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First-Line Trastuzumab Plus Epirubicin and Cyclophosphamide Therapy in Patients With Human Epidermal Growth Factor Receptor 2–Positive Metastatic Breast Cancer: Cardiac Safety and Efficacy Data From the Herceptin, Cyclophosphamide, and Epirubicin (HERCULES) Trial
Abstract
A high incidence of congestive heart failure (CHF) has been observed in patients with metastatic breast cancer (MBC) receiving doxorubicin-based chemotherapy and trastuzumab. The Herceptin, Cyclophosphamide, and Epirubicin (HERCULES) trial evaluated trastuzumab plus cyclophosphamide and the less cardiotoxic anthracycline epirubicin.
This prospective trial combined a phase I dose-finding stage with a phase II randomized stage. In total, 120 patients with human epidermal growth factor receptor 2 (HER2) –positive MBC and adequate cardiac function received first-line trastuzumab (4 mg/kg intravenous loading dose, then 2 mg/kg every week) plus cyclophosphamide (600 mg/m2) and either epirubicin 60 mg/m2 (HEC-60) or 90 mg/m2 (HEC-90) for six cycles, followed by trastuzumab monotherapy until progression. Sixty patients with HER2-negative disease received epirubicin (90 mg/m2) and cyclophosphamide (EC-90) alone. The primary end point was dose-limiting cardiotoxicity (DLC).
Incidence of DLC was 5.0%, 1.7%, and 0% in the HEC-90, HEC-60, and EC-90 arms, respectively. All DLC events were manageable. There were no cardiac-related deaths. Other adverse-event profiles were comparable across the three arms, except febrile neutropenia, which was reported in 10% of the HEC-90 arm compared with 3% of the other arms. Tumor response rates were 57%, 60%, and 25% in the HEC-60, HEC-90, and EC-90 arms, respectively; median time to progression was 12.5, 10.1, and 7.6 months, respectively.
The HEC regimen is a promising treatment option for patients with HER2-positive MBC. The lower incidence of DLC with HEC, compared with the historic incidence associated with trastuzumab plus doxorubicin, supports further evaluation of the regimen, especially in adjuvant or neoadjuvant settings.
In breast cancer, human epidermal growth factor receptor 2 (HER2) overexpression is usually associated with a more aggressive tumor phenotype and poor overall prognosis.1,2 Trastuzumab (Herceptin; F. Hoffmann-La Roche, Basel, Switzerland), a humanized monoclonal antibody against the extracellular domain of HER2, is established as the foundation of care for HER2-positive breast cancer and, in metastatic breast cancer (MBC), is indicated in combination with taxane chemotherapy or as monotherapy.
Anthracyclines are potent compounds for breast cancer, including HER2-positive disease,3 but when combined with trastuzumab, they have been associated with a high risk of severe congestive heart failure (CHF).4 However, multivariate analysis demonstrated that trastuzumab plus chemotherapy was not a significant risk factor for cardiac events.4 In recent trials of trastuzumab combined with chemotherapy or hormonal therapy, the incidence of cardiac events was 1% to 3%.5–8
The anthracycline epirubicin is equally efficacious and less toxic than doxorubicin.9–11 Although cumulative doses of doxorubicin ≥ 450 mg/m2 are associated with potential cardiotoxicity, epirubicin is considered generally devoid of cumulative risk of cardiac events up to a threshold of 1,000 mg/m2.11–14
The Herceptin, Cyclophosphamide, and Epirubicin (HERCULES) trial is a multicenter, phase I to II trial of epirubicin/cyclophosphamide plus trastuzumab as first-line therapy for HER2-positive MBC that was conducted to evaluate the cardiac safety of the regimen. In a parallel arm, patients with HER2-negative MBC received epirubicin/cyclophosphamide only. Preliminary phase I data indicated the feasibility of combining trastuzumab with epirubicin/cyclophosphamide.15 We report phase II results, including cardiac monitoring follow-up data extending beyond 2 years in some patients and efficacy data in a reasonably large cohort.
This multicenter, international, prospective, open-label, parallel-group study incorporated a phase I nonrandomized dose-finding stage and a phase II randomized analysis. On the basis of the phase I results,15 the following two dose levels were selected for phase II: trastuzumab (4 mg/kg intravenous loading dose, then 2 mg/kg) plus cyclophosphamide (600 mg/m2) and epirubicin at either 60 mg/m2 (HEC-60) or 90 mg/m2 (HEC-90). Chemotherapy was administered at intervals of every 3 weeks for six cycles. Trastuzumab was administered at weekly intervals until disease progression, with an option to change to an every-3-week schedule after 1 year. Phase I patients continued to phase II, and additional patients with HER2-positive disease were randomly assigned to receive HEC-60 or HEC-90 until 60 patients were recruited into each arm; 60 patients with HER2-negative disease received epirubicin (90 mg/m2) and cyclophosphamide (EC-90).
A steering committee evaluated cardiac events and determined dose-limiting cardiotoxicity (DLC). The study was approved by the institutional review boards of all participating institutions and fully conformed with the principles of the Declaration of Helsinki. Signed, informed consent was obtained from all patients.
Eligible women (age ≥ 18 years) had histologically and clinically or radiologically confirmed recurrent breast cancer or MBC, with measurable or evaluable disease. Patients older than 70 years were only included after careful individual assessment by an experienced cardiologist based on cardiac history and echocardiogram. An Eastern Cooperative Oncology Group performance status of 0 or 1 and life expectancy of more than 3 months were required. Suitability for epirubicin/cyclophosphamide treatment, as demonstrated by adequate renal, hepatic, hematologic, and metabolic function and cardiac assessment at screening, was mandatory. Adequate cardiac function was defined as a baseline left ventricular ejection fraction (LVEF) ≥ 55% and no serious cardiac illness, including history of CHF, acute myocardial infarction within 6 months, evidence of transmural infarction in echocardiography, evidence of high-risk uncontrolled arrhythmias, angina pectoris requiring antianginal medication, clinically significant valvular heart disease, or poorly controlled hypertension. HER2-positive tumor status required immunohistochemistry 3+ staining or 2+ staining plus fluorescence in situ hybridization positivity.
Exclusion criteria included prior chemotherapy for MBC, treatment with trastuzumab or other anti-HER therapies, or any prior anthracycline exposure. Patients with a history of prior malignancy other than cervical carcinoma in situ and skin cancer (except melanoma) or prior high-dose therapy with peripheral stem-cell transplantation were ineligible, as were patients with CNS or bone metastases as the single metastatic site.
All patients were offered palliative and supportive care for disease-related symptoms. Palliative radiotherapy was administered if it did not compromise the evaluation of the indicator lesion. Nonpermitted concomitant medications included antineoplastic drugs, investigational or unlicensed agents, and prophylactic use of dexrazoxane or granulocyte colony-stimulating factor.
LVEF was evaluated by echocardiography at rest. When determined by Teichholz method, LVEF was recalculated by a cardiologist (M.M.) using the modified Simpson method.16 The steering committee assessed cardiac events on an ongoing basis to determine whether they met the DLC criteria. DLC in phase II was defined as symptomatic heart failure (New York Heart Association [NYHA] class III or IV) associated with an absolute decrease in LVEF of more than 10 percentage points to less than 50%. This definition ensured that any CHF symptom was associated with an LVEF decrease. The steering committee regularly monitored patient outcomes in all treatment arms.
Patients who discontinued study medication for any reason other than withdrawal of consent were observed for cardiac safety until week 103. Cardiac monitoring continued during an extension phase for patients with HER2-positive disease who continued to receive benefit from trastuzumab at the end of week 103. A general physical examination and routine laboratory and blood chemistry analyses were performed at baseline and every 3 weeks.
Tumor response was evaluated every 3 months using WHO criteria. Adverse events (AEs) were recorded throughout treatment and evaluated according to National Cancer Institute Common Toxicity Criteria version 2.0. Cardiac failure was graded according to NYHA classification.
The primary end point was cardiac safety, as assessed by DLC incidence. Secondary end points included safety other than DLC, as defined by National Cancer Institute Common Toxicity Criteria; overall response rate (ORR), defined as partial or complete response; and time to progression (TTP), measured from first administration of study treatment to documented progression. The study incorporated an exploratory analysis of progression-free survival, measured from first administration of study treatment to death or progressive disease.
The study was designed to be descriptive and, therefore, was not powered to detect definitive differences in DLC between groups; each treatment arm contained 60 patients (Fig 1). The HEC combinations were considered tolerable if the DLC rate experienced was less than 10% and if the data set was large enough that a true rate of ≥ 15% could be ruled out statistically with 90% confidence. This equated to fewer than six DLC events per treatment arm.
Fig 1. CONSORT diagram. HEC, trastuzumab, cyclophosphamide, and epirubicin; EC, epirubicin and cyclophosphamide.
Safety and efficacy analyses included all patients who received at least one dose of study medication. Analyses were generally descriptive in nature, and frequency of DLC within the treatment arms, as well as between arms, was described using CIs. Time-to-event data were analyzed using the Kaplan-Meier method.
In total, 182 patients were enrolled at 30 sites in six European countries (60 patients each with HER2-positive MBC in the HEC-60 and HEC-90 arms and 62 patients with HER2-negative disease in the EC-90 arm). Two patients, both in the EC-90 arm, did not receive study medication as a result of protocol violations (progressive symptoms, n = 1; prophylactic granulocyte colony-stimulating factor, n = 1; Fig 2).
Fig 2. Schematic diagram of disposition of patients. HEC, trastuzumab, cyclophosphamide, and epirubicin; EC, epirubicin and cyclophosphamide.
Baseline characteristics in the HER2-positive arms were generally well balanced (Table 1). The HEC-60 arm had a shorter median duration of primary disease and a greater proportion of chemotherapy-naïve patients than the HEC-90 arm. HER2-negative patients had a longer median duration of primary disease compared with HER2-positive patients, and a greater proportion of HER2-negative patients had hormone receptor–positive tumors and had received prior hormonal treatment and radiotherapy. Differences in hormone receptor positivity between HER2-positive and -negative tumors have been reported previously17 and reflect the natural biologic differences between tumor types.
|
| Demographic or Clinical Characteristic | HEC-60 (n = 60) | HEC-90 (n = 60) | EC-90 (n = 60) | |||
|---|---|---|---|---|---|---|
| No. of Patients | % | No. of Patients | % | No. of Patients | % | |
| Age, years | ||||||
| Median | 53.0 | 57.0 | 54.5 | |||
| Range | 31-75 | 27-71 | 31-70 | |||
| Hormone receptor status | ||||||
| ER positive | 24 | 40 | 28 | 47 | 47 | 78 |
| PgR positive | 22 | 37 | 26 | 43 | 42 | 70 |
| ECOG performance status | ||||||
| 0 | 40 | 67 | 39 | 65 | 39 | 65 |
| 1 | 19 | 32 | 21 | 35 | 21 | 35 |
| Median duration of disease, months | 2.3 | 10.7 | 26.8 | |||
| Prior therapy | ||||||
| Hormonal | 15 | 25 | 14 | 23 | 24 | 40 |
| Chemotherapy | 13 | 22 | 20 | 33 | 17 | 28 |
| Radiotherapy | 20 | 33 | 23 | 38 | 31 | 52 |
| Surgery | 43 | 72 | 45 | 75 | 46 | 77 |
| LVEF, % | ||||||
| Median | 66.5 | 65.0 | 66.5 | |||
| Range | 54-80 | 46-80 | 56-78 | |||
NOTE. All percentages have been rounded to the nearest whole number.
Abbreviations: HEC, trastuzumab, cyclophosphamide, and epirubicin; EC, epirubicin and cyclophosphamide; ER, estrogen receptor; PgR, progesterone receptor; ECOG, Eastern Cooperative Oncology Group; LVEF, left ventricular ejection fraction.
All patients had baseline LVEF more than 55%, except two patients in the HEC-60 and HEC-90 arms (values of 54% and 46%, respectively). For all treatment arms, the majority of patients (50% to 62%) had no cardiovascular risk factors; the risk factors that were present were balanced between arms (Appendix Table A1, online only).
At data cutoff, 23 patients remained in the study. The main reason for withdrawal in all arms was disease progression. Withdrawals as a result of AEs, intercurrent illness, and death (including as a result of progression) were observed in only 5%, 8%, and 8% of patients in the HEC-60, HEC-90, and EC-90 arms, respectively.
The median number of cycles of epirubicin and cyclophosphamide was six in all treatment arms. In the HEC-60 and HEC-90 arms, the median number of trastuzumab cycles was 45 and 39, respectively, and median cumulative trastuzumab dose was 6,439 and 5,531 mg, respectively. Median cumulative epirubicin dose was 605, 920, and 936 mg in the HEC-60, HEC-90, and EC-90 arms, respectively.
DLC was experienced by one patient in the HEC-60 arm (1.7%; 95% CI, 0.04% to 8.94%) and three patients in the HEC-90 arm (5.0%; 95% CI, 1.04% to 13.92%; Table 2). All DLC events occurred after the end of chemotherapy administration. All patients experiencing DLC had received six epirubicin cycles (total cumulative dose: 360 and 540 mg/m2 with HEC-60 and HEC-90, respectively). All four DLC events resolved or improved. Treatment for CHF was administered for the three events in the HEC-90 arm; the event in the HEC-60 arm resolved without treatment. Baseline LVEF in patients with DLC ranged from 63% to 70% in the HEC-90 arm and was 54% in the patient in the HEC-60 arm. LVEF at the time of DLC was 30% to 43% overall. No DLCs were associated with EC-90.
|
| End Point | HEC-60 (n = 60) | HEC-90 (n = 60) | EC-90 (n = 60) | |||
|---|---|---|---|---|---|---|
| No. of Patients | % | No. of Patients | % | No. of Patients | % | |
| DLC, defined as symptomatic CHF with LVEF decrease of > 10 percentage points to < 50% | 1 | 1.7 | 3 | 5.0 | — | — |
| CHF not fulfilling criteria for DLC | 1 | 1.7 | 4 | 6.7 | — | — |
| Total patients with LVEF decrease of > 10 percentage points to < 50%* | 4 | 6.7 | 9 | 15.0 | — | — |
| LVEF during treatment/follow-up, % | ||||||
| Median | 59.0 | 57.5 | 61.0 | |||
| Range | 41-75 | 35-69 | 51-76 | |||
| Total patients with ≥ 1 cardiac event | 9 | 15.0 | 14 | 23.3 | 5 | 8.3 |
| Rhythm disturbance requiring treatment | — | — | — | — | 2 | 3.3 |
| Other | 6 | 10.0 | 10 | 16.7 | 4 | 6.7 |
Abbreviations: HEC, trastuzumab, cyclophosphamide, and epirubicin; EC, epirubicin and cyclophosphamide; DLC, dose-limiting cardiotoxicity; CHF, congestive heart failure; LVEF, left ventricular ejection fraction.
*Including four patients with DLC.
One additional cardiac failure event occurred in the HEC-60 arm that did not fulfill the DLC criteria; it was reported by the investigator as an asymptomatic decline in LVEF (NYHA class I). In the HEC-90 arm, four additional patients with cardiac failure not fulfilling DLC were reported (two patients with NYHA class II and two patients with NYHA class I confirmed as asymptomatic by the investigator). No patient experienced CHF of NYHA class III or IV with an LVEF decline of ≤ 10 percentage points or to ≥ 50%. There were no cardiac-related deaths. A more detailed breakdown of cardiac events is provided in Appendix Table A2 (online only).
Over time, median LVEF values for all treatment arms declined but remained greater than 55% (Appendix Fig A1, online only). Four patients (7%) in the HEC-60 arm and nine patients (15%) in the HEC-90 arm experienced asymptomatic LVEF declines of more than 10 percentage points to less than 50% (Table 2).
The most frequent nonhematologic treatment-related AEs were alopecia and nausea; neutropenia was the most common hematologic AE (Table 3). Most AEs were reported with similar frequency across all arms, but febrile neutropenia was more frequent with HEC-90 (10%) than with HEC-60 and EC-90 (both 3%). Grade 3 or 4 AEs were reported for 57% to 63% of patients, and AEs leading to withdrawal of study medication were reported in only 15 patients (five patients in HEC-60, seven patients in HEC-90, and three patients in EC-90). Cardiac AEs represented the most frequent cause of treatment withdrawal.
|
| AE | HEC-60 (n = 60) | HEC-90 (n = 60) | EC-90 (n = 60*) | |||
|---|---|---|---|---|---|---|
| No. of Patients | % | No. of Patients | % | No. of Patients | % | |
| Alopecia | 31 | 52 | 33 | 55 | 34 | 57 |
| Nausea | 25 | 42 | 26 | 43 | 26 | 43 |
| Neutropenia | 21 | 35 | 22 | 37† | 23 | 38‡ |
| Leukopenia | 20 | 33 | 15 | 25† | 21 | 35§ |
| Vomiting | 17 | 28 | 17 | 28 | 17 | 28 |
| Anemia | 12 | 20 | 19 | 32 | 12 | 20 |
| Asthenia | 13 | 22 | 17 | 28 | 8 | 13 |
| Fatigue | 6 | 10 | 12 | 20 | 10 | 17 |
| Stomatitis | 7 | 12 | 12 | 20 | 5 | 8 |
| Diarrhea | 7 | 12 | 11 | 18 | 5 | 8 |
| Headache | 7 | 12 | 13 | 22 | 3 | 5 |
| Pyrexia | 5 | 8 | 13 | 22 | 5 | 8 |
| Nasopharyngitis | 7 | 12 | 8 | 13 | 6 | 10 |
| Cough | 9 | 15 | 6 | 10 | 3 | 5 |
| Constipation | 9 | 15 | 5 | 8 | 1 | 2 |
| Arthralgia | 6 | 10 | 4 | 7 | 4 | 7 |
| Dyspnea | 3 | 5 | 8 | 13 | 3 | 5 |
| Anorexia | 5 | 8 | 6 | 10 | 2 | 3 |
| Pain in extremity | 6 | 10 | 5 | 8 | 2 | 3 |
| Upper abdominal pain | 7 | 12 | 3 | 5 | 2 | 3 |
| Influenza | 8 | 13 | 4 | 7 | — | — |
| Bone pain | 7 | 12 | 2 | 3 | 2 | 3 |
| Febrile neutropenia | 2 | 3 | 6 | 10 | 2 | 3 |
NOTE. All percentages have been rounded to the nearest whole number.
Abbreviations: AE, adverse event; HEC, trastuzumab, cyclophosphamide, and epirubicin; EC, epirubicin and cyclophosphamide.
*Two patients did not receive study medication and were excluded from the safety analysis.
†AE was life threatening in one patient. Other life-threatening AEs were diabetic hyperglycemic coma (one patient in HEC-60), cerebrovascular accident (one patient in HEC-90), and pancytopenia (two patients in EC-90).
‡AE was life threatening in four patients.
§AE was life threatening in three patients.
Life-threatening events and deaths were increased with EC-90 (six and 12 patients, respectively) compared with HEC-60 (one and four patients, respectively) and HEC-90 (three and six patients, respectively). In all arms, deaths were predominantly a result of disease progression (11, four, and five patients in EC-90, HEC-60, and HEC-90, respectively). Two further deaths were caused by sudden death and cerebrovascular accident (EC-90 and HEC-90 arms, respectively).
ORRs for the HEC-60 and HEC-90 arms were 57% (95% CI, 43.2% to 69.4%) and 60% (95% CI, 46.5% to 72.4%), respectively. ORR in the EC-90 arm was 25% (95% CI, 14.7% to 37.9%; Table 4).
|
| Clinical Response | HEC-60 (n = 60) | HEC-90 (n = 60) | EC-90 (n = 60*) | |||
|---|---|---|---|---|---|---|
| No. of Patients | % | No. of Patients | % | No. of Patients | % | |
| Overall response rate | 34 | 57 | 36 | 60 | 15 | 25 |
| Complete response | 12 | 20 | 11 | 18 | 2 | 3 |
| Partial response | 22 | 37 | 25 | 42 | 13 | 22 |
| Stable disease | 18 | 30 | 18 | 30 | 32 | 53 |
| Progressive disease | 4 | 7 | 5 | 8 | 8 | 13 |
| Response not assessed | 4 | 7 | 1 | 2 | 5 | 8 |
NOTE. All percentages have been rounded to the nearest whole number.
Abbreviations: HEC, trastuzumab, cyclophosphamide, and epirubicin; EC, epirubicin and cyclophosphamide.
*Two patients did not receive study medication and were excluded from the analysis.
Median TTP for the HEC arms was similar (HEC-60: 12.5 months; 95% CI, 8.77 to 15.21 months; HEC-90: 10.1 months; 95% CI, 9.23 to 15.38 months; Fig 3). Median TTP in the EC-90 arm was 7.6 months (95% CI, 6.90 to 10.78 months). Median overall survival had not been reached by clinical cutoff.
Fig 3. Kaplan-Meier curve of time to progression. (*) Patients with human epidermal growth factor receptor 2–negative metastatic breast cancer. HEC, trastuzumab, cyclophosphamide, and epirubicin; EC, epirubicin and cyclophosphamide.
This study was undertaken to evaluate cardiac safety of the addition of trastuzumab to epirubicin/cyclophosphamide at two epirubicin dose levels (60 and 90 mg/m2) in patients with MBC. This was a descriptive study and was not powered to detect differences in DLC rates between treatment arms. However, an increased rate of DLC was observed with HEC-90 compared with HEC-60 (5% [three of 60 patients] v 1.7% [one of 60 patients], respectively), with all events recorded after completion of chemotherapy. The frequency of cardiac events observed with HEC-90 was higher than expected in patients receiving a cumulative epirubicin dose between 500 and 600 mg/m2 at day of the cardiac event. This emphasizes the necessity for prolonged cardiac follow-up with the HEC regimen. However, all the DLC events were manageable and improved with or without medication. Changes in LVEF over time showed a similar decrease in all treatment arms. No cardiac deaths occurred.
The incidence of symptomatic CHF in this study is considerably lower than that observed in the trastuzumab/anthracycline arm of the pivotal trastuzumab trial H0648g (28%);18 however, the methodology used in these two trials was different. Results in the HEC-60 arm are more in line with findings from a trial using a nonanthracycline regimen of trastuzumab/docetaxel in MBC,5 in which grade 3 or 4 CHF was observed in only one patient (1%) in the combination arm during study treatment and in a further patient during treatment with an investigational anthracycline 5 months after discontinuation of trastuzumab as a result of disease progression. Our results are also similar to those in recent trials of neoadjuvant/adjuvant trastuzumab,19–22 although the settings are not directly comparable because patients treated for early breast cancer tend to be younger and to have not been pretreated or undergone regular chest radiation therapy. When adjuvant trastuzumab was started after completion of doxorubicin,20 the 3-year cumulative incidence of class III or IV CHF in the North Central Cancer Treatment Group N9831 trial was 3.3%,7 and the 5-year cumulative incidence in the National Surgical Adjuvant Breast and Bowel Project B-31 trial was 3.8%.23 Similarly, in the Herceptin Adjuvant (HERA) trial, 0.6% of patients randomly assigned to 1 year of trastuzumab after (neo)adjuvant chemotherapy had experienced NYHA class III or IV CHF and a decline in LVEF ≥ 10 percentage points below baseline to less than 50% at 1-year median follow-up.6 In HERA, 94% of patients had received at least four cycles of (neo)adjuvant anthracyclines. In three neoadjuvant studies of trastuzumab plus chemotherapy, including anthracyclines, the incidence of serious cardiac events was extremely low (CHF rate of 0% at median follow-up of 16.3 months24; CHF rate of 0% during treatment21; and 3-year cumulative CHF rate of 2.1%22).
The low incidence of cardiac dysfunction observed in previous studies and in the HERCULES trial seems acceptable given the higher efficacy observed with the trastuzumab/chemotherapy combination. Further investigations are warranted to discover whether this incidence can be further reduced by other infusion regimens or cardioprotective measures (eg, use of liposomal doxorubicin).25 Pegylated doxorubicin has been evaluated in numerous phase II studies in patients with MBC, both as monotherapy26 and in combination with trastuzumab,27,28 and has demonstrated strong activity combined with a good cardiac safety profile. It should also be noted that, in patients with advanced disease, chemotherapy agents other than anthracyclines might be more appropriate chemotherapy partners for trastuzumab because the main treatment end points are often quality of life and disease control.
The improved cardiac safety of trastuzumab observed in more recent trials in MBC and early breast cancer may be attributable to more selective eligibility criteria and better cardiac monitoring. Our results show that when a less toxic anthracycline than doxorubicin is used and stringent screening and monitoring procedures are applied, the incidence of CHF compares favorably with previous trials in MBC and can be assumed to be in the range observed in early breast cancer.
In HERCULES, the noncardiac tolerability profile of HEC was also favorable with few differences between the three treatment arms, with the exception of a higher incidence of febrile neutropenia associated with HEC-90 compared with HEC-60.
ORR was approximately 60% for both HEC regimens, and TTP was 12.5 and 10.1 months with HEC-60 and HEC-90, respectively. This is comparable to results observed with trastuzumab/docetaxel in patients with HER2-positive MBC (ORR = 61%; TTP = 11.7 months)5 and superior to outcomes with trastuzumab/anthracyclines in the pivotal H0648g trial.29 In the trastuzumab/docetaxel trial, 60% of patients had received adjuvant anthracyclines. Patients in HERCULES had not received any prior treatment with anthracyclines or trastuzumab, as was standard at the time the trial was initiated. Now it is likely that more patients would be exposed to trastuzumab and anthracyclines before the metastatic setting, and an ongoing phase II trial is evaluating the ORR of trastuzumab plus a taxane as first-line treatment for MBC after prior trastuzumab exposure.
A strength of this study was the central review of echocardiography images. However, a limitation of echocardiography is the considerable variability between patients; research on new methods to detect CHF is ongoing. Other limitations of this study include the withdrawal of the majority of patients within 2 years of trastuzumab initiation as a result of progressive disease and the consequent lack of long-term cardiac data. Finally, this phase II trial was not powered to detect statistical differences between the regimens; therefore, it is difficult to fully evaluate the risk-to-benefit ratio of HEC.
Anthracyclines are potent agents in the treatment of breast cancer,3 and we feel that they should remain an important component of the treatment strategy for HER2-positive disease. Potentially, there are two groups that might benefit from trastuzumab/anthracycline combination—patients with endocrine-responsive disease treated with antihormonal therapy alone in the adjuvant setting and patients treated with taxane therapy in the adjuvant setting without anthracyclines. Given the increasing use of taxane therapy in early disease and the cumulative toxicity that derives from its use, the HEC regimen represents a potentially feasible option for first-line treatment of patients with HER2-positive MBC who have not received prior anthracyclines. Considering the suggested similar efficacy with HEC-60 and HEC-90 but the fewer cardiac events and lower level of febrile neutropenia with HEC-60, the 60 mg/m2 dose of epirubicin should be further investigated.
HERCULES is the largest randomized trial examining two doses of an anthracycline in combination with trastuzumab. Trastuzumab in combination with epirubicin/cyclophosphamide is a feasible and potentially effective regimen for patients with HER2-positive MBC. These phase II data indicate that epirubicin 60 mg/m2 is associated with fewer cardiac events and similar efficacy compared with 90 mg/m2, although the small sample size precludes definite conclusions regarding both relative efficacy and safety. Further studies of the combination are warranted, particularly in the early disease setting.
Supported by F. Hoffmann-La Roche, Basel, Switzerland.
Presented in part at the 14th Annual Congress of the European Cancer Organization, September 23-27, 2007, Barcelona, Spain, and the 30th Annual San Antonio Breast Cancer Symposium, December 13-16, 2007, San Antonio, TX.
Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a “U” are those for which no compensation was received; those relationships marked with a “C” were compensated. 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.
Employment or Leadership Position: Michaela Lehle, Roche (C); Olivier Catalani, Roche (C) Consultant or Advisory Role: Michael Untch, Roche (C), Bristol-Myers Squibb (C); Michael Muscholl, F. Hoffmann-La Roche (C); Rolf Kreienberg, AstraZeneca (C), Novartis (C); Andreas du Bois, Roche (C); Nadia Harbeck, Roche (C), Pfizer (C); Volkmar Müller, Roche (C); Christoph Thomssen, Roche (C), Pfizer (C); Hans-Joachim Lück, Bristol-Meyers Squibb (C), Amgen (C), Novartis (C) Stock Ownership: None Honoraria: Michael Untch, Roche, Pfizer; Michael Muscholl, F. Hoffmann-La Roche; Sergei Tjulandin, AstraZeneca, Merck, sanofi-aventis; Andreas du Bois, Roche; Nadia Harbeck, Roche, Pfizer; Christian Jackisch, Roche; Volkmar Müller, Roche; Christoph Thomssen, Roche, Pfizer; Hans-Joachim Lück, AstraZeneca, Roche, sanofi-aventis Research Funding: Michael Untch, Roche; Michael Muscholl, F. Hoffmann-La Roche; Andreas du Bois, Roche; Volkmar Müller, Roche; Christoph Thomssen, Roche, Pfizer Expert Testimony: Sergei Tjulandin, Amgen (C) Other Remuneration: Volkmar Müller, Roche
Conception and design: Michael Untch, Michael Muscholl, Hans-Gerd Meerpohl, Rolf Kreienberg, Andreas du Bois, Christian Jackisch, Christoph Thomssen, Hans-Joachim Lück
Financial support: Matthias Pauschinger
Administrative support: Christian Jackisch, Matthias Pauschinger
Provision of study materials or patients: Michael Untch, Sergei Tjulandin, Walter Jonat, Mikhail Lichinitser, Alexey G. Manikhas, Alexandra Coumbos, Andreas du Bois, Nadia Harbeck, Christian Jackisch, Volkmar Müller, Matthias Pauschinger, Christoph Thomssen, Hans-Joachim Lück
Collection and assembly of data: Michael Muscholl, Sergei Tjulandin, Alexey G. Manikhas, Alexandra Coumbos, Rolf Kreienberg, Andreas du Bois, Christian Jackisch
Data analysis and interpretation: Michael Untch, Michael Muscholl, Sergei Tjulandin, Walter Jonat, Hans-Gerd Meerpohl, Andreas du Bois, Christian Jackisch, Matthias Pauschinger, Christoph Thomssen, Michaela Lehle, Olivier Catalani
Manuscript writing: Michael Untch, Michael Muscholl, Andreas du Bois, Nadia Harbeck, Christian Jackisch, Volkmar Müller, Christoph Thomssen, Michaela Lehle
Final approval of manuscript: Michael Untch, Michael Muscholl, Sergei Tjulandin, Walter Jonat, Hans-Gerd Meerpohl, Mikhail Lichinitser, Alexey G. Manikhas, Alexandra Coumbos, Rolf Kreienberg, Andreas du Bois, Nadia Harbeck, Christian Jackisch, Volkmar Müller, Matthias Pauschinger, Christoph Thomssen, Michaela Lehle, Olivier Catalani, Hans-Joachim Lück
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Acknowledgment
We thank Tracy McNally who provided medical writing support during the preparation of this article on behalf of F. Hoffmann-La Roche (Basel, Switzerland). Final decisions on article content and wording were made by the authors.
Fig A1. (A-C) Charts outlining left ventricular ejection fraction (LVEF) declines from baseline (BL) for each treatment arm. HEC, trastuzumab, cyclophosphamide, and epirubicin; EC, epirubicin and cyclophosphamide.
|
| Cardiovascular Risk Factor | HEC-60 (n = 60) | HEC-90 (n = 60) | EC-90 (n = 60) | |||
|---|---|---|---|---|---|---|
| No. of Patients | % | No. of Patients | % | No. of Patients | % | |
| Smoking | 9 | 15 | 10 | 17 | 6 | 10 |
| Arterial hypertension | 14 | 23 | 17 | 28 | 12 | 20 |
| Hyperlipidemia | 2 | 3 | 3 | 5 | 1 | 2 |
| Family history | 7 | 12 | 8 | 13 | 7 | 12 |
| Diabetes mellitus | 3 | 5 | 2 | 3 | 3 | 5 |
| None | 32 | 53 | 30 | 50 | 37 | 62 |
Abbreviations: HEC, trastuzumab, cyclophosphamide, and epirubicin; EC, epirubicin and cyclophosphamide.
|
| AE | No. of Patients | ||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| HEC-60 (n = 60) | EC-90 (n = 60) | HEC-90 (n = 60) | |||||||||||||
| Total | Mild | Moderate | Severe | LT | Total | Mild | Moderate | Severe | LT | Total | Mild | Moderate | Severe | LT | |
| Cardiac disorders | |||||||||||||||
| Total patients with ≥ 1 AE | 12 | 10 | 1 | 1 | — | 5 | 3 | 1 | 1 | — | 13 | 4 | 5 | 4 | — |
| Angina pectoris | — | — | — | — | — | — | — | — | — | — | 1 | — | 1 | — | — |
| Arrhythmia | 1 | 1 | — | — | — | — | — | — | — | — | 1 | 1 | — | — | — |
| Atrial fibrillation | — | — | — | — | — | 1 | — | — | 1 | — | 2 | 1 | 1 | — | — |
| Atrioventricular block, first degree | 1 | 1 | — | — | — | — | — | — | — | — | — | — | — | — | — |
| Cardiac discomfort | 1 | 1 | — | — | — | — | — | — | — | — | — | — | — | — | — |
| Cardiac failure | 1 | 1 | — | — | — | — | — | — | — | — | 5 | 1 | 2 | 2 | — |
| Cardiac failure congestive | — | — | — | — | — | — | — | — | — | — | 2 | — | 1 | 1 | — |
| Cardiomyopathy | — | — | — | — | — | — | — | — | — | — | 1 | — | — | 1 | — |
| Extrasystoles | 1 | 1 | — | — | — | — | — | — | — | — | — | — | — | — | — |
| Mitral valve incompetence | — | — | — | — | — | — | — | — | — | — | 1 | — | 1 | — | — |
| Myocardial ischemia | 1 | 1 | — | — | — | — | — | — | — | — | — | — | — | — | — |
| Palpitations | 2 | 1 | — | 1 | — | — | — | — | — | — | 1 | 1 | — | — | — |
| Pericardial effusion | 2 | 2 | — | — | — | 1 | — | 1 | — | — | — | — | — | — | |
| Pericarditis | — | — | — | — | — | — | — | — | — | — | 1 | 1 | — | — | — |
| Sinus tachycardia | — | — | — | — | — | 2 | 2 | — | — | — | — | — | — | — | — |
| Tachycardia | 3 | 2 | 1 | — | — | 2 | 2 | — | — | — | 1 | — | 1 | — | — |
| Ventricular extrasystoles | 1 | 1 | — | — | — | — | — | — | — | — | — | — | — | — | — |
| Ventricular hypokinesia | 1 | 1 | — | — | — | — | — | — | — | — | — | — | — | — | — |
| Total No. of AEs | 19 | 16 | 2 | 1 | — | 7 | 5 | 1 | 1 | — | 18 | 6 | 7 | 5 | — |
| Investigations | |||||||||||||||
| Total patients with ≥ 1 AE | — | — | — | — | — | — | — | — | — | — | 1 | — | 1 | — | — |
| Ejection fraction decreased | — | — | — | — | — | — | — | — | — | — | 1 | — | 1 | — | — |
| Total No. of AEs | — | — | — | — | — | — | — | — | — | — | 1 | — | 1 | — | — |
NOTE. Only the most severe intensity is counted for multiple occurrences of the same AE in one patient. Any difference between the total No. and sum of AEs is a result of missing investigator assessment of intensity.
Abbreviations: AE, adverse event; HEC, trastuzumab, cyclophosphamide, and epirubicin; EC, epirubicin and cyclophosphamide; LT, life threatening.
