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© 1999 American Society for Clinical Oncology Phase II Trial of Liposome-Encapsulated Doxorubicin, Cyclophosphamide, and Fluorouracil as First-Line Therapy in Patients With Metastatic Breast CancerFrom the University of Texas M.D. Anderson Cancer Center, Houston, TX; and The Liposome Company, Inc, Princeton, NJ. Address reprint requests to Vicente Valero, MD, University of Texas M.D. Anderson Cancer Center, Department of Breast Medical Oncology, 1515 Holcombe Blvd, Box 56, Houston, TX 77030; email vvalero{at}mdacc.org
PURPOSE: To determine the efficacy and safety profile, including the risk for cardiac toxicity, of liposome-encapsulated doxorubicin (TLC D-99), fluorouracil (5-FU), and cyclophosphamide as first-line chemotherapy in patients with metastatic breast cancer (MBC). PATIENTS AND METHODS: Forty-one women were registered in this phase II study. All patients had measurable disease and no previous chemotherapy for MBC. Treatment consisted of TLC D-99 60 mg/m2 and cyclophosphamide 500 mg/m2 on day 1 and 5-FU 500 mg/m2 on days 1 and 8 every 3 weeks. Serial cardiac monitoring, including endomyocardial biopsies, was performed.
RESULTS: The overall response rate was 73% (95% confidence interval, 57% to 86%). The median duration of response was 11.2 months, the median time to treatment failure was 8.1 months, and the median overall survival duration was 19.4 months. The median number of cycles per patient was 10. The median cumulative dose of TLC D-99 was 528 mg/m2. Ten patients required hospitalization for febrile neutropenia. Nausea/vomiting, stomatitis, and fatigue higher than grade 2 occurred in 12%, 15%, and 41% of patients, respectively. Twenty-one patients reached a cumulative doxorubicin dose greater than 500 mg/m2. Three patients (7%) were withdrawn from the study due to protocol-defined cardiac toxicity, two because of a decrease in left ventricular ejection fraction to CONCLUSION: This chemotherapy regimen, including TLC D-99, was highly active against MBC and associated with low cardiac toxicity despite high cumulative doses of doxorubicin.
DOXORUBICIN IS THE most commonly used anthracycline and is one of the most active single agents in breast cancer treatment. The response rate in patients with metastatic breast cancer (MBC) varies from 30% to 50%.1 Several randomized, controlled studies assessing the value of doxorubicin-containing versus nondoxorubicin-containing regimens have been conducted. The results of these studies have shown an increase in overall response rate, duration of response, time to progression, and a significant survival advantage associated with doxorubicin-containing regimens.2 The most recent meta-analysis of randomized clinical studies of adjuvant chemotherapy in early breast cancer demonstrated that anthracycline therapy produced a greater reduction of recurrence and mortality rates when compared with nonanthracycline-containing regimens.3 Doxorubicin may exert its antitumor and toxic effects by a number of mechanisms, including intercalative DNA binding, free-radical formation, membrane binding, and metal-ion chelation.4 Acute toxic effects observed after administration of doxorubicin HCl include myelosuppression, alopecia, local injury on extravasation, mucositis, nausea, and vomiting.5 Anthracyclines may induce acute and chronic cardiac toxicity. The acute cardiac events, including arrhythmias, pericarditis/myocarditis, and acute heart failure, are rare. The most common adverse chronic event is life-threatening, cumulative dose-dependent cardiomyopathy, which can lead to congestive heart failure (CHF) in 7% to 42% of patients receiving a total dose of 550 and 900 mg/m2 by bolus, respectively.4,6,7 The risk of cardiomyopathy often leads to the discontinuation of doxorubicin while it is still providing clinical benefit. The pathogenesis of this effect is multifactorial, including free-radical myocyte injury, calcium overload injury, release of vasoactive amines, generation of proinflammatory cytokines, adrenergic dysfunction, inhibition of ubiquinone-requiring enzymes, or a combination of these.4 During administration of conventional doxorubicin, high levels of this toxic agent accumulate in heart tissue. The risk for cardiac toxicity associated with use of doxorubicin is a function of peak drug level and cumulative dose. Several approaches have been used to reduce anthracycline-related cardiac toxicity. Shifting from bolus drug administration to weekly dosing or a prolonged infusion schedule (48 to 96 hours) has been shown to significantly reduce the incidence and severity of cardiac toxicity at equivalent dose levels.4,7-12 The use of the cardioprotective agent dexrazoxane also decreases cardiac toxicity.7,8,13,14 The use of carrier systems, which improve specificity in the delivery of therapeutic drugs, has been investigated in a number of clinical trials; in particular, liposomes have been studied as carriers of a variety of antineoplastic drugs, including doxorubicin.15,16 It has been demonstrated in animals that liposome-encapsulated anticancer drugs are far less toxic than their unencapsulated counterparts.15-17 In addition, when administered intravenously, liposomes concentrate primarily in organs rich in reticuloendothelial cells. Therefore, liposomal delivery of antineoplastic agents may enhance some of their effects by targeting the drug away from healthy tissue or by reducing the dose needed to achieve a cytotoxic effect on tumor cells. This new approach may improve the cardiac safety of doxorubicin. A liposome-encapsulated form of doxorubicin, TLC D-99 (Evacet, The Liposome Company, Inc, Princeton, NJ), was designed to increase the amount of drug delivered to tumors and decrease the amount going to healthy organs, such as the heart. In the TLC D-99 model, doxorubicin is pulled into the interior of the vesicle by the generation of an electropotential across the liposome membrane. This mechanism for remote loading involves the generation of a pH gradient between the inside of the liposome and the extra-liposomal buffer. A phase I clinical trial of TLC D-99 at Roswell Park Memorial Institute demonstrated that myelosuppression was the dose-limiting toxicity.18 Gastrointestinal toxicity was mild in most patients. No abnormalities of hepatic, renal, or cardiac function were seen. The nonmyelosuppressive toxicities encountered were alopecia, malaise, rigors, and fever. In an open-label, noncomparative, single-agent, phase II study, administration of TLC D-99 (75 mg/m2 every 3 weeks) to 32 patients resulted in an overall response rate of 56%.19 Toxicity was tolerable at this dose. Ten patients (31%) had grade 4 leukopenia, and 1 patient (3%) had grade 4 thrombocytopenia. Grade 3 mucositis occurred in 10% of the patients. Cyclophosphamide, free doxorubicin, and fluorouracil (5-FU) are the most commonly used agents in chemotherapy regimens for the treatment of breast cancer. The addition of TLC D-99 to a cyclophosphamide/5-FU regimen may maintain the efficacy of the treatment and may lessen the chance of cardiac toxicity. The purpose of this study was to assess the efficacy of TLC D-99 administered in combination with 5-FU and cyclophosphamide as first-line cytotoxic chemotherapy in patients with MBC. A secondary purpose was to determine the safety of this regimen. Here we present the final results of this phase II clinical trial.
Eligibility All patients had histologically or cytologically proven breast cancer with measurable metastatic disease and any one of the following: estrogen receptor– or progesterone receptor–negative disease at presentation; estrogen receptor– or progesterone receptor–positive disease and failure of adjuvant hormonal therapy or first-line hormonal therapy; or failure of nondoxorubicin-containing adjuvant chemotherapy. Female patients 18 years or older with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 and a life expectancy of at least 12 weeks were eligible. Patients had to have recovered from toxic effects of recent chemotherapy, hormonal therapy, or radiation therapy; no concurrent chemotherapy, hormonal therapy, or immunotherapy was allowed. Patients could receive palliative irradiation but not to areas of measurable disease. Patients had to have adequate bone marrow, hepatic, and cardiac function as evidenced by an absolute neutrophil count greater than 1,500 cells/µL, a platelet count greater than 100,000 cells/µL, a serum total bilirubin level less than 2.0 mg/dL, and an alanine aminotransferase level less than 3 times the upper limit of the institution's normal range. Premenopausal patients were eligible if they were using reliable contraceptive methods. Initially, patients were required to have a left ventricular ejection fraction (LVEF) greater than 60%. However, during the course of this study, following enrollment of the first 16 patients, we changed our LVEF software package from one provided by Siemens (Oakbrook, IL) to one provided by Elscint (Haifa, Israel). Our previous normal range had been 68 ± 10; using the new software, our new normal range fell to 64 ± 15. Therefore, 50 became our low normal value rather than 60. Because what actually changed was the range of normal values, it was decided to lower the inclusion limit to greater than 50 rather than greater than 60 in subsequent patients. Patients were excluded from the study if they had an active second neoplasm (other than carcinoma-in-situ of the cervix or basal cell carcinoma of the skin) in the 10 years before enrollment or if they had received prior anthracycline-containing adjuvant therapy or chemotherapy for metastatic disease. Patients with a history of CHF, significant cardiac arrhythmia, or myocardial infarction during 6 months before enrollment were excluded, as were patients with a history of allergic reactions to eggs or egg products. Institutional review board approval was obtained before the start of the study and was renewed annually. Each patient gave written informed consent before enrollment.
Evaluation of Patients Imaging studies required for tumor measurement were performed every two cycles to confirm a response or to document progressive disease. After a response was achieved, response status was determined every three to four cycles, unless the clinical situation required more frequent evaluation. If initially abnormal, bone surveys were repeated every three cycles. A physical examination was performed before each cycle. Serum for a carcinoembryonic antigen test was obtained every two cycles if it had been elevated initially. Hematology tests were performed on days 10 and 15 of cycle 1; on days 1, 10, and 15 of cycle 2; and on days 1 and 15 of each cycle thereafter. Serum biochemistry tests were repeated before each cycle. LVEF was determined every three cycles, and if a patient was withdrawn from the study for cardiac toxicity, LVEF was determined 4 weeks later. Protocol-defined criteria were used for performing endomyocardial biopsies. Biopsy results were scored according to the modified Billingham methods.20 Cardiac biopsies were performed at approximately 420 mg/m2 (first cohort of six patients), 540 mg/m2 (second cohort of eight patients), and 660 mg/m2 (third cohort of three patients). These groups of patients had subsequent cardiac biopsies after every 120 to 180 mg/m2. All patients whose LVEF declined more than 15% or whose absolute LVEF was less than 40% underwent cardiac biopsies regardless of previous TLC D-99 doses.
Drug Administration Table 1 lists the dose levels of each drug used during the study. After the first cycle, the investigator could increase or decrease the doses of chemotherapy in subsequent cycles based on specific criteria for hematologic (Table 2) and nonhematologic (Table 3) toxicities. Granulocyte colony-stimulating factor administration was allowed during neutropenic periods if fever or documented infection was present.
Treatment with TLC D-99/cyclophosphamide/5-FU was continued for at least two cycles unless there was a rapid progression of disease. Treatment continued for at least 6 months after a complete response (CR) was achieved or after maximum response was achieved for those with a partial response (PR); patients with stable disease continued treatment until disease progression occurred or until they developed significant toxicity.
Patients were withdrawn from the study for any of the following reasons: disease progression, unacceptable toxicity (defined as toxicity that was unpredictable, irreversible, or grade 4 in severity), noncompliance with the protocol, or patient's request. A patient was withdrawn from the study for cardiac toxicity if an endomyocardial biopsy demonstrated
Response Assessment Progression or development of a brain lesion could not be used to change a response evaluation that had been based on other measurable lesions. The time to onset of response was defined as the time from day 1 of treatment to first determination of CR or PR. The duration of response for patients with a CR or PR was defined as the time from day 1 of treatment to first evidence of PD or death. The time to treatment failure was defined as the time from day 1 of treatment to discontinuation of treatment for any reason, lack of response, first evidence of PD, or death. Progression-free survival was defined as the time from day 1 of treatment to the first evidence of PD or death. Overall survival was defined as the time from day 1 of treatment to death.
Toxicity Assessment
The incidence of patients having laboratory abnormalities was determined by worst grade of abnormality, and a count of patients having these laboratory abnormalities was provided. The median change from the baseline value to the last observation for nonhematologic laboratory data was determined. Grades 3 and 4 nonhematologic laboratory toxicities were listed, with the baseline, abnormal, and final values provided. The cycle number and day at the time these toxicities occurred also were shown, as were the cycle number and day the final value was assessed. The incidence of hematologic toxicities (anemia, leukopenia, neutropenia, and thrombocytopenia) was tabulated by cycle of treatment and for all cycles combined by toxicity grade. The time from day 1 of treatment to hematologic recovery also was analyzed. Hematologic recovery was defined as an ANC
Changes in LVEF, endomyocardial biopsy, and incidence of clinical CHF by cumulative lifetime dose of doxorubicin (in 100-mg/m2 increments) were tabulated. Asymptomatic changes in cardiac function were defined as a decrease of LVEF to a final value
Data Analysis
Patient Characteristics The study was closed after 41 patients were enrolled. All patients were assessable for efficacy and safety. The results are current as of June 23, 1998. Patient clinical characteristics are listed in Table 4. In summary, the patients were young (median age, 54 years), had excellent ECOG performance status (  1, 90%), and had minimal previous chemotherapy (nonanthracycline adjuvant chemotherapy, 17%). The median time from initial diagnosis to first dose of study drug was 17 months (range, 0.2 to 116.9 months). The median number of disease sites was three (range, one to five), and the most common disease site was lymph nodes (73%). Of the 41 patients, 17 (41%) had received prior hormonal therapy.
Efficacy
The median time to onset of response was 49 days (range, 21 to 189 days). Median duration of response was 11.2 months (range, 3.9 to 34 months). The median time to treatment failure was 8.1 months (range, 1.6 to 34 months), and the median progression-free survival duration was 8.4 months (range, 1.6 to 34 months) (Fig 1). Thirty-four of the 41 patients (83%) have died, all from progressive malignant disease. No patient died within 30 days of treatment with TLC D-99. The median overall survival duration was 19.4 months (range, 4.2 to 52+ months) (Fig 1). Except for patients with an ECOG performance status of 2 at baseline, the response rate was relatively uniform across prognostic factors (age, performance status, estrogen receptor status, and prior anticancer therapy).
Safety Profile
Cardiac Toxicity
In summary, four patients discontinued treatment because of cardiac events. Three patients were withdrawn because of protocol-defined cardiac toxicity: two had a decrease in LVEF to
The results of this phase II study showed that a regimen of TLC D-99, 5-FU, and cyclophosphamide has significant antitumor activity as first-line therapy in patients with untreated MBC. The overall objective response rate of 73% and the median overall survival duration of 19.4 months are quite comparable with studies conducted by us and others using the same drug combination but with free doxorubicin.1,2,21,22 The substitution of TLC D-99 for free doxorubicin preserved the anthracycline efficacy and confirmed the preclinical data that TLC D-99 is associated with activity similar to that of free doxorubicin. This regimen produced expected levels of hematologic toxicity. The incidence of neutropenic fever was higher than reported with the standard 5-FU, doxorubicin, and cyclophosphamide regimen; however, the patients in this trial received liposomal doxorubicin at a dose of 60 mg/m2 rather than our traditional 50 mg/m2. Nonhematologic adverse events were uncommon, with very few grade 4 nonhematologic toxicities. Fatigue was the most common adverse event. The incidence of mucositis was lower than with a 72- to 96-hour continuous infusion of doxorubicin10 and similar to or lower than that which is seen with rapid intravenous bolus of free doxorubicin. No unexpected adverse events were seen. None of the patients had hand-foot syndrome (palmar-plantar erythrodysesthesia), an adverse event that has been reported elsewhere with other preparations of liposomal-encapsulated doxorubicin.16 Low-grade fever was seen in 10% of the patients after administration, but it did not have any major clinical significance. Alopecia was universal; however, the degree of alopecia was not as severe as that previously reported with free doxorubicin. In fact, several patients had minimal alopecia despite a large cumulative dose of doxorubicin (Fig 3).
Careful serial monitoring of cardiac function was performed in all patients treated on this protocol. Cardiac events were low despite the high cumulative dose of doxorubicin. The median cumulative dose of TLC D-99 was 528 mg/m2. The cumulative dose was greater than 600 mg/m2 in 16 patients, including four patients who received a greater than 800-mg/m2 cumulative dose of TLC D-99. It is estimated that 7% to 18% of patients receiving cumulative doxorubicin doses between 550 and 700 mg/m2 by intermittent bolus infusion develop CHF.4,6,7 The incidence of clinical CHF increases to 27% to 42% in patients receiving cumulative doses of 701 to 900 mg/m2.6,7 No CHF was observed in any individual while on study. In our study, one (2.4%) patient did have CHF during the follow-up period, but clinicopathologic features were consistent with a nonanthracycline event. This patient had received prior radiation therapy to the chest wall. The possibility that TLC D-99 may have accounted for some of her symptoms cannot be excluded. The 2.5% incidence of clinical CHF observed in this trial was low and similar to or lower than that of our historical experience with prolonged infusion or weekly schedules of doxorubicin.7,9,10,23
Subclinical cardiac toxicity as evidenced by a significant decrease in LVEF (to < 45% or a > 10% absolute decrease from baseline) or by abnormal cardiac biopsy was also rare. Only three patients were withdrawn from this study due to protocol-defined cardiac toxicity, even though 21 patients reached a cumulative lifetime doxorubicin dose greater than 500 mg/m2. Subclinical cardiac toxicity, as evidenced by a drop in LVEF to less than 45% at rest, has been seen in 54% to 77% of patients receiving a cumulative free-doxorubicin dose of more than 500 mg/m2.6,7 Nineteen patients had endomyocardial biopsies. The median dose of TLC D-99 was 552 mg/m2. The median biopsy score was 0. Twelve biopsies were performed at a cumulative dose greater than 600 mg/m2. Only one patient had subclinical toxicity (biopsy score 1.5) at 900 mg/m2 of TLC D-99. Most patients receiving a greater than 400-mg/m2 cumulative dose of free doxorubicin by bolus infusion can be expected to show a cardiac biopsy score greater than 1.5.7,9,23 In the M.D. Anderson Cancer Center's trial, no patient had a biopsy score greater than 1.5, although more than one half of the patients received a greater than 500 mg/m2 cumulative dose of TLC D-99. The clinical cardiac safety profile was better than that of our previous experience with free doxorubicin and similar to, if not better than, that of the previously reported weekly, 48-hour, or 96-hour continuous-infusion doxorubicin administration.7,9,10,23 Tables 9 and 10
It should be noted that as a result of the small sample size, the 95% confidence intervals are quite wide, and given the limitations of historical controls, a definite statement regarding the comparative clinical cardiac toxicity of TLC D-99 and free doxorubicin cannot be made on the basis of this trial. Cardiac toxicity usually manifests within the first 3 months after the final dose of doxorubicin, although sometimes it may become evident years after cessation of therapy.4,6,7 Late cardiac toxicity was not seen despite the long follow-up period. There were no cardiac deaths; TLC D-99 administration was associated with clinical CHF (one patient) and subclinical cardiac toxicity (three patients). These results also confirm the preclinical studies in which TLC D-99 had lower gastrointestinal and cardiac toxicity.24 The potential substitution of free doxorubicin by TLC D-99 in new combinations (paclitaxel and doxorubicin; and cyclophosphamide, doxorubicin, and trastuzumab) may reduce the cardiotoxicity associated with these regimens.25,26 In conclusion, the results of this trial show that significant antitumor activity in patients with MBC is achieved by the combination of TLC D-99, 5-FU, and cyclophosphamide. The liposomal encapsulation of doxorubicin permits the administration of a high cumulative dose of doxorubicin. The cardiac safety profile is better than that achieved in previous studies using free doxorubicin and similar to—if not better than—that of the previously reported weekly or 96-hour continuous-infusion doxorubicin administration. The use of this carrier system, TLC D-99, seems to have a better therapeutic index than free doxorubicin; therefore, phase III randomized studies comparing TLC D-99 and free doxorubicin are warranted. The preliminary results of one randomized phase III study show that eight patients had CHF; seven were treated with free doxorubicin and one with TLC D-99 (log-rank test, P = .0003). TLC D-99 is associated with a lower incidence of grade 3 mucositis (9% v 15%) and cardiac events (13% v 27%) than free doxorubicin.27
Supported by a grant from The Liposome Company, Inc, Princeton, NJ
Presented in part at the Chemotherapy Foundation Symposium XII, November 9-11, 1994, New York, NY, and at the 14th Annual Meeting of the American Society of Clinical Oncology, May 15-18, 1995, Los Angeles, CA.
1. Honing SF: Treatment of metastatic disease, hormonal therapy and chemotherapy, in Harris JR, Lippman ME, Morrow M, Hellman S (eds): Breast Diseases. Philadelphia, PA, Lippincott, 1996, pp 669-734 2. A'Hern RP, Smith IE, Ebbs SR: Chemotherapy and survival in advanced breast cancer: The inclusion of doxorubicin in Cooper type regimens. Br J Cancer 67:801-805, 1993[Medline] 3. Early Breast Cancer Trialists' Collaborative Group: Polychemotherapy for early breast cancer: An overview of the randomised trials. Lancet 352:930-942, 1998[Medline]
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Shan K, Lincoff AM, Young JB: Anthracycline-induced cardiotoxicity. Ann Intern Med 125:47-58, 1996 5. Stewart CF, Ratain MJ: Pharmacology of cancer chemotherapy, in DeVita VT, Hellman S, Rosenberg S (eds): Cancer: Principles and Practice of Oncology. Philadelphia, PA, Lippincott, 1997, pp 453-466 6. Von Hoff DD, Layard MW, Basa P, et al: Risk factors for doxorubicin-induced congestive heart failure. Ann Intern Med 91:710-717, 1979 7. Ewer MS, Benjamin RS: Cardiac complications, in Holland JF, Frei III E, Bast RC Jr, et al (eds): Cancer Medicine (ed 3). Baltimore, MD, Williams and Wilkins, 1997, pp 3197-3215 8. Basser RL, Green MD: Complications of treatments: Strategies for prevention of anthracycline cardiotoxicity. Cancer Treat Rev 19:57-77, 1993[Medline] 9. Legha SS, Benjamin RS, Mackay B, et al: Reduction of doxorubicin cardiotoxicity by prolonged continuous intravenous infusion. Ann Intern Med 96:133-139, 1982 10. Hortobagyi GN, Frye D, Buzdar AU, et al: Decreased cardiac toxicity of doxorubicin administered by continuous intravenous infusion in combination chemotherapy for metastatic breast carcinoma. Cancer 63:37-45, 1989[Medline] 11. Chlebowski RT, Paroly WS, Pugh RP, et al: Adriamycin given as a weekly schedule without a loading course: Clinically effective with reduced incidence of cardiotoxicity. Cancer Treat Rep 64:47-51, 1980[Medline] 12. Torti FM, Bristow MF, Howes AE, et al: Reduced cardiotoxicity of doxorubicin delivered on a weekly schedule, assessment by endomyocardial biopsy. Ann Intern Med 99:745-749, 1983
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Basser RL, Sobol MM, Duggan G, et al: Comparative study of the pharmacokinetics and toxicity of high-dose epirubicin with or without dexrazoxane in patients with advanced malignancy. J Clin Oncol 12:1659-1666, 1994
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Swain SM, Whaley FS, Gerber MC, et al: Cardioprotection with dexrazoxane for doxorubicin-containing therapy in advanced breast cancer. J Clin Oncol 15:1318-1332, 1997 15. Perez-Soler R: Liposomes as carriers of antitumor agents: Toward a clinical reality. Cancer Treat Rev 16:67-82, 1989[Medline] 16. Gabizon AA: Liposomal anthracyclines. Hematol Oncol Clin North Am 2:431-439, 1994 17. Creaven PJ, Cowens JW, Ginsberg R, et al: Clinical studies with liposomal doxorubicin. J Liposome Res 1:481-490, 1990
18.
Cowens JW, Creaven PJ, Greco WR, et al: Initial clinical (phase I) trial of TLC D-99 (doxorubicin encapsulated in liposomes). Cancer Res 53:2796-2802, 1993 19. Batist G, Ahlgren P, Panasci L, et al: Phase II study of liposomal doxorubicin (TLCD99) in metastatic breast cancer. Proc Am Soc Clin Oncol 11:82, 1992 (abstr 155) 20. Mackay B, Keyes LM, Benjamin RB, et al: Cardiac biopsy. Texas Society Electron Microscopy J 11:7, 9-11, 14-15, 1980 21. Jones SE, Durie BGM, Salmon SE: Combination chemotherapy with Adriamycin and cyclophosphamide for advanced breast cancer. Cancer 36:90-97, 1975[Medline] 22. Hortobagyi GN, Gutterman JU, Blumenschein GR, et al: Combination chemoimmunotherapy of metastatic breast cancer with 5-fluorouracil, Adriamycin, cyclophosphamide and BCG. Cancer 43:1225-1233, 1979[Medline] 23. Ewer MS, Ali MK, Mackay B, et al: A comparison of cardiac biopsy grades and ejection fraction estimation in patients receiving Adriamycin. J Clin Oncol 2:112-117, 1984[Abstract] 24. Kanter PM, Bullard GA, Pilkiewicz FG, et al: Preclinical toxicology study of liposome-encapsulated doxorubicin (TLC D-99): Comparison with doxorubicin and empty liposomes in mice and dogs. In Vivo 7:85-95, 1993[Medline] 25. Gianni L, Munzone E, Capri G, et al: Paclitaxel by 3-hour infusion in combination with bolus doxorubicin in women with untreated metastatic breast cancer: High antitumor efficacy and cardiac effects in a dose- and sequence-finding study. J Clin Oncol 13:2688-2699, 1995[Abstract] 26. Hudis C, Seidman A, Paton V, et al: Characterization of cardiac dysfunction observed in the Herceptin (trastuzumab) clinical trials. Breast Cancer Res Treat, 50:232, 1998 (abstr 24) 27. Batist G, Winer E, Harris L, et al: Phase III study of liposome-encapsulated doxorubicin (TLC D-99) vs. free doxorubicin in patients with metastatic breast cancer. Breast Cancer Res Treat, 50:233, 1998 (abstr 26) Submitted September 25, 1998; accepted March 11, 1999. This article has been cited by other articles:
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ABSTRACT
INTRODUCTION
grade 1.5 cardiac toxicity or if the LVEF decreased to 
