EORTC 40983
Pre- and Post-Operative Chemotherapy With Oxaliplatin 5FU/LV Versus Surgery Alone in Resectable Liver Metastases From Colorectal Origin - Phase III Study
Phase 3N = 364NCT00006479
- Population
- Resectable liver metastases from colorectal cancer (up to four liver metastases)
- Design
- Randomised, parallel-group phase 3 trial in patients with histologically proven colorectal cancer and up to four liver metastases (aged 18 to 80 years; 78 hospitals in Europe, Australia and Hong Kong per the 2013 report). Patients were centrally randomised (1:1) by minimisation to six cycles of FOLFOX4 before and six cycles after surgery, or to surgery alone. The primary objective was to detect a hazard ratio of 0.71 or less for progression-free survival; the primary analysis was by intention to treat. 364 patients were randomised (182 per group; 171 per group were eligible). The trial was open label.
- Primary endpoint
- PFS
- Arms
- Surgery alone (control, n = 182): Surgery alone
- Perioperative FOLFOX4 (experimental, n = 182): Six cycles of FOLFOX4 before and six cycles after surgery
- People
- Nordlinger B
PFSHR 0.79Δ 36-month PFS+7.3 pointsPFSHR 0.77Δ 36-month PFS+8.1 pointsPFSHR 0.73Δ 36-month PFS+9.2 points
Show the numbers
| Endpoint | Analysis | Perioperative FOLFOX4 | Surgery alone | Effect |
|---|---|---|---|---|
| PFS | primaryNordlinger 2008 | 35.4% at 3 y | 28.1% at 3 y | HR 0.79P=0.058Absolute increase in 3-year progression-free survival of 7.3%. The full text states that all confidence intervals in the report, including those of the hazard ratios, are 95.66% intervals (adjusted for an interim analysis); the abstract prints the 3-year rates with 95.66% intervals (28.1%: 21.3-35.5; 35.4%: 28.1-42.7) and the hazard ratio interval 0.62-1.02. The abstract describes these as the final progression-free survival data at a protocol-unspecified interim time point; the full text calls the result in all randomised patients a trend that was not significant after correction for the timing of surgery. |
| PFSAll eligible patients (171 per group) | exploratoryNordlinger 2008 | 36.2% at 3 y | 28.1% at 3 y | HR 0.77P=0.041Repeat analysis in eligible patients; absolute increase 8.1%. Intervals as printed (95.66% per the full text): rates 21.2-36.6 and 28.7-43.8, hazard ratio 0.60-1.00. |
| PFSPatients undergoing resection | exploratoryNordlinger 2008 | 42.4% at 3 y | 33.2% at 3 y | HR 0.73P=0.025Repeat analysis in patients undergoing resection; absolute increase 9.2%. Intervals as printed (95.66% per the full text): rates 25.3-41.2 and 34.0-50.5, hazard ratio 0.55-0.97. |
| OS | long term-updatemedian follow-up 8.5 yearsNordlinger 2013 | median 61.3 months (51.0–83.4); 51.2% at 5 y (43.6–58.3%) | median 54.3 months (41.9–79.4); 47.8% at 5 y (40.3–55.0%) | HR 0.88 (95% CI 0.68–1.14)P=0.34Overall survival analysis by intention to treat in all randomly assigned patients; deaths: 107 (59%) with perioperative chemotherapy and 114 (63%) with surgery alone. |
| Endpoint | Analysis | Perioperative FOLFOX4 | Surgery alone | Effect |
|---|---|---|---|---|
| PFS | primaryNordlinger 2008 | 35.4% at 3 y | 28.1% at 3 y | HR 0.79P=0.058Absolute increase in 3-year progression-free survival of 7.3%. The full text states that all confidence intervals in the report, including those of the hazard ratios, are 95.66% intervals (adjusted for an interim analysis); the abstract prints the 3-year rates with 95.66% intervals (28.1%: 21.3-35.5; 35.4%: 28.1-42.7) and the hazard ratio interval 0.62-1.02. The abstract describes these as the final progression-free survival data at a protocol-unspecified interim time point; the full text calls the result in all randomised patients a trend that was not significant after correction for the timing of surgery. |
| PFSAll eligible patients (171 per group) | exploratoryNordlinger 2008 | 36.2% at 3 y | 28.1% at 3 y | HR 0.77P=0.041Repeat analysis in eligible patients; absolute increase 8.1%. Intervals as printed (95.66% per the full text): rates 21.2-36.6 and 28.7-43.8, hazard ratio 0.60-1.00. |
| PFSPatients undergoing resection | exploratoryNordlinger 2008 | 42.4% at 3 y | 33.2% at 3 y | HR 0.73P=0.025Repeat analysis in patients undergoing resection; absolute increase 9.2%. Intervals as printed (95.66% per the full text): rates 25.3-41.2 and 34.0-50.5, hazard ratio 0.55-0.97. |
| OS | long term-updatemedian follow-up 8.5 yearsNordlinger 2013 | median 61.3 months (51.0–83.4); 51.2% at 5 y (43.6–58.3%) | median 54.3 months (41.9–79.4); 47.8% at 5 y (40.3–55.0%) | HR 0.88 (95% CI 0.68–1.14)P=0.34Overall survival analysis by intention to treat in all randomly assigned patients; deaths: 107 (59%) with perioperative chemotherapy and 114 (63%) with surgery alone. |
Data table
| Endpoint | HR | 95% CI |
|---|---|---|
| OS | 0.88 | 0.68–1.14 |
- Surgery alone (control)
- Perioperative FOLFOX4 (experimental)
Median-only curves assume a constant hazard (exponential) and fit plateaus, as seen with some immunotherapies, poorly.
Data table (modelled values)
| Months | Surgery alone | Perioperative FOLFOX4 |
|---|---|---|
| 0 | 100.0% | 100.0% |
| 38 | 61.6% | 65.1% |
| 77 | 37.4% | 41.9% |
| 115 | 23.0% | 27.2% |
| 153 | 14.2% | 17.7% |
Appears in
Sources
Nordlinger B, Sorbye H, Glimelius B, Poston GJ, Schlag PM, Rougier P, et al. Perioperative chemotherapy with FOLFOX4 and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC Intergroup trial 40983): a randomised controlled trial. Lancet. 2008;371(9617):1007-16.
Nordlinger B, Sorbye H, Glimelius B, Poston GJ, Schlag PM, Rougier P, et al. Perioperative FOLFOX4 chemotherapy and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC 40983): long-term results of a randomised, controlled, phase 3 trial. Lancet Oncol. 2013;14(12):1208-15.