1 Prevention of cervical cancerTara Rick PA-C St. Catherine University PA program University of Minnesota Health- Hematology & Oncology Good morning. I am covering the prevention portion of our symposium and the most relevant topic to discuss is cervical cancer because there is a disparity of cervical cancer incidence and mortality in LMIC due to the disparity in prevention. And this cancer is completely preventable when screened for and treated for.

2 Disclosure informationI have no financial relationships to disclose

3 Objectives To understand the magnitude of the problemTo explore new guidelines in low resource settings and apply to Tanzania To discuss what may be coming in screening/prevention in the future

4 87% of cervical cancer deaths occur in LMIC’s4th common cancer in women worldwide The global estimate over 500,000 cases and 275,000 deaths Source: Ferlay, 2012

5 incidence/mortality in TanzaniaCountry/Region Incidence Rate (per 100,000) Mortality Rate (per 100,000) World 14 6.8 Africa 27.6 17.5 East Africa 42.7 Tanzania 54 32.4 Age standardized rates. Only a handful of countries have higher rates: Malawi, Mozambique, Zambia and Zimbabwe Causes the most cancer related death in Tanzania which is striking if you think that it only affects half the population There are approximately 11 million women 15 years and older at risk of cervical cancer in Tanzania Source: Ferlay, 2012

6 Challenges leading to high mortalityMajority of women present at late stages (Mlange, 2015) HIV (Morhason-Bello, 2013) Shortage of pathologists- 15, 1:2.5 million (Rambau, 2011) Limited and uncoordinated screening programs (Ministry of Health, 2011) Lack of awareness of cervical cancer/level of education (Lyimo, 2012) (Peters, 2010) Distance to a facility capable of screening/treatment (Lyimo, 2012 & Peters, 2010) Lack of health care provider training/education Poverty (Peters, 2010) 2/3 present at late stage in developing countries Mwanza showed looked at 200 women with histologically proven cervical cancer and 64% were late stage According to lancet oncology, 70% of new HIV cases every year occur in sub-Saharan Africa (Morhason-Bello). Lyimo 2012 study in KCMC catchment area found that knowledge of cervical cancer and distance to a facility that provides screenings were the most important predictors for participation in screening. Other factors included husbands approval, level of education, embarrassment, female health care worker preference. 22% of 354 women had ever been screened for cervical cancer 7% (39) of women (Kilimanjaro area) report having been screened- Cunningham 70% 44 community level providers in Arusha area never received any formal cancer training Peters- the average household expenditure in Tz is $8/mos and in their study of 50 women with cervical cancer at ORCI the average travel cost was $18.

7 The benefit of screeningPrior to the 1960’s US incidence rates were 40.1 in whites and 73.1 in non-whites per 100,00 (ACS 2011). Now 6.6 which is about a 80% reduction of risk Pap was introduced in 1950’s but didn’t really start catching on until the 60’s Source: Wright, 2002

8 The role of Human papillomavirusHuman papillomavirus (HPV) is responsible for >99% of cervical cancers Most women with HPV will clear the virus within a few years HPV 16 &18 cause 70% of cervical cancers (Forman 2012)

9 ASCO guidelines-NEW Screening method Screening age and frequency:HPV testing for all resources HPV positive or no HPV testing Basic : Visual inspection with acetic acid ( VIA) Others: cytology Screening age and frequency: Basic: x in a lifetime (WHO 2014) Limited: every 10 years Enhanced: every 5 years until 2 negative exams. Then every 10 years Max: every 5 years Level of Resource Basic Limited Enhanced Maximum High-quality screening programs can lower the incidence of cervical cancer by up to 80%. Overwhelming evidence that HPV testing is more effective than cytology HPV negative have a low probability to develop cervical cancer in 5-10 years Exiting Screening ·Maximal and enhanced: > 65 years with consistently negative results during past > 15 years ·Limited and basic: < 49 years, resource-dependent; see specific recommendations Source: Jeronimo, 2016

10 ASCO guidelines When screening is abnormalBasic: no histology Others: Colposcopy Treatment of precursor lesions Basic: Cryotherapy Others: Loop electrosurgical excision procedure (LEEP) Follow up 12 month post treatment In the last 3 decades, mass screening in high-resource settings has achieved these reductions in cervical cancer incidence.4 A cervical cancer prevention program will affect the incidence and mortality rates only if women with positive screening results complete proper evaluation and treatment to prevent the progression to invasive cancer. Therefore, one of the critical evaluation indicators for any population-based program is the rate of completion of management and treatment in Women who require it,whichshouldideallybe100%. *For large lesions then referral for LEEP is recommended when possible *Precursor CIN 2 or greater (greater than 2/3 the thickness of the epithelium). CIN1 is not considered a precursor lesion; most cases of CIN1 regress within 6 years. CIN2 is considered an equivocal precancerous diagnosis; that is, some instances of CIN2 are CIN1 or HPV infection,14 and therefore, treatment of all CIN2 may represent Overtreatment. Source: Jeronimo, 2016

11 ASCO guidelines Special populations Qualifying statementWomen who are immunosuppressed should begin screening when they are diagnosed and get screened 2x the general population Qualifying statement In basic settings without current mass screening, infrastructure for HPV testing, diagnosis, and treatment should be developed Source: Jeronimo, 2016

12 How is cervical cancer screened/Treated in TanzaniaHPV testing is not implemented The cervix is evaluated by speculum exam and sprayed with acetic acid (vingear)- VIA Positive VIA are treated immediately with cryotherapy

13 Visual inspection with acetic acid (VIA)Counseling Speculum exam with light source Gloves Clean cervix Spray cervix with 3-5% acetic acid and wait 1-2 min HIV Testing and Counseling

14 Classification of VIA VIA (+) – Small or Large precancerous VIA (-)Unable to read – possible cervicitis Suspicious for cancer

15 Technique  Double-freeze technique (3 – 5 – 3)Cryotherapy Technique  Double-freeze technique (3 – 5 – 3) Freeze 3 min or until you achieve 3 -5 mm ice ball beyond edge of lesion, thaw 5 min and refreeze 3 min Overall cure rate for CIN – ~90% (Sauvaget, 2013) Cryotherapy – causes crystallization of the intracellular water and destroys the tissue/lesions - when you finish freezing, allow the cryotip to “fall-off” the cervix instead of pulling to remove it – less pain and bleeding The type of tip appears to make no difference in treatment of the lesion – controversial Found that the deeper and wide probe was more effective

16 VIA screening w/ Cryo example 5 day screening

17 Lessons learned The power of a bus with a loud speakerHigh acceptability Screening involve HIV counseling and testing 20-50 rather than HPV infections are transient <30 and cervical lesions may regress spontaneously 1-3x in a lifetime

18 A new Cryotherapy program Selian LutheranWe have talked about VIA the past few years at this symposium so I am going to make this very brief and use pictures from some work I have been involved in. VIA- visualization and inspection with acetic acid is a evidence based and cost effective approach to secondary prevention of cervical cancer. Essentially the method is you visualize the cervix with a speculum exam, you look for any gross lesions, cervicitis which would exclude them from the next step which the is application of acetic acid and you set a timer for X min. If you now see a lesion then it is VIA positive and you would immediately treat the patient with cryotherapy (freeze thaw freeze X min). A study from the NEJM showed that 2 VIA is a woman's lifetime has been shown to reduce the lifetime risk of cervical cancer by 76%.

19 screening data 2 cases of early stage CC who had hysterectomy this week. Numbers are low since USAID money has dried up and the team used to go out on weekend outreach and get paid for it. Now they still go, just less frequent because it is harder to find people to volunteer their time

20 VIA and cryotherapy Advantages Disadvantages One visitNon-physicians can perform Electricity independent (if you have solar powered light source) Low cost US $5-12 Reduces mortality (Shastri, 2013) No biopsy. Overtreatment? (Sauvaget, 2011) Gas (NO or CO2) expensive and difficult to procure Women>50-decreasing visibility of transitional zone How can health care provider proficiency be assured? (Yeates, 2016) Yeates 2016 article in Journal Global Oncology asked this question in the Kilimanjaro area where 5 local providers who were already doing VIA got a MOH refresher course then over 9 mos they took pictures of all the cervix’s they screened and texted the images to local experts with their assessment. The first month agreement was 90% but every month after than the agreement was 97%. This can be an excellent platform to strengthen and maintain VIA skills and expertise. And all you need is a mobile network, smart phone, and a solar phone charger. It is again electricity independent and all things pretty common in Tanzania. *Precursor CIN 2 or greater (greater than 2/3 the thickness of the epithelium). CIN1 is not considered a precursor lesion; most cases of CIN1 regress within 6 years. CIN2 is considered an equivocal precancerous diagnosis; that is, some instances of CIN2 are CIN1 or HPV infection,14 and therefore, treatment of all CIN2 may represent Overtreatment. Meta-analysis 80% sensitivity 92% specificity Sauvaget 2011

21 Impact in low resource settingScreening 1x/lifetime around 35 yrs. of age reduces the lifetime risk of cancer by ~25-36% Screening 2x/lifetime reduces the relative cancer risk by an additional 40% Goldie, 2005

22 The future Will a rapid HPV test replace VIA and cytology for the first step of screening? (Sankaranarayanan 2009) Will we be able to visualize the cervix with a inexpensive portable colposcope? (Mueller, 2017) Is a different vaccine needed in regions with high levels of HIV? (Mujuni, 2016) Negative HPV test is more predictive than negative pap for absence of CIN3+ for 5 years (Dillner 2008 This transformational study was published by Joakim Dillner, et al, now at the Karolinska Institute in Stockholm, the first demonstrating that the HPV Test was more predictive than Pap for the ABSENCE of cervical disease ! The strong predictive value of a negative HPV test was later confirmed by Castle et. al. in 2012.

23 HPV testing 14 high risk HPV strains 2.5 hoursRapid HPV (careHPVTM) 14 high risk HPV strains 2.5 hours High sensitivity/specificity Cost US $5-15 Self sampling possible Traditional HPV $100, 4-7h Source: Qiagen website

24 The future of visualization?Point of Care Tampon Colposcope (POCket Colposcope) LED light source Powered by smart phone Disinfected by chlorine solution $<$500 Findings comparable to standard colposcope Encrypted image electronically transmitted to one of a trained panel for quality control and approval of treatment plan Source Mueller J., et al 2017, courtesy of Dr. Peyton Taylor

25 HPV Vaccine Quadrivalent genotypes (HPV 16, 18, 6, 11)Nanovalent vaccine (HPV 16,18, 52, 58, 45+) where HIV is endemic? (Mujuni et al 2016) ASCO guideline 2017-Prioritize girls 9-14 years, 2 doses 5-15 mos apart. Even if vaccination is rapidly employed, several generations of women have already been exposed and are at risk. Without robust screening, millions of women will die of cervical cancer before the impact of HPV vaccines on cervical cancer is observed. Thus, secondary prevention by cervical cancer screening will be needed for the foreseeable future. Barriers: infrastructure, staffing, financing, delivery, politics HIV+ women tend to be positive for multiple genotypes, including uncommon. The studies on HPV genotyping didn’t well represent HIV+ women. Mujuni 255 HIV+ pap screening pt Bugando. 255 HIV+ women pap screening, >50% HPV+ and almost 50% were HR genotypes. 12% had multiple HR and uncommon strains suggesting the need to include uncommon right risk genotypes where HIV is endemic. Interestingly genotype HPV 35 has been found to be common in Africa and not in any vaccine. Source: GAVI website

26 References Ferlay J, Soerjomataram I, Ervik M, et al: GLOBOCAN 2012 v1.1, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11. Lyon, France, International Agency for Research on Cancer, 2014 Mlange R., Matovelo D., Rambau P., Kidenya B. Patient and disease characteristics associated with late tumour stage at presentation of cervical cancer in northwestern Tanzania. BMC Womens Health. 2015 Morhason-Bello I., et al. Challenges and opportunities in cancer control in Africa: a perspective from the African Organisation for Research and Training in Cancer. Lancet Oncology. 2013 Rambau P. Pathology Practice in a Resource-Poor Setting: Mwanza, Tanzania. Archives of Pathology & Laboratory Medicine Cunningham MS, et al. Cervical cancer screening and HPV vaccine acceptibility among rural and urban women in Killimanjaro Region, Tanzania. BMJ Open. 2015 Ministry of Health and Social Welfare [United Republic of Tanzania]. National Cervical Cancer Prevention and Control Strategic Plan Tanzania: Dar es Salaam; pp

27 References Lyimo FS, Beran TN. Demographic, knowledge, attitudinal, and accessibility factors associated with uptake of cervical cancer screening among women in a rural district of Tanzania: three public policy implications. BMC public health. 2012 Peters L., et al. Evidence for the Need of Educational Programs for Cervical Screening in Rural Tanzania. J Cancer Educ Wright TC et al., Carcinoma and other tumors of the cervix. In Kurman R (ed): Blavstein’s Pathology of the Female Genital Tract. 5th ed. New York, Springer-Verlag, 2002 Jeronimo J. et al. Secondary Prevention of Cervical Cancer: ASCO Resource-Stratified Clinical Practice Guideline. WHO. Prevention of cervical cancer through screening using VIA and treatment with cryotherapy. 2012 Shastri S., et al. Effect of VIA Screening by Priary Health Workers: Randomized Controlled Study in Mumbai, India. J Natl Cancer Inst Sauvaget C., et al. Accuracy of visual inspection with acetic acid for cervical cancer screening. Int J Gynaecol Obstet Yeates K., et al. Evaluation of a Smartphone-Based Training Strategy Among Health Care Workers Screening for Cervical Cancer in Northern Tanzania: The Kilimanjaro Method. J Glob Oncol. 2016 Prevention of cervical cancer through screening using visual inspection with acetic acid (VIA) and treatment with cryotherapy. World Health Organization, 2012

28 References Goldie SJ, Gaffiken L, Goldhaber-Fiebert JD, et al. Cost-effectiveness of cervical cancer screening in five developing countries. N Engl J Med (20): Huh W., et al. Use of primary high-risk human papillomavirus testing for cervical cnacer screening: Interim clinical guidance. Gynec Oncol Wright T., et al. Primary cervical cancer screening with human papillomavirus: End of study results from the ATHENA study using HPV as the first-line screening test. Gynec Oncol Sankaranarayanan R., et al. HPV screening for cervical cancer in rural India. N Engl J Med. 2009 Dillner J., et al. Long term predictive values of cytology and human papillomavirus testing in cervical cancer screening: joint European cohort study. BMJ. 2008 Mueller J., et al. International Image Concordance Study to Compare a Point-of-Care Tampon Colposcope with a Standard-of-Care Colposcope. J Low Genit Tract Dis. 2017 Mujuni F et al. Variability of high risk HPV genotypes among HIV infected women in Mwanza, Tanzania- the need for evaluation of current vaccine effectiveness in developing countries. Infect Agent Cancer. 2016; 11:49. Arrossi S., et al. Primary Prevention of Cervical Cancer: American Society of Clinical Oncology Resource-Stratified Guideline. J Glob Oncol. 2017

29 Questions? Ben FranklinThis is a disease that is taking mothers from their children.\ Lets keep these women out of the cancer center