Duration of therapy and maintenance/intermittent chemotherapy in patients with metastatic colorectal cancer (CRC)

The treatment duration is dependent on the treatment aim.

If the intention of treatment is potential conversion to resectability, induction chemotherapy should be continued until potential resectability might be achieved, ideally at least for 3-4 months, with first evaluation after 6-8 weeks, to evaluate whether the chosen regimen is active at all, and if resectability is still not achieved, for up to 6 and 8 months. Further treatment (>8 months) with the same regimen is not recommended, since it is unlikely that by continuation of the same treatment, resectability will be achieved. At this point and, in case of insufficient response within 3-4 months (again judged by the MDT), a switch to alternative chemotherapy could be considered. Cumulative liver toxicity with the risk of perioperative morbidity/mortality and delayed recovery after liver resection will be increased by prolonged treatment duration. However, the potential toxicity of the treatment should be balanced with the potential benefits of achieving a resectable status.

For Group 2 and 3 patients, in clinical trials, the median treatment duration is only 6 months indicating that in many patients (60%-70%) treatment is stopped not because of progression but because of other reasons. Re-induction with the same treatment regimen is recommended in cases whereby treatment was discontinued in the absence of cancer progression. Drug-specific toxicity must be taken into account when deciding to re-induce treatment. For example, in case of oxaliplatin limiting toxicity second-line treatment must be started since oxaliplatin might not be applicable any more.

Treatment break is appropriate in a subset of patients. This requires careful patient selection and close monitoring for disease progression. In patients with aggressive disease and poor prognostic features, survival may be impaired if first-line combination treatment with all drugs is not given continuously until progression. In all other patients, induction chemotherapy (without oxaliplatin) might be stopped after 3-4 months until progression; in case of progression, the same treatment should be reinstituted if feasible (stop go). However, if complete discontinuation of induction chemotherapy is chosen, accurate selection of patients and close monitoring for progression (rather than waiting until progression is clinically evident through symptoms) is strongly recommended.

An alternative to stop and go is the pre-planned treatment intervals and break duration (intermittent treatment) of one or all drugs resulting in comparable overall outcome in comparison to treatment until progression. However, the two approaches, intermittent and stop and go, have not been prospectively compared yet.

The role of maintenance therapy in bevacizumab and anti-EGFR inhibitors was not established as of 2012, when the ESMO guidelines were developed.

The workgroup members unanimously support the general adoption of the ESMO guidelines.

The workgroup members support the following statements as modifications to the ESMO guidelines:

Maintenance bevacizumab/capecitabine may lead to a modest PFS benefit in metastatic CRC.4Two workgroup members felt that maintenance bevacizumab/capecitabines benefit came after bevacizumab/capecitabine and oxaliplatin, a regimen which in itself is not convincingly better than capecitabine/oxaliplatin although widely practiced.

There is limited data (COIN-B)5on the role of intermittent or maintenance scheduling of anti-EGFR inhibitors.