Anthracycline-pretreated Metastatic Breast Cancer Research Articles

A pilot study of weekly versus 3-week docetaxel in combination with capecitabine in patients with anthracycline-pretreated metastatic breast cancer

To evaluate the efficacy and safety of weekly or 3-week docetaxel in combination with capecitabine. 83 Patients with at least one measurable lesion were randomized to receive the treatment arms: docetaxel 37.5 mg/m(2) on days 1 and 8, oral capecitabine 950 mg/m(2) twice daily on days 1-14 (Group A); docetaxel 75 mg/m(2) on days 1, oral capecitabine 950 mg/m(2) twice daily on days 1-14 (Group B). Each cycle was repeated every 3 weeks. Eighty-three patients were enrolled, 78 eligible for tumor assessment. The overall clinical response rate of all groups was 61.4% (51/83). There was no progressive disease (PD) after two cycles. Efficacy outcomes were similar in the two groups. The response rate of group A and B were 61.8% (21/34) and 61.2% (30/49) respectively. There were no drug-related deaths observed. Neutropenia was the most common toxicity. In all, the frequency of Grade 3/4 neutropenia were 45.8% (38/83), but Grade 3/4 neutropenia of Group B 55.1% (27/49) was higher than Group A 32.4% (11/34), P = 0.04. The study confirmed the superior activity of docetaxe-capecitabine combination therapy in anthracycline resistant MBC, and comparing with 3-week schedule, weekly docetaxel plus capecitabine has same high efficacy with a favourable safety profile.

Combination of docetaxel and TSU-68, an oral antiangiogenic agent, in patients with metastatic breast cancer previously treated with anthracycline: Randomized phase II multicenter trial

The novel oral antiangiogenic agent TSU-68 was investigated in patients with metastatic breast cancer. Patients with anthracycline-pretreated metastatic breast cancer were randomly assigned to receive either TSU-68 400mg twice daily on days 1-21 plus docetaxel 60mg/m(2) on day 1 every 3weeks, or docetaxel 60mg/m(2) on day 1 every 3weeks. The primary endpoint was progression-free survival. Between November 2006 and December 2007, 81 patients were included in this study (41 for TSU-68 plus docetaxel and 40 for docetaxel alone). Median progression-free survival was 6.8months (95% confidence interval [CI] = 5.4-12.5months) in the TSU-68 plus docetaxel group and 8.1months (95% CI = 4.0-13.7months) in the docetaxel-alone group (hazard ratio [HR] = 1.0; 95% CI = 0.6-1.8; p = 0.95). There were no significant differences in the overall response rates and overall survival between groups (p = 0.29 and p = 0.42, respectively). In subgroup analysis, TSU-68 plus docetaxel was associated with better overall survival than docetaxel alone in anthracycline-resistant patients (HR = 0.3; 95% CI = 0.1-0.8; p = 0.02). The most frequent adverse events were neutropenia and anorexia in both arms. Although both regimens were well tolerated, grade 3/4 non-hematologic toxicity was more frequently observed in the TSU-68 plus docetaxel group. Combination of TSU-68 and docetaxel is well tolerated but failed to demonstrate superior efficacy over docetaxel alone in anthracycline-pretreated breast cancer patients. As TSU-68 was associated with better survival in the anthracycline-resistant subgroup, it should be further explored in this subgroup.

Phase II and Pharmacological Study of Oral Docetaxel Plus Cyclosporin A in Anthracycline Pre-Treated Metastatic Breast Cancer

Previously, we demonstrated that oral docetaxel plus the P-glycoprotein (Pgp; ABCB1) inhibitor cyclosporin A (CsA) is safe and results in adequate exposure to docetaxel. This phase II study evaluates the anti-tumor activity, safety and pharmacokinetics of oral docetaxel in combination with CsA in women with advanced breast cancer. Patients with measurable advanced breast cancer were given one flat dose of 100 mg oral docetaxel, preceded by one single dose of 15 mg/kg CsA, weekly for 6 weeks in a cycle of 8 weeks. Pharmacokinetic monitoring of docetaxel and CsA was performed in week 1 and 9. Thirty-three patients with a median age of 50 years were recruited. Thirty patients were evaluable for toxicity and twenty-six for response. All had received prior anthracycline treatment. The treatment was generally well tolerated with manageable toxicity although many patients needed a dose reduction, most commonly because of fatigue and uncomplicated neutropenia. The median treatment duration was 16 weeks (range 6 - 32). The overall response rate in evaluable patients was 42% (95% CI: 23 - 63) and the median overall survival was 12.2 months (8.4 - 23.1). The interpatient variability in the area under the curve of 100 mg orally administered docetaxel was moderate, respectively 49 and 30% in week 1 and 9. Weekly oral docetaxel, combined with the booster drug CsA, is an active and safe treatment in anthracycline pre-treated patients with advanced breast cancer.

Abstract OT3-3-08: Eribulin/Cyclophosphamide versus Docetaxel/Cyclophosphamide as Neoadjuvant Therapy in Locally Advanced HER2-Negative Breast Cancer: A Randomized Phase II Trial of the Sarah Cannon Research Institute

Abstract Background: Neoadjuvant chemotherapy for locally advanced breast cancer improves survival and rates of breast-conserving surgery. Pathologic complete response (pCR) after neoadjuvant therapy strongly correlates with improved disease free survival (DFS) and provides an early indicator of treatment efficacy. The expected pCR rate with a standard taxane-containing combination is approximately 18%. Eribulin is a non-taxane synthetic analogue of halichondrin B that inhibits microtubule dynamics by a novel mechanism of action distinct from other tubulin-targeting agents. Eribulin is active against taxane and anthracycline pretreated metastatic breast cancer (MBC) and is well tolerated with a predictable toxicity profile. Substitution of eribulin for docetaxel in a neoadjuvant combination regimen may therefore improve efficacy. This study will evaluate the non-anthracycline eribulin/cyclophosphamide (ErC) and docetaxel/cyclophosphamide (TC) combinations as neoadjuvant therapy. The first ten patients (pts) will be evaluated for tolerability and feasibility of standard prescribed eribulin monotherapy dosing in combination with standard dose cyclophosphamide. Study Objectives: This randomized phase II trial is designed to determine the pCR rate of locally advanced, HER2-negative breast cancer treated with 6 cycles of ErC or TC. The secondary objectives are to evaluate the clinical response rate of ErC as neoadjuvant therapy and to determine the 2 year DFS of pts treated with ErC and TC. Eligibility: Females ≥ 18 years with untreated, locally advanced, HER2-negative breast cancer appropriate for neoadjuvant chemotherapy are eligible. Eligibility criteria include: adenocarcinoma histology; clinical T1-3, N0-2, M0 breast tumors; ECOG PS 0–2; known hormone receptor status at study entry; adequate bone marrow and organ function; willingness to provide archived biopsy specimen for correlative testing. Clinical N3, T1N0M0, and T4 tumors are excluded. Upfront axillary lymph node sampling and/or definitive nodal surgery is permitted, and demonstrated pN3a disease is allowed. Trial Design: A lead-in phase of the trial will enroll 10 pts to be treated with ErC to determine safety and feasibility of the combination. If the safety is confirmed, subsequent pts will be stratified by hormone receptor status (positive vs. triple- negative) and will be randomized in a 2:1 ratio to Arm 1: ErC or Arm 2: TC. Pts on Arm 1 will receive eribulin 1.4 mg/m2 IV (Days 1 & 8) and cyclophosphamide 600 mg/m2 IV (Day 1). Pts on Arm 2 will receive docetaxel 75 mg/m2 IV (Day 1) and cyclophosphamide 600 mg/m2 IV (Day 1). Both regimens are repeated every 21 days for a total of 6 cycles. After completion of neoadjuvant chemotherapy, pts will undergo definitive local surgery, as determined by the treating surgeon. Archival tumor samples and residual tumor tissue at surgery will be collected for biomarker evaluations. A total of 66 pts (Arm 1: 44; Arm 2: 22) will be enrolled to this study. A pCR rate ≥ 18% in patients treated with ErC is considered a study result that merits further evaluation. This trial is pending activation and has a total accrual goal of 76 pts. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr OT3-3-08.

Capecitabine and oxaliplatin in combination as first- or second-line therapy for metastatic breast cancer: a Wisconsin Oncology Network trial

Several cytotoxic chemotherapy regimens are active against metastatic breast cancer; however, benefits are modest and overall prognosis remains limited. For anthracycline and taxane-pretreated metastatic breast cancer, there remains a relative paucity of therapies with significant activity. This Phase II study evaluated the combination of capecitabine and oxaliplatin (XELOX) among patients with metastatic breast cancer being treated in the first- or second-line setting. Patients received oxaliplatin 85 mg/m(2) on days 1 and 15, and capecitabine 1,500 mg/m(2) twice daily on days 1-7 and 15-21 of a 28-day cycle. Patients were treated until progression or intolerable toxicity. The primary objective was to estimate the objective response rate by the Response Evaluation Criteria in Solid Tumors (RECIST) criteria with tumor assessments every 8 weeks. Ten patients were treated of which 3 had received prior neurotoxic therapy in the metastatic setting. There were no confirmed complete responses, 5 patients had partial response, 4 patients had stable disease for at least 24 weeks, and one patient was unevaluable. Median time to progression (TTP) was 10.4 months (95% lower confidence bound [LCB]: 5.75 months), median progression-free survival (PFS) was 14.2 months (95% LCB: 6.14 months), and median overall survival (OS) was 19 months (95% LCB: 12.8 months). Multiple patients experienced pain syndromes and unusual neuropathies. Other common toxicities included fatigue, diarrhea, and nausea. XELOX is a promising regimen for anthracycline-pretreated metastatic breast cancer although careful patient selection is indicated and alternate dosing schedules should be explored to minimize neurologic morbidity.

Bi-weekly docetaxel and gemcitabine regimen in her-2-negative and anthracycline-pretreated metastatic breast cancer patients: a multicenter phase II trial

Bi-weekly gemcitabine (G) in combination with docetaxel (D) is an effective treatment for metastatic breast cancer (MBC) previously treated with adjuvant/neoadjuvant anthracyclines containing regimens with a good toxicity profile. In the present phase II study, we investigated the activity of the same regimen as first-line treatment. Women with breast cancer pretreated in adjuvant/neoadjuvant setting with anthracyclines received bi-weekly G (1,250mg/m² days 1, 15) and D (50mg/m² days 1, 15) every 28days with restaging after 3 and 6 cycles. Overall 42 patients were enrolled. Median age is 48years (range, 31-71years). Eight patients (19%) achieved complete responses, 18 (43%) partial responses for an overall response rate (ORR) of 62%; five patients (12%) obtained stable disease (SD), and 8 (19%) patients had progressive disease (PD). After a median 17-month follow-up, the median time to disease progression was 12months (95% CI, 3-26months) and the median survival time was 27months (95% CI, 4-57months). No grade 4 toxicity was seen except in one patient who developed a grade 4 neutropenia. Grade 3 toxicities were leukopenia (2%), neutropenia (14%), anemia (2%), nausea and vomiting (2%), diarrhea (2%), asthenia (2%), and skin toxicity (12%). The GD bi-weekly regimen is well tolerated and active as first line in anthracyclines-pretreated women with MBC. It appears as an interesting alternative compared to a 3-week schedule whenever hematological toxicity is the main clinical concern.

Weekly docetaxel in metastatic breast cancer patients: No superior benefits compared to three-weekly docetaxel

BackgroundIn anthracycline-pretreated metastatic breast cancer (MBC) patients, it is unknown whether weekly single-agent docetaxel is preferable to 3-weekly docetaxel regarding its toxicity and efficacy profile. Patients and methodsIn this multicenter, randomised, open-label phase III trial, 162 patients were randomised to weekly docetaxel (group A) or 3-weekly docetaxel (group B). The primary end-point was tolerability; secondary end-points were efficacy and quality of life (QoL). ResultsGroup A (weekly docetaxel, n=79) experienced less haematological toxicity, with just 1.3% versus 16.9% febrile neutropenia in group B (3-weekly docetaxel, n=77) (p=0.001). Not this difference, but fatigue and general malaise foremost led to more patient withdrawals in group A (24 versus 12 patients, p=0.032), less patients completing treatment (29 versus 43 patients, p=0.014) and reduced dose-intensity (15.6 versus 26mg/m2/week, 58% versus 70% of projected dose, p=0.017). As a result, 3-weekly docetaxel was related to better overall survival in multivariate analysis (hazard ratio 0.70, p=0.036), although in univariate analysis efficacy was similar in both groups. Reported QoL was similar in both groups, but less effective treatment with more general toxicity led to less completed QoL forms in group A (65.4% versus 50%, p=0.049). ConclusionWeekly docetaxel is less well tolerated than a 3-weekly schedule, due to more non-haematological toxicity, despite less febrile neutropenia. Also, no efficacy benefits can be demonstrated for weekly docetaxel, which may even be inferior based on multivariate analysis. Therefore, a 3-weekly schedule should be preferred in the setting of MBC.

Trastuzumab plus capecitabine and docetaxel as first-line therapy for metastatic breast cancer: Phase II results

1111 Background: In human epidermal growth factor 2 (HER-2)-positive advanced breast cancer, taxanes plus trastuzumab are among the most widely applied options in the first-line setting. The addition of capecitabine to docetaxel significantly improves overall survival in anthracycline-pretreated metastatic breast cancer. We evaluated the efficacy and tolerability of trastuzumab plus capecitabine and docetaxel regimen as first-line therapy. Methods: Patients who had received adjuvant anthracyclines received docetaxel 75 mg/m2 day 1 and capecitabine 950 mg/m2 twice daily, days 1–14, every 3 weeks until disease progression or unacceptable toxicity. Trastuzumab was administered at a dose of 6 mg/kg every 3 weeks. Time to progression (TTP) was defined as primary end point. Results: Twenty eight patients were evaluable (median age 52 years, range 34–70). The regimen achieved objective responses in 11 patients (39%), including complete response in three patients (11%) and partial response in eight patients (28.5%). The median overall survival time was 25.5 months, and the median progression-free survival time was 7.8 months. The safety profile of the combination was favorable and predictable, with a low incidence of grade 3/4 adverse events. The most common adverse events were hand-foot syndrome, and GI toxicities. Severe myelosuppression was rare and cardiac toxicity did not occur. Conclusions: These data confirm that the combination of trastuzumab plus capecitabine and docetaxel is highly active in patients with HER-2-overexpressing anthracycline-pretreated breast cancer, and is well tolerated. No significant financial relationships to disclose.

Low-dose capecitabine plus docetaxel as first-line therapy for metastatic breast cancer: phase II results

The addition of capecitabine to docetaxel significantly improves overall survival in anthracycline-pretreated metastatic breast cancer. We evaluated a low-dose capecitabine-docetaxel regimen as first-line therapy. Patients who had received adjuvant anthracyclines received docetaxel 75 mg/m2 on day 1 and capecitabine 950 mg/m2 twice daily, days 1-14, every 3 weeks until disease progression or unacceptable toxicity. The primary endpoint was time to progression. Forty-five patients were evaluable (median age 56 years, range 35-75). The response rate was 42%, including two complete responses. Nine patients (20%) attained stable disease. Median time to progression was 8 months and median overall survival was 23 months. Five patients (11%) experienced grade 3 neutropenia but febrile neutropenia was absent. Three patients (7%) experienced grade 3 hand-foot syndrome; there was no significant gastrointestinal toxicity. This capecitabine-docetaxel regimen is an active first-line therapy and appears better tolerated than regimens using a higher capecitabine dose. Data from the randomized trial comparing the registered versus a lower capecitabine dose, both in combination with docetaxel, should definitively answer whether a lower dose provides a better safety profile while maintaining the considerable efficacy of this combination.

Severe skin toxicity observed with the combination of capecitabine and weekly paclitaxel in metastatic breast cancer patients

Skin toxicity has recently been recognized as a dose-limiting toxicity of antineoplastic therapy. We report severe skin toxicity observed in anthracycline-pretreated metastatic breast cancer patients receiving the combination of capecitabine and weekly paclitaxel.

Phase II and Pharmacological Study of Oral Paclitaxel (Paxoral) Plus Ciclosporin in Anthracycline-Pretreated Metastatic Breast Cancer

Phase II and Pharmacological Study of Oral Paclitaxel (Paxoral) Plus Ciclosporin in Anthracycline-Pretreated Metastatic Breast Cancer

German Breast Group (GBG)

This section provides current contact details and a summary of recent or ongoing clinical trials being coordinated by German Breast Group (GBG). Clinical trials include: A multi-center randomized Phase III study evaluating 4 cycles of docetaxel, doxorubicin and cyclophosphamide (TAC) versus 4 cycles of vinorelbine and capecitabine (NX) in patients not sufficiently responding to 2 cycles of TAC and 4 cycles of TAC versus 6 cycles of TAC in patients sufficiently responding to 2 cycles of TAC as preoperative treatment of locally advanced (T4 a-d, N0-3,M0) or operable (T ≥ 2 cm, N0-2,M0) primary breast cancer/GBG 24.A multi-center randomized Phase III study to compare capecitabine alone or in combination with trastuzumab in patients with HER-2 positive metastatic breast cancer and progression after previous treatment with trastuzumab (Treatment Beyond Progression, TBP). BIG 3-05-GBG26A Phase III multi-centre double blind randomized trial of celecoxib versus placebo in primary breast cancer patients. BIG 1-03-ICCG/C/20/01 - GBG27 (see also description under ICCG)Prospective Register Study of the German Adjuvant Breast Cancer Study Group (GABG) or Diagnosis and Treatment of Breast Cancer in Pregnancy / BIG 2–03, GBG 29.Ibandronate with or without capecitabine in elderly patients with early breast cancer – ICE – Study / BIG 4-04, GBG 32. (see also description under WSG)GAIN: German Adjuvant Intergroup Node-positive Study. A Phase III trial to compare ETC versus EC-TX and ibandronate versus observation in patients with node-positive primary breast cancer / GBG 33.A randomized, multi-center, open Phase III study comparing the postoperative use of zoledronic acid versus no treatment in patients with histological tumour residuals after preoperative anthracycline and taxane-containing chemotherapy for primary breast cancer (Neo-Adjuvant Trial Add-On) / GBG 36.Prospective randomized multi-center study to prevent chemotherapy-induced ovarian failure with the GnRH-agonist goserelin in young hormone-insensitive breast cancer patients receiving anthracycline-containing (neo-)adjuvant chemotherapy / GBG 37, ZORO-StudyA multi-centre Phase I–II study to investigate the combination of bendamustine with weekly paclitaxel as first or second line therapy in patients with anthracycline-pretreated metastatic breast cancer / GBG 38, Rita – Study.A multi-center Phase II study to determine the efficacy of capecitabine as first line monochemotherapy in patients with HER-2 negative metastatic breast cancer / GBG 39, Monica – Study.GeparQuattro: A randomized Phase III study exploring the efficacy of capecitabine given concomitantly or in sequence to EC – Doc with or without trastuzumab as neoadjuvant treatment of primary breast cancer. A joint study of GBG and AGO / GBG 40.Randomized study comparing 6 × FEC with 3 × FEC followed by 3 × docetaxel in high-risk node-negative patients with operable breast cancer: comparison of efficacy and evaluation of clinico-pathological and biochemical markers as risk selection criteria. A joint study of AGO, the EORTC Receptor and Biomarker Group, and the GBG (GBG 42 / NNBC 3-Europe).

Phase II and pharmacological study of oral paclitaxel (Paxoral) plus ciclosporin in anthracycline-pretreated metastatic breast cancer

Paclitaxel is an important chemotherapeutic agent for breast cancer. Paclitaxel has high affinity for the P-glycoprotein (P-gp) (drug efflux pump) in the gastrointestinal tract causing low and variable oral bioavailability. Previously, we demonstrated that oral paclitaxel plus the P-gp inhibitor ciclosporin (CsA) is safe and results in adequate exposure to paclitaxel. This study evaluates the activity, toxicity and pharmacokinetics of paclitaxel combined with CsA in breast cancer patients. Patients with measurable metastatic breast cancer were given oral paclitaxel 90 mg m−2 combined with CsA 10 mg kg−1 (30 min prior to each paclitaxel administration) twice on one day, each week. Twenty-nine patients with a median age of 50 years were entered. All patients had received prior treatments, 25 had received prior anthracycline-containing chemotherapy and 19 had three or more metastatic sites. Total number of weekly administrations was 442 (median: 15/patient) and dose intensity of 97 mg m−2 week−1. Most patients needed treatment delay and 17 patients needed dose reductions. In intention to treat analysis, the overall response rate was 52%, the median time to progression was 6.5 months and overall survival was 16 months. The pharmacokinetics revealed moderate inter- and low intrapatient variability. Weekly oral paclitaxel, combined with CsA, is active in patients with advanced breast cancer.

A pilot study of weekly versus 3-week docetaxel in combination with capecitabine in patients with anthracycline-pretreated metastatic breast cancer

10771 Background: Capecitabine in combination with docetaxel given every 3 weeks has shown a high degree of activity in anthracycline-pretreated metastatic breast cancer (MBC), but with high toxicities. To improve the therapeutic index, we performed a clinical pilot trial to evaluate the efficacy and safety of weekly or 3-week docetaxel in combination with capecitabine given for 14 days every 21 days. Methods: Patients with at least one measurable lesion were randomized to receive the treatment arms: docetaxel 75mg/m2 on days 1, oral capecitabine 950 mg/m2 twice daily on days 1–14 (Arm A); docetaxel 37.5mg/m2 on days 1 and 8, oral capecitabine 950 mg/m2 twice daily on days 1–14 (arm B). Each cycle was repeated every 3 weeks. Patients remained on study for a maximum 6 cycles or until tumor progression or unacceptable toxicity occurred, response assessments were scheduled every two cycles. Results: 64 pts were enrolled, 62 eligible for safety and tumor assessment. Key baseline variables were well balanced. Dominant site of disease was visceral in 66.1%; 24.2% had ≥3 organ sites of disease; all patients had previously received anthracyclines, 24.2% for MBC. 43. 6% were ER negative and 46.8% were HER-2 overexpress. The overall clinical response rate of all groups was 59.7% (37/62). There was no progressive disease (PD) after two cycles. Efficacy outcomes were similar in the two arms. The response rate of group A and B were 60% (18/30) and 59.4% (19/32) respectively. There were no drug-related deaths observed. Neutropenia was the most common toxicity. In all, the frequence of Grade 3/4 neutropenia were similar in two arm, but Grade 4 neutropenia of Group A 66.7% (20/30) was higher than Group B 34.4% (11/32), P = 0.021. Conclusions: The study confirmed the superior activity of docetaxe-capecitabine combination therapy in anthracycline resistant MBC, and comparing with 3-week schedule, weekly docetaxel plus capecitabine has same high efficacy with a favourable safety profile. No significant financial relationships to disclose.

Docetaxel (T) followed by capecitabine (X) as first-line chemotherapy in patients (pts) with metastatic breast cancer (MBC): Preliminary findings from a phase II study

10692 Background: X and T are highly active single agents in MBC. The XT combination leads to superior overall survival (OS), time to progression (TTP) and response rate (RR) vs. T alone in anthracycline-pretreated MBC [O’Shaughnessy et al. J Clin Oncol 2002]. The aim of this trial was to evaluate the efficacy and safety of sequentially administered T then X as first-line treatment in MBC. Methods: Pts ≥ 18 years with previously untreated, HER2neu-negative MBC, ECOG PS ≤ 2, were included in this prospective, multicenter, non-randomized, phase II study. Pts received 3 cycles of T (100mg/m2 d1) followed by 3 cycles of X (1250mg/m2 bid d1–14), every 3 weeks. Results: To date, 38 pts are evaluable for safety and 33 pts for efficacy. Baseline characteristics: median age 54.4 years (range 33–76); PS ≥ 1 50%; 36 (95%) pts had previous (neo)adjuvant anthracyclines, 8 (21%) concomitant with paclitaxel. The most frequent metastatic sites were: bone 47%, nodes 39% and liver 36%. 69% of pts had ≥ 2 metastatic sites. To date, 38 pts have received 3 cycles of T and 33 have also received 3 cycles of X. A total of 195 cycles have been administered: T 108 cycles (median 3, range 1–3); X 87 cycles (median 3, range 1–3). Dose reductions and interruptions for T vs. X were 32 vs. 21% and 21 vs. 21%, respectively. Median relative dose intensity: T 0.97 (range 0.62–1.00), X 0.93 (range 0.26–1.00). T grade 3/4 toxicities (37 evaluable pts): asthenia 19%, mucositis 16%, nausea 13%, febrile neutropenia 11%, rash 5%, diarrhea 5%, infection 3%. X grade 3/4 toxicities (33 evaluable pts): hand-foot syndrome 9%, diarrhea 9%, vomiting 9%, asthenia 6%, nausea 3%, anorexia 3%. In the 33 pts evaluable for efficacy, the RR was 61%, including 4 CRs and 16 PRs. At a median follow-up of 6.1 months, median TTP has not yet been reached. Conclusions: These preliminary results show that the sequential regimen of T followed by X is feasible, effective and well tolerated in first-line MBC, although giving X before T should also be investigated. Findings from a recent trial of XT vs. T followed by X [Beslija et al. ECCO 2005] suggest that XT should be standard in fit poor-prognosis pts with aggressive disease. No significant financial relationships to disclose.

Phase II study of pegylated liposomal doxorubicin plus vinorelbine in metastatic breast cancer

10718 Background: Pegylated liposomal doxorubicin and vinorelbine are active single agents in metastatic breast cancer (MBC) and lack overlapping toxicity. The possibility of combining these two drugs therefore seems attractive. Methods: Twenty-five patients with MBC entered a phase II study of pegylated liposomal doxorubicin 40 mg/m2 intravenously (i.v.) on day 1 plus vinorelbine 25 mg/m2 i.v. on day 1 and vinorelbine 60 mg/m2 oral on day 14, every 4 weeks. A two-staged Simon accrual design was adopted for this phase II trial. Patients were required to have measurable disease, previous chemotherapy with or without an anthracycline-containing regimen, and a normal left ventricular ejection fraction (LVEF). Results: Twenty-one patients with MBC were eligible, assessable for response and toxicity. The overall response rate (on an intent-to-treat basis) was 36% (9 of 25; 95% CI, 20%-54%). One complete response and 8 partial responses were noted. In addition, 11 patients (44%) had stable disease of > 4 months duration, and 5 patients (20 %) had disease progression. Median time to disease progression was 10 months (range, 3–38 months) and median overall survival was 15 months (range, 4 to > 62 months). Neutropenia was the most frequent toxicity (grade 4 in 30% of patients and 19% of cycles), but neutropenic fever was seen in only 3 cases. No septic deaths occurred. Nonhematologic grade 3 side effects included skin toxicity (palmar-plantar erythrodysesthesia syndrome, 8%) and mucositis (14%). Late alopecia was seen in 51% of patients (grade 1 in 39%, and grade 2 in 12%). The median LVEFs were 64% (range, 50%-81%) at baseline and 62% (range, 37%-70%) after treatment. Only one patient presented an LVEF decrease to < 50%; however, no clinical heart failure was noted, and this patient recovered normal values after cessation of therapy. Conclusions: The combination of pegylated liposomal doxorubicin and vinorelbine can be safely administered to patients with anthracycline-pretreated MBC and is active in this population. Final data analysis will be presented. No significant financial relationships to disclose.

Capecitabine (X) and taxanes in patients (pts) with anthracycline-pretreated metastatic breast cancer (MBC): Sequential vs. combined therapy results from a MOSG randomized phase III trial

570 Introduction: Capecitabine (Xeloda [X]) shows synergy with taxanes and adding X to docetaxel (T) extends overall survival (OS), response rate (RR) and progression free-survival (PFS) beyond T alone. Sequential single-agent therapy could confer convenience benefits and may be more appropriate than combination chemotherapy for some pts. Methods: Pts with anthracycline-pretreated MBC received 3-weekly cycles of 1 of the following regimens: X→taxane (X 1250mg/m2 bid d1–14, followed after progression (PD) by T 100mg/m2 or paclitaxel [P] 175mg/m2 day 1; X+P (X 825mg/m2 bid days 1–14 + P 175mg/m2 day 1) or X+T (X 825mg/m2 bid days 1–14 + T 75mg/m2 day 1). Results: Of the 368 pts enrolled, 91 are either still on therapy or not evaluable. The table shows baseline characteristics, efficacy and safety in evaluable pts. Median follow up is 15.5 months. Median doses for X in each arm (1st cycle vs. 8th cycle, mg/m2 bid): 1218 vs. 1054; 948 vs. 900; 846 vs. 751. Median doses for P and T (1st cycle vs. 8th cycle, mg/m2): 173 vs. 169 and 75 vs. 72, respectively. In the X→taxane arm, 58 pts (64%) received sequential taxane; the remainder did not receive a taxane, either because they were still on X, had CR or had rapid PD. Conclusions: RR is higher with XP and XT, but PFS and OS are similar at a median follow-up of 15.5 months. All regimens were well tolerated with minimal grade 4 AEs. Because there is no clear superiority of sequential vs. combined therapy, pt characteristics are likely to be used to decide which regimen is the most appropriate. [Table: see text] [Table: see text]

Myocardial HER2 expression with 111In-DTPA-trastuzmab scan in patients shortly after anthracycline treatment

3057 Background: The monoclonal antibody trastuzumab, apart from antitumor effect, can induce cardiotoxicity, particularly when combined with anthracyclines. Myocardial HER2 upregulation may serve, transiently, as a compensatory mechanism induced by cardiac stress. Previously we showed in a xenograft model that 111In-DTPA-trastuzumab scintigraphy can detect HER2 positive lesions (Br J Pharmacol 2004;143:99–106) but that myocardial 111In-DTPA-trastuzumab uptake was found in only 1 of 17 anthracycline-pretreated HER2-positive metastatic breast cancer patients (ESMO 2004#50). This low number may be related to the long interval between anthracycline administration (median 11 months) and performed scan in these patients. To evaluate whether myocardial HER2 expression is induced by anthracyclines, we performed 111In-DTPA-trastuzumab scans in patients shortly after anthracycline treatment. Methods: Patients who completed 4–6 cycles of anthracycline-based chemotherapy (< 3 weeks after last dose) underwent gammacamera imaging 48 and 96 h after iv administration of 150 MBq 111In-DTPA-trastuzumab (5mg). Results: 10 anthracycline-treated patients, 8 as adjuvant breast cancer treatment and 2 for metastatic sarcoma have been enrolled. Myocardial 111In-DTPA-trastuzumab uptake was observed in 5/10 anthracycline-treated patients who all were without symptomatic cardiac dysfunction. Conclusions: Shortly after completion of anthracycline treatment myocardial HER2 overexpression was detectable in 50% of the patients. This may be a transient phenomenon. 111In-DTPA-trastuzumab scan after anthracycline treatment prior to adjuvant trastuzumab may identify patients more susceptible for trastuzumab-induced cardiotoxicity. This important observation may add to optimal timing of trastuzumab therapy i.e. when HER2/neu expression in the heart is negative (again). [Table: see text]

A phase II study of weekly docetaxel in patients with anthracycline pretreated metastatic breast cancer

Docetaxel has significant activity in metastatic breast cancer and weekly schedules are associated with less myelosuppression than 3-weekly schedules. We evaluated the toxicity and the activity of weekly docetaxel in anthracycline-pretreated patients. A total of 42 patients were studied. Treatment consisted of docetaxel 35 mg/m2 weekly as a 30-min infusion for 6 weeks followed by a 2-week rest, with dexamethasone 8 mg i.v. pre-medication and 4 mg orally 12-hourly for 48 h following treatment. The median age of the patients was 53 years (range 34-74). Twenty-six (62%) patients had received prior chemotherapy for advanced disease. Patients received a median 10 weeks of treatment (range 1-24). 11 had a partial response (ORR 26%; 95% CI 13-39%), five of whom had relapsed <12 months since the end of previous anthracycline-based chemotherapy. In addition six patients (14%) had stable disease for >16 weeks. Myelosuppression was rare with only 2 patients (5%) experiencing grade 3 neutropenia (no grade 4 neutropenia). Non-haematological grade III toxicities were as follows: fatigue 17%, neuropathy 0%, hyperlacrimation 5%, stomatitis 7%, diarrhoea 14%, and cutaneous toxicity 19%. Skin toxicity consisted of limb/palmar-plantar erythematous reactions, or fixed-plaque erythrodysaesthesia. Weekly docetaxel has moderate activity in women with anthracycline pre-treated breast cancer. Although the level of myelosuppression is lower than 3-weekly regimens, this weekly regimen cannot be recommended due to the significant non-haematological toxicities associated with the treatment.

Gemcitabine plus docetaxel versus capecitabine plus docetaxel forpatients with anthracycline-pretreated metastatic breast cancer: a review of the results of a European Phase III trial

Gemcitabine plus paclitaxel has been shown to be efficacious and safe for the treatment of anthracycline-pretreated metastaticbreast cancer (MBC) patients and was recently approved in this setting. The gemcitabine plus docetaxel combination has also been compared with capecitabine plus docetaxel as first- or second-line treatment for anthracycline-pretreated MBC patients. The trial compared progression-free survival, overall response rate, time to treatment failure, overall survival, toxicity and quality of life. The first results of this trial were reported recently at the American Society of Clinical Oncology (ASCO) meeting. Efficacy was similar in both groups. However, statistically significant differences were found in terms of toxicity. Non-haematological toxicity was low in both treatment arms. However, diarrhoea, mucositis and hand-and-foot syndrome were more pronounced in the capecitabine plus docetaxel arm. In addition, more frequent serious adverse events occurred in the capecitabine plus docetaxel arm, causing discontinuation in 28% of patients. There were two toxic deaths, both in the capecitabine plus docetaxel arm.