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Patients with unresectable metastatic colorectal cancer who experience a chemotherapy-free interval (CFI) following first-line chemotherapy have shorter durations of disease control (DDC) and progression-free survival (PFS) compared with patients who begin maintenance therapy immediately, according to data from a French study. Conducted by Groupe Cooperateur Multidisciplinaire en Oncologie (GERCOR), the OPTIMOX (Optimized Leucovorin [LV]-Fluorouracil [FU]-Oxaliplatin) 2 trial is a follow-up to GERCOR OPTIMOX1. The OPTIMOX1 study demonstrated that discontinuing a FOLFOX7 regimen after 6 cycles and starting on a simplified maintenance regimen of LV plus bolus and infusional FU (LV5FU2) resulted in lower toxicity but was as effective as continuing FOLFOX4 until disease progression or unacceptable toxicity.
In OPTIMOX2, investigators enrolled 202 patients with colorectal cancer at 12 treatment centers in France between February 2004 and April 2006. Over ~3 months, all patients received induction chemotherapy with 6 cycles of a modified FOLFOX7 regimen that used a reduced dose of oxaliplatin and an increased dose of FU. Following chemotherapy, patients were randomized to receive maintenance therapy with the simplified LV5FU2 regimen (n = 98) or no treatment until evidence of disease progression (n = 104). In addition, patients in the LV arm who experienced progression on maintenance therapy could start second-line treatment.
In all, 24 patients experienced disease progression or death during the induction phase of the trial, 24 had salvage surgery of metastases, and 8 discontinued treatment, making them ineligible for the second phase of the trial. Only 63% (n = 62) of patients assigned to receive maintenance therapy with the simplified LV5FU2 regimen continued on to the investigational phase of the trial compared with 81% (n = 84) assigned to a CFI. Patients in the LV arm received maintenance therapy for a median of 4.8 months, and the median CFI lasted 3.9 months.
Patients were assessed at baseline, again after 4 and 6 cycles of treatment, and then every 2 months or every 4 cycles, with tumor response evaluated according to RECIST. The trial’s primary endpoint was median DDC, which was 13.1 months in the maintenance arm versus only 9.2 months in the CFI arm (P = .046). Patients who received maintenance therapy also had a longer median PFS, at 8.6 months compared with 6.6 months for those in the CFI arm (P = .0017). Median overall survival in the LV arm was 23.8 months compared with 19.5 months for the CFI arm (P = .42). The 2-year survival rate was also higher in the LV arm, at 50.0% versus 39.4% for the CFI group.
Following disease progression, 54 patients (81.8%) in the LV arm and 66 patients in the CFI arm (84.6%) were reintroduced to FOLFOX chemotherapy. Patients whose disease progressed on FOLFOX or those with limiting sensory neuropathy were not eligible for reintroduction. Reintroduction occurred at a median of 9 days for patients on maintenance therapy and 8 days for those in the CFI arm. Overall response rate after the initial reintroduction of FOLFOX was 20.4% in the LV group and 30.3% in the CFI group, with the vast majority of patients (90%) who responded to induction FOLFOX responding to treatment. More than half the patients in both arms (59.3% in the LV arm and 57.6% in the CFI arm) achieved partial response plus stable disease.
The majority of patients in each arm who received second-line therapy after progression were given an irinotecan-based regimen: 62 in the LV arm and 53 in the CFI arm. In the LV arm, 15% of patients received bevacizumab (Avastin) in addition to chemotherapy compared with 11% in the CFI arm. Cetuximab (Erbitux) was administered to 6% of patients in the maintenance arm and 2% of patients in the CFI arm. Patients in the LV arm started second-line therapy at a median of 11.7 months after diagnosis compared with 9.4 months for patients in the CFI arm.
The researchers concluded that “maintenance therapy with simplified LV5FU2 after modified FOLFOX7 is an active strategy for treatment of patients with previously untreated metastatic colorectal cancer.” They cautioned that although maintenance therapy was associated with improvement in DDC and PFS, the duration of chemotherapy prior to the CFI was relatively short, at ~3 months. Up to 20% of patients in the CFI arm would likely have continued on induction therapy outside of the trial setting.
The authors also stated that while a CFI might be appropriate for some patients, the decision should be made on an individual basis. “The optimal strategy in patients with metastatic colorectal cancer remains to be defined in a heterogeneous population for whom different goals must be pursued,” the authors wrote. The DREAM (Double Inhibition Reintroduction Erlotinib Avastin Metastatic Colorectal Cancer) GERCOR study (OPTIMOX3) is evaluating monotherapy with targeted drugs as maintenance therapy following a chemotherapy regimen that includes bevacizumab.
Chibaudel B, Maindrault-Goebel F, Lledo G. Can chemotherapy be discontinued in unresectable metastatic colorectal cancer? The GERCOR OPTIMOX2 Study. J Clin Oncol
. 2009;27(34): 5727-5733