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EJSO xx (2015) 1e12 www.ejso.com

Review
Hyperthermic intraperitoneal chemotherapy (HIPEC) and
cytoreductive surgery (CRS) in ovarian cancer:
A systematic review and meta-analysis
Y.R. Huo a,b, A. Richards b, W. Liauw c, D.L. Morris a,b,*
a
Department of Surgery, St George Hospital, University of New South Wales, Kogarah, Sydney, NSW 2217,
Australia
b
St George Clinical School, University of New South Wales, Sydney, NSW, Australia
c
Cancer Care Centre, St George Hospital, Kogarah, Sydney, NSW 2217, Australia
Accepted 24 August 2015
Available online - - -

Abstract

Purpose: Emerging evidence suggests that hyperthermic intraperitoneal chemotherapy (HIPEC) with cytoreductive surgery (CRS) shows a
survival benefit over CRS alone for patients with epithelial ovarian carcinoma (EOC). This systematic review and meta-analysis will assess
the safety and efficacy of HIPEC with CRS for EOC.
Design: Searches of five databases from inception to 17/02/15 was performed. Clinical outcomes were synthesised, with full tabulation of
results.
Results: A total of 9 comparative studies and 28 studies examining HIPEC þ CRS for primary and/or recurrent EOC were included. Meta-
analysis of the comparative studies showed HIPEC þ CRS þ chemotherapy had significantly better 1-year survival compared with
CRS þ chemotherapy alone (OR: 3.76, 95% CI 1.81e7.82). The benefit of HIPEC þ CRS continued for 2-, 3-, 4-, 5- and 8-year survival
compared to CRS alone (OR: 2.76, 95% CI 1.71e4.26; OR: 5.04, 95% CI 3.24e7.85; OR: 3.51, 95% CI 2.00e6.17; OR: 3.46 95% CI
2.19e5.48; OR: 2.42, 95% 1.38e4.24, respectively). Morbidity and mortality rates were similar. Pooled analysis of all studies showed
that among patients with primary EOC, the median, 1-, 3-, and 5-year overall survival rates are 46.1 months, 88.2%, 62.7% and 51%.
For recurrent EOC, the median, 1-, 3-, and 5-year overall survival rates are 34.9 months, 88.6%, 64.8% and 46.3%. A step-wise positive
correlation between completeness of cytoreduction and survival was found.
Conclusion: The addition of HIPEC to CRS and chemotherapy improves overall survival rates for both primary and recurrent EOC.
Ó 2015 Elsevier Ltd. All rights reserved.

Keywords: HIPEC; Hyperthermic intraperitoneal chemotherapy; CRS; Cytoreductive surgery; Ovarian cancer; Meta-analysis; Review

Introduction chemotherapy, more than half of the patients will recur.1,2

The optimal treatment of primary and recurrent epithe-
lial ovarian cancer (EOC) still remains an open and critical
question. In fact, despite the availability of a standard treat-
ment at the time of diagnosis, consisting of optimal cytor-
eduction followed by platinum-based intravenous
* Corresponding author. Level 3, Pitney Building, St George Hospital,
UNSW Department of Surgery, Kogarah, NSW 2217, Australia.
Tel.: þ61 2 9350 2070; fax: þ61 2 9113 3997.
E-mail address: david.morris@unsw.edu.au (D.L. Morris).
Considering the high and fairly constant rate of recurrent
disease in women with EOC, identification of the best treat-
ment to prolong the time to progression and extend overall
survival whilst maintaining the patient’s quality of life
(QoL) is one of the main objectives for gynaecologic oncol-
ogists. Areas of controversy in relation to the standard of
care include the optimal chemotherapy schedule, the timing
and extent of cytoreductive surgery in relation to systemic
therapy, the role of intraperitoneal chemotherapy and the
use of bevacizumab.

http://dx.doi.org/10.1016/j.ejso.2015.08.172
0748-7983/Ó 2015 Elsevier Ltd. All rights reserved.

Please cite this article in press as: Huo YR, et al., Hyperthermic intraperitoneal chemotherapy (HIPEC) and cytoreductive surgery (CRS) in ovarian cancer:
A systematic review and meta-analysis, Eur J Surg Oncol (2015), http://dx.doi.org/10.1016/j.ejso.2015.08.172
2 Y.R. Huo et al. / EJSO xx (2015) 1e12
As EOC remains largely restricted to the abdominal cav-
ity for most of its natural history, administering chemo-
therapy directly into the peritoneal cavity is especially
attractive. Intraperitoneal chemotherapy allows for a
much higher concentration in the peritoneal tumours due
to direct diffusion of the drug from the peritoneal cavity
compared to intravenous chemotherapy, thereby improving
cytotoxicity whilst minimising systemic adverse effects.3
The result of the GOG 172 study showed that following
optimal surgical reduction, intraperitoneal chemotherapy
with intravenous chemotherapy was associated with a
longer median overall survival than intravenous chemo-
therapy alone (65.6 versus 49.7 months with a 21.6%
reduction in death).4 The 10 year follow-up also showed
the risk of death decreased by 12% for each cycle of intra-
peritoneal chemotherapy completed (adjusted HR: 0.88,
95% CI 0.83e0.94).5 Furthermore, a recent meta-analysis
found each 10% increase in the proportion of patients
receiving intraperitoneal chemotherapy was associated
with a significant and independent 3.9-month increase in
median cohort survival time.6 Despite these survival bene-
fits, intraperitoneal chemotherapy hasn’t been widely adop-
ted. This is likely due to toxicity and tolerability issues, as
more than half of the patients have difficulty completing all
six cycles of intraperitoneal chemotherapy.4
Hyperthermic intraperitoneal chemotherapy (HIPEC)
may overcome the problems associated with repetitive intra-
peritoneal chemotherapy administration. In HIPEC, heated
chemotherapy (37e43  C) is perfused into the abdomen
intra-operatively, directly following primary or interval
CRS, or as consolidation therapy at the end of standard ther-
apy following CRS and 6 cycles of chemotherapy.7 In addi-
tion to maintaining the beneficial effects of intraperitoneal
delivery of cytotoxic drugs, the hyperthermia targets heat-
sensitive tumour cells and enhances cancer cell necrosis
and apoptosis.8 HIPEC plus CRS has been shown to improve
the prognosis of peritoneal carcinomatosis for gastric can-
cer,9,10 mesothelioma,11 colorectal cancer12 and pseudomyx-
oma peritonei.13 However, the role of HIPEC plus CRS in the
management of primary and recurrent EOC is immature,14
with the first randomised controlled trial (RCT) recently pub-
lished. The RCT showed HIPEC plus CRS showed a survival
benefit over CRS alone for recurrent EOC.15
This study aims to provide a meta-analysis and systematic
review of the current scientific literature available on the use
of HIPEC þ CRS for primary and recurrent EOC. This study
will evaluate the overall survival, disease free survival and
complication rates, as well as appraising QoL and the influ-
ence of completeness of cytoreduction on overall survival.
Methods
Literature search strategy
The authors have chosen to take a whole literature
approach. An extensive electronic search was performed to
Please cite this article in press as: Huo YR, et al., Hyperthermic intraperitoneal chemotherapy (HIPEC) and cytoreductive surgery (CRS) in ovarian cancer:
A systematic review and meta-analysis, Eur J Surg Oncol (2015), http://dx.doi.org/10.1016/j.ejso.2015.08.172
identify all relevant peer-reviewed articles on HIPEC for
recurrent and primary EOC. A systematic search of MED-
LINE, PubMed, EMBASE, Google Scholar and Cochrane
Database from inception to 17/04/15 was performed. The
search used the terms [‘Hyperthermic intraperitoneal
chemotherapy’ OR ‘HIPEC’ OR ‘intraperitoneal’] AND
[‘ovarian’ OR ‘ovary’] which were searched as text word
and as exploded medical subject headings where possible.
The reference lists of relevant articles were also manually
searched for any other appropriate studies. No language re-
strictions were used in either the search or study selection. A
search for unpublished literature was not performed. Two in-
vestigators (YRH and AR) read the abstracts and used a
standardised data extraction form to identify potentially rele-
vant articles. Full text versions of these relevant articles
were then examined to determine whether they were eligible
for inclusion into this review. Disagreements were resolved
by discussion with a third investigator (DLM).
Selection criteria
Studies were included if they included greater than 10 pa-
tients and adopted the combined CRS and HIPEC treatment
with a diagnosis of primary or recurrent EOC. Studies which
included the results of other gastrointestinal and pelvic malig-
nancies were included if the results of EOC subjects were an-
alysed separately and clearly reported. Abstracts, editorials
and letters were excluded. For institutions that published mul-
tiple studies with accumulating numbers of patients and/or
with increased length of follow-up, only the most recent or
complete reports were included for assessment. CRS consisted
of peritonectomy procedures (anterior parietal peritonectomy,
omentectomy  splenectomy, right and left subphrenic perito-
nectomy, pelvic peritonectomy, and lesser omentectomy with
stripping of the omental bursa  cholecystectomy) and
visceral resections (rectosigmoidectomy, right hemicolec-
tomy, total abdominal colectomy, hysterectomy and bilateral
salpingo-oophorectomy, and small bowel resection).16 HIPEC
could be administered at any of the 5 time points from the
consensus of the Peritoneal Surface Oncology group: (1) at
the time of primary treatment where optimal cytoreduction is
achieved, (2) at the time of interval debulking, (3) as a consol-
idation therapy after complete pathological response following
initial therapy as confirmed by a second-look laparotomy, (4)
at the time of first recurrence and (5) as salvage therapy. Based
on the NHMRC guidelines,17 studies were selected for evalu-
ation if they were Level II (randomised controlled trials
[RCTs]), Level III-1 (pseudorandomised RCT), Level III-2
(comparative studies with concurrent controls) or Level III-3
(comparative studies without concurrent controls) evidence.
Data extraction and critical appraisal
Data extraction collected information on: (1) methodol-
ogy, study and treatment characteristics; (2) quality
criteria17; (3) peri-operative variables; (4) post-operative
 Y.R. Huo et al. / EJSO xx (2015) 1e12
morbidity/mortality outcomes; (5) overall survival (OS)
and disease free survival (DFS). If reported, OS and DFS
were also collated based on for Sugarbaker’s completeness
of cytoreduction (CC) criteria (CC0 [no macroscopic
tumour visible], CC1 [largest residual disease <0.25 cm],
CC2 [0.25e2.5 cm], and CC3 [>2.5 cm])18 or Gynaeco-
logic Oncology Group’s criteria19 (debulking to zero resid-
ual disease [RD0], optimal debulking [0e10 mm, RD1];
suboptimal debulking [>10 mm, RD2]). All data were ex-
tracted and tabulated from relevant tables and figures.
Statistical meta-analysis
Pooled odds ratios (ORs) and 95% confidence interval (CI)
were calculated for the effect of HIPEC þ CRS þ
chemotherapy versus CRS þ chemotherapy alone on OS us-
ing a random effects model.20 We quantified the degree of het-
erogeneity using the I2 statistic, which represents the
percentage of the total variability across studies which is
due to heterogeneity. I2 values of 25%, 50% and 75% corre-
sponded to low, moderate and high degrees of heterogeneity
respectively.21 We quantified publication bias using the Eg-
ger’s regression model,22 with the effect of bias assessed using
the fail-safe number method. The fail-safe number was the
number of studies that we would need to have missed for
our observed result to be nullified to statistical non-
significance at the p-value <0.05 level. Publication bias is
generally regarded as a concern if the fail-safe number is
less than 5n þ 10, with n being the number of studies included
in the meta-analysis.23 All analyses were performed with
Comprehensive Meta-analysis version 2.0 for Windows (Bio-
stat, Englewood, New Jersey, USA) and Review Manager 5.3
for iOS (Copenhagen, The Cochrane Collaboration, 2014).
Results
Study selection
The systematic electronic search led to the identification
of 1175 original articles. Titles and abstracts were examined
and numerous studies were excluded manually for being a
conference abstract, not providing both CRS and HIPEC to
their patients, were in vitro/animal studies or did not provide
separate data for EOC. After the initial evaluation, 55 poten-
tially relevant articles on HIPEC þ CRS for EOC were iden-
tified. Eighteen studies were excluded as 1 was an abstract,
12 were older/smaller studies of included studies that have
more included patients and/or longer follow-up, and 5 did
not provide outcome data for EOC. Finally, 9 comparative
studies (8 HIPEC þ CRS þ chemotherapy vs
CRS þ chemotherapy15,24e30 & HIPEC þ CRS vs systemic
chemotherapy alone31) and 28 HIPEC þ CRS cohort stud-
ies32e59 remained eligible for data extraction (eTable 1;
eFigure 1). All 28 cohort studies were Level III-3 evidence
(eTable 2). In the 9 comparative studies, there was only
one RCT15 that was classified as Level II evidence,17 and
Please cite this article in press as: Huo YR, et al., Hyperthermic intraperitoneal chemotherapy (HIPEC) and cytoreductive surgery (CRS) in ovarian cancer:
A systematic review and meta-analysis, Eur J Surg Oncol (2015), http://dx.doi.org/10.1016/j.ejso.2015.08.172
3
remaining 8 were classified as Level III-2 evidence17
(Table 1). Studies that reported overall survival rates for
CC0 to CC3 were extracted and pooled. Only one study re-
ported quality of life33 and none provided a cost-benefit anal-
ysis pertaining to the application of HIPEC with CRS in this
treatment setting.
Study characteristics
Overall there were 16 studies that had both recurrent and
primary EOC, of which 8 studies separated survival out-
comes for recurrent and primary EOC32,39e41,44,45,56,59
and 8 that did not.28,48,51e54,57,58 There were 6 studies
that only had primary EOC25e27,42,43,46 and 15 that only
had recurrent EOC (eTable 1).15,24,29e31,33e38,47,49,50,55
The type and extent of peritonectomy procedures were not
uniformly reported in the included studies. The HIPEC
chemotherapy used, temperature and duration was described
in all 37 studies (eTable 2). The most commonly used HIPEC
chemotherapy was cisplatin (CDDP) that was used either
alone,26,42,49,50,55 or in combination with other agents such
as doxorubicin,36,37,41,45,56 paclitaxel40 or mitomycin-C34,57
(eTable 2). Median temperature was 41  C and duration of HI-
PEC ranged from 25 to 160 min. The proportion of patients
with platinum-resistant disease and complete cytoreduction
in each study are summarised in eTable 2. In the 8 compara-
tive studies that compared HIPEC þ CRS þ chemotherapy
and CRS þ chemotherapy, all adjuvant chemotherapy were
administered after discharge. In the cohort studies, 3 studies
did not state whether neoadjuvant or adjuvant chemotherapy
was used)37,38,44 (eTable 1). No study used early post-
operative chemotherapy (EPIC).
Meta-analysis outcomes: HIPEC plus CRS þ
chemotherapy vs CRS þ chemotherapy alone
Overall survival
Overall. This meta-analysis showed that HIPEC
þ CRS þ chemotherapy appeared to significantly improve
1-year survival compared with CRS þ chemotherapy
alone (OR: 4.24, 95% CI 2.17e8.30). The benefit of
HIPEC þ CRS þ chemotherapy continued to be statistically
significant for 2-, 3-, 4-, 5- and 8-year survival (OR: 2.57,
95% CI 1.61e4.12; OR: 4.31, 95% CI 2.11e8.81; OR: 2.49,
95% CI 1.51e4.10; OR: 2.53, 95% CI 1.28e5.0; OR: 2.42,
95% CI 1.38e4.24 respectively) (Table 1, Fig. 1). Only one
study reached median overall survival for CRS with and
without HIPEC (64.4 months and 46.4, respectively).26 Two
studies did not reach median survival for HIPEC þ CRS but
reached 51 and 72 months for CRS alone25,27 (Table 1).
Primary EOC In primary EOC, HIPEC þ CRS þ
chemotherapy had better 1-, 2-, 3-, 4-, 5- and 8-year overall
survival compared to CRS þ chemotherapy alone, where
this was statistically significant for all years except 1-year
4 Y.R. Huo et al. / EJSO xx (2015) 1e12

Figure 1. HIPEC þ CRS þ chemotherapy versus CRS þ chemotherapy: Forest plots of overall survival.

Please cite this article in press as: Huo YR, et al., Hyperthermic intraperitoneal chemotherapy (HIPEC) and cytoreductive surgery (CRS) in ovarian cancer:
A systematic review and meta-analysis, Eur J Surg Oncol (2015), http://dx.doi.org/10.1016/j.ejso.2015.08.172
A systematic review and meta-analysis, Eur J Surg Oncol (2015), http://dx.doi.org/10.1016/j.ejso.2015.08.172
Please cite this article in press as: Huo YR, et al., Hyperthermic intraperitoneal chemotherapy (HIPEC) and cytoreductive surgery (CRS) in ovarian cancer:

Table 1
RCTs and comparative studies that compare HIPEC with other treatments for recurrent and primary EOC.
Author Treatment EOC Serous/mucinous/other Arms Chemo N Complete Overall survival (%)
(year) centre (n) resection cc0/cc1/cc2/NR Median 1 yr 2 yr 3 yr 4 yr 5 yr 8 yr

HIPEC þ CRS þ chemo vs CRS þ chemo

Ryu KS (2004)25 Seoul Stage IceIII 27/6/24 CRS þ chemo / HIPEC þ 57 9: >1 cm & NR 100 89 85 83 80 59
primary 48: <1 cm

Y.R. Huo et al. / EJSO xx (2015) 1e12

24/7/29 CRS / chemo þ 60 12: >12 cm & 72 95 74 63 60 60 45
48: <1 cm
III only (61.4%) 21/3/11 CRS þ chemo / HIPEC þ 35 <1 cm residual NR 100 84 80 80 65 65
III only (65%) 17/5/17 CRS / chemo þ 39 <1 cm residual 31 90 60 40 40 40 22
Gori J (2005)26 Bueno Stage IIIceb 21/7/1 CRS þ chemo / HIPEC þ 29 All <2 cm 64.4 97 97 86 79 69 41
Aires primary CRS / chemo þ 19 All <2 cm 46.4 95 95 84 64 58 32
Munoz-Casares Cordoba Recurrent 8/?/6 HIPEC þ CRS/ chemo þ 14 R0-R1 100 64 57
FC (2009)30 6/?/6 CRS / chemo þ 12 R0-R1 92 50 17
Kim JH (2010)27 Seoul Stage IeIIIc 14/?/5 CRS þ chemo / HIPEC þ 19 19/0/0/0 NR 95 89.5 89.5 89.5 84.2 84.2
primary 22/?/2 CRS / chemo þ 24 24/0/0/0 51 96 83 58 54 42 29
Fagotti A Rome Recurrent NS but ratio similar HIPEC þ CRS/ chemo þ 30 100 97 91 75 57
(2012)29 CRS / chemo þ 13 100 83 67 56 41
chemo only þ 24 83 70 66 48 41
Warschkow St Gallen Stage IIIeIV 16/1/3 HIPEC þ CRS / chemo þ 21 19/2/0/0 100 81 81 81 81
R (2012)28 primary & recurrent 71/1/13 CRS / chemo þ 90 33/37/20/0 80 60 56 48 44
Le Brun JF Saint-Herblain Recurrent 23/0/0 2nd-line chemo / HIPEC þ CRS þ 23 15/4/4/0 100 96 96
(2014)24 29/0/0 2nd-line chemo / CRS þ 19 8/2/8/1 89 68 37
Spilioitis J Piraeus Recurrent NS HIPEC þ CRS / chemo þ 60 39/12/9/0 26.7* 88 77 75
(2014)*15 CRS / chemo þ 60 33/20/7/0 13.4* 70 65 18
HIPEC þ CRS vs chemotherapy alone
Safra T (2014)31 Tel Aviv Recurrent NS CRS þ HIPEC  27 100 97 97 87 82 71
Chemo only þ 84 100 96 88 68 52 27
)Randomised controlled trial.

5
6 Y.R. Huo et al. / EJSO xx (2015) 1e12

overall survival (Table 2). These results were pooled from year overall survival compared with CRS þ chemotherapy
three trials, one26 with only Stage III EOC and two25,27 alone (OR 3.48, 95% CI: 1.44e8.44, p ¼ 0.006; OR 7.39,
with Stage IeIII EOC (percentage of Stage III in 95% CI: 2.29e23.86, p < 0.001, respectively). However, the
HIPEC þ CRS/CRS only groups: 61.4%/65%25 and 2-, 4- and 5-year overall survival benefit was not statistically
63.2%/79.2%27). One of these two trials reported survival significant (OR: 2.84, 95% CI: 1.01e7.89, p ¼ 0.05; OR:
outcomes separately for Stage III EOC.25 2.82, 95% CI: 0.71e11.2, p ¼ 0.14; OR: 2.37; 95% CI:
One study showed that HIPEC þ CRS þ chemotherapy had 0.4e14.12, p ¼ 0.34 respectively) (Table 2).
a better 5-year overall survival than CRS þ chemotherapy for
Stage III (53.8 vs 33.3%, p ¼ 0.0015), but not for Stage Ic and
HIPEC timing (CRS þ chemo / HIPEC or
II EOC (78.4 vs 89.6, p ¼ 0.63).25 Further subgroup meta-
HIPEC þ CRS / Chemo)
analysis for only Stage III EOC revealed higher or similar 1-
, 2-, 3-, 4-, 5- and 8-year overall survival of HIPEC þ CRS þ
Four studies used HIPEC after CRS and adjuvant che-
chemotherapy compared to CRS þ chemotherapy alone, with
motherapy,24e27 and four studies performed HIPEC with
all years being statistically significant except year 1 (Table 2).
CRS, followed by adjuvant chemotherapy.15,28e30
Compared to CRS þ chemotherapy alone, HIPEC post-
Recurrent EOC. In recurrent EOC, HIPEC þ CRS
CRS þ chemotherapy had better 1-, 2-, 3-, 4-, 5- and 8-
þ chemotherapy appeared to significantly improve 1- and 3-
year overall survival that was statistically significant for
all years except year 1. In comparison, HIPEC þ CRS fol-
lowed by chemotherapy had significantly better 1-, 2-, 3-
Table 2
and 4-year overall survival compared to
HIPEC þ CRS þ chemotherapy vs CRS þ chemotherapy subgroup meta-
analysis: Primary vs Recurrent EOC, Stage of primary EOC, Time-point of CRS þ chemotherapy alone, however 5-year overall sur-
HIPEC administration. vival was non-significant (p ¼ 0.05) (Table 2).
Overall Study Statistics for each study Heterogeneity
survival N Odds Lower Upper p-Value I2 (%) p-Value Heterogeneity analysis
ratio limit limit
Primary EOC (Stage IeIV) Overall, there was no heterogeneity in 1-, 2-, 4-, 5- or 8-
Year 1 3 2.34 0.50 10.84 0.28 0 0.56 year overall survival between the studies (p ¼ 0.91, 0.78,
Year 2 3 2.57 1.10 5.97 0.03 0 0.80 0.40, 0.10, 0.05, respectively). For primary and recurrent
Year 3 3 2.96 1.49 5.98 0.002 0 0.37
Year 4 3 3.18 1.66 6.07 <0.001 0 0.43
EOC, heterogenity was not present for 1-year overall sur-
Year 5 3 2.93 1.59 5.39 <0.001 20 0.29 vival (p ¼ 0.57 & p ¼ 0.91, respectively). However hetero-
Year 8 3 2.42 1.38 4.24 0.002 66 0.05 geneity was present for 3-year overall survival (I2 ¼ 58%,
Primary EOC (Stage IIIeIV) p ¼ 0.02) (Fig. 1).
Year 1 2 4.41 0.66 29.31 0.12 0 0.39
Year 2 2 3.06 1.12 8.37 0.03 0 0.62
Year 3 2 3.61 1.55 8.37 0.003 62 0.11 Publication bias
Year 4 2 3.69 1.66 8.20 0.001 47 0.17
Year 5 2 2.25 1.07 4.71 0.03 0 0.49
Year 8 2 3.51 1.63 7.55 0.001 68 0.08
Assessment of publication bias using the Egger’s regres-
Recurrent EOC sion model showed publication bias was not present for 1-
Year 1 4 3.48 1.44 8.44 0.006 0 0.91 year (p ¼ 0.90), 2-year (p ¼ 0.34), 3-year (p ¼ 0.86), 4-
Year 2 3 2.84 1.01 7.89 0.05 22 0.28 year (p ¼ 0.26), 5-year (p ¼ 0.051, fail-safe N: 27) or 9-
Year 3 4 7.39 2.29 23.86 <0.001 59 0.06 year (p ¼ 0.50) overall survival. Subgroup analysis re-
Year 4 1 2.82 0.71 11.2 0.14 e e
Year 5 2 2.37 0.4 14.12 0.34 60 0.12
vealed that publication bias for 1-year overall survival in
Year 8 0 e e e e e e primary and recurrent EOC was not present (p ¼ 0.21 &
CRS þ chemo before HIPEC vs CRS þ chemo p ¼ 0.41, respectively).
Year 1 4 2.98 0.77 11.57 0.11 0 0.65
Year 2 4 3.17 1.46 6.89 0.004 0 0.63
Year 3 4 4.10 2.19 7.68 <0.001 56 0.08 Systematic review
Year 4 3 3.18 1.66 6.07 <0.001 0 0.43
Year 5 3 2.93 1.59 5.39 <0.001 20 0.29 The OS, DFS and post-operative complications in all 37
Year 8 3 2.42 1.38 4.24 0.002 66 0.05
HIPEC þ CRS before Chemo vs CRS þ chemo
included studies are described in eTable 1. The number of
Year 1 4 3.68 1.53 8.87 0.004 0 0.71 platinum-sensitive patients (progression-free interval of >6
Year 2 2 2.19 1.16 4.14 0.02 0 0.63 months following optimal standard first-line therapy),
Year 3 4 4.86 1.89 12.5 0.001 54 0.09 completeness of cytoreduction and HIPEC treatment
Year 4 2 3.77 1.55 9.19 0.003 0 0.59 (time-point, dose, temperature and intraperitoneal duration)
Year 5 3 3.18 1.01 10.03 0.05 49 0.14
Year 8 0 e e e e e e
are summarised in eTable 2. Pooled OS stratified by
completeness of cytoreduction are illustrated in Fig. 2.

Please cite this article in press as: Huo YR, et al., Hyperthermic intraperitoneal chemotherapy (HIPEC) and cytoreductive surgery (CRS) in ovarian cancer:
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 Y.R. Huo et al. / EJSO xx (2015) 1e12
Figure 2. Pooled overall survival of all studies according to completeness
of cytoreduction.
Overall survival and disease free survival
For primary EOC, the pooled median, 1-, 2-, 3-, 4-, and
5-year overall survival for HIPEC þ CRS is 46.1 months,
88.2%, 71.3%, 62.7%, 48.9% and 51%. The median, 1-,
2-, 3-, and 5-year DFS is 19.2 months, 62.6%, 24.8%,
12.3%, and 6%, respectively.
For recurrent EOC, the pooled median, 1-, 2-, 3-, 4-, and
5-year overall survival for HIPEC þ CRS is 35.8 months,
88.6%, 76%, 64.8%, 52.1% and 46.3% (eTable 1). The me-
dian, 1-, 2-, 3-, and 5-year DFS is 17.8 months, 54.6%,
19.6%, 14.9%, and 7.9%, respectively (eTable 1).
Completeness of cytoreduction
The pooled median, 1-, 2-, 3-, 4-, and 5-year overall sur-
vival for HIPEC þ CRS for complete cytoreduction (CC0)
is 45 months, 89%, 70%, 59%, 52% and 48%, respectively.
All of these survival outcomes progressively decreased with
each decrease in completeness of cytoreduction, with CC3
having 1-, 2-, 3-, 4-, and 5-year overall survival of 29%,
15%, 0%, 0%, 0%, respectively (eTable 1, Fig. 2).
Only one study59 stratified overall survival rates accord-
ing to the classification described by Gynaecologic
Oncology Group19: debulking to zero residual disease
(RD0); optimal debulking (0e10 mm, RD1); suboptimal
debulking (>10 mm, RD2). RD0 cytoreduction was
achieved in 17, R1 in 11 and R2 in 5. The median OS for
RD0 and RD1 was not reached and RD2 was 10 months.
For RD0, the 1-, 2-, 3-, 4- and 5-year overall survival
was 100%, 100%, 66%, 63%, and 63% respectively. For
RD1, the 1-, 2-, 3-, 4- and 5-year overall survival was
100%, 100%, 50%, 50%, and 50% respectively. For RD2,
the 1-, 2-, 3-, 4- and 5-year overall survival was all 0%.59
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A systematic review and meta-analysis, Eur J Surg Oncol (2015), http://dx.doi.org/10.1016/j.ejso.2015.08.172
7
Platinum resistance
Two studies showed a significant improvement in me-
dian OS in platinum-sensitive patients (progression-free in-
terval of >6 months following optimal standard first-line
therapy) compared to platinum-resistant patients (progres-
sion-free interval <6 months since optimal standard first-
line therapy) (40 vs 20 months, respectively) using univar-
iate and multivariate analysis.53,60 In one study, the median
OS was 33.7 and 20.5 months and the 5-year survival was
32.3% and 14.4% for platinum-sensitive and platinum-
resistant EOC patients, respectively.53 In the other study,
the median OS was 46 and 20 months for platinum-
sensitive and platinum-resistant patients respectively.60
However, the largest cohort study with 474 patients with
recurrent EOC found no significant difference between
platinum-sensitive and platinum-resistant patients treated
with HIPEC after complete cytoreduction, with a median
survival of 51.6 months and 47.2 months, respectively.32
Similarly, another large study found platinum-resistant in-
terval did not influence the median overall survival or
DFS.37 The OS curves of the two groups (sensitive and
resistant) revealed very similar, superimposable patterns
in the first 2 years. Thereafter, the platinum-resistant group
showed an abrupt reduction in the cumulative rate of the
probability of OS, whereas in the platinum-sensitive group
this stabilised at 28% until the end of study period.37
HIPEC chemotherapy agents
One study analysed the effect of chemotherapy agents
on survival in relation to the time point at which they
were used.53 For overall DFS, carboplatin was associated
with an improved OS as compared to mitomycin
(p ¼ 0.003) or cisplatin (p ¼ 0.003). The outcome for pa-
tients with platinum-sensitive recurrence was better with
carboplatin versus cisplatin (p ¼ 0.012) and mitomycin
(p ¼ 0.011), but there was no significant difference between
agents in platinum-resistant disease. However, the numbers
in the carboplatin group were small.
Mortality & morbidity
The pooled median 30-day post-HIPEC mortality rate
for primary and recurrent EOC is 1.8% (range: 0e7.1%)
and 1.8% (range: 0e13.6%), respectively. The pooled rate
of major (Grade IIIeIV) morbidities for primary and recur-
rent EOC is 31.3% (range: 1.8e55.6%) and 26.2%
(1.8e55.6%), respectively. The pooled rate of minor
(Grade IeII) morbidities for primary and recurrent EOC
is 40% (range: 16e60.2%) and 27.5% (16e60.2%), respec-
tively (eTable 1).
In the comparative studies, only one28 of the eight
studies reported complications separately for CRS with
and without HIPEC. They found that CRS alone had a
similar rate of major morbidity compared to
HIPEC þ CRS (26.7% vs 28.6%, respectively), however,
CRS alone had a substantially higher 30-day post-
8 Y.R. Huo et al. / EJSO xx (2015) 1e12
operative mortality rate (11.1% vs 0%, respectively).28 The
causes of death in this study were cardiac or pulmonary
insufficiency in four patients, sepsis in three patients,
multi-organ failure in two patients, and pulmonary embo-
lism in one patient. Selection bias likely accounts for these
results, whereby patients with primary advanced ovarian
cancers who improved following chemotherapy with taxol
or carboplatin were given HIPEC, whilst those that did
not respond did not receive HIPEC.
The average operation duration was 503.3 min for all
studies, 523 min (440e612 min) for primary EOC and mi-
nutes and 493 min (312e600 min) for recurrent EOC. The
average operation time was longer in HIPEC þ CRS
compared to CRS alone (5.2  1 h vs 4  1 h30 and
8.2  1.6 h vs 4.5  1.7 h28), and in CC0/1 compared to
CC2/3 (537 vs 213 min).55
The average length of post-operative hospital stay was 17.4
days overall, 18 days (range: 8e24 days) for primary EOC,
and 16.6 days (range: 5.5e27.6 days) for recurrent EOC
(eTable 1). In the comparative studies, three studies reported
length of stay (LOS) to be longer for HIPEC þ
CRS þ chemotherapy compared to CRS þ chemotherapy
alone (11 vs 17 days,24 14  4 vs 10  4 days,30 32.9 vs
27.5 days28). The likelihood of being admitted into ICU was
also higher with the addition of HIPEC (100 vs 72.2%28).
One study found a longer LOS for CC0-1 vs CC2-3 (17 vs
12 days).55
Quality of life
Only one study examined quality of life (QoL) using the
V FACT-O QoL questionnaire before and after HIPEC with
CRS þ chemotherapy in patients with optimally-
cytoreduced, recurrent, platinum-sensitive ovarian carci-
noma.33 QoL was significantly worse in the immediate
post-operative period compared to pre-surgery (FACT-O
score 126 vs 108, p < 0.05), however improved to within
90% of baseline by the 6-month time point but remained
statistically below the baseline (p < 0.05).33
Discussion
Standard frontline treatment for primary EOC involves
optimal CRS with perioperative chemotherapy adminis-
tered intravenously and/or intraperitoneally with a combi-
nation of platinum- and taxane-based chemotherapy.61,62
The intraperitoneal administration of chemotherapy theo-
retically improves treatment efficacy by targeting therapy
to the site of disease, whilst minimising systemic toxic-
ities.3 However, the full benefits of adjuvant intraperitoneal
therapy are often not achieved as less than half of patients
complete the intraperitoneal chemotherapy regime due to
complications.4
HIPEC is an alternative method for delivering intraperi-
toneal chemotherapy that has not been advocated for clin-
ical practice outside a clinical trial.61,62 Administering
Please cite this article in press as: Huo YR, et al., Hyperthermic intraperitoneal chemotherapy (HIPEC) and cytoreductive surgery (CRS) in ovarian cancer:
A systematic review and meta-analysis, Eur J Surg Oncol (2015), http://dx.doi.org/10.1016/j.ejso.2015.08.172
heated chemotherapy directly into the abdominal cavity al-
lows for a much higher concentration for peritoneal tu-
mours, and is thought to improve its cytotoxic effect.3 It
is described that hyperthermia itself potentiates the effect
of chemotherapy and has a direct cytotoxic effect on
tumour cells.63e65 Numerous comparative studies have
examined the use of HIPEC þ CRS þ chemotherapy
compared to CRS þ chemotherapy alone. The present
meta-analysis of these studies in primary EOC reveals a
statistically significant benefit in 2-, 3-, 4-, 5- and 8-year
survival, as well as having comparable morbidity and mor-
tality rates.
For recurrent EOC, the standard of care is systemic
chemotherapy and whilst often advocated, the role for sec-
ondary CRS is controversial. Treatment with chemotherapy
alone for recurrent disease rarely results in a median OS of
over 30 months. Recent meta-analyses have shown that
CRS with or without chemotherapy may improve long-
term outcomes for patients with localised, resectable disease
that has recurred after a relatively long time interval.66 In
highly selected patients, overall survival ranges between
41 and 60 months67 and a mean weighted median post-
recurrence survival time of 30.3 months.66 In regards to
HIPEC þ CRS, this review identified one caseecontrol
study that matched patients treated with HIPEC þ CRS
with those treated by systemic chemotherapy only (carbopla-
tin and paclitaxel, pegylated liposomal doxorubicin, gemci-
tabine or topotecan). Compared to systemic chemotherapy,
HIPEC þ CRS had significantly higher median DFS (15 vs
6 months) and a 5-year OS rate (79% vs 45%). However,
as the HIPEC þ CRS group did not receive any additional
adjuvant chemotherapy, it is difficult to determine the true
survival of HIPEC þ CRS over systemic chemotherapy.
Furthermore the treatment effect in the HIPEC þ CRS
may be blunted without adjuvant chemotherapy. However
this question was answered in a recent study29 that showed
HIPEC þ CRS þ chemotherapy had a higher 1-, 3- and 5-
year OS rate compared to systemic chemotherapy alone
(100%, 91%, 57% vs 83%, 66%, 41%, respectively).
Additionally, to isolate the benefit for HIPEC alone, the
study also compared HIPEC þ CRS þ chemotherapy to
CRS þ chemotherapy alone.29 The study identified a
significantly higher 2- and 5-year OS rate in those with
HIPEC þ CRS þ chemotherapy compared to
CRS þ chemotherapy (96.7% and 68.4% vs 68.4% and
42.7%, p ¼ 0.017). This meta-analysis pooled the results
from this study and several other comparative studies and
found that HIPEC þ CRS þ chemotherapy had signifi-
cantly better 1- and 3-year OS rate compared
CRS þ chemotherapy alone for recurrent EOC (OR:
3.48; OR: 7.39, all p < 0.01, respectively). These findings
suggest an improvement in overall survival with the addi-
tion of HIPEC to CRS þ chemotherapy for recurrent EOC.
Interestingly, two large studies in this review did not find
a statistically significant difference in overall survival be-
tween platinum-sensitive and platinum-resistant patients
 Y.R. Huo et al. / EJSO xx (2015) 1e12
treated with HIPEC þ CRS.32,37 This is an unexpected
finding as patients with platinum-resistant recurrent EOC
often have a far worse prognosis compared to those with
platinum-sensitive disease when treated with systemic
chemotherapy. Platinum-resistant EOC are typically treated
sequentially with multiple single-agent regimens with non-
platinum chemotherapy agents. Depending on the type of
chemotherapy, the median DFS and OS ranges from 3.1
to 6.7 months and 10.7 to 16.6 months, respectively.68e70
As expected, two cohort studies in this review found a sig-
nificant improvement in median OS in platinum-sensitive
patients compared to platinum-resistant patients when
treated with HIPEC þ CRS (33.7 vs 20.5 months & 46
vs 20 months53,60).
Nevertheless, the more remarkable finding is achieving a
median OS ranging from 20 to 47.2 months in platinum-
resistant EOC patients. The median OS of 47.2 months
was achieved in 223 platinum-resistant recurrent patients,
whereby all patients had undergone complete cytoreduction
and HIPEC.32 Intriguingly, a majority these patients used
cisplatin as the HIPEC agent, despite having platinum-
resistant disease. However, hyperthermia has been shown
to intensify the cytotoxic effects of certain anticancer
agents and/or increasing the penetration of drugs into tissue
such as cisplatin.64 Another contributing factor for the
effectiveness of HIPEC for platinum-resistant EOC may
also be hyperthermia itself having a direct cytotoxic effect
on tumour cells or the exposure or residual cells to high
concentrations of chemotherapy. However these notable
survival rates using HIPEC þ CRS for platinum-resistant
EOC have only been assessed in observational studies.
In both primary and recurrent EOC treated with
HIPEC þ CRS, the importance of complete cytoreduction
remains vital for long-term survival outcomes.6,71 For
CRS alone, the DESKTOP OVAR Trial71 showed that
macroscopically completely resected tumours showed
significantly longer overall survival compared to patients
who had any visible residual tumour. For recurrent EOC,
median survival was 45.2 and 19.7 months in patients
without and with macroscopic tumours, respectively (HR
3.71; 95% CI 2.27e6.05; p < 0.001).71 Furthermore, a
meta-analysis found each 10% increase in the proportion
of patients undergoing complete cytoreduction was associ-
ated with a significant and independent 2.3-month increase
in overall survival.6 Similarly, this review found a step-wise
improvement in overall survival with each improvement in
completeness of cytoreduction. The median 5-year survival
rate for 0 mm, 1e10 mm and >10 mm of residual tumour
was 63%, 50% and 0%, respectively.59 Furthermore, a
similar trend is seen using the Sugarbaker’s criteria where
the 5-year survival rate was 48.4%, 25%, 8.5% and 0%
for CC0, CC1, CC2 and CC3 respectively. These findings
highlight the importance of complete cytoreduction in
CRS independent to the use of HIPEC.
Many criticisms against procedures combining CRS and
HIPEC are due to the high rates of mortality and morbidity
Please cite this article in press as: Huo YR, et al., Hyperthermic intraperitoneal chemotherapy (HIPEC) and cytoreductive surgery (CRS) in ovarian cancer:
A systematic review and meta-analysis, Eur J Surg Oncol (2015), http://dx.doi.org/10.1016/j.ejso.2015.08.172
9
reported for the treatment of non-gynaecologic peritoneal
surface malignancies. This review shows that
HIPEC þ CRS is associated with severe morbidity rates
of 1.8e72.4% and mortality rates of 0e13.6%. However,
treatment related complications from institutions that
routinely perform this procedure are low, with mortality
rates that range from 0 to 1.8%.45,53,55 Only one compara-
tive study compared the complications between CRS with
and without HIPEC. Interestingly, they found that CRS
without HIPEC had a similar rate of major morbidity
compared to CRS with HIPEC (26.7% vs 28.6%, respec-
tively), however, CRS without HIPEC had a substantially
higher 30-day post-operative mortality rate (11.1% vs
0%, respectively).28 As this was reported in only one study,
it may be a chance finding. However, a recent systematic
review of morbidity and mortality results in 24 specialised
peritonectomy treatment centres showed that the majority
of surgical morbidity observed was due to the high-
volume of peritoneal carcinomatosis (i.e. high PCIs of these
patients), rather than the HIPEC procedure itself.72 More-
over, there were no studies that examined the influence of
intraperitoneal chemotherapy concentrations or dose, HI-
PEC duration and temperature on renal or haematological
toxicity. This should be defined in subsequent phase IeII
studies.
Worldwide, 8 RCTs are currently examining CRS with
or without HIPEC; 4 recruiting only advanced EOC,73e76
and 4 recruiting only platinum-sensitive recurrent
EOC.77e80 The results from these RCTs will clarify the
role of HIPEC in the treatment of patients with advanced
and platinum-sensitive recurrent EOC, as well as the
optimal timing of the procedure, HIPEC chemotherapy
drug and QoL for patients. Despite these ongoing trials,
there are studies reporting a remarkable survival benefit
of HIPEC þ CRS for platinum-resistant EOC and unfortu-
nately there are no RCTs are currently examining CRS with
or without HIPEC in platinum-resistant recurrent EOC.
Interestingly, there is one RCT that is currently recruiting
advanced, platinum-sensitive and platinum-resistant recur-
rent EOC patients to compare HIPEC þ CRS with or
without intraperitoneal normothermic chemotherapy.81
The findings in this review should be interpreted in view
of certain limitations. Firstly, the eligibility criteria (tumour
stage, age, follow-up, extent of disease, previous chemo-
therapy and surgery, etc) of patients with EOC were not iden-
tical between studies included. This might influence the
consistency of effects across these included studies and
lead to differences the patient baseline characteristics. How-
ever, this study has attempted to minimise these differences
by stratification of the results. Secondly, the total number of
patients in each study was small. However, our pooled results
reached statistical significance when analysing the benefit in
overall survival with HIPEC þ CRS þ chemotherapy
compared to CRS þ chemotherapy alone. Thirdly, DFS
was often poorly reported in studies, especially within the
comparative studies. Without DFS, it makes it difficult to
10 Y.R. Huo et al. / EJSO xx (2015) 1e12
quantitate the benefit of HIPEC. Finally, there was only one
study that was a RCT. Although the RCT was of high quality
in having described the generation of randomisation, by hav-
ing only one RCT, it makes it difficult to conclude that
HIPEC þ CRS þ chemotherapy is superior to
CRS þ chemotherapy alone for EOC. The results of the
ongoing RCTs73e76 will be essential in determining whether
HIPEC þ CRS þ chemotherapy is appropriate for EOC.
Despite these limitations, this review has numerous strengths
such as being an extensive and comprehensive meta-analysis
and systematic review of the current literature for HIPEC for
EOCs.
Conclusion
In conclusion, there is an emerging body of evidence
that supports the use of HIPEC with CRS and systemic
chemotherapy for primary (Stage III) and recurrent EOC
compared to CRS and chemotherapy alone. Maximal cytor-
eduction remains essential for overall survival rates, even
when HIPEC is used. Ongoing RCTs will further clarify
the role of HIPEC for patients with advanced and recurrent
ovarian cancer.
Disclosure of commercial interest
None.
Conflict of interest
None.
Acknowledgements
None.
Appendix A. Supplementary data
Supplementary data related to this article can be found at
http://dx.doi.org/10.1016/j.ejso.2015.08.172.
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