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SCREENING, PREVENTION, TREATMENT

Disclosure

I have no financial disclosures.

Focus of this presentation

Background

Etiology/History/Prevalence HPV

Screening:

History of cervical cancer screening

Evolution of cervical screening

Prevention: HPV Vaccine

Treatment:

Based on NCCN Guidelines

Cervical Cancer Statistics

13,240 will be diagnosed with cervical

cancer.

4,170 deaths from the disease will

occur.

America Cancer Society, 2018

Cervical Cancer Statistics

5-year survival rate for women with

cervical cancer is 67.4%

10-year survival rate is 64%

Broken down by stage

early stage - 92%

Regional spread - 57%

Distant spread – 17%

Cervical Cancer Statistics

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Cervical Cancer Statistics Cervical Cancer Statistics

Etiology

Human Papillomavirus (HPV)

Small, non-enveloped, DS DNA

E6 and E7 proteins cause oncogenic

transformation

Estimated US incidence – 5.5 million/yr

Average age 15-24 yo

HPV

Over 100 HPV types

40 genotypes known to infect the anogenital

area

“High risk” - 16, 18, 31, 33, 45, 52, 58

“Low risk” – 6 and 11

Risk Factors

First age at intercourse

Number of sexual partners

Likelihood the partner has HPV

CDC HPV related cancers

Rates per 100,000

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Prevalence – Dunne et al.

National Health and Nutrition Examination Survey

N=1921, cervicovaginal swabs for HPV DNA

Overall HPV prevalence was 26.8% 14 to 19 years – 24.5%

20 to 24 years – 44.8%

25 to 29 years – 27.4%

30 to 39 years – 27.5%

40 to 49 years – 25.2%

50 to 59 years – 19.6%

Significant trend of increasing prevalence each year from 14-24, then trend toward significant decrease to age 59

Prevalence

Problem?

Defn - the percentage of a population

that is affected with a particular disease

at a given time

HPV dormancy

Keratinocyte stem cells in the epithelial

basement layer

Can lay dormant for years

Will have a negative HPV swab

Progression to cancer

Infection with HR-HPV

Persistence of the HPV infection

Progression of a clone of epithelial cells

from persistent viral infection to pre-

cancer

Development of carcinoma and invasion

through the basement membrane

Risk of HPV persistence and

progression

Cervical Cancer PAP Smear

50% of women diagnosed with cervical

cancer have never had cervical cytology

Another 10% have not been screened

for > 5 years

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HPV Testing

More sensitive than cervical cytology

alone in detecting high or low grade

cervical histopathology

Poor specificity and poor positive

predictive value

Leads to a higher number of

colposcopies and cervical biopsies

ALTS Trial

Reflex HPV testing as triage

Women with ASCUS interpretation Directed to colposcopy, HPV testing, or repeat

cytology with colposcopy as needed

Conclusions Reflex HPV as sensitive for detecting CIN as

colposcopy

Should be the preferred approach for patients with ASCUS

Majority of LSIL (83%) had HR-HPV

Reflex HPV not cost-effective in this group

HPV Testing

Canadian Cervical Cancer Screening Trial , 2007 (n=10,154) HPV vs conventional PAP smears to detect CIN

2+

Sensitivity - 94.6 vs 55.4% *

Specificity - 94.1 vs 96.8% *

Population Based Screening Study Amsterdam, 2007 (n=17,000) Conventional PAP + HPV vs PAP alone

Detected 70% more lesions at first screening

No difference in overall CIN3 detection after second screening

ATHENA Trial

Addressing the Need for Advanced HPV

Diagnostics study (2008-2009)

N= 47,208

Two phases

Initial baseline results

3 year follow-up

Comparison of cervical

screening strategies

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HPV-vaccine era

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FDA approval of HPV vaccine

June 2006 – approved for girls and

women aged 9-26

October 2009 – approved for boys and

men aged 9-26

December 2014/2015 – approved

Gardasil-9 for use in boys and girls ages

9-26

October 5, 2018 – FDA approval for

Gardasil-9 for men and women 27-45

cdc.org/hpv/infographics/vacc-coverage.html

Biomarkers

May be more important in post-

vaccination era

earlier detection of cervical cancer

improved reproducibility

surveillance of high-risk patients

post-treatment monitoring for recurrence

Biomarkers

p16INK4a Cyclin-dependant kinase inhibitor

Almost all carcinomas and CIN 3 stain

Majority of CIN 2 but few CIN 1

P16 negative lesions may be lower-risk for progression

High p16 on TMA associated with LN metastasis and poorer survival outcomes

Ki-67 Expressed during cell proliferation

Not specific to cervical cancer

When used with p16 shows 94% sensitivity and 90% specificity in detecting CIN 2 or greater

C-myc Increased copy number is prognostic indicator of poor

likelihood of regression

Treatment for Cervical Cancer

Depends on the clinical stage

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Cervical Cancer Staging

Cervical Cancer Staging

Cervical Cancer Staging

Cervical Cancer Staging

Clinically staged Pelvic examination

Speculum, bimanual, and rectovaginal examination for palpation

and inspection of the primary tumor, uterus, vagina, and parametria

Examination for distant metastases

Palpation of groin and supraclavicular lymph nodes

Cervical Cancer Staging

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Pelvic examination Speculum, bimanual, and rectovaginal examination for palpation

and inspection of the primary tumor, uterus, vagina, and parametria

Examination for distant metastases Palpation of groin and supraclavicular lymph nodes

Cervical biopsy Colposcopy with directed cervical biopsy or cervical biopsy without

colposcopy if visible lesion

Conization/Endocervical curettage

Endoscopy Hysteroscopy, cystoscopy or proctoscopy

Imaging studies Intravenous pyelogram (IVP) – Evaluation for urinary tract

obstruction

Imaging with a plain chest radiograph and radiograph of the skeleton

Treatment

Stage

Desire for fertility

Tumor Volume

Medical co-morbidities

Known lymphatic spread

Age

Body habitus

Treatment based on stage

IA1 No LVSI – Cone vs extrafascial

hysterectomy

IA1 w LVSI, IB1, IB2, IIA – Radical

hysterectomy, pelvic lymphadenectomy

IB2, IIA, IIB, IIIA, IIIB, IVA – Concurrent

chemoradiation (consideration for

adjuvant chemotherapy)

IVB – Palliative chemotherapy, clinical

trial or best supportive care

Extrafascial vs Radical hysterectomy

Candidates for fertility preservation

Cervical Cancer

Options

Surgical ○ Radical trachelectomy,

lymphadenectomy

Vaginal

Laparoscopic or robotic

1http://seer.cancer.gov/csr/ 1975_2010/results_single/ sect_01_table.01.pdf, 2Sutton et al, Am. J. Obstet. Gynecol. 1992;166:50–53, 3Shimada et al, Gynecol Oncol. 2006;101(2):234-7. 4Lu et al, Gynecol Oncol. 2013;04:470.

Reconstruction of the uterine corpus to upper vagina after the cerclage is placed

The intent of the radical abdominal trachelectomy is to resect the cervix, upper 1–2 cm of the vagina, parametrium, and paracolpos in a similar manner to a type III radical abdominal hysterectomy but sparing the uterine corpus

Candidates for fertility preservation

Cervical Cancer

Radical abdominal trachelectomy— the cervical tissue and parametria are separated from the fundus

The uterine fundus is reattached to the vaginal apex

The reconstructed fundus with remaining blood supply from the intact utero-ovarian ligaments—uterine serosa without evidence of fundal ischemia

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Candidates for fertility preservation

Cervical Cancer

Obstetric outcomes >250 live births have been reported1

Plante et al, 20082, 20113

Survival outcomes

Recurrence

Mortality

1Lu et al, Gynecol Oncol. 2013;04:470. 2Plante et al, Gynecol Oncol. 2008;111:S105. 3Plante et al, Gynercol Oncol. 2011;121:290-7.

Plante 2008 N=256 pregnancies

Plante 2011 N=106 pregnancies

1st trimester loss 18% 20%

2nd trimester loss 8.6% 3%

3rd trimester delivery 62% 73%

Preterm delivery <37 weeks <32 weeks

28% 12%

18% 4%

Term delivery 40% 55%

Candidates for fertility preservation

Cervical Cancer

Oncologic outcomes

Plante et al, 20081, 20112

○ Risk Factors: 2008

Lesions larger than 2 cms (29 vs 1%)

Presence of LVSI (12 vs 2%)

○ Risk Factors: 2011

Lesions larger than 2 cms

1Plante et al, Gynecol Oncol. 2008;111:S105. 3Plante et al, Gynercol Oncol. 2011;121:290-7.

Plante 2008 N=603 patients (%)

Plante 2011 N=125 patients (%)

Recurrence rate 27 (4.5%) 6 (4.8%)

Death from disease (%)

15 (2.5%) 2 (1.6%)

Abandoned VRT 10-12% 4 (11%)

5 year PFS 96%

Radiation vs Radical Surgery

Equivalent cure rates for stage I and IIA

disease.

Case #1

33 yo G3P3

Post-coital bleeding

Exam showed 3cm friable cervical mass

with no parametrial or vaginal induration

Cervical biopsy – Grade 3 squamous

cell carcinoma

PET/CT Negative

Case #1

Treatment

Robotic-assisted radical hysterectomy with

bilateral salpingectomy and pelvic lymph

node dissection

Pathology

3.2 cm squamous cell carcinoma

No LVSI

Middle 1/3 invasion

Sedlis Criteria

Post surgery recurrence risk:

Intermediate risk: Sedlis: 30%

1. LVSI, outer 1/3, TS any

2. LVSI, middle1/3, TS >2cm

3. LVSI, Super 1/3, TS.5

4. No LVSI/deep/middle 1/3, TS >4

High Risk: 40%

Positive margins, nodes, parametrium

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Case #2

37 yo G2P2

Abnormal pap tests off and on since 20 yo

Cryotherapy 7 years ago

ASCUS pap 2013

Presented with abnormal bleeding and

discharge

Cervical mass seen on exam – Biopsy

proven squamous cell carcinoma

Treatment

Robotic assisted laparoscopic pelvic

lymph node debulking with para-aortic

sampling

Concurrent cisplatin and external beam

radiation therapy

High dose vaginal brachytherapy

Consideration for adjuvant

chemotherapy

Case #3

56 yo

Presented with abnormal bleeding

Last pap 1994

Clinical stage IIB with negative PET

Concurrent chemoradiation

Syed implant for brachytherapy (2/19/2015)

4/2015 No obvious parametrial induration

Case #3

Fell and hit abdomen 5/2015

Biopsied 6/2015

Consistent with metastatic squamous cancer

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Treatment for Recurrent

Cervical Cancer GOG 240

Paclitaxel/cisplatin ± bevacizumab

Paclitaxel/topotecan ± bevacizumab

Results

○ Paclitaxel/topotecan not superior or inferior to paclitaxel/cisplatin

○ Addition of bevacizumab shows improved PFS (8.2m vs 5.9m) and OS (17m vs 13.3m)

Lead to FDA approval of bevacizumab on August 14, 2014

Pembrolizumab (Keytruda)

June 12, 2018 - FDA approved

pembrolizumab (Keytruda, Merck and

Co. Inc.) for patients with recurrent or

metastatic cervical cancer with disease

progression on or after chemotherapy

whose tumors express PD-L1

Keynote 158

Single cohort 98 patients recurrent,

progressive cervical cancer

80% expressed PD-L1

ORR – 14.3% (CR – 2.6%/PR - 11.7%)

Median response duration not reached

91% had response ≥ 6 months

No responders in group without PD-L1

expression

On the Horizon

Advaxis

Engineered Listeria presenting HPV DNA as

foreign agent to stimulate immune system

PARP inhibitors

Cedirinib

potent inhibitor of vascular endothelial

growth factor (VEGF) receptor tyrosine

kinases

Quesitons?

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