Neoadjuvant chemoradiation for locally advanced rectal cancer: a systematic review of the literature with network meta-analysis

Figures & data

Figure 1 Literature search and selection.

Table 1 Characteristics of the studies included in the meta-analysis, by first author

Study	Trial	Country	Study design	Population
Aschele et al (2011)^Citation34	STAR-01	Italy	MC; Ph III	cT3–4/cN0–2, ≤12 cm from AV
				Resectable, NDM
Deng et al (2015)^Citation19	FOWARC	China	MC; Ph III	Stage II (T3–4N0)/stage III (T1–4N1–2), ≤12 cm from AV
Gérard et al (2010)^Citation20	ACCORD 12/0405	France	MC; Ph III	cT2–4/cN0–2, resectable, NDM
	PRODIGE 2
Haddad et al (2017)^Citation17		Iran	SC	cT3–4, and/or N, ≤15 cm from AV
Hofheinz et al (2012)^Citation18		Germany	MC; Ph III	cT3–4N any/cT any N+, ≤16 cm from AV, NDM
Jiao et al (2015)^Citation35		China	SC	Stage II/III, ≤12 cm from AV
Jung et al (2015)^Citation36		Korea	MC; Ph II	cT3–4/N+, ≤12 cm from AV, NDM
Kayal et al (2014)^Citation16		India	SC	cT3–4, and/or N, ≤15 cm from AV, NDM
Mohiuddin et al (2006)^Citation21	RTOG-0012	SB	SC; Ph II	cT3–4, ≤9 cm from AV, NDM
O’Connell et al (2014)^Citation14	R-04	USA	MC; Ph III	Stage II (T3–4N0)/stage III (T1–4N1–2), ≤12 cm from AV
	NSABP, R-04			NDM
Rödel et al (2012)^Citation22	CAO/ARO/AIO-04	Germany	MC; Ph III	cT3–4/cT any N+, ≤12 cm from AV, NDM
Saha et al (2017)^Citation15		India	SC	cT3–4, and/or N, ≤15 cm from AV, NDM
Wiśniowska et al (2016)^Citation13		Poland	Subgroup; MC; Ph III	cT4/fixed cT3
Wong et al (2012)^Citation37	RTOG 0247	USA	MC; Ph II	cT3–4, ≤12 cm from AV, NDM

Abbreviations: AV, anal verge; cN, clinical N staging; cT, clinical T staging; MC, multicenter; NDM, no distant metastases; Ph, phase; SB, Saudi Arabia; SC, single center.

Table 2 Characteristics of neoadjuvant CRT regimes included in the meta-analysis, by first author

Study	Intervala	Regime	Dosage	Radiation, fractions	NP	pCR	Toxic effect	Toxicity
Aschele et al (2011)^Citation34	6–8 weeks	5FU	5FU: 225 mg/m^2/d, 1–5 d/wk ×6 weeks	50.4 Gy, 1.8 Gy ×28	379	62/379	29/379	CTC 2.0
		5FU + OXA	5FU 225 mg/m^2/d, 1–5 d/wk ×6 weeks; OXA 60 mg/m^2, 1 d/wk ×6 weeks	50.4 Gy, 1.8 Gy ×28	368	59/368	85/352
Deng et al (2015)^Citation19	Imm	5FU	400 mg/m^2, 2.4 g/m^2 over 48 hours, 2-week CYC ×5	46.0–50.4 Gy, 1.8–2 Gy ×23–28	165	20/143		CTC 3.0
		5FU + OXA	5FU 400 mg/m^2, 2.4 g/m^2 over 48 hours, 2-week CYC ×5; OXA 85 mg/m^2 D1 of each CYC	46.0–50.4 Gy, 1.8–2 Gy ×23–28	165	41/149
Gérard et al (2010)^Citation20	6 weeks	CAP	CAP 1,600 mg/m^2/d, 1–5 d/wk ×5 weeks	45 Gy, 1.8 Gy ×25	299	40/282	32/293	CTC 3.0
		CAP + OXA	CAP 1,600 mg/m^2/d, 1–5 d/wk ×5 weeks; OXA 50 mg/m^2 1 d/wk ×5 weeks	50 Gy, 2 Gy ×25	299	55/283	74/291
Haddad et al (2017)^Citation17	6–8 weeks	CAP	1,650 mg/m^2/d	50–50.4 Gy	31	4/27		CTC 4.0
		CAP + OXA	CAP 1,650 mg/m^2/d; OXA 60 mg/m^2×1/wk	50–50.4 Gy	32	11/25
Hofheinz et al (2012)^Citation18	4–6 weeks	CAP	1,650 mg/m^2/d during RT	50.4 Gy, 1.8 Gy ×28	81	10/73		CTC 2.0
		5FU	1,000 mg/m^2/d, D1–5 and 29–33 during RT	50.4 Gy, 1.8 Gy ×28	80	4/74
Jiao et al (2015)^Citation35	6–10 weeks	CAP + OXA	CAP 1,600 mg/m^2, D1–14 and 22–25; OXA 60 mg/m^2/d, D1, 8, 22, and 29	50 Gy, 2 Gy ×25	103	24/103	22/103	CTC 3.0
		CAP	1,600 mg/m^2, D1–14 and D22–25	50 Gy, 2 Gy ×25	103	20/103	11/103
Jung et al (2015)^Citation36	4–8 weeks	5FU	400 mg/m^2/d, 3 consecutive days per 4 weeks, 2 CYC	45 Gy, 1.8 Gy ×25, ± boost 5.4 Gy	71	11/66	1/70	CTC 4.0
		CPT-11 +S1	CPT-11 40 mg/m^2, D1, 8, 15, 22, and 29; S1 70 mg/m^2/d of IRR	45 Gy, 1.8 Gy ×25, ± boost 5.4 Gy	71	17/67	5/71
Kayal et al (2014)^Citation16	6–8 weeks	5FU	350 mg/m^2/d, D1–5 and 29–33	50.4 Gy, 1.8 Gy ×28	24	5/24		CTC 4.0
		5FU + CDDP	5FU 350 mg/m^2/d, D1–5 and 29–33; CDDP 100 mg/m^2/d, D1 and 29	50.4 Gy, 1.8 Gy ×28	25	5/25
Mohiuddin et al (2006)^Citation21	4–10 weeks	5FU	225 mg/m^2, 7 d/wk	45.6 Gy, 1.2 Gy bid, +10.8 Gy for T3, +14.4 Gy for T4	52	13/50	20/47	NA
		5FU + CPT-11	5FU 225 mg/m^2/d, 1–5 d/wk (120 h/wk); CPT-11 50 mg/m^2×1/wk, 4 weeks	45 Gy, 1.8 Gy/d, +5.4 Gy for T3; +10.8 Gy for T4	54	14/53	28/51
O’Connell et al (2014)^Citation14	6–8 weeks	5FU	225 mg/m^2/d, 5 d/wk during RT	45 Gy, 1.8 Gy/d, +5.4 Gy for T3, +10.8 Gy for T4	477		84/317	CTC 4.0
		5FU + OXA	5FU 225 mg/m^2/d, 5 d/wk during RT; OXA 50 mg/m^2×1/wk, 5 weeks	45 Gy, 1.8 Gy/d, +5.4 Gy for T3, +10.8 Gy for T4	329		129/322
		CAP	1,650 mg/m^2/d, 5 d/wk during RT	45 Gy, 1.8 Gy/d, +5.4 Gy for T3, +10.8 Gy for T4	472		96/319
		CAP + OXA	CAP 1,650 mg/m^2/d, 5 d/wk during RT; OXA 50 mg/m^2×1/wk, 5 weeks	45 Gy, 1.8 Gy/d, +5.4 Gy for T3, +10.8 Gy for T4	330		135/322
Rödel et al (2012)^Citation22	5–6 weeks	5FU	1,000 mg/m^2/d, D1–5 and 29–33	50.4 Gy, 1.8 Gy ×28	637	81/606	127/624	CTC 3.0
		5FU + OXA	5FU 250 mg/m^2/d, D1–14 and 22–35; OXA 50 mg/m^2/d, D1, 8, 22, and 29	50.4 Gy, 1.8 Gy ×28	628	103/591	140/606
Saha et al (2017)^Citation15	6–8 weeks	CAP + OXA	CAP 2,000 mg/m^2/d, D1–14 and 25–38; OXA 85 mg/m^2, D1 and 29	50.4 Gy, 1.8 Gy ×28	21	5/21		CTC 4.0
		5FU	350 mg/m^2/d, D1–5 and 29–33	50.4 Gy, 1.8 Gy ×28	21	3/21
Wiśniowska et al (2016)^Citation13	6 weeks	5FU + OXA	5FU 325 mg/m^2/d, first and fifth week of IRR; OXA 50 mg/m^2/d, D1, 8, 15, 22, and 29 of IRR	50.4 Gy, 1.8 Gy ×28	69	7/69	21/69	CTC 4.0
		5FU	325 mg/m^2/d, first and fifth week of IRR	50.4 Gy, 1.8 Gy ×28	67	4/67	7/67
Wong et al (2012)^Citation37	4–8 weeks	CAP + CPT- 11	CAP 1,200 mg/m^2/d M-F; CPT-11 50 mg/m^2×1/wk, 4 weeks	45 Gy, 1.8 Gy ×25, + boost 5.4 Gy	73	6/51	14/52	CTC 3.0
		CAP + OXA	CAP 1,200 mg/m^2/d M-F; OXA 50 mg/m^2×1/wk, 5 weeks	45 Gy, 1.8 Gy ×25, + boost 5.4 Gy	73	12/52	14/52

Note:

a Interval between CRT and surgery.

Abbreviations: 5FU, fluorouracil; CAP, capecitabine; CDDP, cisplatin; CPT-11, irinotecan; CRT, chemoradiotherapy; CTC, Common Terminology Criteria; CYC, cycle; Imm, immediately; IRR, irradiation; M-F, Monday to Friday ; NA, not available; NP, number of patients; OXA, oxaliplatin; pCR, pathologic complete response; RT, radiotherapy; S1, combined tegafur, 5-chloro-2,4-dihydroxypyridine, and potassium oxonate.

Figure 2 Risk-of-bias graph.

Note: Red, yellow, and green represent high, unclear, and low risk of bias, respectively.

Figure 3 Risk-of-bias summary.

Note: Red, yellow, and green represent high, unclear, and low risk of bias, respectively.

Figure 4 Network plot of chemoradiotherapy regimens: (A) pCR and (B) toxic effects.

Abbreviations: 5FU, fluorouracil; CAP, capecitabine; CDDP, cisplatin; CPT-11, irinotecan; OXA, oxaliplatin; pCR, pathologic complete response; S1, combined tegafur, 5-chloro-2,4-dihydroxypyridine, and potassium oxonate.

Figure 5 Evidence contribution plot: (A) pCR and (B) toxic effects.

Note: A: 5FU; B: 5FU + OXA; C: CAP; D: CAP + OXA; E: CAP + CPT-11; F: CPT-11+5FU; G: CPT-11+ S1; H: 5FU + CDDP.

Abbreviations: 5FU, fluorouracil; CAP, capecitabine; CDDP, cisplatin; CPT-11, irinotecan; OXA, oxaliplatin; pCR, pathologic complete response; S1, combined tegafur, 5-chloro-2,4-dihydroxypyridine, and potassium oxonate.

Figure 6 Inconsistency test results of the (A) pCR and (B) toxic effects.

Note: A: 5FU; B: 5FU + OXA; C: CAP; D: CAP + OXA.

Abbreviations: 5FU, fluorouracil; CAP, capecitabine; IF, inconsistency factor; OXA, oxaliplatin; pCR, pathologic complete response.

Figure 7 The interval plot of the ORs, their 95% CIs, and prediction intervals (red extensions) of the (A) pCR and (B) toxic effects.

Note: A: 5FU; B: 5FU + OXA; C: CAP; D: CAP + OXA; E: CAP + CPT-11; F: CPT-11+5FU; G: CPT-11+ S1; H: 5FU + CDDP.

Abbreviations: 5FU, fluorouracil; CAP, capecitabine; CDDP, cisplatin; CPT-11, irinotecan; OXA, oxaliplatin; pCR, pathologic complete response; PrI, prediction interval; S1, combined tegafur, 5-chloro-2,4-dihydroxypyridine, and potassium oxonate.

Figure 8 Funnel plot for publication bias in selected studies of the (A) pCR and (B) toxic effects.

Note: A: 5FU; B: 5FU + OXA; C: CAP; D: CAP + OXA; E: CAP + CPT-11; F: CPT-11+5 FU; G: CPT-11+ S1; H: 5FU + CDDP.

Abbreviations: 5FU, fluorouracil; CAP, capecitabine; CDDP, cisplatin; CPT-11, irinotecan; OXA, oxaliplatin; pCR, pathologic complete response; S1, combined tegafur, 5-chloro-2,4-dihydroxypyridine, and potassium oxonate.

Figure 9 SUCRA for the cumulative probabilities of the (A) pCR and (B) toxic effects.

Note: A: 5FU; B: 5FU + OXA; C: CAP; D: CAP + OXA; E: CAP + CPT-11; F: CPT-11+5FU; G: CPT-11+ S1; H: 5FU + CDDP.

Abbreviations: 5FU, fluorouracil; CAP, capecitabine; CDDP, cisplatin; CPT-11, irinotecan; OXA, oxaliplatin; pCR, pathologic complete response; S1, combined tegafur, 5-chloro-2,4-dihydroxypyridine, and potassium oxonate; SUCRA, surface under the cumulative ranking curve.

Table 3 SUCRA of each CRT regime with regard to the rate of pCR

	Treatment	SUCRA	PR a Best	Mean rank
Predictive probabilities	A	25.5	0.2	6.2
	B	50.0	3.2	4.5
	C	66.4	4.5	3.4
	D	89.9	60.0	1.7
	E	45.2	7.2	4.8
	F	33.8	4.3	5.6
	G	58.6	13.9	3.9
	H	30.8	6.7	5.8
Estimated probabilities	A	22.4	0.0	6.4
	B	49.6	1.5	4.5
	C	66.5	1.5	3.3
	D	91.5	63.0	1.6
	E	47.0	7.7	4.7
	F	31.3	3.8	5.8
	G	60.0	15.7	3.8
	H	31.6	6.8	5.8

Notes:

a Probability that the treatment is the best. A: 5FU; B: 5FU + OXA; C: CAP; D: CAP + OXA; E: CAP + CPT-11; F: CPT-11+5 FU; G: CPT-11+ S1; H: 5FU+ CDDP.

Abbreviations: 5FU, fluorouracil; CAP, capecitabine; CDDP, cisplatin; CPT-11, irinotecan; CRT, chemoradiotherapy; OXA, oxaliplatin; pCR, pathologic complete response; S1, combined tegafur, 5-chloro-2,4-dihydroxypyridine, and potassium oxonate; SUCRA, surface under the cumulative ranking curve.

Table 4 SUCRA of each CRT regime with regard to the rate of toxic effect

	Treatment	SUCRA	PR a Best	Mean rank
Predictive probabilities	A	83.7	40.7	2.0
	B	40.0	1.6	4.6
	C	75.7	26.6	2.5
	D	33.9	0.6	5.0
	E	39.4	8.3	4.6
	F	56.5	16.2	3.6
	G	20.8	6.0	5.8
Estimated probabilities	A	87.3	44.7	1.8
	B	38.9	0.0	4.7
	C	79.1	27.4	2.3
	D	31.4	0.0	5.1
	E	36.6	5.9	4.8
	F	56.8	15.9	3.6
	G	19.8	6.1	5.8

Notes:

a Probability that the treatment is the best. A: 5FU; B: 5FU + OXA; C: CAP; D: CAP + OXA; E: CAP + CPT-11; F: CPT-11+5 FU; G: CPT-11+ S1.

Abbreviations: 5FU, fluorouracil; CAP, capecitabine; CDDP, cisplatin; CPT-11, irinotecan; CRT, chemoradiotherapy; OXA, oxaliplatin; S1, combined tegafur, 5-chloro-2,4-dihydroxypyridine, and potassium oxonate; SUCRA, surface under the cumulative ranking curve.

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