Archives: Cancer Types

Cervical Cancer Prevention (PDQ®)–Health Professional Version

Cervical Cancer Prevention (PDQ®)–Health Professional Version

Overview

Note: The Overview section summarizes the published evidence on this topic. The rest of the summary describes the evidence in more detail.

Other PDQ summaries on Cervical Cancer Screening and Cervical Cancer Treatment are also available.

Who Is at Risk?

Carcinogenic types of human papillomavirus (HPV) are the primary, etiologic, infectious agents that cause virtually all cases of cervical cancer. HPV type 16 (HPV-16) and HPV type 18 (HPV-18) are most often associated with invasive disease.[1,2] Because HPV can be transmitted during sexual activity, there is an association between beginning sexual activity at a younger age, as well as having a greater number of lifetime sexual partners and an increased risk of developing cervical cancer.[3] Immunosuppression is another risk factor for cervical cancer; for example, coinfection with HIV may lead to long-term persistence of viral infection (i.e., failure to clear).[4,5] Once HPV infection occurs, several additional risk factors are associated with a higher risk of the eventual development of cervical cancer. These risk factors include high parity, long-term use of oral contraceptives, and active and passive cigarette smoking.[6–8] The risk increases with longer duration and intensity of smoking. Diethylstilbestrol (DES) exposure in utero is also associated with an increased risk of developing cervical dysplasia.[9]

Factors With Adequate Evidence of an Increased Risk of Cervical Cancer

Human papillomavirus (HPV)

Based on solid evidence from observational studies, HPV infection is associated with the development of cervical cancer.

Magnitude of Effect: HPV has been implicated as the primary etiologic infectious agent causing virtually all cases of cervical cancer.

  • Study Design: Evidence obtained from cohort and case-control studies.
  • Internal Validity: Good.
  • Consistency: Good.
  • External Validity: Good.

Immunosuppression

Based on solid evidence, being immunosuppressed is associated with an increased risk of cervical cancer.

  • Study Design: Evidence obtained from cohort and case-control studies.
  • Internal Validity: Good.
  • Consistency: Good.
  • External Validity: Good.

Sexual activity at an early age and with a greater number of partners

Based on solid evidence, sexual activity at a younger age and an increasing number of sexual partners are both associated with an increased risk of HPV infection and subsequent development of cervical cancer.

Magnitude of Effect: Women who experience first sexual intercourse at age 17 years or younger or women who have had six or more lifetime sexual partners have approximately two to three times the risk of squamous cell carcinoma or adenocarcinoma of the cervix, compared with women aged 21 years or older or who have a single sexual partner.[3]

  • Study Design: Evidence obtained from cohort and case-control studies.
  • Internal Validity: Good.
  • Consistency: Good.
  • External Validity: Good.

High parity

Based on solid evidence, high parity is associated with increased risk of cervical cancer in HPV-infected women.

Magnitude of Effect: Among HPV-infected women, those who have had seven or more full-term pregnancies have approximately four times the risk of squamous cell cancer compared with nulliparous women, and HPV-infected women also have two to three times the risk of women who have had one or two full-term pregnancies.[6]

  • Study Design: Evidence obtained from cohort or case-control studies.
  • Internal Validity: Good.
  • Consistency: Good.
  • External Validity: Good.

Long-term use of oral contraceptives

Based on solid evidence, long-term use of oral contraceptives is associated with increased risk of cervical cancer in HPV-infected women.

Magnitude of Effect: Among HPV-infected women, those who used oral contraceptives for 5 to 9 years have approximately three times the incidence of invasive cancer, and those who used them for 10 years or longer have approximately four times the risk.[7]

  • Study Design: Evidence obtained from cohort or case-control studies.
  • Internal Validity: Good.
  • Consistency: Good.
  • External Validity: Good.

Cigarette smoke exposure

Based on solid evidence, cigarette smoking, both active and passive, is associated with an increased risk of cervical cancer in HPV-infected women.

Magnitude of Effect: Among HPV-infected women, current and former smokers have approximately two to three times the incidence of high-grade cervical intraepithelial neoplasia or invasive cancer. Passive smoking is also associated with increased risk but to a lesser extent.

  • Study Design: Evidence obtained from cohort or case-control studies.
  • Internal Validity: Good.
  • Consistency: Good.
  • External Validity: Good.

Diethylstilbestrol (DES) exposure

Based on solid evidence, DES exposure is associated with an increased risk of developing clear cell adenocarcinoma of the cervix.

Magnitude of Effect: About one in 1,000 women exposed to DES in utero will develop a clear cell adenocarcinoma of the cervix.

  • Study Design: Evidence obtained from cohort studies.
  • Internal Validity: Good.
  • Consistency: Good.
  • External Validity: Good.

Factors With Adequate Evidence of a Decreased Risk of Cervical Cancer

Sexual abstinence

Based on solid evidence, abstinence from sexual activity is associated with a near-total reduction in the risk of developing cervical cancer.

Magnitude of Effect: Sexual abstinence essentially precludes HPV transmission.

  • Study Design: Evidence obtained from cohort or case-control studies.
  • Internal Validity: Good.
  • Consistency: Good.
  • External Validity: Good.

Interventions With Adequate Evidence of a Decreased Risk of Cervical Cancer

Note: Based on solid evidence, screening with the Papanicolaou (Pap) test and screening with the HPV DNA test reduces cervical cancer incidence. For more information on these screening tests, see Cervical Cancer Screening.

HPV vaccination: Benefits

Based on solid evidence, vaccination against HPV-16/HPV-18 is effective in preventing HPV infection in HPV-naive individuals and is associated with a reduced incidence of cervical intraepithelial neoplasia 2 and 3. By extrapolation, these vaccines should also be associated with a reduced incidence of cervical cancer.

Magnitude of Effect: Vaccination against HPV-16 and HPV-18 reduces incident and persistent infections with efficacy of 91.6% (95% confidence interval [CI], 64.5%–98.0%) and 100% (95% CI, 45%–100%), respectively.

  • Study Design: Evidence obtained from randomized controlled trials (for intraepithelial precursor lesions) and cohort study analyses (for invasive cervical cancers).
  • Internal Validity: Good.
  • Consistency: Good.
  • External Validity: Good.

HPV vaccination: Harms

Based on solid evidence, harms of HPV vaccines include injection-site reactions, dizziness and syncope, headache, and fever. Vaccination during pregnancy has not been associated with adverse pregnancy outcomes.[10] Allergic reactions occur rarely.

  • Study Design: Evidence obtained from randomized controlled trials.
  • Internal Validity: Good.
  • Consistency: Good.
  • External Validity: Good.

Use of barrier protection during sexual intercourse: Benefits

Based on solid evidence, the use of barrier methods (e.g., condoms) during sexual intercourse is associated with a decreased risk of cervical cancer.

Magnitude of Effect: Total use of barrier protection decreases cervical cancer incidence (relative risk, 0.4; 95% CI, 0.2–0.9).

  • Study Design: Evidence obtained from cohort and case-control studies.
  • Internal Validity: Good.
  • Consistency: Good.
  • External Validity: Good.

Use of barrier protection during sexual intercourse: Harms

Based on fair evidence, the use of barrier methods during sexual intercourse is associated with few serious harms. Barrier methods can break, potentially resulting in unintended pregnancy. Allergic reactions to the barrier material (e.g., natural latex) can occur.

  • Study Design: Evidence obtained from cohort and case-control studies.
  • Internal Validity: Good.
  • Consistency: Good.
  • External Validity: Good.
References
  1. Schiffman M, Castle PE, Jeronimo J, et al.: Human papillomavirus and cervical cancer. Lancet 370 (9590): 890-907, 2007. [PUBMED Abstract]
  2. Trottier H, Franco EL: The epidemiology of genital human papillomavirus infection. Vaccine 24 (Suppl 1): S1-15, 2006. [PUBMED Abstract]
  3. Berrington de González A, Green J; International Collaboration of Epidemiological Studies of Cervical Cancer: Comparison of risk factors for invasive squamous cell carcinoma and adenocarcinoma of the cervix: collaborative reanalysis of individual data on 8,097 women with squamous cell carcinoma and 1,374 women with adenocarcinoma from 12 epidemiological studies. Int J Cancer 120 (4): 885-91, 2007. [PUBMED Abstract]
  4. Abraham AG, D’Souza G, Jing Y, et al.: Invasive cervical cancer risk among HIV-infected women: a North American multicohort collaboration prospective study. J Acquir Immune Defic Syndr 62 (4): 405-13, 2013. [PUBMED Abstract]
  5. Grulich AE, van Leeuwen MT, Falster MO, et al.: Incidence of cancers in people with HIV/AIDS compared with immunosuppressed transplant recipients: a meta-analysis. Lancet 370 (9581): 59-67, 2007. [PUBMED Abstract]
  6. Muñoz N, Franceschi S, Bosetti C, et al.: Role of parity and human papillomavirus in cervical cancer: the IARC multicentric case-control study. Lancet 359 (9312): 1093-101, 2002. [PUBMED Abstract]
  7. Moreno V, Bosch FX, Muñoz N, et al.: Effect of oral contraceptives on risk of cervical cancer in women with human papillomavirus infection: the IARC multicentric case-control study. Lancet 359 (9312): 1085-92, 2002. [PUBMED Abstract]
  8. Appleby P, Beral V, Berrington de González A, et al.: Carcinoma of the cervix and tobacco smoking: collaborative reanalysis of individual data on 13,541 women with carcinoma of the cervix and 23,017 women without carcinoma of the cervix from 23 epidemiological studies. Int J Cancer 118 (6): 1481-95, 2006. [PUBMED Abstract]
  9. Hoover RN, Hyer M, Pfeiffer RM, et al.: Adverse health outcomes in women exposed in utero to diethylstilbestrol. N Engl J Med 365 (14): 1304-14, 2011. [PUBMED Abstract]
  10. Scheller NM, Pasternak B, Mølgaard-Nielsen D, et al.: Quadrivalent HPV Vaccination and the Risk of Adverse Pregnancy Outcomes. N Engl J Med 376 (13): 1223-1233, 2017. [PUBMED Abstract]

Incidence and Mortality

An estimated 13,360 new cervical cancers and 4,320 cervical cancer deaths will occur in the United States in 2025.[1] When corrected for the prevalence of hysterectomy, the mortality rate for Black women is nearly twice the mortality rate for White women.[2] Also, approximately 1,250,000 women will be diagnosed with precancers annually by cytology using the Papanicolaou (Pap) smear. A continuum of pathological changes may be diagnosed, ranging from atypical squamous cells of undetermined significance to low-grade squamous intraepithelial lesions (LSIL) to high-grade squamous intraepithelial lesions (HSIL) to invasive cancer. The precancerous conditions LSIL and HSIL are also referred to as cervical intraepithelial neoplasia (CIN) 1, 2, and 3. Lesions can regress, persist, or progress to an invasive malignancy, with LSIL (CIN 1) more likely to regress spontaneously and HSIL (CIN 2/CIN 3) more likely to persist or progress. The average time for progression of CIN 3 to invasive cancer has been estimated to be 10 to 15 years.[3]

References
  1. American Cancer Society: Cancer Facts and Figures 2025. American Cancer Society, 2025. Available online. Last accessed January 16, 2025.
  2. Beavis AL, Gravitt PE, Rositch AF: Hysterectomy-corrected cervical cancer mortality rates reveal a larger racial disparity in the United States. Cancer 123 (6): 1044-1050, 2017. [PUBMED Abstract]
  3. Holowaty P, Miller AB, Rohan T, et al.: Natural history of dysplasia of the uterine cervix. J Natl Cancer Inst 91 (3): 252-8, 1999. [PUBMED Abstract]

Factors With Adequate Evidence of an Increased Risk of Cervical Cancer

HPV

Epidemiological studies to evaluate risk factors for the development of squamous intraepithelial lesions and cervical malignancy demonstrate conclusively a sexual mode of transmission of a carcinogen.[1] It is now widely accepted that human papillomavirus (HPV) is the primary etiologic infectious agent that causes virtually all cases of cervical cancer.[2,3] Other sexually transmitted factors, including herpes simplex virus 2 and Chlamydia trachomatis, may play a co-causative role.[4] More than 80 distinct types of HPV have been identified, approximately 30 of which infect the human genital tract. HPV type 16 (HPV-16) and HPV type 18 (HPV-18) are most often associated with invasive disease. Characterization of carcinogenic risk associated with HPV types is an important step in the process of developing a combination HPV vaccine for the prevention of cervical neoplasia. In a population-based study of HPV infection and cervical neoplasia in Costa Rica, 80% of high-grade squamous intraepithelial lesions (HSIL) and invasive lesions were associated with HPV infection by one or more of 13 cancer-associated types.[5] In this study, the risk of about 50% of HSIL and invasive cervical cancer was attributable to HPV-16. HPV-18 was associated with 15% of invasive disease but only 5% of HSIL, suggesting that HPV-18 may have a role in more aggressive cases of cervical malignancy. There may be differences in the prevalence and carcinogenic risk of individual high-risk HPV genotypes by race and geographical regions, and additional studies are ongoing.[6]

Immunosuppression

Most cases of HPV infection are resolved by the host immune system. Immunosuppression leads to persistence of viral infection with a subsequent increased risk of cervical neoplasia. Women with immunosuppression resulting from HIV infection have been studied over the past three decades of the AIDS epidemic. In one North American study, a group of 13,690 HIV-infected women were studied for a median of 5 years. The rate of invasive cervical cancer in the HIV-infected women was 26 cases per 100,000 women, and this was approximately four times greater than an HIV-uninfected control group.[7] HIV-infected women with the lowest CD4 lymphocyte counts were at the highest risk of invasive cancer. Women who are immunosuppressed resulting from organ transplantation are also at risk of invasive cervical cancer, and one meta-analysis found a twofold increased risk.[8]

Sexual Activity at an Early Age and With a Greater Number of Partners

HPV infection has been established as a necessary cause of almost all cases of cervical cancer, and the primary mode of transmission is sexual contact. This provides context for the findings that younger age at first intercourse and an increasing number of lifetime sexual partners are both associated with an increased risk of developing cervical cancer. Pooled, individual, patient-level data from 12 cohort and case-control studies demonstrated statistically significantly increased risks of developing cervical cancer in women who were aged 17 years or younger at first intercourse, compared with women who were aged 21 years or older at first intercourse (relative risk [RR] for squamous cell cancer, 2.24; 95% confidence interval [CI], 2.11–2.38 and RR for adenocarcinoma, 2.06; 95% CI, 1.83–2.33). Similar findings were observed in women who had six or more lifetime sexual partners, compared with women who had one lifetime sexual partner (RR for squamous cell cancer, 2.98; 95% CI, 2.62–3.40 and RR for adenocarcinoma, 2.64; 95% CI, 2.07–3.36).[9]

High Parity

High parity has long been recognized as a risk factor for cervical cancer, but the relation of parity to HPV infection was uncertain. A meta-analysis of 25 epidemiological studies, including 16,563 women with cervical cancer and 33,542 women without cervical cancer, showed that the number of full-term pregnancies was associated with increased risk, regardless of age at first pregnancy. This finding was also true if analyses were limited to patients with high-risk HPV infections (RR, 4.99; 95% CI, 3.49–7.13 for seven or more pregnancies vs. no pregnancies; linear trend test X2 = 30.69; P < .001).[10]

Long-Term Use of Oral Contraceptives

Long-term use of oral contraceptives has also been known to be associated with cervical cancer, but its relation to HPV infection was also uncertain. A pooled analysis of HPV-positive women from the studies described above was undertaken. Compared with women who have never used oral contraceptives, those who have used them for fewer than 5 years did not have an increased risk of cervical cancer (odds ratio [OR], 0.73; 95% CI, 0.52–1.03). The OR for women who used oral contraceptives for 5 to 9 years was 2.82 (95% CI, 1.46–5.42), and for 10 or more years, the OR was 4.03 (95% CI, 2.09–8.02).[11] A meta-analysis of 24 epidemiological studies confirmed the increased risk associated with oral contraceptives, which is proportionate to the duration of use. Risk decreases after cessation and returns to normal risk levels in 10 years.[12]

Cigarette Smoke Exposure

Cigarette smoking by women is associated with an increased risk of squamous cell carcinoma.[1,13,14] This risk increases with longer duration and intensity of smoking. The risk among smokers may be present with exposure to environmental tobacco smoke and may be as high as four times that of women who are nonsmokers who are not exposed to environmental smoking.[1] Case-control studies of women infected with HPV have examined the effect of various types and levels of tobacco exposure and found similar results.[14–16]

DES Exposure

Diethylstilbestrol (DES) is a synthetic form of estrogen that was prescribed to pregnant women in the United States between 1940 and 1971 to prevent miscarriage and premature labor. DES is associated with a substantially increased risk of developing clear cell adenocarcinoma of the vagina and cervix among the daughters of women who used the drug during pregnancy (standardized incidence ratio, 24.23; 95% CI, 8.89–52.74); the risk persists as these women age into their 40s.[17] Despite the greatly elevated risk relative to the general population, this type of cancer is still rare; about one in 1,000 daughters exposed to DES will develop a clear cell adenocarcinoma.

DES exposure in utero is also associated with an increased risk of developing cervical dysplasia. An evaluation of three cohorts, including the Diethylstilbestrol Adenosis study, the Dieckmann study, and the Women’s Health Study, with long-term follow-up of more than 4,500 women exposed in utero to DES, found that 6.9% of exposed women developed grade II or higher cervical intraepithelial neoplasia, compared with 3.4% of nonexposed women (hazard ratio, 2.28; 95% CI, 1.59–3.27).[18]

References
  1. Brinton LA: Epidemiology of cervical cancer–overview. IARC Sci Publ (119): 3-23, 1992. [PUBMED Abstract]
  2. Schiffman M, Castle PE, Jeronimo J, et al.: Human papillomavirus and cervical cancer. Lancet 370 (9590): 890-907, 2007. [PUBMED Abstract]
  3. Trottier H, Franco EL: The epidemiology of genital human papillomavirus infection. Vaccine 24 (Suppl 1): S1-15, 2006. [PUBMED Abstract]
  4. Ault KA: Epidemiology and natural history of human papillomavirus infections in the female genital tract. Infect Dis Obstet Gynecol 2006 (Suppl): 40470, 2006. [PUBMED Abstract]
  5. Herrero R, Hildesheim A, Bratti C, et al.: Population-based study of human papillomavirus infection and cervical neoplasia in rural Costa Rica. J Natl Cancer Inst 92 (6): 464-74, 2000. [PUBMED Abstract]
  6. Risley C, Clarke MA, Geisinger KR, et al.: Racial differences in HPV type 16 prevalence in women with ASCUS of the uterine cervix. Cancer Cytopathol 128 (8): 528-534, 2020. [PUBMED Abstract]
  7. Abraham AG, D’Souza G, Jing Y, et al.: Invasive cervical cancer risk among HIV-infected women: a North American multicohort collaboration prospective study. J Acquir Immune Defic Syndr 62 (4): 405-13, 2013. [PUBMED Abstract]
  8. Grulich AE, van Leeuwen MT, Falster MO, et al.: Incidence of cancers in people with HIV/AIDS compared with immunosuppressed transplant recipients: a meta-analysis. Lancet 370 (9581): 59-67, 2007. [PUBMED Abstract]
  9. Berrington de González A, Green J; International Collaboration of Epidemiological Studies of Cervical Cancer: Comparison of risk factors for invasive squamous cell carcinoma and adenocarcinoma of the cervix: collaborative reanalysis of individual data on 8,097 women with squamous cell carcinoma and 1,374 women with adenocarcinoma from 12 epidemiological studies. Int J Cancer 120 (4): 885-91, 2007. [PUBMED Abstract]
  10. International Collaboration of Epidemiological Studies of Cervical Cancer: Cervical carcinoma and reproductive factors: collaborative reanalysis of individual data on 16,563 women with cervical carcinoma and 33,542 women without cervical carcinoma from 25 epidemiological studies. Int J Cancer 119 (5): 1108-24, 2006. [PUBMED Abstract]
  11. Moreno V, Bosch FX, Muñoz N, et al.: Effect of oral contraceptives on risk of cervical cancer in women with human papillomavirus infection: the IARC multicentric case-control study. Lancet 359 (9312): 1085-92, 2002. [PUBMED Abstract]
  12. Appleby P, Beral V, Berrington de González A, et al.: Cervical cancer and hormonal contraceptives: collaborative reanalysis of individual data for 16,573 women with cervical cancer and 35,509 women without cervical cancer from 24 epidemiological studies. Lancet 370 (9599): 1609-21, 2007. [PUBMED Abstract]
  13. Hellberg D, Nilsson S, Haley NJ, et al.: Smoking and cervical intraepithelial neoplasia: nicotine and cotinine in serum and cervical mucus in smokers and nonsmokers. Am J Obstet Gynecol 158 (4): 910-3, 1988. [PUBMED Abstract]
  14. Brock KE, MacLennan R, Brinton LA, et al.: Smoking and infectious agents and risk of in situ cervical cancer in Sydney, Australia. Cancer Res 49 (17): 4925-8, 1989. [PUBMED Abstract]
  15. Ho GY, Kadish AS, Burk RD, et al.: HPV 16 and cigarette smoking as risk factors for high-grade cervical intra-epithelial neoplasia. Int J Cancer 78 (3): 281-5, 1998. [PUBMED Abstract]
  16. Plummer M, Herrero R, Franceschi S, et al.: Smoking and cervical cancer: pooled analysis of the IARC multi-centric case–control study. Cancer Causes Control 14 (9): 805-14, 2003. [PUBMED Abstract]
  17. Verloop J, van Leeuwen FE, Helmerhorst TJ, et al.: Cancer risk in DES daughters. Cancer Causes Control 21 (7): 999-1007, 2010. [PUBMED Abstract]
  18. Hoover RN, Hyer M, Pfeiffer RM, et al.: Adverse health outcomes in women exposed in utero to diethylstilbestrol. N Engl J Med 365 (14): 1304-14, 2011. [PUBMED Abstract]

Factors With Adequate Evidence of a Decreased Risk of Cervical Cancer

Sexual Abstinence

Nearly all cases of cervical cancer are associated with human papillomavirus (HPV) infection, which is transmitted during sexual activity. Therefore, cervical cancer is seen more frequently in women with sexual activity at an early age and with multiple partners.[1] Lifetime abstinence from sexual activity is associated with a near-total reduction in the risk of developing cervical cancer. For more information, see the HPV section.

References
  1. IARC Working Group on the Evaluation of Carcinogenic Risks to Humans: Human papillomaviruses. IARC Monogr Eval Carcinog Risks Hum 100 (Pt B), 255-296, 2012. Available online. Last accessed January 31, 2025.

Interventions With Adequate Evidence of a Decreased Risk of Cervical Cancer

HPV Vaccination

Given the etiological role of human papillomavirus (HPV) in the pathogenesis of cervical neoplasia, vaccines to immunize individuals against HPV infection offer a primary prevention strategy for cervical cancer. A quadrivalent (HPV type 6 [HPV-6], type 11 [HPV-11], type 16 [HPV-16], and type 18 [HPV-18]) vaccine using a late protein L1 construct to induce antibody-mediated immunity was approved for use by the U.S. Food and Drug Administration in 2006; a bivalent (HPV-16, -18) vaccine was approved in 2009; and a vaccine targeting nine HPV types was approved in 2014. Vaccination during pregnancy has not been associated with adverse pregnancy outcomes.[1]

Persistent infection with oncogenic types of HPV, such as HPV-16 and HPV-18, is associated with the development of cervical cancer.[2] A vaccine to prevent HPV infection with oncogenic-type viruses has the potential to reduce the incidence of cervical cancer. A vaccine against HPV-16 using empty-viral capsids called virus-like particles (VLP) was developed and tested for efficacy in preventing persistent infection with HPV-16.

A multicenter, double-blind, placebo-controlled trial enrolled 2,391 women aged 16 to 23 years and randomly assigned them to receive either 40 µg of HPV-16 L1 VLP vaccine or placebo on day 1, at 2 months, and at 6 months. Papanicolaou (Pap) tests and genital samples for HPV-16 DNA were obtained on day 1, at 7 months, and every 6 months for 48 months. Colposcopy and cervical biopsies were obtained when clinically indicated at study exit. Serum HPV-16 antibody titers were obtained at study entry, at 7 months, and then every 6 months. A total of 1,505 women (755 receiving vaccine and 750 receiving placebo) completed all three vaccinations and had follow-up after month 7. After immunization, HPV titers peaked at month 7, declined through month 18, and then stabilized in months 30 through 48. There were no cases of cervical intraepithelial neoplasia (CIN) in the vaccine-treated women, but there were 12 cases in the placebo group (six CIN 2 and six CIN 3). HPV-16 infection that persisted for at least 4 months was seen in seven vaccine-treated women, compared with 111 placebo-treated women.[3]

An international, double-blind, placebo-controlled trial of a bivalent HPV-16/HPV-18 VLP vaccine was performed in 1,113 women aged 15 to 25 years with normal cervical cytology who were seronegative for HPV-16, HPV-18, and 12 other oncogenic HPV types at enrollment. Women received either vaccine or placebo at 0, 1, and 6 months and were assessed by cervical cytology and self-obtained cervicovaginal samples for at least 18 months. A masked treatment-allocation follow-up study was performed for an additional 3 years, for a combined analysis of up to 6.4 years of follow-up. The 12-month persistent infection rate of HPV-16 or HPV-18 in an according-to-protocol cohort (i.e., women who received all three doses of vaccine or placebo on the correct schedule) was 0 of 401 women in the vaccine arm, compared with 20 of 372 women in the placebo arm, with a vaccine efficacy rate of 100% (95% confidence interval [CI], 81.8%–100%). Diagnoses of CIN 2 or higher in a total vaccinated cohort (i.e., women who received at least one dose of vaccine or placebo) were 0 of 481 women in the vaccine arm compared with 9 of 470 women in the placebo arm, with a vaccine efficacy of 100% (95% CI, 51.3%–100%). Adverse events were similar in vaccinated and placebo-treated women. Neither analysis was intention-to-treat (ITT), making it difficult to know what the true vaccine efficacy for either virological or cytohistological end points would be in the routine clinical setting. Furthermore, cytohistological outcomes were reported only as composite end points (CIN 2+), making it impossible to distinguish the vaccine’s efficacy against invasive cervical cancer alone and potentially inflating the observed efficacy by including lesions with a relatively high probability (approximately 50% for CIN 2 [4]) of spontaneous regression.[5] A register-based observational study in England reported the impact of a national bivalent vaccination program on cervical cancer and CIN 3.[6] Routine vaccinations were offered to girls aged 12 to 13 years with a catch-up program for those aged 14 to 18 years. Data from 13.7 million years of follow-up in women aged 20 years to younger than 30 years showed a substantial reduction in cervical cancer and CIN 3 incidence after a national HPV program was introduced. This was especially true in individuals who were offered the vaccine between ages 12 and 13 years (see Table 1).

Table 1. Estimated Relative Reduction in Cervical Cancer or CIN 3 by Age When Vaccine Was Offered Compared With the Reference Unvaccinated Cohort
Estimated Relative Reduction (95% CI)
Age Vaccine Was Offered Cervical Cancer CIN 3
CI = confidence interval; CIN = cervical intraepithelial neoplasia.
16–18 y 34% (25–41) 39% (36–41)
14–16 y 62% (52–71) 75% (72–77)
12–13 y 87% (72–94) 97% (96–78)

A quadrivalent vaccine (HPV types-6, -11, -16, and -18) was evaluated in a multinational, double-blind, randomized controlled trial of 17,622 women aged 15 to 26 years (FUTURE I and II).[7] Women received either the HPV vaccine or placebo at 0, 2, and 6 months; participants were assessed by clinical exam, Pap test, and HPV DNA testing for 4 or more years. Two analyses were reported. One group was considered to be HPV naive: negative to 14 HPV types. The second group was an ITT analysis, which approximates a sexually active population. The composite end point for cervical disease included the incidence of HPV-16/HPV-18–related, CIN 2, CIN 3, adenocarcinoma in situ, or invasive carcinoma. Outcomes were reported as follows:

Table 2. Vaccine Efficacy of the Quadrivalent HPV Vaccine
Population Point Estimate and 95% CI
CI = confidence interval; CIN = cervical intraepithelial neoplasia; HPV = human papillomavirus; ITT = intention-to-treat.
HPV-naive population for HPV-CIN 3 100% (90.5%–100%) for lesions associated with HPV-6, -11, -16, or -18
ITT CIN 3 45.3% (29.8%–57.6%) for lesions associated with HPV-6, -11, -16, or -18

This study also demonstrated decreased rates of abnormal Pap tests and subsequent diagnostic procedures. No cases of invasive cervical cancer were identified during the trial.

A 9-valent HPV (9vHPV) vaccine was studied in another international randomized trial, which included 14,215 women. This new vaccine, 9vHPV, includes the four HPV types in the quadrivalent vaccine, qHPV (6, 11, 16, 18) and also 5 more oncogenic types (31, 33, 45, 52, 58). Sexually active women aged 16 to 26 years with fewer than five lifetime sexual partners received three intramuscular injections (day 1, month 2, and month 6) of either the qHPV vaccine or the 9vHPV vaccine. Women were evaluated every 6 months for up to 5 years. The rate of high-grade cervical, vulvar, or vaginal disease was the same in both groups (14.0 per 1,000 person-years) because of preexisting HPV infection, but the rate of disease related to HPV-31, -35, -45, -52, and -58 was lower in the 9vHPV vaccine group (0.1 vs. 1.6 per 1,000 person-years). Injection-site reactions were more common in the 9vHPV group.[8] Although not addressed in this study, the benefit of HPV vaccination is optimal in younger females before the onset of sexual activity.

All forms of the HPV vaccine are currently recommended by the Centers for Disease Control and Prevention (CDC) in the United States as a two-dose schedule at least 6 months apart for adolescents younger than 15 years. The current CDC recommendation for older individuals is to receive the original three-dose series. Recently, given issues of cost and adherence, there has been published data investigating whether similar vaccine efficacy could be obtainable using a reduced-dose schedule. A post hoc combined analysis of two phase III randomized controlled trials of the bivalent HPV vaccine (the Costa Rica Vaccine Trial and the PApilloma TRIal against Cancer In young Adults [PATRICIA] Trial) found that among women who were not HPV positive at enrollment for the specific virus type being studied, vaccine efficacy against either one-time incident detection of HPV 16/18 or incident infection that persisted at least 6 months was not statistically significantly different for those who received all three, two, or only one of the scheduled HPV vaccine doses (resulting from nonadherence or other factors) for up to 4 years of follow-up. Vaccine efficacy rates for persistent HPV 16/18 infection ranged from 89.1% (95% CI, 86.8%–91.0%) for three doses, to 89.7% (95% CI, 73.3%–99.8%) for two doses, to 96.6% (95% CI, 81.7%–99.8%) for one dose. To date, there are no randomized controlled trials that directly assess this clinical question.[9] A recent international study compared a two-dose schedule with a three-dose schedule in adolescents younger than 15 years who received the 9vHPV vaccine. The antibody response was noninferior in the two-dose schedule, leading to the current recommendation that two doses are sufficient for this age group.[10] Long-term follow-up data from the Costa Rica Vaccine Trial suggested that all HPV-vaccinated women aged 18 to 25 years at the time of initial vaccination remained HPV-16/HPV-18 seropositive more than a decade after initial vaccination, regardless of the number of doses received. The antibody levels were lower in the women who received only one dose than in the women who received two or three doses of the bivalent vaccine, but the levels remained higher than estimated levels achieved via natural immunity. The long-term vaccine efficacy rates against prevalent HPV-16 or HPV-18 infection were 80.2% (95% CI, 70.7%–87.0%) among women who received three doses, 83.8% (95% CI, 19.5%–99.2%) among those who received two doses, and 82.1% (95% CI, 40.2%–97.0%) among those who received one dose.[11] Additionally, there was prolonged efficacy against CIN 2 and CIN 3 after 7 to 11 years of follow-up.[12] The women in this long-term follow-up study were not randomly assigned to one, two, or three doses, and the number of women who received only one dose is low. However, the promising findings of the long-term stability of HPV-antibody levels and vaccine efficacy in women who were older than the recommended age at the time of initial vaccination has influenced the design of a currently ongoing trial, which will answer the question of the efficacy of a single dose more definitively. The ESCUDDO study (NCT03180034) is a trial enrolling adolescent girls who will be randomly assigned to either one dose or two doses of the bivalent or nonavalent vaccines. A concurrent population survey of comparable, unvaccinated, age-matched females in the same region will be used for comparison. Results are anticipated in 2025.

On the basis of their mechanism of action, L1/2 HPV vaccines do not appear to impact preexisting infections. The FUTURE II trial demonstrated a markedly lower vaccine efficacy rate in the total randomized study population, which included individuals who were positive for HPV at baseline, compared with the per-protocol population (44% for lesions associated with HPV-16 or HPV-18, and 17% for lesions associated with any HPV type vs. 98%; see Table 2 above).[7] Additionally, an intermediate analysis of a randomized controlled trial primarily evaluating the efficacy of the HPV-16/18 vaccine in preventing infection found no effect on viral clearance rates in women aged 18 to 25 years who were positive at the time of study enrollment.[13]

The type-specific vaccines, if successful in preventing invasive cancer, will offer protection for only a subset of cases, the proportion of which will vary worldwide.[14] Using data from a multicenter case-control study conducted in 25 countries, it was estimated that a vaccine containing the seven most common HPV types could prevent 87% of cervical cancers worldwide. A vaccine with the two most common strains, HPV-16 and HPV-18, would prevent 71% of cervical cancers worldwide.[14]

There is growing evidence of population-level impacts and herd immunity with HPV vaccination. There are data that explore the impact of national HPV vaccination programs and report on vaccine effectiveness. These data come from studies conducted in different countries throughout the world including England, Denmark, Australia, Costa Rica, and the United States. In England, 15,459 residual genital specimens from women aged 16 to 24 years, collected for Chlamydia trachomatis screening between 2010 and 2016, were utilized for national HPV surveillance.[15] In this study, vaccine effectiveness for HPV-16/HPV-18 was 82% (95% CI, 60.6%–91.8%) for women who were vaccinated before age 15 years. Within the younger age groups, the prevalence of HPV-16/HPV-18 significantly decreased within the postvaccination period between 2010 and 2011 to 2016 from 8.2% to 1.6% in 16 to 18 year olds and from 14.0% to 1.6% in 19 to 21 year olds (compared with 17.6% and 16.9% in the prevaccination era).[15] Data from a Danish nationwide cohort study reported the dose-related effectiveness of the quadrivalent HPV vaccine.[16] In this cohort of 590,083 women aged 17 to 25 years, 215,309 (36%) women were vaccinated at age 16 years or younger, and 40,742 (19%) women received less than three doses. Cervical cancer screening rates were similar in the vaccinated and unvaccinated cohorts. In the overall cohort, there were 5,561 cases of CIN 3+ during the follow-up period. Only 5% of cases were in vaccinated women. The incidence rate was 355 cases per 100,000 person-years in unvaccinated women compared with 41 cases per 100,000 person-years in vaccinated women. The incidence rate was independent of the number of vaccine doses administered (incidence rates 40, 41, 40 cases per 100,000 person-years for 1, 2 and 3 doses, respectively).[16]

A study of cervical HPV DNA among 202 Australian women aged 18 to 24 years who were sampled between 2005 and 2007, before implementation of a national quadrivalent prophylactic HPV vaccine program, compared the results with a matched group of 1,058 women who were sampled in the postvaccination era (2010–2012). This study found an adjusted prevalence ratio (PR) among fully vaccinated women of 0.07 (95% CI, 0.04–0.14; P < .0001) for vaccine-related HPV types and a smaller but statistically significant magnitude of protection of 0.65 (95% CI, 0.43–0.96; P < .03) among unvaccinated women, suggesting herd immunity (protection of unvaccinated individuals).[17] These data strengthen previous results that suggest herd immunity in this population, manifested as a reduction in genital warts among heterosexual men, a group that includes sexual partners of vaccinated women.[18] Data also suggest cross protection against carcinogenic types that are not directly targeted by the quadrivalent vaccine but are included in the new nonvalent HPV vaccine.[17] Pooled data from the Costa Rica Vaccine Trial and PATRICIA Study showed that the AS04-adjuvanted HPV-16/HPV-18 vaccine provides additional cross protection beyond established protected types (e.g., 34/35/39/40/42/43/44/51/52/53/54/56/58/59/66/68/73/70/74; efficacy 9/9%; 95% CI, 1.7%–1.4%). This may partially explain the high efficacy of the AS04-adjuvanted HPV-16/HPV-18 vaccine against CIN 3+ (87.8%; 95% CI, 71.1%–95.7%).[19] A meta-analysis that included data from 14 high-income countries with cumulated data from more than 60 million individuals over 8 years reported an 83% decrease in prevalence of HPV-16 and HPV-18 (RR, 0.17; 95% CI, 0.11–0.25) among girls aged 13 to 19 years. There was also evidence of benefit to a more proximal cancer end point. After 5 to 9 years of HPV vaccination, decreased risk of CIN 2+ was also identified among screened girls aged 15 to 19 years (RR, 0.49; 95% CI, 0.42–0.58), and among women aged 20 to 24 years (RR, 0.69; 95% CI, 0.57–0.84) in comparison to an increase seen among screened and mostly unvaccinated women aged 25 to 29 years (RR, 1.19; 95% CI, 1.06–1.32) and aged 30 to 39 years (RR, 1.23; 95% CI, 1.13–1.34).[20]

Data from the National Health and Nutrition Examination Survey (NHANES) from 2003 to 2018 demonstrated an increasing impact of the HPV vaccination program and herd protection in the United States.[21] Overall, the data demonstrated an increase in HPV vaccination coverage among sexually experienced females and males. Importantly, vaccination before age 15 years also increased from 2011 to 2014 and from 2015 to 2018 in both females (27.2%, 48.6%, respectively) and males (18.6%, 48.7%, respectively). From 2015 to 2018, the 4-valent HPV (4vHPV)-type prevalence among sexually experience females aged 14 to 24 years was 85% overall, 90% in vaccinated females, and 74% in unvaccinated females. Estimates of the vaccine’s effectiveness and its impact among vaccinated females were similar from 2007 to 2010 (64% and 61%, respectively) and from 2011 to 2014 (84% and 89%, respectively). However, in 2015 to 2018, these statistics diverged (60% and 90%, respectively). This indicates that as herd protection increases and prevalence among unvaccinated individuals decreases, vaccine effectiveness can be difficult to estimate (1-prevalence ratio between vaccinated and unvaccinated individuals x 100). In 2013 to 2016, the prevalence of 4vHPV types was 1.8% in sexually experienced males who were vaccinated and 3.5% in sexually experienced males who were unvaccinated (PR, 0.49; 95% CI, 0.11–2.20), resulting in an estimated vaccine effectiveness of 51%. Significant declines were not observed in non–4vHPV-type prevalence for females or males. Although notable limitations of this survey study included self-report of HPV vaccine and dose, small sample sizes, and estimates of the impact and effectiveness based on history of at least one vaccine dose, this nationally representative data reflects an increasing impact of the U.S. vaccination program and herd protection.

Association of HPV vaccination with reduced incidence of invasive cervical cancer

In a nationwide population-based cohort study of the impact of the national vaccination program in Sweden using quadrivalent vaccine, more than 1.67 million women aged 10 to 30 years with no previous history of HPV vaccination were followed through the national registry using individual person linkage.[22] The cumulative risk of cervical cancer by age 30 years was 47 cases per 100,000 in vaccinated women, compared with 94 cases per 100,000 in unvaccinated women (incidence rate ratio [IRR], 0.51; 95% CI, 0.32–0.82, adjusting only for age at follow-up). After adjusting for all collected potential confounding factors, the IRR for women vaccinated before age 17 years was 0.12 (95% CI, 0.00–0.34).

Use of Barrier Protection During Sexual Intercourse

Barrier methods of contraception are associated with a reduced incidence of squamous intraepithelial lesions (SIL) presumptively secondary to protection from sexually transmitted disease.[23,24] The effectiveness of condom use for the prevention of HPV infections has been evaluated in a prospective study of women aged 18 to 22 years who were virgins.[25] The number of vulvovaginal HPV infections was reduced with consistent condom use, and the HPV infection rate was 37.8 infections per 100 patient-years among women whose partners used condoms 100% of the time in the 8 months before testing, compared with 89.3 infections per 100 patient-years among women whose partners used condoms less than 5% of the time (P trend = .005). No cervical SIL were detected among women reporting 100% condom use by their partner.[25]

References
  1. Scheller NM, Pasternak B, Mølgaard-Nielsen D, et al.: Quadrivalent HPV Vaccination and the Risk of Adverse Pregnancy Outcomes. N Engl J Med 376 (13): 1223-1233, 2017. [PUBMED Abstract]
  2. Wallin KL, Wiklund F, Angström T, et al.: Type-specific persistence of human papillomavirus DNA before the development of invasive cervical cancer. N Engl J Med 341 (22): 1633-8, 1999. [PUBMED Abstract]
  3. Mao C, Koutsky LA, Ault KA, et al.: Efficacy of human papillomavirus-16 vaccine to prevent cervical intraepithelial neoplasia: a randomized controlled trial. Obstet Gynecol 107 (1): 18-27, 2006. [PUBMED Abstract]
  4. Castle PE, Schiffman M, Wheeler CM, et al.: Evidence for frequent regression of cervical intraepithelial neoplasia-grade 2. Obstet Gynecol 113 (1): 18-25, 2009. [PUBMED Abstract]
  5. Romanowski B, de Borba PC, Naud PS, et al.: Sustained efficacy and immunogenicity of the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine: analysis of a randomised placebo-controlled trial up to 6.4 years. Lancet 374 (9706): 1975-85, 2009. [PUBMED Abstract]
  6. Falcaro M, Castañon A, Ndlela B, et al.: The effects of the national HPV vaccination programme in England, UK, on cervical cancer and grade 3 cervical intraepithelial neoplasia incidence: a register-based observational study. Lancet 398 (10316): 2084-2092, 2021. [PUBMED Abstract]
  7. FUTURE II Study Group: Quadrivalent vaccine against human papillomavirus to prevent high-grade cervical lesions. N Engl J Med 356 (19): 1915-27, 2007. [PUBMED Abstract]
  8. Joura EA, Giuliano AR, Iversen OE, et al.: A 9-valent HPV vaccine against infection and intraepithelial neoplasia in women. N Engl J Med 372 (8): 711-23, 2015. [PUBMED Abstract]
  9. Kreimer AR, Struyf F, Del Rosario-Raymundo MR, et al.: Efficacy of fewer than three doses of an HPV-16/18 AS04-adjuvanted vaccine: combined analysis of data from the Costa Rica Vaccine and PATRICIA trials. Lancet Oncol 16 (7): 775-86, 2015. [PUBMED Abstract]
  10. Iversen OE, Miranda MJ, Ulied A, et al.: Immunogenicity of the 9-Valent HPV Vaccine Using 2-Dose Regimens in Girls and Boys vs a 3-Dose Regimen in Women. JAMA 316 (22): 2411-2421, 2016. [PUBMED Abstract]
  11. Kreimer AR, Sampson JN, Porras C, et al.: Evaluation of Durability of a Single Dose of the Bivalent HPV Vaccine: The CVT Trial. J Natl Cancer Inst 112 (10): 1038-1046, 2020. [PUBMED Abstract]
  12. Porras C, Tsang SH, Herrero R, et al.: Efficacy of the bivalent HPV vaccine against HPV 16/18-associated precancer: long-term follow-up results from the Costa Rica Vaccine Trial. Lancet Oncol 21 (12): 1643-1652, 2020. [PUBMED Abstract]
  13. Hildesheim A, Herrero R, Wacholder S, et al.: Effect of human papillomavirus 16/18 L1 viruslike particle vaccine among young women with preexisting infection: a randomized trial. JAMA 298 (7): 743-53, 2007. [PUBMED Abstract]
  14. Muñoz N, Bosch FX, Castellsagué X, et al.: Against which human papillomavirus types shall we vaccinate and screen? The international perspective. Int J Cancer 111 (2): 278-85, 2004. [PUBMED Abstract]
  15. Mesher D, Panwar K, Thomas SL, et al.: The Impact of the National HPV Vaccination Program in England Using the Bivalent HPV Vaccine: Surveillance of Type-Specific HPV in Young Females, 2010-2016. J Infect Dis 218 (6): 911-921, 2018. [PUBMED Abstract]
  16. Verdoodt F, Dehlendorff C, Kjaer SK: Dose-related Effectiveness of Quadrivalent Human Papillomavirus Vaccine Against Cervical Intraepithelial Neoplasia: A Danish Nationwide Cohort Study. Clin Infect Dis 70 (4): 608-614, 2020. [PUBMED Abstract]
  17. Tabrizi SN, Brotherton JM, Kaldor JM, et al.: Assessment of herd immunity and cross-protection after a human papillomavirus vaccination programme in Australia: a repeat cross-sectional study. Lancet Infect Dis 14 (10): 958-66, 2014. [PUBMED Abstract]
  18. Donovan B, Franklin N, Guy R, et al.: Quadrivalent human papillomavirus vaccination and trends in genital warts in Australia: analysis of national sentinel surveillance data. Lancet Infect Dis 11 (1): 39-44, 2011. [PUBMED Abstract]
  19. Tota JE, Struyf F, Hildesheim A, et al.: Efficacy of AS04-Adjuvanted Vaccine Against Human Papillomavirus (HPV) Types 16 and 18 in Clearing Incident HPV Infections: Pooled Analysis of Data From the Costa Rica Vaccine Trial and the PATRICIA Study. J Infect Dis 223 (9): 1576-1581, 2021. [PUBMED Abstract]
  20. Drolet M, Bénard É, Pérez N, et al.: Population-level impact and herd effects following the introduction of human papillomavirus vaccination programmes: updated systematic review and meta-analysis. Lancet 394 (10197): 497-509, 2019. [PUBMED Abstract]
  21. Rosenblum HG, Lewis RM, Gargano JW, et al.: Human Papillomavirus Vaccine Impact and Effectiveness Through 12 Years After Vaccine Introduction in the United States, 2003 to 2018. Ann Intern Med 175 (7): 918-926, 2022. [PUBMED Abstract]
  22. Lei J, Ploner A, Elfström KM, et al.: HPV Vaccination and the Risk of Invasive Cervical Cancer. N Engl J Med 383 (14): 1340-1348, 2020. [PUBMED Abstract]
  23. Parazzini F, Negri E, La Vecchia C, et al.: Barrier methods of contraception and the risk of cervical neoplasia. Contraception 40 (5): 519-30, 1989. [PUBMED Abstract]
  24. Hildesheim A, Brinton LA, Mallin K, et al.: Barrier and spermicidal contraceptive methods and risk of invasive cervical cancer. Epidemiology 1 (4): 266-72, 1990. [PUBMED Abstract]
  25. Winer RL, Hughes JP, Feng Q, et al.: Condom use and the risk of genital human papillomavirus infection in young women. N Engl J Med 354 (25): 2645-54, 2006. [PUBMED Abstract]

Latest Updates to This Summary (04/18/2025)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Incidence and Mortality

Updated statistics with estimated new cases and deaths for 2025 (cited American Cancer Society as reference 1).

This summary is written and maintained by the PDQ Screening and Prevention Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® Cancer Information for Health Professionals pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about cervical cancer prevention. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Screening and Prevention Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

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PDQ® Screening and Prevention Editorial Board. PDQ Cervical Cancer Prevention. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /types/cervical/hp/cervical-prevention-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389433]

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Cervical Cancer Treatment (PDQ®)–Health Professional Version

Cervical Cancer Treatment (PDQ®)–Health Professional Version

General Information About Cervical Cancer

Cervical cancer is relatively rare but is diagnosed most frequently in women aged 35 to 44 years.[1] It is the fourth most common cancer in women worldwide for both incidence and mortality, with 661,021 new cases and 348,189 deaths in 2022.[2] Most cases of cervical cancer are preventable with routine screening and treatment of precancerous lesions. As a result, most cervical cancer cases are diagnosed in women who live in regions with inadequate screening protocols.

Incidence and Mortality

Estimated new cases and deaths from cervical (uterine cervix) cancer in the United States in 2025:[3]

  • New cases: 13,360.
  • Deaths: 4,320.

Anatomy

The uterine cervix is contiguous with the uterine body, and it acts as the opening to the body of the uterus. The uterine cervix is a cylindrical, fibrous organ that is an average of 3 to 4 cm in length. The portio of the cervix is visible on vaginal inspection. The opening of the cervix is termed the external os. The os is the beginning of the endocervical canal, which forms the inner aspect of the cervix. At the upper aspect of the endocervical canal is the internal os, a narrowing of the endocervical canal. The narrowing marks the transition from the cervix to the uterine body. The endocervical canal beyond the internal os is termed the endometrial canal.

The cervix is lined by two types of epithelial cells: squamous cells at the outer aspect and columnar, glandular cells along the inner canal. The transition between squamous cells and columnar cells is an area termed the squamocolumnar junction. Most precancerous and cancerous changes arise in this zone.

EnlargeAnatomy of the female reproductive system; drawing shows the uterus, myometrium (muscular outer layer of the uterus), endometrium (inner lining of the uterus), ovaries, fallopian tubes, cervix, and vagina.

Pathogenesis

Cervical carcinoma begins at the squamocolumnar junction. It can involve the outer squamous cells, inner glandular cells, or both. The precursor lesion is dysplasia: cervical intraepithelial neoplasia (CIN) or adenocarcinoma in situ, which can subsequently become invasive cancer. This process can be quite slow. Longitudinal studies have shown that in patients with untreated in situ cervical cancer, 30% to 70% will develop invasive carcinoma over a period of 10 to 12 years. However, in about 10% of patients, lesions can progress from in situ to invasive in less than 1 year. As it becomes invasive, the tumor breaks through the basement membrane and invades the cervical stroma. Extension of the tumor in the cervix may ultimately manifest as ulceration, exophytic tumor, or extensive infiltration of underlying tissue, including the bladder or rectum.

Risk Factors

Increasing age is the most important risk factor for most cancers. The primary risk factor for cervical cancer is human papillomavirus (HPV) infection.[4–7]

Other risk factors for cervical cancer include the following:

  • High parity and HPV infection.[8]
  • Smoking cigarettes and HPV infection.[9]
  • Long-term use of oral contraceptives and HPV infection.[10,11]
  • Immunosuppression.[12,13]
  • Having first sexual encounter at a young age.[14]
  • High number of sexual partners.[14]
  • Exposure to diethylstilbestrol (DES) in utero.[15]

Human papillomavirus (HPV) infection

HPV infection is a necessary step in the development of virtually all precancerous and cancerous lesions. Epidemiological studies convincingly demonstrate that the major risk factor for development of preinvasive or invasive carcinoma of the cervix is HPV infection, far outweighing other known risk factors.

More than 6 million women in the United States are estimated to be infected with HPV. Transient HPV infection is common, particularly in young women,[16] while cervical cancer is rare. The persistence of an HPV infection leads to increased risk of developing precancerous and cancerous lesions.[17,18]

The strain of HPV infection is also important in conferring risk. Multiple subtypes of HPV infect humans; subtypes 16 and 18 have been most closely associated with high-grade dysplasia and cancer. Studies suggest that acute infection with HPV types 16 and 18 conferred an 11-fold to 16.9-fold risk of rapid development of high-grade CIN.[19–21] Further studies have shown that infection with either HPV 16 or 18 is more predictive than cytological screening of high-grade CIN or greater disease, and that the predictive ability is seen for up to 18 years after the initial test.[22–24]

There are two commercially available vaccines that target anogenital-related strains of HPV. The vaccines are directed toward HPV-naïve adolescents and young adults. Although penetration of the vaccine has been moderate, significant decreases in HPV-related diseases have been documented.[25] For more information, see Cervical Cancer Prevention.

Clinical Features

Early cervical cancer may not cause noticeable signs or symptoms.

Possible signs and symptoms of cervical cancer include:

  • Vaginal bleeding.
  • Unusual vaginal discharge.
  • Pelvic pain.
  • Dyspareunia.
  • Postcoital bleeding.

Diagnosis

The following procedures may be used to diagnose cervical cancer:

  • History and physical examination.
  • Pelvic examination.
  • Cervical cytology (Pap smear).
  • HPV test.
  • Endocervical curettage.
  • Colposcopy.
  • Biopsy.

HPV testing

Cervical cytology (Pap smear) has been the mainstay of cervical cancer screening since its introduction. However, molecular techniques for the identification of HPV DNA are highly sensitive and specific. Current screening options include:

  • Cytology alone.
  • Cytology and HPV testing.

HPV testing is suggested when it is likely to successfully triage patients into low- and high-risk groups for a high-grade dysplasia or greater lesion.

HPV DNA tests are unlikely to separate patients with low-grade squamous intraepithelial lesions into those who do and those who do not need further evaluation. A study of 642 women found that 83% had one or more tumorigenic HPV types when cervical cytological specimens were assayed by a sensitive (hybrid capture) technique.[26] The authors of the study and an accompanying editorial concluded that using HPV DNA testing in this setting does not add sufficient information to justify its cost.[26]

HPV DNA testing has proven useful in triaging patients with atypical squamous cells of undetermined significance to colposcopy and has been integrated into current screening guidelines.[26–28]

Other studies show that patients with low-risk cytology and high-risk HPV infection with types 16, 18, and 31 are more likely to have CIN or microinvasive histopathology on biopsy.[19,29–31] One method has also shown that integration of HPV types 16 and 18 into the genome, leading to transcription of viral and cellular messages, may predict patients who are at greater risk of high-grade dysplasia and invasive cancer.[32]

For women older than 30 years who are more likely to have persistent HPV infection, HPV typing can successfully triage women into high- and low-risk groups for CIN 3 or worse disease. In this age group, HPV DNA testing is more effective than cytology alone in predicting the risk of developing CIN 3 or worse.[33] Other studies have shown the effectiveness of a primary HPV DNA–screening strategy with cytology triage over the previously used cytology-based screening algorithms.[34,35]

Prognostic Factors

The prognosis for patients with cervical cancer is markedly affected by the extent of disease at the time of diagnosis. More than 90% of cervical cancer cases can be detected early by using the Pap test and HPV testing.[36] Pap and HPV testing are not performed on approximately 33% of eligible women, which results in a higher-than-expected death rate.

Clinical stage

Clinical stage as a prognostic factor is supplemented by several gross and microscopic pathological findings in surgically treated patients.

Evidence (clinical stage and other findings):

In a large, surgicopathological staging study of patients with clinical stage IB disease reported by the Gynecologic Oncology Group (GOG) GOG-49, the factors that most prominently predicted lymph node metastases and a decrease in disease-free survival were capillary-lymphatic space involvement by tumor, increasing tumor size, and increasing depth of stromal invasion, with the latter being the most important and reproducible.[37,38]

In a study of 1,028 patients treated with radical surgery, survival rates correlated more consistently with tumor volume (as determined by precise volumetry of the tumor) than with clinical or histological stage.[39]

A multivariate analysis of prognostic variables in 626 patients with locally advanced disease (primarily stages II, III, and IV) studied by the GOG identified the following variables that were significant for progression-free interval and survival:[40]

  • Periaortic and pelvic lymph node status.
  • Tumor size.
  • Patient age.
  • Performance status.
  • Bilateral disease.
  • Clinical stage.

The study confirmed the overriding importance of positive periaortic nodes and suggested further evaluation of these nodes in locally advanced cervical cancer. The status of the pelvic nodes was important only if the periaortic nodes were negative. This was also true for tumor size.

It is controversial whether adenocarcinoma of the cervix carries a significantly worse prognosis than squamous cell carcinoma of the cervix.[41] Several population-based and retrospective studies showed a worse outcome for patients with adenocarcinoma, with an increase in distant metastasis compared with those with squamous histology.[42–45] Reports conflict about the effect of adenosquamous cell type on outcome.[46,47] One report showed that approximately 25% of apparent squamous tumors have demonstrable mucin production and behave more aggressively than their pure squamous counterparts, suggesting that any adenomatous differentiation may confer a negative prognosis.[48]

In a large series of cervical cancer patients treated by radiation therapy, the incidence of distant metastases (most frequently to the lung, abdominal cavity, liver, and gastrointestinal tract) was shown to increase as the stage of disease increased, from 3% in stage IA to 75% in stage IVA.[49] A multivariate analysis of factors influencing the incidence of distant metastases showed stage, endometrial extension of tumor, and pelvic tumor control to be significant indicators of distant dissemination.[49]

GOG studies have indicated that prognostic factors vary depending on whether clinical or surgical staging is used and with different treatments. Delay in radiation delivery completion is associated with poorer progression-free survival when clinical staging is used. Stage, tumor grade, race, and age are uncertain prognostic factors in studies using chemoradiation.[50]

Other prognostic factors

Other prognostic factors that may affect outcome include:

  • HIV status: Women with HIV have more aggressive and advanced disease and a poorer prognosis.[51]
  • MYC overexpression: A study of patients with known invasive squamous carcinoma of the cervix found that overexpression of the MYC oncogene was associated with a poorer prognosis.[52]
  • Number of cells in S phase: The number of cells in S phase may also have prognostic significance in early cervical carcinoma.[53]
  • HPV-18 DNA: HPV-18 DNA is an independent adverse molecular prognostic factor. Two studies have shown a worse outcome when HPV-18 was identified in cervical cancers of patients undergoing radical hysterectomy and pelvic lymphadenectomy.[54,55]
  • A polymorphism in the Gamma-glutamyl hydrolase enzyme, which is related to folate metabolism, has been shown to decrease response to cisplatin, and as a result is associated with poorer outcomes.[56]

Follow-Up After Treatment

High-quality studies are lacking, and the optimal follow-up for patients after treatment for cervical cancer is unknown. Retrospective studies have shown that cancer recurrence is most likely within the first 2 years.[57] As a result, most guidelines suggest routine follow-up every 3 to 4 months for the first 2 years, followed by evaluations every 6 months. Most recurrences are diagnosed secondary to new patient symptoms and signs,[58,59] and the usefulness of routine testing, including a Pap smear and chest x-ray, is unclear.

Follow-up should be centered around a thorough history and physical examination with a careful review of symptoms. Imaging should be reserved for evaluation of a positive finding. Patients should be asked about possible warning signs, including:

  • Abdominal pain.
  • Back pain.
  • Painful or swollen leg.
  • Problems with urination.
  • Cough.
  • Fatigue.

The follow-up examination should also screen for possible complications of previous treatment because of the multiple modalities (surgery, chemotherapy, and radiation) that patients often undergo during their treatment.

References
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  29. Tabbara S, Saleh AD, Andersen WA, et al.: The Bethesda classification for squamous intraepithelial lesions: histologic, cytologic, and viral correlates. Obstet Gynecol 79 (3): 338-46, 1992. [PUBMED Abstract]
  30. Cuzick J, Terry G, Ho L, et al.: Human papillomavirus type 16 in cervical smears as predictor of high-grade cervical intraepithelial neoplasia [corrected] Lancet 339 (8799): 959-60, 1992. [PUBMED Abstract]
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  35. Castle PE, Stoler MH, Wright TC, et al.: Performance of carcinogenic human papillomavirus (HPV) testing and HPV16 or HPV18 genotyping for cervical cancer screening of women aged 25 years and older: a subanalysis of the ATHENA study. Lancet Oncol 12 (9): 880-90, 2011. [PUBMED Abstract]
  36. The 1988 Bethesda System for reporting cervical/vaginal cytological diagnoses. National Cancer Institute Workshop. JAMA 262 (7): 931-4, 1989. [PUBMED Abstract]
  37. Delgado G, Bundy B, Zaino R, et al.: Prospective surgical-pathological study of disease-free interval in patients with stage IB squamous cell carcinoma of the cervix: a Gynecologic Oncology Group study. Gynecol Oncol 38 (3): 352-7, 1990. [PUBMED Abstract]
  38. Zaino RJ, Ward S, Delgado G, et al.: Histopathologic predictors of the behavior of surgically treated stage IB squamous cell carcinoma of the cervix. A Gynecologic Oncology Group study. Cancer 69 (7): 1750-8, 1992. [PUBMED Abstract]
  39. Burghardt E, Baltzer J, Tulusan AH, et al.: Results of surgical treatment of 1028 cervical cancers studied with volumetry. Cancer 70 (3): 648-55, 1992. [PUBMED Abstract]
  40. Stehman FB, Bundy BN, DiSaia PJ, et al.: Carcinoma of the cervix treated with radiation therapy. I. A multi-variate analysis of prognostic variables in the Gynecologic Oncology Group. Cancer 67 (11): 2776-85, 1991. [PUBMED Abstract]
  41. Steren A, Nguyen HN, Averette HE, et al.: Radical hysterectomy for stage IB adenocarcinoma of the cervix: the University of Miami experience. Gynecol Oncol 48 (3): 355-9, 1993. [PUBMED Abstract]
  42. Park JY, Kim DY, Kim JH, et al.: Outcomes after radical hysterectomy in patients with early-stage adenocarcinoma of uterine cervix. Br J Cancer 102 (12): 1692-8, 2010. [PUBMED Abstract]
  43. Eifel PJ, Burke TW, Morris M, et al.: Adenocarcinoma as an independent risk factor for disease recurrence in patients with stage IB cervical carcinoma. Gynecol Oncol 59 (1): 38-44, 1995. [PUBMED Abstract]
  44. Lee YY, Choi CH, Kim TJ, et al.: A comparison of pure adenocarcinoma and squamous cell carcinoma of the cervix after radical hysterectomy in stage IB-IIA. Gynecol Oncol 120 (3): 439-43, 2011. [PUBMED Abstract]
  45. Galic V, Herzog TJ, Lewin SN, et al.: Prognostic significance of adenocarcinoma histology in women with cervical cancer. Gynecol Oncol 125 (2): 287-91, 2012. [PUBMED Abstract]
  46. Gallup DG, Harper RH, Stock RJ: Poor prognosis in patients with adenosquamous cell carcinoma of the cervix. Obstet Gynecol 65 (3): 416-22, 1985. [PUBMED Abstract]
  47. Yazigi R, Sandstad J, Munoz AK, et al.: Adenosquamous carcinoma of the cervix: prognosis in stage IB. Obstet Gynecol 75 (6): 1012-5, 1990. [PUBMED Abstract]
  48. Bethwaite P, Yeong ML, Holloway L, et al.: The prognosis of adenosquamous carcinomas of the uterine cervix. Br J Obstet Gynaecol 99 (9): 745-50, 1992. [PUBMED Abstract]
  49. Fagundes H, Perez CA, Grigsby PW, et al.: Distant metastases after irradiation alone in carcinoma of the uterine cervix. Int J Radiat Oncol Biol Phys 24 (2): 197-204, 1992. [PUBMED Abstract]
  50. Monk BJ, Tian C, Rose PG, et al.: Which clinical/pathologic factors matter in the era of chemoradiation as treatment for locally advanced cervical carcinoma? Analysis of two Gynecologic Oncology Group (GOG) trials. Gynecol Oncol 105 (2): 427-33, 2007. [PUBMED Abstract]
  51. Maiman M, Fruchter RG, Guy L, et al.: Human immunodeficiency virus infection and invasive cervical carcinoma. Cancer 71 (2): 402-6, 1993. [PUBMED Abstract]
  52. Bourhis J, Le MG, Barrois M, et al.: Prognostic value of c-myc proto-oncogene overexpression in early invasive carcinoma of the cervix. J Clin Oncol 8 (11): 1789-96, 1990. [PUBMED Abstract]
  53. Strang P, Eklund G, Stendahl U, et al.: S-phase rate as a predictor of early recurrences in carcinoma of the uterine cervix. Anticancer Res 7 (4B): 807-10, 1987 Jul-Aug. [PUBMED Abstract]
  54. Burger RA, Monk BJ, Kurosaki T, et al.: Human papillomavirus type 18: association with poor prognosis in early stage cervical cancer. J Natl Cancer Inst 88 (19): 1361-8, 1996. [PUBMED Abstract]
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  57. Ansink A, de Barros Lopes A, Naik R, et al.: Recurrent stage IB cervical carcinoma: evaluation of the effectiveness of routine follow up surveillance. Br J Obstet Gynaecol 103 (11): 1156-8, 1996. [PUBMED Abstract]
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Cellular Classification of Cervical Cancer

Squamous cell (epidermoid) carcinoma makes up approximately 90% of cervical cancers, and adenocarcinoma makes up approximately 10% of cervical cancers. Adenosquamous and small cell carcinomas are relatively rare. Primary sarcomas of the cervix and primary and secondary malignant lymphomas of the cervix have also been reported.

Stage Information for Cervical Cancer

Carcinoma of the cervix can spread via local invasion, the regional lymphatics, or bloodstream. Tumor dissemination is generally a function of the extent and invasiveness of the local lesion. While cancer of the cervix generally progresses in an orderly manner, occasionally a small tumor with distant metastasis is seen. For this reason, patients must be carefully evaluated for metastatic disease.

Pretreatment surgical staging is the most accurate method to determine the extent of disease,[1] but there is little evidence to demonstrate overall improved survival with routine surgical staging; the staging is usually performed only as part of a clinical trial. Pretreatment surgical staging in bulky but locally curable disease may be indicated in select cases when a nonsurgical search for metastatic disease is negative. If abnormal nodes are detected by computed tomography (CT) scan or lymphangiography, fine-needle aspiration should be negative before a surgical staging procedure is performed.

Tests and procedures to evaluate the extent of the disease include:

  • CT scan.
  • Positron emission tomography scan.
  • Cystoscopy.
  • Laparoscopy.
  • Chest x-ray.
  • Ultrasonography.[2]
  • Magnetic resonance imaging.[2]

FIGO Stage Groupings and Definitions

The Fédération Internationale de Gynécologie et d’Obstétrique (FIGO) and the American Joint Committee on Cancer have designated staging to define cervical cancer; the FIGO system is most commonly used.[3,4]

Table 1. Definitions of FIGO Stage Ia
Stage Description Illustration
FIGO = Fédération Internationale de Gynécologie et d’Obstétrique.
aAdapted from FIGO Committee for Gynecologic Oncology.[3]
bImaging and pathology can be used, when available, to supplement clinical findings with respect to tumor size and extent, in all stages. Pathological findings supersede imaging and clinical findings.
cThe involvement of vascular/lymphatic spaces should not change the staging. The lateral extent of the lesion is no longer considered.
I The carcinoma is strictly confined to the cervix (extension to the corpus should be disregarded).  
IA Invasive carcinoma that can be diagnosed only by microscopy, with maximum depth of invasion ≤5 mm.b
EnlargeStage IA1 and IA2 cervical cancer; drawing shows a cross-section of the cervix and vagina. An inset shows cancer cells in the cervix that can only be seen under a microscope. The cancer in stage IA1 is not more than 3 mm deep. The cancer in stage IA2 is more than 3 but not more than 5 mm deep.
–IA1 –Measured stromal invasion ≤3 mm in depth.  
–IA2 –Measured stromal invasion >3 mm and ≤5 mm in depth.
IB Invasive carcinoma with measured deepest invasion >5 mm (greater than stage IA); lesion limited to the cervix uteri with size measured by maximum tumor diameter.c
–IB1 –Invasive carcinoma >5 mm depth of stromal invasion and ≤2 cm in greatest dimension.
EnlargeStage IB1 cervical cancer; drawing shows a cross-section of the cervix and vagina and cancer in the cervix that is smaller than 2 cm. An inset shows cancer that is more than 5 mm deep. Also shown is a 2-cm scale that shows 10 mm is equal to 1 cm.
–IB2 –Invasive carcinoma >2 cm and ≤4 cm in greatest dimension.
EnlargeStage IB2 and IB3 cervical cancer; drawing shows two cross-sections of the cervix and vagina. The drawing on the left shows stage IB2 cancer in the cervix that is larger than 2 cm but not larger than 4 cm. The drawing on the right shows stage IB3 cancer in the cervix that is larger than 4 cm.
–IB3 –Invasive carcinoma >4 cm in greatest dimension.
Table 2. Definitions of FIGO Stage IIa
Stage Description Illustration
FIGO = Fédération Internationale de Gynécologie et d’Obstétrique.
aAdapted from FIGO Committee for Gynecologic Oncology.[3]
II The cervical carcinoma invades beyond the uterus but has not extended onto the lower third of the vagina or to the pelvic wall.
EnlargeStage II cervical cancer; drawing shows two cross-sections of the uterus, cervix, and vagina. The drawing on the left shows stages IIA1 and IIA2 cancer in the cervix that is 4 cm and has spread to the upper two-thirds of the vagina. The drawing on the right shows stage IIB cancer that has spread from the cervix to the tissue around the uterus.
IIA Involvement limited to the upper two-thirds of the vagina without parametrial involvement.  
–IIA1 –Invasive carcinoma ≤4 cm in greatest dimension.
–IIA2 –Invasive carcinoma >4 cm in greatest dimension.
IIB With parametrial involvement but not up to the pelvic wall.
Table 3. Definitions of FIGO Stage IIIa
Stage Description Illustration
FIGO = Fédération Internationale de Gynécologie et d’Obstétrique.
aAdapted from FIGO Committee for Gynecologic Oncology.[3]
bIsolated tumor cells do not change the stage, but their presence should be recorded.
cAdding notation of r (imaging) and p (pathology) to indicate the findings that are used to allocate the case to stage IIIC. For example, if imaging indicates pelvic lymph node metastasis, the stage allocation would be stage IIIC1r; if confirmed by pathological findings, it would be stage IIIC1p. The type of imaging modality or pathology technique used should always be documented. When in doubt, the lower staging should be assigned.
III The carcinoma involves the lower third of the vagina and/or extends to the pelvic wall and/or causes hydronephrosis or nonfunctioning kidney and/or involves pelvic and/or para-aortic lymph nodes.  
IIIA Carcinoma involves the lower third of the vagina, with no extension to the pelvic wall.
EnlargeStage IIIA cervical cancer; drawing shows a cross-section of the cervix and vagina. Cancer is shown in the cervix and in the full length of the vagina.
IIIB Extension to the pelvic wall and/or hydronephrosis or nonfunctioning kidney (unless known to be due to another cause).
EnlargeStage IIIB cervical cancer; drawing shows cancer in the cervix and pelvic wall. Also shown is cancer blocking the right ureter and an enlarged right ureter and right kidney. The uterus, bladder, and vagina are also shown.
IIIC Involvement of pelvic and/or para-aortic lymph nodes (including micrometastases)b, irrespective of tumor size and extent (with r and p notations).c
EnlargeStage IIIC cervical cancer; drawing shows stage IIIC1 cancer that has spread from the cervix to lymph nodes in the pelvis and stage IIIC2 cancer that has spread from the cervix to lymph nodes in the abdomen near the aorta.
–IIIC1 –Pelvic lymph node metastasis only.  
–IIIC2 –Para-aortic lymph node metastasis.
Table 4. Definitions of FIGO Stage IVa
Stage Description Illustration
FIGO = Fédération Internationale de Gynécologie et d’Obstétrique.
aAdapted from FIGO Committee for Gynecologic Oncology.[3]
IV The carcinoma has extended beyond the true pelvis or has involved (biopsy proven) the mucosa of the bladder or rectum. A bullous edema, as such, does not permit a case to be allotted to stage IV.  
IVA Spread of the growth to adjacent pelvic organs.
EnlargeStage IVA cervical cancer; drawing and inset show cancer that has spread from the cervix to the bladder and rectal wall.
IVB Spread to distant organs.
EnlargeStage IVB cervical cancer; drawing shows other parts of the body where cervical cancer may spread, including the lymph nodes, lung, liver, and bone. An inset shows cancer cells spreading from the cervix, through the blood and lymph system, to another part of the body where metastatic cancer has formed.
References
  1. Gold MA, Tian C, Whitney CW, et al.: Surgical versus radiographic determination of para-aortic lymph node metastases before chemoradiation for locally advanced cervical carcinoma: a Gynecologic Oncology Group Study. Cancer 112 (9): 1954-63, 2008. [PUBMED Abstract]
  2. Epstein E, Testa A, Gaurilcikas A, et al.: Early-stage cervical cancer: tumor delineation by magnetic resonance imaging and ultrasound – a European multicenter trial. Gynecol Oncol 128 (3): 449-53, 2013. [PUBMED Abstract]
  3. Bhatla N, Aoki D, Sharma DN, et al.: Cancer of the cervix uteri: 2021 update. Int J Gynaecol Obstet 155 (Suppl 1): 28-44, 2021. [PUBMED Abstract]
  4. Olawaiye AB, Mutch DG, Bhosale P, et al.: Cervix uteri. In: Goodman KA, Gollub M, Eng C, et al.: AJCC Cancer Staging System. Version 9. American Joint Committee on Cancer; American College of Surgeons, 2020.

Treatment Option Overview for Cervical Cancer

Patterns-of-care studies clearly demonstrate the negative prognostic effect of increasing tumor volume and spread pattern.[1] Treatment, therefore, may vary within each stage as the individual stages are currently defined by Fédération Internationale de Gynécologie et d’Obstétrique (FIGO).

Table 5. Treatment Options for Cervical Cancer
Stage (FIGO Staging Criteria) Treatment Options
FIGO = Fédération Internationale de Gynécologie et d’Obstétrique.
In situ carcinoma of the cervix (this stage is not recognized by FIGO) Conization
Hysterectomy for postreproductive patients
Internal radiation therapy for medically inoperable patients
Stage IA cervical cancer Conization
Total hysterectomy
Modified radical hysterectomy with lymphadenectomy
Radical trachelectomy
Intracavitary radiation therapy
Stages IB, IIA cervical cancer Radiation therapy with concomitant chemotherapy
Radical hysterectomy and bilateral pelvic lymphadenectomy with or without total pelvic radiation therapy plus chemotherapy
Radical trachelectomy
Radiation therapy alone
Immunotherapy
Neoadjuvant chemotherapy (under clinical evaluation)
Intensity-modulated radiation therapy (under clinical evaluation)
Stages IIB, III, and IVA cervical cancer Radiation therapy with concomitant chemotherapy
Interstitial brachytherapy
Neoadjuvant chemotherapy
Immunotherapy
Stage IVB and recurrent cervical cancer Immunotherapy
Radiation therapy and chemotherapy
Palliative chemotherapy and other systemic therapy
Pelvic exenteration
Phase I and phase II clinical trials of new anticancer drugs

Chemoradiation Therapy

Five randomized phase III trials have shown an overall survival advantage for cisplatin-based therapy given concurrently with radiation therapy,[2–6] while one trial examining this regimen demonstrated no benefit.[7] The patient populations in these studies included women with FIGO stages IB2 to IVA cervical cancer treated with primary radiation therapy and women with FIGO stages I to IIA disease who were found to have poor prognostic factors (metastatic disease in pelvic lymph nodes, parametrial disease, or positive surgical margins) at the time of primary surgery.

  • Although the positive trials vary in terms of the stage of disease, dose of radiation, and schedule of cisplatin and radiation, the trials demonstrate significant survival benefit for this combined approach. The risk of death from cervical cancer was decreased by 30% to 50% with the use of concurrent chemoradiation therapy.
  • Based on these results, strong consideration should be given to the incorporation of concurrent cisplatin-based chemotherapy with radiation therapy in women who require radiation therapy for treatment of cervical cancer.[2–6]

Other studies have validated these results.[8–10]

Fluorouracil dosing

The DPYD gene encodes an enzyme that catabolizes pyrimidines and fluoropyrimidines, like capecitabine and fluorouracil. An estimated 1% to 2% of the population has germline pathogenic variants in DPYD, which lead to reduced DPD protein function and an accumulation of pyrimidines and fluoropyrimidines in the body.[11,12] Patients with the DPYD*2A variant who receive fluoropyrimidines may experience severe, life-threatening toxicities that are sometimes fatal. Many other DPYD variants have been identified, with a range of clinical effects.[11–13] Fluoropyrimidine avoidance or a dose reduction of 50% may be recommended based on the patient’s DPYD genotype and number of functioning DPYD alleles.[14–16] DPYD genetic testing costs less than $200, but insurance coverage varies due to a lack of national guidelines.[17] In addition, testing may delay therapy by 2 weeks, which would not be advisable in urgent situations. This controversial issue requires further evaluation.[18]

Surgery and Radiation Therapy

Surgery and radiation therapy are equally effective for early stage, small-volume disease.[19] Younger patients may benefit from surgery to preserve the ovaries and avoid vaginal atrophy and stenosis.

Therapy for patients with cancer of the cervical stump is effective and yields results that are comparable with those seen in patients with an intact uterus.[20]

References
  1. Lanciano RM, Won M, Hanks GE: A reappraisal of the International Federation of Gynecology and Obstetrics staging system for cervical cancer. A study of patterns of care. Cancer 69 (2): 482-7, 1992. [PUBMED Abstract]
  2. Whitney CW, Sause W, Bundy BN, et al.: Randomized comparison of fluorouracil plus cisplatin versus hydroxyurea as an adjunct to radiation therapy in stage IIB-IVA carcinoma of the cervix with negative para-aortic lymph nodes: a Gynecologic Oncology Group and Southwest Oncology Group study. J Clin Oncol 17 (5): 1339-48, 1999. [PUBMED Abstract]
  3. Morris M, Eifel PJ, Lu J, et al.: Pelvic radiation with concurrent chemotherapy compared with pelvic and para-aortic radiation for high-risk cervical cancer. N Engl J Med 340 (15): 1137-43, 1999. [PUBMED Abstract]
  4. Rose PG, Bundy BN, Watkins EB, et al.: Concurrent cisplatin-based radiotherapy and chemotherapy for locally advanced cervical cancer. N Engl J Med 340 (15): 1144-53, 1999. [PUBMED Abstract]
  5. Keys HM, Bundy BN, Stehman FB, et al.: Cisplatin, radiation, and adjuvant hysterectomy compared with radiation and adjuvant hysterectomy for bulky stage IB cervical carcinoma. N Engl J Med 340 (15): 1154-61, 1999. [PUBMED Abstract]
  6. Peters WA, Liu PY, Barrett RJ, et al.: Concurrent chemotherapy and pelvic radiation therapy compared with pelvic radiation therapy alone as adjuvant therapy after radical surgery in high-risk early-stage cancer of the cervix. J Clin Oncol 18 (8): 1606-13, 2000. [PUBMED Abstract]
  7. Pearcey R, Brundage M, Drouin P, et al.: Phase III trial comparing radical radiotherapy with and without cisplatin chemotherapy in patients with advanced squamous cell cancer of the cervix. J Clin Oncol 20 (4): 966-72, 2002. [PUBMED Abstract]
  8. Thomas GM: Improved treatment for cervical cancer–concurrent chemotherapy and radiotherapy. N Engl J Med 340 (15): 1198-200, 1999. [PUBMED Abstract]
  9. Rose PG, Bundy BN: Chemoradiation for locally advanced cervical cancer: does it help? J Clin Oncol 20 (4): 891-3, 2002. [PUBMED Abstract]
  10. Chemoradiotherapy for Cervical Cancer Meta-Analysis Collaboration: Reducing uncertainties about the effects of chemoradiotherapy for cervical cancer: a systematic review and meta-analysis of individual patient data from 18 randomized trials. J Clin Oncol 26 (35): 5802-12, 2008. [PUBMED Abstract]
  11. Sharma BB, Rai K, Blunt H, et al.: Pathogenic DPYD Variants and Treatment-Related Mortality in Patients Receiving Fluoropyrimidine Chemotherapy: A Systematic Review and Meta-Analysis. Oncologist 26 (12): 1008-1016, 2021. [PUBMED Abstract]
  12. Lam SW, Guchelaar HJ, Boven E: The role of pharmacogenetics in capecitabine efficacy and toxicity. Cancer Treat Rev 50: 9-22, 2016. [PUBMED Abstract]
  13. Shakeel F, Fang F, Kwon JW, et al.: Patients carrying DPYD variant alleles have increased risk of severe toxicity and related treatment modifications during fluoropyrimidine chemotherapy. Pharmacogenomics 22 (3): 145-155, 2021. [PUBMED Abstract]
  14. Amstutz U, Henricks LM, Offer SM, et al.: Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Dihydropyrimidine Dehydrogenase Genotype and Fluoropyrimidine Dosing: 2017 Update. Clin Pharmacol Ther 103 (2): 210-216, 2018. [PUBMED Abstract]
  15. Henricks LM, Lunenburg CATC, de Man FM, et al.: DPYD genotype-guided dose individualisation of fluoropyrimidine therapy in patients with cancer: a prospective safety analysis. Lancet Oncol 19 (11): 1459-1467, 2018. [PUBMED Abstract]
  16. Lau-Min KS, Varughese LA, Nelson MN, et al.: Preemptive pharmacogenetic testing to guide chemotherapy dosing in patients with gastrointestinal malignancies: a qualitative study of barriers to implementation. BMC Cancer 22 (1): 47, 2022. [PUBMED Abstract]
  17. Brooks GA, Tapp S, Daly AT, et al.: Cost-effectiveness of DPYD Genotyping Prior to Fluoropyrimidine-based Adjuvant Chemotherapy for Colon Cancer. Clin Colorectal Cancer 21 (3): e189-e195, 2022. [PUBMED Abstract]
  18. Baker SD, Bates SE, Brooks GA, et al.: DPYD Testing: Time to Put Patient Safety First. J Clin Oncol 41 (15): 2701-2705, 2023. [PUBMED Abstract]
  19. Eifel PJ, Burke TW, Delclos L, et al.: Early stage I adenocarcinoma of the uterine cervix: treatment results in patients with tumors less than or equal to 4 cm in diameter. Gynecol Oncol 41 (3): 199-205, 1991. [PUBMED Abstract]
  20. Kovalic JJ, Grigsby PW, Perez CA, et al.: Cervical stump carcinoma. Int J Radiat Oncol Biol Phys 20 (5): 933-8, 1991. [PUBMED Abstract]

Treatment of In Situ Cervical Cancer

Consensus guidelines have been issued for managing women with cervical intraepithelial neoplasia or adenocarcinoma in situ.[1] Properly treated, tumor control of in situ cervical carcinoma should be nearly 100%. Either expert colposcopic-directed biopsy or cone biopsy is required to exclude invasive disease before therapy is undertaken. A correlation between cytology and colposcopic-directed biopsy is also necessary before local ablative therapy is done. Unrecognized invasive disease treated with inadequate ablative therapy may be the most common cause of failure.[2] Failure to identify the disease, lack of correlation between the Pap smear and colposcopic findings, adenocarcinoma in situ, or extension of disease into the endocervical canal makes a laser, loop, or cold-knife conization mandatory.

The choice of treatment depends on the extent of disease and several patient factors, including age, cell type, desire to preserve fertility, and medical condition.

Treatment Options for In Situ Cervical Cancer

Treatment options for in situ cervical cancer include:

  1. Conization.
    • Cold-knife conization (scalpel).
    • Loop electrosurgical excision procedure (LEEP).[3,4]
    • Laser therapy.[5]
  2. Hysterectomy for postreproductive patients.
  3. Internal radiation therapy for medically inoperable patients.

Hysterectomy is the standard treatment for patients with adenocarcinoma in situ. The disease, which originates in the endocervical canal, may be more difficult to completely excise with a conization procedure. Conization may be offered to select patients with adenocarcinoma in situ who desire future fertility.

Conization

When the endocervical canal is involved, laser or cold-knife conization may be used for selected patients to preserve the uterus, avoid radiation therapy, and more extensive surgery.[6]

In selected cases, the outpatient LEEP may be an acceptable alternative to cold-knife conization. This procedure requires only local anesthesia and obviates the risks associated with general anesthesia for cold-knife conization.[7–9] However, controversy exists about the adequacy of LEEP as a replacement for conization; LEEP is unlikely to be sufficient for patients with adenocarcinoma in situ.[10]

Evidence (conization using LEEP):

  1. A trial comparing LEEP with cold-knife cone biopsy showed no difference in the likelihood of complete excision of dysplasia.[6]
  2. Two case reports suggested that the use of LEEP in patients with occult invasive cancer led to an inability to accurately determine depth of invasion when a focus of the cancer was transected.[11]

Hysterectomy for postreproductive patients

Hysterectomy is standard therapy for women with cervical adenocarcinoma in situ because of the location of the disease in the endocervical canal and the possibility of skip lesions in this region, making margin status a less reliable prognostic factor. However, the effect of hysterectomy compared with conservative surgical measures on mortality has not been studied. Hysterectomy may be performed for squamous cell carcinoma in situ if conization is not possible because of previous surgery, or if positive margins are noted after conization therapy. Hysterectomy is not an acceptable front-line therapy for squamous carcinoma in situ.[12]

Internal radiation therapy for medically inoperable patients

For medically inoperable patients, a single intracavitary insertion with tandem and ovoids for 5,000 mg hours (80 Gy vaginal surface dose) may be used.[13]

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References
  1. Wright TC, Massad LS, Dunton CJ, et al.: 2006 consensus guidelines for the management of women with cervical intraepithelial neoplasia or adenocarcinoma in situ. Am J Obstet Gynecol 197 (4): 340-5, 2007. [PUBMED Abstract]
  2. Shumsky AG, Stuart GC, Nation J: Carcinoma of the cervix following conservative management of cervical intraepithelial neoplasia. Gynecol Oncol 53 (1): 50-4, 1994. [PUBMED Abstract]
  3. Wright VC, Chapman W: Intraepithelial neoplasia of the lower female genital tract: etiology, investigation, and management. Semin Surg Oncol 8 (4): 180-90, 1992 Jul-Aug. [PUBMED Abstract]
  4. Bloss JD: The use of electrosurgical techniques in the management of premalignant diseases of the vulva, vagina, and cervix: an excisional rather than an ablative approach. Am J Obstet Gynecol 169 (5): 1081-5, 1993. [PUBMED Abstract]
  5. Tsukamoto N: Treatment of cervical intraepithelial neoplasia with the carbon dioxide laser. Gynecol Oncol 21 (3): 331-6, 1985. [PUBMED Abstract]
  6. Girardi F, Heydarfadai M, Koroschetz F, et al.: Cold-knife conization versus loop excision: histopathologic and clinical results of a randomized trial. Gynecol Oncol 55 (3 Pt 1): 368-70, 1994. [PUBMED Abstract]
  7. Wright TC, Gagnon S, Richart RM, et al.: Treatment of cervical intraepithelial neoplasia using the loop electrosurgical excision procedure. Obstet Gynecol 79 (2): 173-8, 1992. [PUBMED Abstract]
  8. Naumann RW, Bell MC, Alvarez RD, et al.: LLETZ is an acceptable alternative to diagnostic cold-knife conization. Gynecol Oncol 55 (2): 224-8, 1994. [PUBMED Abstract]
  9. Duesing N, Schwarz J, Choschzick M, et al.: Assessment of cervical intraepithelial neoplasia (CIN) with colposcopic biopsy and efficacy of loop electrosurgical excision procedure (LEEP). Arch Gynecol Obstet 286 (6): 1549-54, 2012. [PUBMED Abstract]
  10. Widrich T, Kennedy AW, Myers TM, et al.: Adenocarcinoma in situ of the uterine cervix: management and outcome. Gynecol Oncol 61 (3): 304-8, 1996. [PUBMED Abstract]
  11. Eddy GL, Spiegel GW, Creasman WT: Adverse effect of electrosurgical loop excision on assignment of FIGO stage in cervical cancer: report of two cases. Gynecol Oncol 55 (2): 313-7, 1994. [PUBMED Abstract]
  12. Massad LS: New guidelines on cervical cancer screening: more than just the end of annual Pap testing. J Low Genit Tract Dis 16 (3): 172-4, 2012. [PUBMED Abstract]
  13. Grigsby PW, Perez CA: Radiotherapy alone for medically inoperable carcinoma of the cervix: stage IA and carcinoma in situ. Int J Radiat Oncol Biol Phys 21 (2): 375-8, 1991. [PUBMED Abstract]

Treatment of Stage IA Cervical Cancer

Treatment Options for Stage IA1 Cervical Cancer

Treatment options for stage IA1 cervical cancer include:

  1. Conization.
  2. Total hysterectomy.

Conization

If the depth of invasion is less than 3 mm, no vascular or lymphatic channel invasion is noted, and the margins of the cone are negative, conization alone may be appropriate in patients who wish to preserve fertility.[1]

Total hysterectomy

If the depth of invasion is less than 3 mm, which is proven by cone biopsy with clear margins,[2] no vascular or lymphatic channel invasion is noted, and the frequency of lymph-node involvement is sufficiently low, lymph-node dissection at the time of hysterectomy is not required. Oophorectomy is optional and should be deferred for younger women.

Treatment Options for Stage IA2 Cervical Cancer

Treatment options for stage IA2 cervical cancer include:

  1. Modified radical hysterectomy with lymphadenectomy.
  2. Radical trachelectomy.
  3. Intracavitary radiation therapy.

Modified radical hysterectomy with lymphadenectomy

For patients with tumor invasion between 3 mm and 5 mm, modified radical hysterectomy with pelvic-node dissection has been recommended because of a reported risk of lymph-node metastasis of as much as 10%.[2] Radical hysterectomy with node dissection may also be considered for patients for whom the depth of tumor invasion was uncertain because of invasive tumor at the cone margins.

Evidence (open abdominal surgery [open] versus minimally invasive surgery [MIS]):

  1. A multicenter, international, randomized trial, the Laparoscopic Approach to Cervical Cancer (LACC [NCT00614211]) trial explored the efficacy of radical hysterectomy and staging via open abdominal surgery versus MIS for patients with early-stage cervical cancer.[3] Patients with stages IA1 (with lymphovascular space invasion), IA2, and IB1 disease and histological subtypes of squamous cell, adenocarcinoma, or adenosquamous carcinoma were eligible for inclusion. The primary end point was noninferiority of MIS compared with open surgery. The metric used was the percent of disease-free patients at 4.5 years postsurgery. The secondary end points were a comparison of the recurrence and survival rates between the two groups.

    Of the planned 740 patients, 632 were accrued when the study was stopped early because of an imbalance in deaths between the two groups. Of 631 eligible patients, 319 were assigned to MIS and 312 to open surgery.

    • The disease-free survival (DFS) rate at 4.5 years was 86% for the MIS group and 96.5% for the open-surgery group (95% confidence interval [CI], -16.4 to -4.7). At 3 years, the MIS group had a DFS rate of 91.2% versus 97.1% for the open-surgery group (hazard ratio [HR] for disease recurrence or death, 3.74; 95% CI, 1.63–8.58).
    • The MIS group also had a lower 3-year overall survival (OS) rate (93.8% vs. 99.0% for the open-surgery group; HR for death from any cause, 6.0; 95% CI, 1.77–20.30).[3][Level of evidence A1]

    The study concluded that MIS was inferior to an open abdominal approach and should not replace open surgery as the standard for patients with cervical cancer.

  2. An epidemiological study used two large U.S. databases, the National Cancer Database (NCDB) and the Surveillance, Epidemiology, and End Results (SEER) Database, and confirmed a reduction in OS in patients undergoing MIS radical hysterectomy for stage IA2 and stage IB1 cervical cancer from 2010 to 2013. Additionally, among women who underwent radical hysterectomy in the years 2000 to 2010, there was a decrease in OS after 2006, coincident with the widespread adoption of MIS for cervical cancer.[4][Level of evidence C1]

Although questions remain regarding the use of MIS radical hysterectomy for some subpopulations of good-risk patients, the data from this trial suggest that open abdominal surgery should be considered the standard of care for patients with early-stage cervical cancer who are candidates for radical hysterectomy.

Radical trachelectomy

Patients with stages IA2 to IB disease who desire future fertility may be candidates for radical trachelectomy. In this procedure, the cervix and lateral parametrial tissues are removed, and the uterine body and ovaries are maintained. Most centers use the following criteria for patient selection:

  • Desire for future pregnancy.
  • Age younger than 40 years.
  • Presumed stage IA2 to IB1 disease and a lesion size no greater than 2 cm.
  • Preoperative magnetic resonance imaging that shows a margin from the most distal edge of the tumor to the lower uterine segment.
  • Squamous, adenosquamous, or adenocarcinoma cell types.

Intraoperatively, the patient is assessed in a manner similar to a radical hysterectomy; the procedure is aborted if more advanced disease than expected is encountered. The margins of the specimen are also assessed at the time of surgery, and a radical hysterectomy is performed if inadequate margins are obtained.[5–9]

Intracavitary radiation therapy

Intracavitary radiation therapy is an option when palliative treatment is being considered for women who are not surgical candidates or who have other medical contraindications.

If the depth of invasion is less than 3 mm, no capillary lymphatic space invasion is noted, and the frequency of lymph-node involvement is sufficiently low, external-beam radiation therapy is not required. One or two insertions with tandem and ovoids for 6,500 mg to 8,000 mg hours (100–125 Gy vaginal surface dose) are recommended.[10]

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References
  1. Sevin BU, Nadji M, Averette HE, et al.: Microinvasive carcinoma of the cervix. Cancer 70 (8): 2121-8, 1992. [PUBMED Abstract]
  2. Jones WB, Mercer GO, Lewis JL, et al.: Early invasive carcinoma of the cervix. Gynecol Oncol 51 (1): 26-32, 1993. [PUBMED Abstract]
  3. Ramirez PT, Frumovitz M, Pareja R, et al.: Minimally Invasive versus Abdominal Radical Hysterectomy for Cervical Cancer. N Engl J Med 379 (20): 1895-1904, 2018. [PUBMED Abstract]
  4. Melamed A, Margul DJ, Chen L, et al.: Survival after Minimally Invasive Radical Hysterectomy for Early-Stage Cervical Cancer. N Engl J Med 379 (20): 1905-1914, 2018. [PUBMED Abstract]
  5. Covens A, Shaw P, Murphy J, et al.: Is radical trachelectomy a safe alternative to radical hysterectomy for patients with stage IA-B carcinoma of the cervix? Cancer 86 (11): 2273-9, 1999. [PUBMED Abstract]
  6. Dargent D, Martin X, Sacchetoni A, et al.: Laparoscopic vaginal radical trachelectomy: a treatment to preserve the fertility of cervical carcinoma patients. Cancer 88 (8): 1877-82, 2000. [PUBMED Abstract]
  7. Plante M, Renaud MC, Hoskins IA, et al.: Vaginal radical trachelectomy: a valuable fertility-preserving option in the management of early-stage cervical cancer. A series of 50 pregnancies and review of the literature. Gynecol Oncol 98 (1): 3-10, 2005. [PUBMED Abstract]
  8. Shepherd JH, Spencer C, Herod J, et al.: Radical vaginal trachelectomy as a fertility-sparing procedure in women with early-stage cervical cancer-cumulative pregnancy rate in a series of 123 women. BJOG 113 (6): 719-24, 2006. [PUBMED Abstract]
  9. Wethington SL, Cibula D, Duska LR, et al.: An international series on abdominal radical trachelectomy: 101 patients and 28 pregnancies. Int J Gynecol Cancer 22 (7): 1251-7, 2012. [PUBMED Abstract]
  10. Grigsby PW, Perez CA: Radiotherapy alone for medically inoperable carcinoma of the cervix: stage IA and carcinoma in situ. Int J Radiat Oncol Biol Phys 21 (2): 375-8, 1991. [PUBMED Abstract]

Treatment of Stages IB and IIA Cervical Cancer

Treatment Options for Stages IB and IIA Cervical Cancer

Treatment options for stage IB and stage IIA cervical cancer include:

  1. Radiation therapy with concomitant chemotherapy.
  2. Radical hysterectomy and bilateral pelvic lymphadenectomy with or without total pelvic radiation therapy plus chemotherapy.
  3. Radical trachelectomy.
  4. Radiation therapy alone.
  5. Immunotherapy.
  6. Neoadjuvant chemotherapy (under clinical evaluation).
  7. Intensity-modulated radiation therapy (IMRT) (under clinical evaluation).

Tumor size is an important prognostic factor to carefully evaluate when choosing optimal therapy.[1]

Either radiation therapy or radical hysterectomy and bilateral lymph–node dissection results in cure rates of 85% to 90% for women with Fédération Internationale de Gynécologie et d’Obstétrique (FIGO) stages IA2 and IB1 small-volume disease. The choice of either treatment depends on patient factors and available local expertise. A randomized trial reported identical 5-year overall survival (OS) and disease-free survival (DFS) rates when comparing radiation therapy with radical hysterectomy.[2]

In patients with stage IB2 disease, for tumors that expand the cervix more than 4 cm, the primary treatment should be concomitant chemotherapy and radiation therapy.[3]

Radiation therapy with concomitant chemotherapy

Concurrent cisplatin-based chemotherapy with radiation therapy is the standard of care for women who require radiation therapy for treatment of cervical cancer.[4–10] Radiation therapy protocols for patients with cervical cancer have historically used dosing at two anatomical points, termed point A and point B, to standardize the doses received. Point A is defined as 2 cm from the external os, and 2 cm lateral, relative to the endocervical canal. Point B is also 2 cm from the external os, and 5 cm lateral from the patient midline, relative to the bony pelvis. In general, for smaller tumors, the curative-intent dose for point A is around 70 Gy, whereas for larger tumors, the point A dose may approach 90 Gy.

Evidence (radiation with concomitant chemotherapy):

  1. Three randomized phase III trials have shown an OS advantage for cisplatin-based therapy given concurrently with radiation therapy,[4–7] while one trial that examined this regimen demonstrated no benefit.[8] The patient populations in these studies included women with FIGO stages IB2 to IVA cervical cancer treated with primary radiation therapy, and women with FIGO stages I to IIA disease who, at the time of primary surgery, were found to have poor prognostic factors, including metastatic disease in pelvic lymph nodes, parametrial disease, and positive surgical margins.
    • Although the positive trials vary somewhat in terms of the stage of disease, dose of radiation, and schedule of cisplatin and radiation, the trials demonstrate significant survival benefit for this combined approach.
    • The risk of death from cervical cancer was decreased by 30% to 50% with the use of concurrent chemoradiation therapy.
    • Other trials have confirmed these findings.[9,10]
Brachytherapy

Standard radiation therapy for cervical cancer includes brachytherapy after external-beam radiation therapy (EBRT). Although low-dose rate (LDR) brachytherapy, typically with cesium Cs 137 (137Cs), has been the traditional approach, the use of high-dose rate (HDR) therapy, typically with iridium Ir 192, is rapidly increasing. HDR brachytherapy has the advantages of eliminating radiation exposure to medical personnel, a shorter treatment time, patient convenience, and improved outpatient management. The American Brachytherapy Society has published guidelines for the use of LDR and HDR brachytherapy as components of cervical cancer treatment.[11,12]

Evidence (brachytherapy):

  1. In three randomized trials, HDR brachytherapy was comparable with LDR brachytherapy in terms of local-regional control and complication rates.[13–15][Level of evidence B1]

    Surgery after radiation therapy may be indicated for some patients with tumors confined to the cervix that respond incompletely to radiation therapy or for patients whose vaginal anatomy precludes optimal brachytherapy.[16]

Pelvic node disease

The resection of macroscopically involved pelvic nodes may improve rates of local control with postoperative radiation therapy.[17] Patients who underwent extraperitoneal lymph–node sampling had fewer bowel complications than those who had transperitoneal lymph–node sampling.[18–20] Patients with close vaginal margins (<0.5 cm) may also benefit from pelvic radiation therapy.[21]

Radical hysterectomy and bilateral pelvic lymphadenectomy with or without total pelvic radiation therapy plus chemotherapy

Women with stages IB to IIA disease may consider radical hysterectomy and bilateral pelvic lymphadenectomy.

Evidence (radical hysterectomy and bilateral pelvic lymphadenectomy with or without total pelvic radiation therapy plus chemotherapy):

  1. An Italian group randomly assigned 343 women with stage IB and IIA cervical cancer to surgery or radiation therapy. The radiation therapy included EBRT and one 137Cs LDR insertion, with a total dose to point A from 70 to 90 Gy (median 76 Gy). Patients in the surgery arm underwent a class III radical hysterectomy, pelvic lymphadenectomy, and selective, para-aortic lymph–node dissection. Adjuvant radiation therapy was given to patients with high-risk pathological features in the uterine specimen or positive lymph nodes. Adjuvant radiation therapy was EBRT to a total dose of 50.4 Gy over 5 to 6 weeks.[2][Level of evidence A1]
    • The primary outcome was 5-year OS, with secondary measures of rate of recurrence and complications. With a median follow-up of 87 months, the OS rate was the same in both groups at 83% (hazard ratio [HR], 1.2; 95% confidence interval [CI], 0.7–2.3; P = .8).
    • Complications were highest among the patients who received adjuvant radiation after surgery.
    • In general, radical hysterectomy should be avoided in patients who are likely to require adjuvant therapy.

Evidence (open abdominal surgery [open] versus minimally invasive surgery [MIS]):

  1. A multicenter, international, randomized trial, the Laparoscopic Approach to Cervical Cancer (LACC [NCT00614211]) trial, explored the efficacy of radical hysterectomy and staging via open abdominal surgery (open) versus MIS for patients with early-stage cervical cancer.[22] Patients with stages IA1 (with lymphovascular space invasion), IA2, and IB1 disease and histological subtypes of squamous cell, adenocarcinoma or adenosquamous carcinoma were eligible for inclusion. The primary end point was noninferiority of MIS compared with open surgery; the metric used was the percent of disease-free patients at 4.5 years postsurgery. The secondary end points were a comparison of the recurrence and survival rates between the two groups.

    Of the planned 740 patients, 632 were accrued when the study was stopped early because of an imbalance in deaths between the two groups. Of 631 eligible patients, 319 were assigned to MIS and 312 to open surgery.

    • The DFS rate at 4.5 years was 86% for the MIS group and 96.5% for the open-surgery group (95% CI, -16.4 to -4.7). At 3 years, the MIS group had a DFS rate of 91.2% versus 97.1% for the open-surgery group (HR for disease recurrence or death, 3.74; 95% CI, 1.63–8.58).
    • The MIS group also had a lower 3-year OS rate (93.8% vs. 99.0% for the open-surgery group; HR for death from any cause, 6.0; 95% CI, 1.77–20.30).[22][Level of evidence A1]

    The study concluded that MIS was inferior to an open abdominal approach and should not replace open surgery as the standard for cervical cancer patients.

  2. An epidemiological study using two large U.S. databases (National Cancer Database [NCDB] and Surveillance, Epidemiology, and End Results [SEER] Program database) confirmed a reduction in OS in patients undergoing MIS radical hysterectomy for stage IA2 and stage IB1 cervical cancer from 2010 to 2013. Additionally, among women who underwent radical hysterectomy in the years 2000 to 2010, there was a decrease in OS after 2006, coincident with the widespread adoption of MIS for cervical cancer.[23][Level of evidence C1]

Although questions remain regarding the use of MIS radical hysterectomy for some subpopulations of good-risk patients, the data from this trial suggest that open abdominal surgery should be considered the standard of care for patients with early-stage cervical cancer who are candidates for radical hysterectomy.

Adjuvant radiation therapy postsurgery

Based on recurrence rates in clinical trials, two classes of recurrence risk have been defined. Patients with a combination of large tumor size, lymph vascular space invasion, and deep stromal invasion in the hysterectomy specimen are deemed to have intermediate-risk disease. These patients are candidates for adjuvant EBRT.[24] Patients whose pathology shows positive margins, positive parametria, or positive lymph nodes are high-risk candidates for recurrence.

Evidence (adjuvant radiation therapy postsurgery):

  1. The Gynecologic Oncology Group (GOG) compared adjuvant radiation therapy alone with radiation therapy plus cisplatin plus fluorouracil (5-FU) after radical hysterectomy for patients in the high-risk group. Postoperative patients were eligible if their pathology showed any one of the following: positive parametria, positive margins, or positive lymph nodes. Patients in both arms received 49 Gy to the pelvis. Patients in the experimental arm also received cisplatin (70 mg/m2) and a 96-hour infusion of 5-FU (1,000 mg/m2/d every 3 weeks for four cycles); the first two cycles were concurrent with the radiation therapy.[6][Level of evidence A1]
    • There were 268 patients evaluated with a primary end point of OS. The study results were reported early because of the positive results in other trials of concomitant cisplatin and radiation therapy.
    • The estimated 4-year survival rate was 81% for chemotherapy plus radiation therapy and 71% for radiation therapy alone (HR, 1.96; P = .007).
    • As expected, grade 4 toxicity was more common in the chemotherapy plus radiation therapy group, with hematologic toxicity predominating.

Radical surgery has been performed for small lesions, but the high incidence of pathological factors leading to postoperative radiation with or without chemotherapy make primary concomitant chemotherapy and radiation a more common approach in patients with larger tumors. Radiation in the range of 50 Gy administered for 5 weeks plus chemotherapy with cisplatin with or without 5-FU should be considered in patients with a high risk of recurrence.

Para-aortic nodal disease

After surgical staging, patients found to have small-volume para-aortic nodal disease and controllable pelvic disease may be cured with pelvic and para-aortic radiation therapy.[25] Treatment of patients with unresected para-aortic nodes with extended-field radiation therapy and chemotherapy leads to long-term disease control in patients with low-volume (<2 cm) nodal disease below L3.[18] A single study (RTOG-7920) showed a survival advantage in patients with tumors larger than 4 cm who received radiation therapy to para-aortic nodes without histological evidence of disease.[26] Toxic effects were greater with para-aortic radiation therapy than with pelvic radiation therapy alone but were mostly confined to patients with previous abdominopelvic surgery.[26] The use of intensity-modulated radiation therapy (IMRT) may minimize the effects to the small bowel usually associated with this treatment.[27]

Radical trachelectomy

Patients with presumed early-stage disease who desire future fertility may be candidates for radical trachelectomy. In this procedure, the cervix and lateral parametrial tissues are removed, and the uterine body and ovaries are maintained. The patient selection differs somewhat between groups; however, general criteria include:

  • Desire for future pregnancy.
  • Age younger than 40 years.
  • Presumed stage IA2 to IB1 disease and a lesion size no greater than 2 cm.
  • Preoperative magnetic resonance imaging that shows a margin from the most distal edge of the tumor to the lower uterine segment.
  • Squamous, adenosquamous, or adenocarcinoma cell types.

Intraoperatively, the patient is assessed in a manner similar to a radical hysterectomy; the procedure is aborted if more advanced disease than expected is encountered. The margins of the specimen are also assessed at the time of surgery, and a radical hysterectomy is performed if inadequate margins are obtained.[28–32]

Radiation therapy alone

External-beam pelvic radiation therapy combined with two or more intracavitary brachytherapy applications is appropriate therapy for patients with stage IA2 and IB1 lesions. For patients with stage IB2 and larger lesions, radiosensitizing chemotherapy is indicated. The role of radiosensitizing chemotherapy in patients with stage IA2 and IB1 lesions is untested. However, it may prove beneficial in certain cases.

Immunotherapy

Evidence (immunotherapy):

  1. KEYNOTE-A18 (NCT04221945) was a multicenter, phase III, randomized trial that included 1,060 women with newly diagnosed squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma of the cervix. Patients had stage IB2 or IIB node-positive disease or stage III to IVA disease and had received no prior treatment. Patients were randomly assigned to receive either chemoradiation therapy (with cisplatin) plus pembrolizumab (every 3 weeks for five cycles) or chemoradiation therapy plus placebo. All patients received maintenance therapy with pembrolizumab or placebo every 6 weeks for 15 cycles. All patients received brachytherapy, and 94% of patients had programmed death-ligand 1 (PD-L1)–positive disease. The dual primary end points were progression-free survival (PFS) and OS. The median follow-up time was 17.9 months.[33]
    • The 24-month OS rate was 87% in the pembrolizumab group and 81% in the placebo group (HR, 0.73; 95% CI, 0.49–1.07).[33][Level of evidence B1]
    • There was a statistically significant improvement in PFS (HR, 0.70; 95% CI, 0.55–0.89). The 24-month PFS rate was 68% in the pembrolizumab group and 57% in the placebo group.
    • Patients with stage III or IV disease had a greater improvement in PFS (HR, 0.58; 95% CI, 0.42–0.80).

Neoadjuvant chemotherapy

Several groups have investigated the role of neoadjuvant chemotherapy to convert patients who are conventional candidates for chemoradiation into candidates for radical surgery.[34–38] Multiple regimens have been used; however, almost all use a platinum backbone. The largest randomized trial to date was reported in 2001, and its accrual was completed before the standard of care included the addition of cisplatin to radiation therapy.[39] As a result, the control arm received radiation therapy alone. Although there was an improvement in OS for the experimental arm, the results do not reflect current practice. This study accrued patients with stages IB through IVA disease, but improvement in the experimental arm was only noted for participants with early-stage disease (stages IB, IIA, or IIB).

EORTC-55994 (NCT00039338) randomly assigned patients with stages IB2, IIA2, and IIB cervical cancer to standard chemoradiation or neoadjuvant chemotherapy (with a cisplatin backbone for three cycles) followed by evaluation for surgery. With OS as the primary end point, this trial may delineate whether there is a role for neoadjuvant chemotherapy for this patient population.

IMRT

IMRT is a radiation therapy technique that allows for conformal dosing of target anatomy while sparing neighboring tissue. Theoretically, this technique should decrease radiation therapy–related toxicity, but this could come at the cost of decreased efficacy if tissue is inappropriately excluded from the treatment field. Several institutions have reported their experience with IMRT for postoperative adjuvant therapy in patients with intermediate-risk and high-risk disease after radical surgery.[40–42] A Radiation Therapy Oncology Group (RTOG) phase II trial (RTOG-0418 [NCT00331760]) evaluated the use of IMRT in patients with both cervical and endometrial cancers who require adjuvant radiation therapy.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References
  1. Perez CA, Grigsby PW, Nene SM, et al.: Effect of tumor size on the prognosis of carcinoma of the uterine cervix treated with irradiation alone. Cancer 69 (11): 2796-806, 1992. [PUBMED Abstract]
  2. Landoni F, Maneo A, Colombo A, et al.: Randomised study of radical surgery versus radiotherapy for stage Ib-IIa cervical cancer. Lancet 350 (9077): 535-40, 1997. [PUBMED Abstract]
  3. Eifel PJ, Burke TW, Delclos L, et al.: Early stage I adenocarcinoma of the uterine cervix: treatment results in patients with tumors less than or equal to 4 cm in diameter. Gynecol Oncol 41 (3): 199-205, 1991. [PUBMED Abstract]
  4. Morris M, Eifel PJ, Lu J, et al.: Pelvic radiation with concurrent chemotherapy compared with pelvic and para-aortic radiation for high-risk cervical cancer. N Engl J Med 340 (15): 1137-43, 1999. [PUBMED Abstract]
  5. Keys HM, Bundy BN, Stehman FB, et al.: Cisplatin, radiation, and adjuvant hysterectomy compared with radiation and adjuvant hysterectomy for bulky stage IB cervical carcinoma. N Engl J Med 340 (15): 1154-61, 1999. [PUBMED Abstract]
  6. Peters WA, Liu PY, Barrett RJ, et al.: Concurrent chemotherapy and pelvic radiation therapy compared with pelvic radiation therapy alone as adjuvant therapy after radical surgery in high-risk early-stage cancer of the cervix. J Clin Oncol 18 (8): 1606-13, 2000. [PUBMED Abstract]
  7. Thomas GM: Improved treatment for cervical cancer–concurrent chemotherapy and radiotherapy. N Engl J Med 340 (15): 1198-200, 1999. [PUBMED Abstract]
  8. Pearcey R, Brundage M, Drouin P, et al.: Phase III trial comparing radical radiotherapy with and without cisplatin chemotherapy in patients with advanced squamous cell cancer of the cervix. J Clin Oncol 20 (4): 966-72, 2002. [PUBMED Abstract]
  9. Rose PG, Bundy BN: Chemoradiation for locally advanced cervical cancer: does it help? J Clin Oncol 20 (4): 891-3, 2002. [PUBMED Abstract]
  10. Chemoradiotherapy for Cervical Cancer Meta-Analysis Collaboration: Reducing uncertainties about the effects of chemoradiotherapy for cervical cancer: a systematic review and meta-analysis of individual patient data from 18 randomized trials. J Clin Oncol 26 (35): 5802-12, 2008. [PUBMED Abstract]
  11. Nag S, Chao C, Erickson B, et al.: The American Brachytherapy Society recommendations for low-dose-rate brachytherapy for carcinoma of the cervix. Int J Radiat Oncol Biol Phys 52 (1): 33-48, 2002. [PUBMED Abstract]
  12. Nag S, Erickson B, Thomadsen B, et al.: The American Brachytherapy Society recommendations for high-dose-rate brachytherapy for carcinoma of the cervix. Int J Radiat Oncol Biol Phys 48 (1): 201-11, 2000. [PUBMED Abstract]
  13. Patel FD, Sharma SC, Negi PS, et al.: Low dose rate vs. high dose rate brachytherapy in the treatment of carcinoma of the uterine cervix: a clinical trial. Int J Radiat Oncol Biol Phys 28 (2): 335-41, 1994. [PUBMED Abstract]
  14. Hareyama M, Sakata K, Oouchi A, et al.: High-dose-rate versus low-dose-rate intracavitary therapy for carcinoma of the uterine cervix: a randomized trial. Cancer 94 (1): 117-24, 2002. [PUBMED Abstract]
  15. Lertsanguansinchai P, Lertbutsayanukul C, Shotelersuk K, et al.: Phase III randomized trial comparing LDR and HDR brachytherapy in treatment of cervical carcinoma. Int J Radiat Oncol Biol Phys 59 (5): 1424-31, 2004. [PUBMED Abstract]
  16. Thoms WW, Eifel PJ, Smith TL, et al.: Bulky endocervical carcinoma: a 23-year experience. Int J Radiat Oncol Biol Phys 23 (3): 491-9, 1992. [PUBMED Abstract]
  17. Downey GO, Potish RA, Adcock LL, et al.: Pretreatment surgical staging in cervical carcinoma: therapeutic efficacy of pelvic lymph node resection. Am J Obstet Gynecol 160 (5 Pt 1): 1055-61, 1989. [PUBMED Abstract]
  18. Vigliotti AP, Wen BC, Hussey DH, et al.: Extended field irradiation for carcinoma of the uterine cervix with positive periaortic nodes. Int J Radiat Oncol Biol Phys 23 (3): 501-9, 1992. [PUBMED Abstract]
  19. Weiser EB, Bundy BN, Hoskins WJ, et al.: Extraperitoneal versus transperitoneal selective paraaortic lymphadenectomy in the pretreatment surgical staging of advanced cervical carcinoma (a Gynecologic Oncology Group study). Gynecol Oncol 33 (3): 283-9, 1989. [PUBMED Abstract]
  20. Fine BA, Hempling RE, Piver MS, et al.: Severe radiation morbidity in carcinoma of the cervix: impact of pretherapy surgical staging and previous surgery. Int J Radiat Oncol Biol Phys 31 (4): 717-23, 1995. [PUBMED Abstract]
  21. Estape RE, Angioli R, Madrigal M, et al.: Close vaginal margins as a prognostic factor after radical hysterectomy. Gynecol Oncol 68 (3): 229-32, 1998. [PUBMED Abstract]
  22. Ramirez PT, Frumovitz M, Pareja R, et al.: Minimally Invasive versus Abdominal Radical Hysterectomy for Cervical Cancer. N Engl J Med 379 (20): 1895-1904, 2018. [PUBMED Abstract]
  23. Melamed A, Margul DJ, Chen L, et al.: Survival after Minimally Invasive Radical Hysterectomy for Early-Stage Cervical Cancer. N Engl J Med 379 (20): 1905-1914, 2018. [PUBMED Abstract]
  24. Sedlis A, Bundy BN, Rotman MZ, et al.: A randomized trial of pelvic radiation therapy versus no further therapy in selected patients with stage IB carcinoma of the cervix after radical hysterectomy and pelvic lymphadenectomy: A Gynecologic Oncology Group Study. Gynecol Oncol 73 (2): 177-83, 1999. [PUBMED Abstract]
  25. Cunningham MJ, Dunton CJ, Corn B, et al.: Extended-field radiation therapy in early-stage cervical carcinoma: survival and complications. Gynecol Oncol 43 (1): 51-4, 1991. [PUBMED Abstract]
  26. Rotman M, Pajak TF, Choi K, et al.: Prophylactic extended-field irradiation of para-aortic lymph nodes in stages IIB and bulky IB and IIA cervical carcinomas. Ten-year treatment results of RTOG 79-20. JAMA 274 (5): 387-93, 1995. [PUBMED Abstract]
  27. Poorvu PD, Sadow CA, Townamchai K, et al.: Duodenal and other gastrointestinal toxicity in cervical and endometrial cancer treated with extended-field intensity modulated radiation therapy to paraaortic lymph nodes. Int J Radiat Oncol Biol Phys 85 (5): 1262-8, 2013. [PUBMED Abstract]
  28. Covens A, Shaw P, Murphy J, et al.: Is radical trachelectomy a safe alternative to radical hysterectomy for patients with stage IA-B carcinoma of the cervix? Cancer 86 (11): 2273-9, 1999. [PUBMED Abstract]
  29. Dargent D, Martin X, Sacchetoni A, et al.: Laparoscopic vaginal radical trachelectomy: a treatment to preserve the fertility of cervical carcinoma patients. Cancer 88 (8): 1877-82, 2000. [PUBMED Abstract]
  30. Plante M, Renaud MC, Hoskins IA, et al.: Vaginal radical trachelectomy: a valuable fertility-preserving option in the management of early-stage cervical cancer. A series of 50 pregnancies and review of the literature. Gynecol Oncol 98 (1): 3-10, 2005. [PUBMED Abstract]
  31. Shepherd JH, Spencer C, Herod J, et al.: Radical vaginal trachelectomy as a fertility-sparing procedure in women with early-stage cervical cancer-cumulative pregnancy rate in a series of 123 women. BJOG 113 (6): 719-24, 2006. [PUBMED Abstract]
  32. Wethington SL, Cibula D, Duska LR, et al.: An international series on abdominal radical trachelectomy: 101 patients and 28 pregnancies. Int J Gynecol Cancer 22 (7): 1251-7, 2012. [PUBMED Abstract]
  33. Lorusso D, Xiang Y, Hasegawa K, et al.: Pembrolizumab or placebo with chemoradiotherapy followed by pembrolizumab or placebo for newly diagnosed, high-risk, locally advanced cervical cancer (ENGOT-cx11/GOG-3047/KEYNOTE-A18): a randomised, double-blind, phase 3 clinical trial. Lancet 403 (10434): 1341-1350, 2024. [PUBMED Abstract]
  34. Ferrandina G, Margariti PA, Smaniotto D, et al.: Long-term analysis of clinical outcome and complications in locally advanced cervical cancer patients administered concomitant chemoradiation followed by radical surgery. Gynecol Oncol 119 (3): 404-10, 2010. [PUBMED Abstract]
  35. Ferrandina G, Distefano MG, De Vincenzo R, et al.: Paclitaxel, epirubicin, and cisplatin (TEP) regimen as neoadjuvant treatment in locally advanced cervical cancer: long-term results. Gynecol Oncol 128 (3): 518-23, 2013. [PUBMED Abstract]
  36. Zanaboni F, Grijuela B, Giudici S, et al.: Weekly topotecan and cisplatin (TOPOCIS) as neo-adjuvant chemotherapy for locally-advanced squamous cervical carcinoma: Results of a phase II multicentric study. Eur J Cancer 49 (5): 1065-72, 2013. [PUBMED Abstract]
  37. Manci N, Marchetti C, Di Tucci C, et al.: A prospective phase II study of topotecan (Hycamtin®) and cisplatin as neoadjuvant chemotherapy in locally advanced cervical cancer. Gynecol Oncol 122 (2): 285-90, 2011. [PUBMED Abstract]
  38. Gong L, Lou JY, Wang P, et al.: Clinical evaluation of neoadjuvant chemotherapy followed by radical surgery in the management of stage IB2-IIB cervical cancer. Int J Gynaecol Obstet 117 (1): 23-6, 2012. [PUBMED Abstract]
  39. Benedetti-Panici P, Greggi S, Colombo A, et al.: Neoadjuvant chemotherapy and radical surgery versus exclusive radiotherapy in locally advanced squamous cell cervical cancer: results from the Italian multicenter randomized study. J Clin Oncol 20 (1): 179-88, 2002. [PUBMED Abstract]
  40. Chen MF, Tseng CJ, Tseng CC, et al.: Adjuvant concurrent chemoradiotherapy with intensity-modulated pelvic radiotherapy after surgery for high-risk, early stage cervical cancer patients. Cancer J 14 (3): 200-6, 2008 May-Jun. [PUBMED Abstract]
  41. Hasselle MD, Rose BS, Kochanski JD, et al.: Clinical outcomes of intensity-modulated pelvic radiation therapy for carcinoma of the cervix. Int J Radiat Oncol Biol Phys 80 (5): 1436-45, 2011. [PUBMED Abstract]
  42. Folkert MR, Shih KK, Abu-Rustum NR, et al.: Postoperative pelvic intensity-modulated radiotherapy and concurrent chemotherapy in intermediate- and high-risk cervical cancer. Gynecol Oncol 128 (2): 288-93, 2013. [PUBMED Abstract]

Treatment of Stages IIB, III, and IVA Cervical Cancer

Treatment Options for Stages IIB, III, and IVA Cervical Cancer

Primary tumor size is an important prognostic factor to carefully evaluate when choosing optimal therapy.[1] Survival and local control are better with unilateral rather than bilateral parametrial involvement.[2] Patterns-of-care studies in patients with stages IIIA and IIIB disease indicate that survival is dependent on the extent of the disease, with unilateral pelvic wall involvement predicting a better outcome than bilateral involvement, which in turn predicts a better outcome than involvement of the lower third of the vaginal wall.[2] These studies also reveal a progressive increase in local control and survival paralleling a progressive increase in paracentral (point A) dose and use of intracavitary treatment. The highest rate of central control was seen with paracentral (point A) doses of more than 85 Gy.[3]

Treatment options for stage IIB, stage III, and stage IVA cervical cancer include:

  1. Radiation therapy with concomitant chemotherapy. [4]
  2. Interstitial brachytherapy.
  3. Neoadjuvant chemotherapy.
  4. Immunotherapy.

Radiation therapy with concomitant chemotherapy

Strong consideration should be given to the use of intracavitary radiation therapy and external-beam radiation therapy (EBRT) to the pelvis combined with cisplatin or cisplatin/fluorouracil (5-FU).[5–12]

Evidence (radiation therapy with concomitant chemotherapy):

  1. Five randomized phase III trials have shown an overall survival (OS) advantage for cisplatin-based therapy given concurrently with radiation therapy,[5–10] but one trial that examined this regimen demonstrated no benefit.[13] The patient populations in these studies included women with Fédération Internationale de Gynécologie et d’Obstétrique (FIGO) stages IB2 to IVA cervical cancer treated with primary radiation therapy, and women with FIGO stages I to IIA disease who, at the time of primary surgery, were found to have poor prognostic factors, including metastatic disease in pelvic lymph nodes, parametrial disease, and positive surgical margins.
    • Although the positive trials vary somewhat in terms of the stage of disease, dose of radiation, and schedule of cisplatin and radiation, the trials demonstrate significant survival benefit for this combined approach.
    • The risk of death from cervical cancer was decreased by 30% to 50% with the use of concurrent chemoradiation therapy.

Evidence (low-dose rate vs. high-dose rate intracavitary radiation therapy):

  1. Although low-dose rate (LDR) brachytherapy, typically with cesium Cs 137, has been the traditional approach, the use of high-dose rate (HDR) therapy, typically with iridium Ir 192, is rapidly increasing. HDR brachytherapy provides the advantage of eliminating radiation exposure to medical personnel, a shorter treatment time, patient convenience, and improved outpatient management. The American Brachytherapy Society has published guidelines for the use of LDR and HDR brachytherapy as a component of cervical cancer treatment.[14,15]
  2. In three randomized trials, HDR brachytherapy was comparable with LDR brachytherapy in terms of local-regional control and complication rates.[16–18][Level of evidence B1]
  3. In an attempt to improve upon standard chemoradiation, a phase III randomized trial compared concurrent gemcitabine plus cisplatin and radiation therapy followed by adjuvant gemcitabine and cisplatin (experimental arm) with concurrent cisplatin plus radiation (standard chemoradiation) in patients with stages IIB to IVA cervical cancer.[19][Level of evidence A1] A total of 515 patients from nine countries were enrolled. The schedule for the experimental arm was cisplatin (40 mg/m2) and gemcitabine (125 mg/m2) weekly for 6 weeks, with concurrent EBRT (50.4 Gy in 28 fractions) followed by brachytherapy (30–35 Gy in 96 hours) and then two adjuvant 21-day cycles of cisplatin (50 mg/m2) on day 1 plus gemcitabine (1,000 mg/m2) on days 1 and 8. The standard arm was cisplatin (40 mg/m2) weekly for 6 weeks with concurrent EBRT and brachytherapy as described for the experimental arm.
    • The primary end point was progression-free survival (PFS) at 3 years; however, the study found improvement in the experimental arm for PFS at 3 years (74.4%; 95% confidence interval [CI], 68%–79.8% vs. 65.0%; 95% CI, 58.5%–70.7%); overall PFS (hazard ratio [HR], 0.68; 95% CI, 0.49–0.95); and OS (HR, 0.68; 95% CI, 0.49–0.95). Patients in the experimental arm had increased hematologic and nonhematologic grade 3 or 4 toxic effects, and two deaths in the experimental arm were possibly related to treatment.

    A subgroup analysis showed an increased benefit in patients with a higher stage of disease (stages III–IVA vs. stage IIB), which suggested that the increased toxic effects of the experimental protocol may be justified for these patients.[20] Additional investigation is needed to determine which aspect of the experimental arm led to improved survival (i.e., the addition of the weekly gemcitabine, the adjuvant chemotherapy, or both) and to determine quality of life during and after treatment, a condition that was omitted from the protocol.

Interstitial brachytherapy

For patients who complete EBRT and have bulky cervical disease such that standard brachytherapy cannot be placed anatomically, interstitial brachytherapy has been used to deliver adequate tumoricidal doses with an acceptable toxicity profile.[21]

Neoadjuvant chemotherapy

Several groups have investigated the role of neoadjuvant chemotherapy to convert patients who are conventional candidates for chemoradiation into candidates for radical surgery.[22–26] Multiple regimens have been used; however, almost all use a platinum backbone. The largest randomized trial to date was reported in 2001, and its accrual was completed before the standard of care included the addition of cisplatin to radiation therapy.[27] As a result, although there was an improvement in OS for the experimental arm, the results are not reflective of current practice. This study accrued patients with stages IB through IVA disease, but improvement in the experimental arm was only noted for participants with early-stage disease (stages IB, IIA, or IIB).

EORTC-55994 (NCT00039338) randomly assigned patients with stages IB2, IIA2, and IIB cervical cancer to standard chemoradiation or neoadjuvant chemotherapy (with a cisplatin backbone for three cycles) followed by evaluation for surgery. With OS as the primary end point, this trial may delineate whether there is a role for neoadjuvant chemotherapy for this patient population.

Immunotherapy

Evidence (immunotherapy):

  1. KEYNOTE-A18 (NCT04221945) was a multicenter, phase III, randomized trial that included 1,060 women with newly diagnosed squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma of the cervix. Patients had stage IB2 or IIB node-positive disease or stage III to IVA disease and had received no prior treatment. Patients were randomly assigned to receive either chemoradiation therapy (with cisplatin) plus pembrolizumab (every 3 weeks for five cycles) or chemoradiation therapy plus placebo. All patients received maintenance therapy with pembrolizumab or placebo every 6 weeks for 15 cycles. All patients received brachytherapy, and 94% of patients had programmed death-ligand 1 (PD-L1)–positive disease. The dual primary end points were PFS and OS. The median follow-up time was 17.9 months.[28]
    • The 24-month OS rate was 87% in the pembrolizumab group and 81% in the placebo group (HR, 0.73; 95% CI, 0.49–1.07).[28][Level of evidence B1]
    • There was a statistically significant improvement in PFS (HR, 0.70; 95% CI, 0.55–0.89). The 24-month PFS rate was 68% in the pembrolizumab group and 57% in the placebo group.
    • Patients with stage III or IV disease had a greater improvement in PFS (HR, 0.58; 95% CI, 0.42–0.80).

Lymph Node Management

Patients who are surgically staged as part of a clinical trial and are found to have small-volume para-aortic nodal disease and controllable pelvic disease may be cured with pelvic and para-aortic radiation therapy.[29] Treatment of patients with unresected periaortic nodes with extended-field radiation therapy leads to long-term disease control in patients with low-volume (<2 cm) nodal disease below L3.[30] A single study (RTOG-7920) showed a survival advantage in patients who received radiation therapy to para-aortic nodes without histological evidence of disease.[31] Toxic effects are greater with para-aortic radiation than with pelvic radiation alone but were mostly confined to patients with previous abdominopelvic surgery.[31]

If postoperative EBRT is planned following surgery, extraperitoneal lymph–node sampling is associated with fewer radiation-induced complications than a transperitoneal approach.[32] Patients who underwent extraperitoneal lymph–node sampling had fewer bowel complications than those who had transperitoneal lymph–node sampling.[30,32,33]

The resection of macroscopically involved pelvic nodes may improve rates of local control with postoperative radiation therapy.[34] In addition, prospective data indicated improved outcomes for patients who underwent resection of positive para-aortic lymph nodes before curative intent chemoradiation therapy; however, only patients with minimal nodal involvement (<5 mm) benefited.[35]

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References
  1. Perez CA, Grigsby PW, Nene SM, et al.: Effect of tumor size on the prognosis of carcinoma of the uterine cervix treated with irradiation alone. Cancer 69 (11): 2796-806, 1992. [PUBMED Abstract]
  2. Lanciano RM, Won M, Hanks GE: A reappraisal of the International Federation of Gynecology and Obstetrics staging system for cervical cancer. A study of patterns of care. Cancer 69 (2): 482-7, 1992. [PUBMED Abstract]
  3. Lanciano RM, Martz K, Coia LR, et al.: Tumor and treatment factors improving outcome in stage III-B cervix cancer. Int J Radiat Oncol Biol Phys 20 (1): 95-100, 1991. [PUBMED Abstract]
  4. Monk BJ, Tewari KS, Koh WJ: Multimodality therapy for locally advanced cervical carcinoma: state of the art and future directions. J Clin Oncol 25 (20): 2952-65, 2007. [PUBMED Abstract]
  5. Whitney CW, Sause W, Bundy BN, et al.: Randomized comparison of fluorouracil plus cisplatin versus hydroxyurea as an adjunct to radiation therapy in stage IIB-IVA carcinoma of the cervix with negative para-aortic lymph nodes: a Gynecologic Oncology Group and Southwest Oncology Group study. J Clin Oncol 17 (5): 1339-48, 1999. [PUBMED Abstract]
  6. Morris M, Eifel PJ, Lu J, et al.: Pelvic radiation with concurrent chemotherapy compared with pelvic and para-aortic radiation for high-risk cervical cancer. N Engl J Med 340 (15): 1137-43, 1999. [PUBMED Abstract]
  7. Rose PG, Bundy BN, Watkins EB, et al.: Concurrent cisplatin-based radiotherapy and chemotherapy for locally advanced cervical cancer. N Engl J Med 340 (15): 1144-53, 1999. [PUBMED Abstract]
  8. Keys HM, Bundy BN, Stehman FB, et al.: Cisplatin, radiation, and adjuvant hysterectomy compared with radiation and adjuvant hysterectomy for bulky stage IB cervical carcinoma. N Engl J Med 340 (15): 1154-61, 1999. [PUBMED Abstract]
  9. Peters WA, Liu PY, Barrett RJ, et al.: Concurrent chemotherapy and pelvic radiation therapy compared with pelvic radiation therapy alone as adjuvant therapy after radical surgery in high-risk early-stage cancer of the cervix. J Clin Oncol 18 (8): 1606-13, 2000. [PUBMED Abstract]
  10. Thomas GM: Improved treatment for cervical cancer–concurrent chemotherapy and radiotherapy. N Engl J Med 340 (15): 1198-200, 1999. [PUBMED Abstract]
  11. Rose PG, Bundy BN: Chemoradiation for locally advanced cervical cancer: does it help? J Clin Oncol 20 (4): 891-3, 2002. [PUBMED Abstract]
  12. Chemoradiotherapy for Cervical Cancer Meta-Analysis Collaboration: Reducing uncertainties about the effects of chemoradiotherapy for cervical cancer: a systematic review and meta-analysis of individual patient data from 18 randomized trials. J Clin Oncol 26 (35): 5802-12, 2008. [PUBMED Abstract]
  13. Pearcey R, Brundage M, Drouin P, et al.: Phase III trial comparing radical radiotherapy with and without cisplatin chemotherapy in patients with advanced squamous cell cancer of the cervix. J Clin Oncol 20 (4): 966-72, 2002. [PUBMED Abstract]
  14. Nag S, Chao C, Erickson B, et al.: The American Brachytherapy Society recommendations for low-dose-rate brachytherapy for carcinoma of the cervix. Int J Radiat Oncol Biol Phys 52 (1): 33-48, 2002. [PUBMED Abstract]
  15. Nag S, Erickson B, Thomadsen B, et al.: The American Brachytherapy Society recommendations for high-dose-rate brachytherapy for carcinoma of the cervix. Int J Radiat Oncol Biol Phys 48 (1): 201-11, 2000. [PUBMED Abstract]
  16. Patel FD, Sharma SC, Negi PS, et al.: Low dose rate vs. high dose rate brachytherapy in the treatment of carcinoma of the uterine cervix: a clinical trial. Int J Radiat Oncol Biol Phys 28 (2): 335-41, 1994. [PUBMED Abstract]
  17. Hareyama M, Sakata K, Oouchi A, et al.: High-dose-rate versus low-dose-rate intracavitary therapy for carcinoma of the uterine cervix: a randomized trial. Cancer 94 (1): 117-24, 2002. [PUBMED Abstract]
  18. Lertsanguansinchai P, Lertbutsayanukul C, Shotelersuk K, et al.: Phase III randomized trial comparing LDR and HDR brachytherapy in treatment of cervical carcinoma. Int J Radiat Oncol Biol Phys 59 (5): 1424-31, 2004. [PUBMED Abstract]
  19. Dueñas-González A, Zarbá JJ, Patel F, et al.: Phase III, open-label, randomized study comparing concurrent gemcitabine plus cisplatin and radiation followed by adjuvant gemcitabine and cisplatin versus concurrent cisplatin and radiation in patients with stage IIB to IVA carcinoma of the cervix. J Clin Oncol 29 (13): 1678-85, 2011. [PUBMED Abstract]
  20. Dueňas-González A, Orlando M, Zhou Y, et al.: Efficacy in high burden locally advanced cervical cancer with concurrent gemcitabine and cisplatin chemoradiotherapy plus adjuvant gemcitabine and cisplatin: prognostic and predictive factors and the impact of disease stage on outcomes from a prospective randomized phase III trial. Gynecol Oncol 126 (3): 334-40, 2012. [PUBMED Abstract]
  21. Pinn-Bingham M, Puthawala AA, Syed AM, et al.: Outcomes of high-dose-rate interstitial brachytherapy in the treatment of locally advanced cervical cancer: long-term results. Int J Radiat Oncol Biol Phys 85 (3): 714-20, 2013. [PUBMED Abstract]
  22. Ferrandina G, Margariti PA, Smaniotto D, et al.: Long-term analysis of clinical outcome and complications in locally advanced cervical cancer patients administered concomitant chemoradiation followed by radical surgery. Gynecol Oncol 119 (3): 404-10, 2010. [PUBMED Abstract]
  23. Ferrandina G, Distefano MG, De Vincenzo R, et al.: Paclitaxel, epirubicin, and cisplatin (TEP) regimen as neoadjuvant treatment in locally advanced cervical cancer: long-term results. Gynecol Oncol 128 (3): 518-23, 2013. [PUBMED Abstract]
  24. Zanaboni F, Grijuela B, Giudici S, et al.: Weekly topotecan and cisplatin (TOPOCIS) as neo-adjuvant chemotherapy for locally-advanced squamous cervical carcinoma: Results of a phase II multicentric study. Eur J Cancer 49 (5): 1065-72, 2013. [PUBMED Abstract]
  25. Manci N, Marchetti C, Di Tucci C, et al.: A prospective phase II study of topotecan (Hycamtin®) and cisplatin as neoadjuvant chemotherapy in locally advanced cervical cancer. Gynecol Oncol 122 (2): 285-90, 2011. [PUBMED Abstract]
  26. Gong L, Lou JY, Wang P, et al.: Clinical evaluation of neoadjuvant chemotherapy followed by radical surgery in the management of stage IB2-IIB cervical cancer. Int J Gynaecol Obstet 117 (1): 23-6, 2012. [PUBMED Abstract]
  27. Benedetti-Panici P, Greggi S, Colombo A, et al.: Neoadjuvant chemotherapy and radical surgery versus exclusive radiotherapy in locally advanced squamous cell cervical cancer: results from the Italian multicenter randomized study. J Clin Oncol 20 (1): 179-88, 2002. [PUBMED Abstract]
  28. Lorusso D, Xiang Y, Hasegawa K, et al.: Pembrolizumab or placebo with chemoradiotherapy followed by pembrolizumab or placebo for newly diagnosed, high-risk, locally advanced cervical cancer (ENGOT-cx11/GOG-3047/KEYNOTE-A18): a randomised, double-blind, phase 3 clinical trial. Lancet 403 (10434): 1341-1350, 2024. [PUBMED Abstract]
  29. Cunningham MJ, Dunton CJ, Corn B, et al.: Extended-field radiation therapy in early-stage cervical carcinoma: survival and complications. Gynecol Oncol 43 (1): 51-4, 1991. [PUBMED Abstract]
  30. Vigliotti AP, Wen BC, Hussey DH, et al.: Extended field irradiation for carcinoma of the uterine cervix with positive periaortic nodes. Int J Radiat Oncol Biol Phys 23 (3): 501-9, 1992. [PUBMED Abstract]
  31. Rotman M, Pajak TF, Choi K, et al.: Prophylactic extended-field irradiation of para-aortic lymph nodes in stages IIB and bulky IB and IIA cervical carcinomas. Ten-year treatment results of RTOG 79-20. JAMA 274 (5): 387-93, 1995. [PUBMED Abstract]
  32. Weiser EB, Bundy BN, Hoskins WJ, et al.: Extraperitoneal versus transperitoneal selective paraaortic lymphadenectomy in the pretreatment surgical staging of advanced cervical carcinoma (a Gynecologic Oncology Group study). Gynecol Oncol 33 (3): 283-9, 1989. [PUBMED Abstract]
  33. Fine BA, Hempling RE, Piver MS, et al.: Severe radiation morbidity in carcinoma of the cervix: impact of pretherapy surgical staging and previous surgery. Int J Radiat Oncol Biol Phys 31 (4): 717-23, 1995. [PUBMED Abstract]
  34. Downey GO, Potish RA, Adcock LL, et al.: Pretreatment surgical staging in cervical carcinoma: therapeutic efficacy of pelvic lymph node resection. Am J Obstet Gynecol 160 (5 Pt 1): 1055-61, 1989. [PUBMED Abstract]
  35. Gouy S, Morice P, Narducci F, et al.: Prospective multicenter study evaluating the survival of patients with locally advanced cervical cancer undergoing laparoscopic para-aortic lymphadenectomy before chemoradiotherapy in the era of positron emission tomography imaging. J Clin Oncol 31 (24): 3026-33, 2013. [PUBMED Abstract]

Treatment of Stage IVB and Recurrent Cervical Cancer

Treatment Options for Stage IVB and Recurrent Cervical Cancer

With the exception of immunotherapy, which has provided prolonged disease-free survival, other options are unlikely to result in curative outcomes and are mostly applied for palliative purposes.

Treatment options for stage IVB and recurrent cervical cancer include:

  1. Immunotherapy.
  2. Radiation therapy and chemotherapy.
  3. Palliative chemotherapy and other systemic therapy.
  4. Pelvic exenteration.
  5. Phase I and phase II clinical trials of new anticancer drugs.

Immunotherapy

Based on the results of the phase II KEYNOTE-158 trial (NCT02628067), the U.S. Food and Drug Administration (FDA) approved the anti–programmed cell death-1 (PD-1) immune checkpoint inhibitor, pembrolizumab, for women with recurrent or metastatic cervical cancer whose tumors express programmed death-ligand 1 (PD-L1) (combined positive score [CPS], ≥1). Additional data on the benefits of pembrolizumab have been gathered from several trials.

Evidence (immunotherapy):

  1. The international multicenter BEATcc trial (NCT03556839) included 410 women with stage IVB, persistent, or recurrent squamous cell or adenocarcinoma of the cervix not amenable to curative surgery or radiation therapy. Patients had not received previous systemic therapy. Patients were randomly assigned to receive either bevacizumab plus chemotherapy (carboplatin or cisplatin with paclitaxel) (the control arm) or the experimental arm, which added atezolizumab to the control regimen. The dual primary end points were progression-free survival (PFS) and overall survival (OS), and the trial was biomarker unselective for PD-L1 expression.[1]
    • After a median follow-up of 32.9 months, the median PFS was 10.4 months for patients in the control arm and 13.7 months for patients in the experimental arm (hazard ratio [HR], 0.62; 95% confidence interval [CI], 0.48–0.78; P < .0001). The median OS was 22.8 months for patients in the control arm and 32.1 months for patients in the experimental arm (HR, 0.68; 95% CI, 0.52–0.88; P = .0046).[1][Level of evidence A1]
  2. KEYNOTE-826 (NCT03635567) was a multicenter, phase III, randomized trial that included 617 women with persistent, recurrent, or metastatic adenosquamous or squamous cell carcinoma of the cervix not amenable to curative treatment. Patients had measurable disease. All patients were treated with cisplatin or carboplatin combined with paclitaxel, with the option to add bevacizumab at the treating physician’s discretion. Patients received six cycles and were randomly assigned 1:1 to receive pembrolizumab or placebo every 3 weeks for up to 35 cycles. The median follow-up was 39.1 months, with dual primary end points of PFS and OS. Approximately 89% of women had a PD-L1 CPS score of 1 or higher.[2]
    • The median OS was 26.4 months for patients who received pembrolizumab and 16.8 months for patients who received placebo (HR, 0.63; 95% CI, 0.52–0.77). This benefit was not maintained in women with a CPS score less than 1. The benefit was maintained in the group of women who did not receive bevacizumab.[2][Level of evidence A1]
    • The median PFS was 10.4 months for patients who received pembrolizumab and 8.2 months for patients who received placebo (HR, 0.61; 95% CI, 0.50–0.74).
  3. KEYNOTE-A18 (NCT04221945) was a multicenter, phase III, randomized trial that included 1,060 women with newly diagnosed squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma of the cervix. Patients had stage IB2 or IIB node-positive disease or stage III to IVA disease and had received no prior treatment. Patients were randomly assigned to receive either chemoradiation therapy (with cisplatin) plus pembrolizumab (every 3 weeks for five cycles) or chemoradiation therapy plus placebo. All patients received maintenance therapy with pembrolizumab or placebo every 6 weeks for 15 cycles. All patients received brachytherapy, and 94% of patients had PD-L1–positive disease. The dual primary end points were PFS and OS. The median follow-up time was 17.9 months.[3]
    • The 24-month OS rate was 87% in the pembrolizumab group and 81% in the placebo group (HR, 0.73; 95% CI, 0.49–1.07).[3][Level of evidence B1]
    • There was a statistically significant improvement in PFS (HR, 0.70; 95% CI, 0.55–0.89). The 24-month PFS rate was 68% in the pembrolizumab group and 57% in the placebo group.
    • Patients with stage III or IV disease had a greater improvement in PFS (HR, 0.58; 95% CI, 0.42–0.80).
  4. KEYNOTE-158 (NCT02628067) was a multicenter nonrandomized trial that included 98 patients with recurrent or metastatic cervical cancer. Patients received 200 mg of pembrolizumab every 3 weeks intravenously until unacceptable toxicity or disease progression.[4] A separate analysis was performed in 77 patients whose tumors expressed PD-L1 (CPS ≥1); 92% had squamous histology.
    • The overall response rate among PD-L1–positive patients was 16% (95% CI, 8.8%–25.9%) with 3 complete responses and 10 partial responses; 17 patients were stable.
    • The median PFS was 2.1 months, and OS was 9.4 months in these marker-positive patients.
    • Treatment-related adverse events were noted in 65% of patients. The most common were hypothyroidism (10.2%), decreased appetite (9.2%), fatigue (9.2%), and diarrhea (8.2%).[4][Level of evidence B4]
  5. GOG-0240 (NCT00803062), which enrolled patients with metastatic, persistent, or recurrent cervical carcinoma, was designed to answer the following two questions:[5]
    • Can a nonplatinum combination show improvement over the standard of cisplatin-paclitaxel in this population, which was previously treated with cisplatin during radiation therapy?
    • Can the addition of bevacizumab improve combination chemotherapy in patients with stage IVB, persistent, or recurrent cervical cancer?

    Patients were randomly assigned to one of the following four treatment arms:

    • Cisplatin (50 mg/m2) + paclitaxel (135 mg/m2 or 175 mg/m2) on day 1 (PC).
    • PC + bevacizumab (15mg/kg) on day 1.
    • Topotecan (0.75 mg/m2) on days 1–3 + paclitaxel (175 mg/m2) on day 1 (PT).
    • PT + bevacizumab (15 mg/kg) on day 1.

    Additional study methods and results included the following:

    • The primary end point was OS, and 452 patients were evaluable.
    • The combination PT was not superior to PC and had a HRdeath of 1.2 (99% CI, 0.82–1.76). Previous exposure to platinum did not affect this result.
    • The addition of bevacizumab to combination chemotherapy led to: (1) improved OS: 17 months for chemotherapy plus bevacizumab versus 13.3 months for chemotherapy alone (HR, 0.71; 98% CI, 0.54–0.95) and (2) extended PFS: 8.2 months for chemotherapy plus bevacizumab versus 5.9 months for chemotherapy alone (HR, 0.67; 95% CI, 0.54–0.82).
    • The addition of bevacizumab was well tolerated and showed no difference in quality of life between the two groups.
    • Patients who received bevacizumab were more likely to have grade 3 or higher fistulae (6% vs. 0%), and grade 3 or higher thromboembolic events (8% vs. 1%) compared with patients who received chemotherapy alone.
    • As a result, the addition of bevacizumab may be considered for this patient population.
  6. In a phase III international trial (NCT04697628) 502 women were randomly assigned to receive either tisotumab vedotin (2 mg/kg every 3 weeks) or the investigator’s choice of chemotherapy. Patients had metastatic or recurrent cervical cancer (squamous cell, adenocarcinoma, or adenosquamous histology) with measurable disease after prior systemic therapy (paclitaxel plus a platinum or topotecan, with or without bevacizumab and with or without an anti–PD-1 or anti–PD-L1 agent). One or two prior systemic treatments were required (not including adjuvant, maintenance, or neoadjuvant chemotherapy or chemoradiation therapy). Imaging was done every 6 weeks for 30 weeks and then every 12 weeks thereafter. The primary end point was OS.[6]
    • After a median follow-up of 10.8 months, the median OS was 11.5 months for patients who received tisotumab vedotin and 9.5 months for patients who received chemotherapy.[6][Level of evidence A1]
    • Common adverse events in the tisotumab vedotin group included ocular events (52.8%), peripheral neuropathy (38.4%), and bleeding (42%).

Radiation therapy and chemotherapy

Radiation therapy and chemotherapy (fluorouracil with or without mitomycin) may cure 40% to 50% of patients with recurrence in the pelvis after initial radical surgery.[7]

Palliative chemotherapy and other systemic therapy

Chemotherapy can be used for palliation. Drugs used for palliative chemotherapy are shown in Table 6.

Table 6. Drugs Used to Treat Stage IVB and Recurrent Cervical Cancer
Drug Name Response Rate
Cisplatin [8] 15%–25%
Ifosfamide [9,10] 15%–30%
Paclitaxel [11] 17%
Irinotecan [12] 21% in patients previously treated with chemotherapy
Bevacizumab [13] 11%; 24% survived progression free for at least 6 months, as seen in GOG-0227C (NCT00025233)
Ifosfamide/cisplatin [14,15] 31%
Paclitaxel/cisplatin [16] 46%
Cisplatin/gemcitabine [17] 41%
Cisplatin/topotecan [18] 27%
Cisplatin/vinorelbine [19] 30%
Cisplatin in combination with other drugs

Since the drug was initially introduced in the 1970s, the regimen used most often to treat recurrent cervical cancer has been single-agent cisplatin given intravenously at 50 mg/m² every 3 weeks.[8] The Gynecologic Oncology Group (GOG) reported on sequential randomized trials of combination chemotherapy for stage IVB, recurrent, or persistent cervical cancer.[15,18,20–23]

Evidence (cisplatin in combination with other drugs):

  1. GOG-110, GOG-0179, GOG-0169 (NCT00803062)
    • GOG-110: The ifosfamide + cisplatin combination was superior to cisplatin alone in the secondary end point of response rates, but at the cost of increased toxicity.
    • GOG-0179: The cisplatin + topotecan (CT) doublet combination had a significant advantage in OS compared with cisplatin alone, leading to approval of this indication for topotecan by the FDA. However, cisplatin alone underperformed in this trial because as many as 40% of the patients had already received cisplatin up front as a radiosensitizer.[18]
    • GOG-0169: The paclitaxel + cisplatin (PC) combination, similarly, was superior in response rates and PFS, and its toxicity was similar to that of the single agent except in patients with GOG performance status 2 (scale: 0, asymptomatic–4, totally bedridden). Therefore, PC was chosen as the reference arm in GOG-0204 (NCT00064077).
  2. GOG-0204 enrolled 513 patients and compared four cisplatin-based doublet regimens. The trial was closed early because no one experimental arm was likely to significantly lower the HRdeath relative to PC:[23]
    • 1.15 (95% CI, 0.79–1.67) for vinorelbine + cisplatin (VC).
    • 1.32 (95% CI, 0.91–1.92) for gemcitabine plus cisplatin.
    • 1.27 (95% CI, 0.90–1.78) for CT. Trends in response rate, PFS, and OS favored CT.
    • Patients in the four study arms experienced different grades of neutropenia, infection, and alopecia.[23] There were no differences in health-related quality of life during treatment.[24] However, patients who received PC had more neurological side effects.

Pelvic exenteration

No standard treatment is available for patients with recurrent cervical cancer that has spread beyond the confines of a radiation or surgical field. For locally recurrent disease, pelvic exenteration can lead to 5-year survival rates of 32% to 62% in selected patients.[25,26] These patients are appropriate candidates for clinical trials testing drug combinations or new anticancer agents.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References
  1. Oaknin A, Gladieff L, Martínez-García J, et al.: Atezolizumab plus bevacizumab and chemotherapy for metastatic, persistent, or recurrent cervical cancer (BEATcc): a randomised, open-label, phase 3 trial. Lancet 403 (10421): 31-43, 2024. [PUBMED Abstract]
  2. Monk BJ, Colombo N, Tewari KS, et al.: First-Line Pembrolizumab + Chemotherapy Versus Placebo + Chemotherapy for Persistent, Recurrent, or Metastatic Cervical Cancer: Final Overall Survival Results of KEYNOTE-826. J Clin Oncol 41 (36): 5505-5511, 2023. [PUBMED Abstract]
  3. Lorusso D, Xiang Y, Hasegawa K, et al.: Pembrolizumab or placebo with chemoradiotherapy followed by pembrolizumab or placebo for newly diagnosed, high-risk, locally advanced cervical cancer (ENGOT-cx11/GOG-3047/KEYNOTE-A18): a randomised, double-blind, phase 3 clinical trial. Lancet 403 (10434): 1341-1350, 2024. [PUBMED Abstract]
  4. Chung HC, Schellens JHM, Delord JP, et al.: Pembrolizumab treatment of advanced cervical cancer: updated results from the phase 2 KEYNOTE-158 study. [Abstract] J Clin Oncol 36 (Suppl 18): A-5522, 2018.
  5. Tewari KS, Sill MW, Long HJ, et al.: Improved survival with bevacizumab in advanced cervical cancer. N Engl J Med 370 (8): 734-43, 2014. [PUBMED Abstract]
  6. Vergote I, González-Martín A, Fujiwara K, et al.: Tisotumab Vedotin as Second- or Third-Line Therapy for Recurrent Cervical Cancer. N Engl J Med 391 (1): 44-55, 2024. [PUBMED Abstract]
  7. Thomas GM, Dembo AJ, Black B, et al.: Concurrent radiation and chemotherapy for carcinoma of the cervix recurrent after radical surgery. Gynecol Oncol 27 (3): 254-63, 1987. [PUBMED Abstract]
  8. Thigpen JT, Blessing JA, DiSaia PJ, et al.: A randomized comparison of a rapid versus prolonged (24 hr) infusion of cisplatin in therapy of squamous cell carcinoma of the uterine cervix: a Gynecologic Oncology Group study. Gynecol Oncol 32 (2): 198-202, 1989. [PUBMED Abstract]
  9. Coleman RE, Harper PG, Gallagher C, et al.: A phase II study of ifosfamide in advanced and relapsed carcinoma of the cervix. Cancer Chemother Pharmacol 18 (3): 280-3, 1986. [PUBMED Abstract]
  10. Sutton GP, Blessing JA, McGuire WP, et al.: Phase II trial of ifosfamide and mesna in patients with advanced or recurrent squamous carcinoma of the cervix who had never received chemotherapy: a Gynecologic Oncology Group study. Am J Obstet Gynecol 168 (3 Pt 1): 805-7, 1993. [PUBMED Abstract]
  11. McGuire WP, Blessing JA, Moore D, et al.: Paclitaxel has moderate activity in squamous cervix cancer. A Gynecologic Oncology Group study. J Clin Oncol 14 (3): 792-5, 1996. [PUBMED Abstract]
  12. Verschraegen CF, Levy T, Kudelka AP, et al.: Phase II study of irinotecan in prior chemotherapy-treated squamous cell carcinoma of the cervix. J Clin Oncol 15 (2): 625-31, 1997. [PUBMED Abstract]
  13. Monk BJ, Sill MW, Burger RA, et al.: Phase II trial of bevacizumab in the treatment of persistent or recurrent squamous cell carcinoma of the cervix: a gynecologic oncology group study. J Clin Oncol 27 (7): 1069-74, 2009. [PUBMED Abstract]
  14. Buxton EJ, Meanwell CA, Hilton C, et al.: Combination bleomycin, ifosfamide, and cisplatin chemotherapy in cervical cancer. J Natl Cancer Inst 81 (5): 359-61, 1989. [PUBMED Abstract]
  15. Omura GA, Blessing JA, Vaccarello L, et al.: Randomized trial of cisplatin versus cisplatin plus mitolactol versus cisplatin plus ifosfamide in advanced squamous carcinoma of the cervix: a Gynecologic Oncology Group study. J Clin Oncol 15 (1): 165-71, 1997. [PUBMED Abstract]
  16. Rose PG, Blessing JA, Gershenson DM, et al.: Paclitaxel and cisplatin as first-line therapy in recurrent or advanced squamous cell carcinoma of the cervix: a gynecologic oncology group study. J Clin Oncol 17 (9): 2676-80, 1999. [PUBMED Abstract]
  17. Burnett AF, Roman LD, Garcia AA, et al.: A phase II study of gemcitabine and cisplatin in patients with advanced, persistent, or recurrent squamous cell carcinoma of the cervix. Gynecol Oncol 76 (1): 63-6, 2000. [PUBMED Abstract]
  18. Long HJ, Bundy BN, Grendys EC, et al.: Randomized phase III trial of cisplatin with or without topotecan in carcinoma of the uterine cervix: a Gynecologic Oncology Group Study. J Clin Oncol 23 (21): 4626-33, 2005. [PUBMED Abstract]
  19. Morris M, Blessing JA, Monk BJ, et al.: Phase II study of cisplatin and vinorelbine in squamous cell carcinoma of the cervix: a Gynecologic Oncology Group study. J Clin Oncol 22 (16): 3340-4, 2004. [PUBMED Abstract]
  20. Tewari KS, Monk BJ: Gynecologic oncology group trials of chemotherapy for metastatic and recurrent cervical cancer. Curr Oncol Rep 7 (6): 419-34, 2005. [PUBMED Abstract]
  21. Moore DH, Blessing JA, McQuellon RP, et al.: Phase III study of cisplatin with or without paclitaxel in stage IVB, recurrent, or persistent squamous cell carcinoma of the cervix: a Gynecologic Oncology Group study. J Clin Oncol 22 (15): 3113-9, 2004. [PUBMED Abstract]
  22. Tewari KS, Monk BJ: Recent achievements and future developments in advanced and recurrent cervical cancer: trials of the Gynecologic Oncology Group. Semin Oncol 36 (2): 170-80, 2009. [PUBMED Abstract]
  23. Monk BJ, Sill MW, McMeekin DS, et al.: Phase III trial of four cisplatin-containing doublet combinations in stage IVB, recurrent, or persistent cervical carcinoma: a Gynecologic Oncology Group study. J Clin Oncol 27 (28): 4649-55, 2009. [PUBMED Abstract]
  24. Cella D, Huang HQ, Monk BJ, et al.: Health-related quality of life outcomes associated with four cisplatin-based doublet chemotherapy regimens for stage IVB recurrent or persistent cervical cancer: a Gynecologic Oncology Group study. Gynecol Oncol 119 (3): 531-7, 2010. [PUBMED Abstract]
  25. Alberts DS, Kronmal R, Baker LH, et al.: Phase II randomized trial of cisplatin chemotherapy regimens in the treatment of recurrent or metastatic squamous cell cancer of the cervix: a Southwest Oncology Group Study. J Clin Oncol 5 (11): 1791-5, 1987. [PUBMED Abstract]
  26. Tumors of the cervix. In: Morrow CP, Curtin JP: Synopsis of Gynecologic Oncology. 5th ed. Churchill Livingstone, 1998, pp 107-151.

Latest Updates to This Summary (05/13/2025)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Editorial changes were made to this summary.

This summary is written and maintained by the PDQ Adult Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® Cancer Information for Health Professionals pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of cervical cancer. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

  • be discussed at a meeting,
  • be cited with text, or
  • replace or update an existing article that is already cited.

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewer for Cervical Cancer Treatment is:

  • Olga T. Filippova, MD (Lenox Hill Hospital)

Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website’s Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

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The preferred citation for this PDQ summary is:

PDQ® Adult Treatment Editorial Board. PDQ Cervical Cancer Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /types/cervical/hp/cervical-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389493]

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Vaginal Cancer Treatment (PDQ®)–Health Professional Version

Vaginal Cancer Treatment (PDQ®)–Health Professional Version

General Information About Vaginal Cancer

Go to Patient Version

Carcinomas of the vagina are uncommon tumors comprising about 2% of the cancers that arise in the female genital system.[1] Squamous cell carcinoma (SCC) accounts for approximately 80% to 90% of vaginal cancer cases and adenocarcinoma accounts for 5% to 10% of vaginal cancer cases.[1]

Rarely, melanomas (often nonpigmented), sarcomas, small-cell carcinomas, lymphomas, or carcinoid tumors have been described as primary vaginal cancers. The natural history, prognosis, and treatment of other primary vaginal cancers are different and are not covered in this summary.

Distant hematogenous metastases occur most commonly in the lungs, and, less frequently, in the liver, bone, or other sites.[1]

The American Joint Committee on Cancer staging system classifies tumors in the vagina that involve the cervix of women with an intact uterus as cervical cancers.[2] Therefore, tumors that originated in the apical vagina but extend to the cervix are classified as cervical cancers. For more information, see Cervical Cancer Treatment.

Incidence and Mortality

Estimated new cases and deaths from vaginal and other female genital cancer in the United States in 2025:[3]

  • New cases: 8,070.
  • Deaths: 1,950.

Anatomy

EnlargeAnatomy of the female reproductive system; drawing shows the uterus, myometrium (muscular outer layer of the uterus), endometrium (inner lining of the uterus), ovaries, fallopian tubes, cervix, and vagina.
Normal female reproductive system anatomy.

Risk Factors

Increasing age is the most important risk factor for most cancers. Other risk factors for vaginal cancer include:

  • Human papillomavirus (HPV) infection. SCC of the vagina is associated with a high rate of infection with oncogenic strains of HPV. SCC of the vagina and SCC of the cervix have many common risk factors.[4–6] HPV infection has also been described in a case of vaginal adenocarcinoma.[6] For more information, see Cervical Cancer Treatment.
  • Diethylstilbestrol (DES) exposure in utero. A rare form of adenocarcinoma, known as clear cell carcinoma, occurs in association with in utero exposure to DES, with a peak incidence before age 30 years. This association was first reported in 1971.[7] The incidence of this disease, which is highest for those exposed during the first trimester, peaked in the mid-1970s, reflecting the use of DES in the 1950s. It is extremely rare now.[1] However, women with a known history of in utero DES exposure should be carefully monitored for possible presence of this tumor. (This association was mainly applicable to vaginal cancers diagnosed in younger women since adenocarcinomas that are not associated with DES exposure occur primarily during postmenopausal years.)

    Vaginal adenosis is most commonly found in young women who had in utero exposure to DES and may coexist with a clear cell adenocarcinoma, although it rarely progresses to adenocarcinoma. Adenosis is replaced by squamous metaplasia, which occurs naturally, and requires follow-up but not removal.

  • History of hysterectomy. Women who have had a hysterectomy for benign, premalignant, or malignant disease are at risk of vaginal carcinomas.[8] In a retrospective series of 100 women studied over 30 years, 50% had undergone hysterectomy before the diagnosis of vaginal cancer.[8] In the posthysterectomy group, 31 of 50 women (62%) developed cancers limited to the upper third of the vagina. In women who had not previously undergone hysterectomy, upper vaginal lesions were found in 17 of 50 women (34%).

Clinical Features

Although early vaginal cancer may not cause noticeable signs or symptoms, possible signs and symptoms of vaginal cancer include:

  • Metrorrhagia.
  • Dyspareunia.
  • Pelvic pain.
  • Vaginal mass.
  • Dysuria.
  • Constipation.

Diagnostic Evaluation

The following procedures may be used to diagnose vaginal cancer:

  • History and physical examination.
  • Pelvic examination.
  • Cervical cytology (Pap smear).
  • HPV testing.
  • Colposcopy.
  • Biopsy. If the cervix is intact, biopsies are mandatory to rule out a primary carcinoma of the cervix. Carcinoma of the vulva should also be ruled out.

Prognostic Factors

Prognosis depends primarily on the stage of disease, but survival is reduced among women with the following features:

  • Age older than 60 years.
  • Symptomatic at the time of diagnosis.
  • Lesions of the middle and lower third of the vagina.
  • Poorly differentiated tumors.

In addition, the length of vaginal wall involvement has been found to be associated with survival and stage of disease in patients with vaginal SCC.

Follow-Up After Treatment

Similar to other gynecologic malignancies, the evidence to support surveillance after initial management of vaginal cancer is weak because of a lack of randomized or prospective clinical studies.[9] There is no reliable evidence that routine cytological or imaging procedures in patients improves health outcomes beyond what is achieved by careful physical examination and assessment of new symptoms. Therefore, outside the investigational setting, imaging procedures may be reserved for patients in whom physical examination or symptoms raise clinical suspicion of a recurrence or progression.

References
  1. Eifel PJ, Klopp AH, Berek JS, et al.: Cancer of the cervix, vagina, and vulva. In: DeVita VT Jr, Lawrence TS, Rosenberg SA, et al., eds.: DeVita, Hellman, and Rosenberg’s Cancer: Principles & Practice of Oncology. 11th ed. Wolters Kluwer, 2019, pp 1171-1210.
  2. Vagina. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. Springer; 2017, pp 641–7.
  3. American Cancer Society: Cancer Facts and Figures 2025. American Cancer Society, 2025. Available online. Last accessed January 16, 2025.
  4. Daling JR, Madeleine MM, Schwartz SM, et al.: A population-based study of squamous cell vaginal cancer: HPV and cofactors. Gynecol Oncol 84 (2): 263-70, 2002. [PUBMED Abstract]
  5. Parkin DM: The global health burden of infection-associated cancers in the year 2002. Int J Cancer 118 (12): 3030-44, 2006. [PUBMED Abstract]
  6. Ikenberg H, Runge M, Göppinger A, et al.: Human papillomavirus DNA in invasive carcinoma of the vagina. Obstet Gynecol 76 (3 Pt 1): 432-8, 1990. [PUBMED Abstract]
  7. Herbst AL, Ulfelder H, Poskanzer DC: Adenocarcinoma of the vagina. Association of maternal stilbestrol therapy with tumor appearance in young women. N Engl J Med 284 (15): 878-81, 1971. [PUBMED Abstract]
  8. Stock RG, Chen AS, Seski J: A 30-year experience in the management of primary carcinoma of the vagina: analysis of prognostic factors and treatment modalities. Gynecol Oncol 56 (1): 45-52, 1995. [PUBMED Abstract]
  9. Salani R, Backes FJ, Fung MF, et al.: Posttreatment surveillance and diagnosis of recurrence in women with gynecologic malignancies: Society of Gynecologic Oncologists recommendations. Am J Obstet Gynecol 204 (6): 466-78, 2011. [PUBMED Abstract]

Stage Information for Vaginal Cancer

FIGO Staging System

The Fédération Internationale de Gynécologie et d’Obstétrique (FIGO) and the American Joint Committee on Cancer (AJCC) have designated staging to define vaginal cancer. The FIGO system is the most commonly used staging system for vaginal cancer.[1–3]

Table 1. Carcinoma of the Vaginaa
FIGO Nomenclature
FIGO = Fédération Internationale de Gynécologie et d’Obstétrique.
aAdapted from FIGO Committee on Gynecologic Oncology.[1,2]
Stage I The carcinoma is limited to the vaginal wall.
Stage II The carcinoma has involved the subvaginal tissue but has not extended to the pelvic wall.
Stage III The carcinoma has extended to the pelvic wall.
Stage IV The carcinoma has extended beyond the true pelvis or has involved the mucosa of the bladder or rectum; bullous edemas as such does not permit a case to be allotted to stage IV.
IVa – Tumor invades bladder and/or rectal mucosa and/or direct extension beyond the true pelvis.
IVb – Spread to distant organs.

In addition, the FIGO staging system incorporates a modified World Health Organization prognostic scoring system. The scores from the eight risk factors are summed and incorporated into the FIGO stage, separated by a colon (e.g., stage II:4, stage IV:9, etc.). Unfortunately, a variety of risk-scoring systems have been published, making comparisons of results difficult.

References
  1. FIGO Committee on Gynecologic Oncology: Current FIGO staging for cancer of the vagina, fallopian tube, ovary, and gestational trophoblastic neoplasia. Int J Gynaecol Obstet 105 (1): 3-4, 2009. [PUBMED Abstract]
  2. Adams TS, Rogers LJ, Cuello MA: Cancer of the vagina: 2021 update. Int J Gynaecol Obstet 155 (Suppl 1): 19-27, 2021. [PUBMED Abstract]
  3. Vagina. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. Springer; 2017, pp 641–7.

Treatment Option Overview for Vaginal Cancer

Because vaginal cancer is rare, studies are limited to retrospective case series, usually from single-referral institutions.[Level of evidence C2] During the long span of time covered by these case series, available staging tests and radiation techniques often changed, including the shift to high-energy accelerators and conformal and intensity-modulated radiation therapy.[1,2] Comparing treatment approaches is further complicated by the frequent failure of investigators to provide precise staging criteria (particularly for stage I vs. stage II disease) or criteria for the choice of treatment modality. This has led to a broad range of reported disease control and survival rates for any given stage and treatment modality.[3]

The following factors should be considered when planning treatment for vaginal cancer:

  • Stage and size of the lesion.
  • Ability to retain a functional vagina.
  • Presence or absence of the uterus.
  • Whether the patient has received previous pelvic radiation therapy.
  • Whether the lymphatics drain to pelvic or inguinal nodes or both, depending on tumor location.
  • Proximity of the vagina to the bladder or rectum. This limits surgical treatment options and increases short-term and long-term surgical complications and functional deficits.
  • Proximity to radiosensitive organs or organs that preclude radical resection without unacceptable functional deficits (e.g., bladder, rectum, urethra).

Radiation-induced damage to nearby organs may include:[1,2]

  • Rectovaginal fistulas.
  • Vesicovaginal fistulas.
  • Rectal or vaginal strictures.
  • Cystitis.
  • Proctitis.
  • Premature menopause from ovarian damage.
  • Soft tissue or bone necrosis.

Management of the extremely rare vaginal clear cell carcinoma is similar to the management of squamous cell carcinoma. However, techniques that preserve vaginal and ovarian function should be strongly considered during treatment planning, given the young age of the patients at diagnosis.[4]

Table 2. Treatment Options for Vaginal Cancer
Stage (FIGO Staging System) Treatment Options
FIGO = Fédération Internationale de Gynécologie et d’Obstétrique; SCC = squamous cell carcinoma; VaIN = vaginal intraepithelial neoplasia.
VaIN (this stage is not recognized by FIGO) Laser therapy
Wide local excision
Vaginectomy
Intravaginal chemotherapy
Intracavitary radiation therapy
Imiquimod
Stage I vaginal cancer SCC Radiation therapy
Surgery
Adenocarcinoma Surgery
Radiation therapy
Combined local therapy
Stages II, III, and IVa vaginal cancer (SCC and adenocarcinoma) Radiation therapy
Surgery
Chemoradiation
Stage IVb vaginal cancer (SCC and adenocarcinoma) Radiation therapy

For patients with early-stage vaginal carcinoma, radiation therapy, surgery, or a combination of these treatments are standard. Data from randomized trials are lacking, and the choice of therapy is generally determined by institutional experience and the factors listed above.[3]

For patients with stages III and IVa disease, radiation therapy is standard and includes external-beam radiation therapy (EBRT), alone or with brachytherapy. Regional lymph nodes are included in the radiation portal. When used alone, EBRT involves a tumor dose of 65 Gy to 70 Gy, using shrinking fields, delivered within 6 to 7 weeks. Intracavitary brachytherapy provides insufficient dose penetration for locally advanced tumors, so interstitial brachytherapy is used if brachytherapy is given.[3,5]

For patients with stage IVb or recurrent disease that cannot be managed with local treatments, current therapy is inadequate. No established anticancer drugs have demonstrated proven clinical benefit, although patients are often treated with regimens used to treat cervical cancer. Concurrent chemotherapy, using fluorouracil or cisplatin-based therapy, and radiation are sometimes advocated, based solely on extrapolation from cervical cancer management strategies.[6–8] Evidence is limited to small case series and the incremental impact on survival and local control is not well defined.[Level of evidence C3]

Local control is a problem with bulky tumors. Some investigators have also used concurrent chemotherapy with agents such as cisplatin, bleomycin, mitomycin, floxuridine, and vincristine without improved outcomes.[1] It is an extrapolation from treatment approaches used in cervical cancer, based on shared etiologic and risk factors.

Because vaginal cancer is rare, these patients are candidates for clinical trials of anticancer drugs and/or radiosensitizers to attempt to improve survival or local control. Discussion of clinical trials should be considered with eligible patients. Information about ongoing clinical trials is available from the NCI website.

Fluorouracil Dosing

The DPYD gene encodes an enzyme that catabolizes pyrimidines and fluoropyrimidines, like capecitabine and fluorouracil. An estimated 1% to 2% of the population has germline pathogenic variants in DPYD, which lead to reduced DPD protein function and an accumulation of pyrimidines and fluoropyrimidines in the body.[9,10] Patients with the DPYD*2A variant who receive fluoropyrimidines may experience severe, life-threatening toxicities that are sometimes fatal. Many other DPYD variants have been identified, with a range of clinical effects.[9–11] Fluoropyrimidine avoidance or a dose reduction of 50% may be recommended based on the patient’s DPYD genotype and number of functioning DPYD alleles.[12–14] DPYD genetic testing costs less than $200, but insurance coverage varies due to a lack of national guidelines.[15] In addition, testing may delay therapy by 2 weeks, which would not be advisable in urgent situations. This controversial issue requires further evaluation.[16]

References
  1. Frank SJ, Jhingran A, Levenback C, et al.: Definitive radiation therapy for squamous cell carcinoma of the vagina. Int J Radiat Oncol Biol Phys 62 (1): 138-47, 2005. [PUBMED Abstract]
  2. Tran PT, Su Z, Lee P, et al.: Prognostic factors for outcomes and complications for primary squamous cell carcinoma of the vagina treated with radiation. Gynecol Oncol 105 (3): 641-9, 2007. [PUBMED Abstract]
  3. Eifel PJ, Klopp AH, Berek JS, et al.: Cancer of the cervix, vagina, and vulva. In: DeVita VT Jr, Lawrence TS, Rosenberg SA, et al., eds.: DeVita, Hellman, and Rosenberg’s Cancer: Principles & Practice of Oncology. 11th ed. Wolters Kluwer, 2019, pp 1171-1210.
  4. Senekjian EK, Frey KW, Anderson D, et al.: Local therapy in stage I clear cell adenocarcinoma of the vagina. Cancer 60 (6): 1319-24, 1987. [PUBMED Abstract]
  5. Chyle V, Zagars GK, Wheeler JA, et al.: Definitive radiotherapy for carcinoma of the vagina: outcome and prognostic factors. Int J Radiat Oncol Biol Phys 35 (5): 891-905, 1996. [PUBMED Abstract]
  6. Grigsby PW: Vaginal cancer. Curr Treat Options Oncol 3 (2): 125-30, 2002. [PUBMED Abstract]
  7. Dalrymple JL, Russell AH, Lee SW, et al.: Chemoradiation for primary invasive squamous carcinoma of the vagina. Int J Gynecol Cancer 14 (1): 110-7, 2004 Jan-Feb. [PUBMED Abstract]
  8. Samant R, Lau B, E C, et al.: Primary vaginal cancer treated with concurrent chemoradiation using Cis-platinum. Int J Radiat Oncol Biol Phys 69 (3): 746-50, 2007. [PUBMED Abstract]
  9. Sharma BB, Rai K, Blunt H, et al.: Pathogenic DPYD Variants and Treatment-Related Mortality in Patients Receiving Fluoropyrimidine Chemotherapy: A Systematic Review and Meta-Analysis. Oncologist 26 (12): 1008-1016, 2021. [PUBMED Abstract]
  10. Lam SW, Guchelaar HJ, Boven E: The role of pharmacogenetics in capecitabine efficacy and toxicity. Cancer Treat Rev 50: 9-22, 2016. [PUBMED Abstract]
  11. Shakeel F, Fang F, Kwon JW, et al.: Patients carrying DPYD variant alleles have increased risk of severe toxicity and related treatment modifications during fluoropyrimidine chemotherapy. Pharmacogenomics 22 (3): 145-155, 2021. [PUBMED Abstract]
  12. Amstutz U, Henricks LM, Offer SM, et al.: Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Dihydropyrimidine Dehydrogenase Genotype and Fluoropyrimidine Dosing: 2017 Update. Clin Pharmacol Ther 103 (2): 210-216, 2018. [PUBMED Abstract]
  13. Henricks LM, Lunenburg CATC, de Man FM, et al.: DPYD genotype-guided dose individualisation of fluoropyrimidine therapy in patients with cancer: a prospective safety analysis. Lancet Oncol 19 (11): 1459-1467, 2018. [PUBMED Abstract]
  14. Lau-Min KS, Varughese LA, Nelson MN, et al.: Preemptive pharmacogenetic testing to guide chemotherapy dosing in patients with gastrointestinal malignancies: a qualitative study of barriers to implementation. BMC Cancer 22 (1): 47, 2022. [PUBMED Abstract]
  15. Brooks GA, Tapp S, Daly AT, et al.: Cost-effectiveness of DPYD Genotyping Prior to Fluoropyrimidine-based Adjuvant Chemotherapy for Colon Cancer. Clin Colorectal Cancer 21 (3): e189-e195, 2022. [PUBMED Abstract]
  16. Baker SD, Bates SE, Brooks GA, et al.: DPYD Testing: Time to Put Patient Safety First. J Clin Oncol 41 (15): 2701-2705, 2023. [PUBMED Abstract]

Treatment of Vaginal Intraepithelial Neoplasia

Vaginal intraepithelial neoplasia (VaIN), the presence of noninvasive squamous cell atypia, is classified by the degree of involvement of the epithelium, as follows:

  • VaIN 1 is defined as involvement of the upper one-third of the epithelial thickness.
  • VaIN 2 is defined as involvement of the upper two-thirds of the epithelial thickness.
  • VaIN 3 is defined as involvement of more than two-thirds of the epithelial thickness. VaIN 3 lesions that involve the full thickness of the epithelium are called carcinoma in situ.

VaIN is associated with a high rate of human papillomavirus (HPV) infection and is thought to have an etiology that is similar to that of cervical intraepithelial neoplasia (CIN).[1–3]

The cervix and vulva are carefully evaluated because vaginal carcinoma in situ is associated with other genital neoplasia, and in some cases, may be an extension of CIN. Vaginal carcinoma in situ is often multifocal and commonly occurs in the vaginal vault. For more information, see Cervical Cancer Treatment.

The extent and type of surgical treatment needed is dependent upon anatomical location, evidence of multifocality, general patient comorbidities, and other specific factors (e.g., anatomical distortion of vaginal vault from prior hysterectomy).[4]

Treatment Options for VaIN

The following treatments have not been directly compared in randomized trials, so their relative efficacy is uncertain.[Level of evidence C3]

Treatment options for VaIN include:

  1. Laser therapy [5] after biopsy to rule out invasive components that could be missed with this treatment approach.
  2. Wide local excision with or without skin grafting.[6]
  3. Partial or total vaginectomy, with skin grafting for multifocal or extensive disease.[7]
  4. Intravaginal chemotherapy with 5% fluorouracil (5-FU) cream. This option may be useful in the setting of multifocal lesions.[5,8]
  5. Intracavitary radiation therapy.[9,10] Because of its attendant toxicity and inherent carcinogenicity, this treatment is primarily used in the setting of multifocal or recurrent disease, or when the risk of surgery is high.[1] The entire vaginal mucosa is usually treated.[11]
  6. Imiquimod cream 5%, an immune stimulant used to treat genital warts, is an additional topical therapy that has a reported complete clinical response rate of 50% to 86% in small case series of patients with multifocal high-grade HPV-associated VaIN 2 and VaIN 3.[12] However, it is investigational, and it may have only short-lived efficacy.[13]

Women with VaIN 1 can usually be observed carefully without ablative or surgical treatment because the lesions often regress spontaneously. VaIN 2, the intermediate grade, is managed by careful observation or initial treatment. Although the natural history of VaIN is not precisely known because of its rarity, patients with VaIN 3 are presumed to be at substantial risk of progression to invasive cancer and are treated immediately. Lesions with hyperkeratosis respond better to excision or laser vaporization than to 5-FU.[4]

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References
  1. Eifel PJ, Klopp AH, Berek JS, et al.: Cancer of the cervix, vagina, and vulva. In: DeVita VT Jr, Lawrence TS, Rosenberg SA, et al., eds.: DeVita, Hellman, and Rosenberg’s Cancer: Principles & Practice of Oncology. 11th ed. Wolters Kluwer, 2019, pp 1171-1210.
  2. Daling JR, Madeleine MM, Schwartz SM, et al.: A population-based study of squamous cell vaginal cancer: HPV and cofactors. Gynecol Oncol 84 (2): 263-70, 2002. [PUBMED Abstract]
  3. Smith JS, Backes DM, Hoots BE, et al.: Human papillomavirus type-distribution in vulvar and vaginal cancers and their associated precursors. Obstet Gynecol 113 (4): 917-24, 2009. [PUBMED Abstract]
  4. Wright VC, Chapman W: Intraepithelial neoplasia of the lower female genital tract: etiology, investigation, and management. Semin Surg Oncol 8 (4): 180-90, 1992 Jul-Aug. [PUBMED Abstract]
  5. Krebs HB: Treatment of vaginal intraepithelial neoplasia with laser and topical 5-fluorouracil. Obstet Gynecol 73 (4): 657-60, 1989. [PUBMED Abstract]
  6. Cheng D, Ng TY, Ngan HY, et al.: Wide local excision (WLE) for vaginal intraepithelial neoplasia (VAIN). Acta Obstet Gynecol Scand 78 (7): 648-52, 1999. [PUBMED Abstract]
  7. Indermaur MD, Martino MA, Fiorica JV, et al.: Upper vaginectomy for the treatment of vaginal intraepithelial neoplasia. Am J Obstet Gynecol 193 (2): 577-80; discussion 580-1, 2005. [PUBMED Abstract]
  8. Stefanon B, Pallucca A, Merola M, et al.: Treatment with 5-fluorouracil of 35 patients with clinical or subclinical HPV infection of the vagina. Eur J Gynaecol Oncol 17 (6): 534, 1996. [PUBMED Abstract]
  9. Chyle V, Zagars GK, Wheeler JA, et al.: Definitive radiotherapy for carcinoma of the vagina: outcome and prognostic factors. Int J Radiat Oncol Biol Phys 35 (5): 891-905, 1996. [PUBMED Abstract]
  10. Graham K, Wright K, Cadwallader B, et al.: 20-year retrospective review of medium dose rate intracavitary brachytherapy in VAIN3. Gynecol Oncol 106 (1): 105-11, 2007. [PUBMED Abstract]
  11. Kang J, Wethington SL, Viswanathan A: Vaginal cancer. In: Halperin EC, Wazer DE, Perez CE, et al., eds.: Perez & Brady’s Principles and Practice of Radiation Oncology. 7th ed. Wolters Kluwer, 2018, pp 1786-1816.
  12. Iavazzo C, Pitsouni E, Athanasiou S, et al.: Imiquimod for treatment of vulvar and vaginal intraepithelial neoplasia. Int J Gynaecol Obstet 101 (1): 3-10, 2008. [PUBMED Abstract]
  13. Haidopoulos D, Diakomanolis E, Rodolakis A, et al.: Can local application of imiquimod cream be an alternative mode of therapy for patients with high-grade intraepithelial lesions of the vagina? Int J Gynecol Cancer 15 (5): 898-902, 2005 Sep-Oct. [PUBMED Abstract]

Treatment of Stage I Vaginal Cancer

The treatment options for stage I vaginal cancer have not been directly compared in randomized trials.[Level of evidence C2] Because of differences in patient selection, expertise in treating local disease, and staging criteria, it is difficult to determine whether there are differences in disease control rates.

Treatment Options for Stage I Squamous Cell Carcinoma (SCC) of the Vagina

Treatment options for stage I SCC of the vagina superficial lesions less than 0.5 cm thick include:

  1. Radiation therapy.[1–4]
    • These tumors may respond to intracavitary brachytherapy alone,[1] but treatment usually begins with external-beam radiation therapy (EBRT).[2]
    • EBRT is required for bulky lesions or lesions that encompass the entire vagina.[1] For lesions in the lower third of the vagina, elective radiation therapy is often administered to the patient’s pelvic and/or inguinal lymph nodes.[1,2]
  2. Surgery.[5]
    • Wide local excision or total vaginectomy with vaginal reconstruction may be performed, especially in lesions of the upper vagina. In cases with close or positive surgical margins, adjuvant radiation therapy is often added.[6]

Treatment options for stage I SCC of the vagina lesions more than 0.5 cm thick include:

  1. Surgery.[5]
    • For lesions in the upper third of the vagina, radical vaginectomy and pelvic lymphadenectomy should be considered. Construction of a neovagina may be performed if feasible and if desired by the patient.[6,7]
    • In lesions of the lower third, inguinal lymphadenectomy should be considered. In cases with close or positive surgical margins, adjuvant radiation therapy should be considered.[6]
  2. Radiation therapy.[1–4]
    • EBRT [2] and/or combination of interstitial and intracavitary radiation therapy may be administered to a dose of at least 75 Gy to the primary tumor.[1,8]
    • For lesions of the lower third of the vagina, elective radiation therapy of 45 Gy to 50 Gy is given to the pelvic and/or inguinal lymph nodes.[1,2]

Treatment Options for Stage I Adenocarcinoma of the Vagina

Treatment options for stage I adenocarcinoma of the vagina include:

  1. Surgery.
    • Total radical vaginectomy and hysterectomy with lymph node dissection are indicated because the tumor spreads subepithelially.
    • The deep pelvic lymph nodes are dissected if the lesion invades the upper vagina, and the inguinal lymph nodes are removed if the lesion originates in the lower vagina.
    • Construction of a neovagina may be performed if feasible and if desired by the patient.[6]
    • In cases with close or positive surgical margins, adjuvant radiation therapy is often given.[6,7]
  2. Radiation therapy.
    • Intracavitary and interstitial radiation are administered to a dose of at least 75 Gy to the primary tumor.[1]
    • For lesions in the lower third of the vagina, elective radiation therapy of 45 Gy to 50 Gy is given to the pelvic and/or inguinal lymph nodes.[1,9]
  3. Combined local therapy in selected cases, which may include wide local excision, lymph node sampling, and interstitial therapy.[10]

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References
  1. Perez CA, Camel HM, Galakatos AE, et al.: Definitive irradiation in carcinoma of the vagina: long-term evaluation of results. Int J Radiat Oncol Biol Phys 15 (6): 1283-90, 1988. [PUBMED Abstract]
  2. Frank SJ, Jhingran A, Levenback C, et al.: Definitive radiation therapy for squamous cell carcinoma of the vagina. Int J Radiat Oncol Biol Phys 62 (1): 138-47, 2005. [PUBMED Abstract]
  3. Tran PT, Su Z, Lee P, et al.: Prognostic factors for outcomes and complications for primary squamous cell carcinoma of the vagina treated with radiation. Gynecol Oncol 105 (3): 641-9, 2007. [PUBMED Abstract]
  4. Lian J, Dundas G, Carlone M, et al.: Twenty-year review of radiotherapy for vaginal cancer: an institutional experience. Gynecol Oncol 111 (2): 298-306, 2008. [PUBMED Abstract]
  5. Tjalma WA, Monaghan JM, de Barros Lopes A, et al.: The role of surgery in invasive squamous carcinoma of the vagina. Gynecol Oncol 81 (3): 360-5, 2001. [PUBMED Abstract]
  6. Stock RG, Chen AS, Seski J: A 30-year experience in the management of primary carcinoma of the vagina: analysis of prognostic factors and treatment modalities. Gynecol Oncol 56 (1): 45-52, 1995. [PUBMED Abstract]
  7. Rubin SC, Young J, Mikuta JJ: Squamous carcinoma of the vagina: treatment, complications, and long-term follow-up. Gynecol Oncol 20 (3): 346-53, 1985. [PUBMED Abstract]
  8. Andersen ES: Primary carcinoma of the vagina: a study of 29 cases. Gynecol Oncol 33 (3): 317-20, 1989. [PUBMED Abstract]
  9. Chyle V, Zagars GK, Wheeler JA, et al.: Definitive radiotherapy for carcinoma of the vagina: outcome and prognostic factors. Int J Radiat Oncol Biol Phys 35 (5): 891-905, 1996. [PUBMED Abstract]
  10. Senekjian EK, Frey KW, Anderson D, et al.: Local therapy in stage I clear cell adenocarcinoma of the vagina. Cancer 60 (6): 1319-24, 1987. [PUBMED Abstract]

Treatment of Stages II, III, and IVa Vaginal Cancer

The treatment options for stages II, III, and IVa vaginal cancer have not been directly compared in randomized trials.[Level of evidence C2] As a result of differences in patient selection, expertise in treating local disease, and staging criteria, it is difficult to determine whether there are differences in disease control rates.

Radiation therapy is the most common treatment for patients with stages II, III, and IVa vaginal cancer.

Treatment Options for Stages II, III, and IVa Squamous Cell Carcinoma (SCC) and Adenocarcinoma of the Vagina

Treatment options for stage II SCC and adenocarcinoma of the vagina, stage III SCC and adenocarcinoma of the vagina, and stage IVa SCC and adenocarcinoma of the vagina include:

  1. Radiation therapy.
    • External-beam radiation therapy (EBRT) alone or in combination with interstitial and/or intracavitary brachytherapy.[1–5] For example, EBRT for a period of 5 to 6 weeks (including the pelvic lymph nodes) followed by an interstitial and/or intracavitary implant for a total tumor dose of 75 Gy to 80 Gy and a dose to the lateral pelvic wall of 55 Gy to 60 Gy.[1–3]
    • For lesions in the lower third of the vagina, elective radiation therapy of 45 Gy to 50 Gy is given to the pelvic and/or inguinal lymph nodes.[1,2,6]
  2. Surgery.
    • Radical vaginectomy or pelvic exenteration is performed with or without radiation therapy.[7–10]
  3. Chemoradiation.[11]

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References
  1. Perez CA, Camel HM, Galakatos AE, et al.: Definitive irradiation in carcinoma of the vagina: long-term evaluation of results. Int J Radiat Oncol Biol Phys 15 (6): 1283-90, 1988. [PUBMED Abstract]
  2. Chyle V, Zagars GK, Wheeler JA, et al.: Definitive radiotherapy for carcinoma of the vagina: outcome and prognostic factors. Int J Radiat Oncol Biol Phys 35 (5): 891-905, 1996. [PUBMED Abstract]
  3. Frank SJ, Jhingran A, Levenback C, et al.: Definitive radiation therapy for squamous cell carcinoma of the vagina. Int J Radiat Oncol Biol Phys 62 (1): 138-47, 2005. [PUBMED Abstract]
  4. Tran PT, Su Z, Lee P, et al.: Prognostic factors for outcomes and complications for primary squamous cell carcinoma of the vagina treated with radiation. Gynecol Oncol 105 (3): 641-9, 2007. [PUBMED Abstract]
  5. Lian J, Dundas G, Carlone M, et al.: Twenty-year review of radiotherapy for vaginal cancer: an institutional experience. Gynecol Oncol 111 (2): 298-306, 2008. [PUBMED Abstract]
  6. Andersen ES: Primary carcinoma of the vagina: a study of 29 cases. Gynecol Oncol 33 (3): 317-20, 1989. [PUBMED Abstract]
  7. Rubin SC, Young J, Mikuta JJ: Squamous carcinoma of the vagina: treatment, complications, and long-term follow-up. Gynecol Oncol 20 (3): 346-53, 1985. [PUBMED Abstract]
  8. Stock RG, Chen AS, Seski J: A 30-year experience in the management of primary carcinoma of the vagina: analysis of prognostic factors and treatment modalities. Gynecol Oncol 56 (1): 45-52, 1995. [PUBMED Abstract]
  9. Tjalma WA, Monaghan JM, de Barros Lopes A, et al.: The role of surgery in invasive squamous carcinoma of the vagina. Gynecol Oncol 81 (3): 360-5, 2001. [PUBMED Abstract]
  10. Boronow RC, Hickman BT, Reagan MT, et al.: Combined therapy as an alternative to exenteration for locally advanced vulvovaginal cancer. II. Results, complications, and dosimetric and surgical considerations. Am J Clin Oncol 10 (2): 171-81, 1987. [PUBMED Abstract]
  11. Rajagopalan MS, Xu KM, Lin JF, et al.: Adoption and impact of concurrent chemoradiation therapy for vaginal cancer: a National Cancer Data Base (NCDB) study. Gynecol Oncol 135 (3): 495-502, 2014. [PUBMED Abstract]

Treatment of Stage IVb Vaginal Cancer

Treatment Options for Stage IVb Squamous Cell Carcinoma (SCC) and Adenocarcinoma of the Vagina

Treatment options for stage IVb SCC and adenocarcinoma of the vagina include:

  • Radiation therapy (for palliation of symptoms) with or without chemotherapy.

For patients with stage IVb disease, current therapy is inadequate. No established anticancer drugs have demonstrated clinical benefit, although patients are often treated with regimens used to treat cervical cancer.

Concurrent chemotherapy using fluorouracil or cisplatin-based therapy and radiation therapy is sometimes advocated on the basis of results extrapolated from cervical cancer management strategies.[1–3] Evidence is limited to small case series, and the incremental impact on patient survival and local disease control is not well defined.[Level of evidence C3] For more information, see Cervical Cancer Treatment.

Because stage IVb vaginal cancer is rare, these patients are candidates for clinical trials to improve survival or local control. Information about ongoing clinical trials is available from the NCI website.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References
  1. Grigsby PW: Vaginal cancer. Curr Treat Options Oncol 3 (2): 125-30, 2002. [PUBMED Abstract]
  2. Dalrymple JL, Russell AH, Lee SW, et al.: Chemoradiation for primary invasive squamous carcinoma of the vagina. Int J Gynecol Cancer 14 (1): 110-7, 2004 Jan-Feb. [PUBMED Abstract]
  3. Samant R, Lau B, E C, et al.: Primary vaginal cancer treated with concurrent chemoradiation using Cis-platinum. Int J Radiat Oncol Biol Phys 69 (3): 746-50, 2007. [PUBMED Abstract]

Treatment of Recurrent Vaginal Cancer

Patients with recurrent vaginal cancer have a very poor prognosis. Most recurrences occur in the first 2 years after treatment.

Some patients with centrally recurrent vaginal cancers are candidates for pelvic exenteration or radiation therapy. In a large series, only 5 of 50 patients with recurrence were salvaged using surgery or radiation therapy. All five of these salvaged patients originally presented with stage I or II disease and had tumor recurrence in the central pelvis.[1]

No established anticancer drugs have demonstrated clinical benefit, although patients are often treated with regimens used to treat cervical cancer. If patients are eligible, participation in clinical trials should be considered. Information about ongoing clinical trials is available from the NCI website.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References
  1. Stock RG, Chen AS, Seski J: A 30-year experience in the management of primary carcinoma of the vagina: analysis of prognostic factors and treatment modalities. Gynecol Oncol 56 (1): 45-52, 1995. [PUBMED Abstract]

Latest Updates to This Summary (04/03/2025)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

General Information About Vaginal Cancer

Updated statistics with estimated new cases and deaths for 2025 (cited American Cancer Society as reference 3).

This summary is written and maintained by the PDQ Adult Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® Cancer Information for Health Professionals pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of vaginal cancer. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

  • be discussed at a meeting,
  • be cited with text, or
  • replace or update an existing article that is already cited.

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewers for Vaginal Cancer Treatment are:

  • Fumiko Chino, MD (MD Anderson Cancer Center)
  • Olga T. Filippova, MD (Lenox Hill Hospital)

Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website’s Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

Permission to Use This Summary

PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary].”

The preferred citation for this PDQ summary is:

PDQ® Adult Treatment Editorial Board. PDQ Vaginal Cancer Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /types/vaginal/hp/vaginal-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389242]

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Vaginal Cancer Treatment (PDQ®)–Patient Version

Vaginal Cancer Treatment (PDQ®)–Patient Version

General Information About Vaginal Cancer

Go to Health Professional Version

Key Points

  • Vaginal cancer is a disease in which malignant (cancer) cells form in the vagina.
  • Older age and having an HPV infection are risk factors for vaginal cancer.
  • Signs and symptoms of vaginal cancer include pain or abnormal vaginal bleeding.
  • Tests that examine the vagina and other organs in the pelvis are used to diagnose vaginal cancer.
  • Certain factors affect prognosis (chance of recovery) and treatment options.

Vaginal cancer is a disease in which malignant (cancer) cells form in the vagina.

The vagina is the canal leading from the cervix (the opening of the uterus) to the outside of the body. At birth, a baby passes out of the body through the vagina (also called the birth canal).

EnlargeAnatomy of the female reproductive system; drawing shows the uterus, myometrium (muscular outer layer of the uterus), endometrium (inner lining of the uterus), ovaries, fallopian tubes, cervix, and vagina.
Anatomy of the female reproductive system. The organs in the female reproductive system include the uterus, ovaries, fallopian tubes, cervix, and vagina. The uterus has a muscular outer layer called the myometrium and an inner lining called the endometrium.

Vaginal cancer is not common. There are two main types of vaginal cancer:

  • Squamous cell carcinoma: Cancer that forms in the thin, flat cells lining the inside of the vagina. Squamous cell vaginal cancer spreads slowly and usually stays near the vagina, but may spread to the lungs, liver, or bone. This is the most common type of vaginal cancer.
  • Adenocarcinoma: Cancer that begins in glandular cells. Glandular cells in the lining of the vagina make and release fluids such as mucus. Adenocarcinoma is more likely than squamous cell cancer to spread to the lungs and lymph nodes. A rare type of adenocarcinoma (clear cell adenocarcinoma) is linked to being exposed to diethylstilbestrol (DES) before birth. Adenocarcinomas that are not linked with being exposed to DES are most common in women after menopause.

Older age and having an HPV infection are risk factors for vaginal cancer.

Anything that increases a person’s chance of getting a disease is called a risk factor. Not every person with one or more of these risk factors will develop vaginal cancer, and it will develop in people who don’t have any known risk factors. Talk with your doctor if you think you may be at risk. Risk factors for vaginal cancer include the following:

  • Being 60 years or older.
  • Having a human papilloma virus (HPV) infection, which can be linked to squamous cell carcinoma of the vagina.
  • Being exposed to DES while in the mother’s womb. In the 1950s, the drug DES was given to some pregnant women to prevent miscarriage (premature birth of a fetus that cannot survive). This is linked to a rare form of vaginal cancer called clear cell adenocarcinoma. The rates of this disease were highest in the mid-1970s, and it is extremely rare now.
  • Having had a hysterectomy for tumors that were benign (not cancer) or cancer.

Signs and symptoms of vaginal cancer include pain or abnormal vaginal bleeding.

Vaginal cancer often does not cause early signs or symptoms. It may be found during a routine pelvic exam and Pap test. Signs and symptoms may be caused by vaginal cancer or by other conditions. Check with your doctor if you have any of the following:

Tests that examine the vagina and other organs in the pelvis are used to diagnose vaginal cancer.

In addition to asking about your personal and family health history and doing a physical exam, your doctor may perform the following tests and procedures:

  • Pelvic exam: An exam of the vagina, cervix, uterus, fallopian tubes, ovaries, and rectum. A speculum is inserted into the vagina and the doctor or nurse looks at the vagina and cervix for signs of disease. A Pap test of the cervix is usually done. The doctor or nurse also inserts one or two lubricated, gloved fingers of one hand into the vagina and places the other hand over the lower abdomen to feel the size, shape, and position of the uterus and ovaries. The doctor or nurse also inserts a lubricated, gloved finger into the rectum to feel for lumps or abnormal areas.
    EnlargePelvic exam; drawing shows a side view of the female reproductive anatomy during a pelvic exam. The uterus, left fallopian tube, left ovary, cervix, vagina, bladder, and rectum are shown. Two gloved fingers of one hand of the doctor or nurse are shown inserted into the vagina, while the other hand is shown pressing on the lower abdomen. The inset shows a woman covered by a drape on an exam table with her legs apart and her feet in stirrups.
    Pelvic exam. A doctor or nurse inserts one or two lubricated, gloved fingers of one hand into the vagina and presses on the lower abdomen with the other hand. This is done to feel the size, shape, and position of the uterus and ovaries. The vagina, cervix, fallopian tubes, and rectum are also checked.
  • Pap test: A procedure to collect cells from the surface of the cervix and vagina. A piece of cotton, a brush, or a small wooden stick is used to gently scrape cells from the cervix and vagina. The cells are viewed under a microscope to find out if they are abnormal. This procedure is also called a Pap smear.
    EnlargePap test; drawing shows a side view of the female reproductive anatomy during a Pap test. A speculum is shown widening the opening of the vagina. A brush is shown inserted into the open vagina and touching the cervix at the base of the uterus. The rectum is also shown. One inset shows the brush touching the center of the cervix. A second inset shows a woman covered by a drape on an exam table with her legs apart and her feet in stirrups.
    Pap test. A speculum is inserted into the vagina to widen it. Then, a brush is inserted into the vagina to collect cells from the cervix. The cells are checked under a microscope for signs of disease.
  • Human papillomavirus (HPV) test: A laboratory test used to check DNA or RNA for certain types of HPV infection. Cells are collected from the cervix and DNA or RNA from the cells is checked to find out if an infection is caused by a type of HPV that is linked to cervical cancer. This test may be done using the sample of cells removed during a Pap test. This test may also be done if the results of a Pap test show certain abnormal cervical cells.
  • Colposcopy: A procedure in which a colposcope (a lighted, magnifying instrument) is used to check the vagina and cervix for abnormal areas. Tissue samples may be taken using a curette (spoon-shaped instrument) or a brush and checked under a microscope for signs of disease.
  • Biopsy: The removal of cells or tissues from the vagina and cervix so they can be viewed under a microscope by a pathologist to check for signs of cancer. If a Pap test shows abnormal cells in the vagina, a biopsy may be done during a colposcopy.

Certain factors affect prognosis (chance of recovery) and treatment options.

The prognosis depends on the following:

  • The stage of the cancer (whether it is in the vagina only or has spread to other areas).
  • The size of the tumor.
  • The grade of tumor cells (how different they look from normal cells under a microscope).
  • Where the cancer is within the vagina.
  • Whether there are signs or symptoms at diagnosis.
  • Whether the cancer has just been diagnosed or has recurred (come back).

Treatment options depend on the following:

  • The stage and size of the cancer.
  • Whether the cancer is close to other organs that may be damaged by treatment.
  • Whether the tumor is made up of squamous cells or is an adenocarcinoma.
  • Whether the patient has a uterus or has had a hysterectomy.
  • Whether the patient has had past radiation treatment to the pelvis.

Stages of Vaginal Cancer

Key Points

  • After vaginal cancer has been diagnosed, tests are done to find out if cancer cells have spread within the vagina or to other parts of the body.
  • There are three ways that cancer spreads in the body.
  • Cancer may spread from where it began to other parts of the body.
  • In vaginal intraepithelial neoplasia (VaIN), abnormal cells are found in tissue lining the inside of the vagina.
  • The following stages are used for vaginal cancer:
    • Stage I
    • Stage II
    • Stage III
    • Stage IV
  • Vaginal cancer may recur (come back) after it has been treated.

After vaginal cancer has been diagnosed, tests are done to find out if cancer cells have spread within the vagina or to other parts of the body.

The process used to find out if cancer has spread within the vagina or to other parts of the body is called staging. The information gathered from the staging process determines the stage of the disease. It is important to know the stage in order to plan treatment. The following procedures may be used in the staging process:

  • Chest x-ray: An x-ray of the organs and bones inside the chest. An x-ray is a type of energy beam that can go through the body and onto film, making a picture of areas inside the body.
  • CT scan (CAT scan): A procedure that makes a series of detailed pictures of areas inside the body such as the abdomen or pelvis, taken from different angles. The pictures are made by a computer linked to an x-ray machine. A dye may be injected into a vein or swallowed to help the organs or tissues show up more clearly. This procedure is also called computed tomography, computerized tomography, or computerized axial tomography.
  • MRI (magnetic resonance imaging): A procedure that uses a magnet, radio waves, and a computer to make a series of detailed pictures of areas inside the body. This procedure is also called nuclear magnetic resonance imaging (NMRI).
  • PET scan (positron emission tomography scan): A procedure to find malignant tumor cells in the body. A small amount of radioactive glucose (sugar) is injected into a vein. The PET scanner rotates around the body and makes a picture of where glucose is being used in the body. Malignant tumor cells show up brighter in the picture because they are more active and take up more glucose than normal cells do.
  • Cystoscopy: A procedure to look inside the bladder and urethra to check for abnormal areas. A cystoscope is inserted through the urethra into the bladder. A cystoscope is a thin, tube-like instrument with a light and a lens for viewing. It may also have a tool to remove tissue samples, which are checked under a microscope for signs of cancer.
    EnlargeCystoscopy; drawing shows a side view of the lower pelvis containing the bladder, uterus, vagina, rectum, and anus. A cystoscope (a thin, tube-like instrument with a light and a lens for viewing) is shown passing through the urethra and into the bladder. Fluid is used to fill the bladder. An inset shows a woman lying on an examination table with her knees bent and legs apart. She is covered by a drape. The doctor is looking at an image of the inner wall of the bladder on a computer monitor to check for abnormal areas.
    Cystoscopy. A cystoscope (a thin, tube-like instrument with a light and a lens for viewing) is inserted through the urethra into the bladder. Fluid is used to fill the bladder. The doctor looks at an image of the inner wall of the bladder on a computer monitor to check for abnormal areas.
  • Proctoscopy: A procedure to look inside the rectum and anus to check for abnormal areas, using a proctoscope. A proctoscope is a thin, tube-like instrument with a light and a lens for viewing the inside of the rectum and anus. It may also have a tool to remove tissue samples, which are checked under a microscope for signs of cancer.
  • Biopsy: A biopsy may be done to find out if cancer has spread to the cervix. A sample of tissue is removed from the cervix and viewed under a microscope. A biopsy that removes only a small amount of tissue is usually done in the doctor’s office. A cone biopsy (removal of a larger, cone-shaped piece of tissue from the cervix and cervical canal) is usually done in the hospital. A biopsy of the vulva may also be done to see if cancer has spread there.

There are three ways that cancer spreads in the body.

Cancer can spread through tissue, the lymph system, and the blood:

  • Tissue. The cancer spreads from where it began by growing into nearby areas.
  • Lymph system. The cancer spreads from where it began by getting into the lymph system. The cancer travels through the lymph vessels to other parts of the body.
  • Blood. The cancer spreads from where it began by getting into the blood. The cancer travels through the blood vessels to other parts of the body.

Cancer may spread from where it began to other parts of the body.

When cancer spreads to another part of the body, it is called metastasis. Cancer cells break away from where they began (the primary tumor) and travel through the lymph system or blood.

  • Lymph system. The cancer gets into the lymph system, travels through the lymph vessels, and forms a tumor (metastatic tumor) in another part of the body.
  • Blood. The cancer gets into the blood, travels through the blood vessels, and forms a tumor (metastatic tumor) in another part of the body.

The metastatic tumor is the same type of cancer as the primary tumor. For example, if vaginal cancer spreads to the lung, the cancer cells in the lung are actually vaginal cancer cells. The disease is metastatic vaginal cancer, not lung cancer.

Many cancer deaths are caused when cancer moves from the original tumor and spreads to other tissues and organs. This is called metastatic cancer. This animation shows how cancer cells travel from the place in the body where they first formed to other parts of the body.

In vaginal intraepithelial neoplasia (VaIN), abnormal cells are found in tissue lining the inside of the vagina.

These abnormal cells are not cancer. Vaginal intraepithelial neoplasia (VaIN) is grouped based on how deep the abnormal cells are in the tissue lining the vagina:

  • VaIN 1: Abnormal cells are found in the outermost one third of the tissue lining the vagina.
  • VaIN 2: Abnormal cells are found in the outermost two-thirds of the tissue lining the vagina.
  • VaIN 3: Abnormal cells are found in more than two-thirds of the tissue lining the vagina. When VaIN 3 lesions are found in the full thickness of the tissue lining the vagina, it is called carcinoma in situ.

VaIN may become cancer and spread into the vaginal wall.

The following stages are used for vaginal cancer:

Stage I

In stage I, cancer is only found in the vaginal wall.

Stage II

In stage II, cancer has spread through the wall of the vagina to the tissue around the vagina. Cancer has not spread to the wall of the pelvis.

Stage III

In stage III, cancer has spread to the wall of the pelvis.

Stage IV

Stage IV is divided into stage IVA and stage IVB:

Vaginal cancer may recur (come back) after it has been treated.

The cancer may come back in the vagina or in other parts of the body.

Treatment Option Overview

Key Points

  • There are different types of treatment for patients with vaginal cancer.
  • The following types of treatment are used:
    • Surgery
    • Radiation therapy
    • Chemotherapy
  • New types of treatment are being tested in clinical trials.
    • Immunotherapy
    • Radiosensitizers
  • Treatment for vaginal cancer may cause side effects.
  • Patients may want to think about taking part in a clinical trial.
  • Patients can enter clinical trials before, during, or after starting their cancer treatment.
  • Follow-up tests may be needed.

There are different types of treatment for patients with vaginal cancer.

Different types of treatments are available for patients with vaginal cancer. Some treatments are standard (the currently used treatment), and some are being tested in clinical trials. A treatment clinical trial is a research study meant to help improve current treatments or obtain information on new treatments for patients with cancer. When clinical trials show that a new treatment is better than the standard treatment, the new treatment may become the standard treatment. Patients may want to think about taking part in a clinical trial. Some clinical trials are open only to patients who have not started treatment.

The following types of treatment are used:

Surgery

Surgery is a treatment option for both vaginal intraepithelial neoplasia (VaIN) and vaginal cancer.

The following types of surgery may be used to treat VaIN:

The following types of surgery may be used to treat vaginal cancer:

  • Wide local excision: A surgical procedure that takes out the cancer and some of the healthy tissue around it.
  • Vaginectomy: Surgery to remove all or part of the vagina. Skin grafts from other parts of the body may be needed to reconstruct the vagina.
  • Total hysterectomy: Surgery to remove the uterus, including the cervix. If the uterus and cervix are taken out through the vagina, the operation is called a vaginal hysterectomy. If the uterus and cervix are taken out through a large incision (cut) in the abdomen, the operation is called a total abdominal hysterectomy. If the uterus and cervix are taken out through a small incision in the abdomen using a laparoscope, the operation is called a total laparoscopic hysterectomy.
    EnlargeHysterectomy; drawing shows the female reproductive anatomy, including the ovaries, uterus, vagina, fallopian tubes, and cervix. Dotted lines show which organs and tissues are removed in a total hysterectomy, a total hysterectomy with salpingo-oophorectomy, and a radical hysterectomy. An inset shows the location of two possible incisions on the abdomen: a low transverse incision is just above the pubic area and a vertical incision is between the navel and the pubic area.
    Hysterectomy. The uterus is surgically removed with or without other organs or tissues. In a total hysterectomy, the uterus and cervix are removed. In a total hysterectomy with salpingo-oophorectomy, (a) the uterus plus one (unilateral) ovary and fallopian tube are removed; or (b) the uterus plus both (bilateral) ovaries and fallopian tubes are removed. In a radical hysterectomy, the uterus, cervix, both ovaries, both fallopian tubes, and nearby tissue are removed. These procedures are done using a low transverse incision or a vertical incision.
  • Lymph node dissection: A surgical procedure in which lymph nodes are removed and a sample of tissue is checked under a microscope for signs of cancer. This procedure is also called lymphadenectomy. If the cancer is in the upper vagina, the pelvic lymph nodes may be removed. If the cancer is in the lower vagina, lymph nodes in the groin may be removed.
  • Pelvic exenteration: Surgery to remove the lower colon, rectum, bladder, cervix, vagina, and ovaries. Nearby lymph nodes are also removed. Artificial openings (stoma) are made for urine and stool to flow from the body into a collection bag.

After the doctor removes all the cancer that can be seen at the time of the surgery, some patients may be given radiation therapy after surgery to kill any cancer cells that are left. Treatment given after the surgery, to lower the risk that the cancer will come back, is called adjuvant therapy.

Radiation therapy

Radiation therapy is a cancer treatment that uses high-energy x-rays or other types of radiation to kill cancer cells or keep them from growing. There are two types of radiation therapy:

The way the radiation therapy is given depends on the type and stage of the cancer being treated. External and internal radiation therapy are used to treat vaginal cancer, and may also be used as palliative therapy to relieve symptoms and improve quality of life.

Chemotherapy

Chemotherapy is a cancer treatment that uses drugs to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. When chemotherapy is taken by mouth or injected into a vein or muscle, the drugs enter the bloodstream and can affect cancer cells throughout the body (systemic chemotherapy). When chemotherapy is placed directly into the cerebrospinal fluid, an organ, or a body cavity such as the abdomen, the drugs mainly affect cancer cells in those areas (regional chemotherapy). The way the chemotherapy is given depends on the type and stage of the cancer being treated.

Topical chemotherapy for squamous cell vaginal cancer may be applied to the vagina in a cream or lotion.

New types of treatment are being tested in clinical trials.

This summary section describes treatments that are being studied in clinical trials. It may not mention every new treatment being studied. Information about clinical trials is available from the NCI website.

Immunotherapy

Immunotherapy is a treatment that uses the patient’s immune system to fight cancer. Substances made by the body or made in a laboratory are used to boost, direct, or restore the body’s natural defenses against cancer.

Imiquimod is an immune response modifier that is being studied to treat vaginal lesions and is applied to the skin in a cream.

Radiosensitizers

Radiosensitizers are drugs that make tumor cells more sensitive to radiation therapy. Combining radiation therapy with radiosensitizers may kill more tumor cells.

Treatment for vaginal cancer may cause side effects.

For information about side effects caused by treatment for cancer, visit our Side Effects page.

Patients may want to think about taking part in a clinical trial.

For some patients, taking part in a clinical trial may be the best treatment choice. Clinical trials are part of the cancer research process. Clinical trials are done to find out if new cancer treatments are safe and effective or better than the standard treatment.

Many of today’s standard treatments for cancer are based on earlier clinical trials. Patients who take part in a clinical trial may receive the standard treatment or be among the first to receive a new treatment.

Patients who take part in clinical trials also help improve the way cancer will be treated in the future. Even when clinical trials do not lead to effective new treatments, they often answer important questions and help move research forward.

Patients can enter clinical trials before, during, or after starting their cancer treatment.

Some clinical trials only include patients who have not yet received treatment. Other trials test treatments for patients whose cancer has not gotten better. There are also clinical trials that test new ways to stop cancer from recurring (coming back) or reduce the side effects of cancer treatment.

Clinical trials are taking place in many parts of the country. Information about clinical trials supported by NCI can be found on NCI’s clinical trials search webpage. Clinical trials supported by other organizations can be found on the ClinicalTrials.gov website.

Follow-up tests may be needed.

Some of the tests that were done to diagnose the cancer or to find out the stage of the cancer may be repeated. Some tests will be repeated in order to see how well the treatment is working. Decisions about whether to continue, change, or stop treatment may be based on the results of these tests.

Treatment of Vaginal Intraepithelial Neoplasia (VaIN)

For information about the treatments listed below, see the Treatment Option Overview section.

Treatment of vaginal intraepithelial neoplasia (VaIN) may include the following:

Treatment of Stage I Vaginal Cancer

For information about the treatments listed below, see the Treatment Option Overview section.

Treatment of stage I squamous cell vaginal cancer lesions that are less than 0.5 centimeters thick may include the following:

Treatment of stage I squamous cell vaginal cancer lesions that are more than 0.5 centimeters thick may include the following:

  • Surgery:
    • For lesions in the upper third of the vagina, vaginectomy and lymph node dissection, with or without vaginal reconstruction.
    • For lesions in the lower third of the vagina, lymph node dissection.
  • Radiation therapy may be given after the surgery, which may include:

Treatment of stage I vaginal adenocarcinoma may include the following:

Treatment of Stage II, Stage III, and Stage IVA Vaginal Cancer

For information about the treatments listed below, see the Treatment Option Overview section.

Treatment of stage II, stage III, and stage IVA vaginal cancer is the same for squamous cell cancer and adenocarcinoma. Treatment may include the following:

Treatment of Stage IVB Vaginal Cancer

For information about the treatments listed below, see the Treatment Option Overview section.

Treatment of stage IVB vaginal cancer is the same for squamous cell cancer and adenocarcinoma. Treatment may include the following:

Although no anticancer drugs have been shown to help patients with stage IVB vaginal cancer live longer, they are often treated with regimens used for cervical cancer. For more information, see Cervical Cancer Treatment.

Treatment of Recurrent Vaginal Cancer

For information about the treatments listed below, see the Treatment Option Overview section.

Treatment of recurrent vaginal cancer may include the following:

Although no anticancer drugs have been shown to help patients with recurrent vaginal cancer live longer, they are often treated with regimens used for cervical cancer. For more information, see Cervical Cancer Treatment.

Use our clinical trial search to find NCI-supported cancer clinical trials that are accepting patients. You can search for trials based on the type of cancer, the age of the patient, and where the trials are being done. General information about clinical trials is also available.

To Learn More About Vaginal Cancer

For more information from the National Cancer Institute about vaginal cancer, see the following:

For general cancer information and other resources from the National Cancer Institute, visit:

About This PDQ Summary

About PDQ

Physician Data Query (PDQ) is the National Cancer Institute’s (NCI’s) comprehensive cancer information database. The PDQ database contains summaries of the latest published information on cancer prevention, detection, genetics, treatment, supportive care, and complementary and alternative medicine. Most summaries come in two versions. The health professional versions have detailed information written in technical language. The patient versions are written in easy-to-understand, nontechnical language. Both versions have cancer information that is accurate and up to date and most versions are also available in Spanish.

PDQ is a service of the NCI. The NCI is part of the National Institutes of Health (NIH). NIH is the federal government’s center of biomedical research. The PDQ summaries are based on an independent review of the medical literature. They are not policy statements of the NCI or the NIH.

Purpose of This Summary

This PDQ cancer information summary has current information about the treatment of vaginal cancer. It is meant to inform and help patients, families, and caregivers. It does not give formal guidelines or recommendations for making decisions about health care.

Reviewers and Updates

Editorial Boards write the PDQ cancer information summaries and keep them up to date. These Boards are made up of experts in cancer treatment and other specialties related to cancer. The summaries are reviewed regularly and changes are made when there is new information. The date on each summary (“Updated”) is the date of the most recent change.

The information in this patient summary was taken from the health professional version, which is reviewed regularly and updated as needed, by the PDQ Adult Treatment Editorial Board.

Clinical Trial Information

A clinical trial is a study to answer a scientific question, such as whether one treatment is better than another. Trials are based on past studies and what has been learned in the laboratory. Each trial answers certain scientific questions in order to find new and better ways to help cancer patients. During treatment clinical trials, information is collected about the effects of a new treatment and how well it works. If a clinical trial shows that a new treatment is better than one currently being used, the new treatment may become “standard.” Patients may want to think about taking part in a clinical trial. Some clinical trials are open only to patients who have not started treatment.

Clinical trials can be found online at NCI’s website. For more information, call the Cancer Information Service (CIS), NCI’s contact center, at 1-800-4-CANCER (1-800-422-6237).

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The best way to cite this PDQ summary is:

PDQ® Adult Treatment Editorial Board. PDQ Vaginal Cancer Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /types/vaginal/patient/vaginal-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389348]

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Vaginal Cancer—Health Professional Version

Vaginal Cancer—Health Professional Version

Treatment

PDQ Treatment Information for Health Professionals

More information

Causes & Prevention

NCI does not have PDQ evidence-based information about prevention of vaginal cancer.

More information

Screening

NCI does not have PDQ evidence-based information about screening for vaginal cancer.

More information

Research

Gardasil 9 Vaccine Protects against Additional HPV Types

Supportive & Palliative Care

We offer evidence-based supportive and palliative care information for health professionals on the assessment and management of cancer-related symptoms and conditions.

Cancer Pain Nausea and Vomiting Nutrition in Cancer Care Transition to End-of-Life Care Last Days of Life View all Supportive and Palliative Care Summaries

Vaginal Cancer—Patient Version

Vaginal Cancer—Patient Version

Overview

Infection with human papillomavirus (HPV) causes two-thirds of the cases of vaginal cancer. Vaccines that protect against infection with HPV may reduce the risk of vaginal cancer. When found early, vaginal cancer can often be cured. Explore the links on this page to learn more about vaginal cancer treatment, research, and clinical trials.

Treatment

PDQ Treatment Information for Patients

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Causes & Prevention

NCI does not have PDQ evidence-based information about prevention of vaginal cancer.

More information

Screening

NCI does not have PDQ evidence-based information about screening for vaginal cancer.

More information

Coping with Cancer

The information in this section is meant to help you cope with the many issues and concerns that occur when you have cancer.

Emotions and Cancer Adjusting to Cancer Support for Caregivers Survivorship Advanced Cancer Managing Cancer Care

Research

Gardasil 9 Vaccine Protects against Additional HPV Types

Urethral Cancer Treatment (PDQ®)–Patient Version

Urethral Cancer Treatment (PDQ®)–Patient Version

General Information About Urethral Cancer

Go to Health Professional Version

Key Points

  • Urethral cancer is a disease in which malignant (cancer) cells form in the tissues of the urethra.
  • There are different types of urethral cancer that begin in cells that line the urethra.
  • A history of bladder cancer can affect the risk of urethral cancer.
  • Signs of urethral cancer include bleeding or trouble with urination.
  • Tests that examine the urethra and bladder are used to diagnose urethral cancer.
  • Certain factors affect prognosis (chance of recovery) and treatment options.

Urethral cancer is a disease in which malignant (cancer) cells form in the tissues of the urethra.

The urethra is the tube that carries urine from the bladder to outside the body. In women, the urethra is about 1½ inches long and is just above the vagina. In men, the urethra is about 8 inches long, and goes through the prostate gland and the penis to the outside of the body. In men, the urethra also carries semen.

EnlargeAnatomy of the male urinary system (left panel) and female urinary system (right panel); two-panel drawing showing the right and left kidneys, the ureters, the bladder filled with urine, and the urethra. The inside of the left kidney shows the renal pelvis. An inset shows the renal tubules and urine. Also shown are the prostate and penis (left panel) and the uterus (right panel).
Anatomy of the male urinary system (left panel) and female urinary system (right panel) showing the kidneys, ureters, bladder, and urethra. The inside of the left kidney shows the renal pelvis. An inset shows the renal tubules and urine. Also shown are the prostate and penis (left panel) and the uterus (right panel). Urine is made in the renal tubules and collects in the renal pelvis of each kidney. The urine flows from the kidneys through the ureters to the bladder. The urine is stored in the bladder until it leaves the body through the urethra.

Urethral cancer is a rare cancer that occurs more often in men than in women.

There are different types of urethral cancer that begin in cells that line the urethra.

These cancers are named for the types of cells that become malignant (cancer):

  • Squamous cell carcinoma is the most common type of urethral cancer. It forms in the thin, flat cells in the part of the urethra near the bladder in women, and in the lining of the urethra in the penis in men.
  • Transitional cell carcinoma forms in the area near the urethral opening in women, and in the part of the urethra that goes through the prostate gland in men.
  • Adenocarcinoma forms in the glands that are around the urethra in both men and women.

Urethral cancer can metastasize (spread) quickly to tissues around the urethra and is often found in nearby lymph nodes by the time it is diagnosed.

A history of bladder cancer can affect the risk of urethral cancer.

Anything that increases your chance of getting a disease is called a risk factor. Having a risk factor does not mean that you will get cancer; not having risk factors doesn’t mean that you will not get cancer. Talk with your doctor if you think you may be at risk. Risk factors for urethral cancer include the following:

Signs of urethral cancer include bleeding or trouble with urination.

These and other signs and symptoms may be caused by urethral cancer or by other conditions. There may be no signs or symptoms in the early stages. Check with your doctor if you have any of the following:

  • Trouble starting the flow of urine.
  • Weak or interrupted (“stop-and-go”) flow of urine.
  • Frequent urination, especially at night.
  • Incontinence.
  • Discharge from the urethra.
  • Bleeding from the urethra or blood in the urine.
  • A lump or thickness in the perineum or penis.
  • A painless lump or swelling in the groin.

Tests that examine the urethra and bladder are used to diagnose urethral cancer.

The following tests and procedures may be used:

  • Physical exam and health history: An exam of the body to check general signs of health, including checking for signs of disease, such as lumps or anything else that seems unusual. A history of the patient’s health habits and past illnesses and treatments will also be taken.
  • Pelvic exam: An exam of the vagina, cervix, uterus, fallopian tubes, ovaries, and rectum. A speculum is inserted into the vagina and the doctor or nurse looks at the vagina and cervix for signs of disease. The doctor or nurse also inserts one or two lubricated, gloved fingers of one hand into the vagina and places the other hand over the lower abdomen to feel the size, shape, and position of the uterus and ovaries. The doctor or nurse also inserts a lubricated, gloved finger into the rectum to feel for lumps or abnormal areas.
    EnlargePelvic exam; drawing shows a side view of the female reproductive anatomy during a pelvic exam. The uterus, left fallopian tube, left ovary, cervix, vagina, bladder, and rectum are shown. Two gloved fingers of one hand of the doctor or nurse are shown inserted into the vagina, while the other hand is shown pressing on the lower abdomen. The inset shows a woman covered by a drape on an exam table with her legs apart and her feet in stirrups.
    Pelvic exam. A doctor or nurse inserts one or two lubricated, gloved fingers of one hand into the vagina and presses on the lower abdomen with the other hand. This is done to feel the size, shape, and position of the uterus and ovaries. The vagina, cervix, fallopian tubes, and rectum are also checked.
  • Digital rectal exam: An exam of the rectum. The doctor or nurse inserts a lubricated, gloved finger into the lower part of the rectum to feel for lumps or anything else that seems unusual.
  • Urine cytology: A laboratory test in which a sample of urine is checked under a microscope for abnormal cells.
  • Urinalysis: A test to check the color of urine and its contents, such as sugar, protein, blood, and white blood cells. If white blood cells (a sign of infection) are found, a urine culture is usually done to find out what type of infection it is.
  • Blood chemistry studies: A procedure in which a blood sample is checked to measure the amounts of certain substances released into the blood by organs and tissues in the body. An unusual (higher or lower than normal) amount of a substance can be a sign of disease.
  • Complete blood count (CBC): A procedure in which a sample of blood is drawn and checked for the following:
  • CT scan (CAT scan): A procedure that makes a series of detailed pictures of areas inside the body, such as the pelvis and abdomen, taken from different angles. The pictures are made by a computer linked to an x-ray machine. A dye may be injected into a vein or swallowed to help the organs or tissues show up more clearly. This procedure is also called computed tomography, computerized tomography, or computerized axial tomography.
  • Ureteroscopy: A procedure to look inside the ureter and renal pelvis to check for abnormal areas. A ureteroscope is a thin, tube-like instrument with a light and a lens for viewing. The ureteroscope is inserted through the urethra into the bladder, ureter, and renal pelvis. A tool may be inserted through the ureteroscope to take tissue samples to be checked under a microscope for signs of disease.
    EnlargeDrawing of a female and male ureteroscopy showing the lower pelvis of a female, including the right and left kidneys, renal pelvis, ureter, uterus, bladder, and urethra, and the lower pelvis of a male, including the ureter, bladder, prostate, urethra, and penis. In both the female and male figures, a ureteroscope (a thin, tube-like instrument with a light and a lens for viewing) is shown passing through the urethra into the bladder and ureter. In the female figure, the ureteroscope is also shown passing into the renal pelvis. There is also an inset that shows a person lying on an examination table with their knees bent and legs apart, covered by a drape, and a doctor looking at an image of the inside of the ureter and/or renal pelvis on a computer monitor.
    A ureteroscopy is a procedure that uses a ureteroscope (a thin, tube-like instrument with a light and a lens for viewing) to look inside the ureter and renal pelvis to check for abnormal areas. The ureteroscope is inserted through the urethra into the bladder, ureter, and renal pelvis.
  • Biopsy: The removal of cell or tissue samples from the urethra, bladder, and, sometimes, the prostate gland. The samples are viewed under a microscope by a pathologist to check for signs of cancer.

Certain factors affect prognosis (chance of recovery) and treatment options.

The prognosis and treatment options depend on the following:

  • Where the cancer formed in the urethra.
  • Whether the cancer has spread through the mucosa lining the urethra to nearby tissue, to lymph nodes, or to other parts of the body.
  • Whether the patient is a male or female.
  • The patient’s general health.
  • Whether the cancer has just been diagnosed or has recurred (come back).

Stages of Urethral Cancer

Key Points

  • After urethral cancer has been diagnosed, tests are done to find out if cancer cells have spread within the urethra or to other parts of the body.
  • There are three ways that cancer spreads in the body.
  • Cancer may spread from where it began to other parts of the body.
  • Urethral cancer is staged and treated based on the part of the urethra that is affected.
    • Distal urethral cancer
    • Proximal urethral cancer
  • Bladder and/or prostate cancer may occur at the same time as urethral cancer.
  • Urethral cancer can recur (come back) after it has been treated.

After urethral cancer has been diagnosed, tests are done to find out if cancer cells have spread within the urethra or to other parts of the body.

The process used to find out if cancer has spread within the urethra or to other parts of the body is called staging. The information gathered from the staging process determines the stage of the disease. It is important to know the stage in order to plan treatment.

The following procedures may be used in the staging process:

  • Chest x-ray: An x-ray of the organs and bones inside the chest. An x-ray is a type of energy beam that can go through the body and onto film, making a picture of areas inside the body.
  • CT scan (CAT scan) of the pelvis and abdomen: A procedure that makes a series of detailed pictures of the pelvis and abdomen, taken from different angles. The pictures are made by a computer linked to an x-ray machine. A dye may be injected into a vein or swallowed to help the organs or tissues show up more clearly. This procedure is also called computed tomography, computerized tomography, or computerized axial tomography.
  • MRI (magnetic resonance imaging): A procedure that uses a magnet, radio waves, and a computer to make a series of detailed pictures of the urethra, nearby lymph nodes, and other soft tissue and bones in the pelvis. A substance called gadolinium is injected into the patient through a vein. The gadolinium collects around the cancer cells so they show up brighter in the picture. This procedure is also called nuclear magnetic resonance imaging (NMRI).
  • Urethrography: A series of x-rays of the urethra. An x-ray is a type of energy beam that can go through the body and onto film, making a picture of areas inside the body. A dye is injected through the urethra into the bladder. The dye coats the bladder and urethra and x-rays are taken to see if the urethra is blocked and if cancer has spread to nearby tissue.

There are three ways that cancer spreads in the body.

Cancer can spread through tissue, the lymph system, and the blood:

  • Tissue. The cancer spreads from where it began by growing into nearby areas.
  • Lymph system. The cancer spreads from where it began by getting into the lymph system. The cancer travels through the lymph vessels to other parts of the body.
  • Blood. The cancer spreads from where it began by getting into the blood. The cancer travels through the blood vessels to other parts of the body.

Cancer may spread from where it began to other parts of the body.

When cancer spreads to another part of the body, it is called metastasis. Cancer cells break away from where they began (the primary tumor) and travel through the lymph system or blood.

  • Lymph system. The cancer gets into the lymph system, travels through the lymph vessels, and forms a tumor (metastatic tumor) in another part of the body.
  • Blood. The cancer gets into the blood, travels through the blood vessels, and forms a tumor (metastatic tumor) in another part of the body.

The metastatic tumor is the same type of cancer as the primary tumor. For example, if urethral cancer spreads to the lung, the cancer cells in the lung are actually urethral cancer cells. The disease is metastatic urethral cancer, not lung cancer.

Many cancer deaths are caused when cancer moves from the original tumor and spreads to other tissues and organs. This is called metastatic cancer. This animation shows how cancer cells travel from the place in the body where they first formed to other parts of the body.

Urethral cancer is staged and treated based on the part of the urethra that is affected.

Urethral cancer is staged and treated based on the part of the urethra that is affected and how deeply the tumor has spread into tissue around the urethra. Urethral cancer can be described as distal or proximal.

EnlargeDistal and proximal urethra. Drawing on the left shows the female proximal and distal urethra; also shown are the bladder filled with urine, the ureters, and the uterus. Cross-section drawing on the right shows the male proximal and distal urethra. Also shown are the rectum, prostate gland, penis, and testis.
Anatomy of the distal and proximal urethra. Urine flows out of the bladder and leaves the body through the urethra. The part of the urethra that is closest to the bladder is called the proximal urethra. The part that is closest to where the urine leaves the body is called the distal urethra. The urethra is about 8 inches long in men and about 1½ inches long in women.

Distal urethral cancer

In distal urethral cancer, the cancer usually has not spread deeply into the tissue. In women, the part of the urethra that is closest to the outside of the body (about ½ inch) is affected. In men, the part of the urethra that is in the penis is affected.

Proximal urethral cancer

Proximal urethral cancer affects the part of the urethra that is not the distal urethra. In women and men, proximal urethral cancer usually has spread deeply into tissue.

Bladder and/or prostate cancer may occur at the same time as urethral cancer.

In men, cancer that forms in the proximal urethra (the part of the urethra that passes through the prostate to the bladder) may occur at the same time as cancer of the bladder and/or prostate. Sometimes this occurs at diagnosis and sometimes it occurs later.

Urethral cancer can recur (come back) after it has been treated.

The cancer may come back in the urethra or in other parts of the body.

Treatment Option Overview

Key Points

  • There are different types of treatment for patients with urethral cancer.
  • The following types of treatment are used:
    • Surgery
    • Radiation therapy
    • Chemotherapy
    • Active surveillance
  • New types of treatment are being tested in clinical trials.
  • Treatment for urethral cancer may cause side effects.
  • Patients may want to think about taking part in a clinical trial.
  • Patients can enter clinical trials before, during, or after starting their cancer treatment.
  • Follow-up tests may be needed.

There are different types of treatment for patients with urethral cancer.

Different types of treatments are available for patients with urethral cancer. Some treatments are standard (the currently used treatment), and some are being tested in clinical trials. A treatment clinical trial is a research study meant to help improve current treatments or obtain information on new treatments for patients with cancer. When clinical trials show that a new treatment is better than the standard treatment, the new treatment may become the standard treatment. Patients may want to think about taking part in a clinical trial. Some clinical trials are open only to patients who have not started treatment.

The following types of treatment are used:

Surgery

Surgery to remove the cancer is the most common treatment for cancer of the urethra. One of the following types of surgery may be done:

  • Open excision: Removal of the cancer by surgery.
  • Transurethral resection (TUR): Surgery to remove the cancer using a special tool inserted into the urethra.
  • Electroresection with fulguration: Surgery to remove the cancer by electric current. A lighted tool with a small wire loop on the end is used to remove the cancer or to burn the tumor away with high-energy electricity.
  • Laser surgery: A surgical procedure that uses a laser beam (a narrow beam of intense light) as a knife to make bloodless cuts in tissue or to remove or destroy tissue.
  • Lymph node dissection: Lymph nodes in the pelvis and groin may be removed.
  • Cystourethrectomy: Surgery to remove the bladder and the urethra.
  • Cystoprostatectomy: Surgery to remove the bladder and the prostate.
  • Anterior exenteration: Surgery to remove the urethra, the bladder, and the vagina. Plastic surgery may be done to rebuild the vagina.
  • Partial penectomy: Surgery to remove the part of the penis surrounding the urethra where cancer has spread. Plastic surgery may be done to rebuild the penis.
  • Radical penectomy: Surgery to remove the entire penis. Plastic surgery may be done to rebuild the penis.

If the urethra is removed, the surgeon will make a new way for the urine to pass from the body. This is called urinary diversion. If the bladder is removed, the surgeon will make a new way for urine to be stored and passed from the body. The surgeon may use part of the small intestine to make a tube that passes urine through an opening (stoma). This is called an ostomy or urostomy. If a patient has an ostomy, a disposable bag to collect urine is worn under clothing. The surgeon may also use part of the small intestine to make a new storage pouch (continent reservoir) inside the body where the urine can collect. A tube (catheter) is then used to drain the urine through a stoma.

After the doctor removes all the cancer that can be seen at the time of the surgery, some patients may be given chemotherapy or radiation therapy after surgery to kill any cancer cells that are left. Treatment given after the surgery, to lower the risk that the cancer will come back, is called adjuvant therapy.

Radiation therapy

Radiation therapy is a cancer treatment that uses high-energy x-rays or other types of radiation to kill cancer cells or keep them from growing. There are two types of radiation therapy:

The way the radiation therapy is given depends on the type of cancer and where the cancer formed in the urethra. External and internal radiation therapy are used to treat urethral cancer.

Chemotherapy

Chemotherapy is a cancer treatment that uses drugs to stop the growth of cancer cells, either by killing the cells or by stopping the cells from dividing. When chemotherapy is taken by mouth or injected into a vein or muscle, the drugs enter the bloodstream and can reach cancer cells throughout the body (systemic chemotherapy). When chemotherapy is placed directly into the cerebrospinal fluid, an organ, or a body cavity such as the abdomen, the drugs mainly affect cancer cells in those areas (regional chemotherapy). The way the chemotherapy is given depends on the type of cancer and where the cancer formed in the urethra.

Active surveillance

Active surveillance is following a patient’s condition without giving any treatment unless there are changes in test results. It is used to find early signs that the condition is getting worse. In active surveillance, patients are given certain exams and tests, including biopsies, on a regular schedule.

New types of treatment are being tested in clinical trials.

Information about clinical trials is available from the NCI website.

Treatment for urethral cancer may cause side effects.

For information about side effects caused by treatment for cancer, visit our Side Effects page.

Patients may want to think about taking part in a clinical trial.

For some patients, taking part in a clinical trial may be the best treatment choice. Clinical trials are part of the cancer research process. Clinical trials are done to find out if new cancer treatments are safe and effective or better than the standard treatment.

Many of today’s standard treatments for cancer are based on earlier clinical trials. Patients who take part in a clinical trial may receive the standard treatment or be among the first to receive a new treatment.

Patients who take part in clinical trials also help improve the way cancer will be treated in the future. Even when clinical trials do not lead to effective new treatments, they often answer important questions and help move research forward.

Patients can enter clinical trials before, during, or after starting their cancer treatment.

Some clinical trials only include patients who have not yet received treatment. Other trials test treatments for patients whose cancer has not gotten better. There are also clinical trials that test new ways to stop cancer from recurring (coming back) or reduce the side effects of cancer treatment.

Clinical trials are taking place in many parts of the country. Information about clinical trials supported by NCI can be found on NCI’s clinical trials search webpage. Clinical trials supported by other organizations can be found on the ClinicalTrials.gov website.

Follow-up tests may be needed.

As you go through treatment, you will have follow-up tests or check-ups. Some tests that were done to diagnose or stage the cancer may be repeated to see how well the treatment is working. Decisions about whether to continue, change, or stop treatment may be based on the results of these tests.

Some of the tests will continue to be done from time to time after treatment has ended. The results of these tests can show if your condition has changed or if the cancer has recurred (come back).

Treatment of Distal Urethral Cancer

For information about the treatments listed below, see the Treatment Option Overview section.

Treatment of abnormal cells in the mucosa (inside lining of the urethra that have not become cancer, may include surgery to remove the tumor (open excision or transurethral resection), electroresection with fulguration, or laser surgery.

Treatment of distal urethral cancer is different for men and women.

For women, treatment may include the following:

For men, treatment may include the following:

  • Surgery to remove the tumor (transurethral resection), electroresection and fulguration, or laser surgery for tumors that have not spread deeply into tissue.
  • Surgery to remove part of the penis (partial penectomy) for tumors that are near the tip of the penis. Sometimes nearby lymph nodes are also removed (lymph node dissection).
  • Surgery to remove part of the urethra for tumors that are in the distal urethra but not at the tip of the penis and have not spread deeply into tissue. Sometimes nearby lymph nodes are also removed (lymph node dissection).
  • Surgery to remove the penis (radical penectomy) for tumors that have spread deeply into tissue. Sometimes nearby lymph nodes are also removed (lymph node dissection).
  • Radiation therapy with or without chemotherapy.
  • Chemotherapy given together with radiation therapy.

Use our clinical trial search to find NCI-supported cancer clinical trials that are accepting patients. You can search for trials based on the type of cancer, the age of the patient, and where the trials are being done. General information about clinical trials is also available.

Treatment of Proximal Urethral Cancer

For information about the treatments listed below, see the Treatment Option Overview section.

Treatment of proximal urethral cancer or urethral cancer that affects the entire urethra is different for men and women.

For women, treatment may include the following:

For men, treatment may include the following:

Use our clinical trial search to find NCI-supported cancer clinical trials that are accepting patients. You can search for trials based on the type of cancer, the age of the patient, and where the trials are being done. General information about clinical trials is also available.

Treatment of Urethral Cancer that Forms with Invasive Bladder Cancer

For information about the treatments listed below, see the Treatment Option Overview section.

Treatment of urethral cancer that forms at the same time as invasive bladder cancer may include the following:

If the urethra is not removed during surgery to remove the bladder, treatment may include the following:

Use our clinical trial search to find NCI-supported cancer clinical trials that are accepting patients. You can search for trials based on the type of cancer, the age of the patient, and where the trials are being done. General information about clinical trials is also available.

Treatment of Metastatic or Recurrent Urethral Cancer

For information about the treatments listed below, see the Treatment Option Overview section.

Treatment of urethral cancer that has metastasized (spread to other parts of the body) is usually chemotherapy.

Treatment of recurrent urethral cancer may include one or more of the following:

Use our clinical trial search to find NCI-supported cancer clinical trials that are accepting patients. You can search for trials based on the type of cancer, the age of the patient, and where the trials are being done. General information about clinical trials is also available.

To Learn More About Urethral Cancer

For more information from the National Cancer Institute about urethral cancer, see the following:

For general cancer information and other resources from the National Cancer Institute, visit:

About This PDQ Summary

About PDQ

Physician Data Query (PDQ) is the National Cancer Institute’s (NCI’s) comprehensive cancer information database. The PDQ database contains summaries of the latest published information on cancer prevention, detection, genetics, treatment, supportive care, and complementary and alternative medicine. Most summaries come in two versions. The health professional versions have detailed information written in technical language. The patient versions are written in easy-to-understand, nontechnical language. Both versions have cancer information that is accurate and up to date and most versions are also available in Spanish.

PDQ is a service of the NCI. The NCI is part of the National Institutes of Health (NIH). NIH is the federal government’s center of biomedical research. The PDQ summaries are based on an independent review of the medical literature. They are not policy statements of the NCI or the NIH.

Purpose of This Summary

This PDQ cancer information summary has current information about the treatment of urethral cancer. It is meant to inform and help patients, families, and caregivers. It does not give formal guidelines or recommendations for making decisions about health care.

Reviewers and Updates

Editorial Boards write the PDQ cancer information summaries and keep them up to date. These Boards are made up of experts in cancer treatment and other specialties related to cancer. The summaries are reviewed regularly and changes are made when there is new information. The date on each summary (“Updated”) is the date of the most recent change.

The information in this patient summary was taken from the health professional version, which is reviewed regularly and updated as needed, by the PDQ Adult Treatment Editorial Board.

Clinical Trial Information

A clinical trial is a study to answer a scientific question, such as whether one treatment is better than another. Trials are based on past studies and what has been learned in the laboratory. Each trial answers certain scientific questions in order to find new and better ways to help cancer patients. During treatment clinical trials, information is collected about the effects of a new treatment and how well it works. If a clinical trial shows that a new treatment is better than one currently being used, the new treatment may become “standard.” Patients may want to think about taking part in a clinical trial. Some clinical trials are open only to patients who have not started treatment.

Clinical trials can be found online at NCI’s website. For more information, call the Cancer Information Service (CIS), NCI’s contact center, at 1-800-4-CANCER (1-800-422-6237).

Permission to Use This Summary

PDQ is a registered trademark. The content of PDQ documents can be used freely as text. It cannot be identified as an NCI PDQ cancer information summary unless the whole summary is shown and it is updated regularly. However, a user would be allowed to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks in the following way: [include excerpt from the summary].”

The best way to cite this PDQ summary is:

PDQ® Adult Treatment Editorial Board. PDQ Urethral Cancer Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /types/urethral/patient/urethral-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389384]

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Urethral Cancer Treatment (PDQ®)–Health Professional Version

Urethral Cancer Treatment (PDQ®)–Health Professional Version

General Information About Urethral Cancer

Go to Patient Version

Incidence and Mortality

Urethral cancer is rare. The annual incidence rate for urethral cancer in the Surveillance, Epidemiology, and End Results (SEER) Program database from 1973 to 2002 in the United States was 4.3 per million for men and 1.5 per million for women, with downward trends over the three decades.[1] The incidence was twice as high in African American individuals as in White individuals (5 per million vs. 2.5 per million). Urethral cancers appear to be associated with human papillomavirus (HPV) infection, particularly HPV16, a strain known to cause cervical cancer.[2,3]

Because urethral cancer is rare, nearly all information about its treatment and the outcomes of therapy is derived from retrospective, single-center case series, which represents a very low Level of evidence C3. Most information comes from cases accumulated over many decades at major academic centers.

Anatomy

The female urethra is largely contained within the anterior vaginal wall. In adults, it is about 4 cm in length.

The male urethra, which averages about 20 cm in length, is divided into distal and proximal portions. The distal urethra, which extends from the tip of the penis to just before the prostate, includes the meatus, the fossa navicularis, the penile or pendulous urethra, and the bulbar urethra. The proximal urethra, which extends from the bulbar urethra to the bladder neck, includes the membranous urethra and the prostatic urethra.

EnlargeAnatomy of the male urinary system (left panel) and female urinary system (right panel); two-panel drawing showing the right and left kidneys, the ureters, the bladder filled with urine, and the urethra. The inside of the left kidney shows the renal pelvis. An inset shows the renal tubules and urine. Also shown are the prostate and penis (left panel) and the uterus (right panel).
Anatomy of the male urinary system (left panel) and female urinary system (right panel) showing the kidneys, ureters, bladder, and urethra. The inside of the left kidney shows the renal pelvis. An inset shows the renal tubules and urine. Also shown are the prostate and penis (left panel) and the uterus (right panel). Urine is made in the renal tubules and collects in the renal pelvis of each kidney. The urine flows from the kidneys through the ureters to the bladder. The urine is stored in the bladder until it leaves the body through the urethra.

Prognosis

The prognosis of urethral cancer depends on the following factors:[4–6]

  • Anatomical location.
  • Size.
  • Stage.
  • Depth of invasion.

Superficial tumors in the distal urethra in both women and men are generally curable. However, deeply invasive lesions are rarely curable by any combination of therapies. In men, the prognosis of tumors in the distal (pendulous) urethra is better than for tumors of the proximal (bulbomembranous) and prostatic urethra, which tend to present at more advanced stages.[7,8] Likewise, distal urethral tumors tend to occur at earlier stages in women and to have a better prognosis than proximal tumors.[9]

References
  1. Swartz MA, Porter MP, Lin DW, et al.: Incidence of primary urethral carcinoma in the United States. Urology 68 (6): 1164-8, 2006. [PUBMED Abstract]
  2. Wiener JS, Liu ET, Walther PJ: Oncogenic human papillomavirus type 16 is associated with squamous cell cancer of the male urethra. Cancer Res 52 (18): 5018-23, 1992. [PUBMED Abstract]
  3. Wiener JS, Walther PJ: A high association of oncogenic human papillomaviruses with carcinomas of the female urethra: polymerase chain reaction-based analysis of multiple histological types. J Urol 151 (1): 49-53, 1994. [PUBMED Abstract]
  4. Urethra. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. Springer; 2017, pp. 767–76.
  5. Rabbani F: Prognostic factors in male urethral cancer. Cancer 117 (11): 2426-34, 2011. [PUBMED Abstract]
  6. Dalbagni G, Zhang ZF, Lacombe L, et al.: Female urethral carcinoma: an analysis of treatment outcome and a plea for a standardized management strategy. Br J Urol 82 (6): 835-41, 1998. [PUBMED Abstract]
  7. Dinney CP, Johnson DE, Swanson DA, et al.: Therapy and prognosis for male anterior urethral carcinoma: an update. Urology 43 (4): 506-14, 1994. [PUBMED Abstract]
  8. Dalbagni G, Zhang ZF, Lacombe L, et al.: Male urethral carcinoma: analysis of treatment outcome. Urology 53 (6): 1126-32, 1999. [PUBMED Abstract]
  9. Gheiler EL, Tefilli MV, Tiguert R, et al.: Management of primary urethral cancer. Urology 52 (3): 487-93, 1998. [PUBMED Abstract]

Cellular Classification of Urethral Cancer

In an analysis of Surveillance, Epidemiology, and End Results (SEER) Program data from 1973 to 2002, the most common histological types of urethral cancer were the following:[1]

  • Transitional cell (55%).
  • Squamous cell (21.5%).
  • Adenocarcinoma (16.4%).

Other cell types, such as melanoma, were extremely rare.[1]

The female urethra is lined by transitional cell mucosa proximally and stratified squamous cells distally. Therefore, transitional cell carcinoma is most common in the proximal urethra, and squamous cell carcinoma predominates in the distal urethra. Adenocarcinoma may occur in both locations and arises from metaplasia of the numerous periurethral glands.

The male urethra is lined by transitional cells in its prostatic and membranous portion and stratified columnar epithelium to stratified squamous epithelium in the bulbous and penile portions. The submucosa of the urethra contains numerous glands. Therefore, urethral cancer in men can manifest the histological characteristics of transitional cell carcinoma, squamous cell carcinoma, or adenocarcinoma.

Except for the prostatic urethra, where transitional cell carcinoma is most common, squamous cell carcinoma is the predominant histology of urethral neoplasms. Because transitional cell carcinoma of the prostatic urethra may be associated with transitional cell carcinoma of the bladder and/or transitional cell carcinoma arising in prostatic ducts, it is often treated similarly to these primaries and should be separated from the more distal carcinomas of the urethra.

References
  1. Swartz MA, Porter MP, Lin DW, et al.: Incidence of primary urethral carcinoma in the United States. Urology 68 (6): 1164-8, 2006. [PUBMED Abstract]

Stage Information for Urethral Cancer

Prognosis and treatment decisions are determined by the following:[1]

  • The anatomical location of the primary tumor.
  • The size of the tumor.
  • The stage of the cancer.
  • The depth of invasion of the tumor.

The histology of the primary tumor is of less importance in estimating response to therapy and survival.[2] Endoscopic examination, urethrography, and magnetic resonance imaging are useful in determining the local extent of the tumor.[3,4]

Distal Urethral Cancer

These lesions are often superficial.

  • Female: Lesions of the distal third of the urethra.
  • Male: Anterior, or penile, portion of the urethra, including the meatus and pendulous urethra.

Proximal Urethral Cancer

These lesions are often deeply invasive.

  • Female: Lesions not clearly limited to the distal third of the urethra.
  • Male: Bulbomembranous and prostatic urethra.

Urethral Cancer Associated With Invasive Bladder Cancer

Approximately 5% to 10% of men with cystectomy for bladder cancer may have or may develop urethral cancer distal to the urogenital diaphragm.[5,6]

American Joint Committee on Cancer (AJCC) Stage Groupings and TNM Definitions

The AJCC has designated staging by TNM (tumor, node, metastasis) classification to define urethral cancer.[1]

Male penile urethra and female urethra

Table 1. Definitions of TNM Stages 0is and 0aa
Stage TNM Description
T = primary tumor; N = regional lymph node; M = distant metastasis.
aReprinted with permission from AJCC: Urethra. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 767–76.
0is Tis, N0, M0 Tis = Carcinoma in situ.
N0 = No regional lymph node metastasis.
M0 = No distant metastasis.
0a Ta, N0, M0 Ta = Noninvasive papillary carcinoma.
N0 = No regional lymph node metastasis.
M0 = No distant metastasis.
Table 2. Definition of TNM Stage Ia
Stage TNM Description
T = primary tumor; N = regional lymph node; M = distant metastasis.
aReprinted with permission from AJCC: Urethra. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 767–76.
I T1, N0, M0 T1 = Tumor invades subepithelial connective tissue.
N0 = No regional lymph node metastasis.
M0 = No distant metastasis.
Table 3. Definition of TNM Stage IIa
Stage TNM Description
T = primary tumor; N = regional lymph node; M = distant metastasis.
aReprinted with permission from AJCC: Urethra. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 767–76.
II T2, N0, M0 T2 = Tumor invades any of the following: corpus spongiosum, periurethral muscle.
N0 = No regional lymph node metastasis.
M0 = No distant metastasis.
Table 4. Definitions of TNM Stage IIIa
Stage TNM Description
T = primary tumor; N = regional lymph node; M = distant metastasis.
aReprinted with permission from AJCC: Urethra. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 767–76.
III T1, N1, M0 T1 = Tumor invades subepithelial connective tissue.
N1 = Single regional lymph node metastasis in the inguinal region or true pelvis (perivesical, obturator, internal [hypogastric] and external iliac), or presacral lymph node.
M0 = No distant metastasis.
T2, N1, M0 T2 = Tumor invades any of the following: corpus spongiosum, periurethral muscle.
N1 = Single regional lymph node metastasis in the inguinal region or true pelvis (perivesical, obturator, internal [hypogastric] and external iliac), or presacral lymph node.
M0 = No distant metastasis.
T3, N0, M0 T3 = Tumor invades any of the following: corpus cavernosum, anterior vagina.
N0 = No regional lymph node metastasis.
M0 = No distant metastasis.
T3, N1, M0 T3 = Tumor invades any of the following: corpus cavernosum, anterior vagina.
N1 = Single regional lymph node metastasis in the inguinal region or true pelvis (perivesical, obturator, internal [hypogastric] and external iliac), or presacral lymph node.
M0 = No distant metastasis.
Table 5. Definitions of TNM Stage IVa
Stage TNM Description
T = primary tumor; N = regional lymph node; M = distant metastasis.
aReprinted with permission from AJCC: Urethra. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. New York, NY: Springer, 2017, pp. 767–76.
IV T4, N0, M0 T4 = Tumor invades other adjacent organs (e.g., invasion of the bladder wall).
N0 = No regional lymph node metastasis.
M0 = No distant metastasis.
T4, N1, M0 T4 = Tumor invades other adjacent organs (e.g., invasion of the bladder wall).
N1 = Single regional lymph node metastasis in the inguinal region or true pelvis (perivesical, obturator, internal [hypogastric] and external iliac), or presacral lymph node.
M0 = No distant metastasis.
Any T, N2, M0 TX = Primary tumor cannot be assessed.
T0 = No evidence of primary tumor.
Ta = Noninvasive papillary carcinoma.
Tis = Carcinoma in situ.
T1 = Tumor invades subepithelial connective tissue.
T2 = Tumor invades any of the following: corpus spongiosum, periurethral muscle.
T3 = Tumor invades any of the following: corpus cavernosum, anterior vagina.
T4 = Tumor invades other adjacent organs (e.g., invasion of the bladder wall).
N2 = Multiple regional lymph node metastasis in the inguinal region or true pelvis (perivesical, obturator, internal [hypogastric] and external iliac), or presacral lymph node.
M0 = No distant metastasis.
Any T, Any N, M1 Any T = See descriptions above in this table, stage IV, Any T, N2, M0.
NX = Regional lymph nodes cannot be assessed.
N0 = No regional lymph node metastasis.
N1 = Single regional lymph node metastasis in the inguinal region or true pelvis (perivesical, obturator, internal [hypogastric] and external iliac), or presacral lymph node.
N2 = Multiple regional lymph node metastasis in the inguinal region or true pelvis (perivesical, obturator, internal [hypogastric] and external iliac), or presacral lymph node.
M1 = Distant metastasis.
References
  1. Urethra. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. Springer; 2017, pp. 767–76.
  2. Grigsby PW, Corn BW: Localized urethral tumors in women: indications for conservative versus exenterative therapies. J Urol 147 (6): 1516-20, 1992. [PUBMED Abstract]
  3. Ryu J, Kim B: MR imaging of the male and female urethra. Radiographics 21 (5): 1169-85, 2001 Sep-Oct. [PUBMED Abstract]
  4. Pavlica P, Barozzi L, Menchi I: Imaging of male urethra. Eur Radiol 13 (7): 1583-96, 2003. [PUBMED Abstract]
  5. Mark JR, Hurwitz M, Gomella LG: Cancer of the urethra and penis. In: DeVita VT Jr, Lawrence TS, Rosenberg SA, et al., eds.: DeVita, Hellman, and Rosenberg’s Cancer: Principles & Practice of Oncology. 11th ed. Wolters Kluwer, 2019, pp 1136-44.
  6. Erckert M, Stenzl A, Falk M, et al.: Incidence of urethral tumor involvement in 910 men with bladder cancer. World J Urol 14 (1): 3-8, 1996. [PUBMED Abstract]

Treatment Option Overview for Urethral Cancer

Information about the treatment of urethral cancer and the outcomes of therapy is derived from retrospective, single-center case series and represents a very low Level of evidence C3. Most of this information comes from the small numbers of cases accumulated over many decades at major academic centers. Therefore, the treatment in these reports is usually not standardized and spans eras of shifting supportive care practices. Because urethral cancer is rare, its treatment may also reflect extrapolation from the management of other urothelial malignancies, such as bladder cancer in the case of transitional cancers and anal cancer in the case of squamous cell carcinomas.

Surgery

Surgery is the mainstay of therapy for urethral cancers in both women and men.[Level of evidence C3] The surgical approach depends on tumor stage and anatomic location, and tumor grade plays a less important role in treatment decisions.[1,2] Although the traditional recommendation has been to achieve a 2-cm tumor-free margin, the optimal surgical margin has not been rigorously studied and is not well defined. The role of lymph node dissection is not clear in the absence of clinical involvement, and the role of prophylactic dissection is controversial.[2] Radiation therapy and/or chemotherapy may be added in some cases in patients with extensive disease or in an attempt at organ preservation. However, there are no clear guidelines for patient selection, and the low level of evidence precludes confident conclusions about their incremental benefit.[2,3]

Ablative techniques, such as transurethral resection, electroresection and fulguration, or laser vaporization-coagulation, are used to preserve organ function in cases of superficial anterior tumors, although the supporting literature is scant.[2]

Radiation Therapy

External-beam radiation therapy, brachytherapy, or a combination is sometimes used as the primary therapy for early-stage proximal urethral cancers, particularly in women.[Level of evidence C3] Brachytherapy may be delivered with low-dose-rate iridium Ir 192 sources using a template or urethral catheter. Definitive radiation is also sometimes used for advanced-stage tumors, but because monotherapy of large tumors has shown poor tumor control, it is more frequently incorporated into combined modality therapy after surgery or with chemotherapy.[4] There are no head-to-head comparisons of these various approaches, and patient selection may explain differences in outcomes among the regimens.[Level of evidence C3]

The most commonly used tumor doses are in the range of 60 Gy to 70 Gy. Severe complication rates for definitive radiation therapy are about 16% to 20% and include fistula development, especially for large tumors invading the vagina, bladder, or rectum. Urethral strictures also occur in the setting of urethral-sparing treatment. Toxicity rates increase at doses greater than 65 Gy to 70 Gy. Intensity-modulated radiation therapy has become more common in an attempt to decrease local morbidity of the radiation.[4]

Chemotherapy

The literature on chemotherapy for urethral carcinoma is anecdotal in nature and restricted to retrospective, single-center case series or case reports.[5][Level of evidence C3] A wide variety of agents used alone or in combination have been reported over the years, and their use has largely been extrapolated from experience with other urinary tract tumors.

For squamous cell cancers, agents that have been used in penile cancer or anal carcinoma include the following:[3,5]

  • Cisplatin.
  • Fluorouracil.
  • Bleomycin.
  • Methotrexate.
  • Irinotecan.
  • Gemcitabine.
  • Paclitaxel.
  • Docetaxel.
  • Mitomycin.

Chemotherapy for transitional cell urethral tumors is extrapolated from experience with transitional cell bladder tumors and, therefore, usually contains the following:[1,4–7]

  • Methotrexate, vinblastine, doxorubicin, and cisplatin.
  • Paclitaxel.
  • Carboplatin.
  • Ifosfamide, with occasional complete responses.

Chemotherapy has been used alone for metastatic disease or in combination with radiation therapy and/or surgery for locally advanced urethral cancer. It may be used in the neoadjuvant setting with radiation therapy in an attempt to increase the resectability rate or to preserve organs.[3] However, the impact of any of these regimens on survival is not known for any stage or setting.

Fluorouracil dosing

The DPYD gene encodes an enzyme that catabolizes pyrimidines and fluoropyrimidines, like capecitabine and fluorouracil. An estimated 1% to 2% of the population has germline pathogenic variants in DPYD, which lead to reduced DPD protein function and an accumulation of pyrimidines and fluoropyrimidines in the body.[8,9] Patients with the DPYD*2A variant who receive fluoropyrimidines may experience severe, life-threatening toxicities that are sometimes fatal. Many other DPYD variants have been identified, with a range of clinical effects.[8–10] Fluoropyrimidine avoidance or a dose reduction of 50% may be recommended based on the patient’s DPYD genotype and number of functioning DPYD alleles.[11–13] DPYD genetic testing costs less than $200, but insurance coverage varies due to a lack of national guidelines.[14] In addition, testing may delay therapy by 2 weeks, which would not be advisable in urgent situations. This controversial issue requires further evaluation.[15]

References
  1. Mark JR, Hurwitz M, Gomella LG: Cancer of the urethra and penis. In: DeVita VT Jr, Lawrence TS, Rosenberg SA, et al., eds.: DeVita, Hellman, and Rosenberg’s Cancer: Principles & Practice of Oncology. 11th ed. Wolters Kluwer, 2019, pp 1136-44.
  2. Karnes RJ, Breau RH, Lightner DJ: Surgery for urethral cancer. Urol Clin North Am 37 (3): 445-57, 2010. [PUBMED Abstract]
  3. Cohen MS, Triaca V, Billmeyer B, et al.: Coordinated chemoradiation therapy with genital preservation for the treatment of primary invasive carcinoma of the male urethra. J Urol 179 (2): 536-41; discussion 541, 2008. [PUBMED Abstract]
  4. Koontz BF, Lee WR: Carcinoma of the urethra: radiation oncology. Urol Clin North Am 37 (3): 459-66, 2010. [PUBMED Abstract]
  5. Trabulsi EJ, Hoffman-Censits J: Chemotherapy for penile and urethral carcinoma. Urol Clin North Am 37 (3): 467-74, 2010. [PUBMED Abstract]
  6. VanderMolen LA, Sheehy PF, Dillman RO: Successful treatment of transitional cell carcinoma of the urethra with chemotherapy. Cancer Invest 20 (2): 206-7, 2002. [PUBMED Abstract]
  7. Lin CC, Hsu CH, Huang CY, et al.: Phase II trial of weekly paclitaxel, cisplatin plus infusional high dose 5-fluorouracil and leucovorin for metastatic urothelial carcinoma. J Urol 177 (1): 84-9; discussion 89, 2007. [PUBMED Abstract]
  8. Sharma BB, Rai K, Blunt H, et al.: Pathogenic DPYD Variants and Treatment-Related Mortality in Patients Receiving Fluoropyrimidine Chemotherapy: A Systematic Review and Meta-Analysis. Oncologist 26 (12): 1008-1016, 2021. [PUBMED Abstract]
  9. Lam SW, Guchelaar HJ, Boven E: The role of pharmacogenetics in capecitabine efficacy and toxicity. Cancer Treat Rev 50: 9-22, 2016. [PUBMED Abstract]
  10. Shakeel F, Fang F, Kwon JW, et al.: Patients carrying DPYD variant alleles have increased risk of severe toxicity and related treatment modifications during fluoropyrimidine chemotherapy. Pharmacogenomics 22 (3): 145-155, 2021. [PUBMED Abstract]
  11. Amstutz U, Henricks LM, Offer SM, et al.: Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Dihydropyrimidine Dehydrogenase Genotype and Fluoropyrimidine Dosing: 2017 Update. Clin Pharmacol Ther 103 (2): 210-216, 2018. [PUBMED Abstract]
  12. Henricks LM, Lunenburg CATC, de Man FM, et al.: DPYD genotype-guided dose individualisation of fluoropyrimidine therapy in patients with cancer: a prospective safety analysis. Lancet Oncol 19 (11): 1459-1467, 2018. [PUBMED Abstract]
  13. Lau-Min KS, Varughese LA, Nelson MN, et al.: Preemptive pharmacogenetic testing to guide chemotherapy dosing in patients with gastrointestinal malignancies: a qualitative study of barriers to implementation. BMC Cancer 22 (1): 47, 2022. [PUBMED Abstract]
  14. Brooks GA, Tapp S, Daly AT, et al.: Cost-effectiveness of DPYD Genotyping Prior to Fluoropyrimidine-based Adjuvant Chemotherapy for Colon Cancer. Clin Colorectal Cancer 21 (3): e189-e195, 2022. [PUBMED Abstract]
  15. Baker SD, Bates SE, Brooks GA, et al.: DPYD Testing: Time to Put Patient Safety First. J Clin Oncol 41 (15): 2701-2705, 2023. [PUBMED Abstract]

Treatment of Distal Urethral Cancer

Treatment Options for Female Distal Urethral Cancer

If the malignancy is at or just within the meatus and superficial parameters (stage 0/Tis, Ta), open excision or electroresection and fulguration may be possible. Tumor destruction using neodymium:yttrium-aluminum-garnet (Nd:YAG) or CO2 laser vaporization-coagulation represents an alternative option. For large lesions (T1) and more invasive lesions (T2), brachytherapy or a combination of brachytherapy and external-beam radiation therapy (EBRT) are alternatives to surgical resection of the distal third of the urethra. Patients with T3 distal urethral lesions or lesions that recur after treatment with local excision or radiation therapy require anterior exenteration and urinary diversion.

If inguinal lymph nodes are palpable, frozen section confirmation of a tumor should be obtained. If positive for malignancy, ipsilateral lymph node dissection is indicated. If no inguinal adenopathy exists, lymph node dissection is not generally performed, and the nodes are monitored clinically.

Treatment options for female distal urethral cancer include the following:

  1. Open excision and organ-sparing conservative surgical therapy.[1]
  2. Ablative techniques, such as transurethral resection, electroresection and fulguration, or laser vaporization-coagulation (Tis, Ta, T1 lesions).[2,3]
  3. EBRT, brachytherapy, or a combination of the two (T1, T2 lesions).[4]
  4. Anterior exenteration with or without preoperative radiation and diversion (T3 lesions or recurrent lesions).[2,3]

The level of evidence for these treatment options is Level of evidence C3.

Treatment Options for Male Distal Urethral Cancer

If the malignancy is in the pendulous urethra and is superficial, there is potential for long-term disease-free survival. In the rare cases that involve mucosa only (Tis, Ta), resection and fulguration may be used. For infiltrating lesions in the fossa navicularis, amputation of the glans penis may be adequate treatment. For lesions involving more proximal portions of the distal urethra, excision of the involved segment of the urethra, preserving the penile corpora, may be feasible for superficial tumors. Penile amputation is used for infiltrating lesions. Traditionally, a 2-cm margin proximal to the tumor is used, but the optimal margin has not been well studied. Local recurrences after amputation are rare.

The role of radiation therapy in the treatment of anterior urethral carcinoma in men is not well defined. Some anterior urethral cancers have been cured with radiation alone or a combination of chemotherapy and radiation therapy.[4,5]

If inguinal lymph nodes are palpable, ipsilateral node dissection is indicated after frozen section confirmation of a tumor because a cure is still achievable with limited regional nodal metastases. If no inguinal adenopathy exists, lymph node dissection is not generally performed, and the nodes are monitored clinically.

Treatment options for male distal urethral cancer include the following:

  1. Open-excision and organ-sparing conservative surgery.[1,3]
  2. Ablative techniques, such as transurethral resection, electroresection and fulguration, or laser vaporization-coagulation (Tis, Ta, T1 lesions).[2,3]
  3. Amputation of the penis (T1, T2, T3 lesions).
  4. Radiation (T1, T2, T3 lesions, if amputation is refused).[4]
  5. Combined chemotherapy and radiation therapy.[5]

The level of evidence for these treatment options is Level of evidence C3.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References
  1. Davis JW, Schellhammer PF, Schlossberg SM: Conservative surgical therapy for penile and urethral carcinoma. Urology 53 (2): 386-92, 1999. [PUBMED Abstract]
  2. Mark JR, Hurwitz M, Gomella LG: Cancer of the urethra and penis. In: DeVita VT Jr, Lawrence TS, Rosenberg SA, et al., eds.: DeVita, Hellman, and Rosenberg’s Cancer: Principles & Practice of Oncology. 11th ed. Wolters Kluwer, 2019, pp 1136-44.
  3. Karnes RJ, Breau RH, Lightner DJ: Surgery for urethral cancer. Urol Clin North Am 37 (3): 445-57, 2010. [PUBMED Abstract]
  4. Koontz BF, Lee WR: Carcinoma of the urethra: radiation oncology. Urol Clin North Am 37 (3): 459-66, 2010. [PUBMED Abstract]
  5. Cohen MS, Triaca V, Billmeyer B, et al.: Coordinated chemoradiation therapy with genital preservation for the treatment of primary invasive carcinoma of the male urethra. J Urol 179 (2): 536-41; discussion 541, 2008. [PUBMED Abstract]

Treatment of Proximal Urethral Cancer

Treatment Options for Female Proximal Urethral Cancer

Lesions of the proximal urethra or the entire length of the urethra are usually associated with invasion and a high incidence of pelvic nodal metastases. The prospects for cure are limited except in the case of small tumors. The best results have been achieved with exenterative surgery and urinary diversion, with 5-year survival rates ranging from 10% to 20%.

In an effort to shrink tumor margins, increase the resectability rate of gross tumor, and decrease local recurrence, adjunctive preoperative radiation therapy is a reasonable option. Pelvic lymphadenectomy is performed concomitantly. Ipsilateral inguinal lymph node dissection is indicated only if biopsy specimens of ipsilateral palpable adenopathy are positive on a frozen section. For tumors that do not exceed 2 cm in greatest dimension, radiation alone, nonexenterative surgery alone, or a combination of the two may be sufficient to provide an excellent outcome.

It is reasonable to consider removal of part of the pubic symphysis and the inferior pubic rami to maximize the surgical margin and reduce local recurrence. The perineal closure and vaginal reconstruction can be accomplished with the use of myocutaneous flaps.

The prognosis of female urethral cancer is related to the size of the lesion at presentation. For lesions smaller than 2 cm in diameter, a 5-year survival rate of 60% can be anticipated. For lesions larger than 4 cm in diameter, the 5-year survival rate falls to 13%.

Treatment options for female proximal urethral cancer include the following:

  1. Preoperative radiation followed by anterior exenteration and urinary diversion with bilateral pelvic lymph node dissection, with or without inguinal lymph node dissection.[1]
  2. For tumors that do not exceed 2 cm in greatest dimension, radiation alone, nonexenterative surgery alone, or a combination of the two may be sufficient to provide an excellent outcome.[1,2]

The level of evidence for these treatment options is Level of evidence C3.

Treatment Options for Male Proximal Urethral Cancer

Lesions of the bulbomembranous urethra require radical cystoprostatectomy and en bloc penectomy to achieve adequate margins of resection, minimize local recurrence, and achieve long-term, disease-free survival. Pelvic lymphadenectomy is also performed because of the high incidence of positive lymph nodes and the limited added morbidity.

Despite extensive surgery, local recurrence is common, and this event is invariably associated with eventual death from the disease. Five-year survival rates are only 15% to 20%. In an effort to shrink tumor margins, the use of preoperative adjunctive radiation therapy may be considered. In an effort to increase the surgical margins of dissection, resection of the inferior pubic rami and the lower portion of the pubic symphysis has been used. Urinary diversion is required.[3]

Ipsilateral inguinal lymph node dissection is indicated if palpable ipsilateral inguinal adenopathy is found on physical examination and confirmed to be neoplasm by frozen section.

Treatment options for male proximal urethral cancer include the following:

  1. Preoperative radiation or combined chemotherapy and radiation therapy followed by cystoprostatectomy, urinary diversion, and penectomy with bilateral pelvic lymph node dissection, with or without inguinal lymph node dissection.[4]

The level of evidence for these treatment options is Level of evidence C3.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References
  1. Koontz BF, Lee WR: Carcinoma of the urethra: radiation oncology. Urol Clin North Am 37 (3): 459-66, 2010. [PUBMED Abstract]
  2. Grigsby PW, Corn BW: Localized urethral tumors in women: indications for conservative versus exenterative therapies. J Urol 147 (6): 1516-20, 1992. [PUBMED Abstract]
  3. Su LM, Smith JA Jr.: Laparoscopic and robotic-assisted laparoscopic radical prostatectomy and pelvic lymphadenectomy. In: Wein AJ, Kavoussi LR, Novick AC, et al.: Campbell-Walsh Urology. 10th ed. Elsevier Saunders, 2012, pp 2830-2849.
  4. Karnes RJ, Breau RH, Lightner DJ: Surgery for urethral cancer. Urol Clin North Am 37 (3): 445-57, 2010. [PUBMED Abstract]

Treatment of Urethral Cancer Associated With Invasive Bladder Cancer

Approximately 10% (range, 4%–17%) of patients who undergo cystectomy for bladder cancer can be expected to have or to later develop clinical neoplasm of the urethra distal to the urogenital diaphragm. Factors associated with the risk of urethral recurrence after cystectomy include the following:[1,2]

  • Tumor multiplicity.
  • Papillary pattern.
  • Carcinoma in situ.
  • Tumor location at the bladder neck.
  • Prostatic urethral mucosal or stromal involvement.

The benefits of urethrectomy at the time of cystectomy need to be weighed against the morbidity factors, which include added operating time, hemorrhage, and the potential for perineal hernia. Tumors found incidentally on pathological examination are much more likely to be superficial or in situ in contrast to those that present with clinical symptoms at a later date, when the likelihood of invasion within the corporal bodies is high. The former lesions are often curable, and the latter are only rarely so. Indications for urethrectomy in continuity with cystoprostatectomy are the following:

  • Visible tumor in the urethra.
  • Positive swab cytology of the urethra.
  • Positive margins of the membranous urethra on frozen section taken at the time of cystoprostatectomy.
  • Multiple in situ bladder tumors that extend onto the bladder neck and proximal prostatic urethra.

If the urethra is not removed at the time of cystectomy, follow-up includes periodic cytologic evaluation of saline urethral washings.[2]

Treatment options for urethral cancer associated with invasive bladder cancer include the following:

  1. In continuity cystourethrectomy.
  2. Monitor urethral cytology and delayed urethrectomy, if necessary.

The level of evidence for these treatment options is Level of evidence C3.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References
  1. Mark JR, Hurwitz M, Gomella LG: Cancer of the urethra and penis. In: DeVita VT Jr, Lawrence TS, Rosenberg SA, et al., eds.: DeVita, Hellman, and Rosenberg’s Cancer: Principles & Practice of Oncology. 11th ed. Wolters Kluwer, 2019, pp 1136-44.
  2. Sherwood JB, Sagalowsky AI: The diagnosis and treatment of urethral recurrence after radical cystectomy. Urol Oncol 24 (4): 356-61, 2006 Jul-Aug. [PUBMED Abstract]

Treatment of Metastatic or Recurrent Urethral Cancer

Local recurrences of urethral cancer may be amenable to local modality therapy with radiation or surgery, with or without chemotherapy. For more information, see the Treatment Option Overview for Urethral Cancer section. Metastatic disease may be treated with regimens in common use for other urothelial transitional cell or squamous cell carcinomas, or anal carcinomas, depending on the histology.[1–3]

Treatment options for metastatic or recurrent urethral cancer include the following:

  1. Surgical excision of locally recurrent urethral cancer after radiation therapy should be considered, if feasible.
  2. Combination radiation therapy and wider surgical resection should be considered for locally recurrent urethral cancer after surgery alone.
  3. Clinical trials using chemotherapy should be considered for metastatic urethral cancer. Transitional cell cancer of the urethra may respond favorably to the same chemotherapy regimens used for advanced transitional cell cancer of the bladder.[1–4]

The level of evidence for these treatment options is Level of evidence C3.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References
  1. Mark JR, Hurwitz M, Gomella LG: Cancer of the urethra and penis. In: DeVita VT Jr, Lawrence TS, Rosenberg SA, et al., eds.: DeVita, Hellman, and Rosenberg’s Cancer: Principles & Practice of Oncology. 11th ed. Wolters Kluwer, 2019, pp 1136-44.
  2. Trabulsi EJ, Hoffman-Censits J: Chemotherapy for penile and urethral carcinoma. Urol Clin North Am 37 (3): 467-74, 2010. [PUBMED Abstract]
  3. Lin CC, Hsu CH, Huang CY, et al.: Phase II trial of weekly paclitaxel, cisplatin plus infusional high dose 5-fluorouracil and leucovorin for metastatic urothelial carcinoma. J Urol 177 (1): 84-9; discussion 89, 2007. [PUBMED Abstract]
  4. VanderMolen LA, Sheehy PF, Dillman RO: Successful treatment of transitional cell carcinoma of the urethra with chemotherapy. Cancer Invest 20 (2): 206-7, 2002. [PUBMED Abstract]

Latest Updates to This Summary (07/19/2024)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Treatment Option Overview for Urethral Cancer

Added Fluorouracil dosing as a new subsection.

This summary is written and maintained by the PDQ Adult Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® Cancer Information for Health Professionals pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of urethral cancer. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

  • be discussed at a meeting,
  • be cited with text, or
  • replace or update an existing article that is already cited.

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewers for Urethral Cancer Treatment are:

  • Juskaran S. Chadha, DO (Moffitt Cancer Center)
  • Jad Chahoud, MD, MPH (Moffitt Cancer Center)
  • Timothy Gilligan, MD (Cleveland Clinic Taussig Cancer Institute)

Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website’s Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

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PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary].”

The preferred citation for this PDQ summary is:

PDQ® Adult Treatment Editorial Board. PDQ Urethral Cancer Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: /types/urethral/hp/urethral-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389356]

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Urethral Cancer—Health Professional Version

Urethral Cancer—Health Professional Version

Treatment

PDQ Treatment Information for Health Professionals

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Causes & Prevention

NCI does not have PDQ evidence-based information about prevention of urethral cancer.

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Screening

NCI does not have PDQ evidence-based information about screening for urethral cancer.

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Supportive & Palliative Care

We offer evidence-based supportive and palliative care information for health professionals on the assessment and management of cancer-related symptoms and conditions.

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Urethral Cancer—Patient Version

Urethral Cancer—Patient Version

Overview

Urethral cancer is rare and is more common in men than in women. Urethral cancer can metastasize (spread) quickly to tissues around the urethra and has often spread to nearby lymph nodes by the time it is diagnosed. Explore the links on this page to learn more about urethral cancer treatment and clinical trials.

Treatment

PDQ Treatment Information for Patients

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Causes & Prevention

NCI does not have PDQ evidence-based information about prevention of urethral cancer.

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Screening

NCI does not have PDQ evidence-based information about screening for urethral cancer.

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Coping with Cancer

The information in this section is meant to help you cope with the many issues and concerns that occur when you have cancer.

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