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Originally published as JCO Early Release 10.1200/JCO.2005.03.8331 on May 8 2006 © 2006 American Society of Clinical Oncology. Pegylated Liposomal Doxorubicin and Trastuzumab in HER-2 Overexpressing Metastatic Breast Cancer: A Multicenter Phase II Trial
From the British Columbia Cancer Agency, Vancouver Cancer Centre; British Columbia Cancer Agency, Fraser Valley Cancer Centre, Surrey BC; Toronto Sunnybrook Regional Cancer Centre; Princess Margaret Hospital, Toronto, Ontario; Schering Canada Inc; and McGill University, Jewish General Hospital, Montréal, Québec, Canada Address reprint requests to Stephen Chia, MD, British Columbia Cancer Agency, Vancouver Cancer Centre, 600 W 10th Ave, Vancouver, BC, Canada V5Z 4E6; e-mail: schia{at}bccancer.bc.ca
PURPOSE: Cardiotoxicity precludes the concurrent use of doxorubicin and trastuzumab. Because pegylated liposomal doxorubicin (PLD) has equal efficacy but significantly less cardiotoxicity than conventional doxorubicin, this phase II study assessed the rate of cardiotoxicity and efficacy of first-line PLD plus trastuzumab in HER-2–positive metastatic breast cancer (MBC).
PATIENTS AND METHODS: Women with HER-2–positive, measurable MBC, and a baseline left ventricular ejection fraction (LVEF) RESULTS: Thirty women were enrolled, 13 had received prior adjuvant anthracyclines. A median 5.5 cycles of PLD were administered. Mean baseline LVEF was 62.8%, 59.5% after cycle four, and 58.3% after cycle six. Three patients (10%) developed protocol-defined cardiotoxicity. No patients developed symptomatic CHF. Response rate was 52%, with an additional 38% stable disease rate. At a median follow-up of 13.9 months, the median progression-free survival was 12.0 months; median overall survival has not yet been reached. The most common adverse events were grade 3 hand-foot syndrome (30%) and grade 3/4 neutropenia (27%). CONCLUSION: The combination of PLD and trastuzumab is a well tolerated and active regimen in HER-2-positive MBC. Cardiotoxicity was observed, but limited to asymptomatic declines in LVEF. Further evaluation of this combination is warranted.
Despite improvements in survival over the past decade,1 metastatic breast cancer (MBC) remains an incurable disease and its treatment palliative in intent. The pivotal study of trastuzumab in combination with chemotherapy in women with HER-2-positive MBC is among only a limited number of randomized phase III studies reporting a survival advantage for newer systemic treatments versus standard regimens in MBC.2-7 In HER-2-positive MBC the addition of trastuzumab to either paclitaxel or doxorubicin and cyclophosphamide (AC) significantly improves response rate (RR), time to tumor progression, and overall survival (OS) compared with the identical chemotherapy regimen alone.2 Unfortunately, despite the clinical benefit of the AC and trastuzumab combination, it is associated with an unacceptably high rate of cardiotoxicity and congestive heart failure (CHF). Within the 27% rate of cardiotoxicity seen with concurrent AC and trastuzumab in the phase III trial, approximately two thirds of cases were of New York Heart Association Class III or IV.8 Pegylated liposomal doxorubicin (PLD) was developed in an attempt to modify the toxicity profile of conventional doxorubicin while maintaining its efficacy. In a phase III trial as first-line therapy of MBC, PLD and conventional doxorubicin had comparable efficacy, but PLD was associated with significantly less cardiotoxicity.9 Furthermore in preclinical models the combination of PLD and trastuzumab was found to be synergistic.10
This multicenter phase II study was conducted to assess the safety and efficacy of PLD in combination with trastuzumab in patients with HER-2–positive MBC. The primary objective was to assess the rate of cardiotoxicity of this combination. A two-stage design was used to attain 80% power based on the null hypothesis of a cardiotoxicity rate of
Patients Patients with a histologic diagnosis of invasive breast carcinoma and measurable HER-2–positive metastatic disease were eligible. HER-2 overexpression required either immunohistochemic staining of 3+ or positivity by the fluorescence in situ hybridization technique. In patients with 2+ HER-2 over-expression by immunohistochemic staining, confirmatory fluorescence in situ hybridization testing was required. Prior hormonal therapies were permitted, but no prior chemotherapy or trastuzumab was allowed for the treatment of MBC. Prior exposure to anthracyclines in the adjuvant setting to a maximum cumulative dose of 300 mg/m2 for conventional doxorubicin and 720 mg/m2 for epirubicin was permitted with no minimum treatment free interval mandated. Patients had to be  18 years old, have a Eastern Cooperative Oncology Group performance status of 0 to 2, have a life expectancy longer than 6 months, and an left ventricular ejection fraction (LVEF) 55% by multigated radionuclide angiography (MUGA) scan. Baseline normal hematologic, renal, and liver enzymes were also required, with an AST/ALT  5 times upper limit of normal permitted in the presence of liver metastases. All patients provided signed informed consent. The study was conducted in accordance with the ethical principles that originated in the Declaration of Helsinki and with local research ethics board approval at each participating center.
Treatment As hand-foot syndrome (HFS) was anticipated to be the most common toxicity, the following dose modification schedule for PLD, based on the National Cancer Institute (Bethesda, MD) Common Toxicity Criteria (NCI-CTC) version 2.0 was used. If grade 2 or greater HFS was present on day 1 of a cycle, treatment was delayed 1 week. If grade 2 or greater HFS continued to be exhibited after a treatment delay of 1 week, treatment was delayed an additional week. In patients continuing to exhibit grade 2 HFS after a 2-week dose delay, treatment with PLD was resumed at a 25% dose reduction. In patients with grade 3 or 4 HFS persisting 2 weeks beyond the next scheduled dose, the study regimen was discontinued and the patient withdrawn from the study. In patients with previous grade 3 or 4 HFS that resolved to grade 1, the study drug was held for an additional week. If grade 1 HFS persisted after a 2-week delay in PLD administration, the PLD dose was reduced by 25%. Treatment was not modified in patients experiencing grade 1 HFS on day 1 of a cycle. A similar dose modification scheme for grade 2 to 4 stomatitis was utilized. For grade 2 to 3 neutropenia or thrombocytopenia on day 1 of each cycle, treatment was delayed until recovery to grade 1. For grade 4 neutropenia or thrombocytopenia on day 1 of each cycle, treatment was delayed until recovery to grade 1 and then resumed at a 25% dose reduction. There was no dose modification for trastuzumab.
Treatment was discontinued for disease progression, excessive toxicity, or in patients developing cardiotoxicity. Cardiotoxicity was defined as: clinical signs and symptoms of CHF (dyspnea, orthopnea, S3 gallop, tachycardia, inspiratory crackles) in association with a Prophylactic use of colony-stimulating factors was discouraged. Patients were permitted colony-stimulating factors if they experienced prolonged neutropenia (grade 4 neutropenia lasting > 10 days, or failure of neutrophil count recovery by day 28) or a second episode of febrile neutropenia. Antiemetics were not routinely prescribed during cycle 1, but were permitted during subsequent cycles if required.
Study Outcome Variables Serum cardiac troponin levels were collected at baseline and on day 1 of each cycle to assess for a potential relationship between changes in troponin levels and changes in cardiac function. Blood work was required weekly to assess for hematologic toxicities during the first cycle of therapy and then on day 1 of each subsequent cycle. Other safety data were assessed based on adverse events, laboratory data, and clinical examination. Adverse events were categorized using the NCI-CTC version 2.0 grading system. Prespecified secondary end points were RR, DOR, PFS, and OS. Radiologic imaging was repeated every 8 weeks to evaluate for response. Response was evaluated via bi-dimensional measurement changes using standard World Health Organization criteria. Patients who achieved a complete or partial response were reimaged 4 weeks later to confirm the initial observation. Stable disease was defined as failure to achieve a response or failure to demonstrate progressive disease following two cycles of PLD and trastuzumab. DOR was calculated from the first observation of durable response to the first observation of disease progression, or to death due to any cause. PFS was defined from the start of study drug to the first evidence of progression or death due to any cause. Survival was determined from the time of initial treatment with study drug to death due to any cause. All patients who were alive were observed for a minimum of 1 year for survival.
Statistical Analysis RR, adverse events, LVEF values, use of growth factors, and changes in laboratory parameters were summarized and tabulated. DOR, PFS, and OS were calculated with Kaplan-Meier estimates and curves used to present time-to-event data. All analyses were performed in SAS v8.02 (SAS Institute, Cary, NC) except survival outcomes and figures, which were performed in S-plus (Version 3.3, Statistical Sciences, Seattle, WA) 2000 (Insightful Corp, Seattle, WA).
A total of 30 patients (median age, 57 years; range, 29 to 73 years) were enrolled in four centers (British Columbia Cancer Agency, Vancouver Cancer Centre, Vancouver, Canada, n = 19; McGill University, Jewish General Hospital, Montréal, Canada, n = 6; Toronto Sunnybrook Regional Cancer Centre, Toronto, Canada, n = 3; British Columbia Cancer Agency, Fraser Valley Cancer Centre, Vancouver, Canada, n = 2) across Canada. Eighteen of 30 patients (60%) had tumors that were hormone receptor–positive. Thirteen patients of 30 (43%) received prior adjuvant anthracyclines. The median time from adjuvant anthracycline exposure to enrollment on study was 1.9 years (range, 0.5 years to 8.4 years). Nineteen patients (63%) received prior hormonal therapy, with 14 patients (47%) receiving prior hormonal therapy for the treatment of MBC. The majority of patients (26 of 30 or 87%) had MBC to visceral organs. No differences in patient characteristics were observed between patients accrued from the different centers. Detailed demographics of the study population are documented in Table 1.
A median of 5.5 cycles (range, one cycle to 11 cycles) of PLD was administered during the course of the study. The mean PLD dose was 48.9 mg/m2 per cycle, and the mean cumulative PLD dose was 260 mg/m2 (range, 25 mg/m2 to 550 mg/m2). One patient with significantly elevated liver enzymes from MBC to liver received a significant dose reduction (50%) on cycle one and only received this one cycle before rapid progression and death. Of the 152 total cycles of PLD delivered in this study, only 10 cycles (7%) required a dose reduction, and 22 cycles (15%) required a delay of 1 week or longer. Three patients (10%) received more than six courses of PLD (range, eight cycles to 11 cycles in total). Median duration of follow-up was 13.9 months (range, 1.1 months to 19.8 months).
Changes in Cardiac Function
Three patients (10%; 95% CI, 2.1% to 26.5%) experienced protocol-defined cardiotoxicity based on an absolute decline in LVEF of 15% in an asymptomatic state regardless of the absolute value. Each patient developing cardiac dysfunction had received prior adjuvant anthracyclines. Two patients had an absolute decline in LVEF of 15%, and one patient an absolute fall of 16%. LVEF improved during follow-up in two patients, while the third patient did not have follow-up MUGA scans performed due to rapid progression of disease. An additional four patients (13%) experienced an asymptomatic 10% to 14% decline in LVEF while maintaining an absolute LVEF greater than 50% and did not meet protocol-defined criteria for cardiotoxicity.
Efficacy
PFS and OS At a median follow-up of 13.9 months, nine patients (30%) have progressed and then subsequently died and eight patients (28%) have progressed but were alive at last follow-up. The median PFS was 12.0 months (Fig 2A). Median OS had not been reached at the time of analysis, with 20 patients (69%) still alive at last follow-up (Fig 2B). One-year estimated PFS is 48.9% (95% CI, 32.6% to 73.3%) and 1-year estimated OS is 76.9% (95% CI, 62.1% to 95.1%).
Adverse Events Most adverse events were mild to moderate (NCI-CTC grade 1 to 2). Treatment was discontinued in three patients due to adverse events (HFS, possible cardiotoxicity, and HFS/dyspnea). Only two patients (7%) developed grade 2 alopecia. Despite no routine premedication with antiemetics, there were no episodes of grade 3 or 4 nausea or vomiting. Nine patients (30%) experienced grade 2 nausea and four patients (13%) had grade 2 vomiting. Mucositis was most commonly grade 1 to 2 (43%). Although, there was one case of grade 3 mucositis. The most common adverse event was HFS. Eleven of 30 patients (37%) reported grade 1 or 2 HFS. Grade 3 HFS was reported in 9 of 30 patients (30%); no patient experienced grade 4 HFS. There was one case of grade 4 neutropenia; an additional seven patients (23%) experienced grade 3 neutropenia. There was otherwise minimal bone marrow suppression. Elevated serum troponin levels (grade 4) were noted in only one cycle in one patient, but the elevation did not correlate with any significant change in LVEF. Thus, cardiac troponin levels do not appear to correlate with cardiotoxicity in this population.
Anthracyclines remain among the most active agents in the treatment of breast cancer. As monotherapy for first-line treatment of MBC, they have demonstrated equivalence or superiority to taxanes in the clinically relevant end points of PFS and OS.11-13 However, cumulative dose-related cardiotoxicity is a major limitation to the use of conventional anthracyclines.14-15 Patients with MBC who have risk factors for cardiotoxicity or who received treatment with adjuvant anthracyclines may not be suitable candidates for anthracyclines in the metastatic setting. In a randomized phase III study as first-line therapy in MBC, PLD (50 mg/m2 every 4 weeks) and conventional doxorubicin (60 mg/m2 every 3 weeks) had comparable efficacy in RR, time to tumor progression, and OS, but PLD had significantly less cardiotoxicity.9 In the subgroup of patients who received prior adjuvant anthracyclines, the risk of cardiotoxicity was seven-fold higher with doxorubicin. Thus PLD appears to be a safer alternative to conventional doxorubicin in terms of cardiotoxicity, with also a different side effect profile. HER-2 is overexpressed in up to 20% of breast cancers and is associated with a poor prognosis.16-17 Based on retrospective analyses of several adjuvant trials, HER-2-positive breast cancers appear to be preferentially sensitive to anthracycline regimens versus nonanthracycline regimens.18-19 When doxorubicin is combined with trastuzumab, there is significant clinical benefit.2 Unlike experience with the conventional doxorubicin and trastuzumab combination, in which cardiac toxicity is seen in 27% of patients,8 the incidence of protocol-defined cardiotoxicity seen in our study was 10% and no patient developing cardiotoxicity had symptomatic CHF. There was very little change in LVEF over the first four courses of therapy, and despite a somewhat greater fall by cycle six, the mean and median LVEF remained higher than 55%. Other studies with PLD and trastuzumab,20 and with PLD, docetaxel, and trastuzumab21 have also demonstrated either minimal cardiotoxicity and/or asymptomatic declines in LVEF. Other strategies of combining anthracyclines with trastuzumab have included studies of epirubicin and trastuzumab,22 or of a different liposomal preparation of doxorubicin (TLC D99) and trastuzumab.23 Activity was seen with these anthracycline and trastuzumab combinations (RR, 58% to 71%), as was minimal cardiotoxicity (two of 33 developed cardiotoxicity with TLD D99 and trastuzumab)22 and asymptomatic declines in LVEF (10 of 22 had LVEF fall of > 10% with epirubicin 90 mg/m2 and trastuzumab).23 Our study did not meet the protocol-defined statistical threshold required to demonstrate an absolute decrease in cardiotoxicity rate from 20% to 5%. Our best estimate of the true cardiotoxicity rate with this combination is 10%. The data we present here are consistent with a true cardiotoxicity rate between 2.1% and 26.5%. A larger trial is necessary to produce a better estimate of the true cardiotoxicity rate. The 52% RR in our study is on the lower end of reported RR from other phase II and III trials of vinorelbine and trastuzumab (68%)24 and taxane-platinum and trastuzumab combinations (52% to 79%).25-26 However the median PFS of 12 months seen with PLD and trastuzumab is on the higher of the reported median PFS from the above trials (range, 5.6 to 12.7 months). The combination of PLD plus trastuzumab demonstrates activity as first-line therapy in women with HER-2-positive MBC. There is an observed cardiotoxicity rate with this combination; however, it may be lower than rates with conventional doxorubicin plus trastuzumab. Based on these findings, additional evaluation of PLD plus trastuzumab in HER-2 overexpressing breast cancer is warranted. With recent data in patients with primary operable HER-2-positive breast cancer demonstrating improved disease-free survival, distant disease-free survival, and OS with an adjuvant anthracycline-containing chemotherapy followed by a taxane and trastuzumab combination27 and the significant improvement in the pathologic complete RR with the addition of trastuzumab to a neoadjuvant anthracycline and taxane chemotherapy regimen,28 the combination of PLD and trastuzumab would ideally be suited for further study in these cohort of patients.
Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C) > $100,000 (N/R) Not Required
Supported by Schering Plough and Hoffmann La-Roche. Presented in part at the 40th Annual Meeting of the American Society of Clinical Oncology, New Orleans, LA, June 5-8, 2004. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Chia SK, Speers C, Kang A, et al: The impact of new chemotherapeutic and hormonal agents on the survival of women with metastatic breast cancer (MBC) in a population based cohort. Proc Am Soc Clin Oncol 22:6, 2003 (abstr 22) 2. 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 344:783-792, 2001 3. Buzdar A, Jonat W, Howell A, et al: Anastrozole, a potent and selective aromatase inhibitor, versus megestrol acetate in postmenopausal women with advanced breast cancer: Results of overview analysis of two phase III trials. J Clin Oncol 14:2000-2011, 1996 4. Kaufmann M, Bajetta E, Dirix LY, et al: Exemestane is superior to megestrol acetate following tamoxifen failure in postmenopausal women with advanced breast cancer: Results of a phase III randomized double-blind trial. J Clin Oncol 18:1399-1411, 2000 5. Jones SE, Erban J, Overmoyer B, et al: Randomized phase III study of docetaxel compared to paclitaxel in metastatic breast cancer. J Clin Oncol 23:5542-5551, 2005 6. O'Shaughnessy J, Miles D, Vukelja S, et al: Superior survival with capecitabine plus docetaxel combination therapy in anthracycline-pretreated patients with advanced breast cancer: Phase III trial results. J Clin Oncol 20:2812-2823, 2002 7. 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. J Clin Oncol 17:1413-1424, 1999 8. Seidman A, Hudis C, Pierri MK, et al: Cardiac dysfunction in the trastuzumab clinical trials experience. J Clin Oncol 20:1215-1221, 2002 9. O'Brien MER, Wigler N, Inbar M, et al: Reduced cardiotoxicity and comparable efficacy in a phase III trial of pegylated liposomal doxorubicin HCL (caelyx/doxil) versus conventional doxorubicin for first-line treatment of metastatic breast cancer. Ann Oncol 15:440-449, 2004 10. Konecny G, Pegram MD, Beryt M, et al: Therapeutic advantage of chemotherapy drugs in combination with herceptin against human breast cancer cells with HER-2/neu over-expression. Breast Cancer Res Treat 57:467, 1999[CrossRef][Medline] 11. Sledge GW, Neuberg D, Bernardo P, et al: Phase III trial of doxorubicin, paclitaxel, and the combination of doxorubicin and paclitaxel as front-line chemotherapy for metastatic breast cancer: An intergroup trial (E1193). J Clin Oncol 21:588-592, 2003 12. Paridaens R, Biganzoli L, Bruning P, et al: Paclitaxel versus doxorubicin as first-line single-agent chemotherapy for metastatic breast cancer: A European Organization for Research and Treatment of Cancer randomized study with cross-over. J Clin Oncol 18:724-733, 2000 13. Chan S, Friedrichs K, Noel D, et al: Prospective randomized trial of docetaxel versus doxorubicin in patients with metastatic breast cancer. J Clin Oncol 17:2341-2354, 1999 14. Von Hoff DD, Layard MW, Basa P, et al: Risk factors for doxorubicin-induced congestive heart failure. Ann Intern Med 91:710-717, 1979 15. Swain SM, Whaley FS, Ewer MS: Congestive heart failure in patients treated with doxorubicin: A retrospective analysis of three trials. Cancer 97:2869-2879, 2003[CrossRef][Medline] 16. 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 235:177-182, 1987 17. Ravdin PM, Chamness GC: The c-erbB-2 proto-oncogene as a prognostic and predictive marker in breast cancer: A paradigm for the development of other macromolecular markers—A review. Gene 159:19-27, 1995[CrossRef][Medline] 18. Paik S, Bryant J, Park C, et al: ErbB-2 and response to doxorubicin in patients with axillary lymph node-positive, hormone receptor-negative breast cancer. J Natl Cancer Inst 90:1361-1370, 1998 19. Pritchard KI, O'Malley FA, Audrulis I, et al: Prognostic and predictive value of HER-2/neu in a randomized trial comparing CMF to CEF in premenopausal women with axillary lymph node positive breast cancer (NCIC CTG MA. 5). Proc Am Soc Clin Oncol 21:42a, 2002 (abstr 165) 20. Kim E, Gaiotti DA, Volm MD, et al: Reversible cardiotoxicity from pegylated liposomal doxorubicin plus trastuzumab (herceptin): Results from 2 prospective studies. Breast Cancer Res Treat 88:S204, 2004 (abstr 5058) 21. Wolff AC, Wang M, Sparano JA, et al: Cardiac safety and clinical activity of pegylated liposomal doxorubicin and docetaxel with and without trastuzumab as 1st line chemotherapy in HER2 positive and HER-2 negative metastatic breast cancer: Eastern Cooperative Oncology Group trial E3198. Breast Cancer Res Treat 88:S125, 2004 (abstr 3040) 22. Eidtmann H, Thomseen C, Untch M, et al: Herceptin in combination with epirubicin plus cyclophosphamide: Cardiac safety and efficacy in patients with metastatic breast cancer. Proc Am Soc Clin Oncol 21:60a, 2002 (abstr 236) 23. Theodoulou M, Campos SM, Batist G, et al: TLC D99 (D, Myocet) and herceptin is safe in advanced breast cancer: Final cardiac and safety analysis. Proc Am Soc Clin Oncol 21:55a, 2002 (abstr 216) 24. Burstein HJ, Harris LN, Marcom PK, et al: Trastuzumab and vinorelbine as first-line therapy for HER2-overexpressing metastatic breast cancer: Multicenter phase II trial with clinical outcomes, analysis of serum tumor markers as predictive factors, and cardiac surveillance algorithm. J Clin Oncol 21:2889-2895, 2003 25. Pegram MD, Pienkowski T, Northfelt DW, et al: Results of two open-label, multicenter phase II studies of docetaxel, platinum salts, and trastuzumab in HER2-positive advanced breast cancer. J Natl Cancer Inst 96:759-769, 2004 26. Robert N, Leyland-Jones B, Asmar L, et al: Phase III comparative study of trastuzumab and paclitaxel with and without carboplatin in patients with HER-2/neu positive advanced breast cancer. Breast Cancer Res Treat 76:S37, 2002 (abstr 35)[CrossRef] 27. Romond EH, Perez EA, Bryant J, et al: Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 353:1673-1684, 2005 28. Budzar AU, Ibrahim NK, Francis D, et al: Significantly higher pathologic complete remission rate after neoadjuvant therapy with trastuzumab, paclitaxel, and epirubicin: Results of a randomized trial in human epidermal growth factor receptor-2 positive operable breast cancer. J Clin Oncol 23:3676-3685, 2005 Submitted August 11, 2005; accepted March 16, 2006.
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
= .05). Secondary objectives included assessing the RR, duration of response (DOR), progressive-free survival (PFS), and OS. 
