Advancing gastric cancer treatment: A comprehensive review of hyperthermic intraperitoneal chemotherapy’s role and outcomes

Table 1 Therapeutic use of hyperthermic intraperitoneal chemotherapy, randomized controlled trials: Study and population characteristics

Year	Ref./trial	Arms	Patients cohort	Oncologic exclusion criteria	CY+	PCI	Ascites	Liver mets	Lung mets	Syncronous/metachronous (PM/CY+)
2011	Yang et al[27]	Arm 1: CRS-A (n = 34). Arm 2: CRS-H (n = 34)	68	Any lung metastasis, liver metastasis, prominent retroperitoneal lymph node metastasis	ND	CRS-H arm: 2-36 (median: 15). CRS-A arm: 3-23 (median: 15)	ND	No	No	Synchronous [PM (n = 51)], metachronous [PM (n = 17)]
2014	Rudloff/GYMSSA	Arm 1: FOLFOXIRI alone arm-S. Cht (n = 8). Arm 2: GYMS arm— CRS-H + S. Cht (n = 9)	17	Disease sites other than either peritoneum, lung or liver. Evidence of extensive para-aortic/retro-pancreatic lymph node metastases. Significant ascites	Yes	GYMS arm: PCI ≤ 20, n = 8/9 (89%); PCI = 21, n = 1/9 (11%)	No	Yes	Yes	Synchronous [PM (n = 14); CY+ (n = 1)], metachronous [PM (n = 2)]
2023	Rau/GASTRIPEC-I	Arm 1: CRS-A (n = 53). Arm 2: CRS-H (n = 52)	105	Further distant metastases except Krukenberg tumors. Pretreated with chemotherapy/radiotherapy	No	PCI ≥ 7 (44%)	Yes (40%)	No	No	Synchronous [PM (n = 105)]

CRS-A: Cytoreductive surgery alone; CRS-H: Cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy; CY+: Positive peritoneal cytology; GYMS: Hyperthermic intraperitoneal chemotherapy + systemic FOLFOXIRI; ND: Not declared; PCI: Peritoneal cancer index; PM: Peritoneal metastases; S. Cht: Systemic chemotherapy.

Table 2 Therapeutic use of hyperthermic intraperitoneal chemotherapy, controlled trials: Study and population characteristics

Year	Ref./trial	Controlled trial phase	Patient cohort	Positive peritoneal cytology	PCI	Median PCI	Ascites	N stage	Syncronous metastasis only
2020	Blum Murphy et al[31]	1	27	Yes	< 8 (52%), 8-14 (15%), 15-21 (11%), > 21 (22%)	6	Admitted (41%)	ND	Yes
2020	Yu et al[30]	2	38	Yes	≤ 20 (100%)	8.8	Admitted	72.2% ypN+ (convertion to surgery group)	Yes
2020	PERISCOPE 1	1 and 2	25	Yes	< 7 (100%)	2	ND	68% ypN+	Yes1
2021	Badgwell et al[35]	2	20	Yes	0 (40%), 1-2 (35%), > 3 (25%)	ND	ND	70% ypN+	Yes
2023	Green et al[34]	2	41	Yes	≤ 10 (100%)	2	Excluded if > 500 cc	68% ypN+	Yes

¹Small bowel or mesenteric localizations were excluded.

All patients have peritoneal metastases or positive peritoneal cytology and no liver or lung metastasis. ND: Not declared; PCI: Peritoneal cancer index.

Table 3 Therapeutic use of hyperthermic intraperitoneal chemotherapy, randomized controlled trials: Treatments and outcomes

Year	Ref./trial	Hyperthermic intraperitoneal chemotherapy protocol	Completeness of cytoreduction score (CC 0-1)	Neodjuvant Cht	Neoadjuvant treatment regimen	Adjuvant Cht	Adjuvant treatment regimen	Median OS (month)	1 year OS	2 years OS	3 years OS	Median relapse-free survival (month)
2011	Yang et al[27]	Cisplatin 120 mg + mitomycin C 30 mg for 60-90 minutes	CRS-A: 58.8% (20 of 34), CRS-H: 58.8% (20 of 34)	No	No	Yes	ND	CRS-A: 6.5 months vs CRS-H: 11.0 months	CRS-A: 29.4% vs CRS-H: 41.2%	CRS-A: 5.9% vs CRS-H: 14.7%	CRS-A: 0% vs CRS-H: 5.9%	ND
2014	Rudloff/GYMSSA	Oxaliplatin 460 mg/m2 for 30 minutes. Prior to perfusion: 5-fluorouracil 400 mg/m2 IV and leucovorin 20 mg/m2 IV	CRS-H: 88.8% (8 of 9)	Yes. GYMS arm (n = 6/9), SA arm (n = 7/8)	ND	Yes	FOLFOXIRI	SA arm: 4.3 months vs GYMS arm: 11.3 months	SA arm: 0% vs GYMS arm: 44%	SA arm: 0% vs GYMS arm: 22%	SA arm: 0% vs GYMS arm: 22%	ND
2023	Rau/GASTRIPEC-I	Mitomycin C 15 mg/m2 + cisplatin 75 mg/m2 for 60 minutes	CRS-A: 41.5% (22 of 53), CRS-H: 53.8% (28 of 52)	Yes (all)	HER-2+: Cisplatin, capecitabine, trastuzumab; HER-2-: Epirubicin, oxaliplatin, capecitabine	Yes	HER-2+: Cisplatin, capecitabine, trastuzumab; HER-2-: Epirubicin, oxaliplatin, capecitabine or fluorouracil, leucovorin, oxaliplatin, and docetaxel	CRS-A: 14.9 months vs CRS-H: 14.9 months	CRS-A: 60.5% vs CRS-H: 58.2%	CRS-A: 15.4% vs CRS-H: 25.5%	CRS-A: 0% vs CRS-H: 13.6%	CRS-A: 3.5 months vs CRS-H: 7.1 months

CRS-A: Cytoreductive surgery alone; CRS-H: Cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy; Cht: Chemotherapy; GYMS: Hyperthermic intraperitoneal chemotherapy + systemic FOLFOXIRI; HER-2: Human epidermal growth factor receptor 2; ND: Not declared; OS: Overall survival; SA: FOLFOXIRI alone.

Table 4 Therapeutic use of hyperthermic intraperitoneal chemotherapy, controlled trials: Treatments and outcomes (all patients received neoadjuvant systemic chemotherapy)

Year	Ref./trail	Patient cohort	S. Cht protocol	S. Cht cycles	N-HIPEC	Laparoscopic N-HIPEC	N-HIPEC protocol	N-HIPEC cycles	Convertion to surgery	T-HIPEC protocol	NIPEC	Adjuvant HIPEC bed site	OS media	1 year OS	2 years OS	3 years OS	Relapse-free survival media (month)
2020	Blum Murphy et al[31]	27	5-FU/OX (n = 24%-89%), 5-FU/OX/Pacli (n = 3%-11%)	9 (range 4-24)	Yes	27 patients	Mitomycin C (30 mg) + cisplatin (200 mg). Paclitaxel (dosing was started at 20 mg/m2 and sequentially increased up to 60 mg/m2)	1	CRS-H (6/27), CRS-A (1/27) 25.9%	ND	No	No	ND	73.9%	58.1%	ND	ND
2020	Yu et al[30]	38	Pacli + S1 (Transtuzumab added in HER-2+)	4	Yes	No	Paclitaxel (75 mg/m2) for 60 minutes	2	18 (47.4%)	Paclitaxel (75 mg/m2) for 60 minutes	No	Yes (twice within 72 hours after CRS)	Conversion therapy group 21.1 months	63.2%	47.40%	ND	ND
2020	Koemans/PERISCOPE 1	25	Epirubicin + cisplatin + capecitabin (n = 10), docetaxel + oxaliplatin + capecitabin (n = 7), capecitabin + oxaliplatin (n = 3), 5-FU/OX (n = 2), capecitabin + oxaliplatin (n = 3), Transtuzumab added in HER-2+	3	No	No	No	No	No	Oxaliplatin (460 mg/sm) for 30 minutes	Docetaxel for 90 minutes in a dose-level escalation scheme (0, 50, 75 mg/m2)	No	15 months	ND	ND	ND	12 months
2021	Badgwell et al[35]	20	5-FU+ OX (n = 17/20), Triplet therapy (n = 3/20)	< 8 (20%), 8-10 (75%), > 10 (5%)	Yes	20 patients	Mitomycin C (30 mg) + cisplatin (200 mg) for 60 minutes	2 (n = 5/20), 1 (n = 15/20)	No	Mitomycin C (30 mg) + cisplatin (200 mg) for 60 minutes	No	No	22.1 months	90%	50%	28%	ND
2023	Green et al[34]	41	Fluoruracil, leucovorin, oxaliplatin (56%), fluorouracil, leucovorin, oxaliplatin, and docetaxel (24%), radiotherapy (17%)	ND	Yes	23 patients	Cisplatin (90 mg/mq) + mitomycin C (10 mg/mq or 30 mg/mq) for 60 minutes	1 or 2	No	Cisplatin (90 mg/mq) + mitomycin C (10 mg/mq) for 60 minutes	No	No	24.9 months	ND	ND	25%	7.4 months

CRS: Cytoreductive surgery; HER-2: Human epidermal growth factor receptor 2; HIPEC: Hyperthermic intraperitoneal chemotherapy; ND: Not declared; OS: Overall survival; OX: Oxaliplatin; S. Cht: Systemic chemotherapy; 5-FU: 5-fluorouracil.

Table 5 Prophylactic use of hyperthermic intraperitoneal chemotherapy, randomized controlled trials: Study and population characteristics, treatments and outcomes

Year	Ref.	State	Arms	Patient cohort	HIPEC sample	Oncological admission criteria (TNM stage)	Bedsite HIPEC	HIPEC protocol	Neoadjuvant CHT	Neoadjuvant treatment regimen	Adjuvant Cht	Adjuvant treatment regimen
2014	Cui et al[36]	China	Arm 1: Surgery alone (n = 48). Arm 2: Neoadjuvant Cht + surgery (n = 48). Arm 3: Surgery + postoperative HIPEC (n = 48). Arm 4: Neoadjuvant Cht + surgery + postoperative HIPEC (n = 48)	192	Arm 3 + 4: n = 98	IIIA-IIIC + no Neoadjuvant Cht before enrollement	Yes	Day 1 and 4: 60 mg/m2 cisplatin, 90 minutes. Day 2 and 3: 0.75 g fluorouracil, 90 minutes +1000 cc of perfusate left in place for 23 hours at the end of each cycle	Yes	Paclitaxel, cisplatin, tegafur	Yes, if tumor progression occurred during neodjuvant treatment	Epirubicin, cisplatin, fluorouracil
2019	Reutovich et al[37]	Belarus	Arm 1: Gastrectomy + HIPEC (n = 76). Arm 2: Gastrectomy only (n = 78)	154	76	IIB-IIIC + Borrmann type III-IV	No	Cisplatin 50 mg/m2 + doxorubicin 50 mg/m2, 60 minutes closed abdomen	No	_	No	Not declared
2021	Fan et al[38]	China	Arm 1: S.Cht (n = 17). Arm 2: T-HIPEC + adjuvant S.Cht (n = 33)	50	33	IIIA-B	No	Cisplatin (50 mg/L), 30 minutes	No	_	Yes	S1 + oxaliplatin
2022	Liu et al[39]	China	4 weeks after D2 gastrectomy: Arm 1: Bedside HIPEC + oral S1 treatment; arm 2: IV cisplatin + oral S1 treatment	114	57	III A-B	Yes	Day 1 and 3: Cisplatin (30 mg/m2) + oral S1, (40-60 mg for 14 days)	No	_	Yes	6-8 cycles of IV cisplatin (60 mg/m2) + oral S1 (40-60 mg, 2/day)
2023	Yu et al[40]	China	Arm 1: HIPEC + Cht. Arm 2: Systemic chemotherapy alone	134	67	IIIA and B + no Neoadjuvant Cht before enrollement	Yes	Cisplatin (40 mg/m2), 60 minutes, 2 cycles within 72 hours after surgery	No	_	Yes	6-8 cycles of S1 + oxaliplatin

Cht: Chemotherapy; HIPEC: Hyperthermic intraperitoneal chemotherapy; T-HIPEC: Traditional hyperthermic intraperitoneal chemotherapy; S. Cht: Systemic chemotherapy.

Table 6 Prophylactic use of hyperthermic intraperitoneal chemotherapy, randomized controlled trials: Studies outcomes

Year	Ref.	State	Arms	Median OS	1 year OS	3 years OS	Median RFS	RFS 2 years	RFS 3 years	Peritoneal recurrence
2014	Cui et al[36]	China	Arm 1: Surgery alone (n = 48). Arm 2: Neoadjuvant Cht + surgery (n = 48). Arm 3: Surgery + postoperative HIPEC (n = 48). Arm 4: Neoadjuvant Cht + surgery + postoperative HIPEC (n = 48)	Arm 1: 27 months. Arm 2: 33 months. Arm 3: 32 months. Arm 4: 36 months	Arm 1: 79.2%. Arm 2: 87.5%. Arm 3: 85.4%. Arm 4: 93.7%	Arm 1: 35.4%. Arm 2: 62.5%. Arm 3: 58.3%. Arm 4: 75.0%	Arm 1: 26 months. Arm 2: 28 months. Arm 3: 31 months. Arm 4: 33 months	Arm 1: 66.7%. Arm 2: 77.1%. Arm 3: 83.3%. Arm 4: 87.5%	ND	ND
2019	Reutovich et al[37]	Belarus	Arm 1: Gastrectomy + HIPEC (n = 76). Arm 2: Gastrectomy only (n = 78)	ND	ND	ND	Arm 1: 28 months vs arm 2: 13 months	ND	Arm 1: 47% vs arm 2: 27%	12.8% vs 27.6%
2021	Fan et al[38]	China	Arm 1: S. Cht (n = 17). Arm 2: Traditional-HIPEC + adjuvant S. Cht (n = 33)	ND	ND	Arm 1: 100% vs arm 2: 87.9%	ND	ND	Arm 1: 88.2% vs arm 2: 84.8%	ND
2022	Liu et al[39]	China	4 weeks after D2 gastrectomy: Arm 1: Bedside HIPEC + oral S-1 treatment; arm 2: IV cisplatin + oral S-1 treatment	Arm 1: 42 months vs arm 2: 31 months	ND	ND	Arm 1: 29 months vs arm 2: 15 months	Arm 1: 50.4% vs arm 2: 25.5%	ND	0% vs 7%
2023	Yu et al[40]	China	Arm 1: HIPEC + Cht. Arm 2: Systemic chemotherapy alone	51.4 months	ND	Arm 1: 73.9% vs arm 2: 77.6%	ND	ND	Arm 1: 73.8% vs arm 2: 61.2%	20.9% vs 40.3%

Cht: Chemotherapy; HIPEC: Hyperthermic intraperitoneal chemotherapy; ND: Not declared; OS: Overall survival; RFS: Relapse-free survival; S. Cht: Systemic chemotherapy.