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Prevention of cervical cancer

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Summary Of Evidence
Significance
Evidence Of Benefit

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Information from PDQ -- for Health Professionals

SUMMARY OF EVIDENCE

Note: Separate PDQ summaries on Screening for Cervical Cancer and Cervical Cancer Treatment are also available.

Abundant evidence suggests that regular gynecologic examinations and Pap tests for all women beginning at the onset of sexual activity, or by approximately age 18 years if not sexually active, decreases cervical cancer incidence and mortality. An upper age limit at which such screening ceases to be effective is not known.

Levels of Evidence for preceding statement: 3ai,4ai,5

Evidence obtained from well-designed and conducted cohort or case-control analytic studies, preferably from more than one center or research group that have a cancer mortality endpoint

Ecologic (descriptive) studies that have a cancer mortality endpoint

Opinions of respected authorities based on clinical experience or reports of expert committees

Evidence supports a sexual mode of transmission of a carcinogen and human papillomavirus (HPV) is strongly implicated epidemiologically as the main infectious etiologic agent.[1-3] Barrier methods of contraception lower the incidence of cervical neoplasia, presumptively secondary to lessened exposure to HPV.[4,5]

Levels of Evidence for preceding statement: 3ai,4ai,5

Evidence obtained from well-designed and conducted cohort or case-control analytic studies, preferably from more than one center or research group that have a cancer mortality endpoint

Ecologic (descriptive) studies that have a cancer mortality endpoint

Opinions of respected authorities based on clinical experience or reports of expert committees

Exposure to cigarette smoke is associated with increased risk.[6-8]

Levels of Evidence for preceding statement: 3ai,4ai,5

Evidence obtained from well-designed and conducted cohort or case-control analytic studies, preferably from more than one center or research group that have a cancer mortality endpoint

Ecologic (descriptive) studies that have a cancer mortality endpoint

Opinions of respected authorities based on clinical experience or reports of expert committees

Increased intake of micronutrients and other dietary factors such as carotenoids are associated with decreased risk.

Level of Evidence for preceding statement: 3ai

Evidence obtained from well-designed and conducted cohort or case-control analytic studies, preferably from more than one center or research group that have a cancer mortality endpoint

Education regarding risk factors for cervical cancer may lead to behavioral modification resulting in diminished exposure.

Level of Evidence for preceding statement: 5

Opinions of respected authorities based on clinical experience or reports of expert committees

References:

  1. Ley C, Bauer HM, Reingold A, et al.: Determinants of genital human papillomavirus infection in young women. Journal of the National Cancer Institute 83(14): 997-1003, 1991.
  2. Munoz N, Bosch FX, de Sanjose S, et al.: The causal link between human papillomavirus and invasive cervical cancer: a population-based case-control study in Colombia and Spain. International Journal of Cancer 52(5): 743-749, 1992.
  3. Schiffman MH, Bauer HM, Hoover RN, et al.: Epidemiologic evidence showing that human papillomavirus infection causes most cervical intraepithelial neoplasia. Journal of the National Cancer Institute 85(12): 958-964, 1993.
  4. Parazzini F, Negri E, La Vecchia C, et al.: Barrier methods of contraception and the risk of cervical neoplasia. Contraception 40(5): 519-530, 1989.
  5. Hildesheim A, Brinton LA, Mallin K, et al.: Barrier and spermicidal contraceptive methods and risk of invasive cervical cancer. Epidemiology 1(4): 266-272, 1990.
  6. Brinton LA: Epidemiology of cervical cancer--overview. IARC Scientific Publications 119: 3-23, 1992.
  7. Hellberg D, Nilsson S, Haley NJ, et al.: Smoking and cervical intraepithelial neoplasia: nicotine and cotinine in serum and cervical mucus in smokers and nonsmokers. American Journal of Obstetrics and Gynecology 158(4): 910-913, 1988.
  8. Brock KE, MacLennan R, Brinton LA, et al.: Smoking and infectious agents and risk of in situ cervical cancer in Sydney, Australia. Cancer Research 49(17): 4925-4928, 1989.

SIGNIFICANCE

Incidence and Mortality

An estimated 13,000 new cervical cancers and 4,100 cervical cancer deaths will occur in the United States in 2002.[1] An additional 1,250,000 women will be diagnosed yearly with changes referred to as squamous intraepithelial lesions (SIL) or cervical intraepithelial neoplasia (CIN). These changes form a continuum divided into low- or high-grade SIL or CIN 1, 2, and 3 that reflects increasingly abnormal changes of the affected epithelium. These lesions can persist, regress, or progress to an invasive malignancy. High-grade SIL (CIN 2-3) is more likely to persist or progress and less often regresses spontaneously, while low-grade SIL (CIN 1) often regresses without treatment. The average time for progression of CIN 3 to invasive cancer has been estimated to be 10 to 15 years, based on the mean age of diagnosis of these 2 conditions.[2] There is a small subset of rapidly progressive cervical cancers which are diagnosed within 3 years of a confirmed negative Pap test. These tumors occur in younger women with higher socioeconomic status as compared to a control cervical cancer group. One third of these cancers are adenocarcinomas of endocervical origin which may not be adequately screened by conventional Pap test methods.[3]

Pap Test

The Pap test is a screening tool that identifies women likely to have premalignant disease and at high risk for cervical cancer. The widely used Bethesda System of reporting Pap tests was developed in 1988.[4] The cytologic terms, low- and high-grade squamous intraepithelial lesions (LSIL and HSIL), correlate with the histopathologic diagnoses of CIN 1, and CIN 2-3, respectively. Strengths of this system are that it requires an evaluation of the adequacy of the specimen and encourages a descriptive diagnosis of abnormalities. Abnormalities that do not fulfill the criteria for SIL are termed atypical squamous cells of undetermined significance (ASCUS). Persistent atypical smears should be evaluated colposcopically. An estimated 5% to 10% of patients with this cytologic finding will subsequently be shown to have HSIL or rarely, invasive cancer.[5-7]

Reliability of the smear depends on the technique employed to obtain the cytologic specimen and the adequacy of its review by the cytologist. Pap test failure rate in diagnosing invasive cancer can be as high as 50% [8] emphasizing the need to biopsy any visible lesions of the cervix, even if associated with a normal Pap test. Careful inspection of the cervix and lower genital tract for areas of nodularity and friability should be part of each exam.

The accessibility of the cervix to examination provides a unique opportunity to evaluate the disease status and response to intervention. Commonly employed methods of treatment for premalignant lesions include laser vaporization or excision, cryosurgery, cold knife conization, loop electrosurgical excision, or simple hysterectomy. Strategies to combine diagnosis and treatment such as loop electrosurgical excision procedure (LEEP) may be appropriate, particularly in women for whom follow-up is not effective.[9] Despite the efficacy of excisional treatment of intraepithelial lesions in reducing the risk of developing invasive cervical cancer, the risk of cancer remains elevated above that of the general population and warrants careful follow-up for at least 8 to 10 years.[10] The slow progression of preinvasive disease into invasive cancer and the easy access to visual and cytologic investigation makes squamous intraepithelial lesions an ideal disease for chemoprevention clinical trials. Multiple case-control studies support the chemopreventive role of micronutrients.

References:

  1. American Cancer Society: Cancer Facts and Figures-2002. Atlanta, Ga: American Cancer Society, 2002.
  2. Barron BA, Richart RM: Statistical model of the natural history of cervical carcinoma. II: estimates of the transition time from dysplasia to carcinoma in situ. Journal of the National Cancer Institute 45(5): 1025-1030, 1970.
  3. Schwartz PE, Hadjimichael O, Lowell DM, et al.: Rapidly progressive cervical cancer: the Connecticut experience. American Journal of Obstetrics and Gynecology 175(4): 1105-1109, 1996.
  4. The revised Bethesda System for reporting cervical/vaginal cytologic diagnoses: report of the 1991 Bethesda workshop. Journal of Reproductive Medicine 37(5): 383-386, 1992.
  5. Davey DD, Naryshkin S, Nielsen ML, et al.: Atypical squamous cells of undetermined significance: interlaboratory comparison and quality assurance monitors. Diagnostic Cytopathology 11(4): 390-396, 1994.
  6. Williams ML, Rimm DL, Pedigo MA, et al.: Atypical squamous cells of undetermined significance: correlative histologic and follow-up studies from an academic medical center. Diagnostic Cytopathology 16(1): 1-7, 1997.
  7. Wilbur DC, Bonfiglio TA: Editorial comments: atypical squamous cells in cervical smears - resolving a controversy. Diagnostic Cytopathology 9(4): 427-429, 1993.
  8. Koss LG: Cervical (Pap) smear: new directions. Cancer 71(4, Suppl): 1406-1412, 1993.
  9. Spitzer M, Chernys AE, Seltzer VL: The use of large-loop excision of the transformation zone in an inner-city population. Obstetrics and Gynecology 82(5): 731-735, 1993.
  10. Soutter WP, de Barros Lopes A, Fletcher A, et al.: Invasive cervical cancer after conservative therapy for cervical intraepithelial neoplasia. Lancet 349(9057): 978-980, 1997.

EVIDENCE OF BENEFIT

Risk Factors

Strong risk factors for cervical cancer and its precursors have been identified and include: early age at first intercourse (16 years or younger), a history of multiple sexual partners, a history of genital human papillomavirus (HPV) infection or other sexually transmitted disease, the presence of other genital tract neoplasia, and prior squamous intraepithelial lesion (SIL).[1-5] Many of these factors appear to be surrogate markers for HPV exposure and infection.[6] Additional risk factors include active or passive smoking, a current or past sexual partner with risk factors for sexually transmitted disease, immunodeficiency or HIV positivity, and poor nutrition.[7-9]

Epidemiologic studies to evaluate risk factors for the development of SIL and cervical malignancy demonstrate conclusively a sexual mode of transmission of a carcinogen.[1] It is now widely accepted that HPV is the primary etiologic infectious agent.[6,10,11] Other sexually transmitted factors, including herpes simplex virus 2, may play a cocausative role.[1] The finding of HPV viral DNA integrated in the majority of cellular genomes of invasive cervical carcinomas supports epidemiologic data linking this agent to cervical cancer;[12] however, direct causation has not been demonstrated. There are over 80 distinct types of HPV identified, approximately 30 of which infect the human genital tract. HPV types 16 and 18 are most often associated with invasive disease. Characterization of carcinogenic risk associated with HPV types is an important step in the process of developing a combination HPV vaccine for the prevention of cervical neoplasia. In a population-based study of HPV infection and cervical neoplasia in Costa Rica, 80% of high-grade squamous intraepithelial lesions (HSIL) and invasive lesions were associated with HPV infection by 1 or more of 13 cancer-associated types.[13] In this study, the risk of about half of HSIL and invasive cervical cancer was attributable to HPV 16. HPV 18 was associated with 15% of invasive disease, but only 5% of HSIL, suggesting that HPV 18 may have a role in more aggressive cases of cervical malignancy.

Human Papillomavirus Testing

It is estimated that more than 6 million women in the United States have persistent HPV infection. The FDA has approved a second generation single test, Hybrid Capture II (HC II), that identifies the presence of carcinogenic HPV that can be generated by HPV types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68. It is expected that this test will eventually be integrated into the clinical management of cervical neoplasia, but optimal use of HPV testing will depend on selecting a balance between test sensitivity and specificity that allows identification of clinically significant cases while avoiding clinical interventions that do not benefit and possibly harm the patient.[14] Population-based screening approaches incorporating HPV testing will need to be tailored to the age profile of the population and the prevalence of infection.

HPV testing has also been proposed as a secondary test following an abnormal, equivocal or low-grade, screening cytology result. The utility of HPV testing for determining triage to colposcopy, in the context of an abnormal cytology, is likely to differ in women with low-grade squamous intraepithelial lesions (LSIL) versus those with atypical squamous cells of undetermined significance (ASCUS). A study of women with cytologic diagnoses of LSIL demonstrated a high percentage (83%) with positive HPV DNA test results, limiting the triage utility of the assay. Relatively few women would be spared referral to colposcopy based on a negative HPV result, therefore the cost of testing could not be justified.[15] HPV testing, however, may be an option for women and their doctors to consider after a screening cytology result of ASCUS. In one study of nearly 1,000 women, HPV testing was shown to be as or more sensitive compared to a single repeat cytology test for the colposcopic detection of high-grade cervical intraepithelial neoplasia (CIN) 2-3.[16] The program sensitivity of multiple repeat cytology tests, however, has not been evaluated in comparison to HPV testing.

Users of barrier methods of contraception are associated with a reduced incidence of SIL presumptively secondary to protection from sexually transmitted disease.[17,18] Spermicides may be a contributing influence, as they have been demonstrated to have an antiviral action.[19] Women of grand multiparity are at increased risk for cervical cancer,[20] and long-term users of oral contraceptives (5 years or more) have an increased incidence, particularly of adenocarcinoma.[1,21,22] A relative and possibly absolute increase in mortality in adenocarcinoma of the cervix appears to be occurring, especially in younger women.[23]

Cigarette smoking by women is associated with an increased risk for squamous cell carcinoma.[1,24-26] This risk increases with longer duration and intensity of smoking and may be present with exposure to environmental tobacco smoke as well, being as high as 3 times that of women who are nonsmokers and are not exposed to environmental smoking.[1] Some studies demonstrate an increased risk for current smokers only as opposed to former smokers, suggesting that carcinogens in cigarette smoke exert a late-stage effect on carcinogenesis.[25]

Older women (age 60 and above) are at increased risk for cervical cancer as they are less willing or able to seek medical care for screening for this disease and participate in treatment. Further, their primary care physician has often changed from the obstetrician/gynecologist to the general practitioner with less emphasis on prevention of cervical cancer.[27,28] Minorities including African Americans, Native Americans, and Hispanics (but not Asian Americans) have a higher risk than Caucasians. Much of the difference can be explained by socioeconomic factors and associated risk factors.[29]

Decreased mortality secondary to cytological screening for cervical abnormalities has been demonstrated in multiple, broad-based population studies.[30-32] Unscreened or underscreened high-risk groups should be identified and targeted for screening programs.[33,34] Educational efforts, transportation, efforts to establish a regular health care provider, and screening convenient to the work place have been shown to have a positive impact on women participating in screening.[35-40] In communities where English is a second language, healthcare providers fluent in the native language can effectively facilitate these efforts.[41] Frequently, the high-risk individual is seen at a medical facility for unrelated health issues and is not provided with cytologic screening. Provision of a modality by which hospitals and emergency services could identify and screen these women could potentially further reduce mortality.[42,43]

Dietary Factors

Several case-control studies have investigated the effects of various micronutrients on risk and have found that high dietary carotene and possibly vitamins C and E and folate are associated with reduced risk for cervical cancer.[44-48] Epidemiologic studies of patients with SIL and cervical cancer have suggested that low intake of vitamin A is associated with risk.[49] Both case-control and prospective studies that have evaluated plasma levels of vitamins demonstrated an inverse correlation between beta-carotene levels and cervical neoplasia.[45,50-53] Folate deficiency may play a role in cervical carcinogenesis, possibly by facilitating incorporation of HPV at a fragile genomic site. However, 2 randomized trials of oral folate as a chemopreventive agent have shown no protective effect. A considerable amount of experimental data suggests that vitamin A and its derivatives inhibit HPV-associated proliferation; several trials using retinoids are now nearing completion. A randomized trial using locally applied beta-trans-retinoic acid demonstrated increased regression of CIN 2, but not CIN 3;[54] however, this treatment approach remains experimental. Current standard treatment modalities are extremely effective in eradicating SIL and preventing development of invasive cervical cancer.

Given the etiologic role of HPV in the pathogenesis of cervical neoplasia, vaccines to immunize against HPV infection would offer a primary prevention strategy for cervical cancer. Vaccines using HPV late protein (L1 and L2) constructs to induce antibody-mediated immunity are in clinical trials.[55]

References:

  1. Brinton LA: Epidemiology of cervical cancer--overview. IARC Scientific Publications 119: 3-23, 1992.
  2. Jones CJ, Brinton LA, Hamman RF, et al.: Risk factors for in situ cervical cancer: results from a case-control study. Cancer Research 50(12): 3657-3662, 1990.
  3. Slattery ML, Overall JC, Abbott TM, et al.: Sexual activity, contraception, genital infections, and cervical cancer: support for a sexually transmitted disease hypothesis. American Journal of Epidemiology 130(2): 248-258, 1989.
  4. Walkinshaw SA, Dodgson J, McCance DJ, et al.: Risk factors in the development of cervical intraepithelial neoplasia in women with vulval warts. Genitourinary Medicine 64(5): 316-320, 1988.
  5. Mitchell H, Medley G, Carlin JB: Risk of subsequent cytological abnormality and cancer among women with a history of cervical intraepithelial neoplasia: a comparative study. Cancer Causes and Control 1(2): 143-148, 1990.
  6. Schiffman MH, Bauer HM, Hoover RN, et al.: Epidemiologic evidence showing that human papillomavirus infection causes most cervical intraepithelial neoplasia. Journal of the National Cancer Institute 85(12): 958-964, 1993.
  7. Kjaer SK, de Villiers EM, Dahl C, et al.: Case-control study of risk factors for cervical neoplasia in Denmark. I: role of the male factor in women with one lifetime sexual partner. International Journal of Cancer 48(1): 39-44, 1991.
  8. Schafer A, Friedmann W, Mielke M, et al.: The increased frequency of cervical dysplasia-neoplasia in women infected with the human immunodeficiency virus is related to the degree of immunosuppression. American Journal of Obstetrics and Gynecology 164(2): 593-599, 1991.
  9. Mandelblatt JS, Fahs M, Garibaldi K, et al.: Association between HIV infection and cervical neoplasia: implications for clinical care of women at risk for both conditions. AIDS 6(2): 173-178, 1992.
  10. Ley C, Bauer HM, Reingold A, et al.: Determinants of genital human papillomavirus infection in young women. Journal of the National Cancer Institute 83(14): 997-1003, 1991.
  11. Munoz N, Bosch FX, de Sanjose S, et al.: The causal link between human papillomavirus and invasive cervical cancer: a population-based case-control study in Colombia and Spain. International Journal of Cancer 52(5): 743-749, 1992.
  12. Reeves WC, Rawls WE, Brinton LA: Epidemiology of genital papillomaviruses and cervical cancer. Reviews of Infectious Diseases 11(3): 426-439, 1993.
  13. Herrero R, Hildesheim A, Bratti C, et al.: Population-based study of human papillomavirus infection and cervical neoplasia in rural Costa Rica. Journal of the National Cancer Institute 92(6): 464-474, 2000.
  14. Schiffman M, Herrero R, Hildesheim A, et al.: HPV DNA testing in cervical cancer screening: results from women in a high-risk province of Costa Rica. JAMA: Journal of the American Medical Association 283(1): 87-93, 2000.
  15. 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 Leisions Triage Study (ALTS) Group. Journal of the National Cancer Institute 92(5): 397-402, 2000.
  16. Manos MM, Kinney WK, Hurley LB, et al.: Identifying women with cervical neoplasia: using human papillomavirus DNA testing for equivocal Papanicolaou results. JAMA: Journal of the American Medical Association 281(17): 1605-1610, 1999.
  17. Parazzini F, Negri E, La Vecchia C, et al.: Barrier methods of contraception and the risk of cervical neoplasia. Contraception 40(5): 519-530, 1989.
  18. Hildesheim A, Brinton LA, Mallin K, et al.: Barrier and spermicidal contraceptive methods and risk of invasive cervical cancer. Epidemiology 1(4): 266-272, 1990.
  19. Celentano DD, Klassen AC, Weisman CS, et al.: The role of contraceptive use in cervical cancer: the Maryland Cervical Cancer Case-Control Study. American Journal of Epidemiology 126(4): 592-604, 1987.
  20. Brinton LA, Reeves WC, Brenes MM, et al.: Parity as a risk factor for cervical cancer. American Journal of Epidemiology 130(3): 486-496, 1989.
  21. Brinton LA: Oral contraceptives and cervical neoplasia. Contraception 43(6): 581-595, 1991.
  22. Gram IT, Macaluso M, Stalsberg H: Oral contraceptive use and the incidence of cervical intraepithelial neoplasia. American Journal of Obstetrics and Gynecology 167(1): 40-44, 1992.
  23. Miller BE, Flax SD, Arheart K, et al.: The presentation of adenocarcinoma of the uterine cervix. Cancer 72: 1281-1285, 1993.
  24. Hellberg D, Nilsson S, Haley NJ, et al.: Smoking and cervical intraepithelial neoplasia: nicotine and cotinine in serum and cervical mucus in smokers and nonsmokers. American Journal of Obstetrics and Gynecology 158(4): 910-913, 1988.
  25. Brock KE, MacLennan R, Brinton LA, et al.: Smoking and infectious agents and risk of in situ cervical cancer in Sydney, Australia. Cancer Research 49(17): 4925-4928, 1989.
  26. Ho GY, Kadish AS, Burk RD, et al.: HPV 16 and cigarette smoking as risk factors for high-grade cervical intra-epithelial neoplasia. International Journal of Cancer 78(3): 281-285, 1998.
  27. Power EJ: Pap smears, elderly women, and Medicare. Cancer Investigation 11(2): 164-168, 1993.
  28. Celentano DD, Klassen AC, Weisman CS, et al.: Cervical cancer screening practices among older women: results from the Maryland Cervical Cancer Case-Control Study. Journal of Clinical Epidemiology 41(6): 531-541, 1988.
  29. Schairer C, Brinton LA, Devesa SS, et al.: Racial differences in the risk of invasive squamous-cell cervical cancer. Cancer Causes and Control 2(5): 283-290, 1991.
  30. Laara E, Day NE, Hakama M: Trends in mortality from cervical cancer in the Nordic countries: association with organised screening programmes. Lancet 1(8544): 1247-1249, 1987.
  31. Christopherson WM, Lundin FE, Mendez WM, et al.: Cervical cancer control: a study of morbidity and mortality trends over a twenty-one-year period. Cancer 38(3): 1357-1366, 1976.
  32. Miller AB, Lindsay J, Hill GB: Mortality from cancer of the uterus in Canada and its relationship to screening for cancer of the cervix. International Journal of Cancer 17(5): 602-612, 1976.
  33. Hayward RA, Shapiro MF, Freeman HE, et al.: Who gets screened for cervical and breast cancer? results from a new national survey. Archives of Internal Medicine 148(5): 1177-1181, 1988.
  34. Howard J: "Avoidable mortality" from cervical cancer: exploring the concept. Social Science and Medicine 24(6): 507-514, 1987.
  35. Mamon JA, Shediac MC, Crosby CB, et al.: Inner-city women at risk for cervical cancer: behavioral and utilization factors related to inadequate screening. Preventive Medicine 19(4): 363-376, 1990.
  36. Foster JD, Holland B, Louria DB, et al.: In situ/invasive cervical cancer ratios: impact of cancer education and screening. Journal of Cancer Education 3(2): 121-125, 1988.
  37. Marcus AC, Crane LA, Kaplan CP, et al.: Improving adherence to screening follow-up among women with abnormal Pap smears: results from a large clinic-based trial of three intervention strategies. Medical Care 30(3): 216-230, 1992.
  38. Carney P, Dietrich AJ, Freeman DH: Improving future preventive care through educational efforts at a women's community screening program. Journal of Community Health 17(3): 167-174, 1992.
  39. Andren SM: Cervical cytology screening convenient for the workforce. Journal of the Society of Occupational Medicine 41(4): 168-170, 1991.
  40. Thornton J, Chamberlain J: Cervical screening in the workplace. Community Medicine 11(4): 290-298, 1989.
  41. Harlan LC, Bernstein AB, Kessler LG: Cervical cancer screening: who is not screened and why? American Journal of Public Health 81(7): 885-890, 1991.
  42. Marcus AC, Crane LA, Kaplan CP, et al.: Screening for cervical cancer in emergency centers and sexually transmitted disease clinics. Obstetrics and Gynecology 75(3, Part 1): 453-455, 1990.
  43. Franceschi S, Gorga G, Bidoli E, et al.: Comparison of two different strategies for early diagnosis of cervical neoplasia in the north of Italy: hospital-based and outpatient clinic-based screening. Cervix and the Lower Female Genital Tract 7(2): 145-153, 1989.
  44. Ziegler RG, Brinton LA, Hamman RF, et al.: Diet and the risk of invasive cervical cancer among white women in the United States. American Journal of Epidemiology 132(3): 432-445, 1990.
  45. Slattery ML, Abbott TM, Overall JC, et al.: Dietary vitamins A, C and E and selenium as risk factors for cervical cancer. Epidemiology 1(1): 8-15, 1990.
  46. McPherson RS: Nutritional factors and the risk of cervical dysplasia. Dissertation Abstracts International 51(4): 1769, 1990.
  47. Verreault R, Chu J, Mandelson M, et al.: A case-control study of diet and invasive cervical cancer. International Journal of Cancer 43(6): 1050-1054, 1989.
  48. Burton GW, Ingold KU: beta-Carotene: an unusual type of lipid antioxidant. Science 224(4649): 569-573, 1984.
  49. La Vecchia C, DeCarli A, Fasoli M, et al.: Dietary vitamin A and the risk of intraepithelial and invasive cervical neoplasia. Gynecologic Oncology 30(2): 187-195, 1988.
  50. Harris RW, Forman D, Doll R, et al.: Cancer of the cervix uteri and vitamin A. British Journal of Cancer 53(5): 653-659, 1986.
  51. Orr JW, Wilson K, Bodiford C, et al.: Nutritional status of patients with untreated cervical cancer. II: vitamin assessment. American Journal of Obstetrics and Gynecology 151(5): 632-635, 1985.
  52. Palan PR, Romney SL, Mikhail M, et al.: Decreased plasma beta-carotene levels in women with uterine cervical dysplasias and cancer. Journal of the National Cancer Institute 80(6): 454-455, 1988.
  53. Verreault R, Chu J, Mandelson M, et al.: A case-control study of diet and invasive cervical cancer. International Journal of Cancer 43(6): 1050-1054, 1989.
  54. Meyskens FL, Surwit E, Moon TE, et al.: Enhancement of regression of cervical intraepithelial neoplasia II (moderate dysplasia) with topically applied all-trans-retinoic acid: a randomized trial. Journal of the National Cancer Institute 86(7): 539-543, 1994.
  55. Schiller JT: Papillomavirus-like particle vaccines for cervical cancer. Molecular Medicine Today 5(5): 209-215, 1999.
Date Last Modified: 07/2002

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