Neoadjuvant bevacizumab, trastuzumab, and chemotherapy for primary inflammatory HER2-positive breast cancer (BEVERLY-2): an open-label, single-arm phase 2 study.

BACKGROUND: Bevacizumab and trastuzumab are efficacious for treatment of advanced or HER2-positive metastatic breast cancer; however, few data exist for this regimen in inflammatory breast cancer. In our phase 2 trial, we aimed to assess efficacy and safety of neoadjuvant bevacizumab combined with trastuzumab and chemotherapy in patients with primary HER2-positive inflammatory breast cancer. METHODS: In our phase 2, multicentre, open-label, single-arm, non-comparative trial, we enrolled women (aged ≥ 18 years) with histologically confirmed HER2-positive non-metastatic inflammatory breast cancer at private or public oncology centres in France. Before surgery, patients were treated with fluorouracil, epirubicin, cyclophosphamide, and bevacizumab (cycles 1-4) and docetaxel, bevacizumab, and trastuzumab (cycles 5-8) in 3-week cycles. After surgery, patients received adjuvant radiotherapy, trastuzumab, and bevacizumab. For the primary endpoint, we assessed the proportion of patients who achieved a pathological complete response (defined by central review of surgical specimens according to Sataloff classification, counting missing data as failure) and adverse events in all enrolled patients. This study is registered with ClinicalTrials.gov, number NCT00717405. FINDINGS: Between Oct 23, 2008, and Oct 28, 2009, we enrolled 52 patients at 21 centres. 42 (81%) of 52 patients received all eight cycles of neoadjuvant therapy and 49 (94%) underwent surgery. After neoadjuvant therapy, 33 of 52 patients had a pathological complete response according to central review (63·5%, 95% CI 49·4-77·5). The most common adverse events were asthenia and nausea (both occurred in 36 [69%] of 52 patients). 25 (48%) patients had grade 3-4 neutropenia, which was the most common grade 3-4 adverse event. Only one grade 3 or worse adverse event regarded as related to bevacizumab was reported (hypertension, one patient). Four patients (8%) had cardiac failure. INTERPRETATION: Neoadjuvant treatment with bevacizumab, trastuzumab, and chemotherapy was efficacious and well tolerated in patients with previously untreated primary inflammatory breast cancer. Further confirmation of use of bevacizumab in inflammatory breast cancer is needed. FUNDING: Roche (France).

Eribulin monotherapy versus treatment of physician's choice in patients with metastatic breast cancer (EMBRACE): a phase 3 open-label randomised study.

BACKGROUND: Treatments with survival benefit are greatly needed for women with heavily pretreated metastatic breast cancer. Eribulin mesilate is a non-taxane microtubule dynamics inhibitor with a novel mode of action. We aimed to compare overall survival of heavily pretreated patients receiving eribulin versus currently available treatments. METHODS: In this phase 3 open-label study, women with locally recurrent or metastatic breast cancer were randomly allocated (2:1) to eribulin mesilate (1·4 mg/m(2) administered intravenously during 2-5 min on days 1 and 8 of a 21-day cycle) or treatment of physician's choice (TPC). Patients had received between two and five previous chemotherapy regimens (two or more for advanced disease), including an anthracycline and a taxane, unless contraindicated. Randomisation was stratified by geographical region, previous capecitabine treatment, and human epidermal growth factor receptor 2 status. Patients and investigators were not masked to treatment allocation. The primary endpoint was overall survival in the intention-to-treat population. This study is registered at ClinicalTrials.gov, number NCT00388726. FINDINGS: 762 women were randomly allocated to treatment groups (508 eribulin, 254 TPC). Overall survival was significantly improved in women assigned to eribulin (median 13·1 months, 95% CI 11·8-14·3) compared with TPC (10·6 months, 9·3-12·5; hazard ratio 0·81, 95% CI 0·66-0·99; p=0·041). The most common adverse events in both groups were asthenia or fatigue (270 [54%] of 503 patients on eribulin and 98 [40%] of 247 patients on TPC at all grades) and neutropenia (260 [52%] patients receiving eribulin and 73 [30%] of those on TPC at all grades). Peripheral neuropathy was the most common adverse event leading to discontinuation from eribulin, occurring in 24 (5%) of 503 patients. INTERPRETATION: Eribulin showed a significant and clinically meaningful improvement in overall survival compared with TPC in women with heavily pretreated metastatic breast cancer. This finding challenges the notion that improved overall survival is an unrealistic expectation during evaluation of new anticancer therapies in the refractory setting. FUNDING: Eisai.

Efficacy of trastuzumab in routine clinical practice and after progression for metastatic breast cancer patients: the observational Hermine study.

BACKGROUND: The Hermine study observed the use of trastuzumab for metastatic breast cancer (MBC) in routine practice, including patients who received trastuzumab treatment beyond progression (TBP). PATIENTS AND METHODS: The study observed 623 patients for > or = 2 years. Treatment was given according to oncologists' normal clinical practices. Endpoints included duration of treatment, efficacy, and cardiac safety. The TBP subanalysis compared overall survival (OS) in 177 patients who received first-line trastuzumab and either continued trastuzumab for > or = 30 days following progression or stopped at or before progression. RESULTS: The median treatment duration was 13.3 months. In the first-, second-, and third-line or beyond treatment groups, the median time to progression (TTP) were 10.3 months, 9.0 months, and 6.3 months, and the median OS times were 30.3 months, 27.1 months, and 23.2 months, respectively. Heart failure was observed in 2.6% of patients, although no cardiac-associated deaths occurred. In the TBP subanalysis, the median OS duration from treatment initiation and time of disease progression were longer in patients who continued receiving trastuzumab TBP (>27.8 months and 21.3 months, respectively) than in those who stopped (16.8 months and 4.6 months, respectively). However, the groups were not completely comparable, because patients who continued trastuzumab TBP had better prognoses at treatment initiation. The median TTP was longer in patients who continued trastuzumab TBP (10.2 months) than in those who stopped (7.1 months). CONCLUSION: The Hermine findings confirm that the pivotal trials of first-line trastuzumab treatment in MBC patients are applicable in clinical practice. The subanalysis suggests that trastuzumab TBP offers a survival benefit to MBC patients treated with first-line trastuzumab.

Deterioration of quality of life of high-risk breast cancer patients treated with high-dose chemotherapy: the PEGASE 01 Quality of Life Study.

OBJECTIVE: The aim of this study was to compare the quality of life (QOL) of high-risk breast cancer patients included in a randomized clinical trial (PEGASE 01) comparing conventional chemotherapy versus adding an additional high-dose chemotherapy (HDC) cycle with blood stem cell support. METHODS: A total of 314 patients were included in the clinical trial. QOL evaluations were available for 199 patients. QOL was assessed over a 1-year follow-up period, using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C-30. The results were analyzed using a linear mixed-effects model. RESULTS: Toxicity of HDC has a strong negative impact on patients' QOL during the treatment phase. This negative impact tended to last longer in the HDC group, as for most of the QLQ-C30 scales, the QOL scores of HDC patients tend to improve at a slower rate than that of patients receiving standard chemotherapy. In particular, physical functioning remains deteriorated 1 year after inclusion for HDC patients comparatively to conventional chemotherapy patients (85.99 vs. 76.65, P = 0.021), and the pain score was still higher in the HDC group at that time (28.32 vs. 15.97, P = 0.004). CONCLUSION: HDC has a negative impact on QOL even after treatment phase. In the absence of an overall survival benefit of using HDC for high-risk breast cancer patients, QOL studies with a longer follow-up play an important role in informing the complex trade-off implied by HDC between higher toxicity, reduced risk of relapse, and QOL decrease after the active phase of treatment.

A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer.

BACKGROUND: Tamoxifen, taken for five years, is the standard adjuvant treatment for postmenopausal women with primary, estrogen-receptor-positive breast cancer. Despite this treatment, however, some patients have a relapse. METHODS: We conducted a double-blind, randomized trial to test whether, after two to three years of tamoxifen therapy, switching to exemestane was more effective than continuing tamoxifen therapy for the remainder of the five years of treatment. The primary end point was disease-free survival. RESULTS: Of the 4742 patients enrolled, 2362 were randomly assigned to switch to exemestane, and 2380 to continue to receive tamoxifen. After a median follow-up of 30.6 months, 449 first events (local or metastatic recurrence, contralateral breast cancer, or death) were reported--183 in the exemestane group and 266 in the tamoxifen group. The unadjusted hazard ratio in the exemestane group as compared with the tamoxifen group was 0.68 (95 percent confidence interval, 0.56 to 0.82; P<0.001 by the log-rank test), representing a 32 percent reduction in risk and corresponding to an absolute benefit in terms of disease-free survival of 4.7 percent (95 percent confidence interval, 2.6 to 6.8) at three years after randomization. Overall survival was not significantly different in the two groups, with 93 deaths occurring in the exemestane group and 106 in the tamoxifen group. Severe toxic effects of exemestane were rare. Contralateral breast cancer occurred in 20 patients in the tamoxifen group and 9 in the exemestane group (P=0.04). CONCLUSIONS: Exemestane therapy after two to three years of tamoxifen therapy significantly improved disease-free survival as compared with the standard five years of tamoxifen treatment.

Influence of CA 15-3 blood level and doubling time on diagnostic performances of 18F-FDG PET in breast cancer patients with occult recurrence.

AIM: To evaluate the influence of CA 15-3 blood level and doubling time on diagnostic performances of 18F-FDG PET in breast cancer patients with occult recurrence. MATERIALS AND METHODS: Thirty-five 18F-FDG PET examinations in 32 patients with CA 15-3 blood level above the normal range, and negative conventional imaging within 3 months before PET examination were included in this retrospective study. PET examinations were reviewed blindly by two experienced nuclear medicine physicians who were unaware of any clinical, biological or radiological information. CA 15-3 assays performed prior to the PET examinations and all using the same technique were collected and used for doubling time calculation if (1) no therapeutic modification occurred in the meantime, and (2) the delay between assays was less than 6 months. RESULTS: Median CA 15-3 blood levels were higher in the positive PET group (100 U x ml(-1)) than in the negative group (65 U x ml(-1)) (P=0.04). The likelihood of depicting recurrence was higher in patients with a short doubling time (<180 days) (P=0.05), a CA 15-3 blood level >60 U x ml(-1) (P=0.05), and when a short doubling time was associated with a CA 15-3 blood level >60 U x ml(-1) (P=0.03). CONCLUSIONS: The likelihood of depicting recurrence was influenced by CA 15-3 blood level and doubling time. Further studies are required to confirm that selections of patients based on those criteria could improve the sensitivity of positron emission tomography in the detection of breast cancer recurrence, particularly in the case of low CA 15-3 blood level.

High-dose chemotherapy with haematopoietic stem cell transplantation for metastatic breast cancer patients: final results of the French multicentric randomised CMA/PEGASE 04 protocol.

The aim of our study was to evaluate the impact on time to progression (TTP) and overall survival (OS) of high-dose chemotherapy (HD-CT) over conventional CT in metastatic breast cancer patients. Between 09/92 and 12/96, 61 patients with chemosensitive metastatic breast cancer were randomised between HD-CT using the CMA regimen (Mitoxantrone, Cyclophosphamide, Melphalan) applied as consolidation (32 patients) or maintenance CT (29 patients). At randomisation, 13 patients were in complete response, 47 in partial response and one had stable disease. The median TTPs from randomisation were 6 and 12 months in the standard and intensive groups, respectively (P < 0.0056), with a relapse rate of 86.2% vs. 62.5% at 2 years, and 100% vs. 81.3% at 5 years. The median OS times were 19.3 and 44.1 months, with an OS rate of 13.8% vs. 36.8% at 5 years (P < 0.0294). The CMA regimen could prolong the TTP of patients with chemosensitive metastatic breast cancer. Further studies are needed to determine if this translates into an effect on OS.

Flow cytometry in primary breast carcinomas: prognostic impact of multiploidy and hypoploidy.

BACKGROUND: The aims of the present work were to study the prognostic impact of multiploidy and/or hypoploidy in breast cancers and their relation to other classic clinicopathologic prognostic factors (T, grade, receptors, and lymph node status). METHODS: From 3 January 1990 to 7 January 1999, 1984 previously untreated, invasive breast carcinoma samples were snap frozen for flow-cytometry. RESULTS: Multiploid tumors had the same prognosis as the aneuploid ones, and those with one hypoploid peak had a better prognosis than did the other aneuploid tumors. However, the presence of both multiploid and hypoploid peaks was correlated with a poor outcome, even after multivariate analysis. In this series after quality control, 93.4% of the histograms could be evaluated concerning ploidy; of these 81.6% could be assessed concerning S-phase fraction (SPF) in the entire population and 77.1% in the multiploid population. In the entire population, we performed a multivariate analysis including all relevant prognostic factors remaining after monovariate analysis by using a compound factor (proliferative activity) regrouping SPF and mitotic activity. This analysis showed that lymph node status and proliferative activity correlates with every type of survival, whereas receptor status correlates with all types of survival except recurrence free survival size, correlated with non-metastasis and overall survival. Grade and age correlated only with overall survival and vascular permeations only with disease-free survival. CONCLUSIONS: SPF is a valuable predictor of survival, can be confidently assessed in multiploid histograms, and thus improves the yield of flow cytometry. When combined with mitotic activity, the prognostic impact of SPF is the same as that of lymph node status. Tumors that are hypoploid and multiploid have a significantly worse prognosis.

Natural history of node-negative breast cancer: are conventional prognostic factors predictors of time to relapse?

The purpose of this study was to determine a subpopulation of node-negative breast cancer patients at high risk of metastases and to analyse the relationship between conventional prognostic factors and the onset of metastatic disease. Patients with node-negative breast cancer, who were not receiving systemic adjuvant therapy, were prospectively enrolled into a multicentre study. We studied the onset of metastatic disease in relation to family history, age, and tumour characteristics of 2683 registered patients, 2213 were available for analysis. Median follow-up was 100 months. Metastatic disease-free survival was 88% at 5 years and 80% at 10 years. The two strongest prognostic factors in a multivariate analysis tumour Scraff, Bloom and Richardson (SBR) grade (P<0.0001) and size (P<0.02), were used to classify patients into three groups with different risks of relapse at 10 years: (1) lowest (8.4%) risk: SBR I and < or =1 cm; (2) intermediate (20%) risk: SBR I and >1 cm or SBR II or SBR III and < or =2 cm; (3) highest (32%) risk: SBR II or SBR III and >2 cm. A peak in the incidence of metastases was noted between 2 and 4 years, and a nadir between 6 and 8 years, after surgery. SBR grade is a highly predictive factor in node-negative breast cancer. The time course of the appearance of metastases is not linear. Prognostic factors are related to the height of an early peak in the occurrence of metastases rather than to the timing of this peak.

Can sequential administration minimise the cost of high dose chemotherapy? An economic assessment in inflammatory breast cancer.

OBJECTIVE: To evaluate the potential cost savings of using sequential high dose chemotherapy (HDC), with granulocyte colony-stimulating factor (filgrastim) and stem cell support, rather than single course administration of HDC with bone marrow transplantation (BMT) or peripheral blood stem cell transplantation (PBSCT). PERSPECTIVE: French public hospital perspective. METHODS: Direct medical costs of sequential treatment, estimated on the basis of physical quantities of resources consumed by 95 patients with inflammatory breast cancer (IBC) included in a French pilot multicentric trial (PEGASE 02), were compared with those of historical control groups of patients treated with single course HDC, either with BMT (n = 27) or PBSCT (n = 14). Costs were evaluated in 1998 French francs (1 Euro = 6.55957 French francs). RESULTS: The total cost of sequential HDC was significantly lower than that for single course HDC both with BMT (-29%; 22,755 Euros vs 32,284 Euros; p < 0.001) or PBSCT (-16%; 22,755 Euros vs 27,209 Euros; p = 0.026). This was mainly due to a reduction in the length of hospitalisation in transplantation units. CONCLUSION: According to our results, economic arguments cannot be used against the widespread use of sequential HDC for patients with IBC. However, further economic evaluations based on overall and disease-free survivals alongside a randomised clinical trial are still needed to definitively establish the cost effectiveness of sequential administration of HDC.

Unexpected toxicities in elderly patients treated with oral idarubicin in metastatic breast cancer: the GINECO experience.

AIMS: Chemotherapy can be considered for many elderly patients with metastatic hormone-resistant breast cancer. Idarubicin, the only orally administrated cytotoxic agent belonging to the anthracycline family, may be a potential alternative to intravenous chemotherapy for this population for quality-of-life reasons. MATERIALS AND METHODS: Between November 2000 and June 2001, 26 consecutive patients were included in an open, multicentre, phase II trial. All patients presented with metastatic hormone-resistant breast cancer and were over 70 years old. Eligibility requirements included the following: no prior chemotherapy for their metastatic disease, performance status (PS) 0-2, normal heart function, blood counts and liver function. Treatment consisted of oral idarubicin 20 mg/m2/week, and the dose was individually adjusted according to the observed haematological toxicity. A multi-dimensional geriatric assessment (MGA) was performed at baseline to assess the potential prognostic value of geriatric co-variates (autonomy, physical ability, co-morbidity, nutritional status, cognitive function) on chemotherapy feasibility and efficacy. RESULTS: The trial was stopped after three toxic deaths were recorded. Two patients died of septicaemia with and without neutropenia, and the remaining patient developed congestive heart failure unresponsive to appropriate medication. Treatment was stopped for six other patients because of severe toxicity. Among the 19 patients who could be evaluated, disease had progressed in 14 (74%) at the first evaluation (2 months). Other than poor PS, no particular MGA factor proved helpful in predicting such a poor outcome. CONCLUSION: Owing to the lack of efficacy and unacceptably high toxicity, weekly oral idarubicin should not be given to patients over 70 years old with poor PS and metastatic hormone-resistant breast cancer. The data obtained do not support the use of oral idarubicin in elderly patients, but oral administration of other drugs (vinorelbine, capecitabine) should be assessed, with careful monitoring of the patients, in light of our findings.

Final results of an international retrospective observational study in patients with advanced breast cancer treated with oral vinorelbine-based chemotherapy.

BACKGROUND: Full oral chemotherapy (CT) is an active and convenient therapeutic option for patients with advanced breast cancer (ABC). In this retrospective analysis, we reviewed the characteristics and the outcome of patients treated by oral vinorelbine either as a single-agent or in combination with capecitabine as first- or second-line CT in the metastatic setting. PATIENTS AND METHODS: We analysed 216 patients with ABC who started treatment with a full oral CT at 13 centers and seven countries between 2006 and 2008. To be eligible, patients must have received either as a first-(56%) or second-line (44%) therapy oral vinorelbine as a single-agent (54%) or in combination with capecitabine (46%). RESULTS: Main patients' characteristics in the full population (n=216): median age (range): 61 (32-87) years; categories of age: <50 years: 18%, 50-65 years: 44%, ≥ 65 years: 38%; hormone receptor-positive: 63%; ≥ 2 metastatic sites: 58%; visceral metastases: 49%; prior CT: 86%; prior CT for ABC: 44%; prior anthracycline treatment: 69%; prior taxane treatment: 43%, prior anthracycline plus taxane: 38%; prior endocrine therapy: 63%. Median number of cycles: 6 (range=1-54); 48% of patients received more than 6 cycles. G3/4 toxicities: neutropenia 8%, anaemia 2%, thrombocytopenia 1%, febrile neutropenia/neutropenic infection 2%, nausea 6%, vomiting 4%, diarrhea 6%, fatigue 6%, hand-foot syndrome 14% (combination with capecitabine), neuropathy 1%, alopecia (grade 2) 1%. EFFICACY: disease control was achieved in 77% of patients [95% confidence interval=71-83%], 74% as single-agent, 81% in combination, 82% in first-line, 71% in second-line. Median progression-free survival was 9.7 months [95% confidence interval=8.2-12.6 months] in first-line and 6.6 months [95% confidence interval=5.5-8.5 months] in second-line therapy. Caregivers described these oral regimens as convenient (81%), well-tolerated (84%) and with a good compliance by patients (76%). CONCLUSION: These data from everyday practice confirm, as shown in different clinical trials, that oral vinorelbine is an active and well-tolerated CT for ABC, either as a first- or second-line in patients pre-treated with anthracyclines or taxanes. The convenience of its oral administration in association with its good tolerance profile, allows for continuation of treatment until disease progression without a pre-planned maximum of cycles.

Disease-related outcomes with long-term follow-up: an updated analysis of the intergroup exemestane study.

PURPOSE: Intergroup Exemestane Study (IES), an investigator-led study in 4,724 postmenopausal patients with early-stage breast cancer has demonstrated clinically important benefits from switching adjuvant endocrine therapy after 2 to 3 years of tamoxifen to exemestane. Now, with longer follow-up, a large number of non-breast cancer-related events have been reported. Exploratory analyses describe breast cancer-free survival (BCFS) and explore incidence and patterns of the different competing events. PATIENTS AND METHODS: Patients who were disease-free after 2 to 3 years of adjuvant tamoxifen were randomly assigned to continue tamoxifen or switch to exemestane to complete 5 years of adjuvant endocrine therapy. At this planned analysis, the median follow-up was 91 months. Principal analysis focuses on 4,052 patients with estrogen receptor (ER) -positive and 547 with ER-unknown tumors. RESULTS: In all, 930 BCFS events have been reported (exemestane, 423; tamoxifen, 507), giving an unadjusted hazard ratio (HR) of 0.81 (95% CI, 0.71 to 0.92; P = .001) in favor of exemestane in the ER-positive/ER unknown group. Analysis partitioned at 2.5 years after random assignment showed that the on-treatment benefit of switching to exemestane (HR, 0.60; 95% CI, 0.48 to 0.75; P < .001) was not lost post-treatment, but that there was no additional gain once treatment had ceased (HR, 0.94; 95% CI, 0.80 to 1.10; P = .60). Improvement in overall survival was demonstrated, with 352 deaths in the exemestane group versus 405 deaths in the tamoxifen group (HR, 0.86; 95% CI, 0.75 to 0.99; P = .04). Of these, 222 were reported as intercurrent deaths (exemestane, 107; tamoxifen, 115). CONCLUSION: The protective effect of switching to exemestane compared with continuing on tamoxifen on risk of relapse or death was maintained for at least 5 years post-treatment and was associated with a continuing beneficial impact on overall survival.

One-year longitudinal study of fatigue, cognitive functions, and quality of life after adjuvant radiotherapy for breast cancer.

PURPOSE: Most patients with localized breast cancer (LBC) who take adjuvant chemotherapy (CT) complain of fatigue and a decrease in quality of life during or after radiotherapy (RT). The aim of this longitudinal study was to compare the impact of RT alone with that occurring after previous CT on quality of life. METHODS AND MATERIALS: Fatigue (the main endpoint) and cognitive impairment were assessed in 161 CT-RT and 141 RT patients during RT and 1 year later. Fatigue was assessed with Functional Assessment of Cancer Therapy-General questionnaires, including breast and fatigue modules. RESULTS: At baseline, 60% of the CT-RT patients expressed fatigue vs. 33% of the RT patients (p <0.001). Corresponding values at the end of RT were statistically similar (61% and 53%), and fatigue was still reported at 1 year by more than 40% of patients in both groups. Risk factors for long-term fatigue included depression (odds ratio [OR] = 6), which was less frequent in the RT group at baseline (16% vs. 28 %, respectively, p = 0.01) but reached a similar value at the end of RT (25% in both groups). Initial mild cognitive impairments were reported by RT (34 %) patients and CT-RT (24 %) patients and were persistent at 1 year for half of them. No biological disorders were associated with fatigue or cognitive impairment. CONCLUSIONS: Fatigue was the main symptom in LBC patients treated with RT, whether they received CT previously or not. The correlation of persistent fatigue with initial depressive status favors administering medical and psychological programs for LBC patients treated with CT and/or RT, to identify and manage this main quality-of-life-related symptom.

[Node negative breast cancer. Beyond international consensus: a pragmatic approach]. / Le cancer du sein sans envahissement ganglionnaire. Au-delà des consensus internationaux: une approche pragmatique.

Apart from therapeutic advances related to new treatments, our practices in the management of early breast cancer have been modified by to key organizational settings (1) mass screening, substantially altering the presentation and epidemiology of breast cancer and (2) the development of guidelines to ensure that any patient management is in agreement with the demonstrated impact in the adjuvant treatment. In daily practice, the impact of screening and guidelines recommendations has put us now in a paradoxical situation: while the majority of non-metastatic breast cancers treated in the hexagon are node negative, most of the results of clinical studies on chemotherapy and targeted therapies today arise from populations predominantly node positive. Therefore, it seemed legitimate to convene a working group around a reflection on the directions of adjuvant chemotherapy in a growing node negative population in order to better respond to the questions of the field oncologists, trying to address the discrepancies between different existing guidelines.

Phase III study of bevacizumab plus docetaxel compared with placebo plus docetaxel for the first-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer.

PURPOSE: The efficacy and safety of combining bevacizumab (7.5 and 15 mg/kg) with docetaxel as first-line therapy for human epidermal growth factor receptor 2 (HER2) -negative, locally recurrent or metastatic breast cancer (MBC) was investigated in a three-arm, placebo-controlled, phase III trial. PATIENTS AND METHODS: Patients (N = 736) were randomly assigned to docetaxel 100 mg/m(2) plus either placebo or bevacizumab 7.5 or 15 mg/kg every 3 weeks. The primary end point was progression-free survival (PFS); secondary end points included best overall response, duration of response, time to treatment failure, overall survival, and safety. RESULTS: Combination of bevacizumab 15 mg/kg, but not 7.5 mg/kg, with docetaxel showed superior median PFS (mPFS) to placebo plus docetaxel in unstratified analysis (placebo mPFS, 8.2 months; 7.5 mg/kg mPFS, 9.0 months [hazard ratio (HR), 0.86; P = .12]; 15 mg/kg mPFS, 10.1 months [HR, 0.77; P = .006]) and stratified analysis (placebo mPFS, 8.1 months; 7.5 mg/kg mPFS, 9.0 months [HR, 0.80; P = .045]; 15 mg/kg mPFS, 10.0 months [HR, 0.67; P < .001]). Response rates in patients with measurable disease at baseline also increased with bevacizumab 15 mg/kg (46% [placebo] v 55% [7.5 mg/kg; P = .07] and 64% [15 mg/kg; P < .001]). Combination with bevacizumab had limited impact on the known toxicity profile of docetaxel. CONCLUSION: Combination of bevacizumab with docetaxel did not significantly impact on the safety profile of docetaxel. Bevacizumab 15 mg/kg every 3 weeks significantly increased PFS when combined with docetaxel as first-line therapy for MBC compared with docetaxel plus placebo.

Phase III study of gemcitabine plus docetaxel compared with capecitabine plus docetaxel for anthracycline-pretreated patients with metastatic breast cancer.

PURPOSE: Patients with metastatic breast cancer who are pretreated with anthracyclines frequently receive taxane-based combinations. This phase III study compared the efficacy and safety of gemcitabine-docetaxel (GD) with capecitabine-docetaxel (CD) in advanced breast cancer. PATIENTS AND METHODS: Patients were randomly assigned to GD (G 1,000 mg/m(2) days 1 and 8; D 75 mg/m(2) day 1) or CD (C 1,250 mg/m(2) twice daily days 1 through 14; D 75 mg/m(2) day 1) every 21 days. Comparison of progression-free survival (PFS) was the primary objective. RESULTS: Patient characteristics were balanced between arms (N = 305). Median PFS was 8.05 months (95% CI, 6.60 to 8.71) for GD and 7.98 (95% CI, 6.93 to 8.77) for CD (log-rank P = .121). Overall response rate (ORR) was 32% in both arms, and overall survival (OS) was not different between arms (P = .983). Time to treatment failure (TTF; defined as discontinuation, progressive disease, death as a result of any cause, or the start of a new anticancer therapy) was superior in the GD arm (P = .059). Hematologic toxicity was similar in both arms, except for grades 3 to 4 leukopenia (GD, 78%; CD, 66%; P = .025) and transfusions (GD, 17%; CD, 7%; P = .0051). Grades 3 to 4 diarrhea, mucositis, and hand-and-foot syndrome were significantly higher in the CD arm. Fewer patients in the GD arm discontinued because of drug-related adverse events (13% v 27% in CD; P = .002). CONCLUSION: No difference was observed between GD and CD arms in PFS, ORR, and OS. TTF was longer in the GD arm. These findings, combined with a nonhematologic toxicity profile that favors GD over approved doses of CD, suggest that gemcitabine may be a better option than capecitabine in combination with docetaxel in this clinical setting.

Trastuzumab for patients with axillary-node-positive breast cancer: results of the FNCLCC-PACS 04 trial.

PURPOSE: To evaluate the efficacy of trastuzumab in patients with node-positive breast cancer treated with surgery, adjuvant chemotherapy, radiotherapy, and hormone therapy if applicable. PATIENTS AND METHODS: Three thousand ten patients with operable node-positive breast cancer were randomly assigned to receive adjuvant anthracycline-based chemotherapy with or without docetaxel. Patients who presented human epidermal growth factor receptor 2 (HER2) -overexpressing tumors were secondary randomly assigned to either a sequential regimen of trastuzumab (6 mg/kg every 3 weeks) for 1 year or observation. The primary end point was disease-free survival (DFS). RESULTS: Overall 528 patients were randomly assigned between trastuzumab (n = 260) and observation (n = 268) arm. Of the 234 patients (90%) who received at least one administration of trastuzumab, 196 (84%) received at least 6 months of treatment, and 41 (18%) discontinued treatment due to cardiac events (any grade). At the date of analysis (October 2007), 129 DFS events were recorded. Random assignment to the trastuzumab arm was associated with a nonsignificant 14% reduction in the risk of relapse (hazard ratio, 0.86; 95% CI, 0.61 to 1.22; P = .41, log-rank stratified on pathologic node involvement). Three-year DFS rates were 78% (95% CI, 72.3 to 82.5) and 81% (95% CI, 75.3 to 85.4) in the observation and trastuzumab arms, respectively. CONCLUSION: After a 47-month median follow-up, 1 year of trastuzumab given sequentially after adjuvant chemotherapy was not associated with a statistically significant decrease in the risk of relapse.

Phase I-II study of pegylated liposomal doxorubicin combined with weekly paclitaxel as first-line treatment in patients with metastatic breast cancer.

OBJECTIVES: Pegylated liposomal doxorubicin (PLD) appears to be as active as doxorubicin in first-line metastatic breast cancer (MBC) patients, with lower cardiac toxicity. This phase I-II trial aimed to determine the dose limiting toxicity (DLT) and recommended dose (RD) of a first-line combination of PLD and weekly paclitaxel. METHODS: MBC patients received PLD on day 1, administered over 60 minutes IV. (starting dose 30 mg/m2, escalation by 5 mg/m2 increments), and paclitaxel on days 1, 8, and 15. Initially (schedule A), paclitaxel was administered over 60 minutes (starting dose 80 mg/m2, 10 mg/m2 increments), then (schedule B) over 24 hours on day 1 (at a dose of 70 mg/m2, 10 mg/m2 increments), and in a 60 minute IV infusion at a fixed dose of 90 mg/m2 on days 8 and 15. Pharmacokinetics were assessed during cycle 1 in schedule B. RESULTS: Thirty patients were treated (schedules A = 9; B = 21). Because of cutaneomucous toxicities in all patients in schedule A with discontinuation in 5 patients, schedule B was explored. Two DLTs (febrile neutropenia) occurred, with PLD 35 mg/m2 with paclitaxel 80 mg/m2 day 1 and 90 mg/m2 days 8 and 15 identified as recommended dose. Pharmacokinetic evaluation revealed an interaction, with increased levels of free doxorubicin and PLD during the paclitaxel infusion. CONCLUSIONS: This combination according to schedule and dosages results in cutaneomucous and hematological toxicity, probably because of a pharmacokinetic interaction, which is poorly compatible with a good quality of life for MBC patients.

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.