Background

Cervical cancer is the second most common malignancy in women worldwide, and it remains a leading
cause of cancer-related death for women in developing countries. In the United States, cervical cancer is
relatively uncommon. (See Epidemiology.)

The incidence of invasive cervical cancer has declined steadily in the United States over the past few
decades; however, it continues to rise in many developing countries. The change in the epidemiological
trend in the United States has been attributed to mass screening with Papanicolaou tests.

Because women are screened routinely, the most common finding is an abnormal Papanicolaou test
result (see Clinical). The complete evaluation for cervical cancer should include a Papanicolaou test with
cytobrush and endocervical and endometrial samplings. If the smear result is suggestive of
adenocarcinoma in situ, a cone biopsy should be performed. (See Workup.)

The treatment of cervical cancer varies with the stage of the disease. For early invasive cancer, surgery is
the treatment of choice. In more advanced cases, radiation combined with chemotherapy is the current
standard of care. In patients with disseminated disease, chemotherapy or radiation provides symptom
palliation. (See Treatment.)

Etiology
Early epidemiological data demonstrated a clear association between cervical cancer and sexual activity.
Major risk factors observed were sex at a young age, multiple sexual partners, promiscuous male
partners, and history of sexually transmitted diseases. However, the search for a potential sexually
transmitted carcinogen was unsuccessful until breakthroughs in molecular biology enabled scientists to
detect viral genome in cervical cells.

Strong evidence now implicates human papillomaviruses (HPVs) as prime suspects. [1, 2, 3] HPV viral DNA
has been detected in more than 90% of squamous intraepithelial lesions (SILs) and invasive cervical
cancers compared with a consistently lower percentage in controls. Both animal data and molecular
biologic evidence confirm the malignant transformation potential of papilloma virusinduced lesions. SILs
are found predominantly in younger women, while invasive cancers are detected more often in women
10-15 years older, suggesting slow progression of cancer.

HPV infection occurs in a high percentage of sexually active women. Most of these infections clear
spontaneously within months to a few years, and only a small proportion progress to cancer. This means
that other crucial factors must be involved in the process of carcinogenesis.

Three main factors have been postulated to influence the progression of low-grade SILs to high-grade
SILs. These include the type and duration of viral infection, with high-risk HPV type and persistent
infection predicting a higher risk for progression; host conditions that compromise immunity, such as
multiparity or poor nutritional status; and environmental factors such as smoking, oral contraceptive use,
or vitamin deficiencies.

In addition, various gynecologic factors significantly increase the risk for cervical cancer. These include
early age of first intercourse and higher number of sexual partners.

Human papillomavirus
HPV is a heterogeneous group of viruses that contain closed circular double-stranded DNA. The viral
genome encodes 6 early open reading frame proteins (ie, E1, E2, E3, E4, E6, E7), which function as
regulatory proteins, and 2 late open reading frame proteins (ie, L1, L2), which make up the viral capsid.

To date, 77 different genotypes of HPV have been identified and cloned, among which types 6, 11, 16, 18,
26, 31, 33, 35, 39, 42, 43, 44, 45, 51, 52, 53, 54, 55, 56, 58, 59, 66, and 68 have the propensity to infect
anogenital tissues.

The HPVs that infect the human cervix fall into 2 broad risk categories. The low-risk types, HPV 6b and
11, are associated with low-grade SILs but are never found in invasive cancer. The high-risk types, mostly
 HPV 16 and 18, are found in 50-80% of SILs and in up to 90% of invasive cancers. Although less
common, types 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, and 82 should also be considered
carcinogenic.

The major difference between the 2 types is that after infection, the low-risk HPVs are maintained as
extrachromosomal DNA episomes, while the high-risk HPV genome is found integrated into the host
cellular DNA. The recombination event often leaves E6 and E7 directly coupled to the viral promoter and
enhancer sequences, allowing their continued expression after integration.

Because E7 binds and inactivates the Rb protein while E6 binds p53 and directs its degradation, the
functional loss of both TP53 and the RB genes leads to resistance to apoptosis, causing uncensored cell
growth after DNA damage. This ultimately results in progression to malignancy.

Human immunodeficiency virus

The role of human immunodeficiency virus (HIV) infection in the pathogenesis of cervical cancer is not
fully understood. Studies have shown a higher prevalence of HPV infection in HIV-seropositive women
than in seronegative women, and the HPV prevalence was directly proportional to the severity of
immunosuppression as measured by CD4 counts.

Impaired lymphocyte function has been postulated to enhance latent or subclinical HPV activity, resulting
in a higher rate of persistent infection. Whether HIV has a synergistic effect on HPV infection, either by
direct molecular interaction or through an indirect immunologic effect, remains unclear.

Epidemiology
Cervical cancer is the second most common malignancy in women worldwide, and it remains a leading
cause of cancer-related death for women in developing countries. In the United States, cervical cancer is
relatively uncommon. The incidence of invasive cervical cancer has declined steadily in the United States
over the past few decades; however, it continues to rise in many developing countries. The change in the
epidemiological trend in the United States has been attributed to mass screening with Papanicolaou tests.
[4]

The American Cancer Society estimated that in the United States in 2010, 12,200 new cases of cervical
cancer would be diagnosed.[5] In addition, more than 50,000 cases of carcinoma in situ are diagnosed
each year. Internationally, 500,000 new cases are diagnosed each year. Unlike the United States, where
the annual incidence is 6.8 cases or less per 100,000 women, rates in parts of South America and Africa
range as high as 52.8 cases per 100,000 women.[6]

Race- and age-related demographics

In the United States, cervical cancer is more common in Hispanic, African American, and Native American
women than in white women. The Center for Disease Control and Preventions Surveillance of Screening-
Detected Cancers (Colon and Rectum, Breast, and Cervix)United States, 20042006 reported that
incidence rates of late-stage cervical cancer were highest among women aged 50-79 years and
Hispanics.[7] However, cervical cancer may be diagnosed in any woman of reproductive age.

Prognosis
Prognosis of cervical cancer depends on disease stage. In general, the 5-year survival rates are as
follows:

Stage I - Greater than 90%

Stage II - 60-80%
Stage III - Approximately 50%
Stage IV - Less than 30%
The American Cancer Society estimated that 4,210 women would die of cervical cancer in the United
States in 2010.[5] This represents 1.3% of all cancer deaths and 6.5% of deaths from gynecologic cancers.
 Patient Education
Cervical cancer is overrepresented among underserved and minority groups in the United States. It is
imperative to increase awareness about the benefits of Papanicolaou test screening in these groups.

A Cochrane review found that the best approach to encourage women to undergo cervical screening
involved invitations, such as fixed or open appointments, letters, telephone calls, verbal
recommendations, prompts, and follow-up letters. [8] However, these findings relate to screening in
developed countries, and their relevance to developing countries is unclear. Further studies are required
to determine the effectiveness of promising interventions, such as revealing in an invitation letter the
gender of the smear taker, using a health promotion nurse, the use of lay outreach health workers, and
intensive attempts at recruitment.

For patient education information, see the Cancer and Tumors Center,Women's Health Center,
and Procedures Center, as well as Cervical Cancer,Pap Smear, and Colposcopy.

History
Because women are screened routinely, the most common finding is an abnormal Papanicolaou test
result. Typically, these patients are asymptomatic.

Clinically, the first symptom is abnormal vaginal bleeding, usually postcoital. Vaginal discomfort,
malodorous discharge, and dysuria are not uncommon.

The tumor grows by extending upward to the endometrial cavity, downward to the vagina, and laterally to
the pelvic wall. It can invade the bladder and rectum directly. Symptoms that can evolve, such as
constipation, hematuria, fistula, and ureteral obstruction with or without hydroureter or hydronephrosis,
reflect local organ involvement. The triad of leg edema, pain, and hydronephrosis suggests pelvic wall
involvement.

The common sites for distant metastasis include extrapelvic lymph nodes, liver, lung, and bone.

Physical Examination
In patients with early-stage cervical cancer, physical examination findings can be relatively normal. As the
disease progresses, the cervix may become abnormal in appearance, with gross erosion, ulcer, or mass.
These abnormalities can extend to the vagina. Rectal examination may reveal an external mass or gross
blood from tumor erosion.

Bimanual examination findings often reveal pelvic metastasis. If the disease involves the liver,
hepatomegaly may develop. Pulmonary metastasis usually is difficult to detect upon physical examination
unless pleural effusion or bronchial obstruction becomes apparent. Leg edema suggests
lymphatic/vascular obstruction from tumor.

Diagnostic Considerations
Other disorders to consider in a woman with possible cervical cancer include cervicitis/infection,
particularly granulomatous (which is rare) and vaginal cancer. Another rare possibility is that a primary
cancer elsewhere in the body has metastasized to the cervix.

Differentials
Cervicitis
Endometrial Carcinoma
Pelvic Inflammatory Disease
Uterine Cancer
Vaginitis
Approach Considerations
Complete evaluation should include Papanicolaou test with cytobrush and endocervical and endometrial
samplings. If the smear result is suggestive of adenocarcinoma in situ, a cone biopsy should be
performed. If the pathology still is unclear after the above workup, the patient should have dilatation and
curettage.

Once the diagnosis is established, imaging studies are performed for staging purposes. In the
International Federation of Gynecology and Obstetrics (Federation Internationale de Gynecologie et
dObstetrique [FIGO]) guidelines for staging, procedures are limited to colposcopy, biopsy, conization of
cervix, cystoscopy, and proctosigmoidoscopy.[9]

In the United States, more complex radiologic imaging, such as CT, MRI, and PET scans as well as
surgical staging, are often done to guide therapeutic options.

Also see Cervical Cancer Imaging.

Screening Recommendations
The American Cancer Society (ACS) and the US Preventive Services Task Force (USPSTF) recommend
that all women should begin screening for cervical cancer approximately 3 years after they begin to have
vaginal intercourse, but no later than age 21 years. [10, 11]

Beginning at age 30 years, women who have had 3 consecutive normal Papanicolaou test results may
undergo screening every 2-3 years. Women with high-risk factors (ie, diethylstilbestrol [DES] exposure,
HIV infection, or other immunodeficiencies) should continue yearly screening.

Another option for women aged 30 years and older is to get screened every 3 years with the
conventional-based or liquid-based Papanicolaou test plus HPV DNA test. A study conducted in China
found that HPV DNA testing is highly sensitive and moderately specific for cervical intraepithelial
neoplasia (CIN) grade 3 or worse, including in women aged 35 years or younger.[12] This suggests that
raising the cut-off age for this test may be beneficial.

The ACS recommends that women aged 70 years and older with 3 or more normal consecutive
Papanicolaou test results and no abnormal Papanicolaou test results within the last 10 years may choose
to stop having cervical cancer screening. The USPSTF recommends against routinely screening women
older than 65 years if they have had adequate recent screening with normal Pap smears and are not
otherwise at high risk for cervical cancer.

Women who have had a total hysterectomy may stop having cervical cancer screening. Exceptions are
those who had a hysterectomy due to cervical carcinoma (or preinvasive changes) and women who had a
hysterectomy without removal of the cervix.

Screening for Cervical Cancer

If cervical cancer is the suggested diagnosis, a Papanicolaou test should be performed. Patients with
positive results should be referred to a gynecologist for colposcopy, direct biopsies, and endocervical
curettage.

Papanicolaou test
For many years, the standard method for cervical cancer screening has been the Papanicolaou test.
Retrospective data have shown that screening with a Papanicolaou test reduces the incidence of cervical
cancer by 60-90% and the death rate by 90%.

The false-negative rate of a Papanicolaou test is 20%, which mostly results from sampling error.
Physicians can reduce sampling error by ensuring adequate material is taken from both the endocervical
canal and the ectocervix. Smears without endocervical or metaplastic cells must be repeated. Upon
physical examination, suspicious or grossly abnormal cervical lesions should undergo biopsy regardless
of cytologic findings.

The limitations of the conventional Papanicolaou test include limited sensitivity (51%) and a significant
proportion of inadequate specimens. In addition, accurate interpretation of conventional Papanicolaou
tests are often compromised by the presence of artifacts (eg, blood, mucus, obscuring inflammation,
scant cellular material, air-drying artifact).

In recent years, new technologies have become available. Limited information is available regarding their
sensitivity and specificity compared with the conventional Papanicolaou test. Whether these new methods
improve survival, compared with the conventional Papanicolaou test, is unknown.

ThinPrep Papanicolaou test

The ThinPrep Papanicolaou test samples are collected the same way as the conventional Papanicolaou
test. However, the specimen is placed in a preservative solution rather than on a slide. An automated
processor prepares the sample and makes a uniform slide for review. Mucus and blood are removed in
the process. The ThinPrep Papanicolaou test was approved in 1996 by the US Food and Drug
Administration (FDA) as an alternative to the traditional conventional smear.

Hybrid Capture II assay

The Hybrid Capture II assay for human papillomavirus (HPV) was approved by the FDA in 2003 as a new
approach for cervical cancer. This test is indicated for women aged 30 years and older, in conjunction with
the Papanicolaou test. If both tests are negative, then the next Papanicolaou test can be delayed for 3
years.

HPV test
The HPV test is also useful for interpreting equivocal results from a Papanicolaou test. If a woman has a
Papanicolaou test result showing atypical squamous cells of undetermined significance (ASCUS) and a
positive HPV test, then additional workup with a colposcopy is indicated. Marks et al suggest that the use
of combined oral contraceptives for longer than 6 years may negatively impact early upstream events in
the natural history of HPV infection.[13]

Complete Blood Cell Count and Serum Chemistry

After the diagnosis is established, a complete blood cell count and serum chemistry for renal and hepatic
functions should be ordered. These studies are intended to look for abnormalities from possible
metastatic disease.

Imaging Tests
A routine chest radiograph is obtained to help rule out pulmonary metastasis. Chest radiography may be
considered optional for disease that is stage IB1 or lower.[14]

Consideration should be given to obtaining pelvic ultrasonography before performing uterine curettage.
Ultrasound studies providing adequate definition of the fallopian tubes and ovaries can help identify
primary malignancies of these organs.

A CT scan of the abdomen and pelvis is performed to look for metastasis in the liver, lymph nodes, or
other organs and to help rule out hydronephrosis/hydroureter. Positron emission tomography (PET)-CT
scanning is an alternative to CT.[14]

Also see Cervical Cancer Imaging.

Studies for Patients with Bulky Primary Tumor

In patients with bulky primary tumor, cystoscopy and proctoscopy should be performed in these patients
to help rule out local invasion of the bladder and the colon. Barium enema studies can be used to
evaluate extrinsic rectal compression from the cervical mass.
 Surgical Staging
Clinical staging protocols can fail to demonstrate pelvic and aortic lymph node involvement in 20-50% and
6-30% of patients, respectively. For that reason, surgical staging frequently is recommended.

Pretreatment surgical staging is the most accurate method to determine the extent of disease. However,
little evidence suggests an improvement in overall survival with routine surgical staging. Therefore,
pretreatment surgical staging should be individualized after a thorough nonsurgical workup, including fine-
needle aspiration of lymph nodes, has failed to demonstrate metastatic disease.

Histologic Findings
Precancerous lesions of the cervix usually are detected via Papanicolaou test. The Papanicolaou test
classification system has evolved over the years. Standardized Papanicolaou test reporting emerged from
a 1988 workshop sponsored by the National Cancer Institute. Currently, cervical cytology results are
reported according to the 2001 Bethesda System. [15]

The 2001 Bethesda System for Reporting Cervical Cytologic Diagnoses

Specimen adequacy may be the single most important quality assurance component of the system.
Specimen classifications are as follows:

Satisfactory for evaluation (note presence/absence of endocervical/transformation zone

component)
Unsatisfactory for evaluation (specify reason)
Specimen rejected/not processed (specify reason)
Specimen processed and examined, but unsatisfactory for evaluation of epithelial abnormality
because of (specify reason)
General categorization (optional) is as follows:

Negative for intraepithelial lesion or malignancy

Epithelial cell abnormality
Other
Possible interpretations/results are as follows:

Negative for intraepithelial lesion or malignancy

Observed organisms (eg, Trichomonas, Candida, bacteria) and cellular changes consistent with
herpes simplex virus are reported.
Reporting other non-neoplastic findings is optional (ie, inflammation, atrophy)
Epithelial cell abnormalities
Squamous cell
Atypical squamous cells (ASC)
ASC of undetermined significance (ASCUS)
ASC, cannot exclude high-grade squamous intraepithelial lesion (ASC-H)
Low-grade squamous intraepithelial lesion (LSIL)
Encompassing: human papillomavirus/mild dysplasia/cervical intraepithelial neoplasia (CIN) 1
High-grade squamous intraepithelial lesion (HSIL)
Encompassing: moderate and severe dysplasia, carcinoma in situ, CIN 2, and CIN 3
 Squamous cell carcinoma (see the image below) Squamous cell
cervical carcinoma.
Glandular cell
Atypical glandular cells (AGC) (specify endocervical, endometrial, or not otherwise specified)
AGC, favor neoplastic (specify endocervical or not otherwise specified)
Endocervical adenocarcinoma in situ (AIS)
Adenocarcinoma
Other (List not comprehensive)
Endometrial cells in a woman aged 40 years or older
Automated review and ancillary testing are included as appropriate. Educational notes and suggestions
are optional.

Regarding invasive cervical cancer, the histology of cervical malignancy is predominantly of epithelial
origin, with squamous cell carcinoma as the major group (85%). Less common histologies include
adenocarcinoma, small cell carcinoma, melanoma, and lymphoma.

Two staging systems are frequently used in cervical cancer: FIGO, in collaboration with the World Health
Organization (WHO), and TNM system of the International Union Against Cancer (UICC) and the
American Joint Committee on Cancer (AJCC).[9, 16] (See the tables below.)

Table 1. Cervical Cancer Staging (primary tumor [T]) (Open Table in a new window)

TNM FIGO
Stage Stage

Tx - Primary tumor cannot be assessed

T0 - No evidence of primary tumor

Tis 0 Carcinoma in situ

T1 I Cervical carcinoma confined to uterus (extension to corpus should be disregarded)

T1a IA Invasive carcinoma diagnosed only by microscopy. All macroscopically visible lesions--even with
superficial invasion--are T1b/1B. Stromal invasion with a maximal depth of 5.0 mm measured from
the base of the epithelium and a horizontal spread of 7.0 mm or less. Vascular space involvement,
venous or lymphatic, does not affect classification.

T1a1 IA1 Measured stromal invasion 3 mm or less in depth and 7 mm or less in lateral spread

T1a2 IA2 Measured stromal invasion more than 3 mm but not more than 5 mm with a horizontal spread 7
mm or less

T1b IB Clinically visible lesion confined to the cervix or microscopic lesion greater than IA2

T1b1 IB1 Clinically visible lesion 4 cm or less in greatest dimension

 IB2 Clinically visible lesion more than 4 cm

T2 II Cervical carcinoma invades beyond uterus but not to pelvic wall or to the lower third of vagina

T2a IIA Tumor without parametrial invasion

T2b IIB Tumor with parametrial invasion

T3 III Tumor extends to the pelvic wall and/or involves the lower third of the vagina and/or causes
hydronephrosis or nonfunctioning kidney

T3a IIIA Tumor involves lower third of vagina; no extension to pelvic wall

T3b IIIB Tumor extends to pelvic wall and/or causes hydronephrosis or nonfunctioning kidney

- IV Cervical carcinoma has extended beyond the true pelvis or has involved (biopsy proven) the
bladder mucosa or rectal mucosa. Bullous edema does not qualify as a criteria for stage IV disease.

T4 IVA Spread to adjacent organs (bladder, rectum, or both)

M1 IVB Distant metastasis

Regional lymph nodes (N), AJCC staging only, include paracervical, parametrial, hypogastric (obturator),
common, internal and external iliac, presacral and sacral.

NX: Regional lymph nodes cannot be assessed.

N0: No regional lymph nodes metastasis.
N1: Regional lymph nodes metastasis.
Table 2. AJCC Stage Grouping (Open Table in a new window)

Stage Tumor Node Metastasis

0 Tis N0 M0

IA1 T1a1 N0 M0

IA2 T1a2 N0 M0

IB1 T1b1 N0 M0

IIA T2a N0 M0

IIB T2b N0 M0

IIIA T3a N0 M0

IIIB T1 N1 M0

- T2 N1 M0

- T3a N1 M0
- T3b Any N M0

IVA T4 Any N M0

IVB Any T Any N M1

Approach Considerations
The treatment of cervical cancer varies with the stage of the disease. For early invasive cancer, surgery is
the treatment of choice. In more advanced cases, radiation combined with chemotherapy is the current
standard of care. In patients with disseminated disease, chemotherapy or radiation provides symptom
palliation.

Management of Stage 0 Cancer

Carcinoma in situ (stage 0) is treated with local ablative measures such ascryosurgery, laser ablation, and
loop excision. Hysterectomy should be reserved for patients with other gynecologic indications to justify
the procedure. After local treatment, these patients require lifelong surveillance.

Management of Stage IA Cancer

The treatment of choice for stage IA disease is surgery. Total hysterectomy, radical hysterectomy, and
conization are accepted procedures. Lymph node dissection is not required if the depth of invasion is less
than 3 mm and no lymphovascular invasion is noted.

Selected patients with stage IA1 disease but no lymphovascular space invasion who desire to maintain
fertility may have a therapeutic conization with close follow-up, including cytology, colposcopy, and
endocervical curettage. Patients with medical comorbidities who are not surgical candidates can be
successfully treated with radiation.

According to National Comprehensive Cancer Network guidelines, pelvic radiation therapy is currently a
category 1 recommendation for women with stage IA disease and negative lymph nodes after surgery
who have high-risk factors, including large primary tumor, deep stromal invasion and/or lymphovascular
space invasion.[14]

Management of Stage IB or IIA Cancer

For patients with stage IB or IIA disease, treatment options are either combined external beam radiation
with brachytherapy or radical hysterectomy with bilateral pelvic lymphadenectomy.

Radical trachelectomy with pelvic lymph node dissection is appropriate for fertility preservation in women
with stage IA2 disease, and those with stage IB1 disease whose lesions are 2 cm or smaller. [14]

Analysis of women who underwent radical hysterectomy with lymphadenectomy, from the Surveillance,
Epidemiology, and End Results (SEER) database, revealed that patients with node-negative, early stage
cervical cancer who underwent a more extensive lymphadenectomy had improved survival. [17] Compared
with patients who had fewer than 10 nodes removed, patients with 21-30 nodes removed were 24% less
likely to die, and those with greater than 30 nodes removed were 37% less likely to die from their tumors.

Most retrospective studies have shown equivalent survival rates for both procedures, although such
studies usually are flawed due to patient selection bias and other compounding factors. However, a recent
study showed identical overall and disease-free survival rates. [18]

Quality-of-life data, particularly in the psychosexual area, is relatively scant.

Postoperative radiation to the pelvis decreases the risk of local recurrence in patients with high-risk
factors (positive pelvic nodes, positive surgical margins, and residual parametrial disease). [19] A
randomized trial showed that patients with parametrial involvement, positive pelvic nodes, or positive
surgical margins benefit from a postoperative combination of cisplatin-containing chemotherapy and
pelvic radiation.[20]

Management of Stage IIB-IVA Cancer

For locally advanced cervical carcinoma (stages IIB, III, and IVA), radiation therapy was the treatment of
choice for many years. Radiation therapy begins with a course of external beam radiation to reduce tumor
mass to enable subsequent intracavitary application. Brachytherapy is delivered using afterloading
applicators that are placed in the uterine cavity and vagina.

However, the results from large, well-conducted, prospective randomized clinical trials have demonstrated
a dramatic improvement in survival with the combined use of chemotherapy and radiation. [21, 22,
23]
Consequently, the use of cisplatin-based chemotherapy in combination with radiation has become the
standard of care for patients with locally advanced cervical cancer.[14]

Monk and colleagues studied chemotherapy regimens consisting of cisplatin plus 1 other antineoplastic
agent in advanced and recurrent cervical carcinoma, and found that the various treatment arms were not
superior to the reference arm of paclitaxel and cisplatin for overall survival. Furthermore, the trend for
response rates, progression-free survival, and overall survival favored paclitaxel and cisplatin. [24]

In this study, 513 patients were randomized to 1 of 4 regimens, and, in each regimen, patients received
cisplatin 50 mg/m2 on 1 day every 3 weeks. The following drugs were combined with cisplatin for the 4
regimens: (1) paclitaxel 135 mg/m2 over 24 hours, (2) vinorelbine 30 mg/m2 on days 1 and 8, (3)
gemcitabine 1000 mg/m2 on days 1 and 8, or (4) topotecan 0.75 mg/m 2 on days 1, 2, and 3.

Management of Stage IVB and Recurrent Cancer

These patients are treated with chemotherapy. For many years, single-agent cisplatin represented the
standard of care. However, the combined use of cisplatin and topotecan has been shown to significantly
improve survival compared with single-agent cisplatin. [25]

Gemcitabine plus cisplatin chemoradiotherapy followed by brachytherapy and adjuvant

gemcitabine/cisplatin chemotherapy improved survival outcomes with increased but clinically manageable
toxicity when compared with standard treatment.[26]

Special effort should be made to ensure comprehensive palliative care, including adequate pain control
for these patients. Palliative radiation is often used on an individualized basis to control bleeding, pelvic
pain, or urinary or partial large bowel obstructions from pelvic disease.

Complications of Radiation Therapy

During the acute phase of pelvic radiation therapy, the surrounding normal tissues such as the intestines,
the bladder, and the perineum skin often are affected. Acute adverse GI effects include diarrhea,
abdominal cramping, rectal discomfort, or bleeding. Diarrhea usually is controlled by either loperamide
(Imodium) or atropine sulfate (Lomotil). Small, steroid-containing enemas are prescribed to alleviate
symptoms from proctitis.

Cystourethritis also can occur, which leads to dysuria, frequency, and nocturia. Antispasmodics often are
helpful for symptom relief. Urine should be examined for possible infection. If urinary tract infection is
diagnosed, therapy should be instituted without delay.

Proper skin hygiene should be maintained for the perineum, and topical lotion should be used if erythema
or desquamation occurs.

Late sequelae of radiation usually appear 1-4 years after treatment. The major sequelae include rectal or
vaginal stenosis, small bowel obstruction, malabsorption, and chronic cystitis.
Complications From Surgery
The most frequent complication of radical hysterectomy is urinary dysfunction as a result of partial
denervation of the detrusor muscle. Other complications include foreshortened vagina, ureterovaginal
fistula, hemorrhage, infection, bowel obstruction, stricture and fibrosis of the intestine or rectosigmoid
colon, and bladder and rectovaginal fistulas.

Other Procedures
Invasive procedures such as nephrostomy or diverting colostomy sometimes are performed in this group
of patients to improve their quality of life. Total pelvic exenteration may be considered in patients with an
isolated central pelvic recurrence.

Nutrition
Proper nutrition is important for patients with cervical cancer. Every attempt should be made to encourage
and provide adequate oral food intake.

Nutritional supplements such as Ensure or Boost are used when patients have had significant weight loss
or cannot tolerate regular food due to nausea caused by radiation or chemotherapy. In patients with
severe anorexia, appetite stimulants such as megestrol (Megace) can be prescribed.

For patients who are unable to tolerate any oral intake, percutaneous endoscopic gastrostomy tubes are
placed for nutritional supplementation. In patients with extensive bowel obstruction as a result of
metastatic cancer, hyperalimentation sometimes is used.

Prevention of Human Papillomavirus Infection

Several measures are effective to prevent HPV infection and hence prevent cervical cancer. Sexual
abstinence or barrier protection and/or spermicidal gels during sexual intercourse are protective.
Evidence suggests that HPV vaccines prevent HPV infection. A vaccine for HPV, Gardasil, is approved by
the FDA for girls and women 9 to 26 years of age for prevention of cervical cancer caused by HPV types
6, 11, 16, and 18.[27]

The ACS recommends routine HPV vaccination for girls 11-12 years old; catch up vaccination or
completion of the vaccination series can be conducted up to age 18 years. The ACS found insufficient
data to recommend for or against universal HPV vaccination in women 19-26 years of age, and the ACS
recommends against vaccination after age 26 years. Screening for cervical cancer should continue in
vaccinated women, following the same guidelines as in unvaccinated women. [28]

Consultations
The treatment of cervical cancer frequently requires a multidisciplinary approach. Involvement of a
gynecologic oncologist, radiation oncologist, and medical oncologist may be necessary.

Long-Term Monitoring
A study by Littell et al suggests that women older than 30 years with high-risk, HPV-negative low-grade
squamous intraepithelial lesion (LSIL) have a low risk of CIN. [29] A 1-year follow-up colposcopy should be
considered when CIN occurs in routine practice.

Residual or recurrent CIN grade 2 or 3 cervical cancer develops in 15% of women treated for high-grade
CIN. Kocken et al suggest that the 5-year risk of posttreatment CIN grade 2 or higher in women with 3
consecutive negative cytological smears or negative co-testing for cytology and hrHPV at 6 and 24
months was similar to that of women with normal cytology. This may justify routine-to-regular screening. [30]

Medication Summary
Chemotherapy should be administered in conjunction with radiation therapy to most patients with stage IB
(high risk) to IVA. Cisplatin is the agent used most commonly, although 5-fluorouracil also is used
frequently. For patients with metastatic disease, cisplatin remains the most active agent. Topotecan,
ifosfamide, and paclitaxel also have significant activity in this setting. The combination of topotecan and
cisplatin improves overall survival. However, acute toxicities are also increased.

Chemotherapy Agents
Class Summary
These agents inhibit cell growth and proliferation.
View full drug information
Cisplatin
Intrastrand cross-linking of DNA and inhibition of DNA precursors are among the proposed mechanisms
of action for cisplatin. This agent is used in combination with radiation therapy.
View full drug information
Fluorouracil (Adrucil)
Fluorouracil is a pyrimidine antagonist. Several mechanisms of action have been proposed, including
inhibition of thymidylate synthase and inhibition of RNA synthesis. This agent is also a potent
radiosensitizer.
View full drug information
Ifosfamide (Ifex)
Ifosfamide forms DNA interstrand and intrastrand bonds that interfere with protein synthesis.
View full drug information
Paclitaxel (Abraxane)
The mechanisms of action of paclitaxel are tubulin polymerization and microtubule stabilization.
View full drug information
Topotecan (Hycamtin)
Topotecan inhibits topoisomerase I, inhibiting DNA replication. Patients who have received prior
chemotherapy should be given a lower dose initially.

Vaccines
Class Summary
Two human papillomavirus (HPV) vaccines are now available for prevention of HPV-associated
dysplasias and neoplasias, including cervical cancer, genital warts (condyloma acuminata), and
precancerous genital lesions. The immunization series should be completed in girls and young women
aged 9-26 years.[31]
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Papillomavirus vaccine, quadrivalent (Gardasil)
This quadrivalent HPV recombinant vaccine is the first vaccine indicated to prevent cervical cancer,
genital warts (condyloma acuminata), and precancerous genital lesions (eg, cervical adenocarcinoma in
situ; cervical intraepithelial neoplasia grades 1, 2, and 3; vulvar intraepithelial neoplasia grades 2 and 3;
vaginal intraepithelial neoplasia grades 2 and 3) due to HPV types 6, 11, 16, and 18. Vaccine efficacy is
mediated by humoral immune responses following the immunization series.
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Papillomavirus vaccine, bivalent (Cervarix)
This recombinant HPV vaccine is prepared from the L1 protein of HPV types 16 and 18. It is indicated in
girls and women (ages 10-25 y) for prevention of diseases caused by oncogenic HPV types 16 and 18 (ie,
cervical cancer, cervical intraepithelial neoplasia grade 2 or higher, adenocarcinoma in situ, cervical
intraepithelial grade 1).