Table 1.

Intensifying concurrent chemotherapy regimen.

Trials	Patients (n)	Treatment Methods		Results (Con vs. Exp)	Conclusion	Ref
		RT	Concurrent Chemotherapy
CAO/ARO/AIO-04	Con = 623	50.4 Gy(5 × 1.8 Gy/w)	Con: 5-FU 1000 mg/m2/d d1–5, d29–33	pCR: 13% vs. 17%, p = 0.031	Adding oxaliplatin significantly improved DFS and pCR in patients.	[12,18]
	Exp = 613		Exp: 5-FU 250 mg/m2/d d1–14, d22–35 Oxaliplatin 50 mg/m²/d d1, 8, 22, 29	3 y-DFS: 71.2% vs. 75.9%, p = 0.03
				Preoperative grade 3–4 adverse events: 20% vs. 24%, ns
ACCORD12	Con = 299	Con: 45 Gy (5 × 1.8 Gy/w)	Con: Capecitabine 800 mg/m2 × 2/d 5 d/w	ypCR: 13.9% vs. 19.2%, p = 0.09	The benefit of oxaliplatin was not demonstrated.	[11]
	Exp = 299	Exp: 50 Gy(5 × 2 Gy/w)	Exp: Capecitabine 800 mg/m2 × 2/d 5 d/w Oxaliplatin 50 mg/m2/w qw	Preoperative grade 3 to 4 adverse events: 11% vs. 25%, p < 0.001
STAR-01	Con = 379	50.4 Gy(5 × 1.8 Gy/w)	Con: FU 225 mg/m2/d	pCR: 16% vs. 16%, p = 0.904	Adding oxaliplatin significantly increases toxicity without affecting primary tumor response.	[10]
	Exp = 368		Exp: 5-FU 225 mg/m2/d Oxaliplatin 60 mg/m2/w × 6 w	Preoperative grade 3 to 4 adverse events: 8% vs. 24%, p < 0.001
NSBP R-04	Con = 949	45 Gy or 50.4 Gy or 55.8 Gy (5 × 1.8 Gy/w)	Con: 5-FU 225 mg/m2/d 5 d/w or Capecitabine 825 mg/m2 × 2/d 5 d/w	pCR:17.8% vs. 19.5%, p = 0.42	Adding oxaliplatin did not improve surgical outcomes but added significant toxicity.	[13]
	Exp = 659		Exp: 5-FU 225 mg/m2/d 5 d/w or Capecitabine 825 mg/m2 × 2/d 5 d/w Oxaliplatin 50 mg/m2/w × 5 w	Grade 3 to 5 adverse events: 6.9% vs. 16.5%, p < 0.001
PETACC 6	Con = 543	45 Gy or 50.4 Gy (5 × 1.8 Gy/w)	Con: Capecitabine 2 × 825 mg/m2 × 2/d	pCR: 11.6% vs. 14.0%, p = 0.225	The addition of oxaliplatin to preoperative capecitabine-based chemoradiation and postoperative adjuvant chemotherapy impaired tolerability and feasibility without improving efficacy.	[14]
	Exp = 525		Exp: Capecitabine 2 × 825 mg/m2 × 2/d Oxaliplatin 50 mg/m2/d d1, 8, 15, 22, 29	7 y-DFS: 66.1% vs. 65.5%, p = 0.861
				7 y-OS: 73.5% vs. 73.7%, p = 0.205
FOWARC	Con = 155	Con and Exp1: 46.0 Gy (5 × 2 Gy/w) or 50.4 Gy (5 × 1.8 Gy/w)	Con: (Leucovorin 400 mg/m2 + 5-FU 400 mg/m2 + 5-FU 2.4 g/m2 d1–2/2 w)× 5 cycles	pCR: Con vs. Exp1: 14.0% vs. 27.5%, p = 0.005	mFOLFOX6-based preoperative chemoradiotherapy results in a higher pCR rate than 5-FU-based treatment but did not significantly improve 3 y-DFS.	[16,17]
	Exp1 = 157		Exp1 and Exp2: (Leucovorin 400 mg/m2 + 5-FU 400 mg/m2 + 5-FU 2.4 g/m2 d1–2/2 w + oxaliplatin 85 mg/m2/2 w)× 5 cycles	3 y-DFS: Con vs. Exp1 vs. Exp2: 72.9% vs. 77.2% vs. 73.5%, p = 0.709
	Exp2 = 163			3 y-OS: Con vs. Exp1 vs. Exp2: 91.3% vs. 89.1% vs. 90.7%, p = 0.971
CinClare	Con = 178	50 Gy (5 × 2 Gy/w)	Con: Capecitabine 825 mg/m2 × 2/d 5 d/w Oxaliplatin 130 mg/m2 d1 Capecitabine 1000 mg/m2 × 2/d d1–14	pCR: 15% vs. 30%, p = 0.001	Adding irinotecan guided by the UGT1A1 genotype to capecitabine-based neoadjuvant chemoradiotherapy significantly increased complete tumor response in Chinese patients.	[19]
	Exp = 178		Exp: Capecitabine 625 mg/m2 × 2/d 5 d/w Irinotecan UGT1A1*1*1, 80 mg/m2 /w UGT1A1*1*28, 65 mg/m2/w Irinotecan 200 mg/m2 d1 Capecitabine 1000 mg/m2 2/d d1–14	Grade 3–4 adverse events: 6% vs. 38%, p < 0.001
ARISTOTLE	Con = 284	45 Gy (5 × 1.8 Gy/w)	Con: Capecitabine 900 mg/m2 × 2/d	pCR: 17.4% vs. 20.2%, p = 0.45	The addition of irinotecan did not significantly improve the pCR rate and was associated with a decrease in the RT and capecitabine compliance and a higher rate of adverse events.	[20]
	Exp = 280		Exp: Capecitabine 650 mg/m2 × 2/d Irinotecan 60 mg/m2 /w × 4 w	Grade 3–4 adverse events: 12% vs. 21%, p = 0.004

Exp = Experimental; Exp₁ = Experimental-1; Exp₂ = Experimental-2; Con = Control; DFS = disease-free survival; Gy = Gray; d = day; w = week; y = year; RT = Radiotherapy; pCR = pathological complete response; * is part of the genotyping nomenclature.