Introduction
Epithelial ovarian cancer (EOC) is one of the most frequently
diagnosed malignancies and the leading cause
of death from a gynecological malignancy, accounting
for more than 313,000 new cases annually and more
than 207,000 deaths worldwide.[] Approximately 70%
of all patients are diagnosed in the advanced stage, especially
the International federation of gynecology and
obstetrics (FIGO) Stages IIIC and IV, due to the lack
of specific symptomatology and screening procedures.
Primary debulking surgery (PDS) followed by adjuvant
chemotherapy with paclitaxel plus platinum-based chemotherapy
is the standard treatment for advanced-stage
ovarian cancer.[,] However, complete resection during
cytoreductive surgery is strongly correlated with the
longer survival of patients. Eventually, for these patients,
most of whom are in the advanced stage, the probability
of surgical success is reduced due to the diffuse nature
of many metastatic foci, which often prevents complete
cytoreduction, affecting the prognosis of the patients.
[] In terms of survival, it was shown that the patients
with no macroscopic residual tumor (complete debulking;
R0 resection) were better than the patients with
minimal residual disease (optimal debulking; ≤1 cm,
R1 resection) and those with residual disease (suboptimal
debulking; >1 cm, R2 resection).[]
In patients who are not good candidates for surgery
due to the extensive spread of a tumor, neoadjuvant
chemotherapy (NACT), followed by interval debulking
surgery, are the standard treatment approach.[,]
In retrospective studies, it was observed that the possibility
of optimum debulking increased with NACT,
and surgery-related complications decreased.[,]
However, according to a meta-analysis, even though the increased maximal cytoreduction rate with NACT
increased median survival, delayed surgery had a negative
effect on the overall survival of the patient.[] In
patients who are receiving NACT, the number of chemotherapy
cycles and the optimal time for interval debulking
surgery are important parameters that might
affect the survival outcomes of patients. In a retrospective
analysis on this subject, delayed cytoreduction in
patients who received 5 cycles or more of NACT was
shown to have similar survival outcomes as patients
who received 2-4 cycles of NACT.[]
Another meta-analysis argued that there was no difference
in PFS and OS between NACT and PDS groups
and that the patient group that could benefit from
NACT should be determined based on factors such as
age, stage, performance status, and tumor histology.[]
Other analyses in the literature show no difference in
PFS and OS between the two groups.[,,] Therefore,
the aim of the present study is to compare the clinicopathologic
characteristics and treatment outcomes in
the patients with FIGO Stages 3 and 4 ovarian carcinomas
receiving PDS and the patients receiving NACT.
Methods
The patients with FIGO Stage III or IV, who were 18 years
and over, admitted between 2009 and 2017, diagnosed
with ovarian, tubal, or primary peritoneal serous carcinoma
after exploratory laparotomy, laparoscopy, imageguided
biopsy or surgery and subsequently treated with
chemotherapy or surgery in four centers were included
in the study. Of the patients included, 34 (18%) were receiving
treatment at the Medical Faculty Hospital of Gazi
University, 80 (44%) at Istanbul Dr. Lutfi Kirdar Kartal
Training and Research Hospital, 42 (23%) at the Medical Faculty Hospital of Hacettepe University, and 27 (15%) at
Ankara Dr. Zekai Tahir Burak Women's Health Training
and Research Hospital. The patient's performance status
was evaluated according to the Eastern cooperative oncology
group"s (ECOG) performance criteria. Clinical
staging was done according to the FIGO staging. Treatment
response was assessed according to the criteria of
the response evaluation criteria in solid tumors.
Patients who were diagnosed under 18 and could
not receive treatment (surgery or chemotherapy) due
to their general condition or performance related to
their disease were excluded from the study.
Carboplatin/paclitaxel was administered to 95.6%
(n=88) of the patients in the NACT group in cycles every
21 days, and 4% of the patients were administered
another chemotherapy protocol chosen by the clinician,
with a median of 3 cycles (min: 1-max: 9) NACT.
OS was defined as the date range from diagnosis to
the date of the last follow-up or death, and PSF as the
time to the last control date or date of death in those
without progression (relapse/metastasis) or progression.
Ethics committee approval of the study was obtained
from our institution.
Statistics
All data were analyzed using the SPSS version 22
(Chicago, IL, USA) statistical software. The comparison
of clinicopathological features of NACT and PDS
was examined by the Chi-square test or Fisher's exact
tests. The Student t-test was used to compare continuous
variables. The Mann-Whitney U-test was used for
the groups which were not normally distributed. The
survival rates were calculated according to the Kaplan-
Meier method. A multivariate (Cox regression) analysis
was used to evaluate the independent risk factors that
affected survival. The value of p≤0.05 was considered
to be significant. A correlation test was performed to
determine the correlation between the level of CA125
and the survival times.
Results
The clinicopathological characteristics of the groups
are demonstrated in Table 1. Median age (p<0.001),
median CA125 values (p<0.001), clinical stage
(p<0.001), localization of the tumor with the widest
diameter at diagnosis (p<0.001), histopathology
(p=0.038), surgical resection status (p=0.018), pathological
T stage (p=0.024), and the number of adjuvant
chemotherapy cycles (p<0.001) were not equally distributed
between the groups.
Table 1 Comparison of clinicopathological characteristics and treatment of the groups
Complete response in 14 (15%) patients, partial
response in 68 (74%) patients, stable disease in 6 (7%)
patients, and progressed disease in 4 (4%) patients were
detected in the NACT group. In the NACT group, the
median CA125 level after CT was 41.22 (range, 0-4994).
In the NACT group, 49 (53%) patients underwent
total hysterectomy, bilateral salpingo-oophorectomy,
omentectomy, appendectomy and para-aortic and pelvic
lymphadenectomy, 36 (40%) patients underwent debulking/
cytoreductive surgery, and 7 (7%) patients underwent
total hysterectomy. Bilateral salpingo-oophorectomy and
omentectomy were performed. In the PDS group, surgically
total hysterectomy, bilateral salpingo-oophorectomy,
omentectomy, appendectomy and para-aortic and pelvic
lymphadenectomy in 68 (75%) patients, debulking/cytoreductive
surgery in 22 (24%) patients, and total hysterectomy
in 1 (1%) patient, bilateral salpingo-oophorectomy,
and omentectomy were performed (p=0.01).
The median follow-up period was 27 months (range
2?110), and the median and 2-year OS of all the patients
were found as 49 months and 41%, respectively;
and median and 2-year PFS as 19 months and 43%,
respectively. In addition, a negative correlation was
detected between the OS and PFS periods with the
CA125 levels at diagnosis (p=0.021, r=?0.173 for OS;
p=0.002, r=?0.208 for PFS).
In univariate analyses, prognostic factors affecting
OS were the treatment protocol (NACT vs. PDS,
p<0.001), ECOG PS (p<0.001), age (<70 years old vs.
?70, p=0.002), clinical stage (p=0.042), and the localization
of the tumor with the widest diameter at diagnosis
(p=0.029). In the multivariate analysis, the presence
of NACT (HR: 2.30, 95% CI: 1.25?4.23, p=0.007)
and poor performance (HR: 2.52, 95% CI: 1.18?5.10,
p=0.017) significantly increased risk of death. Table 2
shows the results of univariate and multivariate analyses
for OS. Survival curves of the groups are shown in Figure
1 according to the treatment protocols and in Figure
2 according to ECOG PS. Only surgical resection status
was statistically significant for PFS (p=0.001); however,
no difference was found for the treatment protocol. No
independent prognostic factor was detected for PFS in
the multivariate analysis. Table 3 shows the prognostic
factors affecting PFS. PFS curves of the groups are
shown in Figure 3 according to the treatment protocol
and Figure 4 according to the surgical resection status.
Table 2 Prognostic factors affecting overall survival between the group
Table 3 Prognostic factors affecting progression-free survival between groups
Fig. 1. Overall survival curves according to treatment
protocol (NACT vs PDS).
NACT: Neoadjuvant chemotherapy; PDS: Primary debulking
surgery.
Fig. 2. Overall survival curves according to ECOG PS.
ECOG: Eastern Cooperative Oncology Group; PS: Performance
status.
Fig. 3. Progression-free survival curves according to
treatment protocol.
NACT: Neoadjuvant chemotherapy; PDS: Primary debulking
surgery.
Fig. 4. Progression-free survival curves according to
surgery resection status.
Discussion
In the present study evaluating retrospectively the results
of the patients, who received NACT and PDS in advanced-stage ovarian cancer, it was found that OS was
worse in the patients who received NACT; however, there
was no difference between the groups in terms of PFS. In addition, R0 resection was less provided in the NACT
group. Adverse characteristics for OS were in the NACT
group, poor performance, advanced clinical stage, over 70 years of age, and localization of large tumors outside
the ovary, respectively. Furthermore, poor performance
and being in the NACT group were independent prognostic
factors for OS. Only providing R0 resection was
detected as a good prognostic factor for PFS.
In the study conducted by Schwartz et al.[] to retrospectively
analyze the results of 206 patients to whom
PDS was applied and 59 patients receiving NACT, no
statistically significant difference was found between
the groups regarding median PFS and OS. Although
the patients receiving NACT were older and had worse
performance than the PDS group, survival outcomes
were similar. However, in the current study, the unbalanced
number of patients between the groups, the limited
number of patients receiving neoadjuvant therapy,
and the comparison of the results of the patients in the
NACT group, who could only undergo surgery, should
be considered in the evaluation.[] The studies of European
Organization for Research and Treatment of
Cancer (EORTC) 55971 and CHORUS indicated that NACT was non-inferior when compared to PDS.[,]
In the EORTC 55971, median survival was detected
as 29 months in PDS and 30 months in NACT; and in
the study of CHORUS, median OS was found as 22.6
months versus 24.1 months, respectively.[6,7] In a retrospective
study by Kobal et al.,[] PFS and OS data of
the PDS (n=108) and NACT (n=49) groups were similar.
It was shown that postsurgical complications were
significantly lower in the NACT group. Median OS and
PFS were found at 41.3 and 17.3 months, respectively,
and 34.5 and 18.3 months in the NACT group. In another
randomized study comparing NACT and PDS in
terms of perioperative complications and survival in
171 patients with stage IIIC-IV epithelial ovarian, fallopian
tube, or primary peritoneal cancer, and complete
resection rates were found to be significantly higher
in the NACT group. However, major post-operative
complications were significantly higher in the PDS
group. In this study, similar median PFS and OS were
found between groups such as the EORTC55971 and CHORUS studies.[] In another randomized study,
301 patients were evaluated, but NACT could not be
confirmed to be non-inferior to PDS, and it was interpreted
that NACT may not always replace PDS.[]
However, the present study showed that the PDS group
was longer OS compared with NACT, but not in PFS. It
was observed that the median survival was not reached
yet in the PDS group; however, the median PFS was 24
months, the median OS was 41 months, and the median
PFS was 17 months in the NACT group. However,
it should also be considered that the patients receiving
NACT in the present study have worse clinical characteristics
for OS (advanced age, poor performance, high
CA125 level, advanced stage, extra ovarian spread of
large tumors, and severe high histopathology).
It is known that the surgical resection status in patients
with ovarian cancer, especially providing R0 resection,
significantly affects the survival of the patients.
[,,] Can R0 resection be provided at a higher rate
by giving chemotherapy to patients with advanced stage
and high tumor burden before the surgery? Numerous
studies investigated the answer to this question; however,
the results of the studies are controversial.[,,,-]
The EORTC 55971 study was a multicenter, prospective,
and randomized study that evaluated the treatment
outcomes of NACT (n=334) and PDS (n=336). In the
current study, including almost all Stages III and IV patients, the rate of residual disease of 1 cm after surgery
was higher in the NACT group (80.6% vs. 41.6%). In the
multivariate analysis, the most potent independent factor
predicting survival was the absence of residual tumors
after surgery.[] Similar to EORTC 55971 study,
the CHORUS study is a multicenter, randomized, and
controlled non-inferior study that compares the results
of PDS (n=276) and NACT (n=274). In the present
study, the incidence of a residual tumor of 1 cm and less
after the surgery was 41% in the PDS group and 73% in
the NACT group, and the rate of the patients to whom
R0 resection was provided was found to 17% and 39%,
respectively.[] In the study by Kobal et al.,[] R0 resection
was found to be 53.7% in the PDS group and 77.6%
in the NACT group. In addition, the correlation between
residual disease and survival was revealed in the study.
In another study in which 285 patients were analyzed
retrospectively, residual tumor burden was evaluated as
an independent factor significantly affecting survival.[]
In the present study, surgical resection status was isolated
as a prognostic factor that affects PFS. However, this
significance was not in question for OS. It was observed
that as the residual tumor was reduced, PFS recovered.
In the NACT group, less R0 resection was observed compared
to PDS (48.9% vs. 69.2%, respectively); however, a
higher pT3 stage was seen after the surgery. However, it
should be considered that the extra ovarian localization
of large tumors was higher in the NACT group. It seems reasonable that fewer R0 resections were performed in
the NACT group with higher tumor burden, worse performance,
and older age compared to the younger PDS
group with better clinical features.
In a retrospective analysis evaluating the potential
predictive markers for survival and optimal cytoreduction
of the patients, who underwent interval
debulking surgery only after NACT, it was found that
CA125 reduction kinetics and ascites regression were
associated with interval debulking and the survival
outcomes.[] In the current study, CA125 levels
at diagnosis were significantly higher in the NACT
group than in the PDS group concerning the tumor
burden. Furthermore, a negative correlation was
found between all patients" CA125 levels at diagnosis
and OS and PFS periods. In the study, the NACT
group did not evaluate ascites regression; however,
the correlation between malignant ascites at diagnosis
and OS and PFS was investigated. Malignant ascites at
diagnosis showed an almost statistically significant effect
on PFS but not on OS. Furthermore, the presence
of malignant ascites between the groups was similar.
Cioffi et al.[] examined the effects of patient age
in 102 patients who received NACT. In the study, the
patients were examined in two groups, aged under 70 years old and over, and they showed that the patients
over 70 years old were more suitable for NACT due
to higher comorbidity and poor performance. In the
patients aged 70 and over, median PFS and OS were
significantly lower in the present study (median PFS; 9
months vs. 13 months and median OS; 21 months vs.
29 months, respectively). In addition, advanced age,
stage IV disease, ascites, and residual disease greater
than 1 cm were associated with OS, lower PFS, a high
American Society of Anesthesiologists score, and residual
disease greater than 1 cm.[] In the present study,
there were more patients over 70 years old in the NACT
group compared to PDS. In the study, even though
worse median OS was isolated in patients over 70, this
correlation was not found in PFS. As in other studies,
NACT seems to be used more in the treatment option
in advanced and elderly patients in the current study.
In the evaluation of a subgroup analysis of the
EORTC 55971 study, clinical and pathological characteristics
that could be potential biomarkers were investigated.[
20] The largest metastatic tumor size and stage
of disease were found to be statistically significantly
correlated with 5-year survival. It was shown that stage
IIIC patients with metastatic tumors of ≤45 mm benefited
more from primary surgery, and Stage IV patients with metastatic tumors of >45 mm benefited more from
NACT. Furthermore, the patients with stage IIIC and
large tumors and those with stage IV and less common
diseases benefited equally from both treatments. Survival
outcomes of PDS and NACT treatment groups in
the EORTC 55971 study were similar; however, Stage
IIIC patients with small tumors had better survival with
PDS, and Stage IV patients with large tumors had better
survival with NACT.[] Depending on this analysis,
the current study observed that the patients with large
tumor sizes and advanced stages were mainly treated
with NACT. In the present study, when the patients
were examined in two groups with the largest tumor
size of >5 cm and <5 cm, any correlation was not found
between the largest tumor size and OS and PFS, unlike
other studies. In addition, the extra ovarian spread of the
large tumors was more common in the NACT group.
In a meta-analysis study including 21 studies conducted
between 1989 and 2008, data of the patients with
Stages IIIC and IV EOC, who received NACT, were
compared with PDS. According to this meta-analysis,
patients receiving NACT were evaluated as those with
poor risk factors and a low chance of achieving optimal
cytoreduction.[] In the National Cancer Database
study conducted in 2016, which included 62,727 patients
with Stages IIIC and IV EOC, demographic characteristics,
medical comorbidities, cancer characteristics, and treatment characteristics of the patients were evaluated.
[] Of the patients, 6922 (11%) received NACT, and
31280 (50%) had PDS. It was observed that NACT was
used more in stage IV than in stage IIIC (13% and 9%,
respectively). In addition, the use of NACT increased
over time. Variables associated with the increased use of
NACT were detected as the patients older than 50 had
more comorbid diseases and those with Stage IV and
high-grade epithelial ovarian carcinoma.[] Likewise,
it was observed in the present study that the patients in
the NACT group were older, had more advanced stages,
had poor performance, and had a low chance of complete
resection after the surgery.
Conclusion
Consequently, the present study determined that the OS
of the NACT group was worse, and R0 resection could
be achieved less than the PDS group. This result was suggested
to be related to the selection of patients with poor
characteristics in the NACT group. However, NACT
may continue to be an alternative treatment option in
patients who do not have a chance for PDS that results in
complete resection due to advanced age, comorbidities,
or tumor extent since no difference was shown in PFS
results between the groups. It was also thought that this
result would be different in a study in which the clinicopathological
characteristics of the groups were similar.
Major limitations of the study are retrospective design
and quality of surgery was not controlled, the effect
of surgery is greater in the choice of treatment of patients.
In addition, the side effects of the treatments (surgery,
chemotherapy) administered to the patients and their
effects on quality of life were not evaluated in the study.
Peer-review: Externally peer-reviewed.
Conflict of Interest: All authors declared no conflict of interest.
Ethics Committee Approval: The study was approved by the
Sivas Cumhuriyet University Non-interventional Clinical Research
Ethics Committee (no: 2021-08/37, date: 19/08/2021).
Financial Support: None declared.
Authorship contributions: Concept - A.Ö., O.Y., M.Y.;
Design ? M.Y., A.Ö.; Supervision - M.E.Y., Z.A., K.B.Y., G.T.,
O.Y.; Funding - O.Y., A.Ö.; Materials - M.B., D.T.Ö., M.C.S.,
M.G., M.A.O., M.M.M., B.K.İ.; Data collection and/or processing
- M.Y., M.B., D.T.Ö., U.A., B.K.İ., F.G., V.S.; Data
analysis and/or interpretation - O.Y., M.Y., F.G.; Literature
search - M.Y., A.Ö., O.Y., F.G.; Writing - M.Y., F.G., O.Y.;
Critical review - M.Y., O.Y., A.Ö.
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