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Management of the Abnormal Pap Management of the Abnormal Pap Smear, Cervical Dysplasia, and Smear, Cervical Dysplasia, and
Cervical CancerCervical Cancer
Todd D. Tillmanns MDTodd D. Tillmanns MDAssistant ProfessorAssistant Professor
Department of Obstetrics & GynecologyDepartment of Obstetrics & Gynecology
Division of Gynecologic OncologyDivision of Gynecologic Oncology
University of Tennessee and West ClinicUniversity of Tennessee and West Clinic
E-mail: [email protected]: [email protected]
CREOG OBJECTIVESCREOG OBJECTIVES
Pre-invasive cervical disease:Pre-invasive cervical disease: 1. describe the epidemiology of cervical dysplasia1. describe the epidemiology of cervical dysplasia 2. elicit a pertinent history in a woman with an abnl pap2. elicit a pertinent history in a woman with an abnl pap 3. interpret pap test reports using bethesda classification system and 3. interpret pap test reports using bethesda classification system and determine appropriate follow-up.determine appropriate follow-up. 4.perform and interpret the results of diagnostic procedures for cerivical 4.perform and interpret the results of diagnostic procedures for cerivical dysplasiadysplasia 5. treat cervical dysplasia with modalities, such as: cryosurgery, laser 5. treat cervical dysplasia with modalities, such as: cryosurgery, laser ablation, leep, ckcablation, leep, ckc 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 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 for cervical dysplasiafor cervical dysplasia 8. describe the structural changes in the cervix that are characteristic of 8. describe the structural changes in the cervix that are characteristic of in-utero des exposurein-utero des exposure
Invasive cervical cancer:Invasive cervical cancer: 1. describe the epidemiology of cervical ca1. describe the epidemiology of cervical ca 2. describe the typical clinical manifestations of cervical ca 3. describe the differential diagnosis of cervical ca 4. perform appropriate biopsies to diagnose 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 invasive cervical ca 5. describe the figo staging of cervical ca--maybe throw in your bulls-eye here.here. 6. in consultation with a gyn onc, counsel the patient about the evaluation 6. in consultation with a gyn onc, counsel the patient about the evaluation and treatment (indications, complications) of cervical caand treatment (indications, complications) of cervical ca 7. describe the prognosis7. describe the prognosis 8. describe the impact of treatment of cervical ca on sexual function and 8. describe the impact of treatment of cervical ca on sexual function and manage/refer the patient appropriatelymanage/refer the patient appropriately 9. provide psychosocial support and long-term follow up for patients with 9. provide psychosocial support and long-term follow up for patients with cervical ca.cervical ca.
Natural History of DysplasiaNatural History of Dysplasia
Human Papilloma Virus is etiologic in the development Human Papilloma Virus is etiologic in the development of invasive cervical cancer.of invasive cervical cancer. 99% of cervical cancers worldwide are HPV positive99% of cervical cancers worldwide are HPV positive11
96% of HSIL is HPV positive96% of HSIL is HPV positive22
30% of HPV 16 CIN III will progress to cancer30% of HPV 16 CIN III will progress to cancer Infection with a high-risk or carcinogenic HPV type is Infection with a high-risk or carcinogenic HPV type is
associated w/ 100-fold or greater risk of developing cervical associated w/ 100-fold or greater risk of developing cervical cancer compared to someone who is not infectedcancer compared to someone who is not infected
11Bosch FX, et al. J Natl Cancer Inst 1995; 87:796-Bosch FX, et al. J Natl Cancer Inst 1995; 87:796-802802
22Matsukura M, et al. Int J Cancer 1995; 61:13-22Matsukura M, et al. Int J Cancer 1995; 61:13-22
Risk of Progression to Risk of Progression to CancerCancer
AuthorAuthor CIN ICIN I CIN IICIN II CIN IIICIN III
Ostor AG.Ostor AG. 1%1% 5%5% >12%>12%
Conventional Cervical Cytology Conventional Cervical Cytology (Papanicolaou Smear)(Papanicolaou Smear)
Introduced in 1939Introduced in 1939 Substantially unchanged in 50 yearsSubstantially unchanged in 50 years Responsible for a 76.6% reduction in the incidence of Responsible for a 76.6% reduction in the incidence of
invasive cervical cancer & 74.5% reduction in invasive cervical cancer & 74.5% reduction in mortality in the United States since 1950mortality in the United States since 195011
No randomized controlled trials have evaluated No randomized controlled trials have evaluated efficacyefficacy
Herrero R. Monogr Natl Cancer Inst Herrero R. Monogr Natl Cancer Inst 1996; 21:1-61996; 21:1-6
Conventional Cervical Cytology Conventional Cervical Cytology (Papanicolaou Smear)(Papanicolaou Smear)
Good screening testGood screening test InexpensiveInexpensive High sensitivity & specificityHigh sensitivity & specificity Easy to perform, noninvasive, nonmorbidEasy to perform, noninvasive, nonmorbid ReproducibleReproducible
Screening Guidelines Screening Guidelines Early Detection of Cervical Cancer Early Detection of Cervical Cancer
American Cancer Society 2003American Cancer Society 2003Screening should begin approximately three years after a woman begins having vaginal Screening should begin approximately three years after a woman begins having vaginal
intercourse, but no later than 21 years of ageintercourse, but no later than 21 years of age
Screening should be done every year with regular Pap tests or every two years using Screening should be done every year with regular Pap tests or every two years using
liquid-based testsliquid-based tests
At or after age 30, women who have had three normal test results in a row may get 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 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 systemshe has certain risk factors, such as HIV infection or a weakened immune system
Women 70 and older who have had three or more consecutive Pap tests in the last ten Women 70 and older who have had three or more consecutive Pap tests in the last ten
years may choose to stop cervical cancer screeningyears may choose to stop cervical cancer screening
Screening after a total hysterectomy (with removal of the cervix) is not necessary unless Screening after a total hysterectomy (with removal of the cervix) is not necessary unless
the surgery was done as a treatment for cervical cancerthe surgery was done as a treatment for cervical cancer
Wright et al: ASCCP Cytol
Atypical Squamous CellsAtypical Squamous Cells
ASC:ASC:– Atypical Squamous Cells of Undetermined Significance (ASC-US)Atypical Squamous Cells of Undetermined Significance (ASC-US)– Atypical Squamous Cells cannot exclude HSIL (ASC-Atypical Squamous Cells cannot exclude HSIL (ASC-
ASC is poorly reproducibleASC is poorly reproducible ASC has a 5-17% chance of having CIN II-IIIASC has a 5-17% chance of having CIN II-III CIN III is diagnosed in 24-94% of those with CIN III is diagnosed in 24-94% of those with
ASC-HASC-H Risk of invasive caner Risk of invasive caner
with ASC is low (0.1-0.2 %)with ASC is low (0.1-0.2 %)
Wright et al: ASCCP Cytol Guidelines JAMA 2002;287:2120-2129
Managing ASCManaging ASC Sensitivity of a single repeat test for detecting CIN II-III after ASC Sensitivity of a single repeat test for detecting CIN II-III after ASC
is low (0.67-0.85)is low (0.67-0.85) Colposcopy; mean sensitivity for distinguishing normal from Colposcopy; mean sensitivity for distinguishing normal from
abnormal was 0.96 and weighted specificity was 0.48abnormal was 0.96 and weighted specificity was 0.48 Sensitivity of HPV testing to detect CIN II-III in women with ASC 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 is (0.83-1.0) better than a single Pap. The (-) predictive value for high risk HPV is 0.98high risk HPV is 0.98
Between 31% and 60% of all women with ASC will have high risk Between 31% and 60% of all women with ASC will have high risk HPV, but this decreases with ageHPV, but this decreases with age
Reflex HPV: 40-60% of women will be spared colposcopy and (-) Reflex HPV: 40-60% of women will be spared colposcopy and (-) testing assures women that they do not have a lesiontesting assures women that they do not have a lesion
Wright et al: ASCCP Cytol Guidelines JAMA 2002;287:2120-2129
Repeat CytologyRepeat Cytology@ 4 - 6 mos@ 4 - 6 mos
HPV DNA TestingHPV DNA Testing
ColposcopyColposcopy
Preferred if Preferred if liquid-based cytologyliquid-based cytology
or co-collection availableor co-collection available
““When liquid-based cytology is used, or when co-collection for When liquid-based cytology is used, or when co-collection for HPV DNA testing can be done, "reflex" HPV DNA testing is the HPV DNA testing can be done, "reflex" HPV DNA testing is the preferredpreferred approach” approach”
ASCCP Management Guidelines ASC-US: HPV ASCCP Management Guidelines ASC-US: HPV TestingTesting
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.
Patient Management Using HPV Patient Management Using HPV TriageTriage
Patient Management Using HPV Patient Management Using HPV TriageTriage
ASCUSASCUS
HPV TESTHPV TEST
Low Risk + or HPV–Low Risk + or HPV– HPV +HPV +
Repeat Pap and/or HPV Test in 12 mo. or return to routine screening at discretion of clinician
Repeat Pap and/or HPV Test in 12 mo. or return to routine screening at discretion of clinician
COLPOSCOPYBIOPSY/ABLATION
COLPOSCOPYBIOPSY/ABLATION
ASC Special CircumstancesASC Special Circumstances
Postmenopausal WomenPostmenopausal Women– Using intravaginal estrogen followed one week later Using intravaginal estrogen followed one week later
with Papwith Pap If (-) then repeat 6 months later If (-) then repeat 6 months later Immunosuppressed WomenImmunosuppressed Women
– Referral colposcopy is recommendedReferral colposcopy is recommended Pregnant WomenPregnant Women
– Same as non-pregnantSame as non-pregnant
Wright et al: ASCCP Cytol Guidelines JAMA 2002;287:2120-2129
Atypical Glandular Cells and AISAtypical Glandular Cells and AIS
AGC : Atypical Glandular Cells (endocervical, AGC : Atypical Glandular Cells (endocervical, endometrial, or glandular cells not otherwise endometrial, or glandular cells not otherwise specified)specified)
AGC: Favor NeoplasiaAGC: Favor Neoplasia AIS: Adenocarcinoma in situAIS: Adenocarcinoma in situ
Wright et al: ASCCP Cytol Guidelines JAMA 2002;287:2120-2129
AGC CategoryAGC Category 9-54% of women with AGC have biopsy 9-54% of women with AGC have biopsy
confirmed CINconfirmed CIN 0-8% have AIS0-8% have AIS 1-9% have invasive cancer1-9% have invasive cancer Biopsy confirmed CIN II-III, AIS, or invasive Biopsy confirmed CIN II-III, AIS, or invasive
cancer have been found in 9-41% of women with cancer have been found in 9-41% of women with AGC NOS compared to 27-96% of women with AGC NOS compared to 27-96% of women with AGC “favor neoplasia”AGC “favor neoplasia”
Wright et al: ASCCP Cytol Guidelines JAMA 2002;287:2120-2129
AIS CategoryAIS Category The cytologic interpretation of AIS is associated The cytologic interpretation of AIS is associated
with a very high risk of women having either AIS with a very high risk of women having either AIS (48-69%) or invasive cervical adenocarcinoma (48-69%) or invasive cervical adenocarcinoma (38%).(38%).
Wright et al: ASCCP Cytol Guidelines JAMA 2002;287:2120-2129
Managing AGC and AISManaging AGC and AIS Screening cervical cytology has a sensitivity of only 50%-Screening cervical cytology has a sensitivity of only 50%-
72% for identifying glandular neoplasia72% for identifying glandular neoplasia CIN is the most common neoplasia identified in women CIN is the most common neoplasia identified in women
with the cytologic result of AGCwith the cytologic result of AGC Repeat cervical cytology is less sensitive than colposcopy Repeat cervical cytology is less sensitive than colposcopy
for identifying CIN II-IIIfor identifying CIN II-III This supports using colposcopyThis supports using colposcopy There is a higher risk of CIN II-III, and AIS in There is a higher risk of CIN II-III, and AIS in
premenopausal women compared to menopausal womenpremenopausal women compared to menopausal women ½ of the women with AIS have a coexisting squamous ½ of the women with AIS have a coexisting squamous
lesionlesion
Wright et al: ASCCP Cytol Guidelines JAMA 2002;287:2120-2129
AGC and AIS ManagementAGC and AIS Management Colposcopy and ECC is recommended for women with Colposcopy and ECC is recommended for women with
all subcategories of AGC with the caveat that women all subcategories of AGC with the caveat that women with atypical endometrial cells should have an EMBXwith atypical endometrial cells should have an EMBX
EMBX should be performed in conjunction with EMBX should be performed in conjunction with colposcopy in women older than 35 with AGC and in colposcopy in women older than 35 with AGC and in younger women with AGC with unexplained bleeding or younger women with AGC with unexplained bleeding or AISAIS
There is insufficient data to allow an assessment of HPV There is insufficient data to allow an assessment of HPV DNA testing in the management of women with AGC or DNA testing in the management of women with AGC or AISAIS
Wright et al: ASCCP Cytol Guidelines JAMA 2002;287:2120-2129
AGC favor dysplasiaAGC favor dysplasia AGC favor dysplasia or AIS with (-) colpo should AGC favor dysplasia or AIS with (-) colpo should
receive a diagnostic excisional procedurereceive a diagnostic excisional procedure CKC CKC If no neoplasia identified at initial workup, then If no neoplasia identified at initial workup, then
repeat cytology q 4-6 months until normal x 4repeat cytology q 4-6 months until normal x 4 Acceptable options include referralAcceptable options include referral
Wright et al: ASCCP Cytol Guidelines JAMA 2002;287:2120-2129
LSILLSIL Median rate of LSIL in the USA is 1.6%, but high Median rate of LSIL in the USA is 1.6%, but high
risk populations have reported LSIL rates as high risk populations have reported LSIL rates as high as 7.7%.as 7.7%.
15-30% of women with LSIL on cervical 15-30% of women with LSIL on cervical cytology will have CIN II-III identified on cytology will have CIN II-III identified on subsequent cervical biopsy.subsequent cervical biopsy.
Wright et al: ASCCP Cytol Guidelines JAMA 2002;287:2120-2129
Managing LSILManaging LSIL 53-76% likelihood of abnormal Pap on follow up 53-76% likelihood of abnormal Pap on follow up
cytologycytology 83% of women referred for the evaluation of an 83% of women referred for the evaluation of an
LSIL cytology result tested positive for high risk LSIL cytology result tested positive for high risk HPV types.HPV types.
HPV DNA and LEEP do not appear to be useful HPV DNA and LEEP do not appear to be useful for the initial management of women with LSILfor the initial management of women with LSIL
Colposcopy with directed biopsies is the initial Colposcopy with directed biopsies is the initial best option.best option.
Wright et al: ASCCP Cytol Guidelines JAMA 2002;287:2120-2129
Managing LSIL with Satisfactory Managing LSIL with Satisfactory and Unsatisfactory Colposcopyand Unsatisfactory Colposcopy
Satisfactory ColposcopySatisfactory Colposcopy– ECC is an acceptable option with follow up in 6 months if ECC is an acceptable option with follow up in 6 months if
normalnormal Unsatisfactory Colposcopy:Unsatisfactory Colposcopy:
– ECC in non pregnant with follow up in 6 months if normal –vs- ECC in non pregnant with follow up in 6 months if normal –vs- LEEP ConeLEEP Cone
PregnancyPregnancy– Colposcopy with biopsy only if high grade lesion or cancer is Colposcopy with biopsy only if high grade lesion or cancer is
suspectedsuspected AdolescentsAdolescents
– Acceptable option is follow up in 6 months without colposcopyAcceptable option is follow up in 6 months without colposcopy
Wright et al: ASCCP Cytol Guidelines JAMA 2002;287:2120-2129
CryotherapyCryotherapy Nitrous oxide or CONitrous oxide or CO22 refrigerant refrigerant Lesion covered by probe, lubricantLesion covered by probe, lubricant Freeze 4-6 mm beyond probeFreeze 4-6 mm beyond probe Freeze - Thaw - Freeze TechniqueFreeze - Thaw - Freeze Technique Failure in 7% of 422 CIN III patientsFailure in 7% of 422 CIN III patients11
1(Bryson. Am J Ob Gyn 1985; 151:201-6)1(Bryson. Am J Ob Gyn 1985; 151:201-6)
LEEPLEEP
Transformation zone excised to depth of 7-8 mmTransformation zone excised to depth of 7-8 mm Provides tissue diagnosisProvides tissue diagnosis Easy to performEasy to perform Well tolerated by patientsWell tolerated by patients Can be performed in outpatient settingCan be performed in outpatient setting Success rates 90-96%Success rates 90-96%
Cone BiopsyCone BiopsyIndicationsIndications
(+) ECC(+) ECC Cytologic abnormality not consistent w/ tissue Cytologic abnormality not consistent w/ tissue
diagnosisdiagnosis Unsatisfactory colposcopyUnsatisfactory colposcopy Microinvasion on biopsy, r/o invasive cancerMicroinvasion on biopsy, r/o invasive cancer Adenocarcinoma in situ or invasive adenocarcinomaAdenocarcinoma in situ or invasive adenocarcinoma
Cone BiopsyCone Biopsy2 Methods:2 Methods:
Cold Knife Cone BiopsyCold Knife Cone Biopsy LEEP Cone Biopsy or Laser Cone BiopsyLEEP Cone Biopsy or Laser Cone Biopsy Equivalent results for most indicationsEquivalent results for most indications Exceptions include:Exceptions include:
Microinvasion on biopsy, r/o invasive cancerMicroinvasion on biopsy, r/o invasive cancer Adenocarcinoma in situ or invasive adenocarcinomaAdenocarcinoma in situ or invasive adenocarcinoma
Risk Factor Normal Abnormal p-value (Univariate)
p-value (Multivariate)
Endocervical Curettage
113 (78.5) 31(21.5) 0.104
Unsatisfactory Colposcopy
16 (80.0) 4 (20.0) 0.767
Two-Step Discrepancy
47 (94.0) 3 (6.0) 0.013 0.051
Ablation 25 (78.1) 7 (21.9) 0.558 Age < 21 43 (91.5) 4 (8.5) 0.057 Age 22-34 113 (81.3) 26 (18.7) 0.796 Age > 35 47 (75.8) 15 (24.2) 0.154
Top-Hat Pathology
In Utero Exposure to DESIn Utero Exposure to DES In women exposed to DES in utero, the normal In women exposed to DES in utero, the normal
migration of the squamous epithelium is migration of the squamous epithelium is prematurely halted. prematurely halted.
The original SCJ is often located in the vagina The original SCJ is often located in the vagina rather than on the exocervix.rather than on the exocervix.
In these women the entire cervical portio can be In these women the entire cervical portio can be covered with endocervical columnar epithelium.covered with endocervical columnar epithelium.
Kurman, RJ. Blaustein’s Pathology of the Female Genital Tract 5th edition. 2002 Springer-Verlag. New York. pp.216
Cervical CancerCervical Cancer
2nd most important cancer in women worldwide2nd most important cancer in women worldwide Most important cancer in developing countriesMost important cancer in developing countries11
Approximately 10,370 new cases/yr in U.S.Approximately 10,370 new cases/yr in U.S.22 Approximately Approximately 3,710 deaths/yr in U.S.3,710 deaths/yr in U.S.22
1991-1995 Tennessee ranked 71991-1995 Tennessee ranked 7thth in mortality from Cervical Cancer in mortality from Cervical Cancer Overall 5-year survival is approximately 70%Overall 5-year survival is approximately 70%22
11Int J Cancer 1993; 54:594-606Int J Cancer 1993; 54:594-606 22Cancer Facts and Figures -2005, ACS 2005Cancer Facts and Figures -2005, ACS 2005
44
4041
30 29
47
5139
5
327
19
1642
31
45
43
1
202
28
15
818
13
144610
3848
37
50
3433 11 9
7
21
2422
17
32
2325
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 CancerUnited 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)
Lifetime Probability of Developing Cancer, by Lifetime Probability of Developing Cancer, by Site, Women, US, 1997-1999Site, 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 RiskAll 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
Test Trends in Recent* Pap Prevalence (%), by Test Trends in Recent* Pap Prevalence (%), by Educational Attainment, Women 25 and Older, US, Educational Attainment, Women 25 and Older, US,
1992-20001992-2000
* 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
0
20
40
60
80
100
1992** 1993** 1994** 1995** 1996 1997 1998 1999 2000Year
PrevalencPrevalencee (%) (%)
Less than High School
Some college or greater
High School graduate All women 18 and older
Incidence and Mortality Rates 1997-Incidence and Mortality Rates 1997-2001 by Race/Ethnicity2001 by Race/Ethnicity
American Cancer Society 2005
WhiteWhite African African AmericanAmerican
AsianAsian American American IndianIndian
LatinaLatina
2.62.6 5.65.6 2.82.8 2.82.8 3.63.6
Mortality rates per 100,000 based on 2000 US standard Mortality rates per 100,000 based on 2000 US standard populationpopulation
Cancer Survival*(%) by Site and Race,1992-1998Cancer 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
AfricanAmerica
n
Cervical Cancer: Cervical Cancer: Improved Mortality & Morbidity with Early Improved Mortality & Morbidity with Early
IdentificationIdentification FIGO StageFIGO Stage % Cases% Cases 5-Year Survival5-Year Survival
II 46% 46% 83% 83%
IIII 28% 28% 64% 64%
IIIIII 21% 21% 38% 38%
IVIV 4% 4% 14% 14%
FIGO Annual Report. J Epi & Biostat 1998; FIGO Annual Report. J Epi & Biostat 1998; 3(1)3(1)
Risk FactorsRisk Factors HPV infection (plus cofactors)HPV infection (plus cofactors)11
– Subtypes 16, 18, 31, 35, 39Subtypes 16, 18, 31, 35, 39
Sexual behaviorSexual behavior1-31-3
– Sex at young age; multiple partnersSex at young age; multiple partners
– High parity; race; low socioeconomic statusHigh parity; race; low socioeconomic status
History of smokingHistory of smoking1-31-3
Oral contraceptives (?)Oral contraceptives (?)33
– controversialcontroversial
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. 3. Janicek et al. CA Cancer J 2001;51:92-114.
Presenting SymptomsPresenting Symptoms Pre-invasive diseasePre-invasive disease
– no symptomsno symptoms
Invasive cervical cancerInvasive cervical cancer– abnormal vaginal bleedingabnormal vaginal bleeding
– pelvic pain (locoregional disease)pelvic pain (locoregional disease)
– flank pain (hydronephrosis)flank pain (hydronephrosis)
– triad (siatic pain, leg edema, hydronephrosis)triad (siatic pain, leg edema, hydronephrosis)
» Extensive pelvic wall involvementExtensive pelvic wall involvement
– hematuria, incontinence (bladder involvement)hematuria, incontinence (bladder involvement)
– constipation (external compression of rectum)constipation (external compression of rectum)» not common at early diagnosisnot common at early diagnosis
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.
Cervical Cancer Differential Cervical Cancer Differential DiagnosisDiagnosis
Cervical condyloma or dysplasiaCervical condyloma or dysplasia Uterine cancer extending to cervixUterine cancer extending to cervix Metastatic disease to cervixMetastatic disease to cervix Cervical or endometrial polypCervical or endometrial polyp
Diagnostic ModalitiesDiagnostic Modalities Clinical staging (FIGO)Clinical staging (FIGO) EUA, Cystoscopy, Proctoscopy, appropriate EUA, Cystoscopy, Proctoscopy, appropriate
biopsiesbiopsies CKC only for microscopic diseaseCKC only for microscopic disease Review Bulls Eye and treatment based on stageReview Bulls Eye and treatment based on stage
FIGO StagingFIGO StagingStage 0 Carcinoma in situ, intraepithelial
carcinoma, no stromal invasion
Stage I Carcinoma confined to cervix
Stage II Extends beyond cervix but not pelvicwall
Involves vagina but not lower third
Stage III Extends onto pelvic side wall, lowerthird of vagina
Hydronephrosis
Stage IV Extends beyond pelvis Involves bladder/rectum mucosa
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.
Cervical CancerCervical Cancer: : Improved Mortality & Improved Mortality & Morbidity with Early IdentificationMorbidity with Early Identification
FIGO StageFIGO Stage % Cases% Cases 5-Year Survival5-Year Survival
II 46% 46% 83% 83%
IIII 28% 28% 64% 64%
IIIIII 21% 21% 38% 38%
IVIV 4% 4% 14% 14%
FIGO Annual Report. J Epi & Biostat 1998; 3(1)FIGO Annual Report. J Epi & Biostat 1998; 3(1)
Counseling Patient After Diagnosis Counseling Patient After Diagnosis of Cervical Cancerof Cervical Cancer
Treatment modalities based on stageTreatment modalities based on stage Side effects and toxicities of whole pelvic Side effects and toxicities of whole pelvic
radiation and brachytherapy with chemotherapyradiation and brachytherapy with chemotherapy Sexual side effects of different treatmentSexual side effects of different treatment
– Vaginal shorteningVaginal shortening– Vaginal coaptation with radiation therapyVaginal coaptation with radiation therapy– Radiation necrosisRadiation necrosis– Loss of ovarian functionLoss of ovarian function– Decreased lubricationDecreased lubrication
Follow Up After First Line Follow Up After First Line TherapyTherapy
Every 3 months for the first 2 yearsEvery 3 months for the first 2 years Every 6 months for the following 3 yearsEvery 6 months for the following 3 years Pap smear at each visitPap smear at each visit 85% of patients that recur will recur in 2 years85% of patients that recur will recur in 2 years
ChemotherapyChemotherapy Advanced/recurrent diseaseAdvanced/recurrent disease
– Agents with > 15% response Agents with > 15% response cyclophosphamidecyclophosphamide ifosfamide ifosfamide melphalanmelphalan
cisplatincisplatin carboplatin carboplatin doxorubicindoxorubicin
topotecantopotecan irinotecanirinotecan methotrexatemethotrexate
vincristinevincristine vindesinevindesine vinorelbinevinorelbine
paclitaxel/docetaxelpaclitaxel/docetaxel 5-FU5-FU
– Platinum regimens commonly usedPlatinum regimens commonly used
– Combination regimensCombination regimens
» PreviouslyPreviously Higher ORR but no survival advantage vs single-agentsHigher ORR but no survival advantage vs single-agents
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.
PDQ®. Cervical Cancer Treatment. http://cancer.gov/cancer_information/PDQ. Lastmodified 6/03. Rein DT, et al. Anti-Cancer Drugs 2001;12:787-795.
Advanced Cervical CancerAdvanced Cervical Cancer
AuthorAuthor StageStage nn TreatmentTreatment 3 yr Med 3 yr Med Surv (%)Surv (%)
PFSPFS
P-val (RR)P-val (RR)Whitney et al. 1999Whitney et al. 1999 IIb-IVaIIb-IVa 177177
191191
EB + ICRT + PFEB + ICRT + PF
EB + ICRT + HUEB + ICRT + HU
6767
5757
0.03 (0.79)0.03 (0.79)
Morris et al. 1999Morris et al. 1999 IIb-IVaIIb-IVa 195195
193193
EB + ICRT + PFEB + ICRT + PF
EB + ICRT EB + ICRT
7676
6363
Rose et al. 1999Rose et al. 1999 IIb-IVaIIb-IVa 176176
173173
177177
EB + ICRT + PEB + ICRT + P
EB + ICRT + PFHUEB + ICRT + PFHU
EB + ICRT + HUEB + ICRT + HU
6565
6565
4747
0.001 (0.57)0.001 (0.57)
0.001 (0.55)0.001 (0.55)
EB=external beam, ICRT=intracavitary radiation therapy, P=platinum, F=5-FU, HU=hydroxyurea
Recurrent DiseaseRecurrent DiseaseTreatment in the 80’s and 90’sTreatment in the 80’s and 90’s
Platinum-based therapies most effectivePlatinum-based therapies most effective Cisplatin more active than carboplatinCisplatin more active than carboplatin 3 ways to increase response without prolonging survival3 ways to increase response without prolonging survival
– Increase platinum doseIncrease platinum dose– Add ifosfamide to cisplatinAdd ifosfamide to cisplatin– Add paclitaxel to cisplatinAdd paclitaxel to cisplatin
Thus, single agent cisplatin at 50 mg/m2 became the best Thus, single agent cisplatin at 50 mg/m2 became the best choicechoice
Cisplatin 50 mg/m2Cisplatin 50 mg/m2
Topotecan 0.75 mg/m2/d1-3Topotecan 0.75 mg/m2/d1-3Cisplatin 50 mg/m2 d1Cisplatin 50 mg/m2 d1
293 patients
Cervical cancer
Stage IV
Recurrent
Persistent
RRAANNDDOOMMIIZZEE
Long H, et al SGO 2004
GOG 179 SchemaGOG 179 Schema
Treatment of recurrent disease - Treatment of recurrent disease - 20042004
•1º endpoint : Survival1º endpoint : Survival•2º endpoints: PFS,ORR, QOL, toxicity2º endpoints: PFS,ORR, QOL, toxicity
Results GOG 179Results GOG 179
Topotecan plusCisplatin(N=148)
Cisplatin
(N=145)
Overall ResponseRate 27%* 13%
MedianPFS
(months)4.6† 2.9
Median Survival(months) 9.4‡ 6.5
*P = 0.004; †P = 0.014; ‡P = 0.017PFS = progression-free survival
Long III HJ. SGO 35th Annual Meeting 2004 [Abstract 9]
Chemotherapy for recurrent Chemotherapy for recurrent disease – 2004disease – 2004
GOG 179 – Predictor of responseGOG 179 – Predictor of response Prior cisplatin therapy with RTPrior cisplatin therapy with RT
No prior platinumNo prior platinum Prior platinumPrior platinum
CDDP armCDDP arm 20%20% 8%8%
TOPO/CDDP armTOPO/CDDP arm 39%39% 15%15%
• Platinum-free interval• Performance status• Site of recurrence – higher in non-irradiated sites
Adverse Events GOG 179Adverse Events GOG 179Grade 3/4 Adverse
Events(% patients)
Topotecan +Cisplatin(N=148)
Cisplatin
(N=145)Neutropenia 70% 1%
Anemia 37% 23%
Febrile neutropenia/infection
16% 8%
Nausea/emesis 13%/14% 8%/8%
Metabolic 12% 10%
Long III HJ. SGO 35th Annual Meeting 2004 [Abstract 9]
Summary GOG 179Summary GOG 179 Statistically significant prolonged survival for patients treated Statistically significant prolonged survival for patients treated
with topotecan plus cisplatin vs. cisplatin alonewith topotecan plus cisplatin vs. cisplatin alone QOL scores remained stable during treatment compared to QOL scores remained stable during treatment compared to
baselinebaseline– No statistical differences between treatment groupsNo statistical differences between treatment groups
Adverse events more frequent in the combination armAdverse events more frequent in the combination arm
Long III HJ. SGO 35th Annual Meeting 2004 [Abstract 9]Monk BJ. SGO 35th Annual Meeting 2004 [Abstract 125]
Future DirectionsFuture Directions
GOG 204GOG 204 - Cervical cancer stage IVB, recurrent, - Cervical cancer stage IVB, recurrent, persistent persistent
Potential benefit in resecting Potential benefit in resecting grossly involved nodesgrossly involved nodes
University of Minnesota experienceUniversity of Minnesota experience– 266 patients underwent extraperitoneal staging 266 patients underwent extraperitoneal staging
prior to RTprior to RT
– Extended field RT if PA nodes positiveExtended field RT if PA nodes positive
– Similar survival to microscopic nodes and grossly Similar survival to microscopic nodes and grossly involved but resectable nodes suggesting a involved but resectable nodes suggesting a therapeutic benefit from surgerytherapeutic benefit from surgery
Cosin et al, Cancer 1998; 82:2241
SUMMARYSUMMARY CDDP + WPR + ICRT for advanced stage CDDP + WPR + ICRT for advanced stage
cervical cancercervical cancer Recurrence: ProtocolRecurrence: Protocol CDDP + Topotecan CDDP + Topotecan Role of EPLND?Role of EPLND? Close follow up every 3 months x 2 years then Close follow up every 3 months x 2 years then
every 6 months x 3 years with Paps at each visitevery 6 months x 3 years with Paps at each visit