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 11,150 new cases 3,670 deaths 1:168 Lifetime risk 1. American Cancer Society. Cancer Facts & Figures. 2007. Atlanta, GA; 2007

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

Cervical CA International estimates Approximately 570,000 cases expected worldwide each year 275,000 deaths Number one cancer killer of women worldwide

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

Cervical Cancer

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.

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

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.

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. The American Cancer Society cervical cancer screening guidelines state that women should begin screening approximately three years after she 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 tests in a row may get screened every 2-3 years. Women 70 and older who have had three or more consecutive normal Pap tests in the last 10 years may choose to stop cervical cancer screening. American Cancer Society. Cancer Facts & Figures. 2004. Atlanta, GA; 2005

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.

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

Cell Type Squamous Cell Carcinoma 80-85% AdenoCarcinoma 15% Adenosquamous Others

Staging Clinical Staged Disease Physical Exam Blood Work Cystoscopy Proctoscopy IVP

Staging Cervical Cancer Stage I Confined to Cervix Ia1 <3 mm deep, < 7 mm wide Ia2 >3 <5 mm deep, Ib1 < 4cm Ib2 > 4 cm

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.

Staging Stage II Upper 2/3 vagina or Parametrial involvement IIA Upper 2/3 vagina with no Parametrial IIB Parametrial Involvement

Staging Stage III Lower 1/3 Vagina, Sidewall or ureteral involvement IIIA Lower 1/3 of Vagina IIIB Sidewall or Ureteral Involvement

Staging Stage IV Bladder, Rectal or Distal Spread IVA Bladder or Rectal Involvement IVB Distal Spread

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

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

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

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

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.

Recurrent Cervical Cancer: GOG 169 Moore DH et al. J Clin Oncol 22:3113-3119. 2004

Topotecan in Recurrent Cervical Cancer – Overview of Phase II Studies Reference Regimen Evaluable Prior CT ORR Median OS (n) Single Agent (dailyx5): Bookman 1.5mg/m2/d 40 85% 13% 6.6 mo Muderspach 1.5mg/m2/d 43 None 19% 6.4 mo Noda 1.2mg/m2/d 22 82% 18% NR Combinations: Fiorica Topo + cisplatin 32 None 28% 10 mo Tiersten Topo + paclitaxel 13 33% 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

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)

Survival By Treatment Group GOG 179 Rx Group Alive Dead Total Cisplatin 17 129 146 Cis+Topo 29 118 147 Survival By Treatment Group Proportion Surviving Months on Study 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 24 12 36

GOG Protocol 179 Response rates based on previous cisplatin therapy (with RT) No Prior Platinum Prior Platinum CDDP arm 20% 8% CDDP/Topo arm 39% 15%

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?

Survival Stage Rad Hyst Chemo/XRT Ib 85-95% 85-90% IIb N/A 70-80% IIIb 55-65%

Vulvar Cancer 3870 new cases 2005 870 deaths Approximately 5% of Gynecologic Cancers American Cancer Society. Cancer Facts & Figures. 2004. Atlanta, GA; 2005

Vulvar Cancer 85% Squamous Cell Carcinoma 5% Melanoma 2% Sarcoma 8% Others

Vulvar Cancer Biphasic Distribution Average Age 70 years 20% in patients UNDER 40 and appears to be increasing

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

Vulvar Cancer Paget’s Disease of Vulva 10% will be invasive 4-8% association with underlying Adenocarcinoma of the vulva

Symptoms Most patients are treated for “other” conditions 12 month or greater time from symptoms to diagnosis

Symptoms Pruritus Mass Pain Bleeding Ulceration Dysuria Discharge Groin Mass

Symptoms May look like: Raised Erythematous Ulcerated Condylomatous Nodular

Vulvar Cancer IF IT LOOKS ABNORMAL ON THE VULVA BIOPSY!

Tumor Spread Very Specific nodal spread pattern Direct Spread Hematogenous

Staging Based on TNM Surgical Staging Tumor size Node Status Metastatic Disease

Staging Stage I T1 N0 M0 Tumor ≤ 2cm IA ≤1 mm depth of Invasion IB 1 mm or more depth of invasion

Staging Stage II T2 N0 M0 Tumor >2 cm Confined to Vulva or Perineum

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

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

Staging Stage IVB Any T Any N M1 Any distal mets including pelvic nodes

Treatment Primarily Surgical Wide Local Excision Radical Excision Radical Vulvectomy with Inguinal Node Dissection Unilateral Bilateral Possible Node Mapping, still investigational

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

Treatment Special Tumor Verrucous Carcinoma Indolent tumor with local disease, rare mets UNLESS given radiation, becomes Highly malignant and aggressive Excision or Vulvectomy ONLY

Vulva 5 year survival Stage I 90 Stage II 77 Stage III 51 Stage IV 18 Hacker and Berek, Practical Gynecologic Oncology 4th Edition, 2005

Recurrence Local Recurrence in Vulva Reexcision or radiation and good prognosis if not in original site of tumor Poor prognosis if in original site

Recurrence Distal or Metastatic Very poor prognosis, active agents include Cisplatin, mitomycin C, bleomycin, methotrexate and cyclophosphamide

Melanoma 5% of Vulvar Cancers Not UV related Commonly periclitoral or labia minora

Melanoma Microstaged by one of 3 criteria Clark’s Level Chung’s Level Breslow

Melanoma Treatment Wide local or Wide Radical excision with bilateral groin dissection Interferon Alpha 2-b

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

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

Vaginal Carcinoma Squamous Cell 80-85% Clear Cell 10% Sarcoma 3-4% Melanoma 2-3%

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

Vaginal Cancer Etiology Mimics Cervical Carcinoma HPV 16 and 18

Staging Stage I Confined to Vaginal Wall Stage II Subvaginal tissue but not to pelvic sidewall Stage III Extended to pelvic sidewall Stage IVA Bowel or Bladder Stage IVB Distant mets

Treatment Surgery with Radical Hysterectomy and pelvic lymph dissection in selected stage I tumors high in Vagina All others treated with radiation with chemosensitization

5 year Survival Stage I 70% Stage II 51% Stage III 33% Stage IV 17%