A Phase II Neoadjuvant Trial of Sequential Nanoparticle Albumin-Bound Paclitaxel Followed by 5-Fluorouracil/Epirubicin/Cyclophosphamide in Locally Advanced Breast Cancer

BackgroundNeoadjuvant chemotherapy has become standard treatment for women with locally advanced breast cancer (LABC). Various regimens have explored the addition of newer agents to determine safety and efficacy. The aim of this phase II study was to incorporate albumin-bound paclitaxel with sequential anthracycline-based therapy.Patients and MethodsSixty-six women with LABC but without prior treatment and regardless of hormone receptor or HER2 status were enrolled. All patients were to receive albumin-bound paclitaxel weekly for 12 weeks followed by 5-fluorouracil/epirubicin/cyclophosphamide (FEC) every 3 weeks for 4 cycles. Trastuzumab was allowed in HER2-positive (HER2⁺) patients. Primary endpoint was pathologic complete response (pCR; CR) in breast. Secondary endpoints included pCR in breast and nodes, clinical CR, 2-year progression-free survival, and overall survival.ResultsSixty-five patients received at least 1 dose of chemotherapy and were included in this analysis. Sixty-three patients completed 4 cycles of albumin-bound paclitaxel. Sixty-two patients received at least 1 dose of FEC, and 58 completed 4 cycles. Seventeen of 19 HER2⁺ women received trastuzumab. The pCR in breast was 29% (19 of 65). For the HER2⁺ subset, the pCR was 58% (11 of 19). Both albumin-bound paclitaxel and FEC were well tolerated. The most significant toxicities were grade 2/3 neuropathy (16%) with albumin-bound paclitaxel and grade 3/4 febrile neutropenia (7%) with FEC.ConclusionAlbumin-bound paclitaxel given over 12 weeks is well tolerated. Albumin-bound paclitaxel should be further evaluated in a randomized setting in both adjuvant and neoadjuvant trials.     

A phase II trial of gemcitabine/carboplatin with or without trastuzumab in the first-line treatment of patients with metastatic breast cancer

PurposeThe purpose of this study was to evaluate the efficacy and toxicity of the combination of gemcitabine and carboplatin (and with trastuzumab in patients with HER2-positive disease) as first-line treatment for patients with metastatic breast cancer (MBC).Patients and MethodsSeventy-four patients who had received no previous chemotherapy for MBC were enrolled. Patients with HER2-negative breast cancer received treatment with gemcitabine 1000 mg/m² intravenously (I.V.) on days 1 and 8 and carboplatin area under the curve (AUC) 5 I.V. on day 1. Cycles were repeated every 21 days. Patients with HER2-positive disease also received trastuzumab 8-mg/kg I.V. loading dose, then 6 mg/kg I.V. every 21 days. After the first 29 patients were treated, the carboplatin dose was lowered to AUC 4. Patients were re-evaluated every 6 weeks; responses were measured using Response Evaluation Criteria in Solid Tumors criteria.ResultsIn patients with HER2-negative disease, gemcitabine/carboplatin produced a 34% major response rate; an additional 28% of patients had stable disease ≥ 6 months (overall disease control rate, 62%). Gemcitabine/carboplatin/trastuzumab produced an overall response rate of 66%, with a disease control rate of 77%. Grade 3/4 myelosuppression was common, even after reduction of the carboplatin dose. Only 3 patients treated with the lower dose regimen developed neutropenia and fever, but platelet and red blood cell transfusions were necessary in 24% and 40% of patients, respectively. Trastuzumab did not add to hematologic toxicity. Severe nonhematologic toxicity was uncommon.ConclusionGemcitabine/carboplatin and gemcitabine/carboplatin/trastuzumab are active first-line regimens for patients with MBC. The gemcitabine/carboplatin combination causes more grade 3/4 myelosuppression than other standard combination regimens for MBC; however, severe nonhematologic toxicity is minimal.     

A phase II trial of trastuzumab plus weekly ixabepilone and carboplatin in patients with HER2-positive metastatic breast cancer: an Eastern Cooperative Oncology Group Trial

The epothilone B analogue, ixabepilone, binds to β-tubulin, is effective for taxane-refractory metastatic breast cancer (MBC), and may be given every 3 weeks or weekly. We evaluated the efficacy of weekly ixabepilone (I) plus trastuzumab (T) and carboplatin (C) as first line therapy in HER2 + MBC. Patients with HER2+ (3+ by IHC or FISH amplified) MBC received I (15 mg/m² IV) and C (area under the curve, AUC = 2 IV) on days 1, 8, and 15 of a 28-day cycle for a maximum of 6 cycles, plus weekly T (4 mg/kg loading dose then 2 mg/kg IV) during chemotherapy then every 3 weeks (6 mg/kg IV) until disease progression. The primary objective was to determine whether the combination was associated with a response rate (RR) of at least 75%. Fifty-nine patients were treated, and 39 had HER2 overexpression confirmed in a central lab (cHER2+). For all treated patients, objective response occurred in 26 patients (44%; 95% CI 31–58%), median time to progression was 8.2 months (95% CI 6.3–9.9), and median overall survival was 34.7 months (95% CI 25.7 to [not reached]). Results were comparable for cHer2+ cancers. Grade 3–4 adverse events included neutropenia (49%), thrombocytopenia (14%), fatigue (12%), nausea (7%), diarrhea (7%), and neuropathy (7%). One patient died from treatment complications during cycle 1. Weekly ixabepilone and carboplatin plus trastuzumab have an acceptable toxicity profile, but are not likely to be associated with an RR of 75% in HER2+ MBC. Efficacy appears comparable to paclitaxel, carboplatin, and trastuzumab.     

Pegylated liposomal doxorubicin in combination with cyclophosphamide and trastuzumab in HER2-positive metastatic breast cancer patients: efficacy and cardiac safety from the GEICAM/2004–05 study

BackgroundIn order to determine the feasibility of substituting pegylated liposomal doxorubicin (PLD) for doxorubicin in combination with cyclophosphamide and trastuzumab as adjuvant therapy, we conducted a phase II study of the combination as first-line therapy in human epidermal growth factor receptor 2 (HER2) overexpressing metastatic breast cancer (MBC).MethodsPLD 50 mg/m² and cyclophosphamide 600 mg/m² were administered every 4 weeks for six cycles; trastuzumab (4 mg/kg loading dose, then 2 mg/kg) was administered weekly for 24 weeks. The primary end point was objective response rate (ORR), and the secondary end points included time to progression (TTP), overall survival (OS), and safety.ResultsAmong the 48 evaluable patients, ORR was 68.8% [95% confidence interval (CI) 55.69% to 81.91%], with 6 patients (12.5%) achieving a complete response and 27 (56.2%) a partial response. The median TTP was 12 months (95% CI 9–15.1 months), and the median OS was 34.2 months (95% CI 27.2–41.2 months). Febrile neutropenia was seen in three patients, grade 3 hand–foot syndrome in 29.2% of patients, and grade 3–4 mucositis in 22.9% of patients. Symptomatic congestive heart failure was not observed, and 16.7% of patients experienced grade 2 asymptomatic left ventricular systolic dysfunction.ConclusionThe combination of PLD–cyclophosphamide–concurrent trastuzumab is a feasible, safe, and effective first-line regimen for HER2-overexpressing MBC.     

Study of three-weekly docetaxel and weekly trastuzumab treatment in HER 2-overexpressing metastatic breast cancer patients

Docetaxel and trastuzumab can be considered to be active drugs for HER 2-overexpressing metastatic breast cancer (MBC). This study was conducted to determine the activity of combination therapy with docetaxel and trastuzumab in MBC patients (pts) by assessing the response rate (RR), time to progression (TTP) and safety. We administered the combination of docetaxel 70 mg/m2 every 3 weeks and trastuzumab using a 4 mg/kg loading dose and thereafter 2 mg/kg weekly. One cycle was three weeks. Between March 2002 and May 2003, 40 pts with HER 2-positive (3+by immunohistochemistry 39, FISH+1) MBC were enrolled in this study, and 39 pts proved eligible. The overall RR was 72% (28/39) [95%CI 55.1%-85.0%], with 6 CR, 22 PR, 7 SD, 1 PD and 3 NE. The median follow-up time was 14.3 months, while the TTP was 6.5 months (range, 0.6-19.8), median OS has not yet been reached. The number of pts assessable for safety was 40. Hematological Grade 3-4 toxicities were leukopenia 87.5% (35/40) and neutropenia 82.5% (33/40). Non-hematological Grade 3 toxicities were weight gain in 2 pts, and anorexia, neuropathy, fever and rash in one pt each. The combination of docetaxel and trastuzumab was a well-tolerated and very active regimen for the treatment of pts with HER 2-overexpressing MBC.     

Weekly Gemcitabine and Trastuzumab in the Treatment of Patients With HER2-Overexpressing Metastatic Breast Cancer

BackgroundThe use of trastuzumab in combination with either a taxane or vinorelbine has improved the efficacy of treatment for women with HER2-positive (HER+) breast cancer. We investigated the activity and toxicity of the gemcitabine/trastuzumab combination as first- or second-line treatment in women with HER2+ metastatic breast cancer (MBC).Patients and MethodsForty-one women with HER2+ MBC were treated with gemcitabine 1000 mg/m² intravenously (I.V.) days 1, 8, and 15 and trastuzumab 4-mg/kg I.V. loading dose and then 2 mg/kg weekly. Cycles were repeated every 28 days. Patients were evaluated after 8 weeks of treatment; responders/stable patients continued treatment until progression.ResultsPatients received a median of 28 weeks of treatment. Eleven of 37 evaluable patients (30%; 95% CI, 17%–46%) had major responses. The median progression-free survival (PFS) was 4 months (95% CI, 1.9–5.3 months), with a 1-year PFS of 17%. Four of 15 patients (27%) who had previously received trastuzumab for MBC had partial responses. The gemcitabine/trastuzumab combination was well tolerated.ConclusionThe combination of gemcitabine and trastuzumab is an active regimen but appears less active than trastuzumab in combination with either taxanes or vinorelbine. The role of gemcitabine/trastuzumab (versus gemcitabine alone) in women who have already received a trastuzumab-containing regimen for HER2+ MBC is not defined by this study.     

Phase II study of trastuzumab plus gemcitabine in chemotherapy-pretreated patients with metastatic breast cancer

We evaluated the efficacy and toxicity of trastuzumab plus gemcitabine in patients with HER2-positive metastatic breast cancer (MBC). Sixty-four patients were enrolled, the majority of whom (95%) had been treated with an anthracycline and a taxane before study enrollment. Eligible women were treated with gemcitabine (1200 mg/m(2) weekly for 2 weeks with the third week off on a 21-day cycle) plus weekly doses of trastuzumab (4-mg/kg loading dose; 2 mg/kg thereafter) until disease progression. The median patient age was 55 years, and the median number of previously administered (including adjuvant) chemotherapy regimens was 3. Twenty-two patients were scored as 2+ for HER2 expression by immunohistochemistry; 39 patients scored 3+. Three patients were assessed as HER2-negative on central pathology review and were ineligible for evaluation. Fifty-nine of the 61 patients remained evaluable for response. The objective response rates were 38% in the intent-to-treat population (23 of 61) and 44% among the 39 patients with HER2 3+ expression. The median response duration was 5.8 months, median overall survival was 14.7 months, and median time to disease progression was 5.8 months. Trastuzumab plus gemcitabine was well tolerated. No cases of clinical congestive heart failure occurred. Grade 3/4 toxicities included asthenia in 4 patients, fever in 4, neutropenia in 18, dyspnea in 6, abdominal or back pain in 3, and edema and nausea in 1 patient each. The combination of trastuzumab plus gemcitabine appears to be well tolerated and effective for patients with HER2-positive MBC previously treated with chemotherapy.     

Phase II trial of gemcitabine/carboplatin (plus trastuzumab in HER2-positive disease) in patients with metastatic breast cancer

BACKGROUND: Gemcitabine and carboplatin have significant preclinical synergy, and both provide synergistic antitumor activity in metastatic breast cancer (MBC) when used in combination with trastuzumab. The gemcitabine/ cisplatin combination is highly active in MBC with response rates (RRs) of approximately 50% in anthracycline- and taxane-pretreated patients and up to 80% in untreated subjects. This phase II trial studied the efficacy and safety of gemcitabine/carboplatin with or without trastuzumab in patients with MBC. PATIENTS AND METHODS: Patients were stratified into 3 groups: group 1, HER2-positive; group 2, HER2-negative and taxane- naive/remote (no taxanes within past 2 years); and group 3, HER2-negative and previous taxane therapy. Included were women aged > or = 18 years, Eastern Cooperative Oncology Group performance status of 0-2, with Response Evaluation Criteria in Solid Tumors-defined measurable MBC; HER2-negative or HER2 (3+) by immunohistochemistry or fluorescence in situ hybridization positive. All cycles were repeated every 14 days. On day 1, gemcitabine 1500 mg/m2 over 30 minutes was administered followed by carboplatin area under the curve of 2.5. Group 1 also received trastuzumab 8 mg/kg on day 1 of each cycle followed by 4 mg/kg for every 2 weeks thereafter. RESULTS: One hundred fifty patients were registered (50, 51, and 49 in groups 1, 2, and 3, respectively). The overall RRs were 64%, 27%, and 32%, respectively, with median time to progression of 7.2, 5.5, and 4.4 months, respectively. Overall, grade 3/4 toxicities included neutropenia (45%), leukopenia (17%), and thrombocytopenia (7%). Alopecia was infrequent: grade 1 (34%) and grade 2 (3%), and there was no significant cardiac toxicity. CONCLUSION: Gemcitabine/carboplatin/trastuzumab is highly active in patients with HER2-positive MBC. Gemcitabine/carboplatin is active in patients with HER2-negative MBC independent of previous taxane therapy. Gemcitabine/carboplatin with or without trastuzumab administered every 2 weeks is associated with a low frequency of serious toxicity.     

Feasibility and cardiac safety of pegylated liposomal doxorubicin plus trastuzumab in heavily pretreated patients with recurrent HER2-overexpressing metastatic breast cancer

BACKGROUND: Few studies have evaluated concomitant pegylated liposomal doxorubicin (PLD) plus trastuzumab as therapy for HER2-overexpressing metastatic breast cancer (MBC). This open-label, prospective, phase II trial assessed the safety and efficacy of this regimen, with cardiac tolerance as the principal focus. PATIENTS AND METHODS: Women with HER2-overexpressing recurrent MBC, baseline left ventricular ejection fraction >or= 55%, and no history of serious cardiac illness were eligible; preexisting cardiac risk factors, including previous anthracyclines and previous trastuzumab for MBC, were allowed. Patients received weekly trastuzumab and every-3-week PLD until progression, prohibitive toxicity, or patient refusal. Left ventricular ejection fraction was assessed during and after therapy. Grade 3/4 congestive heart failure (CHF) was monitored for premature closure. RESULTS: The trial closed after 2.5 years for slow accrual. Twelve patients were enrolled: 7 had received adjuvant anthracyclines; 9 had received previous MBC treatment, of whom 7 had received trastuzumab in combination with chemotherapy. Patients received a mean of 4.8 cycles of PLD; 8 patients experienced stable disease; 4 patients experienced progression. Mean left ventricular ejection fraction levels did not change substantially: 60.4%, 57%, 60.3%, and 56.8% at baseline, after cycle 2, after cycle 4, and after completion of treatment, respectively. No patients experienced grade 4 CHF. One patient discontinued treatment after grade 3 CHF. Three patients experienced grade 2 left ventricular dysfunction, of whom 2 discontinued treatment. Cardiac function improved in all 4 patients after going off study. Other adverse events were generally mild (grade 1/2) and infrequent. CONCLUSION: Pegylated liposomal doxorubicin plus trastuzumab might be an option for heavily pretreated patients with recurrent HER2-overexpressing MBC.     

What is the best schedule for administration of gemcitabine-taxane?

Until recently, standard adjuvant chemotherapy for metastatic breast cancer (MBC) consisted of anthracycline-based regimens, followed by a taxane. However, data suggest that taxane-based combinations can be more effective than taxanes alone for the second part of treatment. Synergy between paclitaxel and gemcitabine was demonstrated in vitro when paclitaxel was followed by gemcitabine. Dose-dense regimens administered every 2 weeks are more effective than standard 3 weekly regimens. In a phase II study, gemcitabine plus paclitaxel every 2 weeks as first-line chemotherapy of MBC was associated with an overall response rate (ORR) of 71%. Women with HER2 ECD-positive tumours have a poor ORR (40%) to first-line chemotherapy. The addition of trastuzumab to dose-dense paclitaxel-gemcitabine as first-line chemotherapy in women with HER2-positive MBC was associated with a dramatic increase in ORR to 78%, with no serious toxicity observed. Two phase III clinical trials of gemcitabine-paclitaxel as adjuvant chemotherapy in women with histologically-confirmed MBC are currently underway. Preliminary data show that this drug combination is well-tolerated, and the efficacy results are eagerly awaited.     

Preliminary safety and efficacy of first-line pertuzumab combined with trastuzumab and taxane therapy for HER2-positive locally recurrent or metastatic breast cancer (PERUSE)

BackgroundPertuzumab combined with trastuzumab and docetaxel is the standard first-line therapy for HER2-positive metastatic breast cancer, based on results from the phase III CLEOPATRA trial. PERUSE was designed to assess the safety and efficacy of investigator-selected taxane with pertuzumab and trastuzumab in this setting.Patients and methodsIn the ongoing multicentre single-arm phase IIIb PERUSE study, patients with inoperable HER2-positive advanced breast cancer (locally recurrent/metastatic) (LR/MBC) and no prior systemic therapy for LR/MBC (except endocrine therapy) received docetaxel, paclitaxel or nab-paclitaxel with trastuzumab [8 mg/kg loading dose, then 6 mg/kg every 3 weeks (q3w)] and pertuzumab (840 mg loading dose, then 420 mg q3w) until disease progression or unacceptable toxicity. The primary end point was safety. Secondary end points included overall response rate (ORR) and progression-free survival (PFS).ResultsOverall, 1436 patients received at least one treatment dose (initially docetaxel in 775 patients, paclitaxel in 589, nab-paclitaxel in 65; 7 discontinued before starting taxane). Median age was 54 years; 29% had received prior trastuzumab. Median treatment duration was 16 months for pertuzumab and trastuzumab and 4 months for taxane. Compared with docetaxel-containing therapy, paclitaxel-containing therapy was associated with more neuropathy (all-grade peripheral neuropathy 31% versus 16%) but less febrile neutropenia (1% versus 11%) and mucositis (14% versus 25%). At this preliminary analysis (52 months’ median follow-up), median PFS was 20.6 [95% confidence interval (CI) 18.9–22.7] months overall (19.6, 23.0 and 18.1 months with docetaxel, paclitaxel and nab-paclitaxel, respectively). ORR was 80% (95% CI 78%–82%) overall (docetaxel 79%, paclitaxel 83%, nab-paclitaxel 77%).ConclusionsPreliminary findings from PERUSE suggest that the safety and efficacy of first-line pertuzumab, trastuzumab and taxane for HER2-positive LR/MBC are consistent with results from CLEOPATRA. Paclitaxel appears to be a valid alternative taxane backbone to docetaxel, offering similar PFS and ORR with a predictable safety profile.ClinicalTrials.govNCT01572038.     

Biweekly docetaxel and weekly trastuzumab treatment in HER 2-overexpressing metastatic breast cancer patients

Docetaxel and trastuzumab can be considered to be active drugs for HER 2-overexpressing metastatic breast cancer (MBC). This study was conducted to determine the activity of combination therapy with docetaxel and trastuzumab in MBC patients by assessing the response rate (RR), time to progression (TTP) and safety. We administered the combination of docetaxel 30-40 mg/m(2) biweekly and trastuzumab using a 4 mg/kg loading dose and thereafter 2 mg/kg weekly. Between October 2001 and December 2004, 14 patients with HER 2 positive (3+ by immunohistochemistry) MBC were enrolled in this study. The overall RR was 50.0% (7/14), with 1 CR, 6 PR, 3 NC and 4 PD. Median follow-up time was 15.0 months, while the median TTP was 10.8 months,and the median OS 21.8 months.     

Phase II multicenter trial of albumin-bound paclitaxel and capecitabine in first-line treatment of patients with metastatic breast cancer

BackgroundCapecitabine, a tumor-activated oral fluoropyrimidine, and albumin-bound paclitaxel (ab-paclitaxel) have substantial single-agent activity in patients with metastatic breast cancer (MBC). Taxane and antimetabolite doublets have improved efficacy compared with single agents. This phase II open-label trial was designed to test the safety and efficacy of capecitabine and ab-paclitaxel in previously untreated MBC.Patients and MethodsPatients received capecitabine (825 mg/m² orally twice daily, approximately 12 hours apart, on days 1 to 15) and ab-paclitaxel (125 mg/m² intravenously on days 1 and 8 of each cycle with no premedication) every 3 weeks. The primary endpoint was overall objective response rate (ORR), with evaluation performed after every 2 cycles. Entry criteria included measurable MBC, human epidermal growth factor receptor 2 (HER2) negativity, Eastern Cooperative Oncology Group (ECOG) performance status 0-2, no previous chemotherapy for metastatic disease, and > 6 months since adjuvant fluoropyrimidine or paclitaxel treatment.ResultsFifty patients received at least 1 dose of study drug, with 46 patients evaluable for efficacy evaluation. Three hundred seventy-four cycles of therapy were delivered. Eighty percent of patients completed 8 cycles. The ORR was 61% (complete response [CR], 4%; partial response [PR], 57%), and 7 patients had sustained (≥ 24 weeks) stable disease for a clinical benefit rate of 76.1%. The median progression-free survival (PFS) was 10.6 months, and the median overall survival was 19.9 months. The most common adverse events (AEs) that were ≥ grade 3 were pain, hand-foot syndrome, and neutropenia.ConclusionThe combination of weekly ab-paclitaxel plus daily capecitabine orally at these doses and scheduling was well tolerated and showed substantial efficacy.     

Phase II Trial of Weekly Docetaxel,Vinorelbine, and Trastuzumab in the First-Line Treatment of Patients with HER2-Positive Metastatic Breast Cancer

BackgroundThe combinations of trastuzumab/docetaxel and trastuzumab/vinorelbine are highly active in the treatment of patients with HER2-positive metastatic breast cancer (MBC). We investigated the feasibility and safety of a 3-drug combination of trastuzumab, docetaxel, and vinorelbine as first-line therapy in this patient group.Patients and MethodsSixty patients with previously untreated, measurable HER2-positive MBC (immunohistochemistry 3+ and/or fluorescence in situ hybridization positive) were treated with docetaxel 30 mg/m² intravenously (I.V.) and vinorelbine 25 mg/m² I.V. on days 1 and 8 of each 3-week cycle. Trastuzumab was given weekly (4-mg/kg loading dose followed by 2 mg/kg/week). Patients were evaluated after 6 weeks; responders/stable patients continued treatment until progression.ResultsPatients received a median of 11 treatment cycles (range, 1–22 cycles). Forty-one of 60 patients (68%) had major responses (16 complete responses [27%], 25 partial responses [42%]). An additional 13 patients (22%) had stable disease for ≥ 6 months. After a median follow-up of 58 months, median progression-free survival was 12 months (95% CI, 9.1–16.3 months), and the median overall survival was 40.8 months (95% CI, 25-not reached). Neutropenia (72% grade 4) was the most common hematologic toxicity; 8 patients were hospitalized for febrile neutropenia. A total of 67% of patients required dose modifications for neutropenia during cycles 1 or 2. Other grade 3/4 toxicities included fatigue (12%), hyperglycemia (7%), and myalgias (7%). There were no treatment-related deaths.ConclusionThe combination of trastuzumab, docetaxel, and vinorelbine is highly active as first-line treatment for patients with HER2-positive MBC. However, this regimen offers no obvious advantages over other less myelosuppressive trastuzumab-containing regimens, and its routine use is not supported by the study.     

Phase II study of weekly paclitaxel and trastuzumab in anthracycline- and taxane-pretreated patients with HER2-overexpressing metastatic breast cancer

Synergism between anti-HER2 monoclonal antibody (trastuzumab) and paclitaxel has been shown in vitro and in vivo. In previous experiences, weekly administration of trastuzumab and paclitaxel has shown significant activity in metastatic breast cancer. In this phase II study, we evaluated the activity and the toxicity of this weekly regimen in anthracycline- and taxane-pretreated patients with HER2-overexpressing metastatic breast cancer. Between November 1999 and July 2001, 25 patients were treated with trastuzumab (4 mg kg(-1) i.v. loading dose followed by 2 mg kg(-1) i.v. week(-1)) and paclitaxel (60-90 mg m(-2) h(-1) i.v. infusion week(-1)). The treatment was planned to continue until disease progression or prohibitive toxicity; in patients with responsive or stable disease, after 6 months of therapy, the decision to stop paclitaxel while continuing weekly trastuzumab was left to the physicians' judgement. At the median follow-up of 19.6 months (range 9.2-38.1), all patients are evaluable for response and toxicity. We obtained four (16%) complete responses (CR), 10 (40%) partial responses (PR), four (16%) stable diseases and seven (28%) disease progressions. The response rate (CR+PR) was 56% (95% CI, 36.5-75.5%). The median duration of response was 10.4 months (range 4.1-24.2+). Median time to progression was 8.6 months (range 2.5-24.2+). The toxicity was mild; five patients experienced fever and chills during the first infusion of trastuzumab (20%); leukopenia grade 2 was recorded in one patient (4%). Two patients (8%) came off study for grade 3 cardiotoxicity (after 9 and 17 weeks of treatment, respectively): both had already received anthracyclines and taxanes. Onycholysis grade 2 was observed in five patients (20%). These results confirm that weekly administration of trastuzumab and paclitaxel is active in anthracycline- and taxane-pretreated metastatic breast cancer patients HER2-overexpressing. Since cardiac disfunctions grade 3 were observed (8%), we recommend that cardiac function should be monitored in these patients.     

Phase II trial of trastuzumab followed by weekly paclitaxel/carboplatin as first-line treatment for patients with metastatic breast cancer.

PURPOSE: To determine the response rate of trastuzumab as first-line therapy in patients with HER-2 overexpressing metastatic breast cancer. To assess the feasibility and toxicity of weekly paclitaxel/carboplatin with or without trastuzumab following initial treatment with trastuzumab. PATIENTS AND METHODS: Sixty-one patients received trastuzumab (8 mg/kg followed by 4 mg/kg/wk) for 8 weeks. Responding patients received 8 additional weeks of trastuzumab (4 mg/kg/wk), and then proceeded to receive trastuzumab (2 mg/kg) in combination with paclitaxel 70 mg/m(2) and carboplatin (area under the curve, 2) weekly for 6 weeks followed by 2 weeks rest. Stable patients after the initial 8 weeks of trastuzumab proceeded to treatment with trastuzumab, paclitaxel, and carboplatin. Patients with disease progression during the initial 8 weeks had the trastuzumab discontinued and were treated with weekly paclitaxel/carboplatin. RESULTS: Weekly paclitaxel/carboplatin with or without trastuzumab was well tolerated. Fifty-two patients were assessable for response and all 61 patients were assessable for survival. Seventeen (33%) of 52 patients experienced a minor/partial response to single-agent trastuzumab and received 8 additional weeks of single-agent trastuzumab. Fifteen (29%) of 52 patients had stable disease and proceeded to receive paclitaxel/carboplatin/trastuzumab. Thirty-one patients with measurable disease were assessable for response after initial single-agent trastuzumab followed by paclitaxel/carboplatin/trastuzumab. An overall response rate of 84% (eight complete responses/18 partial responses), median time to progression of 14.2 months, and median overall survival of 32.2 months was reported with the triplet combination. In the patients treated with paclitaxel/carboplatin alone after disease progression on initial single-agent trastuzumab, an overall response rate of 69% (one complete response/10 partial responses), median time to progression of 8.3 months, and median overall survival of 22.2 months was reported. Median time to progression for all 61 patients is 10 months and the median overall survival is 26.7 months. CONCLUSION: This trial confirms the activity and tolerability of weekly paclitaxel/carboplatin alone or in combination with trastuzumab in women with HER-2 overexpressing metastatic breast cancer.     

Phase II study of weekly albumin-bound paclitaxel for patients with metastatic breast cancer heavily pretreated with taxanes

PURPOSE: Nanoparticle albumin-bound paclitaxel, a solvent-free, albumin-bound paclitaxel, demonstrated antitumor activity in patients with taxane-naive metastatic breast cancer (MBC). We examined albumin-bound paclitaxel (100 mg/m2 or 125 mg/m2 administered weekly) to determine the antitumor activity in patients with MBC whose disease progressed despite conventional taxane therapy. PATIENTS AND METHODS: Women with MBC that was previously treated with taxanes were eligible for participation. Taxane failure was defined as metastatic disease progression during taxane therapy or relapse within 12 months of adjuvant taxane therapy. Primary objectives were response rates (RRs) and the safety/tolerability of albumin-bound paclitaxel. RESULTS: Women were treated with albumin-bound paclitaxel 100 mg/m2 (n = 106) or 125 mg/m2 (n = 75) on days 1, 8, and 15 of a 28-day cycle. Response rates were 14% and 16% for the 100-mg/m2 and 125-mg/m2 cohorts, respectively; an additional 12% and 21% of patients, respectively, had stable disease (SD) > or = 16 weeks. Median progression-free survival times were 3 months at 100 mg/m2 and 3.5 months at 125 mg/m2; median survival times were 9.2 months and 9.1 months, respectively. Survival was similar for responding patients and those with SD. No severe hypersensitivity reactions were reported. Patients who developed treatment-limiting peripheral neuropathy typically could be restarted on a reduced dose of albumin-bound paclitaxel after a 1-2-week delay. Grade 4 neutropenia occurred in < 5% of patients. CONCLUSION: Albumin-bound paclitaxel 100 mg/m2 given weekly demonstrated the same antitumor activity as albumin-bound paclitaxel 125 mg/m2 weekly and a more favorable safety profile in patients with MBC that had progressed with previous taxane therapy. Survival of patients with SD > or = 16 weeks was similar to that of responders.     

Continuation of trastuzumab beyond disease progression is feasible and safe in patients with metastatic breast cancer: a retrospective analysis of 80 cases by the hellenic cooperative oncology group

Despite the widespread use of trastuzumab in the management of patients with HER2-overexpressing metastatic breast cancer, its optimal duration of administration is unknown. We retrospectively reviewed the medical records of 80 such patients who received trastuzumab monotherapy or combination chemotherapy beyond disease progression in order to register their clinical course. Median age of the patients was 54 years. Ninety-one percent had 3+ HER2 overexpression and 9% had 2+ HER2 overexpression. Fifty-six percent of patients had previously been treated with chemotherapy for advanced disease. The most commonly used combinations in first- and second-line treatments were trastuzumab with paclitaxel and trastuzumab with vinorelbine, respectively. In total, 32 responses were observed, most of them during the second or third line of treatment. Severe toxicities frequently seen (in = 5% of patients) were neutropenia (25%), thrombocytopenia (11.5%), infection (10%), peripheral neuropathy (9%), nausea/vomiting (6%), stomatitis (6%), diarrhea (6%), constipation (6%), edema (6%), and myalgias/arthralgias (5%). Median survival from diagnosis of advanced disease was 43.4 months (range, 6.4-91.7+), whereas median survival from disease progression after trastuzumab administration was 22.2 months (range, 0.01-32.9+). In conclusion, this retrospective analysis suggests that continuation of trastuzumab beyond disease progression in patients with HER2-overexpressing metastatic breast cancer is feasible and safe. Randomized studies are warranted.     

Weekly trastuzumab and paclitaxel therapy for metastatic breast cancer with analysis of efficacy by HER2 immunophenotype and gene amplification.

PURPOSE: This phase II study evaluated weekly trastuzumab and paclitaxel therapy in women with HER2-normal and HER2-overexpressing metastatic breast cancer. Efficacy was correlated with immunohistochemical and fluorescent in situ hybridization (FISH) assay results. PATIENTS AND METHODS: Eligible patients had bidimensionally measurable metastatic breast cancer. Up to three prior chemotherapy regimens, including prior anthracycline and taxane therapy, were allowed. Trastuzumab 4 mg/kg and paclitaxel 90 mg/m2 were administered on week 1, with trastuzumab 2 mg/kg and paclitaxel 90 mg/m2 administered on subsequent weeks. HER2 status was evaluated using four different immunohistochemical assays and FISH. RESULTS: Patients received a median of 25 weekly infusions (range, one to 85 infusions). Median delivered paclitaxel dose-intensity was 82 mg/m2/wk (range, 52 to 90 mg/m2/wk). The intent-to-treat response rate for all 95 patients enrolled was 56.8% (95% confidence interval, 47% to 67%). A response rate of 61.4% (4.5% complete response, 56.8% partial response) was observed in 88 fully assessable patients. In patients with HER2-overexpressing tumors, overall response rates ranged from 67% to 81% compared with 41% to 46% in patients with HER2-normal expression (ranges reflect the different assay methods used to assess HER2 status). Differences in response rates between patients with HER2-overexpressing tumors and those with normal HER2 expression were statistically significant for all assay methods, with CB11 and TAB250 antibodies and FISH having the strongest significance. Therapy was generally well tolerated, although three patients had serious cardiac complications. CONCLUSION: Weekly trastuzumab and paclitaxel therapy is active in women with metastatic breast cancer. Therapy was relatively well tolerated; however, attention to cardiac function is necessary.     

Phase II Multicenter Study of Docetaxel and Bevacizumab With or Without Trastuzumab as First-Line Treatment for Patients With Metastatic Breast Cancer

BackgroundAdding bevacizumab to docetaxel or paclitaxel in the first-line improves the progression-free survival (PFS) of metastatic breast cancer (MBC) patients. Docetaxel has been studied with bevacizumab at the maximally tolerated dose of 100 mg/m². We investigated the effects of combining bevacizumab with docetaxel (75 mg/m²) with or without trastuzumab for human epidermal growth factor receptor 2–positive (HER2⁺) and HER2–negative (HER2⁻) patients, respectively.Patients and MethodsWe conducted a phase II study, stratified by HER2 status, of patients with locally advanced breast cancer or MBC who had received no prior chemotherapy for metastatic disease and showed no evidence or history of central nervous system metastases. Stratum 1 (HER2⁻) treatment consisted of bevacizumab (15 mg/kg) followed by docetaxel (75 mg/m²) administered every 3 weeks; stratum 2 (HER2⁺) treatment was the same as that of stratum 1 with the addition of trastuzumab (8 mg/kg loading dose on day 2 of cycle 1, and 6 mg/kg on day 1 of all subsequent cycles).ResultsThe trial accrued 73 patients (stratum 1, 52 patients; stratum 2, 21 patients). The most common grade 3 or 4 adverse event (all strata) was fatigue (stratum 1, 11.5%; stratum 2, 10%). The incidence of grade 3 hypertension was 6% for stratum 1 and 5% for stratum 2. The median PFS was 8.4 months (95% CI, 5.2-10.4 months) in stratum 1; the median PFS in stratum 2 was 13.3 months (95% CI, 11.9-35.4 months). The overall response rate for stratum 1was 58% and for stratum 2 was 81%, and the clinical benefit rates were 67% and 81%, respectively.ConclusionIn first-line treatment of MBC, adding docetaxel (75 mg/m²) to bevacizumab administered every 3 weeks in HER2⁻ patients, and docetaxel plus trastuzumab plus bevacizumab treatment in HER2⁺ patients are feasible and safe, with high response rates and promising PFS compared with those of bevacizumab-naive historic controls.