Applications of cryotherapy in premalignant and malignant esophageal disease: Preventing, treating, palliating disease and enhancing immunogenicity?

Table 1 Studies on spray cryotherapy for the treatment of Barrett esophagus

Ref.	Study design	Subjects	Cryogen	Baseline histology	BE length	Treatments performed	Cycles × seconds	Previous therapy	Efficacy	Safety, n	FU, months	BB, n (%)	Recurrence, n (%)
Johnston et al[118], 2005	Prospective, single center	11	LN	IM: 3; LGD: 7; HGD: 1	4.6	4 (1-6)	2 × 20	NR	CE-D: 100%; CE-IM: 61%	Pain: 2	12 (6-20)	0	NR
Dumot et al[119], 2009	Prospective, single center	31	LN	HGD: 26; IMC: 5	6.1	5 (3-7)	3 × 20; 4 × 10	EMR: 4; PDT: 3; APC: 2	CE-D: 33%; CE-IM: 3%	Pain: 10; stricture: 3; perforation: 1; ulcer: 1	12 (6-24)	NR	9 (64)
Greenwald et al[120], 2010	Retrospective, multicenter	79	LN	T1: 60; T2: 16; T3: 2; T4: 1	4.01	3 (1-25)	3 × 20	ER: 27; concurrent CT/EBRT: 12; PDT: 11; EBRT: 7; concurrent CT/EBRT then esophagectomy: 2; APC: 2; CT: 1; Stent: 1; RFA: 1	CR2: 61%	Pain: 20; stricture: 10	10.6 ± 8.4	NR	NR
Greenwald et al[121], 2010	Retrospective, multicenter	77	LN	IM: 7; HGD: 45; IMC: 25	4.0	4 (1-10)	3 × 20; 4 × 10	NR	CE-D: 88%; CE-IM: 53%	Pain: 57; stricture: 3; perforation: 1; ulcer: 1	11 (2-20)	NR	NR
Shaheen et al[34], 2010	Retrospective, multicenter	98	LN	HGD	5.3	3	2 × 20; 4 × 10	EMR: 22; PDT: 6; RFA: 6; APC: 2; surgery: 2	CE-D: 87%; CE-IM: 57%	Stricture: 3; pain: 2; rectal bleeding: 1	10.5 ± 8.3	2 (3)	NR
Halsey et al[35], 2011	Retrospective, single center	36	LN	HGD	3.0	NR	NR	EMR: 7	CE-D: 97%; CE-IM: 92%	NR	24 (12-29)	0	11 (30)
Xue et al[30], 2011	Prospective, single center	22	CO2	IM: 16; LGD: 6	2.6	2 (1-3)	5-7 × 20-30	APC: 2	CE-D: NR; CE-IM: 91%	Pain: 2	10 (6-18)	2 (9)	3 (14)
Gosain et al[36], 2013	Retrospective, single center	32	LN	HGD: 32	3.0	4 (3-5)	4 × 10	EMR: 6	CE-D: 97%; CE-IM: 81%	Stricture: 3	37.8 ± 9.7	NR	6 (19)
Canto et al[27], 2015	Retrospective, single center	64	CO2	HGD: 50; IMC: 14	5.9	4	4-8 × 10-15	RFA: 28; PDT: 22; EMR: 19; surgery: 2	CE-D: 89%; CE-IM: 55%	Pain: 5; stricture: 1	50 (8-80)	5 (7)	20 (31)
Sengupta et al[61], 2015	Retrospective, single center	16	LN	Indefinite for dysplasia: 1; LGD: 6; HGD: 7; IMC: 2	7.0	3	2 × 20	RFA: 16; EMR: 3	CE-D: 75%; CE-IM: 31%	Stricture: 3; ulcer: 2; perforation: 1	8 (2-25)	NR	0 (0)
Verbeek et al[31], 2015	Prospective, single center	10	CO2	IM: 4; LGD: 5; HGD: 1	5.0	2.5 (2.0-4.0)	6 × 20	EMR: 9	CE-D: 44%; CE-IM: 11%	Pain: 6; laceration: 2; perforation: 1	6	0	NR
Ghorbani et al[37], 2016	Prospective, multicenter	96	LN	LGD: 32; HGD: 64	4.5	3.3	2-3 × 20; 4 × 10	EMR: 19; RFA: 10; PDT: 5; APC: 2; surgery: 2	CE-D: 84%; CE-IM: 64%	Pain: 36; bleeding: 1; stricture: 1	21 (12-24)	NR	NR
Ramay et al[33], 2017	Retrospective, single center	3 years: 50	LN	HGD; IMC3	3.5	3 (2-5)	2 × 20; 3 × 20; 4 × 10	EMR: 14	3 years: CE-D: 94%; CE-IM: 82%	NR	36	NR	3 years: 16 (33)
		5 years: 40							5 years: CE-D: 88%; CE-IM: 75%		60		5 years: 9 (23)
Suchniak-Mussari et al[122], 2017	Retrospective, single center	33	LN	IM: 5; LGD: 5; HGD: 15; IMC: 8	3.3	2 (1-9)	2 × 20	EMR: 33; RFA or PDT: 6	CE-D: 84%; CE-IM: 49%	Strictures: 5; pain: 2; bleeding: 1	2.3 (1-4)	NR	NR
Trindade et al[62], 2017	Retrospective, multicenter	18	LN	IM: 7; LGD: 4; HGD: 7	4.0	3	2 × 20	RFA: 11; EMR: 5	CE-D: 72%; CE-IM: 50%	0	4 (3-11)	NR	0 (0)
Thota et al[42], 2018	Retrospective, multicenter	81	LN	LGD: 11; HGD: 49; IMC: 21	5.2	3 (2-5)	2-3 × 20	EMR: 25	CE-D: 79%; CE-IM: 41%	NR	31.8 (13-51)	NR	9 (14)
Trindade et al[123], 2018	Retrospective, multicenter	27	LN	LGD: 5; HGD: 22	5.0	3 (1-12)	2 × 20	EMR: 27	CE-D: 82%; CE-IM: 70%	0	24 (12-66)	NR	3 (11)
Solomon et al[70], 2019	Prospective, multicenter	35	LN	IM: 6; LGD: 12; HGD: 9; IMC: 8	6.1	NR	2 × 20	EMR: 7	NR	Pain: 10; bleeding: 1	0.75	NR	NR
Spiceland et al[63], 2019	Retrospective, single center	46	LN and CBA	LGD: 15; HGD: 25; IMC: 6	≥ 3.0	2 (0-10)	NR	RFA: 46; EMR: 23	CE-D: 83%; CE-IM: 46%	Stricture: 3	NR	NR	2 (4)
Kaul et al[43], 2020	Retrospective, single center	57	LN	LGD: 8; HGD: 20; T1a: 18; ≥ T1b: 11	6.2	3	2-4 × 10-30	EMR: 39; RFA: 19	CE-D: 98%; CE-IM: 75%	Bleeding: 1; perforation: 1	58	NR	7 (21)
Alshelleh et al[124], 2021	Retrospective, single center	25	LN	LGD: 9; HGD/IMC: 16	3.6	2.8 (2-5)	NR	EMR: 15	CE-D: 96%; CE-IM: 80%	Stricture: 3	15 (9-18)	NR	NR
Fasullo et al[71], 2022	Retrospective, multicenter	62	LN	LGD: 36; HGD: 19; IMC: 7	4.7	5 ± 3.4	1-3 × 20-30	Treatment naïve: 62	CE-D: 71%; CE-IM: 66%	0	> 12	NR	6 (14)
Genere et al[125], 2022	Retrospective, single center	23	LN	LGD: 7; HGD: 15; EAC: 1	8.0	4	4-5 × 20	RFA: 23; EMR: 13	CE-D: 52%; CE-IM: 30%	Stricture: 6	28	NR	8 (35)
Eluri et al[32], 2024	Prospective, multicenter	138	LN	LGD: 33; HGD: 68; IMC: 37	2.8	2	2-3 × 20-30	EMR: 65; RFA: 47	2 years: CE-D: 84%; CE-IM: 66%	Stricture: 7; pain: 1; perforation: 1	34 ± 20	NR	6 (9)
									3 years: CE-D: 92%; CE-IM: 67%

¹Tumor length instead of Barrett esophagus length.

²Complete response defined as complete local tumor eradication with endoscopic biopsy confirmation of the lack of residual disease.

³The number of patients for each histologic diagnosis was not reported.

BE: Barrett esophagus; FU: Follow-up; BB: Buried Barrett; LN: Liquid nitrogen; IM: Intestinal metaplasia; LGD: Low-grade dysplasia; HGD: High-grade dysplasia; CE-D: Complete eradication of dysplasia; CE-IM: Complete eradication of intestinal metaplasia; NR: Not reported; IMC: Intramucosal carcinoma; EMR: Endoscopic mucosal resection; PDT: Photodynamic therapy; APC: Argon plasma coagulation; ER: Endoscopic resection; CT: Chemotherapy; EBRT: External beam radiotherapy; CR: Complete response; RFA: Radiofrequency ablation; CO₂: Carbon dioxide; CBA: Cryoballoon ablation; EAC: Esophageal adenocarcinoma.

Table 2 Studies on liquid nitrogen spray cryotherapy for palliation of dysphagia in patients with advanced esophageal cancer

Ref.	Study design	Histopathology, n	Concurrent chemotherapy, n	Number of treatments per patient1	Tumor sites treated1	Cycles per tumor site1	Freeze time, seconds/cycle	Dysphagia on a 5-point Likert score2	FU, months1	Survival, n (months)	Procedure-related adverse events, n	Other palliation needed, n
Kachaamy et al[83], 2018	Retrospective, multicenter	EAC: 47; SCC: 2	33	2 (1-6)	2.5 (1.0-11.0)	3 (1-4)	20 (20-30)	Pre: 2.6; post week 2: 1.7	6.2 (0-27.0)	20	Pain: 5; perforation: 1; stricture: 1; bradycardia: 1	Dilatation: 3; stent: 2
Shah et al[85], 2019	Prospective, multicenter	EAC: 15; SCC: 6	0	1	2 (1-3)	4 (3-8)	30 (20-40)	Pre: 1.8; post week 1: 0.8; post week 2: 1.3	1	19	Pain: 1; obstruction due to tumor slough: 1	Feeding tube: 2; stent: 1
Eluri et al[126], 2021	Prospective, multicenter	EAC: 45; SCC: 4	0	4 (2-7)3	NR	3	30	Pre: 1.7; post: NR	11 ± 74	24 (12)	195	Stent: 14; feeding tube: 4
Hanada et al[84], 2022	Retrospective, single center	EAC: 41; SCC: 15	0	4 (1-12)	NR	2-5	20	NR	25.6 ± 29.04	NR	Dilatation: 16; bleeding: 2; perforation: 1	Stent: 13
Kachaamy et al[16], 2023	Prospective, multicenter	EAC: 51; SCC: 2; NET: 2	44	3 (1-5 or > 5)6	2 (1-10)	3 (1-4)	20 (20-30)	Pre: 1.9; post last FU: 1.3	15.3 (1.0-66.0)	8 (16)	Pain: 3; bradycardia: 1	Dilatation: 7; radiation: 3; stent: 2; botulin injection: 1

¹Reported as median with minimum and maximum value.

²5-point dysphagia Likert score, 0 = no dysphagia, 1 = dysphagia to solids, 2 = dysphagia to semi-solids, 3 = dysphagia to liquids, 4 = dysphagia to own saliva.

³Interquartile range instead of minimum and maximum value.

⁴Mean and standard deviation.

⁵The specific type of adverse event has not been reported.

⁶The exact maximum number of treatments has not been reported.

FU: Follow-up; EAC: Esophageal adenocarcinoma; SCC: Squamous cell carcinoma; NR: Not reported; NET: Neuroendocrine tumor.