Eric Lucas

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.

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.

Immunogenicity and HPV infection after one, two, and three doses of quadrivalent HPV vaccine in girls in India: a multicentre prospective cohort study

Summary Background An increase in worldwide HPV vaccination could be facilitated if fewer than three doses of vaccine are as effective as three doses. We originally aimed to compare the immunogenicity and frequency of persistent infection and cervical precancerous lesions caused by vaccine-targeted HPV after vaccination with two doses of quadrivalent vaccine on days 1 and 180 or later, with three doses on days 1, 60, and 180 or later, in a cluster-randomised trial. Suspension of the recruitment and vaccination due to events unrelated to our study meant that some enrolled girls could not be vaccinated and some vaccinated girls received fewer than the planned number of vaccinations by default. As a result, we re-analysed our data as an observational cohort study. Methods Our study was designed to be done in nine locations (188 clusters) in India. Participants were unmarried girls aged 10–18 years vaccinated in four cohorts: girls who received three doses of vaccine on days 1, 60, and 180 or later, two doses on days 1 and 180 or later, two doses on days 1 and 60 by default, and one dose by default. The primary outcomes were immunogenicity in terms of L1 genotype-specific binding antibody titres, neutralising antibody titres, and antibody avidity after vaccination for the vaccine-targeted HPV types 16, 18, 6, and 11 and incident and persistent infections with these HPVs. Analysis was per actual number of vaccine doses received. This study is registered with ISRCTN, number ISRCTN98283094; and with ClinicalTrials.gov, number NCT00923702. Findings Vaccination of eligible girls was initiated on Sept 1, 2009, and continued until April 8, 2010. Of 21 258 eligible girls identified at 188 clusters, 17 729 girls were recruited from 178 clusters before suspension. 4348 (25%) girls received three doses, 4979 (28%) received two doses on days 1 and 180 or later, 3452 (19%) received two doses at days 1 and 60, and 4950 (28%) received one dose. Immune response in the two-dose HPV vaccine group was non-inferior to the three-dose group (median fluorescence intensity ratio for HPV 16 1·12 [95% CI 1·02–1·23] and for HPV 18 1·04 [0·92–1·19]) at 7 months, but was inferior in the two-dose default (0·33 [0·29–0·38] for HPV 16 and 0·51 [0·43–0·59] for HPV 18) and one-dose default (0·09 [0·08–0·11] for HPV 16 and 0·12 [0·10–0·14] for HPV 18) groups at 18 months. The geometric mean avidity indices after fewer than three doses by design or default were non-inferior to those after three doses of vaccine. Fewer than three doses by design and default induced detectable concentrations of neutralising antibodies to all four vaccine-targeted HPV types, but at much lower concentration after one dose. Cervical samples from 2649 participants were tested and the frequency of incident HPV 16, 18, 6, and 11 infections was similar irrespective of the number of vaccine doses received. The testing of at least two samples from 838 participants showed that there was no persistent HPV 16 or 18 infections in any study group at a median follow-up of 4·7 years (IQR 4·2–5·1). Interpretation Despite the limitations imposed by the suspension of the HPV vaccination, our findings lend support to the WHO recommendation of two doses, at least 6 months apart, for routine vaccination of young girls. The short-term protection afforded by one dose of HPV vaccine against persistent infection with HPV 16, 18, 6, and 11 is similar to that afforded by two or three doses of vaccine and merits further assessment. Funding Bill & Melinda Gates Foundation.

Organised colorectal cancer screening in Lampang Province, Thailand: preliminary results from a pilot implementation programme

Objective Colorectal cancer (CRC) is the third-most and fifth-most common cancer in men and women, in Thailand. The increasing CRC incidence and mortality can be reduced by screening and treating adenomas and early cancers. A pilot CRC screening programme using immunochemical faecal occult blood testing (iFOBT) and colonoscopy for test-positives were implemented through the routine Government Health Services in Lampang Province, to inform the acceptability, feasibility and scaling-up of screening in Thailand. This report describes the implementation, coverage and performance indicators of this project. Design A target population aged 50–65 years was informed about and invited face to face to undergo CRC screening by community health workers (HWs). The HWs provided faecal sample collection kits and participants brought their samples to one of the primary health units or community hospitals where nurses performed iFOBT. iFOBT-positive persons were referred for colonoscopy at the Lampang cancer hospital, and endoscopic polypectomy/biopsies were performed according to the colonoscopic findings. Those with confirmed CRC received appropriate treatment. Results Of the 127 301 target population, 62.9% were screened using iFOBT between April 2011 and November 2012. Participation was higher among women (67.8%) than men (57.8%) and lower in 50–54 year-old persons than in 60–65-year-olds. Of those screened, 873 (1.1%) were found positive; positivity was higher in men (1.2%) than in women (1.0%). To date 627 (72.0%) iFOBT-positive persons have had colonoscopy in which 3.7% had CRC and 30.6% had adenomas. Conclusions The successful implementation of the pilot CRC screening with satisfactory process measures indicate the feasibility of scaling-up organised CRC screening through existing health services in Thailand.

Survival from digestive cancer in emerging countries in Asia and Africa.

The incidence of digestive cancer, including cancer of the esophagus, stomach, colon, and liver, is analyzed in developing and less developed countries in Africa, Asia, the Caribbean, and Latin America. The analysis is based on cancer registries for observed values, on a recent monograph published at International Agency for Research on Cancer and on the GLOBOCAN 2008 database for estimations. For all tumor sites analyzed, the incidence is lower in these countries than in developed countries of Europe, North America, and Japan. The 5-year relative survival from digestive cancer is also lower. In developing countries, there is room for prevention of cancer burden through lifestyle interventions and through improved early detection of cancer.

Breast Cancer Awareness among Middle Class Urban Women--a Community-Based Study from Mumbai, India.

Targeting breast cancer awareness along with comprehensive cancer care is appropriate in low and middle income countries like India, where there are no organized and affordable screening services. It is essential to identify the existing awareness about breast cancer in the community prior to launching an organized effort. This study assessed the existing awareness about breast cancer amongst women and their health seeking practices in an urban community in Mumbai, India. A postal survey was undertaken with low or no cost options for returning the completed questionnaires. The majority of the women were aware about cancer but awareness about symptoms and signs was poor. Women were willing to accept more information about cancer and those with higher awareness scores were more likely to seek medical help. They were also more likely to have undergone breast examination in the past and less likely to use alternative medicines. High income was associated with better awareness but this did not translate into better health seeking behaviour. Organized programmes giving detailed information about breast cancer and its symptoms are needed and women from all income categories need to be encouraged for positive change towards health seeking. Further detailed studies regarding barriers to health seeking in India are necessary.

Role of mucosal high-risk human papillomavirus types in head and neck cancers in central India: Role of HPV in Indian head and neck cancer

Mucosal high‐risk (HR) human papillomaviruses (HPV) cause a subset of head and neck cancers (HNC). The HPV‐attributable fraction of HNC varies substantially between countries. Although HNC has a very high incidence in the Indian subcontinent, information on the contribution of HPV infection is limited. Here, we evaluated the HPV‐attributable fraction in HNC (N = 364) collected in a central region of India. HNC from three different anatomical subsites were included, namely, oral cavity (n = 252), oropharynx (n = 53) and hypopharynx/larynx (n = 59). In this retrospective study, HPV‐driven HNC were defined by presence of both viral DNA and RNA. Overexpression of p16INK4a was also evaluated. HR‐HPV DNA was detected in 13.7% of the cases; however, only 2.7% were positive for both HPV DNA and RNA. The highest percentage of HPV DNA/RNA double positivity was found in oropharynx (9.4%), followed by larynx (1.7%) and oral cavity (1.6%) (p = 0.02). More than half of HPV DNA/RNA‐positive cases were p16INK4a‐negative, while a considerable number of HPV RNA‐negative cases were p16INK4a‐positive (17.9%). HPV16 was the major type associated with HNC (60.0%), although cases positive for HPV18, 35 and 56 were also detected. Our data indicate that the proportion and types of mucosal HR‐HPV associated with HNC in this central Indian region differ from those in other (developed) parts of the world. This may be explained by differences in smoking and/or sexual behaviour compared with North America and northern Europe. Moreover, we show that p16INK4a staining appeared not to be a good surrogate marker of HPV transformation in the Indian HNC cases.

Organization and evaluation of a pilot cervical cancer screening program in Morocco

To evaluate a pilot program for early detection of cervical cancer using visual inspection with acetic acid (VIA) and the loop electrosurgical excision procedure (LEEP) in one region of Morocco.

Breast Cancer Screening Program in Morocco: Status of implementation, organization and performance: Evaluation of Breast Cancer Screening Program

Breast Cancer Screening Program was introduced and rolled out in Morocco in 2010. Women between 40 and 69 years are screened at the primary health centers (PHC) with clinical breast examination (CBE). A comprehensive evaluation of the program was conducted in 2016–2017 for quality assurance and mid‐term course correction. The evaluation process involved: in‐depth interviews of program managers; focus group discussions with service‐providers of screening, diagnosis and treatment; supportive supervisory visits to randomly selected PHCs and diagnostic centers; desk review of the national guidelines and other published documents; and analysis of the performance data compiled by the program‐in‐charge. We found that the program has strong political support, a well‐organized management structure and documented national policy and protocol. In absence of a mechanism to identify and invite the eligible women individually, the program is opportunistic in nature. Every PHC is provided with an annual target to be screened. A highly visible annual campaign to educate and motivate women has a major impact on participation. Record keeping and data collection are paper‐based. In the years 2015 and 2016, 1.1 and 1.5 million women were screened, respectively. In the year 2015, 62.8% of the annual target population was covered, CBE positivity was 3.2%, a further assessment rate of screen‐positive women was 34.1% and the breast cancer detection rate was 1.0/1000 women. Systematic paper‐based data collection enabled the assessment of some of the process and outcome indicators. The screening coverage was moderate and the cancer detection rate was low.

Development and validation of a protocol for optimizing the use of paraffin blocks in molecular epidemiological studies: The example from the HPV-AHEAD study

Worldwide use of formalin-fixed paraffin-embedded blocks (FFPE) is extensive in diagnosis and research. Yet, there is a lack of optimized/standardized protocols to process the blocks and verify the quality and presence of the targeted tissue. In the context of an international study on head and neck cancer (HNC)—HPV-AHEAD, a standardized protocol for optimizing the use of FFPEs in molecular epidemiology was developed and validated. First, a protocol for sectioning the FFPE was developed to prevent cross-contamination and distributed between participating centers. Before processing blocks, all sectioning centers underwent a quality control to guarantee a satisfactory training process. The first and last sections of the FFPEs were used for histopathological assessment. A consensus histopathology evaluation form was developed by an international panel of pathologists and evaluated for four indicators in a pilot analysis in order to validate it: 1) presence/type of tumor tissue, 2) identification of other tissue components that could affect the molecular diagnosis and 3) quality of the tissue. No HPV DNA was found in sections from empty FFPE generated in any histology laboratories of HPV-AHEAD consortium and all centers passed quality assurance for processing after quality control. The pilot analysis to validate the histopathology form included 355 HNC cases. The form was filled by six pathologists and each case was randomly assigned to two of them. Most samples (86%) were considered satisfactory. Presence of >50% of invasive carcinoma was observed in all sections of 66% of cases. Substantial necrosis (>50%) was present in <2% of samples. The concordance for the indicators targeted to validate the histopathology form was very high (kappa > 0.85) between first and last sections and fair to high between pathologists (kappa/pabak 0.21–0.72). The protocol allowed to correctly process without signs of contamination all FFPE of the study. The histopathology evaluation of the cases assured the presence of the targeted tissue, identified the presence of other tissues that could disturb the molecular diagnosis and allowed the assessment of tissue quality.