Effects of neoadjuvant chemotherapy vs chemoradiotherapy in the treatment of esophageal adenocarcinoma: A systematic review and meta-analysis

Table 1 Characteristic of the studies

Ref.	Design	Center	Country	Year	Number of patients	nCT	nCRT	AC, %
Stahl et al[44], 2017	RCT, Phase III	1	Germany	N/A	119	59	60	100
Burmeister et al[43], 2011	RCT, Phase II	1	Australia	N/A	75	36	39	100
Visser et al[42], 2018	PSM	1	Australia	2000-2017	262	131	131	100
Markar et al[41], 2017	PSM	10	United Kingdom	2001-2012	442	221	221	100
Goense et al[40], 2017	PSM	1	Netherlands	2006-2015	172	86	86	100
Favi et al[39], 2017	PSM	1	Germany	2011-2015	80	40	40	100
Anderegg et al[35], 2017	Cohort, PID	3	Netherlands	2005-2011	313	137	176	100
Spicer et al[38], 2016	Cohort, PID	3	United States	2002-2012	214	114	100	100
Luc et al[36], 2015	Cohort, PID	1	France	2000-2012	116	61	55	100
Münch et al[37], 2018	Cohort, PCCR	70	Germany	1998-2014	135	71	64	100

RCT: Randomized controlled trial; PSM: Propensity score matched cohort; PID: Prospective institutional databases; PCCR: Population-based clinical cancer registry; N/A: Not applicable; nCT: Neoadjuvant chemotherapy; nCRT: Neoadjuvant chemoradiotherapy; AC: Adenocarcinoma.

Table 2 Characteristic of the neoadjuvant regimen, n (%)

Ref.	nCT	nCRT
	Chemotherapy	Chemotherapy	Irradiation
Stahl et al[44], 2017	15 × weekly CFFa	15 × weekly CFFa followed by 3 wk course of CRT + 1 cycle CE	30 Gy in 15 fractions of 2 Gy in 3 wk
Burmeister et al[43], 2011	C (80 mg/m2) + iv 5-FU (1000 mg/m2/d) on days 1 and 21	CF + RT, 5-FU reduced to 800 mg/m2/d (on day 21)	35 Gy in 15 fractions in 3 wk (on day 21)
Visser et al[42], 2018	OEO2	OEO2 + RT	35 Gy in 15 fractions or 45 Gy in 25 fractions
	MAGIC	DCF (2 cycles pre-operatively) + RT	45 Gy in 25 fractions
	DCF (2 cycles pre-operatively)	CROSS (since 2015)	41.4 Gy in 23 fractions of 1.8 Gy in 5 wk
	Cisplatin + 5-FU: 92 (70)	Cisplatin + 5-FU: 94 (72)	35 Gy: 69 (53)
	Epirubicin, cisplatin, 5-FU: 30 (23)	Epirubicin, cisplatin, 5-FU: 2 (2)	41 Gy: 14 (11)
	Carboplatin + paclitaxel: 0 (0)	Carboplatin + paclitaxel: 20 (15)	45 Gy: 40 (31)
	Other: 9 (7)	Other: 15 (11)	Other: 8 (6)
Markar et al[41], 2017	mainly MAGIC, OEO2 or OEO5 regimens[8,10,45]	CROSS regimen[7,46]	41.4 Gy in 23 fractions of 1.8 Gy in 5 wk
Goense et al[40], 2017	ECX	CROSS regimen[7,46]	41.4 Gy in 23 fractions of 1.8 Gy in 5 wk
Favi et al[39] , 2017	FLOT[47]	CROSS regimen[7,46]	41.4 Gy in 23 fractions of 1.8 Gy in 5 wk
Anderegg et al[35], 2017	ECX	CROSS regimen[7,46]	41.4 Gy in 23 fractions of 1.8 Gy in 5 wk
Spicer et al[38], 2016	Cornell: Platinum or taxane-based doublet, or both	concurrent ChT + RT	50.4 Gy
	McGill: DCF (3 cycles)[48]
Luc et al[36], 2015	DCF (3 cycles pre- and postoperatively)	continuous iv 5-FU 750 mg/m2/d on days 1–5 by, C 20 mg/m2 on day 1	45 Gy for 5 d per week at 1.8 Gy/d (started on day 28 along with the second CT cycle)
Münch et al[37], 2018	N/A	N/A	N/A

OEO2: Two cycles of cisplatin and 5-fluoruracil (5-FU). OEO5: Five cycles of cisplatin and 5-FU. CFFa: 15 × weekly 5-FU (2000 mg/m², 24 h infusion)/Fa (500 mg/m², 2 h infusion) and biweekly cisplatin (50 mg/m², 1 h infusion), in 14 wk. MAGIC: Protocol epirubicin, cisplatin, and 5-FU for three cycles before andthree cycles after esophagectomy (EGJ Siewert II EAC and good vital status). DCF: Docetaxel 75 mg/m² (on day 1), cisplatin 75 mg/m² (on day 1), and 5-FU 750 mg/m²/d by continuous infusion on days 2–5, (day 1 = day 22 = day 43). CROSS: With concurrent weekly administration of carboplatin (targeted at an area under the curve of 2 mg/mL per min) and paclitaxel (50 mg/m² of body-surface area). Forty-one four Gy in 23 fractions of 1.8 Gy in 5 wk. FLOT: 5-FU/leucovorin, oxaliplatin, and docetaxel 50 mg/m² every 2 wk. ECX: Pre- and postoperative 3-wk cycles epirubicin (50 mg/m²) and cisplatin (60 mg/m²), followed by 1000 mg/m² of capecitabine twice daily for 14 d or 625 mg/m² of capecitabine twice daily for 21 d. Adaptations to the regimen such as dose reduction or change of regimen to oxaliplatin or 5-FU were applied when necessary. C: Cisplatin; F: Fluorouracil; P: Paclitaxel; Fa: Folinic acid; E: Etoposide; N/A: Not applicable; nCT: Neoadjuvant chemotherapy; nCRT: Neoadjuvant chemoradiotherapy; AC: Adenocarcinoma; CRT: Chemoradiotherapy; CT: Chemotherapy; RT: Radiotherapy; 5-FU: 5-fluoruracil.

Table 3 Results using the risk of bias tool 2

Ref.	D1	D2	D3	D4	D5	Overall
Stahl et al[44], 2017	+	+	+	+	+	+
Burmeister et al[43], 2011	+	+	+	+	+	+
Visser et al[42], 2018	!	+	+	+	+	!
Markar et al[41], 2017	!	+	+	+	+	!
Goense et al[40], 2017	!	+	+	+	+	!
Favi et al[39], 2017	!	+	+	+	+	!
Anderegg et al[35], 2017	!	+	+	+	+	!
Spicer et al[38], 2016	!	+	+	+	+	!
Luc et al[36], 2015	!	+	+	+	+	!
Münch et al[37], 2018	!	+	+	!	+	!

+: Low risk; !: Some concerns; -: High risk. D1: Randomization process; D2: Deviation from the intended interventions; D3: Missing outcome data; D4: Measurement of the outcome; D5: Selection of the reported result.