Introduction
In cancer treatment, staging is an essential tool for
comparison of therapeutic outcomes, classification of prognostic factors, and deciding treatment. The
International Federation of Gynecology and Obstetrics
(FIGO) staging has played a central role all over
the world providing easier comparisons of treatment results and aiding to make diagnosis and planning
treatment for gynecologic malignancies. In 1970,
FIGO introduced the first staging system for cervical
uterine cancer.[] Until now, the FIGO staging was
based mainly on clinical examination with the addition
of certain procedures that were allowed by FIGO
to change the staging. In 2018, this has been revised by
the FIGO Gynecologic Oncology Committee to allow
radiological and pathological findings, where available,
to assign the stage. The revised staging was presented
at the FIGO XXII World Congress of Gynecology and
Obstetrics.[] Table 1 summarizes the changes in uterine
cervical cancer (UCC).
Table 1: Changes in cervical cancer staging system in new FIGO 2018
Staging according to the previous systems was inadequate;
with 20-40% of Stage IB-IIIB cancers understaged
and up to 64% of Stage IIIB cancers overstaged.[-] They did not include assessment of lymph
node metastases (LNM), an important determinant for
prognosis and treatment planning. Moreover, radical
trachelectomy, an emerging fertility-preserving technique
in which the uterine corpus is anastomosed to
the vagina to treat many women diagnosed during
their reproductive years, was not a consideration with
these previous staging systems.[] The revisions introduced
in the 2018 FIGO staging system are intended
to address the gap between the staging formalism and
routine clinical practice and to explicitly acknowledge
the role that advanced imaging has come to play in the
care of women with cervical uterine cancer.[] In addition,
new staging system clearly reflects the importance
of LNM as a major prognostic factor in UCC.
After the change of staging system, all authorities
expected to see a significant advance to stratify patients
with different prognosis. In the perspective of new
changes in staging system, we compared FIGO 2009
and 2018 staging systems in patients with operated
UCC receiving adjuvant radiotherapy+/?chemotherapy
(RT+/-CT) in our RT center.
Methods
We evaluated the medical files of UCC patients treated
at the Ege University, Department of Radiation Oncology
between January 2008 and December 2017. All
patients underwent surgery before RT. The surgical
procedure was usually total abdominal hysterectomy
with bilateral salpingo-oophorectomy (TAH-BSO) in
addition to pelvic and/or para-aortic lymph node dissection
(LND), and partial or total omentectomy with
peritoneal washing cytology. Patients with metastatic
disease and patients receiving definitive RT were excluded
from this analysis. All patients were staged according
to both 2009 and 2018 staging systems.
Post-operative RT+CT was applied in patients with
LNM, positive and/or close surgical margin, bulky tumor
(>4 cm), and parametrial involvement, whereas
post-operative RT was applied to patients with suboptimal
surgery and/or with lymphovascular space involvement.
Weekly concomitant cisplatin with the dose
of 40 mg/m2 was administered to patients received concomitant
CT with RT. RT consisted of external RT and
intracavitary brachytherapy. External RT was applied
with 6-18 MV linear accelerators to all patients. External
RT was applied with 1.8 Gy daily fractions with a
median total dose of 45 Gy (45-59.4 Gy). Brachytherapy
was applied with high-dose rate afterloader microSelectron
device to 0.5 cm depth from mucosal surface.
Brachytherapy dose and fractionation were 3×600 cGy.
Patients were followed with physical and gynecological
examination, pap smear, and laboratory tests at
3-month intervals for the first 2 years, at 6-month intervals
for 3 years, and annually thereafter. For survival
endpoints - locoregional control (LRC), progressionfree
survival (PFS), disease-specific survival (DSS), and
overall survival (OS)-time interval was defined as the
time from surgery to the date of first relapse, diseasespecific
death, or any death.
Statistical analysis was performed using SPSS version
21.0 (SPSS, Chicago, Illinois). The Kaplan-Meier
method was performed for OS, and PFS rates and the
survival curves were compared by non-parametric survival
analysis (log-rank test). All time-related events
(failure or death) were calculated from the diagnosis to
last follow-up or death. P<0.05 was considered statistically
significant.
Results
The medical records of 184 eligible patients with histologically
confirmed UCC were evaluated. The median
age was 49 years (range, 18-80 years). The most commonly
seen histopathologic diagnosis was squamous cell
carcinoma (SCC) in 129 (70%) patients. Other subtypes
were as follows: Adenocarcinoma (17%), adenosquamous
(9%), clear cell (3%), and undifferentiated (1%).
Surgical procedure was in the form of Wertheim surgery
in 96 patients (52%) and TAH-BSO only in 26 patients
(14%). Pelvic LND was performed only in 32 patients
(17.5%), and pelvic lymph node (LN) sampling was performed
in 30 patients (16.5%). The median and mean
number of LNs dissected were 18 and 19, respectively.
One hundred and sixty-six patients (87.5%) received
both external RT and intracavitary brachytherapy, and
23 (12.5%) patients were treated only with external RT.
The median external pelvic RT dose was 45 Gy (range,
45-59.4 Gy), and median para-aortic dose was 45 Gy.
One hundred and six (57.6%) patients received concomitant
weekly cisplatin with median 3 courses. Patient
and treatment characteristics are listed in Table 2.
Table 2: Patient and disease characteristics
The median follow-up time was 61.5 months (range,
8-132 moths). One hundred and fifty-one (82%) patients
were alive, and 144 (94%) of these were free of
disease at the time of this analysis. One hundred and
sixty-four patients were in the routine follow-up until
the time of death or the last follow-up visit. The other
20 (11%) patients, who were lost to follow-up, were received
from general citizenship information systems
and/or phone calls. Forty patients were alive with disease
at their last follow-up records: 10 with pelvic wall,
9 with vaginal cuff, 13 with distant metastasis, and 8
with both lymphatic and distant metastasis. The median
time for locoregional failure and distant metastasis
were 25 months (range, 8-88 months) and 38
months (range, 12-118 months).
Stage migration was recorded in 130 patients
(70.7%) in data when FIGO 2018 staging system was
used. There was not seen any stage change for the patients
with Stage IIIB and IVA in compatible with staging systems. The most remarkable stage migration was
detected for Stage I patients. A total of 119 (64.6%) patients
with Stage I showed stage migration. About 47.8%
of this migration was seen within Stage I itself according
to new FIGO 2018 staging system. The remaining 31 patients (16.8%) with Stage I disease were upstaged
to Stage IIIC disease. In addition, 11 patients (6%) with
Stage II were upstaged to Stage IIIC with new staging
system (Table 3). We compared the stage migration in
terms of histopathology (SCC vs. non-SCC). However,
we could not find any difference between the stage migration
and the histopathology of patients (p>0.05).
Table 3: The patient data restaged with new FIGO 2018
staging system
Five-year LRC, PFS, DSS, and OS rates were 91%,
88%, 91%, and 83%, respectively. In Table 4, OS and disease-free survival (DFS) rates according to both
FIGO 2009 and FIGO 2018 were shown. The first thing
should be said that all the treatment outcomes were observed
excellent with both staging system. The remarkable
point in this table was that the survival rates of
both Stages I and II were increased due to the fact that
the patients with LNM were staged as IIIC. As a result
of this, treatment outcomes of both Stages I and II were
detected higher in FIGO 2018.
Table 4: Five-year overall, local recurrence-free, disease-free, and metastasis-free survival rates of patients according to
both FIGO 2009 and FIGO 2018 staging systems
FIGO 2018 divided Stage IB into three subgroups
according to tumor size.[] Overall and PF survival
curves were similar for Stage IB2 and IB3 in new FIGO
2018 staging system. Stage IBI had better OS curve
than the others in both staging systems (Fig. 1). On the
other hand, PFS curve of Stage IBI was not better than
the others (Fig. 1). It could be argued that as followup
time became longer, patients with Stage IB3 disease
would show decreased treatment outcomes.
Fig 1: Kaplan-Meier overall and progression-free survival curves for Stage IB tumors.
FIGO: International Federation of Gynecology and Obstetrics.
LN metastasis has been a new parameter in UCC
staging with FIGO 2018 due to known worse treatment
outcome of it.[] Small tumors with LNM upstaged to
Stage IIIC.
In this current study, pelvic +/- para-aortic lymphatic
dissection was performed in 159 (86.4%) patients
and para-aortic lymphatic dissection was added to pelvic
lymphatic dissection in 76 (41.3%) patients. The detecting
way of LNM has not made any change in new staging
system. In other words, lymphatic metastasis could be
shown by pathologically or by radiologically. In our series,
we had only three radiologic Stage IIIC patients. We
detected pelvic LNM in 40 (21.7%) and para-aortic LNM
in 6 (3.3%) patients. Totally, 46 (25%) patients had LNM,
43 of them were pathologically detected, in our data.
We compared the OS and PFS rates in terms of
both pelvic (Stage IIIC1) and para-aortic LN metastasis
(Stage IIIC2). Five-year OS and PFS rates were
75.1% and 61.7% for the patients with pelvic LNM
(Stage IIIC1). We could not show statistically significant
difference for OS rates for pelvic LNM (75.1% vs.
85.9%, p=0.183). On the other hand, PFS rates were affected
unfavorably with pelvic LNM (61.7% vs. 83.6%,
p=0.004) (Fig. 2). Five-year OS and PFS rates were
44.4% and 50.0% for the patients with para-aortic LNM
(Stage IIIC2). Both OS (44.4% vs. 84.4%, p=0.006) and
PFS (50.0% vs. 84.1%, p=0.001) rates were significantly
affected by para-aortic LNM (Fig. 3).
Fig 2: Kaplan-Meier survival curves according to pelvic lymphatic involvement.
Fig 3: Kaplan-Meier survival curves according to para-aortic lymphatic involvement.
We grouped patients according to stage migration as:
(1) Within Stage I, (2) Stage II upstaged to stage IIIC,
and (3) Stage I upstaged to Stage IIIC. The Kaplan-Meier
plot for stage migration showed discriminative survival
curves for upstaging to Stage IIIC disease. In accordance
with literature, the patients had stage migration within
Stage I had significantly better OS and PFS rates than the
others, with 5-year OS and PFS rates of 87.7% and 96.5%,
respectively. The worse treatment results were detected
the patients with Stage II upstaged to Stage IIIC disease
in terms of both OS and PFS rates, with 5-year OS and
PFS rates of 62.3% and 60.6%, respectively (Fig. 4).
Fig 4: Kaplan-Meier survival curves according to stage migration.
Discussion
Globally, cervical cancer continues to be one of the
most common cancers among females, being the fourth most common after breast, colorectal, and lung cancer.
In 2012, it was estimated that there were approximately
527.600 new cases of cervical cancer with 265.700 deaths
annually.[] In low- and middle-income countries, it is
more common, being the second most common cancer
in incidence among women and the third most common
in terms of mortality.[] Recent developments in
imaging technology, radiotherapeutic approaches, biological
target therapy, and increased use of minimally
invasive surgery have drastically changed the paradigm
for the management of women with cervical cancer. Until
now, the FIGO staging system was based primarily on
clinical examination with limited additional diagnostic
procedures allowed by the FIGO staging system.[,]
There is only one recent report which could be found
in literature regarding new FIGO 2018 staging system.
[] This report aimed to validate the revised FIGO
2018 staging system for cervical cancer, with a particular
focus on Stage IB and Stage III disease. Based on this
validation analysis of Matsuo et al. using the National
Cancer Institute's Surveillance, Epidemiology, and End
Results (SEER) program between 1988 and 2014, the
revised FIGO staging system for cervical cancer is useful
to distinguish survival groups. Applying the new
system, Stage IB1 and Stage IB2 disease have distinct
characteristics and outcomes. It has been shown that
Stage IB1 disease is more likely to be low grade and
has adenocarcinoma histology, whereas Stage IB2 distasisease is more likely to be high grade and has squamous
histology.[] We could not show any relation between
histopathological tumor type and FIGO staging in our
cohort. In addition, they concluded that patients with
Stage IB2 disease have a nearly 2-fold increased risk of
cervical cancer death compared to those with Stage IB1 disease. Similar with this, we detected that Stage IBI
had better OS curve than the others in both staging system.
On the other hand, we could not show statistically
significant difference in terms of treatment outcomes
between new IB staging groups. By the help of focusing
new predictive molecular and/or genetic biomarkers, we might present new factors for distinguishing Stage
IB disease rather than tumor size.
Another major change in the FIGO 2009 staging
system is the inclusion of LN status into Stage III disease.[] Patients who have documented pelvic and/
or para-aortic LN metastasis are specifically staged
as Stage IIIC. Under the revised system, radiographic
and/or histological findings are allowed to assign
Stage IIIC disease. Stage IIIC1 is designated when only
pelvic LN metastasis is detected, while Stage IIIC2 is
designated when para-aortic LN metastasis is documented
by either method. In the validation analysis
of Matsuo et al.,[] they evaluated 11.733 women
with Stage III UCC. They found that Stage IIIC1 disease
was also more likely to have adenocarcinoma or
adenosquamous histology and to be higher grade but
have smaller tumor size (all, p<0.001). However, we
could not show any statistically significant difference
between Stage IIIC disease and histology. In Stage III
disease, survival of women with Stage IIIC1 disease is
greater for those patients with Stage IIIA or Stage IIIB
disease. The analysis showed 5-year cancer-specific
survival rates of 46.0% for Stage IIIA disease, 42.6%
for Stage IIIB disease, and 62.1% for Stage IIIC1 disease
in the trial of Matsuo et al.[] Interestingly, this
current study did not have patient with Stage IIIA. In
addition, we had only one patient Stage IIIB disease.
Therefore, we could not compare the treatment results for the patient with these Stage III disease subgroups.
In our trial, we found that 5-year OS and PFS
rates were 75.1% and 61.7% for the patients with Stage
IIIC1 disease. It is important not to miss that Stage
IIIC1 disease reflects a heterogeneous group of tumors
with a wide range of survivals based on local tumor
factors. Patients with metastatic para-aortic LNs
are managed with concurrent CRT, and these patients
would be staged as Stage IIIC2 in the new FIGO 2018
system. Kidd et al.[] demonstrated >35% DSS for
patients with Stage IIIC2 disease. In this current data,
5-year OS and PFS rates were 44.4% and 50.0% for
the patients with Stage IIIC2 disease. Some patients
with supraclavicular only LN metastasis have been
shown to achieve long-term DFS. With help of this
knowledge, Zighelboim et al.[] indicated that some
patients who receive external beam RT and CT for
limited oligometastatic disease may also have a prolonged
DFS.
The FIGO classification system combines the most
basic parameters of gynecologic malignancies to stratify
patients according to extent of disease, to decide the better
treatment modality, and to develop a common language
for the future testing of cancer treatment strategies.
[] FIGO 2018 staging system examines both clinical and
radiological findings, as well. Although the patient number
is low compared to large multi-institutional series,
the uniform risk-adapted treatment in our patients gives us valuable information about the ability of old and new
staging systems for discriminating the survival outcomes
(Fig. 5). Our data showed that there were no major differences
between FIGO 2009 and 2018 staging systems in
terms of OS and PFS rates when comparisons were made
as Stage I and II in FIGO 2009 versus 2018. Major difference
was seen for the patients with Stage I and II disease
upstaged to Stage III disease in terms of both OS and
PFS. The worse treatment outcomes were detected for
the patients with Stage II disease upstaged to Stage IIIC
disease. Based on this result, it might be argued that not
only LNM both also primary tumor involvement should
be kept on mind while deciding treatment approach. The
survival curves between stages were separated clearly
with the use of FIGO 2018 (Fig. 5).
Fig 5: Kaplan-Meier survival curves showing the stage distributions both between FIGO 2009 and FIGO 2018.
FIGO: International Federation of Gynecology and Obstetrics.
A strength of this study is that this is likely the first
single institutional study to examine the comparison
of the two staging system for operated UCC. Out of
this current study, there is only one population-based
study, done by Matsuo et al.,[] using SEER data. Our
results are important in terms of including homogenous
patient data and using modern treatment techniques.
On the other hand, limitation of this study includes
that this is a retrospective study, and there may
be missing confounding surgical pathological and follow-
up evaluations.
Conclusion
The updated FIGO staging system for invasive operated
UCC incorporates imaging and pathological findings.
Our results suggest us that the major improvement of
2018 staging system for UCC is that it produced better
discrimination in terms of survival outcome in patients
with LNM both pelvic and para-aortic. In addition, the
hope is that these revisions will improve the accuracy
of staging and this will be reflected a more refined understanding
of prognostic groups, which will facilitate
better treatment for women with invasive UCC.
Peer-review: Externally peer-reviewed.
Conflict of Interest: All authors declared no conflict of interest.
Ethics Committee Approval: The study was approved by
the Ege University Faculty of Medicine Clinical Research
Ethics Committee (No: 18-10.2T/36, Date: 01/11/2018).
Financial Support: None declared.
Authorship contributions: Concept - F.S., B.B., S.A., Z.Ö.;
Design - F.S., B.B., S.A., Z.Ö.; Supervision - F.S., B.B., S.A.,
Z.Ö.; Funding - F.S., B.B., S.A., Z.Ö.; Materials - F.S., B.B.,
S.A., Z.Ö.; Data collection and/or processing - F.S., B.B.,
S.A., Z.Ö.; Data analysis and/or interpretation- F.S., B.B.,
S.A., Z.Ö.; Literature search - F.S., B.B., S.A., Z.Ö.; Writing
- F.S., B.B., S.A., Z.Ö.; Critical review - F.S., B.B., S.A., Z.Ö.
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