Second- and further-line treatment in patients with metastatic colorectal cancer (CRC)

Second line is defined as when the first-line chemotherapy backbone has to be changed.

The general sequence is either FU/oxaliplatin followed by FU/irinotecan or the reverse sequence, which yields similar results in terms of OS.

5-FU can and should be used again in second and further lines, despite proven resistance to first-line combination. Continuation of bevacizumab with changed chemotherapy backbone in second-line increases OS after progression with first-line bevacizumab and chemotherapy [ML18147 study: OS at 12 months 48% vs 42% in bevacizumab plus chemotherapy group vs chemotherapy alone] (ML18147 study: Median OS in the bevacizumab plus chemotherapy group was 11.2 months (95% CI 10.4-12.2) vs 9.8 months (8.9-10.7) for chemotherapy (HR 0.81, 95% CI 0.69-0.94; p=0.0062). 5-FU and bevacizumab could be continued throughout first and second-line treatment, and solely irinotecan and oxaliplatin will be exchanged by each other.

For EGFR antibodies, there is no clear data on the efficacy of continuing EGFR antibodies beyond progression.

After FOLFOX combination chemotherapy (with or without bevacizumab), aflibercept and bevacizumab in combination with FOLFIRI are active with increase in PFS and OS.

Second-line FOLFOX and bevacizumab is superior in terms of ORR, PFS and OS compared with FOLFOX after failure of FU/irinotecan. (E3200: OS at 12 months 58% vs 45% in group receiving bevacizumab in combination with FOLFOX4 vs those treated with FOLFOX4 alone; bevacizumab in combination with FOLFOX4 had a median survival of 12.9 months compared with 10.8 months for those treated with FOLFOX4 alone; HR 0.75; p=0.0011.)

Second-line treatment with aflibercept plus FOLFIRI is superior in terms of response rate (RR), PFS and OS compared with FOLFIRI after failure of FOLFOX. (Velour study: OS at 12 months 50% vs 44% in alibercept plus FOLFIRI vs placebo plus FOLFIRI.)

(Velour study: Median OS with aflibercept + FOLFIRI vs placebo + FOLFIRI 13.50 vs 12.06 months, HR 0.817; p=0.0032. 2 year survival rate 28% vs 18.7%)

For KRAS wild-type patients not previously treated with anti EGFR antibodies, cetuximab with or without irinotecan and panitumumab with or without FOLFIRI are possible options.

In patients refractory to FU, oxaliplatin, irinotecan, anti EGFR antibodies (only KRAS wild-type), bevacizumab, and regorafenib, treatment with fluoropyrimidines and mitomycin or reintroduction of oxaliplatin (and irinotecan) results in very limited improvement in some patients treated last line. However, despite poor data, these treatment strategies may be appropriate in selected patients.

Last line salvage treatment with regorafenib is superior to placebo in terms of OS. (CORRECT: OS at 12 months: ~25% in both arms, OS at 6 months 52% vs 48% in regorafenib group vs placebo group)

(CORRECT: HR for OS was 0.77 for regorafenib vs placebo (95% CI 0.64-0.94; p=00052; Median OS was 6.4 months in the regorafenib group and 5.0 in the placebo group. The OS rate was 80.3% in the regorafenib group and 72.7% in the placebo group at 3 months, 52.5% and 43.5%, respectively, at 6 months, 38.2% and 30.8%, respectively, at 9 months, and 24.3% and 24.0%, respectively, at 12 months.

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

The workgroup members unanimously support the following statement as modification 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 tumour is found to have a mutation in KRAS or NRAS.