Abstract

Background

We determined the objective response rates produced by pegylated liposomal doxorubicin (PLD) plus carboplatin with/without trastuzumab (Herceptin).

Patients and methods

Patients with measurable disease were stratified by taxane treatment history and human epidermal growth factor receptor-2 status. Treatment: PLD 30 mg/m2 followed by carboplatin, day 1 of each 28-day cycle; human epidermal growth factor receptor-2 (HER2)-positive patients also received trastuzumab.

Results

Arm 1 received PLD plus carboplatin (N = 41 arm 1a, taxane naive; N = 42 arm 1b, taxane pretreated); Arm 2 patients received PLD plus carboplatin + Herceptin (N = 46). Overall response rates: 31%, 31%, and 56%, respectively. Median overall survival durations were not reached in arm 1a and were 13 and 33 months for arms 1b and 2. Median progression-free survival: 8, 5, 10 months, respectively. Grades 3–4 treatment-related toxic effects for arms 1a, 1b, 2, respectively, were neutropenia 22%, 31%, 35%; thrombocytopenia 34%, 26%, 17%; and fatigue 2%, 14%, 13%.

Conclusions

PLD plus carboplatin has moderate antitumor activity and excellent tolerability. Herceptin and PLD plus carboplatin in HER2-positive patients have antitumor activity without significant cardiac toxicity. Toxicity results suggest that PLD can be combined with Herceptin with minimal cardiac toxicity.

introduction

Pegylated liposomal doxorubicin (PLD) has been shown to produce low rates of cardiac toxicity while producing objective response rates (ORRs) of 22%–52% in metastatic breast cancer (MBC) [1–5]. Carboplatin (Cb) produces less nephrotoxicity, neurotoxicity, ototoxicity, and emesis than cisplatin does [6] and is an active agent in MBC [7]. In this study, we explored the effect of combining PLD (doxorubicin HCl liposome injection, Doxil®, Ortho Biotech Products, LP), carboplatin (Cb, Bristol–Myers Squibb Inc.), and trastuzumab (H, Herceptin®, Genentech Inc.) in MBC.

Phase II results of the combination of PLD (50 mg/m2) with Cb [area under the concentration curve (AUC) = 5] have shown the regimen to be safe and highly effective in patients with relapsed advanced ovarian cancer [8]. However, phase III trials of PLD, 30 mg/m2 with Cb (AUC = 5) given every 4 weeks, have been undertaken in ovarian cancer because of the better tolerability of the regimen [9]. Chia et al. [10] demonstrated that the combination of PLD + H was an active combination with limited cardiotoxicity in the first-line treatment of human epidermal growth factor receptor-2-positive (HER2+) MBC.

Pegram et al. [11] evaluated cisplatin in combination with trastuzumab in 39 extensively pretreated MBC patients who had progressed on standard chemotherapy; 90% of these patients had been treated with two or more prior chemotherapeutic regimens. The overall ORR was 24% [all partial responses (PR)] and one additional patient achieved PR with maintenance therapy with a median duration of response of 5 months. The most frequent grades 3–4 adverse events (AEs) in the main phase of the study were nausea or vomiting, or both nausea and vomiting together (18%), asthenia (13%), and thrombocytopenia (10%).

In our multicenter phase II study, we evaluated the clinical benefit of PLD combined with Cb in MBC patients, with H added to the regimen in HER2+ MBC patients. The aim was to develop an active regimen that produced minimal alopecia and cardiotoxicity while providing a safe and effective anthracycline-based treatment option in the palliative setting.

materials and methods

eligibility

Eligibility criteria included ≥18 years of age, documented MBC, known HER2 status with a positive status defined as IHC3+ or amplified by FISH, and at least one measurable lesion per RECIST. Patients should not have had prior treatment with PLD or Cb but may have had adjuvant H or adjuvant chemotherapy if completed >1 year before the study. Subjects may have received prior anthracyclines as adjuvant chemotherapy (cumulative dose <300 mg/m2 prior doxorubicin or <450 mg/m2 prior epirubicin). The taxane-pretreated patients (adjuvant or metastatic) may have had no more than one prior chemotherapy regimen for MBC. Taxane-naive patients must have had no prior chemotherapy for MBC. Patients must have had normal cardiac function [left ventricular ejection fraction (LVEF)] by multi-gated angiogram (MUGA) or echocardiography. The patients must have had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) zero to two and normal renal, hepatic, and bone marrow function. Nonprotocol therapy was not permitted. No patient with another malignancy within the last 5 years was permitted. Pregnant or breastfeeding women were prohibited from participating in this study.

study design

This was an open label, nonrandomized noncomparative phase II study. Patients were stratified into HER2+ and HER2− groups at registration; HER2− patients were further stratified into taxane-naive and taxane-pretreated groups. Study participants received PLD and Cb on day 1 of each 28-day cycle. In addition, HER2+ patients received H on days 1 and 15 of every cycle.

An interim safety assessment was carried out on the first 12 patients receiving PLD and Cb and H to assess the incidence of congestive heart failure (CHF) or an absolute decrease in LVEF of >15% or a decrease in LVEF below normal in four or more patients after less than six cycles of therapy.

The protocol was approved by a central institutional review board with jurisdiction over the specific sites that registered patients on the study, and all patients were required to sign an informed consent form before being enrolled in the study.

treatment

HER2− patients in arms 1a (taxane naive) and 1b (taxane pretreated) received PLD 30 mg/m2 i.v. and Cb AUC = 5 on day 1 of each 28-day cycle. HER2+ patients (arm 2) received the same regimen as arm 1 but in addition received H on days 1 and 15 at 4 mg/kg (loading dose of 8 mg/kg on day 1 of cycle 1 only). Treatment with both agents was continued until disease progression or unacceptable toxicity; if either PLD or carboplatin was withheld for any reason, the other drug could still be administered at the discretion of the treating physician.

assessments

At baseline, the following assessments were carried out: complete medical history and physical examination, assessment of ECOG PS, pregnancy test (if applicable), complete blood count (CBC), comprehensive metabolic panel (CMP), calculation of creatinine level and creatinine clearance (ClCr), physical and radiological assessment of disease, and assessment of LVEF. Assessments of toxicity were done at every clinic visit.

During treatment, most assessments were repeated before the start of each cycle; physical and radiological assessment of disease was done every other cycle (every 8 weeks). HER2− patients (arms 1a and 1b) had an LVEF assessment by MUGA or echocardiography carried out when they reached a lifetime dose of doxorubicin 400 mg/m2 and at every subsequent 90 mg/m2. For HER2+ patients (arm 2), an LVEF assessment (MUGA or echocardiography) was carried out every 3 months and anytime clinical evidence was present of cardiac dysfunction, at the discretion of the treating physician. End of treatment, assessments were done within 7 days of the last dose.

criteria for assessing response and toxicity

Toxic effects were graded using the National Cancer Institute—Common Toxicity Criteria for Adverse Events (NCI–CTCAE), version 3 [12]. Responses were assessed using standardized previously published RECIST criteria (v1.0) [13].

statistical analysis

The primary objective for this study was analysis of the ORRs for the two treatment arms. It was hypothesized that the ORR would be 50% [95% confidence interval (CI) 35% to 65%] with PLD + Cb based on ORRs achieved with active doublet combination chemotherapy in first-line MBC and 60% (95% CI 45% to 75%) with PLD + Cb + H. PLD + Cb patients were stratified into two groups, and with 10% possible early dropout, a total of 136 patients were needed.

The intent to treat (ITT) population consisted of all patients registered on the study; the assessable population was all eligible patients who received one or more dose of the study drug, and the safety population was all patients who received one or more dose of the study drug.

ORR and the clinical benefit rate [CBR, defined as complete response (CR) + PR + SD (≥6 months)] were calculated for each of the three groups by using the assessable population, and the 95% CI was estimated by implementing the exact binomial method. Time-to-response and duration of response, two secondary objectives related to ORR, were analyzed using simple descriptive statistics and Kaplan–Meier methods [14], respectively. The Kaplan–Meier method was also applied for analysis of three time-to-event variables (ITT population): time to progression, progression-free survival (PFS), and overall survival (OS), which were also secondary objectives.

Dosage, dose intensity, and dose modifications were summarized using descriptive statistics. AEs, including alopecia and need for a wig or head covering, were coded in CoSTART and graded by NCI–CTCAE, version 3 [12]. AEs were collected throughout the whole study, but only AEs related to the study drug and those resulting in dose modification or discontinuation were tabulated. The need for a wig or head covering was assessed for each patient.

results

patient characteristics

A total of 136 MBC patients were registered between 21 December 2005 and 22 May 2008 and were enrolled in the study. Patient demographics and disease characteristics are shown in Table 1. One patient was assigned to arm 1a because she was incorrectly recorded as being HER2− at baseline; however, that patient was determined to be HER2+ and was treated with the H-containing regimen. This patient was included in the arm 2 analysis of safety and response. Patient disposition is summarized in the CONSORT diagram (supplemental Figure S1, available at Annals of Oncology online). Some patients had undergone chemotherapy before study entry: 13 in arm 1a, 45 in arm 1b, and 21 in arm 2. Of these, 7 (54%) in arm 1a, 36 (80%) in arm 1b, and 20 (95%) in arm 2 had received chemotherapy with doxorubicin (Adriamycin).

Table 1.

Summary of demographics at baseline (ITT population)

Patient characteristics Arm 1a Arm 1b Arm 2 
 PLD + Cb (N = 43) PLD + Cb (N = 46) PLD + Cb  + H (N = 47) 
 HER2−/ taxane naive HER2−/ taxane pretreated HER2+ 
 N (%) N (%) N (%) 
Patient populations    
 ITTa 43 46 47 
 Assessable 39b 42 45b 
 Safety 41 42 46 
Sex    
 Female 42 (98) 46 (100) 47 (100) 
 Male 1 (2) 
Race    
 Caucasian 30 (70) 34 (74) 37 (79) 
 African American 10 (23) 8 (17) 7 (15) 
 Hispanic 3 (7) 4 (9) 2 (4) 
 Pacific Islander 1 (2) 
Age (years)    
 Median (range) 61 (28–85) 52 (30–72) 54 (29–78) 
ECOG PS    
 0 24 (56) 33 (72) 32 (68) 
 1 18 (42) 12 (26) 15 (32) 
 2 1 (2) 
 Missing 1 (2) 
Disease-free intervalc    
 Number of patients 33 45 36 
 Median (months) (range) 25 (<1–291) 27 (<1–154) 34 (<1–218) 
Sites of metastasis    
 Bone 25 (58) 24 (52) 24 (51) 
 Visceral 28 (65) 32 (70) 37 (79) 
 Soft tissue/lymph node 28 (65) 24 (52) 27 (57) 
ER/PR Status    
 ER+/PR+ 21 (49) 23 (50) 20 (43) 
 ER+/PR− or ER−/PR+ 10 (23) 3 (7) 6 (13) 
 ER−/PR− 12 (28) 20 (43) 21 (45) 
Prior therapy    
 Chemotherapy 13 (30) 45 (98) 21 (45) 
  Doxorubicin 7 (16) 36 (78) 20 (43) 
  Taxane 45 (98) 14 (30) 
 Endocrine 20 (47) 24 (52) 13 (28) 
 Trastuzumab 1 (2) 1 (2) 
 No prior therapy 3 (7) 1d (2) 9 (19) 
Patient characteristics Arm 1a Arm 1b Arm 2 
 PLD + Cb (N = 43) PLD + Cb (N = 46) PLD + Cb  + H (N = 47) 
 HER2−/ taxane naive HER2−/ taxane pretreated HER2+ 
 N (%) N (%) N (%) 
Patient populations    
 ITTa 43 46 47 
 Assessable 39b 42 45b 
 Safety 41 42 46 
Sex    
 Female 42 (98) 46 (100) 47 (100) 
 Male 1 (2) 
Race    
 Caucasian 30 (70) 34 (74) 37 (79) 
 African American 10 (23) 8 (17) 7 (15) 
 Hispanic 3 (7) 4 (9) 2 (4) 
 Pacific Islander 1 (2) 
Age (years)    
 Median (range) 61 (28–85) 52 (30–72) 54 (29–78) 
ECOG PS    
 0 24 (56) 33 (72) 32 (68) 
 1 18 (42) 12 (26) 15 (32) 
 2 1 (2) 
 Missing 1 (2) 
Disease-free intervalc    
 Number of patients 33 45 36 
 Median (months) (range) 25 (<1–291) 27 (<1–154) 34 (<1–218) 
Sites of metastasis    
 Bone 25 (58) 24 (52) 24 (51) 
 Visceral 28 (65) 32 (70) 37 (79) 
 Soft tissue/lymph node 28 (65) 24 (52) 27 (57) 
ER/PR Status    
 ER+/PR+ 21 (49) 23 (50) 20 (43) 
 ER+/PR− or ER−/PR+ 10 (23) 3 (7) 6 (13) 
 ER−/PR− 12 (28) 20 (43) 21 (45) 
Prior therapy    
 Chemotherapy 13 (30) 45 (98) 21 (45) 
  Doxorubicin 7 (16) 36 (78) 20 (43) 
  Taxane 45 (98) 14 (30) 
 Endocrine 20 (47) 24 (52) 13 (28) 
 Trastuzumab 1 (2) 1 (2) 
 No prior therapy 3 (7) 1d (2) 9 (19) 

aSeven patients in the ITT population were not treated for the following reasons: arm 1a—one patient had a decline in baseline performance status; arm 1b—four patients (n = 1 each) had aspartate transaminase abnormality at baseline, decline of pulmonary status, liver failure, and patient request all before first treatment day; and arm 2—two patients (n = 1 each) were not treated at physician request and patient request.

bOne patient was incorrectly determined as ‘HER2−’ and was allocated to PLD + Cb arm at registration. She was found to be HER2+ shortly after registration and thus patient started the relevant PLD + Cb + H regimen. Therefore, in this report, the patient would be considered in PLD + Cb (taxane naive) group for analyses using ITT population and PLD + Cb + H group for analyses within the safety and assessable populations; refer to Figure 1 for other reasons not evaluable.

cCalculated from date of diagnosis to date of first metastasis.

dThis patient had no prior therapy and should have been assigned to the taxane-naive group.

Cb, carboplatin; ECOG PS, Eastern Cooperative Oncology Group performance status; ER, estrogen receptor; PR, progesterone receptor; H, trastuzumab; HER2+, Her2/neu IHC or FISH+; ITT, intent to treat; PLD, pegylated liposomal doxorubicin.

Figure 1.

(A) Kaplan–Meier plot of survival by cohort. (B) Kaplan–Meier plot of progression-free survival (PFS) by cohort. OS, overall survival.

Figure 1.

(A) Kaplan–Meier plot of survival by cohort. (B) Kaplan–Meier plot of progression-free survival (PFS) by cohort. OS, overall survival.

treatment outcomes

Antitumor activity data are summarized in Table 2. The ORRs for taxane-naive and taxane-pretreated patients were 31% each and 56% for HER2+ patients. The median durations of response, for patients achieving CR or PR, were 11, 7, and 12 months for these three groups, respectively (Table 2). In the HER2− patients, regardless of estrogen receptor status, ∼30% of patients achieved a response. CBRs were 54%, 40%, and 67%, respectively. The median survival has not been achieved in the taxane-naive group but was 13 and 33 months for the taxane-pretreated and HER2+ patients, respectively (Figure 1A). Survival at 12 months for the three treatment groups was 83%, 56%, and 90%, for the taxane-naive, taxane-pretreated, and HER2+ groups, respectively. Median PFS for the three treatment groups was 8, 5, and 10 months, respectively; PFS at 12 months was 36%, 18%, and 48%, respectively (Figure 1B). Median time to progression for the cohorts was nearly identical to those seen for PFS.

Table 2.

Overall responses (per protocol/assessable population)

 Arm 1a Arm 1b Arm 2 
 PLD + Cb (N = 39) PLD + Cb (N = 42) PLD + Cb + H (N = 45) 
 HER2−/taxane naive HER2−/taxane pretreated HER2+ 
  N % (95% CI) N % (95% CI) N % (95% CI) 
Response 
 Complete response (CR) 
 Partial response (PR) 11 28 10 24 21 47 
 Stable disease (SD) 18 46 18 43 12 27 
 Progressive disease (PD) 21 21 13 
 Not assessablea 
 Response (CR + PR) 12 31 (17–48) 13 31 (18–47) 25 56 (40–70) 
 Clinical benefitb 21 54 (37–70) 17 40 (26–57) 30 67 (51–80) 
Time-to-response (months)    
 CR/PR patients (n12 13 25 
 Median (range) 2 (2–13) 2 (2–14) 1.7 (0.9–7) 
Duration of response (months)    
 Median (range) 11 (<1–15) 7 (3–13) 12 (2–17) 
 Arm 1a Arm 1b Arm 2 
 PLD + Cb (N = 39) PLD + Cb (N = 42) PLD + Cb + H (N = 45) 
 HER2−/taxane naive HER2−/taxane pretreated HER2+ 
  N % (95% CI) N % (95% CI) N % (95% CI) 
Response 
 Complete response (CR) 
 Partial response (PR) 11 28 10 24 21 47 
 Stable disease (SD) 18 46 18 43 12 27 
 Progressive disease (PD) 21 21 13 
 Not assessablea 
 Response (CR + PR) 12 31 (17–48) 13 31 (18–47) 25 56 (40–70) 
 Clinical benefitb 21 54 (37–70) 17 40 (26–57) 30 67 (51–80) 
Time-to-response (months)    
 CR/PR patients (n12 13 25 
 Median (range) 2 (2–13) 2 (2–14) 1.7 (0.9–7) 
Duration of response (months)    
 Median (range) 11 (<1–15) 7 (3–13) 12 (2–17) 

aThese five patients were not assessable for response because they had no assessment of response after the baseline assessments of disease. However, they are included in the protocol-defined assessable population in assessing ORR and CBR.

bCBR = CR + PR + SD (≥6 months).

Cb, carboplatin; CBR, clinical benefit rate; H, trastuzumab; HER2+, Her2/neu IHC or FISH+; ORR, objective response rate; PLD, pegylated liposomal doxorubicin.

drug delivery

Patients in arms 1a, 1b, and 2 received a median (and range) of 6 (1–29), 5 (1–20), and 6 (1–20) cycles, respectively. A summary of dosing information, including cumulative dose and dose intensity, is included in supplemental Table S1 (available at Annals of Oncology online).

toxicity

The most common grades 3–4 treatment-related toxic effects for taxane-naive, taxane-pretreated, and HER2+ patients, respectively, were neutropenia 22%, 31%, 35%; thrombocytopenia 34%, 26%, 17%; leukopenia 7%, 19%, 17%; anemia 12%, 17%, 11%; and fatigue 2%, 14%, 13%. Notably, absent was significant skin toxicity from PLD, with no grades 3–4 toxicity; only five patients experienced grade 2 skin toxicity, primarily as hand-foot syndrome (HFS). Treatment-related infusion/allergic/hypersensitivity reactions were noted in six patients. Only one patient discontinued study treatment due to an infusion/allergic reaction. Grades 2–4 toxic effects reported in two or more patients are summarized in Table 3. Three patients had >15% absolute decreases in LVEF during the study (two taxane-naive (arm 1a) and 1 HER+ (arm 2) patients). Grade 2 alopecia occurred in 5%, 0%, 9% of patients (taxane naive, taxane pretreated, HER2+, respectively); grade 1 alopecia rates were 15%, 7%, 26%. The ‘need for wig or head covering’ rate, related to study treatment, was documented in 10%, 0%, and 7% of patients. Three patients died within the 30 days following their last dose of the study drug; two patients’ deaths were attributed to progressive disease. The third patient's death, due to CHF, occurred before cycle 2 in arm 1a (PLD + Cb, taxane naive). Although the patient had a baseline LVEF of 70%, she had a prestudy history of remote transient CHF; thus, the AE was deemed unrelated to the study treatment. Less than 15% of patients in each group (12%, 13%, and 15%) discontinued due to AEs.

Table 3.

Selected grades 2–4 treatment-related toxic effects

Adverse event Arm 1a Arm 1b Arm 2 
 Taxane naive Taxane pretreated HER2+ 
 PLD + Cb, N = 41 PLD + Cb, N = 42 PLD + Cb + H, N = 46 
 Grade 2 Grade 3 Grade 4 Grade 2 Grade 3 Grade 4 Grade 2 Grade 3 Grade 4 
Hematologic  
 Anemia 13 (32) 3 (7) 2 (5) 6 (14) 6 (14) 1 (2) 9 (20) 5 (11) 
 Leukopenia 1 (2) 3 (7) 6 (14) 5 (12) 3 (7) 7 (15) 6 (13) 2 (4) 
 Neutropenia 7 (17) 6 (15) 3 (7) 6 (14) 10 (24) 3 (7) 8 (17) 11 (24) 5 (11) 
 Thrombocytopenia 3 (7) 5 (12) 9 (22) 3 (7) 3 (7) 8 (19) 4 (9) 4 (9) 4 (9) 
Nonhematologic  
 Hypersensitivity reaction 1 (2) 2 (5) 1 (2) 1 (2) 
 Alopecia 2 (5) NA NA NA NA 4 (9) NA NA 
 Anorexia 1 (2) 5 (12) 1 (2) 3 (7) 
 Diarrhea 2 (5) 1 (2) 3 (7) 
 Fatigue 11 (27) 1 (2) 10 (24) 6 (14) 5 (11) 6 (13) 
 Hand-foot syndrome 3 (7) 1 (2) 1 (2) 
 Nausea 6 (15) 10 (24) 4 (9) 4 (9) 
 Vomiting 3 (7) 3 (7) 2 (5) 2 (4) 2 (4) 
 Mucositis 1 (2) 2 (5) 1 (2) 5 (11) 1 (2) 
Adverse event Arm 1a Arm 1b Arm 2 
 Taxane naive Taxane pretreated HER2+ 
 PLD + Cb, N = 41 PLD + Cb, N = 42 PLD + Cb + H, N = 46 
 Grade 2 Grade 3 Grade 4 Grade 2 Grade 3 Grade 4 Grade 2 Grade 3 Grade 4 
Hematologic  
 Anemia 13 (32) 3 (7) 2 (5) 6 (14) 6 (14) 1 (2) 9 (20) 5 (11) 
 Leukopenia 1 (2) 3 (7) 6 (14) 5 (12) 3 (7) 7 (15) 6 (13) 2 (4) 
 Neutropenia 7 (17) 6 (15) 3 (7) 6 (14) 10 (24) 3 (7) 8 (17) 11 (24) 5 (11) 
 Thrombocytopenia 3 (7) 5 (12) 9 (22) 3 (7) 3 (7) 8 (19) 4 (9) 4 (9) 4 (9) 
Nonhematologic  
 Hypersensitivity reaction 1 (2) 2 (5) 1 (2) 1 (2) 
 Alopecia 2 (5) NA NA NA NA 4 (9) NA NA 
 Anorexia 1 (2) 5 (12) 1 (2) 3 (7) 
 Diarrhea 2 (5) 1 (2) 3 (7) 
 Fatigue 11 (27) 1 (2) 10 (24) 6 (14) 5 (11) 6 (13) 
 Hand-foot syndrome 3 (7) 1 (2) 1 (2) 
 Nausea 6 (15) 10 (24) 4 (9) 4 (9) 
 Vomiting 3 (7) 3 (7) 2 (5) 2 (4) 2 (4) 
 Mucositis 1 (2) 2 (5) 1 (2) 5 (11) 1 (2) 

Alopecia grade 1—arm 1 taxane naive n = 6 (15%), arm 1 taxane pretreated n = 3 (7%), arm 2 n = 12 (26%).

Cb, carboplatin; H, trastuzumab; HER2+, Her2/neu IHC or FISH+; PLD, pegylated liposomal doxorubicin.

discussion

This report details the findings of a prospective phase II study of combined PLD with carboplatin (and trastuzumab in patients with HER2+ disease) in MBC. The safety and efficacy of PLD as single-agent therapy for the treatment of MBC has been previously reviewed and investigated [15–18]. Lyass et al. [16] conducted a dose-ranging study involving 45 previously treated MBC patients, who received PLD at doses of 35–70 mg/m2 every 3–6 weeks; 71% of the patients had received prior anthracyline. The overall response rate was 33%, median PFS was 7.5 months, and median OS was 16 months. The reported rates of HFS or palmar-plantar erythrodysesthesia (PPE) grades 2–3 and grades 2–4 stomatitis were 40% and 62%, respectively. In another trial, Ranson et al. [17] treated 71 MBC patients with PLD at doses of 45–60 mg/m2 every 3–4 weeks for a maximum of six cycles; none had received prior anthracyclines. The ORR was 31% and treatment was generally well tolerated, except for grades 2–4 skin toxicity, which was reported in 54% of patients.

Kolaric et al. [19] conducted a phase II study of single-agent Cb in 20 previously untreated MBC patients. Cb was administered at a dose of 400 mg/m2 on day 1 every 3 weeks and produced a 20% response rate with an average duration of 4 months. Martin et al. [20] reported that chemo-naive MBC patients who received Cb 400 mg/m2 every 4 weeks achieved a 35% response rate. Interestingly, patients with prior exposure to chemotherapy did not respond to Cb therapy. O’Brien et al. [21] conducted a phase II study of single-agent Cb in 40 MBC patients, one-third of whom had received prior first-line chemotherapy for metastatic disease, receiving AUC of 7 with each course of Cb repeated every 4 weeks. The overall response rate was 25%. The study confirmed reports indicating that Cb had moderate activity in chemo-naive patients but not in previously treated patients.

Earlier studies of PLD + Cb, in cancers other than MBC (including uterine, cervix, ovarian, peritoneal, endometrial, and solid tumors), have demonstrated that this combination is active and safe. Verschraegen et al. [22] evaluated this combination in squamous cell cancer of the cervix, producing responses in 38% of the 29 assessable patients. Infusion reactions led to drug discontinuation in three patients. In a separate phase I study of PLD + Cb conducted by Gonçalves et al. [23], no cardiac toxicity was observed. Lê et al. [24] conducted a multicenter phase II study using PLD + Cb, which produced a 33% ORR. Although 12 of 51 patients had infusion reactions, only 1 patient discontinued due to this toxicity. Pignata et al. [25] reported the combination's safety as first-line therapy in 50 ovarian cancer patients; Cb AUC = 5 plus PLD 30 mg/m2 were administered every 3 weeks for up to six cycles. Treatment delays were frequent; 68% of patients delayed at least one cycle of therapy due to toxic effects, and 86% of all patients completed the planned number of cycles. Hematologic toxic effects were common, and grades 3–4 AEs were frequent; however, 4% of patients experienced grade 1 heart rhythm abnormalities and another 6% experienced grade 2 alopecia (100% of patients experienced some degree of hair loss). PPE/HFS occurred in 14% of patients (10% grade 1, 2% each grade 2 and 3). There have been many other published reports of phase II [26–32] and III [33] studies evaluating this combination in recent years, mostly in ovarian cancer.

A phase II trial of PLD and H in HER2+ MBC assessed the cardiotoxicity and efficacy of the combination therapy [34]; 16 patients with HER2+ MBC were enrolled and treated with first- (N = 10) or second-line (N = 6) PLD 40 mg/m2 every 4 weeks for six up to nine cycles and weekly H; 13% of patients had received prior anthracylines. The ORR was 33%, and clinical benefit was achieved in 50% of patients. With a median follow-up of 15 months, median PFS was 10 months and median OS was 16 months. Grades 2–3 skin toxic effects, specifically HFS, were reported by 13% of patients, and no significant cardiac toxicity was observed.

The clinical utility of PLD and H was also studied in another phase II trial of 30 MBC patients; 43% had received prior adjuvant anthracyclines [3]. PLD 50 mg/m2 was given every 4 weeks for six cycles with weekly H. A median of six cycles of PLD were administered. The ORR was 52%; the median PFS was 12 months, and median OS had not been reached at a median follow-up of 14 months. Ten percent of the patients developed protocol-defined cardiotoxicity (absolute decline in LVEF of ≥15%). The most common AE was HFS; 11/30 patients (37%) developed grades 1–2 HFS, and 30% had grade 3 HFS.

Venturini et al. [35] conducted a phase II study of non-PLD in combination with trastuzumab and docetaxel as first-line therapy for MBC. They evaluated cardiotoxicity (decreased LVEF to <45% or a decrease of at least 20% from baseline), general toxicity, and the activity of this drug combination. Thirty-one patients with MBC who had not undergone previous chemotherapy were included. They received 50 mg/m2 of non-PLD, 75 mg/m2 docetaxel, and 2 mg/kg/week of trastuzumab for up to eight cycles, followed by trastuzumab alone for up to 52 weeks. Three patients developed cardiotoxicity during treatment, and two other patients developed cardiotoxicity after the study ended. Hematological toxicity, alopecia, asthenia, and fever were the most common AEs. Best overall response was 66%. Median time to progression was 13 months. These findings indicate that the combination of non-PLD, docetaxel, and trastuzumab has acceptable cardiac and general toxicity and may be a good choice as first-line therapy in MBC.

The current prospective stratified study evaluated PLD and Cb (with H in HER2+ MBC) on a 28-day cycle. Arm 1 (PLD + Cb) enrolled HER2− patients and was stratified by prior taxane treatment history [N = 43 taxane naive (arm 1a) and N = 46 taxane pretreated (Arm 1b)]; arm 2 HER2+ patients (N = 47) for PLD + Cb + H. Some patients in each arm had received prior anthracycline chemotherapy. Based on the findings of previous studies of Cb alone [19–21] or in combination with PLD [22–24], which showed positive responses of 20%, 35%, and 25% in MBC and other cancers, we chose to use PLD + Cb for this study. Interestingly, the combination of PLD + Cb produced response rates of 31% in the HER2− population, regardless of the patients’ prior taxane treatment history, suggesting that this combination may be noncross resistant with the taxanes. The addition of H (arm 2) resulted in a 56% response rate, which is an improvement on the 33% ORR observed with PLD 40 mg/m2 + H [34] and similar to the 52% ORR seen with PLD 50 mg/m2 + H. However, in our study, lowering the PLD dose to 30 mg/m2 every 4 weeks and adding carboplatin substantially reduced the nonhematologic toxic effects associated with high-dose PLD.

Toxicity was generally mild with the PLD/Cb regimen with the addition of Cb, leading mainly to grade 4 thrombocytopenia in ∼20% of patients. However, no clinically significant bleeding complications occurred, and this toxicity was manageable with dose reduction. The lack of grade 2 alopecia and clinically significant cardiac toxicity were favorable safety aspects of these regimens. Infusion reactions were uncommon in this study, most likely due to the use of the steroid antiemetic premedication before carboplatin and possibly due to the lower dose of PLD utilized in this study.

The combination of PLD + Cb has moderate antitumor activity and is well tolerated. Trastuzumab added to PLD + Cb has substantial antitumor activity in HER2+ patients without significant cardiotoxicity. Because of this excellent safety profile, the addition of trastuzumab to PLD + Cb may be a good first-line therapy in HER2+ MBC patients.

funding

This study was supported by funds from Ortho Biotech, LP, Raritan, NJ. Clinical trials.gov registration number NCT00303108.

disclosure

Dr JOS has received honoraria from Johnson and Johnson. All other authors have declared no conflicts of interest.

acknowledgements

We thank the patients who shared their experiences with US Oncology physicians (supplemental Appendix, available at Annals of Oncology online), the site coordinators in the field, (especially Cheryl Kettle-Goswick, RN), program manager Laura Guerra, RN, and data reviewer Tracy Locke, RHIA, who assured the accuracy and integrity of the data. We also thank Kristi A. Boehm, MS, for assisting with the writing of this manuscript and for her editorial support and Feng Zhan, PhD, for his data analyses.

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