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International Journal of Gynecological Cancer
IS CYTOREDUCTIVE SURGERY WITH PERIOPERATIVE INTRAPERITONEAL
CHEMOTHERAPY JUSTIFIED AS UPFRONT TREATMENT IN LOCALLY
ADVANCED EPITHELIAL OVARIAN CANCER?
--Manuscript Draft-Manuscript Number:
Full Title:
IS CYTOREDUCTIVE SURGERY WITH PERIOPERATIVE INTRAPERITONEAL
CHEMOTHERAPY JUSTIFIED AS UPFRONT TREATMENT IN LOCALLY
ADVANCED EPITHELIAL OVARIAN CANCER?
Short Title:
INTRAPERITONEAL CHEMOTHERAPY IN OVARIAN CANCER
Article Type:
Original Study
Keywords:
Cytoreductive surgery; peritoneal carcinomatosis; Ovarian cancer; HIPEC
Corresponding Author:
Antonios-Apostolos K Tentes, M. D.
Didimotichon General Hospital
Didimotichon, Evros GREECE
Corresponding Author Secondary
Information:
Corresponding Author's Institution:
Didimotichon General Hospital
Corresponding Author's Secondary
Institution:
First Author:
Antonios-Apostolos K Tentes, M. D.
First Author Secondary Information:
Order of Authors:
Antonios-Apostolos K Tentes, M. D.
Theodosios B Palaskas, Professor
Konstantinos M Stamou, MD, PhD
Chrysostomos E Stoforos, Assistant Professor
Nicolaos Pallas, MD
Christina Karamveri, MD
Dimitrios Kyziridis, MD
Christos Hristakis, MD
Order of Authors Secondary Information:
Manuscript Region of Origin:
GREECE
Abstract:
Objective: Perioperative intraperitoneal chemotherapy after maximal cytoreductive
surgery has been used in the treatment of recurrent or persistent epithelial ovarian
cancer. The purpose of the study is the evaluation of the effect of hyperthermic
intraoperative intraperitoneal chemotherapy (HIPEC) as upfront treatment in advanced
ovarian cancer.
Material/Methods: This is a prospective observational study of 166 women that
underwent 189 cytoreductive surgical operations for locally advanced epithelial ovarian
cancer. HIPEC was used in 135 cases (71.4%), and in 55 cases (29.1%) as upfront
treatment. Clinical indicators were correlated to four qualitative variables; morbidity,
hospital mortality, survival, and recurrences.
Results: HIPEC as upfront treatment in ovarian cancer was found to be related to
recurrence (p=0.001) but not to overall survival. The prognostic variables of survival
were the performance status, the completeness of cytoreduction, and the use of
HIPEC (p<0.001). The prognostic variables of recurrence were the degree of
differentiation, and the use of systemic chemotherapy (p=0.05).
Conclusion: HIPEC combined with maximal cytoreductive surgery may be used with
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promising results as upfront treatment in patients with advanced epithelial ovarian
cancer. Prospective randomized trials are required.
Suggested Reviewers:
Paul H Sugarbaker
Director, Medstar Washington Hospital Center
[email protected]
Specialist on cytoreductive surgery and intraperitoneal chemotherapy
Jesus Esquivel
Director, Cancer Treatment Centers of America
[email protected]
Specialist on cytoreductive surgery and intraperitoneal chemotherapy
Opposed Reviewers:
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Cover Letter
Antonios-Apostolos K. Tentes, MD
Director, Surgical Oncology
Metropolitan Hospital
Venizelou 1
New Faliro, 18547
Greece
Tel: +302104807177
Fax: +302104809293
Mobile: +306974703016
To the Editor
International Journal of Gynecological Cancer
Dear Sir,
It would be very kind of you to accept the manuscript “IS CYTOREDUCTIVE SURGERY WITH
PERIOPERATIVE INTRAPERITONEAL CHEMOTHERAPY JUSTIFIED AS UPFRONT TREATMENT IN
LOCALLY ADVANCED EPITHELIAL OVARIAN CANCER?” for consideration and possible
publication in your journal. The manuscript has not been under consideration in any other
journal and has not been presented elsewhere.
All the authors have equally contributed to the preparation of the manuscript and agree with
the results.
Sincerely yours
Antonios-Apostolos K. Tentes, MD
Figure
Figure 1
Figure 2
LEGENDS
Figure 1: Overall survival in patients receiving HIPEC as upfront treatment. Blue
line=patients with HIPEC as upfront treatment. Green line=remaining patients with
HIPEC.
Figure 2: Survival of patients in relation with PSS. Green line=patients with PPS-0.
Yellow line=patients with PSS-1, Blue line=patients with PSS-2, and Red line=patients
with PSS-3.
Table
Table 1: Patients’ general characteristics
No of patients
%
90-100%
156
82.5
70-80%
30
15.9
50-60%
3
1.6
Large volume
163
86.2
Small volume
26
13.8
CC-0
114
55
CC-1
59
31.2
CC-2
11
5.8
CC-3
15
7.9
PSS-0
85
45
PSS-1
17
9
PSS-2
63
33.3
PSS-3
24
12.7
1-13
89
47.1
14-20
47
24.9
21-39
53
28
HIPEC
135
71.4
Performance status
Tumor volume
CC-score
PSS
PCI
Table 2: Peritonectomy procedures
Type of procedure
No
Pelvic peritonectomy
121
Greater omentectomy
119
Right subdiaphragmatic
86
Lesser omentectomy
87
Epigastric peritonectomy
73
Splenectomy
59
Right parietal peritonectomy
54
Cholecystectomy+resection of the omental bursa
51
Left parietal peritonectomy
43
Left subdiaphragmatic peritonectomy
40
Table 3: Postoperative complications in 63 patients (33.3%)
complication
No of pts
%
Anastomotic failure
17
26.9
Wound infection
11
17.5
Respiratory
8
12.7
Postoperative bleeding
2
3.2
Ileus
1
1.5
Urinary infection
2
3.2
Cardiac
2
3.2
Renal failure
1
1.5
Hepatic failure
1
1.5
Enterocutaneous fistula
2
3.2
Purulent peritonitis
8
12.7
Intra-abdominal abscess
3
4.7
Pancreatitis
1
1.5
Central line infection
4
6.4
Table 4: univariate and multivariate analysis for recurrence
Univariate
Multivariate
variable
P value
P value
Systemic chemotherapy
<0.001
0.05
HIPEC
0.01
HIPEC as upfront treatment
<0.001
G
0.02
Tumor volume
0.04
PSS
0.05
CC-score
0.01
Metastatic lymph nodes
0.01
Table 5: univariate and multivariate analysis of survival
univariate
multivariate
P value
P value
Performance status
0.001
<0.001
HIPEC
0.04
<0.001
variable
PCI
<0.001
PSS
<0.001
CC
<0.001
Ascites
0.02
<0.001
0.05
Title Page
IS CYTOREDUCTIVE SURGERY WITH PERIOPERATIVE INTRAPERITONEAL
CHEMOTHERAPY JUSTIFIED AS UPFRONT TREATMENT IN LOCALLY
ADVANCED EPITHELIAL OVARIAN CANCER?
AUTHORS AND AFFILIATIONS
Antonios-Apostolos K. Tentes, Director, Surgical Oncology, Peritoneal Surface
Malignancy Program, Metropolitan Hospital, Venizelou 1, 18547, N. Faliro, Greece,
[email protected]
Theodosios B. Palaskas, Professor, Department of Economics and Regional
Development, Panteion University, 136 Singrou Av, 17576, Athens, Greece,
[email protected]
Konstantinos Stamou, General Surgeon, Surgical Oncology, Peritoneal Surface
Malignancy Program, Metropolitan Hospital, Venizelou 1, 18547, N. Faliro, Greece,
[email protected]
Chrysostomos E. Stoforos, Assistant Professor, Department of Economics and
Regional Development, Panteion University, 136 Singrou Av, 17576, Athens, Greece,
[email protected]
Nicolaos Pallas, General Surgeon, Surgical Oncology, Peritoneal Surface Malignancy
Program, Metropolitan Hospital, Venizelou 1, 18547, N. Faliro, Greece,
[email protected]
Christina Karamveri, General Surgeon, Surgical Oncology, Peritoneal Surface
Malignancy Program, Metropolitan Hospital, Venizelou 1, 18547, N. Faliro, Greece,
[email protected]
Dimitrios Kyziridis, General Surgeon, Euromedica Kyanous Stavros, Viziis 1, 54636,
Thessaloniki, Greece, [email protected]
Christos Hristakis, Director, Surgical Oncology, Euromedica Kyanous Stavros, Viziis
1, 54636, Thessaloniki, Greece, [email protected]
Vasilios Kyriakopoulos. Anesthesiologist, Metropolitan Hospital, Venizelou 1, 18547,
N. Faliro, Greece, [email protected]
ADDRESS FOR CORRESPENDENCE
Antonios-Apostolos K. Tentes
Director, Surgical Oncology, Peritoneal Surface Malignancy Program, Metropolitan
Hospital, New Faliro, Greece, 18547
Tel: +302104807177, fax: +302104809293
e-mail: [email protected]
Manuscript (All Manuscript Text Pages in MS Word format,
including References and Figure Legends)
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IS CYTOREDUCTIVE SURGERY WITH PERIOPERATIVE INTRAPERITONEAL
CHEMOTHERAPY JUSTIFIED AS UPFRONT TREATMENT IN LOCALLY
ADVANCED EPITHELIAL OVARIAN CANCER?
ABSTRACT
Objective: Perioperative intraperitoneal chemotherapy after maximal cytoreductive
surgery has been used in the treatment of recurrent or persistent epithelial ovarian
cancer. The purpose of the study is the evaluation of the effect of hyperthermic
intraoperative intraperitoneal chemotherapy (HIPEC) as upfront treatment in advanced
ovarian cancer.
Methods/Materials: This is a prospective observational study of 166 women that
underwent 189 cytoreductive surgical operations for locally advanced epithelial ovarian
cancer. HIPEC was used in 135 cases (71.4%), and in 55 cases (29.1%) as upfront
treatment. Clinical indicators were correlated to four qualitative variables; morbidity,
hospital mortality, survival, and recurrences.
Results: HIPEC as upfront treatment in ovarian cancer was found to be related to
recurrence (p=0.001) but not to overall survival. The prognostic variables of survival
were the performance status, the completeness of cytoreduction, and the use of HIPEC
(p<0.001). The prognostic variables of recurrence were the degree of differentiation,
and the use of systemic chemotherapy (p=0.05).
Conclusion: HIPEC combined with maximal cytoreductive surgery may be used with
promising results as upfront treatment in patients with advanced epithelial ovarian
cancer. Prospective randomized trials are required.
KEY-WORDS
Cytoreductive surgery, peritoneal carcinomatosis, ovarian cancer, HIPEC
INTRODUCTION
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Cytoreductive surgery followed by systemic adjuvant chemotherapy is considered the
standard treatment for advanced epithelial ovarian cancer [1]. Despite a favorable initial
response, the majority of patients eventually develop local-regional recurrence leading
to poor overall outcome with 5-year survival rate not exceeding 30% and the disease
free survival not exceeding 18 months [2-3].
Perioperative intraperitoneal chemotherapy, after maximal cytoreductive surgery, has
been shown to be effective in the treatment of pseudomyxoma peritonei [4], diffuse
malignant peritoneal mesothelioma [5], and gastrointestinal cancer with peritoneal
carcinomatosis [6]. This treatment strategy has been used as an alternative in recurrent
and persistent ovarian cancer [7-10] and as upfront treatment in ovarian cancer with its
role not yet clear [8, 11]. Ovarian cancer is a disease that almost until the end remains
confined to the peritoneal surfaces. Under such circumstances the use of
intraperitoneally administered chemotherapy may be effective in eradicating the
microscopic residual tumor load. So far, the proper timing for the use of intraperitoneal
chemotherapy has not been clarified.
The purpose of the study is to evaluate the effect of HIPEC after extensive
cytoreductive surgery as upfront treatment in locally advanced epithelial ovarian
cancer.
MATERIALS AND METHODS
This is a prospective observational study designed in 2002 for women with locally
advanced epithelial ovarian cancer. The medical records of the patients that underwent
treatment until 2013 were included in the analysis. All patients were treated by the same
surgical team. The protocol was approved by the Ethical Committee of the Hospital and
all patients gave written informed consent.
Patient selection
Women with FIGO stage III ovarian cancer with good performance status (Karnofsky
performance scale ≥ 50%) capable to undergo major surgery were included in the study.
The patients were diagnosed either at the time of initial diagnosis, or at recurrence, or
even when found to be treatment-refractory. The adopted exclusion criteria were
evidence of unresectable disease at preoperative evaluation, white blood cell count
<4000/mm3, platelets <100 000, blood urea level > 50mg/dl, creatinine level > 1.5
mg/dl, abnormal liver function other than bile duct obstruction, patient unable to
undergo major surgery according to anesthesiological assessment. Disease was
considered “unresectable” if gross small bowel infiltration was evident or distant
metastases were present.
Preoperative assessment included physical examination, hematological-biochemical
examinations, tumor markers (CEA, CA-125), and abdominal and thoracic CT-scan.
Treatments
A midline incision from the xiphoid process to the pubic symphysis was always used
for maximal exposure of the abdomen. The extent and distribution of peritoneal
carcinomatosis was assessed after complete lysis of the adhesions and the Peritoneal
Carcinomatosis Index (PCI) was calculated [12-3]. Prior surgical score (PSS) was
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always assessed according to available previous surgical reports. Patients that did not
undergo previous surgery were assessed as PSS-0. Patients that underwent biopsy or
surgery in one abdominopelvic region were assessed as PSS-1. Patients with previous
history of surgery in 2-5 abdominopelvic regions were assessed as PSS-2, and those
with history of surgery in > 5 regions as PSS-3 [13].
Standard peritonectomy procedures were used with the intent of resecting the entire
macroscopically visible tumor load [14]. The completeness of cytoreductive surgery
was assessed after the completion of surgery using Sugarbaker’s criteria as CC-0, CC1, CC-2, and CC-3 [13-4]. Large volume disease was considered as peritoneal deposits
with lesion size greater than 0.5cm or confluence of lesions.
HIPEC with the Coliseum technique was always administered after tumor resection and
before the reconstruction of the alimentary tract. HIPEC was possible with a continuous
closed circuit of four drains (two inlet and two outlet), one heat exchanger, and two
roller pumps connected to the inlet and outlet drains (Sun-Chip, Gamida Tech, France).
The cytostatic drugs were diluted in 2-3 liters of Ringer’s Lactate solution and the intraabdominal temperature was maintained at 42.5-430C during perfusion. Cis-platin (50
mg/m2) in combination with doxorubicin (15 mg/m2) were used in chemotherapy naïve
patients, or in platinum sensitive patients for 90 min. Platinum resistant patients
received melphalan (70 mg/m2) or gemcitabine (1000 mg/m2) for 60 minutes.
Early postoperative intraperitoneal chemotherapy (EPIC) was given through a
Tenckhoff catheter during the first 5 postoperative days. The chemotherapy regimen
was 5-fluorouracil (400 mg/m2) diluted in 1.5lit of D1.5W.
HIPEC and EPIC was used in CC-1 patients, while CC-2 and CC-3 patients did not
receive intraperitoneal chemotherapy.
Adjuvant systemic chemotherapy was recommended to all patients and was left to the
discretion of the attending medical oncologist or the multidisciplinary team.
All patients remained for a minimum of 24 hours in the ICU after surgery. Patients
treated with EPIC remained in the ICU for 5 additional days postoperatively until the
completion of treatment. Postoperative complications were recorded and assessed
according to the following criteria. The uncomplicated patients were assessed as Grade
0. Complications that required minor intervention, oral antibiotics, bowel rest or
monitoring were assessed as Grade 1. Complications that required IV antibiotics or
bowel rest or chest tube draining were assessed as Grade 2, those that required hospital
re-admission or surgical or radiological intervention as Grade 3, those that produced
chronic disability or organ resection or bowel diversion as Grade 4, and those that
resulted to death as Grade 5. Grade 1 and 2 were assessed as minor complications and
Grade 3-5 as major complications. Advanced age was regarded as age over 65 years.
Survival was estimated from the time of surgery until the last follow-up or the time of
death.
Follow-up
All patients were followed-up every four months for the first year and every six months
for the next 4 years with physical, hematological-biochemical examinations, tumor
markers (CEA, CA-125), abdominal and thoracic CT-scan. Recurrences and the sites
of recurrence were recorded. No patient was lost during follow-up.
Statistical analysis
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Statistical analysis was possible using the SPSS (Statistical Package for Social
Sciences), version 17. Pearson, Kendall's Tau_b and Spearman's rho were applied to
test for the existence of correlation between the variables of interest depending on
whether they were dichotomous or continuous. Mean comparison was made possible
using ANOVA, Kruskal-Wallis, Mann-Whitney and the Pearson’s chi-square tests
depending on the nature of the data set. Multivariate analysis of survival was possible
with the Cox proportional hazard model for the identification of the prognostic
variables of survival. Cut off points were set at clinically important values or after
examining different possible points. Logistic regression analysis was applied to identify
the prognostic variables of recurrence, hospital mortality, and morbidity. A two-tailed
p value < 0.05 was considered statistically significant.
RESULTS
From 2003 until 2012, 166 women with locally advanced epithelial ovarian cancer
underwent 189 cytoreductive operations. The mean age of the patients was 58.3+12
(16-86) years. The patients’ general characteristics are listed in Table1. The mean PCI
was 14.8. Complete or near complete cytoreduction (CC-0 and CC-1) was possible in
163 patients (86.2%). HIPEC was used in 135 cases (71.4%), and as upfront treatment
in 55 (29.1%) cases. Adjuvant systemic chemotherapy with carboplatin and taxanes
was given in 134 (70.9%) women. The remainder did not receive adjuvant
chemotherapy. The peritonectomy procedures that were performed are listed in Table
2. In addition to these procedures, appendectomy was performed in 30 cases, segmental
intestinal resection in 28, colectomy other than sub-total and low anterior resection in
19, abdominopelvic lymph node resection in 19, sub-total colectomy in 17, and
gastrectomy in 14 cases.
Postoperative Morbidity
Hospital morbidity was recorded in 63 patients (33.3%) (Table 3). The re-operation rate
was 2.9% (4 patients). Grade 1, Grade 2, Grade 3, Grade 4, and Grade 5 complications
comprised 4.4% (6 patients), 11.0% (15 patients), 8.8% (12 patients), 11.7% (16
patients), and 4.4% (6 patients) respectively. The performance status, the tumor
volume, the completeness of cytoreduction, the presence of ascites, the extent of
peritoneal dissemination, and the use of HIPEC as upfront treatment were found to be
related to morbidity (p<0.05). The prognostic variables of morbidity were found to be
the PCI (HR=2.873, p<0.001, 95% CI=1.882-3.003).
Hospital mortality
The hospital mortality was 2.6% (5 patients). Correlation Kendall’s Tau analysis
showed that PSS, and PCI were related to hospital mortality (p<0.05). Multivariate
analysis suggested that PSS was the single prognostic indicator of hospital mortality
(HR=0.378, p<0.001, 95% CI=0.138-1.038).
Follow-up
The median follow-up time was 16 months (1-111). During follow-up 94 patients
(49.7%) were recorded with recurrence. Distant and local-regional recurrences were
recorded in 37 (19.6%), and 57 (30.2%) patients respectively. The use of systemic
chemotherapy, HIPEC, the degree of differentiation, the tumor volume, the PSS, the
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CC-score, and the presence of metastasis to lymph nodes were closely related to the
development of recurrences. The degree of differentiation, and systemic chemotherapy
were found to be the prognostic indicators of recurrence (Table 4).
Survival
The overall 5-year, and the median survival was 41%, and 51 months respectively.
Univariate analysis showed that the performance status, the degree of differentiation,
the PCI, the PSS, the CC-score, the presence of ascites, and the use of HIPEC were
found to be strongly related to survival (Table 5). The use of HIPEC as upfront
treatment showed that there was a trend of significantly better survival (64% vs 40%,
p=0.069) (Figure 1). 5-year survival rate in patients with PSS-0 was 62% (Figure 2).
Multivariate analysis showed that the CC-score, the performance status, and the use of
HIPEC were found to be the prognostic indicators of survival (Table 5).
DISCUSSION
Cytoreductive surgery is the first line of treatment for advanced epithelial ovarian
cancer [15]. What remains at the discretion of the surgeon, the medical oncologist and
the Multidisciplinary Team, is the classification of patients as “operable” or
“inoperable”. The patients are then stratified to either receive “upfront surgery” or “neoadjuvant chemotherapy”. This unintentionally biased selection and the rather arbitrary
concept of “maximal surgical effort” remain the weak points of many otherwise
brilliant clinical trials on overall survival of epithelial ovarian cancer.
The earliest recognized predictor of survival and recurrence in ovarian cancer is the
volume of the residual disease [16]. Retrospective studies [17] and meta-analyses
confirmed this result [18]. Published data and the personal expertise of surgeons led to
a gradual change from the concept of “tumor debulking” to “complete cytoreduction”.
Cytoreductive surgery was advanced by P.H. Sugarbaker who suggested that maximal
cytoreduction is possible by standard peritonectomy procedures [13]. This approach
has been proved effective in rare malignancies like mesothelioma or pseudomyxoma
peritonei and it drew the attention of general surgeons and gynecologists who treat
patients with advanced ovarian cancer [7-10], which is more frequent than peritoneal
mesothelioma. This demanding approach should become more readily available to
patients, and this can happen mostly in designated referral centers where complete or
near complete cytoreduction can be achieved [19]. The experience of the same standard
surgical unit may explain the achieved 86.2% of CC-0 and CC-1 operations despite the
rather high median PCI of our patients. A direct implication of surpassing the learning
curve in cytoreductive surgery is the re-direction of more patients towards upfront
surgical treatment.
Cytoreductive surgery is about learning to operate according to the physiology of the
peritoneal surface malignancy. For example, the greater omentum has been recognized
as the most important site of absorption of the peritoneal fluid [13]. As a result, total
greater omentectomy with skeletonization of the greater curvature of the stomach is
required and not only infracolic omentectomy. The majority of PSS-2 patients had
previously undergone infracolic omentectomy and all had been found to have residual
disease in the remnant of the greater omentum. Therefore, additional resection of the
remnant of the greater omentum was required. The lesser omentum is another important
site of peritoneal fluid absorption [19]. To our opinion lesser omentectomy is always
required among other peritonectomies in advanced ovarian cancer even if the lesser
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omentum is not involved. In cases with extensive peritoneal involvement resection of
various organs is mandatory: splenectomy, segmental intestinal resection, partial or
sub-total colectomy if the entire large bowel is involved, antrectomy, sub-total
gastrectomy or even total gastrectomy may be required if the stomach is involved [201].
Complex surgery that involves all abdominal regions in cancer patients carries a high
morbidity rate. The extent of peritoneal carcinomatosis among other indicators has been
shown to be a significant prognostic factor for postoperative morbidity and in-hospital
mortality [20-2]. In our study morbidity was found to be strongly related to PCI and
this should be distinctly disclosed to all patients. Usually a high PCI means that more
organ resections should be performed. Although not yet statistically evident, it is our
belief that a deliberate use of temporary or permanent stomas may decrease the overall
morbidity. Mortality is a consequence of high morbidity rate and is more often related
to surgical septic complications [22]. Overtreatment of very sick patients leads to the
conclusion that the combination of HIPEC and EPIC increases postoperative mortality.
Even if complete cytoreduction has been achieved and no macroscopically visible
tumor has been left behind, microscopic residual disease always remains in the
peritoneal cavity. The eradication of the microscopic residual tumor may be possible
with the use of intraperitoneal administration of cytotoxic drugs. However,
intraperitoneal chemotherapy is not effective in eradicating residual tumor with
diameter > 2.5mm because the cytostatic drugs cannot penetrate deeper than 2.5-3mm.
Therefore, patients that underwent CC-2 cytoreduction did not receive perioperative
intraperitoneal chemotherapy. The intraperitoneal administration of chemotherapy as
first line treatment in ovarian cancer has been studied in a small number of randomized
phase III clinical trials. Kirmani has failed to show any difference in response and
survival in a trial with limited number of patients randomized to receive intraperitoneal
cis-platin and etoposide versus intravenous cis-platin and cylophosphamide [23]. On
the other hand, Alberts in a larger trial showed that patients treated with intraperitoneal
cis-platin and intravenous cyclophosphamide had significantly improved survival
compared to patients treated with intravenous cis-platin and cyclophosphamide [24]. A
third randomized trial has shown that intravenous carboplatin followed by
intraperitoneal paclitaxel and intravenous cisplatin yielded significant improvement in
progression free-survival compared to intravenous cisplatin and paclitaxel [25]. In these
studies, the patients received normothermic intraperitoneal chemotherapy. Another trial
with a variability in what is described as residual disease failed to demonstrate any
benefit for patients receiving intraperitoneal chemotherapy [26]. Armostrong et al. has
shown that patients treated with intravenous paclitaxel combined with intraperitoneal
cisplatin and paclitaxel had significantly improved survival compared to patients
treated with intravenous paclitaxel and cisplatin [27].
A recent French Multicenter study showed that the PCI proved to be the most important
prognostic factor of survival. Some irregularities in results may be explained as the
effect of the learning curve and the spread of the cases in many centers [28]. In general,
it appears that intraperitoneal chemotherapy, when maximal cytoreduction is possible
may offer a survival benefit to women with advanced ovarian cancer. Complete or near
complete cytoreduction was possible in 86.2% of the patients although half of them had
extensive peritoneal carcinomatosis. As a consequence, patients with a high PCI value
(>13) should not necessarily be excluded from aggressive cytoreductive surgery; this is
also supported by several other studies [5, 28].
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Maximal cytoreduction in combination with HIPEC has until recently been reserved
for women undergoing secondary cytoreduction because this approach is considered as
salvage treatment for platinum resistant patients or for patients with recurrence. There
is evidence that both the overall survival and the disease free survival rate are
acceptable when HIPEC is used in treatment naïve patients [8, 11]. However, it is
doubtful whether overall survival is significantly increased. Although the analysis of
the data shows that HIPEC is a prognostic indicator of survival, and is strongly related
to recurrence, HIPEC as upfront treatment has shown a trend to statistical significance,
but not strictly significant. A significant prognostic factor of survival that was probably
underestimated in the past is the extent of previous surgery which is assessed by the
PSS. This implies that the initial cytoreduction is of utmost importance for long-term
survival [7, 29]. Bearing in mind that the initial surgical effort is a significant indicator
for long-term survival and that the rate of recurrence is still high after standard
treatment with maximal cytoreduction, HIPEC may be justified as an adjunct to upfront
treatment for advanced ovarian cancer [8, 11]. According to our data, PSS-0 women
treated with maximal cytoreduction combined with HIPEC and adjuvant systemic
chemotherapy are offered the significant benefit of 62% 5-year survival. A possible
systematic error in our, and many other studies, may arise from the quality of
information we receive about the completeness of cytoreduction at the time of initial
surgery. Presumably, if those patients had a high rate of suboptimal debulking this could
overestimate the survival advantage in patients who received upfront combination
cytoreduction and HIPEC compared to those who did not. Nevertheless, when complete
cytoreduction is achieved upfront, patients get the most out of all possible treatments.
It will be very difficult to actually prove in a randomized trial if it is extensive surgery
or HIPEC that makes the difference in survival. Complex abdominal surgery, the
surgeon’s estimate of what constitutes “operable disease” and what is a “CC-0
operation” will never be factors applicable to proper statistical analysis. What seems
reasonable today is to refer advanced ovarian cancer patients to designated peritoneal
surface malignancy centers where patients will be treated by gynecologic oncologists
and general surgeons dedicated to peritoneal surface malignancy program.
Conclusion: Perioperative intraperitoneal chemotherapy integrated in maximal
cytoreductive surgery with standard peritonectomy procedures may be used with
promising results as upfront treatment in patients with epithelial ovarian cancer.
Prospective randomized trials are required to document this finding.
CONFLICT OD INTEREST
No conflict of interest
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