6 months versus 12 months of adjuvant trastuzumab for patients with HER2-positive early breast cancer (PHARE) : a randomised phase 3 trial
Copyright © 2013 Elsevier Ltd. All rights reserved..
BACKGROUND: Since 2005, 12 months of adjuvant trastuzumab has been the standard treatment for patients with HER2-positive early-stage breast cancer. However, the optimum duration of treatment has been debated. We did a non-inferiority trial of a shorter exposure of 6 months versus the standard 12 months of trastuzumab for patients with early breast cancer.
METHODS: We did an open-label, randomised, phase 3 trial in 156 centres in France. Patients with HER2-positive early breast cancer who had received at least four cycles of chemotherapy, had breast-axillary surgery, and had received up to 6 months of trastuzumab (administered by intravenous infusions over 30-90 min every 3 weeks; initial loading dose 8 mg/kg; 6 mg/kg thereafter) before randomisation were eligible. Patients were randomly assigned via central randomisation procedure with web-based software to continue trastuzumab for another 6 months (12 months total duration; control group) or to discontinue trastuzumab at 6 months (6 months total duration; experimental group). Randomisation was stratified by concomitant or sequential administration of trastuzumab with chemotherapy, oestrogen-receptor status, and centre using a minimisation algorithm. The primary endpoint was disease-free survival, with a prespecified non-inferiority margin of 1·15. Analyses were done in the intention-to-treat population. This study is registered at ClinicalTrials.gov, number NCT00381901.
FINDINGS: 1691 patients were randomly assigned to receive 12 months of trastuzumab and 1693 to receive 6 months of trastuzumab; 1690 patients in each group were included in the intention-to-treat analyses. After a median follow-up of 42·5 months (IQR 30·1-51·6), 175 disease-free survival events were noted in the 12-month group and 219 in the 6-month group. 2-year disease-free survival was 93·8% (95% CI 92·6-94·9) in the 12-month group and 91·1% (89·7-92·4) in the 6-month group (hazard ratio 1·28, 95% CI 1·05-1·56; p=0·29). 119 (93%) of the 128 cardiac events (clinical or based on assessment of left ventricular ejection fraction) occurred while patients were receiving trastuzumab. Significantly more patients in the 12-month group experienced a cardiac event than did those in the 6-month group (96 [5·7%] of 1690 patients vs 32 [1·9%] of 1690 patients, p<0·0001).
INTERPRETATION: After 3·5 years follow-up, we failed to show that 6 months of treatment with trastuzumab was non-inferior to 12 months of trastuzumab. Despite the higher rates of cardiac events, 12 months of adjuvant trastuzmab should remain the standard of care.
FUNDING: French National Cancer Institute.
| Errataetall: |
CommentIn: Lancet Oncol. 2013 Jul;14(8):678-9. - PMID 23764182 |
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2013 |
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| Erschienen: |
2013 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:14 |
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| Enthalten in: |
The Lancet. Oncology - 14(2013), 8 vom: 13. Juli, Seite 741-8 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Pivot, Xavier [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 09.09.2013 Date Revised 09.04.2022 published: Print-Electronic ClinicalTrials.gov: NCT00381901 CommentIn: Lancet Oncol. 2013 Jul;14(8):678-9. - PMID 23764182 Citation Status MEDLINE |
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| doi: |
10.1016/S1470-2045(13)70225-0 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 245 | 1 | 0 | |a 6 months versus 12 months of adjuvant trastuzumab for patients with HER2-positive early breast cancer (PHARE) |b a randomised phase 3 trial |
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| 500 | |a CommentIn: Lancet Oncol. 2013 Jul;14(8):678-9. - PMID 23764182 | ||
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| 520 | |a Copyright © 2013 Elsevier Ltd. All rights reserved. | ||
| 520 | |a BACKGROUND: Since 2005, 12 months of adjuvant trastuzumab has been the standard treatment for patients with HER2-positive early-stage breast cancer. However, the optimum duration of treatment has been debated. We did a non-inferiority trial of a shorter exposure of 6 months versus the standard 12 months of trastuzumab for patients with early breast cancer | ||
| 520 | |a METHODS: We did an open-label, randomised, phase 3 trial in 156 centres in France. Patients with HER2-positive early breast cancer who had received at least four cycles of chemotherapy, had breast-axillary surgery, and had received up to 6 months of trastuzumab (administered by intravenous infusions over 30-90 min every 3 weeks; initial loading dose 8 mg/kg; 6 mg/kg thereafter) before randomisation were eligible. Patients were randomly assigned via central randomisation procedure with web-based software to continue trastuzumab for another 6 months (12 months total duration; control group) or to discontinue trastuzumab at 6 months (6 months total duration; experimental group). Randomisation was stratified by concomitant or sequential administration of trastuzumab with chemotherapy, oestrogen-receptor status, and centre using a minimisation algorithm. The primary endpoint was disease-free survival, with a prespecified non-inferiority margin of 1·15. Analyses were done in the intention-to-treat population. This study is registered at ClinicalTrials.gov, number NCT00381901 | ||
| 520 | |a FINDINGS: 1691 patients were randomly assigned to receive 12 months of trastuzumab and 1693 to receive 6 months of trastuzumab; 1690 patients in each group were included in the intention-to-treat analyses. After a median follow-up of 42·5 months (IQR 30·1-51·6), 175 disease-free survival events were noted in the 12-month group and 219 in the 6-month group. 2-year disease-free survival was 93·8% (95% CI 92·6-94·9) in the 12-month group and 91·1% (89·7-92·4) in the 6-month group (hazard ratio 1·28, 95% CI 1·05-1·56; p=0·29). 119 (93%) of the 128 cardiac events (clinical or based on assessment of left ventricular ejection fraction) occurred while patients were receiving trastuzumab. Significantly more patients in the 12-month group experienced a cardiac event than did those in the 6-month group (96 [5·7%] of 1690 patients vs 32 [1·9%] of 1690 patients, p<0·0001) | ||
| 520 | |a INTERPRETATION: After 3·5 years follow-up, we failed to show that 6 months of treatment with trastuzumab was non-inferior to 12 months of trastuzumab. Despite the higher rates of cardiac events, 12 months of adjuvant trastuzmab should remain the standard of care | ||
| 520 | |a FUNDING: French National Cancer Institute | ||
| 650 | 4 | |a Clinical Trial, Phase III | |
| 650 | 4 | |a Comparative Study | |
| 650 | 4 | |a Journal Article | |
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| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
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| 650 | 7 | |a Antineoplastic Agents |2 NLM | |
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| 700 | 1 | |a Lortholary, Alain |e verfasserin |4 aut | |
| 700 | 1 | |a Espié, Marc |e verfasserin |4 aut | |
| 700 | 1 | |a Fumoleau, Pierre |e verfasserin |4 aut | |
| 700 | 1 | |a Serin, Daniel |e verfasserin |4 aut | |
| 700 | 1 | |a Jacquin, Jean-Philippe |e verfasserin |4 aut | |
| 700 | 1 | |a Jouannaud, Christelle |e verfasserin |4 aut | |
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| 700 | 1 | |a Abadie-Lacourtoisie, Sophie |e verfasserin |4 aut | |
| 700 | 1 | |a Tubiana-Mathieu, Nicole |e verfasserin |4 aut | |
| 700 | 1 | |a Cany, Laurent |e verfasserin |4 aut | |
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| 700 | 1 | |a Cals, L |e investigator |4 oth | |
| 700 | 1 | |a Chaigneau, L |e investigator |4 oth | |
| 700 | 1 | |a Demarchi, F |e investigator |4 oth | |
| 700 | 1 | |a N'Guyen, T |e investigator |4 oth | |
| 700 | 1 | |a Stein, U |e investigator |4 oth | |
| 700 | 1 | |a Villanueva, C |e investigator |4 oth | |
| 700 | 1 | |a Bréau, J L |e investigator |4 oth | |
| 700 | 1 | |a Chouahnia, A K |e investigator |4 oth | |
| 700 | 1 | |a Saintigny, P |e investigator |4 oth | |
| 700 | 1 | |a Boué, F |e investigator |4 oth | |
| 700 | 1 | |a de Saint-Hilaire, P |e investigator |4 oth | |
| 700 | 1 | |a Guimont, I |e investigator |4 oth | |
| 700 | 1 | |a Grossat, N |e investigator |4 oth | |
| 700 | 1 | |a Valenza, B |e investigator |4 oth | |
| 700 | 1 | |a Lévy, E |e investigator |4 oth | |
| 700 | 1 | |a Médioni, J |e investigator |4 oth | |
| 700 | 1 | |a Delbaldo, C |e investigator |4 oth | |
| 700 | 1 | |a Grenier, J |e investigator |4 oth | |
| 700 | 1 | |a Pouessel, D |e investigator |4 oth | |
| 700 | 1 | |a Lavau-Denès, S |e investigator |4 oth | |
| 700 | 1 | |a Falandry, C |e investigator |4 oth | |
| 700 | 1 | |a Fournel-Fédérico, C |e investigator |4 oth | |
| 700 | 1 | |a Freyer, G |e investigator |4 oth | |
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| 700 | 1 | |a Trillet-Lenoir, V |e investigator |4 oth | |
| 700 | 1 | |a Bons, F |e investigator |4 oth | |
| 700 | 1 | |a Auclerc, G |e investigator |4 oth | |
| 700 | 1 | |a Chièze, S |e investigator |4 oth | |
| 700 | 1 | |a Raban, N |e investigator |4 oth | |
| 700 | 1 | |a Tournigand, C |e investigator |4 oth | |
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| 700 | 1 | |a Capitain, O |e investigator |4 oth | |
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| 700 | 1 | |a Maillart, P |e investigator |4 oth | |
| 700 | 1 | |a Soulié, P |e investigator |4 oth | |
| 700 | 1 | |a Bonnefoi, H |e investigator |4 oth | |
| 700 | 1 | |a Durand, M |e investigator |4 oth | |
| 700 | 1 | |a Madranges, N |e investigator |4 oth | |
| 700 | 1 | |a Mauriac, L |e investigator |4 oth | |
| 700 | 1 | |a Chollet, P |e investigator |4 oth | |
| 700 | 1 | |a Dillies, A F |e investigator |4 oth | |
| 700 | 1 | |a Durando, X |e investigator |4 oth | |
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