1. 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

2. 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 Atlanta, GA; 2007

3. 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 Atlanta, GA; 2005

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

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

6. Cervical Cancer

7. 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.

8. 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

9. 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.

10. 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 Atlanta, GA; 2005

11. 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.

12. 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

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

15. Staging Clinical Staged Disease Physical Exam Blood Work Cystoscopy
Proctoscopy
IVP

16. 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

17. 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.

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

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

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

21. 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

24. 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

25. 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

26. 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

27. 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.

28. Recurrent Cervical Cancer: GOG 169
Moore DH et al. J Clin Oncol 22:

29. 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: Muderspach LI, et al., Gynecologic Oncology 2001;81: Noda K, et al. Proc Am Soc Clin Oncol 1996;15:280 [Abstract 754]. Fiorica J, et al. Gynecol Oncol 2002;85: Tiersten AD, et al. Gyn Oncol 2004;92:

30. 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/d 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)

31. Survival By Treatment Group
GOG 179
Rx Group Alive Dead Total Cisplatin Cis+Topo
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

32. 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%

33. 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?

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

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

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

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

38. 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

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

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

43. Symptoms Pruritus Mass Pain Bleeding Ulceration Dysuria Discharge
Groin Mass

44. Symptoms May look like: Raised Erythematous Ulcerated Condylomatous
Nodular

45. Vulvar Cancer
IF IT LOOKS ABNORMAL ON THE VULVA
BIOPSY!

46. Tumor Spread Very Specific nodal spread pattern Direct Spread
Hematogenous

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

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

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

50. 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

51. 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

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

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

54. 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

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

56. 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

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

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

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

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

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

62. Vaginal Carcinoma 2140 new cases projected 2005
810 deaths projected 2005
Represents 2-3% of Pelvic Cancers
American Cancer Society. Cancer Facts & Figures Atlanta, GA; 2005

63. 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

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

65. Clear Cell Carcinoma Associated with DES Exposure In Utero
DES used as anti abortifcant from
500+ cases confirmed by DES Registry
Usually occurred late teens

66. Vaginal Cancer Etiology
Mimics Cervical Carcinoma
HPV 16 and 18

67. 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

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

69. 5 year Survival
Stage I 70%
Stage II 51%
Stage III 33%
Stage IV 17%