Role of radiation therapy in neoadjuvant era in patients with locally advanced rectal cancer

Table 1 Randomized trials comparing the role of radiation therapy as preoperative treatment vs surgery alone in patients with locally advanced rectal cancer

Ref.	n	Treatment arms	Local recurrence	Overall survival
Kapiteijn et al[11], 2001 (the Dutch colorectal cancer group)	1861	Arm 1(924 patients): preoperative RT (5 Gy × 5 d) followed by TME	2 yr of follow-up	2-yr survival rate
			2.4% in the RT + S group	82.0% RT + S
		Arm 2 (937 patients): TME alone	8.2% S only group	81.8% S alone
			(P < 0.001)	(P = 0.84)
Pahlman[5], 1997 (Swedish rectal cancer trial)	1168	Arm 1 (553 patients): preoperative RT (25 Gy delivered in five fractions in 1 wk) followed by S	5 yr of follow-up	5-yr survival rate
			11% in the RT + S group	58.0% RT + S
		Arm 2 (557 patients): S alone	27% S only group	48.0% S alone
			(P < 0.001)	(P = 0.004)
van Gijn et al[14], 2011	1805	Arm 1 (897 patients): preoperative RT (5 Gy × 5 d) followed by TME	10 yr of follow-up	10-yr survival rate
			5% in the RT + S group	50% RT + S
		Arm 2 (908 patients): TME alone	11% S only group	40% S alone
			(P < 0.0001)	(P = 0.032)

TME: Total mesorectal excision; RT: Radiation therapy; S: Surgery.

Table 2 Randomized trials of preoperative radiation therapy in locally advanced rectal carcinoma focusing on time of surgery after radiation therapy

Author, year published	n	Treatment arms-Time to S	Tumor down-staging rate	Overall survival
Pach et al[15], 2011	154	Arm 1 (77 patients): preoperative RT (5 Gy × 5 d) followed by TME on d 7-10 after RT	13% in Arm 1 vs	5-yr survival rate
			44.2% in Arm 2	63.0% in Arm 1 vs
		Arm 2 (77 patients): T preoperative RT (5 Gy × 5 d) followed by TME on after 4-5 wk	(P < 0.001)	73.0% in Arm 2
				(P = 0.24)
Eitta et al[16], 2010	32	Arm 1 (16 patients): preoperative SCRT (5 Gy × 5 d) followed by S on one week after SCRT	21.4% in Arm 1 vs	2-yr survival rate
			60% in Arm 2	64.0% RT + S vs
		Arm 2 (16 patients): T preoperative LCRT (45 Gy/5 wk/25 fractions) followed by S on 4-6 wk after LCRT	(P = 0.008)	66.0% S alone
				(P = 0.389)

TME: Total mesorectal excision; RT: Radiation therapy; S: Surgery; SCRT: Sort course radiation therapy; LCRT: Long curse radiation therapy.

Table 3 Randomized trials of preoperative radiation therapy combined with chemotherapy in locally advanced rectal carcinoma

Author, year published	n	Treatment arms	Local recurrence	Overall survival
Gérard et al[18], 2006 (FFCD-9203)	742	Arm 1 (367 patients): preoperative RT (45 Gy/25 fractions/5 wk) followed by TME between 3-10 wk after RT	At 5 yr follow-up	5-yr survival rate
			16.5% Arm 1	67.9% Arm 1
		Arm 2 (375 patients): preoperative RT (45 Gy/25 fractions/5 wk) + CH (2 cycles: first on days 1-5 of RT and the second on days 29-33 of RT) followed by TME between 3-10 wk after CHRT	8.1% Arm 2	67.4% Arm 2
			(P = 0.004)	(P = 0.684)
Bosset et al[19], 2006 (the EORTC Radiotherapy Group Trial 22921)	1011	Arm 1 (252 patients): preoperative RT (45 Gy/25 fractions/5 wk) followed by TME between 3-10 wk after RT	5 yr of follow-up	5-yr survival rate
			17.1% Arm 1	63.2% Arm 1
		Arm 2 (253 patients): Same RT as in Arm 1 + 2 cycles of CH (days 1-5 and 29-33 of RT) + TME between 3-10 wk after CHRT	8.7% Arm 2	63.2% Arm 2
			9.6% Arm 3	67.2% Arm 3
		Arm 3 (253 patients): Same RT as in Arm 1 + TME between 3-10 wk after RT + 4 cycles of CH postoperative	7.6% Arm 4	67.2% Arm 4
			(P = 0.002)	(P = 0.12)
		Arm 4 (253 patients) Same RT as in Arm 1 + 2 cycles of CH (days 1-5 and 29-33 of RT) + TME between 3-10 wk after CHRT + 2 cycles of CH postoperative
Bujko et al[20], 2005	312	Arm 1 (155 patients): preoperative RT (5 Gy × 5 d) followed by TME at 7 d after RT	4 yr of follow-up	4-yr survival rate
			59% Arm 1	67.2% Arm 1
		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 between 4-6 wk later. The cycle consisted of leucovorin 20 mg/m2 per day and, 10-20 min later, 5-fluorouracil 325 mg/m2 per day, both administered as rapid infusion on 5 consecutive days	14.2% Arm 2	66.2% S alone
			(P = 0.170)	(P = 0.960)

TME: Total mesorectal excision; RT: Radiation therapy; CHRT: Chemo-radiation therapy; CH: Chemotherapy (Leukovorin 20 mg/m² per day was delivered intravenously immediately before administration of Fluorouracil and Fluorouracil 350 mg/m² per day was delivered during 20 min in 100 mL of saline infusion, 1 h before RT).

Table 4 Randomized trials of preoperative chemo-radiotherapy vs postoperative chemo-radiotherapy in locally advanced rectal carcinoma

Author, year published	n	Treatment arms	Disease free survival-local relapse	Overall survival
Roh et al[22], 2009 (NSABP R-03)	267	Arm 1 (130 patients): preoperative CHRT: Chemo cycle 1: FU 500 mg/m2 once per week for 6 wk + LV 500 mg/m2 once per week for 6 wk followed by RT: 45 Gy in 25 fractions with a 5.4 Gy boost within the original margins of treatment + 2 cycles of FU 325 mg/m2 for 5 d LV 20 mg/m2 for 5 d (1st and 5th week of RT) followed by chemo cycles 4-7 as cycle 1	At 5 yr follow-up	5-yr survival rate
			64.7% DSF in Arm 1	74.5% Arm 1
			53.4% DSF in Arm 2	65.6% Arm 2
			(P = 0.011)	(P = 0.065)
		Arm 2 (137patients): postoperative CHRT: same as in Arm 1
Sauer et al[6], 2004 (German study)	823	Arm 1 (421 patients): preoperative CHRT: 50, 4 Gy/28 fractions/5 fractions weekly + FU 1000 mg/m2 120 h continuous infusion in first and fifth week of RT followed by 4 cycles of FU 500 mg/m2 per day/five times weekly every 4 wk followed by TME 6 wk after CHRT	5 yr of follow-up	5-yr survival rate
			6.0% LR in Arm 1	76.0% Arm 1
			13% LR in Arm 2	74.0% Arm 2
			(P = 0.006)	(P = 0.80)
		Arm 2 (402 patients): postoperative CHRT: same as in Arm 1 except a 5.4 Gy boost in RT
Sauer et al[23], 2012 (CAO/ARO/AIO-94 trial: results after 10 yr follow-up)	823	Arm 1 same as in above trial	10-yr of follow-up	10-yr survival rate
		Arm 2 same as in above trial	7.1% LR in Arm 1	59.6% in Arm 1
			10.1% in Arm 2	59.9% in Arm 2
			(P = 0.48)	(P = 0.85)

RT: Radiation therapy; CHRT: Chemo-radiation therapy; FU: Fluorouracil; LV: Leukovorin; DFS: Disease free survival; LR: Local relapse.