The GERCOR OPTIMOX1 study showed that stopping oxaliplatin after six cycles of infusional FU, LV, and oxaliplatin chemotherapy (FOLFOX7) in patients with advanced colorectal cancer then continuing maintenance therapy with a simplified LV plus bolus and infusional FU regimen alone achieves equivalent efficacy results to continuing FOLFOX4 until progression or toxicity. Stopping oxaliplatin after six cycles also reduced toxicity. The GERCOR OPTIMOX2 study evaluated whether FU maintenance therapy is really necessary, i.e. could a complete treatment break (chemotherapy-free interval) be given before reintroducing FOLFOX treatment? It was to have randomised 600 patients to allow detection of a 20% absolute difference in 2-year survival. However, the investigators terminated this study when bevacizumab was approve in France, as the trial could not continue with the regimens as used initially, and it appeared that the addition of bevacizumab would render the results uninterpretable. Data from 202 randomised patients with untreated metastatic colorectal cancer in the now relatively underpowered study have been published in the Journal of Clinical Oncology.

The patients were randomised to one of the following arms:

• 6 cycles of modified FOLFOX7 (mFOLFOX7) followed by simplified leucovorin plus bolus and infusional fluorouracil until progression (arm 1 or maintenance arm, n = 98)

• 6 cycles of mFOLFOX7 before a complete stop of chemotherapy (arm 2 or chemotherapy-free interval [CFI] arm, n = 104)

Reintroduction of mFOLFOX7 was scheduled after tumour progression in both arms. The primary study end point was duration of disease control (DDC).

The following findings were reported:

• Median DDC was 13.1 months in patients assigned to the maintenance arm and 9.2 months in patients assigned to the CFI arm (P = 0.046).

• Median progression-free survival (PFS) and overall survival were 8.6 and 23.8 months, respectively, in the maintenance arm and 6.6 and 19.5 months, respectively, in the CFI arm.

• Median duration of maintenance therapy (arm 1) and CFIs (arm 2) were 4.8 months and 3.9 months, respectively.

• Overall response rates were 59.2% and 59.6% for the initial FOLFOX chemotherapy and 20.4% and 30.3% for FOLFOX reintroduction in arms 1 and 2, respectively.

The researchers conclude that “planned complete discontinuation of chemotherapy had a negative impact on DDC and PFS compared with the maintenance therapy strategy. These results suggest that chemotherapy discontinuation cannot be decided before therapy is initiated in patients with advanced colorectal cancer.”

An accompanying editorial discusses how these results can best be integrated into every day management, stressing that “a complete stop of all therapy is not the correct strategy." However the author acknowledges that no patient could, or should, be treated continuously with first-line therapy for a prolonged length of time, and intermittent treatment breaks are necessary, but this requires both clinical judgment and individualisation. He adds that there is a “need to identify, whether by biomarker or clinical parameters, meaningful ways to predict therapeutic intensity and the use of treatment holidays remains a subject for active investigation.”