Cervical Cancer Treatment (PDQ®): Treatment - Health Professional Information [NCI]

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Cervical Cancer Treatment

General Information About Cervical Cancer

Incidence and Mortality

Estimated new cases and deaths from cervical (uterine cervix) cancer in the United States in 2014:[1]

  • New cases: 12,360.
  • Deaths: 4,020.

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 2014. Atlanta, Ga: American Cancer Society, 2014. Available online. Last accessed March 26, 2014.
2. The 1988 Bethesda System for reporting cervical/vaginal cytological diagnoses. National Cancer Institute Workshop. JAMA 262 (7): 931-4, 1989.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
13. Maiman M, Fruchter RG, Guy L, et al.: Human immunodeficiency virus infection and invasive cervical carcinoma. Cancer 71 (2): 402-6, 1993.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
25. Richart RM, Wright TC Jr: Controversies in the management of low-grade cervical intraepithelial neoplasia. Cancer 71 (4 Suppl): 1413-21, 1993.
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.
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.

Cellular Classification of Cervical Cancer

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

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 Uteria

Stage
a Adapted from FIGO Committee on Gynecologic Oncology.[2]
b All macroscopically visible lesions—even with superficial invasion—are 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 tissue—superficial or glandular. The depth of invasion should always be reported in mm, even in those cases with "early (minimal) stromal invasion" (~1 mm).
The involvement of vascular/lymphatic spaces should not change the stage allotment.
c On 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.
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.

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.
2. Pecorelli S: Revised FIGO staging for carcinoma of the vulva, cervix, and endometrium. Int J Gynaecol Obstet 105 (2): 103-4, 2009.
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.

Treatment Option Overview

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.
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.
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.
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.
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.
6. Thomas GM: Improved treatment for cervical cancer--concurrent chemotherapy and radiotherapy. N Engl J Med 340 (15): 1198-200, 1999.
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.
8. Rose PG, Bundy BN: Chemoradiation for locally advanced cervical cancer: does it help? J Clin Oncol 20 (4): 891-3, 2002.
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.
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.
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.
12. Kovalic JJ, Grigsby PW, Perez CA, et al.: Cervical stump carcinoma. Int J Radiat Oncol Biol Phys 20 (5): 933-8, 1991.
13. Monk BJ, Montz FJ: Invasive cervical cancer complicating intrauterine pregnancy: treatment with radical hysterectomy. Obstet Gynecol 80 (2): 199-203, 1992.
14. Hopkins MP, Morley GW: The prognosis and management of cervical cancer associated with pregnancy. Obstet Gynecol 80 (1): 9-13, 1992.
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.

Stage 0 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. 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. The World Health Organization has made recommendations about the use of cryotherapy for providers in low-resource settings and has recognized the need to consider the availability of cryotherapy in relation to the availability of other treatment options.[3]

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.[4,5] However, controversy exists as to the adequacy of LEEP as a replacement for conization.[6] A trial comparing LEEP with cold-knife cone biopsy showed no difference in the likelihood of complete excision of dysplasia.[7] 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.[8]

In a randomized, double-blind, placebo-controlled, phase II trial of 59 patients, a vaginal preparation of imiquimod, an immune-modulating agent, showed improved clearance rates for cervical intraepithelial neoplasia (CIN), or CIN 2/3, and high-risk human papillomavirus.[9] This is the first proven medical treatment for preinvasive cervical disease; however, the vaginal preparation is not yet commercially available.

Standard treatment options:

Methods to treat ectocervical lesions include the following:

1. LEEP.[10,11]
2. Laser therapy.[12]
3. Conization.
4. Cryotherapy.[13]
5. Total abdominal or vaginal hysterectomy for postreproductive patients, only if excisional biopsy is not feasible.
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.[14]

After treatment for CIN, women remain at a higher risk of developing cervical cancer, even if they follow accepted posttreatment screening guidelines.[15]

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.
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.
3. Santesso N, Schünemann H, Blumenthal P, et al.: World Health Organization Guidelines: Use of cryotherapy for cervical intraepithelial neoplasia. Int J Gynaecol Obstet 118 (2): 97-102, 2012.
4. 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.
5. 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.
6. 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.
7. 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.
8. 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.
9. Grimm C, Polterauer S, Natter C, et al.: Treatment of cervical intraepithelial neoplasia with topical imiquimod: a randomized controlled trial. Obstet Gynecol 120 (1): 152-9, 2012.
10. 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.
11. 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.
12. Tsukamoto N: Treatment of cervical intraepithelial neoplasia with the carbon dioxide laser. Gynecol Oncol 21 (3): 331-6, 1985.
13. 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.
14. 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.
15. Rebolj M, Helmerhorst T, Habbema D, et al.: Risk of cervical cancer after completed post-treatment follow-up of cervical intraepithelial neoplasia: population based cohort study. BMJ 345: e6855, 2012.

Stage IA Cervical Cancer

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 Gy–125 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.
2. Jones WB, Mercer GO, Lewis JL Jr, et al.: Early invasive carcinoma of the cervix. Gynecol Oncol 51 (1): 26-32, 1993.
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.
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.

Stage IB Cervical Cancer

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. Radical hysterectomy and bilateral pelvic lymphadenectomy.
2. 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]
3. Radiation therapy plus chemotherapy with cisplatin or cisplatin/5-FU for patients with bulky tumors.[11,12,13,14,15,16,20]
4. Radiation therapy. External-beam pelvic radiation therapy combined with two or more intracavitary brachytherapy applications is appropriate therapy for patients with 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.[21,22,23][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.[24,25] For patients with stage IB2 lesions, radiosensitizing chemotherapy is indicated. A meta-analysis, which is evaluating the role of radiosensitizing chemotherapy in IA2 and IB1 lesions, suggests a likely benefit from the addition of platinum-based radiosensitizing chemotherapy, although numbers are small in this patient population.[26]

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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
14. 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.
15. 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.
16. Thomas GM: Improved treatment for cervical cancer--concurrent chemotherapy and radiotherapy. N Engl J Med 340 (15): 1198-200, 1999.
17. 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.
18. Rose PG, Bundy BN: Chemoradiation for locally advanced cervical cancer: does it help? J Clin Oncol 20 (4): 891-3, 2002.
19. 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.
20. 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.
21. 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.
22. 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.
23. 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.
24. 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.
25. 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.
26. Rosa DD, Medeiros LR, Edelweiss MI, et al.: Adjuvant platinum-based chemotherapy for early stage cervical cancer. Cochrane Database Syst Rev 6: CD005342, 2012.

Stage IIA Cervical Cancer

Either radiation therapy or radical hysterectomy results in cure rates of 75% to 80%. The selection of either option depends on patient factors and local expertise. A randomized trial reported identical 5-year overall survival (OS) and disease-free survival rates when radiation therapy was compared with 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 patients with bulky (>6 cm) endocervical squamous cell carcinomas or adenocarcinomas, treatment with high-dose radiation therapy will achieve local control and survival rates comparable to treatment with radiation therapy plus hysterectomy. Surgery after radiation therapy may be indicated for some patients with tumors confined to the cervix that respond incompletely to radiation therapy or in whom vaginal anatomy precludes optimal brachytherapy.[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.[4] The resection of macroscopically involved pelvic nodes may improve rates of local control with postoperative radiation therapy.[5] Treatment of patients with unresected periaortic nodes with extended-field radiation therapy 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 who received radiation therapy to para-aortic nodes without histologic evidence of disease.[7] Toxic effects were greater with para-aortic radiation than with pelvic radiation 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) after radical surgery 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,[11,12,13,14,15,16,17] while one trial examining this regimen demonstrated no benefit.[18] 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 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 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. Intracavitary radiation therapy combined with external-beam pelvic radiation therapy plus chemotherapy with cisplatin or cisplatin/5-FU for patients with bulky tumors.[11,12,13,14,15,16,20] 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 to LDR brachytherapy in terms of local-regional control and complication rates.[21,22,23][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.[24,25] Radiation therapy to para-aortic nodes may be indicated in primary tumors 4 cm or larger.
2. Radical hysterectomy and pelvic lymphadenectomy. Radical surgery has been performed for small lesions, but the high incidence of compromised margins, parametrial spread, and positive nodes leading to postoperative radiation with or without chemotherapy make primary concomitant chemotherapy and radiation a more common approach.
3. Postoperative total pelvic radiation therapy plus chemotherapy following radical hysterectomy and bilateral pelvic lymphadenectomy. Radiation therapy 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 with positive pelvic nodes, positive surgical margins, and residual parametrial disease.[11,12,13,14,15,16]

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage IIA 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.
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.
3. Thoms WW Jr, Eifel PJ, Smith TL, et al.: Bulky endocervical carcinoma: a 23-year experience. Int J Radiat Oncol Biol Phys 23 (3): 491-9, 1992.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
14. 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.
15. 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.
16. Thomas GM: Improved treatment for cervical cancer--concurrent chemotherapy and radiotherapy. N Engl J Med 340 (15): 1198-200, 1999.
17. 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.
18. 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.
19. Rose PG, Bundy BN: Chemoradiation for locally advanced cervical cancer: does it help? J Clin Oncol 20 (4): 891-3, 2002.
20. 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.
21. 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.
22. 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.
23. 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.
24. 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.
25. 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.

Stage IIB Cervical Cancer

The size of the primary tumor is an important prognostic factor and should be carefully evaluated in choosing optimal therapy.[1] Survival and local control are better with unilateral rather than bilateral parametrial involvement.[2] 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.[3] If postoperative external-beam radiation therapy (EBRT) is planned following surgery, extraperitoneal lymph node sampling is associated with fewer radiation-induced complications than a transperitoneal approach.[4] The resection of macroscopically involved pelvic nodes may improve rates of local control with postoperative radiation therapy.[5] Treatment of patients with unresected periaortic nodes with extended-field radiation therapy 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 who received radiation therapy to para-aortic nodes without histologic evidence of disease.[7] Toxic effects are greater with para-aortic radiation than with pelvic radiation 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.[4,6,8]

Five randomized, phase III trials have shown an overall survival advantage for cisplatin-based therapy given concurrently with radiation therapy, [9,10,11,12,13,14,15] while one trial examining this regimen demonstrated no benefit.[16] 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 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 demonstrated 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.[9,10,11,12,13,14,15,16,17]

In an attempt to improve on 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 stage IIB to IVA cervical cancer.[18][Level of evidence: 1iiA] A total of 515 patients from 9 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 external-beam radiation therapy (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 external-beam radiation therapy and brachytherapy as described for the experimental arm.

The primary endpoint was PFS at 3 years; however, the study found improvement in the experimental arm for PFS at 3 years (74.4% [95% CI, 68%–79.8%] vs. 65.0% [95% CI, 58.5%–70.7%]; overall PFS [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 and 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 (stage III–IVA vs. stage IIB), and suggests that the increased toxic effects of the experimental protocol may be justified for these patients.[19] 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 quality of life during and after treatment, the data for which were omitted from the protocol.

Standard treatment options:

  • Radiation therapy plus chemotherapy: Intracavitary radiation therapy and EBRT to the pelvis combined with cisplatin or cisplatin/fluorouracil.[9,10,11,12,13,14,20]

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.[21,22,23][Level of evidence: 1iiDii] The American Brachytherapy Society has published guidelines for the use of LDR and HDR brachytherapy as a component of cervical cancer treatment.[24,25]

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage IIB 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. 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.
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.
3. 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.
4. 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.
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.
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.
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.
8. 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.
9. 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.
10. 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.
11. 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.
12. 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.
13. 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.
14. Thomas GM: Improved treatment for cervical cancer--concurrent chemotherapy and radiotherapy. N Engl J Med 340 (15): 1198-200, 1999.
15. 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.
16. 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.
17. Rose PG, Bundy BN: Chemoradiation for locally advanced cervical cancer: does it help? J Clin Oncol 20 (4): 891-3, 2002.
18. 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.
19. 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.
20. 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.
21. 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.
22. 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.
23. 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.
24. 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.
25. 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.

Stage III Cervical Cancer

The size of the primary tumor is an important prognostic factor and should be carefully evaluated in choosing optimal therapy.[1] Patterns-of-care studies in stage IIIA/IIIB patients 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]

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 external-beam pelvic and para-aortic radiation therapy. If postoperative external-beam radiation therapy (EBRT) is planned following surgery, extraperitoneal lymph node sampling is associated with fewer radiation-induced complications than a transperitoneal approach.[4] The resection of macroscopically involved pelvic nodes may improve rates of local control with postoperative radiation therapy.[5] Treatment of patients with unresected periaortic nodes with extended-field radiation therapy leads to long-term disease control in those patients with low volume (<2 cm) nodal disease below L3. Patients who underwent extraperitoneal lymph node sampling had fewer bowel complications than those who had transperitoneal lymph node sampling.[6]

Five randomized, phase III trials have shown an overall survival advantage for cisplatin-based therapy given concurrently with radiation therapy,[7,8,9,10,11,12,13] while one trial examining this regimen demonstrated no benefit.[14] 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 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 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.[7,8,9,10,11,12,13,14,15]

In an attempt to improve on 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 stage IIB to IVA cervical cancer.[16][Level of evidence: 1iiA] A total of 515 patients from 9 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 external-beam radiation (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 external-beam radiation and brachytherapy as described for the experimental arm.

The primary endpoint was PFS at 3 years; however, the study found improvement in the experimental arm for PFS at 3 years (74.4% [95% CI, 68%–79.8%]) vs. 65.0% [95% CI, 58.5%–70.7%]; overall PFS [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 and 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 higher stage of disease (stage III–IVA vs. stage IIB), suggesting that the increased toxic effects of the experimental protocol may be justified for these patients.[17] 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 quality of life during and after treatment, which was omitted from the protocol.

Standard treatment options:

  • Radiation therapy plus chemotherapy. Intracavitary radiation and EBRT to the pelvis combined with cisplatin or cisplatin/fluorouracil.[7,8,9,10,11,12,18]

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 advantages 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.[19,20,21][Level of evidence: 1iiDii] The American Brachytherapy Society has published guidelines for the use of LDR and HDR brachytherapy as a component of cervical cancer treatment.[22,23]

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage III 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. 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.
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.
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.
4. 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.
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.
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.
7. 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.
8. 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.
9. 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.
10. 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.
11. 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.
12. Thomas GM: Improved treatment for cervical cancer--concurrent chemotherapy and radiotherapy. N Engl J Med 340 (15): 1198-200, 1999.
13. 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.
14. 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.
15. Rose PG, Bundy BN: Chemoradiation for locally advanced cervical cancer: does it help? J Clin Oncol 20 (4): 891-3, 2002.
16. 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.
17. 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.
18. 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.
19. 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.
20. 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.
21. 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.
22. 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.
23. 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.

Stage IVA Cervical Cancer

The size of the primary tumor is an important prognostic factor and should be carefully evaluated in choosing optimal therapy.[1] 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.

Five randomized, phase III trials have shown an overall survival advantage for cisplatin-based therapy given concurrently with radiation therapy,[2,3,4,5,6,7,8] while one trial examining this regimen demonstrated no benefit.[9] 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 who, at the time of primary surgery, were found to have poor prognostic factors, which include the following:

  • Metastatic disease in pelvic lymph nodes.
  • Parametrial disease.
  • Positive surgical margins.

Although the positive trials vary somewhat in terms of 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.[2,3,4,5,6,7,8,9,10]

In an attempt to improve on 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 stage IIB to IVA cervical cancer.[11][Level of evidence: 1iiA] A total of 515 patients from 9 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 external-beam radiation (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 external-beam radiation and brachytherapy as described for the experimental arm.

The primary endpoint was PFS at 3 years; however, the study found improvement in the experimental arm for PFS at 3 years (74.4% [95% CI, 68%–79.8%]) vs. 65.0% [95% CI, 58.5%–70.7%]; overall PFS [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 and 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 higher stage of disease (stage III–IVA vs. stage IIB), suggesting that the increased toxic effects of the experimental protocol may be justified for these patients.[12] 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 quality of life during and after treatment, which was omitted from the protocol.

Standard treatment options:

  • Radiation therapy plus chemotherapy: Intracavitary radiation therapy and external-beam pelvic radiation therapy combined with cisplatin or cisplatin/fluorouracil.[2,3,4,5,6,7,13]

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.[14,15,16][Level of evidence: 1iiDii] The American Brachytherapy Society has published guidelines for the use of LDR and HDR brachytherapy as a component of cervical cancer treatment.[13,17,18]

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage IVA 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. 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.
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.
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.
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.
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.
6. 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.
7. Thomas GM: Improved treatment for cervical cancer--concurrent chemotherapy and radiotherapy. N Engl J Med 340 (15): 1198-200, 1999.
8. 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.
9. 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.
10. Rose PG, Bundy BN: Chemoradiation for locally advanced cervical cancer: does it help? J Clin Oncol 20 (4): 891-3, 2002.
11. 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.
12. 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.
13. 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.
14. 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.
15. 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.
16. 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.
17. 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.
18. 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.

Stage IVB Cervical Cancer

No standard chemotherapy treatment that provides substantial palliation is available for patients with stage IVB cervical cancer. These patients are appropriate candidates for clinical trials testing single agents or combination chemotherapy employing agents listed below or new anticancer treatments in phase I and II clinical trials.[1]

Standard treatment options:

1. Radiation therapy may be used to palliate central disease or distant metastases.
2. Chemotherapy. Tested drugs include the following:
  • Cisplatin (15%–25% response rate).[1,2]
  • Ifosfamide (31% response rate).[3]
  • Paclitaxel (17% response rate).[4,5,6]
  • Ifosfamide-cisplatin.[7,8]
  • Irinotecan (21% response rate in patients previously treated with chemotherapy).[9]
  • Paclitaxel/cisplatin (46% response rate).[10]
  • Cisplatin/gemcitabine (41% response rate).[11]
  • Cisplatin/topotecan (27% response rate).[12]

Treatment options under clinical evaluation:

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

Information about ongoing clinical trials is available from the NCI Web site.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage IVB 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. 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.
2. 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.
3. 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.
4. Kudelka AP, Winn R, Edwards CL, et al.: Activity of paclitaxel in advanced or recurrent squamous cell cancer of the cervix. Clin Cancer Res 2 (8): 1285-8, 1996.
5. Thigpen T, Vance RB, Khansur T: The platinum compounds and paclitaxel in the management of carcinomas of the endometrium and uterine cervix. Semin Oncol 22 (5 Suppl 12): 67-75, 1995.
6. 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.
7. 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.
8. 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.
9. 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.
10. 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.
11. 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.
12. Long HJ 3rd, Bundy BN, Grendys EC Jr, 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.

Recurrent Cervical Cancer

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 a 5-year survival rate of 32% to 62% in selected patients.[1,2,3] These patients are appropriate candidates for clinical trials testing drug combinations or new anticancer agents.

The Gynecologic Oncology Group (GOG) has reported on several randomized phase III trials, (GOG-0179 [NCT00003945], GOG-0240 [NCT00803062]) in this setting. Single-agent cisplatin administered intravenously at 50 mg/m² every 3 weeks was the most-used regimen to treat recurrent cervical cancer since it was initially introduced in the 1970s.[4,5]

Various combinations containing cisplatin [4,5] failed to reach their primary endpoint of improving survival, however, a doubling of the cisplatin dose-rate did improve survival. Combinations with paclitaxel and with ifosfamide improved response rates (RR), but they did so at a cost of much greater toxicity, especially with the latter drug. A survival advantage over cisplatin was obtained with the cisplatin + topotecan (CT) doublet [5] leading to approval of this indication for topotecan by the U.S. Food and Drug Administration. However, in this study, cisplatin underperformed because many patients had received this drug earlier as a radiosensitizer. (Refer to Stages IIA, IIB, III, and IVA for more information on chemoradiation and the drug cisplatin, in particular.) Therefore, cisplatin plus paclitaxel (CP) was the reference arm in GOG-0204 (NCT00064077).

The GOG has reported on sequential randomized trials dealing with chemotherapy for stage IVB, recurrent, or persistent cervical cancer.[5,6,7,8,9] In the initial trial, the primary endpoint of exceeding the survival observed with cisplatin alone was not reached. However, in these trials:

  • The ifosfamide + cisplatin combination was superior to cisplatin alone in the secondary endpoint of RR but at the cost of increased toxicity.
  • The paclitaxel + cisplatin (PC) combination, similarly, was superior in RR and progression-free survival (PFS), and its toxicity was similar to the single agent except in patients with GOG performance status 2 (scale: 0, asymptomatic–4, totally bedridden).
  • The CT doublet combination had a significant advantage in overall survival (OS) compared with cisplatin alone, but cisplatin alone underperformed in this trial because as many as 40% of the patients had already received cisplatin up front as a radiosensitizer.

GOG-0204 enrolled 513 patients, leading to an early closure because no one experimental arm was likely to significantly lower the hazard ratio of death (HRdeath) relative to PC:1.15 (95% confidence interval [CI], 0.79–1.67) for vinorelbine + cisplatin (VC), 1.32 (95% CI, 0.91–1.92) for gemcitabine plus cisplatin (GC), and 1.27 (95% CI, 0.90–1.78) for CT. Trend in RR, PFS, and OS favored CT.[10][Level of evidence: 1iiA] The patients in the various arms of the study differed in the extent of neutropenia, infection, and alopecia that they experienced,[10] but none of the patients in the study arms differed in health-related quality of life during treatment.[11] However, there were more neurologic side effects for PC.

Interim results for GOG-0240 (NCT00803062) were presented in abstract form and showed that 452 patients with stage IVB, recurrent, or persistent cervical cancer were randomly assigned to chemotherapy versus chemotherapy plus bevacizumab-containing regimens.[12] The chemotherapy regimens were cisplatin (50 mg/m2) plus paclitaxel (135–175 mg/m2) and topotecan (0.75 mg/m2 d1–d3) plus paclitaxel (175 mg/m2 d1). The bevacizumab dose was 15 mg/kg, and cycles were every 21 days unless toxicity, progression, or complete response were noted.

Preliminary results showed the topotecan-paclitaxel combination was not superior to the cisplatin-paclitaxel combination. The addition of bevacizumab led to improved median OS when compared with chemotherapy alone (17 months versus 13.3 months, respectively). The HRdeath was 0.71 when regimens were compared with and without bevacizumab [97.6% CI, 0.54–0.95; 1-sided P = .0035]. The bevacizumab-containing regimens were associated with more grade 3 or 4 bleeding, thrombosis and embolism, and gastrointestinal fistula.[12][Level of evidence: 1iiA]

Standard treatment options:

1. For recurrence in the pelvis following radical surgery, radiation therapy in combination with chemotherapy (fluorouracil with or without mitomycin) may cure 40% to 50% of patients.[13]
2. Chemotherapy can be used for palliation. Tested drugs include the following:
  • Cisplatin (15%–25% RR).[6]
  • Ifosfamide (15%–30% RR).[14,15]
  • Paclitaxel (17% RR).[16]
  • Irinotecan (21% RR in patients previously treated with chemotherapy).[17]
  • Bevacizumab (11% RR, 24% survived progression free for at least 6 months; as seen in GOG-0227C [NCT00025233]).[18]
  • Ifosfamide + cisplatin.[7,19]
  • PC (46% RR).[20]
  • GC (41% RR).[21]
  • CT (27% RR).[5]
  • VC (30% RR).[22]

Treatment options under clinical evaluation:

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

Information about ongoing clinical trials is available from the NCI Web site.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with recurrent 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. 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.
2. Tumors of the cervix. In: Morrow CP, Curtin JP: Synopsis of Gynecologic Oncology. 5th ed. New York, NY: Churchill Livingstone, 1998, pp 107-151.
3. Schmidt AM, Imesch P, Fink D, et al.: Indications and long-term clinical outcomes in 282 patients with pelvic exenteration for advanced or recurrent cervical cancer. Gynecol Oncol 125 (3): 604-9, 2012.
4. Tewari KS, Monk BJ: Gynecologic oncology group trials of chemotherapy for metastatic and recurrent cervical cancer. Curr Oncol Rep 7 (6): 419-34, 2005.
5. Long HJ 3rd, Bundy BN, Grendys EC Jr, 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.
6. 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.
7. 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.
8. 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.
9. 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.
10. 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.
11. 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.
12. Tewari KS, Sill M, Long HJ, et al.: Incorporation of bevacizumab in the treatment of recurrent and metastatic cervical cancer: a phase III randomized trial of the Gynecologic Oncology Group. [Abstract] J Clin Oncol 31 (Suppl 15): A-3, 2013.
13. 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.
14. 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.
15. 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.
16. 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.
17. 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.
18. 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.
19. 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.
20. 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.
21. 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.
22. 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.

Changes to This Summary (03 / 14 / 2014)

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 Cervical Cancer

Updated statistics with estimated new cases and deaths for 2014 (cited American Cancer Society as reference 1).

Stage 0 Cervical Cancer

Added text to state that the World Health Organization has made recommendations about the use of cryotherapy for providers in low-resource settings and has recognized the need to consider the availability of cryotherapy in relation to the availability of other treatment options (cited Santesso et al. as reference 3).

Added text to state that in a randomized, double-blind, placebo-controlled, phase II trial of 59 patients, a vaginal preparation of imiquimod, an immune-modulating agent, showed improved clearance rates for cervical intraepithelial neoplasia (CIN), or CIN 2/3, and high-risk human papillomavirus (cited Grimm et al. as reference 9).

Revised text to add only if excisional biopsy is not feasible to the total abdominal or vaginal hysterectomy for postreproductive patients treatment option.

Added text to state that after treatment for CIN, women remain at a higher risk of developing cervical cancer, even if they follow accepted posttreatment screening guidelines (cited Rebolj et al. as reference 15).

Stage IB Cervical Cancer

Added text to state that a meta-analysis, which is evaluating the role of radiosensitizing chemotherapy in IA2 and IB1 lesions, suggests a likely benefit from the addition of platinum-based radiosensitizing chemotherapy, although numbers are small in this patient population (cited Rosa et al. as reference 26).

Stage IIB Cervical Cancer

Added text about a phase III randomized trial that compared concurrent gemcitabine plus cisplatin and radiation therapy followed by adjuvant gemcitabine and cisplatin with concurrent cisplatin plus radiation in patients with stage IIB to IVA cervical cancer (cited 2011 Dueñas-González et al. as reference 18).

Added text to state that the primary endpoint was progression-free survival (PFS) at 3 years; however, the study found improvement in the experimental arm for PFS at 3 years. Added that patients in the experimental arm had increased hematologic and nonhematologic grade 3 and 4 toxic effects, and two deaths in the experimental arm were possibly related to treatment. Also added that a subgroup analysis showed an increased benefit in patients with a higher stage of disease and suggests that the increased toxic effects of the experimental protocol may be justified for these patients (cited 2012 Dueňas-González et al. as reference 19).

Stage III Cervical Cancer

Added text about a phase III randomized trial that compared concurrent gemcitabine plus cisplatin and radiation therapy followed by adjuvant gemcitabine and cisplatin with concurrent cisplatin plus radiation in patients with stage IIB to IVA cervical cancer (cited 2011 Dueñas-González et al. as reference 16).

Added text to state that the primary endpoint was PFS at 3 years; however, the study found improvement in the experimental arm for PFS at 3 years. Added that patients in the experimental arm had increased hematologic and nonhematologic grade 3 and 4 toxic effects, and two deaths in the experimental arm were possibly related to treatment. Also added that a subgroup analysis showed an increased benefit in patients with a higher stage of disease and suggests that the increased toxic effects of the experimental protocol may be justified for these patients (cited 2012 Dueňas-González et al. as reference 17).

Stage IVA Cervical Cancer

Added text about a phase III randomized trial that compared concurrent gemcitabine plus cisplatin and radiation therapy followed by adjuvant gemcitabine and cisplatin with concurrent cisplatin plus radiation in patients with stage IIB to IVA cervical cancer (cited 2011 Dueñas-González et al. as reference 11).

Added text to state that the primary endpoint was PFS at 3 years; however, the study found improvement in the experimental arm for PFS at 3 years. Added that patients in the experimental arm had increased hematologic and nonhematologic grade 3 and 4 toxic effects, and two deaths in the experimental arm were possibly related to treatment. Also added that a subgroup analysis showed an increased benefit in patients with a higher stage of disease, and suggests that the increased toxic effects of the experimental protocol may be justified for these patients (cited 2012 Dueňas-González et al. as reference 12).

Recurrent Cervical Cancer

Added Schmidt et al. as reference 3.

Added text about interim results for GOG-0240 presented in abstract form that showed 452 patients with stage IVB, recurrent, or persistent cervical cancer were randomly assigned to chemotherapy versus chemotherapy plus bevacizumab-containing regimens (cited Tewari et al. as reference 12).

Added text to state that preliminary results for GOG-0240 showed the topotecan-paclitaxel combination was not superior to the cisplatin-paclitaxel combination. The addition of bevacizumab led to improved median overall survival when compared with chemotherapy alone. The hazard ratio for death was 0.71 when regimens were compared with and without bevacizumab. The bevacizumab-containing regimens were associated with more grade 3 or 4 bleeding, thrombosis and embolism, and gastrointestinal fistula (level of evidence 1iiA).

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 NCI's Comprehensive Cancer Database 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 who care for cancer 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 Cervical Cancer Treatment are:

  • Leslie R. Boyd, MD (New York University Medical Center)
  • Franco M. Muggia, MD (New York University Medical Center)

Any comments or questions about the summary content should be submitted to Cancer.gov through the Web site's Contact Form. 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:

National Cancer Institute: PDQ® Cervical Cancer Treatment. Bethesda, MD: National Cancer Institute. Date last modified <MM/DD/YYYY>. Available at: http://cancer.gov/cancertopics/pdq/treatment/cervical/HealthProfessional. Accessed <MM/DD/YYYY>.

Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in Visuals Online, a collection of over 2,000 scientific images.

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Last Revised: 2014-03-14

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