Article

Paclitaxel as HIPEC-Drug after Surgical Cytoreduction for

Ovarian Peritoneal Metastases: A Randomized Phase III Clinical
Trial (HIPECOVA)
Pedro Villarejo Campos 1,2, *,† , Susana Sánchez García 3,† , Mariano Amo-Salas 4 , Esther García Santos 3 ,
Carlos López de la Manzanara 5 , Ana Alberca 6 , David Padilla-Valverde 3 , Francisco Javier Redondo Calvo 7
and Jesús Martín 3

1 Department of Surgery, Fundación Jiménez Díaz University Hospital, Avda. Reyes Católicos, 2,
28040 Madrid, Spain
2 Department of Surgery, Universidad Autónoma de Madrid, C/Arzobispo Morcillo s/n, 28034 Madrid, Spain
3 Department of Surgery, General University Hospital of Ciudad Real, C/Obispo Rafael Torija, s/n,
13005 Ciudad Real, Spain; susaga@[Link] (S.S.G.); epgarcias@[Link] (E.G.S.);
davidp@[Link] (D.P.-V.); jesusmartin57@[Link] (J.M.)
4 Department of Mathematics, University of Castilla-La Mancha, Camino de Moledores, s/n,
13071 Ciudad Real, Spain; [Link]@[Link]
5 Department of Gynaecology, General University Hospital of Ciudad Real, C/Obispo Rafael Torija, s/n,
13005 Ciudad Real, Spain; [Link]@[Link]
6 Department of Surgery, General University Hospital of Jaén, 23007 Jaén, Spain;
[Link]@[Link]
7 Department of Anaesthesia, General University Hospital of Ciudad Real, C/Obispo Rafael Torija, s/n,
13005 Ciudad Real, Spain; fjredondo@[Link]
* Correspondence: [Link]@[Link]
† These authors contributed equally to this work.

Abstract: Multidisciplinary strategies have transformed the management of advanced ovarian cancer.
We aimed to evaluate the effectiveness of paclitaxel in hyperthermic intraperitoneal chemotherapy
Citation: Villarejo Campos, P.;
(HIPEC) following surgical cytoreduction for ovarian peritoneal metastases in a randomized phase III
Sánchez García, S.; Amo-Salas, M.;
trial conducted between August 2012 and December 2019. Seventy-six patients were randomized to
García Santos, E.; López de la
Manzanara, C.; Alberca, A.;
either the HIPEC or no HIPEC group. Although median values for the primary endpoints (recurrence-
Padilla-Valverde, D.; Redondo Calvo, free survival (RFS) and overall survival (OS)) revealed superior outcomes for the HIPEC (RFS:
F.J.; Martín, J. Paclitaxel as 23 months, OS: 48 months) over the control group (RFS: 19 months, OS: 46 months), these differences
HIPEC-Drug after Surgical were not statistically significant (p = 0.22 and p = 0.579). Notably, the HIPEC group demonstrated
Cytoreduction for Ovarian Peritoneal significantly higher 5-year OS and 3-year RFS rates (47.2% and 47.5%) compared to patients without
Metastases: A Randomized Phase III HIPEC (34.5% and 21.3%). Stratification according to Peritoneal Surface Disease Severity Score
Clinical Trial (HIPECOVA). Curr. (PSDSS) showed improved OS and RFS for patients with lower PSDSS (I–II) in the HIPEC-treated
Oncol. 2024, 31, 660–671. https:// group (p = 0.033 and p = 0.042, respectively). The Clavien–Dindo classification of adverse event
[Link]/10.3390/curroncol31020048
grades revealed no significant differences between HIPEC and controls (p = 0.482). While overall
Received: 12 November 2023 results were not statistically significant, our long-term follow-up emphasized the potential benefit of
Revised: 13 January 2024 HIPEC-associated cytoreduction with paclitaxel, particularly in selected ovarian cancer patients with
Accepted: 22 January 2024 lower PSDSS indices.
Published: 24 January 2024

Keywords: advanced or recurrent ovarian cancer; HIPEC; paclitaxel; cytoreduction; peritoneal

metastases; peritoneal surface disease severity score

Copyright: © 2024 by the authors.

Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and
1. Introduction
conditions of the Creative Commons Epithelial ovarian cancer (EOC) is one of the most fatal gynecological malignancies,
Attribution (CC BY) license (https:// and is particularly prevalent among elderly individuals, with a higher incidence in the sixth
[Link]/licenses/by/ and seventh decades of life. Most patients with EOC present with peritoneal metastasis at
4.0/). the time of diagnosis [1].

Curr. Oncol. 2024, 31, 660–671. [Link] [Link]

Curr. Oncol. 2024, 31 661

Standard treatment for advanced-stage ovarian cancer involves cytoreductive surgery

(CRS) in combination with platinum-based chemotherapy. Optional locoregional therapies
within the abdominal cavity may also be included [2].
The peritoneal spread and distribution of ovarian cancer make this malignancy an
ideal target for intraperitoneal chemotherapy (IP). IP capitalizes on the pharmacokinetic and
pharmacodynamic advantages of the drugs administered, allowing high intraperitoneal
drug concentrations with minimal systemic absorption due to the role played by the
peritoneal–plasma barrier [3]. This strategy enables a direct, localized cytotoxic effect on
tumor cells [4].
The addition of hyperthermia to standard chemotherapy heightens the therapeutic
benefits of chemotherapy drugs due to the synergistic effect of the two treatments and
induces production of heat shock proteins in cancer cells [5].
Hyperthermic intraperitoneal chemotherapy (HIPEC) may be performed intraopera-
tively following CRS as part of a single surgical intervention. The HIPEC procedure can
have a duration of 30, 60, 90, or 120 min and be performed by the open (coliseum) or
closed abdomen technique [6], although many different approaches for HIPEC have been
described in the literature [7].
The addition of HIPEC after complete cytoreduction has been shown to be effective in
treating advanced and recurrent EOC [8–10].
Paclitaxel, which has optimal pharmacokinetic properties for intraperitoneal adminis-
tration, is sustained at high concentrations within the peritoneal cavity compared to plasma
levels [11]. This property is partly attributable to its high molecular weight (853.906 g/mol),
which impedes penetration through the peritoneal barrier, thereby resulting in minimal
systemic absorption [8].
While the synergy between paclitaxel and hyperthermia remains a topic of debate,
the combined use of paclitaxel and hyperthermia in HIPEC therapy has demonstrated
both safety [12] and efficacy [13,14] in the treatment of patients with peritoneal metastases
of ovarian origin. Although research has suggested using paclitaxel as a single drug for
HIPEC in these patients [13–16], to date, no randomized clinical trials have evaluated
this approach.
This clinical trial aims to evaluate the efficacy and safety of HIPEC with paclitaxel
after complete cytoreduction in EOC with peritoneal involvement, regardless of primary
or recurrent origin. Focus is placed on assessing the potential superiority of HIPEC using
paclitaxel compared to standard treatment. HIPEC was performed in accordance with
the closed abdomen technique and using the CO2 recirculation system developed by
our group in 2014, which enhanced temperature homogeneity and optimized solution
distribution [17–19].
Patient selection, which is critical to the success of HIPEC therapy in treating peritoneal
metastases, remains a primary challenge [20]. The Peritoneal Surface Disease Severity Score
(PSDSS) is a predictive tool that identifies patients likely to benefit from aggressive treat-
ments such as cytoreduction and HIPEC. This scoring system assesses clinical symptoms,
the extent of peritoneal metastases (Peritoneal Carcinomatosis Index, PCI), and primary
tumor histopathology to categorize patients into any of the four scores indicated by the
PSDSS (Supplementary Table S1). Notably, this index has proven effective in defining
peritoneal carcinomatosis of ovarian origin [21,22]. In the present study, we used the
PSDSS to stratify patients within both groups and conducted analyses of the primary study
objectives based on this index.

2. Materials and Methods

2.1. Patients and Trial Design
HIPECOVA is a single-center, randomized phase 3 clinical trial conducted in women
with peritoneal involvement of primary EOC (International Federation of Gynecology and
Obstetrics (FIGO) stages II, III, and IV) [23] or tumor recurrence, in whom complete cy-
Curr. Oncol. 2024, 31 662

toreduction was achieved. Randomization was performed intraoperatively once complete

cytoreduction was successful.
Patients who were ineligible because of the extent of their peritoneal disease (assessed
by diagnostic imaging) and where complete cytoreduction was not possible received neoad-
juvant chemotherapy with paclitaxel (175 mg/m2 ) and carboplatin (6 AUC). Subsequently,
patients in whom a response to therapy was evidenced on imaging studies obtained after
3 cycles were eligible for interval surgery. Since the purpose of this research was to assess
the added benefit of HIPEC with paclitaxel, patients with complete cytoreduction observed
during interval surgery were also included and randomized intraoperatively.
This clinical trial was designed and performed by the multidisciplinary team deliv-
ering treatment for ovarian cancer and peritoneal carcinomatosis at General University
Hospital of Ciudad Real. The study protocol was approved by the local ethics committee
(no. 2011-006319-69, date of approval 25 April 2012). The HIPECOVA trial was authorized
by the Spanish Drug Agency (EudraCT 2011006319-69) and registered in the ClinicalTri-
[Link] database (NCT02681432).
The trial’s inclusion and exclusion criteria described below are available on the Clinical-
[Link] registry website ([Link] (accessed
on 15 December 2023).

2.2. Inclusion Criteria

• Female patients were eligible for inclusion if they were between 18 and 80 years of age
and presented with histologically confirmed primary or recurrent EOC with peritoneal
involvement. Women of childbearing age were required to have a negative pregnancy
test to take part.
• Completeness of cytoreduction score (CC): CC0 (no visible residual tumor after
surgery) or CC1 (less than 0.25 cm).
• No extra-abdominal tumor disease.
• Absence of heart failure. Adequate renal and hepatic function.
• Eastern Cooperative Oncology Group performance status of 0–2 or Karnofsky
score ≥70%.
The completeness of the cytoreduction surgery was a determining factor in the patient
inclusion criteria. Complete cytoreduction was defined by Jónsdóttir et al. as CC0 (no
residual disease) and CC1 (residual tumor < 2.5 mm) [24].

2.3. Exclusion Criteria

• Patients with unresectable disease or incomplete cytoreduction.
• Contraindications for treatment with paclitaxel: patients with severe hypersensitivity
to paclitaxel or any of its excipients, pregnancy or lactation, and patients with baseline
neutrophil counts <1500/mm3 (<1000/mm3 for patients with Kaposi sarcoma). Pa-
clitaxel is also contraindicated in patients with concurrent severe infections such as
the following:
• Extra-abdominal metastases or unresectable liver metastases;
• Presence of other malignant tumor disease;
• Multi-segmental complete bowel obstruction;
• Patients with severe medical conditions precluding compliance with the study or that
introduce an unacceptable risk;
• Patients who refuse treatment or do not consent to participate in the study.

2.4. Treatment Groups and Follow-Up

• HIPEC arm: CRS and hyperthermic intraperitoneal chemotherapy with paclitaxel
(175 mg/m2 ) for 60 min at a temperature of 42–43 ◦ C (closed abdomen technique)
followed by postoperative systemic intravenous (IV) chemotherapy with carboplatin
(AUC = 6) and paclitaxel (175 mg/m2 ) for 6 cycles.
Curr. Oncol. 2024, 31 663

• Non-HIPEC arm: CRS followed by postoperative systemic IV chemotherapy with

carboplatin (AUC = 6) and paclitaxel (175 mg/m2 ) for 6 cycles.
HIPEC was performed using a closed abdomen and CO2 recirculation system. When
required, anastomosis was completed before the HIPEC procedure. Following CRS, inflow
and outflow catheters were positioned in the upper and lower abdominal cavities, respec-
tively. Additionally, a CO2 inflow catheter was placed in the right abdominal cavity. After
inserting these catheters and a gas exchange device into the abdominal wall, the skin was
closed to enable application of the paclitaxel solution, covering the entire peritoneal surface
(Supplementary Figure S1).
The perfusion solution consisted of 1.36% glucose and 25 mmol/L bicarbonate (peri-
toneal dialysis solution). During the HIPEC procedure, a perfusion of chemotherapy and
CO2 was recirculated into the abdominal cavity, generating a turbulent flow to enhance the
drug distribution across both visceral and peritoneal surfaces. Following the treatment, the
abdominal cavity was opened, washed, and closed. Subsequently, all patients were closely
monitored in the Intensive Care Unit (ICU) for the initial 2–3 days.
After hospital discharge, patients underwent regular follow-up, including physical
examinations, CA-125 measurements, and computed tomography or positron emission
tomography scans every 4 months for the first 2 years, followed by assessments every 6
months up to 3 years.
In cases of suspected recurrent disease, the diagnosis was based on the findings of
imaging tests and elevation of the tumor marker CA-125. The existence of recurrence was
subsequently confirmed by histological examination.

2.5. Endpoints
Primary endpoints included recurrence-free survival (RFS) and overall survival (OS).
RFS was defined as the time from randomization to disease recurrence, defined according
to the Response Evaluation Criteria in Solid Tumors. OS was defined as the time elapsed
between randomization and the date of death or the end of the study.
Secondary endpoints included postoperative complications (adverse events within
30 days post-operatively) defined according to the National Cancer Institute criteria and
the Common Terminology Criteria for AE (CTCAE).

2.6. Statistical Analysis

The study sample was calculated considering a 0.05 alpha risk, 0.20 beta risk, and
difference of survival rate of 0.3 between arms based on the recurrence-free survival and
using the method of sample size calculation for a log-rank test, indicating a requirement
of 47 patients per arm to detect statistically significant differences (p < 0.05). Throughout
the study period, 102 patients were assessed for eligibility, although the target sample size
could not be reached due to a lower-than-expected participation rate. Consequently, the
randomized sample comprised 76 patients, which carries with it a potential loss of signifi-
cance. Subsequent exclusions reduced the final analysis to 32 patients in the experimental
group and 23 in the control group.
Data collection was carried out by a group of data managers belonging to the research
team and using an electronic database.
Statistical analysis was performed using the SPSS software package for Windows
(IBM SPSS Statistics v.24) (International Business Machines Corporation, Armonk, NY,
USA). Descriptive analyses were undertaken using means and standard deviations for
quantitative variables and absolute and relative frequencies for qualitative variables. The
Pearson Chi-square test was used to analyze the association between qualitative variables.
Finally, the survival analysis was performed using the Kaplan–Meier method and Cox
regression analysis, and the log-rank test was used to study the statistical differences
between survival curves in qualitative variables. The median length of follow-up was
estimated using the reverse Kaplan–Meier method.
 Kaplan–Meier method and Cox regression analysis, and the log-rank test was used to
study the statistical differences between survival curves in qualitative variables. The
median length of follow-up was estimated using the reverse Kaplan–Meier method.

Curr. Oncol. 2024, 31 3. Results 664

3.1. Patient Enrollment and Surgery-Related Characteristics

This single-center trial involved 102 eligible patients identified from August 2012 to
3. Results
December 2019. Of these, 90 provided preoperative consent, with 76 patients randomized
3.1. Patient Enrollment and Surgery-Related Characteristics
intraoperatively into the control (n = 35) and experimental groups (n = 41). Further ex-
Thisreduced
clusions single-center trial
the final involved
analysis 102patients
to 32 eligiblein
patients identified from
the experimental groupAugust
and 232012 to
in the
December 2019. Of these, 90 provided preoperative consent, with 76 patients
control group. Figure 1 contains a detailed CONSORT flow diagram depicting patient randomized
intraoperatively
exclusions into the control (n = 35) and experimental groups (n = 41). Further
and allocations.
exclusions reduced the final analysis to 32 patients in the experimental group and 23
in the control group. Figure 1 contains a detailed CONSORT flow diagram depicting
patient exclusions and allocations.

Figure 1. CONSORT flow diagram.

Baseline demographics showed no significant differences between the groups, ensur-

Figure 1. CONSORT flow diagram.
ing homogeneity in the baseline variables (Table 1). FIGO stage IIIC was the most common
stageBaseline
observed (54.6%). Tumors
demographics with high-grade
showed serous
no significant histologybetween
differences were thethe
most frequently
groups, en-
observed (63.6%).
suring homogeneity in the baseline variables (Table 1). FIGO stage IIIC was the most
No significant differences in PCI values were noted between the two arms, either
common stage observed (54.6%). Tumors with high-grade serous histology were the most
before or during CRS (p = 0.666 and p = 0.720, respectively). The PCI before surgery and
frequently observed (63.6%).
during CRS demonstrated associations with RFS (hazard ratio (HR) = 1.074 (95% CI, 1.003
to 1.150; p = 0.04)) and HR = 1.069 (95% CI, 1.015 to 1.125; p = 0.011), respectively.
Surgical procedures included upfront CRS in 26 patients (14 in the no HIPEC arm, 12
in the HIPEC arm), interval CRS in 26 patients (19 in the no HIPEC group, 7 in the HIPEC
group), and secondary surgery in 3 patients (2 in the no HIPEC arm, 1 in the HIPEC arm).
The duration of surgery was significantly longer in the HIPEC arm (352.3 ± 98.3 min)
compared to the no HIPEC arm (280 ± 73.48 min) due to the additional 60 minutes required
for the HIPEC procedure.
An association was found between the number of peritonectomy procedures and OS
(HR = 1.150; 95% CI, 1.039 to 1.274; p = 0.007) and with RFS (HR = 1.172; 95% interval CI,
1.035 to 1.327; p = 0.012).
Curr. Oncol. 2024, 31 665

In terms of the cytoreduction score reached in the included patients, 52 patients

achieved complete cytoreduction (CCR-0), while 3 patients, with PCI value over 20, had a
residual tumor of less than 2.5 mm (CCR-1).

Table 1. Baseline characteristics of patients.

HIPEC NO HIPEC p-Value

AGE (years) 60.34 (±11.7) 60.22 (±12.93) 0.969
BMI (kg/m2 ) 27.96 (±4.63) 26.46 (±4.62) 0.255
AH 15 (27.3%) 6 (10.9%) 0.118
DM 6 (10.9%) 2 (3.6%) 0.446
ASA
-I - 3 (5.5%) - 4 (7.3%)
- II - 18 (32.7%) - 14 (25.5%) 0.3
- III - 11 (20%) - 4 (7.3%)
- IV - 0 (0%) - 1 (1.8%)
TUMOR HISTOLOGIC TYPE
- Serous - 24 (43.6%) - 16 (29.1%)
- Mucinous - 3 (5.5%) - 1 (1.8%)
0.878
- Endometrioid - 2 (3.6%) - 2 (3.6%)
- Clear-cell - 2 (3.6%) - 3 (5.5%)
- Other - 1 (1.8%) - 1 (0.8%)
SURGERY TYPE
- Primary surgery - 12 (21.8%) - 14 (25.5%)
0.118
- Interval surgery - 19 (34.5%) - 7 (12.7%)
- Secondary surgery - 1 (1.8%) - 2 (3.6%)
HISTOLOGIC GRADE
- Low grade - 4 (7.3%) - 0 (0%)
0.234
- Intermediate grade - 9 (16.4%) - 7 (12.7%)
- High grade - 19 (34.5%) - 16 (29.1%)
LYMPH NODES
- Positive - 13 (23.6%) - 11 (20%) 0.783
- Negative - 19 (34.5%) - 12 (21.8%)
FIGO STAGE
- IIa - 3 (5.5%) - 2 (3.6%)
- IIb - 2 (3.6%) - 1 (1.8%)
- IIIa - 1 (1.8%) - 1 (1.8%)
0.929
- IIIb - 1 (1.8%) - 2 (3.6%)
- IIIc - 16 (29.1%) - 14 (25.5%)
- IVa - 3 (5.5%) - 1 (1.8%)
- IVb - 6 (19.9%) - 2 (3.6%)
CT-PET PCI
- <10 - 19 (35.2%) - 14 (25.9%)
0.666
- 11–20 - 11 (20.4%) - 7 (13%)
- >20 - 1 (1.9%) - 2 (3.7%)
Surgery PCI
- <10 - 22 (40%) - 14 (25.9%)
0.72
- 11–20 - 8 (14.5%) - (14.5%)
- >20 - 2 (3.6%) - 1 (1.8%)
BMI: Body Mass Index; AH: Arterial Hypertension; DM: Diabetes Mellitus; CT: Computerized Tomography; PCI:
Peritoneal Cancer Index.

3.2. Survival Outcomes

The median length of follow-up was 32 months. Throughout this period, 50.9% of the
patients experienced disease recurrence, while 34.5% died due to tumor progression. The
Curr. Oncol. 2024, 31 666

survival analysis results for key surgical outcome variables are presented in Supplementary
Table S2.
Curr. Oncol. 2024, 31, FOR PEER REVIEW 8
The median OS (48 vs. 46 months, p = 0.579) and RFS (23 vs. 19 months, p = 0.22) showed
no significant differences between the HIPEC and no HIPEC groups, respectively (Figure 2).
Curr. Oncol. 2024, 31, FOR PEER REVIEW 8
However, the HIPEC group exhibited notably higher 5-year OS and 3-year RFS rates (47.2%
and 47.5%, respectively) compared to the no HIPEC group (34.5% and 21.3%, respectively).

Figure
Figure 2. Median
2. Median
Figure OSOS
2. Median
and
and
OS and
RFS
RFS survival
survival
RFS
inHIPEC
survival in
HIPECvs.
in HIPEC
vs.
vs. no
nono
HIPEC
HIPEC
HIPEC
group.
group.
group.

Treatment
Treatment
Treatment with
with HIPEC
HIPEC
with HIPECdid didnot
did notincrease
not increaseoverall
increase overall
overall survival
survival
survival in
in patients
patients
in patients treated treated
with with
treated with
primary
primary cytoreduction
cytoreduction
primary cytoreduction(p(p= ==0.246)
(p 0.246) orinterval
0.246) or
or intervalsurgery
interval surgery
surgery (p =(p0.584)
== 0.584)
0.584) versus
versusversus the
thecontrol
the control [Link].
control group.
HIPEC HIPEC
HIPEC treatment
treatment
treatment also also
also did
notnot
diddid not improve
improve
improve RFSRFS
inin
RFS patients
in treated
patients
patients treated with with
treated
with primary
primary cy-
primary cy-
cytoreduc-
tion (ptoreduction
= 0.234),(p(p
toreduction = =0.234),
0.234),surgery
interval interval surgery
interval surgery
(p (p(p= =0.242),
= 0.242), or or
0.242),
or secondary
secondary secondary cytoreduction (p(p== 0.157)
cytoreduction
cytoreduction 0.157)
(p = 0.157)
versus
versus the controlgroup.
group.
theversus
control thegroup.
control
3.3. Subgroup Analysis Based on PSDSS Score
[Link]. Subgroup
Subgroup AnalysisBased
Analysis BasedononPSDSS
PSDSSScore
Score
Within the HIPEC group, patients with a PSDSS of I or II demonstrated notably
Within
Within
higher OS theHIPEC
the
and HIPEC
RFS group,topatients
group,
compared patients withscores
with
patients with PSDSS
of III of
a PSDSS II or
of IV
or (p =IIII0.033
or demonstrated
demonstrated notably
and p = 0.042, notably
higher
higher OSOS and
and RFScompared
RFS
respectively) compared
(Figure totopatients
patients
3). Conversely, with
with
in the scores group,
scores
no HIPEC of III
III or
ornoIV
IV (p
(p==0.033
differences0.033and
andpob-
were p= =
0.042,
0.042,
respectively)
respectively) (Figure
served in(Figure
RFS 3). 3).
between Conversely,
Conversely,
patients within in the
the
PSDSS no no HIPEC
I–IIHIPEC
versus group,
group,
III–IV (p no no differences
differences
= 0.310). werewere ob-
observed
served
in RFS in RFS patients
between between with
patients
PSDSSwithI–II
PSDSS I–II III–IV
versus versus(pIII–IV (p = 0.310).
= 0.310).

Figure 3. Median OS and RFS in HIPEC group based on PSDSS Score.

Figure 3. Median OS and RFS in HIPEC group based on PSDSS Score.

Figure 3. Median OS and RFS in HIPEC group based on PSDSS Score.
Curr. Oncol. 2024, 31 667

3.4. Adverse Events

According to the Clavien–Dindo classification, minor complications (grades I–IIIa)
were observed in 26 patients (47.2%): 11 in the HIPEC group and 15 patients not undergoing
HIPEC. Hematological complications were found to be the most prevalent adverse event,
affecting 24.1% of patients (14.8% in the no HIPEC arm and 9.3% in the HIPEC arm, p = 0.74).
Severe complications (grades IIIb–V) were observed in 7 patients (12.7%), including
5 in the HIPEC group and 2 in the no HIPEC group. Among these, 3 patients (5.6%)
experienced grade V adverse events involving multi-organ failure after postoperative
perforation or intestinal leakage (1 in the no HIPEC arm and 2 in the HIPEC arm).
Additionally, 22 patients (40%) experienced no adverse events within 30 days post-
surgery. Notably, there were no significant differences in adverse events of any grade
observed between the two groups (p = 0.482) (Supplementary Table S3).

4. Discussion
Meta-analyses of published evidence consistently find that complete macroscopic
removal of tumor disease is the main prognostic factor for improving both OS and RFS in
advanced ovarian cancer [25].
In patients with recurrent ovarian cancer, surgical cytoreduction plays a pivotal role in
OS [26].
In recent years, the integration of HIPEC therapy into primary cytoreduction, interval
surgery, or secondary surgery for advanced ovarian cancer has gained increasing attention
despite the lack of standardized protocols. Table 2 summarizes the outcomes of the major
randomized clinical trials conducted to date.

Table 2. HIPEC randomized clinical trials in ovarian cancer.

Median PFS
Author and HIPEC Drug HIPEC Median OS
Clinical Trial N Surgery or DFS or p-Value
Year (mg/m2 ) (minutes) (months)
RFS (months)
Primary and
2 center Interval 19.8 vs. 18.8 69.5 vs. 61.3 p > 0.05
Lim (2022)
Phase III 184 Cisplatin 75 90
[27]
KOV-HIPEC-01 Interval 17.4 vs. 15.4 61.8 vs. 48.2 p < 0.05
subgroup
Interval
Single-center 18 vs. 12 p > 0.05
Cascales (2022) Subgroup
Phase III 71 Cisplatin 75 60 52 vs. 45
[28] with
CARCINOHIPEC 24.1 vs. 9.4 p < 0.05
suprameso-
colic disease
Secondary
Zivanovic (2021) Single-center
98 for platinum- Carboplatin 800 90 15.7 vs. 12.3 59.7 vs. 52.5 p ≥ 0.05
[29] Phase II
sensitive
Multicenter
Driel (2018)
Phase III 245 Interval Cisplatin 100 90 14.2 vs. 10.7 45.7 vs. 33.9 p < 0.05
[9]
OVHIPEC
Secondary Cisplatin 100
Spiliotis (2015) Single-center for platinum- Paclitaxel 175
120 60 26.7 vs. 13.4 p < 0.05
[10] Phase III sensitive and Doxorubicin 35
resistant Mitomycin 15
Abbreviations: N, number of patients; PFS, progression-free survival; DFS, disease-free survival; RFS, recurrence-
free survival; OS, overall survival.

Notably, HIPEC therapy in advanced ovarian cancer has shown significant efficacy,
particularly in association with interval surgery, cisplatin being commonly used as the
primary HIPEC drug [9,27,28]. For the treatment of recurrent ovarian cancer, HIPEC
therapy combined with secondary surgery has involved multiple drug regimens, leading
to more varied and inconclusive outcomes [10,29].
Curr. Oncol. 2024, 31 668

The Dutch OVHIPEC clinical trial, a multicenter study of 245 patients, demonstrated
that adding HIPEC (cisplatin 100 mg/m2 at 40 ◦ C over 90 min) to interval surgery after
neoadjuvant treatment increased RFS (14.2 vs. 10.7 months, HR = 0.66, p = 0.003) and OS
(45.7 vs. 33.9 months, HR = 0.67, p = 0.02) in primary ovarian cancer (FIGO III) [9].
A Korean randomized clinical trial (NCT010191636) including 184 patients with ad-
vanced ovarian cancer (FIGO III and IV) undergoing primary or interval surgery found
no survival advantage in terms of OS (69.5 vs. 61.3 months, p = 0.52) or progression-free
survival (PFS) (19.8 vs. 18.8 months, p = 0.43). However, in the subgroup undergoing inter-
val surgery after neoadjuvant chemotherapy, the addition of HIPEC (cisplatin 75 mg/m2
at 41.5 ◦ C over 90 min) showed favorable outcomes, presenting improved PFS (17.4 vs.
15.4 months, p = 0.04) and OS (61.8 vs. 48.2 months, p = 0.04). Conversely, for patients
undergoing primary CRS, HIPEC did not demonstrate the same benefits [27].
In a prospective phase 3 clinical trial in Spain led by Cascales et al., the efficacy of interval
CRS combined with HIPEC using cisplatin (75 mg/m2 for 60 min at 42 ◦ C) was investigated in
patients with advanced ovarian cancer and peritoneal metastases. Among the 71 participants,
36 underwent interval surgery, while 35 received interval surgery coupled with HIPEC. The
primary endpoint was disease-free survival (DFS), with secondary endpoints encompassing
OS, morbidity, and quality of life (QoL). No statistically significant differences were observed
in median DFS, median OS, or overall morbidity rates between the groups. Nevertheless,
in the subgroup of patients with disease presence in the supramesocolic compartment, ad-
ministration of HIPEC was linked to improved DFS (9.4 months in the control group and
24.1 months in the experimental group; p = 0.031). Interestingly, the incorporation of HIPEC
had no notable impact on patient QoL across the evaluated dimensions [28].
The randomized phase II clinical trial by Zivanovic et al. involved 98 patients with
recurrent advanced ovarian cancer. The trial used carboplatin at a dose of 800 mg/m2
for 90 minutes as the HIPEC drug. While the median PFS was 15.7 months compared to
12.3 months, and the median OS was 59.7 versus 52.5 months, the observed differences were
not statistically significant (p = 0.05 and 0.32, respectively). Despite being well-tolerated,
the use of HIPEC with carboplatin did not result in superior clinical outcomes [29].
In contrast, the Greek clinical trial, involving 120 patients and conducted as a single-
center study, revealed that combining HIPEC (at 42.5 ◦ C for 60 min) with CRS for recurrent
ovarian cancer led to a significant increase in median survival (26.7 months vs. 13.4 months,
p < 0.006) and 3-year survival rates (75% vs. 18%). Various HIPEC drugs were employed,
such as cisplatin (100 mg/m2 ) and paclitaxel (175 mg/m2 ) for platinum-sensitive disease,
and doxorubicin (35 mg/m2 ) and paclitaxel (175 mg/m2 ) or mitomycin (15 mg/m²) for
platinum-resistant disease [10].
While platinum-based compounds, particularly carboplatin and cisplatin, along with
paclitaxel, are the standard chemotherapeutic agents for first-line treatment in ovarian
cancer, cisplatin has historically been the drug of choice in HIPEC for advanced ovarian
cancer. However, the favorable pharmacokinetic properties and promising outcomes of
paclitaxel for treating peritoneal carcinomatosis originating from ovarian cancer [14] led
us to conduct a clinical trial aimed at assessing its efficacy. The HIPECOVA trial was
designed to investigate the impact of HIPEC with paclitaxel following surgical treatment
for peritoneal metastases in both primary and recurrent advanced ovarian cancer. Our
study primarily focused on evaluating the effects of the treatment on RFS and OS. Although
the trial did not definitively establish the superiority of HIPEC therapy involving paclitaxel
after cytoreduction in enhancing survival outcomes for advanced ovarian cancer, whether
applied during primary, interval, or secondary surgeries for relapse, our findings emphasize
the need for a thorough and comprehensive evaluation.
Based on available data, anticipated outcomes in the control group for advanced
ovarian cancer indicate a median RFS range of 11 to 16.4 months and a median OS ranging
between 23 and 44.3 months [29]. However, the results among patients in the HIPEC group
were more favorable, achieving a median RFS and OS of 23 and 48 months, respectively,
suggesting notably improved outcomes, which can be deemed optimal.
Curr. Oncol. 2024, 31 669

When considering the adverse events associated with CRS and HIPEC, this combined
treatment consistently demonstrates varying perioperative mortality rates, spanning from
0% to 18%, along with morbidity rates that fall between 30% and 70% [30]. In our study,
grades IIIa–IIIb adverse events were observed in 14.6% of patients, while no grade IV events
were reported. Notably, no significant differences in adverse events of any grade were
observed between the groups (p = 0.482), which is consistent with other clinical trials [9].
The observed complication rates remain comparable to those reported in other studies.
Hematological complications were noted in 24.1% of cases, consistent with the reported
incidence range of hematological toxicity, which spans from 4% to 39%. Additionally, 2.2%
of patients developed intestinal leakage, which is lower than the described range for grade
III/IV gastrointestinal complications, typically reported between 4.5% and 19% [30]. In
summary, this randomized clinical trial did not reveal a significantly different incidence of
adverse events compared to similar studies.
Strengths: One of the primary strengths of this clinical trial lies in its innovative
approach, as it employs paclitaxel as a single-agent HIPEC, a relatively uncommon but
highly promising treatment strategy for advanced or recurrent ovarian cancer. The phar-
macokinetic profile of paclitaxel lends itself to intraperitoneal administration, potentially
enhancing its therapeutic efficacy in this context. Moreover, the single-center design of
this trial, together with the fact that the study was managed by a cohesive research team,
enhances its reliability by minimizing potential biases and ensuring a uniform approach to
data collection and analysis.
Limitations: Despite these strengths, the study has several limitations. Firstly, the
number of patients enrolled was low, owing to multiple factors such as patient reluctance to
accept randomized treatments, disparities between intraoperative findings and definitive
histopathological results, and non-adherence to established monitoring protocols. This
limited sample size may affect the generalizability of the results and the statistical power of
the study. Additionally, the assumption that HIPEC therapy was considered to be effective
solely based on surgical control of peritoneal disease, irrespective of its association with
primary, interval, or secondary surgeries, may have led to an overestimation of treatment
effectiveness. Implementing randomized stratification may have improved the quality of
this research and yielded more robust outcomes.

5. Conclusions
The outcomes of this initial phase III randomized clinical trial evaluating the efficacy
of HIPEC with paclitaxel following cytoreduction in advanced ovarian cancer reveal no
statistically significant differences between the treatment and control groups. Despite the
overall results lacking statistical significance, our extended follow-up reveals a sustained
positive trend in both overall survival and disease-free survival. Notably, this benefit
is particularly evident in selected ovarian cancer patients with lower Peritoneal Surface
Disease Severity (PSDSS) indices, suggesting a potential benefit of cytoreduction associated
with HIPEC with paclitaxel. This promising observation warrants further investigation to
better understand and confirm its clinical implications.

Supplementary Materials: The following supporting information can be downloaded at https:

//[Link]/article/10.3390/curroncol31020048/s1: Figure S1: Closed abdomen and CO2
recirculation system; Table S1: Peritoneal Surface Disease Severity Score (PSDSS); Table S2: Results
of the survival analysis of the main variables related to surgery outcomes; Table S3: Complications
according to the Clavien–Dindo classification.
Author Contributions: Conceptualization, P.V.C. and D.P.-V.; Methodology, C.L.d.l.M., D.P.-V. and
F.J.R.C.; Software, A.A.; Validation, F.J.R.C. and J.M.; Formal analysis, M.A.-S.; Investigation, S.S.G.,
A.A. and E.G.S.; Resources, C.L.d.l.M. and J.M.; Data curation, S.S.G., A.A., D.P.-V. and E.G.S.;
Writing—original draft preparation, P.V.C., M.A.-S. and S.S.G.; Writing—review and editing, P.V.C.,
S.S.G., E.G.S., D.P.-V., J.M., A.A., C.L.d.l.M., F.J.R.C. and M.A.-S.; Visualization, D.P.-V. and F.J.R.C.; Su-
pervision, J.M. and C.L.d.l.M.; Project management, S.S.G., C.L.d.l.M. and P.V.C.; Funding acquisition,
P.V.C. All authors have read and agreed to the published version of the manuscript.
Curr. Oncol. 2024, 31 670

Funding: This study was funded by Instituto de Salud Carlos III (ISCIII) through the project
PI20/01052. The General University Hospital of Ciudad Real has also contributed its own resources
to conduct this clinical trial.
Institutional Review Board Statement: The present study was approved by the Research Ethics
Committee of the University General Hospital of Ciudad Real (no. 2011-006319-69, date of approval
25 April 2012). The procedures followed were in accordance with the Code of Ethics of the World
Medical Association (Declaration of Helsinki) and with the protocols and requirements established
by the Spanish Agency of Medicines and Medical Devices.
Informed Consent Statement: Informed consent was obtained from all subjects involved in the study.
Data Availability Statement: The datasets analyzed during the current study are available from the
corresponding author upon reasonable request.
Acknowledgments: The authors would like to thank Javier Sánchez Menor and Pilar Marta for their
technical assistance and Oliver Shaw for revising the manuscript in aspects related to the English
language. We are also grateful to Jesús Fernández Sanz and Alberto Martínez Albalat for their support
of this project.
Conflicts of Interest: The authors declare no conflicts of interest. The funders had no role in the design
of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or
in the decision to publish the results.

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