated liposomal doxorubicin 20 mg/m² on day 1 (the dose was escalated by 20% each cycle until the maximum-tolerated dose was reached) every 21 days, the objective response rate was 33%.²⁰ Our efficacy results compare favorably in terms of response rates with those reported in these initial studies, further supporting the clinical utility of pegylated liposomal doxorubicin plus gemcitabine combination therapy in patients with metastatic breast cancer.

Because a common goal when treating metastatic breast cancer is maintaining quality of life, choosing a treatment regimen with a modest toxicity profile is an important consideration. While anthracyclines remain the mainstay of treatment for metastatic breast cancer, the use of doxorubicin in clinical practice is limited by its associated toxicities, particularly cardiotoxicity. These potential cardiac effects often limit repeated use of the drug, especially in the elderly and in those patients with a history of cardiac disease; therefore, the recommended lifetime cumulative dose of doxorubicin is 450 to 550 mg/m².²⁷ While this study was not conducted to specifically evaluate cardiac safety, cardiac function was monitored. Only one patient had a transient decrease of greater than 20% in LVEF during the study. This result is consistent with those from previous studies that have demonstrated improved cardiac safety with pegylated liposomal doxorubicin versus conventional doxorubicin, even at doses exceeding the recommended maximum lifetime cumulative doxorubicin dose.^4–6 In fact, reduced cardiotoxicity, with significantly fewer clinical cardiac events, has been reported in a study comparing pegylated liposomal doxorubicin with conventional doxorubicin in patients with metastatic breast cancer.⁴

In addition to the improved cardiac safety profile demonstrated by pegylated liposomal doxorubicin compared with conventional doxorubicin, pegylated liposomal doxorubicin also exhibits reduced myelosuppression, alopecia, nausea, and vomiting.⁴ When used in combination with gemcitabine, another agent with a modest toxicity profile, treatment was well tolerated, with no unexpected adverse events observed. While hematologic toxicity was the most common grade 3 to 4 event, the incidence was low (0% to 37%) in comparison with studies of other combination chemotherapy regimens (63% to 94%) for the treatment of metastatic breast cancer.^28,29 Moreover, few of the hematologic-related events in this study resulted in neutropenic complications. The modest toxicity profile of pegylated liposomal doxorubicin in combination with gemcitabine is a major advantage for this regimen, because it is important to balance the side effect profile and antitumor activity profile (therapeutic ratio) to optimize the management of metastatic breast cancer.

Hand-foot syndrome is a schedule-related adverse event often observed in patients treated with pegylated liposomal doxorubicin. In this study, however, where lower doses of pegylated liposomal doxorubicin were administered, the occurrence of hand-foot syndrome was infrequent, and most cases were mild and did not require discontinuation of treatment. The lower incidence of hand-foot syndrome is likely related to the lower doses of pegylated liposomal doxorubicin used in this trial. Based on prior studies with pegylated liposomal doxorubicin, a dose of less than 50 mg/m² administered every 4 weeks is recommended to minimize the incidence and severity of hand-foot syndrome in patients treated with pegylated liposomal doxorubicin for metastatic breast cancer.^2,30

Results of this study demonstrate that pegylated liposomal doxorubicin in combination with gemcitabine is effective and well tolerated in patients with metastatic breast cancer. Response rates were high, median overall survival was 16.1 months, and approximately 78% of patients derived clinical benefit from treatment. Cardiac toxicity was minimal, with a transient decrease in LVEF observed in only one patient, with resolution shortly after study completion. While this study focused on patients who had not received previous treatment for metastatic disease, because of the modest and non-overlapping toxicity profiles of both pegylated liposomal doxorubicin and gemcitabine, this combination may also be a viable therapeutic option for patients who have failed previous treatments for metastatic breast cancer.

	NOTES

 
Supported by a research grant from Ortho Biotech Products LP, Bridgewater, NJ, and Eli Lilly and Company, Indianapolis, IN.

Results previously presented at the San Antonio Breast Cancer Symposium, December 11–14, 2002, San Antonio, TX.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
1. Gabizon A, Martin F: Polyethylene glycol-coated (pegylated) liposomal doxorubicin: Rationale for use in solid tumors. Drugs 54:15–21, 1997 (suppl 4)

2. Ranson MR, Carmichael J, O’Byrne K, et al: Treatment of advanced breast cancer with sterically stabilized liposomal doxorubicin: Results of a multicenter phase II trial. J Clin Oncol 15:3185–3191, 1997[Abstract]

3. Lyass O, Uziely B, Ben-Yosef R, et al: Correlation of toxicity with pharmacokinetics of pegylated liposomal doxorubicin (Doxil) in metastatic breast carcinoma. Cancer 89:1037–1047, 2000[CrossRef][Medline]

4. Wigler N, O’Brien M, Rosso R, et al: Reduced cardiac toxicity and comparable efficacy in a phase III trial of pegylated liposomal doxorubicin (CAELYX^TM/Doxil) vs. doxorubicin for first-line treatment of metastatic breast cancer. Proc Am Soc Clin Oncol 21:45a, 2002 (abstr 177)

5. Safra T, Muggia F, Jeffers S, et al: Pegylated liposomal doxorubicin (Doxil): Reduced clinical cardiotoxicity in patients reaching or exceeding cumulative doses of 500 mg/m². Ann Oncol 11:1029–1033, 2000[Abstract/Free Full Text]

6. Berry G, Billingham M, Alderman E, et al: The use of cardiac biopsy to demonstrate reduced cardiotoxicity in AIDS Kaposi’s sarcoma patients treated with pegylated liposomal doxorubicin. Ann Oncol 9:711–716, 1998[Abstract/Free Full Text]

7. Overmoyer B, Silverman P, Holder L, et al: Doxil and intravenous cyclophosphamide as first-line therapy for patients with metastatic breast cancer (MBC): Interim results of an ongoing pilot trial. Breast Cancer Res Treat 50:324, 1998 (abstr 536)

8. Jones V, Finucane D, Rodriguez R, et al: Phase II study of weekly paclitaxel (Taxol) and liposomal doxorubicin (Doxil) in patients with locally advanced and metastatic breast cancer. Proc Am Soc Clin Oncol 21:113a, 2000 (abstr 451)

9. Gogas H, Papadimitriou C, Kalofonos HP, et al: Neoadjuvant chemotherapy with a combination of pegylated liposomal doxorubicin (Caelyx^TM) and paclitaxel in locally advanced breast cancer: A phase II study by the Hellenic Cooperative Oncology Group. Ann Oncol 13:1737–1742, 2002[Abstract/Free Full Text]

10. Sparano JA, Malik U, Rajdev L, et al: Phase I trial of pegylated liposomal doxorubicin and docetaxel in advanced breast cancer. J Clin Oncol 19:3117–3125, 2001[Abstract/Free Full Text]

11. Martin M, Casado A, Garcia-Carbonero I, et al: Phase II study of pegylated liposomal doxorubicin plus vinorelbine in metastatic breast cancer patients with prior anthracycline treatment. Proc Am Soc Clin Oncol 21:38b 2002 (abstr 1965)

12. Park JW, Stauffer P, Diederich C, et al: Hyperthermia (HT) + Doxil significantly enhances drug delivery and efficacy in metastatic breast cancer of the chest wall (CW): A phase I/II study. Proc Am Soc Clin Oncol 20:47a 2001 (abstr 184)

13. Huang P, Chubb S, Hertel LW, et al: Action of 2', 2'-difluorodeoxycytidine on DNA synthesis. Cancer Res 51:6110–6117, 1991[Abstract/Free Full Text]

14. Plunkett W, Huang P, Gandhi V: Preclinical characteristics of gemcitabine. Anticancer Drugs 6:7–13, 1995 (suppl 6)

15. Plunkett W, Huang P, Xu YZ, et al: Gemcitabine: Metabolism, mechanisms of action, and self-potentiation. Semin Oncol 22:3–10, 1995 (4 suppl 11)[Medline]

16. Carmichael J, Possinger K, Phillip P, et al: Advanced breast cancer: A phase II trial with gemcitabine. J Clin Oncol 13:2731–2736, 1995[Abstract]

17. Blackstein M, Vogel CL, Ambinder R, et al: Gemcitabine as first-line therapy in patients with metastatic breast cancer: A phase II trial. Oncology 62:2–8, 2002[Medline]

18. Spielmann M, Llombart-Cussac A, Kalla S, et al: Single-agent gemcitabine is active in previously treated metastatic breast cancer. Oncology 60:303–307, 2001[CrossRef][Medline]

19. Wong Z-W, Khoo K-S, Shah VA, et al: Phase I/II study of pegylated liposomal doxorubicin (PLD) and gemcitabine (G) as first-line therapy for metastatic breast cancer (MBC). Proc Am Soc Clin Oncol 21:49b, 2002 (abstr 2008)

20. Rivera E, Valero V, Syrewicz L, et al: Phase I study of Stealth liposomal doxorubicin in combination with gemcitabine in the treatment of patients with metastatic breast cancer. J Clin Oncol 19:1716–1722, 2001[Abstract/Free Full Text]

21. Zubrod CG, Schneiderman M, Frei E, et al: Appraisal of methods for the study of chemotherapy of cancer in man: Comparative therapeutic trial of nitrogen mustard and thio phosphoamide. J Chron Dis 11:7–33, 1960

22. Miller AB, Hoogstraten B, Staquet M, et al: Reporting results of cancer treatment. Cancer 47:207–214, 1981[CrossRef][Medline]

23. D’Agostino G, Ferrandina G, Garganese G, et al: Phase I study of gemcitabine and liposomal doxorubicin in relapsed ovarian cancer. Oncology 62:110–114, 2002[CrossRef][Medline]

24. Tobias D, Runowicz C, Mandeli J, et al: A phase I trial of gemcitabine and Doxil for recurrent epithelial ovarian cancer. Proc Am Soc Clin Oncol 19:392a, 2000 (abstr 1551)

25. D’Agostino G, Ludovisi M, Ferrandina G, et al: The liposomal doxorubicin (CAE) and gemcitabine (GEM) combination is active in relapsed ovarian cancer: A phase II study. Proc Am Soc Clin Oncol 21:219a, 2002 (abstr 875)

26. Horwood K, Colosimo M, Wyld D, et al: A phase II trial of gemcitabine and liposomal doxorubicin in platinum-resistant ovarian cancer (PROC). Proc Am Soc Clin Oncol 21:223a, 2002 (abstr 888)

27. Adriamycin RDF/Adriamycin PFS (doxorubicin hydrochloride for injection [package insert]). Kalamazoo, MI, Pharmacia & Upjohn Company, 2002

28. Nabholtz JM, Senn HJ, Bezwoda WR, et al: Prospective randomized trial of docetaxel versus mitomycin plus vinblastine in patients with metastatic breast cancer progressing despite previous anthracycline-containing chemotherapy: 304 study group. J Clin Oncol 17:1413–1424, 1999[Abstract/Free Full Text]

29. Mackey JR, Paterson A, Dirix LY, et al: Final results of the phase III randomized trial comparing docetaxel (T), doxorubicin (A) and cyclophosphamide (C) to FAC as first line chemotherapy (CT) for patients (pts) with metastatic breast cancer (MBC). Proc Am Soc Clin Oncol 21:35a, 2002 (abstr 137)

30. Perez AT, Domenech GH, Frankel C, et al: Pegylated liposomal doxorubicin (Doxil) for metastatic breast cancer: the Cancer Res Network, Inc., experience. Cancer Invest 20:22–29, 2002 (suppl 2)

Submitted March 18, 2003; accepted June 11, 2003.

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