Taxane-pretreated Metastatic Breast Cancer Research Articles

Gemcitabine and Vinorelbine Combination Chemotherapy in Anthracycline- and Taxane-pretreated Advanced Breast Cancer

Anthracycline and taxanes are effective agents in advanced breast cancer and prolong survival times. Some patients achieve prolongation of life with capecitabine, gemcitabine, or vinorelbine, even after failure of both anthracycline and taxanes. We analyzed the efficacy and toxicity of gemcitabine and vinorelbine combination chemotherapy in anthracycline- and taxane-pretreated advanced breast cancer. The medical records of anthracycline- and taxane-pretreated metastatic breast cancer patients who received gemcitabine and vinorelbine combination chemotherapy at the Seoul National University Hospital were reviewed. Gemcitabine (1,000 mg/m(2)) and vinorelbine (25 mg/m(2)) were administered intravenously on days 1 and 8 every 3 weeks. Between 2000 and 2006, 57 patients were eligible (median age, 45 years), and the median number of previous chemotherapy regimens was 3 (range, 1 approximately 5). The overall response rate was 30% (95% CI, 18.1 approximately 41.9), and the disease control rate was 46% (PR, 30%; SD, 16%). The median duration of follow-up was 33.4 months, the median time-to-progression (TTP) was 3.9 months, and the median overall survival was 10.8 months. None of the patients with patients with anthracycline and taxane primary resistance showed a response and the median TTP for these patients was significantly shorter than that of other patients (1.9 vs. 4.4 months; p=0.018). Although the efficacy was unsatisfactory in patients with both anthracycline and taxane primary resistance, gemcitabine and vinorelbine combination chemotherapy showed comparable efficacy in anthracycline- and/or taxane-sensitive patients and the patients with secondary resistance, even after failure of second-line therapy. Grade 3/4 hematologic toxicities included neutropenia (18.1%) and febrile neutropenia (0.3%), and non-hematologic toxicities were tolerable. Gemcitabine and vinorelbine combination chemotherapy in anthracycline- and taxane-pretreated advanced breast cancer was effective and tolerable.

Biweekly administration of gemcitabine and cisplatin chemotherapy in patients with anthracycline and taxane-pretreated metastatic breast cancer

Gemcitabine and cisplatin are the active agents in metastatic breast cancer pretreated with anthracycline and/or taxane as a second line treatment. The present study was designed to assess the efficacy and safety of this regimen given biweekly schedule in these patients. Twenty-seven women, median age 57, with metastatic breast cancer previously treated with anthracycline and taxane were eligible for enrollment. Gemcitabine was administered intravenously on days 1 and 15 at a dose of 2,000 mg/m(2) and Cisplatin was given intravenously on day 1 and 15 at a dose of 50 mg/m(2). Treatment cycles were repeated on an outpatient basis every 28 days. Of all 27 evaluable patients, the overall response rate was 26% (7 of 27; 95% CI: 11-46%) with seven all partial responses. The stable diseases were found in 9 (33%) patients. At the time of last follow-up, 11 (41%) of the patients died of their disease progression. The median overall survival duration was 7.4 +/- 2.8 months. The 1-year overall survival rate was 46.9% +/- 12.3. Hematological toxicity was not found as the principal dose-limiting toxicity. Severe (grade III/IV) neutropenia was observed only one (4%) patients. No patient was complicated by febrile neutropenia and G-CSF usage was not performed. Grade III and IV anemia were seen in only 4 (15%) and thrombocytopenia was noted only one (4%) patients. Severe hepatic (n = 2) and renal toxicity (n = 1) were observed and these all recovered completely without complication. Several other severe non-hematological side effects were managed easily. Permanent dose reductions were necessary in 9 (33%) patients and chemotherapy administration was also delayed in 7 (26%) patients because of delayed both hematological and non-hematological toxicity recovery. Treatment was discontinued in one (4%) patient due to severe fatigue and deteriorating performance status. In conclusion, gemcitabine and cisplatin combination therapy with this biweekly schedule and dosage is moderately active and extremely safe in patients with metastatic breast cancer previously treated with anthracycline and taxanes.

Anti-tumor activity of capecitabine and vinorelbine in patients with anthracycline- and taxane-pretreated metastatic breast cancer: Findings from the EORTC 10001 randomized phase II trial

The aim of this randomized phase II study was to evaluate the anti-tumor activity and safety of capecitabine and vinorelbine in patients with metastatic breast cancer pretreated with taxanes and anthracyclines. We planned to randomize 72 patients to capecitabine 1250 mg/m 2 orally bid days 1–14 or vinorelbine 30 mg/m 2 i.v. days 1 and 8, both given every 3 weeks. The study was stopped due to poor accrual with 47 patients enrolled. Responses were seen in 2/23 patients treated with capecitabine (8.7%; 95% CI 1.1–29.0) and 3/24 patients treated with vinorelbine (12.5%; 95% CI 2.7–32.4). Median progression-free survival was 2.8 and 2.6 months, and median overall survival was 9.3 and 11.0 months, in the capecitabine and vinorelbine arms, respectively. There was more hematologic toxicity, neurotoxicity, and nausea/vomiting with vinorelbine and more diarrhea and hand-foot syndrome with capecitabine. The anti-tumor activity of capecitabine and vinorelbine seems to be comparable, but the toxicity profiles are different.

Weekly administration of bendamustine as salvage therapy in metastatic breast cancer: final results of a phase II study

Single-agent bendamustine has shown promise in the treatment of metastatic breast cancer. As toxicity was low after weekly administration of this drug in other solid tumors, the present double-center phase II trial was conducted to evaluate the efficacy and toxicity of weekly bendamustine as salvage treatment in metastatic breast cancer. A total of 34 patients with anthracycline (88%) and/or taxane (71%) pretreated for metastatic breast cancer received 60 mg/m bendamustine on day 1, 8 and 15 every 28 days for six cycles. In addition, 10 patients with HER2/neu-overexpressing tumors either continued (five patients) or started treatment with 2 mg/kg trastuzumab weekly (loading dose 4 mg/kg) at study entry. Patients had predominantly visceral disease and had received one (88%) or two chemotherapy regimens for metastatic breast cancer. All patients were eligible for toxicity and 27 for response evaluation. No grade 3 or 4 hematologic toxicity occurred. Only three patients experienced grade 3 nonhematologic toxicity. Five patients (19%) reached a partial response. Stable disease for at least 6 months was achieved in eight patients, for a clinical benefit rate of 48%. The median progression-free survival and median overall survival were 6 months (range, 1-16) and 15 months (range, 2-28), respectively. We conclude that weekly bendamustine is a valid treatment option in patients with anthracycline-pretreated and/or taxanepretreated metastatic breast cancer; in particular, due to its low toxicity profile. Future trials should evaluate higher single doses of bendamustine in a weekly schedule.

Combination chemotherapy with gencitabine and cisplatin in anthracycline and taxane pretreated metastatic breast cancer

1108 Background: Metastatic breast cancer (MBC) anthracycline (A) and taxane (T) resistant has a complicated management.Combination chemotherapy, even in 2nd line, may have advantages over single agent therapy. Gencitabine (G) - cisplatin (C) combinations have been used as synergistic salvage therapy in MBC and it’s another option for patients with important symptoms and aggressive visceral disseminated disease. Methods: This trial analyses the safety and efficacy of G-C in A-T pretreated MBC. Eligibility criteria include: confirmatory pathological analyses; measurable disease; adequate performance status, organ and hematological functions. It was not allowed patients with exclusive bone metastasis. They received IV G 750mg/m2 and C 30mg/m2, both d1 and d8 every three weeks for 6 cycles up to a maximum of 9 cycles. Response evaluation was performed every third cycle and in the end of treatment. Results: From February 2005 through December 2006, 31 patients have been evaluated for response and toxicity from G-C combination. For 20/31 patients this treatment was 2nd line palliative chemotherapy. 26/31 received at least 3 or more cycles (medium 4 cycles) and no one treatment was discontinued due to toxicity. The most frequent site of metastasis was lung (20/31), followed by hepatic in 13 patients, bone in 11, skin in 10, lymph nodes in 7, brain metastasis in 3 and pericardium in only one. Each patient had at least lung or hepatic metastasis and medium of 2 different metastatic sites. According to RECIST criteria, partial response were observed in 8/31, stable disease in 17/31 (55%) and progressive disease in 6 patients. 90% of cycles were given at full dose and at the right time. Hematological toxicity was modest with grade 2–3 (NCI-CTC) leucopenia in 58/140 cycles, grade 1–2 anemia in 40/140, grade 1–2 thrombocytopenia in 27/140 and was none febrile neutropenia. Non hematological toxicity: grade 2 fatigue in 4 patients and grade 2 nausea in 6/31. Following 22 months, global survival was at mean 4.8 months. Conclusions: Combination chemotherapy with gencitabine 750mg/m2 and cisplatin 30mg/m2 both d1 and d8 is feasible and effective in A-T pretreated MBC and demonstrated good tolerance with low intensity of collateral effects. No significant financial relationships to disclose.

Efficacy of Lower Dose Capecitabine in Patients with Metastatic Breast Cancer and Factors Influencing Therapeutic Response and Outcome

Capecitabine exerts considerable therapeutic efficacy in metastatic breast cancer (MBC) patients previously treated with anthracyclines and taxanes. In this study, the efficacy and safety of lower dose capecitabine (2000 mg/m(2)/d) in patients with anthracycline- and taxane-pretreated MBC were studied with a special emphasis on the potential predictors of time to tumor progression (TTP) and response to the capecitabine treatment. The overall response rate (ORR) was 17%. The median TTP was 5 months. Among various factors analyzed, univariate analysis showed that a performance status (PS) of 2 and the presence of visceral metastases were inversely correlated with TTP. Multivariate analysis showed that a poor PS score was associated with impaired TTP. Our study indicates that lower dose capecitabine has substantial antitumor activity and a favorable safety profile in the treatment of anthracycline- and taxane-pretreated MBC. Also, only performance score was demonstrated to be a significant parameter affecting TTP.

European Organization for Research and Treatment of Cancer – Breast Cancer Group (EORTC BCG)

This section provides current contact details and a summary of recent or ongoing clinical trials being coordinated by European Organization for Research and Treatment of Cancer – Breast Cancer Group (EORTC BCG). Clinical trials include: Postoperative adjuvant chemotherapy followed by adjuvant tamoxifen versus nil for node-negative and node-positive patients with operable breast cancer. EORTC Study No. 10901Randomized phase III study comparing short, intensive preoperative combination chemotherapy with similar therapy given postoperatively. EORTC Trial No. 10902Phase III randomized trial investigating the role of internal mammary and medial supraclavicular (IM-MS) lymph node chain irradiation in stage I–III breast cancer (joint study of the EORTC Radiotherapy Cooperative Group and the EORTC Breast Cancer Cooperative Group). EORTC Study No. 10925/22922A survey of the Breast International Group (BIG) to assess the attitude of patients aged <35 years, with early breast cancer, toward the risk of loss of fertility related to adjuvant therapies. BIG 3-98/EORTC 10002LAMANOMA: Conservative local treatment versus mastectomy after induction chemotherapy in locally advanced breast cancer: a randomized phase III study. BIG 2-00/EORTC Study No. 10974/22002p53 study: First prospective intergroup translational research trial assessing the potential predictive value of p53 using a functional assay in yeast in patients with locally advanced/inflammatory or large operable breast cancer, prospectively randomized to a taxane versus non-taxane regimen. BIG 1-00/EORTC 10994After mapping of the axilla: radiotherapy or surgery AMAROS. EORTC 10981/22023A randomized phase II–III trial evaluating the efficacy of capecitabine and vinorelbine in anthracycline and taxane pretreated metastatic breast cancer. EORTC 10001/160010Phase I study of lonafarnib (SCH 66336) in combination with Herceptin plus paclitaxel in HER-2 neu overexpressing breast cancer. EORTC 10051/16023MINDACT trial: A prospective, randomized study comparing the Amsterdam 70-gene expression signature (Mammaprint) with common clinical pathological criteria in selecting patients for adjuvant chemotherapy in node-negative breast cancer. BIG 3-04/EORTC 10041

A phase II study of an oxaliplatin/vinorelbine/5-fluorouracil combination in patients with anthracycline-pretreated and taxane-pretreated metastatic breast cancer

The aim of this phase II study was to evaluate safety and efficacy of an oxaliplatin/vinorelbine/5-fluorouracil (FON) combination in anthracycline and taxane-pretreated metastatic breast cancer patients. The following treatment was given: on day 1 of a 21-day cycle, oxaliplatin 130 mg/m (2-h intravenous infusion); on days 1 and 5, vinorelbine [dose level (DL) 1: 17.5 mg/m; DL2: 22 mg/m]; on days 1-5, continuous infusion 5-fluorouracil (DL1: 600 mg/m/day; DL2: 750 mg/m/day). Forty-seven patients were treated (DL1: 43; DL2: 4). Median age was 54 years; 68% had liver metastases, 53% were taxane refractory/resistant and 38% were anthracycline refractory/resistant. Patients received a median of six treatment cycles. Of 46 eligible patients, 16 had partial response; the overall response rate was 34.8% (95% confidence interval 21.3-50.3%), 11 had stable disease lasting more than 4 months. Median follow-up was 13.0 months, median time to progression 5.7 months and estimated overall survival 18.8 months. DL2 was too toxic with three patients having grade 3-4 toxicity, including one death. At DL1, 26 patients (60%) experienced grade 3-4 neutropenia (six febrile neutropenia) and eight had grade 3 oxaliplatin-specific peripheral neuropathy after a median of 646.4 mg/m oxaliplatin (range 124-1619 mg/m). Oxaliplatin (130 mg/m, day 1)/vinorelbine (17.5 mg/m, days 1,5)/5-fluorouracil (600 mg/m/day, days 1-5) demonstrate encouraging activity and a manageable safety profile in anthracycline- and taxane-pretreated metastatic breast cancer patients.

Long median survival with capecitabine (X) single-agent therapy for patients (pts) with anthracycline- and taxane-pretreated metastatic breast cancer (MBC)

10710 Background: X (Xeloda) is an oral fluoropyrmidine with consistently high activity in MBC, a good safety profile with little myelosuppression and no alopecia, and the convenience of oral administration. The addition of X to docetaxel in anthracycline-pretreated pts also increases survival. This non-randomized phase II study was conducted to evaluate the efficacy, safety and impact on quality of life (QoL) of X in pts with MBC pretreated with anthracyclines and taxanes. Main findings from this trial have been published previously [Fumoleau et al. Eur J Cancer 2004;40:536–42]. Here we present mature data after a follow-up of 48 months. Methods: Pts with anthracycline- and taxane-pretreated MBC received X 1250 mg/m2 twice daily on days 1–14 every 3 weeks for a median of 6 cycles (range 1–15). Results: Baseline characteristics of the 126 pts enrolled were typical of a pretreated MBC population. X achieved complete/partial response or stable disease in 63% of patients (overall response rate, 28%). Median time to progression was 4.9 months (95% CI: 4.0–6.4).Median duration of response was 5.9 months (95% CI: 4.5–12.7). The only grade 3/4 events occurring in ≥ 10% of patients were diarrhea (10%) and HFS (21%). The most common grade 3/4 laboratory abnormality was granulocytopenia (14%). After a follow-up of 48 months, 8 patients are still alive. Updated median overall survival is 15.9 months (95% CI: 13.5–21.3). 1-, 2- and 3-year survival rates are 63%, 37% and 17%, respectively. QoL assessment showed that X treatment was associated with an increase in mean Global Health Score up to cycle 6, with the increase maintained at subsequent evaluations. Conclusions: X is highly active in patients with anthracycline- and taxane-pretreated MBC, leading to a long median survival of 15.9 months. X is also well tolerated and improves QoL. [Table: see text]

Quality of life (QoL) improvements in 1,464 patients (pts) with metastatic breast cancer (MBC) receiving capecitabine (X) in Brazil: Updated results from a large pt cohort, including analysis as a function of pts’ ECOG PS

8599 Background: The oral fluoropyrimidine capecitabine is highly active and well tolerated as single-agent therapy and extends survival when added to docetaxel in pretreated MBC. QoL data would enhance understanding of X’s pt benefits. Methods: QoL was evaluated in women with anthracycline ± taxane-pretreated MBC while receiving X (baseline, before cycle 1, at weeks 7 and 13, and at treatment end) using EORTC QLQ C-30 (v3.0) and BR-23 questionnaires. We used linear models with repeated measures (generalized estimating questions technique) and SAS (v8.2) to determine improvement, stabilization or worsening of QoL scores from week 7 onwards. Each questionnaire item was analyzed as a function of pts’ ECOG status before first cycle and the evaluation periods. Results: Baseline characteristics of the 1,464 evaluable pts were: median age 54 years (range 22–92); 42% had ECOG 0. As expected, pts with worse initial PS (ECOG ≥2) had lower mean scores during treatment. Regardless of baseline ECOG score, X therapy was associated with significant (p<0.0001 unless stated) improvements in pts’ perception of: role functioning (p=0.001), pain, nausea/vomiting, fatigue, constipation, emotional functioning, and global health status. Capecitabine was also associated with significant improvements in pts’ perception of systemic therapy side effects (p<0.0001), breast symptoms (p<0.0001), arm symptoms (p=0.0047), hair loss (p<0.0001), and future perspective (p<0.0001). Conclusions: Pts receiving X had substantial improvements in almost all functional and symptomatic QoL domains. These findings highlight the importance of considering QoL and other measurable benefits of oral treatments alongside well-established measures of clinical evaluation in pts with metastatic disease. The QoL benefits, together with other proven clinical outcomes, suggest that early use of X in MBC would be of benefit to pts. No significant financial relationships to disclose.

Weekly Cisplatin plus Capecitabine in Metastatic Breast Cancer Patients Heavily Pretreated with both Anthracycline and Taxanes

Background: Treating patients with anthracycline- and taxane-pretreated metastatic breast cancer is challenging. This study evaluated the activity and safety of a combination of cisplatin and capecitabine in this setting. Patients and Methods: Thirty-nine consecutive patients entered the study. All had experienced failures or relapse after previous treatment with anthracyclines and taxanes plus/minus other chemotherapeutic regimens. The present treatment consisted of intravenous cisplatin 20 mg/m² every week for 6 weeks, followed by 1 week of rest, and oral capecitabine 1,000 mg/m² twice daily for 14 days, followed by a 7-day rest period. Results: Objective response was obtained in 14 patients (35.9%), with complete remission in 3 (7.7%). Median time to progression was 5.2 months and survival was 10.9 months in the entire population and 8.7 and 16.5 months in the responding patients, respectively. The dose-limiting toxicity for the regimen was leucopenia, while gastrointestinal discomfort was the most frequent cause of capecitabine reduction or delay. Conclusions: The cisplatin and capecitabine combination regimen is active and manageable. It seems to be non-cross resistant to anthracyclines and taxanes.

High efficacy of gemcitabine and cisplatin in patients with predominantly anthracycline- and taxane-pretreated metastatic breast cancer

Effective and tolerable regimens are sought specifically in patients who have been pretreated with anthracyclines and taxanes. Gemcitabine and cisplatin demonstrated synergistic activity in vitro and provides a new mechanism of drug interaction. Previously treated patients with metastatic breast cancer (MBC) were enrolled in a multicentre phase II study. Treatment consisted of gemcitabine (750 mg/m(2)) and cisplatin (30 mg/m(2)) given on day 1 and 8 every 3 weeks. Thirty-eight patients were recruited, all of whom had previously received chemotherapy (35 pretreated with taxanes, 33 pretreated with anthracyclines). A median of 5 cycles of the study treatment was delivered. There were 2 complete and 13 partial responses, for an overall response rate of 40% (95% confidence interval: 23-56%). Thirteen patients (35%) had stable disease. Tumour response appeared independent of previously applied chemotherapy. Median time-to-progression was 6 months and median overall survival was 13.5 months. Main toxicities were leucopenia and thrombocytopenia (grade 3/4 in 26 and 16% of cycles, respectively). Non-haematological toxicity was rarely severe. Combination chemotherapy with gemcitabine and cisplatin given on 2 out of 3 weeks is well tolerated and active in heavily pretreated patients with MBC, even after prior exposure to anthracyclines and taxanes.

Gemcitabine as prolonged infusion and vinorelbine in anthracycline and/or taxane pretreated metastatic breast cancer: a phase II study

Gemcitabine and vinorelbine are active agents for the treatment of metastatic breast cancer. Prolonged infusion of gemcitabine can result in higher levels of active metabolites compared to shorter administration. This phase II trial was initiated to evaluate the efficacy and tolerability of gemcitabine as prolonged infusion in combination with vinorelbine in anthracycline and/or taxane pretreated patients with metastatic breast cancer. Patients who had received one prior line of chemotherapy for metastatic disease were treated with gemcitabine (350 mg/m2 as 4 h infusion) and vinorelbine (25 mg/m2 on days 1 and 8. Treatment was repeated every 3 weeks for a maximum of six cycles. Of 26 patients enrolled, 84% had received prior anthracycline treatment and 50% prior taxane therapy. In total, one complete and six partial responses were achieved, accounting for an overall response rate of 30.4%. The clinical benefit rate was 47.8%. Median duration of response and median time to progression were 7.3 months and 4.6 months, respectively. Median overall survival was 14.5 months. Although the predominant toxicity was myelosuppression with grade 3/4 neutropenia in 42% of patients, few neutropenic complications resulted. Non-hematological toxicity was generally moderate. Most common non-hematologic toxicities were nausea, vomiting, alopecia, peripheral neuropathy and elevation of liver enzymes. Gemcitabine as prolonged infusion and vinorelbine are a safe and effective combination treatment in anthracycline and/or taxane pretreated patients. Approximately 47.8% of patients derived clinical benefit from treatment. This regimen represents a therapeutic option for patients receiving second-line therapy for metastatic breast cancer.

Phase II trial of KOS-862 (epothilone D) in anthracycline and taxane pretreated metastatic breast cancer

778 Background: KOS-862 (K) is genetically-produced epothilone D, a naturally occurring macrolide. K has preclinical activity in multiple breast cancer models, including taxane-resistant cell lines. A phase II trial was implemented to determine antitumor activity of K in women with anthracycline (A) and taxane (T) pretreated metastatic breast cancer (MBC). Methods: Pts with MBC + A & T treatment failure are eligible. Treatment failure is defined as disease progression after receipt of both A and T (adjuvant or metastatic setting) or inability to tolerate these agents (toxicity). All pts are ECOG 0–1. Pts with baseline neuropathy > gr 1 or CNS metastases are excluded. K administered as 100 mg/m2 iv over 90 min wkly x 3 Q 4 wks. H1 + H2 antagonists & corticosteroids are given 30–60 min before K as infusion reaction prophylaxis. PK sampling for K + its seco-metabolite collected up to 48 hr post C1D1. Results: 12 women (10 evaluable) have received K. Mean number of K cycles 2.6 (1–6). Three pts had > 4 K cycles. Two pts have had confirmed PR, including 1 pt with hepatic-metastases who had > 50% tumor reduction & normalization of CA 27–29. This pt’s prior treatments include adjuvant AC+T and 6 mo. docetaxel for metastatic disease shortly before trial entry. K-related toxicities (event/grade-#pts) include: peripheral neuropathy (1–2, 2–4, 3–1), paresthesia/hypoesthesia (1–4, 2–1), ataxia (2–1, 3–1), cognitive disorder (2–1), dizziness (1–2), diarrhea (1–4), nausea (1–2), anorexia (2–1), flushing (1–1, 2–1), & fatigue (1–4). Several pts with neurotoxicity (including responders) have been successfully retreated with K dose reduction (75 mg/m2). PK: mean KOS-862 Cmax 4.6±3.0 μg/mL, AUCinf 26 ± 31 h•μg/mL, Vz 196 ± 137 L and T1/2 12 ± 5 hr. Seco-metabolite 39±25% of K. Conclusions: Initial phase II results demonstrate encouraging antitumor activity for K (2 of 10 eval pts) in A & T pretreated MBC. Pts with K toxicities have been successfully retreated with 25% dose reduction. Accrual is anticipated to 53 evaluable pts in order to determine the antitumor activity of K in MBC. Updated response & PK data will be presented. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Hoffmann-La Roche Hoffmann-La Roche

Quality of life (QoL) improvements in patients (pts) with metastatic breast cancer (MBC) receiving capecitabine (X)

8036 Background: The oral fluoropyrimidine X is highly active and well tolerated as single-agent therapy and extends survival when added to docetaxel in MBC. In addition to response rates and survival times, pt preference for oral therapy and QoL are increasingly important considerations in MBC. QoL data would add to understanding the pt benefits of X. Methods: QoL was evaluated in women with anthracycline +/- taxane-pretreated MBC while receiving X (baseline, before cycle 1, at weeks 7 and 13, and at treatment end) using EORTC QLQ C-30 (v3.0) and BR-23 questionnaires. We used linear models with repeated measures (generalized estimating questions technique) and SAS (v8.2) to determine improvement, stabilization or worsening of QoL scores from week 7 on onwards. Results: Baseline characteristics of the 907 evaluable pts were: median age 53 years (range 22–90), median ECOG PS 1 (range 0–4), and most pts (82%) were Caucasian. Of these, at least 70% had stable or improved QoL for most scales during X treatment, including functional QoL (QLQ C-30 and QLQ BR-38) and symptomatic QoL (QLQ C-30). Pts receiving X also had a significant, sustained improvement (p<0.0001 unless stated) in the following: global health status; role and emotional functioning; social functioning (p=0.0054); fatigue (p=0.0002); nausea/vomiting; pain; insomnia; appetite loss; constipation; diarrhea (p=0.0005); financial problems; body image; future perspective; systemic therapy side effects; breast symptoms; arm symptoms (p=0.0006); and hair loss. Conclusions: Pts receiving X had a significant and sustained improvement in global health status, with substantial improvements in almost all functional and symptomatic QoL domains. These findings highlight the importance of considering QoL and other measurable benefits of oral treatments alongside well-established measures of clinical evaluation in pts with metastatic disease. The QoL benefits, together with other proven clinical outcomes, suggest that earlier use of X in MBC would be of benefit to pts. No significant financial relationships to disclose.

Lower dose capecitabine has a more favorable therapeutic index in metastatic breast cancer: retrospective analysis of patients treated at M. D. Anderson Cancer Center and a review of capecitabine toxicity in the literature

Capecitabine is active against anthracycline- and taxane-pretreated metastatic breast cancer. Post-marketing use of capecitabine at the FDA-approved dose (2500 mg/m2/day) leads to unacceptable toxicity in many patients. Dose reductions anecdotally improve tolerability without compromising efficacy. This retrospective analysis was designed to verify these anecdotal reports. We retrospectively reviewed the records of 141 consecutive patients with metastatic breast cancer identified from pharmacy records as receiving capecitabine outside of a clinical trial between May 1998 and February 1999. Responses were defined as clinical improvement (ID), stabilization of disease (SD) for 6 weeks or longer, or progression (PD). Patients were grouped according to the starting dose level of capecitabine: A=2500+/-5% (dose range 2385-2560) mg/m2/day; B=2250+/-5% (range 2130-2350) mg/m2/day; C < or = 2000+5% (range 1000-2100) mg/m2/day. We also reviewed the safety profile of capecitabine at these doses and performed a safety review of capecitabine in phase II and III metastatic breast and colorectal cancer trials. Clinical data were available for 113 patients (105 for response, 106 for toxicity). The median age was 52.5 years and the mean number of prior metastatic chemotherapy regimens was 2 (range 0-7). The mean capecitabine starting dose was 2220 mg/m2/day and the median number of cycles administered was 4 (range 1-19). The mean tolerated dose was 2040 mg/m2/day (range 960-2670). Grade 3/4 toxic effects at dose levels A, B and C, respectively, included palmar-plantar erythrodysesthesia (33%, 63%, 20%), diarrhea (13%, 12%, 3%), stomatitis (8%, 0%, 3%), and nausea/vomiting (4%, 6%, 5%). Forty per cent of all patients required capecitabine dose reductions; fewer patients treated with 2000 mg/m2/day required dose modification (28%). Five per cent of the patients required discontinuation of capecitabine owing to toxicity. Patients started at the lowest doses of capecitabine did not have poorer response rates or shorter time to progression. This retrospective analysis supports a starting dose of 2000 mg/m2/day because of its superior therapeutic index; however, patients may still have toxic effects and individualization of dosing is necessary. A phase III, multicenter, randomized study to establish the safety and efficacy of different doses of capecitabine is urgently needed.

A Phase II Trial of Gemcitabine in Patients with Metastatic Breast Cancer Previously Treated with an Anthracycline and Taxane

Purpose This study was designed to evaluate the efficacy and safety of single-agent gemcitabine for the treatment of patients with anthracycline- and taxane-pretreated metastatic breast cancer (MBC). Eligible patients were required to have bidimensionally measurable MBC that had been treated with 2–4 prior chemotherapy regimens that included an anthracycline and a taxane. Gemcitabine was delivered at a dose of 800 mg/m 2 on days 1, 8, and 15 of a 28-day cycle until evidence of disease progression. Patients and Methods Twenty-two patients were enrolled and included in the safety analysis; 18 patients were evaluable for response. The median age of patients was 54 years (range, 36–70 years). The mean number of prior chemotherapy regimens for metastatic disease was 2.3, and the mean dose of gemcitabine delivered was 911 mg/m 2(range, 600–1600 mg/m 2). Results Overall, gemcitabine was well tolerated with minimal grade 3 toxicities; the only grade 4 toxicity was 1 case of pulmonary embolus. Three patients had evidence of partial tumor regression (17%; 95% CI, 4%–41%), and 1 patient had a 41% decrease in tumor volume, including liver metastasis. Conclusions Gemcitabine is active and well tolerated as monotherapy given in heavily pretreated patients with MBC after anthracyclines and taxanes. The activity and safety reported in this trial are consistent with previous reports in similar patients.

Gemcitabine-taxane experience in the treatment of metastatic breast cancer

Management of metastatic breast cancer (MBC) is difficult and overall response rates (ORR) resulting from anthracycline and taxane-based regimens remain modest. The antimetabolite drug gemcitabine has been shown to have high activity when used as first-line treatment of MBC, particularly when incorporated into combined therapy regimens. Gemcitabine-containing regimens have also been used successfully as salvage therapy in women with anthracycline or taxane-pretreated MBC. Phase II clinical studies have demonstrated high ORR with gemcitabine-docetaxel (ORR: 36-65.5%) and gemcitabine-paclitaxel (ORR: 40-68%) combination regimens. A highly favourable risk-benefit ratio has also been reported for gemcitabine-containing triplets such as gemcitabine-paclitaxel-epirubicin (ORR: 92%) and gemcitabine-paclitaxel-doxorubicin (ORR: 80.4%). Gemcitabine-containing regimens have a favourable toxicity profile with few serious toxic events reported. An important step forward in the evaluation of novel chemotherapeutic regimes for MBC is establishing a correlation between disease markers and response to therapy. Preliminary data suggest that there is a close relationship between HER2 extracellular domain levels (>30 ng/ml) and treatment outcome. HER2-positive patients had a lower ORR to gemcitabine-paclitaxel chemotherapy than women who were HER2-negative. Further studies to establish a link between other breast cancer markers and predicted response to treatment are warranted.

Capecitabine (X) in elderly patients (pts) with hormone-refractory metastatic breast cancer (MBC)

839 Background: X (Xeloda) is the reference treatment in anthracycline- and taxane-pretreated MBC, based on consistent high activity, a good safety profile with little myelosuppression and no alopecia, and evidence that its addition to docetaxel extends survival. Tolerability and efficacy also make X an interesting drug in elderly pts with hormone-refractory disease. Methods: Between May 2002 and Sep 2003, 18 elderly MBC pts received X 1000 mg/m2 twice daily on days 1–14, every 3 weeks. Study objectives were efficacy and safety of X and its impact on quality of life (QoL), assessed via the Clinical Benefit Response (CBR) every third cycle of treatment. Results: Pt characteristics were: median age 70 years (range 68–73); median ECOG PS 1 (range 0–2); 100% with visceral metastases and 53% with >2 metastatic sites. All pts had received prior adjuvant chemotherapy and at least one previous hormonal therapy for advanced disease. A total of 142 cycles were administered (median 6 cycles per pt). After 3 cycles, 5 pts (28%) showed a partial response (PR), 8 (44%) had stable disease (SD) and 1 had a minor response, resulting in a disease control rate of 78%. Biochemical response (CEA and/or CA 15.3 reduction) was observed in 56% of pts. SD has been maintained in 11 pts after 6 cycles, 5 pts after 9 cycles and 1 after 12 cycles. Treatment was well tolerated, the most common grade 3 events being mucositis (7%) and hand-foot syndrome (7%). There were no grade 3/4 hematological toxicities. All adverse events were easily managed with dose adjustments and supportive therapies as required. As a result, pt compliance was 100% with appreciable benefits in terms of pain and QoL (positive CBR in 56% of pts). Conclusions: These preliminary data indicate that X at this dose is active and well tolerated in elderly pts with hormone-refractory MBC. This dosing regimen also warrants study as first-line treatment in pts with less aggressive MBC who might not be suitable for combination therapy. No significant financial relationships to disclose.

Oral capecitabine in anthracycline- and taxane-pretreated advanced/metastatic breast cancer

An open-label, non-randomized, compassionate-use study was carried out to investigate the effects of oral capecitabine at a dose of 1 250 mg/m2 twice daily on days 1 to 14 every 21 days in anthracycline- and taxane-pretreated advanced/metastatic breast cancer patients. Forty-eight patients were enrolled from April 2000 to December 2001. Twenty-four patients (50%) had metastases to the liver, 18 to bone, 13 to lung, 10 to regional lymph nodes, 8 to pleura, 7 to the thoracic wall, 5 to skin, 3 to the mediastinum, 1 to breast and 1 had metastasis to the abdomen. Thirty-three patients (69%) had metastases to more than one site. Median age of the patients was 55 years (range 35–74). Three patients had an ECOG performance status (PS) of 0, 32 PS 1 and 13 PS 2, respectively. Fourteen patients (29%; 95% CI 16 to 42%) obtained a partial response (PR) while 16 (33%) had stable disease (SD) as the best response, of whom 6 had stabilization for more than 24 weeks. This gives a clinical benefit (PR+SD>24 weeks) of 42% (95% CI 28 to 56). Dose reduction was necessary in 29% of the patients. Median dose reduction was 25%. Grades 2 and 3 hand-foot syndrome (PPE) was observed in 17 patients (36%). Eleven patients experienced grades 2 and 3 gastrointestinal toxicity, and haematological toxicity grade 3 was observed in 3 patients (6%). Median time to progression was 107 days (CI 95% 85 to 129), and median overall survival was 281 days (CI 95% 164 to 398). Third-line, oral capecitabine in anthracycline- and taxane-pretreated metastatic breast cancer appears to be effective and has an acceptable toxicity profile.