Randomized Trial of Induction Chemotherapy in Metastatic CRC
Randomized Trial of Induction Chemotherapy in Metastatic CRC
Background In a randomized trial with a median follow-up of 18.4 months, 6 months of induction chemotherapy with a three-drug regimen comprising 5-fluorouracil (by continuous infusion)–leucovorin, irinotecan, and oxaliplatin (FOLFOXIRI) demonstrated statistically significant improvements in response rate, radical surgical resection of metastases, progression-free survival, and overall survival compared with 6 months of induction chemotherapy with fluorouracil–leucovorin and irinotecan (FOLFIRI).
Methods From November 14, 2001, to April 22, 2005, we enrolled 244 patients with metastatic colorectal cancer. To evaluate if the superiority of FOLFOXIRI is maintained in the long term, we updated the overall and progression-free survival data to include events that occurred up to February 12, 2009, with a median follow-up of 60.6 months. We performed a subgroup and a risk-stratified analysis to examine whether outcomes differed in specific patient subgroups, and we analyzed the results of treatment after progression. Survival curves were estimated by the Kaplan–Meier method. Multivariable Cox regression models were fit to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). All statistical tests were two-sided.
Results FOLFOXIRI demonstrated statistically significant improvements in median progression-free survival (9.8 vs 6.8 months, HR for progression = 0.59, 95% CI = 0.45 to 0.76, P < .001) and median overall survival (23.4 vs 16.7 months, HR for death = 0.74, 95% CI = 0.56 to 0.96, P = .026) with a 5-year survival rate of 15% (95% CI = 9% to 23%) vs 8% (95% CI = 4% to 14%). The improvements in progression-free survival and, to a lesser extent, in overall survival were evident even when the analysis excluded patients who received radical resection of metastases. With regard to the risk-stratified analysis, FOLFOXIRI results in longer progression-free survival and overall survival than FOLFIRI in all risk subgroups.
Conclusions Six months of induction chemotherapy with FOLFOXIRI is associated with a clinically significant improvement in the long-term outcome compared with FOLFIRI with an absolute benefit in survival at 5 years of 7%.
Colorectal carcinoma is one of the most common cancers in Western countries, and a considerable proportion of colorectal cancer patients die as a result of the metastatic spread of their disease. The availability of three active cytotoxic agents (fluoropyrimidines, irinotecan, and oxaliplatin), two classes of biological agents (monoclonal antibodies that block vascular endothelial growth factor and epidermal growth factor receptor), and the expanded indications for surgical resection of metastases have considerably improved the prognosis of patients with metastatic colorectal cancer. Nevertheless, the long-term outcomes of these patients are still unsatisfactory given their median survival of just more than 20 months and a 5-year survival of less than 10%.
Chemotherapy remains the primary therapeutic option for patients with metastatic colorectal cancer, and the development of more efficacious chemotherapy regimens is of crucial interest. An additional critical and unresolved issue is the optimal duration of chemotherapy. Indeed, in the large majority of clinical trials, treatment was continued until progression of disease, whereas in clinical practice, treatment is often discontinued after a definite period of time. Although several randomized trials have demonstrated that intermittent treatment did not result in worse outcomes compared with continuous treatment until progression of disease, the two optimized leucovorin–fluorouracil–oxaliplatin (OPTIMOX) trials that evaluated oxaliplatin discontinuation and reintroduction in a stop-and-go strategy have suggested that a complete chemotherapy-free interval after 3 months of induction chemotherapy may be detrimental compared with continuous maintenance therapy.
In this context, we studied a 6-month induction treatment by using a three-drug regimen comprising 5-fluorouracil (by continuous infusion)–leucovorin, irinotecan, and oxaliplatin (ie, FOLFOXIRI) in an attempt to expose all patients with metastatic colorectal cancer to the three active cytotoxic agents with the goals of improving tumor response rates, increasing the rate of radical surgery of metastases, and improving survival. There are data from patients with metastatic colorectal cancer that support an association between tumor response to chemotherapy and efficacy. In addition, a direct correlation was demonstrated between the activity of chemotherapy (in terms of response rate) and the rate of radical resection of metastases among patients with unresectable metastatic disease at presentation (and this strategy of chemotherapy followed by radical surgical resection of metastases led to better long-term survival). Moreover, the "exposure" of patients with advanced colorectal cancer to all three active cytotoxic agents is associated with survival. As previously reported, on behalf of the Gruppo Oncologico Nord Ovest (GONO), we conducted a randomized trial comparing FOLFOXIRI with fluorouracil (by infusion)–leucovorin and irinotecan (FOLFIRI) as a first-line treatment in patients with metastatic colorectal cancer. On the basis of the current knowledge and standard clinical practice at the time the study was designed, we scheduled a maximum of 6 months of induction chemotherapy. The trial demonstrated an increased activity and efficacy of the three-drug regimen. After a median follow-up of 18.4 months, the confirmed response rate was statistically significantly higher in the FOLFOXIRI arm than in the FOLFIRI arm (60% vs 34%, P < .001), as was the rate of secondary radical surgical resection of metastases among all patients (15% vs 6%, P = .03) and among patients with liver metastases only (36% vs 12%, P = .017). Median progression-free survival was longer in the FOLFOXIRI arm than in the FOLFIRI arm (9.8 vs 6.9 months; hazard ratio [HR] of disease progression = 0.63, 95% confidence interval [CI] = 0.47 to 0.81, P = .006), as was median overall survival (22.6 vs 16.7 months; HR of death = 0.70, 95% CI = 0.50 to 0.97, P = .03). Compared with FOLFIRI, FOLFOXIRI was associated with a modest increase in the incidence of grade 2 or 3 peripheral neurotoxicity (0% vs 19%, P = .001) and of grade 3 or 4 neutropenia (28% vs 50%, P = .001), but the incidence of febrile neutropenia (3% vs 5%) and of grade 3 or 4 diarrhea (12% vs 20%) were not statistically significantly different, and there were no treatment-related deaths.
Here we report the final analysis of this trial, after a median follow-up of 5 years, to evaluate whether the superiority of FOLFOXIRI was maintained in the long term. We also performed subgroup and risk-stratified analyses, with risk defined according to the Kohne prognostic model, to explore whether any clinical factor predicts differential likelihood of benefit from the treatment. Finally, we analyzed the outcomes of patients who received treatment after disease progression to examine whether they were negatively affected by FOLFOXIRI.
Abstract and Introduction
Abstract
Background In a randomized trial with a median follow-up of 18.4 months, 6 months of induction chemotherapy with a three-drug regimen comprising 5-fluorouracil (by continuous infusion)–leucovorin, irinotecan, and oxaliplatin (FOLFOXIRI) demonstrated statistically significant improvements in response rate, radical surgical resection of metastases, progression-free survival, and overall survival compared with 6 months of induction chemotherapy with fluorouracil–leucovorin and irinotecan (FOLFIRI).
Methods From November 14, 2001, to April 22, 2005, we enrolled 244 patients with metastatic colorectal cancer. To evaluate if the superiority of FOLFOXIRI is maintained in the long term, we updated the overall and progression-free survival data to include events that occurred up to February 12, 2009, with a median follow-up of 60.6 months. We performed a subgroup and a risk-stratified analysis to examine whether outcomes differed in specific patient subgroups, and we analyzed the results of treatment after progression. Survival curves were estimated by the Kaplan–Meier method. Multivariable Cox regression models were fit to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). All statistical tests were two-sided.
Results FOLFOXIRI demonstrated statistically significant improvements in median progression-free survival (9.8 vs 6.8 months, HR for progression = 0.59, 95% CI = 0.45 to 0.76, P < .001) and median overall survival (23.4 vs 16.7 months, HR for death = 0.74, 95% CI = 0.56 to 0.96, P = .026) with a 5-year survival rate of 15% (95% CI = 9% to 23%) vs 8% (95% CI = 4% to 14%). The improvements in progression-free survival and, to a lesser extent, in overall survival were evident even when the analysis excluded patients who received radical resection of metastases. With regard to the risk-stratified analysis, FOLFOXIRI results in longer progression-free survival and overall survival than FOLFIRI in all risk subgroups.
Conclusions Six months of induction chemotherapy with FOLFOXIRI is associated with a clinically significant improvement in the long-term outcome compared with FOLFIRI with an absolute benefit in survival at 5 years of 7%.
Introduction
Colorectal carcinoma is one of the most common cancers in Western countries, and a considerable proportion of colorectal cancer patients die as a result of the metastatic spread of their disease. The availability of three active cytotoxic agents (fluoropyrimidines, irinotecan, and oxaliplatin), two classes of biological agents (monoclonal antibodies that block vascular endothelial growth factor and epidermal growth factor receptor), and the expanded indications for surgical resection of metastases have considerably improved the prognosis of patients with metastatic colorectal cancer. Nevertheless, the long-term outcomes of these patients are still unsatisfactory given their median survival of just more than 20 months and a 5-year survival of less than 10%.
Chemotherapy remains the primary therapeutic option for patients with metastatic colorectal cancer, and the development of more efficacious chemotherapy regimens is of crucial interest. An additional critical and unresolved issue is the optimal duration of chemotherapy. Indeed, in the large majority of clinical trials, treatment was continued until progression of disease, whereas in clinical practice, treatment is often discontinued after a definite period of time. Although several randomized trials have demonstrated that intermittent treatment did not result in worse outcomes compared with continuous treatment until progression of disease, the two optimized leucovorin–fluorouracil–oxaliplatin (OPTIMOX) trials that evaluated oxaliplatin discontinuation and reintroduction in a stop-and-go strategy have suggested that a complete chemotherapy-free interval after 3 months of induction chemotherapy may be detrimental compared with continuous maintenance therapy.
In this context, we studied a 6-month induction treatment by using a three-drug regimen comprising 5-fluorouracil (by continuous infusion)–leucovorin, irinotecan, and oxaliplatin (ie, FOLFOXIRI) in an attempt to expose all patients with metastatic colorectal cancer to the three active cytotoxic agents with the goals of improving tumor response rates, increasing the rate of radical surgery of metastases, and improving survival. There are data from patients with metastatic colorectal cancer that support an association between tumor response to chemotherapy and efficacy. In addition, a direct correlation was demonstrated between the activity of chemotherapy (in terms of response rate) and the rate of radical resection of metastases among patients with unresectable metastatic disease at presentation (and this strategy of chemotherapy followed by radical surgical resection of metastases led to better long-term survival). Moreover, the "exposure" of patients with advanced colorectal cancer to all three active cytotoxic agents is associated with survival. As previously reported, on behalf of the Gruppo Oncologico Nord Ovest (GONO), we conducted a randomized trial comparing FOLFOXIRI with fluorouracil (by infusion)–leucovorin and irinotecan (FOLFIRI) as a first-line treatment in patients with metastatic colorectal cancer. On the basis of the current knowledge and standard clinical practice at the time the study was designed, we scheduled a maximum of 6 months of induction chemotherapy. The trial demonstrated an increased activity and efficacy of the three-drug regimen. After a median follow-up of 18.4 months, the confirmed response rate was statistically significantly higher in the FOLFOXIRI arm than in the FOLFIRI arm (60% vs 34%, P < .001), as was the rate of secondary radical surgical resection of metastases among all patients (15% vs 6%, P = .03) and among patients with liver metastases only (36% vs 12%, P = .017). Median progression-free survival was longer in the FOLFOXIRI arm than in the FOLFIRI arm (9.8 vs 6.9 months; hazard ratio [HR] of disease progression = 0.63, 95% confidence interval [CI] = 0.47 to 0.81, P = .006), as was median overall survival (22.6 vs 16.7 months; HR of death = 0.70, 95% CI = 0.50 to 0.97, P = .03). Compared with FOLFIRI, FOLFOXIRI was associated with a modest increase in the incidence of grade 2 or 3 peripheral neurotoxicity (0% vs 19%, P = .001) and of grade 3 or 4 neutropenia (28% vs 50%, P = .001), but the incidence of febrile neutropenia (3% vs 5%) and of grade 3 or 4 diarrhea (12% vs 20%) were not statistically significantly different, and there were no treatment-related deaths.
Here we report the final analysis of this trial, after a median follow-up of 5 years, to evaluate whether the superiority of FOLFOXIRI was maintained in the long term. We also performed subgroup and risk-stratified analyses, with risk defined according to the Kohne prognostic model, to explore whether any clinical factor predicts differential likelihood of benefit from the treatment. Finally, we analyzed the outcomes of patients who received treatment after disease progression to examine whether they were negatively affected by FOLFOXIRI.
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