How to select the optimal treatment for first line metastatic colorectal cancer

Table 1 Prognostic scores/health assessments

Score	Risk category	Factors
“Kohne” score[13]	Low risk	ECOG 0/1 and only one tumour site
	Intermediate risk	ECOG 0/1, ALP < 300 U/L and more than one tumour site or ECOG > 1 and WBC < 1 × 1010/L and only one tumour site
	High risk	ECOG 0/1 and more than one tumour site and ALP ≥ 300 U/L or ECOG > 1 and more than one tumour site or ECOG > 1 and WBC > 1 × 1010/L
FOCUS 2[15]	Comprehensive health assessment at baseline limited health Assessment during course of treatment (excluding MMSE and CCI)	Weight change Timed 20 metre walk MMSE CCI Patient completed questionnaire (social activity, physical fitness, symptoms, overall quality of life and depression)

ECOG: Eastern collaborative oncology group performance status; ALP: Alkaline phosphatase; WBC: White blood cells; MMSE: Mini mental state examination; CCI: Charlson comorbidity index.

Table 2 European Society for Medical Oncology clinical groups for first line treatment stratification[10]

ESMO group	Clinical presentation	Treatment aim	Treatment intensity
0	Clearly R0-resectable liver and/or lung metastases	Decrease risk of or delay relapse	FOLFOX
1	Liver and/or lung metastases only which:Might become resectable after induction chemotherapy	Maximum tumour shrinkage	Three or four drug combination
2	Multiple metastases/sites, with:Rapid progression and/orTumour-related symptoms/risk of rapid deterioration	Immediate clinically relevant response or at least tumour control	Three or four drug combination
3	Multiple metastases/sites without option for resection and no major symptoms or severe comorbidity	Abrogation of further progressionTumour shrinkage less relevantLow toxicity essential	Consider sequential approach: start withSingle agent, orDoublet with low toxicity

ESMO: European Society for Medical Oncology.

Table 3 Available treatment regimens for first-line metastatic colorectal cancer

Treatment intensity	Molecular factor	Regimens
Single agent		5FU/LVCapecitabin
Two-drug		Capecitabin/bevacizumab
		FOLFOX/XELOXFOLFIRI/XELIRI
Three-drug	RAS wt	FOLFOX + panitumumabFOLFIRI + cetuximab
	Independent of RAS status	FOLFOX/XELOX + bevacizumabFOLFIRI/XELIRI + bevacizumabFOLFOXIRI
Four-drug		FOLFOXIRI + bevacizumab

Combination chemotherapy with 5-fluorouracil, folinic acid (5FU/LV), and oxaliplatin (FOLFOX), or irinotecan (FOLFIRI) or both (FOLFOXIRI), or capecitabine and oxaliplatin (XELOX) or irinotecan (XELIRI).

Table 4 Efficacy and tolerability of three to four drug first line regimen

Regimen	Efficacy				Tolerability
	PFS		OS		Grade 3/4 AE	SAE	Fatal AEs
	RAS wt	RAS mut	RAS wt	RAS mut
FOLFOX + panitumumab[25]	10.1	7.31	25.8	15.51	84%	40%	5%
FOLFIRI + cetuximab[4,62]	10.59.9 (KRAS exon 2)	NR1	33.123.5 (KRAS exon 2)	NR1	71%-79%	26%	NR
FOLFOX/XELOX + bevacizumab[56]	9.4		21.3		80%	NR	2%
FOLFIRI + bevacizumab[7,62]	10.4	NR	25.9	NR	NR	20%	3.5%
	9.7		25.8
FOLFOXIRI + bevacizumab[7]	12.1		31.0		NR	20%	2.8%

¹These fields only informative (epidermal growth factor receptor antibodies not licensed for RAS mutated tumours). Combination chemotherapy with 5-fluorouracil, folinic acid, and oxaliplatin (FOLFOX), or irinotecan (FOLFIRI) or both (FOLFOXIRI), or capecitabine and oxaliplatin (XELOX). PFS: Progression free survival; OS: Overall survival; AE: Adverse events; SAE: Severe adverse events; NR: Not reported.