Evolving treatment strategies for colorectal cancer: A critical review of current therapeutic options

Table 1 Tumor node metastasis clinical classification (colon and rectum cancer)

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 subserosa or into non-peritonealized pericolic or perirectal tissues
T4	Tumor directly invades other organs or structures and/or perforates visceral peritoneum
T4a	Tumor perforates visceral peritoneum
T4b	Tumor directly invades other organs or structures
Nx	Regional lymph nodes cannot be assessed
N0	No regional lymph node metastasis
N1	Metastasis in 1-3 regional lymph nodes
N1a	Metastasis in 1 regional lymph node
N1b	Metastasis in 2-3 regional lymph nodes
N1c	Tumor deposit(s), i.e., satellites, in the subserosa, or in non-peritonealized pericolic or perirectal soft tissue without regional lymph node metastasis
N2	Metastasis in 4 or more regional lymph nodes
N2a	Metastasis in 4-6 regional lymph nodes
N2b	Metastasis in 7 or more regional lymph nodes
M0	No distant metastasis
M1	Distant metastasis
M1a	Metastasis confined to one organ [liver, lung, ovary, non-regional lymph node(s)]
M1b	Metastasis in more than one organ or the peritoneum

AJCC: American joint committee on cancer[4].

Table 2 Tumor node metastasis stage grouping (colon and rectum cancer)

Stage 0	Tis	N0	M0
Stage I	T1, T2	N0	M0
Stage II	T3, T4	N0	M0
Stage IIA	T3	N0	M0
Stage IIB	T4a	N0	M0
Stage IIC	T4b	N0	M0
Stage III	Any T	N1, N2	M0
Stage IIIA	T1, T2	N1	M0
	T1	N2a	M0
Stage IIIB	T3, T4a	N1	M0
	T2, T3	N2a	M0
	T1, T2	N2b	M0
Stage IIIC	T4a	N2a	M0
	T3, T4a	N2b	M0
	T4b	N1, N2	M0
Stage IVA	Any T	any N	M1a
Stage IVB	Any T	any N	M1b

AJCC: American joint committee on cancer[4].

Table 3 Major neoadjuvant therapy trials

Ref.	n	Treatment arms	Local recurrence rate	Overall survival rate
Upsala Trial[23]	471	Arm 1 (236): preoperative RT (25.5 Gy delivered in 5-7 d) Arm 2 (235): postoperative RT (60 Gy delivered in 8 wk)	5 yr of follow-up Arm 1: 12% Arm 2: 21% P = 0.02	5-yr survival rate Arm 1: 42% Arm 2: 38% P = 0.42
Stockholm I Trial[24]	849	Arm 1 (423 patients): 25 Gy during 5-7 d followed by surgery Arm 2 (421 patients): surgery alone	Median follow-up time of 107 mo Arm 1: 14% Arm 2: 28% P < 0.01	Median follow-up time of 107 mo No significant difference between groups
Swedish Rectal Cancer Trial[25]	1168	Arm 1 (553 patients): preoperative RT - 25 Gy delivered in five fractions in 1 wk, followed by surgery Arm 2 (557 patients): Surgery alone	5 yr of follow-up Arm 1: 11% Arm 2: 27% P < 0.001	5-yr survival rate Arm 1: 58.0% Arm 2: 48.0% P = 0.004
Dutch TME Trial[26]	1861	Arm 1 (924 patients): preoperative RT (5 Gy × 5 d) followed by TME Arm 2 (937): TME alone	2 yr of follow-up Arm 1: 2.4% Arm 2: 8.2% P < 0.001	2-yr survival rate Arm 1: 82.0% Arm 2: 81.8% P = 0.84
Stockholm II Trial[27]	557	Arm 1 (272): preoperative radiotherapy (25 Gy in one week) followed by surgery within a week Arm 2 (285): surgery alone	Median follow-up was 8.8 yr Arm 1: 12% Arm 2: 25% P < 0.001	Median follow-up 8.8 yr Arm 1: 39% Arm 2: 36% P = 0.2
German Rectal Cancer Study Group[28]	823	Arm 1 (421 patients): preoperative CHRT: 50.4 Gy/28 fractions/5 fractions weekly and fluorouracil (continuous infusion) in first and fifth week of RT. TME after 6 wk Additional 4 cycles of FU every 4 wk Arm 2 (402 patients): postoperative CHRT (same as in Arm 1 except a 5.4 Gy boost in RT)	5 yr of follow-up Arm 1: 6.0% Arm 2: 13% P = 0.006	5-yr survival rate Arm 1: 76.0% Arm 2: 74.0% P = 0.80
Polish Rectal Cancer Trial[29]	312	Arm 1 (155 patients): preoperative RT (5 Gy × 5 d) followed by TME at 7 d after RT Arm 2 (157 patients): preoperative RT (45 Gy/25 fractions/5 wk) + 2 cycles of chemotherapy on weeks 1 and 5 of RT followed by TME 4-6 wk later. The cycle consisted of leucovorin + fluorouracil both administered as rapid infusion on 5 consecutive days	4 yr of follow-up Arm 1: 9% Arm 2: 14.2% P = 0.170	4-yr survival rate Arm 1: 67.2% Arm 2: 66.2% P = 0.960
MRC CR07 and NCIC CTG C016[30]	1350	Arm 1 (674 patients): short-course radiotherapy (25 Gy/5 fractions) followed by surgery. Arm 2 (676 patients): initial surgery with selective postoperative chemoradiotherapy (45 Gy in 25 fractions plus 5-fluorouracil) restricted to patients with involvement of the circumferential resection margin.	3 yr of follow-up Arm 1: 4.0% Arm 2: 10.6% P < 0. 01	Estimated 5-yr survival rate Arm 1: 70.3% Arm 2: 67.9% P = 0.40

RT: Radiotherapy; TME: Total mesorectal excision; CHRT: Chemoradiotherapy; FU: Fluorouracil.

Table 4 Locoregional recurrence in patients with complete clinical response who did not proceed to rectal resection n (%)

Ref.	No. of patients	T2	Radiotherapy	Chemotherapy	Complete clinical response	Locoregional recurrence
Nakagawa et al[41]	52	No	45-50.4 Gy, 28 fractions, 38 d	Fluorouracil + leucovorin	10 (19.2)	8 (80)
Habr-Gama et al[42]	360	Yes (14%)	50.4 Gy, 28 fractions, 5-6 wk	Fluorouracil + leucovorin	99 (27.5)	6 (6)
Lim et al[43]	48	T1/t2 (33%)	Mean 50 Gy, 25 fractions	Fluorouracil	27 (56)	11 (23)
Hughes et al[44]	58	No	45 Gy, 25 fractions, 33 d	Fluorouracil + leucovorin	10 (17)	6 (60)
Dalton et al[45]	49	No	45 Gy, 25 fractions, 33 d	Capecitabine	12 (24)	6 (50)
Maas et al[46]	192	Yes (24%)	50.4 Gy, 28 fractions, 6 wk	Capecitabine	21 (10.9)	1 (5)