Cervical Cancer (PDQ®): Treatment

General Information

Note: Estimated new cases and deaths from cervical (uterine cervix) cancer in the United States in 2005:[1]

• New cases: 10,370.
• Deaths: 3,710.

The prognosis for patients with cervical cancer is markedly affected by the extent of disease at the time of diagnosis. Because a vast majority (greater than 90%) of these cases can and should be detected early through the use of the Pap smear,[2] the current death rate is far higher than it should be and reflects that, even today, Pap smears are not done on approximately one third of eligible women.

Among the major factors that influence prognosis are stage, 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), 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 stage II, III, and IV) studied by the GOG revealed that periaortic and pelvic lymph node status, tumor size, patient age, and performance status were significant for progression-free interval and survival. The study confirms the overriding importance of positive periaortic nodes and suggests 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.

Bilateral disease and clinical stage were also significant for survival.[6] 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 with increasing stage of disease from 3% in stage IA to 75% in stage IVA. 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]

Controversy remains over whether or not adenocarcinoma of the cervix carries a significantly worse prognosis than squamous cell carcinoma of the cervix.[8] There are conflicting reports regarding the effect of adenosquamous cell type on outcome.[9,10] A report demonstrated 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.[11] The decreased survival is mainly due to more advanced stage and nodal involvement rather than cell type as an independent variable. Human immunodeficiency virus-infected women have more aggressive and advanced disease and a poorer prognosis.[12] 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.[13] Number of cells in S phase may also have prognostic significance in early cervical carcinoma.[14]

Molecular techniques for the identification of human papillomavirus (HPV) DNA are highly sensitive and specific. It is estimated that more than 6 million women in the United States 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.[15,16] 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 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 do not need further evaluation. A study of 642 such women found that 83% had 1 or more tumorigenic HPV types when cervical cytologic specimens were assayed by a sensitive (hybrid capture) technique.[17] The authors of the study and of an accompanying editorial conclude that using HPV DNA testing in this setting does not add sufficient information to justify its cost.[17,18] Whether HPV DNA testing will prove useful in patients with atypical squamous cells of undetermined significance is being studied by the same group.[17] 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.[16,19-21] One method has also shown that integration of HPV types 16 and 18 into the genome, leading to transcription of both viral and cellular messages, may predict patients who are at greater risk for high-grade dysplasia and invasive cancer.[22] Studies [16,23] 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, 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.

References

1. American Cancer Society.: Cancer Facts and Figures 2005. Atlanta, Ga: American Cancer Society, 2005. Also available online. Last accessed May 20, 2005. 
2. The 1988 Bethesda System for reporting cervical/vaginal cytological diagnoses. National Cancer Institute Workshop. JAMA 262 (7): 931-4, 1989.  [PUBMED Abstract]
3. Delgado G, Bundy B, Zaino R, et al.: Prospective surgical-pathological study of disease-free interval in patients with stage IB squamous cell carcinoma of the cervix: a Gynecologic Oncology Group study. Gynecol Oncol 38 (3): 352-7, 1990.  [PUBMED Abstract]
4. Zaino RJ, Ward S, Delgado G, et al.: Histopathologic predictors of the behavior of surgically treated stage IB squamous cell carcinoma of the cervix. A Gynecologic Oncology Group study. Cancer 69 (7): 1750-8, 1992.  [PUBMED Abstract]
5. Burghardt E, Baltzer J, Tulusan AH, et al.: Results of surgical treatment of 1028 cervical cancers studied with volumetry. Cancer 70 (3): 648-55, 1992.  [PUBMED Abstract]
6. Stehman FB, Bundy BN, DiSaia PJ, et al.: Carcinoma of the cervix treated with radiation therapy. I. A multi-variate analysis of prognostic variables in the Gynecologic Oncology Group. Cancer 67 (11): 2776-85, 1991.  [PUBMED Abstract]
7. Fagundes H, Perez CA, Grigsby PW, et al.: Distant metastases after irradiation alone in carcinoma of the uterine cervix. Int J Radiat Oncol Biol Phys 24 (2): 197-204, 1992.  [PUBMED Abstract]
8. Steren A, Nguyen HN, Averette HE, et al.: Radical hysterectomy for stage IB adenocarcinoma of the cervix: the University of Miami experience. Gynecol Oncol 48 (3): 355-9, 1993.  [PUBMED Abstract]
9. Gallup DG, Harper RH, Stock RJ: Poor prognosis in patients with adenosquamous cell carcinoma of the cervix. Obstet Gynecol 65 (3): 416-22, 1985.  [PUBMED Abstract]
10. Yazigi R, Sandstad J, Munoz AK, et al.: Adenosquamous carcinoma of the cervix: prognosis in stage IB. Obstet Gynecol 75 (6): 1012-5, 1990.  [PUBMED Abstract]
11. Bethwaite P, Yeong ML, Holloway L, et al.: The prognosis of adenosquamous carcinomas of the uterine cervix. Br J Obstet Gynaecol 99 (9): 745-50, 1992.  [PUBMED Abstract]
12. Maiman M, Fruchter RG, Guy L, et al.: Human immunodeficiency virus infection and invasive cervical carcinoma. Cancer 71 (2): 402-6, 1993.  [PUBMED Abstract]
13. Bourhis J, Le MG, Barrois M, et al.: Prognostic value of c-myc proto-oncogene overexpression in early invasive carcinoma of the cervix. J Clin Oncol 8 (11): 1789-96, 1990.  [PUBMED Abstract]
14. Strang P, Eklund G, Stendahl U, et al.: S-phase rate as a predictor of early recurrences in carcinoma of the uterine cervix. Anticancer Res 7 (4B): 807-10, 1987 Jul-Aug.  [PUBMED Abstract]
15. Schiffman MH, Bauer HM, Hoover RN, et al.: Epidemiologic evidence showing that human papillomavirus infection causes most cervical intraepithelial neoplasia. J Natl Cancer Inst 85 (12): 958-64, 1993.  [PUBMED Abstract]
16. Brisson J, Morin C, Fortier M, et al.: Risk factors for cervical intraepithelial neoplasia: differences between low- and high-grade lesions. Am J Epidemiol 140 (8): 700-10, 1994.  [PUBMED Abstract]
17. Human papillomavirus testing for triage of women with cytologic evidence of low-grade squamous intraepithelial lesions: baseline data from a randomized trial. The Atypical Squamous Cells of Undetermined Significance/Low-Grade Squamous Intraepithelial Lesions Triage Study (ALTS) Group. J Natl Cancer Inst 92 (5): 397-402, 2000.  [PUBMED Abstract]
18. Follen M, Richards-Kortum R: Emerging technologies and cervical cancer. J Natl Cancer Inst 92 (5): 363-5, 2000.  [PUBMED Abstract]
19. Tabbara S, Saleh AD, Andersen WA, et al.: The Bethesda classification for squamous intraepithelial lesions: histologic, cytologic, and viral correlates. Obstet Gynecol 79 (3): 338-46, 1992.  [PUBMED Abstract]
20. Cuzick J, Terry G, Ho L, et al.: Human papillomavirus type 16 in cervical smears as predictor of high-grade cervical intraepithelial neoplasia [corrected] Lancet 339 (8799): 959-60, 1992.  [PUBMED Abstract]
21. Richart RM, Wright TC Jr: Controversies in the management of low-grade cervical intraepithelial neoplasia. Cancer 71 (4 Suppl): 1413-21, 1993.  [PUBMED Abstract]
22. Klaes R, Woerner SM, Ridder R, et al.: Detection of high-risk cervical intraepithelial neoplasia and cervical cancer by amplification of transcripts derived from integrated papillomavirus oncogenes. Cancer Res 59 (24): 6132-6, 1999.  [PUBMED Abstract]
23. Koutsky LA, Holmes KK, Critchlow CW, et al.: A cohort study of the risk of cervical intraepithelial neoplasia grade 2 or 3 in relation to papillomavirus infection. N Engl J Med 327 (18): 1272-8, 1992.  [PUBMED Abstract]

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