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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). 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. B. C. D. When she becomes sexually active Before the age of 26 She should definitely receive the first dose now Never, that’s an invitation for promiscuous sexual activity 4 Overview of Female Malignancies • The Global Burden of Disease 2000 Study BMC Cancer. 2002 Dec 26;2:37. 5 http://www.cdc.gov/uscs 6 Cervical Cancer Epidemiology 5 year survival = 68% 12,900 4,100 http://seer.cancer.gov/statfacts/html/cervix.html 7 Risk by Age Median Age at Diagnosis = 49 yrs http://seer.cancer.gov/statfacts/html/cervix.html 8 Cervical CA Stage and Survival Screening and Early Detection is KEY!!!!! http://seer.cancer.gov/statfacts/html/cervix.html 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 13th in cancer deaths of women ▫ 2nd most common malignancy in women 20-39 yo • Nearly 70% reduction over past 5 decades CA Cancer J Clin. 2014;64(1):9. 10 Decreasing Mortality 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 12 Risk Factors • HPV ▫ Number of sexual partners ▫ Partner’s number of sexual partners ▫ Early age of first sexual intercourse • Cervical Cancer ▫ Genital HPV infection ▫ High parity ▫ Cigarette smoking ▫ Early oral contraceptive use ▫ Poor diet - Vitamin A or C deficiency ▫ Low socioeconomic class Int J Cancer 2006; 118(12):3030–3044. Ho GY. N Engl J Med.1998; 338 :423 –428 13 Pathology ~15 years 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 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 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 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 Br J Cancer. 2006 Dec 4;95(11):1459-66. Lancet Oncol. 2005 May;6(5):271-8. 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 19 Cervarix • Bivalent HPV vaccine (types 16, 18) • Indicated in females age 10 - 25 • Administration ▫ 3 IM injections at 0, 1, and 6 months ▫ Cost ~$130/dose (Am. Cancer Society) • Continue to follow screening guidelines 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 www.npr.org/2011/09/19/140543977/hpv-vaccine-the-sciencebehind-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 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 Ann Intern Med 132 (10): 810-9, 2000. Acta Cytol 35 (1): 8-14, 1991 Jan-Feb. 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? 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% 26 Abnormal Findings 0.15% cancer 1.14% cancer 27 Miley C’s report says ASC-US • What is this and what does it mean? 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 29 Treatment Based on Pap Smear Results Pap Test Result Tests and/or treatments may include ASC-US HPV testing - Repeat Pap test - Colposcopy and biopsy ASC-H Colposcopy and biopsy AGC Colposcopy and biopsy and/or endocervical curettage AIS Colposcopy and biopsy and/or endocervical curettage LSIL Colposcopy and biopsy HSIL Colposcopy and biopsy and/or endocervical curettage Further treatment with LEEP, cryotherapy, laser therapy, conization, or hysterectomy 30 Colposcopy and Endocervical Curettage • Primary method of evaluating women with abnormal Pap tests ▫ Exam allowing the cervix to be viewed through a microscope 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? 33 Clinical Presentation and Diagnosis Symptoms Diagnostics • Often asymptomatic (Screening) • Vaginal discharge • Postcoital spotting/bleeding • Pelvic pain • Flank pain • Weight loss • Incontinence • Signs/Symptoms • Tissue required for diagnosis ▫ Pap smear ▫ Colposcopy ▫ Endocervical curettage (ECC) ▫ Conization 34 Conization 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 Cancer 67 (11): 2776-85, 1991. JAMA 262 (7): 931-4, 1989. 36 Simplified Staging 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? 38 Stage IB 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 NCCN Guidelines. Cervical Cancer. V1.2014. 40 Early Stage Treatment Stage •0 •I • IIA Intervention Local surgical removal Hysterectomy +/- lymph node sampling or radiation* Hysterectomy + lymph node sampling or radiation +/- chemotherapy* *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 Stage Intervention IIB Radiation therapy plus chemotherapy Radiation therapy plus chemotherapy Radiation therapy plus chemotherapy III IVA 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 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 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 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) 46 Cervical Cancer Stage 0/I* Stage IIB-IVA Stage IVB Surgery no adjuvant Radiation + chemotherapy Palliative therapy Recurrent Disease Radiation with chemotherapy and/or surgery * High risk stage I (i.e., IB) should receive adjuvant therapy 47 Conclusions • Prevention ▫ Behavioral changes ▫ HPV vaccine • Screening, screening, screening… • Outcome related to clinical stage • Multimodality approach • Chemotherapy Chemotherapy in advanced disease does not change overall survival of patients 48 Questions?