Surendra Shastri

HPV Screening for Cervical Cancer in Rural India

BACKGROUND In October 1999, we began to measure the effect of a single round of screening by testing for human papillomavirus (HPV), cytologic testing, or visual inspection of the cervix with acetic acid (VIA) on the incidence of cervical cancer and the associated rates of death in the Osmanabad district in India. METHODS In this cluster-randomized trial, 52 clusters of villages, with a total of 131,746 healthy women between the ages of 30 and 59 years, were randomly assigned to four groups of 13 clusters each. The groups were randomly assigned to undergo screening by HPV testing (34,126 women), cytologic testing (32,058), or VIA (34,074) or to receive standard care (31,488, control group). Women who had positive results on screening underwent colposcopy and directed biopsies, and those with cervical precancerous lesions or cancer received appropriate treatment. RESULTS In the HPV-testing group, cervical cancer was diagnosed in 127 subjects (of whom 39 had stage II or higher), as compared with 118 subjects (of whom 82 had advanced disease) in the control group (hazard ratio for the detection of advanced cancer in the HPV-testing group, 0.47; 95% confidence interval [CI], 0.32 to 0.69). There were 34 deaths from cancer in the HPV-testing group, as compared with 64 in the control group (hazard ratio, 0.52; 95% CI, 0.33 to 0.83). No significant reductions in the numbers of advanced cancers or deaths were observed in the cytologic-testing group or in the VIA group, as compared with the control group. Mild adverse events were reported in 0.1% of screened women. CONCLUSIONS In a low-resource setting, a single round of HPV testing was associated with a significant reduction in the numbers of advanced cervical cancers and deaths from cervical cancer.

ACCURACY OF VISUAL SCREENING FOR CERVICAL NEOPLASIA: RESULTS FROM AN IARC MULTICENTRE STUDY IN INDIA AND AFRICA

Visual inspection‐based screening tests, such as visual inspection with 4% acetic acid (VIA) and with Lugols iodine (VILI), have been proposed as alternatives to cytology in mass screening programs. To date, there is only limited information on the accuracy of these tests in detecting High‐grade Squamous Intraepithelial Lesions (HSIL). Eleven cross‐sectional studies involving 56,939 women aged 25–65 years were conducted in Burkina Faso, Congo, Guinea, India, Mali and Niger to evaluate the accuracy of VIA and VILI performed by health workers. A common protocol and questionnaire was used. For final diagnosis, all women were investigated with colposcopy and biopsies were taken when necessary. Data from the studies were pooled to calculate sensitivity, specificity and predictive values of the tests for the detection of HSIL. Of the screened women, 16.1% and 16.4% were positive on examination using, respectively, VIA and VILI; 1,063 were diagnosed with HSIL. The pooled sensitivity, specificity, positive and negative predictive values for VIA were 76.8% (95% CI: 74.2–79.4%), 85.5% (95% CI: 85.2–85.8%), 9.4% (95% CI:8.8–10.8%) and 99.5% (95% CI:99.4–99.6%), respectively. The values were 91.7% (95% CI: 89.7–93.4%), 85.4% (95% CI: 85.1–85.7%), 10.9% (95% CI: 10.2–11.6%) and 99.8% (95% CI:99.7–99.9%), respectively for VILI. The range of sensitivity and specificity for VIA was 56.1–93.9% and 74.2–93.8%, respectively, between studies and were 76.0–97.0 % and 73.0–91.3% for VILI. VILI had a significantly higher sensitivity than VIA in detecting HSIL, but specificity was similar. VILI appears to be a more accurate visual test for use in screening and treatment programs in low‐resource settings.

Pooled analysis of the accuracy of five cervical cancer screening tests assessed in eleven studies in Africa and India.

Cervical cancer is the main cancer among women in sub‐Saharan Africa, India and other parts of the developing world. Evaluation of screening performance of effective, feasible and affordable early detection and management methods is a public health priority. Five screening methods, naked eye visual inspection of the cervix uteri after application of diluted acetic acid (VIA), or Lugols iodine (VILI) or with a magnifying device (VIAM), the Pap smear and human papillomavirus testing with the high‐risk probe of the Hybrid Capture‐2 assay (HC2), were evaluated in 11 studies in India and Africa. More than 58,000 women, aged 25–64 years, were tested with 2–5 screening tests and outcome verification was done on all women independent of the screen test results. The outcome was presence or absence of cervical intraepithelial neoplasia (CIN) of different degrees or invasive cervical cancer. Verification was based on colposcopy and histological interpretation of colposcopy‐directed biopsies. Negative colposcopy was accepted as a truly negative outcome. VIA showed a sensitivity of 79% (95% CI 73–85%) and 83% (95% CI 77–89%), and a specificity of 85% (95% CI 81–89%) and 84% (95% CI 80–88%) for the outcomes CIN2+ or CIN3+, respectively. VILI was on average 10% more sensitive and equally specific. VIAM showed similar results as VIA. The Pap smear showed lowest sensitivity, even at the lowest cutoff of atypical squamous cells of undetermined significance (57%; 95% CI 38–76%) for CIN2+ but the specificity was rather high (93%; 95% CI 89–97%). The HC2‐assay showed a sensitivity for CIN2+ of 62% (95% CI 56–68%) and a specificity of 94% (95% CI 92–95%). Substantial interstudy variation was observed in the accuracy of the visual screening methods. Accuracy of visual methods and cytology increased over time, whereas performance of HC2 was constant. Results of visual tests and colposcopy were highly correlated. This study was the largest ever done that evaluates the cross‐sectional accuracy of screening tests for cervical cancer precursors in developing countries. The merit of the study was that all screened subjects were submitted to confirmatory investigations avoiding to verification bias. A major finding was the consistently higher sensitivity but equal specificity of VILI compared with VIA. Nevertheless, some caution is warranted in the interpretation of observed accuracy measures, since a certain degree of gold standard misclassification cannot be excluded. Because of the correlation between visual screening tests and colposcopy and a certain degree of over‐diagnosis of apparent CIN2+ by study pathologists, it is possible that both sensitivity and specificity of VIA and VILI were overestimated. Gold standard verification error could also explain the surprisingly low sensitivity of HC2, which contrasts with findings from other studies.

Challenges to effective cancer control in China, India, and Russia

Cancer is one of the major non-communicable diseases posing a threat to world health. Unfortunately, improvements in socioeconomic conditions are usually associated with increased cancer incidence. In this Commission, we focus on China, India, and Russia, which share rapidly rising cancer incidence and have cancer mortality rates that are nearly twice as high as in the UK or the USA, vast geographies, growing economies, ageing populations, increasingly westernised lifestyles, relatively disenfranchised subpopulations, serious contamination of the environment, and uncontrolled cancer-causing communicable infections. We describe the overall state of health and cancer control in each country and additional specific issues for consideration: for China, access to care, contamination of the environment, and cancer fatalism and traditional medicine; for India, affordability of care, provision of adequate health personnel, and sociocultural barriers to cancer control; and for Russia, monitoring of the burden of cancer, societal attitudes towards cancer prevention, effects of inequitable treatment and access to medicine, and a need for improved international engagement.

A cluster randomized controlled trial of visual, cytology and human papillomavirus screening for cancer of the cervix in rural India†

The impact of screening by visual inspection with acetic acid (VIA), cytology or HPV testing on cervical cancer incidence and mortality is investigated in a cluster randomized controlled trial in India. We report findings after the screening phase, when 52 clusters, with a total of 142,701 women aged 30–59 years in Osmanabad District, India, were randomized into 4 arms for a single round of screening by trained midwives with either VIA, cytology or HPV testing as well as a control group. All laboratory tests were done locally. Test‐positive women underwent investigations (colposcopy/biopsy) and treatment in the base hospital. Data on participation, test positivity, positive predictive value and detection rates of cervical neoplasia were analyzed using cluster design methodology. Of the eligible women, 72–74% were screened. Test positivity rates were 14.0% for VIA, 7.0% for cytology and 10.3% for HPV. The detection rate of high‐grade lesions was similar in all intervention arms (0.7% for VIA, 1.0% for cytology and 0.9% for HPV testing) (p = 0.06, Mann‐Whitney test). While the detection rate for VIA dropped to 0.5% with declining test positivity during the course of the study, it remained constant for cytology and HPV testing. Over 85% of women with high‐grade lesions received treatment. Our results show that a high level of participation and good‐quality cytology can be achieved in low‐resource settings. VIA is a useful alternative but requires careful monitoring. Detection rates obtained by HPV testing were similar to cytology, despite higher investments.

A cluster randomized, controlled trial of breast and cervix cancer screening in Mumbai, India: methodology and interim results after three rounds of screening

Cervix and Breast cancers are the most common cancers among women worldwide and extract a large toll in developing countries. In May 1998, supported by a grant from the NCI (US), the Tata Memorial Hospital, Mumbai, India, started a cluster‐randomized, controlled, screening‐trial for cervix and breast cancer using trained primary health workers to provide health‐education, visual‐inspection of cervix (with 4% acetic acid‐VIA) and clinical breast examination (CBE) in the screening arm, and only health education in the control arm. Four rounds of screening at 2‐year intervals will be followed by 8 years of monitoring for incidence and mortality from cervix and breast cancers. The methodology and interim results after three rounds of screening are presented here. Good randomization was achieved between the screening (n = 75360) and control arms (n = 76178). In the screening arm we see: High screening participation rates; Low attrition; Good compliance to diagnostic confirmation; Significant downstaging; Excellent treatment completion rate; Improving case fatality ratios. The ever‐screened and never‐screened participants in the screening arm show significant differences with reference to the variables religion, language, age, education, occupation, income and health‐seeking behavior for gynecological and breast‐related complaints. During the same period, in the control arm we see excellent participation rate for health education; Low attrition and a good number of symptomatic referrals for both cervix and breast.

Accuracy of human papillomavirus testing in primary screening of cervical neoplasia: Results from a multicenter study in India

The knowledge that cervical neoplasia are caused by human papillomavirus (HPV) infection has led to the evaluation of its role in screening. We evaluated the accuracy of HPV testing by Hybrid capture II (HC II) method in detecting cervical intraepithelial neoplasia grade 2 and 3 (CIN 2 and 3) lesions in 4 cross‐sectional studies with common protocol and questionnaire in 3 different locations (Kolkata, Mumbai and Trivandrum) in India. These studies involved 18,085 women aged 25–65 years. The reference standard for final diagnosis was a combination of colposcopy/biopsy. All women were investigated with colposcopy and 3,116 received directed biopsy. The sensitivity of HPV testing for detecting CIN 2–3 lesions varied from 45.7% to 80.9% across the study sites; the specificity varied from 91.7% to 94.6% and the positive predictive value from 6.7% to 13.7%. Retesting of 298 randomly chosen denatured samples in France revealed an agreement rate of 85.9% and a κ‐value of 0.72. Although HPV testing seems to be a promising approach for cervical cancer prevention, a large range in sensitivity was observed in our study, possibly due to variations in the quality of specimen collection and reference standards. A higher sensitivity was associated with the center performing the test well. Further developments in terms of more reproducible, less expensive and less sophisticated testing are essential to make the test feasible and effective in low‐resource settings.

Concurrent evaluation of visual, cytological and HPV testing as screening methods for the early detection of cervical neoplasia in Mumbai, India

OBJECTIVE Naked eye visual inspection with acetic acid (VIA), magnified VIA (VIAM), visual inspection with Lugols iodine (VILI), cytology and human papillomavirus (HPV) testing were evaluated as screening methods for the detection of high-grade squamous intraepithelial lesions (HSIL) of the uterine cervix in a cross-sectional study in Mumbai, India. METHODS Cytology, HPV testing, VIA, VIAM and VILI were carried out concurrently for 4039 women aged 30-65 years. All women were investigated with colposcopy and biopsies were taken from 939 women who had colposcopic abnormalities. The reference standard for final disease status was histology or negative colposcopy. The presence of HSIL was confirmed in 57 women (1.4%). The test characteristics for each method were calculated using standard formulae. RESULTS The sensitivities of cytology, HPV testing, VIA, VIAM and VILI were 57.4%, 62.0%, 59.7%, 64.9%, and 75.4%, respectively (differences were not statistically significant). The specificities were 98.6%, 93.5%, 88.4%, 86.3%, and 84.3%, respectively. Adding a visual test to cytology or HPV testing in parallel combination resulted in a substantial increase in sensitivity, with a moderate decrease in specificity. The parallel combination of VILI and HPV testing resulted in a sensitivity of 92.0% and a specificity of 79.9%. CONCLUSION As a single test, cytology had the best balance of sensitivity and specificity. Visual tests are promising in low-resource settings, such as India. The use of both VIA and VILI may be considered where good quality cytology or HPV testing are not feasible. The sensitivity of cytology and HPV testing increased significantly when combined with VIA or VILI.

Effect of VIA Screening by Primary Health Workers: Randomized Controlled Study in Mumbai, India

BACKGROUND Cervical cancer is the leading cause of cancer mortality among women in India. Because Pap smear screening is not feasible in India, we need to develop effective alternatives. METHODS A cluster-randomized controlled study was initiated in 1998 in Mumbai, India, to investigate the efficacy of visual inspection with acetic acid (VIA) performed by primary health workers in reducing cervical cancer mortality. Four rounds of cancer education and VIA screening were conducted at 24-month intervals in the screening group, whereas cancer education was offered once at entry to the control group. The study was planned for 16 years to include four screening rounds followed by four monitoring rounds. We present results after 12 years of follow-up. Poisson regression method was used to calculate the rate ratios (RRs); two-sided χ(2) was used to calculate the probability. RESULTS We recruited 75360 women from 10 clusters in the screening group and 76178 women from 10 comparable clusters in the control group. In the screening group, we achieved 89% participation for screening and 79.4% compliance for diagnosis confirmation. The incidence of invasive cervical cancer was 26.74 per 100000 (95% confidence interval [CI] = 23.41 to 30.74) in the screening group and 27.49 per 100000 (95% CI = 23.66 to 32.09) in the control group. Compliance to treatment for invasive cancer was 86.3% in the screening group and 72.3% in the control group. The screening group showed a statistically significant 31% reduction in cervical cancer mortality (RR = 0.69; 95% CI = 0.54 to 0.88; P = .003). CONCLUSIONS VIA screening by primary health workers statistically significantly reduced cervical cancer mortality. Our study demonstrates the efficacy of an easily implementable strategy that could prevent 22000 cervical cancer deaths in India and 72600 deaths in resource-poor countries annually.

Determinants of women’s participation in cervical cancer screening trial, Maharashtra, India

OBJECTIVE To determine the factors associated with participation in cervical cancer screening and follow-up treatment in the context of a randomized controlled trial. The trial was initiated to evaluate the efficacy and cost effectiveness of visual inspection with acetic acid, cytological screening and testing for human papillomavirus in reducing the incidence of and mortality from cervical cancer in Maharashtra, India. METHODS Between October 1999 and November 2003 women aged 30-59 years were randomized to receive one of the three tests or to a control group. Participation was analysed for all three intervention arms. The differences between those who were screened versus those who were not was analysed according to the sociodemographic characteristics of the 100,800 eligible women invited for screening. Those who were treated versus those who were not were analysed according to the sociodemographic characteristics of the 932 women diagnosed with high-grade lesions. Participation in screening and compliance with treatment were also analysed according to the type of test used. FINDINGS Compared with women who were not tested, screened women were younger (aged 30-39), better educated and had ever used contraception. A higher proportion of screened women were married and a lower proportion had never been pregnant. Of the 932 women diagnosed with high-grade lesions or invasive cancer, 85.3% (795) received treatment. Women with higher levels of education, who had had fewer pregnancies and those who were married were more likely to comply with treatment. There were no differences in rates of screening or compliance with treatment when results were analysed by the test received. CONCLUSIONS Irrespective of the test being used, good participation levels for cervical cancer screening can be achieved in rural areas of developing countries by using appropriate strategies to deliver services. Communication methods and delivery strategies aimed at encouraging older, less-educated women, who have less contact with reproductive services, are needed to further increase screening uptake.