Cédric Mahé

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.

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.

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.

Initial results from a randomized trial of cervical visual screening in rural south India

The impact of a single round of screening of visual inspection with acetic acid (VIA) on cervical cancer incidence and mortality was investigated in a cluster randomized trial in south India. Women 30–59 years of age in 113 clusters in Dindigul District were randomized to VIA screening (57 clusters, 48,225 women) by nurses and to a control group (56 clusters, 30,167 women). 30,577 eligible women were screened between May 2000 and April 2003; 2,939 (9.6%) screen‐positive women were investigated with colposcopy by nurses and 2,777 (9.1%) women had biopsy. CIN 1 was diagnosed in 1,778 women, CIN 2‐3 lesions were found in 222, and there were 69 screen detected invasive cervical cancers. The detection rates of lesions per 1,000 screened women were 58.2 for CIN 1, 7.3 for CIN 2‐3, and 2.3 for invasive cancer. The detection rate of high‐grade lesions in our study was 2–3‐fold higher than those observed in repeatedly screened populations in developed countries. 71% of women with CIN 1 and 80% of those with CIN 2‐3 lesions accepted cryotherapy provided by nurses and surgical treatment by mid‐level clinicians. Overall, 97 and 34 incident cervical cancer cases were observed in the intervention and control arms, respectively. The intervention arm accrued 124,144 person years and the control arm accrued 90,172 during the study period. The age standardized cervical cancer incidence rates were 92.4/100,000 person‐years in the intervention and 43.1/100,000 in the control arms. In the screened arm, 35.0% of cases were in Stage I as opposed to none in the control arm. The preliminary findings from our study indicate that not only is a VIA‐based screening programme feasible, safe and acceptable to a population in rural settings, it also results in early detection of cervical neoplasia.

Interim results from a cluster randomized controlled oral cancer screening trial in Kerala, India

A cluster randomized controlled oral cancer screening trial is on-going in the Trivandrum district, India, to evaluate the efficacy of screening in reducing oral cancer mortality. Subjects, aged 35 years and above, in 13 clusters in the Trivandrum district, India, were randomized to the intervention (screening) group (7 clusters, 78969 subjects) to receive three rounds of screening by oral visual inspection by trained health workers at 3-year intervals or to a control group (6 clusters, 74739 subjects). Two rounds of screening were completed between 1995 and 2002 during which 69896 (88.5%) subjects were screened at least once, and 59.7% of the 4408 screen-positive subjects were further investigated. In the intervention group, 344404 person-years were accrued and 329326 person-years were in the control group. In the intervention group, 149 incident oral cancer cases and 65 deaths from oral cancer were observed, and 106 incident cases and 62 deaths from oral cancer were observed in the control group. The programme sensitivity for detection of oral precancerous lesions and cancer was 81.5% and the programme specificity was 84.8%; the programme positive predictive value was 39.6%. In the intervention group 37.6% of the cases were in stages I-II, as opposed to 18.9% in the control group. The 3 year survival rate was 57.5% in the intervention and 38.8% in the control group (P<0.05). The age standardized oral cancer mortality rates were 21.2/100000 person-years in the intervention and 21.3/100000 in the control group. After completing two rounds of screening, oral cancer mortality rates were similar in both study groups.

Accuracy of conventional cytology: results from a multicentre screening study in India.

Objective: We conducted a multi-centre cross-sectional study in India to evaluate the accuracy of conventional cytology to detect high-grade squamous intraepithelial lesions (HSIL). Setting: Cross-sectional studies in Jaipur, Kolkata, Mumbai and Trivandrum, India, during 1999-2003. Methods: A common protocol and questionnaire were used to test 22,663 women aged 25-65 years with conventional cytology in five cross-sectional studies. Three thresholds were used to define test positivity: atypical squamous cells of uncertain significance (ASCUS), low-grade squamous intra-epithelial lesion (LSIL), or HSIL. All screened women were investigated with colposcopy, and biopsies were taken when necessary. The reference standard for final disease status was histology or negative colposcopy. Data from the studies were pooled to evaluate the test characteristics for the detection of histologically confirmed HSIL. Results: The test positivity rates of cytology were 8.8% at ASCUS, 6.2% at LSIL and 1.8% at HSIL thresholds, and 355 women had histologically confirmed HSIL while 74 had invasive cancer. The pooled sensitivity, specificity, positive and negative predictive values at ASCUS threshold were 64.5%, 92.3%, 11.8% and 99.4% respectively. The corresponding values at LSIL threshold were 58.0%, 94.9%, 15.2% and 99.3%, while at the HSIL threshold they were 45.4%, 99.2%, 46.3% and 99.1%. The sensitivity varied between 37.8-81.3% at ASCUS , 28.9-76.9% at LSIL and 24.4-72.3% at HSIL thresholds. A significantly low sensitivity was observed in women aged 25-39 years (p<0.001). The wide variation in sensitivity across study sites persisted even after age standardisation. Conclusion: The sensitivity of cytology varied widely between the study sites. Findings from our study and other reviews indicate that sustained efforts in improving sampling, preparation and reading of cytological specimens and improvements in clinical judgement are essential to achieve concurrently high sensitivity and specificity.

Screening for cervical cancer in India: How much will it cost? A trial based analysis of the cost per case detected

The cost and cost effectiveness of screening previously unscreened women by VIA, cytology or HPV testing was investigated within a large cluster randomised trial involving 131,178 women in rural India. All resources involved in implementation, training, management, recruitment, screening and diagnosis were identified and costed. We estimated the total costs and detection rates for each cluster and used these data to calculate an average cluster cost and detection rate for each screening approach. These estimates were combined to estimate a cost per case of cervical intraepithelial neoplasia grade 2/3 or invasive cancer (CIN 2/3+) detected. The average total costs per 1,000 women eligible for screening were US

Correlation between the DNA global methylation status and progesterone receptor expression in normal endometrium, endometrioid adenocarcinoma and precursors

3,917, US

Screening test accuracy studies: how valid are our conclusions? Application to visual inspection methods for cervical screening

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