Management of the Abnormal Pap Smear, Cervical Dysplasia, and Cervical Cancer Todd D. Tillmanns MD Assistant Professor Dep...
CREOG OBJECTIVES <ul><li>Pre-invasive cervical disease: </li></ul><ul><li>1. describe the epidemiology of cervical dysplas...
Natural History of Dysplasia <ul><li>Human Papilloma Virus is etiologic in the development of invasive cervical cancer. </...
Relative Risk of Cervical Cancer by HPV Type
Electron Micrograph of HPV
Cervical Histology Showing HPV & Koilocytes
Cervical Cytology Showing HPV & Koilocytes
Risk of Progression to Cancer >12% 5% 1% Ostor AG. CIN III CIN II CIN I Author
Conventional Cervical Cytology (Papanicolaou Smear) <ul><ul><li>Introduced in 1939 </li></ul></ul><ul><ul><li>Substantiall...
Conventional Cervical Cytology (Papanicolaou Smear) <ul><ul><li>Good screening test </li></ul></ul><ul><ul><li>Inexpensive...
Screening Guidelines  Early Detection of Cervical Cancer American Cancer Society 2003 <ul><li>Screening should begin appro...
Atypical Squamous Cells <ul><li>ASC: </li></ul><ul><ul><li>Atypical Squamous Cells of Undetermined Significance (ASC-US) <...
Managing ASC <ul><li>Sensitivity of a single repeat test for detecting CIN II-III after ASC is low (0.67-0.85) </li></ul><...
Repeat Cytology @ 4 - 6 mos HPV DNA Testing Colposcopy Preferred if  liquid-based cytology or co-collection available “ Wh...
Patient Management Using HPV Triage   ASCUS HPV TEST Low Risk + or  HPV – HPV  + Repeat Pap and/or HPV Test in 12 mo. or r...
ASC Special Circumstances <ul><li>Postmenopausal Women </li></ul><ul><ul><li>Using intravaginal estrogen followed one week...
Atypical Glandular Cells and AIS <ul><li>AGC : Atypical Glandular Cells (endocervical, endometrial, or glandular cells not...
AGC Category <ul><li>9-54% of women with AGC have biopsy confirmed CIN </li></ul><ul><li>0-8% have AIS </li></ul><ul><li>1...
AIS Category <ul><li>The cytologic interpretation of AIS is associated with a very high risk of women having either AIS (4...
Managing AGC and AIS <ul><li>Screening cervical cytology has a sensitivity of only 50%-72% for identifying glandular neopl...
AGC and AIS Management <ul><li>Colposcopy and ECC is recommended for women with all subcategories of AGC with the caveat t...
AGC favor dysplasia <ul><li>AGC favor dysplasia or AIS with (-) colpo should receive a diagnostic excisional procedure   ...
LSIL <ul><li>Median rate of LSIL in the USA is 1.6%, but high risk populations have reported LSIL rates as high as 7.7%. <...
Managing LSIL <ul><li>53-76% likelihood of abnormal Pap on follow up cytology </li></ul><ul><li>83% of women referred for ...
Managing LSIL with Satisfactory and Unsatisfactory Colposcopy <ul><li>Satisfactory Colposcopy </li></ul><ul><ul><li>ECC is...
Transformation Zone
Cryotherapy <ul><li>Nitrous oxide or CO 2  refrigerant </li></ul><ul><li>Lesion covered by probe, lubricant </li></ul><ul>...
LEEP <ul><li>Transformation zone excised to depth of 7-8 mm </li></ul><ul><li>Provides tissue diagnosis </li></ul><ul><li>...
Cone Biopsy <ul><li>Indications </li></ul><ul><ul><li>(+) ECC </li></ul></ul><ul><ul><li>Cytologic abnormality not consist...
Cone Biopsy <ul><li>2 Methods: </li></ul><ul><ul><li>Cold Knife Cone Biopsy </li></ul></ul><ul><ul><li>LEEP Cone Biopsy or...
Cervical Conization
 
In Utero Exposure to DES <ul><li>In women exposed to DES in utero, the normal migration of the squamous epithelium is prem...
Cervical Cancer <ul><li>2nd most important cancer in women worldwide </li></ul><ul><li>Most important cancer in developing...
44 40 41 30 29 47 51 39 5 3 27 19 16 42 31 45 43 1 20 2 28 15 8 18 13 14 4 6 10 38 48 37 50 34 33 11 9 7 21 24 22 17 32 23...
Lifetime Probability of Developing Cancer, by Site, Women, US, 1997-1999 Source: Surveillance, Epidemiology, and End Resul...
Test Trends in Recent* Pap Prevalence (%), by Educational Attainment, Women 25 and Older, US,  1992-2000 * A Pap test with...
Incidence and Mortality Rates 1997-2001 by Race/Ethnicity American Cancer Society 2005 Mortality rates per 100,000 based o...
Cancer Survival*(%) by Site and Race,1992-1998 *5-year relative survival rates based on follow up of patients through 1999...
Cervical Cancer:  Improved Mortality & Morbidity with Early Identification <ul><li>FIGO Stage   % Cases   5-Year Survival ...
Risk Factors <ul><li>HPV infection (plus cofactors) 1 </li></ul><ul><ul><li>Subtypes 16, 18, 31, 35, 39 </li></ul></ul><ul...
Presenting Symptoms <ul><li>Pre-invasive disease   </li></ul><ul><ul><li>no symptoms </li></ul></ul><ul><li>Invasive cervi...
Cervical Cancer Differential Diagnosis <ul><li>Cervical condyloma or dysplasia </li></ul><ul><li>Uterine cancer extending ...
Diagnostic Modalities <ul><li>Clinical staging (FIGO) </li></ul><ul><li>EUA, Cystoscopy, Proctoscopy, appropriate biopsies...
FIGO Staging <ul><ul><li>Eifel et al. Carcinoma of the Cervix. In: Devita et al (eds). CA Principles & Practice of Oncol, ...
Cervical Cancer :  Improved Mortality & Morbidity with Early Identification <ul><li>FIGO Stage   % Cases   5-Year Survival...
Counseling Patient After Diagnosis of Cervical Cancer <ul><li>Treatment modalities based on stage </li></ul><ul><li>Side e...
Follow Up After First Line Therapy <ul><li>Every 3 months for the first 2 years </li></ul><ul><li>Every 6 months for the f...
Chemotherapy <ul><li>Advanced/recurrent disease   </li></ul><ul><ul><li>Agents with > 15%  response  </li></ul></ul><ul><u...
Advanced Cervical Cancer EB=external beam, ICRT=intracavitary radiation therapy, P=platinum, F=5-FU, HU=hydroxyurea 65 65 ...
Recurrent Disease Treatment in the 80’s and 90’s <ul><li>Platinum-based therapies most effective </li></ul><ul><li>Cisplat...
<ul><li>Cisplatin 50 mg/m2 </li></ul><ul><li>Topotecan 0.75 mg/m2/d1-3 </li></ul><ul><li>Cisplatin 50 mg/m2 d1 </li></ul>T...
Results GOG 179 Long III HJ.  SGO 35 th  Annual Meeting 2004 [Abstract 9]
Progression-free survival
Overall survival
Chemotherapy for recurrent disease – 2004 <ul><li>GOG 179 – Predictor of response </li></ul><ul><li>Prior cisplatin therap...
Adverse Events GOG 179 Long III HJ.  SGO 35 th  Annual Meeting 2004 [Abstract 9]
Summary GOG 179 <ul><li>Statistically significant prolonged survival for patients treated with topotecan plus cisplatin vs...
Future Directions <ul><li>GOG 204  - Cervical cancer stage IVB, recurrent, persistent  </li></ul>
Potential benefit in resecting grossly involved nodes <ul><li>University of Minnesota experience </li></ul><ul><ul><li>266...
SUMMARY <ul><li>CDDP + WPR + ICRT for advanced stage cervical cancer </li></ul><ul><li>Recurrence: Protocol   CDDP + Topo...
THANK YOU ! Questions / Comments ?
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  • Servikal Displazi -Pap Smear - Serviks Kanseri - www.jinekolojivegebelik.com

    1. 1. Management of the Abnormal Pap Smear, Cervical Dysplasia, and Cervical Cancer Todd D. Tillmanns MD Assistant Professor Department of Obstetrics & Gynecology Division of Gynecologic Oncology University of Tennessee and West Clinic E-mail: [email_address]
    2. 2. CREOG OBJECTIVES <ul><li>Pre-invasive cervical disease: </li></ul><ul><li>1. describe the epidemiology of cervical dysplasia </li></ul><ul><li>2. elicit a pertinent history in a woman with an abnl pap </li></ul><ul><li>3. interpret pap test reports using bethesda classification system and </li></ul><ul><li>determine appropriate follow-up. </li></ul><ul><li>4.perform and interpret the results of diagnostic procedures for cerivical </li></ul><ul><li>dysplasia </li></ul><ul><li>5. treat cervical dysplasia with modalities, such as: cryosurgery, laser </li></ul><ul><li>ablation, leep, ckc </li></ul><ul><li>6. manage the complications resulting in the treatment of cervical dysplasia 7. establish an appropriate follow-up plan for a woman who has been treated </li></ul><ul><li>for cervical dysplasia </li></ul><ul><li>8. describe the structural changes in the cervix that are characteristic of </li></ul><ul><li>in-utero des exposure </li></ul><ul><li>Invasive cervical cancer: </li></ul><ul><li>1. describe the epidemiology of cervical ca </li></ul><ul><li>2. describe the typical clinical manifestations of cervical ca 3. describe the differential diagnosis of cervical ca 4. perform appropriate biopsies to diagnose invasive cervical ca 5. describe the figo staging of cervical ca--maybe throw in your bulls-eye </li></ul><ul><li>here. </li></ul><ul><li>6. in consultation with a gyn onc, counsel the patient about the evaluation </li></ul><ul><li>and treatment (indications, complications) of cervical ca </li></ul><ul><li>7. describe the prognosis </li></ul><ul><li>8. describe the impact of treatment of cervical ca on sexual function and </li></ul><ul><li>manage/refer the patient appropriately </li></ul><ul><li>9. provide psychosocial support and long-term follow up for patients with </li></ul><ul><li>cervical ca. </li></ul>
    3. 3. Natural History of Dysplasia <ul><li>Human Papilloma Virus is etiologic in the development of invasive cervical cancer. </li></ul><ul><ul><li>99% of cervical cancers worldwide are HPV positive 1 </li></ul></ul><ul><ul><li>96% of HSIL is HPV positive 2 </li></ul></ul><ul><ul><li>30% of HPV 16 CIN III will progress to cancer </li></ul></ul><ul><ul><li>Infection with a high-risk or carcinogenic HPV type is associated w/ 100-fold or greater risk of developing cervical cancer compared to someone who is not infected </li></ul></ul><ul><ul><li> 1 Bosch FX, et al. J Natl Cancer Inst 1995; 87:796-802 </li></ul></ul><ul><ul><li> 2 Matsukura M, et al. Int J Cancer 1995; 61:13-22 </li></ul></ul>
    4. 4. Relative Risk of Cervical Cancer by HPV Type
    5. 5. Electron Micrograph of HPV
    6. 6. Cervical Histology Showing HPV & Koilocytes
    7. 7. Cervical Cytology Showing HPV & Koilocytes
    8. 8. Risk of Progression to Cancer >12% 5% 1% Ostor AG. CIN III CIN II CIN I Author
    9. 9. Conventional Cervical Cytology (Papanicolaou Smear) <ul><ul><li>Introduced in 1939 </li></ul></ul><ul><ul><li>Substantially unchanged in 50 years </li></ul></ul><ul><ul><li>Responsible for a 76.6% reduction in the incidence of invasive cervical cancer & 74.5% reduction in mortality in the United States since 1950 1 </li></ul></ul><ul><ul><li>No randomized controlled trials have evaluated efficacy </li></ul></ul><ul><ul><li> Herrero R. Monogr Natl Cancer Inst 1996; 21:1-6 </li></ul></ul>
    10. 10. Conventional Cervical Cytology (Papanicolaou Smear) <ul><ul><li>Good screening test </li></ul></ul><ul><ul><li>Inexpensive </li></ul></ul><ul><ul><li>High sensitivity & specificity </li></ul></ul><ul><ul><li>Easy to perform, noninvasive, nonmorbid </li></ul></ul><ul><ul><li>Reproducible </li></ul></ul>
    11. 11. Screening Guidelines Early Detection of Cervical Cancer American Cancer Society 2003 <ul><li>Screening should begin approximately three years after a woman begins having vaginal intercourse, but no later than 21 years of age </li></ul><ul><li>Screening should be done every year with regular Pap tests or every two years using liquid-based tests </li></ul><ul><li>At or after age 30, women who have had three normal test results in a row may get screened every 2-3 years. However, doctors may suggest a woman get screened more if she has certain risk factors, such as HIV infection or a weakened immune system </li></ul><ul><li>Women 70 and older who have had three or more consecutive Pap tests in the last ten years may choose to stop cervical cancer screening </li></ul><ul><li>Screening after a total hysterectomy (with removal of the cervix) is not necessary unless the surgery was done as a treatment for cervical cancer </li></ul>Wright et al: ASCCP Cytol
    12. 12. Atypical Squamous Cells <ul><li>ASC: </li></ul><ul><ul><li>Atypical Squamous Cells of Undetermined Significance (ASC-US) </li></ul></ul><ul><ul><li>Atypical Squamous Cells cannot exclude HSIL (ASC- </li></ul></ul><ul><li>ASC is poorly reproducible </li></ul><ul><li>ASC has a 5-17% chance of having CIN II-III </li></ul><ul><li>CIN III is diagnosed in 24-94% of those with ASC-H </li></ul><ul><li>Risk of invasive caner </li></ul><ul><li>with ASC is low (0.1-0.2 %) </li></ul>Wright et al: ASCCP Cytol Guidelines JAMA 2002;287:2120-2129
    13. 13. Managing ASC <ul><li>Sensitivity of a single repeat test for detecting CIN II-III after ASC is low (0.67-0.85) </li></ul><ul><li>Colposcopy; mean sensitivity for distinguishing normal from abnormal was 0.96 and weighted specificity was 0.48 </li></ul><ul><li>Sensitivity of HPV testing to detect CIN II-III in women with ASC is (0.83-1.0) better than a single Pap. The (-) predictive value for high risk HPV is 0.98 </li></ul><ul><li>Between 31% and 60% of all women with ASC will have high risk HPV, but this decreases with age </li></ul><ul><li>Reflex HPV: 40-60% of women will be spared colposcopy and (-) testing assures women that they do not have a lesion </li></ul>Wright et al: ASCCP Cytol Guidelines JAMA 2002;287:2120-2129
    14. 14. Repeat Cytology @ 4 - 6 mos HPV DNA Testing Colposcopy Preferred if liquid-based cytology or co-collection available “ When liquid-based cytology is used, or when co-collection for HPV DNA testing can be done, &quot;reflex&quot; HPV DNA testing is the preferred approach” ASCCP Management Guidelines ASC-US: HPV Testing Wright TC Jr, Cox JT, Massad LS, Twiggs LB, Wilkinson EJ, for 2001 ASCCP-Sponsored Consensus Conference. 2001 Consensus Guidelines for the management of women with cervical cytological abnormalities. JAMA. 2002;287:2120-2129.
    15. 15. Patient Management Using HPV Triage ASCUS HPV TEST Low Risk + or HPV – HPV + Repeat Pap and/or HPV Test in 12 mo. or return to routine screening at discretion of clinician COLPOSCOPY BIOPSY/ABLATION
    16. 16. ASC Special Circumstances <ul><li>Postmenopausal Women </li></ul><ul><ul><li>Using intravaginal estrogen followed one week later with Pap  If (-) then repeat 6 months later </li></ul></ul><ul><li>Immunosuppressed Women </li></ul><ul><ul><li>Referral colposcopy is recommended </li></ul></ul><ul><li>Pregnant Women </li></ul><ul><ul><li>Same as non-pregnant </li></ul></ul>Wright et al: ASCCP Cytol Guidelines JAMA 2002;287:2120-2129
    17. 17. Atypical Glandular Cells and AIS <ul><li>AGC : Atypical Glandular Cells (endocervical, endometrial, or glandular cells not otherwise specified) </li></ul><ul><li>AGC: Favor Neoplasia </li></ul><ul><li>AIS: Adenocarcinoma in situ </li></ul>Wright et al: ASCCP Cytol Guidelines JAMA 2002;287:2120-2129
    18. 18. AGC Category <ul><li>9-54% of women with AGC have biopsy confirmed CIN </li></ul><ul><li>0-8% have AIS </li></ul><ul><li>1-9% have invasive cancer </li></ul><ul><li>Biopsy confirmed CIN II-III, AIS, or invasive cancer have been found in 9-41% of women with AGC NOS compared to 27-96% of women with AGC “favor neoplasia” </li></ul>Wright et al: ASCCP Cytol Guidelines JAMA 2002;287:2120-2129
    19. 19. AIS Category <ul><li>The cytologic interpretation of AIS is associated with a very high risk of women having either AIS (48-69%) or invasive cervical adenocarcinoma (38%). </li></ul>Wright et al: ASCCP Cytol Guidelines JAMA 2002;287:2120-2129
    20. 20. Managing AGC and AIS <ul><li>Screening cervical cytology has a sensitivity of only 50%-72% for identifying glandular neoplasia </li></ul><ul><li>CIN is the most common neoplasia identified in women with the cytologic result of AGC </li></ul><ul><li>Repeat cervical cytology is less sensitive than colposcopy for identifying CIN II-III </li></ul><ul><li>This supports using colposcopy </li></ul><ul><li>There is a higher risk of CIN II-III, and AIS in premenopausal women compared to menopausal women </li></ul><ul><li>½ of the women with AIS have a coexisting squamous lesion </li></ul>Wright et al: ASCCP Cytol Guidelines JAMA 2002;287:2120-2129
    21. 21. AGC and AIS Management <ul><li>Colposcopy and ECC is recommended for women with all subcategories of AGC with the caveat that women with atypical endometrial cells should have an EMBX </li></ul><ul><li>EMBX should be performed in conjunction with colposcopy in women older than 35 with AGC and in younger women with AGC with unexplained bleeding or AIS </li></ul><ul><li>There is insufficient data to allow an assessment of HPV DNA testing in the management of women with AGC or AIS </li></ul>Wright et al: ASCCP Cytol Guidelines JAMA 2002;287:2120-2129
    22. 22. AGC favor dysplasia <ul><li>AGC favor dysplasia or AIS with (-) colpo should receive a diagnostic excisional procedure  CKC </li></ul><ul><li>If no neoplasia identified at initial workup, then repeat cytology q 4-6 months until normal x 4 </li></ul><ul><li>Acceptable options include referral </li></ul>Wright et al: ASCCP Cytol Guidelines JAMA 2002;287:2120-2129
    23. 23. LSIL <ul><li>Median rate of LSIL in the USA is 1.6%, but high risk populations have reported LSIL rates as high as 7.7%. </li></ul><ul><li>15-30% of women with LSIL on cervical cytology will have CIN II-III identified on subsequent cervical biopsy. </li></ul>Wright et al: ASCCP Cytol Guidelines JAMA 2002;287:2120-2129
    24. 24. Managing LSIL <ul><li>53-76% likelihood of abnormal Pap on follow up cytology </li></ul><ul><li>83% of women referred for the evaluation of an LSIL cytology result tested positive for high risk HPV types. </li></ul><ul><li>HPV DNA and LEEP do not appear to be useful for the initial management of women with LSIL </li></ul><ul><li>Colposcopy with directed biopsies is the initial best option. </li></ul>Wright et al: ASCCP Cytol Guidelines JAMA 2002;287:2120-2129
    25. 25. Managing LSIL with Satisfactory and Unsatisfactory Colposcopy <ul><li>Satisfactory Colposcopy </li></ul><ul><ul><li>ECC is an acceptable option with follow up in 6 months if normal </li></ul></ul><ul><li>Unsatisfactory Colposcopy: </li></ul><ul><ul><li>ECC in non pregnant with follow up in 6 months if normal –vs- LEEP Cone </li></ul></ul><ul><li>Pregnancy </li></ul><ul><ul><li>Colposcopy with biopsy only if high grade lesion or cancer is suspected </li></ul></ul><ul><li>Adolescents </li></ul><ul><ul><li>Acceptable option is follow up in 6 months without colposcopy </li></ul></ul>Wright et al: ASCCP Cytol Guidelines JAMA 2002;287:2120-2129
    26. 26. Transformation Zone
    27. 27. Cryotherapy <ul><li>Nitrous oxide or CO 2 refrigerant </li></ul><ul><li>Lesion covered by probe, lubricant </li></ul><ul><li>Freeze 4-6 mm beyond probe </li></ul><ul><li>Freeze - Thaw - Freeze Technique </li></ul><ul><li>Failure in 7% of 422 CIN III patients 1 </li></ul>1(Bryson. Am J Ob Gyn 1985; 151:201-6)
    28. 28. LEEP <ul><li>Transformation zone excised to depth of 7-8 mm </li></ul><ul><li>Provides tissue diagnosis </li></ul><ul><li>Easy to perform </li></ul><ul><li>Well tolerated by patients </li></ul><ul><li>Can be performed in outpatient setting </li></ul><ul><li>Success rates 90-96% </li></ul>
    29. 29. Cone Biopsy <ul><li>Indications </li></ul><ul><ul><li>(+) ECC </li></ul></ul><ul><ul><li>Cytologic abnormality not consistent w/ tissue diagnosis </li></ul></ul><ul><ul><li>Unsatisfactory colposcopy </li></ul></ul><ul><ul><li>Microinvasion on biopsy, r/o invasive cancer </li></ul></ul><ul><ul><li>Adenocarcinoma in situ or invasive adenocarcinoma </li></ul></ul>
    30. 30. Cone Biopsy <ul><li>2 Methods: </li></ul><ul><ul><li>Cold Knife Cone Biopsy </li></ul></ul><ul><ul><li>LEEP Cone Biopsy or Laser Cone Biopsy </li></ul></ul><ul><ul><li>Equivalent results for most indications </li></ul></ul><ul><ul><li>Exceptions include: </li></ul></ul><ul><ul><ul><li>Microinvasion on biopsy, r/o invasive cancer </li></ul></ul></ul><ul><ul><ul><li>Adenocarcinoma in situ or invasive adenocarcinoma </li></ul></ul></ul>
    31. 31. Cervical Conization
    32. 33. In Utero Exposure to DES <ul><li>In women exposed to DES in utero, the normal migration of the squamous epithelium is prematurely halted. </li></ul><ul><li>The original SCJ is often located in the vagina rather than on the exocervix. </li></ul><ul><li>In these women the entire cervical portio can be covered with endocervical columnar epithelium. </li></ul>Kurman, RJ. Blaustein’s Pathology of the Female Genital Tract 5 th edition. 2002 Springer-Verlag. New York. pp.216
    33. 34. Cervical Cancer <ul><li>2nd most important cancer in women worldwide </li></ul><ul><li>Most important cancer in developing countries 1 </li></ul><ul><li>Approximately 10,370 new cases/yr in U.S. 2 Approximately 3,710 deaths/yr in U.S. 2 </li></ul><ul><ul><li>1991-1995 Tennessee ranked 7 th in mortality from Cervical Cancer </li></ul></ul><ul><li>Overall 5-year survival is approximately 70% 2 </li></ul><ul><li> 1 Int J Cancer 1993; 54:594-606 </li></ul><ul><li> 2 Cancer Facts and Figures -2005, ACS 2005 </li></ul>
    34. 35. 44 40 41 30 29 47 51 39 5 3 27 19 16 42 31 45 43 1 20 2 28 15 8 18 13 14 4 6 10 38 48 37 50 34 33 11 9 7 21 24 22 17 32 23 25 46 49 Age-adjusted Death Rate (Rank) 2.6-2.3 (31-40) 3.1-2.6 (22-30) 3.4-3.1 (11-21) 3.8-4.8 (1-10) Age-adjusted* Death Rates and Rank from Cervical Cancer United States 1996-2000 *Age-adjusted to 2000 population -Rank 1 is worst; 51 is best. -Rates are per 100,000 36 35 12 26 2.3-1.8 (41-51)
    35. 36. Lifetime Probability of Developing Cancer, by Site, Women, US, 1997-1999 Source: Surveillance, Epidemiology, and End Results Program, 1973-1999, Division of Cancer Control and Population Sciences, National Cancer Institute, 2002. Site Risk All sites 1 in 3 Breast 1 in 8 Lung & bronchus 1 in 17 Colon & rectum 1 in 18 Uterine corpus 1 in 37 Non-Hodgkin lymphoma 1 in 56 Ovary 1 in 58 Pancreas 1 in 80 Melanoma 1 in 81 Urinary bladder 1 in 88 Uterine cervix 1 in 123
    36. 37. Test Trends in Recent* Pap Prevalence (%), by Educational Attainment, Women 25 and Older, US, 1992-2000 * A Pap test within the past three years. **Includes fewer than 50 states and District of Columbia Source: Behavior Risk Factor Surveillance System, 1992-1995, 1996-1997, 1998, 1999, 2000, National Center for Chronic Disease Prevention and Health Promotion, Center for Disease Control and Prevention,1997, 1999, 2000, 2000, 2001 Prevalence (%) Less than High School Some college or greater High School graduate All women 18 and older
    37. 38. Incidence and Mortality Rates 1997-2001 by Race/Ethnicity American Cancer Society 2005 Mortality rates per 100,000 based on 2000 US standard population 3.6 2.8 2.8 5.6 2.6 Latina American Indian Asian African American White
    38. 39. Cancer Survival*(%) by Site and Race,1992-1998 *5-year relative survival rates based on follow up of patients through 1999. Source: Surveillance, Epidemiology, and End Results Program, 1973-1999, Division of Cancer Control and Population Sciences, National Cancer Institute, 2002. All Sites 64 53 11 Breast (female) 88 73 15 Colon & rectum 63 53 10 Esophagus 15 8 7 Leukemia 47 38 9 Non-Hodgkin lymphoma 56 46 10 Oral cavity 59 35 24 Prostate 98 93 5 Urinary bladder 82 65 17 Uterine cervix 72 60 12 Uterine corpus 86 61 25 Site White % Difference African American
    39. 40. Cervical Cancer: Improved Mortality & Morbidity with Early Identification <ul><li>FIGO Stage % Cases 5-Year Survival </li></ul><ul><li>I 46% 83% </li></ul><ul><li>II 28% 64% </li></ul><ul><li>III 21% 38% </li></ul><ul><li>IV 4% 14% </li></ul><ul><li> FIGO Annual Report. J Epi & Biostat 1998; 3(1) </li></ul>
    40. 41. Risk Factors <ul><li>HPV infection (plus cofactors) 1 </li></ul><ul><ul><li>Subtypes 16, 18, 31, 35, 39 </li></ul></ul><ul><li>Sexual behavior 1-3 </li></ul><ul><ul><li>Sex at young age; multiple partners </li></ul></ul><ul><ul><li>High parity; race; low socioeconomic status </li></ul></ul><ul><li>History of smoking 1-3 </li></ul><ul><li>Oral contraceptives (?) 3 </li></ul><ul><ul><li>controversial </li></ul></ul><ul><ul><li>1. Eifel et al. Carcinoma of the Cervix. In: Devita et al (eds). CA Principles & Practice of Oncol, 6th ed. Lippincott Williams & Wilkins, Phila, PA, 2001;1526-1550. 2. ACS. Cancer Facts & Figures 2004. </li></ul></ul><ul><ul><li>3. Janicek et al. CA Cancer J 2001;51:92-114. </li></ul></ul>
    41. 42. Presenting Symptoms <ul><li>Pre-invasive disease </li></ul><ul><ul><li>no symptoms </li></ul></ul><ul><li>Invasive cervical cancer </li></ul><ul><ul><li>abnormal vaginal bleeding </li></ul></ul><ul><ul><li>pelvic pain (locoregional disease) </li></ul></ul><ul><ul><li>flank pain (hydronephrosis) </li></ul></ul><ul><ul><li>triad (siatic pain, leg edema, hydronephrosis) </li></ul></ul><ul><ul><ul><li>Extensive pelvic wall involvement </li></ul></ul></ul><ul><ul><li>hematuria, incontinence (bladder involvement) </li></ul></ul><ul><ul><li>constipation (external compression of rectum) </li></ul></ul><ul><ul><ul><li>not common at early diagnosis </li></ul></ul></ul><ul><ul><li>Eifel et al. Carcinoma of the Cervix. In: Devita et al (eds). CA Principles & Practice of Oncol, 6th ed. Lippincott Williams & Wilkins, Phila, PA, 2001;1526-1550 . </li></ul></ul>
    42. 43. Cervical Cancer Differential Diagnosis <ul><li>Cervical condyloma or dysplasia </li></ul><ul><li>Uterine cancer extending to cervix </li></ul><ul><li>Metastatic disease to cervix </li></ul><ul><li>Cervical or endometrial polyp </li></ul>
    43. 44. Diagnostic Modalities <ul><li>Clinical staging (FIGO) </li></ul><ul><li>EUA, Cystoscopy, Proctoscopy, appropriate biopsies </li></ul><ul><li>CKC only for microscopic disease </li></ul><ul><li>Review Bulls Eye and treatment based on stage </li></ul>
    44. 45. FIGO Staging <ul><ul><li>Eifel et al. Carcinoma of the Cervix. In: Devita et al (eds). CA Principles & Practice of Oncol, 6th ed. Lippincott Williams & Wilkins, Phila, PA, 2001;1526-1550. </li></ul></ul>
    45. 46. Cervical Cancer : Improved Mortality & Morbidity with Early Identification <ul><li>FIGO Stage % Cases 5-Year Survival </li></ul><ul><li>I 46% 83% </li></ul><ul><li>II 28% 64% </li></ul><ul><li>III 21% 38% </li></ul><ul><li>IV 4% 14% </li></ul>FIGO Annual Report. J Epi & Biostat 1998; 3(1)
    46. 47. Counseling Patient After Diagnosis of Cervical Cancer <ul><li>Treatment modalities based on stage </li></ul><ul><li>Side effects and toxicities of whole pelvic radiation and brachytherapy with chemotherapy </li></ul><ul><li>Sexual side effects of different treatment </li></ul><ul><ul><li>Vaginal shortening </li></ul></ul><ul><ul><li>Vaginal coaptation with radiation therapy </li></ul></ul><ul><ul><li>Radiation necrosis </li></ul></ul><ul><ul><li>Loss of ovarian function </li></ul></ul><ul><ul><li>Decreased lubrication </li></ul></ul>
    47. 48. Follow Up After First Line Therapy <ul><li>Every 3 months for the first 2 years </li></ul><ul><li>Every 6 months for the following 3 years </li></ul><ul><li>Pap smear at each visit </li></ul><ul><li>85% of patients that recur will recur in 2 years </li></ul>
    48. 49. Chemotherapy <ul><li>Advanced/recurrent disease </li></ul><ul><ul><li>Agents with > 15% response </li></ul></ul><ul><ul><ul><li>cyclophosphamide ifosfamide melphalan </li></ul></ul></ul><ul><ul><ul><li>cisplatin carboplatin doxorubicin </li></ul></ul></ul><ul><ul><ul><li>topotecan irinotecan methotrexate </li></ul></ul></ul><ul><ul><ul><li>vincristine vindesine vinorelbine </li></ul></ul></ul><ul><ul><ul><li>paclitaxel/docetaxel 5-FU </li></ul></ul></ul><ul><ul><li>Platinum regimens commonly used </li></ul></ul><ul><ul><li>Combination regimens </li></ul></ul><ul><ul><ul><li>Previously </li></ul></ul></ul><ul><ul><ul><ul><li>Higher ORR but no survival advantage vs single-agents </li></ul></ul></ul></ul><ul><ul><li>Eifel et al. Carcinoma of the Cervix. In: Devita et al (eds). CA Principles & Practice of Oncol, 6th ed. Lippincott Williams & Wilkins, Phila, PA, 2001;1526-1550. </li></ul></ul><ul><ul><li>PDQ ® . Cervical Cancer Treatment. http://cancer.gov/cancer_information/PDQ. Lastmodified 6/03 . Rein DT, et al. Anti-Cancer Drugs 2001;12:787-795. </li></ul></ul>
    49. 50. Advanced Cervical Cancer EB=external beam, ICRT=intracavitary radiation therapy, P=platinum, F=5-FU, HU=hydroxyurea 65 65 47 76 63 67 57 3 yr Med Surv (%) 0.001 (0.57) 0.001 (0.55) 0.03 (0.79) PFS P-val (RR) EB + ICRT + P EB + ICRT + PFHU EB + ICRT + HU 176 173 177 IIb-IVa Rose et al. 1999 EB + ICRT + PF EB + ICRT 195 193 IIb-IVa Morris et al. 1999 EB + ICRT + PF EB + ICRT + HU 177 191 IIb-IVa Whitney et al. 1999 Treatment n Stage Author
    50. 51. Recurrent Disease Treatment in the 80’s and 90’s <ul><li>Platinum-based therapies most effective </li></ul><ul><li>Cisplatin more active than carboplatin </li></ul><ul><li>3 ways to increase response without prolonging survival </li></ul><ul><ul><li>Increase platinum dose </li></ul></ul><ul><ul><li>Add ifosfamide to cisplatin </li></ul></ul><ul><ul><li>Add paclitaxel to cisplatin </li></ul></ul><ul><li>Thus, single agent cisplatin at 50 mg/m2 became the best choice </li></ul>
    51. 52. <ul><li>Cisplatin 50 mg/m2 </li></ul><ul><li>Topotecan 0.75 mg/m2/d1-3 </li></ul><ul><li>Cisplatin 50 mg/m2 d1 </li></ul>Treatment of recurrent disease - 2004 293 patients Cervical cancer Stage IV Recurrent Persistent R A N D O M I Z E Long H, et al SGO 2004 GOG 179 Schema <ul><li>1º endpoint : Survival </li></ul><ul><li>2º endpoints: PFS,ORR, QOL, toxicity </li></ul>
    52. 53. Results GOG 179 Long III HJ. SGO 35 th Annual Meeting 2004 [Abstract 9]
    53. 54. Progression-free survival
    54. 55. Overall survival
    55. 56. Chemotherapy for recurrent disease – 2004 <ul><li>GOG 179 – Predictor of response </li></ul><ul><li>Prior cisplatin therapy with RT </li></ul><ul><li>Platinum-free interval </li></ul><ul><li>Performance status </li></ul><ul><li>Site of recurrence – higher in non-irradiated sites </li></ul>15% 39% TOPO/CDDP arm 8% 20% CDDP arm Prior platinum No prior platinum
    56. 57. Adverse Events GOG 179 Long III HJ. SGO 35 th Annual Meeting 2004 [Abstract 9]
    57. 58. Summary GOG 179 <ul><li>Statistically significant prolonged survival for patients treated with topotecan plus cisplatin vs. cisplatin alone </li></ul><ul><li>QOL scores remained stable during treatment compared to baseline </li></ul><ul><ul><li>No statistical differences between treatment groups </li></ul></ul><ul><li>Adverse events more frequent in the combination arm </li></ul>Long III HJ. SGO 35 th Annual Meeting 2004 [Abstract 9] Monk BJ. SGO 35 th Annual Meeting 2004 [Abstract 125]
    58. 59. Future Directions <ul><li>GOG 204 - Cervical cancer stage IVB, recurrent, persistent </li></ul>
    59. 60. Potential benefit in resecting grossly involved nodes <ul><li>University of Minnesota experience </li></ul><ul><ul><li>266 patients underwent extraperitoneal staging prior to RT </li></ul></ul><ul><ul><li>Extended field RT if PA nodes positive </li></ul></ul><ul><ul><li>Similar survival to microscopic nodes and grossly involved but resectable nodes suggesting a therapeutic benefit from surgery </li></ul></ul>Cosin et al, Cancer 1998; 82:2241
    60. 61. SUMMARY <ul><li>CDDP + WPR + ICRT for advanced stage cervical cancer </li></ul><ul><li>Recurrence: Protocol  CDDP + Topotecan </li></ul><ul><li>Role of EPLND? </li></ul><ul><li>Close follow up every 3 months x 2 years then every 6 months x 3 years with Paps at each visit </li></ul>
    61. 62. THANK YOU ! Questions / Comments ?

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