Types of Cancer   /   Gynecologic Cancers   /   Cervical Cancer   /   NCI Resources

NCI/PDQ^® Health professionals: Cervical Cancer Treatment (PDQ®)

National Cancer Institute
Last Modified: June 22, 2012

TABLE OF CONTENTS

• General Information About Cervical Cancer
  • Incidence and Mortality
  • Prognostic Factors
  • Invasive Carcinomas of the Uterine Cervix
  • Human Papillomavirus Infection and Cervical Cancer
  • Related Summaries

• Cellular Classification of Cervical Cancer

• Stage Information for Cervical Cancer
  • Definitions: FIGO

• Treatment Option Overview

• Stage 0 Cervical Cancer
  • Current Clinical Trials

• Stage IA Cervical Cancer
  • Current Clinical Trials

• Stage IB Cervical Cancer
  • Current Clinical Trials

• Stage IIA Cervical Cancer
  • Current Clinical Trials

• Stage IIB Cervical Cancer
  • Current Clinical Trials

• Stage III Cervical Cancer
  • Current Clinical Trials

• Stage IVA Cervical Cancer
  • Current Clinical Trials

• Stage IVB Cervical Cancer
  • Current Clinical Trials

• Recurrent Cervical Cancer
  • Current Clinical Trials

• Changes to This Summary (06/22/2012)

• About This PDQ® Summary
  • Purpose of This Summary
  • Reviewers and Updates
  • Levels of Evidence
  • Permission to Use This Summary
  • Disclaimer
  • Contact Us

• Get More Information From NCI

General Information About Cervical Cancer

Back Up

Incidence and Mortality

Estimated new cases and deaths from cervical (uterine cervix) cancer in the United States in 2012: 1

• New cases: 12,170.
• Deaths: 4,220.

Prognostic Factors

The prognosis for patients with cervical cancer is markedly affected by the extent of disease at the time of diagnosis. A vast majority (>90%) of these cases can and should be detected early through the use of the Pap test and human papillomavirus (HPV) testing; however, 2 the current death rate is far higher than it should be, which reflects that, even today, the Pap test and HPV testing are not done on approximately 33% of eligible women. Clinical stage, however, as a prognostic factor must be supplemented by several gross and microscopic pathologic findings in surgically treated patients. These include: volume and grade of tumor, histologic type, lymphatic spread, and vascular invasion.

In a large surgicopathologic staging study of patients with clinical stage IB disease reported by the Gynecologic Oncology Group (GOG) (GOG-49), the factors that predicted most prominently for 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 most important and reproducible. 3 4 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 clinical or histologic stage. 5

A multivariate analysis of prognostic variables in 626 patients with locally advanced disease (primarily stages II, III, and IV) studied by the GOG identified several variables that were significant for progression-free interval and survival: 6

• 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.

In a large series of cervical cancer patients treated by radiation therapy, the incidence of distant metastases (most frequently to 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. 7 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. 7

GOG studies have indicated that prognostic factors vary whether clinical or surgical staging are utilized, and with treatment. Delay in radiation delivery completion is associated with poorer progression-free survival when clinical staging is used. It is unclear whether stage, tumor grade, race, and age hold up as prognostic factors in studies utilizing chemoradiation. 8

Invasive Carcinomas of the Uterine Cervix

Whether adenocarcinoma of the cervix carries a significantly worse prognosis than squamous cell carcinoma of the cervix remains controversial. 9 Reports conflict about the effect of adenosquamous cell type on outcome. 10 11 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. 12 The decreased survival is mainly the result of more advanced stage and nodal involvement rather than cell type as an independent variable. Women with human immunodeficiency virus have more aggressive and advanced disease and a poorer prognosis. 13 A study of patients with known invasive squamous carcinoma of the cervix found that overexpression of the C-myc oncogene was associated with a poorer prognosis. 14 The number of cells in S phase may also have prognostic significance in early cervical carcinoma. 15 HPV type 18 DNA has been found to be an independent adverse molecular prognostic factor. Two studies have shown a worse outcome when identified in cervical cancers of patients undergoing radical hysterectomy and pelvic lymphadenectomy. 16 17

Human Papillomavirus Infection and Cervical Cancer

Molecular techniques for the identification of HPV DNA are highly sensitive and specific. More than 6 million women in the United States are estimated to have HPV infection, and proper interpretation of these data is important. Epidemiologic studies convincingly demonstrate that the major risk factor for development of preinvasive or invasive carcinoma of the cervix is HPV infection, which far outweighs other known risk factors such as high parity, increasing number of sexual partners, young age at first intercourse, low socioeconomic status, and positive smoking history. 18 19 Some patients with HPV infection appear to be at minimal increased risk for development of cervical preinvasive and invasive malignancies, while others appear to be at significant risk and are candidates for intensive screening programs and/or early intervention.

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 cytologic specimens were assayed by a sensitive (hybrid capture) technique. 20 The authors of the study and of an accompanying editorial concluded that using HPV DNA testing in this setting does not add sufficient information to justify its cost. 20 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. 20 21 22 Patients with an abnormal cytology of a high-risk type (Bethesda classification) should be thoroughly evaluated with colposcopy and biopsy.

Other studies show patients with low-risk cytology and high-risk HPV infection with types 16, 18, and 31 are more likely to have cervical intraepithelial neoplasia (CIN) or microinvasive histopathology on biopsy. 19 23 24 25 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 for high-grade dysplasia and invasive cancer. 26 Studies suggest that acute infection with HPV types 16 and 18 conferred an 11- to 16.9-fold risk of rapid development of high-grade CIN, 19 27 but there are conflicting data requiring further evaluation before any recommendations may be made. Patients with low-risk cytology and low-risk HPV types have not been followed long enough to ascertain their risk. At present, studies are ongoing to determine how HPV typing can be used to help stratify women into follow-up and treatment groups. HPV typing may prove useful, particularly in patients with low-grade cytology or cytology of unclear abnormality. At present, how therapy and follow-up should be altered with low- versus high-risk HPV type has not been established.

Related Summaries

Other PDQ® summaries containing information related to cervical cancer include the following:

• Cervical Cancer Prevention
• Cervical Cancer Screening
• Unusual Cancers of Childhood (childhood cancer of the cervix)

References:

1. American Cancer Society.: Cancer Facts and Figures 2012. Atlanta, Ga: American Cancer Society, 2012. Available online [PUBMED Abstract]
2. The 1988 Bethesda System for reporting cervical/vaginal cytological diagnoses. National Cancer Institute Workshop. JAMA 262 (7): 931-4, 1989. [PUBMED Abstract]
3. 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]
4. 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]
5. 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]
6. 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]
7. 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]
8. 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]
9. 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]
10. 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]
11. 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]
12. 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]
13. Maiman M, Fruchter RG, Guy L, et al.: Human immunodeficiency virus infection and invasive cervical carcinoma. Cancer 71 (2): 402-6, 1993. [PUBMED Abstract]
14. 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]
15. 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]
16. 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]
17. Lai CH, Chang CJ, Huang HJ, et al.: Role of human papillomavirus genotype in prognosis of early-stage cervical cancer undergoing primary surgery. J Clin Oncol 25 (24): 3628-34, 2007. [PUBMED Abstract]
18. Schiffman MH, Bauer HM, Hoover RN, et al.: Epidemiologic evidence showing that human papillomavirus infection causes most cervical intraepithelial neoplasia. J Natl Cancer Inst 85 (12): 958-64, 1993. [PUBMED Abstract]
19. Brisson J, Morin C, Fortier M, et al.: Risk factors for cervical intraepithelial neoplasia: differences between low- and high-grade lesions. Am J Epidemiol 140 (8): 700-10, 1994. [PUBMED Abstract]
20. Human papillomavirus testing for triage of women with cytologic evidence of low-grade squamous intraepithelial lesions: baseline data from a randomized trial. The Atypical Squamous Cells of Undetermined Significance/Low-Grade Squamous Intraepithelial Lesions Triage Study (ALTS) Group. J Natl Cancer Inst 92 (5): 397-402, 2000. [PUBMED Abstract]
21. Wright TC Jr, Massad LS, Dunton CJ, et al.: 2006 consensus guidelines for the management of women with abnormal cervical cancer screening tests. Am J Obstet Gynecol 197 (4): 346-55, 2007. [PUBMED Abstract]
22. Wright TC Jr, 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]
23. 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]
24. 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]
25. Richart RM, Wright TC Jr: Controversies in the management of low-grade cervical intraepithelial neoplasia. Cancer 71 (4 Suppl): 1413-21, 1993. [PUBMED Abstract]
26. Klaes R, Woerner SM, Ridder R, et al.: Detection of high-risk cervical intraepithelial neoplasia and cervical cancer by amplification of transcripts derived from integrated papillomavirus oncogenes. Cancer Res 59 (24): 6132-6, 1999. [PUBMED Abstract]
27. Koutsky LA, Holmes KK, Critchlow CW, et al.: A cohort study of the risk of cervical intraepithelial neoplasia grade 2 or 3 in relation to papillomavirus infection. N Engl J Med 327 (18): 1272-8, 1992. [PUBMED Abstract]

Cellular Classification of Cervical Cancer

Back Up

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

Stage Information for Cervical Cancer

Back Up

Cervical carcinoma has its origins at the squamous-columnar junction whether in the endocervical canal or on the portion of the cervix. The precursor lesion is dysplasia or carcinoma in situ (cervical intraepithelial neoplasia [CIN]), which can subsequently become invasive cancer. This process can be quite slow. Longitudinal studies have shown that in untreated patients with 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 a period of 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 bladder or rectum.

In addition to local invasion, carcinoma of the cervix can spread via 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 Because there is little evidence to demonstrate overall improved survival with routine surgical staging, the staging usually should be 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 scan or lymphangiography, fine-needle aspiration should be negative before a surgical staging procedure is performed.

Definitions: FIGO

The Féderation Internationale de Gynécologie et d'Obstétrique (FIGO) and the American Joint Committee on Cancer (AJCC) have designated staging to define cervical cancer; the FIGO system is most commonly used. 2 3

Table 1. Carcinoma of the Cervix Uteri^a

^aAdapted from FIGO Committee on Gynecologic Oncology.^bAll macroscopically visible lesionseven with superficial invasionare allotted to stage IB carcinomas. Invasion is limited to a measured stromal invasion with a maximal depth of 5.00 mm and a horizontal extension of not >7.00 mm. Depth of invasion should not be >5.00 mm taken from the base of the epithelium of the original tissuesuperficial or glandular. The depth of invasion should always be reported in mm, even in those cases with "early (minimal) stromal invasion" (~1 mm).^cOn rectal examination, there is no cancer-free space between the tumor and the pelvic wall. All cases with hydronephrosis or nonfunctioning kidney are included, unless they are known to be the result of another cause.

Stage
I	The carcinoma is strictly confined to the cervix (extension to the corpus would be disregarded).
IA	Invasive carcinoma, which can be diagnosed only by microscopy with deepest invasion 5 mm and largest extension 7 mm.
IA1	Measured stromal invasion of 3.0 mm in depth and extension of 7.0 mm.
IA2	Measured stromal invasion of >3.0 mm and not >5.0 mm with an extension of not >7.0 mm.
IB	Clinically visible lesions limited to the cervix uteri or preclinical cancers greater than stage IA.b
IB1	Clinically visible lesion 4.0 cm in greatest dimension.
IB2	Clinically visible lesion >4.0 cm in greatest dimension.
II	Cervical carcinoma invades beyond the uterus but not to the pelvic wall or to the lower third of the vagina.
IIA	Without parametrial invasion.
IIA1	Clinically visible lesion 4.0 cm in greatest dimension.
IIA2	Clinically visible lesion >4.0 cm in greatest dimension.
IIB	With obvious parametrial invasion.
III	The tumor extends to the pelvic wall and/or involves lower third of the vagina and/or causes hydronephrosis or nonfunctioning kidney.c
IIIA	Tumor involves lower third of the vagina with no extension to the pelvic wall.
IIIB	Extension to the pelvic wall and/or hydronephrosis or nonfunctioning kidney.
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 organs.
IVB	Spread to distant organs.
2
The involvement of vascular/lymphatic spaces should not change the stage allotment.

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. Pecorelli S: Revised FIGO staging for carcinoma of the vulva, cervix, and endometrium. Int J Gynaecol Obstet 105 (2): 103-4, 2009. [PUBMED Abstract]
3. Cervix uteri. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 395-402. [PUBMED Abstract]

Treatment Option Overview

Back Up

Standard treatments for patients with cervical cancer include:

• Surgery.
• Radiation therapy.
• Chemotherapy.

Five randomized phase III trials (GOG-85, RTOG-9001, GOG-120, GOG-123, and SWOG-8797) have shown an overall survival advantage for cisplatin-based therapy given concurrently with radiation therapy, 1 2 3 4 5 6 while one trial examining this regimen demonstrated no benefit. 7 The patient populations in these studies included women with Féderation 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 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. 1 2 3 4 5 6 7 8 9

Surgery and radiation therapy are equally effective for early-stage small-volume disease. 10 Younger patients may benefit from surgery in regard to ovarian preservation and avoidance of vaginal atrophy and stenosis.

Patterns of care studies clearly demonstrate the negative prognostic effect of increasing tumor volume. Treatment, therefore, may vary within each stage as currently defined by FIGO and will depend on tumor bulk and spread pattern. 11

Therapy of patients with cancer of the cervical stump is effective, yielding results comparable to those seen in patients with an intact uterus. 12

Treatments under clinical evaluation for patients with cervical cancer include:

• New anticancer drugs in phase I and phase II clinical trials.

Cervical cancer during pregnancy

During pregnancy, no therapy is warranted for preinvasive lesions of the cervix, including carcinoma in situ, though expert colposcopy is recommended to exclude invasive cancer. Treatment of invasive cervical cancer during pregnancy depends on the stage of the cancer and gestational age at diagnosis. The traditional approach is to recommend immediate therapy appropriate for the disease stage when the cancer is diagnosed before fetal maturity and to delay therapy only if the cancer is detected in the final trimester. 13 14 However, other reports suggest that deliberate delay of treatment to allow improved fetal outcome may be a reasonable option for patients with stage IA and early IB cervical cancer. 15

References:

1. 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]
2. 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]
3. 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]
4. 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]
5. Peters WA 3rd, Liu PY, Barrett RJ 2nd, 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]
6. Thomas GM: Improved treatment for cervical cancer--concurrent chemotherapy and radiotherapy. N Engl J Med 340 (15): 1198-200, 1999. [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. Rose PG, Bundy BN: Chemoradiation for locally advanced cervical cancer: does it help? J Clin Oncol 20 (4): 891-3, 2002. [PUBMED Abstract]
9. 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]
10. 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]
11. 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]
12. Kovalic JJ, Grigsby PW, Perez CA, et al.: Cervical stump carcinoma. Int J Radiat Oncol Biol Phys 20 (5): 933-8, 1991. [PUBMED Abstract]
13. Monk BJ, Montz FJ: Invasive cervical cancer complicating intrauterine pregnancy: treatment with radical hysterectomy. Obstet Gynecol 80 (2): 199-203, 1992. [PUBMED Abstract]
14. Hopkins MP, Morley GW: The prognosis and management of cervical cancer associated with pregnancy. Obstet Gynecol 80 (1): 9-13, 1992. [PUBMED Abstract]
15. Hunter MI, Tewari K, Monk BJ: Cervical neoplasia in pregnancy. Part 2: current treatment of invasive disease. Am J Obstet Gynecol 199 (1): 10-8, 2008. [PUBMED Abstract]

Stage 0 Cervical Cancer

Back Up

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. Even so, 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 will also depend on several patient factors including age, desire to preserve fertility, and medical condition. Most importantly, the extent of disease must be known.

In selected cases, the outpatient loop electrosurgical excision procedure (LEEP) may be an acceptable alternative to cold-knife conization. This quickly performed in-office procedure requires only local anesthesia and obviates the risks associated with general anesthesia for cold-knife conization. 3 4 However, controversy exists as to the adequacy of LEEP as a replacement for conization. 5 A trial comparing LEEP with cold-knife cone biopsy showed no difference in the likelihood of complete excision of dysplasia. 6 However, 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. 7

Standard treatment options:

Methods to treat ectocervical lesions include the following:

1. LEEP. 8 9
2. Laser therapy. 10
3. Conization.
4. Cryotherapy. 11
5. Total abdominal or vaginal hysterectomy for postreproductive patients.
6. Internal radiation therapy for medically inoperable patients.

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

Total abdominal or vaginal hysterectomy is an accepted therapy for the postreproductive age group and is particularly indicated when the neoplastic process extends to the inner cone margin. 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. 12

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage 0 cervical cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References:

1. Wright TC Jr, 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 TC Jr, 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]
4. 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]
5. 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]
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. 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]
8. 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]
9. 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]
10. Tsukamoto N: Treatment of cervical intraepithelial neoplasia with the carbon dioxide laser. Gynecol Oncol 21 (3): 331-6, 1985. [PUBMED Abstract]
11. Benedet JL, Miller DM, Nickerson KG, et al.: The results of cryosurgical treatment of cervical intraepithelial neoplasia at one, five, and ten years. Am J Obstet Gynecol 157 (2): 268-73, 1987. [PUBMED Abstract]
12. 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]

Stage IA Cervical Cancer

Back Up

Equivalent treatment options:

1. Total hysterectomy. 1 If the depth of invasion is less than 3 mm proven by cone biopsy with clear margins 2 and no vascular or lymphatic channel invasion is noted, the frequency of lymph node involvement is sufficiently low that lymph node dissection is not required. Oophorectomy is optional and should be deferred for younger women.
2. 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 wishing to preserve fertility. 1
3. Modified radical hysterectomy. For patients with tumor invasion between 3 mm and 5 mm, radical hysterectomy with pelvic node dissection has been recommended because of a reported risk of lymph node metastasis of as much as 10%. 2 However, a study suggests that the rate of lymph-node involvement in this group of patients may be much lower and questions whether conservative therapy might be adequate for patients believed to have no residual disease following conization. 3 Radical hysterectomy with node dissection may also be considered for patients where the depth of tumor invasion was uncertain because of invasive tumor at the cone margins.
4. Intracavitary radiation therapy alone. If the depth of invasion is less than 3 mm and no capillary lymphatic space invasion is noted, the frequency of lymph node involvement is sufficiently low that 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 Gy125 Gy vaginal surface dose) are recommended. 4 Radiation therapy should be reserved for women who are not surgical candidates.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage IA cervical cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

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 Jr, et al.: Early invasive carcinoma of the cervix. Gynecol Oncol 51 (1): 26-32, 1993. [PUBMED Abstract]
3. Creasman WT, Zaino RJ, Major FJ, et al.: Early invasive carcinoma of the cervix (3 to 5 mm invasion): risk factors and prognosis. A Gynecologic Oncology Group study. Am J Obstet Gynecol 178 (1 Pt 1): 62-5, 1998. [PUBMED Abstract]
4. 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]

Stage IB Cervical Cancer

Back Up

Either radiation therapy or radical hysterectomy and bilateral lymph node dissection results in cure rates of 85% to 90% for women with Féderation 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 rates when comparing radiation therapy to radical hysterectomy. 1 The size of the primary tumor is an important prognostic factor and should be carefully evaluated in choosing optimal therapy. 2 For adenocarcinomas that expand the cervix more than 4 cm, the primary treatment should be concomitant chemotherapy and radiation therapy. 3

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 and concomitant chemotherapy. 4 The resection of macroscopically involved pelvic nodes may improve rates of local control with postoperative chemotherapy and radiation therapy. 5 Treatment of patients with unresected periaortic nodes with extended-field radiation therapy and chemotherapy leads to long-term disease control in those patients with low volume (<2 cm) nodal disease below L3. 6 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 histologic evidence of disease. 7 Toxic effects were greater with para-aortic radiation therapy than with pelvic radiation therapy alone but were mostly confined to patients with prior abdominopelvic surgery. 7 Patients who underwent extraperitoneal lymph node sampling had fewer bowel complications than those who had transperitoneal lymph node sampling. 6 8 9 Patients with close vaginal margins (<0.5 cm) may also benefit from pelvic radiation therapy. 10

Five randomized phase III trials have shown an OS advantage for cisplatin-based therapy given concurrently with radiation therapy, 11 12 13 14 15 16 while one trial examining this regimen demonstrated no benefit. 17 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, which included the following:

• Metastatic disease in pelvic lymph nodes.
• Parametrial disease.
• 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. 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. 11 12 13 14 15 16 17 18 19

Standard treatment options:

1. Radiation therapy. External-beam pelvic radiation therapy combined with two or more intracavitary brachytherapy applications is appropriate therapy for stage IA2 and IB1 lesions. 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 outpatient management. In three randomized trials, HDR brachytherapy was comparable with LDR brachytherapy in terms of local-regional control and complication rates. 20 21 22[Level of evidence: 1iiDii] The American Brachytherapy Society has published guidelines for the use of LDR and HDR brachytherapy as components of cervical cancer treatment. 23 24 For stage IB2 lesions, radiosensitizing chemotherapy is indicated. The role of radiosensitizing chemotherapy in IA2 and IB1 lesions is untested and likely to be of only marginal benefit since the cure rates with radiation alone exceed or approach 90%.
2. Radical hysterectomy and bilateral pelvic lymphadenectomy.
3. Postoperative total pelvic radiation therapy plus chemotherapy following radical hysterectomy and bilateral pelvic lymphadenectomy. Radiation in the range of 50 Gy administered for 5 weeks plus chemotherapy with cisplatin with or without fluorouracil (5-FU) should be considered in patients at high risk of recurrence including those with positive pelvic nodes, positive surgical margins, and residual parametrial disease. 11 12 13 14 15 16
4. Radiation therapy plus chemotherapy with cisplatin or cisplatin/5-FU for patients with bulky tumors. 11 12 13 14 15 16 25

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage IB cervical cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References:

1. 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]
2. 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]
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. 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]
5. 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]
6. 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]
7. 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]
8. 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]
9. 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]
10. 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]
11. 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]
12. 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]
13. 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]