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Cervical Cancer
View online at http://pier.acponline.org/physicians/diseases/d643/d643.html
Module Updated:
CME Expiration:
2013-07-01
2016-07-01
Author
Asra Khan, MD, FACP
Table of Contents
1. Prevention .........................................................................................................................2
2. Screening ..........................................................................................................................4
3. Diagnosis ..........................................................................................................................7
4. Consultation ......................................................................................................................11
5. Hospitalization ...................................................................................................................12
6. Therapy ............................................................................................................................13
7. Patient Education ...............................................................................................................18
8. Follow-up ..........................................................................................................................19
References ............................................................................................................................20
Glossary................................................................................................................................23
Tables...................................................................................................................................25
Figures .................................................................................................................................31
Quality Ratings: The preponderance of data supporting guidance statements are derived from:
level 1 studies, which meet all of the evidence criteria for that study type;
level 2 studies, which meet at least one of the evidence criteria for that study type; or
level 3 studies, which meet none of the evidence criteria for that study type or are derived from expert opinion, commentary, or consensus.
Study types and criteria are defined at http://smartmedicine.acponline.org/criteria.html
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CME Statement: The American College of Physicians is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide
continuing education for physicians. The American College of Physicians designates this enduring material for a maximum of 1 AMA PRA Category 1
CreditTM. Physicians should claim only credit commensurate with the extent of their participation in the activity. Purpose: This activity has been
developed for internists to facilitate the highest quality professional work in clinical applications, teaching, consultation, or research. Upon completion
of the CME activity, participants should be able to demonstrate an increase in the skills and knowledge required to maintain competence, strengthen
their habits of critical inquiry and balanced judgement, and to contribute to better patient care. Disclosures: Asra Khan, MD, FACP, current author of
this module, has no financial relationships with pharmaceutical companies, biomedical device manufacturers, or health-care related organizations.
Deborah Korenstein, MD, FACP, Co-Editor, PIER, has no financial relationships with pharmaceutical companies, biomedical device manufacturers, or
health-care related organizations. Richard B. Lynn, MD, FACP, Co-Editor, PIER, has no financial relationships with pharmaceutical companies,
biomedical device manufacturers, or health-care related organizations.
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Cervical Cancer
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1. Prevention
Consider educating patients about measures that may decrease the
risk of cervical cancer.
1.1 Consider educating patients about safe sexual practices to decrease the
risk of cervical cancer.
Recommendations
• Advise patients to:
Limit their number of sexual partners
Avoid intercourse at an early age
Use condoms to decrease the risk of acquiring HPV
• See module Human Papillomavirus.
Evidence
• Epidemiologic studies have shown that women with multiple sexual partners have an increased risk
of developing cervical cancer. Relative risk is 2.1 [CI, 1.1 to 2.7] for ≥6 lifetime sexual partners
(1).
• Epidemiologic studies have shown that women who have had intercourse at an early age have an
increased risk of developing cervical cancer. Relative risk is 2.9 [CI, 1.3 to 2.4] for ages 14 to 15 at
first sexual intercourse (1).
Rationale
• HPV is sexually transmitted and can cause cervical dysplasia and cervical cancer.
• Increasing the number of sexual partners increases exposure to HPV.
• Intercourse at an early age (under ages 13 to 15) exposes the cervix to HPV when it is most
vulnerable.
• Intercourse with the use of condoms helps decrease the exposure to HPV.
Comments
• Although HPV is sexually transmitted and can cause cervical dysplasia and cervical cancer, HPV
infection is very common. Most women who have had sexual intercourse have been exposed to
HPV; therefore, care must be taken when counseling patients about HPV infection because it does
not carry the same connotations as other sexually transmitted diseases (i.e., HPV on a Pap smear
does not signify infidelity in the relationship).
• There are multiple types of HPV. The major high-risk types are 16 and 18.
• There is considerable controversy regarding the association between use of oral contraceptives and
cervical cancer.
• According to a meta-analysis of 28 studies including 12,531 women with cervical cancer, the
relative risk of cervical cancer increases with duration of oral contraceptive use. Compared with
women who never used oral contraceptives, those who used oral contraceptives for less than 5
years had a relative risk of 1.1 (CI, 1.1 to 1.2), those who used them for 5 to 9 years had a
relative risk of 1.6 (CI, 1.4 to 1.7), and those who used them for 10 years or more had a relative
risk of 2.2 (CI, 1.9 to 2.4) (2).
1.2 Consider advising patients to avoid smoking to decrease the risk of
cervical cancer.
Recommendations
• Advise patients not to smoke in an effort to decrease their risk of developing cervical cancer.
• See module Smoking Cessation.
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Evidence
• Epidemiologic studies have shown that women who have smoked are at increased risk of
developing cervical cancer. Smokers have a relative risk of 3.4 [CI, 2.1 to 5.6] (3).
• Mean nicotine in the cervical mucus of smokers was 1056 ng/mL vs. 43 ng/mL in nonsmokers (4).
Rationale
• Women who smoke have an increased risk of developing cervical dysplasia and cancer because of
the carcinogenic and immunosuppressive effect that smoking has on the cervix.
Comments
• Second-hand smoke is also a risk factor for cervical cancer (5). Nonsmokers exposed to secondhand smoke for ≥3 hours a day have a relative risk of 3.0 [CI, 1.3 to 7.0] (3).
1.3 Vaccinate young women against HPV to reduce the risk of cervical cancer.
Recommendations
• Recommend the quadrivalent HPV vaccine for females aged 11 to 12 years.
Give three doses of the vaccine, with the second dose 2 months after the initial dose and the third dose 6
months after the initial dose
• Recommend catch-up vaccination for females aged 13 to 26 years who have not been previously
vaccinated.
Evidence
• A 2007 statement from the Advisory Committee on Immunization Practices of the CDC
recommended the HPV vaccine for cervical cancer prevention for girls age 11 to 12, noting that the
vaccine could be given as early as age 9, and as late as age 26 (6).
• Clinical trials indicate that the vaccine has high efficacy in preventing persistent HPV infection and
cervical cancer precursor lesions caused by HPV types 16 and 18 and genital warts caused by HPV
types 6 and 11 among females who have not already been infected with the respective HPV type
(7; 8).
Rationale
• Sequelae of infection of the female genital tract with high-risk HPV subtypes include cervical
dysplasia and squamous cell carcinoma.
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2. Screening
Screen all women at risk for cervical cancer using cervical
cytology.
2.1 Screen women between the ages of 21 and 65 for cervical cancer every 3
years using cervical cytology.
Recommendations
• Initiate screening with cervical cytology at age 21 and conduct screening every 3 years with
cervical cytology.
• In women ages 30 to 65, consider screening every 5 years with cervical cytology plus HPV testing.
• Screen high-risk women more often including women who have been exposed to DES, are HIV
positive, have a history of CIN 2/3, or are otherwise immunocompromised.
• High-value care: Discontinue screening in women older than age 65 who have had prior adequate
screening unless they have history of high-grade dysplasia (CIN2 or worse).
• High-value care: Discontinue screening in women who have had hysterectomy with removal of
the cervix unless they have history of high-grade dysplasia (CIN2 or worse).
• If cervical cytology result is:
Satisfactory and negative for intraepithelial lesion or malignancy, repeat cervical cytology at the scheduled
interval
Unsatisfactory, repeat within 3 to 6 months
ASC-US, refer for colposcopy, obtain HPV DNA testing, or repeat cytology at 6 and 12 months
ASC-H, HSIL, squamous cell cancer, or atypical glandular cells, refer for colposcopy
• Repeat the Pap test in 1 year in females under age 20 with ASC-US or LSIL instead of following the
adult recommendations noted above.
• See table The Bethesda System for Reporting Results of Cervical Cytology.
• See module Papanicolaou Smear.
Evidence
• Recommendations are based on the 2012 guideline from the U.S. Preventive Services Task Force
(9) and the 2012 consensus guideline from the American Cancer Society, American Society for
Colposcopy and Cervical Pathology, and the American Society for Clinical Pathology, which
recommended every 5-year screening of women over age 30 with cytology plus HPV testing as a
preferred strategy (10). The 2009 guidelines from the American Congress of Obstetricians and
Gynecologists are similar (11).
• A 2011 systematic review found that liquid-based cytology and conventional cytology have
equivalent sensitivity and specificity (12).
• Multiple epidemiologic studies have shown that women who are screened with cervical cytology
have a significant reduction (95%) in developing cervical cancer and dying of cervical cancer (13).
In a retrospective study, the implementation of cervical cytology screening programs in British
Columbia resulted in the incidence of cervical cancer decreasing by 85% between 1955 and 1988
(14).
• One study evaluated 128,805 women who initially had a normal Pap smear result. The incidence of
HSIL suggestive of cancer was 25 per 10,000 women who had a second smear performed within 9
to 12 months of the first. This figure increased to 29 per 10,000 women for patients who had their
second smear at 13 to 24 months and to 33 per 10,000 women for patients whose second Pap
smear was performed 25 to 36 months after initial screening. These differences did not reach
statistical significance (15).
• The effect of screening interval was evaluated in 938,576 women under age 65. In patients who
had three or more negative test results, the excess risk for cervical cancer if screening were to be
performed every 3 years instead of annually was 3 in 100,000 (16).
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• After 3 consecutive, yearly, negative cytology smears, the risk of cervical cancer is reduced to
approximately 1/100,000/years (13).
• National consensus guidelines from the American Society for Colposcopy and Cervical Pathology
recommend less aggressive follow-up for adolescents with ASC-US and LSIL due to the extremely
low risk of malignancy in this population (17).
Rationale
• Women who have annual cervical cytology decrease their risk of dying of cervical cancer by 95%.
2.2 Consider screening women ages 30 to 65 every 5 years using the
combination of cervical cytology and HPV DNA testing.
Recommendations
• Consider combining cervical cytology and HPV DNA testing every 5 years in women ages 30 to 65:
If both test results are negative, repeat combination screening every 5 years but not more frequently
If cytology is negative and HPV testing is positive, defer colposcopy but repeat both tests in 6 to 12 months
If cytology shows atypical cells of undetermined significance and HPV testing is negative, defer colposcopy
and repeat both tests, but repeat cytology in 12 months
If cytology shows atypical cells of undetermined significance and HPV testing is positive, refer for
colposcopy
If cytology shows atypical squamous cells-high grade, LSIL, or HSIL and HPV testing is negative, refer for
colposcopy
Evidence
• A 2012 guideline from the American Cancer Society, American Society for Colposcopy and Cervical
Pathology, and the American Society for Clinical Pathology recommended testing every 5 years
with cervical cytology and HPV testing as the preferred screening strategy in women aged 30 to 65
(18).
• A systematic review of the accuracy of screening tests for cervical cancer found that the addition of
HPV testing to cytology increases sensitivity but decreases specificity slightly compared with
cytology alone. HPV testing alone had performance characteristics similar to those of HPV testing
with cytology (12).
• Testing for high-risk HPV identifies more women with high-grade dysplasia than does a single
cervical cytology sample (19; 20; 21; 22).
• The sensitivity obtained by combining the two methods of screening exceeds 95% in most studies
(19; 20; 21; 22).
• Prevalence of HPV DNA positivity falls after the late teens and early twenties. In contrast, the
incidence of high-grade dysplasia rises and peaks among women in their late twenties and early
thirties (23; 24).
• There is a high NPV for underlying high-grade dysplasia in women with negative HPV and negative
cytology results. Prospective studies indicate that the incidence of high-grade dysplasia during the
subsequent 3 years is less than 2.0 per 1000 women whose results are negative on both tests
(25).
• The addition of an HPV test to the Pap test to screen women in their mid-30s for cervical cancer
reduces the incidence of grade 2 or 3 cervical intraepithelial neoplasia or cancer detected by
subsequent screening examinations (26).
• National consensus guidelines indicate that colposcopy should be performed in women who are HPV
high risk DNA positive and have a cytology result of atypical cells of undetermined significance
(23).
• Recommendations are based on the 2012 guideline from the U.S. Preventive Services Task Force
(9) and the 2012 consensus guideline from the American Cancer Society, American Society for
Colposcopy and Cervical Pathology, and the American Society for Clinical Pathology (10).
• National consensus guidelines indicate that women who are high-risk HPV DNA negative and have a
cytology result of ASC-US can be followed with repeated cytology in 12 months (23).
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Rationale
• The addition of HPV testing to cervical cytology increases the diagnostic accuracy of cervical cancer
screening.
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3. Diagnosis
Use history, physical, and laboratory results to make a diagnosis of
cervical cancer.
3.1 Use history to elicit risk factors or symptoms of cervical cancer.
Recommendations
• Ask about factors that increase risk of cervical cancer:
Multiple sexual partners
Early age of first intercourse
Smoking
• Ask about factors that can indicate cervical cancer:
Postcoital bleeding, which is commonly the first symptom of cervical cancer
The “terrible triad” of advanced cervical cancer (sciatic back pain, hydroureter, leg swelling)
Foul-smelling vaginal discharge
Change in urinary or bowel habits
Evidence
• Early age of first intercourse (RR, 1.8 [CI, 1.3 to 2.4]), multiple sexual partners (RR, 2.1 [CI, 1.1
to 2.7]) (1), and smoking (RR, 3.4 [CI 2.1 to 5.6]) (3) increase the chance of HPV causing cervical
dysplasia and cancer.
• Epidemiologic studies have shown that postcoital bleeding is the most common symptom of
invasive cervical cancer. Sixty percent of patients with cervical cancer present with abnormal
vaginal bleeding (27).
• Epidemiologic studies have also shown that other symptoms of cervical cancer include the “terrible
triad” (9%), foul-smelling vaginal discharge (4%), and changes in urinary or bowel habits (4%)
(27).
Rationale
• A careful history may be helpful in identifying patients at high risk for developing cervical cancer.
• Early age of first intercourse, multiple sexual partners, and smoking increase the chance of HPV
causing cervical dysplasia and cancer.
• As cancer grows on the cervix, the first symptom is frequently bleeding after intercourse because
of direct trauma.
• As cervical cancer invades through the parametrium to the pelvic sidewall, it can cause blockage of
the ureter (hydroureter), infiltrate nerves along the uterosacral ligament and sacrum (sciatic back
pain) and cause pressure on the iliac vessels (leg swelling).
• Large exophytic tumors and large ulcerative lesions can become necrotic and produce a foulsmelling vaginal discharge that is usually slightly green or pink in color.
• Advanced cervical cancer may impinge on the urinary bladder, ureters, or rectosigmoid, causing
change in urinary or bowel habits.
Comments
• Although postcoital bleeding is the most common symptom of cervical cancer, most women with
postcoital bleeding do not have cervical cancer. It is frequently caused by glands on the cervix
(such as in pregnancy or women taking birth control pills), cervicitis, or lack of estrogen in the
postmenopausal woman.
• Although other causes of vaginal discharge such as cervicitis and vaginitis are much more common
than cervical cancer, examination of the cervix and a Pap smear must be performed in any patient
with persistent vaginal discharge.
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3.2 Use physical examination to look for signs of cervical cancer.
Recommendations
• On physical examination look for:
Exophytic or ulcerative lesion on the cervix
Firmness in the parametrium
Leg swelling
Right upper quadrant mass and tenderness
Left supraclavicular lymphadenopathy (Virchow's node)
• See figure Cervical Cancer.
Evidence
• Recommendations are based on consensus in a review article (14).
Rationale
• Most cervical cancers are easily identified on speculum exam by the presence of a red exophytic or
ulcerative lesion on the cervix.
• As cervical cancer advances, it spreads to the lateral tissue around the cervix called the
parametrium; frequently, this can be detected on bimanual rectovaginal exam by feeling firmness
in the parametrium.
• Advanced cervical cancer approaching the pelvic sidewalls may cause leg swelling by compressing
the iliac vessels and by lymphatic blockage.
• Metastatic disease to the liver may present with right upper quadrant abdominal mass and
tenderness.
• Metastatic disease may be detected by lymphadenopathy in the left supraclavicular area (Virchow's
node).
Comments
• Physical examination alone is not an effective screening tool for cervical cancer.
3.3 Obtain appropriate laboratory testing to help diagnose cervical cancer.
Recommendations
• Perform:
Pap smear in any patient with postcoital bleeding
Colposcopy in any patient with an abnormal Pap smear showing HSIL, microinvasive, or invasive cancer
Biopsy on any grossly visible abnormality of the cervix
• See table Laboratory and Other Studies for Cervical Cancer.
Evidence
• The Pap smear is an excellent screen for cervical cancer. Epidemiologic studies have shown that
yearly Pap smears reduce the risk of developing and dying of cervical cancer by 95% (13).
• In a meta-analysis of nine studies including 6281 patients, colposcopy had a sensitivity of 96% and
specificity of 69% in differentiating normal cervix from high-grade dysplasia and cancer (28).
Rationale
• A Pap smear can detect precancer (cervical dysplasia) and microinvasive and small invasive
cancers of the cervix.
• Colposcopic examination of the cervix can detect early cervical cancer.
• Most precancers (cervical dysplasia) and some early cancers are not visible to the naked eye.
• The colposcope is a low-powered magnification device that permits the identification of mucosal
abnormalities characteristic of dysplasia or invasive cancer.
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• Biopsy should be performed on grossly abnormal lesions of the cervix to determine the histologic
diagnosis and to exclude invasive cancer.
Comments
• Even if the Pap test result does not show squamous intraepithelial lesion or cancer, biopsy should
be performed on grossly abnormal lesions of the cervix.
3.4 Obtain imaging studies to help stage cervical cancer.
Recommendations
• Obtain the following in all patients with cervical cancer:
Chest x-ray
IVP or abdominal/pelvic CT
Examination under anesthesia with cystoscopy and proctoscopy
• See table Laboratory and Other Studies for Cervical Cancer.
• See table FIGO Staging of Cervical Cancer.
Evidence
• The recommended staging of cervical cancer includes chest x-ray, IVP, and examination under
anesthesia with cystoscopy and proctoscopy (29).
• In a retrospective study of 817 patients, 1% of patients with invasive cervical cancer with no
pulmonary symptoms had pulmonary metastasis (30).
• CT can help in the evaluation of lymph node metastasis. In a prospective study of 320 patients,
evaluation of nodal metastasis by CT had a sensitivity of 34%, specificity of 96%, and falsenegative rate of 18% (31).
Rationale
• Cervical cancer is clinically staged and the recommended staging includes chest x-ray, IVP, and
examination under anesthesia with cystoscopy and proctoscopy.
• Proper staging of any cancer helps with prognosis, tailoring of treatment, and gives a small survival
advantage.
• Chest x-ray is required to detect asymptomatic lung metastasis.
• Invasion of the parametrium with cervical cancer can result in hydroureter, which can be detected
by IVP and would stage the cancer as a 3B.
• Abdominal/pelvic CT can also detect hydroureter as well as suspicious hepatic or pelvic/aortic
lymph node metastasis.
• Anesthesia is needed for proper relaxation so adequate examination of the vagina and
parametrium can be performed along with cystoscopy and proctoscopy.
Comments
• Patients with 1A or small 1B1 tumors may undergo renal ultrasound instead of IVP as a less
expensive and safer examination for hydronephrosis.
• In the U.S., a CT of the abdomen and pelvis is frequently performed instead of IVP in patients with
apparent advanced cervical cancer; however, for clinical staging, only the presence of hydroureter
on the CT can be used. Routine CT scanning of the abdomen and pelvis cannot be used in the
clinical staging of cervical cancer because the staging system is international and the cost of
performing CT on all patients with cervical cancer in developing countries is prohibitive.
Asymptomatic liver metastasis or lymph node metastasis identified on CT would be used for
treatment but would not change the clinical staging.
• Because CT scanning fails to detect periaortic metastasis in approximately 25% of patients with
advanced cervical cancer (stage 2B to 4A), gynecologic oncologists are routinely performing
retroperitoneal or laparoscopic pelvic and periaortic lymphadenectomies to better help surgically
stage patients. Again, because cervical cancer is clinically staged, the results of periaortic lymph
node assessment will be used for tailoring treatment but would not change the clinical stage (31).
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3.5 Consider diagnoses other than cervical cancer in patients with an
abnormal Pap smear result, postcoital bleeding, or lesions on the cervix.
Recommendations
• Consider:
Dysplasia as a differential diagnosis for a high-grade Pap smear result
Glands on the cervix (pregnancy or use of birth control pills), cervicitis, or lack of estrogen in
postmenopausal women as differential diagnoses for postcoital bleeding
Cervical polyps, cervical cysts (Nabothian cyst), leiomyomas, or metastatic spread of other cancers to the
cervix (such as endometrial cancer) as differential diagnoses for lesion on the cervix
• See table Differential Diagnosis of Cervical Cancer.
Evidence
• Consensus.
Rationale
• There are other possible causes of an abnormal Pap test result, postcoital bleeding, and a lesion on
the cervix besides cervical cancer.
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4. Consultation
Consider consultation for diagnosis and proper clinical staging of
cervical cancer. Consult appropriate specialists for help in
managing patients with cervical cancer.
4.1 Consider consultation with a gynecologist for diagnosis and a gynecologic
oncologist for clinical staging of cervical cancer.
Recommendations
• Consider consultation with:
A gynecologist for colposcopy for women with a Pap smear showing HSIL or cancer
A gynecologic oncologist for proper clinical staging of cervical cancer
Evidence
• Colposcopy has a sensitivity of 96% and specificity of 69% differentiating normal cervix from highgrade cervical dysplasia and cancer (28).
Rationale
• Pap smear is a screening test and must be verified by colposcopy and biopsy.
• Precancers (cervical dysplasia) and some early cancers are not visible to the naked eye.
• The colposcope is a low-powered magnification device that permits the identification of mucosal
abnormalities characteristic of dysplasia or invasive cancer.
• Expertise is needed for proper clinical staging of cervical cancer to determine prognosis, tailor
treatment, and allow a small survival advantage.
4.2 Consider referral to a gynecologic oncologist or medical oncologist as
needed for management of patients with documented cervical cancer.
Recommendations
• Obtain consultation with a gynecologic oncologist for women with documented cervical cancer to:
Perform proper and cost-efficient staging
Perform the specific surgery
Assist the radiation oncologist in radiation treatment
Administer radiation sensitizing chemotherapy during external beam radiation
Administer primary chemotherapy in patients with distant recurrence or distant metastasis
• Consult a medical oncologist to administer radiation sensitizing or primary chemotherapy.
Evidence
• Consensus.
Rationale
• Cervical cancer needs to be properly staged and managed by a subspecialist who is well informed
and trained in all aspects of management.
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5. Hospitalization
Consider hospitalizing patients with symptoms of cervical cancer
that cannot be treated on an outpatient basis or for surgery.
5.1 Consider hospitalizing women with cervical cancer with excessive vaginal
bleeding, uncontrolled pain, serious infection, or for surgery.
Recommendations
• Hospitalize women with:
Excessive vaginal bleeding from cervical cancer causing hemodynamic instability for blood transfusions and
for control of hemorrhage; vaginal packing to control hemorrhage; and additional steps as needed such as
suturing, embolization, radiation therapy, or surgery
Severe pelvic and back pain from cervical cancer for intravenous narcotics for control of pain, to be
followed by long-acting oral or transdermal pain medication
Stage 3B disease and hydronephrosis who develop pyelonephritis, sepsis, or both for ureteral
decompression along with antibiotic treatment
Stage 1 and 2 cervical cancer who require hysterectomy for postoperative inpatient care
Evidence
• Consensus.
Rationale
• Women with hemodynamic instability for bleeding require supportive care.
• Patients with severe pain require acute pain control with intravenous narcotics.
• Patients whose hydronephrosis causes pyelonephritis, sepsis, or both require decompression and
antibiotics.
• Patients requiring hysterectomy need postoperative hospitalization.
Comments
• Vaginal packing to control hemorrhage from cervical cancer must be firm. Loose packing will only
temporarily conceal active bleeding.
• Of the gynecologic malignancies, advanced and recurrent cervical cancer tends to be the most
painful. Invasion through the cardinal ligament to the pelvic sidewall or through the uterosacral
ligaments to the sacrum tends to cause severe pelvic and low back pain radiating down the
buttocks.
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6. Therapy
Consider surgery and radiation to be the main treatments for
cervical cancer; consider chemotherapy concurrent with external
beam radiation for treatment of cervical cancer and in patients
with distant metastasis.
6.1 Consider surgery in patients with stage 1A1 to 2A cervical cancer.
Recommendations
• Consider:
LEEP or cone, abdominal or vaginal hysterectomy, or modified radical hysterectomy in patients with stage
1A1 cancer
Modified radical hysterectomy in patients with stage 1A2 cervical cancer
Radical hysterectomy in patients with stage 1B1, 1B2 and 2A cervical cancer
Evidence
• Stage 1A1 cancers have a small chance of lymph node metastasis and recurrence, allowing for
conservative surgical resection such as abdominal or vaginal hysterectomy. Patients desiring to
preserve fertility may be treated with cervical cone or LEEP providing the margins are free of
disease. In a retrospective Medline literature search of 2369 cases of stage 1A1 cervical cancer, the
incidence of lymph node metastasis and recurrence and death were <1% (32).
• Patients with stage 1A2 cervical cancer have an increased chance of recurrence and nodal
metastasis and therefore require definitive cancer treatment. However, because their cervical
disease is still microscopic, a modified radical hysterectomy rather than a radical hysterectomy can
be performed to decrease morbidity. In a retrospective Medline review of 422 cases of stage 1A2
disease, lymph node metastases were found in 8% of patients and recurrence and death occurred
in 3% of patients (32).
• Patients with stage 1B and 2A tumors may undergo radical hysterectomy with lymphadenectomy.
The overall cure rate is approximately 85%. In a prospective surgical pathologic study by the
Gynecologic Oncology Group of 732 patients, there was an 86% survival rate following radical
hysterectomy (33).
• In a prospective randomized trial of 343 patients comparing surgery to primary radiation for stage
1B to 2A cancer, overall survival rate was 83% in both groups (34).
Rationale
• Stage 1A1 cancers have a small chance of recurrence and lymph node metastasis, and thus
younger women wishing fertility may be treated with LEEP or conization instead of hysterectomy to
preserve childbearing.
• Patients who have finished childbearing, especially those who have had repeated dysplasias or
microinvasive cancers in the past, may undergo vaginal, abdominal or modified radical
hysterectomy to decrease the chance of recurrence.
• Once cervical cancer has extended to stage 1A2 or above, LEEP, cone or abdominal or vaginal
hysterectomy alone cannot cure the patient because an adequate margin and lymphadenectomy
has not been performed.
• Patients with stage 1A2 cervical cancer may undergo modified radical hysterectomy, which has
fewer complications than a radical hysterectomy.
• Once a tumor has become grossly invasive, (stage 1B and 2A) a radical hysterectomy is required to
insure that the tumor is removed en bloc with an adequate margin and regional
lymphadenectomies (the modified Halsted philosophy of cancer surgery).
Comments
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• Newer techniques of radical hysterectomy include using surgical staples (35) and laparoscopic
radical hysterectomy (36). In a prospective study of 100 consecutive radical hysterectomies
performed by the surgical stapling technique, operative time and blood loss were significantly
reduced, although survival, recurrence, and complication rates were similar to the traditional
technique (35). In a retrospective review, 19 patients underwent laparoscopic radical hysterectomy
with a 90% success rate. Blood loss and hospital stay were reduced whereas operative time was
increased with the laparoscopic approach (36).
6.2 Consider primary radiation therapy with radiation sensitizing
chemotherapy for any stage of cervical cancer.
Recommendations
• Consider primary radiation therapy for patients with:
Stage 1 and 2 cervical cancers who are not surgical candidates or who do not want surgery
Stage 2B to 4A cervical cancer
• Administer daily external beam radiotherapy delivered to the entire pelvis, including the pelvic
nodes, for 5 to 6 weeks followed by an intracavitary treatment of brachytherapy radiation to give a
higher local dose to the mid pelvis (see information on radiation sensitizing chemotherapy).
• Administer weekly cisplatin, 40 mg/m2, during the 4 to 6 weeks of external beam radiation.
• See table Drug Treatment for Cervical Cancer.
Evidence
• In a prospective randomized trial of 343 patients comparing surgery to primary radiation for stages
1B to 2A cancer, overall survival rate was 83% in both groups (34).
• Prospective randomized trials have shown approximately a 10% to 15% increased survival with the
addition of radiation sensitizing chemotherapy. Of 388 patients with stage 1B2 to 4A disease
treated with cisplatin and 5-FU vs. radiation alone, the overall survival was increased to 73% with
chemotherapy vs. 58% with radiation alone (37).
• In a similar prospective study of 526 patients, weekly cisplatin increased survival to 65% vs. 47%
with radiation alone (38).
• In a similar group of 368 patients, cisplatin and 5-FU increased survival to 67% vs. 57% with
radiation alone (39).
• In high-risk stage 1 and 2A disease, radiation sensitizing chemotherapy has also been shown to be
effective (40).
• In a prospective randomized trial of 243 high-risk stage 1A2 to 2A patients, the addition of cisplatin
and 5-FU increased survival to 87% from 77% with radiation alone (40).
• In a similar group of 369 patients, weekly cisplatin increased survival to 83% from 74% with
radiation alone (41).
• A systematic review of 24 trials including 4921 patients showed that chemoradiation improved
overall survival by 10% and progression-free survival by 13%, regardless of whether platinum was
used (42).
• A multicenter study of 526 women with locally advanced cervical cancer randomized to one of
three chemotherapy regimens during pelvic radiation—single-agent cisplatin, cisplatin-based
combination chemotherapy, or hydroxyurea—showed increased survival with single-agent cisplatin
or cisplatin-based combination chemotherapy (43).
Rationale
• Patients with early cervical cancer who are not surgical candidates or who do not wish surgery may
undergo primary radiation therapy.
• Once a tumor has grown into the parametrium or lower vagina (stage 2B to 4A), adequate margins
cannot be obtained by surgery; therefore, patients need to be treated with radiotherapy.
• Radiation-sensitizing chemotherapy increases the response to radiation by facilitating additional
tumor cell killing.
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• Chemotherapy helps in redistribution, which encourages cells in the resting phase (G0, which are
not sensitive to radiation) to be recruited into the active phase of the cell cycle and which would
therefore be more sensitive to radiation.
• Because of the direct killing of tumor cells by chemotherapy, the tumor tends to shrink more
rapidly, and thus the hypoxic tumor cells (which are relatively resistant to radiation) receive more
blood supply and oxygenation, becoming more sensitive to radiation.
• Radiation-sensitizing chemotherapy is not regarded as an adequate systemic therapy because the
drugs are given in too low a dose and over too short a time period.
Comments
• Although platinum and the combination of platinum and 5-FU are relatively equivalent, weekly
cisplatin is the preferred radiation sensitizer because of ease of administration and decreased
toxicity.
• In younger, sexually active patients, radical hysterectomy is generally preferred over primary
radiotherapy because radiotherapy obliterates ovarian function and causes scarring of the upper
vagina resulting in painful intercourse.
• The charge for external beam and brachytherapy radiation is significantly greater than radical
hysterectomy.
6.3 Consider pelvic exenteration for patients who develop midline pelvic
recurrence after radiation therapy for cervical cancer.
Recommendations
• Consider pelvic exenteration for patients:
With recurrent or persistent cancer of the cervix after radiation therapy
Who are good surgical candidates
With no evidence of metastatic disease
Evidence
• In a review of 100 patients undergoing pelvic exenteration, 61% of patients were cured at 5 years
(44).
Rationale
• Pelvic exenteration consists of resection of the uterus, vagina, bladder, and rectosigmoid.
• The only chance for cure in patients with recurrent or persistent cancer of the cervix in the
midpelvis after radiation therapy is exenteration; these patients have already received the
maximum dose of radiation and therefore additional radiation would cause excessive morbidity.
• Chemotherapy is not effective following high-dose radiation because radiation fibrosis prevents
adequate drug delivery.
Comments
• Reconstructive surgery techniques have been added to total pelvic exenterations to improve quality
of life. These techniques include vaginal reconstruction, colonic J pouch rectal reanastomosis, and
continent urinary conduits.
6.4 Consider special management of patients with cervical cancer diagnosed
in pregnancy.
Recommendations
• Base management of patients with cervical cancer in pregnancy on cancer stage and duration of
pregnancy, e.g.:
Stage 1A1 disease, follow until term and deliver vaginally
Stage 1A2 to 2A disease with pregnancy <20 weeks, consider immediate treatment or follow to fetal
maturity before treatment
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Stage 2B to 4A disease with pregnancy <20 weeks, consider immediate treatment without regard to the
pregnancy
Any stage with pregnancy >24 weeks, follow to fetal maturity before treatment
Evidence
• Consensus.
Rationale
• Of cancers occurring during pregnancy, cervical cancer is one of the most common.
• Treatment is based on stage, but the timing of treatment is influenced by the duration of the
pregnancy.
Comments
• Full informed consent should be given to the mother and father about the risks to both mother and
fetus. Some mothers are willing to put their health at risk in order to allow the fetus to progress to
maturity.
• Patients with stage 1B to 4A tumors should not be delivered vaginally because of increased
hemorrhage, infection, and spread of tumor.
6.5 Consider chemotherapy for patients with distant recurrence and with
stage 4 disease with distant metastasis.
Recommendations
• Consider chemotherapy for patients with recurrence outside the pelvis and with stage 4 disease
with distant metastasis.
• Give cisplatin, 50 mg/m2 intravenously, every 3 weeks.
• Consider other active agents, including:
Paclitaxel, 135 mg/m 2, every 3 weeks
5-FU, 1000 mg/m2·d, for 4 days every 4 weeks
Topotecan, 1.5 mg/m2·d, for 5 days every 4 weeks
Ifosfamide, 1.2 to 1.5 g/m2·d, for 5 days every 4 weeks
• Consider combination chemotherapy such as cisplatin/paclitaxel, cisplatin/topotecan, and
cisplatin/ifosfamide to increase response rate.
• See table Drug Treatment for Cervical Cancer.
Evidence
•
•
•
•
•
•
In a review of 968 patients, the overall response rate to cisplatin was 25% (45).
In a prospective study of 52 patients, paclitaxel had a response rate of 17% (46).
In a review of 270 patients, the response rate to 5-FU was 13% (45).
In a prospective trial of 49 patients, topotecan had a response rate of 19% (47).
In a prospective trial of 56 patients, ifosfamide had a response rate of 16% (48).
In a prospective randomized trial of 438 patients, cisplatin and ifosfamide had a response rate of
31% vs. 18% with cisplatin alone (49).
Rationale
• Once cervical cancer has spread from the pelvis, pelvic surgery and pelvic radiation are no longer
options, and chemotherapy is needed to treat distant disease.
• Cisplatin is the most active chemotherapeutic agent in treating cervical cancer.
Comments
• In general, when cervical cancer recurs in the pelvis following radiation, there is no response to
chemotherapy because the fibrosis and scarring from the previous radiation prohibits drug delivery.
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7. Patient Education
Inform patients about the management, course, and prognosis of
cervical cancer.
7.1 Provide patients with cervical cancer with details of treatment and
subsequent follow-up and prognosis.
Recommendations
• Initiate discussions about:
Stage of disease
Prognosis
Therapeutic options
Benefits and risks of surgery, radiation, and chemotherapy
Need for follow-up
Evidence
• Consensus.
Rationale
• Patient education is a key component in adherence to treatment and optimizing management.
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8. Follow-up
Schedule periodic posttreatment surveillance for all patients with
cervical cancer.
8.1 Schedule periodic posttreatment cancer surveillance at regular intervals
during the first 5 years after diagnosis and perform frequent Pap smears.
Recommendations
• Schedule regular follow-ups every 3 months for the first year, every 4 months for the second year,
then every 6 months until 5 years.
• At follow-up visits include history, physical examination, and vaginal cuff Pap smear.
• Note that patients with advanced disease may require chest x-rays, CT scans, or both of the
abdomen and pelvis.
Evidence
• In a retrospective review of 249 patients, 89% of recurrences occur within the first 2 years after
treatment (50).
• A Pap smear should be obtained at each visit because in a retrospective review of 1847 cases, 72%
of vaginal recurrences are asymptomatic and are detected by abnormal cytologic smears (51).
Rationale
• Routine examination may allow for early detection of recurrence.
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Glossary
5-FU
5-fluorouracil
ASC-H
atypical squamous cells; cannot exclude a high-grade squamous intraepithelial lesion
ASC-US
atypical squamous cells of undetermined significance
BUN
blood urea nitrogen
CBC
complete blood count
CDC
Centers for Disease Control and Prevention
CI
confidence interval
CT
computed tomography
DES
diethylstilbestrol
DNA
deoxyribonucleic acid
FIGO
International Federation of Gynecology and Obstetrics
G0
Gap 0; resting phase of the cell cycle
HIV
human immunodeficiency virus
HPV
human papillomavirus
HSIL
high-grade squamous intraepithelial lesion(s)
IVP
intravenous pyelogram
LEEP
loop electrical excision procedure
LSIL
low-grade squamous intraepithelial lesion(s)
RR
relative risk
SEER
Surveillance, Epidemiology, and End Results program
Terms
Brachytherapy
Radiation sources inserted directly onto the tumor
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Cervical dysplasia
Precancerous cervical lesion on biopsy
Conization
Surgical excision of the cervix
External beam radiation
Outpatient daily radiation treatments to the pelvis, usually consisting of 25 sessions over 5 weeks
Parametrium
Ligaments and adipose tissue around the cervix
Radical hysterectomy
An extended type of hysterectomy which includes removing the uterus along with the parametrium
Squamous intraepithelial lesion, high grade
Possible precancerous cervical lesion on Pap smear
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Tables
Laboratory and Other Studies for Cervical Cancer
Test
Sensitivity (%)
Specificity (%)
Pap smear
Notes
Annual Pap smears reduce the risk of dying from
cervical cancer by 95% (13)
Colposcopy
96
69
Used to direct cervical biopsies after Pap smear
that show HSIL or cancer (28)
Cervical biopsy
Helps differentiate cervical dysplasia from
microinvasive and invasive cancer
Chest x-ray
Used in staging of cervical cancer to detect
asymptomatic lung metastasis (1%) (30)
IVP
Used in staging to determine hydroureter, which
would mean the tumor is stage 3B
Renal ultrasound
May be used as a substitute for IVP in apparent
early cancers
CT scan of abdomen and pelvis
34
96
Exam under anesthesia with cystoscopy and
proctoscopy
May be used to help direct therapy but is not used
as a part of staging (31)
Used to help determine stage to detect regional
spread
CT = computed tomography; HSIL = high-grade squamous intraepithelial lesion(s); IVP = intravenous pyelogram.
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Differential Diagnosis of Cervical Cancer
Disease
Characteristics
Dysplasia
Abnormal Pap test result
Needs colposcopy and biopsy
Normal cervical glands
Glands on the cervix (such as in pregnancy or women on birth control pills). Associated with postcoital
bleeding
Obtain Pap smear
Cervicitis
Postcoital bleeding
There are no discrete lesions on the cervix, but rather the cervix is red and inflamed. Needs biopsy if
Pap smear result is abnormal
Cervical atrophy
Postcoital bleeding
Vagina and cervix tend to be pale and atrophic. Needs to have Pap smear
Cervical polyp
Abnormal-appearing cervix
Tends to be discrete, movable lesion. Needs biopsy
Cervical cysts
Abnormal-appearing cervix
Tend to be well-circumscribed lesions on the cervix. If diagnosis is questionable, needs biopsy
Metastatic disease to the cervix
Abnormal-appearing cervix
The cervix tends to be normal in color and appearance but is firm on palpation. Needs biopsy
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Drug Treatment for Cervical Cancer
Drug or Drug Class
Dosing
2
Side Effects
Precautions
Clinical Use
Cisplatin is the most active
chemotherapeutic agent for cervical
cancer
Cisplatin
40 mg/m IV weekly during external
beam radiation. 50 mg/m2 IV every 3
weeks as primary chemotherapy
Risk of infection or bleeding. SIADH,
hyperuricemia, alopecia, peripheral
neuropathy, visual impairment,
injection site reactions, secondary
malignancy, elevated hepatic enzymes,
cardiac or vascular toxicity, TLS
Severe nephrotoxicity, severe
myelo-suppression, severe nausea and
vomiting, ototoxicity, anaphylactic
reactions. Avoid overdose and
confusion with carboplatin. Avoid with:
CrCl<30, pregnancy. Decrease dose if
CrCl<60. Give IV hydration when
administered
Paclitaxel
135 mg/m2 IV every 3 weeks
Myelosuppression, risk of infection or
bleeding. Peripheral neuropathy,
alopecia, edema, fever, asthenia,
injection site reactions, myalgia,
arthralgia, hypotension, ECG
abnormalities, vomiting, diarrhea,
stomatitis, radiation recall reaction,
elevated hepatic enzymes
Treatment facility required.
Anaphylaxis. Avoid with low neutrophil
counts. Avoid with pregnancy. Avoid
extravasation. Must premedicate.
Decrease dose with hepatic disease.
Metabolized by CYPs 3A4, 2C8 and Pgp.
Fluorouracil, 5-FU
1000 mg/m2·d continuous IV infusion
for 4 days every 4 weeks
Myelosuppression, risk of infection or
bleeding. Vomiting, diarrhea, anorexia,
GI bleeding, stomatitis, hand and foot
syndrome, neurotoxicity, lacrimation,
cardiotoxicity, injection site reactions,
photosensitivity
Hospitalize for first course of
therapy due to severe toxic reactions.
Avoid with pregnancy. Consider dose
reduction with hepatic disease
Ifosfamide (Ifex)
1.2-1.5 g/m2 IV qd for 5 days every 4
weeks
Risk of infection or bleeding. Alopecia,
vomiting, renal insufficiency,
cardiotoxicity, secondary malignancy
Hemorrhagic cystitis, CNS toxicity,
severe myelosuppression. Avoid with
pregnancy. Decrease dose if CrCl<60.
Substrate of CYPs 3A4 and 2B6. Give
vigorous hydration and mesna
Topotecan (Hycamtin)
1.5 mg/m2 qd for 5 days every 4 weeks
Risk of infection or bleeding. Vomiting,
diarrhea, constipation, abdominal pain,
anorexia, stomatitis, alopecia, fever,
asthenia, pain, dyspnea, fatigue,
rigors, rash, ILD, infertility
Myelosuppression. Avoid with
pregnancy. Avoid extravasation. May
need to decrease dose with CKD.
= black box warning; bid = twice daily; CKD = chronic kidney disease; CNS = central nervous system; CrCl = creatinine clearance; CV = cardiovascular; CYP = cytochrome P450 isoenzyme; ECG =
electrocardiogram; GI = gastrointestinal; ILD = interstitial lung disease; IM = intramuscular; IV = intravenous; P-gp = P-glycoprotein; PO = oral; q12hr = every 12 hours; qd = once daily; qid = four times
daily; SC = subcutaneous; SCr = serum creatinine; SIADH = syndrome of inappropriate secretion of antidiuretic hormone; tid = three times daily; TLS = tumor lysis syndrome
PIER provides key prescribing information for practitioners but is not intended to be a source of comprehensive drug information.
PIER is copyrighted ©2013 by the American College of Physicians. 190 N. Independence Mall West, Philadelphia, PA 19106, USA.
Page 26 of 29
Cervical Cancer
The Bethesda System for Reporting Results of Cervical Cytology
Specimen adequacy
Satisfactory
Unsatisfactory
Interpretation/result
Negative for intraepithelial lesion or malignancy
Epithelial cell abnormalities
Squamous cells
ASC-H
LSIL
HSIL
Squamous cell carcinoma
Glandular cell abnormalities
Atypical glandular cells
Atypical glandular cells, favor neoplastic
Endocervical adenocarcinoma in situ
Adenocarcinoma
ASC-H = atypical squamous cells; cannot exclude a high-grade squamous intraepithelial lesion; ASC-US = atypical squamous cells of undetermined significance; HSIL = high-grade squamous intraepithelial
lesion(s); LSIL = low-grade squamous intraepithelial lesion(s).
PIER is copyrighted ©2013 by the American College of Physicians. 190 N. Independence Mall West, Philadelphia, PA 19106, USA.
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Cervical Cancer
FIGO Staging of Cervical Cancer
Stage 1A1
Microscopic cervical cancer which is measured <3 mm depth of invasion and <7 mm horizontal spread
Stage 1A 2
Microscopic cervical cancer with a depth between 3 to 5 mm and <7 mm horizontal spread
Stage 1B1
Microscopic cervical cancer with dimensions >stage 1A2 or any gross lesion <4 cm in width
Stage 1B2
Gross lesion >4 cm in width
Stage 2A
Cervical cancer extending to the upper 2/3 of the vagina
Stage 2B
Cervical cancer extending into the parametrium but not to the pelvic sidewall
Stage 3A
Cervical cancer extending to the lower 1/3 of the vagina
Stage 3B
Cervical cancer extending to the pelvic sidewall and/or causing hydronephrosis
Stage 4A
Cervical cancer extending into the mucosa of the bladder or the rectum
Stage 4B
Cervical cancer with metastatic spread to distant organs
FIGO = International Federation of Gynecology and Obstetrics.
PIER is copyrighted ©2013 by the American College of Physicians. 190 N. Independence Mall West, Philadelphia, PA 19106, USA.
Page 28 of 29
Cervical Cancer
Top
Figures
Cervical Cancer
This patient presented with erosion to her cervix due to low grade cervical carcinoma. The most common signs of cervical cancer are vaginal bleeding between menstrual periods or
after menopause, postcoital vaginal bleeding, and abnormal vaginal discharge. Direct examination usually shows an abnormal cervix, although a tumor in the cervical canal may be
difficult to see. The diagnosis is usually established by punch biopsy of obvious lesions or by colposcopy with directed biopsy. The image is reproduced from the CDC Public Health
Image Library.
PIER is copyrighted ©2013 by the American College of Physicians. 190 N. Independence Mall West, Philadelphia, PA 19106, USA.
Page 29 of 29