Management of the Abnormal Pap Smear, Cervical Dysplasia, and Cervical Cancer Todd D. Tillmanns MD...

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Management of the Abnormal Management of the Abnormal Pap Smear, Cervical Pap Smear, Cervical Dysplasia, and Cervical Dysplasia, and Cervical Cancer Cancer Todd D. Tillmanns MD Todd D. Tillmanns MD Assistant Professor Assistant Professor Department of Obstetrics & Gynecology Department of Obstetrics & Gynecology Division of Gynecologic Oncology Division of Gynecologic Oncology University of Tennessee and West Clinic University of Tennessee and West Clinic E-mail: [email protected] E-mail: [email protected]

Transcript of Management of the Abnormal Pap Smear, Cervical Dysplasia, and Cervical Cancer Todd D. Tillmanns MD...

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

Relative Risk of Cervical CancerRelative Risk of Cervical Cancerby HPV Typeby HPV Type

Electron Micrograph of HPVElectron Micrograph of HPV

Cervical Histology ShowingCervical Histology ShowingHPV & KoilocytesHPV & Koilocytes

Cervical Cytology ShowingCervical Cytology ShowingHPV & KoilocytesHPV & Koilocytes

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

Transformation ZoneTransformation Zone

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

Cervical ConizationCervical Conization

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]

Progression-free survivalProgression-free survival

Overall survivalOverall survival

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

THANK YOU !THANK YOU !Questions / Comments ?Questions / Comments ?