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High rate of extra-haematological toxicity compromises dose-dense sequential adjuvant chemotherapy for breast cancer.

ABSTRACT: BACKGROUND: A dose-dense strategy has been considered to improve results of adjuvant chemotherapy for breast cancer. This randomised phase II trial investigated the feasibility of this approach with sequential anthracyclines and taxanes-based chemotherapy. METHODS: Patients with high-risk node-positive breast cancer were treated with three cycles of fluorouracil 500?mg?m(-2), epirubicin 100?mg?m(-2), cyclophosphamide 500?mg?m(-2) (FEC 100) followed by three cycles of docetaxel 100?mg?m(-2) delivered at 2-weekly intervals supported by primary prophylaxis with filgrastim. All patients were randomised to either uninterrupted treatment (arm A) or to have a 2-week additional period of rest between the FEC and docetaxel (arm B). The primary endpoint was the rate of success of chemotherapy delivery. Using a two-stage Fleming design, 120 patients were required with one interim analysis. RESULTS: In March 2005, enrolment was stopped into arm A after the observation of severe skin toxicities. Following the planned interim analysis, the study was closed because of the high rate of grade 3/4 skin toxicities in both arms (arm A: 32.4% and arm B: 18.9%). CONCLUSION: Sequential dose-dense FEC 100 followed by docetaxel 100?mg?m(-2) is not feasible. Feasibility still depends largely on several factors including the choice of drugs, dosage and sequence of administration.

SUBMITTER: Brain E

PROVIDER: S-EPMC3242527 | biostudies-literature | 2011 Nov

REPOSITORIES: biostudies-literature

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High rate of extra-haematological toxicity compromises dose-dense sequential adjuvant chemotherapy for breast cancer.

Brain E E Levy C C Serin D D Roché H H Spielmann M M Delva R R Veyret C C Mauriac L L Rios M M Martin A L AL Jimenez M M Asselain B B Gauthier M M Bonnetain F F Fumoleau P P

British journal of cancer 20111018 10

<h4>Background</h4>A dose-dense strategy has been considered to improve results of adjuvant chemotherapy for breast cancer. This randomised phase II trial investigated the feasibility of this approach with sequential anthracyclines and taxanes-based chemotherapy.<h4>Methods</h4>Patients with high-risk node-positive breast cancer were treated with three cycles of fluorouracil 500 mg m(-2), epirubicin 100 mg m(-2), cyclophosphamide 500 mg m(-2) (FEC 100) followed by three cycles of docetaxel 100 m ...[more]

PMID: 22009030

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Project description:HER2 and TOP2A parameters (gene status, mRNA and protein expression) have individually been associated with the outcome of patients treated with anthracyclines. The aim of this study was to comprehensively evaluate the prognostic/predictive significance of the above parameters in early, high-risk breast cancer patients treated with epirubicin-based, dose-dense sequential adjuvant chemotherapy.In a series of 352 breast carcinoma tissues from patients that had been post-operatively treated with epirubicin-CMF with or without paclitaxel, we assessed HER2 and TOP2A gene status (chromogenic in situ hybridization), mRNA expression (quantitative reverse transcription PCR), as well as HER2 and TopoIIa protein expression (immunohistochemistry).HER2 and TOP2A amplification did not share the same effects on their downstream molecules, with consistent patterns observed in HER2 mRNA and protein expression according to HER2 amplification (all parameters strongly inter-related, p values < 0.001), but inconsistent patterns in the case of TOP2A. TOP2A gene amplification (7% of all cases) was not related to TOP2A mRNA and TopoIIa protein expression, while TOP2A mRNA and TopoIIa protein were strongly related to each other (p < 0.001). Hence, TOP2A amplified tumors did not correspond to tumors with high TOP2A mRNA or TopoIIa protein expression, while the latter were characterized by high Ki67 scores (p = 0.003 and p < 0.001, respectively). Multivariate analysis adjusted for nodal involvement, hormone receptor status, Ki67 score and HER2/TOP2A parameters revealed HER2/TOP2A co-amplification (21.2% of HER2 amplified tumors) as an independent favorable prognostic factor for DFS (HR = 0.13, 95% CI: 0.02-0.96, p = 0.046); in contrast, increased HER2/TOP2A mRNA co-expression was identified as an independent adverse prognostic factor for both DFS (HR = 2.41, 95% CI: 1.31-4.42, p = 0.005) and OS (HR = 2.83, 95% CI: 1.42-5.63, p = 0.003), while high TOP2A mRNA expression was an independent adverse prognostic factor for OS (HR = 2.06, 95% CI: 1.23-3.46, p = 0.006). None of the parameters tested was associated with response to paclitaxel.This study confirms the favorable prognostic value of HER2/TOP2A co-amplification and the adverse prognostic value of high TOP2A mRNA expression extending it to the adjuvant treatment setting in early high-risk breast cancer. The strong adverse prognostic impact of high HER2/TOP2A mRNA co-expression needs further validation in studies designed to evaluate markers predictive for anthracyclines.Australian New Zealand Clinical Trials Registry ACTRN12611000506998.

Project description:BackgroundDose-dense sequential chemotherapy including anthracyclines and taxanes has been established in the adjuvant setting of high-risk operable breast cancer. However, the preferable taxane and optimal schedule of administration in a dose-dense regimen have not been defined yet.MethodsFrom July 2005 to November 2008, 1001 patients (990 eligible) were randomized to receive, every 2 weeks, 3 cycles of epirubicin 110 mg/m2 followed by 3 cycles of paclitaxel 200 mg/m2 followed by 3 cycles of intensified CMF (Arm A; 333 patients), or 3 cycles of epirubicin followed by 3 cycles of CMF, as in Arm A, followed 3 weeks later by 9 weekly cycles of docetaxel 35 mg/m2 (Arm B; 331), or 9 weekly cycles of paclitaxel 80 mg/m2 (Arm C; 326). Trastuzumab was administered for one year to HER2-positive patients post-radiation.ResultsAt a median follow-up of 60.5 months, the 3-year disease-free survival (DFS) rate was 86%, 90% and 88%, for Arms A, B and C, respectively, while the 3-year overall survival (OS) rate was 96% in all arms. No differences were found in DFS or OS between the combined B and C Arms versus Arm A (DFS: HR = 0.81, 95% CI: 0.59-1.11, P = 0.20; OS: HR = 0.84, 95% CI: 0.55-1.30, P = 0.43). Among the 255 patients who received trastuzumab, 189 patients (74%) completed 1 year of treatment uneventfully. In all arms, the most frequently reported severe adverse events were neutropenia (30% vs. 27% vs. 26%) and leucopenia (12% vs. 13% vs. 12%), while febrile neutropenia occurred in fifty-one patients (6% vs. 4% vs. 5%). Patients in Arm A experienced more often severe pain (P = 0.002), neurological complications (P = 0.004) and allergic reactions (P = 0.004), while patients in Arm B suffered more often from severe skin reactions (P = 0.020).ConclusionsNo significant differences in survival between the regimens were found in the present phase III trial. Taxane scheduling influenced the type of severe toxicities. HER2-positive patients demonstrated comparable 3-year DFS and OS rates with those reported in other similar studies.Trial registrationAustralian New Zealand Clinical Trials Registry ACTRN12610000151033.

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High rate of extra-haematological toxicity compromises dose-dense sequential adjuvant chemotherapy for breast cancer.

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High rate of extra-haematological toxicity compromises dose-dense sequential adjuvant chemotherapy for breast cancer.

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