Local Treatment of Unresectable Colorectal Liver Metastases: Results of a Randomized Phase II Trial

Abstract

Background: Tumor ablation is often employed for unresectable colorectal liver metastases. However, no survival benefit has ever been demonstrated in prospective randomized studies. Here, we investigate the long-term benefits of such an aggressive approach.

Methods: In this randomized phase II trial, 119 patients with unresectable colorectal liver metastases (n < 10 and no extrahepatic disease) received systemic treatment alone or systemic treatment plus aggressive local treatment by radiofrequency ablation ± resection. Previously, we reported that the primary end point (30-month overall survival [OS] > 38%) was met. We now report on long-term OS results. All statistical tests were two-sided. The analyses were according to intention to treat.

Results: At a median follow up of 9.7 years, 92 of 119 (77.3%) patients had died: 39 of 60 (65.0%) in the combined modality arm and 53 of 59 (89.8%) in the systemic treatment arm. Almost all patients died of progressive disease (35 patients in the combined modality arm, 49 patients in the systemic treatment arm). There was a statistically significant difference in OS in favor of the combined modality arm (hazard ratio [HR] = 0.58, 95% confidence interval [CI] = 0.38 to 0.88, P = .01). Three-, five-, and eight-year OS were 56.9% (95% CI = 43.3% to 68.5%), 43.1% (95% CI = 30.3% to 55.3%), 35.9% (95% CI = 23.8% to 48.2%), respectively, in the combined modality arm and 55.2% (95% CI = 41.6% to 66.9%), 30.3% (95% CI = 19.0% to 42.4%), 8.9% (95% CI = 3.3% to 18.1%), respectively, in the systemic treatment arm. Median OS was 45.6 months (95% CI = 30.3 to 67.8 months) in the combined modality arm vs 40.5 months (95% CI = 27.5 to 47.7 months) in the systemic treatment arm.

Conclusions: This phase II trial is the first randomized study demonstrating that aggressive local treatment can prolong OS in patients with unresectable colorectal liver metastases.

Figure 1.

CONSORT flow diagram. PD = progressive disease; PFS = progression-free survival; RFA = radiofrequency ablation.

Figure 2.

Kaplan-Meier curves for overall survival in patients with unresectable colorectal liver metastases treated by systemic treatment alone or combined modality treatment by systemic treatment plus aggressive local treatment by radiofrequency ablation ± resection (P = .01). P value was calculated using a two-sided log-rank test.

Figure 3.

Kaplan-Meier curves for progression-free survival in patients with unresectable colorectal liver metastases treated by systemic treatment alone or combined modality treatment by systemic treatment plus aggressive local treatment by radiofrequency ablation ± resection (P = .005). P value was calculated using a two-sided log-rank test.

Figure 4.

Cumulative incidence of hepatic progressions in patients with unresectable colorectal liver metastases treated by systemic treatment alone or combined modality treatment by systemic treatment plus aggressive local treatment by radiofrequency ablation ± resection (P < .001). P value was calculated using a two-sided Gray test.

Figure 5.

Cumulative incidence of extrahepatic progressions in patients with unresectable colorectal liver metastases treated by systemic treatment alone or combined modality treatment by systemic treatment plus aggressive local treatment by radiofrequency ablation ± resection (P = .73). P value was calculated using a two-sided Gray test.