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Seminars in Oncology Nursing 000 (2019) 1 9

Contents lists available at ScienceDirect

Seminars in Oncology Nursing

journal homepage: www.elsevier.com/locate/ysonu

Cervical Cancer: An Overview of Pathophysiology and Management

Cynae A. Johnson, DNP, WHNP-BC, OCNÒ ,*, Deepthi James, DNP, APRN, FNP-C,
Amelita Marzan, MS, APRN, FNP-C, OCNÒ , Mona Armaos, MSN, APRN, FNP-C
Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX

A R T I C L E I N F O A B S T R A C T

Key Words: Objective: To provide an overview of the etiology, prevention, diagnosis, treatment, and long-term survivor-
cervical cancer ship concerns surrounding cervical cancer.
prevention Data Sources: A review of articles dated 2006 2018 from PubMed.
treatment Conclusion: The landscape for cervical cancer is changing dramatically because of vaccine-driven prevention.
survivorship
Despite these advances, there are both newly diagnosed individuals as well as survivors of cervical cancer
who require continued evidence-based care.
Implication for Nursing Practice: Nurses are integral in diverse settings to promote prevention through timely
vaccination, as well as to educate patients about the signs, symptoms, and management of cervical cancer
when it occurs.
© 2019 Published by Elsevier Inc.

Cancer of the cervix is predominantly caused by persistent Human
Papilloma Virus (HPV) infections. Out of 200 identified HPV types, 12
have been designated as carcinogenic by the International Agency for
Research on Cancer, with HPV-16 accounting for 50% and HPV-18
accounting for 10% of cervical cancer cases, respectively.1 Infection
with one of these two strains of HPV accounts for a 435-fold and 248-
fold increase in cancer risk, respectively, as compared with an unin-
fected individual.2 Persistent viral infection with high-risk HPV geno-
types are the causative agent and can be detected in 99.7 % of
patients with cervical cancer worldwide.3 HPV infection is sexually
transmitted and roughly 80% of women will be infected at some point
in their life time, many by the age of 45.4 HPV infection is often con-
tracted during adolescence and early adulthood,5 and because the
infection is asymptomatic it may take 10 to 15 years to manifest
changes in the cervix.6 Since the introduction of HPV vaccines, cervi-
cal cancer rates have decreased by 1% to 1.9% annually,1,7 suggesting
that prevention is an integral part of overall cervical cancer manage-
ment. This article presents an evidence-based overview of the patho-
physiology, diagnosis, treatment, long-term management, and
prevention of cervical cancer, with particular attention given to the
role of nurses in managing this disease.
Incidence and Mortality
Cervical cancer is the third leading malignancy among women
after breast and colorectal cancers worldwide, with 569,000 new
cases each year.8,9 Over 13,000 new cases and 4,100 cervical cancer
deaths are estimated to occur in 2018.10 Cervical cancer occurs at dis-
proportionately higher rates in less developed countries, likely
because of reduced access to screening and the high cost of HPV vac-
cines.11 HPV infection is associated with the majority of cervical can-
cer cases, with HPV-16 and -18 identified as the most carcinogenic
subtypes, accounting for over 50% and 10% of cases, respectively.11
Additional subtypes have been identified, though less frequently, in
cervical cancer cases. These include HPV-31, -33, and -45, each associ-
ated with approximately 5% of cases, HPV-52 with 3%, and HPV-35 and
-58 each with 2%.1,8 It is important to note that, while rare, HPV-nega-
tive cases have been identified; in one study such cases were associ-
ated with adenocarcinomas, advanced stage presentation, and poorer
disease-free survival when compared with HPV-positive cases.12
Risk Factors

Risk factors of cervical cancer include both behavioral and infec-

* Address correspondence to: Cynae A. Johnson, DNP, WHNP-BC, OCNÒ , Advanced
Practice Provider, Department of Gynecologic Oncology and Reproductive Medicine,
The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 1362,
Houston, TX 77030.
E-mail address: cynae.johnson@mdanderson.org (C.A. Johnson).
tious contributors. Behavioral contributors include sexual activity
and lifestyle factors (see Table 1). Cervical cancer is caused by HPV
virus in a sexually active person. It is not transmitted genetically and
diet has no role in preventing cervical cancer.
Age of first sexual intercourse increases the risk for cervical cancer,13
with first sexual encounter at a younger age or proximity to menarche
increasing risk.14 Sexual intercourse before 18 years of age contributes

https://doi.org/10.1016/j.soncn.2019.02.003
0749-2081/© 2019 Published by Elsevier Inc.
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Table 1
Risk factors.
Age of first sexual intercourse
Multiple partners
Parity
Smoking
Co-infections
Prolonged use of oral contraception
Cervix dysplasia
to a two-fold increase in the risk of developing cervical cancer when
compared with the age of first intercourse greater than 21 years of age.
In comparison with one partner, the risk approximately doubles with
two partners and triples with six or more partners.15
Parity is a risk factor. Age less than 18 years at full-term pregnancy
and multiple pregnancies ( 4 vaginal births) have been associated as
risk factors for HPV infection and/or cervical cancer.16,17
Smoking contributes to the risk of cervical cancer. Tobacco
byproducts destroy the DNA cells in the cervix, which may contribute
to the progression of cervical cancer, potentially doubling the risk of
cervical cancer occurrence when compared with nonsmokers.18 Fur-
ther, smokers may have a compromised immune system to fight
against HPV infections, increasing the likelihood of progression from
HPV infection to cervical malignancy.19
Sexually transmitted disease with chlamydia and genital herpes is
associated with increased risk of HPV infection.16 Co-infection with
human immunodeficiency virus infection (HIV) may weaken the
immune systems to control HPV infection.16
Prolonged use of oral contraceptives for more than 5 years
increases the risk of cervical cancer.16 The risk increases 1.9-fold for
every 5 years of oral contraceptive use.1,16
Women treated for cervical intraepithelial neoplasia have a 2- to
3-fold increased risk of developing cervical cancer in the future.16
Prevention
Cervical cancer is a highly preventable disease with declining inci-
dence because of effective screening and vaccination to prevent the
most carcinogenic strains of HPV.20 Key prevention initiatives include
completing the recommended vaccination series, standardized
screening, and education about contributing factors to encourage
avoidance of associated risks. Condom use is reported as approxi-
mately 70% effective in reducing the transmission of HPV.17
HPV Vaccination
The first HPV vaccine, Gardasil (Merck & Co., Kenilworth, NJ), was
approved by the US Food and Drug Administration in 2006 and dem-
onstrated efficacy in preventing infection from four HPV strains
(HPV-6, -11, -16, and -18).21 A 9-valent HPV vaccine (GardasilÒ 9) cov-
ering HPV strains 6, 11, 16, 18, 31, 33, 45, 52, and 58, received US Food
and Drug Administration approval in December 2014 and is now the
only available HPV vaccine in the United States (US).21,22 HPV vacci-
nation is recommended to start at age 11 or 12 years but may be
administered as early as age 9, and through age 26 if not previously
vaccinated.23 The vaccine may be administered in two doses to indi-
viduals who receive them 6 to 12 months apart before their 15th
birthday, or in three doses for individuals beginning the series at
15 years of age or older, for immune-compromised individuals aged
9 to 26, or for those who receive the doses less than 5 months apart.24
Cervical Screening
Regardless of vaccination status, consistent cervical cancer screen-
ing is recommended beginning at age 21 in the US.16 Papanicolaou
cytology (Pap) tests are the current standard for screening.1 Starting
at age 30, women should undergo a well women/pelvic exam annu-
ally, Pap test every 3 years, with HPV co-testing every 5 years until
age 65.25 Women who are at high risk of cervical cancer should be
tested often as per the recommendation of the health care team.24
The Pap smear has a sensitivity of 55.4% and HPV co-testing has a sen-
sitivity of 94.6%.26 In addition to the cytology testing provided by Pap
tests, HPV assays have also been indicated as sensitive, particularly in
the evaluation of high-risk strains and detection of cervical intraepi-
thelial neoplasia 2+ and 3+.24
Education
The Centers for Disease Control and Prevention emphasizes the role
of preventative education in supporting awareness of HPV, its risk fac-
tors, and ways to reduce risk. The preteen vaccine campaign imparts
knowledge to parents, caregivers, physicians, and pediatricians about
the Centers for Disease Control and Prevention’s vaccination recom-
mendations, which include the HPV vaccine for children.27 It is recom-
mended that health care providers discuss HPV vaccination as a
routine cancer prevention vaccine.28 Despite demonstrated efficacy of
the vaccine, its use continues to be limited by perceptions of its safety,
efficacy, and potential social sequelae.28 Given that vaccination is rec-
ommended beginning as early as age 9 and up to age 26,20 parental
consent is often required for minors to receive the vaccination. Among
concerns expressed by parents and guardians is the belief that vaccina-
tion will remove perceived barriers to or encourage youth to engage in
earlier sexual intercourse, the occurrence of which has been exten-
sively studied and for which no scientific evidence exists to support
sexual disinhibition after vaccination.28 HPV vaccine uptake has also
been associated with the discussion of the vaccine between parent and
provider and the strength of the recommendation for vaccination put
forth by the provider.29 Evidence-based conversations should be
focused on endorsement of the HPV vaccination, discussion of any
potential side effects and benefits, and emphasis on its role in cancer
prevention.29
Disease Management
Despite prevention and screening recommendations,30 cervical can-
cer continues to occur, necessitating an understanding of clinical presen-
tation, physical assessment, diagnosis, staging, and disease treatment.
Clinical Presentation
While early stage cervical cancer is often asymptomatic, the most
common symptoms at presentation are irregular or heavy vaginal
bleeding, particularly following intercourse.31,32 Some women may
present with a vaginal discharge that may be watery, mucoid, or
purulent and malodorous.31 For advanced disease, patients may pres-
ent with pelvic or lower back pain that may radiate along the poste-
rior side of the lower extremities.31 Bowel and/or bladder changes,
such as pressure-related complaints, hematuria, hematochezia, or
vaginal passage of urine or stool, may suggest advanced disease.
Physical Examination
A pelvic examination should be performed in women with symp-
toms suspicious for cervical cancer.33 Speculum examination may
reveal a normal cervix or a visible lesion. Large tumors may appear to
replace the cervix entirely. Any questionable lesion should be biop-
sied. A thorough pelvic examination includes a rectovaginal examina-
tion to assess the tumor size and vaginal or parametrial involvement.
Other suspicious findings in physical examination are palpable groin
or supraclavicular lymph nodes. In asymptomatic women, cervical
cancer may be diagnosed as a result of Pap smears or when a visible
lesion is incidentally found during a pelvic examination.
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Diagnostic Testing
Colposcopy is considered the definitive diagnostic test in the pres-
ence of abnormal examination or Pap test results.33 If a woman
presents with nonvisible lesion, evaluation includes cone biopsy with
endocervical curettage, chest x-ray, HIV testing, hepatitis screening,
and Rapid Plasma Reagin test.33 If a visible lesion is noted, initial eval-
uation would include a physical exam, complete blood count, cervical
biopsy, chest x-ray, and HIV testing.34 Imaging studies are not typi-
cally part of the cervical cancer diagnosis, but in some cases a posi-
tron emission testing, computerized tomography, pelvic magnetic
resonance imaging, and cystoscopy/proctoscopy are used for staging
and evaluation of women with a known malignancy.35
Cervical cancer is diagnosed based on the histologic evaluation of a
cervical biopsy. The two most common histopathologic types of cervi-
cal cancer include squamous cell carcinoma (up to 85% of cases)15,35
and adenocarcinoma (up to 25%), including adenosquamous, and other
histologies (6%).15,36 Additional yet uncommon histologies include
small cell or neuroendocrine, clear cell, and serous papillary.36 Nonsqu-
amous presentations are associated with a poorer prognosis.35
Stage IV: when the cancer has spread to the bladder, rectum, or other
parts of the body.31,35,37
Treatment
Cervical cancer therapies are determined based on several fac-
tors, including the stage of the cancer, whether the cancer has
metastasized to other parts of the body, the size of the tumor, and
the patient’s age and overall health. Treatment guidelines, recently
updated by the National Comprehensive Cancer Network,34 include
surgery, radiation, and chemotherapy alone or in combination,
delineated as fertility sparing or nonfertility sparing (outlined in
Tables 3 through 6).
If a woman is pregnant, the therapy depends on the stage of preg-
nancy and the stage of cervical cancer, and should be determined in
collaboration with the patient.38 If in the third trimester of pregnancy
or if the cancer is early stage without metastasis, treatment may be
delayed until childbirth.39

Cervical Cancer Staging Surgical Treatment

Cervical cancer staging is the most prognostic factor, followed by
nodal status, tumor volume, depth of cervical stromal invasion, and lym-
phovascular space invasion. Prognosis is worse for women with involved
pelvic or para-aortic nodes. The International Federation of Gynecology
and Obstetrics is the most commonly used staging for cervical cancer
(Table 2).35,37 Most types of cancer have stages I IV. However, there are
some types of cancer, including cervical cancer, which has stage 0 to IV.31
Stage 0: when abnormal cells are found in the inner lining of the cer-
vix. Stage 0 is also called carcinoma in situ;
Stage I: when the cancer is confined in the cervix only;
Stage II: when the cancer has spread beyond the cervix but has not
spread to the pelvic wall or to the lower third of the vagina;
Stage III: when the cancer has spread to the lower third of the vagina and/
or may have spread to the pelvic wall, and/or has caused kidney injury;
Surgery is part of treatment for many cases of cervical cancer
(Table 3).32,34 For small precancerous lesions (carcinoma in situ) or
cervical cancer contained in the cervix (stage I), cryosurgery (cryo-
therapy), laser surgery, loop electrosurgical excision procedure,
conization, hysterectomy, and bilateral salpingo-oophorectomy may
be used.32 For larger cervical cancer lesions (usually up to 4 5 cm in
width), trachelectomy (a fertility-sparing procedure) and radical hys-
terectomy may be used. These surgeries can be performed with a lap-
aroscope, using a robotic machine, or with larger abdominal incision
(laparotomy).32 Following primary surgery, the pathologic discovery
of unexpected tumor extension (eg, deep invasion, lymphovascular
invasion, parametrial involvement or nodal metastasis) may warrant
further therapy with adjuvant radiation or chemoradiation. Other
surgery types include pelvic exenterations, which are complex sur-
gery procedures that may be performed for disease recurrence. A lap-
aroscopic retroperitoneal lymph node dissection is an advanced
procedure to assist in planning the surgery and determine the extent
of disease metastases.32,34,40

Table 2
International Federation of Gynecology and Obstetrics (FIGO) Staging37

FIGO Stages Definition

0 Abnormal cells are found in the inner lining of the cervix. These abnormal cells may become cancer and spread to nearby normal tissue. Stage 0 is called carci-
noma in situ (CIS).
I Cervical carcinoma confined to cervix (extension to corpus should be disregarded)
IA Invasive carcinoma diagnosed only by microscopy, with maximum depth of invasion <5 mm.
IA1 Measured stromal invasion <3 mm or less in depth.
IA2 Measured stromal invasion more than ≥3 mm and <5 mm in depth.
IB Clinically visible lesion confined to the cervix or microscopic lesion greater than IA2
IB1 Invasive carcinoma ≥5 mm depth of stromal invasion, and <2 cm in greatest dimension
IB2 Invasive carcinoma ≥cm and <4cm in greatest dimension.
IB3 Invasive carcinoma ≥4 cm in greatest dimension
II Cervical carcinoma invades beyond uterus but not to pelvic wall or to lower third of vagina
IIA Tumor without parametrial invasion or involvement of the lower one-third of the vagina
IIA1 Clinically visible lesion <4 cm in greatest dimension with involvement of less than the upper two-thirds of the vagina
IIA2 Clinically visible lesion more than >4cm in greatest dimension with involvement of less than the upper two-thirds of the vagina
IIB Tumor with parametrial invasion but not up to the pelvic wall
III Tumor extends to pelvic wall and/or involves lower third of vagina, and/or causes hydronephrosis or nonfunctioning kidney, and/or involves pelvic and/or
para-aortic lymph nodes
IIIA Tumor involves lower third of vagina, no extension to pelvic wall
IIIB Tumor extends to pelvic wall and/or causes hydronephrosis or nonfunctioning kidney
IIIC Tumor involves pelvic and/or para-aortic lymph nodes, irrespective of tumor size and extent
IV Tumor invades mucosa of bladder or rectum (biopsy proven), and/or extends beyond true pelvis
IVA Tumor has spread to adjacent pelvic organs
IVB Tumor has spread to distant organs
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Table 3
Surgical Treatment Options for Cervical Cancer34

Procedure Description Possible Indications

Cryosurgery (Cryotherapy) An instrument freezes and destroys precancerous lesions In situ carcinoma
Laser surgery A narrow laser beam destroys precancerous cells In situ carcinoma
Loop electrosurgical excision procedure (LEEP) Electrical current is passed through a thin wire hook to In situ carcinoma
remove precancerous cells
Conization The use of a surgical or laser knife which removes tissue In situ carcinoma or Stage IA1.
from the affected cervix in the shape of a cone Used for fertility sparing for select cases of early
stage disease
Simple hysterectomy Surgical removal of the uterus In post-reproductive patients, in situ carcinoma, if
conization is not possible or in the presence of pos-
itive margins post-conization
Total hysterectomy with bilateral salpingo-oophorec- Surgical removal of the entire uterus, cervix, fallopian In situ carcinoma if conization is not possible or in the
tomy, with or without lymphadenectomy tubes and both ovaries presence of positive margins post-conization.
Stage IA1 without LVSI
Modified radical hysterectomy with The uterus, cervix, upper part of the vagina, and ligaments Stage IA1 with LVSI or IA2
lymphadenectomy and tissues that closely surround these organs are
removed. Nearby lymph nodes are removed. In this
type of surgery, not as many tissues and/or organs are
removed as in a radical hysterectomy.
Radical hysterectomy and pelvic node dissection The cervix, uterus, part of the vagina, the tissues sur- Stage IB1, and non-bulky Stage IIA dsease
rounding the cervix (parametria) and nearby lymph
nodes are removed.
Radical trachelectomy and pelvic node dissection The cervix and surrounding tissue are surgically removed Stage IA1 with LVSI or IB1 (fertility sparing)
but not the body/fundus of the uterus
Pelvic exenteration In addition to the organs and tissues removed in a radical Recurrent Advanced Disease
hysterectomy, the bladder, vagina, rectum, and part of
the colon are removed.
Adapted with permission from the NCCN Guidelines® for Cervical Cancer V.3.2019. © 2019 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guide-
lines and illustrations herein may not be reproduced in any form for any purpose without the express written permission of the NCCN. NCCN makes no warranties of any kind
whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.

Radiation chemotherapy agents, Cisplatin, Paclitaxel, and Carboplatin have

For very large lesions (larger than 4 cm) or metastatic cervical can-
cer, radiation with concurrent chemotherapy is usually the standard
of care for primary treatment. The type of chemotherapy used will be
discussed in the next section. Radiation therapy may be used instead
of surgery, or as an adjuvant therapy following surgery. Three
types of RT may be used to treat cervical cancer: external RT,
including intensity-modulated radiotherapy (IMRT), and internal
RT (brachytherapy). Table 4 provides additional descriptions of
radiation treatment options.34,39
shown the most consistent activity as single agents.31 Various chemo-
therapy regimens have been evaluated and noted to have high
response rates, even in patients with metastatic and/or recurrent dis-
ease who have previously been treated with RT. Platinum-based che-
motherapy, in combination with bevacizumab include, cisplatin/
paclitaxel, carboplatin/paclitaxel, or topotecan/paclitaxel are the pre-
ferred approach (Table 5).31,32,34 Palliative chemotherapy is indicated
for patients with performance status >2, with the goal of relieving
symptoms and improving quality of life.31

Chemotherapy Immunotherapy

Chemotherapy has typically been used for advanced or recurrent
disease that can no longer be treated or managed by surgery or
RT.31,32 Today, chemotherapy has taken a much bigger role as part of
definitive treatment for cervical cancer. For newly diagnosed cervical
cancer stage I-IB2 or higher, Cisplatin or Cisplatin in combination
with Fluorouracil chemotherapy can be given along with RT as a
radiosensitizer to help the radiation work better. Among the
Immunotherapy uses medicines that stimulate the one’s own
immune system to recognize and destroy cancer cells. An important
part of the immune system is its ability to use molecules, also known
as “checkpoints,” to turn on (or off) to activate an immune response.
Cancer cells often use these checkpoints to avoid being attacked by
the immune system; however, newer drugs have been able to target
these checkpoints to help fight cancer.

Table 4
Radiation Treatment Options for Cervical Cancer33,38

Type of Radiation Description Possible Indication

External beam radiation therapy (EBRT) The most common type of radiation therapy used for cancer treatment. A machine Stage IB1 - not surgical candidate,
is used to aim high-energy rays (or beams) from outside the body into the Stage IB2 or higher
tumor.
Internal radiation therapy implants Also called brachytherapy or seed implantation. It delivers a high dose of radiation Stage IB1- not surgical candidate
(brachytherapy) directly to the tumor and helps spare nearby tissues. With internal radiation Stage IB2 or higher
therapy, the oncologist implants or inserts radioactive materials at the site of the
tumor.
Intensity-modulated radiotherapy An advanced type of radiation therapy used to treat cancer and noncancerous Stage IB1- not surgical candidate
(IMRT) tumors. IMRT uses advanced technology to manipulate photon and proton Stage IB2 or higher
beams of radiation to conform to the shape of a tumor.
Adapted with permission from the NCCN Guidelines® for Cervical Cancer V.3.2019. © 2019 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guide-
lines and illustrations herein may not be reproduced in any form for any purpose without the express written permission of the NCCN. NCCN makes no warranties of any kind
whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.
 ARTICLE IN PRESS
C.A. Johnson et al. / Seminars in Oncology Nursing 00 (2019) 1 9 5

Table 5
Chemotherapy Treatment Options for Cervical Cancer33

Type of Chemotherapy Description Possible Indication

Single Agents Cisplatin (standard of care), Paclitaxel, and Carboplatin For newly diagnosed Stage IB2 or higher, usually
given concurrent with radiation therapy
Combination regimens Platinum-based chemotherapy,cisplatin/paclitaxel, carboplatin/paclitaxel, or Advanced or recurrent cervical cancer
topotecan/paclitaxel in combination with bevacizumab.
Palliative Chemotherapy In addition to skillful use of narcotics, sedatives, and anxiolytics, the judicious use of Palliative or Supportive Care
chemotherapy and radiation therapy, symptom management, as well as emotional
and social support for the patient and her family, are mostly recommended.
Adapted with permission from the NCCN Guidelines® for Cervical Cancer V.3.2019. © 2019 National Comprehensive Cancer Network, Inc. All rights reserved. The NCCN Guide-
lines and illustrations herein may not be reproduced in any form for any purpose without the express written permission of the NCCN. NCCN makes no warranties of any kind
whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.

One immune checkpoint inhibitor, pembrolizumab, was granted
accelerated approval by the US Food and Drug Administration on June 12,
2018 for use in women with advanced recurrent (unresectable and/or
metastatic) cervical cancer following progression during or after standard
chemotherapy (Table 6).41 Pembrolizumab was the first immune check-
point inhibitor approved to treat cervical cancer. The approval was based
on the phase 2 Study of Pembrolizumab (MK-3475) in participants with
advanced solid tumors (MK-3475-158/KEYNOTE-158) (NCT02628067). To
receive treatment, the patient’s tumor must be tested and express pro-
grammed-death ligand 1 (PD-L1). Of the 98 women in the study, 77 had
tumors that expressed PD-L1. Durable response of 6 months or longer
was observed in 10 of the 11 women who responded.42
Clinical Trials and Updates in the Management of Cervical Cancer
Advances in the care and management of patients with cervical
cancer are ongoing. Over the past decade, techniques and research
strategies have focused on improving cervical cancer screening and
prevention. The following highlights several research platforms
focused on screening, conservative management for women desiring
fertility-sparing treatment, immunotherapy, and targeted therapy
using vaccine trials for treatment of cervical cancers. These therapies
are offering hope to many patients with cervical cancer who otherwise
had limited options following progression on standard chemotherapy.
HPV screening
Clinicians are still working to improve ways to screen patients for
cervical cancer. A current trial, Effect of human papillomavirus self-col-
lection on cervical cancer screening in high risk women: My Body, My
Test 3 (MBMT-3) (NCT02651883) investigates the use of a HPV self-
collection kit in screening high-risk women for cervical cancer.
This randomized clinical trial studies how well a HPV self-collec-
tion kit increases the completion of cervical cancer screening among
under-screened women receiving enhanced reminders; examines
the possible mechanism explaining the interventions effect, or lack of
effect; and estimates the incremental cost per additional woman
completing screening by adding at-home screening.43
Fertility-Sparing Clinical Trials
The Conservative surgery in treating patients with low-risk stage Ia2 or
Ib1 cervical cancer (NCT01048853) is available to women interested in
preserving their fertility.44 The primary objective of this phase 2 trial is
to evaluate the safety and feasibility of performing conservative surgery
in woman with early stage cervical cancer. Secondary objectives are to
estimate the cervical cancer recurrence rate at 2 years in women treated
with conservative surgery; compare pelvic lymph node involvement;
estimate the sensitivity of sentinel lymph node biopsy in patients treated
with radical hysterectomy; compare the treatment-associated morbidity;
and assess quality-of-life factors such as sexual functioning, symptoms,
and satisfaction with health care decisions in this group of patients.
Immunotherapy Clinical Trials
There are several clinical trials investing the use of immunether-
apy agents and cervical cancer. When traditional first-line treatments
such as surgery and chemoradiation have failed, second-line options
are limited. Clinicians have now focused many treatment efforts
toward using immunetherapy for treatment.
As previously mentioned, pembrolizumab is now approved as a
standard treatment for patients with cervical cancer with a PD-L1
mutation. It is important to understand that many clinical trials
involving immunotherapy agents may prohibit previous treatment
with checkpoint inhibitor therapy, such as pembrolizumab. Clinicians
should have discussions with patients to present all available treat-
ment options, so patients can make sound decisions for treatment.
We will discuss a few of the current trials available below.
Use of single-agent checkpoint inhibitors have proven effective for
treatment in many cancers, including cervical cancers. Clinicians are
now focused on investigating combination therapy to determine if
improved survival outcomes can be achieved. One trial, Nivolumab
and Ipilimumab in Treating Patients with Rare Tumor (NCT02834013) is
a phase 2 study with the primary objective of evaluating the
Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1
overall response rate in subsets of patients with advanced rare can-
cers.45 This trial opened in July 2016 and is actively recruiting.

Table 6
Immunotherapy treatment options for cervical cancer.

Type Description Indication Nursing Considerations

Pembrolizumab (Keytruda; Merck, Kenil- Humanized anti-PD-1 antibody. The rec- Treatment for patients with recurrent or The most common adverse reactions are
worth, NJ): approved by the US Food ommended pembrolizumab dose for metastatic cervical cancer with disease fatigue, pain, pyrexia, peripheral
and Drug Administration on June 12, treatment of cervical cancer is 200 mg progression on or after chemotherapy edema, musculoskeletal pain, diarrhea/
2018 IV every 3 weeks whose tumors express PD-L1 (com- colitis, abdominal pain, nausea/vomit-
bined proportion score [CPS] 1). ing, constipation, decreased appetite,
hemorrhage, urinary tract infection,
infections, rash, hypothyroidism, head-
ache, and dyspnea
Data from: Broderick J. FDA approves pembrolizumab for PD-L1+ cervical cancer.41
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6 C.A. Johnson et al. / Seminars in Oncology Nursing 00 (2019) 1 9
Special attention has been focused on developing vaccine trials for
HPV-positive related cancers. Vaccine therapy and cyclophosphamide
in treating patients with HLA-A*02 positive relapsed, refractory, or
metastatic HPV16-related oropharyngeal, cervical, or anal cancer
(NCT02865135) is a phase 2B/2 study. Currently recruiting, it uses a
vaccine made from a gene-modified virus that may help the body
build an effective immune response to kill tumor cells. Using this in
combination with cyclophosphamide, a drug used to stop the growth
of tumor cells, the study aims to prove that the treatment combina-
tion works better on patients with HPV-16-related cancer.46
Clinicians are also investigating the role of checkpoint inhibitors in
combination with RT. The Stereotactic Ablative Radiotherapy (SABR) in
Combination with Durvalumab and Tremelimumab in Patients with Cervi-
cal, Vaginal, or Vulvar Cancer (NCT03452332) trial is a phase 1 multi-
center study with the primary objective of assessing dose-limiting tox-
icities while monitoring clinical response rate by RECIST criteria.47
Recently, clinicians are investigating a new phenomenon involv-
ing the use of autologous tumor-infiltrating lymphocytes with adop-
tive cell therapy. Study of LN-145, Autologous Tumor Infiltrating
Lymphocytes in the Treatment of Patients with Cervical Carcinoma
(NCT03108495) is a phase 2, multicenter study to evaluate the effi-
cacy and safety of using the patient’s own tumor lymphocyte cells,
which are genetically expanded in the lab and reintroduced to the
patient via intravenous infusion. This is a treatment similar to a “mini
bone marrow transplant” and can be very challenging for patients.48
Of note, the side effect profile of patients receiving immunether-
apy treatment is quite different then traditional chemotherapy. As
one’s immune system is activated to fight cancer, it can also cause
inflammatory reponses in other systemic organs, causing pneumnitis,
colitis, dermatitis, etc. Combining checkpoint inhibitor agents can be
challenging because it can increase the incidence of these immune-
related adverse events. Patients on immunetherapy should be
observed very closely for side effects because the symptoms can arise
at any time during the treatment period, and oftentimes after treat-
ment has ceased.
Researchers will continue to increase and optimize immunether-
apy clinical trials because they may have a promising future for the
management of cervical cancer.
Survivorship Considerations
A gynecologic cancer diagnosis and subsequent treatment may
cause significant morbidity leading to increased distress levels and
poorer quality of life for survivors. Given that many cases of cervical
cancer occur before age 49, it is important to consider the long-term
side effects of treatment that potentially could affect quality of life.49
Although these young women may achieve better survival outcomes,
they may also suffer from long-term sequelae associated with their
treatment, such as bowel or bladder dysfunction, premature ovarian
failure, and loss of fertility.50 It is imperative for the health care team
to address these issues before initiating treatment and to follow-up
into long-term survivorship.
Sequelae Specific to Radical Surgery and Chemoradiation
Radical hysterectomy differs from a simple hysterectomy because
it involves dissecting the tissues surrounding the uterus, including
the cervix, upper portion of the vagina, parametria, and uterosacral
ligaments.40 Excision of the parametria can often disrupt the sympa-
thetic and parasympathetic nerves to the bladder and rectum, ulti-
mately causing urinary urgency and incontinence, constipation,
incomplete stool evacuation, and fecal incontinence. Chemoradiation
can lead to similar multi-organ dysfunction. Many side effects are
acute (especially following radical surgery); however, some side
effects can persist and/or develop for more than 15 to 20 years after
cancer treatment.51
Complete pelvic lymphadenectomy is performed as part of the
standard surgery and can lead to lymphedema. Separation of the ute-
rosacral ligaments may disrupt ovarian blood flow causing premature
ovarian failure, and resection of the upper vagina may lead to sexual
dysfunction secondary to a shortened vagina. Patients who receive
chemoradiation can also experience sexual dysfunction because of
radiation treatment effects, as well as loss of ovarian function. Modi-
fied surgeries are being performed, including “nerve-sparing” radical
hysterectomy; although not standard practice, this technique has
become a popular treatment that minimizes postoperative functional
morbidity without compromising the overall quality of cancer treat-
ment.52 Common physiologic and psychosexual sequelae are
described in detail below.
Bladder dysfunction
Bladder dysfunction is more common in cervical cancer survivors
treated with chemoradiation rather than radical hysterectomy. Uri-
nary symptoms are usually limited to the postoperative period fol-
lowing radical hysterectomy and include urinary frequency, urgency,
dysuria, and hematuria.53,54 RT treatment toxicities include detrusor
instability (overactive bladder), bladder ulceration, incontinence, and
development of vesicovaginal fistula (abnormal connection between
the bladder and the vagina).54
One study comparing urinary tract toxicities associated with RT or
radical hysterectomy of 70 women previously treated for cervical
cancer resulted in similar rates of symptoms (77% v 71%, respec-
tively).55 The incidence and type of toxicities differed between the
two groups. Patients treated with RT experienced higher increased
bladder sensation (45% v 11%).55 Patients treated with radical hyster-
ectomy experienced a significantly higher proportion of straining
symptoms compared with those treated with RT (31% v 9%).55
Management of late genitourinary effects include assessment for
urinary tract infections, pharmacologic management with ibuprofen,
phenazopyridine (Pyridium) for dysuria, and anticholinergics such as
oxybutynin (Ditropan), tolderodine (Detrol), and trospium (Sanctura)
for detrusor instability.56 Referrals to urogynecologists and undergo-
ing urodynamic testing can also be performed.56 Hemorrhagic cystitis
can be treated with laser fulguration or hyperbaric oxygen. Vesicova-
ginal fistulas should first undergo biopsy to rule out recurrence; treat-
ment may require fulguration, surgical repair, and rarely urinary
diversion.56
Bowel dysfunction
Bowel dysfunction has proven to be a greater source of distress for
women treated with RT than surgery.57 Symptoms of bowel dysfunc-
tion following RT include diarrhea, nausea, emesis, and fecal urgency
and incontinence. Patients who undergo radical surgery may experi-
ence constipation, incomplete emptying, and fecal incontinence,
which usually resolve within 2 years after hysterectomy.58 Similar to
bladder symptoms experienced as a result of RT, bowel dysfunction
symptoms appear to stabilize 2 to 3 years following therapy. How-
ever, nearly 50% of survivors continue to experience symptoms that
negatively impact their quality of life 20 years post-treatment.51,53
Modifications have been implemented to reduce RT treatment
sequelae, including use of IMRT In a study comparing 46 patients
receiving IMRT with 25 patients receiving conformal RT, Chopra
et al59 reported that restricting small and large bowel dose volume
can reduce the incidence of severe late bowel toxicity to <5%.
Another study also showed patients receiving IMRT experienced
lower acute and chronic toxicities compared with conventional RT.60
Management of chronic radiation enteritis involves a multidisci-
plinary team of radiation oncologist, gastroenterologist, medical
oncologist, surgeons, nutritionists, and nursing staff. Use of vitamin
B12 and cholestyramine may be useful in treatment malabsorption,
and antidiarrheal agents such as loperamide may also be helpful.56
Surgical resection may be indicated for repair of persistent intestinal
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C.A. Johnson et al. / Seminars in Oncology Nursing 00 (2019) 1 9
ileus, fistula, and removal of adhesions.61 Proctitis can be treated sup-
portively with oral anti-inflammatory and anti-motility agents, intes-
tinal protectants, and probiotics, and if bleeding were to develop
consideration of endoscopic argon-plasma coagulation and hyper-
baric oxygen have proven beneficial.56,62
Sexual dysfunction
Sexual dysfunction can occur following radical hysterectomy and
pelvic radiation. Women can experience vaginal stenosis (narrowing
or shortening of the vagina), decreased lubrication and dryness, diffi-
culty achieving sexual arousal, and reduced overall sexual satisfac-
tion.54,63,64 Vaginal stenosis can occur as soon as 26 days or as late as
5.5 years from definitive treatment.65 Early onset of menopause or
premature ovarian failure typically occurs within the first 6 months
after RT and can also impact sexual function; increasing vaginal dry-
ness and causing vasomotor symptoms.66 These symptoms can be
managed supportively with oral, topical, or vaginal estrogen/proges-
terone therapy.56 Patients have also reported improvement in dys-
pareunia, chronic pelvic pain symptoms, and overall quality of life
following RT with pelvic physiotherapy.64,67 Larger randomized clini-
cal studies are needed to determine the true efficacy of pelvic physio-
therapy in this patient population. They also have more recurrent
gynecologic symptoms such as menopausal flushing, vaginal dryness,
and decreased orgasm.68
It is common for patients to have sexual concerns, but have diffi-
culty addressing these problems with their provider. It is important
to be aware that although patients may not discuss sexual issues, it
does not mean they do not have a problem. To break the barriers for
sexual complaints, the health care team must address that sexual
health is an important part of the treatment plan and that there are
resources available for any problems patients may experience.69 Fur-
thermore, sexual assessment can be included in routine visits so that
patients will feel that it is something common and will develop a
sense of comfort in discussing sensitive issues about their sexuality.
Consequently, women should thoroughly be counseled regarding the
side effects of treatment as discussed previously. Each person is
unique in what they define as sexual dysfunction. It is important to
assess what causes sexual distress in the patient to determine how to
solve it.69
Lymphedema
Lymphedema can occur following radical surgery, especially if
complete pelvic lymphadenectomy was performed and following
RT.70 Nearly one in four women reported lymphedema symptoms
that severely impacted their overall quality of life 5 years following
radical hysterectomy.48 Lymphedema symptoms may be managed
supportively with compression stockings and/or physical therapy
with a lymphedema specialist. Additionally, the National Comprehen-
sive Cancer Network supports sentinel lymph node mapping for
select patients with early stage disease in efforts to decrease the
sequelae of lymph node dissection.34
Fatigue
The true incidence of fatigue in long-term cervical cancer survi-
vors is not well established. It is estimated that up to 33% of cervical
cancer survivors report fatigue 2 years and longer after treatment;
however, more investigation in this area is needed.53
Psychosocial issues
Many cancer survivors experience psychosocial sequelae follow-
ing treatment, and this can be especially true for cervical cancer sur-
vivors. The occurrence of cervical cancer among individuals with
lower educational and socioeconomic status levels, multiple medical
comorbidities, and lack of social support can affect their ability to
recover and heal from treatment-related side effects.70 Fear of recur-
rence and body image issues can also impact and lower self-esteem.
7
Loss of femininity as a result of having undergone hysterectomy and
decreased sexual desire as a result of premature menopause can neg-
atively affect one’s romantic relationships and impact the patient’s
caregiver and social network.54,70 Osann et al68 reported that patients
who underwent radiation have increased levels of psychological dis-
tress, including depression and anxiety.
Reproductive outcomes following fertility-sparing surgery
Favorable outcomes following radical trachelectomy and cerclage
occur in the majority of women.71 Thorough preoperative counseling
is mandatory to ensure that women have realistic expectations with
respective fertility issues following the radical trachelectomy. The
first trimester miscarriage following radical trachelectomy is compa-
rable with the general population rate (16% to 20%).71,72 However,
the rate of second trimester miscarriage following radical trachelec-
tomy is higher than the general population (9.5 v 4%).71,72 There is
also a risk for high recent preterm labor and delivery following radical
trachelectomy because of mechanical factors (the uterus post-trau-
matic pressure on this or cervix causing premature opening) or infec-
tious factors (impaired endocervical mucous plug does not provide
adequate barrier against ascending infection).73 Nurses can advocate
and assist patients in assisting patients to get referrals to infertility
specialist to understand their potential risk and obstetric outcomes
before undergoing fertility-sparing surgery for cervical cancer.
Clinical Trials for Symptom Management
There are a few clinical trials focused on addressing quality-of-life
and long-term survivorship issues. Studying the physical function and
quality of life before and after surgery in patients with stage I cervical
cancer (NCT01649089) examines changes before and after nonradical
surgical treatment (simple hysterectomy or cone biopsy [fertility
preservation] and pelvic lymphadenectomy) on function outcomes of
bladder, bowel, sexual function, and incidence and severity of lymph-
edema for patients with stage IA1 to IB1 cervical cancer. Secondary
outcomes will evaluate if nonradical surgery demonstrates greater
physical function and less toxicity compared with historical data on
radical surgery, incidence and treatment-related adverse events, and
changes in quality of life.74
Vaginal stenosis and dyspareunia is a significant issue for women
following pelvic RT. Pelvic physiotherapy in the prevention of vaginal
stenosis secondary to the radiotherapy (PPPVSSR) (NCT03090217) is a
randomized controlled trial designed to test a pelvic physiotherapy
protocol on an incidence rate of vaginal stenosis in women with
gynecologic cancer undergoing gynecologic brachytherapy. Of note,
this study is only available in Brazil.75
Post-treatment Surveillance
Regardless of treatment type, follow-up visits should include a
complete physical examination, history, and pelvic-rectal examina-
tion, preferably with an oncologist or physician experienced in man-
aging patients with cancer. Follow-up visits are recommended every
3 to 6 months in the first 2 years, and every 6 to 12 months in years 3
through 5.32 Computerized tomography and positron emission test-
ing scans should be utilized if clinically indicated, and patients may
return to general screening and examinations after 5 years of recur-
rence-free follow-up.32
Nursing Implications
Nurses have a significant role in supporting cervical cancer screen-
ing, prevention, treatment, and follow-up.76 Each begins with an
understanding of the cultural nuances that influence patients’
engagement with and use of health care. Priorities should include
promoting surveillance and prevention, contributing to care
 ARTICLE IN PRESS
8 C.A. Johnson et al. / Seminars in Oncology Nursing 00 (2019) 1 9
management during treatment, assessing for long-term sequelae,
educating about prevention for secondary malignancy, and ensuring
sensitivity toward and cultural awareness of the unique physiological
and psychosexual needs of diverse patient populations.
Nurses across practice settings are uniquely positioned to promote
prevention and screening. School nurses have an integral role in pro-
moting HPV vaccination among school-aged children.77 Advanced
practice nurses have proven integral in supporting cervical cancer
screening adherence, particularly in underserved settings.78 Partner-
ing with and training support staff, such as patient service coordina-
tors, has also proven effective in improving cervical screening
uptake.79 Nurses have also been trained to perform screening proce-
dures, including colposcopy,76 which can promote increased screen-
ing compliance by making these services readily available in diverse
settings.
As outlined earlier, there are numerous physical and psychosexual
sequelae of cervical cancer treatment that may persist long after the
completion of treatment. Nurses may be the first point of contact for
women entering the health care system for cervical cancer diagnosis
and treatment, and can therefore address existing health issues and
potential disease and treatment sequelae at the beginning of cancer
treatment, as part of an interprofessional approach to care manage-
ment.69 Cervical cancer and its treatment can contribute to psycho-
logical distress, such as depression, anxiety, and negative body
image.54 It is important to educate women and their sex partners
regarding the changes that treatment will cause to their bodies. This
begins with a culturally sensitive approach to assessing patients’ sex-
ual needs, recognizing distinct cultural, religious, and sexual consid-
erations for each patient. In addition to the potential stigma of cancer
itself, insensitivity toward sexual diversity can further stigmatize vul-
nerable populations who report the experience of perceived or inten-
tional discrimination in the context of their care.80 This is particularly
true for sexual and gender minority patients, who are formally recog-
nized as a health disparity population,81 and for whom participation
in cervical cancer screening can be influenced by perceived biases
and barriers.82,83
Nurses are integral to the provision of holistic care to patients,
from the promotion of vaccination for adolescents and young adults
to the evidence-based care of individuals through treatment and into
survivorship. Through education of evidence-based standards of care
for prevention, screening, treatment, and survivorship, nurses are
well-positioned to lead and support care for this population.
Conclusion
There have been advances in research for the management of cer-
vical cancer in the last decade. Focus continues to be on prevention,
preserving fertility, and immunetherapy treatments. Further research
will be needed to continue to monitor obstetric outcomes, as well as
potential immune-related toxicities in this patient population. As his-
tory has demonstrated in other vaccines that have prevented dis-
eases, such as polio or mumps, the HPV vaccine can aid in making
cervical cancer a disease of the past. After receiving HPV vaccination,
young patients need to be educated about the importance of having
annual pelvic exam and Pap smears every 3 years or at the recom-
mended screening intervals. As more women become protected from
HPV, they will be able to live longer and enjoy their roles as mothers,
daughters, or career-focused women. Nurses have a significant
opportunity to impact patient education and advocate to reduce the
incidence and progression of cervical cancer in society.
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Cynae A. Johnson, DNP, WHNP-BC, OCNÒ : Advanced Practice Provider, Department of
Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson
Cancer Center, Houston, TX.
Deepthi James, DNP, APRN, FNP-C: Advanced Practice Provider, Department of Gyneco-
logic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer
Center, Houston, TX.
Amelita Marzan, MS, APRN, FNP-C, OCNÒ : Advanced Practice Provider, Department of
Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson
Cancer Center, Houston, TX.
Mona Armaos, MSN, APRN, FNP-C: Advanced Practice Provider, Department of Gyneco-
logic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer
Center, Houston, TX.