Gynecologic Oncology 92 (2004) 147 151

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Efficacy of intraperitoneal cisplatin as consolidation therapy in

patients with pathologic complete remission following front-line
therapy for epithelial ovarian cancer
Consolidative intraperitoneal cisplatin in ovarian cancer
Erkan Topuz, a Yesim Eralp, a,* Sezer Saglam, a Pinar Saip, a Adnan Aydiner, a
Sinan Berkman, b and Ekrem Yavuz c
b

a
Istanbul University Institute of Oncology, Istanbul, Turkey
Department of Gynecology and Obstetrics, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey
c
Department of Pathology, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey

Received 14 March 2003

Abstract
Objective. The aim of this study is to evaluate the efficacy of intraperitoneal cisplatin as consolidation treatment in epithelian ovarian
cancer patients with complete pathologic response following front-line platin-based chemotherapy.
Patients and method. Thirty patients who had no evidence of disease as assessed by second-look laparotomy following chemotherapy for
stage III epithelial ovarian cancer were given three courses of intraperitoneal cisplatin (100 mg/m2) with three weekly intervals as
consolidation therapy.
Results. Median age was 50 years. After a median follow-up period of 37 months, 16 patients are being followed with no evidence of
disease. Eleven patients developed recurrent disease. Median disease-free survival was 50 months. Median overall survival is not reached.
WHO grades 3 4 toxicity criteria were emesis in 19 patients (63.3%), abdominal pain in 5 (16.7%) and nephrotoxicity in 2 (6.7%) patients.
Catheter-related complications were infection/peritonitis in one and catheter malfunction in one patient. There were no serious hematologic
side effects that required transfusions or caused treatment delays. None of the patients developed serious neurologic toxicity. Treatment had
to be stopped early in four patients who refused further treatment due to abdominal pain, nausea ::and vomiting. Dose reductions were
required in five patients.
Conclusion. Our results suggest that intraperitoneal cisplatin is a feasible regimen that may provide a favorable outcome in terms of
progression-free survival in patients with a complete pathologic response following front-line treatment for ovarian cancer. Further
randomized trials are required to evaluate the role of consolidation treatment in this setting.
D 2003 Elsevier Inc. All rights reserved.
Keywords: Ovarian cancer; Consolidation; Intraperitoneal treatment

Introduction
The overall survival rate for patients with recurrent
ovarian cancer is poor. Despite high response rates attained
with primary platin-based chemotherapy, about 50% of
patients without any clinical evidence of disease will be
found to have pathologic complete response at second-look
* Corresponding author. Istanbul University Institute of Oncology,
Capa-Topkapi 34390, Istanbul, Turkey. Fax: +90-212-534-8078.
E-mail address: yeralp@yahoo.com (Y. Eralp).
0090-8258/$ - see front matter D 2003 Elsevier Inc. All rights reserved.
doi:10.1016/j.ygyno.2003.10.002

laparotomy. Almost half of these patients are expected to

recur after a mean interval of 24 months [1]. Consequently,
numerous clinical strategies are being evaluated in an effort
to prevent or delay recurrences in patients who achieve a
clinical complete remission [1,2]. Due to a lack of randomized data, the optimal management of advanced ovarian
cancer patients who have completed postoperative chemotherapy and are pathologically in complete remission has
not been established yet.
Since the peritoneal cavity is the most common site of
tumor recurrence after initial surgical treatment of ovarian

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E. Topuz et al. / Gynecologic Oncology 92 (2004) 147151

cancer, consolidation with intraperitoneal chemotherapy

may be a logical strategy in patients with small volume
disease. Regional delivery of drugs inside the peritoneal
cavity has the advantage of attaining high drug concentrations within five to six layers of tumor cells, while preventing some of the toxicities associated with intravenous
treatment, depending on the pharmacologic properties of
the agent used [3]. Cisplatin is one of the most active drugs
against ovarian carcinoma and some of its pharmacological
features make this agent specifically beneficial for intraperitoneal administration. Following intraperitoneal injection,
the ratio of total cisplatin exposure for the peritoneal cavity
to that of the plasma is 12-fold. Furthermore, it does not
cause clinically significant chemical peritonitis [4,5].
The beneficial role of intraperitoneal cisplatin in the
primary treatment setting has been confirmed by three
randomized trials [6 8]. Although the role of intraperitoneal
chemotherapy in the consolidative setting is not clearly
established yet, limited phase II data suggest a favorable
outcome compared to histologic controls in a subset of
patients with complete remission following primary treatment. In this study, we investigated the role of intraperitoneal cisplatin as consolidation treatment in patients who
have achieved pathologic complete response following
initial treatment with platinum-based combinations.

Materials and methods

Patient characteristics
Between 1990 and 2001, 30 patients with stage III
epithelial ovarian cancer were included in this phase II trial
to evaluate the efficacy of intraperitoneal cisplatin as consolidation therapy. Patients were considered ineligible if
there was any histologic, cytologic or clinical evidence of
persistent disease or adhesions which could interfere with
intraperitoneal distribution of the drug. Eligibility criteria
were age younger than 70 years, Karnofsky performance
status of 80% or greater, absence of myocardial, hepatic,
renal, neurologic impairment or insulin-dependent diabetes
mellitus and adequate bone marrow reserve. Patients were
required to have a leucocyte count >3000/mm3, platelet
count >100,000/mm3, serum creatinin <1.5 mg/dl and serum
bilirubin <1.5 mg/dl before enrollment.
All patients had received six cycles of intravenous
platinum-based combination chemotherapy after initial
debulking surgery. Chemotherapy regimens employed were
cisplatin and cyclophosphamide combination in 6 (20.0%)
patients; cisplatin and paclitaxel combination in 12 patients
(40.0%); cisplatin, adriamycin and cyclophosphamide combination in 5(16.6%) patients; carboplatin and paclitaxel
combination in 7(23.3%) patients. Following completion of
primary chemotherapy patients with normal abdominal
computerized tomography scans, normal chest X-rays and
normal CA125 levels underwent second-look laparotomy

for pathological evaluation. This procedure was performed

through a vertical incision extending above the umbilicus.
At least three peritoneal washings from the pelvic cul-desac, the left and right paracolic gutters were submitted
separately for cytologic examination. Intraperitoneal injections were performed through subcutaneous implantable
ports and catheters (T2035/460 mm-F 14-76, B.Braun
Celsite Port Germany) which were placed during secondlook laparotomy in 28 patients and single-used needles (3G
14. B.Braun Melsungen AG, Germany) in the remaining 2
patients. Needles were introduced percutaneously into the
peritoneum though the left lower quadrant of the abdomen
after infiltrating the skin and subcutaneous tissue with 1%
xylocain. Patients with pathologically confirmed complete
remission at second-look laparotomy were given three
courses of intraperitoneal chemotherapy.
Treatment plan
Chemotherapy was administered intraperitoneally via the
implantable ports every 3 weeks for three cycles starting
within 6 weeks after the second-look laparotomy. Patients
received 2000 ml of intravenous hydration fluids during
intraperitoneal therapy. Cisplatin was diluted in a volume of
1000 ml 0.9% saline solution at a dose of 100 mg/m2 and
given as a 2-h infusion following administration of 1000 ml
additional 0.9% saline to distend the abdomen and ensure
adequate distribution. All patients received intravenous
serotonin antagonists and dexamethasone premedication 15
min before treatment followed by oral antiemetic treatment
for 3 days. Intravenous hydration and antiemetic treatment
were given additionally during the second and third days in
case of grades 3 4 emesis that were not resolved with oral
treatment. Patients with abdominal pain from distension
received analgesics as required according to the severity of
the abdominal pain. Prophylactic hemopoietic growth factors were not routinely employed in this study.
Toxicity evaluations
Routine laboratory work-up and physical examination
were performed every 3 weeks before treatment. Toxicity
was graded according to the WHO toxicity criteria. Patients
were required to have adequate white blood cell (3000/
mm3), neutrophil (1500/mm3) and platelet (>100.000/mm3)
counts before each cycle. If blood counts were lower than
the threshold values listed above, treatment was delayed
until adequate hematologic recovery. Cisplatin dose was
reduced by 25% in patients with hematologic toxicity that
caused a delay of more than 1 week for initiation of the next
cycle or in patients with grades 3 4 abdominal pain or
emesis that were not resolved by routine measures. If serum
creatinin level was higher than 1.5 mg/dl, treatment was
withheld and adequate vigorous hydration with intravenous
fluids was started until serum creatinin levels were restored.
Cisplatin dose was reduced by 25% if the calculated GFR

E. Topuz et al. / Gynecologic Oncology 92 (2004) 147151

was between 50 and 75 ml/min and discontinued permanently if GFR was lower than 50 ml/min. Patients with any
unacceptable toxicity relating to intraperitoneal administration were excluded.
Follow-up criteria
All patients underwent clinical and radiologic assessment
after three cycles by serum CA125 levels and abdominal CT
scans obtained at 10-mm intervals. Patients were followedup regularly with three monthly intervals for 2 years, six
monthly intervals for the next 3 years and annually thereafter. Those with progressive disease were administered
second-line combination chemotherapy as appropriate.

149

Table 2
WHO grades 3 4 toxicity
n
Hematologic
Anemia
Leucopenia
Non-hematologic
Emesis
Abdominal pain
Nephrotoxicity
Neurotoxicity
Catheter-related
Infection/peritonitis
Malfunction

0
0

0
0

19
7
2
0

63.3
23.3
6.7
0

2
1

6.7
3.3

n = number of patients, % represents the ratio of patients with the given

toxicity among the whole group.

Statistical evaluations
Statistical analyses were performed by the statistical
programming package SPSS for Windows Release 10.2.1
(SPSS Inc., Chicago, IL). Overall and disease-free survival
were calculated by the Kaplan Meier method. Disease-free
survival was accepted as the time elapsed between secondlook laparotomy and first evidence of recurrence or last
follow-up examination. Overall survival was accepted as the
period between date of initial diagnosis and death or last
follow-up examination.

Results
Patient characteristics are presented in Table 1. The
median age of the patients was 50.6 years (range 28 68).
Toxicity
There were no serious hematologic side effects that
required transfusions or caused treatment delays. None of
Table 1
Patient characteristics
n

Menopausal status
Premenopausal
Perimenopausal
Postmenopausal

6
1
23

20
3.3
76.6

Stage
III A
III B
III C

7
1
22

23.3
3.3
73.3

Histology
Serous cystadenocarcinoma
Endometrioid carcinoma
Undifferentiated carcinoma
Clear cell carcinoma

19
4
5
2

63.3
13.3
16.7
6.7

n = number of patients, % represents the ratio of patients among the whole

group.

the patients developed serious neurologic toxicity. Totally,

86 courses of intraperitoneal chemotherapy were administered, all of which were available for toxicity assessment.
Treatment had to be stopped early in five patients who
refused further treatment due to severe abdominal pain (n =
2), emesis (n = 2) and catheter-related infection (n = 1).
Dose reductions were required in nine cycles administered
to five patients (Table 2).
Grades 3 4 nephropathy were observed in two patients
(2.3%), one of which was grade 4 nephrotoxicity developed
after the last cycle and required continuous hemodialysis. In
the remaining patients with less severe nephrotoxicity,
treatment was withheld until normal renal functions were
resumed.
Fourteen patients (16.2%) had self-limited grades 1 2
abdominal pain. Five patients (16.7%) developed grades
3 4 pain, which was relieved by supportive medical
therapy. Two patients discontinued treatment after second
and third cycles because of severe abdominal pain unresolved by routine analgesic treatment. One patient encountered peritonitis due to a catheter infection that was
treated successfully with antibiotics and did not interfere
with the planned treatment schedule. Another patient with
catheter-related infection quit intraperitoneal chemotherapy
after second course. There was one catheter malfunction
due to insufficient fibrosis of catheter to abdomen wall
which was relieved by a surgical intervention after the
first cycle. There were no chemotherapy-related fatal
complications.
Grades 3 4 nausea were encountered in 19 patients
(63.3%). Intractable nausea and vomiting led to dose reduction in five patients (16.7%). Four patients were hospitalized
for rehydration.
Survival
After a median follow-up period of 36.7 months (range:
9.7 82), 16 (55.17%) patients are alive with no evidence of
disease. Five patients have died due to disease progression

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E. Topuz et al. / Gynecologic Oncology 92 (2004) 147151

Fig. 1. Disease-free survival.

and one patient is lost to follow-up after recurrence. Median

survival was not reached. Overall survival at 5 years and
mean survival were 64.8% and 69.1 months (F4.7, 95%
confidence interval 59.7 78.38), respectively.
Eleven patients (37.93%) have recurred during followup. Disease-free survival at 4 years was 50.1% (F12.8).
Median disease-free survival was 50.1 months (F11.7 95%
confidence interval 27.03 73.17, range: 9.7 82 months)
(Fig. 1).

Discussion
Ovarian cancer patients who have no residual disease
after front-line chemotherapy are under considerable risk for
recurrence. It has been shown that almost half of these
patients will finally relapse after a median disease-free
interval of 24 months [1]. Over the last couple of decades,
numerous efforts have been placed to identify effective
consolidation treatment programs in this subset of patients.
Although the benefit of consolidation treatment has not been
clearly established yet, a recently reported study by the
Gynecologic Oncology Group provides evidence favoring
this approach. In this study, investigators looked at two
different schedules of consolidation treatment with intravenous paclitaxel in patients with clinical complete remission
after primary chemotherapy. This study was closed early
with a significant improvement in disease-free survival
favoring the prolonged regimen compared to the shorter
program [9].
Accumulating evidence suggests that intraperitoneal
treatment is an effective and a feasible approach in the
primary treatment of patients with small volume disease.
Three randomized studies have shown improved overall or
disease-free survival with combinations including intraperitoneal cisplatin in patients with optimally resected advanced stage disease [6 8]. Since the trials are designed
for the primary treatment setting, it should be pointed out
that these sets of data cannot be extrapolated to our patient
population.

In the current study, we have investigated the efficacy of

three courses of intraperitoneal cisplatin in patients with a
complete pathologic response to front-line platinum-based
chemotherapy. There are a few clinical trials suggesting that
intraperitoneal treatment may provide benefit in terms of
progression-free survival in this subset of patients [10 13].
Nevertheless, due to a lack of randomized data, the benefit
of intraperitoneal chemotherapy in the consolidative setting
is still controversial.
Median disease-free survival in our group of patients is
52 months, which compares favorably to those reported
previously. In an earlier trial that evaluated the role of
intraperitoneal cisplatin given at 80 mg/m2 as consolidation
therapy following negative second-look laparotomy, the
median time to recurrence was determined as 18 months
[10]. The authors emphasized the requirement for further
studies to determine the role of consolidation treatment in
ovarian cancer patients who have been attained complete
response with primary chemotherapy. The largest series has
been published by Barakat et al. [11] who have reported
their long-term follow-up data on 433 patients that have
received generally platinum-based intraperitoneal chemotherapy over a 14-year period. Complete pathologic responders constituted 20% of the whole group. The diseasefree survival in this subset was 32 months after a median
follow-up period of 2.7 years. Another trial by the same
investigators investigated the efficacy of intraperitoneal
cisplatin and etoposide combination in 11 patients with
pathologic complete remission [12]. At a median followup period of 36 months, the median disease-free survival
was not reached. The rate of relapse was substantially lower
in patients who received the whole planned dose (28%)
compared to those who required dose reductions (50%). A
retrospective comparison with a group of patients who had
not received consolidation treatment revealed a median
disease-free survival of 29 months, which led to the conclusion that intraperitoneal consolidation therapy may result
in improved disease-free survival [1]. A similar result was
obtained in a trial by Menczer et al. [13], where they looked
at the efficacy of single agent cisplatin given at 200 mg/m2
with thiosulphate protection as consolidation treatment in 24
patients with a pathologic complete response. The median
disease-free survival was reported as 35 months and the
authors concluded that short-term intraperitoneal cisplatin
should be considered for consolidation in patients with no
residual disease after front-line chemotherapy.
In our study, severe toxicity was not frequent with the
exception of grades 3 4 emesis which were encountered in
63.3% of the patient group (19 patients). Despite the high
incidence, severe nausea was controlled in most of the
patients and dose reductions due to intractable emesis were
required in two patients. Severe abdominal pain was the
second most frequent side effect related to intraperitoneal
chemotherapy, which was observed in seven patients. Although it is not possible to make direct comparisons with the
available data, our patients seem to have experienced a

E. Topuz et al. / Gynecologic Oncology 92 (2004) 147151

higher incidence of emesis and abdominal pain. In their

extensive evaluation, Barakat et al. [11] have reported
severe emesis in 3.2% and abdominal pain in 1.5% of the
whole patient group, which are considerably lower compared to our group. The incidence of severe nephrotoxicity
seen in our patients was similar to that reported by Menczer
et al. [13] (7% vs. 8%) who used twice the dose of cisplatin
employed in our study. In the GOG 172 trial, serious renal
toxicity was reported as 6% in the investigational arm that
included an identical dose of cisplatin as ours in addition to
paclitaxel [8].
Interestingly, our patients did not experience severe
neuropathy, which is comparable to those trials that
employed similar cisplatin doses [11,12]. Serious neurotoxicity has been reported by others that have utilized
higher-dose platin regimens, reaching 200 mg/m2 [13,14].
Furthermore, catheter-related complications were rarely
encountered and self-limiting. Severe events such as organ
perforation or sepsis were not seen throughout the study
period. In the study by Barakat et al. [11], organ perforation and sepsis were reported in 2 (0.4%) and 14 patients
(3.4%), respectively. Since the latter study is a retrospective
evaluation of a heterogenous patient group, direct comparisons can be misleading. In addition to the present study,
our previous experience has shown that, despite a high
incidence of renal toxicity and emetogenic potential due to
cisplatin, complications related to intraperitoneal therapy
per se are not considerable [15,16]. Consistent with previous data, the manageable toxicity profile and prolonged
disease-free survival suggest that intraperitoneal consolidation treatment with cisplatin is a feasible approach in the
consolidative setting. However, this outcome should be
evaluated with caution in the context of the study design
itself, as encouraging results obtained by small phase II trials
are not always reproducible by randomized trials. Nevertheless, our study as well as others discussed above provide
rationale to pursue this approach further. Further large-scale
randomized trials are required to determine whether intraperitoneal consolidation treatment yields survival benefit in
selected patients with ovarian cancer who are in complete
remission following front-line chemotherapy.

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