1. Cervical Cancer Kelley Ratermann, PharmD Hematology/Oncology Clinical Pharmacist

2. Objectives Identify risk factors of this disease. Understand the importance of screening and prevention. Understand the staging process of cervical cancer. Evaluate individual patients and select the most appropriate treatment option(s). 2

3. Case 1 Miley C. is a 13 YOF that just transitioned from middle school to junior high. Her pediatrician proposes Gardasil administration during her annual wellness check. As her parent, when do you feel it is appropriate for Miley to receive this vaccine? A.When she becomes sexually active B.Before the age of 26 C.She should definitely receive the first dose now D.Never, that’s an invitation for promiscuous sexual activity 3

4. Overview of Female Malignancies The Global Burden of Disease 2000 Study 4 BMC Cancer. 2002 Dec 26;2:37.

5. 5 http://www.cdc.gov/uscs

6. 6 Cervical Cancer Epidemiology 12,900 4,100 5 year survival = 68% http://seer.cancer.gov/statfacts/html/cervix.html

7. 7 Median Age at Diagnosis = 49 yrs http://seer.cancer.gov/statfacts/html/cervix.html Risk by Age

8. 8 Screening and Early Detection is KEY!!!!! http://seer.cancer.gov/statfacts/html/cervix.html Cervical CA Stage and Survival

9. Epidemiology Estimated 12,360 new cases in 2014 ▫4,020 deaths Annual pap smears in the US: 50-60 million ▫3.5 million abnormal ▫2.5 million undergo colposcopy Ranked 13 th in cancer deaths of women ▫2 nd most common malignancy in women 20-39 yo Nearly 70% reduction over past 5 decades CA Cancer J Clin. 2014;64(1):9. 9

10. Decreasing Mortality 10 Prevention Early Detection Treatment

11. Decreasing Cervical Cancer Mortality Minimize HPV exposure risks Minimize persistent HPV via vaccine Screen +/- remove precancerous cells Catch and treat cervical cancer early 11

12. Risk Factors Cervical Cancer ▫Genital HPV infection ▫High parity ▫Cigarette smoking ▫Early oral contraceptive use ▫Poor diet - Vitamin A or C deficiency ▫Low socioeconomic class HPV ▫Number of sexual partners ▫Partner’s number of sexual partners ▫Early age of first sexual intercourse Ho GY. N Engl J Med.1998; 338 :423 –428 12 Int J Cancer 2006; 118(12):3030–3044.

13. Pathology There are four major steps in cervical cancer development 1.Oncogenic HPV infection 2.Persistence of the HPV infection 3.Progression of a clone of epithelial cells 4.Development of carcinoma and invasion through the basement membrane ~15 years 13

14. 14 http://gtbinf.wordpress.com/2013/11/09/42

15. HPV The majority of cervical cancer contain HPV DNA ▫93-100% Oncogenic types HPV types 16 and 18 (> 70%) 5-year survival rates correspond with HPV subtype E6 and E7 oncoproteins ▫Effect on cell cycle, association with RB, p53 15

16. Prevention Avoiding risk factors ▫STOP smoking ▫Decrease number of sexual partners ▫Delay onset of intercourse Vaccination ▫CDC recommends for girls age 11 or 12 (allows to begin at age 9) ▫Give for ages 13-26 if previously not vaccinated/did not complete series 16 Lancet Oncol. 2005 May;6(5):271-8.

17. Vaccine Data FUTURE I Trial (no exposure) ▫5,500 women ages 16-24 randomized ▫Vaccine 100% effective in women with no exposure FUTURE II Trial (previously exposed) ▫12,100 women ages 15-26 randomized ▫Vaccine reduced rates of all cervical lesions, regardless of previous HPV exposure Led to approval of Gardasil in June of 2006 17 Lancet Oncol. 2005 May;6(5):271-8. Br J Cancer. 2006 Dec 4;95(11):1459-66.

18. Gardasil Quadrivalent HPV vaccine ▫Types 6, 11, 16, 18 Indicated in females 9 – 26 yo ▫AND males Administration ▫3 IM injections at 0, 2, and6 months ▫Cost: ~$145/dose (CDC) Continue to follow screening guidelines 18

19. Cervarix Bivalent HPV vaccine (types 16, 18) Indicated in females age 10 - 25 Administration ▫3 IM injections at 0, 1, and6 months ▫Cost ~$130/dose (Am. Cancer Society) Continue to follow screening guidelines 19

20. Vaccination Unknowns Duration of efficacy (7 and 9 yrs) ▫What if you don’t get all three shots? Optimal age for vaccination Cost effectiveness of widespread vaccination ▫Treatment abnormal pap smears rather than upfront vaccine 20 www.npr.org/2011/09/19/140543977/hpv-vaccine-the-science- behind-the-controversy

21. Screening Annually for life if risk factors present Annually for life if personal hx cervical cancer or HIV+ May stop if: ▫TAH/BSO including removal of cervix (unless for tx of cervical cancer) ▫Women >70 yo with intact cervix  > 3 consecutive, normal cervical cytology tests within previous 10yrs 21 http://www.cancer.org/cancer/news/new-screening-guidelines-for-cervical-cancer

22. Pap(anicolaou) Smear Only ~6% abnormal Shown to decrease morbidity/mortality Sensitivity from single test (55-80%) ▫High false negative rate Repeated tests improve sensitivity Part of OC prescribing, but direct link is missing 22 Acta Cytol 35 (1): 8-14, 1991 Jan-Feb. Ann Intern Med 132 (10): 810-9, 2000.

23. Back to Miley C… You read in US Weekly that Miley recently went on a bender and had sexual intercourse with several individuals. She asks, “for a friend,” about cervical cancer risk after an abnormal pap smear. What questions do you need to ask to help her understand her risk? 23

24. 24 Grading of Cervical Cancer http://www.jci.org/articles/view/28607/figure/2

25. Histology and HPV Squamous (69%) HPV 16 – 59% HPV 18 – 13% HPV 58 – 5% HPV 33 – 5% HPV 45 – 4% Adenocarcinoma (25%) HPV 16 – 36% HPV 18 – 37% HPV 45 – 5% HPV 31 – 2% HPB 33 – 2% 25

26. Abnormal Findings 26 0.15% cancer 1.14% cancer

27. Miley C’s report says ASC-US What is this and what does it mean? 27

28. Bethesda System of Reporting ASC–US—atypical squamous cells of undetermined significance ASC-H - atypical squamous cells; cannot exclude a high-grade squamous intraepithelial lesion LSIL—low-grade squamous intraepithelial lesion HSIL—high-grade squamous intraepithelial lesion AGC—atypical glandular cells AIS—endocervical adenocarcinoma in situ 28

29. Treatment Based on Pap Smear Results Pap Test Result Tests and/or treatments may include ASC-USHPV testing - Repeat Pap test - Colposcopy and biopsy ASC-HColposcopy and biopsy AGCColposcopy and biopsy and/or endocervical curettage AISColposcopy and biopsy and/or endocervical curettage LSILColposcopy and biopsy HSILColposcopy and biopsy and/or endocervical curettage Further treatment with LEEP, cryotherapy, laser therapy, conization, or hysterectomy 29

30. Colposcopy and Endocervical Curettage Primary method of evaluating women with abnormal Pap tests ▫Exam allowing the cervix to be viewed through a microscope 30

31. 31

32. Miley’s new symptoms About 10 years later – Miley comes in and is asking about some new mild symptoms: abnormal vaginal discharge, spotting after intercourse, and mild pelvic pain. Are these consistent w/ cervical cancer? 32

33. Clinical Presentation and Diagnosis SymptomsDiagnostics Often asymptomatic (Screening) Vaginal discharge Postcoital spotting/bleeding Pelvic pain Flank pain Weight loss Incontinence 33 Signs/Symptoms Tissue required for diagnosis ▫Pap smear ▫Colposcopy ▫Endocervical curettage (ECC) ▫Conization

34. Conization 34

35. Prognostic Factors Stage (Primary prognostic guide) ▫Size of primary tumor ▫Presence of lymph node metastases Other High Risk Features ▫Lymph-vascular invasion ▫Tumor grade - poorly differentiated is worse 35 JAMA 262 (7): 931-4, 1989. Cancer 67 (11): 2776-85, 1991.

36. Simplified Staging 36 NCCN Guidelines. Cervical Cancer. V1.2014.

37. Miley C’s follow-up MC is diagnosed w/ stage IB cervical cancer. How does this compare to most women? What is her prognosis? What treatment should she receive? 37

38. Stage IB 38

39. Treatment Options Surgery ▫Hysterectomy +/- lymph node sampling (no sampling if depth < 3mm – negative margins) Radiation (non-surgical candidates) ▫External beam (invasion > 3 mm) ▫Brachytherapy Chemotherapy (with or without XRT) Multimodality treatment is common 39 NCCN Guidelines. Cervical Cancer. V1.2014.

40. Early Stage Treatment StageIntervention 0Local surgical removal IHysterectomy +/- lymph nodesampling or radiation* IIAHysterectomy + lymph node sampling or radiation +/- chemotherapy* 40 *MC’s stage = High Risk Patients (tumor > 4 cm or + lymph nodes or + margins) should receive adjuvant chemotherapy and radiation NCCN Guidelines. Cervical Cancer. V1.2014.

41. Locally Advanced Treatment 41 StageIntervention IIBRadiation therapy plus chemotherapy III Radiation therapy plus chemotherapy IVA Radiation therapy plus chemotherapy NCCN Guidelines. Cervical Cancer. V1.2014.

42. Treatment of Stage IIB, III, and IVA Radiation is the primary treatment ▫Whole pelvis radiation therapy ▫Brachytherapy Chemosensitization ▫Reduces the risk of death by 6% and increases PFS by 8% ▫Cisplatin monotherapy* ▫Cisplatin + 5-FU ▫Paclitaxel ▫Mitomycin ▫Hydroxyurea ▫Bleomycin ▫Carboplatin 42 J ClinOncol2008; 26:5802-12

43. Cisplatin Cisplatin is cornerstone of therapy – several regimens used GOG 1235 ▫Concurrent chemo and XRT >> than sequential GOG 1203 ▫Cisplatin 40 mg/m2 IV weekly x 6 with XRT* SWOG 87974/GOG 851 ▫Cisplatin 75 mg/m2 IV day 1 with XRT and 5FU 1 gram/m2/day day 1-5 ▫Repeat every 3 weeks * Recommended 43 NCCN Guidelines. Cervical Cancer. V1.2014.

44. Metastatic Disease (IVB) Treatment Cure is not achievable Goal is palliation No standard of care Local radiation may help with palliation CLINICAL TRIALS 44

45. Treatment: Metastatic disease Palliative Radiation Chemotherapy: ▫Cisplatin (15%-25% response rate) ▫Ifosfamide (31% response rate) ▫Paclitaxel (17% response rate) ▫Ifosfamide-cisplatin (31% response rate) ▫Irinotecan (21% response rate in patients previously treated with chemotherapy) ▫Paclitaxel/cisplatin (46% response rate) ▫Cisplatin/gemcitabine (41% response rate) 45

46. Stage 0/I* Surgery no adjuvant Recurrent Disease Stage IVB Cervical Cancer Radiation + chemotherapy Stage IIB-IVA Palliative therapy Radiation with chemotherapy and/or surgery * High risk stage I (i.e., IB) should receive adjuvant therapy 46

47. Conclusions Prevention ▫Behavioral changes ▫HPV vaccine Screening, screening, screening… Outcome related to clinical stage Multimodality approach Chemotherapy 47 Chemotherapy in advanced disease does not change overall survival of patients

48. Questions? 48