Cytoreductive surgery and intraperitoneal chemotherapy for colorectal peritoneal metastases

Table 1 Summary of study design, treatment indications and treatment protocols for studies included in systematic review process n (%)

Ref.	Time frame	n	Study design (evidence level)	Indication	Extent of CPM	Treatment summary	Technique	Intraperitoneal chemotherapeutic regimen
Portilla et al[33]	1985-1996	18	Case series (3)	rCPM1	PCI < 12, 10/18 (60)	CRS + EPIC	Closed technique	POD 1: MMC in 1 L 1.5% dextrose peritoneal dialysis solution (10-12.5 mg/m2)
					PCI > 12, 8/18 (38)			POD 2-6: 5-FU in 1 L 1.5% dextrose peritoneal dialysis solution + 50 mEq sodium bicarbonate
Witkamp et al[34]	1995-1997	29	Case series (3)	CPM2	-	CRS + HIPEC	Closed technique	MMC 35 mg/m2 in 3-4 L of isotonic dialysis fluid at a temperature of 40 °C-41 °C for 90 min
Pilati et al[35]	1995-2001	34	Case series (3)	CPM2	-	CRS + HIPEC	10/34 closed technique	MMC (3.3 mg/m2 per liter) + cisplatin (25 mg/m2 per liter) for 90 min at temperature of 41 °C-42 °C
							14/34 open technique
Verwaal et al[36]	1995-2003	106	Case series (3)	rCPM2	-	CRS + HIPEC	Closed abdomen technique	MMC 35 mg/m2 in 3-4 L of isotonic dialysis fluid at a temperature of 40 °C-41 °C for 90 min
Glehen et al[37]	1989-2002	53	Multicentre case series (3)	CPM2	Stage2 I 13/53 (25)	CRS + HIPEC	Closed abdomen technique	MMC 40-60 mg in 4-6 L of perfusate at a temperature of 46 °C-48 °C for 90 min
					Stage II 8/53 (15)
					Stage III 7/53 (13)
					Stage IV 25/53 (47)
Mahteme et al[53]	1991-1999	36 (18 vs 18)	Case-control (2-)	CPM2	-	Treatment arm: CRS + EPIC (n = 18)	Closed abdomen technique	EPIC protocol: 5-FU 550 mg/m2 in 500 mL normal saline administered intraperitoneally from POD 1. IV infusion of leucovorin (60 mg/m2) commenced at 60 min after initiation of PIC. Regimen offered 1-8 courses as tolerated with 4-6 wk interval between cycles.
						Control arm: Systemic CT only		Systemic CT protocol: Chemotherapeutic regimen not specified
Glehen et al[38]	1987-2002	506	Multinational case series (3)	CPM3	Limited 171/506	(n = 18)CRS + HIPEC and/or EPIC	Open or closed technique	HIPEC protocol: Various (MMC alone 274/506; MMC + cisplatin 48/506; oxaliplatin 32/506; other 29/506)
					Extended 329/506			EPIC protocol: Various (MMC alone 2/506; MMC + 5-FU 113/506; 5-FU alone 95/506; other 7/506)
Shen et al[39]	1991-2002	77	Case series (3)	CPM3	-	CRS + HIPEC		40 mg MMC introduced into dialysis fluid for 120 min at ≥ 38.5 °C
Cavaliere et al[40]	1996-2005	120	Multicentre case series (3)	CPM1	-	CRS + HIPEC	Closed abdomen technique Open 56.7%	109/120: MMC (3.3 mg/m2 per liter) and cisplatin (25 mg/m2 per liter) at 41.5 °C-43 °C for 60-90 min
							Closed 43.3%	11/120: oxaliplatin (460 mg/m2) for 30 min after IV 5-FU and leucovorin
Kianmanesh et al[41]	1996-2006	43	Case series (3)	CPM3	Stage2 I/II 10/43 (23)	CRS + HIPEC	Open technique	MMC 120 mg + cisplatin 200 mg/m2 at 41 °C-43 °C for 90 to 120 min
					Stage III 6/43 (14)
					Stage IV 27/43 (63)
Gusani et al[42]	2002-2005	28	Case series (3)	CPM2	-	CRS + HIPEC	Closed technique	MMC 30-40 mg in 3 L saline solution at temperature of 40 °C for 100 min
Verwaal et al[26]	1998-2001	105 (54 vs 51)	Randomized trial (1-)	CPM2	-	Treatment arm: CRS + HIPEC (n = 54)	Open coliseum technique	HIPEC protocol: MMC 17.5 mg/m2 at 40 °C for 90 min
						Control arm: Systemic CT only (n = 51)		Systemic CT protocol: 5-FU (400 mg/m2) + leucovorin (80 mg/m2) weekly for 26 wk
Yan et al[62]	1997-2007	50	Case series (3)	CPM3	PCI < 10 20/50	CRS + HIPEC	Open coliseum technique	MMC 10-12.5 mg/m2 in 3 L of 1.5% dextrose peritoneal dialysis solution for 90 min at 42 °C
					PCI 10-20 23/50
					PCI > 20 7/50
Elias et al[54]	1998-2003	96 (48 vs 48)	Case-control (2-)	CPM3	Treatment arm: Limited 27/48 Extended 21/48	Treatment arm: CRS + HIPEC (n = 48)	-	HIPEC protocol: Oxaliplatin 460 mg/m2 in 2 L/m2 at 43 °C for 30 min. Before HIPEC (during CRS) patients received IV 5-FU 400 mg/m2 + leucovorin 20 mg/m2
					Control arm:	Control arm:		Systemic CT protocol:
					Limited 26/48 Extended 17/48Not recorded 5/48	Systemic CT only (n = 48)		Various regimens (5-FU based 46/48; Capecitabine based 1/48; Camptothecin 1/48)
Varban et al[43]	1991-2007	142	Case series (3)	CPM3	-	CRS + HIPEC	Closed technique	MMC 40 mg at 40.5 °C-42.5 °C for 120 min
Vaira et al[44]	1997-2008	40	Case series (3)	CPM2	PCI > 16 11/40	CRS + HIPEC	Closed technique	Cisplatin (100 mg/m2) + MMC (16 mg/m2) at 41.5 °C for 30 min
					PCI < 16 29/40			OR
								Oxaliplatin (460 mg/m2) + IV 5-FU at 42 °C for 30 min
								OR
								MMC (35 mg/m2) at 40.5 °C for 60 min
Glehen et al[45]	1989-2007	523	Multi-centre case series (3)	CPM3	-	CRS + HIPEC and/or EPIC	Various techniques	HIPEC protocol: MMC (30-50 mg/m2) with or without cisplatin (50-100 mg/m2) delivered over 60-120 min at 41 °C-42.5 °C
								OR
								Oxaliplatin (360-460 mg/m2) +/- irinotecan (100-200 mg/m2) +/- IV 5-FU and leucovorin delivered over 30 min at 43 °C
								EPIC protocol: Abdominal cavity filled at the end of surgery with 1 L/m2 Ringer lactate. EPIC lasted 5 d (POD 1-5); POD 1: MMC (10 mg/m2); POD 2-5: 5FU (600 mg/m2)
Franko et al[55]	2001-2007	105 (67 vs 38)	Case-control (2-)	CPM2	-	Treatment arm: CRS+ HIPEC (n = 67)	Closed abdomen technique	HIPEC protocol: MMC 40 mg for 100 min
						Control arm: Systemic CT only (n = 38)		Systemic CT protocol: Chemotherapeutic regimen(s) not clearly described
Quenet et al[46]	1998-2007	146	Case series (3)	CPM3	PCI < 10 69/146	CRS + HIPEC	Closed technique	IV 5-FU (400 mg/m2) + leucovorin (20 mg/m2) followed by: ip oxaliplatin (460 mg/m2) in 2 L/m2 dextrose
					PCI 11-19 57/146			OR
					PCI >20 20/146			ip oxaliplatin (300 mg/m2) + ip irinotecan (200 mg/m2) in 2 L/m2 dextrose
Cashin et al[57]	1993-2008	32 (16 vs 16)	Case-control (2-)	CPM2	HIPEC group: Mean PCI 14.4	CRS + HIPEC (n = 16)	HIPEC:Open coliseum techniqueEPIC: Closed technique	HIPEC protocol: Oxaliplatin 460 mg/m2 for 30 min at 41 °C-42 °C combined with IV 5-FU (450-500 mg/m2) + leucovorin (25-30 mg/m2)
					EPIC group: Mean PCI 13.2	CRS + EPIC (n = 16)		EPIC protocol: 5-FU (500-600 mg/m2) + IV leucovorin (20-30 mg/m2) once daily for 86-d cycles
Passot et al[47]	1991-2010	120	Case series (3)	CPM3	Stage2 I-II 41/120	CRS + HIPEC	Closed technique	MMC + irinotecan or oxaliplatin
					Stage III-IV 79/120			Exact dosing protocol not described
					Mean PCI 8.2
Hompes et al[48]	2004-2008	48	Case series (3)	CPM2	Median PCI 11 (1-22)	CRS + HIPEC	Open coliseum technique	IV folinic acid (20 mg/m2) + 5-FU (400 mg/m2) followed by ip oxaliplatin (460 mg/m2) in 2 L/m2 5% glucose solution at 41 °C-42 °C for 30 min
Cashin et al[56]	1996-2010	151 (69 vs 57)	Case control (2-)	CPM3	PCI 1-10 49/151	CRS+ HIPEC (n = 69)	HIPEC: Open coliseum technique	HIPEC protocol: MMC ip (30 mg/m2) for 90 min at 41 °C-42 °C OR oxaliplatin (460 mg/m2) ip for 30 min at 41 °C-42 °C + IV 5-FU (400 mg/m2) and calcium folinate (60 mg/m2) OR oxaliplatin (360 mg/m2) ip + irinotecan (360 mg/m2) for 30 min at 41 °C-42 °C + IV 5-FU (450-500 mg/m2) and calcium folinate (60 mg/m2)
					PCI 11-20 45/151	CRS + EPIC (n = 57)	EPIC: Closed technique	EPIC protocol: 5-FU (500-600 mg/m2) ip + IV leucovorin (60 mg/m2) once daily for 8 6-d cycles
					PCI 21-39 56/151
Klaver et al[49]	1996-2010	24	Case series (3)	CPM14	-	CRS+ HIPEC (12/24)	Open coliseum technique	HIPEC protocol: ip chemotherapy (MMC or oxaliplatin; dosing not stated) at 42 °C for 90 min
						CRS + EPIC (6/24)		EPIC protocol: 5-FU (650-800 mg/m2 per day) in 1 L 1.5% dextrose for 23 h on POD 1-5
						CRS + HIPEC + EPIC (6/24)
Turrini et al[50]	2004-2010	26	Case series (3)	CPM1	-	CRS + HIPEC	Open coliseum technique	Oxaliplatin ip (460 mg/m2) in 2 L/m2 dextrose solution at 43 °C for 30 min after 1 h infusion of IV 5-FU (400 mg/m2) + leucovorin (20 mg/m2)
Haslinger et al[51]	2003-2011	38	Case series (3)	CPM2	-	CRS+ HIPEC	Closed technique	MMC 40 mg at temperature of 41 °C for 60-120 min
Yonemura et al[52]	2004-2012	142	Case series (3)	CPM3	-	CRS + HIPEC	-	MMC 20 mg/m2 + cisplatin 100 mg/m2 in $L saline at 42 °C-43 °C for 60 min

¹Not stated clearly whether patients with distant metastases to other sites included/excluded;

²Patients with distant metastases excluded;

³Cases with extra-abdominal metastatic involvement excluded (LN positive and liver metastasised cases included);

⁴All patients ≥ 70 years of age. PCI: Peritoneal cancer index; CRS: Cytoreductive surgery; EPIC: Early post-operative intraperitoneal chemotherapy; POD: Postoperative day; MMC: Mytomycin C; HIPEC: Hyperthermic intra-peritoneal chemotherapy.