Systemic treatment for metastatic colorectal cancer

Table 1 Modifiable and non-modifiable risk factors and preventive factors for colorectal cancer

	Modifiable	Non-modifiable
Risk factors	Excess body fat	Family history of CRC
	Sedentary life-style	Advanced polyps
	Westernized diet	Polyposis syndrome (FAP, MAP)
	Processed meats	Lynch syndrome (HNPCC)
	Red meats	Black people
		Older age
		Male
Preventive factors	High fiber diet	Female
	Whole grain diet
	No alcohol
	No smoking

CRC: Colorectal cancer; FAP: Familial adenomatous polyposis; HNPCC: Hereditary non-polyposis colorectal cancer; MAP: MUTYH-associated polyposis.

Table 2 Chemotherapy and targeted therapies for metastatic colorectal cancer patients

Ref.	Country	Drug(s)	Number of patients	Study phase	ORR, %	Mean OS in mo	Mean PFS in mo	Results
Resectable CLM with no extra-hepatic metastasis
Gruenberger et al[42]	Austria	Capecitabine, oxaliplatin plus bevacizumab	56	2	73.2	-	-	Bevacizumab can be safely administered until 5 wk before liver resection in patients with metastatic CRC without increasing the rate of surgical or wound healing complications or the severity of bleeding
Bridgewater et al[43]	United Kingdom	Oxaliplatin, L-folinic acid, fluorouracil or capecitabine, oxaliplatin plus cetuximab	257	3	-	81.0/55.4 (Chemo/Chemo+)	22.2/15.5 (Chemo/Chemo+)	In the perioperative setting, patients with operable diseases are at a disadvantage in terms of OS; hence, cetuximab should not be used in this setting
Unresectable CLM with potential for resection and no extra-hepatic metastasis
Wong et al[44]	United Kingdom	Capecitabine, oxaliplatin plus bevacizumab	46	-	78.0	-	-	A high response rate for patients with CLMs with poor-risk features not selected for upfront resection and converted 40% of patients to resectability
Gruenberger et al[45]	United Kingdom, Austria, France, and Spain	Bevacizumab plus FOLFOX-6 (5-fluorouracil folinic acid oxaliplatin) or FOLFOXIRI (5-fluorouracil folinic acid oxaliplatin irinotecan)	80	2	81/62 (BF/BF6)	-	18.6/11.5 (BF/BF6)	In patients with CLM that were originally unresectable, bevacizumab-FOLFOXIRI was correlated with better response and resection rates as well as a longer PFS than bevacizumab-mFOLFOX-6
Garufi et al[47]	Italy	Cetuximab plus chrono-IFLO (chrono-irinotecan 5-fluorouracil leucovorin oxaliplatin)	43	2	-	37	-	Cetuximab in combination with chrono-IFLO resulted in 60% full resectability of CLM patients
Folprecht et al[48]	Germany	Cetuximab plus FOLFOX (5-fluorouracil folinic acid oxaliplatin) or FOLFOXIRI (5-fluorouracil folinic acid oxaliplatin irinotecan)	56/55 (CFX/CFI)	-	-	35.7/29.0 (CFX/CFI)	10.8/10.5 (CFX/CFI)	Both FOLFOX/FOLFIRI with cetuximab appear to be effective conversion therapy regimens in patients with KRAS codon 12/13/61 wild-type tumors. Thus, liver surgery can be deemed curative or as a second line of therapy in people who are not cured
Unresectable CLM
Rivera et al[50]	Spain, Germany, United States, Belgium, Switzerland, and Italy	mFOLFOX6 plus panitumumab or bevacizumab	170/156 (RAS WT/RAS WT/BRAF WT)	-	RAS WT 65/60, RAS WT/BRAF WT 65/62 (FXP/FXB)	RAS WT 36.9/28.9, RAS WT/BRAF WT 46.3/28.9 (FXP/FXB)	RAS WT 12.8/10.1, RAS WT/BRAF WT 13.1/10.1 (FXP/FXB)	Panitumumab in combination with mFOLFOX6 is a successful first-line therapy for individuals with RAS WT and RAS WT/BRAF WT mCRC
Stintzing et al[53]	Germany	FOLFIRI (5-fluorouracil leucovorin irinotecan) plus cetuximab or bevacizumab	400	3	65.3/58.7 (FIC/FIB)	33.1/25.0 (FIC/FIB)	10.3/10.2 (FIC/FIB)	In the first-line therapy of patients with RAS wild-type metastatic colorectal cancer, FOLFIRI with cetuximab may be preferable than FOLFIRI plus bevacizumab
Pfeiffer et al[58]	Denmark	Trifluridine plus tipiracil hydrochloride (TAS-102) or TAS-102 plus bevacizumab	47/46 (T/TB)	2	51/67 (T/TB)	6.7/9.4 (T/TB)	2.6/4.6 (T/TB)	In terms of efficacy and safety, bevacizumab may be an effective companion for TAS-102 in patients with chemorefractory metastatic colorectal cancer
Cremolini et al[59]	Italy	Cetuximab plus irinotecan	13/12 (RWT/RMT)	2	-	12.5/5.2 (RWT/RMT)	4.0/1.9 (RWT/RMT)	In patients with RAS and BRAF wild-type mCRC who have acquired resistance to first-line irinotecan and cetuximab-based treatment, a re-challenge approach with cetuximab and irinotecan may be effective. The examination of RAS mutational status on cDNA may aid in the selection of potential patients
Sartore-Bianchi et al[60]	Italy	Panitumumab (re-challenge)	25	-	30	13.7	4	Interventional liquid biopsies can be used efficiently and safely to guide anti-EGFR re-challenge treatment with panitumumab in patients with mCRC
Kopetz et al[63]	United States	Irinotecan cetuximab or irinotecan cetuximab plus vemurafenib	50/50 (IC/ICV)	-	-	12/12 (IC/ICV)	2.0/4.2 (IC/ICV)	Vemurafenib in combination with cetuximab and irinotecan is an active combination that increases PFS. This is a well-planned research based on a solid grasp of the mechanisms of adaptive resistance in mCRC
Tabernero et al[64]	United States, France, Italy, Spain, United Kingdom, Germany, Australia, Hong Kong, Norway, Switzerland, Japan, South Korea, and the Netherlands	Encorafenib cetuximab binimetinib or encorafenib cetuximab or FOLFIRI cetuximab	224/220/221 (3D/2D/CD)	3	26.8/19.5/1.8 (3D/2D/CD)	9.3/9.3/5.9 (3D/2D/CD)	-	When compared to conventional chemotherapy, encorafenib plus cetuximab improved OS, ORR, and progression-free survival in previously treated patients with metastatic disease. Encorafenib with cetuximab is a new standard-of-care regimen for previously treated patients with BRAF V600E mCRC, according to main and revised studies
Siena et al[68]	United States, Italy, United Kingdom, Spain, and Japan	Trastuzumab deruxtecan (DS-8201)	53/7/18 (A/B/C)	2	45.3 (A)	5.4 (A)	6.9 (A)	Trastuzumab deruxtecan shown promising and sustained effect in HER2-positive mCRC that was resistant to conventional therapy, as well as a favorable safety profile
Mayer et al[71]	Belgium, Italy, Japan, Spain, Australia, and United States	Trifluridine plus tipiracil hydrochloride (TAS-102) or placebo	800 (2:1)	-	1.6/0.4 (TAS/placebo)	7.1/5.3 (TAS/placebo)	2.0/1.7 (TAS/placebo)	A significant number of Japanese and Western patients with mCRC who had had a lot of prior treatment, including those whose condition was resistant to fluorouracil, were shown to respond clinically to TAS-102

2D: Encorafenib plus cetuximab; 3D: Encorafenib plus cetuximab plus binimetinib; A: Cohort A; B: Cohort B; BF: Bevacizumab plus FOLFOXIRI; BF6: Bevacizumab plus FOLFOX-6; BRAF: Protein kinase B-Raf; C: Cohort C; CD: FOLFIRI plus cetuximab; CFI: Cetuximab plus FOLFOXIRI; CFX: Cetuximab plus FOLFOX; CRC: Colorectal cancer; EGFR: Epidermal growth factor receptor; FIB: FOLFIRI plus bevacizumab; FIC: FOLFIRI plus cetuximab; FOLFIRI: Folinic acid, fluorouracil, and irinotecan hydrochloride; FXB: mFOLFOX6 plus bevacizumab; FXP: mFOLFOX6 plus panitumumab; HER2: Human epidermal growth factor receptor 2; IC: Irinotecan plus cetuximab; ICV: Irinotecan plus cetuximab plus vemurafenib; mCRC: Metastatic colorectal cancer; ORR: Objective response rate; OS: Overall survival; PFS: Progression-free survival; RAS: Rat sarcoma virus; RMT: Rat sarcoma virus mutate-type; RWT: Rat sarcoma virus wild-type; T: Trifluridine plus tipiracil hydrochloride; TB: Trifluridine plus tipiracil hydrochloride plus bevacizumab; WT: Wild-type.