Pretreated Advanced Breast Cancer Patients Research Articles

Abstract P5-18-10: Mecapegfilgrastim for primary prophylaxis of neutropenia in 355 HER2+ breast cancer patients treated with neoadjuvant docetaxel in combination with trastuzumab and/or pyrotinib: Exploratory analysis from randomized, double-blind, phase 3 PHEDRA study

Abstract Background: A dose relationship may exist for both antitumor activity and toxicity of docetaxel in breast cancer (BC) patients, while 86% grade 4 neutropenia and 12% febrile neutropenia (FN) were reported when pretreated advanced breast cancer (ABC) patients received 100 mg/m2 docetaxel monotherapy without hematopoietic support. PHEDRA was a randomized, double-blind, multicenter, phase 3 study comparing the efficacy and safety of adding pyrotinib to trastuzumab and docetaxel as neoadjuvant treatment in women with HER2+ early or locally ABC (ClinicalTrials.gov: NCT03588091). We conducted this exploratory analysis to evaluate the effectiveness of mecapegfilgrastim, a long-acting recombinant human granulocyte colony-stimulating factor (rhG-CSF), as primary prophylaxis for neoadjuvant chemotherapy-induced neutropenia in BC patients. Methods: Patients with HER2-positive early or locally ABC were randomly assigned (1:1) to pyrotinib arm receiving 4 neoadjuvant cycles of docetaxel (100 mg/m2 iv d1 q3w), trastuzumab (8 mg/kg iv, cycle 1 d1, then 6 mg/kg d1 q3w), and pyrotinib (400 mg po qd, d1-21, q3w) or placebo arm with placebo, trastuzumab and docetaxel. Per protocol, patients were required to receive a single, 6-mg fixed dose of mecapegfilgrastim on Day 2 of each cycle. Other G-CSF was permitted if mecapegfilgrastim was unavailable at the local center or patients occurred mecapegfilgrastim intolerance. The incidence of neutropenia, FN, time to first neutropenia onset, duration per neutropenia event and cumulative neutropenia duration during neoadjuvant treatment period; and the incidences of grade 3/4 neutropenia, FN and decreased WBC count in Cycle 1 to 4 (C1-4) were presented. The data cutoff date was April 30, 2021. Results: Between July 23, 2018 and January 8, 2021, 355 patients were randomized (pyrotinib arm, n=178; placebo arm, n=177). Among them, 291 (82.0%) patients received a single, 6-mg fixed dose of mecapegfilgrastim in Cycle 1 and 270 (76.1%) patients received mecapegfilgrastim in each of the 4 cycles. Grade 3/4 neutropenia was reported in 33 (18.5%) patients in the pyrotinib arm and 36 (20.3%) patients in the placebo arm. Five (2.8%) patients in the pyrotinib arm and 2 (1.1%) patients in the placebo arm developed FN (5 FN occurred in C1; 2 FN occurred in C2). Median duration of grade 3/4 neutropenia was 3 days in the pyrotinib group and 3 days in the placebo group. Median cumulative duration of grade 3/4 neutropenia was 4 days and 3 days in the pyrotinib group and the placebo group, respectively. Grade 3/4 neutropenia mainly occurred during the first cycle of treatment for both pyrotinib (13.5%) and placebo arm (15.8%), reduced in the second cycle (5.9% vs 4.0%) and thereafter (C3: 1.8% vs 3.4%; C4: 2.4% vs 1.7%). Similar trends were observed for grade 3/4 WBC count decreased in Cycle 1 to 4. No grade 4 infection occurred. Overview of neutropenia, FN and WBC count decreased was summarized in Table 1. Consistent findings were observed in 291 mecapegfilgrastim treated patients. Conclusion: The exploratory analysis demonstrated 6-mg fixed dose of mecapegfilgrastim was effective when administrated as primary prophylaxis for neoadjuvant chemotherapy-induced neutropenia, which could be considered as a new treatment option for its advantage of once-per-cycle dosing and convenient dose management. Table 1.Overview of neutropenia, febrile neutropenia and WBC count decrease during neoadjuvant treatment period.Docetaxel+Trastuzumab+Pyrotinib(N=178)Docetaxel+Trastuzumab+Placebo (N=177)All randomized patients(N=355)Neutropenia, n (%)Any grade57 (32.0)54 (30.5)111 (31.3)Grade 16 (3.4)5 (2.8)11 (3.1)Grade 218 (10.1)13 (7.3)31 (8.7)Grade 315 (8.4)20 (11.3)35 (9.9)Grade 418 (10.1)16 (9.0)34 (9.6)Median time to first onset (IQR), days7 (6-63)6 (6-49)7 (6-53)Median duration per grade 3 or higher neutropenia, days (range)3 (1-16)3 (2-12)3 (1-16)Median cumulative duration of grade 3 or higher neutropenia, days (range)4 (2-16)3 (2-14)3 (2-16)FN, n (%)5 (2.8)2 (1.1)7 (2.0)Grade 3 or higher neutropenia, n (%) *Cycle 124 (13.5)28 (15.8)52 (14.6)Cycle 210 (5.9)7 (4.0)17 (4.9)Cycle 33 (1.8)6 (3.4)9 (2.6)Cycle 44 (2.4)3 (1.7)7 (2.1)Grade 3 or higher FN, n (%) *Cycle 12 (1.1)2 (1.1)4 (1.1)Cycle 22 (1.2)02 (0.6)Cycle 3000Cycle 4000Grade 3 or higher WBC count decreased, n (%) *Cycle 120 (11.2)20 (11.3)40 (11.3)Cycle 28 (4.7)2 (1.1)10 (2.9)Cycle 32 (1.2)1 (0.6)3 (0.9)Cycle 44 (2.4)2 (1.1)6 (1.8)Note: IQR, interquartile range; FN, febrile neutropenia; WBC, white blood cell.*The denominator indicates number of patients with mecapegfilgrastim for prophylaxis use in this cycle. Citation Format: Min He, Benlong Yang, Jiong Wu, Zhenzhen Liu, Hongjian Yang, Jinhai Tang, Kun Wang, Yunjiang Liu, Haibo Wang, Peifen Fu, Shuqun Zhang, Qiang Liu, Zefei Jiang, Shusen Wang, Jian Huang, Chuan Wang, Shu Wang, Yongsheng Wang, Linlin Zhen, Xiaoyu Zhu, Shulin Liu, Ping Yan, Jianjun Zou. Mecapegfilgrastim for primary prophylaxis of neutropenia in 355 HER2+ breast cancer patients treated with neoadjuvant docetaxel in combination with trastuzumab and/or pyrotinib: Exploratory analysis from randomized, double-blind, phase 3 PHEDRA study [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-18-10.

Everolimus plus exemestane in hormone-receptor-positive, HER2-negative locally advanced or metastatic breast cancer: incidence and time course of adverse events in the phase IIIb BALLET population

The addition of everolimus to exemestane therapy significantly improves progression-free survival in postmenopausal patients with hormone-receptor (HR)-positive HER2-negative endocrine-resistant breast cancer. However, the safety profile of this schedule still might be optimized. Patients included in the BALLET trial were assessed. The objectives of this analysis were to provide additional information on the safety profile of this schedule depending on prior anticancer therapies and to characterize the time course of adverse events (AEs) and serious AEs (SAEs) of clinical interest throughout the study period. Non-infectious pneumonitis (NIP), stomatitis, asthenia and weight loss were selected as AEs of clinical interest. The safety population of this analysis comprised 2131 patients. There were similar incidences of AEs and SAEs of clinical interest regardless of previous anticancer therapies. Most stomatitis and asthenia events occurred within the first three months. Incidence of weight loss appeared to plateau except in the case of grade 3-4 events, which occurred rarely. The incidence of any grade NIP (between 2 to 6%) and grade 3-4 NIP (between 0 to 1%) was low across the study, but steady. Everolimus plus exemestane is a well-known therapeutic option for aromatase inhibitor pretreated advanced breast cancer patients, and its toxicity profile is similar to that described in previous studies. Close monitoring, especially within the first three months, early intervention with preventive measures and patient education to help recognize the first signs and symptoms of AEs, will help to reduce their incidence and severity.

Eribulin plus trastuzumab in pretreated HER2-positive advanced breast cancer patients: safety and efficacy. An Italian experience.

Background:Chemotherapy plus targeted therapy is the established treatment for human epidermal growth factor receptor 2 (HER2)–overexpressing breast cancer (BC). Limited data regarding the safety and activity of the combination of eribulin and trastuzumab (E/T) in pretreated HER2-positive advanced BC (ABC) are available. The aim of this observational, retrospective, multicenter study was to examine the tolerability and the clinical activity of E/T in this setting.Methods:Patients treated with eribulin mesylate plus standard dose of trastuzumab were included. Data on overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety were reported.Results:Between October 2012 and November 2015, 24 consecutive patients with HER2-positive ABC were included. All patients were heavily pretreated: the median number of prior chemotherapy regimens for ABC was 3 (range 2–9). The median number of cycles with E/T was 11.5 (range 2–26). The ORR was 41.7%. Median PFS was 5.4 months, median postprogression survival was 5.4 months, and median OS was 8 months. Neutropenia was the most common grade 3/4 clinical adverse event (16.7%).Conclusions:Tolerability and clinical activity of the E/T combination schedule are encouraging. The results of this study indicate that this combination might be considered for treatment of pretreated HER2 ABC.

The relative effectiveness of eribulin for advanced breast cancer treatment: a study of the southeast Netherlands advanced breast cancer registry

Background: Eribulin provided significant overall survival (OS) benefit in heavily pretreated advanced breast cancer patients in the EMBRACE trial. We investigated the use of eribulin in daily clinical practice, the relative effectiveness of eribulin versus non-eribulin chemotherapy, and the safety of eribulin in real-world patients included in the SOutheast Netherlands Advanced BREast cancer (SONABRE) registry.Material and methods: Patients treated with eribulin and eligible patients for eribulin who received a different chemotherapy (i.e., non-eribulin group) in ten hospitals in 2013–2017 were included. A multivariate matching algorithm was applied to correct for differences in baseline characteristics between the groups, including the number of previous treatment lines. Progression-free survival (PFS) and OS of eribulin were compared with the matched non-eribulin group through Kaplan-Meier curves and multivariate Cox proportional hazard models. The occurrence of dose delay and reduction was described.Results: Forty-five patients received eribulin according to its registration criteria and 74 patients were eligible for eribulin but received non-eribulin chemotherapy. Matching increased the similarity in baseline characteristics between the eribulin and non-eribulin groups. Median PFS was 3.5 months (95% confidence interval (CI): 2.7–5.5) in the eribulin group and 3.2 months (95% CI: 2.0–4.8) in the matched non-eribulin group (adjusted hazard ratio (HR): 0.83, 95% CI: 0.49–1.38). Median OS was 5.9 months (95% CI: 4.6–11.0) and 5.2 months (95% CI: 4.6–9.5) in the eribulin and non-eribulin groups, respectively (adjusted HR: 0.66, 95% CI: 0.38–1.13). Dose delay or reduction occurred in 14 patients (31%) receiving eribulin.Conclusions: No difference in PFS and OS was observed between eribulin and non-eribulin treated patients. Eribulin had a manageable toxicity profile.

247P - Safety and efficacy of eribulin plus trastuzumab in pretreated HER2-positive advanced breast cancer (ABC) patients. An Italian multicenter experience

247P - Safety and efficacy of eribulin plus trastuzumab in pretreated HER2-positive advanced breast cancer (ABC) patients. An Italian multicenter experience

Eribulin plus trastuzumab in pretreated HER2-positive advanced breast cancer (ABC) patients: Results on safety and efficacy—An Italian multicenter experience.

e12087Background: Chemotherapy (CT) plus targeted therapy is the established treatment for HER2 overexpressing breast cancer (BC) patients (pts). The debate about anti-HER2 combination beyond standard therapies is still unresolved. Limited data regarding the safety and activity of the combination of eribulin and trastuzumab (E/T) in pretreated HER2-positive advanced breast cancer (ABC) are available. The aim of this observational, retrospective, multicenter study was to examine the tolerability and the clinical activity of eribulin plus trastuzumab in this setting. Methods: Pts treated with eribulin mesylate (1.23 mg/m2 administered via intravenous infusion on Days 1 and 8 each 21-day cycle) plus standard dose of trastuzumab (16 pts received 3-week schedule: 8 mg/kg load, 6 mg/kg q 3 weeks; 3 pts received weekly schedule: 4 mg/kg load, 2 mg/kg q week) were included. Data on overall response rate (ORR), progression free survival (PFS), post-progression survival (PPS), overall survival (OS) and safety were ...

Real-life effectiveness of T-DM1 in heavily pretreated HER2-positive advanced breast cancer patients: An Italian observational study.

e12019Background: T-DM1 showed remarkable activity in metastatic (m) HER-2 positive breast cancer (BC) and it recently was approved for clinical use in patients (pts) who previously failed trastuzumab and taxanes. The impact of drug prescription in real life compared with the findings reported in clinical trials exerting a strict accrual criteria has been rarely assessed. We investigated use and effectiveness of T-DM1 in daily practice. Methods: We included all pts with HER2-positive mBC, diagnosed in 12 Italian oncology hospitals between 2013 and 2015. Our aim was to assess the actual use of T-DM1 in HER2 positive mBC pts and its efficacy in clinical practice. Results: The data of 119 pts were retrospectively collected. The median age was 49 years (28-78), visceral metastases were present in 91 pts (77%) and brain metastases in 44 (37%). It is noteworthy that 29 pts (24%) received T-DM1 as second-line, 42 (35%) as third-line, and 43 (36%) as fourth- or further-line option. Moreover, 4 pts had TDM-1 as fi...

Abstract P1-15-21: Safety of eribulin mesylate and concomitant palliative radiotherapy for metastatic breast cancer: A single-center experience

Abstract Background. Eribulin mesylate is a recently approved new therapeutic option for patients with metastatic breast cancer (BC). It is a structurally simplified synthetic analogue of halichondrin B that inhibits the growth phase of microtubule dynamics and sequesters tubulin into non-productive aggregates, inhibiting microtubule polymerization, and inducing irreversible mitotic block at G2-M phases and apoptosis. Three phase II trials of eribulin in chemotherapy pretreated advanced BC patients were completed. In all these studies, eribulin showed a manageable tolerability profile, with most of the common drug-related adverse events being neutropenia, fatigue, alopecia, nausea, and anemia, according to the phase I trials findings. Eribulin was also associated with an overall low incidence of peripheral neuropathy. When new chemotherapy options become available, one of the most important questions regarding the sequence of treatments is to address the safety of concomitant radiation treatments. Recently has been reported a clinical case treated with eribulin mesylate and whole-brain radiotherapy (RT) in a heavily pretreated patient with multiple visceral and bone metastases from triple negative breast cancer. In our knowledge this is the first analysis focusing on the safety of eribulin in patients concomitantly treated with palliative RT. Methods. All patients where heavily pretreated for metastatic breast cancer (≥4 previous chemotherapy lines), including anthracyclines and taxanes-based regimens. Patients received eribulin mesylate (1.4 mg/m2 i. v., on days 1 and 8, of a 21-day cycle). Tumor response was assessed using the Response Evaluation Criteria in Solid Tumors (RECIST), every 8 weeks, or sooner if disease progression was suspected. Safety was assessed according to National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 4.0. Measures of bone-pain scores and analgesic consumption were evaluated at each visit, using a patient-rated scoring system. Results. Concerning 25 consecutive treated patients, median performance status at baseline was 2 (range 1-3). A median of 4 cycles of eribulin (range 2-10) were administered. All patients received palliative bone RT during eribulin treatment. No suspension or delay in chemotherapy administration was necessary. 20/25 cases underwent spinal bone irradiation; 8 Gy in single fraction was given in 13/25 patients, 12 cases received 20 Gy in 5 fractions. The overall response rate was 24% and the clinical benefit rate was 40%. Toxicity was manageable and in line with main published series; the most frequent grade 3 hematologic adverse events were neutropenia (56%), and anemia (20%). Bone pain scores fell within a few weeks and remained below baseline value throughout the analysis. The mean pain score was 2 at baseline and 0.7 at the end of observation period. The mean analgesic score was 1.8 at baseline and 1.6 at the end of follow-up. Conclusions. Our clinical practice experience supports the evidence that eribulin has clinical activity and is characterized by a manageable safety profile, also when combined to palliative RT. Concomitant treatment is feasible also in patients heavily pretreated, and with poor performance status. Citation Format: Icro Meattini, Vieri Scotti, Carla De Luca Cardillo, Beatrice Detti, Vanessa Di Cataldo, Lorenzo Livi. Safety of eribulin mesylate and concomitant palliative radiotherapy for metastatic breast cancer: A single-center experience [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-15-21.

Eribulin for Advanced Breast Cancer: A Drug Evaluation

Eribulin is a synthetic microtubule dynamics inhibitor that was developed from a marine natural product halichondrin B. It exhibited in vitro and in vivo activities against a wide number of malignancies. A number of advanced phase trials showed improved survival following eribulin treatment in pretreated advanced breast cancer patients. This review provides an overview of the background to the therapeutic use of eribulin in oncology, including its pharmacology, pharmacokinetics, clinical efficacy, safety, and potential economic factors.

Safety and efficacy of metronomic non-pegylated liposomal encapsulated doxorubicin in heavily pretreated advanced breast cancer patients

Metronomic administration of the same chemotherapy agents (lower doses with closer intervals) may optimize their antiangiogenic properties. The aim of our study was to determine the efficacy and safety of a metronomic regimen based in non-pegylated liposomal doxorubicin (NPLD) in advanced breast cancer patients. Clinical records of patients with pretreated advanced breast cancer and who were treated with the Metronomic-Cooper-type regimen consisting of weekly fixed doses of NPLD (30 mg IV) plus 5-Fluorouracil (5-FU) (500 mg IV) plus vincristine (0.25 mg IV) and daily oral cyclophosphamide (50 mg) plus prednisone (20 mg) were reviewed. In 84 pretreated patients, a tumor response was observed in 38 patients (45 %); stable disease was observed in 23 patients (27 %). Median progression-free survival (PFS) time to progression was 8.4 months and median overall survival (OS) was 21 months. The most common grade 2-3 hematologic adverse event was neutropenia, which was observed in 47 patients (56 %). Febrile neutropenia was observed in 10 patients (12 %). The most common non-hematologic adverse events were asthenia and mucositis which were observed in 60 patients (71 %) and 26 patients (31 %), respectively. Three patients (4 %) experienced an asymptomatic decline of the left ventricular ejection fraction. NPLD-based metronomic regimen was effective and safe in pretreated advanced breast cancer patients. It could be considered as an appealing option to treat patients previously exposed to anthracyclines.

5FU Continuous Infusion in Heavily Pretreated Advanced Breast Cancer Patients

Background: Despite advances in the first- and secondline treatment of advanced breast cancer, optimal therapy thereafter remains controversial. Treatment of heavily pretreated patients is not standardized, often of low efficacy, and limited by comorbidity. In these patients, an effective treatment with low toxicity is needed. Patients and Methods: We retrospectively analyzed all metastatic breast cancer patients treated with 5-fluorouracil as continuous infusion (CI-5FU) with daily doses of 150–300 mg/m². Results: 43 patients were treated with CI-5FU until disease progression. The median number of metastatic sites was 3. Most patients were heavily pretreated with a median of 3 palliative chemotherapies (range 1–11). 42 patients were evaluable for objective response; among them 5 (12%) showed a partial response (PR) and 6 (15%) showed stable disease (SD) lasting at least 6 months, leading to a clinical benefit (CB) rate (complete response + PR + SD ≧ 6 months) of 27%. The median time to progression of patients with CB was 10 months (range 3–22). Overall survival of all patients from the start of CI-5FU was 8 months (range 1–75) and from the time of first metastases 42 months (range 9–281). Toxicity was low even in patients with hepatic insufficiency. Conclusion: CI-5FU showed a positive efficacy/toxicity ratio. Taking into account the high number of previous treatments, it results in a remarkable CB rate of 27%.

Concomitant docetaxel plus gemcitabine versus sequential docetaxel followed by gemcitabine

1106 Background: Docetaxel plus Gemcitabine represent an active combination in anthracycline pretreated advanced breast cancer patients (pts.). Impact of sequential administration of these drugs is unclear. This trial aimed to compare concomitant DG with sequential D->G in anthracycline pretreated advanced breast cancer patients. Methods: Pts. pretreated with anthracyclines in the (neo)adjuvant or metastatic setting were randomized to receive either: 8 cycles Gemcitabine 1,000 mg/m2 on days 1 and 8, plus Docetaxel 75 mg/m2 on day 8 (DG), or 4 cycles Docetaxel 100 mg/m2 on day 1, followed by four cycles Gemcitabine 1,250 mg/m2 on days 1 and 8 (D->G), in a 21-day schedule. The primary endpoint was time to disease progression (TTDP), secondary endpoints were overall response rate (ORR), response duration (RD), overall survival (OS) and toxicity. Sample size was calculated to be 430. Due to poor recruitment the trial was closed after randomization of 100 pts. Results: Between September 2002 and March 2006, 100 pts. at 14 centers in 7 countries were randomly assigned to DG (n=46) or D->G (n=54). The median age was 53 vs 55 years in DG and D->G arms, 52%/50% vs 55/47 were ER/PR positive, 23% vs 17 were HER2 positive, 52%/44% vs 42/47% had liver/lung metastases at baseline. Grade 3/4 adverse events encompassed leukopenia (29% in DG; 68% in D->G), neutropenia (49 vs 83%) (p<0.001 for both) and febrile neutropenia (4 vs 9%). One treatment-related death due to enterocolitis was reported in the DG arm. ORR, RD, TTDP and OS were similar in both arms. Conclusions: The present data suggest that sequential D->G treatment produced significantly more episodes of hematologic toxicity. Regarding efficacy no trend in favor of any regimen was observed. Efficacy Parameters DG (n=45) D->G (n=53) ORR (%) 31% 28% RD (months) 5.4 7.8 Median TTDP (months) 7.0 6.7 Median OS (months) 15.5 15.9 Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Eli Lilly Eli Lilly

Tailored low-dose gemcitabine-cisplatin combination is a feasible and effective treatment in heavily pretreated advanced breast cancer patients

837 Background: Combining gemcitabine (G) plus cisplatin (C) at low doses is effective in advanced breast cancer. We sought to determine if this was clinically meaningful in women relapsing after a...

Weekly Docetaxel/Paclitaxel in Pretreated Metastatic Breast Cancer

The purpose of our study was to evaluate the feasibility and efficacy of weekly docetaxel/paclitaxel in pretreated advanced breast cancer patients. Twenty-six patients with metastatic breast cancer were included in this study. Three different schedules of treatment were administered. The starting schedule, A1, consisted of docetaxel 60 mg/m 2 on day 1 plus paclitaxel 60 mg/m 2 over 1 hour, weekly for 18 weeks; this schedule was considered feasible if at least 70% of the planned doses were given on time and without reduction. Schedule A2 consisted of the same doses administered on days 1 and 8 every 3 weeks, and schedule B consisted of docetaxel 25 mg/m 2 followed by paclitaxel 40 mg/m 2 for 1 hour on days 1 and 8 every 3 weeks for a total of 6 cycles. All patients had received prior anthracyclines, and 19 patients were pretreated with taxanes. Seventy-seven percent of patients had received at least 2 prior lines of chemotherapy. Twenty-five patients are assessable for toxicity and efficacy. A total of 109 cycles of chemotherapy have been administered, with a median of 4 cycles per patient (range, 1-8 cycles). The median delivered dose intensity was 27 mg/m 2/week for paclitaxel (range, 18-50 mg/m 2/week) and 17 mg/m 2/week (range, 12-39 mg/m 2/week) for docetaxel. Six patients received schedule A1. This schedule was considered not feasible due to neutropenia grade > 2, mucositis, and diarrhea grade 2, which required dose reduction/ omission in 33% of administrations. For this reason, treatment in the following 5 patients was omitted on day 15 (schedule A2). Schedule B was found to be more feasible with 16% of dose reductions/omissions. The overall response rate was 68% (95% CI, 50%–86%) with a median duration of response of 10 months (range, 2- 18+ months). Treatment was well tolerated; myelosuppression was rare and grade 3 cutaneous toxicity was observed in only 2 patients. In conclusion, weekly docetaxel/paclitaxel is active at low dosages and was well tolerated as salvage chemotherapy in metastatic breast cancer. This regimen represents a valid option as a salvage treatment in taxane- and anthracycline-pretreated patients.

New Approaches to Breast Cancer

Oxaliplatin is a platinum compound that inhibits DNA synthesis. This drug has a broad spectrum of antineoplastic activity, and its results in breast cancer are promising. We began a phase II study in pretreated advanced breast cancer patients using oxaliplatin together with 5-fluorouracil and folinic acid, a combination based on the efficacy of both drugs in breast cancer and their different toxicity profiles. Seventeen patients with advanced breast cancer were treated with oxaliplatin, 5-fluorouracil, and folinic acid, and preliminary data were analyzed. The mean number of courses per patient was 2.82 (range 1-8). The main toxicity was gastrointestinal, with nausea and vomiting G2-3 in 53% of the patients. Hematologic toxicity was moderate with neutropenia G2-3 in 13% of the patients. Among 10 evaluable patients we obtained partial response in one and stabilized the disease in two patients. No data on survival were evaluated. The small number of enrolled and evaluable patients does not permit any conclusions to be drawn. The study is ongoing.

Respuesta terapéutica a gemcitabina en cáncer de mama avanzado en relación con factores immunohistoquímicos

Advanced breast cancer has a poor prognosis. Gemcitabine, a desoxycitidine analogue, has shown 25% to 37% overall response in advanced cases. We have evaluated the efficacy and safety of gemcitabine in patients with advanced breast cancer heavily pretreated and to correlated responses with immunohistochemical factors. Patients were treated at doses of 1,250 mg/m2/week/q/month, for at least two cycles. Age, HER2/neu,p53, hormonal receptors, angiogenesis, site and number of metastases, number of cycles received, Karnofsky's score, progression free survival, overall survival and side effects were evaluated.From January 1996 to November 1999, 19 women were included, mean age 52.3±12.7; range: 31 to 84 years. Immunohistochemical factors were determined in 10 patients and resulted positive 52.6%; overexpression of c-erbB-2 in 5 patients,p53 in 5, estrogen receptor in 4, progesterone receptor in 3. Gemcitabine was applied as second line in 6 patients, third in 6, fourth in 3, fifth in one and sixth in one too. Mean Karnofsky score at the start of treatment 81.05±11; range: 70 to 100: after second and third cycles 82.1±11.3 (60–100) and at the end 78.9±11.5 (60–100); p=0.666. Patients received 2–10 cycles of treatment. Mean metastasic sites 2.7±1.2; range: 1 to 5; two complete responses, 10.5%; partial 6 (31.5%), response rate 42%, stable 7 and progression 4. Progression free survival 8.5±4.8 months, range 2 to 19. Overall survival 10.4±6.8 mos, two to 23. Forteen patients have died with tumor (73.6%), 4 are alive with tumor (21%); and only one is alive without tumor. We did not identify relationship between tumor response and immunohistochemical factors, c-erbB-2, p=0.519;p53, p=0.519; estrogen receptor, p=0.236 and progesterone receptor; p=0.673. Side effects were observed in 9, thrombocytopenia grade I-II in 5 patients, neutropenia grade I-II in 7 and anemia grade II-III in 3. Nausea, vomiting, dysuria and alopecia in two patients.Gemcitabine is active in heavily pretreated advanced breast cancer patients showing low grade side effects. Apparently, there is not relationship between tumor response and immunohistochemical factors.

Single-agent oxaliplatin in pretreated advanced breast cancer patients: A phase II study

Oxaliplatin (L-OHP), a new platinum analogue, is an active drug in colorectal and ovarian cancer. In this phase II study we explored tolerability and activity of oxaliplatin as a single agent in metastatic breast carcinoma patients. Fourteen anthracycline pretreated advanced breast cancer patients were enrolled. Oxaliplatin was given at 130 mg/m2 on day 1 and repeated every three weeks. Analysis of toxicity, response rate and survival was performed. The median number of courses per patient was four (range 2 6). The median administered dose-intensity was 43.3 mg/m2/week (range 32.5-43.3) which represents 100% of projected dose-intensity. No severe toxicity was encountered. Three patients developed acute transient laryngeal symptoms. Three patients displayed a partial response (21%), (95% confidence interval (CI): 0%-43%), two stable disease (14%) and nine progressed (64%). Response lasted five, four and five months respectively. Median survival was 12 months. In this limited experience, oxaliplatin appeared to be well tolerated and moderately active in advanced anthracycline-pretreated breast cancer patients. Combination chemotherapy with other active drugs such as 5-fluorouracil (5-FU), anthracyclines and taxanes should represent the next step of development of this new drug.

Weekly docetaxel plus gemcitabine or vinorelbine in refractory advanced breast cancer patients: A parallel dose-finding study

The objective of this study was to determine the docetaxel MTD when combined with gemcitabine or vinorelbine in advanced breast cancer patients who had received previous anthracycline-based chemotherapy for advanced disease. Advanced breast cancer patients aged between 18 and 70 with ECOG PS 0-2 who had not responded to, or had relapsed after, first-line anthracycline-based chemotherapy, were randomized to receive either gemcitabine 1000 mg/m2 or vinorelbine 25 mg/m2 in combination with escalating doses of docetaxel (starting from 30 mg/m2), all on days 1 and 8 every three weeks. Escalation was stopped if > 33% of patients treated at a given dose level showed DLT at the first cycle. A total of 34 patients with locally advanced (8) or metastatic disease (26) were treated, for a total of 94 cycles delivered. Nineteen patients received docetaxel in combination with gemcitabine and 15 with vinorelbine. All patients had been pretreated with anthracyclines, and 24 of 34 had also received weekly dose-dense paclitaxel. A docetaxel dose of 40/m2 proved to be safe when combined on days 1 and 8 with gemcitabine, while a dose of 35 mg/m2 was tolerated in combination with vinorelbine. Overall, nine episodes of DLT, all of them neutropenia, occurred at the first cycle. Considering all 94 cycles, grades 3 or 4 neutropenia and thrombocytopenia occurred in 15 (44%), and 7 (20%) patients. Non-hematologic toxicity was mild, except for three cases of grade 2 peripheral neuropathy. All patients were assessed for response on an 'intent-to-treat' basis. Overall, five partial responses were recorded (docetaxel + gemcitabine = 3 and docetaxel + vinorelbine = 2), for a 15% (95% CI: 5%-31%) overall response rate. Only 1 of 24 (4%) patients who had received weekly dose-dense paclitaxel responded to treatment. The weekly docetaxel administration in combination with either gemcitabine or vinorelbine is a well-tolerated treatment for heavily pretreated advanced breast cancer patients. This approach, although sometimes capable of achieving a major response, does not seem advisable in advanced breast cancer patients refractory to both anthracyclines and paclitaxel.

Efficacy and safety of docetaxel (Taxotere™) in heavily pretreated advanced breast cancer patients: the French compassionate use programme experience

The aim of this investigation was to assess retrospectively docetaxel safety and efficacy in advanced breast cancer patients in a French compassionate use programme. Patients had received >1 prior chemotherapy regimen for advanced disease, were either anthracycline-resistant (that is progressed within 6 months after anthracycline-based chemotherapy) or had received the maximum cumulative dose. The recommended docetaxel dose was 100 mg/m 2/cycle (75 mg/m 2 in case of liver function impairment: transaminases >1.5×upper limit of normal (ULN), alkaline phosphatases >3×ULN). Between August 1993 and December 1995, 889 patients were treated in 67 French centres, of whom 870 were evaluable for safety and 825 were evaluable for patient and treatment characteristics and efficacy. 20.5% (of the 825 patients evaluable for baseline characteristics) had poor performance status (PS≥2), 49.3% liver metastasis and 9.6% biological liver dysfunction. 98.4% had been previously treated by anthracyclines, 50.8% had resistant disease and 37.1% had received >2 prior palliative chemotherapy lines. The most frequent severe toxicity, febrile neutropenia (reported in 223/870 (25.6%) patients evaluable for safety), caused 10 deaths, 6 of these being patients with severe liver impairment before inclusion. Fluid retention syndrome and other common non-haematological toxicities were well tolerated. 3.1% (28/889) of all patients and 11.4% of those with liver dysfunction, died from treatment-related causes. The overall response rate in 825 assessable patients was 22.9% (95% confidence interval (CI): 20.2–26.2%). Median time to treatment failure was 4 months (95% CI: 3.6–4.3) and median survival was 9.8 months (95% CI: 8.8–10.7). This report on the largest series of unselected advanced breast cancer patients treated with docetaxel, supports previous phase II studies, confirming docetaxel's utility in patients relapsing after failing anthracycline-containing palliative chemotherapy.

P909. VNB and 5FU prolonged infusion in pretreated advanced breast cancer patients

P909. VNB and 5FU prolonged infusion in pretreated advanced breast cancer patients