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]

CREOG OBJECTIVES Pre-invasive cervical disease: 1. describe the epidemiology of cervical dysplasia 2. elicit a pertinent history in a woman with an abnl pap 3. interpret pap test reports using bethesda classification system and determine appropriate follow-up. 4.perform and interpret the results of diagnostic procedures for cerivical dysplasia 5. treat cervical dysplasia with modalities, such as: cryosurgery, laser ablation, 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 for cervical dysplasia 8. describe the structural changes in the cervix that are characteristic of in-utero des exposure Invasive cervical cancer: 1. 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 invasive cervical ca 5. describe the figo staging of cervical ca--maybe throw in your bulls-eye here. 6. in consultation with a gyn onc, counsel the patient about the evaluation and treatment (indications, complications) of cervical ca 7. describe the prognosis 8. describe the impact of treatment of cervical ca on sexual function and manage/refer the patient appropriately 9. provide psychosocial support and long-term follow up for patients with cervical ca.

Pre-invasive cervical disease:

1. describe the epidemiology of cervical dysplasia

2. elicit a pertinent history in a woman with an abnl pap

3. interpret pap test reports using bethesda classification system and

determine appropriate follow-up.

4.perform and interpret the results of diagnostic procedures for cerivical

dysplasia

5. treat cervical dysplasia with modalities, such as: cryosurgery, laser

ablation, 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

for cervical dysplasia

8. describe the structural changes in the cervix that are characteristic of

in-utero des exposure

Invasive cervical cancer:

1. 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 invasive cervical ca 5. describe the figo staging of cervical ca--maybe throw in your bulls-eye

here.

6. in consultation with a gyn onc, counsel the patient about the evaluation

and treatment (indications, complications) of cervical ca

7. describe the prognosis

8. describe the impact of treatment of cervical ca on sexual function and

manage/refer the patient appropriately

9. provide psychosocial support and long-term follow up for patients with

cervical ca.

Natural History of Dysplasia Human Papilloma Virus is etiologic in the development of invasive cervical cancer. 99% of cervical cancers worldwide are HPV positive 1 96% of HSIL is HPV positive 2 30% of HPV 16 CIN III will progress to cancer 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 1 Bosch FX, et al. J Natl Cancer Inst 1995; 87:796-802 2 Matsukura M, et al. Int J Cancer 1995; 61:13-22

Human Papilloma Virus is etiologic in the development of invasive cervical cancer.

99% of cervical cancers worldwide are HPV positive 1

96% of HSIL is HPV positive 2

30% of HPV 16 CIN III will progress to cancer

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

1 Bosch FX, et al. J Natl Cancer Inst 1995; 87:796-802

2 Matsukura M, et al. Int J Cancer 1995; 61:13-22

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) Introduced in 1939 Substantially unchanged in 50 years 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 No randomized controlled trials have evaluated efficacy Herrero R. Monogr Natl Cancer Inst 1996; 21:1-6

Introduced in 1939

Substantially unchanged in 50 years

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

No randomized controlled trials have evaluated efficacy

Herrero R. Monogr Natl Cancer Inst 1996; 21:1-6

Conventional Cervical Cytology (Papanicolaou Smear) Good screening test Inexpensive High sensitivity & specificity Easy to perform, noninvasive, nonmorbid Reproducible

Good screening test

Inexpensive

High sensitivity & specificity

Easy to perform, noninvasive, nonmorbid

Reproducible

Screening Guidelines Early Detection of Cervical Cancer American Cancer Society 2003 Screening should begin approximately three years after a woman begins having vaginal intercourse, but no later than 21 years of age Screening should be done every year with regular Pap tests or every two years using liquid-based tests 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 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 Screening after a total hysterectomy (with removal of the cervix) is not necessary unless the surgery was done as a treatment for cervical cancer Wright et al: ASCCP Cytol

Screening should begin approximately three years after a woman begins having vaginal intercourse, but no later than 21 years of age

Screening should be done every year with regular Pap tests or every two years using liquid-based tests

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

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

Screening after a total hysterectomy (with removal of the cervix) is not necessary unless the surgery was done as a treatment for cervical cancer

Atypical Squamous Cells ASC: Atypical Squamous Cells of Undetermined Significance (ASC-US) Atypical Squamous Cells cannot exclude HSIL (ASC- ASC is poorly reproducible ASC has a 5-17% chance of having CIN II-III CIN III is diagnosed in 24-94% of those with ASC-H Risk of invasive caner with ASC is low (0.1-0.2 %) Wright et al: ASCCP Cytol Guidelines JAMA 2002;287:2120-2129

ASC:

Atypical Squamous Cells of Undetermined Significance (ASC-US)

Atypical Squamous Cells cannot exclude HSIL (ASC-

ASC is poorly reproducible

ASC has a 5-17% chance of having CIN II-III

CIN III is diagnosed in 24-94% of those with ASC-H

Risk of invasive caner

with ASC is low (0.1-0.2 %)

Managing ASC Sensitivity of a single repeat test for detecting CIN II-III after ASC is low (0.67-0.85) Colposcopy; mean sensitivity for distinguishing normal from abnormal was 0.96 and weighted specificity was 0.48 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 Between 31% and 60% of all women with ASC will have high risk HPV, but this decreases with age Reflex HPV: 40-60% of women will be spared colposcopy and (-) testing assures women that they do not have a lesion Wright et al: ASCCP Cytol Guidelines JAMA 2002;287:2120-2129

Sensitivity of a single repeat test for detecting CIN II-III after ASC is low (0.67-0.85)

Colposcopy; mean sensitivity for distinguishing normal from abnormal was 0.96 and weighted specificity was 0.48

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

Between 31% and 60% of all women with ASC will have high risk HPV, but this decreases with age

Reflex HPV: 40-60% of women will be spared colposcopy and (-) testing assures women that they do not have a lesion

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, "reflex" 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.

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

ASC Special Circumstances Postmenopausal Women Using intravaginal estrogen followed one week later with Pap  If (-) then repeat 6 months later Immunosuppressed Women Referral colposcopy is recommended Pregnant Women Same as non-pregnant Wright et al: ASCCP Cytol Guidelines JAMA 2002;287:2120-2129

Postmenopausal Women

Using intravaginal estrogen followed one week later with Pap  If (-) then repeat 6 months later

Immunosuppressed Women

Referral colposcopy is recommended

Pregnant Women

Same as non-pregnant

Atypical Glandular Cells and AIS AGC : Atypical Glandular Cells (endocervical, endometrial, or glandular cells not otherwise specified) AGC: Favor Neoplasia AIS: Adenocarcinoma in situ Wright et al: ASCCP Cytol Guidelines JAMA 2002;287:2120-2129

AGC : Atypical Glandular Cells (endocervical, endometrial, or glandular cells not otherwise specified)

AGC: Favor Neoplasia

AIS: Adenocarcinoma in situ

AGC Category 9-54% of women with AGC have biopsy confirmed CIN 0-8% have AIS 1-9% have invasive cancer 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” Wright et al: ASCCP Cytol Guidelines JAMA 2002;287:2120-2129

9-54% of women with AGC have biopsy confirmed CIN

0-8% have AIS

1-9% have invasive cancer

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”

AIS Category The cytologic interpretation of AIS is associated with a very high risk of women having either AIS (48-69%) or invasive cervical adenocarcinoma (38%). Wright et al: ASCCP Cytol Guidelines JAMA 2002;287:2120-2129

The cytologic interpretation of AIS is associated with a very high risk of women having either AIS (48-69%) or invasive cervical adenocarcinoma (38%).

Managing AGC and AIS Screening cervical cytology has a sensitivity of only 50%-72% for identifying glandular neoplasia CIN is the most common neoplasia identified in women with the cytologic result of AGC Repeat cervical cytology is less sensitive than colposcopy for identifying CIN II-III This supports using colposcopy There is a higher risk of CIN II-III, and AIS in premenopausal women compared to menopausal women ½ of the women with AIS have a coexisting squamous lesion Wright et al: ASCCP Cytol Guidelines JAMA 2002;287:2120-2129

Screening cervical cytology has a sensitivity of only 50%-72% for identifying glandular neoplasia

CIN is the most common neoplasia identified in women with the cytologic result of AGC

Repeat cervical cytology is less sensitive than colposcopy for identifying CIN II-III

This supports using colposcopy

There is a higher risk of CIN II-III, and AIS in premenopausal women compared to menopausal women

½ of the women with AIS have a coexisting squamous lesion

AGC and AIS Management 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 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 There is insufficient data to allow an assessment of HPV DNA testing in the management of women with AGC or AIS Wright et al: ASCCP Cytol Guidelines JAMA 2002;287:2120-2129

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

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

There is insufficient data to allow an assessment of HPV DNA testing in the management of women with AGC or AIS

AGC favor dysplasia AGC favor dysplasia or AIS with (-) colpo should receive a diagnostic excisional procedure  CKC If no neoplasia identified at initial workup, then repeat cytology q 4-6 months until normal x 4 Acceptable options include referral Wright et al: ASCCP Cytol Guidelines JAMA 2002;287:2120-2129

AGC favor dysplasia or AIS with (-) colpo should receive a diagnostic excisional procedure  CKC

If no neoplasia identified at initial workup, then repeat cytology q 4-6 months until normal x 4

Acceptable options include referral

LSIL Median rate of LSIL in the USA is 1.6%, but high risk populations have reported LSIL rates as high as 7.7%. 15-30% of women with LSIL on cervical cytology will have CIN II-III identified on subsequent cervical biopsy. Wright et al: ASCCP Cytol Guidelines JAMA 2002;287:2120-2129

Median rate of LSIL in the USA is 1.6%, but high risk populations have reported LSIL rates as high as 7.7%.

15-30% of women with LSIL on cervical cytology will have CIN II-III identified on subsequent cervical biopsy.

Managing LSIL 53-76% likelihood of abnormal Pap on follow up cytology 83% of women referred for the evaluation of an LSIL cytology result tested positive for high risk HPV types. HPV DNA and LEEP do not appear to be useful for the initial management of women with LSIL Colposcopy with directed biopsies is the initial best option. Wright et al: ASCCP Cytol Guidelines JAMA 2002;287:2120-2129

53-76% likelihood of abnormal Pap on follow up cytology

83% of women referred for the evaluation of an LSIL cytology result tested positive for high risk HPV types.

HPV DNA and LEEP do not appear to be useful for the initial management of women with LSIL

Colposcopy with directed biopsies is the initial best option.

Managing LSIL with Satisfactory and Unsatisfactory Colposcopy Satisfactory Colposcopy ECC is an acceptable option with follow up in 6 months if normal Unsatisfactory Colposcopy: ECC in non pregnant with follow up in 6 months if normal –vs- LEEP Cone Pregnancy Colposcopy with biopsy only if high grade lesion or cancer is suspected Adolescents Acceptable option is follow up in 6 months without colposcopy Wright et al: ASCCP Cytol Guidelines JAMA 2002;287:2120-2129

Satisfactory Colposcopy

ECC is an acceptable option with follow up in 6 months if normal

Unsatisfactory Colposcopy:

ECC in non pregnant with follow up in 6 months if normal –vs- LEEP Cone

Pregnancy

Colposcopy with biopsy only if high grade lesion or cancer is suspected

Adolescents

Acceptable option is follow up in 6 months without colposcopy

Transformation Zone

Cryotherapy Nitrous oxide or CO 2 refrigerant Lesion covered by probe, lubricant Freeze 4-6 mm beyond probe Freeze - Thaw - Freeze Technique Failure in 7% of 422 CIN III patients 1 1(Bryson. Am J Ob Gyn 1985; 151:201-6)

Nitrous oxide or CO 2 refrigerant

Lesion covered by probe, lubricant

Freeze 4-6 mm beyond probe

Freeze - Thaw - Freeze Technique

Failure in 7% of 422 CIN III patients 1

LEEP Transformation zone excised to depth of 7-8 mm Provides tissue diagnosis Easy to perform Well tolerated by patients Can be performed in outpatient setting Success rates 90-96%

Transformation zone excised to depth of 7-8 mm

Provides tissue diagnosis

Easy to perform

Well tolerated by patients

Can be performed in outpatient setting

Success rates 90-96%

Cone Biopsy Indications (+) ECC Cytologic abnormality not consistent w/ tissue diagnosis Unsatisfactory colposcopy Microinvasion on biopsy, r/o invasive cancer Adenocarcinoma in situ or invasive adenocarcinoma

Indications

(+) ECC

Cytologic abnormality not consistent w/ tissue diagnosis

Unsatisfactory colposcopy

Microinvasion on biopsy, r/o invasive cancer

Adenocarcinoma in situ or invasive adenocarcinoma

Cone Biopsy 2 Methods: Cold Knife Cone Biopsy LEEP Cone Biopsy or Laser Cone Biopsy Equivalent results for most indications Exceptions include: Microinvasion on biopsy, r/o invasive cancer Adenocarcinoma in situ or invasive adenocarcinoma

2 Methods:

Cold Knife Cone Biopsy

LEEP Cone Biopsy or Laser Cone Biopsy

Equivalent results for most indications

Exceptions include:

Microinvasion on biopsy, r/o invasive cancer

Adenocarcinoma in situ or invasive adenocarcinoma

Cervical Conization

In Utero Exposure to DES In women exposed to DES in utero, the normal migration of the squamous epithelium is prematurely halted. The original SCJ is often located in the vagina rather than on the exocervix. In these women the entire cervical portio can be covered with endocervical columnar epithelium. Kurman, RJ. Blaustein’s Pathology of the Female Genital Tract 5 th edition. 2002 Springer-Verlag. New York. pp.216

In women exposed to DES in utero, the normal migration of the squamous epithelium is prematurely halted.

The original SCJ is often located in the vagina rather than on the exocervix.

In these women the entire cervical portio can be covered with endocervical columnar epithelium.

Cervical Cancer 2nd most important cancer in women worldwide Most important cancer in developing countries 1 Approximately 10,370 new cases/yr in U.S. 2 Approximately 3,710 deaths/yr in U.S. 2 1991-1995 Tennessee ranked 7 th in mortality from Cervical Cancer Overall 5-year survival is approximately 70% 2 1 Int J Cancer 1993; 54:594-606 2 Cancer Facts and Figures -2005, ACS 2005

2nd most important cancer in women worldwide

Most important cancer in developing countries 1

Approximately 10,370 new cases/yr in U.S. 2 Approximately 3,710 deaths/yr in U.S. 2

1991-1995 Tennessee ranked 7 th in mortality from Cervical Cancer

Overall 5-year survival is approximately 70% 2

1 Int J Cancer 1993; 54:594-606

2 Cancer Facts and Figures -2005, ACS 2005

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)

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

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

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

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

Cervical Cancer: Improved Mortality & Morbidity with Early Identification FIGO Stage % Cases 5-Year Survival I 46% 83% II 28% 64% III 21% 38% IV 4% 14% FIGO Annual Report. J Epi & Biostat 1998; 3(1)

FIGO Stage % Cases 5-Year Survival

I 46% 83%

II 28% 64%

III 21% 38%

IV 4% 14%

FIGO Annual Report. J Epi & Biostat 1998; 3(1)

Risk Factors HPV infection (plus cofactors) 1 Subtypes 16, 18, 31, 35, 39 Sexual behavior 1-3 Sex at young age; multiple partners High parity; race; low socioeconomic status History of smoking 1-3 Oral contraceptives (?) 3 controversial 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.

HPV infection (plus cofactors) 1

Subtypes 16, 18, 31, 35, 39

Sexual behavior 1-3

Sex at young age; multiple partners

High parity; race; low socioeconomic status

History of smoking 1-3

Oral contraceptives (?) 3

controversial

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 Symptoms Pre-invasive disease no symptoms Invasive cervical cancer abnormal vaginal bleeding pelvic pain (locoregional disease) flank pain (hydronephrosis) triad (siatic pain, leg edema, hydronephrosis) Extensive pelvic wall involvement hematuria, incontinence (bladder involvement) constipation (external compression of rectum) not 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 .

Pre-invasive disease

no symptoms

Invasive cervical cancer

abnormal vaginal bleeding

pelvic pain (locoregional disease)

flank pain (hydronephrosis)

triad (siatic pain, leg edema, hydronephrosis)

Extensive pelvic wall involvement

hematuria, incontinence (bladder involvement)

constipation (external compression of rectum)

not 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 Diagnosis Cervical condyloma or dysplasia Uterine cancer extending to cervix Metastatic disease to cervix Cervical or endometrial polyp

Cervical condyloma or dysplasia

Uterine cancer extending to cervix

Metastatic disease to cervix

Cervical or endometrial polyp

Diagnostic Modalities Clinical staging (FIGO) EUA, Cystoscopy, Proctoscopy, appropriate biopsies CKC only for microscopic disease Review Bulls Eye and treatment based on stage

Clinical staging (FIGO)

EUA, Cystoscopy, Proctoscopy, appropriate biopsies

CKC only for microscopic disease

Review Bulls Eye and treatment based on stage

FIGO Staging 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.

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 : Improved Mortality & Morbidity with Early Identification FIGO Stage % Cases 5-Year Survival I 46% 83% II 28% 64% III 21% 38% IV 4% 14% FIGO Annual Report. J Epi & Biostat 1998; 3(1)

FIGO Stage % Cases 5-Year Survival

I 46% 83%

II 28% 64%

III 21% 38%

IV 4% 14%

Counseling Patient After Diagnosis of Cervical Cancer Treatment modalities based on stage Side effects and toxicities of whole pelvic radiation and brachytherapy with chemotherapy Sexual side effects of different treatment Vaginal shortening Vaginal coaptation with radiation therapy Radiation necrosis Loss of ovarian function Decreased lubrication

Treatment modalities based on stage

Side effects and toxicities of whole pelvic radiation and brachytherapy with chemotherapy

Sexual side effects of different treatment

Vaginal shortening

Vaginal coaptation with radiation therapy

Radiation necrosis

Loss of ovarian function

Decreased lubrication

Follow Up After First Line Therapy Every 3 months for the first 2 years Every 6 months for the following 3 years Pap smear at each visit 85% of patients that recur will recur in 2 years

Every 3 months for the first 2 years

Every 6 months for the following 3 years

Pap smear at each visit

85% of patients that recur will recur in 2 years

Chemotherapy Advanced/recurrent disease Agents with > 15% response cyclophosphamide ifosfamide melphalan cisplatin carboplatin doxorubicin topotecan irinotecan methotrexate vincristine vindesine vinorelbine paclitaxel/docetaxel 5-FU Platinum regimens commonly used Combination regimens Previously Higher 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/recurrent disease

Agents with > 15% response

cyclophosphamide ifosfamide melphalan

cisplatin carboplatin doxorubicin

topotecan irinotecan methotrexate

vincristine vindesine vinorelbine

paclitaxel/docetaxel 5-FU

Platinum regimens commonly used

Combination regimens

Previously

Higher 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 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

Recurrent Disease Treatment in the 80’s and 90’s Platinum-based therapies most effective Cisplatin more active than carboplatin 3 ways to increase response without prolonging survival Increase platinum dose Add ifosfamide to cisplatin Add paclitaxel to cisplatin Thus, single agent cisplatin at 50 mg/m2 became the best choice

Platinum-based therapies most effective

Cisplatin more active than carboplatin

3 ways to increase response without prolonging survival

Increase platinum dose

Add ifosfamide to cisplatin

Add paclitaxel to cisplatin

Thus, single agent cisplatin at 50 mg/m2 became the best choice

Cisplatin 50 mg/m2 Topotecan 0.75 mg/m2/d1-3 Cisplatin 50 mg/m2 d1 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 1º endpoint : Survival 2º endpoints: PFS,ORR, QOL, toxicity

Cisplatin 50 mg/m2

Topotecan 0.75 mg/m2/d1-3

Cisplatin 50 mg/m2 d1

1º endpoint : Survival

2º endpoints: PFS,ORR, QOL, toxicity

Results GOG 179 Long III HJ. SGO 35 th Annual Meeting 2004 [Abstract 9]

Progression-free survival

Overall survival

Chemotherapy for recurrent disease – 2004 GOG 179 – Predictor of response Prior cisplatin therapy with RT Platinum-free interval Performance status Site of recurrence – higher in non-irradiated sites 15% 39% TOPO/CDDP arm 8% 20% CDDP arm Prior platinum No prior platinum

GOG 179 – Predictor of response

Prior cisplatin therapy with RT

Platinum-free interval

Performance status

Site of recurrence – higher in non-irradiated sites

Adverse Events GOG 179 Long III HJ. SGO 35 th Annual Meeting 2004 [Abstract 9]

Summary GOG 179 Statistically significant prolonged survival for patients treated with topotecan plus cisplatin vs. cisplatin alone QOL scores remained stable during treatment compared to baseline No statistical differences between treatment groups Adverse events more frequent in the combination arm Long III HJ. SGO 35 th Annual Meeting 2004 [Abstract 9] Monk BJ. SGO 35 th Annual Meeting 2004 [Abstract 125]

Statistically significant prolonged survival for patients treated with topotecan plus cisplatin vs. cisplatin alone

QOL scores remained stable during treatment compared to baseline

No statistical differences between treatment groups

Adverse events more frequent in the combination arm

Future Directions GOG 204 - Cervical cancer stage IVB, recurrent, persistent

GOG 204 - Cervical cancer stage IVB, recurrent, persistent

Potential benefit in resecting grossly involved nodes University of Minnesota experience 266 patients underwent extraperitoneal staging prior to RT Extended field RT if PA nodes positive Similar survival to microscopic nodes and grossly involved but resectable nodes suggesting a therapeutic benefit from surgery Cosin et al, Cancer 1998; 82:2241

University of Minnesota experience

266 patients underwent extraperitoneal staging prior to RT

Extended field RT if PA nodes positive

Similar survival to microscopic nodes and grossly involved but resectable nodes suggesting a therapeutic benefit from surgery

SUMMARY CDDP + WPR + ICRT for advanced stage cervical cancer Recurrence: Protocol  CDDP + Topotecan Role of EPLND? Close follow up every 3 months x 2 years then every 6 months x 3 years with Paps at each visit

CDDP + WPR + ICRT for advanced stage cervical cancer

Recurrence: Protocol  CDDP + Topotecan

Role of EPLND?

Close follow up every 3 months x 2 years then every 6 months x 3 years with Paps at each visit

THANK YOU ! Questions / Comments ?