1. Cancer Cervix By Maged Abd El Fattah Amine Assistant Lecturer Of Medical Oncology South Egypt Cancer Institute 3.2015

2. 3/3/2015 *Outline: - Introduction and Epidemiology. - Aetiology and Risk factors. - Pathology. - Diagnosis. - Treatment. - Screening and Prevention. - Conclusions. 2 Cancer Cervix

3. Introduction and Epidemiology 3/3/2015 3 Cancer Cervix

4. - Cervical cancer is the third most common cancer in women, with an estimated 529 828 new cases and 275 128 deaths reported worldwide in 2008. - Mean age for cervical cancer is 50 years and it peaks at 35-40 years and 60-64 years. - More than 85% of the global burden occurs in developing countries, where it accounts for 13% of all female cancers. - the age standardized mortality rate is 10/10 000, more than three times higher than in developed countries. 3/3/2015 4 Cancer Cervix

5. Aetiology and Risk factors 3/3/2015 5 Cancer Cervix

6. - Sexuel intercourse at an early age. - Multiple sexuel partners. - Young age at first pregnancy. - Cigarette smoking. - HSV infection. - HPV infection. Risk Factors: - Sexuel intercourse at an early age. - Multiple sexuel partners. - Young age at first pregnancy. - Cigarette smoking. - HSV infection. - HPV infection. 3/3/2015 6 Cancer Cervix

7. - It is common knowledge that the most important cause of cervical cancer is persistent papillomavirus infection. - The human papillomavirus (HPV) is detected in 99% of cervical tumors, in particular the oncogenic subtypes such as HPV 16 and 18. 3/3/2015 7 Cancer Cervix HPV in Cancer Cervix

8. 3/3/2015 8 Cancer Cervix *Types of HPV: - Low risk types: 6 and 11  Sqcc -High risk Types: -Mostly types16, 18, 31, and 33; Other types: (35, 39, 45, 51, 52, 56, 58)  both Sqcc and Adeno. - Type 18 is associated with: - Poorly differentiated histology. - Higher incidence of lymph node metastases.

9. HPV as an etiology

10. Pathology 3/3/2015 10 Cancer Cervix

11. - The WHO recognizes three categories of epithelial tumors of the cervix: a- Squamous cell carcinomas account for ∼ 70%–80%. b- Adenocarcinomas for ∼ 10%–15%. c- Other epithelial tumors including neuroendocrine tumors and undifferentiated carcinoma. - Grossly, Carcinomas can be exophytic, growing out of the surface, or endophytic with stromal infiltration with minimal surface growth. 3/3/2015 11 Cancer Cervix

12. Staging 3/3/2015 12 Cancer Cervix

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15. * Tumor risk assessment includes: - tumor size, stage, depth of tumor invasion, lymph node status, lymphovascular space involvement (LVSI), and histological subtype. - Lymph node status and number of lymph nodes involved are the most important prognostic factors. In stages IB-IIA, the 5-year survival rate without lymph node metastasis and with lymph node metastasis is 88%–95% and 51%–78%, respectively. 3/3/2015 15 Cancer Cervix

16. Diagnosis 3/3/2015 16 Cancer Cervix

17. Presentation: Vaginal bleeding. Discharge. Back pain. Superficial ulceration. Exophytic tumor. May spread to the vaginal fornices, parametria, bladder or rectum. S & S of distant spread. 3/3/2015 17 Cancer Cervix

18. Diagnostic work-up: History and Physical examination. Chest X-ray, CBC, LFTs, RFTs, Urinalysis. Cystoscopy, Rectosigmoidoscopy ( if Stage > 3). Optional: MRI, CT, US, IVP, PET scan. Cervical biopsy. 3/3/2015 18 Cancer Cervix

19. Treatment 3/3/2015 19 Cancer Cervix

20. - Depending on stage, primary treatment consists of surgery, radiotherapy, or a combination of radiotherapy and chemotherapy. - Several factors affect the decision, include: 1- PS. 2- Operability. 3- Fertility status. 4- Tumor stage. 5- Pathological adverse risk factor i.e. LVI, Grade, margin, histological type. - Fertlity preservation is not applicable to patients with neuroendocrinal tumor or minimal deviation adenocarcinoma (adenoma malignum) because of lack of data. - Depending on stage, primary treatment consists of surgery, radiotherapy, or a combination of radiotherapy and chemotherapy. - Several factors affect the decision, include: 1- PS. 2- Operability. 3- Fertility status. 4- Tumor stage. 5- Pathological adverse risk factor i.e. LVI, Grade, margin, histological type. - Fertlity preservation is not applicable to patients with neuroendocrinal tumor or minimal deviation adenocarcinoma (adenoma malignum) because of lack of data. 3/3/2015 20 Cancer Cervix

21. Stage Ia 3/3/2015 21 Cancer Cervix Alternative ttt For fertility sparing Primary tttRisk factorStage ConizationExtrafascial Hystrectomy -ve margin Ia1 No LVSI Radical Trachlectomy + Pelvic LN dissection +/- PALN Modified radical hystrectomy + Pelvic LN dissection +/- PALN +ve margin Radical Trachlectomy + Pelvic LN dissection +/- PALN Modified radical hystrectomy + Pelvic LN dissection +/- PALN Ia1 with LVSI Or Ia2

22. Stage Ib and Stage IIa 3/3/2015 22 Cancer Cervix Alternative tttPrimary tttStage Pelvic RT + Brachytherapy(dose 80-85gy) +/-CCRT Radical Hystrectomy + Pelvic LN dissection +/- PALN Ib1 And IIa1 Radical Hystrectomy + Pelvic LN dissection +/- PALN Definitive pelvic RT + Brachytherapy (dose >85gy) + CCT Cispltin based Ib2 And IIa2

23. Management of stage I tumor Adjuvant therapy i. Observation only: Negative surgical margin. Negative surgical margin. Negative pelvic node. Negative pelvic node. Not bulky tumor. Not bulky tumor. No parametrium involvement. No parametrium involvement. ii. Chemoradiation ± vaginal brachytherapy: Margin: Positive Surgical margin or close vaginal margins (<0.5 cm). Margin: Positive Surgical margin or close vaginal margins (<0.5 cm). Nodal status: Positive pelvic node. Nodal status: Positive pelvic node. Bulky primary tumor. Bulky primary tumor. Parametrium involvement. Parametrium involvement.

24. Management of stage I tumor Adjuvant therapy iii. Chemoradiation + Para-aortic LN RTH ± vaginal brachytherapy: Positive Para-aortic LN + negative other metastatic workup Positive Para-aortic LN + negative other metastatic workup iv. Radiotherapy without concurrent chemotherapy: Indicated in stage Ia2, Ib1, Ib2 with negative nodes but with these risk factors Indicated in stage Ia2, Ib1, Ib2 with negative nodes but with these risk factors Lymphovascular invasion Lymphovascular invasion Deep stromal invasion (> 1/3 of the stroma) Deep stromal invasion (> 1/3 of the stroma) Bulky primary tumor (> 4cm in size) Bulky primary tumor (> 4cm in size) N.B.: The use of concurrent chemotherapy in these conditions is controversy. N.B.: The use of concurrent chemotherapy in these conditions is controversy.

25. Stage IIb and Stage III and Stage IVa 3/3/2015 25 Cancer Cervix Accurate Radiological staging (By CT, MRI and /or PET scan) then: 1.Negative PALN and Negative other metastatic workup Chemoradiation + brachytherapy. 2.Positive PALN & Negative other metastatic workup Chemoradiation + Para-aortic LN RTH ± brachytherapy. 3.Positive other metastatic workup Systemic treatment

26. Stage IVb/Recurrence 3/3/2015 26 Cancer Cervix -Patients with metastatic or recurrent cervical cancer are commonly symptomatic. The role of chemotherapy in such patients is palliative. - Doublets have better Response rate than Cisplatin alone.

27. Stage IVb/Recurrence 3/3/2015 27 Cancer Cervix -A recent phase III trial assessed four cisplatin-doublet regimens (cisplatin–paclitaxel, cisplatin–topotecan, cisplatin–gemcitabine, and cisplatin– vinorelbine). No significant differences in overall survival were seen; however, the trends for response rate, PFS, and OS suggest that cisplatin–paclitaxel is the preferred regimen. - Although Cisplatin-gemcitabine was not superior to Cisplatin and paclitaxel, but it was tolerable (JCOG0505).

28. Target therapy Bevacizumab Bevacizumab It is considered as second line single agent therapy for advanced cervical cancer (But still controversy till now) It is considered as second line single agent therapy for advanced cervical cancer (But still controversy till now) Erlotinib Erlotinib The combination of E+ CRT is feasible and showed encouraging data (CR rate of 92.6%) The combination of E+ CRT is feasible and showed encouraging data (CR rate of 92.6%)

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30. Screening and Prevention 3/3/2015 30 Cancer Cervix

31. - Cervical cancer is a preventable disease due to: a) long Long pre- cancer state and; b) effective screening program 3/3/2015 31 Cancer Cervix

32. A) Primary prevention: 1. Avoid HPV exposure. 2. HPV vaccination: 1. Bivalent (HPV 16/18) Cervarix® Contains the L1 protein from two types of HPV (16, 18). I.M. injection 3 shots 0, 1 and 6 month. 2. Quadrivalent (HPV 6/11/16/18) Gardasil® Contains the L1 protein from four types of HPV (16, 18, 6, and 11). I.M. injection 3 shots 0, 2 and 6 month. 3/3/2015 32 Cancer Cervix

33. Recommendations of vaccination The American College of Obstetricians and Gynecologists (ACOG), in conjunction with the Advisory Committee on Immunization Practices (ACIP): 1-Routine vaccination of female at 12 years of age. 2- Ideally vaccine should be administered before onset of sexual activity. 3- Vaccination is recommended for females13-26 years of age who have not been previously vaccinated. 4- Females 26 years of age or younger who are lactating/breastfeeding or are immuno-compromised may be vaccinated. 5- NOT recommended for pregnant women. 6- The HPV vaccine does not eliminate the need for cervical cytology screening. 3/3/2015 33 Cancer Cervix

34. Secondary prevention (Screening and Early detection RecommendationParameters at 21 years old, regardless of sexual historyAge to start screening Screen with cytology alone every 3 years. * HPV testing should not be used in this age group. Screening interval age 21–29 Screen with both cytology and HPV testing every 5 years (preferred) or cytology alone every 3 years. Screening by HPV testing alone is generally not recommended. Screening interval age 30-65

35. Secondary prevention (Screening and Early detection RecommendationParameters Age 65 If the woman has adequate negative prior screening and is not otherwise at high risk for cervical cancer Age to stop screening Screen according to the same recommendations as for unvaccinated women HPV- vaccinated women

36. Pap test 3/3/2015 36 Cancer Cervix

37. Conclusions 3/3/2015 37 Cancer Cervix

38. - Cervical cancer still represents a major public health problem even in developed countries. - HPV plays an essential role in pathogenesis of cervical cancer. - Cervical cancer is a preventable disease due to effective screening and early detection. - Effective ttt could achieve cure in 80 % of early stage (I-II) and 60 % of stage (III). 3/3/2015 38 Cancer Cervix

39. Any Questions 3/3/2015 39 Cancer Cervix

40. THANK YOU 3/3/2015 40 Cancer Cervix