Anthracycline-resistant Disease Research Articles

Molecular basis for the development of novel taxanes in the treatment of metastatic breast cancer

The identification of taxanes proved to be a significant advance in the treatment of breast cancer. First-generation taxanes achieved 35% to 55% response rates for women not previously treated with anthracyclines and exceeded 20% for anthracycline-resistant disease. Consequently, taxanes were established as a standard of care in metastatic disease. Subsequent research evaluated taxane monotherapy and combination therapy with other cytotoxic agents, as well as optimal dose and administration schedules to maximize efficacy while minimizing toxicities. Clinical trials suggested the optimal administration schedule and dose for paclitaxel was 80 mg/m 2 weekly, and this weekly schedule is commonly used. However, the solvents required for administration of first-generation taxanes are associated with significant toxicities and undermined clinical efficacy. These factors motivated development of taxane formulations that would enhance the therapeutic index and minimize toxicities. This article reviews the rationale for development of novel taxane formulations and emerging research regarding new formulations including oral taxanes, paclitaxel poliglumex, and vitamin E-based paclitaxel emulsion.

A phase II trial of docetaxel (Taxotere®) as second-line chemotherapy in patients with metastatic breast cancer

The efficacy and tolerability of docetaxel 100 mg/m(2) every 3 weeks as second-line chemotherapy in patients with metastatic breast cancer was investigated. In addition, the efficacy of a 3-day prophylaxis against cumulative dose-related fluid retention was examined with methylprednisolone 32 mg twice daily for 3 days starting 12 and 3 h before the docetaxel infusion together with oral cetirizine 10 mg 12 and 3 h before start of docetaxel for prevention of acute hypersensitivity reactions. According to the intent to treat-analysis 35% (95%CI: 25; 46) of the 94 patients entered responded to therapy. Their median survival was 12 months (range 0-20 months). The respective response rate for the 87 patients eligible for response evaluation was 37% (95%CI: 27; 48). Their median duration of response was 8 months (range 3-12 months), their median time to progression was 4 months (range 1-12 months). The corresponding response rate in the eligible patient cohort with anthracycline-resistant disease was 28% (95%CI: 15; 45) and increased to 44% (95%CI: 30; 59) in the cohort with non-anthracycline-resistant disease. Patients with visceral metastases responded in 36% and patients with > or = 3 organs involved in 33%. In a retrospective analysis, the 3-day premedication of corticosteroids and antihistamines proved to be as effective as the established but more toxic 5-day regimen in delaying and preventing the occurrence of docetaxel derived toxicities especially the cumulative fluid retention. In conclusion, docetaxel represents one of the most active agents for second-line treatment of metastatic breast cancer, especially for anthracycline-resistant patients. Due to comparable effectiveness of the 5-day regimen which is widely used by others and the 3-day premedication tested in this trial the latter proved to be more favourable and was therefore recommended for future therapies.

Progress in systemic therapy for breast cancer: an overview and perspectives

This review will focus on progress for advanced and early breast cancer in systemic medical therapy, which consists of three main modalities: endocrine therapy (ET), chemotherapy (CT) and biological therapies (BTs). In advanced disease, we did witness two consecutive shifts in our classical sequence of ET: in the first one, the potent third-generation aromatase inhibitors took the second place after tamoxifen failure (a shift that is level 1 evidence based), making megestrol acetate a third option, while in the second, they are challenging tamoxifen as the ‘gold standard’ first line ET (a shift that is level 2 evidence based). As far as CT is concerned, most of the progress has been seen in anthracycline-resistant disease with the taxanes (docetaxel in particular) becoming the preferred treatment option on a level 1 evidence basis. In patients with no or limited anthracycline exposure, at least 10 randomised clinical trials involving the taxanes have been conducted, but in view of their conflicting results, no new standard of care has emerged. Third-line CT following anthracyclines and taxanes remains a wide-open research opportunity, with oral capecitabine being the only agent approved in this indication. Herceptin® (trastuzumab) is the first BTs available for the treatment of breast cancer. Its impressive clinical activity in metastatic breast cancer (MBC) prompted the registration of the drug for use as monotherapy in patients with HER-2 overexpressing MBC who have failed anthracyclines and taxanes, as well as for use upfront in combination with paclitaxel. There is substantial room for further progress with the use of Herceptin® in the management of breast cancer and much hope is placed in the combination of Herceptin® with other agents targeting important signaling pathways, such as the MAPKinase pathway or the PI 3 kinase cell survival pathway. Such strategies will be briefly discussed. In the area of early breast cancer management, BTs (namely Herceptin® and bisphosphonates) are being evaluated in randomised clinical trials, while ET has consolidated its prominent role for all women whose tumours express hormone receptors, as outlined in the 2000 NIH Consensus Conference and in the latest treatment guidelines proposed by the St-Gallen consensus panel in 2001. Substantial mutations in our standards of care are also expected in the field of adjuvant ET, with the early positive results of the large ATAC trial showing superior efficacy and tolerability of anastrozole over tamoxifen. The added benefits from adjuvant CT in patients receiving optimal ET remain difficult to ascertain and may be quite small in certain sub-groups. Only translational research efforts carry the hope for a much needed understanding of this complex interplay between ET and CT. With further improvement expected with new hormonal agents, it is possible that the role of CT will diminish in the future management of endocrine-responsive breast cancer, while the role of ET±BTs will grow.

Gemcitabine combined with paclitaxel or paclitaxel/trastuzumab in metastatic breast cancer

The combination of gemcitabine and paclitaxel in metastatic breast cancer is attractive because of the good single-agent activity of each, the different mechanisms of antitumor effect, and the, generally, nonoverlapping toxicity profiles of the agents. Phase II trials of the combination indicate response rates of 45% to 55% and median survival of 12 months in extensively pretreated patients, including those with anthracycline-resistant disease, and a response rate of 69% in patients with newly recurrent metastatic breast cancer. The combination was well tolerated, with severe hematologic toxicity being infrequent. The combination of gemcitabine, paclitaxel, and trastuzumab in patients with HER2-positive metastatic breast cancer with no prior chemotherapy in the metastatic setting produced a response rate of 71% and median response duration of 11 months. The combination was safe and well tolerated, with no unexpected toxicities being observed. Both combinations warrant additional study in metastatic breast cancer. Semin Oncol 30 (supl 3):19-21. © 2003 Elsevier Inc. All rights reserved.

Gemcitabine combined with paclitaxel or paclitaxel/trastuzumab in metastatic breast cancer

The combination of gemcitabine and paclitaxel in metastatic breast cancer is attractive because of the good single-agent activity of each, the different mechanisms of antitumor effect, and the, generally, nonoverlapping toxicity profiles of the agents. Phase II trials of the combination indicate response rates of 45% to 55% and median survival of 12 months in extensively pretreated patients, including those with anthracycline-resistant disease, and a response rate of 69% in patients with newly recurrent metastatic breast cancer. The combination was well tolerated, with severe hematologic toxicity being infrequent. The combination of gemcitabine, paclitaxel, and trastuzumab in patients with HER2-positive metastatic breast cancer with no prior chemotherapy in the metastatic setting produced a response rate of 71% and median response duration of 11 months. The combination was safe and well tolerated, with no unexpected toxicities being observed. Both combinations warrant additional study in metastatic breast cancer. Semin Oncol 30 (supl 3):19-21. © 2003 Elsevier Inc. All rights reserved.

Gemcitabine combined with paclitaxel or paclitaxel/trastuzumab in metastatic breast cancer.

The combination of gemcitabine and paclitaxel in metastatic breast cancer is attractive because of the good single-agent activity of each, the different mechanisms of antitumor effect, and the, generally, nonoverlapping toxicity profiles of the agents. Phase II trials of the combination indicate response rates of 45% to 55% and median survival of 12 months in extensively pretreated patients, including those with anthracycline-resistant disease, and a response rate of 69% in patients with newly recurrent metastatic breast cancer. The combination was well tolerated, with severe hematologic toxicity being infrequent. The combination of gemcitabine, paclitaxel, and trastuzumab in patients with HER2-positive metastatic breast cancer with no prior chemotherapy in the metastatic setting produced a response rate of 71% and median response duration of 11 months. The combination was safe and well tolerated, with no unexpected toxicities being observed. Both combinations warrant additional study in metastatic breast cancer.

Single-agent gemcitabine as second- and third-line treatment in metastatic breast cancer

In the present study, 25 patients with breast cancer pretreated with one or two anthracycline-based regimens for visceral metastases were enrolled. Patients were treated with gemcitabine 1250 mg/m2on days 1, 8 and 15, q28d. Nine patients received gemcitabine as second-line treatment, whereas 16 patients received gemcitabine as third-line cytotoxic treatment, respectively.In the second-line setting, two (22%) patients gained PR (RR 22%) and four (44%) patients experienced SD (P=0.2), respectively. In the third-line-setting, one (6%) patient gained CR, one patient PR (6%) and four patients (25%) SD, respectively, resulting in a response rate (RR) of 12%.In the second-line-setting, median time to progression was 5.1±4.0 months (range: 1.6–13.9) versus 3.5–2.5 months (range: 1.3–10.4) in the third-line-setting. Median overall survival was 12.6±9.1 months (range: 3.9–30.8) versus 7.5±6.7 months (range: 2.0–26.0), respectively. Overall, no patient experienced treatment limiting toxicities.We conclude from the present study that gemcitabine induced an overall RR of 16% following prior treatment with anthracyclines. However, median time to progression and median overall survival were limited. In the search for efficacious treatment of patients with metastatic breast cancer, gemcitabine constitutes a valid tool in anthracycline-resistant disease and thus might represent a valuable option for combination chemotherapy in controlled trials in this condition.

Taxanes for Breast Cancer: An Evidence-Based Review of Randomized Phase II and Phase III Trials

The taxanes paclitaxel and docetaxel have an important role in the treatment of breast cancer, and numerous randomized trials have evaluated their efficacy for this indication. A systematic, evidence-based review was performed, which included all randomized, controlled trials evaluating taxanes for the treatment of early- or advanced-stage breast cancer that were identified in CANCERLIT and MEDLINE searches. The primary objectives of this review were to determine the dose and schedule for each taxane that was associated with the most favorable therapeutic index, and to determine whether (and under what circumstances) the taxanes improved survival. The search revealed 18 randomized phase II (n=1) or phase III (n=17) trials. For metastatic breast cancer, the dose and schedule associated with the most favorable therapeutic index for paclitaxel was 175 mg/m 2 given as a 3-hour infusion every 3 weeks, and docetaxel was 60-100 mg/m 2 given as a 1-hour infusion every 3 weeks. Survival was improved under the following circumstances: (1) when 4 cycles of paclitaxel (175 mg/m 2 every 3 weeks) was given following 4 cycles of conventional doxorubicincyclophosphamide for axillary node-positive operable breast cancer, (2) when trastuzumab was added to paclitaxel as first-line therapy for metastatic breast cancer that overexpressed HER2/ne u, and (3) when docetaxel was given as second-line therapy for anthracycline-resistant disease. Although a survival benefit was found for taxanes as a component of first-line therapy in two of six trials, the interpretation of both positive trials was confounded by a lack of crossover to taxane therapy in those who were initially randomized to receive standard therapy. The taxanes improve survival in patients with early-stage breast cancer and selected patients with metastatic breast cancer. Further research is necessary in order to identify the efficacy of docetaxel relative to paclitaxel, the optimal dose of docetaxel, the role of weekly taxane therapy, the role of trastuzumab plus taxanes in early-stage disease, and whether taxanes are more effective when given concomitantly or sequentially in patients with early-stage disease.

Paclitaxel in combination with weekly 24-hour infusional 5-fluorouracil plus leucovorin in the second-line treatment of metastatic breast cancer: Results of a phase II study

To evaluate the antitumor activity in terms of response rate (RR), time to progression (TTP) and survival of paclitaxel in combination with weekly 24-hour infusional 5-fluorouracil (5-FU)/leucovorin in pretreated metastatic breast cancer (MBC). Fifty-four patients with bidimensionally measureable disease were included during phase II. Thirty-two had anthracycline resistant disease. Treatment consisted of 5-FU (24-hour i.v. infusion) 2.0 g/m2, leucovorin (two-hour i.v. infusion prior to 5-FU) 500 mg/m2, weekly for six weeks (day 1, 8, 15, 22, 29, 36) and paclitaxel (three-hour i.v. infusion) 175 mg/m2 was administered additionally on days 1 and 22, q 50 days. We observed complete remissions in 4% of patients (2 of 54), partial remissions in 55% (30 of 54), stable disease in 37% (20 of 54) and progressive disease in 4% (2 of 54). The overall RR was 59% (95% CI 48%-72%). The RR in 32 patients with anthracycline resistant disease was 59% (19 of 32). The median duration of response was 12 months (3-22), median TTP eight months (2-22) and median survival time 15 months (2-28). Neutropenia was common, but of CTC grade 2 or 3 in most patients. Nonhematologic toxicities mostly consisted of CTC grade 1 and 2 myalgia, diarrhea, mucositis, nausea and vomiting. Paclitaxel combined with weekly 24-hour infusional 5-FU/leucovorin is well tolerated in the second line treatment of MBC. High efficacy was documented even in the treatment of anthracycline resistant disease, which warrants further evaluations.

Docetaxel Chemotherapy Induces Transverse Superficial Loss of the Nail Plate

The taxoids, docetaxel and paclitaxel, are a new family of effective chemotherapy agents. Paclitaxel provides a survival benefit in patients with advanced ovarian cancer, and both are the most effective drugs in patients with breast cancer and anthracycline-resistant disease. Nail disorders are commonly observed in patients treated with docetaxel. 1 We have observed a striking example of multiple transverse loss of the nail plate from all fingernails and toenails in a woman receiving a docetaxel infusion for treatment of advanced breast cancer. Report of a Case. A 37-year-old woman was treated for an infiltrating ductal carcinoma of the breast by mastectomy. Adjuvant treatment included standard chemotherapy (fluorouracil, epirubicin, and cyclophosphamide), medical castration, and radiotherapy of the chest wall and supraclavicular area. Sixteen months later, a chest wall recurrence developed. A second-line chemotherapy regimen for advanced breast cancer was administered. The treatment consisted of a combination of docetaxel, 75 mg/m 2

Docetaxel chemotherapy induces transverse superficial loss of the nail plate

The taxoids, docetaxel and paclitaxel, are a new family of effective chemotherapy agents. Paclitaxel provides a survival benefit in patients with advanced ovarian cancer, and both are the most effective drugs in patients with breast cancer and anthracycline-resistant disease. Nail disorders are commonly observed in patients treated with docetaxel.¹We have observed a striking example of multiple transverse loss of the nail plate from all fingernails and toenails in a woman receiving a docetaxel infusion for treatment of advanced breast cancer. <h3>Report of a Case.</h3> A 37-year-old woman was treated for an infiltrating ductal carcinoma of the breast by mastectomy. Adjuvant treatment included standard chemotherapy (fluorouracil, epirubicin, and cyclophosphamide), medical castration, and radiotherapy of the chest wall and supraclavicular area. Sixteen months later, a chest wall recurrence developed. A second-line chemotherapy regimen for advanced breast cancer was administered. The treatment consisted of a combination of docetaxel, 75 mg/m²

Dose-finding study of paclitaxel and cyclophosphamide in advanced breast cancer

The toxicity profile of prolonged infusions of paclitaxel in combination with cyclophosphamide in metastatic breast cancer has already been defined. The objective of this dose-finding study was to determine the maximum tolerable doses (MTDs) of shorter (three-hour) infusions of paclitaxel in combination with i.v. bolus cyclophosphamide in patients who had previously received a maximum of one chemotherapy for advanced breast carcinoma. The MTD of the same regimen with granulocyte colony-stimulating factor (G-CSF) support was then established. Eighty women with metastatic breast cancer received a total of 352 fully evaluable courses of therapy. The starting doses were paclitaxel 135 mg/m2 and cyclophosphamide 750 mg/m2 given every three weeks. At least three patients were treated at each dose level and if there were dose-limiting toxic effects during the first cycles three additional patients were entered. G-CSF support (5 micrograms/kg s.c.) was added to the second cycle if specific dose-limiting toxicities had occurred during the first cycle. The MTD was defined as the dose level at which more than two of six patients presented dose-limiting toxicities during the first cycle. Febrile neutropenia (n = 4) and severe thrombocytopenia (n = 1) defined the MTDs of paclitaxel as 200 mg/ m2 and of cyclophosphamide as 2,000 mg/m2 with or without G-CSF in patients with and, respectively, without prior chemotherapy for advanced disease. Non-hematologic toxicity was moderate. Recommended doses were 200 mg/m2 of paclitaxel and 1,750 mg/m2 of cyclophosphamide with or without G-CSF in patients with and, respectively, without prior chemotherapy. The overall response rate was 25% and 50%, respectively, in patients with and without prior chemotherapy for metastatic disease. Complete remissions (9%) were reported only in patients without prior chemotherapy; antitumour activity in women with anthracycline-resistant disease, with an 8% response rate (95% CI: 1%-26%), was poor. Paclitaxel at 200 mg/m2 and cyclophosphamide at 1,750 mg/m2 can be safely administered every three weeks to women with advanced breast cancer. The moderate antitumour activity observed with the schedule tested argues against its use as initial therapy for advanced breast cancer.

Metastatic breast cancer.

The management of metastatic breast cancer continues to provide enormous challenges. The taxanes have significant activity in patients with resistant disease, and combination regimens are being evaluated as first-line therapy. The combination of paclitaxel and doxorubicin appears to have substantial activity, but troublesome cardiac toxicity has been noted in a recently reported study. Docetaxel has been shown to be very active in initial phase II evaluation, notably in women with anthracycline-resistant disease. The controversy over high-dose therapy continues, and its role in the management of metastatic breast cancer outside the confines of clinical trials remains unclear. The HER-2 protein appears to be a predictive factor for patients with metastatic disease. Antibody therapy directed at this target can produce responses in a proportion of patients. Bisphosphonates appear to be beneficial to patients with lytic bony metastases when administered in conjunction with cytotoxic or hormonal therapy.

Treatment of advanced breast cancer

Metastatic breast cancer is a major and increasing public health problem. The 5-year survival for this disease is only 15%, and while hormonal and chemotherapeutic options have had a significant impact on long-term survival for patients with localized disease, treatment for disseminated disease remains essentially palliative. New treatment options are urgently needed to improve the prospects for patients with metastatic breast cancer, particularly for those with disease characteristics indicating a particularly poor prognosis. Docetaxel (Taxotere) is a promising new drug and has shown encouraging activity in patients with disease resistant to anthracyclines and in patients with visceral metastases, both of which indicate a poor prognosis. Although docetaxel is, at present, only licensed for use in patients with anthracycline-resistant disease, this highly active drug should now be developed for first-line treatment, and eventually for adjuvant use.

Treatment of patients resistant to anthracycline therapy

The results of three multicentre phase II trials in which docetaxel (Taxotere) was used in previously treated patients with metastatic breast cancer resistant to anthracyclines or anthracenediones are summarized here. Docetaxel was given to a total of 134 patients who had evidence of disease progression while receiving anthracyclines or anthracenediones for metastatic disease or had relapsed during adjuvant therapy which included these agents. The overall response rate (ORR) across the three studies was 41% in an intent-to-treat analysis. The median duration of response varied from 24 to 28 weeks between studies and the median survival varied from 9 to 12 months. The response rate was well maintained in evaluable patients with visceral metastases (ORR 43%), or multiple (> 2) sites of disease (ORR 48%). These response rates are the highest ever reported for a single agent in patients with anthracycline-resistant disease. The recommended dose and schedule for docetaxel (100 mg/m2 intravenously over 1-h every 3 weeks), which was used in all three studies, was found to be well tolerated, with neutropenia as the most common toxicity (grade 4 in 90% of patients) and febrile neutropenia requiring hospitalisation occurring in only 4% of cycles of therapy.

Treatment of advanced breast cancer

Metastatic breast cancer is a major and increasing public health problem. The 5-year survival for this disease is only 15%, and while hormonal and chemotherapeutic options have had a significant impact on long-term survival for patients with localized disease, treatment for disseminated disease remains essentially palliative. New treatment options are urgently needed to improve the prospects for patients with metastatic breast cancer, particularly for those with disease characteristics indicating a particularly poor prognosis. Docetaxel (Taxotere) is a promising new drug and has shown encouraging activity in patients with disease resistant to anthracyclines and in patients with visceral metastases, both of which indicate a poor prognosis. Although docetaxel is, at present, only licensed for use in patients with anthracycline-resistant disease, this highly active drug should now be developed for first-line treatment, and eventually for adjuvant use.

Management of chemotherapy-resistant breast cancer

The second workshop of the European School of Oncology Task Force Programme on Breast Cancer — Management of Chemotherapy- Resistant Disease took place in London on 10–11 November 1995. The first workshop focused on the problems of anthracycline resistant disease and highlighted the need for operational definitions of anthracycline resistance when comparing novel approaches. The purpose of the present workshop was to appraise further the problem of chemoresistant breast cancer and examine the prospects for circumventing drug resistance.

Docetaxel: a new defence in the management of breast cancer

The results of nine phase II trials of docetaxel in the first- and second-line treatment of patients with advanced breast cancer are summarized. All 316 patients included in this report received docetaxel at a dose of 100 mg/m2 administered over 1 h every 3 weeks on an outpatient basis. One hundred and fifty-four patients received docetaxel as first-line therapy for advanced disease, half of whom had received prior adjuvant chemotherapy (finished at least 1 year previously). An overall response rate of 59% (95% CI: 51-67) was achieved in these patients, with a median duration of response of 8.3 months and a median time to progression of 4.9 months. Similar results were seen in a subgroup of 68 patients with liver metastases. Among the 162 patients given docetaxel as second-line therapy, 134 had strictly defined anthracycline-resistant disease; 73 had liver metastases. The combined overall response rate for anthracycline-resistant patients in two US studies was 48% (95% CI: 37-59) while that in a multicenter French study was 29% (95% CI: 18-44). The median duration of response in each case was 6.3 and 5.5 months, respectively, with an overall median survival duration of 11 and 10 months, respectively. Among patients with liver metastases, second-line treatment with docetaxel achieved an overall response rate of 32%, a median duration of response of 7.8 months and a median survival duration of 9 months. These results for docetaxel as both first- and second-line therapy are comparable with those achieved with doxorubicin and are particularly promising in patients with liver metastases and anthracycline-resistant disease.