CLINICAL OBSTETRICS AND GYNECOLOGY
Volume 63, Number 1, 3–11
Updates in Cervical
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Cancer Treatment
EMILY K. HILL, MD
Division of Gynecologic Oncology, University of Iowa Hospitals
and Clinics, Iowa City, Iowa
Abstract: Although rates of cervical cancer in the
United States have been declining due to vaccination
and screening efforts, it remains the fourth most
common cancer in women worldwide and is still far
from being eradicated, even in developed nations.
This review discusses recent developments in cervical
cancer treatment and reviews the literature supporting
recent practice changes encompassing staging, surgi-
cal management, radiation, chemotherapy, targeted
agents including immunotherapy, and imaging.
Key words: cervical cancer, radical hysterectomy,
immunotherapy, staging, chemotherapy
Introduction
Despite effective vaccines and screening
modalities for cervical dysplasia and cer-
vical cancer, cervical cancer continues to
be the fourth most common cancer in
women worldwide with over 500,000 new
cases yearly and about half that number
of deaths.1 In developed countries, the
rates of cervical cancer are lower due to
increased access to prevention and screening,
however, despite this, there are still expected
to be 13,170 new cases and 4250 of deaths
due to cervical cancer in women in the
United States in 2019 (https://seer.cancer.
Correspondence: Emily K. Hill, MD, Division of
Gynecologic Oncology, University of Iowa Hospitals
and Clinics, 200 Hawkins Drive, Iowa City, IA.
E-mail: emily-k-hill@uiowa.edu
The author declares that she has nothing to disclose.
CLINICAL OBSTETRICS AND GYNECOLOGY
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Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.
gov/statfacts/html/cervix.html). Although
early-stage cervical cancer can have excel-
lent prognosis and be cured with surgery,
chemoradiation or a combination of treat-
ment modalities, advanced cervical cancer
is often incurable and once recurrent,
relatively refractory to treatment. Although
there is a dearth of research funding on
cervical cancer relative to other women’s
cancers, there have been practice-changing
developments in the past several years and
ongoing studies seek to further improve
care of women with this disease.
STAGING UPDATES
Cervical cancers have historically been
staged clinically, with previous International
Federation of Gynecology and Obstetrics
(FIGO) staging systems allowing informa-
tion from physical examination and a few
rudimentary imaging studies to be included
in the formal stage of a patient. The reason
for this was the importance of having a
staging system that was accessible to pro-
viders and patients in lower resource settings
where advanced imaging such as computed
tomography (CT) or positron emission to-
mography (PET) scan may not be readily
available. In these staging systems, surgico-
pathologic or advanced imaging findings
such as lymph node involvement did not
/ VOLUME 63 / NUMBER 1 / MARCH 2020
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 4 Hill

change the stage of a patient and therefore the subdesignation of “r” if the nodes are
can make cross-patient comparisons in positive by radiologic findings versus “p” for
research difficult as patients may have the pathologically confirmed nodal disease.
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advanced disease on imaging or surgical In addition, women with imaging showing

findings but would still be assigned an distant metastatic disease would be assigned
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early-stage based on clinical examination.
To help alleviate some of these issues, in
2018 FIGO presented and published new
staging criteria for cervical cancer. This
staging system includes pathologic and
imaging findings to be included in the
stage assigned to patients (Fig. 1).
The major changes in this new system
include that positive pelvic or para-aortic
lymph nodes now upstage a patient to
stage IIIC1 for pelvic node involvement and
IIIC2 for para-aortic nodal involvement, and
stage IVB in the new system, even if not
pathologically confirmed. Another change
for microscopic early-stage disease is that
the dimensions to assign patients to either
stage IA1 or IA2 no longer include the length
of the tumor and focus mainly on depth of
cervical stromal invasion, ranging up to <5
mm in depth. The horizontal extent was
removed as it was felt to be subject to
artefactual errors. The stage IB groupings
have been modified to include 3 categories:
Ib1 which is ≥ 5 mm stromal invasion but

FIGURE 1. FIGO staging of cancer of the cervix uteri (2018). When in doubt, the lower staging
should be assigned. aImaging and pathology can be used, where available, to supplement clinical
findings with respect to tumor size and extent, in all stages. bThe involvement of vascular/
lymphatic spaces does not change the staging. The lateral extent of the lesion is no longer
considered. cAdding notation of r (imaging) and p (pathology) to indicate the findings that are
used to allocate the case to stage IIIC. Example: If imaging indicates pelvic lymph node meta-
stasis, the stage allocation would be stage IHClr, and if confirmed by pathologic findings, it
would be stage IIIClp. The type of imaging modality or pathology technique used should always
be documented. Reproduced with permission from Bhatla et al.1

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<2 cm in greatest tumor dimension, Ib2
which is > 2 cm but <4 cm, and Ib3 which
is ≥ 4 cm. Last, uterine corpus involvement
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was removed from the staging as it does not
affect prognosis or management.
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These findings were presented at the
FIGO XXII World Congress of Gynecology
and Obstetrics in Rio de Janeiro, Brazil in
October 2018 and published that same
month. These new staging criteria were based
upon validation analysis using the National
Cancer Institute’s Surveillance, Epidemiol-
ogy, and End Results (SEER) program and
distinguish groups based on survival.2 Until
these new staging criteria are widely accepted,
experts recommend specifying tumor size and
staging system used when reporting FIGO
stage.3
IMAGING
Although the historical standard for identi-
fying nodal disease, including para-aortic
nodal disease to determine the extent of
radiation fields, has been lymphadenectomy,
the adoption of CT or PET CT as an
alternative has become common and was
first incorporated into a GOG clinical trial in
as an acceptable alternative to surgical nodal
assessment in GOG 165.4 There is meta-
analysis showing pooled sensitivity and spe-
cificity of PET CT scan for pelvic lymph
node metastasis identification of 0.79 and
0.99 and for para-aortic node metastasis of
0.84 and 0.95.5 However, this question was
further looked at in the recent ACRIN6671/
GOG0233 trial, a prospective study where
patients with loco regionally advanced cer-
vical cancer underwent both concurrent
diagnostic contrast-enhanced CT scan and
PET scan, followed by pelvic and para-
aortic lymphadenectomy, to see if PET with
CT was better than CT alone.6 They com-
pared imaging findings with surgical patho-
logic findings to determine if the addition of
PET improved diagnostic accuracy. They
found that in 153 patients, 43 had positive
nodes. Mean sensitivities for detection of
abdominal lymph node metastases were
0.50 (PET with CT) and 0.42 (CT only)
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Updates in Cervical Cancer Treatment 5
(P = 0.052). Pelvic node detection was better
with sensitivities of 0.83 (PET with CT) and
0.79 (CT only). There were no statistically
significant differences in either sensitivity or
specificity between the use of PET plus CT
versus CT alone. The authors concluded that
addition of PET to CT resulted in statistically
borderline improvement in sensitivity to
detect abdominal nodal metastasis in cervical
cancer but that this does not justify use of
PET with CT over CT alone to determine the
upper extent of lymph node metastases. This
also begs the question of whether pathologic
assessment of the lymph nodes should be the
standard care, given the poor diagnostic
accuracy of either imaging modality in this
study, particularly for para-aortic disease.
SURGICAL UPDATES
Early cervical cancers are treated in most
cases with surgical interventions including
cervical conization, radical trachelectomy,
simple, and radical hysterectomy both
with and without lymphadenectomy. Tra-
ditionally, radical hysterectomy has been
performed via laparotomy, as this was the
only surgical modality available, particu-
larly in resource-poor environments. More
recently, as minimal invasive surgery tech-
niques have evolved both laparoscopic and
robotic approaches to radical hysterectomy
have become commonplace and compre-
hensive guidelines including National Com-
prehensive Cancer Network (NCCN) and
European Society of Gynaecologic Oncology
have included minimally invasive surgery
(MIS) approaches as acceptable options for
treatment of IA2-IIA cervix cancer. This was
based on retrospective data showing less
blood loss, decreased hospital stay, and lower
postoperative complications with MIS
techniques and without associated worsen
disease-free or overall survival (OS). How-
ever, cancer outcomes with these techni-
ques had not been studied in a prospective
trial until recently when the Laparoscopic
Approach to Cervical Cancer trial (LACC
Trial), was published in November 2018.7
This international, randomized controlled
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 6 Hill
trial randomized women with stage IA1
(with lymphovascular invasion), IA2, and
IB2 cervical cancer to either MIS or open
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surgery. There were over 600 patients total
and 91% had stage IB1 disease and the
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majority of the MIS patients underwent
laparoscopy (only 15% robotics). The 2
groups were similar with regard to tumor
features and use of adjuvant therapy, but
the rate of disease-free survival at 4.5 years
was significantly worse in the MIS group
(86% vs. 96.5%). MIS approach was asso-
ciated with a hazard ratio (HR) of disease
recurrence or death of 3.74 [95% confi-
dence interval (CI): 1.63-8.58] and this
remained after adjusting for potentially
confounding factors. OS at 3 years was
lower in the MIS group (93.8% vs. 99.0%).
The LACC trial results were published
in conjunction with a epidemiologic study
evaluating the association of survival and
minimally invasive radical hysterectomy
in the same journal issue by Melamed
et al.8 This was a cohort study of women
who underwent radical hysterectomy for
IA2 or IB1 cervical cancer from 2010 to
2013 at Commission on Cancer-accred-
ited hospitals and an interrupted time-
series analysis of women undergoing
radical hysterectomy from 2000 to 2010
using the SEER database. They found a
significant increase in 4-year mortality in
women undergoing MIS radical hysterec-
tomy compared with open surgery (9.1%
vs. 5.3%, HR: 1.65, 95% CI: 1.22-2.22).
They also found that before the adoption
of MIS radical hysterectomy, 4-year rela-
tive survival rate for women undergoing
radical hysterectomy was stable, but that
after adoption (after 2006), it declined by
a rate of 0.8% per year (P = 0.01). This
corroborative study suggested that MIS
radical hysterectomy was associated with
a shorter OS.
Although the reason for the decreased
survival outcomes with MIS is poorly
understood, this has resulted in the gyne-
cologic oncology community re-evaluating
the role of MIS radical hysterectomy,
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particularly in stage IB1 cervical cancers
> 2 cm, as this was the main group studied
in the LACC trial. Many centers have
reverted to performing open surgery as a
standard of care.
Another surgical innovation in cervical
cancer that has been recently understudy
is sentinel lymph node biopsy. In the wake
of the LACC trial results suggesting
worse cancer outcomes for MIS surgery,
the future role of sentinel node biopsy
(SNB) in cervical cancer is unclear but
before that, it was an area of new inves-
tigation. The goal behind exploring SNB
in cervical cancer follows the logic used in
endometrial and vulvar cancer that the
majority of lymphadenectomies are neg-
ative and so if key information about the
patient’s nodal status can be obtained
with a less invasive and extensive proce-
dure, risks of complete lymphadenectomy
including lymphedema might be miti-
gated. NCCN guidelines do offer SNB
as an alternative to complete lymphade-
nectomy but caution against use in tu-
mors > 2 cm, as some studies show lower
detection rates and higher false-negative
rates.9 Although most early studies used
blue dye and technetium-99 radiotracer,
recent studies that parallel endometrial
cancer SNB techniques have used indoc-
yanine green (ICG) which is visualized on
a near-infrared camera. In a retrospective
review of 30 patients with an ICG sentinel
node protocol including both SNB and
full pelvic lymphadenectomy, there was
bilateral mapping in 86.7% of cases, most
frequently in the hypogastric region fol-
lowed by obturator and external iliac. The
majority of patients had clinical stage IB1
disease (90%) and squamous cell carcino-
ma (67%) with median tumor size 2.0 cm.
The study showed that 5 patients (16.7%)
had positive nodes, all of which were detected
by the sentinel node protocol without need
for completion lymphadenectomy. Three had
clinically enlarged sentinel nodes, 1 had a
clinically enlarged nonsentinel node and the
other had cytokeratin positive cells in a

sentinel node.10 Another retrospective review
from MD Anderson of 188 women with
early-stage cervical cancer showed at least 1
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sentinel node identified in 90%, bilateral
detection in 62% and 19% positive nodes,
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with a sensitivity of 96.4%, negative predic-
tive values of 99.3% and false negative rate of
3.6%.11 They used a variety of mapping
agents and surgical approaches and the only
difference in mapping was seen in women
with body mass index > 30 kg/m2. It remains
to be seen how clinicians will move forward
with the previously accumulating SNB data,
now what many are reverting to open radical
hysterectomy which is less conducive to SNB,
particularly with ICG dye as it requires a
near-infrared camera which is usually used in
conjunction with MIS surgery.
Another evolving area relating to surgical
management of early cervical cancer are
retrospective studies that suggest that there
may be a role for less aggressive surgical
management of smaller cervical tumors. In a
recent paper discussing management of low
risk, early-stage cervical cancer, pathologic
findings from these patients from assorted
retrospective studies were reviewed. In gen-
eral, they suggest that for women with a
subset of IA2-Ib1 cervical cancers, those with
tumors size under 2 cm, with <10 mm of
stromal invasion and no lymphovascular
invasion, that management with either cone
and lymphadenectomy or simple hysterec-
tomy with lymphadenectomy may be
reasonable to substitute for radical trachelec-
tomy and radical hysterectomy.12 One of the
largest data sets comes from Covens et al,13
who reported that in 842 patients with stage
IA1-Ib1 cervical cancer where they found
that in radical hysterectomy specimens, that
in 536 patients with negative nodes, tumor
size <2 cm, and stromal invasion <10 mm,
the incidence of parametrial involvement was
<0.6%. These questions are currently under
further study in 3 prospective trials includ-
ing the ConCerv trial through MD
Anderson (https://clinicaltrials.gov/ct2/
show/NCT01048853), the SHAPE trial
through the Gynecologic Cancer Inter-
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Updates in Cervical Cancer Treatment 7
group (https://clinicaltrials.gov/ct2/show/
NCT01658930), and GOG 278 (https://
clinicaltrials.gov/ct2/show/NCT01649089)
through the NRG.
RADIATION UPDATES
Radiation and chemoradiation are corner-
stone treatments in many locally advanced or
metastatic cervical cancers. One of the more
recent developments in the field of radiation
therapy for cervical cancers is the use of
image-guided interstitial radiation rather
than conventional intracavitary vaginal bra-
chytherapy for bulky cervical tumors. The
multicenter European EMBRACE study
was started in 2008 to evaluate the outcome
of image-guided adaptive brachytherapy
(IGABT) in locally advanced cervical cancer,
and subsequently, retroEMBRACE, a retro-
spective study of patients treated with CT or
MRI-based IGABR, was performed. retro-
EMBRACE showed that with systematic
use of IGABT, using combined intracavitary
and interstitial applicators, the minimum
dose covering 90% of high-risk clinical target
volume was increased and patients with
larger tumors (high-risk clinical target vol-
ume > 30 cm3) had a 10% improvement
3-year local control rate.14 These studies
combined showed excellent local and pelvic
control with IGABT techniques, with
3-year pelvic control rates of 96%, 89%,
and 73% for stage IB, IIB, and IIIB disease,
which are superior to historical control
rates of intracavitary vaginal brachyther-
apy alone with reduced toxicities. The
EMBRACE II is an ongoing study, ini-
tiated in 2018, that combines intensity-
modulated radiotherapy and MRI-based
IGABT with concurrent chemotherapy.15
CHEMOTHERAPY AND TARGETED
AGENT UPDATES
There have been few practice-changing
studies in chemotherapy for cervical can-
cer in the past 5 years, likely due to the
low response rates and overall poor prog-
nosis of women requiring systemic che-
motherapy for recurrent or metastatic
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 8 Hill
cervical cancer as well as the relative
rarity of the disease. One of the relatively
recent publications that changed the
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standard of care in women with advanced
or metastatic cervical cancer was the
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publication of GOG 240, which showed
improved survival with the antiangiogen-
esis inhibitor bevacizumab (Avastin; Gen-
entech, South San Francisco, CA) and
helped clarify the role of a nonplatinum
combination. This phase III trial random-
ized women with advanced or metastatic
cervical cancer to chemotherapy with
either cisplatin and paclitaxel or topote-
can and paclitaxel and with or without
bevacizumab.16 In total, 452 women were
enrolled and the topotecan-paclitaxel reg-
imen was not found to be superior to
cisplatin-paclitaxel, HR for death 1.20.
The addition of bevacizumab increased
the median OS from 13.3 to 17.0 months
(HR death: 0.71, 98% CI: 0.54-0.95) and
had a higher response rate (36% vs. 48%,
P = 0.008). There was increased toxicity
with the addition of bevacizumab including
hypertension, thromboembolic events, and
gastrointestinal fistulas but the drug was
overall well-tolerated. Although these OS
numbers emphasize the overall poor prog-
nosis of this patient group, the improved
survival led this to become the standard of
care for advanced and recurrent cervical
cancer patients.
Some providers have wondered about
using carboplatin instead of cisplatin in
this recurrent cancer cohort, given it is a
more favorable toxicity profile. JCOG0505
was a phase III noninferiority trial pub-
lished in 2015, which randomized women
with metastatic or recurrent cervical cancer
to paclitaxel and cisplatin versus paclitaxel
and carboplatin with the primary endpoint
of OS.17 In the 253 enrolled patients, the
HR for OS was 0.994 (90% CI: 0.79-1.25,
noninferiority P = 0.32) with median OS
18.3 and 17.5 months, respectively. The
study did show decreased survival out-
comes with carboplatin versus cisplatin in
those were the patients who had not had
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prior cisplatin. In this subset, the HR was
1.571 (95% CI: 1.06-2.32) with a medial OS
of 23.2 (cisplatin) versus 13.0 months (car-
boplatin). The authors conclude that given
improved tolerability, paclitaxel/carbopla-
tin should be the standard of care with the
exception of patient who has not previously
received cisplatin.
IMMUNOTHERAPY
Although metastatic and recurrent cervi-
cal cancer patients, unfortunately, have a
poor prognosis, there has been a recent
development within the field of immuno-
therapy, which led to a new accelerated
the Food and Drug Administration
(FDA) drug approval with the last year.
The approval of pembrolizumab (Keytruda;
Merck & Co., Kenilworth, NJ) was released
on June 12, 2018 for patients with recurrent
or metastatic cervical cancer with dis-
ease progression on or after chemother-
apy whose tumors express programmed
death-ligand 1 (combined positive score
≥ 1) as determined by an FDA-app-
roved test (www.fda.gov/drugs/resources-
information-approved-drugs/fda-approves-
pembrolizumab-advanced-cervical-cancer-
disease-progression-during-or-after-chemo
therapy). This was based upon the KEY-
NOTE-158 Trial, which was a larger phase
II basket trial with cohorts of various
tumor types. The cervical cancer cohort
had 98 patients with recurrent or meta-
static cervical cancer, and approval was
based on the 79% (n = 77) of patients who
had received > 1 prior lines of chemo-
therapy and who had tumor testing positive
for programmed death-ligand 1 defined as a
combined positive score of ≥ 1. The overall
response rate was 14.3% with 3 complete and
9 partial responses. The median duration of
response was not reached (range: 3.7 to 18.6
+ mo) and 91% had a duration of response
> 6 months. The most common toxicities
included hypothyroidism (10.2%), decreased
appetite and fatigue (both 9.2%). 12.2% of
patients had treatment-related grade 3 or 4
toxicities.18 Although the response rates are
 Updates in Cervical Cancer Treatment 9

still not > 15%, the durability of the response age group to include men and women ages
and manageable toxicity profile make this a 27 to 45 years in October 2018 (www.fda.
novel and appealing option for women who gov/news-events/press-announcements/fda-
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have progressed on chemotherapy. approves-expanded-use-gardasil-9-include-

individuals-27-through-45-years-old). This
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CERVICAL CANCER PREVENTION will increase availability and insurance

UPDATES
With the advent of the Papanicolaou test in
the 1940s and subsequently human papil-
lomavirus (HPV) testing, rates of cervical
cancer in countries with access to these
screening tests have gone down substan-
tially. In addition, since 2006 the availabil-
ity of HPV vaccines also have had the
potential to further reduce not only rates
of cervical cancer but also HPV infection
and cervical dysplasia precursors to
cancer.19 There are several recent updates
related to primary and secondary preven-
tion. The first is the recent FDA approval
of the nonovalent HPV vaccine for a wider
coverage of the vaccine for primary pre-
vention in a wider age group in the United
States. In terms of cervical cancer screening
in the United States, the American Society
for Cervical Colposcopy (ASCCP) has
recently introduced updated guidelines on
management of abnormal cytology and
HPV, which a focus on a risk-based assess-
ment. The ASCCP Risk-Based Manage-
ment Consensus Guidelines are based on a
consensus of nearly 20 professional organ-
izations with the goal of using current and
past results to create individualized assess-
ments of a patient’s risk of progressing to
precancer or cancer, rather than considering

TABLE 1. Worldwide Estimated Number of Vaccinated Females and Human Papillomavirus

Vaccine Coverage by October 2014
Coverage Among Coverage Among
Total Female Targeted Population
Population (95% CI) (All Ages) (95% CI)

#Vaccinated Females
(Millions) (95% CI) All Ages Age 10-20 y All
Full course
vaccination
Worldwide 46.9 (39.0-55.3) 1.4% (1.1-1.6) 6.1% (4.9-7.4) 39.7% (33.0-46.8)
Less developed 15.0 (10.4-20.3) 0.5% (0.4-0.7) 2.7% (1.8-3.6) 71.3% (49.6-96.6)
regions
More developed 31.9 (25.7-38.7) 5.4% (4.4-6.5) 33.6% (25.9-41.7) 32.9% (26.5-39.8)
regions
Full course
vaccination by
geographical
region
Africa 1.6 (0.9-2.6) 0.3% (0.2-0.5) 1.2% (0.7-2.0) 88% (46.5-100.0)
Asia 4.2 (2.4-6.3) 0.2% (0.1-0.3) 1.1% (0.6-1.7) 57.2% (32.6-85.5)
Europe 14.0 (12.0-16.1) 4.3% (3.7-5.0) 31.1% (26.1-36.5) 39.2% (33.7-45.2)
Latin America/ 11.6 (7.1-16.6) 3.8% (2.3-5.4) 19.0% (11.6-27.3) 71.0% (43.6-100.0)
Carribean
North America 13.1 (8.0-18.9) 7.3% (4.5-10.5) 35.6% (18.5-56.6) 24.6% (15.1-35.5)
Oceania 2.4 (1.6-3.3) 12.7% (8.6-17.3) 35.9% (18.8-56.0) 62.2% (42.1-84.6)

CI indicates confidence interval.

Adapted with permission from Bruni et al.20 Adaptations are themselves works protected by copyright. So in order to publish
this adaptation, authorization must be obtained both from the owner of the copyright in the original work and from the owner
of copyright in the translation or adaptation.

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 10 Hill
test results in isolation with the goal of
increasing accuracy and reducing complex-
ity for providers and patients. The ASCCP
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had a period of open comment available
through September 1, 2019 and then the
hCywCX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC4/OAVpDDa8KKGKV0Ymy+78= on 05/05/2023
Guidelines Working Groups will review
comments and revise guidelines with the
plan to make the guidelines available for
use in 2020 (www.asccp.org/consensus-
guidelines). Unfortunately, despite the pres-
ence of both screening and vaccines, lack of
access to these preventative interventions
both internationally and in the United States
have limited their rate of uptake and efforts
to broaden availability and implementation
of vaccine are ongoing (Table 1).20
Conclusions
Although the overarching goal is to eradicate
cervical cancer with improved vaccination
and screening rates, until we reach that goal,
there are ongoing research efforts to improve
the treatment of women with cervical cancer.
Because of the multidisciplinary nature of the
treatment of cervical cancer, these develop-
ments are broad and include new staging
paradigms, research on outcomes of surgical
approaches, cytotoxic chemotherapy, tar-
geted agents and immune therapy, as well
as radiation and imaging.
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