International Journal of Hyperthermia

ISSN: 0265-6736 (Print) 1464-5157 (Online) Journal homepage: http://www.tandfonline.com/loi/ihyt20

Cytoreductive surgery and hyperthermic

intraperitoneal chemotherapy for the treatment
of advanced epithelial and recurrent ovarian
carcinoma: a single center experience

Maja J. Pavlov, Miljan S. Ceranic, Stojan M. Latincic, Predrag V. Sabljak,

Dragutin M. Kecmanovic & Paul H. Sugarbaker

To cite this article: Maja J. Pavlov, Miljan S. Ceranic, Stojan M. Latincic, Predrag V.
Sabljak, Dragutin M. Kecmanovic & Paul H. Sugarbaker (2017): Cytoreductive surgery and
hyperthermic intraperitoneal chemotherapy for the treatment of advanced epithelial and recurrent
ovarian carcinoma: a single center experience, International Journal of Hyperthermia, DOI:
10.1080/02656736.2017.1371341

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Published online: 07 Sep 2017.

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 INTERNATIONAL JOURNAL OF HYPERTHERMIA, 2017
https://doi.org/10.1080/02656736.2017.1371341

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for the

treatment of advanced epithelial and recurrent ovarian carcinoma: a single
center experience
Maja J. Pavlova,b, Miljan S. Ceranica,b, Stojan M. Latincicb, Predrag V. Sabljaka,c, Dragutin M. Kecmanovica,b and
Paul H. Sugarbakerd
a
School of Medicine, University of Belgrade, Belgrade, Serbia; bDepartment for Colorectal and Pelvic Surgery, First Surgical Clinic, Clinical
Center of Serbia, Belgrade, Serbia; cDepartment for Esophagogastric Surgery, First Surgical Clinic, Clinical Center of Serbia, Belgrade, Serbia;
d
Center for Gastrointestinal Malignancies, MedStar Washington Cancer Institute, MedStar Washington Hospital Center, Washington, DC, USA
Downloaded by [Australian Catholic University] at 07:29 09 September 2017

ABSTRACT ARTICLE HISTORY

Background: With standard treatment of epithelial ovarian cancer (EOC), prognosis is very poor. The Received 31 October 2016
aim of this study is to show early and late results in patients who underwent cytoreductive surgery Revised 20 August 2017
and intraperitoneal chemotherapy. Accepted 20 August 2017
Patients and methods: This was a retrospective single centre study. All patients with advanced and Published online 6 Septem-
ber 2017
recurrent ovarian cancer treated with cytoreductive surgery and hyperthermic intraperitoneal chemo-
therapy (HIPEC) or modified early postoperative intraperitoneal chemotherapy (EPIC) were included in KEYWORDS
the study. Cytoreductive surgery;
Results: In the period 1995–2014, 116 patients were treated, 55 with primary EOC and 61 with recur- ovarian; cancer;
rent EOC. The mean age was 59 years (26–74). Statistically, median survival time was significantly lon- hyperthermic intraperitoneal
ger in the group with primary advanced cancer of the ovary (41.3 months) compared to relapsed chemotherapy (HIPEC)
ovarian cancer (27.3 months). Survival for the primary EOC was 65 and 24% at 3 and 5 years, respect-
ively. Survival for recurrent EOC was 33 and 16% at 3 and 5 years, respectively. Mortality was 1/116
(0.8%). Morbidity was 11/116 (9.5%). Peritoneal cancer index (PCI) was
20 in 59 (51%) patients and
statistically, their average survival was significantly longer than in the group of 57 (49%) patients with
PCI >20 (p ¼ 0.014).
Conclusions: In advanced or recurrent EOC, a curative therapeutic approach was pursued that com-
bined optimal cytoreductive surgery and intraperitoneal chemotherapy. PCI and timing of the interven-
tion (primary or recurrent) were the strongest independent prognostic factors.

Introduction Although 70–80% of patients respond to first-line carboplatin

Epithelial ovarian cancer (EOC) is the seventh most common
cancer diagnosed in women with 240 000 new cases and
150 000 deaths worldwide in 2012. EOC is the fifth most
common cancer among women and is the leading cause of
death from gynecological cancers in the United States [1].
The average age of patients at diagnosis was 63 years and
at the time of diagnosis, 65–70% of patients had advanced
disease (stage III or IV) [2].
For patients under 25 years at the time of the first preg-
nancy and delivery, the use of oral contraceptives and/or
breastfeeding has a reduced risk of ovarian cancer.
Nulliparous women and those older than 35 years at preg-
nancy are at increased risk of developing EOC. Patients who
have BRCA1 and BRCA2 mutations have a 15% risk of ovarian
cancer [3]. Recent data suggests that hormone therapy and
the presence of pelvic inflammatory disease may increase the
risk of ovarian cancer [2].
Standard treatment plans for patients with EOC is debulk-
ing surgery and the use of platinum-based chemotherapy.
and paclitaxel, the 5-year survival rate is less than 25% [4].
Spiliotis et al. randomised 120 patients with stage III or IV
OC that had recurred after debulking and systemic chemo-
therapy to CRS with HIPEC vs. CRS without HIPEC. Both
groups of patients received systemic chemotherapy. These
researchers observed a significant increase in mean survival
in the HIPEC group (26.7 vs. 13.4 months, p < 0.006) with
3-year survival at 75 vs. 18% (p < 0.01) [5]. Currently ongoing
clinical trials (CHORINE, CHIPOR and OVHIPEC) may add more
evidence of the importance of these procedures in the treat-
ment of advanced ovarian cancer.
Numerous studies have shown that optimal cytoreductive
surgery with minimal residual disease is significantly associ-
ated with increased survival time [6,7]. According to the lit-
erature data, the proportion of patients who underwent
optimal cytoreduction varies from 15–85% [8]. Griffiths et al.
in 1975, showed that in patients with advanced ovarian can-
cer a significant prognostic factor was optimal cytoreduction
and minimal residual disease. Hoskins and Gynecologic

CONTACT Dragutin M. Kecmanovic kecmanovicdragutin@gmail.com Professor of Surgery, School of Medicine, University of Belgrade, Dr Subotic 8, 11000
Belgrade, Department for Colorectal and Pelvic Surgery, First Surgical Clinic, Clinical Center of Serbia, Koste Todorovic 6, Belgrade, Serbia
ß 2017 Informa UK Limited, trading as Taylor & Francis Group
 2 M. J. PAVLOV ET AL.
Oncology Group (GOG) showed that the sub-optimal cytore-
duction, regardless of the diameter of the residual disease,
does not contribute to improved survival [9]. These research-
ers compared two groups of patients with advanced ovarian
cancer. Patients with residual disease of less than 2 cm
showed no significantly better survival compared to the
group with residual disease greater than 2 cm. Chi et al. [6]
analysed a group of 282 patients who underwent surgery for
advanced ovarian cancer in the period 1987–1994. Significant
prognostic factors affecting the survival were the presence or
absence of ascites, the size of residual disease and age of
patients. It is not demonstrated that there is an impact on
survival until the residual disease is reduced to less than
1 cm. Cytoreduction to less than 1 cm was achieved in 25%
of patients with overall survival of 34 months for the whole
282 patient group [10]. The most common cause of a large
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percentage of sub-optimal resection is that patients with dis-
semination and infiltration of the omentum (tissue below the
stomach and above the column that is not resected), dia-
phragm, gallbladder, falciform ligament, liver and spleen
were declared inoperable [11]. It is necessary to achieve max-
imum cytoreduction – less than 1 cm of residual disease in
the largest diameter [11]. Extensive cytoreduction of the
upper abdomen is recommended for patients who are able
to tolerate the procedure [12].
The primary aim of this study was to analyse morbidity
and mortality with the use of intraperitoneal cisplatin and
doxorubicin after maximal cytoreductive surgery in patients
with peritoneal dissemination of EOC. The secondary object-
ive was to determine overall survival and 3- and 5-year dis-
ease-free survival.
Materials and methods
This retrospective, non-randomised study was conducted at
the Department of Colorectal and Pelvic Oncological Surgery,
First Surgical Clinic of the Clinical Center of Serbia during the
period 1995–2014 after being authorised by the Ethics
Committee. Patients had advanced primary (FIGO IIIC-IV) or
recurrent ovarian cancer.
The inclusion criteria were carcinomatosis from ovarian
cancer confirmed by a pathologist, the absence of extra-
abdominal metastasis and satisfactory renal and cardio-
respiratory status. Primary cytoreductive surgery (surgery
with the aim of complete resection of all macroscopic
tumours in patients with first diagnosis of advanced ovarian
cancer before any other treatment) and HIPEC or modified
EPIC was performed in all patients with primary ovarian can-
cer without neoadjuvant chemotherapy.
Surgery for platinum sensitive recurrent ovarian cancer
(patients with recurrence more than six months after com-
plete response) and surgery for platinum-resistant recurrent
ovarian cancer (patients with persistent disease after frontline
treatment or recurrence within six months) and HIPEC or
modified EPIC was performed in all patients with recurrent
ovarian cancer.
The exclusion criteria were the presence of extra-abdom-
inal metastasis, poor general condition, renal insufficiency
and heart failure or the existence of a lesion in the CNS.
Diagnostic studies
All patients were subjected to abdominal physical examin-
ation, rectoscopy, complete blood count, complete metabolic
panel, Ca-125, X-ray of the chest, MSCT (multi-slice computed
tomography) or MRI of the abdomen and pelvis. The age of
patients, PCI, stage of disease, type of surgical procedures
performed, postoperative residual disease (CC score), hist-
ology and 3- and 5-year survival were also recorded.
The extent of the disease after laparotomy was deter-
mined by PCI. The abdomen and pelvis were divided into 13
regions and the size of the lesion was scored as 0–3. The
maximum score was 39 [13].
The completeness of cytoreduction was scored by
Sugarbaker’s method: CC0, without residual disease; CC1,
residual nodules smaller than 2.5 mm; CC2, 2.5 mm to 2.5 cm;
CC3, residual nodules greater than 2.5 cm [14].
Cytoreductive surgery
Surgical treatment was performed according to Sugarbaker’s
method. After careful abdominal exploration, a median lapar-
otomy (from pubis to xyphoid) was performed. Surgical
resections were performed according to the rules of onco-
logical surgery with a goal to resect all visible tumours in the
peritoneal cavity. Electro-resections with monopolar dia-
thermy were used for the resection of peritoneal deposits.
The LigaSure impact (Covidien, Plymouth, MN) was used for
omentectomy and dissection in the pelvis. Bowel anastomo-
ses were made before the implementation of modified EPIC
method by closed procedures or closed HIPEC.
Modified EPIC method with moderate hyperthermia
After surgical procedures, modified EPIC was performed by
closed technique. Immediately before wound closure, doxo-
rubicin, (0.1 mg/kg/day, max. 10 mg/day) dissolved in two
litres of warm Ringer’s lactate (40  C) was administered dir-
ectly into the abdominal cavity. Four abdominal drains were
closed during the intraperitoneal intraoperative chemother-
apy and released after 2 h. During the next five days, cisplatin
(15 mg/m2; max. 30 mg/day) dissolved in two litres of warm
Ringer’s lactate (50  C) was administered through four
abdominal drains. Ringer’s lactate was heated up to 50  C,
allowing it to cool down to 40  C prior to entering the
abdominal cavity. The temperature of the solution was con-
stantly monitored using a contact thermometer placed on
the abdominal drains. The drains were placed sub-phrenically
and in the pelvic cavity, bilaterally.
HIPEC by the closed method
Intraperitoneal chemotherapy with cisplatin (15 mg/m2; max.
30 mg) and doxorubicin (0.1 mg/kg, max. 10 mg) at 42  C was
delivered after all resections and anastomoses were com-
pleted using the BelmontV Hyperthermia Pump(Belmont
R
instrument corporation, Billerica, MA). The pump for HIPEC
included four closed suction drains placed intra-abdominally,
 INTERNATIONAL JOURNAL OF HYPERTHERMIA 3

specifically one beneath each hemidiaphragm and two in the
pelvis.
Morbidity was reported according to the National Cancer
Institute Common Toxicity Criteria: grade I postoperative
complication - no intervention was required for resolution,
grade II - medical treatments were required for resolution,
grade III- required an invasive intervention, such as a radio-
logical intervention for resolution and grade IV- postopera-
tive complications required urgent definitive intervention,
such as returning to the operating room or ICU for resolution
and grade V - death related to an adverse event [15].
At discharge, patients were referred to an oncologist for
further treatment with systemic chemotherapy (3–6 cycles)
and postoperative follow-up.
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histological subtype, PCI, CC-score and surgical variables are
given in Table 1.
The mean age was 59 years (26–74). The median duration
of surgery was 4 h and 42 min (3 h 30 min – 6 h 20 min).
Median blood loss was 526 millilitres (280–1450 ml).
Statistically, median survival time was significantly longer
in the group with a primary advanced cancer of the
ovary (41.3 months) compared to relapsed ovarian cancer
(27.3 months).
Survival for the primary EOC was 65 and 24% at 3- and
5-years, respectively. Survival for recurrent EOC was 33 and
16% at 3-and 5-years, respectively. Mortality was 1/116
(0.8%). Morbidity was 11/116 (9.5%).
After laparotomy, all patients received cytoreductive sur-
gery involving one or more of the following procedures, as
shown in Table 2.

Selection criteria
Modified EPIC was applied prior to obtaining the HIPEC PCI score
pump (until 2008); thus, surgery time was the only criterion
Median peritoneal cancer index (PCI) was 19.9 (5–32), SD 6.3.
for the selection of the procedure type.

CC score
Statistics and data processing
In our series of patients, we achieved a CC0 in 102 patients
Statistical analysis was performed using SPSS 22 (SPSS Inc.,
(88%), CC1 in 10 (9%) and CC2 in 4 (3%). In 112 patients (97%),
Chicago, IL) with the Kaplan-Meier method and survival
curves (univariate analyses) were compared using a log-rank Table 2. Surgical procedures performed in all patients with ovarian cancer.
test. Hypothesis comparisons were performed using the Chi- Total hysterectomy with salphingo-oophorectomy 55
square test for contingency tables, the Mann-Whitney U test Lesser omentectomy 5
and T-Test for two independent means. A two-tailed test Pelvic peritonectomy 10
Extended peritonectomy (pelvic peritonectomy plus bilateral flank 78
resulting in p < 0.05 was considered to be statistically and partial upper quadrant Peritonectomies)
significant. Total peritonectomy (extended peritonectomy plus diaphragmatic 28
surfaces and Glisson’s capsule, lesser omentum and omental bursa)
Distal pancreatectomy 2
Cholecystectomy 7
Results Partial gastrectomy 2
Splenectomy 13
In the period from 1995–2014, 116 patients were treated; 55 Hartmann resection 5
had primary and 61 had recurrent cancer. Fifty-six patients Total colectomy with terminal ileostomy 16
with ovarian cancer underwent CRS þ modified EPIC and 60 Greater omentectomy 111
Low anterior resection of rectum with anastomosis 84
patients underwent CRS þ HIPEC. In the recurrent ovarian Total pelvic exenteration 4
cancer group, eight were platinum-resistant and 53 were Appendectomy 36
Urinary bladder resection 7
platinum-sensitive patients. Details of patient characteristics,

Table 1. Patients characteristics according to origin (primary or recurrent).

N (%) Primary % Recurrent % p value
116 55 61
Age (year) Mean 58.9 (26–74), SD 8.9 59.1 58.7 0.424878a
Histological subtype
Serous 72 38 52.78 34 47.22 0.52b
Undifferentiated 22 13 59.09 9 40.91
Endometrioid 11 7 63.64 4 36.36
Mucinous 6 3 50.00 3 50.00
Clear cell 3 1 33.33 2 66.67
Carcinosarcoma 2 1 50.00 1 50.00
Intraperitoneal chemotherapy method
Modified EPIC 56 21 37.50 35 62.50 0.059c
HIPEC 60 33 55.00 27 45.00
PCI Mean 19,9 (5–32) SD 6,3 19.5 20.3 0.23986a
CC-score
0–1 112 70 62.50 42 37.50 0.13043b
2–3 4 1 25.00 3 75.00
a
T-Test for 2 Independent Means.
b
Mann-Whitney U Test.
c
chi-square tests.
 4 M. J. PAVLOV ET AL.
optimal cytoreduction was achieved. Statistically, median sur-
vival time was significantly longer in the CC0 and CC1 group
compared to CC2 and CC3 group (p ¼ 0.002).
Morbidity/mortality
Eleven patients (9.5%) developed postoperative complica-
tions – Grade II: two patients had thrombocytopenia and
anaemia which required cessation of chemotherapy and
administration of blood, frozen plasma and albumin. One
patient had a transient metabolic acidosis, one had a wound
infection and three patients had nausea and vomiting and
three cases of postoperative prolonged bowel obstruction
was reported which was resolved by conservative treatment;
Grade IV: one anastomotic leak requiring reoperation and
Grade V: one patient (0.8%) died due to cerebrovascular
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insult.
Survival
There was no statistically significant difference (p > 0.05)
between modified EPIC and HIPEC groups.
The median survival time was significantly longer in the
group with a primary advanced cancer of the ovary (40.3
months) than in recurrent ovarian cancer (27.6 months)
(p ¼ 0.014) (Figure 1). Survival for the primary EOC was 65
and 24% at 3- and 5-years, respectively. Three-year survival
for recurrent EOC was 33% and 16% at 5-years. PCI was less
than or equal to 20 for 59 patients (51%) and statistically
their average survival was significantly longer than in the
group of 57 (49%) of patients with PCI more than 20
(p < 0.01) (Figure 2).
Figure 1. Comparison of survival curves for patients with primary and recurrent ovarian cancer.
Discussion
Survival statistics
This retrospective, single centre study that included
116 patients is a series of selected patients with peritoneal
metastases from ovarian cancer treated with CRS and HIPEC.
This combined treatment yields a median survival of 40,
three months for advanced EOC and 27, six months for recur-
rent EOC.
Chua et al. reported (review) median overall survival
ranged from 22 to 64 months, overall 3-year survival rate
ranged from 35 to 63% and 5-year survival rate ranged from
12 to 66% [16].
If we compare our results with the Bakrin et al. French
multicenter retrospective cohort study of 566 patients [17],
we can see that for advanced EOC, median overall survival
was 35.4 months (our result 40.3). The survival rates at 3-
and 5-years were 47 (65%) and 17% (24%), respectively.
Better overall survival may be explained by smaller percent
of patients in which CC2–3 resection had been performed.
For recurrent EOC, the median overall survival was
45.7 months (27.6). The overall survival rates at 3- and
5-years were 59 (33%) and 37% (16), respectively. Average
PCI in our study population was 20.3, while in Bakrin et al.
group it was eight, with similar percent of patients with
CC2–3 resection.
The third GOG study, GOG 172, published by Armstrong
et al. [18] showed the median duration of progression-free
survival in the intravenous-therapy (intravenous paclitaxel
plus cisplatin) and intraperitoneal-therapy (intravenous pacli-
taxel plus intraperitoneal cisplatin and paclitaxel) groups was
18.3 and 23.8 months, respectively. The median duration of

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Figure 2. Comparison of survival curves for patients with PCI of 20 or less vs. more than 20.
overall survival in the intravenous therapy and intraperitoneal
therapy groups was 49.7 and 65.6 months, respectively.
Above the fact that additional intraperitoneal therapy
improves survival rates, we can acknowledge that in patients
in which suboptimal cytoreduction had been performed sur-
vival rates were significantly lower (39.1 vs. 78.2 months).
This fact only strengthens the need for complete
cytoreduction.
Completeness of cytoreduction
In the past, CRS with residual malignant deposits greater
than 1 cm and less than 2 cm was considered optimal and in
subsequent years, there was a change of attitude, with
researchers determining that it is necessary to undergo a
complete surgical resection of all visible tumour deposits.
The Gynecologic Cancer Interstudy Group (GCIG) has
changed the official nomenclature and requirements for peri-
tonectomy and multi-visceral resection, depending on the
degree of peritoneal metastasis. The DESKTOP 1 study con-
ducted by the AGO has identified the following parameters
for the possibility of complete resection in patients with
recurrent ovarian cancer: good general health, absence of
residual disease after surgery EOC, early initial FIGO stage
and absence of ascites according to radiological examina-
tions. If all of these factors were positive, completeness of
resection was achieved in 79% of patients. If all factors were
positive, then completeness is achieved in 43% of patients
[19]. Major study limitation is absence of clear parameters for
avoiding the radical surgery. Also, complete cytoreduction
was performed in only 24% of patients with peritoneal car-
cinomatosis. This can be explained by insufficient training of
gynaecologists in performing cytoreduction of upper
INTERNATIONAL JOURNAL OF HYPERTHERMIA 5
abdomen. In our study, 97% of patients had optimal cytore-
duction, whaich corresponds to the results of Bakrin et al.
[17] (92,1%, 474 pt.) and Coccolini et al. [20], (100%, 54 pt.).
Morbidity and mortality rates vary from centre to centre.
Average morbidity (within 30 days) ranges from 19.2 to 34%.
The complication rate was not significantly different in the
treatment of recurrent ovarian cancer in relation to primary
debulking surgery mortality rate is 0.7–2.8% in the primary
and in recurrent EOC 1.2–5.5% [21]. Our morbidity rate was
9% and five patients had minor complications of Grade I and
II. We did not have grade III complications, while we had two
grade IV complications. Mortality was 0.8%, which is consist-
ent with the results of published studies. Chua et al. [16]
reviewed 895 patients from 19 different studies. The mortal-
ity rate ranged from 0 to 10%. Grade I morbidity ranged
from 6–70%, grade II morbidity 3–50%, grade III morbidity
0–40% and grade IV morbidity ranged from 0–15%. Common
postoperative complications were ileus, anastomotic leakage,
bleeding, wound infection, toxicity, pleural effusion, infec-
tions, fistula, transient hepatitis and thrombocytopenia.
Mortality and morbidity rates depended on the patient’s age,
general condition of the patient, the number and type of
resection procedures and duration of HIPEC. A very important
factor is the surgical learning curve and experience of the
entire team. If we examine the Table 2 with surgical proce-
dures in ovarian cancer we can conclude that a gynaecolo-
gist oncologist alone or with the help of experienced
gastrointestinal surgeons must be trained to perform cytore-
duction of the upper parts of the abdomen in the addition
to the standard pelvic surgery. This statement agrees with
the results and the conclusions drawn by Chi et al. [11].
Tan et al. [22] showed that there were no significant OS
and DFS differences between the EPIC and no EPIC groups,
 6 M. J. PAVLOV ET AL.
which may result in increased morbidity and longer hospital-
isation. In our patients, there were no significant OS differen-
ces between modified EPIC and HIPEC groups. McConnell
et al. [23] showed comparable results: the use of EPIC, in
combination with CRS and HIPEC, is associated with an
increased rate of complications without significant OS and
DFS differences.
New investigative techniques such as fluid and CO2 recir-
culation using the closed abdomen technique (PRS-1.0
Combat) show that closed abdomen intraperitoneal
chemo-hyperthermia by a fluid and CO2 recirculation system
(PRS-1.0 CombatV) can be a safe and feasible model for
R
the treatment of peritoneal carcinomatosis of ovarian cancer
origin [24].
Conclusions
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Patients with EOC and peritoneal dissemination have poor
survival. Patients with primary cancer and PCI less than 20
can expect better survival; therefore, it is critical to perform
optimal treatment, which includes CC0/CC1 CRS and it is
necessary to achieve maximum cytoreduction.
A multidisciplinary approach to patients with advanced
EOC allows optimisation of the treatment strategy based on
patients characteristics (age, performance/nutritional status,
co-morbidities, functional status) and tumour diffusion (eval-
uated pre- and intra-operatively).
Gynecologists alone or with the help of experienced
gastrointestinal surgeons should be able to do the following:
cytoreduction in the upper abdomen, peritonectomy, total
omentectomy and resection of the bowel when necessary.
Disclosure statement
No potential conflict of interest was reported by the authors.
Funding
This study was supported by the grant from the Serbian Ministry of
Science [Project No. 41033].
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