Efficacy and safety of intraoperative radiotherapy in rectal cancer: A systematic review and meta-analysis

Table 1 Baseline characteristics of the included studies

Ref.	Year	Location	Time frame	Type	Patients, n IORT/ non-IORT	Age in yr, mean IORT non-IORT	Follow-up in mo, mean IORT non-IORT	Resection margin	Clinical stages, %	PR-RT, %	CT, %	PO-RT, %	IORT dose in Gy mean	NOS score
Willett et al[23]	1991	United States	1978-1988	Observational studies	20; 21/22; 2	64 v	26 v	R0; R1/R2	NA	100	NA	0	15	7
Suzuki et al[24]	1995	Germany	1981-1988	Observational studies	42/64	64.3 v	44 v	R1/R2	NA	NA	NA	98	20	8
Huber et al[25]	1996	Germany	1989-1993	Observational studies	36/18	NA	25.5 v	R0/R1/R2	T3 (50); T4 (50)	50	100	50	15	8
Wiig et al[26]	2002	Norway	1990-1999	Observational studies	59/48	NA	NA	R0/R1/R2	NA	100	NA	NA	15-20	8
Ratto et al[27]	2003	Italy	1990-1997	Observational studies	19/24	62	74 v	NA	T3 (7); T4 (93)	NA	NA	NA	10-15	7
Sadahiro et al[28]	2004	Japan	1991-2001	Observational studies	99/68	60 61	67 v	NA	T1/T2 (29); T3 (59); T4 (12)	100	53	0	17.3	7
Ferenschild et al[29]	2006	Netherlands	1987-2001	Observational studies	30/93	66 v	25 v	R0	T2 (14); T3 (57); T4 (25)	100	NA	0	10	9
Masaki et al[30]	2008	Japan	2000-2007	RCT	19/22	NA	34 v	NA	T1/T2 (11); T3 (89)	NA	37	NA	18-20 f	RCT
Valentini et al[31]	2009	Italy	1991-2006	Observational studies	11/35	62 v	80 v	R0	T4 (100)	NA	NA	NA	10-15 f	7
Dubois et al[32]	2011	France	1993-2001	RCT	72/68	62.5 64.5	60 v	NA	T3/T4 (100)	100	25	NA	18	RCT
Zhang et al[35]	2014	China	1996-2007	Observational studies	45/46	61 61	72.9 v	NA	T3 (100)	NA	100	51	20	8
Alberda et al[33]	2014	Netherlands	1996-2012	Observational studies	21; 22/31; 17	66 59/61 56	38 39/23 12	R0/R1	T3 (41); T4 (59)	NA	NA	NA	10	8
Klink et al[34]	2014	Germany	2004-2012	Observational studies	52/111	62 63	NA	R0	T3/T4 (100)	NA	NA	NA	10-20 f	9
Zhang et al[36]	2015	China	1994-2007	Observational studies	71/77	58 63	72.3 v	R0/R1/R2	T2 (6); T3 (52); T4 (42)	NA	100	100	15	7
Masaki et al[19]	2020	Japan	2000-2017	RCT	38/38	NA	72 v	R0/R1	T1/T2 (17); T3 (80); T4 (3)	NA	NA	NA	18-20 f	RCT

CT: Chemotherapy; f: Range reported with no mean/median; IORT: Intraoperative radiotherapy; NA: Not reported; non-IORT: Non-intraoperative radiotherapy; PO-RT: Post-operative radiotherapy; PR-RT: Pre-operative radiotherapy; RCT: Randomized controlled trial; v: Reported for IORT and non-IORT combined.

Table 2 Outcome indicators of the included studies

Ref. %	Surgery, %	Resection margin %	5-yr OS, % IORT non-IORT %	5-yr DFS, % IORT non-IORT %	5-yr LC, % IORT non-IORT %	Complications, % IORT non-IORT
Willett et al[23]	NA	R0; R1/R2	NA	53 60; 32 NA	88 71; 60 0	Abscess (5); Fistulae (7) Wound (5); Anastomotic leakage (2) Ureteric obstruction (2) Sacral necrosis (2)	NA
Suzuki et al[24]	LAR (57); APR (35); Hartmann (6)	R1/R2	19 7.3	30 5.9	60 7	Pelvic abscess (12) Fistula (2) Perineal wound (7); Small bowel obstruction (14) Ureteral obstruction (7)	Pelvic abscess (11) Fistula (6) Perineal wound (2); Small bowel obstruction (5) Ureteral obstruction (2)
Huber et al[25]	LAR (84); APR (16)	R0/R1/R2	40 20	28 NA	80 24	Wound (45) Sacral wound dehiscence (21); Neurogenic bladder dysfunction (8)	Wound (58) Sacral wound dehiscence (26); Neurogenic bladder dysfunction (11)
Wiig et al[26]	LAR (31); APR (10); Hartmann (19)	R0/R1/R2	30 35	NA	44 28	Abscess (24) wound (3) Anastomotic leakage (3); Late perineal healing (10)	Abscess (29) wound (13) Anastomotic leakage (13); Late perineal healing (2)
Ratto et al[27]	LAR (33); APR (56)	NA	NA	47 39	91 57	NA
Sadahiro et al[28]	LAR (54); APR (46)	NA	79 58	71 54	98 84	Anastomotic leakage (6) Wound (23) Bleeding (3) Neurogenic bladder dysfunction (2)	Anastomotic leakage (3) Wound (12) Bleeding (1) Neurogenic bladder dysfunction (4)
Ferenschild et al[29]	NA	R0	56 66	NA	71 72	NA
Masaki et al[30]	TME (100)	NA	64 NA	60 NA	95 95	Anastomotic breakdown (25) Intrapelvic abscess (14)	Anastomotic breakdown (14) Intrapelvic abscess (21)
Valentini et al[31]	APR (56)	R0	19.4 16.3	41.1 16.8	79.5 23.7	NA
Dubois et al[32]	APR (20)	NA	77 75	62 66	92 93	Anastomotic leakage (8.5) Re-operation (11.3) Infectious complications (9.9) Medical complications (7.0) Sacral necrosis (1.5)	Anastomotic leakage (4.4) Re-operation (8.8) Infectious complications (11.8) Medical complications (2.9)
Zhang et al[35]	TME (80)	NA	84 86	71 73	84 86	Grade 3 diarrhea (3) numbness and motor weakness (4.4)	Leukopenia (10.9) Grade 3 diarrhea (14) incomplete intestinal obstruction (6.5) acute mucositis of the anal verge (23.9)
Alberda et al[33]	TME (100)	R0; R1	63 81; 41 13	NA	70 79; 84 41	Abdominal/perineal wound infections (31) abscess (6) Anastomotic leakage (2) Urinary tract infection (8) Cardiac (6)	Abdominal/perineal wound infection (23) abscess (13) Anastomotic leakage (3) Urinary tract infection (8) Cardiac (3)
Klink et al[32]	NA	R0	NA	NA	NA	Postoperative bleeding (0) Anastomotic leakage (11) Surgical site infection (15) Abscess (10) Fistula (2) Stenosis (4) Bladder dysfunction (8) Urethral leakage (0) Sexual dysfunction (2)	Postoperative bleeding (4) Anastomotic leakage (14) Surgical site infection (9) Abscess (5) Fistula (0) Stenosis (1) Bladder dysfunction (10) Urethral leakage (1) Sexual dysfunction (3)
Zhang et al[36]	TME (100)	R0/R1/R2	74.6 66.2	69 58.5	89.7 79	Incomplete intestinal obstruction (4) Hydronephrosis (7)	Incomplete intestinal obstruction (2.6) Hydronephrosis (10)
Masaki et al[19]	TME (100)	R0/R1	71.5 81.8	NA	87.6 91.7	Anastomotic leakage (29) abscess (18) Small bowel obstruction (13)	Anastomotic leakage (13) abscess (11) Small bowel obstruction (18)

APR: Abdominoperineal resection; DFS: Disease-free survival; LAR: Low anterior resection; LC: Local control; NA: Not reported; non-IORT: Non-Intraoperative radiotherapy; OS: Overall survival; TME: Total mesorectal excision.

Table 3 Results of meta-analysis and subgroup analysis by intraoperative radiotherapy compared with non-intraoperative radiotherapy for rectal cancer

Outcome indicators	Study type	NO of study	Patients, n IORT non-IORT	HR/OR/WMD (95% CI)	P value	Heterogeneity, χ2/ I2/ P value
5-yr overall survival	RCT	3	129 95	0.68 (0.29-1.63)	0.390	2.92/31.4%/0.233
	Observational studies	6	321 292	0.81 (0.66-1.11)	0.189	2.21/0.0%/0.819
	Totality	9	450 387	0.80 (0.60-1.06)	0.126	5.16/0.0%/0.740
5-yr disease free survival	RCT	2	91 57	1.61 (0.74-3.53)	0.231	0.60/0.0%/0.440
	Observational studies	4	235 212	0.89 (0.68-1.16)	0.374	1.72/0.0%/0.633
	Totality	6	326 269	0.94 (0.73-1.22)	0.650	4.33/0.0%/0.503
5-yr local control	RCT	3	129 95	1.37 (0.35-5.35)	0.655	1.33/24.8%/0.249
	Observational studies	11	487 511	3.38 (1.73-6.57)	0.000	41.31/73.4%/0.000
	Totality	14	616 606	3.07 (1.66-5.66)	0.000	43.42/70.9%/0.000
Abscess	RCT	2	57 60	1.83 (0.65-5.11)	0.252	0.01/0.0%/0.905
	Observational studies	4	205 262	0.94 (0.53-1.66)	0.833	1.99/0.0%/0.575
	Totality	6	262 322	1.10 (0.67-1.80)	0.713	3.22/0.0%/0.665
Fistulae	RCT	1	72 68	0.75 (0.30-1.88)	0.542	0.00/NA/NA
	Observational studies	2	94 175	1.22 (0.08-18.77)	0.888	2.02/50.4%/0.156
	Totality	3	166 243	0.79 (0.33-1.89)	0.600	2.07/3.2%/0.356
Wound complications	RCT	1	72 68	0.75 (0.30-1.88)	0.542	0.00/NA/NA
	Observational studies	7	385 393	1.06 (0.47-2.37)	0.893	16.09/62.7%/0.013
	Totality	8	457 461	1.21 (0.62-2.36)	0.575	17.01/58.8%/0.017
Anastomotic leakage	RCT	3	129 95	2.18 (0.89-5.33)	0.087	0.11/0.0%/0.946
	Observational studies	4	262 266	0.66 (0.31-1.41)	0.283	2.46/0.0%/0.482
	Totality	7	391 361	1.09 (0.59-2.02)	0.775	6.57/8.7%/0.363
Neurogenic bladder dysfunction	Observational studies	3	187 197	0.69 (0.31-1.55)	0.369	0.27/0.0%/0.874

HR: Hazard ratio; IORT: Intraoperative radiotherapy; NA: Not reported; non-IORT: Non-Intraoperative radiotherapy; OR: Odds ratio; RCT: Randomized controlled trial; WMD: Weighted mean difference.