Hyperbaric oxygen therapy as a complementary treatment for radiation proctitis: Useless or useful? – A literature review

Table 1 Classification of stages/grades of radiation proctitis

Ref.	Stages/grades	Description
Sherman[27], 1954	I-IV	Based on endoscopic findings: I: (a) Localised erythema and telangiectasia, friable mucosa with easy bleeding: no ulceration or stricture formation, and (b) More diffuse erythema along with periproctitis, marked pain, and sensitivity; II: Presence of ulceration with a greyish tenacious slough, usually involving the anterior rectal wall, and proctitis with grade I lesions; III: Presence of rectovaginal fistulae or bowel perforation and varying degrees of proctitis with ulceration; IV: Presence of rectovaginal fistulae or bowel perforation and varying degrees of proctitis with ulceration.
Dean and Taylor[28], 1960	I-III	Based on clinical and endoscopic findings: I: Symptoms: Rectal bleeding, tenesmus, sphincter instability, mucoid discharge; endoscopic findings of vascular congestion, friability of the mucosa, mucosal thickening, mucoid discharge; II: Same symptoms as before; endoscopic findings of ulcerations, underlying thrombosis of the small vessels; III: Same symptoms as before plus perineal sepsis, incontinence, diarrhoea, perianal purulent discharge; endoscopic findings of necrosis, fistulae, strictures.
Gilinsky et al[29], 1983	Normal; Mild; Moderate; Severe	Based on endoscopic findings: Score 0: Normal mucosa; Score 3: Erythema and/or telangiectasia, oedema, thickening, pallor of mucosa; Score 6: Friability; Score 9: Ulceration and/or necrosis.
Langberg et al[30], 1992	1-3	Based on histopathologic findings: Thickening of serosa: (1) Slight thickening of serosa, hyperplasia of peritoneal mesothelium; and (2) Marked thickening of serosa; and (3) Extreme thickening and fibrosis serosa. Mucosal alterations: (1) Small superficial ulcerations; and (2) Ulcerations involving more than half of the intestinal circumference. Epithelial atypia: (1) Abnormally oriented crypts; (2) Irregular crypt regeneration with atypical epithelial cells; and (3) Adenocarcinoma. Vascular sclerosis: (1) Slight double normal thickness, broadened and hyalinised collagen fibres; (2) Submucosa three to four times normal thickness, abnormal collagen fibres; and (3) Massive fibrosis including muscularis. Lymph congestion: (1) Dilated lymph vessels or cystic collections of lymph. Ileitis cystica profunda: (1) Submucosal glandular inclusions; (2) Submucosal cysts with polypoid elevation of the mucosa; and (3) Large cysts extending into the muscularis.
Chutkan et al[31], 1997	0-4	Based on clinical findings: 0: No haemorrhage; 1: Blood on toilet paper or mixed with faeces; 2: Drops of blood in the toilet; 3: Severe haemorrhage with expulsion of clots; 4: Haemorrhage that requires transfusion.
Wachter et al[32], 2000. Vienna Rectoscopy Score	0-5	Based on endoscopic findings: Score 0: Congested mucosa (grade 1); Score 1: Congested mucosa (grade 2), telangiectasia (grade 1); Score 2: Congested mucosa (grade 3), telangiectasia (grade 2); Score 3: Congested mucosa (any grade), telangiectasia (grade 3), ulceration (grade 1); Score 4: Congested mucosa (any grade), telangiectasia (any grade), ulceration (grade 2), stricture (grade 1); Score 5: Congested mucosa (any grade), telangiectasia (any grade), ulceration (grade 3), stricture (grade 2), necrosis (any grade).
Zinicola et al[33], 2003. Bleeding Scale for Radiation-Induced Haemorrhagic Proctitis	0-4	Based on clinical findings: 0: No bleeding; 1: Intermittent bleeding (once weekly or less); 2: Persistent bleeding (twice or more weekly); 3: Daily bleeding or anaemia; 4: Require blood transfusion.
Chi et al[34], 2005. RTD grading scale	0-3	Based on RTD endoscopic findings: 0: Normal mucosa; 1: < 10 telangiectasias; 2: > 10 telangiectasias; 3: Confluent lesions, active bleeding or friable mucosa.
Ehrenpreis et al[35], 2005. Radiation Proctopathy System Assessment Scale (RPSAS)	1-5	Based on clinical findings: Diarrhoea. Urgency. Rectal pain. Tenesmus. Rectal bleeding. Faecal incontinence. Severity: 1: No problem. 2: Mild problem–can be ignored when you do not think about it. 3: Moderate problem–cannot be ignored; no effect on ADL. 4: Severe problem–influences your concentration on ADL. 5: Very severe problem–markedly influences your ADL and/or requires rest. Frequency: 1: Monthly; 2: Weekly; 3: Several times per week; 4: Daily; 5: Throughout the day.
Cox et al[36], 1995. Late Radiation Morbidity Scoring Criteria Radiation Therapy Oncology Group/European Organisation for Research and Treatment of Cancer	0-5. Late (> 3 mo)	Based on clinical and imaging findings: 0: No changes; 1: Mild diarrhoea, mild cramping, bowel movement 5 times daily, slight rectal discharge or bleeding; 2: Moderate diarrhoea or colic, bowel movement > 5 times daily, excessive rectal mucus or intermittent bleeding; 3: Obstruction or bleeding requiring surgery; 4: Necrosis, perforation, or fistulae; 5: Death related to adverse event.
NCI CTCAE version 5.0[37], 2017	1-5	Based on clinical findings: 1: Mild adverse event; rectal discomfort, intervention not indicated; 2: Moderate adverse event; rectal discomfort, passing blood or mucus, medical intervention indicated, limiting instrumental ADL; 3: Severe and undesirable adverse event, faecal urgency or stool incontinence, limiting self-care ADL; 4: Life-threatening or disabling adverse event, urgent intervention needed; 5: Death related to adverse event.

ADL: Activities of daily living; RTD: Rectal telangiectasia density.

Table 2 Summary of the case-series or clinical trials described in the literature regarding the use of hyperbaric oxygen therapy in the treatment of radiation proctitis

Ref.	Study design	Patients (n)	RP stages/grades, patients (n)	Other (previous) treatments (%)	HBOT protocol	Nº sessions	Overall response rate (%)	Complete response (%)	Follow-up period (mo)
Bouachour et al[45], 1990	Retrospective	8	NA	100%	2.5 ATA, 90 min, twice daily (4 wk)-> Once daily	80 ± 10	87.5%	75%	[4-20]
Feldmeier et al[46], 1996	Retrospective	7	RTOG/EORTC[36]: 4	28.6%	2.4 ATA, 90 min, 5 ×/wk	24 [3-50]	57%	57%	NA
Warren et al[47], 1997	Retrospective	14	Bleeding (n = 11); Diarrhoea (n = 5); Rectal pain (n = 4); Tenesmus (n = 2)	78.6%	2.0 ATA, 120 min, 5-6/wk; 2.35 ATA, 90 min, 5 ×/wk	39 [20-72]	64.3%	57.1%	14.6 [2-35]
Woo et al[48], 1997	Retrospective	18	Bleeding (n = 17); Diarrhoea (n = 8); Rectal pain (n = 4); Incontinence (n = 4)	77.7%	2.0 ATA, 105 min, 6 ×/wk	24 [40]	55.5%; Incontinence 75%; Diarrhoea 50%; Rectal pain 50%; Haemorrhage 41.2%	11.1%; 50%; 25%; 25%; 23.5%	14 [65]
Bredfeldt and Hampson[49], 1998	Retrospective	19	NA	NA	2.36 ATA, 90 min, 5 ×/wk	30	84%	47%	NA
Ugheoke et al[50], 1998	Retrospective	8	NA	NA	2.5 ATA, 90 min, 5 ×/wk	28 [20-40]	62.5%	NA	NA
Carl et al[51], 1998	Retrospective	2	Bleeding (n = 1); Rectal pain (n = 1)	NA	2.4 ATA, 90 min, 5 ×/wk	38, 40	50%	50%	NA
Gouëllo et al[52], 1999	Retrospective	36	LENT-SOMA: Grade 1 (n = 1); Grade 2 (n = 11); Grade 3 (n = 16); Grade 4 (n = 8)	NA	2.5 ATA, 90 min, 5 ×/wk	67 (mean)	66%	25%	52
Kitta et al[53], 2000	Retrospective	4	Bleeding (n = 3); Rectal pain (n = 1)	100%	2.0 ATA, 60 min, 5 ×/wk	37.5 [30-60]	75%	25%	NA
Bem et al[54], 2000	Retrospective	2	Dean and Taylor[28]: I-II	100%	2.4 ATA, 90 min, 5 ×/wk	60, 60	100%	100%	[3-48]
Roque et al[55], 2001	Retrospective	6	NA	NA	2.5 ATA, 90 min, 5 ×/wk	37 [20-60]	85%	NA	NA
Mayer et al[56], 2001	Retrospective	10	RTOG/EORTC[36]: Grade 2 (n = 4); Grade 3 (n = 6)	Majority (% not stated)	2.2-2.4 ATA, 60 min, 7 ×/wk	28 [13-60]	90%	30%	15.3 [7.5-26.9]
Boyle et al[57], 2002	Retrospective	19	NA	NA	2.0 ATA, 120 min, 5 ×/wk	59 [27-80]	68%	NA	NA
Jones et al[58], 2006	Retrospective	10	LENT-SOMA: Grade 2 (n = 7); Grade 3 (n = 3)	100%	2.0-2.5, 90 min, 5 ×/wk	40 [36-41]	77%; Haemorrhage 88.8%; Diarrhoea 80%; Rectal pain 80%	44.4%; 60%; 20%	25 [6-43]
Dall’Era et al[59], 2006	Retrospective	27	RTOG/EORTC[36]: 3-4	100%	2.4 ATA, 90 min, 7-7 ×/wk	36 [29-60]	66.6%; Haemorrhage 76%; Rectal pain 75%; Faecal urgency 75%; Rectal ulcer 50%	37%; 48%; 0%; 50%; 21%	13 [1-60]
Fink et al[60], 2006	Retrospective	4	NA	100%	2.4 ATA, 90 min, 5 ×/wk	31 [28-37]	75%	25%	33
Girnius et al[61], 2006	Retrospective	9	Bleeding Scale for Radiation-Induced Haemorrhagic Proctitis[33]: Grade 2 (n = 1); Grade 3 (n = 3); Grade 4 (n = 5)	100%	2.5 ATA, 90 min, 5 ×/wk	58 [22-80	100%	77.7%	17 [1-77]
Marshall et al[16], 2007	Retrospective	65 (15 with lesions beyond the rectum)	Bleeding (n = 54); Diarrhoea (n = 25); Rectal pain (n = 25); Tenesmus, urgency, incontinence (n = 13); Malnutrition, weight loss (n = 7); Bloating, cramping (n = 6); Nausea, emesis (n = 5); Fistulae (n = 2); Total parenteral nutrition (n = 2)	65%	2.36 ATA, 90 min, 5 ×/wk	30-> If partial response-> 60	68% (all patients); 65% (rectum); 73% (proximal sites); Haemorrhage 70%; Other symptoms 58% (including pain relief, improved nutritional status and intestinal transit, closure of fistulae)	43%; 39%; 60%; 75%; 33%	23 [1-70]
Sidik et al[62,63], 2007	Prospective, randomised clinical trial	HBOT 32; Comparator33	LENT-SOMA: HBOT, mean 7.7 ± 2.0; Control, mean 6.8 ± 2.3. Karnofsky scale: HBOT, mean 73.8 ± 6; Control, mean 74.6 ± 8.3	NA	HBOT, Protocol not reported vs Comparator described as “symptomatic treatment”	HBOT, Minimum 18 sessions	Outcomes poorly reported (losses to follow-up, not all patient data provided)	NA	6
Safra et al[64], 2008	Retrospective	6	NCI CTCAE[37]: Mean 3.3 [2-4]	100%	2.0 ATA, 90 min, 7 ×/wk	27 [16-40]. Not only RP	100%	16.7%	NA
Clarke et al[65], 2008	Randomised, double-blind, sham-controlled, crossover allowed (“HORTIS”)	HBOT 76; Comparator74	LENT-SOMA: HBOT, mean 12.55; Sham, mean 12.84	100%	HBOT, 2.0 ATA, 90 min, 5 ×/wk vs Sham treatment 1.34-> 1.1 ATA O2 21%, 90 min, 5 ×/wk	30-> 40	HBOT: 88.9%. Improved bowel-specific and bowel bother and function QoL scores (before crossover) vs Sham treatment: 62.5%	HBOT: 7.9% vs Sham: 0%	25 [12-60]
Alvaro-Villegas et al[66], 2011	Prospective, non-randomised clinical trial	HBOT 17; Comparator14	LENT-SOMA: HBOT, 12.1 ± 2.9; APC, 13.3 ± 2.9	NA	HBOT 2.0-2.5 ATA, 90 min, 5 ×/wk vs Non-contact APC, 2.3 mm diameter catheter, 1.6 L/min flow rate at 60 W, mean 3 ± 1 (SD) sessions	HBOT, 35 ± 5 vs APC, 3 ± 1	HBOT: 82% vs APC: 87%	NA	3
Oliai et al[67], 2012	Retrospective	4	LENT-SOMA: Mean 0.66 [0.36-0.93]. Severity of rectal bleeding: Persistent (n = 3), Occasional (n = 1)	100%	2.0 ATA, 90-105 min, 5 ×/wk	37.5 [30-40]	75%	50%	NA
Carvalho et al[68], 2014	Retrospective	30	NA	NA	2.5 ATA, 100 min, 5 ×/wk	66 [38-80]	96.7%	73.3%	NA
Tahir et al[69], 2015	Retrospective	59	NA	NA	2.4 ATA, 70 min, 7x/wk	NA	95%	51%	Major response 15 [2-76]. Minor response 20 [1-84]
Glover et al[70], 2016	Randomised, double-blind, sham-controlled phase 3 clinical trial (“HOT2”)	Ratio 2:1; HBOT 55; Comparator29	LENT-SOMA: Grade 2; Grade 1 with intermittent symptoms. IBDQ bowel function component (n/IQR): HBOT 48 (42-52); Sham 51 (44-59). IBDQ rectal bleeding (n/IQR): HBOT 3 (2-4); Sham 3 (2-4). NCI CTCAE[64]: Grade 1-3, 46 (55%). EORTC QLQ-CR38 Question 59: Grade 1-3, 47 (59%)	100%	HBOT 2.4 ATA, 90 min, 5 ×/wk vs Sham treatment 1.34 ATA O2 21%, 90 min, 5 ×/wk	40 (89% of patients) < 38 (11% of patients)	HBOT: IBDQ bowel function component (n/IQR): Δ 3.5 (-3-11). IBDQ rectal bleeding (n/IQR): Δ 3 (1-3) vs Sham treatment: IBDQ bowel function component (n/IQR): Δ 4 (-6-9); IBDQ rectal bleeding (n/IQR): Δ 1 (1-2)	NA	13.2 [12.4-14.2]
Yoshimizu et al[71], 2017	Retrospective	5	Sherman[27]: Grade II (n = 3); Grade III (n = 1); Grade IV (n = 1)	NA	2.5 ATA, 60 min, 5 ×/wk	76 [40-100]	100%	20%	NA

APC: Argon plasma coagulation; ATA: Atmosphere absolute; HBOT: Hyperbaric oxygen therapy; IBDQ: Inflammatory Bowel Disease Questionnaire; IQR: Interquartile range; min, minute; NA: Not available or not applicable; NCI CTCAE: National Cancer Institute Common Terminology Criteria for Adverse Events; O₂: Oxygen; QoL: Quality of life; RP: Radiation proctitis; SD: Standard deviation; Δ: Median change from baseline to 12 mo.