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The Oncologist, Vol. 8, Suppl 2, 10–16, August 2003
© 2003 AlphaMed Press

Liposomal Anthracyclines: Adjuvant and Neoadjuvant Therapy for Breast Cancer

Susana Campos

Dana-Farber Cancer Institute, Brigham and Women’s Cancer Center, Boston, Massachusetts, USA

Correspondence: Susana Campos, M.D., M.P.H., Dana-Farber Cancer Institute, Brigham and Women’s Cancer Center, 44 Binney Street, Boston, Massachusetts 02115, USA. Telephone: 617-632-3800; Fax: 617-632-3479; e-mail: Susana_Campos{at}dfci.harvard.edu


   LEARNING OBJECTIVES
Top
 Learning Objectives
Abstract
 Introduction
 Anthracycline-Containing...
 Liposomal Anthracyclines
 Conclusions
 References
 
After completing this course, the reader will be able to:

  1. Describe the role of conventional anthracyclines in the adjuvant breast cancer setting.
  2. Discuss the efficacies and tolerabilities of liposomal anthracyclines as neoadjuvant therapy in patients with locally advanced breast cancer.
  3. Explain the rationale for the future study of liposomal anthracyclines in adjuvant therapy for patients with early-stage breast cancer.

Access and take the CME test online and receive one hour of AMA PRA category 1 credit at CME.TheOncologist.com


   ABSTRACT
Top
 Learning Objectives
 Abstract
Introduction
 Anthracycline-Containing...
 Liposomal Anthracyclines
 Conclusions
 References
 
Conventional anthracyclines, particularly doxorubicin, have played an important role in the treatment of patients with breast cancer for many decades. Conventional doxorubicin has shown excellent antitumor activity in the metastatic, neoadjuvant, and adjuvant settings. However, its clinical utility is limited due to acute and chronic toxicities, particularly cardiotoxicity, myelosuppression, nausea and vomiting, and alopecia. Liposomal doxorubicin formulations (liposomal doxorubicin [D-99] and pegylated liposomal doxorubicin) currently under investigation for the treatment of breast cancer have demonstrated similar efficacies and favorable toxicity profiles compared with conventional doxorubicin in patients with metastatic breast cancer. These agents have also shown efficacy and tolerability in several small studies as neoadjuvant therapy in patients with locally advanced breast cancer. While there are currently no studies with liposomal doxorubicin or pegylated liposomal doxorubicin as adjuvant therapy, their demonstrated activities and tolerabilities in the metastatic and neoadjuvant settings provide the rationale for the future study of these agents in adjuvant therapy for patients with early-stage breast cancer.

Key Words. Anthracyclines • Liposome • Adjuvant chemotherapy • Neoadjuvant therapy • Breast neoplasms


   INTRODUCTION
Top
 Learning Objectives
 Abstract
 Introduction
Anthracycline-Containing...
 Liposomal Anthracyclines
 Conclusions
 References
 
Conventional anthracyclines, particularly doxorubicin, continue to be an important component of breast cancer treatment regimens. In addition to being a mainstay of therapy in the adjuvant and neoadjuvant settings, anthracyclines are frequently used in chemotherapy regimens for metastatic breast cancer (MBC) [1, 2]. A variety of chemotherapy regimens employing conventional anthracyclines is used in the adjuvant setting (Table 1Go) [3-10]. Anthracycline-containing regimens have demonstrated small but significant advantages in survival over nonanthracycline-containing regimens [1]. While conventional doxorubicin has demonstrated excellent antitumor activity in patients with breast cancer [1, 11, 12], its clinical utility is somewhat limited due to associated toxicities [11, 12]. Three liposomal formulations have been developed to increase the therapeutic index of anthracyclines, and these are currently being studied in patients with breast cancer. This article focuses on the role of liposomal anthracyclines in the metastatic setting and the neoadjuvant setting (i.e., patients with locally advanced breast cancer [LABC]) and addresses the potential use of these agents in the adjuvant setting.


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  		Table 1. Summary of studies using anthracycline-based combinations as adjuvant therapy
 

   ANTHRACYCLINE-CONTAINING REGIMENS IN THE ADJUVANT SETTING
Top
 Learning Objectives
 Abstract
 Introduction
 Anthracycline-Containing...
Liposomal Anthracyclines
 Conclusions
 References
 
Results of a recent meta-analysis of data from more than 100 prospective randomized trials of adjuvant therapy (2000 Overview) by the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) suggest a definite advantage when a conventional anthracycline is incorporated into the chemotherapy regimen in the adjuvant setting. In a comparison of anthracycline-containing regimens with cyclophosphamide/methotrexate/fluorouracil (CMF), there was a highly statistically significant difference in favor of the anthracyclinecontaining regimens in terms of relapse-free (61.4% versus 57.9%, p = 0.0005) and overall (68.0% versus 63.4%, p < 0.00001; EBCTCG, Oxford, 2000) survival rates. In comparison with CMF, anthracycline-containing polychemotherapy produced significantly lower recurrence (11% ± 3% proportional reduction, p = 0.0005) and death (16% ± 3%, p < 0.00001) rates. The benefits persisted for 10 years, with absolute gains of approximately 4% in recurrence and survival. The extent to which this difference was due to greater efficacies of anthracycline-based regimens in certain subgroups (i.e., patients with human epidermal growth factor receptor 2 [HER-2]-positive tumors) is unknown. It is important to note that the 2000 Overview did not stratify the findings regarding the superiority of anthracycline-containing regimens by shorter anthracycline-type regimens (doxorubicin/cyclophosphamide [AC] for four cycles) versus longer regimens (cyclophosphamide/epirubicin/fluorouracil [CEF] or cyclophosphamide/doxorubicin/fluorouracil [CAF] for six cycles). The results of the Overview, however, may be confounded not only by the number of cycles of anthracycline-based regimens administered, but also by the incorporation of 5-fluorouracil, the use of oral versus i.v. cyclophosphamide, and the type of anthracycline employed. Regardless, it appears that the use of an anthracycline in early-stage breast cancer is important in terms of its beneficial effects on patient relapse-free and overall survival rates.

Results of a large study conducted by Levine and colleagues further support the role of conventional anthracyclines in the treatment of early-stage breast cancer [13]. That study compared the efficacy and safety of CMF with that of CEF. Patients (n = 710) were randomly assigned to receive either CMF (cyclophosphamide, 100 mg/m2 orally days 1-14, methotrexate, 40 mg/m2 i.v. days 1 and 8, and fluorouracil, 600 mg/m2 i.v. days 1 and 8) or CEF (cyclophosphamide, 75 mg/m2 orally days 1-14, epirubicin, 60 mg/m2 i.v. days 1 and 8, and fluorouracil, 500 mg/m2 i.v. days 1 and 8) monthly for 6 months. Patients who received the CEF regimen demonstrated significantly greater relapse-free survival (63% versus 53%, p = 0.009) and overall survival (77% versus 70%, p = 0.03) rates than patients who received CMF therapy. In terms of tolerability, patients in the CEF arm experienced more acute toxicities than patients in the CMF arm. Updated results were presented at the recent 2002 San Antonio Breast Cancer Symposium meeting [7]. After a median follow-up of 106 months, the 10-year disease-free survival rate was 52% for patients who received CEF compared with 45% for patients who received CMF. The hazard ratio was 1.31 (p = 0.005). The corresponding data for 10-year overall survival rates were 62% and 58%, respectively, with a hazard ratio of 1.18 (CMF versus CEF, p = 0.047).

The use of anthracyclines may be a more important consideration in the subset of women (approximately 25%-30%) with breast cancers that overexpress HER-2 [14]. HER-2 expression has been shown to affect response to therapy. Retrospective trials examining the use of anthracycline-based therapy in patients with HER-2-positive disease include the Cancer and Leukemia Group B (CALGB) protocol 8541 and the National Surgical Adjuvant Breast and Bowel Project (NSABP) protocols B-19 and B-11. Results from the CALGB protocol 8541 trial suggest that anthracycline dose intensity may be important, based on the better responses observed in HER-2-positive women treated with conventional doxorubicin, 60 mg/m2, versus 30 mg/m2 [15]. The NSABP protocol B-11 trial found that anthracycline-based therapy produced a longer disease-free survival time, but not overall survival time, in patients with HER-2-positive disease compared with HER-2-negative disease. Similar results supporting a potential benefit with doxorubicin-based chemotherapy in patients with tumors overexpressing HER-2 were reported from another retrospective analysis comparing FAC with CMF [16]. It is important to note the retrospective nature of those reports.

While conventional doxorubicin has demonstrated antitumor activity in the adjuvant setting, its clinical utility is limited by both acute and chronic toxicities. Acute toxicities associated with conventional doxorubicin include myelosuppression, nausea and vomiting, and mucositis. Although often underrated, alopecia is clearly an important factor for patients and is a consequence of conventional doxorubicin therapy. The most serious conventional doxorubicin-induced toxicity is irreversible cardiac damage, which limits the cumulative lifetime dose. Doxorubicin-induced cardiotoxicity is discussed in detail elsewhere in this supplement [17]. In addition, a greater toxicity is observed when conventional doxorubicin is combined with biological therapy; for example, in a study by Slamon and colleagues, the combination of conventional doxorubicin and trastuzumab provided good response rates (56%) at the expense of a high incidence of cardiac toxicity [18].

Options exist to attenuate the cardiac toxicity associated with conventional anthracyclines. In the metastatic setting, the risk of cardiac toxicity may be reduced by limiting the cumulative anthracycline dose, by using a 48- or 96-hour continuous infusion schedule [19], by using a cardioprotectant (e.g., dexrazoxane) [20, 21], or by choosing an anthracycline formulation with a lower potential for cardiac toxicity, such as a liposomal anthracycline.


   LIPOSOMAL ANTHRACYCLINES
Top
 Learning Objectives
 Abstract
 Introduction
 Anthracycline-Containing...
 Liposomal Anthracyclines
Conclusions
 References
 
Liposomal anthracycline formulations were developed in an effort to improve upon the therapeutic index of conventional anthracyclines, while maintaining their widespread antitumor activity. Three liposomal anthracyclines are currently being studied in breast cancer: liposomal daunorubicin (DaunoXome®; Gilead Sciences, Inc.; San Dimas, CA; http://www.gilead.com), liposomal doxorubicin (D-99, MyocetTM; Elan Pharmaceuticals; Princeton, NJ; http://www.elan.com), and pegylated liposomal doxorubicin (Doxil® is marketed and distributed in the U.S. by Ortho Biotech Products; L.P., Bridgewater, NJ; http://www.orthobiotech.com; Caelyx® is distributed outside the U.S. by Schering-Plough Corporation; Kenilworth, NJ; http://www.schering-plough.com).

Liposomal Anthracyclines for MBC
In comparison with conventional doxorubicin, liposomal formulations of doxorubicin have demonstrated similar efficacies and favorable toxicity profiles, including less cardiac toxicity, in patients with MBC [22, 23]. Liposomal daunorubicin is seldom used for breast cancer, however, early phase I data showed limited activity in patients with MBC [24]. Several phase II and phase III studies support the use of liposomal doxorubicin (D-99) as monotherapy or in combination with other agents in patients with MBC, with response rates (RR = complete response + partial response) ranging from 26%-73% (Table 2Go) [22, 25-27]. Multiple clinical trials with pegylated liposomal doxorubicin, as monotherapy and in combination with other agents, also have demonstrated efficacy and tolerability in the metastatic setting, with RRs ranging from 27%-75% (Table 2Go) [23, 28-32].


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  		Table 2. Liposomal anthracyclines for MBC
 
Wigler and colleagues recently reported a randomized trial of patients assigned to receive pegylated liposomal doxorubicin or conventional doxorubicin as first-line treatment for MBC. The primary end points of the study included progression-free survival and cardiac toxicity. Progression-free survival and overall survival were similar for the two groups of patients. However, a significantly lower risk of developing clinical cardiac events was reported with pegylated liposomal doxorubicin compared with conventional doxorubicin (p < 0.001) [23].

Liposomal Anthracyclines in Combination with Trastuzumab
Liposomal doxorubicin has also been studied in combination with trastuzumab in a phase I/II trial in patients with locally advanced, inflammatory, or metastatic breast cancer (n = 39) [33]. Treatment included liposomal doxorubicin, 60 mg/m2 every 3 weeks, and trastuzumab, 4 mg/kg loading dose followed by 2 mg/kg weekly. Patients could have received from 0 to 2 prior lines of therapy, and previous trastuzumab exposure was permitted. The median patient age was 48 years (range 30-74 years). Liposomal doxorubicin demonstrated efficacy in this combination (overall RR = 59%), with documented cardiac tolerability. Cardiac toxicity was reported in two patients: one patient experienced an asymptomatic decrease in left ventricular ejection fraction (LVEF), and one patient developed symptoms of congestive heart failure (CHF). Both patients had received prior conventional doxorubicin, 240 mg/m2. The combination was otherwise well tolerated, and the toxicities were manageable and reversible. Neutropenic fever occurred in <1.0% of patients, grade 4 neutropenia occurred in 4.6%, and grade 3/4 nausea/vomiting occurred in 5.1%. There was also a low incidence of alopecia. Results from this small, prospective study pave the way for further studies exploring the use of biological therapy with liposomal anthracyclines.

Liposomal Anthracyclines in the Neoadjuvant Setting
While we know that liposomal doxorubicin and pegylated liposomal doxorubicin are active in MBC, how do we transition these agents into the adjuvant setting? Several early clinical trials have shown the efficacy and tolerability of liposomal doxorubicin and pegylated liposomal doxorubicin as neoadjuvant therapy for LABC (Table 3Go).


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  		Table 3. Liposomal anthracyclines as neoadjuvant therapy for LABC
 

Liposomal Doxorubicin in LABC
A phase I study was conducted to determine the optimal doses, efficacy, and safety of liposomal doxorubicin in combination with gemcitabine and docetaxel as neoadjuvant therapy in patients with LABC [34]. While this regimen would not likely be used in the adjuvant setting, the results of the study are still noteworthy. Patients (n = 20) were treated with liposomal doxorubicin and docetaxel on day 1 and with gemcitabine as a 4-hour infusion on day 4 every 3 weeks. All patients also received G-CSF. The activity of the combination was excellent, with a preliminary RR of 88%. Dose-limiting toxicities included diarrhea, infection, and stomatitis. No cardiac toxicity was observed. Based on these findings, the recommended doses for phase II study were liposomal doxorubicin, 60 mg/m2, gemcitabine, 350 mg/m2, and docetaxel, 75 mg/m2, every 3 weeks.

Pegylated Liposomal Doxorubicin in LABC
A very small study was initiated to evaluate the efficacy of pegylated liposomal doxorubicin in the neoadjuvant setting for patients with LABC [35]. Seven women with untreated LABC (T4 N1, T3 N1) were enrolled. Patients received pegylated liposomal doxorubicin, 50 mg/m2 every 4 weeks, followed by modified radical mastectomy or breast conservation, if feasible. Adjuvant treatment consisted of six cycles of paclitaxel 175 mg/m2 followed by local radiation therapy with or without tamoxifen 20 mg/day (if the tumor expressed estrogen receptors). RR was low (28%), and toxicities included mucositis, palmar-plantar erythrodysesthesia/hand-foot syndrome (PPE/HFS), alopecia, and rash. No patients were able to undergo breast conservation.

Pegylated liposomal doxorubicin in combination with cyclophosphamide was evaluated as neoadjuvant therapy in patients with LABC (n = 32, 30 evaluable patients; stage T3, n = 7, stage T4, n = 3) in a recent phase II study from Thailand [36]. Patients in that study were treated with pegylated liposomal doxorubicin, 35 mg/m2, in combination with cyclophosphamide, 600 mg/m2, every 3 weeks for three cycles. Patients who responded to therapy underwent a modified radical mastectomy followed by pegylated liposomal doxorubicin/ cyclophosphamide for four cycles and then local radiation therapy plus tamoxifen for 5 years in those patients with estrogen receptor/progesterone receptor-positive tumors. In contrast with the previous study, the overall RR was 73% (22 partial responses). Grade 3/4 toxicities associated with this regimen included anemia, leukopenia, neutropenia, nausea and vomiting, stomatitis, alopecia, PPE/HFS, and infusion-related reactions. The investigators concluded that pegylated liposomal doxorubicin in combination with cyclophosphamide was an effective regimen in LABC, with less myelosuppression and alopecia than AC.

The combination of pegylated liposomal doxorubicin and paclitaxel was studied in a phase II trial in newly diagnosed patients with LABC (n = 35) [37]. Patients received pegylated liposomal doxorubicin, 35 mg/m2, in combination with paclitaxel, 175 mg/m2, every 3 weeks for six cycles. The median patient age was 53 years (range 26-73 years), with 15 premenopausal and 20 postmenopausal women enrolled. The objective RR was 71%, with six complete responses and 19 partial responses. Three patients had pathologic complete responses. Adverse events included grade 3 skin toxicity in four (11%) patients, PPE/HFS in three (9%) patients, leukopenia in four (11%) patients, and alopecia in 29 (83%) patients. The high incidence of alopecia was likely due to paclitaxel. There was no grade 3/4 neurotoxicity, and thrombocytopenia and nausea and vomiting were uncommon. In addition, there was no effect on cardiac function. The authors suggested lengthening the treatment interval to every 4 weeks to minimize skin toxicities.

Despite a lack of abundant data in this setting, the initial results from these small studies suggest that pegylated liposomal doxorubicin in combination with cyclophosphamide or paclitaxel is effective and tolerable in the neoadjuvant setting in patients with LABC. There were no reports of cardiotoxicity, and other toxicities were generally mild and manageable. Based on these findings, further study of combination neoadjuvant regimens that incorporate pegylated liposomal doxorubicin in patients with LABC is justified.

Liposomal Anthracyclines in the Adjuvant Setting
Conventional doxorubicin is commonly used as adjuvant therapy in patients with breast cancer; however, as noted previously, it is associated with many acute and chronic toxicities [1, 2]. Compared with conventional doxorubicin in patients with MBC, liposomal doxorubicin and pegylated liposomal doxorubicin demonstrated similar efficacies and favorable toxicity profiles, with better cardiac safety and less alopecia, nausea and vomiting, and myelosuppression [22, 23]. In addition, liposomal doxorubicin and pegylated liposomal doxorubicin are effective and well tolerated as neoadjuvant therapy for patients with LABC. Therefore, a rationale exists for the use of liposomal doxorubicin or pegylated liposomal doxorubicin in the adjuvant setting. Our roundtable of experts discussed the question: "Do liposomal anthracyclines have a role in adjuvant therapy for breast cancer?" The topic generated several points that deserve consideration.

There is a substantial amount of promising data demonstrating the efficacy and tolerability of pegylated liposomal doxorubicin in patients with MBC, either as a single agent [23] or in combination with gemcitabine or paclitaxel [30, 32]. However, the question remains whether a large phase III trial that compares pegylated liposomal doxorubicin with a standard regimen as front-line therapy for MBC is necessary to justify the use of this agent in the adjuvant setting. Essentially, pegylated liposomal doxorubicin has already shown similar efficacy to that of conventional doxorubicin, with a better toxicity profile [23]. At the same time, we are still in the infancy of adjuvant therapy as it relates to the use of anthracyclines. Adjuvant anthracyclines have been used for approximately 20 years, and long-term follow-up data, especially in younger patients, are only now becoming available.

As we now question the expanded role of anthracyclines in the adjuvant setting, it is reasonable to propose that a less cardiotoxic agent be studied. While evidence shows that there is a better toxicity profile with liposomal doxorubicin formulations, including less cardiotoxicity, alopecia, and nausea and vomiting, it is important to establish not only the efficacies of these agents in the adjuvant setting, but also the pharmacoeconomic consequences of using these agents in the adjuvant setting.


   CONCLUSIONS
Top
 Learning Objectives
 Abstract
 Introduction
 Anthracycline-Containing...
 Liposomal Anthracyclines
 Conclusions
References
 
As discussed in detail in this supplement, liposomal anthracyclines, or more specifically, liposomal doxorubicin and pegylated liposomal doxorubicin, have demonstrated efficacies and tolerabilities in patients with MBC, with favorable toxicity profiles compared with conventional doxorubicin. Liposomal doxorubicin and pegylated liposomal doxorubicin are also effective and well tolerated as neoadjuvant therapy in patients with LABC. While there are currently no studies of liposomal doxorubicin or pegylated liposomal doxorubicin as adjuvant therapy, we have concluded that rationale exists for their study and use in that setting.


   ACKNOWLEDGMENT
Top
 Learning Objectives
 Abstract
 Introduction
 Anthracycline-Containing...
 Liposomal Anthracyclines
 Conclusions
 References
 
S.C. is a member of the Speaker’s Bureau for Pharmacia and Ortho Biotech.


   FOOTNOTES
Top
 Learning Objectives
 Abstract
 Introduction
 Anthracycline-Containing...
 Liposomal Anthracyclines
 Conclusions
 References
 
This material is protected by U.S. Copyright law. Unauthorized reproduction is prohibited. For reprints contact: Reprints{at}AlphamedPress.com


   REFERENCES
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 Learning Objectives
 Abstract
 Introduction
 Anthracycline-Containing...
 Liposomal Anthracyclines
 Conclusions
 References
 

  1. Winer EP, Morrow M, Osborne CK et al. Malignant tumors of the breast. In: DeVita VT, Hellman S, Rosenberg RA, eds. Cancer: Principles & Practice of Oncology, Sixth Edition. Philadelphia: Lippincott Williams & Wilkins, 2001:1651-1717.
  2. Sparano JA, Winer EP. Liposomal anthracyclines for breast cancer. Semin Oncol 2001;28(suppl 12):32–40.[CrossRef]
  3. Carpenter JT, Velez-Garcia E, Aron BS et al. Five year results of a randomized comparison of cyclophosphamide, doxorubicin (Adriamycin) and fluorouracil (CAF) vs. cyclophosphamide, methotrexate and fluorouracil (CMF) for node positive breast cancer: a Southeastern Cancer Study Group Study. Proc Am Soc Clin Oncol 1994;13:66.
  4. French Adjuvant Study Group. Benefit of a high-dose epirubicin regimen in adjuvant chemotherapy for node-positive breast cancer patients with poor prognostic factors: 5-year follow-up results of French Adjuvant Study Group 05 randomized trial. J Clin Oncol 2001;19:602–611.[Abstract/Free Full Text]
  5. Henderson IC, Berry DA, Demetri GD et al. Improved outcomes from adding sequential paclitaxel but not from escalating doxorubicin dose in an adjuvant chemotherapy regimen for patients with node-positive primary breast cancer. J Clin Oncol 2003;21:976–983.[Abstract/Free Full Text]
  6. Hutchins L, Green S, Ravdin P et al. CMF versus CAF with and without tamoxifen in high-risk node-negative breast cancer patients and a natural history follow-up study in low-risk node-negative patients: first results of intergroup trial INT 0102. Proc Am Soc Clin Oncol 1998;17:1a.
  7. Pritchard KI, Levine MN, Bramwell VHC et al. A randomized trial comparing CEF to CMF in premenopausal women with node positive breast cancer: update of NCIC CTG MA.5. Breast Cancer Res Treat 2002;76:S33.
  8. Mamounas EP, Bryant J, Lembersky BC et al. Paclitaxel (T) following doxorubicin/cyclophosphamide (AC) as adjuvant chemotherapy for node-positive breast cancer: results from NSABP B-28. Poster presented at the 39th Annual Meeting of the American Society of Clinical Oncology, Chicago, Illinois, May 31-June 3, 2003.
  9. Fisher B, Brown AM, Dimitrov NV et al. Two months of doxorubicin-cyclophosphamide with and without interval reinduction therapy compared with 6 months of cyclophosphamide, methotrexate, and fluorouracil in positive-node breast cancer patients with tamoxifen-nonresponsive tumors: results from the National Surgical Adjuvant Breast and Bowel Project B-15. J Clin Oncol 1990;8:1483–1496.[Abstract]
  10. Citron ML, Berry DA, Cirrincione C et al. Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: first report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741. J Clin Oncol 2003;21:1431–1439.[Abstract/Free Full Text]
  11. Hortobagyi GN. Anthracyclines in the treatment of cancer: an overview. Drugs 1997;54(suppl 4):1–7.
  12. Maluf FC, Spriggs D. Anthracyclines in the treatment of gynecologic malignancies. Gynecol Oncol 2002;85:18–31.[CrossRef][Medline]
  13. Levine MN, Bramwell VH, Pritchard KI et al. Randomized trial of intensive cyclophosphamide, epirubicin, and fluorouracil chemotherapy compared with cyclophosphamide, methotrexate, and fluorouracil in premenopausal women with node-positive breast cancer. National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 1998;16:2651–2658.[Abstract]
  14. Slamon DJ, Clark GM, Wong SG et al. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 1987;235:177–182.[Abstract/Free Full Text]
  15. Thor AD, Berry DA, Budman DR et al. erbB-2, p53, and efficacy of adjuvant therapy in lymph node-positive breast cancer. J Natl Cancer Inst 1998;90:1346–1360.[Abstract/Free Full Text]
  16. Vera R, Albanell J, Lirola JL et al. HER2 overexpression as a predictor of survival in a trial comparing adjuvant FAC and CFM in breast cancer. Proc Am Soc Clin Oncol 1999;18:71a.
  17. Safra T. Cardiac safety of liposomal anthracyclines. The Oncologist 2003;8(suppl 2):17–24.[Abstract/Free Full Text]
  18. Slamon DJ, Leyland-Jones B, Shak S et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 2001;344:783–792.[Abstract/Free Full Text]
  19. 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 1989;63:37–45.[CrossRef][Medline]
  20. Swain SM, Whaley FS, Gerber MC et al. Cardioprotection with dexrazoxane for doxorubicin-containing therapy in advanced breast cancer. J Clin Oncol 1997;15:1318–1332.[Abstract/Free Full Text]
  21. Swain SM, Whaley FS, Gerber MC et al. Delayed administration of dexrazoxane provides cardioprotection for patients with advanced breast cancer treated with doxorubicin-containing therapy. J Clin Oncol 1997;15:1333–1340.[Abstract/Free Full Text]
  22. Harris L, Batist G, Belt R et al. Liposome-encapsulated doxorubicin compared with conventional doxorubicin in a randomized multicenter trial as first-line therapy of metastatic breast carcinoma. Cancer 2002;94:25–36.[CrossRef][Medline]
  23. Wigler N, O’Brien M, Rosso R et al. Reduced cardiac toxicity and comparable efficacy in a phase III trial of pegylated liposomal doxorubicin (CAELYXTM/Doxil) vs. doxorubicin for first-line treatment of metastatic breast cancer. Poster presented at the 38th Annual Meeting of the American Society of Clinical Oncology, Orlando, Florida, May 18-21, 2002.
  24. O’Byrne KJ, Thomas AL, Sharma RA et al. A phase I dose-escalating study of DaunoXome, liposomal daunorubicin, in metastatic breast cancer. Br J Cancer 2002;87:15–20.[CrossRef][Medline]
  25. Shapiro CL, Ervin T, Welles L et al. Phase II trial of high-dose liposome-encapsulated doxorubicin with granulocyte colony-stimulating factor in metastatic breast cancer. TLC D-99 Study Group. J Clin Oncol 1999;17:1435–1441.[Abstract/Free Full Text]
  26. Batist G, Ramakrishnan G, Rao CS et al. Reduced cardiotoxicity and preserved antitumor efficacy of liposome-encapsulated doxorubicin and cyclophosphamide compared with conventional doxorubicin and cyclophosphamide in a randomized, multicenter trial of metastatic breast cancer. J Clin Oncol 2001;19:1444–1454.[Abstract/Free Full Text]
  27. Valero V, Buzdar AU, Theriault RL et al. Phase II trial of liposome-encapsulated doxorubicin, cyclophosphamide, and fluorouracil as first-line therapy in patients with metastatic breast cancer. J Clin Oncol 1999;17:1425–1434.[Abstract/Free Full Text]
  28. 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 1997;15:3185–3191.[Abstract]
  29. 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 1998;50:324.
  30. 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 2000;19:113a.
  31. Sparano JA, Malik U, Rajdev L et al. Phase I trial of pegylated liposomal doxorubicin and docetaxel in advanced breast cancer. J Clin Oncol 2001;19:3117–3125.[Abstract/Free Full Text]
  32. Rivera E, Valero V, Arun B et al. Phase II study of pegylated liposomal doxorubicin in combination with gemcitabine in patients with metastatic breast cancer. J Clin Oncol 2003 (in press).
  33. Theodoulou M, Campos SM, Batist G et al. TLC D99 (D, Myocet) and Herceptin (H) is safe in advanced breast cancer (ABC): final cardiac safety and efficacy analysis. Proc Am Soc Clin Oncol 2002;21:55a.
  34. Possinger K, Krocker J, Fritz J et al. Primary chemotherapy for locally advanced breast cancer (LABC) with gemcitabine (G) as prolonged infusion, liposomal doxorubicin (M) and docetaxel (T): results of a phase I trial. Proc Am Soc Clin Oncol 2002;21:40b.
  35. Hurley J, Restrepo A, Boggs J et al. The use of neoadjuvant Doxil in the treatment of stage III breast cancer. Proc Am Soc Clin Oncol 1999;18:96a.
  36. Srimuninnimit V, Sinlarantana P, Bhothisuwan K et al. Phase II study with the combination of pegylated liposomal doxorubicin (Caelyx) and cyclophosphamide (CC) in locally advanced breast cancer (LABC). Proc Am Soc Clin Oncol 2002;21:70a.
  37. Gogas H, Papadimitriou C, Kalofonos HP et al. Neoadjuvant chemotherapy with a combination of pegylated liposomal doxorubicin (Caelyx) and paclitaxel in locally advanced breast cancer: a phase II study by the Hellenic Cooperative Oncology Group. Ann Oncol 2002;13:1737–1742.[Abstract/Free Full Text]
Received July 7, 2003; accepted for publication August 4, 2003.




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Liposomal Anthracyclines for Breast Cancer: Overview
Oncologist, August 1, 2003; 8(90002): 1 - 2.
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E. Rivera
Liposomal Anthracyclines in Metastatic Breast Cancer: Clinical Update
Oncologist, August 1, 2003; 8(90002): 3 - 9.
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A. C. Wolff
Liposomal Anthracyclines and New Treatment Approaches for Breast Cancer
Oncologist, August 1, 2003; 8(90002): 25 - 30.
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