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Cervical/Vulvar/Vaginal Cancer. Steve Remmenga, M.D. The McClure L Smith Professor of Gynecologic Oncology Division of Gynecologic Oncology Department of OB/GYN University of Nebraska Medical Center. Cervical Cancer. Estimated incidence and mortality in the United States (2007)¹

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Cervical vulvar vaginal cancer l.jpg

Cervical/Vulvar/Vaginal Cancer

Steve Remmenga, M.D.

The McClure L Smith Professor of Gynecologic Oncology

Division of Gynecologic Oncology

Department of OB/GYN

University of Nebraska Medical Center


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Cervical Cancer

  • Estimated incidence and mortality in the United States (2007)¹

    • 11,150 new cases

    • 3,670 deaths

    • 1:168 Lifetime risk

1. American Cancer Society. Cancer Facts & Figures. 2007. Atlanta, GA; 2007


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Cervical Cancer

  • <2% of all cancer deaths in women (twice as deadly in African-American women)

  • 5-year survival: 71%

1. American Cancer Society. Cancer Facts & Figures. 2004. Atlanta, GA; 2005


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Cervical CA

  • International estimates

    • Approximately 570,000 cases expected worldwide each year

    • 275,000 deaths

    • Number one cancer killer of women worldwide


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Pap Smear

  • With the advent of the Pap smear, the incidence of cervical cancer has dramatically declined


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Cervical Cancer


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Cervical CA Etiology

  • Cervical cancer is a sexually transmitted disease.

  • HPV DNA is present in virtually all cases of cervical cancer and precursors.

  • Some strains of HPV have a predilection to the genital tract and transmission is usually through sexual contact (16, 18 High Risk).

  • Little understanding of why small subset of women are affected by HPV.

  • HPV may be latent for many years before inducing cervical neoplasia.


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Cervical CA Risk Factors

  • Early age of intercourse

  • Number of sexual partners

  • Smoking

  • Lower socioeconomic status

  • High-risk male partner

  • Other sexually transmitted diseases

  • Up to 70% of the U.S. population is infected with HPV


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Prevention

  • Educate all providers, men and women regarding HPV and the link to cervical cancer.

  • Adolescents are an especially high-risk group due to behavior and cervical biology.

  • Delay onset of sexual intercourse.

  • Condoms may help prevent sexually transmitted disease.


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Screening Guidelines for the Early Detection of Cervical Cancer, American Cancer Society 2003

  • Screening should begin approximately three years after a women 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.

American Cancer Society. Cancer Facts & Figures. 2004. Atlanta, GA; 2005


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Pap Smear

  • Single Pap false negative rate is 20%.

  • The latency period from dysplasia to cancer of the cervix is variable.

  • 50% of women with cervical cancer have never had a Pap smear.

  • 25% of cases and 41% of deaths occur in women 65 years of age or older.


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Symptoms of Invasion

  • May be silent until advanced disease develops

  • Post-coital bleeding

  • Foul vaginal discharge

  • Abnormal bleeding

  • Pelvic pain

  • Unilateral leg swelling or pain

  • Pelvic mass

  • Gross cervical lesion


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Cell Type

  • Squamous Cell Carcinoma 80-85%

  • AdenoCarcinoma15%

  • Adenosquamous

  • Others


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Staging

  • Clinical Staged Disease

    • Physical Exam

    • Blood Work

    • Cystoscopy

    • Proctoscopy

    • IVP


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Staging Cervical Cancer

  • Stage IConfined to Cervix

    • Ia1<3 mm deep, < 7 mm wide

    • Ia2>3 <5 mm deep,

    • Ib1< 4cm

    • Ib2> 4 cm


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Microscopic Disease

  • Squamous carcinoma of the cervix that has <3mm invasion from the basement membrane

  • The diagnosis must be based on a cone or hysterectomy specimen.

  • No lymph-vascular invasion

  • May be successfully treated with fertility preservation in selected patients

  • These patients should all be referred for consultation.


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Staging

  • Stage II Upper 2/3 vagina or Parametrial involvement

  • IIAUpper 2/3 vagina with no Parametrial

  • IIBParametrial Involvement


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Staging

  • Stage III Lower 1/3 Vagina, Sidewall or ureteral involvement

  • IIIA Lower 1/3 of Vagina

  • IIIB Sidewall or Ureteral Involvement


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Staging

  • Stage IV Bladder, Rectal or Distal Spread

  • IVA Bladder or Rectal Involvement

  • IVB Distal Spread


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Treatment of Early Disease

  • Conization or simple hysterectomy (removal of the uterus) - microinvasive cancer

  • Radical hysterectomy - removal of the uterus with its associated connective tissues, the upper vagina, and pelvic lymph nodes. Ovarian preservation is possible.

  • Chemoradiation therapy


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Advanced Disease

  • Chemoradiation is the mainstay of treatment

    • 4-5 weeks of external radiation

    • Two or more implants (brachytherapy)

    • Concurrent Cisplatin-based chemotherapy significantly improves the chances of survival

    • Radiation treats the primary tumor and adjacent tissues and lymph nodes

    • Chemotherapy acts as a radiation sensitizer and may also control distant disease


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What is Standard Therapy for Stage IB2 - IVA Cervical Carcinoma?

  • External beam pelvic radiation (4,000 to 6,000 cGy)

  • Brachytherapy (8,000 to 8,500 cGy to Point A)

  • I.V. Cisplatin chemotherapy

    • Cisplatin 40mg/m2 (Max dose 70mg) IV q wk during RT (6wks)

GOG 120-NEJM 340(15):1144, 1999


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Symptoms of Recurrence

  • Weight loss, fatigue and anorexia

  • Abnormal vaginal bleeding

  • Pelvic pain

  • Unilateral leg swelling or pain

  • Foul discharge

  • Signs of distant metastases

  • NOTE: must distinguish radiation side effects from recurrent cancer


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Management of Recurrence

  • Chemoradiation may be curative or palliative, especially in women who have not received prior radiation therapy.

  • Isolated soft tissue recurrence may occasionally be treated by resection with long-term survival.


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Recurrent Cervical Cancer: GOG 169

Moore DH et al. J Clin Oncol 22:3113-3119. 2004


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Topotecan in Recurrent Cervical Cancer – Overview of Phase II Studies

ReferenceRegimen Evaluable Prior CTORRMedian OS

(n)

Single Agent (dailyx5):

Bookman1.5mg/m2/d4085%13%6.6 mo

Muderspach1.5mg/m2/d43None19%6.4 mo

Noda1.2mg/m2/d2282%18%NR

Combinations:

FioricaTopo + cisplatin32None28%10 mo

TierstenTopo + paclitaxel1333%54%8.6 mo

  • Bookman MA et al. Gynecol Oncol 2000; 77: 446-449. . Muderspach LI, et al., Gynecologic Oncology 2001;81: 213-215. Noda K, et al. Proc Am Soc Clin Oncol 1996;15:280 [Abstract 754]. Fiorica J, et al. Gynecol Oncol 2002;85:89-94. Tiersten AD, et al. Gyn Oncol 2004;92:635-638


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Recurrent Cervical Cancer:GOG 179

Regimen I

Cisplatin 50 mg/m²

Cervix Cancer

Stage IV B or Regimen II

Recurrent Topotecan 0.75 g/m²/d1-3 Cisplatin 50 mg/m² d 1

R

A

N

D

O

M

I

Z

E

Long HJ, et al. Gynecol Oncol 2004; 92:397(SGO)


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SurvivalBy Treatment Group

1.0

Rx Group Alive Dead Total Cisplatin 17 129 146 Cis+Topo 29 118 147

0.9

0.8

0.7

Proportion Surviving

0.6

0.5

0.4

0.3

0.2

0.0

0.1

Months on Study

0

12

24

36

GOG 179


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GOG Protocol 179

Response rates based on previous

cisplatin therapy (with RT)

No Prior PlatinumPrior Platinum

CDDP arm20%8%

CDDP/Topo arm39%15%


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Comparing GOG 169 to 179

  • Studies from two different eras

    • 169 before Chemo-RT

    • 179 during transition to Chemo-RT

  • Both showed no QoL disturbance with more aggressive regimens

  • In the new era chemo/RT

    • Response rate to CDDP less

    • Survival after single agent CDDP less

    • Survival advantage when add Topotecan

    • Survival Advantage when add Paclitaxel?


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Survival


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Vulvar Cancer

  • 3870 new cases 2005

  • 870 deaths

  • Approximately 5% of Gynecologic Cancers

American Cancer Society. Cancer Facts & Figures. 2004. Atlanta, GA; 2005


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Vulvar Cancer

  • 85% Squamous Cell Carcinoma

  • 5% Melanoma

  • 2% Sarcoma

  • 8% Others


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Vulvar Cancer

  • Biphasic Distribution

  • Average Age 70 years

  • 20% in patients UNDER 40 and appears to be increasing


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Vulvar Cancer Etiology

  • Chronic inflammatory conditions and vulvar dystrophies are implicated in older patients

  • Syphilis and lymphogranuloma venereum and granuloma inguinal

  • HPV in younger patients

  • Tobacco


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Vulvar Cancer

  • Paget’s Disease of Vulva

    • 10% will be invasive

    • 4-8% association with underlying Adenocarcinoma of the vulva


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Symptoms

  • Most patients are treated for “other” conditions

  • 12 month or greater time from symptoms to diagnosis


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Symptoms

  • Pruritus

  • Mass

  • Pain

  • Bleeding

  • Ulceration

  • Dysuria

  • Discharge

  • Groin Mass


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Symptoms

  • May look like:

    • Raised

    • Erythematous

    • Ulcerated

    • Condylomatous

    • Nodular


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Vulvar Cancer

  • IF IT LOOKS ABNORMAL ON THE VULVA

  • BIOPSY!

  • BIOPSY!

  • BIOPSY!


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Tumor Spread

  • Very Specific nodal spread pattern

  • Direct Spread

  • Hematogenous


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Staging

  • Based on TNM Surgical Staging

    • Tumor size

    • Node Status

    • Metastatic Disease


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Staging

  • Stage I T1 N0 M0

    • Tumor ≤ 2cm

    • IA≤1 mm depth of Invasion

    • IB1 mm or more depth of invasion


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Staging

  • Stage II T2 N0 M0

    • Tumor >2 cm

    • Confined to Vulva or Perineum


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Staging

  • Stage III

    • T3 N0 M0

    • T3 N1 M0

    • T1 N1 M0

    • T2 N1 M0

      • Tumor any size involving lower urethra, vagina, anus OR unilateral positive nodes


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Staging

  • Stage IVA

    • T1 N2 M0

    • T2 N2 M0

    • T3 N2 M0

    • T4 N any M0

      • Tumor invading upper urethra, bladder, rectum, pelvic bone or bilateral nodes


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Staging

  • Stage IVB

    • Any T Any N M1

      • Any distal mets including pelvic nodes


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Treatment

  • Primarily Surgical

    • Wide Local Excision

    • Radical Excision

    • Radical Vulvectomy with Inguinal Node Dissection

      • Unilateral

      • Bilateral

      • Possible Node Mapping, still investigational


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Treatment

  • Local advanced may be treated with Radiation plus Chemosensitizer

  • Positive Nodal Status

    • 1 or 2 microscopic nodes < 5mm can be observed

    • 3 or more or >5mm post op radiation


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Treatment

  • Special Tumor

    • Verrucous Carcinoma

      • Indolent tumor with local disease, rare mets UNLESS given radiation, becomes Highly malignant and aggressive

      • Excision or Vulvectomy ONLY


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Vulva 5 year survival

  • Stage I90

  • Stage II77

  • Stage III51

  • Stage IV18

Hacker and Berek, Practical Gynecologic Oncology 4th Edition, 2005


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Recurrence

  • Local Recurrence in Vulva

    • Reexcision or radiation and good prognosis if not in original site of tumor

    • Poor prognosis if in original site


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Recurrence

  • Distal or Metastatic

    • Very poor prognosis, active agents include Cisplatin, mitomycin C, bleomycin, methotrexate and cyclophosphamide


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Melanoma

  • 5% of Vulvar Cancers

  • Not UV related

  • Commonly periclitoral or labia minora


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Melanoma

  • Microstaged by one of 3 criteria

    • Clark’s Level

    • Chung’s Level

    • Breslow


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Melanoma Treatment

  • Wide local or Wide Radical excision with bilateral groin dissection

  • Interferon Alpha 2-b


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Vaginal Carcinoma

  • 2140 new cases projected 2005

  • 810 deaths projected 2005

  • Represents 2-3% of Pelvic Cancers

American Cancer Society. Cancer Facts & Figures. 2004. Atlanta, GA; 2005


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Vaginal Cancer

  • 84% of cancers in vaginal area are secondary

    • Cervical

    • Uterine

    • Colorectal

    • Ovary

    • Vagina

Fu YS, Pathology of the Uterine Cervix, Vagina and Vulva, 2nd ed. 2002


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Vaginal Carcinoma

  • Squamous Cell80-85%

  • Clear Cell10%

  • Sarcoma3-4%

  • Melanoma2-3%


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Clear Cell Carcinoma

  • Associated with DES Exposure In Utero

    • DES used as anti abortifcant from 1949-1971

    • 500+ cases confirmed by DES Registry

    • Usually occurred late teens


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Vaginal Cancer Etiology

  • Mimics Cervical Carcinoma

    • HPV 16 and 18


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Staging

  • Stage IConfined to Vaginal Wall

  • Stage IISubvaginal tissue but not to pelvic sidewall

  • Stage IIIExtended to pelvic sidewall

  • Stage IVABowel or Bladder

  • Stage IVBDistant mets


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Treatment

  • Surgery with Radical Hysterectomy and pelvic lymph dissection in selected stage I tumors high in Vagina

  • All others treated with radiation with chemosensitization


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5 year Survival

  • Stage I70%

  • Stage II51%

  • Stage III33%

  • Stage IV17%


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