Fluorouracil and dose-dense chemotherapy in adjuvant treatment of patients with early-stage breast cancer: An open-label, 2 × 2 factorial, randomised phase 3 trial

Lucia Del Mastro, Sabino De Placido, Paolo Bruzzi, Michele De Laurentiis, Corrado Boni, Giovanna Cavazzini, Antonio Durando, Anna Turletti, Cecilia Nisticò, Enrichetta Valle, Ornella Garrone, Fabio Puglisi, Filippo Montemurro, Sandro Barni, Andrea Ardizzoni, Teresa Gamucci, Giuseppe Colantuoni, Mario Giuliano, Adriano Gravina, Paola PapaldoClaudia Bighin, Giancarlo Bisagni, Valeria Forestieri, Francesco Cognetti

Research output: Contribution to journalArticle

Abstract

Background Whether addition of fluorouracil to epirubicin, cyclophosphamide, and paclitaxel (EC-P) is favourable in adjuvant treatment of patients with node-positive breast cancer is controversial, as is the benefit of increased density of dosing. We aimed to address these questions in terms of improvements in disease-free survival. Methods In this 2 × 2 factorial, open-label, phase 3 trial, we enrolled patients aged 18-70 years with operable, node positive, early-stage breast cancer from 81 Italian centres. Eligible patients were randomly allocated in a 1:1:1:1 ratio with a centralised, interactive online system to receive either dose-dense chemotherapy (administered intravenously every 2 weeks with pegfilgrastim support) with fluorouracil plus EC-P (FEC-P) or EC-P or to receive standard-interval chemotherapy (administered intravenously every 3 weeks) with FEC-P or EC-P. The primary study endpoint was disease-free survival, assessed with the Kaplan-Meier method in the intention-to-treat population. Our primary comparisons were between dose schedule (every 2 weeks vs every 3 weeks) and dose type (FEC-P vs EC-P). This study is registered with ClinicalTrials.gov, number NCT00433420. Findings Between April 24, 2003, and July 3, 2006, we recruited 2091 patients. 88 patients were enrolled in centres that only provided standard-intensity dosing. After a median follow-up of 7·0 years (interquartile range [IQR] 4·5-6·3), 140 (26%) of 545 patients given EC-P every 3 weeks, 157 (29%) of 544 patients given FEC-P every 3 weeks, 111 (22%) of 502 patients given EC-P every 2 weeks, and 113 (23%) of 500 patients given FEC-P every 2 weeks had a disease-free survival event. For the dose-density comparison, disease-free survival at 5 years was 81% (95% CI 79-84) in patients treated every 2 weeks and 76% (74-79) in patients treated every 3 weeks (HR 0·77, 95% CI 0·65-0·92; p=0·004); overall survival rates at 5 years were 94% (93-96) and 89% (87-91; HR 0·65, 0·51-0·84; p=0·001) and for the chemotherapy-type comparison, disease-free survival at 5 years was 78% (75-81) in the FEC-P groups and 79% (76-82) in the EC-P groups (HR 1·06, 0·89-1·25; p=0·561); overall survival rates at 5 years were 91% (89-93) and 92% (90-94; 1·16, 0·91-1·46; p=0·234). Compared with 3 week dosing, chemotherapy every 2 weeks was associated with increased rate of grade 3-4 of anaemia (14 [1·4%] of 988 patients vs two [0·2%] of 984 patients; p=0·002); transaminitis (19 [1·9%] vs four [0·4%]; p=0·001), and myalgias (31 [3·1%] vs 16 [1·6%]; p=0·019), and decreased rates of grade 3-4 neutropenia (147 [14·9%] vs 433 [44·0%]; p

Original languageEnglish
Pages (from-to)1863-1872
Number of pages10
JournalLancet
Volume385
Issue number9980
DOIs
Publication statusPublished - May 9 2015

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Adjuvant Chemotherapy
Fluorouracil
Breast Neoplasms
Epirubicin
Paclitaxel
Cyclophosphamide
Disease-Free Survival
Therapeutics
Drug Therapy
Survival Rate
Online Systems
Myalgia
Neutropenia
Anemia
Appointments and Schedules

ASJC Scopus subject areas

  • Medicine(all)

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Fluorouracil and dose-dense chemotherapy in adjuvant treatment of patients with early-stage breast cancer : An open-label, 2 × 2 factorial, randomised phase 3 trial. / Del Mastro, Lucia; De Placido, Sabino; Bruzzi, Paolo; De Laurentiis, Michele; Boni, Corrado; Cavazzini, Giovanna; Durando, Antonio; Turletti, Anna; Nisticò, Cecilia; Valle, Enrichetta; Garrone, Ornella; Puglisi, Fabio; Montemurro, Filippo; Barni, Sandro; Ardizzoni, Andrea; Gamucci, Teresa; Colantuoni, Giuseppe; Giuliano, Mario; Gravina, Adriano; Papaldo, Paola; Bighin, Claudia; Bisagni, Giancarlo; Forestieri, Valeria; Cognetti, Francesco.

In: Lancet, Vol. 385, No. 9980, 09.05.2015, p. 1863-1872.

Research output: Contribution to journalArticle

Del Mastro, L, De Placido, S, Bruzzi, P, De Laurentiis, M, Boni, C, Cavazzini, G, Durando, A, Turletti, A, Nisticò, C, Valle, E, Garrone, O, Puglisi, F, Montemurro, F, Barni, S, Ardizzoni, A, Gamucci, T, Colantuoni, G, Giuliano, M, Gravina, A, Papaldo, P, Bighin, C, Bisagni, G, Forestieri, V & Cognetti, F 2015, 'Fluorouracil and dose-dense chemotherapy in adjuvant treatment of patients with early-stage breast cancer: An open-label, 2 × 2 factorial, randomised phase 3 trial', Lancet, vol. 385, no. 9980, pp. 1863-1872. https://doi.org/10.1016/S0140-6736(14)62048-1
Del Mastro, Lucia ; De Placido, Sabino ; Bruzzi, Paolo ; De Laurentiis, Michele ; Boni, Corrado ; Cavazzini, Giovanna ; Durando, Antonio ; Turletti, Anna ; Nisticò, Cecilia ; Valle, Enrichetta ; Garrone, Ornella ; Puglisi, Fabio ; Montemurro, Filippo ; Barni, Sandro ; Ardizzoni, Andrea ; Gamucci, Teresa ; Colantuoni, Giuseppe ; Giuliano, Mario ; Gravina, Adriano ; Papaldo, Paola ; Bighin, Claudia ; Bisagni, Giancarlo ; Forestieri, Valeria ; Cognetti, Francesco. / Fluorouracil and dose-dense chemotherapy in adjuvant treatment of patients with early-stage breast cancer : An open-label, 2 × 2 factorial, randomised phase 3 trial. In: Lancet. 2015 ; Vol. 385, No. 9980. pp. 1863-1872.
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abstract = "Background Whether addition of fluorouracil to epirubicin, cyclophosphamide, and paclitaxel (EC-P) is favourable in adjuvant treatment of patients with node-positive breast cancer is controversial, as is the benefit of increased density of dosing. We aimed to address these questions in terms of improvements in disease-free survival. Methods In this 2 × 2 factorial, open-label, phase 3 trial, we enrolled patients aged 18-70 years with operable, node positive, early-stage breast cancer from 81 Italian centres. Eligible patients were randomly allocated in a 1:1:1:1 ratio with a centralised, interactive online system to receive either dose-dense chemotherapy (administered intravenously every 2 weeks with pegfilgrastim support) with fluorouracil plus EC-P (FEC-P) or EC-P or to receive standard-interval chemotherapy (administered intravenously every 3 weeks) with FEC-P or EC-P. The primary study endpoint was disease-free survival, assessed with the Kaplan-Meier method in the intention-to-treat population. Our primary comparisons were between dose schedule (every 2 weeks vs every 3 weeks) and dose type (FEC-P vs EC-P). This study is registered with ClinicalTrials.gov, number NCT00433420. Findings Between April 24, 2003, and July 3, 2006, we recruited 2091 patients. 88 patients were enrolled in centres that only provided standard-intensity dosing. After a median follow-up of 7·0 years (interquartile range [IQR] 4·5-6·3), 140 (26{\%}) of 545 patients given EC-P every 3 weeks, 157 (29{\%}) of 544 patients given FEC-P every 3 weeks, 111 (22{\%}) of 502 patients given EC-P every 2 weeks, and 113 (23{\%}) of 500 patients given FEC-P every 2 weeks had a disease-free survival event. For the dose-density comparison, disease-free survival at 5 years was 81{\%} (95{\%} CI 79-84) in patients treated every 2 weeks and 76{\%} (74-79) in patients treated every 3 weeks (HR 0·77, 95{\%} CI 0·65-0·92; p=0·004); overall survival rates at 5 years were 94{\%} (93-96) and 89{\%} (87-91; HR 0·65, 0·51-0·84; p=0·001) and for the chemotherapy-type comparison, disease-free survival at 5 years was 78{\%} (75-81) in the FEC-P groups and 79{\%} (76-82) in the EC-P groups (HR 1·06, 0·89-1·25; p=0·561); overall survival rates at 5 years were 91{\%} (89-93) and 92{\%} (90-94; 1·16, 0·91-1·46; p=0·234). Compared with 3 week dosing, chemotherapy every 2 weeks was associated with increased rate of grade 3-4 of anaemia (14 [1·4{\%}] of 988 patients vs two [0·2{\%}] of 984 patients; p=0·002); transaminitis (19 [1·9{\%}] vs four [0·4{\%}]; p=0·001), and myalgias (31 [3·1{\%}] vs 16 [1·6{\%}]; p=0·019), and decreased rates of grade 3-4 neutropenia (147 [14·9{\%}] vs 433 [44·0{\%}]; p",
author = "{Del Mastro}, Lucia and {De Placido}, Sabino and Paolo Bruzzi and {De Laurentiis}, Michele and Corrado Boni and Giovanna Cavazzini and Antonio Durando and Anna Turletti and Cecilia Nistic{\`o} and Enrichetta Valle and Ornella Garrone and Fabio Puglisi and Filippo Montemurro and Sandro Barni and Andrea Ardizzoni and Teresa Gamucci and Giuseppe Colantuoni and Mario Giuliano and Adriano Gravina and Paola Papaldo and Claudia Bighin and Giancarlo Bisagni and Valeria Forestieri and Francesco Cognetti",
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TY - JOUR

T1 - Fluorouracil and dose-dense chemotherapy in adjuvant treatment of patients with early-stage breast cancer

T2 - An open-label, 2 × 2 factorial, randomised phase 3 trial

AU - Del Mastro, Lucia

AU - De Placido, Sabino

AU - Bruzzi, Paolo

AU - De Laurentiis, Michele

AU - Boni, Corrado

AU - Cavazzini, Giovanna

AU - Durando, Antonio

AU - Turletti, Anna

AU - Nisticò, Cecilia

AU - Valle, Enrichetta

AU - Garrone, Ornella

AU - Puglisi, Fabio

AU - Montemurro, Filippo

AU - Barni, Sandro

AU - Ardizzoni, Andrea

AU - Gamucci, Teresa

AU - Colantuoni, Giuseppe

AU - Giuliano, Mario

AU - Gravina, Adriano

AU - Papaldo, Paola

AU - Bighin, Claudia

AU - Bisagni, Giancarlo

AU - Forestieri, Valeria

AU - Cognetti, Francesco

PY - 2015/5/9

Y1 - 2015/5/9

N2 - Background Whether addition of fluorouracil to epirubicin, cyclophosphamide, and paclitaxel (EC-P) is favourable in adjuvant treatment of patients with node-positive breast cancer is controversial, as is the benefit of increased density of dosing. We aimed to address these questions in terms of improvements in disease-free survival. Methods In this 2 × 2 factorial, open-label, phase 3 trial, we enrolled patients aged 18-70 years with operable, node positive, early-stage breast cancer from 81 Italian centres. Eligible patients were randomly allocated in a 1:1:1:1 ratio with a centralised, interactive online system to receive either dose-dense chemotherapy (administered intravenously every 2 weeks with pegfilgrastim support) with fluorouracil plus EC-P (FEC-P) or EC-P or to receive standard-interval chemotherapy (administered intravenously every 3 weeks) with FEC-P or EC-P. The primary study endpoint was disease-free survival, assessed with the Kaplan-Meier method in the intention-to-treat population. Our primary comparisons were between dose schedule (every 2 weeks vs every 3 weeks) and dose type (FEC-P vs EC-P). This study is registered with ClinicalTrials.gov, number NCT00433420. Findings Between April 24, 2003, and July 3, 2006, we recruited 2091 patients. 88 patients were enrolled in centres that only provided standard-intensity dosing. After a median follow-up of 7·0 years (interquartile range [IQR] 4·5-6·3), 140 (26%) of 545 patients given EC-P every 3 weeks, 157 (29%) of 544 patients given FEC-P every 3 weeks, 111 (22%) of 502 patients given EC-P every 2 weeks, and 113 (23%) of 500 patients given FEC-P every 2 weeks had a disease-free survival event. For the dose-density comparison, disease-free survival at 5 years was 81% (95% CI 79-84) in patients treated every 2 weeks and 76% (74-79) in patients treated every 3 weeks (HR 0·77, 95% CI 0·65-0·92; p=0·004); overall survival rates at 5 years were 94% (93-96) and 89% (87-91; HR 0·65, 0·51-0·84; p=0·001) and for the chemotherapy-type comparison, disease-free survival at 5 years was 78% (75-81) in the FEC-P groups and 79% (76-82) in the EC-P groups (HR 1·06, 0·89-1·25; p=0·561); overall survival rates at 5 years were 91% (89-93) and 92% (90-94; 1·16, 0·91-1·46; p=0·234). Compared with 3 week dosing, chemotherapy every 2 weeks was associated with increased rate of grade 3-4 of anaemia (14 [1·4%] of 988 patients vs two [0·2%] of 984 patients; p=0·002); transaminitis (19 [1·9%] vs four [0·4%]; p=0·001), and myalgias (31 [3·1%] vs 16 [1·6%]; p=0·019), and decreased rates of grade 3-4 neutropenia (147 [14·9%] vs 433 [44·0%]; p

AB - Background Whether addition of fluorouracil to epirubicin, cyclophosphamide, and paclitaxel (EC-P) is favourable in adjuvant treatment of patients with node-positive breast cancer is controversial, as is the benefit of increased density of dosing. We aimed to address these questions in terms of improvements in disease-free survival. Methods In this 2 × 2 factorial, open-label, phase 3 trial, we enrolled patients aged 18-70 years with operable, node positive, early-stage breast cancer from 81 Italian centres. Eligible patients were randomly allocated in a 1:1:1:1 ratio with a centralised, interactive online system to receive either dose-dense chemotherapy (administered intravenously every 2 weeks with pegfilgrastim support) with fluorouracil plus EC-P (FEC-P) or EC-P or to receive standard-interval chemotherapy (administered intravenously every 3 weeks) with FEC-P or EC-P. The primary study endpoint was disease-free survival, assessed with the Kaplan-Meier method in the intention-to-treat population. Our primary comparisons were between dose schedule (every 2 weeks vs every 3 weeks) and dose type (FEC-P vs EC-P). This study is registered with ClinicalTrials.gov, number NCT00433420. Findings Between April 24, 2003, and July 3, 2006, we recruited 2091 patients. 88 patients were enrolled in centres that only provided standard-intensity dosing. After a median follow-up of 7·0 years (interquartile range [IQR] 4·5-6·3), 140 (26%) of 545 patients given EC-P every 3 weeks, 157 (29%) of 544 patients given FEC-P every 3 weeks, 111 (22%) of 502 patients given EC-P every 2 weeks, and 113 (23%) of 500 patients given FEC-P every 2 weeks had a disease-free survival event. For the dose-density comparison, disease-free survival at 5 years was 81% (95% CI 79-84) in patients treated every 2 weeks and 76% (74-79) in patients treated every 3 weeks (HR 0·77, 95% CI 0·65-0·92; p=0·004); overall survival rates at 5 years were 94% (93-96) and 89% (87-91; HR 0·65, 0·51-0·84; p=0·001) and for the chemotherapy-type comparison, disease-free survival at 5 years was 78% (75-81) in the FEC-P groups and 79% (76-82) in the EC-P groups (HR 1·06, 0·89-1·25; p=0·561); overall survival rates at 5 years were 91% (89-93) and 92% (90-94; 1·16, 0·91-1·46; p=0·234). Compared with 3 week dosing, chemotherapy every 2 weeks was associated with increased rate of grade 3-4 of anaemia (14 [1·4%] of 988 patients vs two [0·2%] of 984 patients; p=0·002); transaminitis (19 [1·9%] vs four [0·4%]; p=0·001), and myalgias (31 [3·1%] vs 16 [1·6%]; p=0·019), and decreased rates of grade 3-4 neutropenia (147 [14·9%] vs 433 [44·0%]; p

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