UCBG 2-08: 5-year efficacy results from the UNICANCER-PACS08 randomised phase III trial of adjuvant treatment with FEC100 and then either docetaxel or ixabepilone in patients with early-stage, poor prognosis breast cancer.

PURPOSE: UNICANCER-PACS08 compared adjuvant FEC (5-FU; epirubicin; cyclophosphamide) then docetaxel to FEC then ixabepilone in poor prognosis early breast cancer (BC). We evaluated whether replacing docetaxel with ixabepilone would increase 5-year disease-free survival (DFS). PATIENTS AND METHODS: Triple-negative breast cancer (TNBC) or oestrogen receptor (ER)+/progesterone receptor (PR)-/HER2- BC patients were randomised to receive standard FEC (3 cycles) followed by 3 cycles of either docetaxel (100 mg/m2) or ixabepilone (40 mg/m2). Radiotherapy was mandatory after conservative surgery; ER+ patients received endocrine therapy. RESULTS: Seven hundred sixty-two patients were enrolled between October 2007 and September 2010. Baseline characteristics were balanced between arms. Median follow-up was 66.7 months. Median DFS was not reached; 5-year DFS rate was 76% with docetaxel and 79% with ixabepilone (hazard ratio [HR] = 0.80; 95% confidence interval [CI] = 0.58-1.10; p = 0.175). Median overall survival (OS) was not reached; 5-year OS rate was 86% versus 84% (HR = 0.97; 95% CI = 0.66-1.42; p = 0.897). TNBC patients treated with ixabepilone had a 23% lower risk of relapse compared to docetaxel (HR for DFS = 0.77; 95% CI = 0.53-1.11; p = 0.168). DFS was longer with ixabepilone than docetaxel in patients with grade II-III lymphocytic infiltration (HR = 0.55; 95% CI = 0.29-1.05; p = 0.063). All patients experienced ≥1 adverse events (AEs): 75% reported grade III-IV AEs and two (<1%) had grade V AEs (both with neutropenia and infection receiving ixabepilone). CONCLUSION: After adjuvant FEC, ixabepilone was comparable to docetaxel for treating poor prognosis early BC patients. The benefit of ixabepilone in subgroups (patients with TNBC and grade II-III lymphocytic infiltration) requires further evaluation.

RESILIENCE: Phase III Randomized, Double-Blind Trial Comparing Sorafenib With Capecitabine Versus Placebo With Capecitabine in Locally Advanced or Metastatic HER2-Negative Breast Cancer.

INTRODUCTION: Sorafenib is a multikinase inhibitor with antiangiogenic/antiproliferative activity. In this randomized, double-blind, placebo-controlled phase III trial, we assessed first- or second-line capecitabine with sorafenib or placebo in patients with locally advanced/metastatic HER2-negative breast cancer resistant to a taxane and anthracycline and with known estrogen/progesterone receptor status. PATIENTS AND METHODS: A total of 537 patients were randomized to capecitabine 1000 mg/m2 orally twice per day for days 1 to 14 every 21 days with oral sorafenib 600 mg/d or placebo. The primary end point was progression-free survival (PFS). Patients were stratified according to hormone receptor status, previous chemotherapies for metastatic breast cancer, and geographic region. RESULTS: Treatment with sorafenib with capecitabine, compared with capecitabine with placebo, did not prolong median PFS (5.5 vs. 5.4 months; hazard ratio [HR], 0.973; 95% confidence interval [CI], 0.779-1.217; P = .811) or overall survival (OS; 18.9 vs. 20.3 months; HR, 1.195; 95% CI, 0.943-1.513; P = .140); or enhance overall response rate (ORR; 13.5% vs. 15.5%; P = .515). Any grade toxicities (sorafenib vs. placebo) included palmar-plantar erythrodysesthesia syndrome (PPES; 79.2% vs. 59.6%), diarrhea (47.3% vs. 37.8%), mucosal inflammation (15.4% vs. 6.7%), and hypertension (26.2% vs. 5.6%). Grade 3/4 toxicities included PPES (15.4% vs. 7.1%), diarrhea (4.2% vs. 6.4%), and vomiting (3.5% vs. 0.7%). CONCLUSION: The combination of sorafenib with capecitabine did not improve PFS, OS, or ORR in patients with HER2-negative advanced breast cancer. Rates of Grade 3 toxicities were higher in the sorafenib arm.

Optimal duration of adjuvant chemotherapy for high-risk node-negative (N-) breast cancer patients: 6-year results of the prospective randomised multicentre phase III UNICANCER-PACS 05 trial (UCBG-0106).

PURPOSE: Optimal duration of adjuvant chemotherapy in the treatment of early-stage breast cancer remained to be investigated rigorously for the standard regimens in widespread use in North America (doxorubicin/cyclophosphamide, AC) and Europe (5-fluorouracil/epirubicin/cyclophosphamide, FEC). Whether six cycles of FEC 100 present an advantage, or not, compared with only four cycles was tested directly in a phase III prospective multicentre trial. PATIENTS AND METHODS: Between 2002 and 2006, 1515 women between 18 and 65°years of age, with node negative N(-) high-risk early-stage breast cancer, were included in the study following breast surgery and axillary lymph node dissection or procedure by sentinel node technique. Inclusion in the study required tumour size T ≥ 1 cm and at least one of the high-risk factors: T > 2 cm, negative oestrogen receptor/progesterone receptor (ER- and PR-), Scarff-Bloom-Richardson (SBR) grade II or III and age ≤ 35°years. Patients were randomly assigned to either six FEC 100 (Arm A) or four FEC 100 (Arm B). The trial was powered to detect an absolute difference ≥6% in disease-free survival (DFS) at 5°years. RESULTS: At 6.1°years median follow-up, with 91 (12%) events recorded in Arm A versus 106 (14%) in Arm B, no statistically significant risk increase was associated with four versus six FEC 100: DFS (hazard ratio (HR) = 1.18; CI 95% [0.89-1.56], P = .24) and overall survival (OS) (HR = 1.39; CI 95% [0.91-2.13], P = .12). CONCLUSION: Differences in chemotherapy duration did not induce notably different outcomes in our cohort of high-risk patients. CLINICAL TRIAL REGISTRY NUMBER: NCT00055679, Agence National de Sécurité du Médicament (ANSM) - France.

Circulating oxysterol metabolites as potential new surrogate markers in patients with hormone receptor-positive breast cancer: Results of the OXYTAM study.

Accumulating evidence indicates that cholesterol oxygenation products, also known as oxysterols (OS), are involved in breast cancer (BC) promotion. The impact of Tam, as well as aromatase inhibitors (AI), an alternative BC endocrine therapy (ET), on OS metabolism in patients is currently unknown. We conducted a prospective clinical study in BC patients receiving Tam (n=15) or AI (n=14) in adjuvant or in metastatic settings. The primary end point was the feasibility of detecting and quantifying 11 different OS in the circulation of patients before and after 28days of treatment with Tam or AI. Key secondary end points were the measurements of variations in the concentrations of OS according to differences between patients and treatments. OS profiling in the serum of patients was determined by gas chromatography coupled to mass spectrometry. OS profiling was conducted in all patients both at baseline and during treatment regimens. An important inter-individual variability was observed for each OS. Interestingly 5,6ß-epoxycholesterol relative concentrations significantly increased in the entire population (p=0.0109), while no increase in Cholestane-triol (CT) levels was measured. Interestingly, we found that, in contrast to AI, Tam therapy significantly decreased blood levels of 24-hydroxycholesterol (24-HC), 7α-HC and 25-HC (a tumor promoter) (p=0.0007, p=0.0231 and p=0.0231, respectively), whereas 4ß-HC levels increased (p=0.0010). Interestingly, levels of 27-HC (a tumor promoter) significantly increased in response to AI (p=0.0342), but not Tam treatment. According to these results, specific OS are promising candidate markers of Tam and AI efficacy. Thus, further clinical investigations are needed to confirm the use of oxysterols as biomarkers of both prognosis and/or the efficacy of ET.

Dermatological adverse events with taxane chemotherapy.

Taxanes (docetaxel and paclitaxel) are among the most commonly prescribed anticancer drugs approved for the treatment of metastatic or locally advanced breast, non-small cell lung, prostate, gastric, head and neck, and ovarian cancers, as well as in the adjuvant setting for operable node-positive breast cancers. Although the true incidence of dermatological adverse events (AEs) in patients receiving taxanes is not known, and has never been prospectively analysed, they clearly represent one of the major AEs associated with these agents. With an increase in the occurrence of cutaneous AEs during treatment with novel targeted and immunological therapies when used in combination with taxanes, a thorough understanding of reactions attributable to this class is imperative. Moreover, identification and management of dermatological AEs is critical for maintaining the quality of life in cancer patients and for minimizing dose modifications of their antineoplastic regimen. This analysis represents a systematic review of the dermatological conditions reported with the use of these drugs, complemented by experience at comprehensive cancer centres. The conditions reported herein include skin, hair, and nail toxicities. Lastly, we describe the dermatological data available for the new, recently FDA-and EMA- approved, solvent-free nab-paclitaxel.

Effect of obesity on disease-free and overall survival in node-positive breast cancer patients in a large French population: a pooled analysis of two randomised trials.

BACKGROUND: To examine the association between baseline body mass index (BMI), and disease-free survival (DFS) and overall survival (OS) in a large French early-stage breast cancer population included in the UNICANCER Programme d'Action Concerté Sein-01 (PACS01) and PACS04 phase III randomised trials. METHODS: After a median follow-up of 5.9years, this report analyses 4996 patients with node-positive breast cancer, and randomly assigned to adjuvant anthracycline-based chemotherapy combined or not with taxanes. Univariate analyses were used to study the effects of well known prognostic factors and BMI on DFS and OS. BMI was obtained at baseline, before chemotherapy initiation, and obesity was defined as a BMI⩾30kg/m(2). Cox proportional hazards regression models were secondly used to assess the influence of BMI after adjusting for other factors. Exhaustive analysis of the dose intensity delivered was also studied for comparison between obese and non-obese patients. RESULTS: Obese patients initially present with more advanced disease at diagnosis compared to non-obese patients. By univariate analysis, obesity was moderately associated with poorer DFS (hazard ratio (HR)=1.18 [1.01-1.39] P=0.04), but mostly with poorer OS (HR=1.38 [1.13-1.69] P=0.002). Delivered dose intensity of anthracyclines and taxanes was not significantly different between obese and non-obese patients. After adjustment for disease characteristics, BMI had no influence either on DFS or OS. CONCLUSION: This report suggests that in a French population, obesity has no impact on breast cancer prognosis when modern adjuvant chemotherapy, at the appropriate dose intensity, is delivered.

A phase 3 tRial comparing capecitabinE in combination with SorafenIb or pLacebo for treatment of locally advanced or metastatIc HER2-Negative breast CancEr (the RESILIENCE study): study protocol for a randomized controlled trial.

BACKGROUND: Sorafenib is an oral multikinase inhibitor with antiangiogenic/antiproliferative activity. A randomized phase 2b screening trial in human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer demonstrated a significant improvement in progression-free survival (PFS) when sorafenib was added to capecitabine versus placebo (median 6.4 versus 4.1 months; hazard ratio = 0.58; P = 0.001). Most drug-related adverse events were Grade 1/2 in severity with the exception of Grade 3 hand-foot skin reaction/syndrome (44% versus 14%, respectively). These results suggest a role for the combination of sorafenib and capecitabine in breast cancer and supported a phase 3 confirmatory trial. Here we describe RESILIENCE - a multinational, double-blind, randomized, placebo-controlled, phase 3 trial - assessing the addition of sorafenib to first- or second-line capecitabine in advanced HER2-negative breast cancer. METHODS/DESIGN: Eligibility criteria include ≥18 years of age, ≤1 prior chemotherapy regimen for metastatic disease, and resistant to/failed taxane and anthracycline or no indication for further anthracycline. Prior treatment with a vascular endothelial growth factor inhibitor is not allowed. Patients with significant cardiovascular disease or active brain metastases are not eligible. Patients are stratified by hormone-receptor status, geographic region, and prior metastatic chemotherapy status and randomized (1:1) to capecitabine (1000 mg/m2 orally twice daily (BID), days 1 to 14 of 21) in combination with sorafenib (orally BID, days 1 to 21, total dose 600 mg/day) or matching placebo. Capecitabine and sorafenib/placebo doses can be escalated to 1250 mg/m2 BID and 400 mg BID, respectively, as tolerated, or reduced to manage toxicity. Dose re-escalation after a reduction is allowed for sorafenib/placebo but not for capecitabine. This dosing algorithm was designed to mitigate dermatologic and other toxicity, in addition to detailed guidelines for prophylactic and symptomatic treatment. Radiographic assessment is every 6 weeks for 36 weeks, and every 9 weeks thereafter. The primary endpoint is PFS by blinded independent central review (Response Evaluation Criteria in Solid Tumors 1.1 criteria). Secondary endpoints include overall survival, time to progression, overall response rate, duration of response, and safety. Enrollment began in November 2010 with a target of approximately 519 patients. DISCUSSION: RESILIENCE will provide definitive PFS data for the combination of sorafenib and capecitabine in advanced HER2-negative breast cancer and better characterize the benefit-to-risk profile. TRIAL REGISTRATION: Clinicaltrials.gov, NCT01234337.

Failure event types and prognostic factors after node-positive breast cancer in patients treated by adjuvant chemotherapy: impact on follow-up.

PURPOSE: The role of post-therapeutic follow-up for breast cancer patients (pts) is open to debate. The aim of this study was to identify prognostic factors associated with the type of first event. METHODS: Data of 2,820 pts included in three adjuvant trials for node-positive breast cancer were used. Competing risk methodology was used to identify prognostic factors associated with time to first failure according to type of event. RESULTS: After a median follow-up of 53 months, 732 pts had disease-related events (114 locoregional, 58 contralateral, and 560 distant metastasis). The prognostic factors associated with high locoregional recurrence were young age, number of positive lymph nodes and grade III. In multivariate analysis, the type of first event influenced post-relapse survival. Nottingham Prognostic Index identified three groups of pts at different risk of relapse. CONCLUSION: Early relapse is rare in the first year after surgery and is associated with more aggressive disease. Using the Nottingham Prognostic Index, it is possible to identify pts at lower risks of relapse for whom it seems reasonable to limit the frequency of routine follow-up during the first years. For pts at higher risk of locoregional recurrence, regular follow-up should be maintained in order to detect potential curative events.

Sorafenib in combination with capecitabine: an oral regimen for patients with HER2-negative locally advanced or metastatic breast cancer.

PURPOSE: Sorafenib is a multikinase inhibitor with antiangiogenic/antiproliferative activity. A randomized, double-blind, placebo-controlled phase IIB trial assessed sorafenib with capecitabine for locally advanced or metastatic human epidermal growth factor receptor 2 (HER2) -negative breast cancer. PATIENTS AND METHODS: Patients were randomly assigned to first- or second-line capecitabine 1,000 mg/m(2) orally twice a day for days 1 to 14 of every 21-day cycle with sorafenib 400 mg orally twice a day or placebo. The primary end point was progression-free survival (PFS). RESULTS: In total, 229 patients were enrolled. The addition of sorafenib to capecitabine resulted in a significant improvement in PFS versus placebo (median, 6.4 v 4.1 months; hazard ratio [HR], 0.58; 95% CI, 0.41 to 0.81; P = .001) with sorafenib favored across subgroups, including first-line (HR, 0.50; 95% CI, 0.30 to 0.82) and second-line (HR, 0.65; 95% CI, 0.41 to 1.04) treatment. There was no significant improvement for overall survival (median, 22.2 v 20.9 months; HR, 0.86; 95% CI, 0.61 to 1.23; P = .42) and overall response (38% v 31%; P = .25). Toxicities (sorafenib v placebo) of any grade included rash (22% v 8%), diarrhea (58% v 30%), mucosal inflammation (33% v 21%), neutropenia (13% v 4%), hypertension (18% v 12%), and hand-foot skin reaction/hand- foot syndrome (HFSR/HFS; 90% v 66%); grade 3 to 4 toxicities were comparable between treatment arms except HFSR/HFS (44% v 14%). Reasons for discontinuation in the sorafenib and placebo arms included disease progression (63% v 82%, respectively), adverse events (20% v 9%, respectively), and death (0% v 1%, respectively). CONCLUSION: Addition of sorafenib to capecitabine improved PFS in patients with HER2-negative advanced breast cancer. The dose of sorafenib used in this trial resulted in unacceptable toxicity for many patients. A phase III confirmatory trial has been initiated with a reduced sorafenib dose.

Motesanib, or open-label bevacizumab, in combination with paclitaxel, as first-line treatment for HER2-negative locally recurrent or metastatic breast cancer: a phase 2, randomised, double-blind, placebo-controlled study.

BACKGROUND: Vascular endothelial growth factor (VEGF) has a crucial role in angiogenesis, and is a valid target in metastatic breast cancer. Motesanib is an investigational oral inhibitor of VEGF receptors. We aimed to determine whether treatment with motesanib plus paclitaxel is better than placebo plus paclitaxel in patients with HER2-negative locally recurrent or metastatic breast cancer. METHODS: Between Dec 1, 2006, and July 4, 2008, patients with untreated HER2-negative metastatic breast cancer were randomly assigned (using a randomisation list created by personnel not associated with the study) in a 1:1:1 ratio to paclitaxel (90 mg/m(2) on days 1, 8, and 15 every 3 weeks) plus either masked motesanib 125 mg orally once per day (n=91), masked placebo orally once per day (n=94), or open-label bevacizumab 10 mg/kg intravenously on days 1 and 15 of each 28-day cycle (n=97), after stratification according to adjuvant or neoadjuvant chemotherapy (taxane-containing regimens vs other regimens vs none), number of metastatic sites (<3 vs ≥3), and hormone receptor status (positive vs negative). Placebo was provided as a replica of motesanib 25 mg tablets. The primary endpoint was objective response rate (ORR) based on the population as assigned to treatment. This trial is registered with ClinicalTrials.gov, number NCT00356681. FINDINGS: ORRs for the motesanib group and the placebo group did not differ significantly (49%vs 41%; absolute difference 8% [95% CI -6 to 22]; p=0.31). The ORR in the bevacizumab group (52%) was similar to that in the motesanib group. The most common grade 3 or higher adverse events included diarrhoea (18 of 92 patients in the motesanib group, none of 89 patients in the placebo group, and four of 96 patients in the bevacizumab group), fatigue (11, eight, and six), hypertension (11, one, and seven), and peripheral sensory neuropathy (ten, seven, and 19). More patients in the motesanib group had serious adverse events than did those in the placebo or bevacizumab groups (34, 26, and 21 patients, respectively); the most common of these in the motesanib group were gastrointestinal in nature. INTERPRETATION: Data from this trial do not support the further investigation of motesanib at this dose and schedule in this population. FUNDING: Amgen.

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.

A 38-gene expression signature to predict metastasis risk in node-positive breast cancer after systemic adjuvant chemotherapy: a genomic substudy of PACS01 clinical trial.

Currently, no prognostic gene-expression signature (GES) established from node-positive breast cancer cohorts, able to predict evolution after systemic adjuvant chemotherapy, exists. Gene-expression profiles of 252 node-positive breast cancer patients (median follow-up: 7.7 years), mostly included in a randomized clinical trial (PACS01), receiving systemic adjuvant regimen, were determined by means of cDNA custom array. In the training cohort, we established a GES composed of 38 genes (38-GES) for the purpose of predicting metastasis-free survival. The 38-GES yielded unadjusted hazard ratio (HR) of 4.86 (95% confidence interval = 2.76-8.56). Even when adjusted with the best two clinicopathological prognostic indexes: Nottingham prognostic index (NPI) and Adjuvant!, 38-GES HRs were 3.30 (1.81-5.99) and 3.40 (1.85-6.24), respectively. Furthermore, 38-GES improved NPI and Adjuvant! classification. In particular, NPI intermediate-risk patients were divided into 2/3 close to low-risk group and 1/3 close to high-risk group (HR = 6.97 [2.51-19.36]). Similarly, Adjuvant! intermediate-risk patients were divided into 2/3 close to low-risk group and 1/3 close to high-risk group (HR = 4.34 [1.64-11.48]). The 38-GES was validated on gene-expression datasets from three external node-positive breast cancer subcohorts (n = 224) generated from different microarray platforms, with HR = 2.95 (1.74-5.01). Moreover, 38-GES showed prognostic performance in supplementary cohorts with different lymph-node status and endpoints (1,040 new patients). The 38-GES represents a robust tool able to type systemic adjuvant treated node-positive patients at high risk of metastatic relapse, and is especially powerful to refine NPI and Adjuvant! classification for those patients.

Sequential adjuvant epirubicin-based and docetaxel chemotherapy for node-positive breast cancer patients: the FNCLCC PACS 01 Trial.

PURPOSE: The PACS 01 trial compared six cycles of fluorouracil, epirubicin, and cyclophosphamide (FEC) with a sequential regimen of three cycles of FEC followed by three cycles of docetaxel (FEC-D) as adjuvant treatment for women with node-positive early breast cancer. PATIENTS AND METHODS: Between June 1997 and March 2000, 1,999 patients with operable node-positive breast cancer were randomly assigned to either FEC every 21 days for six cycles, or three cycles of FEC followed by three cycles of docetaxel, both given every 21 days. Hormone-receptor-positive patients received tamoxifen for 5 years after chemotherapy. The primary end point was 5-year disease-free survival (DFS). RESULTS: Median follow-up was 60 months. Five-year DFS rates were 73.2% with FEC and 78.4% with FEC-D (unadjusted P = .011; adjusted P = .012). Multivariate analysis adjusted for prognostic factors showed an 18% reduction in the relative risk of relapse with FEC-D. Five-year overall survival rates were 86.7% with FEC and 90.7% with FEC-D, demonstrating a 27% reduction in the relative risk of death (unadjusted P = .014; adjusted P = .017). The incidence of grade 3 to 4 neutropenia, the need for hematopoietic growth factor, and incidence of nausea/vomiting were higher with FEC. Docetaxel was associated with more febrile neutropenia in the fourth cycle, stomatitis, edema, and nail disorders. Though rare overall, there were fewer cardiac events after FEC-D (P = .03), attributable mainly to the lower anthracycline cumulative dose. CONCLUSION: Sequential adjuvant chemotherapy with FEC followed by docetaxel significantly improves disease-free and overall survival in node-positive breast cancer patients and has a favorable safety profile.

Epirubicin-based chemotherapy as adjuvant treatment for poor prognosis, node-negative breast cancer: 10-year follow-up results of the French Adjuvant Study Group 03 trial.

We evaluated the contribution of an epirubicin-based adjuvant chemotherapy on disease-free survival (DFS) in poor prognosis, node-negative breast cancer (BC) patients. Poor prognostic factors were defined as: pathologic tumor size >or= 4 cm, estrogen-receptor negative, and progesterone-receptor negative. Scarff-Bloom Richardson grade 2 tumors must have two of these factors, and only one in case of grade 3. Between 1988 and 1994, 328 patients were randomized to receive either no systemic treatment (control, n = 161), or fluorouracil 500 mg/m(2), epirubicin 50 mg/m(2), cyclophosphamide 500 mg/m(2), 6 cycles every 21 days (FEC50, n = 167), without any hormonal treatment. The median follow up was 114 months. The 10-year DFS rates were 64 and 71%, respectively (p = 0.23). In the Cox regression model, independent prognostic factors of relapse were the number of nodes examined < 10 (p = 0.002), BCS (p = 0.01), and premenopausal status (p = 0.04). In this model, the relative risk of relapse was 1.46 (CI95 %: 1.05-1.87) in favor of FEC50. In patients who underwent BCS, 21 % developed a local relapse (24 versus 18 %, respectively). The 10-year local DFS was 70.5 and 79.3 %, respectively (p = 0.27). The 10-year overall survival was not different (74.1 versus 70.7 %, p = 0.82). After 10 years of follow-up, the FEC50 regimen reduced the risk of relapse in poor-prognosis node-negative BC patients. The incidence of local relapse was high, and probably related to inclusion criteria. Epirubicin was probably underdosed in such patients, and ongoing studies using 100 mg/m(2) of epirubicin will give us the answer in a near future.

Inflammatory breast cancer outcome with epirubicin-based induction and maintenance chemotherapy: ten-year results from the French Adjuvant Study Group GETIS 02 Trial.

BACKGROUND: The authors evaluated the long-term efficacy and side effects in patients with nonmetastatic, unilateral, inflammatory breast cancer (IBC) who received homogeneous treatment with intensive induction chemotherapy followed by a maintenance regimen. METHODS: One hundred twenty patients were randomized to receive high-dose fluorouracil, epirubicin, and cyclophosphamide (FEC-HD) (fluorouracil 750 mg/m(2) on Days 1 to 4, epirubicin 35 mg/m(2) on Days 2 to 4, and cyclophosphamide 400 mg/m(2) on Days 2 to 4 for 4 cycles every 21 days) with or without lenograstim. Locoregional treatment consisted of surgery and/or radiotherapy. Maintenance chemotherapy was FEC 75 (fluorouracil 500 mg/m(2), epirubicin 75 mg/m(2), and cyclophosphamide 500 mg/m(2) on Day 1 every 21 days for 4 cycles). No hormone treatment was allowed. RESULTS: The safety of the FEC-HD regimen was described previously. Among 102 patients who underwent surgery, a pathologic complete response (pCR) was achieved by 23.5% of patients with breast tumors and by 31.4% of patients with involved axillary lymph nodes. The overall pCR rate was 14.7%. One hundred nine patients received FEC 75. After a median 10 years of follow-up, the disease-free survival (DFS) and overall survival (OS) rates were 35.7% and 41.2%, respectively. The median DFS was 39 months (95% confidence interval [95% CI], 25-53 months), and the median survival was 61 months (95% CI, 43-79 months). Five patients developed a temporary decrease in left ventricular ejection fraction without congestive heart failure. In the lenograstim group, 1 patient developed acute myeloblastic leukemia M2, and 1 patient developed myelodysplastic syndrome. CONCLUSIONS: FEC-HD induction chemotherapy followed by FEC 75 maintenance regimen had moderate and acute long-term toxicities and lead to high DFS and OS rates in patients with IBC.

Impact of uncertainty on cost-effectiveness analysis of medical strategies: the case of high-dose chemotherapy for breast cancer patients.

OBJECTIVES: The object of this study was to determine, taking into account uncertainty on cost and outcome parameters, the cost-effectiveness of high-dose chemotherapy (HDC) compared with conventional chemotherapy for advanced breast cancer patients. METHODS: An analysis was conducted for 300 patients included in a randomized clinical trial designed to evaluate the benefits, in terms of disease-free survival and overall survival, of adding a single course of HDC to a four-cycle conventional-dose chemotherapy for breast cancer patients with axillary lymph node invasion. Costs were estimated from a detailed observation of physical quantities consumed, and the Kaplan-Meier method was used to evaluate mean survival times. Incremental cost-effectiveness ratios were evaluated successively considering disease-free survival and overall survival outcomes. Handling of uncertainty consisted in construction of confidence intervals for these ratios, using the truncated Fieller method. RESULTS: The cost per disease-free life year gained was evaluated at 13,074 Euros, a value that seems to be acceptable to society. However, handling uncertainty shows that the upper bound of the confidence interval is around 38,000 Euros, which is nearly three times higher. Moreover, as no difference was demonstrated in overall survival between treatments, cost-effectiveness analysis, that is a cost minimization, indicated that the intensive treatment is a dominated strategy involving an extra cost of 7,400 Euros, for no added benefit. CONCLUSIONS: Adding a single course of HDC led to a clinical benefit in terms of disease-free survival for an additional cost that seems to be acceptable, considering the point estimate of the ratio. However, handling uncertainty indicates a maximum ratio for which conclusions have to be discussed.

Epirubicin increases long-term survival in adjuvant chemotherapy of patients with poor-prognosis, node-positive, early breast cancer: 10-year follow-up results of the French Adjuvant Study Group 05 randomized trial.

PURPOSE: The French Adjuvant Study Group 05 (FASG-05) showed that fluorouracil 500 mg/m2, cyclophosphamide 500 mg/m2, and epirubicin 100 mg/m2 (FEC 100) was superior to the same regimen with epirubicin 50 mg/m2 (FEC 50) in terms of disease-free survival (DFS) and overall survival (OS) in adjuvant treatment of early breast cancer. We report 10-year data on efficacy, and long-term side effects for FASG-05. PATIENTS AND METHODS: We randomly assigned 565 patients to treatment with FEC 50 or FEC 100 after surgery. Postmenopausal patients also received tamoxifen for 3 years, and almost all patients (96%) also received radiotherapy. RESULTS: Median follow-up was 110 months. The 10-year DFS was 45.3% (95% CI, 41.9% to 48.7%) with FEC 50 and 50.7% (95% CI, 47.3% to 54.1%) with FEC 100 (Wilcoxon P = .036; log-rank P = .08). The 10-year OS was 50.0% (95% CI, 46.7% to 53.3%) with FEC 50 and 54.8% (95% CI, 51.3% to 58.3%) with FEC 100 (Wilcoxon P = .038; log-rank P = .05). Delayed cardiac toxicity (before relapse) occurred in four patients (1.5%) in the FEC 50 arm and three patients (1.1%) in the FEC 100 arm. Cardiac toxicity after relapse occurred in six (4.3%) and five (4.1%) patients treated with FEC 50 and FEC 100, respectively. CONCLUSION: Treatment with adjuvant FEC 100 demonstrated superior DFS and OS versus FEC 50 at 10 years of follow-up. This survival advantage was not offset by long-term complications such as cardiac toxicity and second malignancy. Given the risk-benefit ratio, FEC 100 is a more optimal regimen for long-term survival in patients with poor prognosis.

Long-term cardiac follow-up in relapse-free patients after six courses of fluorouracil, epirubicin, and cyclophosphamide, with either 50 or 100 mg of epirubicin, as adjuvant therapy for node-positive breast cancer: French adjuvant study group.

PURPOSE To evaluate long-term cardiac function in patients without disease who had received six cycles of fluorouracil 500 mg/m(2), epirubicin 50 mg/m(2), and cyclophosphamide 500 mg/m(2) (FEC 50) or the same regimen with epirubicin 100 mg/m(2) (FEC 100) as adjuvant chemotherapy for node-positive breast cancer in the French Adjuvant Study Group-05 trial. PATIENTS AND METHODS One hundred fifty patients (FEC 50, n = 65; FEC 100, n = 85) who were without disease and who gave their informed consent were enrolled for long-term cardiac assessment. The assessment included cardiac events occurring after the end of chemotherapy, vital signs, concomitant disease, ECG, isotopic left ventricular ejection fraction (LVEF), and echographic parameters. Abnormal files were blindly reviewed by cardiologists and oncologists. Results The median follow-up time was 102 months. After FEC 100, LVEF was less than 50% in five patients (radioisotopic method), and two patients experienced congestive heart failure (CHF) that was possibly related to treatment. Asymptomatic left ventricular dysfunction (LVD) was experienced in 18 patients after FEC 100 and in one patient after FEC 50. In these patients, treatment causality was probable in eight patients. Two additional years after this assessment, all 18 patients were still asymptomatic. CONCLUSION After more than 8 years of follow-up, the cardiac toxicity observed after adjuvant treatment with FEC 100 comprised two cases of well-controlled CHF and 18 cases of asymptomatic LVD. In the majority of women with primary breast cancer, the benefits of treatment with FEC 100 in terms of disease-free and overall survival outweigh the risks, and cardiac risk factors should be carefully evaluated in patient selection.