Technologies for cervical cancer

detection, diagnosis, monitoring and

treatment in low-resource settings

4th WHO Global Forum on Medical Devices

Visakhapatnam, Andhra Pradesh, India
Agenda

 Background

 Screen & Treat: technical guidance

 Technical Guidance and Specifications

– Diagnostics
– Treatment

 Next Steps

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Cervical Cancer - Disease Context

 Primarily caused by persistent Human Papilloma Virus (HPV) infections.

 HPV, a DNA virus, has over 100 documented genotypes

– 40 of which are known to infect the anogenital tract.
– Between 12 and 14 are “high risk” genotypes, those that can cause progression
to cancer1.

 Cervical cancer is slow-growing. Its progression through precancerous

changes provides opportunities for:
1. Prevention;
2. Early detection; and,
3. Treatment

 Cervical cancer can be altogether eliminated.

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HPV and Cervical Cancer

 Cervical cancer remains one of the gravest threats to women’s

lives worldwide;

 Cervical cancer is caused by high-risk types of HPV;

– HPV 16 and 18: most common high-risk HPV types to cervical cancer
– Responsible for approximately 70% of cervical cancer cases.

 HPV is currently the most common sexually transmitted

infection (STI)
– 80% of women can be infected at some point in their lifetime;
– Most of infection clear naturally

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Life Course Approach to Cervical Cancer Prevention and Control

Primary Prevention Secondary Prevention Tertiary Prevention

Girls 9-14 years Women > 30 years of age All women as needed
• HPV vaccination Treatment of invasive cancer at any age and
Girls and boys, as appropriate “Screen and treat” – single visit approach palliative care
•Health information and warnings about •Ablative surgery
tobacco use • Point-of-care rapid HPV testing for high risk •Radiotherapy
•Sexuality education tailored to age & culture HPV types •Chemotherapy
•Condom promotion/provision for those • Followed by immediate treatment •Palliative Care
engaged in sexual activity • On site treatment
•Male circumcision

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Cervical Cancer: an Avoidable NCD with Gross Inequities

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May 2018: WHO Director General’s Call to Action to Eliminate
Cervical Cancer as a Public Health Problem

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 Increasing Access to Interventions for control towards
elimination

Control: Targets of
90% and
Elimination by
70% 2085 /2090
Cervical cancer cases/100,000

Elimination at 4 / 100,000

2020 2030 2060 2120

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 2020-2030 Acceleration plan towards elimination

Vision: A world without cervical cancer

Goal: below 4 cases of cervical cancer per 100,000 woman-years

90% 70% 30%

TARGETS
2030

of women screened with reduction in mortality

of girls fully vaccinated
an HPV test at 35 and 45 from cervical cancer
with HPV vaccine by 15
years of age years of age and 90%
managed appropriately

The 2030 targets and elimination threshold are subject to revision depending on the outcomes of the
modeling and the WHO approval process

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Strategy towards the elimination of cervical cancer as a
global public health problem: key outputs by 2030

1
Guiding principles: life course and public health approach, social justice and
equity, integrated people-centered health services

KEY OUTPUTS
2 Increased
Increased
coverage of
Increased coverage of
diagnosis &
coverage of HPV screening &
treatment for
vaccination treatment of pre-
invasive cancer
cancer lesions
and palliative care

3 Accelerators

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 5.1 Vaccinate: key component of the comprehensive
prevention and control strategy

 Two safe, effective vaccines that prevent infections from high-risk HPV
types 16 and 18 are presently licensed in most countries.

 One of the HPV vaccines (quadri- and nono-valent), also prevents

infections from HPV types 6 and 11, which cause 90% of anogenital warts

Target: 90% of girls fully vaccinated w HPV vaccine by 15 years of age

– Introduced in 85 countries by October 2018

– Coverage varies between less than 10% and more than 90%

 Vaccines do not cover all cancer-causing HPV types and do not treat pre-
existing infections; thus, ongoing screening is mandatory.

 Accelerated focus needed in Africa and Southern Asia

*2030 targets & elimination threshold are subject to revision depending on outcomes of the modeling & the WHO approval process.

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 5.2 Screen & Treat: reduces loss to follow-up, and can reduce
the time lag for women to receive treatment

 Early detection by screening all women in the target age-group, followed

by treatment of detected precancerous lesions, can prevent the majority
of cervical cancers.

 Cervical cancer screening should be performed at least once for every

woman in the target age group where most benefit can be achieved.

Target: 70% of women screened with an HPV test at 35 and 45 years of age
& 90% of the one screened positive managed appropriately

 Devices that can detect HPV, cytology and VIA play an important role in
cervical cancer prevention programs.

 Accordingly, effective and appropriate technologies for the treatment of

precancerous lesions be used: LEEP, cryotherapy, or thermal ablation.
*2030 targets & elimination threshold are subject to revision depending on outcomes of the modeling & the WHO approval process.

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5.3 Invasive Cancer Management

 Women diagnosed with early invasive cervical cancer can usually be

cured with effective treatment.

 It is important for health-care providers at all levels to be able to

recognize and promptly manage common symptoms and signs of cervical
cancer.

 The definitive diagnosis of invasive cervical cancer is made by

histopathological examination of a biopsy.

Target: 30% reduction of mortality from cervical cancer

 Treatment options include surgery, radiotherapy and chemotherapy;

these may be used in combination. If left untreated, invasive cervical
cancer is almost always fatal.

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 Working Groups: Taking Forward the Roadmap
of Activities and Stakeholder Coordination
Technical Task Team
(Membership: WHO Co-Chair; invitations to agencies and partners to join the 7 Working Groups)

WG 1 WG 2 WG 4 WG 5 WG 6 WG 7
Cervical Advocacy com- Impact Increasing Monitoring Research
WG 3 Cancer munications, & Modeling, Access to and
Elimination civil society Costing and Inter- Surveillance
WHO Recom- Strategic mobilization Financing ventions
mendations Documents and
(internal only) and Action engagement
Plan

5.1 5.2 5.3

Vaccines Screening & Invasive
Treatment Cancer
Manage-
ment

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Agenda

 Background

 Screen & Treat: technical guidance

 Technical Guidance and Specifications Chapters

– Diagnostics
– Treatment

 Next Steps

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Screen & Treat
Technical guidance and specifications - why?

 A key gap identified was the lack of technical guidance and specifications
for the majority of cervical cancer related tests and treatment
technologies.

 Technical specifications and guidance documents are critical in

facilitating the procurement, supply, or use of quality, appropriate
technologies.

 A strong focus of these documents will be the application in resource-

limited settings where existing guidance (if at all) is limited or
contextually unsuitable.

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Screen & Treat
Technical guidance and specifications – what?

 Current efforts will cover technical guidance and specifications for the
diagnostics and treatment of precancerous lesions for the prevention of
cervical cancer in terms of:
– Quality
– Performance
– Operational characteristics

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 Screen & Treat
Technical guidance and specifications – how?

 These will be useful for Policy-

makers, Managers, Procurement
officers, Professional health
workers, and even
manufacturers for:
– Procuring;
– Supplying; or,
– Using devices
for treating cervical precancer.

 These documents will fit into the

WHO repository of resources, to
be used alongside:

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Agenda

 Background

 Screen & Treat: technical guidance

 Technical Guidance and Specifications Chapters

– Diagnostics
– Treatment

 Next Steps

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Outline for the forthcoming Technical Guidance and
specification document

 Section 1: Screening and Diagnosis

WHO technical guidance &
– HPV NAT IVD specifications
– VIA Medical devices for
the diagnosis and treatment of
– Colposcope
pre-cancerous lesions for the
prevention of cervical cancer
 Section 2: Treatment
– Thermal Ablation
– Cryotherapy
– LEEP

 Section 3: Additional information

– WHO Infection Prevention and Control
– Procurement guidance
– Technical knowledge gaps or areas identified for further research

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HPV NAT IVD (1 of 4): Background

 Because HPV is the causative agent of cervical cancer, detection of HPV

has the potential to improve cervical cancer prevention programs

 HPV is a relatively small double stranded DNA virus that is present and
accessible in infected exfoliated cell specimens, allowing detection by
molecular nucleic acid tests (NAT) that utilize primers and probes to
amplify DNA or RNA targets

 HPV NATs for qualitative detection of high risk genotypes cover a range
of specifications:
– DNA and RNA-based technologies
• rtPCR, probe hybridization, invader signal, microarray PCR, TMA, NASBA
– Reporting out pooled and/or individual genotypes
– Internal controls for sample adequacy and to rule out inhibitory substances
– Manual, high throughput automated and point-of-care methodology

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HPV NATs (2 of 4): Considerations When Implementing

 Specimen acquisition:
– Health-care provider collected
• Need for exam table/light, specula, gloves, sterilization equipment
– Self-collected
• In clinic or home-based

 Performance of NATs:
– Laboratory or point-of-care
– Infrastructure and equipment considerations
• Are electricity, running water, refrigeration/freezing required?
• Possible need for specimen racks, pipettes/tips, centrifuge, heating blocks, disinfectants
– Workflow: batch or single samples, throughput requirements

 Interpretation of Results
– Health-care provider training in interpretation and next steps essential

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HPV NATs (3 of 4): Strengths and Limitations

 HPV NATs have the potential to improve cervical cancer prevention

programs by improving sensitivity of precancer detection

 Provide objective screening results

 Allow for self-collected sampling

 Workflow flexibility:
– Laboratory- vs clinic-based
– Manual, automated or point-of-care platforms

 Infrastructure requirements and equipment may not be accessible in LRS

 Need for trained health-care providers and laboratory personnel

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HPV NAT IVD (4 of 4): Technical Specification Guidance

 Clinical Performance:
– At least 90% of sensitivity of the designated comparator for detection of CIN2 or
greater
– Not less than 98% of specificity of the designated comparator
– lower bound of agreement not less than 87% for inter- and intra-laboratory
reproducibility
 Analytic performance:
– Sensitivity: (Limit of Detection) dependent on genotype detected, characteristics of
particular test
– Specificity: cross-reactivity with a panel of organisms (to include those common to
female urogenital tract) and low risk HPV genotypes; assessment of effect of
endogenous and exogenous interfering substances in cervical specimens
 Operational requirements
– Infrastructure, equipment, specimen throughput, reagent storage, waste disposal:
key considerations that are dependent on particular test and need to be addressed

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VIA (1 of 2): Background

 Visual Inspection with Acetic Acid (VIA) is a technique for the detection
of pre-cancerous or cancerous lesions in the cervix.

 The application of dilute acetic acid on such lesions triggers whitening of

these regions.

 VIA is a relatively simple, low-cost VIA Screening Results:

method presenting immediate results. Negative Positive

 A positive result can be followed by

immediate treatment (i.e. single-visit
approach).

 VIA is subjective and depends on the

skills and experience of the provider. Image source: Jhpiego, 2015

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VIA (2 of 2): Technical Specification Guidance

 Glacial (water-free) acetic acid is the base for this medium; household
white vinegar is another source of concentrated acetic acid.

 A 5% acetic acid solution must be used.

 A pharmacist, chemist or chemical supplier can make dilute (5%) acetic

acid according to the following:
– Use glacial acetic acid (water-free acetic acid) or acetic acid with known
concentration (above 5%)
Total parts of water = [% concentrate/% dilute] − 1
– E.g. preparing a 5% solution from a 20% concentrated acetic acid solution:
20%
Total parts of water = 5% − 1 = 3 → 3 parts water to 1 part
concentrate, by volume

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Colposcope (1 of 3): Background

 A colposcope is an instrument that provides strong light and magnifies a

field, allowing specific patterns in the epithelial (surface) layer and
surrounding blood vessels to be examined.

 Colposcopes are used on patients with positive screening results, to:

– verify the presence, extent, and type of pre-cancer or cancer;
– to guide biopsies of any areas that appear abnormal; and,
– to help determine more appropriate treatment (cryotherapy, LEEP, or TA).

 Colposcopy requires highly trained providers and is not an appropriate

screening tool, nor is colposcopy a required step between screening and
treatment.

 More recently, colposcopes are being designed as handheld, specialized

video or digital camera tools.

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Colposcope (2 of 3): Strengths and limitations

 Colposcopy can be used to guide a biopsy of an

abnormal area.

 Colposcopes are expensive, specialized pieces of

equipment.

 Colposcopy is resource intensive; it requires provider

training, specialized equipment and pathology services.

 It should not be used as a screening method.

 If the procedure is not readily available, this can create

bottlenecks in the system, leading to patients being
lost to follow-up.

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Colposcope (3 of 3): Technical Specification Guidance

 Optical magnification: 2x-15x, continuous or discrete.

 Working distance: 300 mm.

 Manual or autofocus.

 Colposcope head including eyepiece distance should be high and

maneuverable.

 Must be attached to a stand or easily fixed onto a stand for hands-free

visualization during treatment.

 Light source: halogen or LED, with green light filter.

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Thermal Ablation (1 of 3): Background

 Thermal ablation has been used effectively in some settings for many
years, especially for the treatment of endometriosis.

 Thermal ablation uses low heat to destroy lesions.

 It has limited side-effects, is inexpensive compared with other treatment

options, it is not dependent on a continuous supply chain, and is
technically simple to implement.

 Only recently have handheld devices come on the market, making the
method more suitable for LRS (benchtop models are cumbersome and
reliant on mains, though highly effective).

 Thermal ablation can be performed immediately after screening, by a

range of trained healthcare providers across all levels of health systems.

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Thermal Ablation (2 of 3): Strengths and limitations

 The equipment is simple &

relatively inexpensive.

 External gas is not required.

 Electricity is not necessarily required; can function

off of portable batteries/power-supply.

 In the context of a screen & treat approach, a

screen-positive result can be followed by an offer of
treatment at the same visit, maximizing treatment
coverage and reducing loss to follow-up.

 This treatment method does not produce a

specimen for pathological examination.

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Thermal Ablation (3 of 3): Technical Specification Guidance

 Handheld (rechargeable) or benchtop (plug-in)

 Compatible for use with at least two probes with different-sized tips
– Standard tip diameters: 16 mm and 19 mm
– A flat tip and a tip with a nipple for placement into the cervical canal

 Heat to 100-120°C and has a depth penetration of 4-7mm

 Typical duty cycle:

– 8 seconds of heat up;
– 20-45 seconds of treatment; and
– 10 seconds to cool down.

 Tips should be easily decontaminated, cleaned, and sterilized or

disinfected between patients.

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Cryotherapy (1 of 3): Background

 Cryotherapy eliminates precancerous areas on the cervix by applying a

highly cooled metal disc (cryoprobe) to the cervix and freezing the
abnormal areas (along with normal areas) covered by it.

 Supercooling of the cryoprobe is accomplished using a coolant gas

(either compressed carbon dioxide, CO2, or nitrous oxide, N2O), thus
relies on a complex supply chain.

 Cryotherapy can be performed immediately after screening, usually by a

wide range of trained health care providers across all levels of the health
system, and has long been the standard in LRS.

 It takes ~15 minutes and is generally well tolerated, associated with only
mild discomfort, and thus does not require anaesthesia. The treated area
takes about a month to regenerate.

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Cryotherapy (2 of 3): Strengths and limitations

 The equipment is simple &

relatively inexpensive.

 Electricity is not required.

 In the context of a screen & treat approach, a

screen-positive result can be followed by an
offer of treatment at the same visit, maximizing
treatment coverage and reducing loss to follow-up.

 This treatment method does not produce a specimen

for pathological examination.

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Cryotherapy (3 of 3): Technical Specifications Overview

 Can be consoles or stand-alone or handheld units.

 The probe has a closed system in which the cryogen travels to and
circulates in the probe head, then back through probe for exhausting.
(An open system is not suitable for CO2 and N2O)

 Contact between supercooled metal probe tip and epithelium results in

tissue necrosis. The following table indicates treatment temperatures:

Source: Colposcopy and Treatment of Cervical Cancer, IARC 2017

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LEEP (1 of 3): Background

 LEEP – Loop Electrosurgical Excision Procedure – is the removal of

abnormal areas from the cervix and the entire transformation zone using:
1 – A thin wire loop powered by an
1 2
electrosurgical unit (ESU), which
cuts and coagulates at the same
time; after which,
2 – A ball electrode is used on the
tissue to complete the coagulation.
3
3 – Tissue removed can be sent for
examination to the histopathology
laboratory, allowing the extent of the lesion to be assessed.

 The procedure can be performed under local anesthesia on an outpatient

basis and usually takes 10-15 minutes; however, a patient should stay in-
facility for a few hours to assure bleeding does not occur.

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LEEP (2 of 3): Strengths and limitations

 LEEP is a relatively simple surgical procedure, but it should only be

performed by an intensively trained health-care provider with
demonstrated competence in the procedure

 Recognizing and managing intraoperative and postoperative

complications, such as bleeding or infection is crucial; LEEP is best carried
out in at least secondary-level facilities where backup care is available.

 The histology specimen can have charred borders, making lesion margins
difficult to interpret.

 LEEP:
– Relies on dependable, quality power supply
– Uses sophisticated equipment that requires maintenance.

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LEEP (3 of 3): Technical Specifications Overview

 Equipments needed: ESU (with probes), colposcope,

optional (UPS), speculum

 ESU specification for LEEP:

– Reliable power supply. Metal casing case. Foot pedal
control
– Function:
• coagulation mode: up to 80 W / 150 Ω, cutting mode: up
to 110 -200 W / 300 -400 Ω;
• LEEP specific: blended current option available,
coagulation maximum > 60 W, cutting maximum > 60 W.
WHO comprehensive guide to cervical cancer control, 2014
– Electrode: wired, various sizes and shapes (minimum
ball electrode, square loop electrode, semicircular loop
electrode), made of stainless steel or tungsten wire.

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Agenda

 Background

 Screen & Treat: technical guidance

 Technical Guidance and Specifications Chapters

– Diagnostics
– Treatment

 Next Steps

39 |
Current timeline

Nov-Dec 2018 Dec-Jan 2019 Jan-Feb 2019 25 Feb 2019

•Develop
Document
comprehensive Draft Review Print
finalization
draft

Consultants will There are two review Authors will address The final document
author individual cycles: questions, will be sent to print.
chapters and WHO 1)During the Global comments and/or
will compile chapters Forum for Medical concerns raised
into a single Devices; and, during the review.
comprehensive draft. 2)Review by GMTA/ After which WHO will
HTAi & expert work on layout,
group design, technical
editing and proofing.

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Output: A new technical guidance and specification document!

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Next steps

 To follow will be technical guidance and specifications for diagnostics

and technologies for invasive cervical cancer treatment:
– Surgical procedures;
– Radiotherapy; and,
– Chemotherapy.

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