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Last Updated: 6/22/2015  

Cervical Cancer

  • Advise patients to avoid smoking to decrease the risk for cervical cancer.

  • Vaccinate young women and young men against HPV to reduce the risk for cervical cancer.

  • Screen women between the ages of 21 and 30 for cervical cancer every 3 years using cervical cytology.

  • Screen women ages 30 to 65 every 3 years using cervical cytology, or every 5 years using the combination of cervical cytology and HPV DNA co-testing.

  • Screen HPV-vaccinated women using the standard age-based recommendations

  • Do not screen for cervical cancer in women over age 65 who have had adequate prior screening unless there is a history of high-grade precancerous abnormality or cervical cancer within the last 20 years.

  • Do not screen for cervical cancer in women who have had a hysterectomy with removal of the cervix unless there is a history of high-grade precancerous abnormality or cervical cancer.

  • Recognize postcoital bleeding as the most common presenting symptom of cervical cancer.

  • Perform colposcopy in any patient with an abnormal Pap smear showing HSIL, microinvasive cancer, or invasive cancer.

  • Perform colposcopy in any patient with a grossly abnormal cervix, even if the Pap smear is normal.

  • Obtain examination under anesthesia, chest radiograph, and IVP for staging of all women with cervical cancer.

  • Consider MRI or CT of abdomen and pelvis for further investigation of local spread for women with invasive cervical cancer on biopsy.

  • Recommend surgery, radiation, and/or chemoradiation based on clinical stage.

  • For women with cervical cancer diagnosed in pregnancy, adjust management based on cancer stage and duration of pregnancy.

Inform patients about safe sexual practices to decrease the risk for HPV transmission and cervical cancer. 
  • Advise patients to:

    • Limit their number of sexual partners

    • Avoid intercourse at an early age

    • Use condoms to decrease the risk for acquiring HPV

  • See module Human Papillomavirus.

Evidence
  • A 2014 guideline on HPV vaccination from the Advisory Committee on Immunization Practices of the CDC stated that behaviors proven to reduce risk for HPV transmission include abstaining from sexual activity (i.e., any genital contact with another person), being in a monogamous relationship with one partner, limiting the number of sex partners, choosing a partner who has had no or few previous sex partners, consistent and correct condom use, and male circumcision (1).

  • A 2011 Cochrane review of interventions for encouraging sexual behaviors intended to prevent cervical cancer included 23 RCTs, most conducted in the United States. Statistically significant effects for behavioral outcomes (e.g., increasing condom use) were common. Abstaining from or reducing sexual activity had no statistically significant effects. There were few statistically significant effects on biological (STI) outcomes (2).

  • A 2006 meta-analysis of 25 epidemiologic studies including 16,563 women with cervical carcinoma and 33,542 controls without cervical carcinoma found that early age at first full-term pregnancy was associated with increased risk for invasive cervical carcinoma and carcinoma in situ. The RR for first full-term pregnancy at age <17 years compared with ≥25 years was 1.77 (CI, 1.42 to 2.23) for invasive cervical carcinoma and 1.78 (CI, 1.26 to 2.51) for carcinoma in situ (3).

  • In an epidemiologic study of 1009 Colombian and 1012 Finnish female participants aged 16 to 23 year who were enrolled in a phase III trial of HPV vaccine, the interval between menarche and first sexual intercourse was assessed as a risk factor for cervical atypia. Those with first sexual intercourse within 3 years of menarche had a greater risk for cytologic abnormalities (OR, 1.65; CI, 1.02 to 2.68; P=0.04) and high-grade cervical disease (OR, 3.56; CI, 1.02 to 12.47; P=0.05) (4).

  • Epidemiologic studies have shown that women with multiple sexual partners have an increased risk for developing cervical cancer. Relative risk is 2.0 [CI, 1.91 to 2.09] for two to five lifetime sexual partners and 2.98 [CI, 2.62 to 3.40] for six or more lifetime partners (5).

  • Epidemiologic studies indicate that women who have had intercourse at an early age have an increased risk for developing cervical cancer of 2.24 (CI, 2.11 to 2.38) for age younger than 18 years at first sexual intercourse (5).

Rationale
  • HPV is sexually transmitted and is central to the development of 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.

  • Condom use reduces but does not eliminate exposure to HPV, HPV infection, cervical dysplasia, and cancer.

Comments
  • HPV is the causative agent of cervical cancer and can be detected in 99.7% of cervical cancers (6).

  • 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, including low-risk and high-risk types. High-risk HPV types are oncogenic and considered the causative agents in cervical cancer. Approximately 15 types are known to be oncogenic. The major high-risk types are types 16 and 18 and are found in more than 70% of all cervical cancers (7).

  • Data suggest an association between the use of oral contraceptives and cervical cancer. The reasons for this increased risk have not yet been elucidated.

  • According to a 2007 meta-analysis of 24 studies including 16,573 women with cervical cancer and 35,509 without cervical cancer, the relative risk for cervical cancer increases with duration of oral contraceptive use. Compared with women who never used oral contraceptives, those who used oral contraceptives for ≥5 years had a relative risk of 1.90 (CI, 1.69 to 2.13). Relative risk declined with increased time since last use. After 10 years of no use, the relative risk returned to that of never-users (8).

Advise patients to avoid smoking to decrease the risk for cervical cancer. 
  • Advise patients not to smoke in an effort to decrease their risk for developing cervical cancer.

  • See module Smoking Cessation.

Evidence
  • A 2006 meta-analysis of 23 epidemiologic studies including 13,541 women with carcinoma of the cervix and 23,017 control women without cervical carcinoma found that the risk for squamous cell carcinoma increased in current smokers with the number of cigarettes smoked per day and with younger age at starting smoking. A significantly increased risk for squamous cell carcinoma of the cervix was found in current compared with never smokers (RR, 1.60 [CI, 1.48 to 1.73]; P<0.001) and in past smokers (RR, 1.12 [CI, 1.01 to 1.25]). In current smokers, the RR for squamous cell carcinoma increased with increasing number of cigarettes smoked per day and also with younger age at starting smoking. In data restricted to women who tested positive for HPV DNA, current smokers had a significantly increased risk for squamous cell carcinoma compared with never smokers (RR, 1.95 [CI, 1.43 to 2.65]). After 10 years of smoking cessation, the risk returned to baseline (9).

  • Mean nicotine in the cervical mucus of smokers was 1056 ng/mL vs. 43 ng/mL in nonsmokers (10).

Rationale
  • Women who smoke have an increased risk for 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 (11). Nonsmokers exposed to second-hand smoke for ≥3 hours a day have a relative risk of 3.0 [CI, 1.3 to 7.0] (12).

Vaccinate young women against HPV to reduce the risk for cervical cancer. 
  • Recommend three doses of the bivalent or quadrivalent HPV vaccine for female patients aged 11 to 12 years.

    • Initial dose

    • Second dose 2 months after the initial dose

    • Third dose 6 months after the initial dose

  • Consider providing HPV vaccine for girls as young as age 9.

  • Recommend catch-up vaccination for females aged 13 to 26 years who have not been previously vaccinated or who have not completed their vaccine series.

Evidence
  • A 2014 guideline on HPV vaccination from the Advisory Committee on Immunization Practices of the CDC recommended the quadrivalent or bivalent HPV vaccine for cervical cancer prevention for girls aged 11 or 12 years, with the option to begin vaccination at age 9. The committee also recommended vaccination for female patients aged 13 to 26 years who were not previously vaccinated. The guideline specifically recommended vaccination of immunocompromised patients through age 26 if not previously vaccinated (1).

  • A 2011 systematic review and meta-analysis assessing the efficacy and safety of HPV vaccination against cervical cancer precursor events included seven trials and 44,142 females. The reviewers found that HPV vaccines were highly efficacious against 6-month persistent infection with HPV types 16 and 18 (RR, 0.24 [CI, 0.14 to 0.42] in intention-to-treat analysis). RRs were 0.47 (CI, 0.36 to 0.61) and 0.16 (CI, 0.08 to 0.34) for HPV-16-related and HPV-18-related CIN grade 2 or higher in the intention-to-treat populations, respectively, with similar efficacy against CIN grade 1 or higher. Serious adverse events did not differ significantly between vaccine and control groups (13).

Rationale
  • Sequelae of infection of the female genital tract with high-risk HPV subtypes include cervical dysplasia and squamous cell carcinoma.

Comments
  • The optimal time for HPV immunization is before an individual's sexual debut.

  • The HPV vaccines do not treat or accelerate the clearance of preexisting vaccine-type HPV infections or related disease.

Vaccinate young men against HPV to reduce the risk for cervical cancer in women. 
  • Recommend three doses of the bivalent or quadrivalent HPV vaccine for male patients aged 11 to 12 years.

    • Initial dose

    • Second dose 2 months after the initial dose

    • Third dose 6 months after the initial dose

  • Consider providing the quadrivalent HPV vaccine for boys as young as age 9.

  • Recommend catch-up vaccination for males aged 13 to 26 years who have not been previously vaccinated or who have not completed their vaccine series.

Evidence
  • A 2014 guideline on HPV vaccination from the Advisory Committee on Immunization Practices of the CDC recommended the quadrivalent HVP vaccine for boys aged 11 or 12 years, with the option to begin vaccination at age 9. The committee also recommended vaccination for males aged 13 to 21 years who were not previously vaccinated, and noted that previously unvaccinated men aged 22 to 26 may also be vaccinated. The guideline specifically recommended vaccination of immunocompromised patients and men who have sex with men through age 26 if not previously vaccinated (1).

Rationale
  • Vaccination of males would reduce transmission of HPV to females and decrease resulting infection, disease, and cancer in females.

Comments
  • The optimal time for HPV immunization is before an individual's exposure to HPV through sexual contact.

  • The HPV vaccine does not treat or accelerate the clearance of preexisting vaccine-type HPV infections or related disease.

  • The cost-effectiveness of routine vaccination of boys in addition to vaccination of girls remains under investigation. Vaccination of the population of young men who have sex with men is likely to be cost-effective for non-cervical cancer preventive purposes.

Screen women between the ages of 21 and 29 for cervical cancer every 3 years using cervical cytology. 
  • Clinicians should not screen average-risk women younger than 21 years for cervical cancer.

  • Clinicians should start screening average-risk women for cervical cancer at age 21 years once every 3 years with cytology (Pap tests without HPV tests).

  • Clinicians should not screen average-risk women for cervical cancer with cytology more often than once every 3 years.

  • Clinicians may use a combination of Pap and HPV testing once every 5 years in average-risk women aged 30 years or older who prefer screening less often than every 3 years.

  • Clinicians should not perform HPV testing in average-risk women younger than 30 years.

  • Clinicians should stop screening average-risk women older than 65 years for cervical cancer who have had 3 consecutive negative cytology results or 2 consecutive negative cytology plus HPV test results within 10 years, with the most recent test done within 5 years.

  • Clinicians should not screen average-risk women of any age who have had a hysterectomy with removal of the cervix for cervical cancer.

  • Clinicians should not perform cervical cancer screening with a bimanual pelvic examination.

  • For women with chronic immunosuppression or HIV infection, initiate screening at time of initial intercourse.

  • Screen high-risk women more often, including women with:

    • History of DES exposure

    • History of CIN 2/3 or cervical cancer

    • HIV infection

    • Other immunocompromised state (e.g., history of organ transplant)

  • For immunocompromised women, consider screening twice in the first year, then annually.

  • In women ages 21 to 29 screened with cervical cytology:

    • If cervical cytology result is satisfactory and negative for intraepithelial lesion or malignancy, repeat cervical cytology at the scheduled interval

    • If the result is unsatisfactory, repeat within 3 to 6 months

    • If the result shows ASC-US, refer for colposcopy, obtain HPV DNA testing, or repeat cytology at 6 and 12 months

    • If the result shows ASC-H, HSIL, squamous cell cancer, or atypical glandular cells, refer for colposcopy

  • In women under age 21 with a cytology result showing ASC-US or LSIL, repeat cytology in 1 year.

  • Discontinue screening in women who have had hysterectomy with removal of the cervix unless they have history of high-grade dysplasia (CIN grade 2 or worse).

  • See table The Bethesda System for Reporting Results of Cervical Cytology.

  • See module Papanicolaou Smear.

Evidence
  • The 2015 ACP best practice advice article describes indications for cervical cancer screening in asymptomatic, average-risk women aged 21 years or older (14).

  • The ACP High Value Care Task Force published advice on screening for cancer and advice on a value framework for cancer screening which provided suggested screening practices for patients at average risk for developing breast, cervical, ovarian, prostate, or colorectal cancers. The task force based their high-value care advice on their narrative review of clinical guidelines and evidence syntheses from the relevant major medical societies, the U.S. Preventive Services Task Force, the American Cancer Society, and additional literature searches on databases for modeling studies and cost estimations (15; 16).

  • A 2012 guideline on cervical cancer screening from the U.S. Preventive Services Task Force recommended, based on high-quality evidence, screening for cervical cancer in women ages 21 to 65 years with cytology (Pap smear) every 3 years; recommended against screening for cervical cancer with HPV testing, alone or in combination with cytology, in women younger than age 30 years; and recommended against screening for cervical cancer in women younger than age 21 years. Recommendations were based on a systematic review of data demonstrating reduction in cervical cancer rates by 60% to 90% within 3 years of implementation for populations naïve to screening, and 20% to 60% reductions in North American and European populations in incidence of cervical cancer mortality after the onset of population screening (17).

  • A 2012 consensus guideline on screening for the prevention and early detection of cervical cancer from the American Cancer Society, American Society for Colposcopy and Cervical Pathology, and the American Society for Clinical Pathology recommended screening beginning at age 21, then every 3 years from ages 21 to 29 using cytology alone (18).

  • The 2012 guideline from the American Congress of Obstetricians and Gynecologists on screening for cervical cancer recommended screening beginning at age 21, then every 3 years from ages 21 to 29 using cytology alone. The guideline recommended more frequent screening in persons with HIV infection; immunocompromise (e.g., solid organ transplant); DES exposure; or history of CIN grade 2, CIN grade 3, or cervical cancer (19).

  • A 2012 updated consensus guideline from the American Society for Colposcopy and Cervical Pathology for the management of abnormal cervical cancer screening tests recommended less aggressive follow-up for adolescents with ASC-US and LSIL because of the extremely low risk for malignancy in this population (20).

  • A 2011 systematic review found that liquid-based cytology and conventional cytology have equivalent sensitivity and specificity (21).

  • 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 (22).

  • 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 Pap 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 (23).

  • 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 (24).

  • After 3 consecutive, yearly, negative cytology Pap smears, the risk for cervical cancer is reduced to approximately 1/100,000/years (25).

Rationale
  • Women ages 21 to 29 may transiently test positive for HPV without persistent high-risk status, so routine HPV testing may lead to overdiagnosis and harms of invasive testing and treatments.

Comments
  • The optimal time for HPV immunization is before an individual's exposure to HPV through sexual contact.

  • Terminology differs for cytology and histology of abnormal precancerous cervical changes. Cytology (Pap smear) findings are described as low-grade squamous intraepithelial lesions (LSIL) or high-grade squamous intraepithelial lesions (HSIL). Histology may be classified into LSIL/HSIL as well but is more commonly classified as CIN grade 1, 2, or 3 using the Bethesda classification system. CIN grade 1 histology corresponds with LSIL on cytology, while CIN grades 2 and 3 correspond with HSIL.

Screen women ages 30 to 65 every 3 years using cervical cytology, or every 5 years using the combination of cervical cytology and HPV DNA co-testing. 
  • In women ages 30 to 65, screen for cervical cancer every 3 years using cervical cytology, or (preferred) every 5 years using the combination of cervical cytology and HPV DNA co-testing.

  • Screen high-risk women more often, including women with:

    • History of DES exposure

    • History of CIN 2/3 or cervical cancer

    • HIV infection

    • Other immunocompromised state (e.g., history of organ transplant)

  • For immunocompromised women, consider screening twice in the first year, then annually.

  • For patients screened with cervical cytology alone every 3 years:

    • If cervical cytology result is satisfactory and negative for intraepithelial lesion or malignancy, repeat cervical cytology in 3 years

    • If the result is unsatisfactory, repeat within 3 to 6 months

    • If the result shows ASC-US, refer for colposcopy, perform HPV DNA testing, or repeat cytology at 6 and 12 months

    • If the result shows ASC-H, HSIL, squamous cell cancer, or atypical glandular cells, refer for colposcopy

  • For patients screened with the preferred regimen of cervical cytology and HPV DNA co-testing every 5 years:

    • 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

  • Discontinue screening in women older than age 65 who have had prior adequate screening unless they have history of high-grade dysplasia (CIN grade 2 or worse).

    • Adequate screening is defined as three consecutive negative cytology test results or two consecutive HPV/Pap co-tests with negative results in the 10 years before stopping, with the most recent test within 5 years.

    • Continue testing for 20 years after management of high-grade dysplasia (CIN grade 2 or worse).

  • Discontinue screening in women who have had hysterectomy with removal of the cervix unless they have history of high-grade dysplasia (CIN grade 2 or worse).

  • See table The Bethesda System for Reporting Results of Cervical Cytology.

  • See module Papanicolaou Smear.

Evidence
  • The 2015 ACP best practice advice article describes indications for cervical cancer screening in asymptomatic, average-risk women aged 21 years or older (14).

  • A 2012 guideline on cervical cancer screening from the U.S. Preventive Services Task Force recommended, on the basis of high-quality evidence, screening for cervical cancer in women age 30 to 65 years with cytology and HPV co-testing every 5 years. The guideline recommended against screening for cervical cancer with HPV testing, alone or in combination with cytology, in women younger than age 30 years, and recommended against screening for cervical cancer in women younger than age 21 years (17)

  • 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 ages 30 to 65 (18).

  • A 2012 guideline from the American Congress of Obstetricians and Gynecologists on screening for cervical cancer recommended screening women ages 30 to 65 every 5 years with cytology and HPV co-testing as the preferred screening method; screening every 3 years with cytology alone was recommended as an acceptable alternative method. The guideline recommended more frequent screening in persons with HIV; immunocompromise (solid organ transplant); DES exposure; or history of CIN grade 2, CIN grade 3, or cervical cancer (19).

  • A 2011 systematic review of the accuracy of screening tests for cervical cancer found that the addition of HPV testing to cytology increases sensitivity but slightly decreases specificity compared with cytology alone. HPV testing alone had performance characteristics similar to those of HPV testing with cytology (21).

  • Testing for high-risk HPV identifies more women with high-grade dysplasia than does a single cervical cytology sample (26; 27; 28; 29).

  • The sensitivity obtained by combining the two methods of screening exceeds 95% in most studies (26; 27; 28; 29).

  • 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 (30; 31).

  • There is a high negative predictive value 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 (32).

  • The addition of an HPV test to the Pap test to screen women in their mid-thirties for cervical cancer reduces the incidence of grade 2 or 3 cervical intraepithelial neoplasia or cancer detected by subsequent screening examinations (33).

Rationale
  • The addition of HPV testing to cervical cytology increases the diagnostic accuracy of cervical cancer screening.

Screen HPV-vaccinated women using the standard age-based recommendations. 
  • Screen HPV vaccinated women using the standard age-based recommendations.

Evidence
  • A 2012 guideline from the American Cancer Society, American Society for Colposcopy and Cervical Pathology, and the American Society for Clinical Pathology on screening for the prevention and early detection of cervical cancer recommended that screening practices should not change on the basis of HPV vaccination status, citing consensus opinion. Opinion was based on mathematical models of incomplete vaccination protection combined with reduced screening that would lead to predicted reductions in life expectancy (18)

  • The 2012 guideline from the American Congress of Obstetricians and Gynecologists on screening for cervical cancer recommended, on the basis of expert opinion, that screening practices should not change according to HPV vaccination status and should follow standard age-based recommendations (19).

Rationale
  • Not all women receive HPV vaccination before sexual exposure.

  • Vaccine outcomes may inform future recommendations regarding screening, but those data will require time to collect.

  • Complacency regarding screening could offset the benefits of HPV vaccination if screening intervals are reduced in the absence of evidence.

Do not screen for cervical cancer in women older than age 65 who have had adequate prior screening unless they have a history of high-grade precancerous pathology or cervical cancer within the last 20 years. 
  • Do not screen for cervical cancer in women older than age 65 who have had adequate prior screening unless they have a history within the past 20 years of:

    • CIN grade 2 or 3

    • Cervical cancer

  • Consider screening in women older than age 65 years who have never been screened.

  • Once screening is discontinued after age 65, do not resume screening even if the patient reports a new sexual partner.

Evidence
  • The 2015 ACP best practice advice article describes indications for cervical cancer screening in asymptomatic, average-risk women aged 21 years or older (14).

  • A 2012 guideline on cervical cancer screening from the U.S. Preventive Services Task Force recommended, on the basis of moderate- to high-quality evidence, that screening for cervical cancer not be performed in women after age 65 if they have had adequate prior screening and are not at high risk for cervical cancer. The guideline defined adequate prior screening as three consecutive negative cytology results or two consecutive negative HPV results within 10 years before cessation of screening, with the most recent test occurring within 5 years. The guideline further stated that routine screening should continue for at least 20 years after spontaneous regression or appropriate management of a high-grade precancerous lesion, even if this extends screening past age 65 years (17).

  • A 2012 guideline from the American Cancer Society, the American Society for Colposcopy and Cervical Pathology, and the American Society for Clinical Pathology on screening for the prevention and early detection of cervical cancer recommended that women older than 65 years of age with evidence of adequate negative prior screening and no history of CIN grade 2 or higher within the last 20 years not be screened for cervical cancer with any modality. The guideline further recommended that once screening is discontinued, it should not resume for any reason, even if a woman reports having a new sexual partner. The age at which to discontinue was based on expert opinion, while the authors cited high-level evidence that the natural history of the disease makes it improbable that benefits of screening will outweigh harms of discomfort and false-positive results (18)

  • A 2012 guideline from the American Congress of Obstetricians and Gynecologists on screening for cervical cancer recommended, on the basis of good and consistent evidence, that screening by any modality be discontinued after age 65 years in women with evidence of adequate negative prior screening results and no history of CIN grade 2 or higher. Adequate negative prior screening results were defined as three consecutive negative cytology results or two consecutive negative co-test results within the previous 10 years, with the most recent test performed within the past 5 years (19).

Rationale
  • The natural history of cervical cancer requires decades to progress to clinically significant disease, so screening for precancerous lesions in low-risk women older than age 65 is of limited benefit and the benefits do not outweigh the potential harms.

  • While exposure to new sexual partners older than age 65 may require assessment for STIs or other pelvic health concerns, cervical cancer screening is not indicated because of the slow natural history of HPV and cervical cancer.

  • After menopause, the positive predictive value of Pap testing is low, resulting in greater false-positive rates and increased harms of additional procedures, discomfort, and anxiety.

Do not screen for cervical cancer in women who have had a hysterectomy with removal of the cervix unless there is a history of high-grade precancerous pathology or cervical cancer. 
  • Do not screen for cervical cancer in women who have had a hysterectomy with removal of the cervix (total hysterectomy) unless there is a history of:

    • CIN grade 2 or 3

    • Cervical cancer

  • For women with a history of CIN grade 2 or higher before total hysterectomy, continue cytology screening of the vaginal cuff for 20 years after surgery.

Evidence
  • A 2012 guideline on cervical cancer screening from the U.S. Preventive Services Task Force recommended, on the basis of moderate- to high-quality evidence, that screening for cervical cancer not be performed in women who have had a hysterectomy with removal of the cervix and who do not have a history of a high-grade precancerous lesion (CIN grade 2 or 3) or cervical cancer (17).

  • A 2012 guideline from the American Cancer Society, the American Society for Colposcopy and Cervical Pathology, and the American Society for Clinical Pathology on screening for the prevention and early detection of cervical cancer recommended that women at any age after a hysterectomy with removal of the cervix who have no history of CIN grade 2, CIN grade 3, or cervical cancer not be screened for vaginal cancer with any modality. The guideline stressed that evidence of adequate negative prior screening result is not required (18).

  • A 2012 guideline from the American Congress of Obstetricians and Gynecologists on screening for cervical cancer recommended, on the basis of good and consistent evidence, that in women who have had a hysterectomy with removal of the cervix (total hysterectomy) and have never had CIN grade 2 or higher, routine cytology screening and HPV testing should be discontinued and not restarted for any reason (19).

Rationale
  • Primary vaginal cancer is a rare malignancy, and vaginal cytologic testing has a low predictive value.

  • Women who have had high-grade cervical lesions before hysterectomy can develop recurrent neoplasia at the vaginal cuff. Continued screening with cytology is considered prudent for 20 years on the basis of no reported cases beyond that time span.

Recognize postcoital bleeding as the most common presenting symptom of cervical cancer, and use history to elicit risk factors or associated symptoms. 
  • Recognize that irregular vaginal bleeding is commonly the first symptom of cervical cancer, including spontaneous or contact (postcoital) bleeding.

  • Ask about factors that increase risk for cervical cancer:

    • Multiple sexual partners

    • Early age of first intercourse

    • Smoking

  • Ask about other symptoms that can indicate 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
  • A 2006 meta-analysis of 25 epidemiologic studies including 16,563 women with cervical carcinoma and 33,542 controls without cervical carcinoma found that early age at first full-term pregnancy was associated with increased risk for invasive cervical carcinoma and carcinoma in situ. The RR for first full-term pregnancy at age <17 years compared with ≥25 years was 1.77 (CI, 1.42 to 2.23) for invasive cervical carcinoma and 1.78 (CI, 1.26 to 2.51) for carcinoma in situ (3).

  • A 2006 meta-analysis of 23 epidemiologic studies including 13,541 women with carcinoma of the cervix and 23,017 control women without cervical carcinoma found that the risk for squamous cell carcinoma increased in current smokers with the number of cigarettes smoked per day and with younger age at starting smoking. A significantly increased risk for squamous cell carcinoma of the cervix was found in current compared with never smokers (RR, 1.60 [CI, 1.48 to 1.73]; P<0.001) and in past smokers (RR, 1.12 [CI, 1.01 to 1.25]). In current smokers, the RR for squamous cell carcinoma increased with increasing number of cigarettes smoked per day and also with younger age at starting smoking. In data restricted to women who tested positive for HPV DNA, there was a significantly increased risk in current compared with never smokers for squamous cell carcinoma (RR, 1.95 [CI, 1.43 to 2.65]). After 10 years of smoking cessation, the risk returned to baseline (9).

  • In an epidemiologic study of 1009 Colombian and 1012 Finnish females aged 16-23 who were enrolled in a phase III trial of HPV vaccine, the interval between menarche and first sexual intercourse was assessed as a risk factor for cervical atypia. Those with first sexual intercourse within 3 years of menarche had a greater risk for cytologic abnormalities (OR, 1.65 [CI, 1.02 to 2.68]; P=0.04) and high-grade cervical disease (OR, 3.56 [CI, 1.02 to 12.47]; P=0.05) (4).

  • Epidemiologic studies have shown that women with multiple sexual partners have an increased risk for cervical cancer. Relative risk is 2.0 [CI, 1.91 to 2.09] for 2 to 5 lifetime sexual partners and 2.98 [CI, 2.62 to 3.40] for ≥6 lifetime partners (5).

  • According to epidemiologic studies, women who had intercourse at an early age have an increased risk for cervical cancer. Relative risk is 2.24 (CI, 2.11 to 2.38) for age <18 years at first sexual intercourse (5).

  • 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 (34).

  • Epidemiologic studies have shown that symptoms of cervical cancer other than postcoital bleeding include the “terrible triad” (9%), foul-smelling vaginal discharge (4%), and changes in urinary or bowel habits (4%) (34).

Rationale
  • Taking a careful history may help identify patients at high risk for 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 foul-smelling 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.

Exam for signs of cervical cancer. 
  • On physical exam 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
  • Mainly consensus.

  • A 2007 narrative review of the diagnosis and management of cervical cancer described common clinical presentations, including early asymptomatic state (noted on screening), spontaneous or contact bleeding, pain with lymph node involvement, serosanguinous foul-smelling vaginal discharge, or backache (35).

  • A 1996 narrative review of cancer of the cervix discussed common presenting signs (22).

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 exam alone is not an effective screening tool for cervical cancer. While some lesions are grossly exophytic, others may not be appreciable, even when invasive.

Obtain cytology and biopsy specimens to diagnose cervical cancer. 
  • Perform a Pap smear in any patient with postcoital bleeding

  • Perform colposcopy in any patient with an abnormal Pap smear showing HSIL, microinvasive cancer, or invasive cancer, with biopsy or conization of grossly visible abnormalities of the cervix.

  • Perform colposcopy in any patient with a grossly abnormal cervix, even if the Pap smear is normal.

Evidence
  • A 2000 systematic review of accuracy of the Pap test in screening for and follow-up of cervical cytologic abnormalities found that estimates of sensitivity and specificity varied greatly in individual studies; in 12 studies with the least biased estimates, sensitivity ranged from 30% to 87% and specificity ranged from 86% to 100% (36).

  • A 1998 meta-analysis of colposcopy for the diagnosis of squamous intraepithelial lesions included nine studies and 6281 patients. Colposcopy had a sensitivity of 96% and specificity of 69% in differentiating normal cervix from high-grade dysplasia and cancer (37).

  • In a diagnostic-accuracy assessment trial comparing specimens obtained from abnormal- and normal-appearing colposcopic sites, colposcopy had a sensitivity of 0.714 and a specificity of 0.877 in a diagnostic testing cohort with test threshold of prior HSIL. In a screening cohort without abnormal Pap findings, colposcopy performed poorly, with an area under the receiver-operating curve of 0.587 (38).

  • Epidemiologic studies have shown that yearly Pap smears reduce the risk for developing and dying of cervical cancer by 95% (25).

Rationale
  • Most precancers (cervical dysplasia) and some early cancers are not visible to the naked eye.

  • A Pap smear can detect precancer (cervical dysplasia) and microinvasive and small invasive cancers of the cervix.

  • Because Pap smear is insufficiently sensitive to rule out cancer when the prior probability is high, colposcopy should be considered when the cervix is grossly abnormal even if the Pap cytology result is normal.

  • Colposcopic examination of the cervix can detect early cervical cancer.

  • The colposcope, a low-powered magnification device, permits the identification of mucosal abnormalities characteristic of dysplasia or invasive cancer.

  • Biopsy should be performed on grossly abnormal lesions of the cervix to determine the histologic diagnosis and to exclude microinvasive or grossly invasive cancer.

Obtain imaging and other studies to stage and further evaluate a diagnosis of cervical cancer. 
  • Obtain staging studies for all patients with cervical cancer:

    • Chest radiography to detect asymptomatic lung metastatsis

    • IVP to detect hydroureter

      • Renal ultrasonography may be considered as an alternative in women at low risk for pelvic spread

    • Examination under anesthesia, with cystoscopy and proctoscopy if concern for bladder or bowel involvement

  • Consider additional (nonstaging) imaging to direct therapy:

    • MRI, CT, or PET/CT of abdomen/pelvis to assess for local invasion and lymph node involvement

  • See table FIGO Staging of Cervical Cancer.

Evidence
  • A 2012 European Society for Medical Oncology guideline on diagnosis, treatment, and follow-up of cervical cancer recommended use of FIGO staging for cervical cancer based on tumor extension, and size, vaginal, and/or parametrial involvement, and bladder/rectum tumor extension by use of clinical exam, chest radiography, and IVP; the guideline recommended CT for detection of pathologic lymph nodes, MRI of the abdomen and pelvis for assessment of tumor size and extension, and consideration of PET for assessment of lymph nodes that are not macroscopically enlarged or in distant sites (39).

  • A 2009 FIGO guideline on staging classifications and clinical management of gynecologic cancers established clinical-diagnostic stages 1 (confined to uterus), 2 (invasion beyond the uterus but not to the pelvic wall or lower third of the vagina), 3 (extension to the pelvic wall or lower third of the vagina), and 4 (invasion of the bladder mucosa or rectum or extension beyond the pelvis), with substages determined by tumor size and specific locations of spread (40).

  • In a retrospective study of 817 patients, 1% of patients with invasive cervical cancer with no pulmonary symptoms had pulmonary metastasis (41).

  • 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 false-negative rate of 18% (42).

Rationale
  • Cervical cancer is clinically staged on the basis of tumor spread, and the recommended staging includes chest radiography, IVP, and examination under anesthesia with cystoscopy and proctoscopy.

  • Proper staging of any cancer helps with prognosis and tailoring of treatment, and gives a small survival advantage.

  • Chest radiography is required to detect asymptomatic lung metastasis.

  • Invasion of the parametrium with cervical cancer can result in hydroureter, which can be detected by IVP.

  • Both MRI and CT of the abdomen and pelvis 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 stage 1A or small 1B1 tumors may undergo renal ultrasound instead of IVP as a less expensive and safer examination for hydronephrosis.

  • In the United States, MRI or 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 imaging can be used. Routine imaging of the abdomen and pelvis is not used in the international staging system of cervical cancer because the cost of performing MRI or CT on all patients with cervical cancer in developing countries is prohibitive.

  • Asymptomatic liver metastasis or lymph node metastasis identified on MRI or CT would be used for treatment but would not change the clinical staging.

  • Because CT 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 (42).

Consider the differential diagnoses of an abnormal Pap smear result, postcoital bleeding, or lesions on the cervix. 
  • In the differential diagnosis of a high-grade Pap smear result, consider dysplasia, which is differentiated on colposcopy with biopsy.

  • In the differential diagnosis of postcoital bleeding, consider:

    • Normal cervical glands (seen in pregnancy or with use of birth control pills)

    • Cervicitis (generalized redness and inflammation, without a discreet lesion)

    • Lack of estrogen in postmenopausal women (atrophic, pale cervix)

  • In the differential diagnosis of gross abnormalities of the cervix, consider:

    • Cervical polyps (discreteand movable, with benign biopsy result)

    • Leiomyomas

    • Metastatic spread of other cancers to the cervix (such as endometrial 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, with many diagnoses requiring biopsy for differentiation.

Consult a gynecologist for diagnosis and a gynecologic oncologist for clinical staging of cervical cancer. 
  • Consult a gynecologist for colposcopy diagnosis in women with:

    • Pap smear cytology showing HSIL or cancer

    • A grossly abnormal cervix, even if the Pap smear is normal

  • Consult with a gynecologic oncologist for proper clinical staging of cervical cancer

Evidence
  • A 2012 European Society for Medical Oncology guideline on diagnosis, treatment, and follow-up of cervical cancer recommended use of FIGO staging for cervical cancer based on tumor extension, size, vaginal and/or parametrial involvement, and bladder/rectum tumor extension by use of clinical exam (39).

  • A 1998 meta-analysis of colposcopy for the diagnosis of squamous intraepithelial lesions included nine studies and 6281 patients. Colposcopy had a sensitivity of 96% and specificity of 69% in differentiating normal cervix from high-grade dysplasia and cancer (37).

  • In a diagnostic-accuracy assessment trial comparing specimens obtained from abnormal- and normal-appearing colposcopic sites, colposcopy had a sensitivity of 0.714 and a specificity of 0.877 in a diagnostic testing cohort with test threshold of prior HSIL (38).

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, a low-powered magnification device, 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.

Consult with a gynecologic oncologist or medical oncologist for management of patients with documented cervical cancer. 
  • Obtain consultation with a gynecologic oncologist for women with documented cervical cancer to:

    • Perform proper and cost-efficient staging

    • Determine the recommended degree of surgery based on clinical stage

    • 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.

  • Consider referring patients with recurrent or metastatic cervical cancer for enrollment in clinical trials.

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.

Consider hospitalizing women with cervical cancer with excessive vaginal bleeding, uncontrolled pain, or serious infection. 
  • Hospitalize women with excessive vaginal bleeding from cervical cancer causing hemodynamic instability for:

    • Blood transfusion

    • Vaginal packing to control hemorrhage

    • Additional steps as needed: suturing, embolization, radiation therapy, or surgery

  • Hospitalize women with severe pelvic and back pain from cervical cancer that requires intravenous narcotics for pain control.

  • Hospitalize women with hydronephrosis who develop pyelonephritis, sepsis, or both for:

    • Ureteral decompression

    • Antibiotic treatment

Evidence
  • Consensus.

Rationale
  • Women with hemodynamic instability from bleeding require supportive care.

  • Patients with severe pain may require acute pain control with intravenous narcotics.

  • Patients whose hydronephrosis causes pyelonephritis, sepsis, or both require decompression and antibiotics.

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.

Hospitalize women with cervical cancer as needed for surgery. 
  • Hospitalize women with stage 1 and 2 cervical cancer who require hysterectomy, for postoperative inpatient care.

Evidence
  • Consensus.

Rationale
  • Patients requiring hysterectomy need postoperative hospitalization.

Recommend surgery in patients with stage 1A1 to 2A cervical cancer. 
  • In women with stage 1A1 cervical cancer, recommend:

    • LEEP or cone excision OR

    • Abdominal, laparoscopic/robotic, or vaginal hysterectomy OR

    • Modified radical hysterectomy (abdominal, laparoscopic, robotic)

  • In women with stage 1A1 cervical cancer with lymphovascular space involvement or women with stage 1A2 cervical cancer, recommend modified radical hysterectomy.

  • In women with stage 1B1, 1B2, or 2A cervical cancer, recommend radical hysterectomy.

Evidence
  • A 2012 European Society for Medical Oncology guideline on diagnosis, treatment, and follow-up of cervical cancer recommended standards for surgical approaches, as determined by stage and by the presence or absence of involvement of the lymphovascular space (43).

  • A prospective surgical pathologic study by the Gynecologic Oncology Group of 732 patients found an 86% survival rate after radical hysterectomy (44).

  • 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 (45).

  • A prospective study of 100 consecutive radical hysterectomies performed by the surgical stapling technique showed that operative time and blood loss were significantly reduced, but survival, recurrence, and complication rates were similar to those seen with the traditional technique (46).

  • In a retrospective MEDLINE literature search of 2369 cases of stage 1A1 cervical cancer, the combined incidence of lymph node metastasis, recurrence, and death was <1% (47).

  • 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 (47).

  • 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 (40 [14599873]).

  • Several retrospective studies have demonstrated that robotic laparoscopic radical hysterectomies result in significantly less blood loss at the time of surgery, shorter hospital stays, decreased infectious morbidity, and oncologic outcomes similar to those with open radical hysterectomies (48; 49, 50).

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 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.

  • Once a tumor has become grossly invasive (stage 1B and 2A) a radical hysterectomy is required to ensure that the tumor is removed en bloc with an adequate margin and regional lymphadenectomies (the modified Halsted philosophy of cancer surgery). The overall cure rate is approximately 85%.

Comments
  • Over the past several years, the use of robotic surgery for cervical cancer has increased.

Consider primary radiation therapy with radiation sensitizing chemotherapy for any stage of cervical cancer. 
  • 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.

  • Administer weekly cisplatin, 40 mg/m2, during the 4 to 6 weeks of external beam radiation.

  • See table Drug Treatment for Cervical Cancer.

Evidence
  • A 2012 European Society for Medical Oncology guideline on diagnosis, treatment, and follow-up of cervical cancer recommended chemoradiotherapy, noting that women with advanced stage IB2–IIA/B disease may benefit more from chemoradiotherapy than patients with stage III and IVA. Chemoradiotherapy for locally advanced disease conferred a 5-year survival benefit of 8%, for locoregional disease-free survival of 9%, and metastases-free survival of 7%. The guideline noted that while non-platinum-based regimens appear to be as efficient as platinum-based chemotherapy, the most common regimen is cisplatin monotherapy, 40 mg/m2 weekly (39).

  • A 2005 Cochrane review of concomitant chemotherapy and radiation therapy for cervical cancer included 24 trials and 4921 patients. The reviewers found that chemoradiation improved overall survival by 10% and progression-free survival by 13%, regardless of whether platinum was used (51).

  • 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 (45).

  • 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 (52).

  • In a similar prospective study of 526 patients, weekly cisplatin increased survival to 65% vs. 47% with radiation alone (53).

  • In 368 patients, cisplatin and 5-FU increased survival to 67% vs. 57% with radiation alone (54).

  • In high-risk stage 1 and 2A disease, radiation sensitizing chemotherapy is also effective (55).

  • 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 (55).

  • In a similar group of 369 patients, weekly cisplatin increased survival to 83% from 74% with radiation alone (56).

  • A multicenter study of 526 women with locally advanced cervical cancer randomly assigned 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 (57).

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.

  • 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.

Consider pelvic exenteration for patients who develop midline pelvic recurrence after radiation therapy for cervical cancer. 
  • Consider pelvic exenteration (removal of all pelvic organs including bladder and/or rectum) 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
  • A 2014 Cochrane review of exenterative surgery for recurrent gynecologic malignancies found no RCTs or concurrent nonrandomized comparison studies that analyzed exenterative surgery versus medical management (58).

  • In a series of 100 patients undergoing pelvic exenteration, 61% of patients were cured at 5 years (59).

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 and because cervical cancer does not tend to be a chemosensitive disease.

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.

For women with cervical cancer diagnosed in pregnancy, adjust management according to cancer stage and duration of pregnancy. 
  • Base management of patients with cervical cancer in pregnancy on cancer stage and duration of pregnancy:

    • 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

    • 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
  • Mainly consensus.

  • A 2014 narrative review of management of gynecologic cancers during pregnancy provided an overview of accepted practice for cervical cancers detected during pregnancy (60).

Rationale
  • Patients with stage 1B to 4A tumors should deliver vaginally because of increased hemorrhage, infection, and risk for spread of tumor.

  • Treatment is based on stage, but the timing of treatment is influenced by the duration of the pregnancy.

Comments
  • Of cancers occurring during pregnancy, cervical cancer is one of the most common.

  • 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.

Consider chemotherapy for patients with distant recurrence and with stage 4 disease with distant metastasis. 
  • 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/m2, 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, carboplatin/paclitaxel, cisplatin/topotecan, cisplatin/gemcitabine, and cisplatin/ifosfamide to increase response rate.

  • Consider adding bevacizumab to combination chemotherapy to improve overall survival.

  • See table Drug Treatment for Cervical Cancer.

Evidence
  • In a review of 968 patients, the overall response rate to cisplatin was 25% (61).

  • In a prospective study of 52 patients, paclitaxel had a response rate of 17% (62).

  • In a review of 270 patients, the response rate to 5-FU was 13% (61).

  • In a prospective trial of 49 patients, topotecan had a response rate of 19% (63).

  • In a prospective trial of 56 patients, ifosfamide had a response rate of 16% (64).

  • In a prospective randomized trial of 438 patients, cisplatin and ifosfamide had a response rate of 31% vs. 18% with cisplatin alone (65).

  • In a prospective randomized trial of 452 patients, the addition of bevacizumab to combination chemotherapy in patients with recurrent, persistent, or metastatic disease increased medial overall survival by 3.7 months (66).

  • In a prospective trial of 280 patients, the combination of cisplatin and paclitaxel had a response rate of 37% vs. 19% with cisplatin alone (67).

  • A prospective randomized trial of 513 patients comparing cisplatin-containing doublet combinations found no significant difference in response rate or overall survival between cisplatin/gemcitabine, cisplatin/topotecan, cisplatin/vinorelbine, and cisplatin/paclitaxel; however, cisplatin/paclitaxel was best tolerated (68).

Rationale
  • Once cervical cancer has spread from the pelvis, pelvic surgery and pelvic radiation are no longer curative options, and chemotherapy is needed to treat distant disease.

  • Cisplatin is the most active chemotherapeutic agent in treating cervical cancer.

Comments
  • Doublet therapy containing platinum agents is superior to treatments with cisplatin alone. The combination of cisplatin and paclitaxel is the best-tolerated doublet therapy.

  • 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.

  • Consider referring patients with recurrent or metastatic cervical cancer for clinical trials.

Provide patients with cervical cancer with details of treatment and subsequent follow-up and prognosis. 
  • Initiate discussions about:

    • Stage of disease

    • Prognosis

    • Therapeutic options

    • Benefits and risks of surgery, radiation, and chemotherapy

    • Need for follow-up

  • Inform patients of the need for follow-up Pap smears and clinical pelvic exams after treatment

  • Educate patients regarding signs and symptoms of recurrence (e.g., pelvic or low back pain, edema, renal obstructive symptoms, vaginal bleeding/discharge, dyspareunia).

Evidence
  • Consensus.

Rationale
  • Patient education is a key component in adherence to treatment and optimizing management.

Counsel patients regarding the risks for sexual dysfunction after treatment, and offer sexual health counseling. 
  • Before treatment, inform patients of the risks for vaginal dryness, dyspareunia, and sexual dissatisfaction, particularly after radiotherapy.

  • Offer sexual health/function counseling after treatment.

  • Offer vaginal dilators for patients who have undergone radiation therapy

Evidence
  • Mainly consensus.

  • A 2014 systematic review of quality of life and sexual function of patients with cervical cancer after treatment found 15 studies of good methodology showing that vaginal dryness, dyspareunia, short vagina, and sexual dissatisfaction were prominent concerns in women after radiotherapy (69).

  • A 2006 narrative review of sexual function after gynecologic cancer provided an overview of practical advice, including formal sexual counseling and therapy to improve sexual function and relieve anxiety (70).

Rationale
  • Women experience long-term sexual function changes after cancer therapy for gynecologic cancer, and their ability to cope with these changes may benefit from counseling and support.

  • Chemotherapy can induce premature menopause; bilateral oophorectomy induces surgical menopause.

  • Women may not independently voice concerns regarding their sexual health unless asked.

Schedule periodic posttreatment cancer surveillance at regular intervals during the first 5 years after diagnosis, including frequent Pap smears. 
  • Schedule regular follow-up visits:

    • Every 3 months for the first year

    • Every 4 months for the second year

    • Every 6 months for years 3 through 5 after treatment.

    • Annually after 5 years

  • At follow-up visits include history, physical exam, and vaginal cuff Pap smear.

  • Note that patients with advanced disease may require surveillance chest radiography, CT, or MRI/CT of the abdomen and pelvis or PET/CT 3 to 6 months after chemoradiation to evaluate for persistent disease or early recurrence. After that, imaging tests are performed only as clinically indicated

Evidence
  • A 2012 European Society for Medical Oncology guideline on diagnosis, treatment, and follow-up of cervical cancer recommended clinical surveillance with gynecologic exam, including Pap smear every 3 months for 2 years, then every 6 months for the next 3 years, then yearly thereafter. CT or PET/CT was noted as being performed as clinically indicated (39).

  • In a retrospective review of 249 patients, 89% of recurrences occur within the first 2 years after treatment (71).

  • In a retrospective review of 1847 cases, 72% of vaginal recurrences were asymptomatic and were detected by abnormal cytologic smears (72).

Rationale
  • Routine examination may allow for early detection of recurrence.

Comments
  • Educate patients about symptoms of recurrent cancer.

Table Grahic Jump Location
 Drug Treatment for Cervical Cancer

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Drug or Drug ClassDosingSide EffectsPrecautionsClinical Use
blackboxiconCisplatin40 mg/m2 IV weekly during external beam radiation. 50 mg/m2 IV every 3 weeks as primary chemotherapyRisk for infection or bleeding. SIADH, hyperuricemia, alopecia, peripheral neuropathy, visual impairment, injection site reactions, secondary malignancy, elevated hepatic enzymes, cardiac or vascular toxicity, TLSblackboxicon 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 administeredCisplatin is the most active chemotherapeutic agent for cervical cancer
blackboxiconPaclitaxel135 mg/m2 IV every 3 weeksMyelosuppression, risk for 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 enzymesblackboxicon 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 P-gp.
blackboxiconFluorouracil, 5-FU1000 mg/m2·d continuous IV infusion for 4 days every 4 weeksMyelosuppression, risk for infection or bleeding. Vomiting, diarrhea, anorexia, GI bleeding, stomatitis, hand and foot syndrome, neurotoxicity, lacrimation, cardiotoxicity, injection site reactions, photosensitivityblackboxicon Hospitalize for first course of therapy due to severe toxic reactions. Avoid with pregnancy. Consider dose reduction with hepatic disease
blackboxiconIfosfamide (Ifex)1.2-1.5 g/m2 IV qd for 5 days every 4 weeksRisk for infection or bleeding. Alopecia, vomiting, renal insufficiency, cardiotoxicity, secondary malignancyblackboxicon 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
blackboxiconTopotecan (Hycamtin)1.5 mg/m2 qd for 5 days every 4 weeksRisk for infection or bleeding. Vomiting, diarrhea, constipation, abdominal pain, anorexia, stomatitis, alopecia, fever, asthenia, pain, dyspnea, fatigue, rigors, rash, ILD, infertilityblackboxicon Myelosuppression. Avoid with pregnancy. Avoid extravasation. May need to decrease dose with CKD.

blackboxicon = 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

ACP Smart Medicine provides key prescribing information for practitioners but is not intended to be a source of comprehensive drug information.

Table Grahic Jump Location
 The Bethesda System for Reporting Results of Cervical Cytology

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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).

Table Grahic Jump Location
 FIGO Staging of Cervical Cancer

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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 two thirds 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. Data obtained from 40.

  • 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.
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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

CDC

Centers for Disease Control and Prevention

CIN

cervical intraepithelial neoplasia

CT

computed tomography

DES

diethylstilbestrol

DNA

deoxyribonucleic acid

FIGO

International Federation of Gynecology and Obstetrics

G0

Gap 0; resting phase of the cell cycle

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)

MRI

magnetic resonance imaging

OR

odds ratio

Pap

Papanicolaou (smear)

PET

positron emission tomography

RCT

randomized, controlled trialRR

RR

relative risk

STI

sexually transmitted infection


DOI: 10.7326/d643
The information included herein should never be used as a substitute for clinical judgment and does not represent an official position of ACP.
Author(s) and Disclosures:
James Fanning, DO has nothing to disclose. Nikki Neubauer, MD has nothing to disclose. Anna Strohl, MD, MD has nothing to disclose.

One or more of the present or past ACP Smart Medicine physician editors worked on this module and had nothing to disclose: Davoren Chick, MD, FACP; Deborah Korenstein, MD, FACP; Marjorie Lazoff, MD, FACP; Richard Lynn, MD, FACP.

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