Prognostic value and adverse events of cytoreductive surgery with hyperthermic intraperitoneal chemotherapy in primary advanced and platinum-sensitive recurrent epithelial ovarian cancer: a systematic review and meta-analysis

Figures & data

Figure 1. PRISMA guided flow diagram of study selection for inclusion in this review and meta-analysis.

Figure 2. Funnel plot of studies evaluating the publication bias of PFS and OS between HIPEC and No-HIPEC.

Table 1. The characteristics of the included studies. CRS + HIPEC vs CRS.

Study cohort	Study design	Year	Study region	NO. of patients	Age(years) (median, range) or (mean, SD)	Primary /Recurrent	Stage	Outcome	NACT	Operation	Postoperative chemotherapy	NOS score	PCI score	Cytoreduction	HIPEC regime	HIPEC °C	HIPEC duration	HIPEC times
Bae et al.^a	Retrospective cohort study	2007	South Korea	44/24	50.1 ± 12.4/ 49.5 ± 8.6/ 50.0 ± 11.7	Primary	IIIa–IIIc	OS/PFS/AE	–	PDS	Single; combination chemotherapy	8	NR	Residual mass ≥1cm 10 (22.2%)/9 (40.9%)/9 (31.0%); <1 cm 35 (77.8%)/13 (59.1%)/20 (69.0%)	carboplatin (350mg/m^2); paclitaxel (175 mg/m^2)	43 °C–45 °C	90 min	1
Cascales -Campos et al.	Retrospective cohort study	2014	Spain	52/35	57 (29–73)	Primary	IIIc–IV	PFS/AE	Platinum and taxanes, 3–4 cycles	PDS/IDS	platinum and taxanes, 6–8 cycles	7	9 (3–26)/ 6 (3–16), p < .01	NR	Paclitaxel (60 mg/m^2)	42 °C	90 min	1
Ceresoli et al.	Retrospective case-control study	2018	Italy	28/28	58.99/61.55	Primary	IIIc–IV	OS/PFS/AE	carboplatin and paclitaxel	IDS	NR	6	8.25 (6.79)/6.36 (6.19)	CC0: 23 (92.9)/23 (92.9); CC1: 1 (3.6)/1 (3.6)	cisplatin (100 mg/m^2) and paclitaxel (175 mg/m^2)	41.5 °C	90 min	1
Gori et al.	retrospective study	2005	Argentina	29/19	55.5	Primary	IIIc–IVb	OS	–	PDS	cisplatin (75–100 mg/m^2), 6 cycles and cyclophosphamide (600 mg/m^2)	6	NR	Complete /Optimal(<2 cm) cytoreduction	cisplatin (100 mg/m^2)	>42 °C	60 min	1
Jou et al.	Retrospective cohort study	2020	US	20/48	21–83	Primary	IIIc–IVb	OS/PFS/AE	Carboplatin and paclitaxel; carboplatin and taxotere; carboplatin, paclitaxel and bevacizumab; other, 3–6 cycles	IDS	Carboplatin and paclitaxel; carboplatin and taxotere; carboplatin, paclitaxel and bevacizumab; other, 3–6 cycles	8	17.5 (17.9), 0–34/N/A	CC0–1: 20/36 (75.0%); CC2: 0/12 (25.0%)	NR	NR	NR	NR
Lei et al.	Retrospective cohort study	2020	China	425/159	55.0 (10.5)	Primary	III	OS/AE	–	PDS	NR	8	NR	Residual mass ≤1 cm 312 (73.4)/109 (68.6); >1 cm 113 (26.6)/50 (31.4)	Cisplatin (50 mg/m^2)	43 °C	60 min	SD = 2.8(0.8)
Mendivil et al.	Retrospective case-control study	2017	US	69/69	59.8 (11.3) /62.9 (10.5)	Primary	IIIa–IV	OS/PFS	11 (15.9)/17 (24.6)	PDS/IDS	Paclitaxel (80 mg/m^2) and carboplatin (AUC 6), 6 cycles	7	NR	Optimal cytoreduction 69/64 (92.7); Sub-optimal 0/5 (7.3)	Carboplatin (AUC 10)	41.5 °C	90 min	1
van Driel et al.	RCT	2018	Netherlands	122/123	61 (55–66) /63 (56–66)	Primary	III	OS/PFS/AE	Carboplatin (AUC 5–6) and paclitaxel (175 mg/m^2), 3 cycles	IDS	Carboplatin and paclitaxel, 3 cycles	6^c	NR	R1–R2: 119 (98%)/120 (98%)	Cisplatin (100 mg/m^2)	40 °C	90 min	1
Lim et al.	RCT	2022	South Korea	92/92	52.0 (46–59.5) /53.5 (47.5–61.0)	Primary	III–IV	OS/PFS/AE	Carboplatin (AUC 5) and paclitaxel (175 mg/m^2), 3 cycles/-	PDS/IDS	Paclitaxel and carboplatin, 6 cycles	8^c	0–5, 22 (23.9)/29 (31.5); 6–10, 70 (76.1)/63 (68.5)	Residual tumor <1 cm	Cisplatin (75 mg/m^2)	41.5 °C	90 min	1
Gruner et al.	Retrospective study	2021	US	21/40	63.1 ± 9.2 /66.3 ± 9.5	Primary	III–IV	PFS/EA	NR	IDS	NR	7	NR	Residual tumor <1 cm	NR	NR	NR	NR
He et al.	Retrospective study	2021	China	121/76	58.38 (10.89) /55.20 (10.87)	Primary	III	OS/PFS/AE	Carboplatin (AUC 5–6) and paclitaxel (175 mg/m^2), 2–4 cycles	IDS	Paclitaxel (175 mg/m^2) and carboplatin (AUC 5–6,) 3–4 cycles	7	NR	Optimal (R0 + R1) 113 (93.4)/70 (92.1); Sub-optimal (residual disease >1 cm) 8 (6.6)/6 (7.9)	cisplatin (60 mg/m^2)	42 °C–43 °C	60 min	3 (day 1/3/5)
Antonio et al.	RCT	2022	Spain	36/35	NR	Primary	III–IV	OS/PFS	Carboplatin (AUC 5) and paclitaxel (175 mg/m^2), 3–4 cycles	IDS	Carboplatin (AUC 5) and paclitaxel (175 mg/m^2), 6 cycles	6^c	NR	optimal-complete	Carboplatin AUC 5 and paclitaxel (175 mg/m^2)	42 °C	60 min	1
Baiocchi et al.	Retrospective cohort study	2016	Brazil	29/50	30–80	Recurrent	III–IV	OS/PFS	–	SCR	NR	7	≤6, 15 (51.7)/24 (53.3); >6, 14 (48.3)/21 (46.7); Missing 0/5	CC0–1 27: (93.1)/42 (87.5); CC2–3: 2 (6.8)/6 (12.5); Missing 0/2	Mitomycin C (10 mg/m^2) and cisplatin (50 mg/m^2) /cisplatin(50 mg/m^2) and doxorubicin /cisplatin alone (50 mg/m^2) /oxaliplatin alone	41 °C–42 °C	Over 90 min	1
Cascales -Campos et al.	Retrospective cohort study	2015	Spain	32/22	56.4 ± 10.8 /57.4 ± 9.7	Recurrent	I–II 7/9; III–IV 25/13	PFS/AE	NR	SCR	Paclitaxel (175 mg/m^2) and carboplatin (AUC 6), 6 cycles	6	8 (2–23)/4 (2–16), p =.001	NR	Paclitaxel (60 mg/m^2)	42 °C	90 min	1
Fagotti et al	Prospective case control study	2012	Italy	30/37	51 (41–63)/55 (32–69)	Recurrent	I–II 4/5; III–IV 26/32	OS/PFS	–	SCR	Platinum-based chemotherapy	6	NR	CC0: 29 (96.7%)/37; CC1: 1(3.3%)/0	Oxaliplatin (460 mg/m^2)	41.5 °C	30 min	1
Le Brun et al.	Retrospective case-control study	2014	France	23/19	>55 years 16/13	Recurrent	I–II 2/1; III–IV 21/18	OS	Platinum-based second-line chemotherapy, 6 cycles	SCR	NR	7	NR	Complete secondary surgery, CC0	Cisplatin, Eloxatin or mitomycin	42 °C	Cisplatin 60 min; Eloxatin and mitomycin 30 min	1
Munoz et al	Retrospective study	2009	Spain	12/14	54/54	Recurrent	NR	OS	–	SCR	Cisplatin (75 mg/m^2) or carboplatin (AUC 5–6), combined with paclitaxel (175 mg/m^2), 6 cycles	7	NR	Residual tumor ≤1 cm	Paclitaxel (60 mg/m^2)	41 °C–43 °C	Over 60 min	1
Spiliotis et al.^b	RCT	2015	Greece	60/60	58.3/58.1	Recurrent	IIIc 41/35; IV 19/25	OS	–	SCR	NR	4^c	<5, 7(11.7%)/8(13.3%); ≥5, <10, 24(40%)/22(36.7%); ≥10, 29(48.3%)/30(50%)	CC0 39(65%)/33(55%); CC1 12(20%)/20(33.3%); CC2 9(15%)/7(11.7%)	PS cisplatin (100 mg/m^2) and paclitaxel (175 mg/m^2); PR doxorubicin (35 mg/m^2) and paclitaxel (175  mg/m^2) /mitomycin (15 mg/m^2)	42.5ºC	60 min	1
Zivanovic et al.	RCT	2021	US	49/49	NR	Recurrent	NR	PFS/OS	–	SCR	Carboplatin-based chemotherapy	3^c	NR	NR	Carboplatin (800 mg/m^2)	NR	90 min	1
Charo et al	Retrospective study	2020	US	152/20014	NR	NR	NR	AE	NR	NR	NR	5	NR	NR	NR	NR	NR	NR
Ghirardi et al.	Retrospective study	2020	Italy	52/51	58 (28–69) /59 (40-70)	Primary	IIIC 34/26 IVA 4/5 IVB 14/20	AE	Carboplatin only; Carboplatin-paclitaxel; carboplatin-paclitaxel and bevacizumab; Carboplatin-paclitaxel, bevacizumab, and immunotherapy	IDS	NR	8	NR	NR	Cisplatin (100 mg/m^2)	41 °C	90 min	1

NR: not report; SD: Standard Deviation; OS: Overall Survival; PFS: Progression Free Survival; PDS: Primary Cytoreductive Surgery; IDS: Interval Cytoreductive Surgery; SCR: Secondary Cytoreductive Surgery; NACT: neoadjuvant chemotherapy; IP: intraperitoneal; PCI: peritoneal cancer index; CC: completeness of cytoreduction score; CC0: no macroscopic tumor visible; CC1: largest residual tumor ≤2.5 mm; CC2: largest residual tumor >2.5 mm and ≤2.5 cm; CC3: largest residual tumor >2.5 cm; Residual disease after surgery, R-1: no visible tumor, complete cytoreduction; R-2a: tumor nodules ≤2.5 mm; R-2b: tumor nodules >2.5 mm and ≤10 mm; Suboptimal (incomplete) cytoreduction: residual tumor >1 cm; –: not performed; min: minutes; PS: Platinum sensitive; PR: Platinum resistance; AE: adverse events.

HIPEC-carboplatin and HIPEC-paclitaxel group was separately analyzed for PFS and OS. Platinum-sensitive relapse was included and platinum-resistance relapse was excluded from the analysis of OS.

^aThe outcome of HIPEC-carboplatin and HIPEC- paclitaxel was dividually evaluated.

^bOnly the PS patients were included in the final assessment.

^cJadad score.

Figure 3. Forest plots showing the effect of HIPEC on the survival of EOC.

Table 2. Meta-analysis estimates of adverse events between HIPEC and No-HIPEC.

Category	HIPEC	No HIPEC	OR (95%)	p value	I^2(%)
Procedure-related complications	28/180	1483/20042	1.93 [1.24, 3.01]	<.01	0
Intraoperative complication
Any grade	11/52	17/51	0.54 [0.22, 1.30]	.17	/
III–IV grade	3/20	1/48	8.29 [0.81, 85.26]	.08	/
Postoperative complications
Any grade	36/52	25/51	2.34 [1.05, 5.23]	.04	/
III–IV grade	22/72	9/99	7.04 [0.23, 214.75]	.26	91
Individual adverse events
III–IV grade	141/335	124/291	1.21 [0.80, 1.83]	.36	0
Ostomies	4/84	1/57	2.10 [0.32, 13.77]	.44	0
Intra-abdominal bleeding
Any grade	5/631	11/355	0.31 [0.11, 0.86]	.02	0
III–IV grade	2/547	1/282	1.06 [0.13, 8.60]	.96	0
Pleural effusion	28/477	8/210	1.55 [0.70, 3.46]	.28	0
Thromboembolic event	29/781	14/490	1.65 [0.87, 3.13]	.13	0
Infection (Incisional and abdominal infection)
Any grade	100/944	785/20468	1.04 [0.54, 1.99]	.91	70
III–IV grade	42/780	32/498	1.38 [0.48, 3.99]	.55	54
III–IV grade abdominal infection	5/20	0/48	34.42 [1.80, 658.27]	.02	/
Ileus
Any grade	55/827	44/479	0.95 [0.61, 1.47]	.82	42
III–IV grade	26/355	17/339	1.42 [0.75, 2.68]	.28	0
Blood transfusion	56/105	45/97	1.59 [0.89, 2.85]	.12	49
Cardiotoxicity
Any grade	58/639	55/374	0.97 [0.50, 1.89]	.93	27
III–IV grade	3/567	2/330	1.79 [0.30, 10.53]	.52	6
Pulmonary event (hypoxia, expiratory distress, Dyspnea, and ARDS)
Any grade	94/671	89/396	1.01 [0.65, 1.55]	.98	20
III–IV grade	16/639	7/374	2.10 [0.85, 5.21]	.11	0
Pulmonary infection
Any grade	55/547	19/282	1.15 [0.66, 2.01]	.61	0
III–IV grade	1/547	2/282	0.40 [0.06, 2.86]	.36	0
Gastrointestinal events
Nausea	468/760	229/450	1.50 [1.02, 2.20]	.04	51
Vomiting	344/760	157/450	1.06 [0.47, 2.39]	.89	88
Diarrhea	97/639	63/374	1.22 [0.83, 1.78]	.32	0
Constipation	76/639	84/374	0.68 [0.47, 0.99]	.04	0
Hematologic events
Anemia
Any grade	536/827	265/479	1.01 [0.47, 2.18]	.97	61
III–IV grade	141/760	73/450	1.15 [0.58, 2.25]	.69	50
Leukopenia	341/705	137/356	1.80 [1.33, 2.44]	<.01	48
Neutropenia	312/517	127/251	1.62 [1.18, 2.21]	<.01	0
Thrombocytopenia	147/705	62/356	1.33 [0.95, 1.88]	.10	3
Electrolyte disturbance
Any grade	510/760	209/450	2.13 [0.69, 6.55]	.19	88
III–IV grade	199/760	62/450	3.49, [2.34, 5.19]	<.01	0
Hypoalbuminemia
Any grade	413/425	140/159	4.67 [2.21, 9.87]	<.01	/
I–II grade	381/425	123/159	2.53 [1.56, 4.12]	<.01	/
III–IV grade	15/425	3/159	1.90 [0.54, 6.66]	.31	/
Abdominal pain
Any grade	250/668	157/358	0.90, [0.58, 1.38]	.62	52
III–IV grade	12/668	10/358	0.80, [0.34, 1.88]	.60	0
Neurotoxicity	127/639	116/374	1.10 [0.72, 1.68]	.67	0

I² = /, only one study was included.

Data availability statement

Data availability is not applicable to this article as no new data were created or analyzed in this study.