First-line systemic chemotherapy in patients with metastatic colorectal cancer (CRC)

The selection of the first-line regimen depends on the chosen treatment strategy (Table 1). In the absence of conclusive comparative data, options in Table 1 should be regarded as proposals rather than as strong recommendations, reflecting the available options and the likelihood of efficacy with respect to the specific treatment aim in the different disease groups. They can be modified according to individual patients' situations and experience. The majority of the proposals are not supported by sufficient randomized data but rather by small trials and retrospective subgroup analyses.

For Group 1 patients: Downsizing by induction chemotherapy (conversion therapy) enabling secondary surgery is the only means of giving the potential of long-term survival or cure in an otherwise incurable/palliative situation. Data emerging from randomized and single-arm trials suggest that the addition of a targeted agent (bevacizumab or EGFR-antibody) to a doublet or even to a triplet might lead to a higher R0 resection rate in liver limited disease. The combination of a chemodoublet with EGFR-antibodies has led to high overall response rate (ORR) of 75%-80% of liver metastasis and higher resection rates accordingly (although still low in absolute numbers) in patients with liver limited unresectable metastatic KRAS wild-type CRC. In contrast, the combination of a FU with oxaliplatin and bevacizumab has led to a non-significant trend of an increased resection rate compared with the chemo-backbone alone, although no increase in response rate was shown. FOLFOXIRI could be an alternative to FOLFIRI/FOLFOX combined with EGFR-antibodies, and is the preferred option if targeted drugs, in particular EGFR-antibodies, are not available, and in particular for KRAS mutant tumours.

For Group 2 and 3 patients: A retrospective pooled analysis revealed a correlation between improved survival and the availability of 5-FU/LV, oxaliplatin and irinotecan at some point during the course of the disease.

In Group 3 patients, large trials evaluated different sequential approaches. Although ORR and PFS were improved with upfront combination treatment, OS was similar for both approaches with a non-significant median difference of 1 month. Comparable results could be shown in an elderly and/or frail population in the FOCUS 2 trial.3Upfront single-agent fluoropyrimidine does not have a significant negative impact on final outcome, although these studies reported a lower OS (<20 months), as would nowadays be expected (>20 months) at least in a patient population mainly from Group 2 and 3. Patient selection may well explain these differences.

Watchful waiting can be recommended in patients with the following criteria: low tumour burden, but not eligible for secondary resection, indolent disease, asymptomatic, patient is fully informed and agrees to this approach, and the patient is monitored frequently. It should be noted that the three pivotal trials from the 5-FU only era have conflicting outcomes.

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

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

Recent data has demonstrated that anti-EGFR therapy should be reserved for patients wildtype for KRAS and NRAS (exons 2, 3 and 4). Testing of KRAS and NRAS mutational status should be performed for patients for whom anti-EGFR therapy is considered. Anti-EGFR therapy should not be used in patients whose tumours are found to have mutation in KRAS or NRAS. In addition, the aggregate data from randomized trials suggests that anti-EGFR therapy added to either FOLFIRI or FOLFOX is efficacious and can confer a DFS and/or OS advantage in RAS wildtype metastatic CRC.

Whilst FOLFOXIRI may be considered in selected Group 1 patients, it should be balanced against the elevated risk of substantial toxicity.