Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in gastric cancer

Table 1 Published studies of prophylactic hyperthermic intraperitoneal chemotherapy in gastric cancer

Ref.	Type of study	Inclusion criteria	Treatment arms(No. of Patients )	Drugs used for IPC	Curative surgery	Complications	Post-op mortality	Survival	Peritoneal recurrence
Koga et al[65], 1988	RCT	Serosa+	Surgery + HIPEC (26) vs surgery alone (21)	MMC	100% vs 100%	Leak 3.1% vs 7.1%	NA	30 mo	NA
								83% vs 67%
Hamazoe et al[67], 1994	RCT	Serosa+	Surgery + HIPEC (42) vs surgery alone (40)	MMC	95% vs 88%	Leak 4.8% vs 7.5%	0% vs 0%	5-yr	39% vs 59% (death due to PC)
								64% vs 52%
								Median survival
								77 mo vs 66 mo
Fujimura et al[72], 1994	RCT	Serosa+	Surgery + HIPEC (22) vs surgery + CNPP (18) vs surgery alone (18 controls)	MMC	NA	30% vs 0% (perfusion vs surgery 40 pts vs 18)	NA	3-yr	9% vs 22% vs 22% (death due to PC)
				CDDP				68% vs 51% vs 23% (P < 0.01)
Ikeguchi et al[73], 1995	RCT	Serosa+	Surgery + HIPEC (78) vs surgery alone (96)	MMC	100% vs 100%	1.2% vs 2.08%	NA	5-yr	35% vs 40% (death due to PC)
								51% vs 46%
								5-yr
								66% vs 44%
								(in 1-9 LN +)
Fujimoto et al[74], 1999	RCT	Serosa+	Surgery + HIPEC (71) vs surgery alone (70)	MMC	94.3% vs 92.8%	2.8% vs 2.8%	0% vs 0%	2-yr	1.4% vs 23% (P = 0.00008)
								88% vs 77%
								4-yr
								76% vs 58%
								8-yr
								62% vs 49%
								(P = 0.03)
Hirose et al[75], 1999	Prospective case control	Serosa+	Surgery + HIPEC (15) vs surgery alone (40)	MMC	NA	60% vs 42.5%	0% vs 12.5%	3-yr	26% vs 45%
				CDDP Etoposide				49% vs 29%
								5-yr
								39% vs 17%
								Median survival
								33 mo vs 22 mo (P = 0.01)
Yonemura et al[76], 2001	RCT	Serosa+	Surgery + HIPEC (48) vs Surgery + CNPP (44) vs Surgery alone (47)	MMC	100% vs 100% vs 100%	19% vs 14% vs 19%	4% vs 0% vs 4%	5-yr	13% vs 15% (HIPEC vs surgery)
				CDDP				61% vs 43% vs 42%
Kim et al[77], 2001	Prospective controlled study	Serosa+	Surgery + HIPEC (52) vs surgery alone (51)	MMC	NA	36.5% vs 33.3%	NA	5-yr	7.6% vs 25% (isolated PC)
								33% vs 27%
								5-yr
								42% vs 25%
								(in stage IIIB)

NA: Not available, PC: Peritoneal carcinomatosis; pts: Patients; IPC: Intraperitoneal chemotherapy; MMC: Mitomycin-C; CDDP: Cisplatin.

Table 2 Meta-analyses of trials of prophylactic hyperthermic intraperitoneal chemotherapy

Author, year, outcome measure	No. of RCTs/ No. of patients	Type of IPC	Mortality	Bone marrow suppression	Intra-abdominal abscess	Anastomotic leak	Survival	Recurrence
Xu et al[86], 2004, OR	11/1161	HIPEC	NA	NA	NA	NA	0.51 (0.4-0.65; < 0.00001)	NA
		IPC ± CH
Yan et al[83], 2007, HR for survival, RR for others	10/1474	HIPEC	1.03 (0.28-3.75; 0.96)	4.33 (1.49-12.61; 0.007)	2.37 (1.49-12.61; 0.004)	1.01 (0.47-2.17; 0.98)	3-yr for HIPEC	Locoregional
		NIIC					0.60 (0.43-0.83; 0.002)	0.84 (0.30-2.31; 0.73)
		EPIC
		DPIC
Sun et al[81], 2012, RR	10/1062	HIPEC	NA	1.68 (0.62-4.58; 0.3)	NA	0.52 (0.16-1.73; 0.29)	0.73 (0.64-0.83; 0.007)	Overall
								0.45 (0.28-0.72; 0.001)
Huang et al[84], 2012, HR for survival, OR for others	10/1376	HIPEC	2.29 (0.66-9.63; 0.25)	6.74 (1.83-18.02; 0.003)	3.57 (1.49-8.67; 0.004)	1.04 (0.44-2.44; 0.10)	For HIPEC	Peritoneal recurrence 0.69 (0.36-1.33; 0.26)
		IPC + CH					0.60 (0.46-0.79; < 0.01)
		EPIC
		NIIC
Mi et al[82], 2013, RR	16/1906	HIPEC	NA	1.10 (0.53-2.29;0.8)	NA	0.86 (0.38-1.95;0.72)	5-yr	5-yr overall
							2.49 (1.97-3.14; < 0.00001)	0.47 (0.39-0.56; < 0.00001)
Coccolini et al[85], 2014, OR	12/2145	HIPEC	NA	1.82 (1.29-2.57; 0.0006)			3-yr	Peritoneal recurrence
		IPC + CH		Overall morbidity			0.31 (0.20-0.47; < 0.0001)
		EPIC						0.50 (0.37-0.68; < 0.0001)
		NIIC					5-yr
							0.89 (0.49-1.63; 0.71)

OR: Odds ratio; HR: Hazard ratio; RR: Relative risk; HIPEC: Hyperthermic intraperitoneal chemotherapy; IPC: Intraperitoneal chemotherapy; CH: Activated carbon particles; EPIC: Early postoperative intraperitoneal chemotherapy; NIIC: Normothermic intraoperative intraperitoneal chemotherapy; DPIC: Delayed postoperative intraperitoneal chemotherapy.

Table 3 Hyperthermic intraperitoneal chemotherapy in the treatment of established peritoneal carcinomatosis from gastric cancer

Ref.	Country	Type of study	No. of patients study arm control		Drug used for HIPEC, dose	Duration (min)	Complete cytoreduction	Morbidity	Mortality	Outcome
Fujimoto et al[66], 1990	Japan	Prospective	20 (surgery + HIPEC)	7 ( only surgery)	MMC 10 μg/mL	120	NA	NA	NA	6 mo survival: 94% vs 57%, P = 0.001
										2-yr: 45%
										Death due to Peritoneal recurrence: 10% vs 100%
Yonemura et al[91], 1991	Japan	Prospective	41	Nil	MMC 5 μg/mL	40-60		12%	0%	Median survival: 14.5 mo
					CDDP 30 μg/mL					3-yr: 28.5%
Yonemura et al[26], 1996	Japan	Prospective	83 (surgery + HIPEC)	Nil	MMC 30 mg	60	33.7%			5-yr survival (overall: 11%, CCR0/1: 17%, CCR2: 2%)
					CDDP 300 mg
					Etoposide 150 mg					Median survival CCR0: 13.9, CCR ≥ 1: 6.8 mo
Fujimoto et al[92], 1997	Japan	Prospective case-control	48 (surgery + HIPEC)	18 (only surgery)	MMC 10 μg/mL	120				1,3,5,8-yr survival (HIPEC vs control: 54% vs 11%, 42% vs 0%, 31% vs 0%, 25% vs 0%; P = 0.001)
										2, 4, 8-yr survival - P1, P2, P3 - 73%, 62%, 0%; 56%, 62%, 0%; 56%, 21%, 0% (P1 vs P3: P = 0.000524; P2 vs P3: P = 0.00329).
										Death due to peritoneal recurrence-HIPEC vs control 27% vs 94% (P = 7.077 × 100-7).
Glehen et al[94], 2004	France	Prospective	49 (CRS + HIPEC)	Nil	MMC 40-60 mg	90	10.2%	Overall - 27%	4%	Median survival (overall: 10.3 mo; CCR0/1 vs CCR2: 21.3 mo vs 6.6 mo, P < 0.001; Gilly Stage I/II PC vs stage III/IV PC: 19 mo vs 6.6 mo, P = 0.004)
								Extensive CRS - 47%
										5-yr survival (overall: 16%, CCR0/1: 29.4%, Gilly Stage I/II PC: 30%)
Hirose et al[75], 1999	Japan	Prospective case- control	17 (CRS +HIPEC)	20 (CRS alone)	MMC 20 mg	50	HIPEC vs control-	HIPEC vs control - 35.2 vs 20%	HIPEC vs control - 5.8% vs 0%	Median survival: HIPEC vs control: 11 mo vs 6 mo
					CDDP 100 mg					1-yr survival: HIPEC vs control: 44.4% vs 15.8%, P = 0.04
					Etoposide 100 mg		29.4% vs 15%
Hall et al[99], 2004	United States	Prospective case-control	34 (CRS +HIPEC)	40- no PC (only surgery)	MMC 40 mg	120	R0-21%	35%	0%	Median survival (CRS + HIPEC): Overall: 8 mo; R0/1 vs, R2: 11.2 mo vs 3.3 mo, P = 0.01
							R1-14%			2-yr survival - R0/1 vs, R2-45 vs 8%
Yonemura et al[95], 2005	Japan	Retrospective	42 (peritonectomy [P] + HIPEC)	65 (conventional surgery [C] + HIPEC)	MMC 30 mg	60	Overall 43.9%	Overall - 21.5%	Overall 2.8%	Median survival: Overall: 11 mo; CCR0: 15.5 mo; CCR ≥ 1: 7.9 mo (all patients);
					CDDP 300 mg		P + HIPEC 69% C + HIPEC 28%	P + HIPEC- 43%	P + HIPEC- 7%	CCR0: 19.2 mo; CCR ≥ 1: 7.8 mo (P + HIPEC patients)
					Etoposide 150 mg			C + HIPEC - 8%	C + HIPEC- 0%	5-yr survival: overall-6.7%; P + HIPEC-27%; CCR0: 13%, CCR ≥ 1%-2%
Scaringi et al[100], 2008	France	Retrospective	37 (26 with PC)	Nil	MMC 120 mg	60-90	30.7%	27% (all patients)	3.8%	Median survival:
					CDDP 200 mg/m2					CCR0 vs CCR2- 15 mo vs 3.9 mo, P = 0.007
										Gilly stage 1 and 2 vs 3 and 4: 15 mo vs 4 mo, P = 0.01
Glehen et al[96], 2010	France	Retrospective	159 (CRS + HIPEC and/or EPIC)	Nil	HIPEC:		56.0%	27.8%	6.5%	Median survival: overall: 9.2 mo, CCR0: 15 mo
					MMC 30-50 mg/m2± Cisplatin 50-100 mg/m2	60-120				5-yr survival: overall: 13%; CCR0: 23%
					Oxaliplatin 360-460 mg/m2± irinotecan 100-200 mg/m2± iv 5-FU and leucovorin
					EPIC:	30
					MMC 10 mg/m2	Day 1
					5-FU 600 mg/m2	Days 2-5
Yang et al[101], 2010	China	Prospective	28 (CRS + HIPEC)	Nil	MMC 30 mg	90-120	CCR0-39.2% CCR1-21.4%	14.3%	0%	2-yr survival - 43%
					CDDP 120 mg					Median survival (mo):
										PCI ≤ 20 vs PCI > 20-27.7 vs 6.4, P = 0.0001
										CCR0 vs CCR1 vs CCR2 and 3- 43 vs 9.5 vs 7.5, P = 0.001
Yang et al[97], 2011	China	Randomised controlled trial	34 (CRS + HIPEC)	34 (only CRS)	MMC 30 mg	60-90	58.8% each arm	HIPEC vs control - 14.7% vs 11.7%	Nil	Median survival (mo):
					CDDP 120 mg					HIPEC vs control- 11 vs 6.5, P = 0.04 (all pts)
										HIPEC vs control: 12 vs 6.5, P = 0.02 (synchronous PC)
										1,2 3-yr survival (HIPEC vs control):
										41.2 vs 29.4%, 14.7 vs 5.9%, 5.9% vs 0%
Magge et al[102], 2014	United States	Prospective	23 (CRS + HIPEC)	Nil	MMC 40 mg	100	95.6%	52%	4.3%	Median survival: 9.5 mo
										3-yr survival: 18%

MMC: Mitomycin C; CDDP: Cisplatin; CCR: Cytoreductive score; 5-FU: 5-fluorouracil; HIPEC: Hyperthermic intraperitoneal chemotherapy; CRS: Cytoreductive surgery; MMC: Mitomycin-C.