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Perioperative chemotherapy with FOLFOX4 and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC Intergroup trial 40983): a randomised controlled trial.

Nordlinger B, Sorbye H, Glimelius B, Poston GJ, Schlag PM, Rougier P, Bechstein WO, Primrose JN, Walpole ET, Finch-Jones M, Jaeck D, Mirza D, Parks RW, Collette L, Praet M, Bethe U, Van Cutsem E, Scheithauer W, Gruenberger T, EORTC Gastro-Intestinal Tract Cancer GroupCancer Research UKArbeitsgruppe Lebermetastasen und-tumoren in der Chirurgischen Arbeitsgemeinschaft Onkologie (ALM-CAO)Australasian Gastro-Intestinal Trials Group (AGITG)Fédération Francophone de Cancérologie Digestive (FFC - Lancet (2008)

Bottom Line: Primary analysis was by intention to treat.Analyses were repeated for all eligible (171 vs 171) and resected patients (151 vs 152).Perioperative chemotherapy with FOLFOX4 is compatible with major liver surgery and reduces the risk of events of progression-free survival in eligible and resected patients.

View Article: PubMed Central - PubMed

Affiliation: Centre Hospitalier Universitaire Ambroise Paré, Assistance Publique Hôpitaux de Paris, Departments of Surgery and Oncology, Boulogne-Billancourt, France. bernard.nordlinger@apr.aphp.fr

ABSTRACT

Background: Surgical resection alone is regarded as the standard of care for patients with liver metastases from colorectal cancer, but relapse is common. We assessed the combination of perioperative chemotherapy and surgery compared with surgery alone for patients with initially resectable liver metastases from colorectal cancer.

Methods: This parallel-group study reports the trial's final data for progression-free survival for a protocol unspecified interim time-point, while overall survival is still being monitored. 364 patients with histologically proven colorectal cancer and up to four liver metastases were randomly assigned to either six cycles of FOLFOX4 before and six cycles after surgery or to surgery alone (182 in perioperative chemotherapy group vs 182 in surgery group). Patients were centrally randomised by minimisation, adjusting for centre and risk score. The primary objective was to detect a hazard ratio (HR) of 0.71 or less for progression-free survival. Primary analysis was by intention to treat. Analyses were repeated for all eligible (171 vs 171) and resected patients (151 vs 152). This trial is registered with ClinicalTrials.gov, number NCT00006479.

Findings: In the perioperative chemotherapy group, 151 (83%) patients were resected after a median of six (range 1-6) preoperative cycles and 115 (63%) patients received a median six (1-8) postoperative cycles. 152 (84%) patients were resected in the surgery group. The absolute increase in rate of progression-free survival at 3 years was 7.3% (from 28.1% [95.66% CI 21.3-35.5] to 35.4% [28.1-42.7]; HR 0.79 [0.62-1.02]; p=0.058) in randomised patients; 8.1% (from 28.1% [21.2-36.6] to 36.2% [28.7-43.8]; HR 0.77 [0.60-1.00]; p=0.041) in eligible patients; and 9.2% (from 33.2% [25.3-41.2] to 42.4% [34.0-50.5]; HR 0.73 [0.55-0.97]; p=0.025) in patients undergoing resection. 139 patients died (64 in perioperative chemotherapy group vs 75 in surgery group). Reversible postoperative complications occurred more often after chemotherapy than after surgery (40/159 [25%] vs 27/170 [16%]; p=0.04). After surgery we recorded two deaths in the surgery alone group and one in the perioperative chemotherapy group.

Interpretation: Perioperative chemotherapy with FOLFOX4 is compatible with major liver surgery and reduces the risk of events of progression-free survival in eligible and resected patients.

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Related in: MedlinePlus

Progression-free survival by treatment group(A) All randomly assigned patients. (B) All eligible patients. (C) All resected patients. For all patients randomly assigned and those who were eligible, no surgery or no resection were regarded as events for the primary endpoint of progression-free survival. PeriOpCT=perioperative chemotherapy with fluorouracil or leucovorin, and oxaliplatin.
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fig2: Progression-free survival by treatment group(A) All randomly assigned patients. (B) All eligible patients. (C) All resected patients. For all patients randomly assigned and those who were eligible, no surgery or no resection were regarded as events for the primary endpoint of progression-free survival. PeriOpCT=perioperative chemotherapy with fluorouracil or leucovorin, and oxaliplatin.

Mentions: The HR for progression-free survival was 0·79 (95·66% CI 0·62–1·02; p=0·058) in all randomly assigned patients corresponding to a 7·3% increase in the rate of progression-free survival at 3 years from 28·1% (21·3–35·3) to 35·4% (28·1–42·7) with chemotherapy and to an increase of the median progression-free survival from 11·7 months to 18·7 months (figure 2). An analysis of only patients who were eligible to enter the trial showed an HR of 0·77 (0·60–1·00, p=0·041), corresponding to an 8·1% increase in the rate of progression-free survival at 3 years from 28·1% (21·2–36·6) to 36·2% (28·7–43·8) with chemotherapy (figure 2). In the 303 patients in whom resection was actually achieved after study entry, the analysis showed that the HR was 0·73 (0·55–0·97, p=0·025) and the rate of progression-free survival at 3 years was increased by 9·2% from 33·2% (25·3–41·2) to 42·4% (34·0–50·5) (figure 2).


Perioperative chemotherapy with FOLFOX4 and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC Intergroup trial 40983): a randomised controlled trial.

Nordlinger B, Sorbye H, Glimelius B, Poston GJ, Schlag PM, Rougier P, Bechstein WO, Primrose JN, Walpole ET, Finch-Jones M, Jaeck D, Mirza D, Parks RW, Collette L, Praet M, Bethe U, Van Cutsem E, Scheithauer W, Gruenberger T, EORTC Gastro-Intestinal Tract Cancer GroupCancer Research UKArbeitsgruppe Lebermetastasen und-tumoren in der Chirurgischen Arbeitsgemeinschaft Onkologie (ALM-CAO)Australasian Gastro-Intestinal Trials Group (AGITG)Fédération Francophone de Cancérologie Digestive (FFC - Lancet (2008)

Progression-free survival by treatment group(A) All randomly assigned patients. (B) All eligible patients. (C) All resected patients. For all patients randomly assigned and those who were eligible, no surgery or no resection were regarded as events for the primary endpoint of progression-free survival. PeriOpCT=perioperative chemotherapy with fluorouracil or leucovorin, and oxaliplatin.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2277487&req=5

fig2: Progression-free survival by treatment group(A) All randomly assigned patients. (B) All eligible patients. (C) All resected patients. For all patients randomly assigned and those who were eligible, no surgery or no resection were regarded as events for the primary endpoint of progression-free survival. PeriOpCT=perioperative chemotherapy with fluorouracil or leucovorin, and oxaliplatin.
Mentions: The HR for progression-free survival was 0·79 (95·66% CI 0·62–1·02; p=0·058) in all randomly assigned patients corresponding to a 7·3% increase in the rate of progression-free survival at 3 years from 28·1% (21·3–35·3) to 35·4% (28·1–42·7) with chemotherapy and to an increase of the median progression-free survival from 11·7 months to 18·7 months (figure 2). An analysis of only patients who were eligible to enter the trial showed an HR of 0·77 (0·60–1·00, p=0·041), corresponding to an 8·1% increase in the rate of progression-free survival at 3 years from 28·1% (21·2–36·6) to 36·2% (28·7–43·8) with chemotherapy (figure 2). In the 303 patients in whom resection was actually achieved after study entry, the analysis showed that the HR was 0·73 (0·55–0·97, p=0·025) and the rate of progression-free survival at 3 years was increased by 9·2% from 33·2% (25·3–41·2) to 42·4% (34·0–50·5) (figure 2).

Bottom Line: Primary analysis was by intention to treat.Analyses were repeated for all eligible (171 vs 171) and resected patients (151 vs 152).Perioperative chemotherapy with FOLFOX4 is compatible with major liver surgery and reduces the risk of events of progression-free survival in eligible and resected patients.

View Article: PubMed Central - PubMed

Affiliation: Centre Hospitalier Universitaire Ambroise Paré, Assistance Publique Hôpitaux de Paris, Departments of Surgery and Oncology, Boulogne-Billancourt, France. bernard.nordlinger@apr.aphp.fr

ABSTRACT

Background: Surgical resection alone is regarded as the standard of care for patients with liver metastases from colorectal cancer, but relapse is common. We assessed the combination of perioperative chemotherapy and surgery compared with surgery alone for patients with initially resectable liver metastases from colorectal cancer.

Methods: This parallel-group study reports the trial's final data for progression-free survival for a protocol unspecified interim time-point, while overall survival is still being monitored. 364 patients with histologically proven colorectal cancer and up to four liver metastases were randomly assigned to either six cycles of FOLFOX4 before and six cycles after surgery or to surgery alone (182 in perioperative chemotherapy group vs 182 in surgery group). Patients were centrally randomised by minimisation, adjusting for centre and risk score. The primary objective was to detect a hazard ratio (HR) of 0.71 or less for progression-free survival. Primary analysis was by intention to treat. Analyses were repeated for all eligible (171 vs 171) and resected patients (151 vs 152). This trial is registered with ClinicalTrials.gov, number NCT00006479.

Findings: In the perioperative chemotherapy group, 151 (83%) patients were resected after a median of six (range 1-6) preoperative cycles and 115 (63%) patients received a median six (1-8) postoperative cycles. 152 (84%) patients were resected in the surgery group. The absolute increase in rate of progression-free survival at 3 years was 7.3% (from 28.1% [95.66% CI 21.3-35.5] to 35.4% [28.1-42.7]; HR 0.79 [0.62-1.02]; p=0.058) in randomised patients; 8.1% (from 28.1% [21.2-36.6] to 36.2% [28.7-43.8]; HR 0.77 [0.60-1.00]; p=0.041) in eligible patients; and 9.2% (from 33.2% [25.3-41.2] to 42.4% [34.0-50.5]; HR 0.73 [0.55-0.97]; p=0.025) in patients undergoing resection. 139 patients died (64 in perioperative chemotherapy group vs 75 in surgery group). Reversible postoperative complications occurred more often after chemotherapy than after surgery (40/159 [25%] vs 27/170 [16%]; p=0.04). After surgery we recorded two deaths in the surgery alone group and one in the perioperative chemotherapy group.

Interpretation: Perioperative chemotherapy with FOLFOX4 is compatible with major liver surgery and reduces the risk of events of progression-free survival in eligible and resected patients.

Show MeSH
Related in: MedlinePlus