India is a high-risk country for cervical cancer accounting for 25% (126,000 new cases, 71,000 deaths around the year 2000) of the world burden.1 The age-standardized incidence rates varies between 11–55/100,000 women in different regions.2, 3 Most cases present in advanced stages and the overall 5-year survival is <40%.4 Although prevention of cervical cancer is a priority of the National Cancer Control Programme of India, no organized screening programs exist in the country. The financial and logistics burden of operating an organized screening programme based on cytology is considerable, and has encouraged the evaluation of alternative methods such as visual inspection with acetic acid (VIA).5, 6, 7, 8
VIA is a simple, inexpensive test that can be provided by midwives, nurses and health workers. The sensitivity and specificity of VIA have been widely studied and found to be satisfactory.6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 Although model based studies17, 18 suggest VIA will be a cost-effective method of reducing cervical cancer burden, reduced incidence and mortality from cervical cancer following VIA screening has not yet been demonstrated in real programs. Such evidence from randomized intervention trials is valuable in guiding cervical cancer control policies in low-resource settings because the most persuasive evidence for the benefit of a cancer screening test comes from a randomized controlled clinical trial.
A cluster randomized, controlled intervention trial was initiated in May 2000 in a previously unscreened high-risk population in Dindigul District, Tamil Nadu, India, as a collaborative project between the Christian Fellowship Community Health Centre (CFCHC), Ambillikai, Dindigul district and the International Agency for Research on Cancer (IARC), Lyon, France. A high incidence (ASR: 55/100,000 women) of cervical cancer is observed in this backward rural district.3 The objective was to evaluate the efficacy of a single round of VIA screening provided by nurses, and associated with appropriate treatment approaches, in reducing incidence of and mortality from cervical cancer. There is a cancer treatment facility in the district and 4 tertiary cancer care hospitals are located within a radius of 100 kilometers. The screening was completed in April 2003 and we report the preliminary results of our study.
MATERIAL AND METHODS
Our study was designed as a cluster randomized intervention trial. One hundred thirteen village panchayaths (a local administrative structure consisting of 4–23 villages), covered by the population-based cancer registry of Ambillikai, Dindigul district, south India (Fig. 1), were randomized to an intervention group to receive a single round of VIA screening (57 village panchayaths, 504 villages) and to a control group (56 village panchayaths, 331 villages) (Fig. 2). Our study was reviewed and approved by the institutional review committees of the CFCHC and the IARC
The project infrastructure comprised of a project office with a central clinic, examination couches, colposcopes, equipment for cryotherapy and loop electrosurgical excision procedure (LEEP), a mobile generator, halogen focusing lamps, sterilization instruments, vaginal specula, biopsy punches and other instruments and consumables, (gloves, cotton, acetic acid, Lugol's iodine, Monsel's paste, formalin, decontaminants, nitrous oxide gas, loops, ball electrodes, etc.) vehicles for conducting field clinics and computers for data entry. This was organized before the commencement of screening.
Apparently healthy women 30–59 years of age with an intact uterus and no past history of cervical neoplasia were eligible to participate in the study. All households in the study villages were enumerated, using a household form, to identify and prepare a list of the eligible women. Each eligible woman was assigned a unique number, based on the cluster, village, house and individual numbers.
At the time of enumeration, a female health worker explained the nature of the study and the risk factors, prevention, early detection and treatment of cervical cancer to the eligible women. A printed consent form was read out, and the signature or left thumb impression of willing eligible women was obtained in the presence of a witness (usually a relative or neighbor). The health worker then interviewed the eligible women using a structured individual questionnaire to collect information on socio-demographic and reproductive variables. None of the participants in our study (with the exception of 2) had any prior screening for cervical cancer.
Training of project staff
Eight nurses with 3 years of nursing education after 10 years of schooling were trained in VIA, colposcopy and cryotherapy in a 3-week training course, using manuals prepared by the IARC.19, 20 The training included lectures, discussions, review of photographs of normal and abnormal cervix, as well as clinical sessions to observe and practice the techniques. The training was provided by experts from India and abroad. Three doctors were trained in VIA, colposcopy, cryotherapy and LEEP. A surgeon was trained in cold knife conization. The pathologists (n = 3) and the laboratory technicians (n = 2), responsible for processing and reporting on biopsy material, received special reorientation training sessions.
The competency of nurses and doctors were evaluated by ascertaining their ability to correctly assess 36 photographs of cervices to which acetic acid had been applied and 50 colpophotographs. All the providers were able to correctly assess more than two-thirds of the photographs before they commenced routine screening activities in the project. Periodic refresher courses were conducted every 4-months during the study to maintain competency.
Motivation and invitation of women for screening
Civic leaders, municipal representatives, office bearers of women's organizations, primary health care workers of the government health services and local volunteers in each village panchayaths were contacted and the project was explained to them. They constituted the local resource personnel to motivate women to participate in the study. A meeting of these persons and eligible women and their partners and relatives was conducted in each village to explain about cervical cancer prevention and to provide information on the project. The public were addressed by a medical officer and health worker. Health workers and local resource persons personally invited eligible women in the intervention group, 2 days before the organization of the screening clinic. All invited women were provided with a card indicating the date, time and place of screening. Women in the control group were given health education on cervical cancer and they were advised on how to avail themselves of cervical cancer prevention services from CHCHC and other hospitals. No active intervention was provided for the control group.
Screening and investigations
Screening clinics were organized in local primary health centres, municipal offices, schools, women's club buildings and in selected houses on a scheduled basis in the intervention villages. The clinic instruments and consumables were transported from the project office to the village clinics. The nature of the test, investigations and treatment were explained to women attending screening. In the screening clinic, each participant was placed in a modified lithotomy position and a nurse exposed and examined the cervix with the aid of a speculum and a bright halogen focus lamp. Acetic acid (4%) was then applied to the cervix using a cotton swab and excess mucus was cleared. VIA findings were noted 1 min after the application and the test result was recorded as negative or positive, based on the criteria given in Table I. VIA-negative women were reassured and medication was prescribed if they suffered from cervical inflammation.
Table I. Definition of VIA Test Results
VIA test result
No acetowhite lesions
Acetowhitening on endocervical polyps, nabothian cysts
Faint, ill defined, pinkish-white or bluish-white, translucent acetowhite lesions on the cervix
Patchy, discontinuous acetowhite areas on the cervix
Dot-like or streak-like acetowhitening on the cervix
Prominent white line-like acetowhitening of the squamocolumnar junction
Angular, geographic acetowhite lesions far away from the squamocolumnar junction
Opaque, dull, well-defined, confluent acetowhite lesions touching the squamocolumnar junction or close to the external os
Large, opaque, dense, well defined, acetowhite lesions surrounding the cervical os
Warts and leukoplakia close to the squamocolumnar junction turning intensely white after application of acetic acid
Dense, opaque acetowhitening of clinically visible ulceroproliferative growth of the cervix
The further investigations proposed were explained to VIA-positive women. Those consenting to these were examined by colposcopy (using 9–12× magnification) by a nurse, under the supervision of a medical officer, who was consulted whenever in doubt. A colposcopic diagnosis was made in terms of normal, inflammation, probable low-grade lesion (CIN 1), probable high-grade lesion (CIN 2-3), probable invasive cancer and frank invasive cancer.20 Punch biopsies were obtained from any abnormal areas on the cervix under colposcopic guidance. Biopsy specimens were processed in the pathology laboratory of the screening project and the slides were reported on by 1 of 4 pathologists at the PSG Institute of Medical Sciences and Research (Coimbatore, India).
Treatment of precancerous lesions
Women with colposcopically diagnosed low- and high-grade lesions, meeting all of the following 4 criteria, were advised to be treated immediately, by cryotherapy, after a directed biopsy. The criteria included: the lesion involves <3 quadrants of the transformation zone; no extension of the lesion into the endocervical canal; no extension of the lesion on to the vaginal walls; and the whole lesion could be covered by the cryoprobe. Before treatment, the nurse explained the outcome of colposcopy and the treatment procedure, potential benefits and side effects, complications of cryotherapy and encouraged the woman to accept immediate treatment. Cryotherapy was carried out using nitrous oxide refrigerant, with a 20–24 mm ectocervical cryo probe tip with a shallow nipple by standard double-freeze technique (3-min freeze; 5-min thaw; 3-min freeze; thaw). No local anesthesia or analgesics were used before the procedure. All the treated women received prophylactic antibiotic treatment with oral metronidazole and doxycycline for 5 days. Women were given home-care instructions and were asked to avoid sexual intercourse for 4 weeks. They were instructed to return to the clinic immediately if they had fever for more than 2 days or had bleeding severe enough to involve passing blood clots or severe lower abdominal pain.
Women with lesions more extensive than those eligible for cryotherapy were given an appointment to visit the central clinic at the CFCHC for LEEP or cold knife conization. LEEP was done by the surgeon under local anesthesia. Cold knife conization was carried out under general anesthesia.
Women treated for CIN were each given an appointment for a follow-up visit 1-year after treatment to assess the cervix and to rule out cervical neoplasia. At follow-up, VIA and colposcopy were done and biopsies were taken from colposcopically abnormal areas.
Treatment for invasive cancer
Women with suspected invasive cancers were referred to the clinical oncology department of the CFCHC or to 1 of 4 tertiary cancer care centres near the district for investigations, staging and treatment.
All project staff received periodic refresher training during the course of the study. Internal and external quality control measures were introduced for colposcopy and pathology.
Evaluation of the project
The evaluation of our project will be based on several measures of process (input) and outcome, both intermediate and final. Process measures to be evaluated include: proportion of eligible women screened, of women screened positive, of women investigated for diagnosis, of women with CIN and invasive cancer receiving treatment and of treated women who presented for follow-up at 1-year.
The intermediate outcome measures include: detection rates of CIN and invasive cancer, programme sensitivity to detect invasive cancer (calculated as the proportion of screen-detected biopsy confirmed cancer cases among the total invasive cancer cases recorded along the follow-up in the intervention arm), positive predictive value to detect both CIN 2-3 lesions and invasive cancer in the screened arm, stage distribution and survival of invasive cervical cancer patients in the study arms. Comparison of incidence and mortality from invasive cervical cancer between the study groups will be the final outcome measures for evaluation of the intervention.
A variety of methods will be used to collect information on incidence of and mortality from cervix cancer. The Ambillikai population-based cancer registry monitors cancer incidence in the study areas and the registry database is linked to the study database, to identify those invasive cervical cancers occurring in the study population. Mortality data are abstracted from the death registers of the village panchayaths and the primary health centres. Active follow-up of all eligible women included in the study will be carried out during 2004–2012 by health workers making house visits. This will permit more accurate information on person-years, vital status of study participants and will provide additional information on cervical cancer incidence and mortality among the study participants. In fact, the active follow-up of the population has been ongoing since September 2003.
Our study has been planned to have a 80% power at 5% significance level to detect a 50% reduction in cumulative mortality rate from cervical cancer at 10 years from enrollment.21 The death rate from cervical cancer in women 30–59 years of age has been estimated to be around 20/100,000. We have assumed clusters of an average of 600 eligible women to provide about 4,900 person-years of observation after 10 years (drop-out rate at 10 years assumed to be 25%). Taking into account the effect of the intra-cluster correlation, we assumed a coefficient of variation of 0.3 i.e., the true rates of death from cervical cancer would vary between 8/100,000 and 32/100,000 in the control group. This leads to a design effect of 1.08 and we thus have to randomize at least 52 clusters in each arm.21 The sample size requirement seems to be satisfied up to now because our study involves 56 and 57 clusters and an average of 694 eligible women per cluster.
Data management and statistical analysis
Data entry was carried out by 2 data entry operators in the study site, using an Access database. Data analysis is carried out using STATA 7.0. The characteristics of participating women, process and outcome measures are described as proportions. For calculation of incidence rates, the number of person-years in both groups was calculated from the date of enumeration of the individual to 30 April 2003 or death. The age-standardized incidence and mortality rates were calculated by directly standardizing with the world standard population.2
Of the 49,386 women 30–59 years of age enumerated in the intervention arm, 48,225 were found to be eligible to participate in the study who constituted the intervention arm. Of these, 30,577 (63.4%) were screened with VIA; 30,167 eligible women enumerated in the control villages constituted the control arm (Fig. 2). The characteristics of the study groups are given in Table II. Around 70% of the women had no formal education; half were 30–39 years of age; >70% had a household monthly income <2,000 Rupees (40$ or Euros). More than 50% of the women had undergone tubal ligation for birth control. The distribution of religion, marital status, income and parity were similar in the study groups but significant differences were observed for other variables.
Table II. Characteristics of Women in the Dindigul District Study
Numbers for each category do not always add up to the total number of women due to some missing information. Values are n (%).
Type of house
<12 months ago
>12 months ago
Total number of pregnancies
Screened women that were VIA-positive (Fig. 2) totaled 2,939 (9.6%). Test positivity declined with increasing age (Fig. 3). All screen-positive women had colposcopy; 2,777 (94.5%) of them received biopsy. A final diagnosis of CIN 1 occurred in 1,778 women; 222 had CIN 2-3 and 69 had screen-detected invasive cancer. The detection rate of CIN and invasive cancers in the screened arm by age group is shown in Figure 4. Women 30–39 years of age had a higher detection rate of CIN 2-3 lesions, whereas older women had a higher frequency of invasive cancer. Of the women in the control group, 1.7% (n = 500) requested and had screening with VIA at the CFCHC during May 2000–June 2003 after their enumeration and health education. Seven women were detected with CIN 2-3 lesions and treated.
Ninety-seven women in the intervention and 34 in the control groups were diagnosed with invasive cervical cancer between May 2000–April 2003. In the intervention arm, 69 cases were detected in VIA-positive women, 7 cancers occurred in women who were VIA-negative on screening (false-negative cancers) within 2 years from screening, 13 cancers occurred in eligible women who did not participate in screening (non-responders) and 8 cancers occurred in women after randomization, but before being invited for screening. The programme sensitivity to detect invasive cancer was 71.1% (69/97 cases); the positive predictive value for detecting both CIN 2-3 and invasive cancer was 8.7% (291/2939 VIA-positive women). One-third of the cases in the intervention arm were diagnosed in Stage I whereas 75% in the control arm were diagnosed in Stage III. There were no Stage I cases in the control group (Table III). In the intervention group, in group 30–39 years of age, 16 of 23 (69.6%) cancers were in Stage I as opposed to 18 (24.3%) of the 74 cancers in those 40–59 years of age.
Table III. Stage Distribution of Invasive Cervical Cancer by Study Arms
Intervention arm n(%)
Control arm n (%)
As of 30 April 2003, a total of 124,144 person-years were accrued in the intervention arm and 90,172 person-years in the control arm, after the enrollment. The crude-incidence rate of cervical cancer was 78.1/100,000 person-years in the intervention and 37.7/100,000 in the control arms. The corresponding age-standardized incidence rates were 92.4/100,000 and 43.1/100,000, respectively. The age-specific incidence of cervical cancer in the study arms is shown in Figure 5. Active detection of prevalent cases resulted in significantly higher incidence of cervical cancer in all age groups in the intervention arm as compared to the control arm.
Two-thirds of women with CIN 1, four-fifths with CIN 2-3 lesions and three-fourths with invasive cancer received treatment (Fig. 2). Among CINs, 1,288 women (1,179 CIN 1 and 109 CIN 2-3 lesions) received cryotherapy; of these, 983 (76.3%) received treatment in the same visit and others during a second visit. One hundred forty-eight (84 CIN 1 and 64 CIN 2-3 lesions) had LEEP and 5 CIN 2-3 had cold knife conization. At the time of this reporting, of the 953 women treated for CIN who were eligible for follow-up at 1 year, 222 (23.3%) actually reported.
The ultimate proof of efficacy of screening for cervical cancer is its ability to prevent invasive cancer. The most persuasive scientific evidence for the benefit of a cancer screening test comes from a randomized clinical trial where the endpoint is a reduction in incidence of or mortality from the disease of interest. Previously reported studies of VIA have primarily addressed the test characteristics6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 and a recent study described the feasibility, acceptability and safety of immediate cryotherapy post testing.22 Whether a VIA screening programme will be followed by a reduction in disease burden, and the costs involved in avoiding cases or saving lives (using programme-based data) remain to be established. Only evidence from randomized intervention trials can provide the necessary information on these points, to enable informed decisions to be taken on the implementation of visual screening in developing countries.
All screening programs require investments to ensure recruitment of women and investigation/treatment of screen-positive subjects. Although diagnosis (by colposcopy or biopsy) and treatment is the conventional approach for screen-positive women, a single-visit approach usually involves immediate treatment for most test-positive women with diagnostic investigations restricted to women with large lesions or suspect invasive cancer. It is important to establish that the savings in costs achieved by this simple screening method and the reduced number of recalls are not offset by the costs involved in investigating and treating a large proportion (around 10–15%) of women participating in the single-visit approach.
Currently, VIA is being evaluated in 3 randomized intervention trials in India.5 Ours is the first randomized intervention trial of cervical cancer screening in a developing country reporting preliminary results in terms of the feasibility, participation, detection rates of cervical neoplasia and stage shift in a large-scale VIA screening programme. We set out to evaluate a low intensity, once in a life-time, VIA screening, because frequently repeated screening is generally not feasible and is unrealistic in most low-resource countries. We adapted the conventional approach of investigating test positive women with colposcopy and biopsy, but encouraged treatment of precancers suitable for cryotherapy at the same visit. Household enumeration and personal interviews allowed the calculation of the distribution of reproductive and socio-economic variables in the study groups. As a community-based intervention, clusters of villages were randomized to minimize the potential for contamination between intervention and control groups and for logistic reasons. A significant imbalance in the distribution of socio-economic variables were observed between the study arms. The differences in the baseline characteristics of the study arms seem to be probably due to the small numbers of clusters in relation to the large population studied and due to inter-cluster heterogeneity. In the final analysis, an adjustment for these factors will be carried out.
The overall test-positivity in our study was <10%. It has ranged between 10–30% in most cross-sectional studies of VIA.7, 11, 12, 13, 14, 15, 16 There is a learning curve for VIA test providers. The test positivity was around 17% in the beginning of the study and it reduced to 8% after 6 months; but the detection rates of high-grade lesions and invasive cancer did not drop over time. The nurse providers did not demonstrate a ‘fatigue’ effect and did not lose interest in performing the procedures over time. The low VIA positivity (<5%) in older women (>45 years) seems to be due to the movement of the transformation zone and the squamocolumnar junction into the cervical canal. Inability to detect endocervical lesions is a disadvantage of VIA.
The main focus in our study was to detect and treat CIN to prevent future cancers. As expected, a high prevalence of lesions was observed in young women, as compared to older women. The detection rate of CIN 2-3 lesions in our screened arm was 2- to 3-fold higher than those reported from frequently screened populations in developed countries. For instance, the detection rate of CIN 2-3 lesions was 1.9/1,000 women (30–60 years, screened once in 5-years) in Finland during 1996.23 It was 3.3/1,000 women (25–64 years) in England during 1999/200024 and 3.2/1,000 women (30–59 years) in Australia during 1997–1998.25 The ratio of low-grade to high-grade lesions ranged from 0.5:1 to 1.4:1 in these populations as opposed to 8.1:1 in our study. It is obvious that VIA leads to excess detection of low-grade abnormalities.
The detection rate of invasive cancer exceeded CIN 2-3 disease after the age of 45 years. This has an important implication in countries with no treatment facilities for invasive cancer. The increased incidence of invasive cervical cancer observed in the intervention arm is due to the active detection of preclinical (21 Stage IA and 13 Stage IB cancers) and prevalent cases by VIA. It is important to note that the vast majority of cancers detected in those under 40 years of age were Stage I cancers, indicating the ability of VIA and colposcopy to detect preclinical invasive cancers. The cancer registry may still find clinically detected cases in the study arms during the years 2000–2003 up to mid 2005, hence, the incidence rates reported here should be considered as minimal rates. Seven of 27,638 VIA-negative women were diagnosed with invasive cervical cancer within 1–2 years from screening, yielding a provisional longitudinal false negative rate of 0.03% for invasive cancer, which is reassuring.
Of the 1,052 women not treated at the first visit (to consult with their spouse and family members, for example), only 495 (47.1%) turned up to receive treatment. On a similar note, only 25% of women treated for CIN reported for 1-year scheduled follow-up after treatment. These findings clearly establish the high loss to follow-up when recalls are involved. This has an important implication on participation if cytology-based screening programs, which rely on recall for investigating/treating screen-positive women, are contemplated for implementation in developing countries. Ensuring satisfactory adherence to recall will prove challenging and will require additional resources. For a high degree of success in terms of participation, programs with as few recalls as possible are clearly preferable. We did note, however, that 76.3% of the patients eligible for cryotherapy accepted treatment during the first visit.
The initial results from our study indicate that VIA-based screening programs result in early detection of cases and that it is feasible, safe and acceptable to the population in rural settings. Two-thirds of the eligible women participated in screening and a significant proportion of women with CIN accepted treatment by nurses in field conditions and LEEP by mid-level clinicians. No major complications, such as bleeding and pelvic inflammatory disease, were reported after cryotherapy; only one of the 148 women treated with LEEP required blood transfusion and suturing. Our study establishes that trained nurses may be efficiently used to screen, investigate (by colposcopy) and to provide cryotherapy in the field and that women accept a VIA-based programme with nurse providers.
We are planning active follow-up of the study arms by house visits on an annual basis over the next 10 years, in addition to collection of incidence data from the cancer registry and mortality data from existing death registers, to obtain as much complete information on cancer occurrence and vital events in the study arms. In due course, we believe that this should permit a valid and reliable evaluation of the impact of VIA screening on cervical cancer burden in our study.
The authors gratefully acknowledge the generous support of the Bill & Melinda Gates Foundation to our study through the Alliance for Cervical Cancer Prevention (ACCP). We are grateful to Dr. S.S. Sundar (John Radcliffe Hospital, Oxford, UK) for her assistance in training and quality control of colposcopy and treatment of CIN in our study. The authors are grateful to the numerous women's organizations, panchayath office bearers, voluntary organizations, staff of the local health services and civic leaders in the project area who facilitated the conduct of our study. The authors thank Mrs. E. Bayle for her help in the preparation of this manuscript.