Fluorouracil and dose-dense adjuvant chemotherapy in patients with early-stage breast cancer (GIM2): end-of-study results from a randomised, phase 3 trial
Mené en Italie sur 2 091 patientes atteintes d'un cancer du sein de stade précoce avec envahissement ganglionnaire (durée médiane de suivi : 15,1 mois), cet essai de phase III évalue l'efficacité, du point de vue de la survie sans maladie, et la toxicité de l'ajout du fluorouracile à une chimiothérapie adjuvante à base d'épirubicine, de cyclophosphamide et de paclitaxel, puis détermine la modalité d'administration optimale (schéma posologique avec doses intensifiées ou doses standard)
Background : Previous analyses of the GIM (Gruppo Italiano Mammella) 2 study showed that addition of fluorouracil to epirubicin, cyclophosphamide, and paclitaxel in patients with node-positive early breast cancer does not improve outcome, whereas dose-dense chemotherapy induces a significant improvement in both disease-free survival and overall survival as compared with a standard schedule. Here, we present long-term results of the study.
Methods : In this 2 × 2 factorial, open-label, randomised, phase 3 trial, we enrolled patients aged 18–70 years with operable, node-positive, breast cancer with Eastern CooperativeOncology Group performance status of 0–1 from 81 hospitals in Italy. Eligible patientswere randomly allocated (1:1:1:1) to one of the four following study groups: four cycles of standard-interval intravenous EC (epirubicin 90 mg/m2 and cyclophosphamide 600 mg/m2) on day 1 every 3 weeks, followed by four cycles of intravenous paclitaxel (175 mg/m2) on day 1 every 3 weeks (q3EC-P group); four cycles of intravenous FEC (fluorouracil600 mg/m2, epirubicin 90 mg/m2, and cyclophosphamide 600 mg/m2) on day 1 every 3 weeks, followed by four cycles of intravenous paclitaxel (175 mg/m2) on day 1 every 3 weeks (q3FEC-P group); dose-dense EC-P regimen, with the same dosesand drugs as the q3EC-P group but administered every 2 weeks (q2EC-P group); and thedose-dense FEC-P regimen, with the same doses and drugs as the q3FEC-P group but givenevery 2 weeks (q2FEC-P). Randomisation, with stratification by centre, with permutedblocks of size 12, was done with a centralised, interactive, internet-based systemthat randomly generated the treatment allocation. The primary endpoint was disease-free survival in the intention-to-treat population, comparing different chemotherapy schedule (dose-dense vs standard-dose intervals) and regimen (FEC-P vs EC-P). Safety population included all patients that received at least one dose ofany study drug according to the treatment received. This trial is registered with ClinicalTrials.gov, NCT00433420, and is now closed.
Findings : Between April 24, 2003, and July 3, 2006, 2091 patients were randomly assigned totreatment: 545 to q3EC-P, 544 to q3FEC-P, 502 to q2EC-P, and 500 to q2FEC-P. 88 patients were enrolled in centres providing only standard interval schedule and were assignedonly to q3FEC-P and q3EC-P; thus, 2091 patients were included in the intention-to-treatanalysis for the comparison of EC-P (1047 patients) versus FEC-P (1044 patients) and2003 patients were included in the intention-to-treat analysis for the comparisonof dose-dense (1002 patients) versus standard interval analysis (1001 patients). Aftera median follow-up of 15·1 years (IQR 8·4–16·3), median disease-free survival wasnot significantly different between FEC-P and EC-P groups (17·09 years [95% CI 15·51–notreached] vs not reached [17·54–not reached]; unadjusted hazard ratio 1·12 [95% CI 0·98–1·29];log-rank p=0·11). Median disease-free survival was significantly higher in the dose-denseinterval group than the standard-interval group (not reached [95% CI 17·45–not reached] vs 16·52 [14·24–17·54]; 0·77 [95% CI 0·67–0·89]; p=0·0004). The most common grade 3–4adverse events were neutropenia (200 [37%] of 536 patients in the q3EC-P group vs 257 [48%] of 533 in the q3FEC-P group vs 50 [10%] of 496 q2EC-P vs 97 [20%] of 492) and alopecia (238 [44%] vs 249 [47%] vs 228 [46%] vs 235 [48%]). During extended follow-up, no further grade 3–4 adverse events or deathsrelated to toxic-effects were reported. Treatment-related serious adverse events werereported in nine (2%) patients in the q3EC-P group, seven (1%) in the q3FEC-P group,nine (2%) in the q2EC-P group, and nine (2%) in the q2FEC-P group. No treatment-relateddeaths occurred.
Interpretation : Updated results from the GIM2 study support that optimal adjuvant chemotherapy for patients with high-risk early breast cancer should not include fluorouracil and should use a dose-dense schedule.
The Lancet Oncology , résumé, 2021