8th Postgraduate Course for Training in Reproductive Medicine and Reproductive Biology

A Demonstration Project for Cervical Cancer screening
using the « see and treat » approach

S. Bomfim Hyppolito
Federal University of Ceara
Fortaleza-Ceara-Brazil

with the tutorial assistance of
Dr. Saloney Nazeer
Department of Obstetrics and Gynecology
University of Geneva

Summary

Visual inspection of the cervix with acetic acid wash (Acetic Acid Test -AAT) is a promising alternative to cytology for cervical cancer screening in low-resource settings. It also can enhance cytological test where it is already being used ,due to the low sensitivity rate which is being demonstrated for Papsmear, in countries with poor quality control. This study is designed to establish the characteristics of AAT (sensitivity, specificity) when performed by nurses in a developing country setting.

Methods

In a population-based project with community health education promotion ,3.000 women will be screened by nurses and physicians in a cross-sectional study conducted at primary care clinics in rural districts of the State of Ceara, Brazil. Naked-ey visual inspection of the cervix with acetic acid wash (4%) , as well as Pap smears, to compare their performances, and HPV-DNA sampling will be taken to assess quality in both tests. Colposcopy with biopsy, as indicated, will be used as the reference tests. Both test-positive and samples of test-negative subjects will be referred for the reference standard.

Outcome

• AAT should pick up at least 70% of high-grade lesion cases (i.e., 70% sensitivity for this grade lesion).
• Confidence level of 95%
• Power of 80%
• Desired precision =+/- .05
• Disease rate for high-grade lesions = 7/1.000
• 20% of all women testing (AAT and PAP) negative on screening would receive the Colposcopy reference test.

Hypothesis

• H1 - AAT is as sensitive test as Papsmear (in some places even more) , so it can be used as a first screening approach to enhance cytology test.
• H2 - AAT does not have a high specificity as Papsmear so its positive cases can be tested by Papsmear as a second screening approach.

key words: Cervical cancer screening, visual inspection, Papsmear, sensitivity, specificity, Acetic Acid Test, AAT

Introduction

Cervical cancer is known as having the most higher incidence form of cancer affecting women in the world. It is estimated an incidence of 450.000 new cases a year and it is expected a 300.000 death in this same period, due to cervical cancer (19)

It can also be stated that cervical cancer incidence is extremely high in Latin America and Southeast Asia, meanwhile this incidence in European countries, Australia and North America are considered low.( 5 ) In the countries of Latin American and the Caribbean, cervical carcinoma incidence rates are the highest in the world and this cancer is the fourth leading cause of death among women 15-64 years of age (2)

Epidemiology of Cancer of the Cervix in Brazil

In Brazil, according to data from the Cancer National Institute (1)cervical cancer incidence remains among the highest in Latin America. Studying data gathered by the five centers that collect Population-based data on cervical cancer, which are located in the five different Brazilian geographic regions, we see that Belem and Goiania (representing North and Central regions) are leading on the disease, followed by Fortaleza, Porto Alegre and Campinas, which represent Northeast, South and Southeast regions, respectively.

(*) Incidence rate/100.000 inhabitants selected by age in the world population of 1960.

Consequently, after a higher morbidity, North and Northeast regions have a higher mortality of cervical cancer, than Eastern and Southern states. In 1989 cervical cancer was responsible for 16.6% of all women's mortality in North and 13.1% in Northeastern states, as well. As a matter of fact it was responsible for 15% of all women's deaths in Brazil between 1979 to 1992.

Indeed, mortality rate of cervical cancer is not decreasing at all. The National Cancer Institute projected for 1997, 20.500 new cases of cervical cancer in Brazil and that, 5.760 women were expected to dye because of it.

In addition to the high incidence, Cervical cancer in Brazil is also detected in advanced stages. Reviewing the Rio de Janeiro Cancer Hospital records of 1994, it was found that 77% of the women were on stage II, III and IV, and it is demonstrated as follows:

Cervical cancer cases distribution according to stage of the disease - Hospital do Cancer/INCA - 1994 - Rio de Janeiro

Source: Registro de Cancer do Hospital do Cancer/INCA

Another problem of vital importance is the absolute lack of data, and the ones which are available are not updated ,as it could be seen by the figures we have presented up to now. The only information which could be obtained in 1997, were the ones which have been shown.This makes it very difficult to monitor and evaluate impact of any intervention.

Existing Health Care Infrastructure & current situation on Cervical Cancer screening

Where screening programs have become widely available, deaths from cervical cancer have been considerably reduced and cancer is diagnosed at an earlier stage, when curative treatment is available. In developed countries where Pap smears (coupled with education and good follow up) form the basis for cancer screening, death due to cervical cancer have decreased by 70% or more . Cervical cancer is nowadays uncommon in Canada, for instance, with an estimated incidence of 1,350 cases and 390 deaths in 1996, according to Canadian Cancer Statistics 1996.(10)

However, this did not happen in Brazil. Our infrastructure on public heath posts is poor and pap smear screening based program is mostly non-existent, or of low quality. Even when it is properly done, it is often available only in urban settings or from the private sector which serves a relatively small proportion of the female population and more often, there is no subsequent curative treatment of pre-invasive lesions.

Recently a bibliographic review has been done (4) to assess the effectiveness of cytology Pap smear as a screening test to early detection of Low and High Grade Squamous Intraepithelial Lesions (LHSIL and HGSIL) and cervical cancer, as well. It has been recognized that cytology as a screening test has never been properly tested . The eight randomized trials which have been done during the last ten years and were included on said paper, were not evaluating cytology test exclusively but, comparing its results with other screening tests (HPV-DNA and cervicography), using different slide preparation techniques , different devices to collect the smears and several target groups of women that may have brought confounding variables due to different hazardous conditions influencing sensitivity and specificity rates. Anyway, the overall sensitivity rates for cytology test on those studies could hardly reach a medium rate of 60.0%. It means that a large number of women who have had a negative test is outreached for treatment, as there is a consensus among patients and also among some clinicians that pap tests are infallible. It really has a considerable high specificity, (running from 82.0% to 99.7%, according to the already mentioned bibliographic review) that may give a good assurance that the tests which found to be positive, come from women who have the disease. It also must be said that those rates are addressing to HGSIL, including microcarcinoma. Lower results in cytology test are met when the cut-off point is for LGSIL (when really prevention takes place) and when cervical cancer is frankly invasive, as well.

On the other hand, screening for precancerous lesion without providing adequate treatment or poor follow up of patients due to large distances between rural population and the urban health settings or a nonexistent referral system at all, explains the inefficiency in decreasing the disease incidence and mortality rate of most developing world countries, and Brazil is no exception.

Alternative technologies for cervical cancer screening must be encouraged, proper clinical follow-up of women with abnormal findings should take place, and cervical lesions that require treatment should be excised or destroyed.

Oncogenic HPV TYPES (16, 18, 31, 33, 35) are now incriminated as a cause of squamous intraepithelial lesions that may progress to cervical cancers (14-17). Viral testing would appear to hold considerable promise in assessing women with LGSIL to screen for high risk in developing Cervical Cancer. However, to date, the clinical value of testing for the simple presence of HPV-DNA has been clouded by the fact that in 10% to 25% of apparently healthy women, these agents are exfoliated in morphologically normal cells (7-15).

Recognizing this, attention has recently focused on alternative means of providing cervical cancer screening (3-9-11-18) and treatment of early intraepithelial neoplasia (8-13-16). Perhaps the most promising among these methods is visual inspection with acetic acid (AAT). Published experiences with the acid test screening method (washing the cervix with 4-5% acetic acid solution and then visually inspection of the cervix for evidence of disease with the naked eye) show its advantages over traditional screening techniques in low-resource settings. This include immediate feedback to the patient regarding her test results and, importantly, the potential to provide treatment immediately after the test (6-12).

Considering the encouraging results of the studies which have already been mentioned, we propose this preventive cervical cancer demonstration project, to address the need of lowering of the incidence of the disease and diminishing the most advanced stages which lead to the death of thousands of women in developing countries, chiefly in the most poor rural regions like that of Northeast Brazil.

Protocol of the proposed Demonstration Study

Objective

To evaluate applicability of unaided visual inspection of Cervix with Acetic Acid Test (AAT) to enhance the existing cytological based screening program in resource constraint settings.

Sub-Objectives

• To increase population coverage for cervical cancer screening in the region.
• To decrease Pap smear load on the limited laboratory facilities in the region by selectively screening patients who need Pap smear.
• To increase patients` compliance by promoting awareness through Health Education and by decreasing the time period between screening and treating squamous intraepithelial lesion using the « see and treat » approach.
• To evaluate validity of Pap smear in this region.
• To study the performance of nurses and physicians in applying both acid test and Pap smear test in rural area settings.
• To determine the incidence of mild and severe dysplasia and cancer as well, in selected population groups which will be representative of general population in urban and rural areas.
• To find out the correlation of HPV-DNA positive test with Squamous Intraepithelial lesion (SIL) in the studied region.

Hypothesis

• H1 - AAT is as sensitive test as Papsmear (in some places even more) , so it can be used as a first screening approach to enhance cytology test.
• H2 - AAT does not have a high specificity as Papsmear so its positive cases can be tested by Papsmear as a second screening approach.

Study Design

This is a population-based randomized clinical trial. The investigation will be conducted in two phases: a diagnostic and a treatment approach.

Phase I

Recruitment and screening

Lectures will be given on churches of different districts in rural counties, to inform population and chiefly women who are sexually active (18 to 70 years old), about cervical cancer and improve their awareness toward the possibility of preventing it by attending the screening and the following treatment of precancerous lesions on designated dates and settings.

On a one day basis, women will be screened for cervical cancer through AAT, and cytology test. After being randomly assigned to a nurse or a physician, they will be first screened Papsmear then AAT test. Using an unlubricated bivalve speculum inserted in the vagina , Papsmear will be collected with the wooden Ayre spatula being scraped around the cervix, catching its entire transformation zone to obtain the adequate specimen (this is the currently used way for collecting Pap smear in the region).

Immediately after obtaining a cytology specimen, visual inspection of the exposed cervix is initiated by first thoroughly cleansing away any excess mucus with a dry cotton -tipped applicator. Next another cotton-tipped applicator soaked in 4% acetic acid is applied to the cervix. With the aid of a common spot-light used for out-patient gynecological exam, the nurse or the physician will then visualize the cervix. Clinical and AAT findings will be recorded on the patients registry card, according to the following categories:

Clinical diagnosed abnormality (2 and 3) with AAT negative will be scheduled for future investigation after Pap smear and receives immediate appropriate treatment. Cervical cancer (3) is immediately referred

If AAT assessment is abnormal or AAT diagnosis is normal but the Pap smear is abnormal, the woman is scheduled for a colposcopy test . The results of all Pap smears (when they become available) will be conveyed to local community leaders for patients recall and the women with an abnormal first screening test will attend locally a colposcopic examination. At this time it will be collected material for HPV-DNA testing of all women attending colposcopy and punch biopsy will be performed in all colposcopic positive cases. If no lesion is noted during colposcopy and the patient has not an HPV positive test, she will be reassured and asked to return to her local or closest clinic every year for routine follow-up. Women assessed as abnormal on colposcopy (confirmed, if indicated by biopsy) will be referred for appropriate treatment. HPV positive tests with negative colposcopic test will be followed on a the same bases as the negative cases, but with appropriate counseling.

Phase II

Treatment will take place in the same primary setting for LGSIL (mild dysplasias) using the eletrocauterization procedure (which is commonly available on health post located in the urban area of the rural counties), and patients will be counseled for follow-up.

HGSIL (severe dysplasias and microcarcinomas) will be referred to the University Hospital where a cone Loop excision will take place. Invasive carcinoma will be referred directly to National Cancer Institute, next to the University Hospital where the patients will be assessed and treatment can take place both with radiotherapy and or surgery, at the tertiary level of attention.

Independence of investigator assessment

Patients will be randomly assigned to a nurse or a physician. AAT will be performed at the same time the Pap smear sample is taken by both types of professionals. The Papsmears will then be analyzed by cytotechnicians, blinded to the AAT results. Colposcopy results will also be recorded without knowledge of the AAT or Pap smear results. Biopsies will be read without knowledge of any test result but final biopsy (Loop cone biopsies) results will be recorded after considering the Pap smear , colposcopy and HPV test.

Quality control

A 10% random sample of AAT test and PAP test assessed as test-negative will be tested for colposcopy. The positive ones will be assigned for colposcopy and will follow the other procedures already being described for AAT and PAP positive tests.

Sample size and Outcomes

Based on results from a pilot test (3), performed by the University Hospital (Maternidade Escola Assis Chateaubriand - MEAC) in rural areas similar to the ones which will be studied, the incidence of HGSIL and above was 7/1.000 women screened, similar to the same results obtained in ever screened women in urban areas and periurban areas who attend the same University Hospital.

• That AAT should pick up at least 70% of high-grade lesion cases (i.e., 70% sensitivity for this grade lesion).
• Confidence level of 95%
• Power of 80%
• Desired precision = ± .05
• Disease rate for high-grade lesions = 7/1.000
• 20% of all women testing (AAT and PAP) negative on screening would receive the colposcopy reference test.

Statistical analyses

Univariate analyses will be conducted for screening and diagnostic test results. Sensitivity and specificity analyses will be carried out using standard formulae for these test qualities. Confidence intervals (95%) will be calculated for all test characteristics measured.

Provider training/standardization

• Refresher training of nurse/physician in speculum examination
• Training in AAT using both JHPIEGO Atlas and the other one developed at the Department of Gynecology and Obstetrics of the University of Geneva by Dr.Saloney Nazeer, for screening washing portio with a 4% acid acetic solution.
• Training for HPV-DNA sampling
• Standardization in sampling the entire transformation zone for PAP smear
• Standardization for colposcopy screening and punch biopsy technique
• Standardization in treatment at primary levels (electrocauterization) and in tertiary level (Loop conization).
• Referral and contra-referral system assurance and data collection registry.

Bibliography

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2. Alleyne G, Early detection of cervical cancer. From the Director, Bulletin of the Pan Am Health Org 1996 Dec;30(4):283.
3. Blumenthal P, Gaffikin L, Maier N, Riseborough P, Workshop proceedings. Issues in cervical cancer:seeking alternatives to cytology, march 2-4, 1994, RH Training Materials JHPIEGO 1994.
4. Bomfim-Hyppolito S, Systematic bibliographic review, cytology as a cervical cancer screening test: how effective is it? Geneva,1998, unpublished .
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Edited by Aldo Campana,