As reported in The Lancet Oncology by Lucia Del Mastro, MD, and colleagues, end-of-study findings from the Italian phase III GIM2 trial after a median follow-up of 15 years indicate that the addition of fluorouracil to adjuvant epirubicin, cyclophosphamide, and paclitaxel did not improve outcomes in patients with node-positive early breast cancer. Researchers also reported that dose-dense treatment was superior to standard-interval treatment.
Study Details
In the multicenter, open-label, 2 × 2 factorial trial, 2,091 patients were randomly assigned 1:1:1:1 between April 2003 and July 2006 to receive either:
- Four cycles of standard-interval epirubicin and cyclophosphamide on day 1 every 3 weeks, followed by four cycles of paclitaxel on day 1 every 3 weeks (q3EC-P group, n = 545)
- Four cycles of fluorouracil, epirubicin, and cyclophosphamide on day 1 every 3 weeks, followed by four cycles of paclitaxel on day 1 every 3 weeks (q3FEC-P group, n = 544)
- Epirubicin, cyclophosphamide, and paclitaxel (EC-P) with the same doses as the q3EC-P group but given every 2 weeks ([dose-dense] q2EC-P group, n = 502)
- Fluorouracil, epirubicin, cyclophosphamide, and paclitaxel (FEC-P) with the same doses as the q3FEC-P group but given every 2 weeks ([dose-dense] q2FEC-P group, n = 500).
The primary endpoint was disease-free survival, comparing dose-dense vs standard-interval treatment and the FEC-P vs EC-P regimens. A total of 2,091 patients were included in the intention-to-treat analysis for the comparison of EC-P (n = 1,047) vs FEC-P (n = 1,044), and 2,003 patients were included in the intention-to-treat analysis for comparison of dose-dense treatment (n = 1,002) vs standard-interval treatment (n = 1,001).
Previous analyses of the trial showed that the addition of fluorouracil to EC-P did not improve outcomes and that dose-dense treatment significantly improved disease-free survival and overall survival vs a standard-interval treatment.
Key Findings
Median follow-up was 15.1 years (interquartile range = 8.4–16.3 years).
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.— Lucia Del Mastro, MD, and colleagues
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Median disease-free survival was 17.09 years (95% confidence interval [CI] = 15.51 years to not reached) in the FEC-P group vs not reached (95% CI = 17.54 years to not reached) in the EC-P group (hazard ratio [HR] = 1.12, 95% CI = 0.98–1.29, P = .11). Estimated rates of disease-free survival at 15 years were 55.4% vs 59.4%. There were 250 deaths in the FEC-P group vs 223 deaths in the EC-P group; median overall survival was not reached (95% CI = not reached to not reached) vs not reached (95% CI = not reached to not reached), with a hazard ratio of 1.13 (95% CI = 0.94–1.36, P = .18).
Median disease-free survival was not reached (95% CI = 17.45 years to not reached) in the dose-dense group vs 16.52 years (95% CI = 14.24–17.54 years) in the standard-interval group (HR = 0.77, 95% CI = 0.67–0.89, P = .0004). Estimated rates of disease-free survival at 15 years were 61.1% vs 52.5%. Death occurred in 197 patients in the dose-dense group vs 254 patients in the standard-interval group; median overall survival was not reached (95% CI = not reached to not reached) vs not reached (95% CI = not reached to not reached), with a hazard ratio of 0.72 (95% CI = 0.60–0.86, P = .0004).
During the extended follow-up, no further grade 3 or 4 adverse events were observed and no treatment-related deaths occurred.
The investigators concluded, “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.”
Dr. Del Mastro, of UO Clinica di Oncologia Medica, IRCCS Ospedale Policlinico San Martino, Genova, is the corresponding author for The Lancet Oncology article.
Disclosure: The study was funded by Bristol Myers Squibb, Pharmacia, Dompè Biotec Italy, the Italian Ministry of Health, Fondazione Italiana per la Ricerca sul Cancro, and Alliance Against Cancer. For full disclosures of the study authors, visit thelancet.com.
