Colorectal cancer: From prevention to personalized medicine

Table 1 Characteristics of some colorectal cancer screening programs worldwide

Country	Test	Periodicity	Target population (age)	Year2
Germany1	FOBT	Annual	50-54	1971
	FOBT or CS	Biennial/Every 10 yr	≥ 55
Italy	FOBT	Biennial	50-69/74	1982
	FS	Once-only	58-60
Israel	FOBT	Annual	50-74	early 1990s
Japan	FOBT	Annual	≥ 40	1992
United States1	FOBT	Annual	50-75	1994
	FS/FOBT	Every 5/Every 3 yr
	CS	Every 10 yr
Taiwan	FOBT	Biennial	50-69	1995
Spain	FOBT	Biennial	50-69	2000
Poland1	CS	Periodic	50-66	2000
Czech Republic1	FOBT	Annual	50-54	2000
	FOBT/CS	Biennial/Every 10 yr	≥ 55
France	FOBT	Biennial	50-74	2002
Finland	FOBT	Biennial	60-69	2004
South Korea	FOBT	Annual	≥ 50	2004
Latvia1	FOBT	Annual	≥ 50	2005
Australia	FOBT	Biennial	55-74	2002
England	FOBT	Biennial	50-74	2006
The Netherlands	FOBT	Biennial	60-69	2006
Canada				2007
Ontario	FOBT	Biennial	≥ 50
Manitoba	FOBT	Biennial	50-74
Croatia	FOBT	Biennial	50-74	2007
Scotland	FOBT	Biennial	50-74	2007
Sweden	FOBT	Biennial	60-69	2008

¹Most countries have population-based screening programs (national or regional) except Czech Republic, Germany, Latvia, Poland and United States (which all have opportunistic screening).

²It refers to the year which some kind of screening began (pilot, population-based or opportunistic). FOBT: Fecal occult blood test; FS: Flexible Sigmoidoscopy; CS: Colonoscopy.

Table 2 Main colorectal cancer screening tools

Test	Sensitivity	Specificity	Considerations
Colonoscopy		90%	It requires a bowel cleansing preparation and sedation.
Adenoma ≤ 5 mm	70%-79%		Risk of severe complications.
Adenoma 6-9 mm	80%-92%		Not well accepted by population.
Adenoma ≥ 10 mm	92%-99%
CRC	92%-99%
Sigmoidoscopy1		92%	It requires less preparation.
Adenoma ≤ 5 mm	70%-79%		Sedation it is not necessary.
Adenoma 6-9 mm	80%-92%		Proximal lesions are not detected
Adenoma ≥ 10 mm	92%-99%
CRC	90%-92%
gFOBT standard		95%-99%	Dietary and pharmacological interactions.
Adenoma ≤ 5 mm	1%-5%		3 samples
Adenoma 6-9 mm	5%-13.7%
Adenoma ≥ 10 mm	8.9%-27.5%
CRC	25%-50%
gFOBT sensitive		90%-95%	Dietary and pharmacological interactions.
Adenoma ≤ 5 mm	5%-10%		3 samples
Adenoma 6-9 mm	10%-26.2%
Adenoma ≥ 10 mm	17.7%-49.4%
CRC	50%-87%
FIT		92.5%-98%	The sample needs to be refrigerated.
Adenoma ≤ 5 mm	2%-7.5%
Adenoma 6-9 mm	7.5%-24.0%
Adenoma ≥ 10 mm	16%-48%
CRC	50%-87%

¹Sensitivity and specificity only for distal lesions. Data based on the report “Evaluating test strategies for colorectal cancer screening: a decision analysis for the US Preventive Services Task Force”. Available from: URL: http://www.uspreventiveservicestaskforce.org/uspstf08/colocancer/cartzaubtab2.htm. DCBE: Double-contrast barium enema; gFOBT: Guayac fecal occult blood test; FIT: Immunochemical fecal occult blood test; CRC: Colorectal cancer.

Table 3 Fecal DNA markers for advanced adenoma and colorectal cancer n (%)

Marker	Study	Sensitivity		Specificity
		CRC	Adenoma > 1 cm
Meth vimentin	Chen et al[166]	43 (46)	-	178 (90)
	Itzkowitz et al[167]	29 (73)	-	106 (89)
	Li et al[168]	9 (41)	9 (45)	63 (95)
Meth SFRP2	Huang et al[169]	49 (94)	11 (53)	23 (96)
	Wang et al[170]	60 (87)	21 (62)	28 (93)
Meth TFPI2	Glöckner et al[171]	36 (76)	4 (21)	-
Meth ITGH4	Ausch et al[172]	-	9 (69)	22 (79)
Meth Spastic paraplegia-20	Zhang et al[173]	77 (80)	-	30 (100)
Meth PHACTR3	Bosch et al[174]	(50-60)	(17-29)	(92-98)
Meth TFPI2, long DNA	Zhang et al[175]	52 (87)	4 (44)	25 (83)
APC, KRAS, p53, long DNA	Imperiale et al[102]	16 (52)	84 (12)	1344 (94)
APC, KRAS, p53, long DNA	Alhquist et al[103]	3 (25)	47 (8)	2246 (96)
APC, KRAS, Meth vimentin	Alhquist et al[103]	11 (58)	55 (45)	63 (84)
Meth SFRP2, HPPI, MGMT	Huang et al[169]	50 (96)	15 (71)	23 (96)
Meth APC, ATM, hMLH1, sFRP2, HLTF, MGMT, and GSTP1	Leung et al[176]	15 (75)	17 (68)	27 (90)
Meth vimentin, long DNA	Itzkowitz et al[167]	68 (83)	6 (86)	298 (82)
Meth RASSF2 or SFRP2	Nagasaka et al[177]	63 (75)	25 (44)	101 (89)
Meth BMP3, hDNA, KRAS, APC	Zou et al[100]	67 (91)	21 (78)	85 (85)
Meth vimentin, MLH1, MGMT	Baek et al[178]	45 (75)	31 (60)	32 (87)
Meth RARB2, p16INK4a, MGMT, APC	Azuara et al[179]	16 (62)	8 (40)	20 (100)
KRAS, a actina Meth NDRG4, BMP3, vimentin, TFPI2	Ahlquist et al[107]	214 (85)	72 (54)	264 (90)
β-actin, KRAS, meth BMP3 and NDRG4, fecal hemoglobin	Lidgard et al[105]	91 (98)	48 (57)	139 (90)

Meth: Methylation; CRC: Colorectal cancer; APC: Adenomatous polyposis coli gene.

Table 4 Fecal RNA markers for colorectal adenoma and colorectal cancer n (%)

Marker	Sample	Study	Sensitivity		Specificity
			CRC	Adenoma
CDA, MGC20553, BANK1, BCNP1, MS4A1	Blood	Han et al[138]	30 (88)	-	27 (64)
ANXA3, CLEC4D, LMNB1, PRRG4, TNFAIP6, VNN1, IL2RB	Plasma	Marshall et al[180]	145 (72)	-	146 (70)
ANXA3, CLEC4D, TNFAIP6, LMNB1, PRRG4, VNN1, IL2RB	Plasma	Yip et al[181]	60 (61)	-	85 (77)
MicroRNA (miRNA-21, miRNA-106a)	Fecal	Link et al[113]	(74)	-	(79)
MicroRNA-L6	Plasma	Schiedeck et al[182]	145 (79)	-	45 (100)
MicroRNA (miRNA-92)	Plasma	Ng et al[142]	80 (89)	-	35 (70)
MicroRNA (miRNA-92a, miRNA-21)	Fecal	Wu et al[183]	63 (72)	32 (56)	74 (73)
ANXA3, CLEC4D, LMNB1, PRRG4, TNFAIP6, VNN1, IL2RB	Plasma	Chao et al[184]	215 (78)	-	215 (66)
COX2, matrix metalloproteinase 7	Fecal	Takai et al[111]	56 (90)	-	29 (100)

Table 5 Serum DNA markers for adenoma and colorectal cancer n (%)

Marker	Study	Sensitivity		Specificity
		CRC	Adenoma
APC, KRAS, p53	Wang et al[185]	36 (46)	-	50 (100)
APC mutation	Diehl et al[121]	16 (73)	1 (9)	33 (100)
APC, MLH1, HLTF	Leung et al[186]	3-28 (6-57)	-	37-41 (90-100)
Meth SEPT9	Lofton-Day et al[134]	92 (69)	-	154 (86)
	Grützmann et al[133]	73 (58)	3 (18)	165 (90)
	deVos et al[131]	62 (69)	-	132 (89)
	Tóth et al[187]	88 (96)	-	78 (85)
TMEF2, NGFR, SEPT9	Lofton-Day et al[134]	40-69 (30-52)	-	170 (95)
Meth on 10 genes	Lee et al[188]	210 (87)	48 (75)	254 (92)
Meth Vimentin	Li et al[168]	48 (59)	-	102 (93)

TMEF2: Transmembrane protein with EGF–like and follistatin–like and two follistatin-like domains 2; SEPT9: Septin 9; Meth: Methylation; CRC: Colorectal cancer; APC: Adenomatous polyposis coli gene; MLH1: MutL homolog 1; HLTF: Helicase-like transcription factor.

Table 6 TNM classification of colorectal cancer

T = Primary tumor

TX = Primary tumor cannot be assessed

T0 = No evidence of primary tumor

Tis = Carcinoma in situ: intraepithelial or invasion of lamina propria

T1 = Tumor invades submucosa

T2 = Tumor invades muscularis propria

T3 = Tumor invades through the muscularis propia into subserosa or into nonperitonealized pericolic or perirectal tissues

T4a = Tumor penetrates to the surface of the visceral peritoneum

T4b = Tumor directly invades or is adherent to other organs or structures

N = Regional lymph nodes

NX = Regional lymph nodes cannot be assessed

N0 = No regional lymph node metastasis

N1a = Metastasis in one regional lymph node

N1b = Metastasis in two to three regional lymph nodes

N1c = Tumor deposit(s) in the subserosa, mesentery, or nonperitonealized pericolic or perirectal tissues without regional nodal metastasis

N2a = Metastasis in four to six regional lymph nodes

N2b = Metastasis in seven or more regional lymph nodes

M = Distant metastasis

MX = Distant metastasis cannot be assessed

M0 = No distant metastasis

M1a = Distant metastasis to one organ or site

M1b = Distant metastasis to more than one organ/site or the peritoneum

Staging

Stage I (T1-T2, N0, M0)

Stage IIA (T3, N0, M0)

Stage IIB (T4a, N0, M0)

Stage IIC (T4b, N0, M0)

Stage IIIA (T1-T2, N1, M0 and T1, N2a, M0)

Stage IIIB (T1-T2, N2b, M0; T2-T3, N2a, M0 and T3-T4a, N1, M0)

Stage IIIC (T3-T4a, N2b, M0 and T4b, N1-N2, M0 and T4a, N2a, M0)

Stage IVA (any T, any N and M1a)

Stage IVB (any T, any N and M1b)

Table 7 Systemic treatment of colon cancer

Adjuvant therapy (stage III and stage II with high-risk features for systemic recurrence)

FOLFOX

CapeOx

If oxaliplatin is contraindicated or elderly patients

Capecitabine

5-FU/Leucovorin

Metastatic disease (stage IV)

Resectable disease (lung, hepatic or peritoneal metastasis)

Consider surgery and/or locoregional treatment (radiofrequency, stereotactic radiotherapy) and 6 mo of perioperative chemotherapy (FOLFOX, CapeOx preferred)

Potentially resectable

FOLFOX

FOLFIRI

FOLFOXIRI

Cetuximab + FOLFIRI (only KRAS wild type)

Panitumumab + FOLFOX (only KRAS wild type)

Bevacizumab + FOLFOX

Unresectable (palliative)

FOLFOX

CapeOx

FOLFIRI

FOLFOX + Bevacizumab

CapeOx + Bevacizumab

FOLFOX + Panitumumab (only KRAS wild type)

FOLFIRI + Panitumumab (only KRAS wild type)

FOLFIRI + Cetuximab (only KRAS wild type)

FOLFIRI + Aflibercept

Capecitabine

5-FU/Leucovorin

Cetuximab + Irinotecan (only KRAS wild type)

Cetuximab monotherapy (only KRAS wild type)

Panitumumab monotherapy (only KRAS wild type)

Regorafenib