Anthracycline-resistant Metastatic Breast Cancer Research Articles

Abstract P5-20-08: Phase II trial of ixabepilone (Ixa) and dasatinib (D) for treatment of metastatic breast cancer (MBC)

Abstract Background: Ixa is a novel semi-synthetic epothilone microtubule blocking agent with activity in taxane and anthracycline-resistant MBC. D is a potent small molecule tyrosine kinase inhibitor with substantial activity against SRC family non-receptor kinases, known to play multiple roles in promoting tumor growth and metastases. D inhibits cellular SRC autophosphorylation in cell lines that highly express SRC and inhibits in vivo activation in a broad array of tumors in nude mice. Ixa and D have synergistic effects in preclinical models suggesting this strategy would be of clinical benefit as combination therapy. A phase I trial of the combination determined the maximally tolerated doses of ixabepilone at 20 mg/m2 weekly and dasatinib 100 mg po daily with objective responses seen. Neutropenia was the dose limiting toxicity. Methods: Multicenter single arm phase II trial. Eligibility: Measurable or evaluable disease by RECIST 1.0, ECOG PS 0–2, HER2− or HER2 refractory, no CYP 3A4 inducers or inhibitors, no H2 blockers or PPIs, no pleural/pericardial effusion, exposure to 1 or 2 prior lines of chemotherapy in the metastatic setting, peripheral neuropathy ≤ grade 1. The primary endpoint was progression-free survival (PFS). Assessment for response was performed every 8 weeks. The treatment schedule was D at 100 mg po daily starting day 1, and Ixa 20 mg/m2 Day 1, 8, 15 every 28 days (1 cycle). Results: The study met its accrual goal with 50 patients (pts) enrolled on the phase II dosing, including six from the phase I portion. As of May 21, 2012, 47 pts are evaluable. The median age was 55 (range, 34–70), 19 African-American, 46 ECOG PS 0–1, median number of metastatic sites, three. Forty pts had prior taxanes, 24 prior anthracyclines. Median PFS was 6.0 months (95% CI, 2.9–8.0), achieving pre-specified value of interest for further study of the combination. The overall unconfirmed response rate was 14.9% with a clinical benefit rate (CR+PR + stable at 24 weeks) of 25.5%. Six pts continued D monotherapy after eight cycles of Ixa + D. All-grade adverse events (AEs) occurring in >15% of pts included anemia (45%), neutropenia (32%), nausea (51%), vomiting (32%) diarrhea (51%), fatigue (53%), anorexia (25%) dysgeusia (32%), headache (28%), peripheral neuropathy (34%) cough (28%) alopecia (21%) and hypokalemia (19%). Grade 3/4 adverse events occurred in 30 patients, with only four experiencing grade 4 AEs, three neutropenia and one chest pain. No grade 3/4 febrile neutropenia occurred. Grade 3 AEs of interest included two pts with peripheral neuropathy and 1 with pleural effusion. Conclusions: The combination of Ixabepilone weekly + Dasatinib orally daily is an active and well tolerated regimen in pretreated MBC with manageable toxicity. Updated results will be reported. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-20-08.

A multicenter phase II study of TSU-68, an oral multiple tyrosine kinase inhibitor, in combination with docetaxel in metastatic breast cancer patients with anthracycline resistance

TSU-68 is a novel multiple tyrosine kinase inhibitor that inhibits vascular endothelial growth factor receptor-2, platelet-derived growth factor receptor, and fibroblast growth factor receptor. This open-label, non-comparative, multicenter phase II study evaluated TSU-68 in combination with docetaxel in patients with metastatic breast cancer that had relapsed within 1 year despite prior treatment with an anthracycline-containing regimen. TSU-68 was orally administered on days 1-21, and docetaxel was intravenously delivered on day 1. The regimen was repeated every 21 days. Primary endpoint was objective response rate according to the RECIST guidelines version 1.0. TSU-68 in combination with docetaxel produced objective responses in 21.1% and clinical benefits in 42.1% of the patients, respectively (1 complete response, 3 partial response, and 4 stable disease for at least 24 weeks, n = 19). Median time to progression was 148 days, and median overall survival was 579 days. The common adverse drug reactions were leukopenia, neutropenia, nail disorder, malaise, dysgeusia, alopecia, and edema. TSU-68 in combination with docetaxel showed a promising antitumor response with manageable toxicity in patients with anthracycline-resistant metastatic breast cancer. Further studies are warranted in a different population of breast cancer or other solid cancers.

Abstract 4714: Phase I/II trial of ixabepilone (Ixa) and dasatinib (D) for treatment of metastatic breast cancer (MBC)

Abstract Background: Ixa is a novel microtubule blocking epothilone with activity in taxane and anthracycline-resistant MBC. D is a potent small molecule tyrosine kinase inhibitor with substantial activity against SRC family non-receptor kinases, known to play multiple roles in promoting tumor growth and metastases. D inhibits cellular SRC autophosphorylation in cell lines that highly express SRC and inhibits in vivo activation in a broad array of tumors in nude mice. D was safe as a single agent in MBC with modest single agent activity. Ixa and D have synergistic effects in preclinical models suggesting this strategy would be of clinical benefit as combination therapy. Methods: Open label multicenter dose escalation trial determining the maximally tolerated dose (MTD) and the dose-limiting toxicity (DLT) of the combination of Ixa + D followed by a phase II component evaluating efficacy. In phase I, up to four dose range cohorts were planned. In each dose level (DL), three patients (pts) initially enrolled and escalated until > 1/3 pts on a DL exhibited DLT. The MTD was defined at the DL at which < 1/6 pts experienced DLT. Eligibility included MBC previously treated with 1-2 prior lines of therapy, Grade < 1 peripheral neuropathy, ability to take oral medications, HER2- or HER2-directed therapy resistant, ECOG PS 0-2, no pleural/pericardial effusions, QTc interval <450 msec. DL 0 was Ixa 16 mg/m2 IV day 1, 8, 15 of a 28-day cycle with D100 mg QD PO daily. DL 1: Ixa 20 mg/m2; D100 mg QD; DL2: Ixa 20 mg/m2; D140 mg QD. Adverse event grading by CTCAE 3.0. Results: Twelve pts were treated during the phase I portion, 3 at DL 0, 6 at DL 1 and 3 at DL 2. Median age was 52.3, 25% African-American, ECOG 0 three pts, ECOG 1, 9 pts. Prior chemotherapy: 10 received two lines, 2 one line. The MTD was established at DL 1, Ixa 20 mg/m2 day 1, 8, 15, and D 100 mg QD daily Q 28 days. At DL 2, DLT of leucopenia and thrombocytopenia occurred in 2 patients. Grade 3 non-hematologic adverse events occurring in >1 pt included diarrhea in 2 and fatigue in 2. No grade 4 non-hematologic toxicity was seen. One pt developed grade1 pleural effusion and 2 had grade 1/2 peripheral neuropathy. Other grade 1/2 AEs included rash, cough, dyspnea, muscle pain, pyrexia and anorexia. 2/12 pts achieved a partial response (25%) and 4 (33%) achieved stable disease. Two pts remain on study at cycle 10+ and at cycle 7+. Dose delays /reductions were not required during DL 0 until cycle 4 but dose delays occurred from cycle 1 onward in DL 1 and 2. Conclusions: Ixa + D can be safely delivered at clinically relevant doses to pts with MBC. A MTD of Ixa at 20 mg/m2 weekly 3/4 wks and D at 100 mg QD was established with clinical activity seen at this dose level. The phase II portion is actively accruing pts. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4714. doi:10.1158/1538-7445.AM2011-4714

Capecitabine combined with weekly docetaxel in Chinese patients > 65 years with anthracycline-resistant metastatic breast cancer.

There are no data on more tolerable capecitabine doses in elderly patients in Chinese population. The aim of this study was to evaluate the activity and safety of capecitabine combined with weekly docetaxel for the treatment of anthracycline-resistant metastatic breast cancer (MBC) in older Chinese patients. MBC patients aged > 65 years pretreated with 1 - 5 prior chemotherapy regimens, including an anthracycline, received oral capecitabine 825 mg/m(2) twice daily, days 1 - 14, plus docetaxel 30 mg/m(2) on days 1 and 8 every 21 days. All 41 enrolled patients received at least 1 dose of treatment and were evaluable for safety; 38 received at least 2 cycles (median 4, range 2 - 8) and were evaluable for efficacy. The overall objective response rate was 47%, including complete responses in 8% of patients. Median time to progression was 8.9 months. Median overall survival was 17.6 months. The most common side effects were haematological and gastrointestinal toxicities and hand-foot syndrome. The only grade 3/4 adverse events were neutropenia (12%), alopecia (7%), grade 3 nausea and vomiting (2%) and grade 3 nail toxicity (2%). Capecitabine 825 mg/m(2) twice daily plus weekly docetaxel is active with an acceptable safety profile in Chinese women > 65 years with anthracycline-resistant MBC. Efficacy and tolerability compare favourably with previously reported trials evaluating higher capecitabine doses in combination with 3-weekly or weekly docetaxel.

Efficacy of Nab-paclitaxel in patients with poor prognostic factors or with anthracycline-resistant metastatic breast cancer (MBC)

1082 Background: Nanoparticle albumin-bound-paclitaxel (nab-pac) demonstrated significant antitumor activity in patients with MBC compared with solvent-based paclitaxel. This retrospective analysis evaluated the antitumor activity of nab-pac in patients with MBC who were previously treated with anthracycline, had visceral (lung and/or liver) disease, or had ≥ 3 sites of metastases. Methods: Pts (N = 531) were evaluated from a phase II and a phase III study of nab-pac (Gradishar et al. J Clin Oncol. 2005;23:7794–7803). In the phase III study, pts (including first- and second-line pts) received nab-pac 260 mg/m2 q3w (A) or paclitaxel 175 mg/m2 q3w (B). In the phase II study, first-line pts received nab-pac 300 mg/m2 q3w (C), 100 mg/m2 qw (D), 150 mg/m2 qw (E); or docetaxel 100 mg/m2 q3w (F). Results: See Table. Conclusions: Nab-pac, weekly or every 3 weeks, has significant antitumor activity in patients with MBC regardless of baseline factors (eg, anthracycline use, visceral disease, or ≥ 3 sites of metastasis). Prior anthracycline Pts with visceral disease Pts with ≥3 sites of metastasis Nab-pac 77 77 62 Paclitaxel 78 81 52 Nab-pac 24 81 54 Docetaxel 24 88 59 Overall response rate (%) Overall response rate (%) Overall response rate (%) A* 34 34 26 B* 18 19 17 P-value 0.002 0.002 0.092 C 45 45 46 D 53 61 69 E 68 75 70 F 28 37 29 P-value † 0.062 0.003 0.004 Time to progression/Progression-free survival (months) Time to progression/Progression-free survival (months) Time to progression/Progression-free survival (months) A*‡ 5.3 5.0 4.5 B*‡ 3.8 3.8 3.7 P-value 0.004 0.036 0.053 C 7.9 10.9 10.2 D 7.2 7.5 7.4 E 11.4 13.1 12.9 F 5.5 7.8 7.6 P-value † 0.031 0.242 0.557 Overall survival (months) Overall survival (months) Overall survival (months) A* 14.9 13.1 14.2 B* 12.0 12.3 11.0 P-value 0.049 0.945 0.154 C,D,E,F NA NA NA Pts treated 1st- and 2nd-line; † Comparing nab-pac and docetaxel overall; ‡ TTP in the ph III trial Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Abraxis Bioscience Abraxis Abraxis

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.

Biweekly docetaxel and vinorelbine with granulocyte colony-stimulating factor support for patients with anthracycline-resistant metastatic breast cancer

This phase II trial evaluated the efficacy and toxicity of vinorelbine 25 mg/m2 plus docetaxel 60 mg2/m administered on day 1, every 2 weeks with granulocyte colony-stimulating factor support (G-CSF, 5 microg/kg/day, days 3-7) as primary prophylaxis in patients with histologically confirmed metastatic breast cancer (MBC) and previously treated with anthracyclines in the adjuvant or in the first-line setting. A total of 48 patients received 352 cycles (median 8, range 2-10). All patients were included in the efficacy and safety evaluation on an intent-to-treat analysis. Eight patients (17%) showed a complete response and 14 patients (29%) showed a partial response. Overall response rate was 46% [95% confidence interval (CI) 33-60]. The median duration of response was 10.0 months. With a median follow-up of 18.0 months, the median time to progression was 11.9 months and the median overall survival was 27.1 months. The most frequently reported grade 3/4 hematological toxicity was neutropenia (19% of patients, 4% of cycles). Febrile neutropenia was reported in six patients (13%) and 7 cycles (2%), but no toxic deaths were reported. The most common grade 3/4 non-hematological toxicity was asthenia (17% of patients, 6% of cycles) and nail toxicity (15% of patients, 3% of cycles). In conclusion, biweekly docetaxel plus vinorelbine with G-CSF support is active and well tolerated as chemotherapy for patients with MBC resistant to anthracyclines. G-CSF support is recommended for lowering the incidence and severity of neutropenia and febrile neutropenia.

Biweekly Docetaxel and Vinorelbine in Anthracycline-Resistant Metastatic Breast Cancer

The aim of this study was to determine the efficacy and toxicity of a biweekly combination of docetaxel and vinorelbine in patients with metastatic breast cancer (MBC) previously treated with anthracyclines. Eligible patients (n = 49) with MBC received vinorelbine, 25 mg/m2, followed by docetaxel, 60 mg/m2. Cycles were repeated every 14 days for a total of 8 planned cycles. Response rate was evaluated every 4 cycles. All 49 patients were evaluable for safety and 44 for efficacy. Vinorelbine plus docetaxel resulted in an overall response rate of 45% (CI 95%: 31–60) with 2 (4%) complete responses and 18 (41%) partial responses. Patients with visceral metastasis achieved a lower response rate than those without (33% versus 60%, p = 0.044). Time to progression was 11.0 months (CI 95%: 8.6–13.5), and median overall survival was 12.7 months (CI 95%: 9.0–16.4). The most common grade III to IV hematologic adverse events was neutropenia (65% of patients). Febrile neutropenia was observed in 9 cycles (3%) and in 7 patients (14%). Grade III to IV nonhematologic toxicity was rare. Biweekly combination of docetaxel and vinorelbine is an effective and well-tolerated regimen in anthracycline-resistant MBC.

Oral fluoropyrimidines among the new drugs for patients with metastatic breast cancer.

Although drugs such as the taxoids and vinorelbine have increased the options available for anthracycline-resistant metastatic breast cancer, new therapeutic options are needed, particularly for taxoid-refractory tumours. Increasing emphasis is being placed on the development of oral agents, which many patients prefer provided efficacy is not compromised, particularly if the oral agents are less toxic than current intravenous agents. Capecitabine, a new, oral fluoropyrimidine, mimics continuous infusion 5-FU and is activated preferentially at the tumour site. Phase II studies of capecitabine have demonstrated encouraging response rates in patients with few further treatment options (20% response with an additional 43% achieving stable disease in paclitaxel-refractory patients; 36% response with a further 23% achieving stable disease in anthracycline-refractory patients). In addition, a randomized, phase II trial demonstrated a response rate of 30% (95% Cl: 19–43%) with capecitabine as first-line treatment for metastatic breast cancer, compared with 16% (95% Cl: 5–33%) in patients receiving low-dose CMF. These trials also showed that capecitabine has a favourable safety profile typical of infused fluoropyrimidines. Both alopecia and myelosuppression were rare. Capecitabine may therefore provide an effective, well-tolerated and convenient alternative to intravenous cytotoxic agents, not only in taxoid-resistant patients, but also in anthracycline-resistant metastatic breast cancer or as first-line therapy. Furthermore, the low incidence of myelosuppression makes capecitabine an attractive agent for incorporation into combination regimens with agents such as epirubicin/doxorubicin, the taxoids and vinorelbine. © 2001 Cancer ResearchCampaign http://www.bjcancer.com

Docetaxel monotherapy in heavily pretreated metastatic breast cancer: a multicenter, community-based feasibility trial.

To evaluate the efficacy and safety of docetaxel in heavily pretreated and anthracycline-resistant patients with metastatic breast cancer in an outpatient setting. Between February 1996 and June 1998, 98 consecutive patients who had progressed during or relapsed following prior anthracycline-containing chemotherapy were enrolled into the trial. Docetaxel was administered at a dose of 100 mg/m2 by intravenous infusion every 3 weeks. The administration of colony-stimulating factors was at the discretion of the attending physician. Premedication with dexamethasone was mandatory for all patients. Of the 98 patients, 93 were evaluable for toxicity and response. Patients had received two palliative regimens (median, range 1-5) prior to docetaxel treatment. The most frequent toxicity observed was leukopenia grade III and IV (WHO grading system) which occurred in 47% of patients (grade IV only in 14%). Except for alopecia grade III (64% of patients), nonhematologic side effects grade III-IV were rare (1-7% of patients) and included nausea, stomatitis, diarrhea, peripheral neuropathy, fluid retention and pulmonary toxicities. There were no treatment-related deaths. Objective responses occurred in 40% of patients (CR 6%, PR 34%), and stable disease in 38% of patients. The median duration of response was 5.3 months (range 0.7-18.1 months) while the median survival was 15 months (range 2 36 months). Docetaxel is a highly active agent in patients with anthracycline-resistant metastatic breast cancer, even in heavily pretreated patients, with moderate toxicity.

Monotherapy with docetaxel in the second- or third-line treatment of anthracycline-resistant metastatic breast cancer

International Journal of Gynecology & ObstetricsVolume 70, Issue S5 p. E15-E15 Free communications breast cancer: Diagnosis and treatments Monotherapy with docetaxel in the second- or third-line treatment of anthracycline-resistant metastatic breast cancer T. Brodowicz, T. BrodowiczSearch for more papers by this authorW.J. Köstler, W.J. KöstlerSearch for more papers by this authorS. Tomek, S. TomekSearch for more papers by this authorI. Vaclavik, I. VaclavikSearch for more papers by this authorV. Herscovici, V. HerscoviciSearch for more papers by this authorC. Wiltschke, C. WiltschkeSearch for more papers by this authorG.G. Steger, G.G. StegerSearch for more papers by this authorC.C. Zielinski, C.C. ZielinskiSearch for more papers by this author T. Brodowicz, T. BrodowiczSearch for more papers by this authorW.J. Köstler, W.J. KöstlerSearch for more papers by this authorS. Tomek, S. TomekSearch for more papers by this authorI. Vaclavik, I. VaclavikSearch for more papers by this authorV. Herscovici, V. HerscoviciSearch for more papers by this authorC. Wiltschke, C. WiltschkeSearch for more papers by this authorG.G. Steger, G.G. StegerSearch for more papers by this authorC.C. Zielinski, C.C. ZielinskiSearch for more papers by this author First published: 16 July 2010 https://doi.org/10.1016/S0020-7292(00)82369-3AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article. Volume70, IssueS52000Pages E15-E15 RelatedInformation

Cost-utility analysis of chemotherapy using paclitaxel, docetaxel, or vinorelbine for patients with anthracycline-resistant breast cancer.

Paclitaxel, docetaxel, and vinorelbine have been approved for chemotherapy in patients with advanced breast cancer that is resistant to anthracyclines. Selecting which agent to use is difficult because each possesses advantages and disadvantages related to clinical response, toxicity, method of administration, and cost. A cost-utility analysis was therefore performed to create a rank order on the basis of effectiveness, quality of life, and economic considerations. Eighty-eight anthracycline-resistant breast cancer patients who had received paclitaxel (n = 34), docetaxel (n = 29), or vinorelbine (n = 25) during the past 2 years were identified. Total resource consumption was collected, which included expenditures for chemotherapy, supportive care, laboratory tests, management of adverse effects, and all related physician fees. Utilities from 25 oncology care providers and 25 breast cancer patients were estimated using the time trade-off technique. The economic estimates from the chart review and clinical data from the literature were then modeled using the principles of decision analysis. Each of the three drugs led to a similar duration of quality-adjusted progression-free survival (paclitaxel, 37.2 days; docetaxel, 33.6 days; vinorelbine, 38.0 days). Vinorelbine was the least costly strategy, with an overall treatment expenditure of Can $3,259 per patient, compared with Can $6,039 and Can $10,090 for paclitaxel and docetaxel, respectively. Palliative chemotherapy with vinorelbine in anthracycline-resistant metastatic breast cancer patients has economic advantages over the taxanes and provides at least equivalent quality-adjusted progression-free survival. These benefits are largely related to its lower drug acquisition cost and better toxicity profile.

Efficacy and toxicity of some chemotherapeutic regimes in heavely pretreated anthracycline-resistant metastatic breast cancer (ARMBC)

Efficacy and toxicity of some chemotherapeutic regimes in heavely pretreated anthracycline-resistant metastatic breast cancer (ARMBC)

Xeloda® in the Treatment of Metastatic Breast Cancer

There are few treatment options available for patients with metastatic breast cancer who have failed anthracycline- and paclitaxel-based chemotherapy. Xeloda^® (capecitabine) is a novel selectively tumoractivated^TM fluoropyrimidine carbamate producing clinically active levels of 5-fluorouracil (5-FU) at the tumor site. Xeloda is active in breast cancer and is administered orally. It is the only registered treatment for patients in whom anthracycline and taxoid treatment has failed. In a phase II trial of 163 paclitaxel-refractory patients with metastatic breast cancer, the overall response rate with Xeloda was 20%, with three complete responses, and the median survival was 12.8 months. A total of 20% of patients experienced a Clinical Benefit Response (a composite assessment of clinical benefit). Furthermore, Xeloda was well tolerated; the most common treatment-related adverse events were hand-foot syndrome, diarrhea, nausea, vomiting, and fatigue. Two additional studies of Xeloda in patients with metastatic breast cancer have also been completed. In the first study, patients with anthracycline-resistant metastatic breast cancer received either Xeloda or paclitaxel; the response rates were 36 and 26%, respectively. In the second study, women aged ≧55 years received first-line treatment with either Xeloda or cyclophosphamide/methotrexate/5-FU. The response rates were 25 and 16%, respectively. These studies show that Xeloda is an active agent in the treatment of metastatic breast cancer with the additional advantage of oral administration.

The economic advantages of response in the treatment of advanced breast cancer

SummaryThe introduction of a new class of drugs, the taxoids, has dramatically improved the outlook for patients with advanced, metastatic breast cancer. Second-line monotherapy with the most effective taxoid, docetaxel, in patients with anthracycline-resistant metastatic breast cancer, shows an overall response rate up to 55% in this patient population. Increased response rate is associated with improved quality of life for these patients.We carried out a cost analysis to determine the economic benefits of being in a response state compared with the other health states associated with advanced breast cancer: stable, progressive or terminal disease.We found that the cost of care for responders is 40% of that for early progressive disease and just over a third of that for late progressive disease. The costs associated with stable disease are only a little less than those for progressive disease, and are more than double the costs for patients who have responded to chemotherapy. The costs during terminal disease are the highest, and are more than nine times those associated with caring for responders.Our findings confirm other studies which demonstrate that the cost of chemotherapy can be offset against the reduction in costs incurred for patients who remain in healthier states for longer. The key parameter determining the economic efficiency of treatments for advanced breast cancer is response rate.

Ifosfamide given by continuous-intravenous infusion in association with vinorelbine in patients with anthracycline-resistant metastatic breast cancer: A phase I–II clinical trial

Vinorelbine (VNR) is highly active in metastatic breast cancer (MBC) and has shown an overall response rate of 40%-50% as first-line treatment. In vitro, a synergy has been observed between this drug and ifosfamide (IFX). In addition, the pharmacokinetics of IFX suggest that it may have greater activity when given by continuous-intravenous infusion (c.i.v.i.). The aim of this study was, therefore, to assess the antitumor efficacy and toxicity of the combination of bolus VNR and c.i.v.i. IFX as second-line therapy in anthracycline-resistant breast cancer patients. Forty-two patients with MBC who had already received anthracycline-based chemotherapy were treated with a regimen consisting of IFX, by c.i.v.i. for 72 hours and bolus VNR. The courses were repeated every three weeks for a maximum of eight cycles. Four dose intensification steps were planned: IFX, 1.5 g/m2 on days 1-3 + VNR, 30 mg/m2 on day 1 (six patients); IFX, 2 g/m2 on days 1-3 + VNR, 25 mg/m2 on day 1 (six patients); IFX, 1.8 mg/m2 on days 1-3 + VNR, 25 mg/m2 on days 1 and 8 (six patients); IFX, 2 g/m2 on days 1-3 + VNR, 25 mg/m2 on days 1 and 8 (24 patients). Sodium-2-mercaptoethane sulfonate (mesna) was associated with IFX at an infusion ratio of 1:1 and, once the infusion was completed, per os every four hours for three times. All of the 42 patients entered were assessable for toxicity, and 41 of them for response. Neutropenia was the most frequently-occurring toxicity, but only five patients at the highest dose level (11.9%) presented grade 4, and none of those at the first three steps. Other significant toxic effects were mild (only grade I-II). The median relative dose intensity was 95% at the highest dose level and all of the treatments were administered on an out-patient basis. The overall response rate was 36.5% with a CR rate of 4.8% (two of 41 patients, all at the highest dose level) and a PR rate of 31.7% (13 of 41 patients). The median response duration was 7.0 months (range 2-13 months). The present phase I-II study shows that the IFX and VNR combination is an active and well-tolerated treatment in MBC and provides an alternative to taxanes for patients previously treated with anthracyclines.

Cost-utility analysis of taxane therapy.

A cost-utility analysis of docetaxel versus paclitaxel in patients with anthracycline-resistant metastatic breast cancer was reviewed. Cost-utility analysis provides estimates of the additional cost of a new therapy per quality-adjusted life-year (QALY) saved or gained. Utility scores measure the strength of a patient's preference for a given health state or outcome. Few studies have evaluated preferences in patients receiving cancer treatment. Since docetaxel may represent an advance in the management of anthracycline-resistant recurrent metastatic breast cancer, a decision-analysis model was developed to evaluate the pharmacoeconomics of this drug versus those of paclitaxel. Although the overall treatment costs of docetaxel were slightly higher than those of paclitaxel, docetaxel was associated with a gain of 0.0905 QALY per patient. This gain in QALYs is equivalent to 33 days of perfect health, which represents a substantial proportion of the life expectancy of one of these patients (typically no longer than nine months). The incremental cost-utility ratio associated with docetaxel therapy was estimated to be $4011 per QALY. Compared with paclitaxel, docetaxel for anthracycline-resistant metastatic breast cancer is within the acceptable range of cost-effectiveness ratios for most medical interventions. Cost-utility analysis is a valuable technique for evaluating new antineoplastic regimens that offer some treatment benefit but do not prolong survival compared with other therapeutic options.

655 - Toxicity and effect of single agent vinorelbine (V) in anthracycline-resistant metastatic breast cancer (ARMBC). Preliminary results of a phase I–II study by the danish breast cancer cooperative group (DBCG)

655 - Toxicity and effect of single agent vinorelbine (V) in anthracycline-resistant metastatic breast cancer (ARMBC). Preliminary results of a phase I–II study by the danish breast cancer cooperative group (DBCG)

Hydroxyurea did not enhance the clinical response to vinblastine in patients with anthracycline-resistant metastatic breast cancer.

Vinblastine is commonly used in metastatic breast cancer after anthracycline failure. The response rate to vinblastine is approximately 20%, with short duration of response. In vitro studies have shown that the addition of hydroxyurea resulted in increased accumulation of vinblastine in tumor cells and in loss of double minutes. We evaluated the combination of vinblastine and hydroxyurea in patients with anthracycline-resistant metastatic breast cancer. Fourteen assessable patients with metastatic breast cancer were entered in the study. All patients had progressed on anthracyclines or progressed within 8 months of stopping anthracyclines. Patients received hydroxyurea (500 mg orally) every Monday, Wednesday and Friday starting one week before the first course of chemotherapy and continuing throughout treatment until disease progression. Vinblastine (6 mg/m2) was given intravenously every 21 days, The median number of courses for vinblastine was 3.5 (range, 1-6). Three patients had partial responses in soft tissue metastases (21%). Four patients had stable disease. Four patients had > grade 2 neutropenia, and 1 patient had grade 4 thrombocytopenia. There were 2 cases of grade 3 constipation, 2 of grade 3 nausea, and 1 each of grade 2 neuropathy and myalgia. There was no treatment-related mortality. Low-dose hydroxyurea in combination with vinblastine has a 21% response rate in metastatic breast cancer after anthracycline failure. Toxicity was mild and generally reversible. At the adopted dose schedule of hydroxyurea, the antitumor activity of vinblastine in anthracycline-resistant metastatic breast cancer did not appear to be enhanced.

PP-8-28 Usefulness of a combination chemoendocrine therapy of mitoxantrone, doxifluridine and medroxyprogesterone acetate for anthracycline-resistant advanced or metastatic breast cancer

PP-8-28 Usefulness of a combination chemoendocrine therapy of mitoxantrone, doxifluridine and medroxyprogesterone acetate for anthracycline-resistant advanced or metastatic breast cancer