1. Vesna Kesić Institute of Obstetrics and Gynecology Clinical Center of Serbia EASO Masterclass in Clinical Oncology 27-29. October, 2011, Amman, Jordan Cervical Cancer - State of Art -

2. It has been estimated that approximately 500 000 women develop cervical cancer every year, and 260 000 women die of the disease. WHO, 2009

4. Life-time risk (%) for cervical cancer USA 0,83 Scandinavia 1,01 India 2,22 South Amerika 5,31 5.8 West Asia 7.4 East Asia 7.4 Australia/N. Zeal. 7.7 North America 9.0 North Europe 10.0 West Europe 10.7 South Europe 12.1 North Africa 14.5 East Europe 18.7 South East Asia 26.2 South Cent. Asia 28.0 Central Africa 28.6 South America 29.3 West Africa 30.6 Central. America 38.2 South Africa 42.7 East Africa

5. Incidence of Cervical Cancer per 100,000 Females in Arab World < 4.0 4.0 – 7.9 8.0 – 11.9 12.0 – 15.9 ≥ 16.0 Algeria Map produced by Prof. Inas Elattar Pakistan Pakistan Morocco Afghanistan Palestine Bahrain Iran Iraq Sudan Somalia Libya Egypt Saudi Arabia Oman Yemen UAE Jordan Qatar Kuwait Syria Lebanon Djibouti

6. Two key reasons : 1. The vast majority of women still know little about cervical cancer or what they should do to prevent it. 2. Many countries have ineffective prevention programmes or no prevention programmes at all.

7. As the consequence, a high proportion of cervical cancer is diagnosed when already advanced and metastatic, leading to low probability of cure and high mortality rates . 85% Cervical Cancer: Groote Schuur Hospital, 1984 – 2000 (n = 3098)

8. Every 2 minutes , one women dies of cervical cancer !

9. Most of these deaths could be prevented!

11. Cervical cancer Human papiloma virus (HPV) infection has a causal role in the development of cervical cancer. HPV infection 99.7% !

12. 10 years > 5 years Normal HPV H-SIL Cancer Cervical carcinogenesis

13. Majority of HPV infections are transient and will resolve spontaneously within two years. The 5-year clearance rate of HPV is 92%

14. Human papiloma virus (HPV) infection is necessary for the development of H-SIL and invasive cancer but it is not a sufficient cause.

15. Cervical carcinogenesis

16. HPV infe c tion Low-grade changes High-grade lesions Cancer 300 milion s 30 milion s 10 milion s 0. 5 milion s HPV E6, E7 Cellular changes Many years 8-15 HPV infe ction Parkin DM, Bray F, Ferlay J, Pisani P. CA Cancer J Clin. 2005;55:74–108 World Health Organization. Geneva, Switzerland: World Health Organization; 1999:1–22. Number of cases 0.15% ! Estimated World Burden of HPV-related Disease and Diagnoses

17. Is it possible ? Preven tion of Cervical Cancer

18. Natural history of cervical cancer and prevention Precancerous lesion Invasive disease Normal Cervix Persistent infection with HR types HPV Clearance Progression Initial HPV infection

19. HPV va ccine

20. Vaccination is not a substitute for routine cervical cancer screening Vaccinated females should have cervical cancer screening as recommended !

21. C ytology George Pappanicolao u , 1945

22. Colposcopy Hans Hinselmann, 1920

23. Cervical cancer has become detectable and curable disease.

24. Biops y and/or ECC H istopathology

25. Invasive cervical cancer

27. Staging of cervical cancer is based on clinical evaluation The next step – staging !

30. FIGO 2009 Stage of the disease I II III IV Surgery Radiation

31. Surgery is the mainstay of treatment in early-stage disease, whilst radiotherapy is used for more advanced stages. Treatment of Cervical Cancer

32. Treatment of Early Stage Cervical Cancer

33. Most patients with early stage cervical cancer are treated by either radical surgery or radical radiotherapy. Both treatment modalities have proven to be equally effective . Landoni et al : Lancet 1997 350 535- 540

38. Modern approach to the surgical management of cervical cancer Conservative Radical for early disease for advanced disease Tailored

42. x The diagnosis of stage Ia cervical cancer should be based on conization !

43. If distant spread is very unlikely, simple but complete excision of the lesion suffices. If it is likely that the cancer has spread, than an extended operation should be performed.

44. Depth of invasion LVSI Risk of node metastases 0-3 - < 1 / 1000 0-3 + 2 / 100 3-5 - 2/ 100 3-5 + 5 / 100 Stage Ia cervical cancer

46. Early invasive cervical cancer - stage Ib-IIa -

47. Stage Ib1 < 4 cm Stage Ib2 > 4cm Stage IIa

48. Parametria Lymphnodes Uterus Radical Hysterectomy

53. T y p e II I T ype II Types of hysterectomy- Piver 40% Magrina, 1995 0.8% Urinary dysfunction 7% 1.1% Thromboembolism 0.3% 0.5% Deaths 1% 0.3% Digestive fistulas 4.8% 0.3% Urinary fistulas Type III Type II Complication

54. Nerve sparing radical hysterectomy

55. Cervical cancer- R i sk for lymphnode metasta ses Modified from Barakat, Bevers. Handbook of gynecologic oncology, 2000 40 55 IVa 30 45 III 20 25-35 IIb 11-13 20-25 IIa 20 25 Ib2 2 16 Ib1 < 1 4.8 Ia2 0 < 1 Ia1 % paraaortic pN1 % pelvic pN1 Stage

59. Prognostic significance of lymph node metastases 5-year survival Negative pelvic lymphnodes ………… 89% . Positive pelvic lymph nodes ………… 59%

62. Adjuvant therapy in early cervical cancer For adjuvant irradiation - High risk, negative nodes - Positive nodes (1-3) - Poorly differentiated or undiferentiated tumor (G3) - LVSI (lympho-vascular space invasion) - Primary tumor > 3cm (tumor-cervix volume > 3cm ) - Endocervical invasion (barrel shaped ) - Inadequate surgery - Insufficient HP report For adjuvant chemo-irradiation - Positive resection margins - Involvement of parametria - Residual tumor

63. Postoperative pelvic radiation in patients with nodal metastases has been the standard approach. It increases local control, but not the overall survival , due to inability of adjuvant pelvic irradiation to influence distant metastases

64. Stage Ib2

67. The survival of patients that had bulky nodes removed has been significantly improved compared to those who had not the nodes resected (31% vs 6%) Hacker et al. Int. J Gynecol Cancer, 1995;5: 250-256 1. KiKim et al. Gynecol Oncol, 1998; 69: 243-7

69. Extended-field radiotherapy is the standard part of treatment achieving the long-term survival of 30-40% for stage Ib patients with positive PALN. Consistent benefit of concurrent chemo-radiation with Cis-platin based chemotrerapy incorporated in extended-field irradiation.

71. Neo-adjuvant chemotherapy followed by radical surgery has emerged as a possible alternative to conventional chemo-radiation, which may improve a survival in patients with stage Ib2 disease Benedetti -Panici P.J Clin Oncol, 2002; 20: 179-188 Tierney J. Eur J Cancer, 2003; 39: 2470-2486 14%

77. Exenteration Survival Anterior exenteration: 30-60% Posterior exenteration: 20-46%

79. Cervical cancer- survival by FIGO stage FIGO 25. Annual report, 1996-1998 98.7% 95.9%

80. The incidence of cervical cancer in one country is an indicator of how much the whole society takes care about its women.