ORIGINAL STUDY

Does Modality of Adjuvant Chemotherapy After Interval

Surgical Debulking Matter in Epithelial Ovarian Cancer?
An Exploratory Analysis
Nashmia Joudallah Al Mutairi, MD and Tien Le, MD

Objectives: This article aimed to study the role of adjuvant intraperitoneal (IP) chemotherapy after neoadjuvant chemotherapy and optimal interval surgical debulking.
Method: All patients with epithelial ovarian cancer treated with neoadjuvant chemotherapy were retrospectively reviewed from 2007 to 2009. Demographics, related diseases, and
survival outcome data were abstracted from the medical records. W2 statistics were applied to
categorical variables. Cox regression was used to model progression-free survival (PFS),
adjusting for age, residual status, and use of adjuvant IP chemotherapy. All P values less than
0.05 were considered statistically significant.
Results: Sixty-five patients were reviewed. The median age was 63.3 years. The majority
had stage III disease with serous histology. Optimal residual (G1 cm) after interval debulking
was achieved in 34 (54%) of 63 patients. Sixteen patients chose to receive adjuvant IP
chemotherapy. The median follow-up was 26.2 months. Fifty-one patients had progressed,
with a median PFS of 17.5 months. Adjuvant IP chemotherapy was not predictive of PFS
(hazard ratio, 0.91; 95% confidence interval [CI], 0.24Y3.44; P = 0.89). The estimated
median overall survival was 37.8 months (95% CI, 29.9Y45.7) in the intravenous group
versus 48.1 months (95% CI, 37.9Y58.3) in the IP-treated patients (P = 0.162).
Conclusions: Adjuvant IP chemotherapy was not predictive of survival after neoadjuvant
chemotherapy in our small exploratory study. The role of IP chemotherapy in this setting
needs to be further studied in a larger prospective patient cohort.
Key Words: Intraperitoneal chemotherapy, Interval debulking, Neoadjuvant
chemotherapy
Received June 5, 2013, and in revised form November 15, 2013.
Accepted for publication November 17, 2013.
(Int J Gynecol Cancer 2014;24: 461Y467)

Division of Gynecologic Oncology, Department of Obstetrics,

Gynecology and Newborn Care, University of Ottawa, Ottawa,
Ontario, Canada.
Address correspondence and reprint requests to Nashmia
Joudallah Al Mutairi, MD, Division of Gynecologic Oncology,
Ottawa General Hospital, 501 Smyth RdVRoom 8130,
Ottawa, Ontario, Canada K1H 8L6.
E-mail: nashmia-j@hotmail.com; nalmutairi@toh.on.ca.
The research project was funded by an educational research grant
from Roche Pharmaceuticals.
The authors declare no conflicts of interest.
Copyright * 2014 by IGCS and ESGO
ISSN: 1048-891X
DOI: 10.1097/IGC.0000000000000066
International Journal of Gynecological Cancer

ovarian cancer (EOC) is the second most common

E pithelial
gynecologic cancer in North America, causing more

deaths than all other gynecologic cancers combined.1 The

high case-fatality rate is related to the relative absence of specific signs and symptoms in early stages. As a result, the majority of patients will present at an advanced stage (III/IV) at
the time of diagnosis.2
The standard management for metastatic EOC consists
of an initial maximal cytoreductive effort, followed by adjuvant
intravenous (IV) platinum- and taxane-based chemotherapy.3Y6
Despite this aggressive therapeutic approach, most patients
with advanced ovarian cancer will eventually relapse and die of
progressive disease. Many studies have demonstrated that one

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Al Mutairi and Le

International Journal of Gynecological Cancer

of the strongest predictors of survival is the achievement of

optimal residual disease after primary surgical debulking, most
commonly defined as having no tumor nodule larger than
1 cm.7Y9 Because ovarian cancers are often widely metastatic at
the time of the presentation and commonly associated with poor
performance status, radical tumor debulking procedures to
obtain optimal residuals can be quite challenging. In Canadian
centers, the optimal primary debulking rate was reported to be
only approximately 44% in a recently completed prospective
trial.10 A higher rate of optimal resection has been achieved
when radical upper abdominal surgical procedures are routinely
used with acceptable morbidity,5 but this is not commonly
practiced in Canada. Patients poor performance status also
might preclude extended radical tumor debulking efforts at the
time of the presentation for concerns of prolonged postoperative
recovery and delays in starting adjuvant chemotherapy.
To address these management challenges, neoadjuvant
chemotherapy followed by interval surgical debulking has been
proposed as a potential alternative strategy to primary surgical
debulking.10 A meta-analysis of 21 studies on the use of
neoadjuvant chemotherapy published in 2009 suggested that
this was associated with an increased rate of optimal debulking
in patients with a high risk for suboptimal debulking at presentation. However, the improved surgical outcome did not
translate into a better overall survival (OS).11 In addition,
2 recent meta-analyses further suggested that neoadjuvant
chemotherapy seemed to be inferior to primary surgical
debulking.12,13 However, these analyses mostly included
studies where patients were commonly triaged toward neoadjuvant treatment because of the presence of significant
medical comorbidities or the presence of large bulky tumors,
making selection bias unavoidable and proper comparison
with standard treatment difficult.
In 2010, the European Organisation for Research and
Treatment of Cancer published the matured results of a prospective randomized phase 3 trial comparing primary debulking
surgery followed by standard platinum- or taxane-based chemotherapy with neoadjuvant chemotherapy followed by interval debulking surgery (IDS) in women with bulky stage IIIC
and IV EOCs.10 Consistent with other retrospective reports,
postoperative morbidity and mortality were lower in the neoadjuvant group compared with those in the control (primary
debulking surgery) group. The OS and progression-free survival (PFS) were not inferior between the study and control
group in the intention-to-treat analysis.10
The survival benefits of adjuvant intraperitoneal (IP)
chemotherapy after optimal primary cytoreductive surgery
(PCRS) have been well established. A meta-analysis of 6 randomized clinical trials (SWOG-8501/ECOG/GOG-104,14
GOG-172,15 NWOG,16 UCSD,17 SWOG/ECOG/GOG-114,18
and Yen et al19) on the efficacy of adjuvant IP chemotherapy
after optimal primary debulking surgery has shown consistent significant improvement in both PFS and OS. The pooled
hazard ratio (HR) for PFS for IP cisplatin treatment as
compared with that for IV treatment was 0.792 (95% confidence interval [CI], 0.688Y0.912; P = 0.001). The pooled
HR for the OS of IP cisplatin treatment as compared with that
of IV treatment was 0.799 (95% CI, 0.702-0.910; P =
0.0007). As expected, treatment-related toxicities were more

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commonly seen in the IP compared with the IV chemotherapy

group.20
To date, few studies have examined the benefits of IP
chemotherapy after optimal IDS in a neoadjuvant setting.21,22
Currently, The National Cancer Institute of Canada Clinical Trials Group is accruing patients on a large multicenter
prospective randomized phase 3 clinical trials (OV21) to investigate the potential benefit of IP versus IV chemotherapy
to address this question.
We evaluated the impact of IP adjuvant chemotherapy
in unselected, consecutive, neoadjuvantly treated patients with
EOC compared with that of IV adjuvant therapy after optimal
interval surgical debulking.

METHODOLOGY
A retrospective chart review was performed to identify
all consecutive unselected patients diagnosed with epithelial
ovarian/peritoneal or fallopian tube carcinoma from 2007 to
2009, who were treated on the neoadjuvant protocol at the
Ottawa Regional Cancer Centre. The Ottawa Hospital research ethics board granted ethical approval for the study.
According to our protocol, all patients with clinical
and radiographic findings consistent with stage III/IV disease without evidence of acute abdomen or gastrointestinal/
genitourinary obstruction would undergo a diagnostic core
biopsy of the most accessible lesion under computed tomography guidance for tissue diagnosis, with the intention to start
neoadjuvant chemotherapy. A histologic confirmation of a
primary gynecologic malignancy supported by immunohistochemistry is a prerequisite for the initiation of neoadjuvant
chemotherapy. Three to 4 cycles of neoadjuvant chemotherapy consisting of carboplatin (area under the curve [AUC], 6)
and paclitaxel (175 mg/m2) were administered intravenously
every 21 days. An IDS was scheduled approximately 4 weeks
after the third or fourth cycle, regardless of the observed
clinical or biochemical responses to neoadjuvant therapy.
Before the surgery, patients were counseled about the potential risks and benefits of IP chemotherapy and offered
adjuvant IP treatment if optimal debulking (G1-cm residuals)
was achieved. Radical upper abdominal debulking procedures
were not routinely used in our center during the study period.
Patients were reassessed approximately 4 weeks after
the surgery with the intention to continue with an additional
3 to 4 more cycles of chemotherapy to complete their primary
treatment. Those left with suboptimal residuals and those with
optimal residuals who chose not to receive IP chemotherapy
based on preoperative counseling were given additional 3 to 4
more cycles of IV chemotherapy, similar to the regimen in the
neoadjuvant phase. Optimally debulked patients given consent for adjuvant IP chemotherapy were administered 3 IP
chemotherapy cycles using a regimen similar to the GOG-172
study protocol consisting of IV paclitaxel (135 mg/m2) over
24 hours on day 1, followed by IP cisplatin (100 mg/m2) on
day 2, and paclitaxel (60 mg/m2) on day 8, to be repeated
every 3 weeks.
After the completion of all prescribed frontline therapies, patients were seen every 3 months during the first 3 years
and every 6 months thereafter, with CA-125 measurement
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International Journal of Gynecological Cancer

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Modality of Adjuvant Chemotherapy

TABLE 1. Cohorts Demographics Summary

Age, Median
(Range), y
Overall cohort

63.3 (25.8Y85.4)

Suboptimally
debulked group

59.2 (25.8Y81.1)

Optimally debulked
groupVadjuvant
IV treated

69.8 (44.5Y85.4)

Optimally debulked
groupVadjuvant
IP treated

64.1 (48.4Y72.6)

ECOG
Performance
Status, n (%)

Disease Stage
at Diagnosis,
n (%)

CA-125 Level
at Diagnosis,
Median (Range)

CA-125 Level
Before Interval
Debulking,
Median (Range)

0: 24/65
1: 34/65
2: 7/65
0: 8/30
1: 19/30
2: 3/30
0: 9/18
1: 6/18
2: 3/18
0: 2/16
1: 14/16
2: 0/16

3: 56/65 (86)
4: 9/65 (14)

1221 (72Y36,963)

72 (6Y1980)

3: 27/30 (90)
4: 3/30 (10)

1131 (128Y36,963)

176 (12Y1980)

3: 12/18 (67)
4: 6/18 (33)

1500 (303Y13,000)

84 (6Y456)

(37)
(52)
(11)
(27)
(63)
(10)
(50)
(33)
(17)
(13)
(87)
(0)

and clinical assessment at each visit. Computed tomography

imaging is considered only if there is a strong suspicion for
disease progression based on CA-125 elevation and/or suspicious clinical signs or symptoms.
Patients demographics, surgical pathologic data, and
survival outcomes were manually abstracted from paper-based

3: 16/16 (100)
4: 0/16 (0)

809 (72Y9369)

54 (13Y737)

medical records and cross-referenced to patients electronic

medical records to ensure accuracy.
Descriptive statistics were used to summarize the patientsdemographics and surgical pathologic data. W2 tests were
performed to detect significant associations between categorical variables. Cox proportional hazard regression models were

TABLE 2. Surgical Pathologic Findings Based on Available Data

Tumor Grade,
n (%)

Histology,
n (%)

Overall cohort

1: 1/63 (1.5)
2: 3/63 (5)
3: 59/63 (93.5)

Serous: 58/65 (89)

Nonserous: 7/65 (11)

Suboptimally
debulked group

1: 0/30 (0)
2: 2/30 (7)
3: 28/30 (93)

Serous: 27/30 (90)

Nonserous: 3/30 (10)

Optimally debulked
groupVadjuvant
IV treated

1: 1/18 (6)
2: 1/18 (6)
3: 16/18 (89)

Serous: 15/18 (83)

Nonserous: 3/18 (17)

Optimally debulked
groupVadjuvant
IP treated

1: 0/16 (0)
2: 0/16 (0)
3: 16/16 (100)

Serous: 15/16 (94)

Nonserous: 1/16 (6)

Residual Disease
Distribution,
n (%)

Modality of Adjuvant
Therapy Postsurgical
Debulking, n (%)

Microscopic: 20/63 (32)

Micro to G1 cm: 14/63 (22)
1Y2 cm: 9/63 (14)
92 cm: 20/63 (32)
Microscopic: 0/30 (0)
Micro to G1 cm: 0/30 (0)
1Y2 cm: 9/30 (30)
92 cm: 21/30 (70)
Microscopic: 11/18 (61)
Micro to G1 cm: 7/18 (39)
1Y2 cm: 0/18 (0)
92 cm: 0/18 (0)
Microscopic: 9/16 (56)
Micro to G1 cm: 7/16 (44)
1Y2 cm: 0/16 (0)
92 cm: 0/16 (0)

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None: 2/65 (3)

IV: 47/65 (72)
IP: 16/65 (25)
None: 2/30 (7)
IV: 28/30 (93)
IP: 0/30 (0)
IV: 18/18 (100)
IP: 0/18 (0)

IV: 0/16 (0)

IP: 16/16 (100)

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International Journal of Gynecological Cancer

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FIGURE 1. Kaplan-Meier survival estimates for PFS and OS in the entire study cohort (optimal and suboptimal
residuals, regardless of treatment received).
built to model the time to first progression, taking into account
the effects of age, residual status (optimal vs suboptimal), and
type of adjuvant chemotherapy (IP vs IV). The backward

stepwise variable selection strategy was used to obtain the most

parsimonious model. Kaplan-Meier analysis allowed for the
estimation of OS for each cohort. Log-rank statistics were used

FIGURE 2. Kaplan-Meier PFS estimates in optimally debulked patients stratified by adjuvant chemotherapy regimen.

464

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International Journal of Gynecological Cancer

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Modality of Adjuvant Chemotherapy

FIGURE 3. Kaplan-Meier OS estimates in optimally debulked patients stratified by adjuvant chemotherapy

regimen (IV/IP).
to compare survival curves. All P values less than 0.05 were
considered to be statistically significant. Statistical analyses
were performed using SPSS version 16 for Windows (SPSS Inc,
Chicago, Ill; 2007).

RESULTS
Sixty-five patients were identified from the Division of
Gynecologic Oncology surgical database. The median age at
the time of diagnosis was 63.3 years (range, 25.8Y85.4 years).
Of the 65 patients, 47 (75%) presented with significant abdominal distension as their presenting complaint. The majority of the cohort had stage III disease (86%), serous histology
(89%), and grade 3 tumors (94%). The median CA-125 levels at
diagnosis and immediately before the IDS were 1221 and 72,
respectively. The median number of neoadjuvant chemotherapy
cycles administered was 3. Tables 1 and 2 summarize the relevant demographic and surgical pathologic data for the overall
study cohort and the subgroups, respectively.
All but one patient underwent an attempt at IDS regardless of his or her response to neoadjuvant chemotherapy.
This patient was deemed to be at a very high risk for laparotomy and was analyzed with the subgroup having suboptimal residual disease based on her follow-up assessment
after 3 cycles of chemotherapy. No grade 3 or 4 postoperative
complication was encountered. An optimal residual of less
than 1 cm was achieved in 34 (54%) of 63 patients. Of these
34 patients, 20 (32%) had a microscopic residual disease, with
the remaining 14 (22%) having a macroscopic disease of less
than 1 cm. Twenty-nine patients (46%) had suboptimal residual
disease. Sixteen patients with optimal residual disease received
adjuvant IP chemotherapy with the other half continuing on
with additional IV chemotherapy postoperatively, as per their
preoperative decision. Two patients did not receive any adjuvant
chemotherapy because of poor performance status.

The median follow-up time was 26.2 months. Disease

progression occurred in 51 (86%) of 59 patients, with an
estimated median PFS of 17.5 months for the whole cohort.
Elevation of CA-125 level was the first sign of recurrence in
36 (61%) of 59 patients. Figure 1 shows the Kaplan-Meier
curves for OS and PFS in the whole cohort. Figures 2 and 3
show similar estimates in patients with optimal residuals treated
with IP and IV adjuvant chemotherapy, respectively. Approximately half of the patients with recurrent disease had a
progression-free interval of at least 6 months. They were all retreated with platinum-based chemotherapy. The overall response rate (complete and partial response) to the subsequent
second-line therapy was 44%.
Progression-free survival was modeled using Cox regression, adjusted for age, residual disease status, and type
of adjuvant chemotherapy (IP vs IV). The use of adjuvant
IP chemotherapy was not significantly predictive of improved survival, with an HR of 0.91 (95% CI, 0.24Y3.44; P =
0.89). Only suboptimal residual disease was of borderline

TABLE 3. Follow-up Survival Outcome at Last Visit

Follow-up time, median (range), mo
26.2 (1Y66)
Progression-free interval, median (range), mo 17.5 (6Y45)
Disease progression, n (%)
Yes
51/59 (86.0)
No
8/59 (14.0)
Patient status at last follow-up, n (%)
No evidence of disease
8/65 (12.3)
Alive with disease
31/65 (47.7)
Died of disease
26/65 (40.0)

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International Journal of Gynecological Cancer

Al Mutairi and Le

significance in predicting a shortened time to progressive

disease, with an HR of 2.19 (95% CI, 0.94Y5.14; P = 0.07).
At the last follow-up, 21 (40%) of 47 patients had died
of the disease in the IV group and 5 (31.3%) of 16 patients had
died in the IP-treated group (P = 0.56). Table 3 summarizes
the survival outcomes observed at the last follow-up. The
estimated median survival time was 41.3 months (95% CI,
32.9Y49.5) in the IV group versus 51.3 months (95% CI,
41.9Y60.8) in the IP cohort (P = 0.18). Figure 3 plots the
overall estimated survival curve for the 2 study groups (adjuvant IV vs IP chemotherapy).

DISCUSSION
The survival benefit of IP chemotherapy over IV chemotherapy in patients with optimal residual disease after
primary debulking surgery has been well established based on
a number of prospective randomized clinical trials.14Y20
Theoretically, this benefit is derived from the exposure of
tumor cells to a very high concentration of chemotherapy
drugs in the peritoneal cavity for a prolonged period, enhancing tumor cell kill activity.23
It is uncertain if a similar benefit can be extrapolated to
patients started on neoadjuvant chemotherapy, who had undergone an optimal interval surgical debulking. In 2009, the
Southwest Oncology Group conducted a phase 2 study of
neoadjuvant chemotherapy followed by interval debulking in
women with stage III and IV epithelial ovarian, fallopian tube,
or primary peritoneal cancer. In this study, women with adenocarcinoma on biopsy or peritoneal cytology consistent
with stage III/IV (pleural effusions only) epithelial ovarian,
fallopian tube, or primary peritoneal carcinoma were treated
with neoadjuvant IV paclitaxel at 175 mg/m2 combined with
carboplatin (AUC, 6) every 21 days for 3 cycles, followed by
debulking surgery. If optimally debulked, patients received IV
paclitaxel (175 mg/m2) and IP carboplatin (AUC, 5) on day 1
as well as IP paclitaxel (60 mg/m2) on day 8, every 28 days for
6 cycles. At a median follow-up of 21 months, the observed
PFS and OS for the 26 patients who received IV and IP adjuvant chemotherapy were 29 and 34 months, respectively.24
In contrast to this study, the median PFS for our patients who
received IP adjuvant chemotherapy was only 17.5 months.
This difference might be due to the differences in dose intensity, use of different platinum drugs, number of chemotherapy cycles performed after surgery (3 vs 6), and treatment
interval (21 vs 28 days) between the 2 IP protocols. Similar to
our study, Nelson et al21 compared 38 patients treated with IP
chemotherapy after neoadjuvant chemotherapy and optimal
IDS with 29 patients who had optimal PCRS, also receiving
IP chemotherapy. The recurrence rates for patients who
completed 4 or more cycles of IP chemotherapy in the IDS
and PCRS groups were 58% and 35%, respectively. The
median time to recurrence was shorter than expected with the
use of IP chemotherapy after neoadjuvant chemotherapy,
compared with those in previous trials.15
We observed that adjuvant IP chemotherapy was not
predictive of survival after neoadjuvant chemotherapy in our
small exploratory study. We hypothesize the following reasons for these findings. First, it is conceivable that after

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exposure to neoadjuvant chemotherapy, the residual tumor

cells at the time of interval surgery would be expected to be
relatively more platinum resistant compared with residual
tumor cells left after primary up-front surgery, thereby decreasing the expected benefit of increased dose intensity as
provided by the IP route. This is supported by Matsuo et al25
who studied the prevalence of platinum and taxane resistance
in epithelial ovarian, fallopian, and primary peritoneal carcinomas. In this report, platinum resistance was documented
to be more common after neoadjuvant chemotherapy compared with PCRS without previous chemotherapy (odds ratio,
5.4; 95% CI, 1.3Y23.2; P = 0.027). Second, the benefits of IP
chemotherapy are theorized to be dependent largely on direct
tumor cell exposure to a very high concentration of cytotoxic
drugs. Because of the commonly observed extensive tumor
fibrosis after neoadjuvant chemotherapy and adhesions after
radical debulking surgery, this might result in suboptimal
drug distribution and absorption in residual tumor masses,
decreasing the anticipated benefit. Third, the number of IP
chemotherapy cycles to achieve optimal benefits has not yet
been defined in a neoadjuvant setting. After the primary
initial optimal debulking surgery, all IP protocols had recommended at least 6 cycles of adjuvant treatment. In our
cohort, the median number of IP cycles given was 3. We might
not have fully exploited the full benefit of IP chemotherapy
because of the limited treatment in our current protocol. As
reported by the study of Tewari et al26 on the long-term outcomes of patients treated with IP chemotherapy on GOG
protocols 172 and 114 presented at the Society of Gynecologic
Oncologist 2013 annual meeting, patients who completed 5 or
6 cycles of IP therapy had a 5-year OS of 59%, compared with
18% versus 33%, with 1 or 2 versus 3 or 4 cycles, respectively
(P G 0.001), suggesting that at least 6 cycles of chemotherapy
would be preferred to maximize the benefits. Lastly, a recent
report had suggested that there exists a significant risk of
underestimating the residual disease after neoadjuvant chemotherapy secondary to the chemotherapy effect causing inflammation and fibrosis.27 This can potentially result in the use
of IP chemotherapy in patients with more than 1 cm of residual
disease in our IP cohort, leading to a lower observed survival
because these poor prognostic patients would have been included with good prognosis patients, diluting the potential
additional benefit of IP chemotherapy.
There are a number of important limitations in our
study. As with any retrospective review, there are unavoidable
selection biases and unknown confounders that cannot be
identified and corrected. Our follow-up time was relatively
short, and our small sample size provided only limited statistical power for a comprehensive statistical analysis. We
cannot make a definitive conclusion or recommendations
based on the current exploratory analysis. The roles of IP
chemotherapy after neoadjuvant chemotherapy will need to
be further studied and defined in a larger prospective cohort.
Currently, the National Cancer Institute of Canada is accruing
patients to prospective randomized phase 3 trials (OV21) to
evaluate the survival benefit of IP versus IV adjuvant chemotherapy in patients treated with neoadjuvant chemotherapy,
which will further guide oncologists on the application of IP
chemotherapy in this patient cohort.
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International Journal of Gynecological Cancer

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Future research on IP chemotherapy in the neoadjuvant

setting will need to address a number of important unresolved
issues such as the optimal number of IP cycles to be given
after neoadjuvant therapy, the use of IP carboplatin instead of
cisplatin to limit toxicities, the role of concurrent consolidation bevacizumab in combination with IP therapy, and the
incorporation of dose-dense strategy into the current standard
of care.

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