Vaccine efficacy against persistent human papillomavirus (HPV) 16/18 infection at 10 years after one, two, and three doses of quadrivalent HPV vaccine in girls in India: a multicentre, prospective, cohort study.

BACKGROUND: A randomised trial designed to compare three and two doses of quadrivalent human papillomavirus (HPV) vaccine in adolescent girls in India was converted to a cohort study after suspension of HPV vaccination in trials by the Indian Government. In this Article, the revised aim of the cohort study was to compare vaccine efficacy of single dose to that of three and two doses in protecting against persistent HPV 16 and 18 infection at 10 years post vaccination. METHODS: In the randomised trial, unmarried girls aged 10-18 years were recruited from nine centres across India and randomly assigned to either two doses or three doses of the quadrivalent HPV vaccine (Gardasil [Merck Sharp & Dohme, Whitehouse Station, NJ, USA]; 0·5 mL administered intramuscularly). After suspension of recruitment and vaccination, the study became a longitudinal, prospective cohort study by default, and participants were allocated to four cohorts on the basis of the number vaccine doses received per protocol: the two-dose cohort (received vaccine on days 1 and 180 or later), three-dose cohort (days 1, 60, and 180 or later), two-dose default cohort (days 1 and 60 or later), and the single-dose default cohort. Participants were followed up yearly. Cervical specimens were collected from participants 18 months after marriage or 6 months after first childbirth, whichever was earlier, to assess incident and persistent HPV infections. Married participants were screened for cervical cancer as they reached 25 years of age. Unvaccinated women age-matched to the married vaccinated participants were recruited to serve as controls. Vaccine efficacy against persistent HPV 16 and 18 infections (the primary endpoint) was analysed for single-dose recipients and compared with that in two-dose and three-dose recipients after adjusting for imbalance in the distribution of potential confounders between the unvaccinated and vaccinated cohorts. This trial is registered with ISRCTN, ISRCTN98283094, and ClinicalTrials.gov, NCT00923702. FINDINGS: Vaccinated participants were recruited between Sept 1, 2009, and April 8, 2010 (date of vaccination suspension), and followed up over a median duration of 9·0 years (IQR 8·2-9·6). 4348 participants had three doses, 4980 had two doses (0 and 6 months), and 4949 had a single dose. Vaccine efficacy against persistent HPV 16 and 18 infection among participants evaluable for the endpoint was 95·4% (95% CI 85·0-99·9) in the single-dose default cohort (2135 women assessed), 93·1% (77·3-99·8) in the two-dose cohort (1452 women assessed), and 93·3% (77·5-99·7) in three-dose recipients (1460 women assessed). INTERPRETATION: A single dose of HPV vaccine provides similar protection against persistent infection from HPV 16 and 18, the genotypes responsible for nearly 70% of cervical cancers, to that provided by two or three doses. FUNDING: Bill & Melinda Gates Foundation.

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

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.

Prevention of Cervix Cancer in India.

Cervical cancer is the fourth most common cancer among women globally and the second most common cancer among Indian women. India alone bears 23% of the global cervical cancer burden. In India, population-based cervical cancer screening is largely nonexistent in most regions due to competing healthcare priorities, insufficient financial resources and a limited number of trained providers. Hence, most of the cases present in advanced stages of the disease, thus leading to increased mortality and reduced survival. Various screening options like cytology, visual-based screening and testing for high-risk HPV are available. Several cross-sectional studies have looked at the comparative efficacy of different screening tests. Three important randomized controlled trials from India have shown the efficacy of screening once in a life time with HPV DNA, one-time screening with VIA by trained nurses and four-time screening with VIA by trained primary health workers, reducing mortality due to cervical cancers. Prevention of cervical cancers with two-dose HPV vaccination and early detection of precancerous cervical lesions of the eligible population through screening and their appropriate treatment with a single-visit 'screen-and-treat' approach appear to be promising for low-middle-income countries including India.

Global strategies for cervical cancer prevention.

PURPOSE OF REVIEW: Cervical cancer still remains the fourth most common cancer, affecting women worldwide with large geographic variations in cervical cancer incidence and mortality rates. There exist vast disparities in cervix cancer control and prevention efforts globally. The present review addresses the current developments in cervical cancer prevention and control across both high-income countries and low-middle income countries and attempts to identify new strategies that might help address the gaps in cervical cancer care disparities globally. RECENT FINDINGS: Paradigms for cervix cancer screening are changing in high-resource settings from cytology-based screening to adoption of molecular screening and cotesting to achieve program effectiveness. Low-middle income countries with larger burden of cervical cancer continue to face financial and logistic limitations to make both cervix cancer screening and human papillomavirus vaccine available to their populations. Alternative low-cost screening technologies, operationally feasible implementation strategies, reduction of cost of procurement and delivery approaches for human papillomavirus vaccine need assessment to decrease cancer care disparities. SUMMARY: Efforts directed toward cervix cancer prevention and early detection for improvements in cervical cancer outcomes of incidence and mortality have to be proportionately matched by access to acceptable standards of cancer care.

Recommendations for screening and early detection of common cancers in India.

Cancers of the breast, uterine cervix, and lip or oral cavity are three of the most common malignancies in India. Together, they account for about 34% of more than 1 million individuals diagnosed with cancer in India each year. At each of these cancer sites, tumours are detectable at early stages when they are most likely to be cured with standard treatment protocols. Recognising the key role that effective early detection and screening programmes could have in reducing the cancer burden, the Indian Institute for Cytology and Preventive Oncology, in collaboration with the US National Cancer Institute Center for Global Health, held a workshop to summarise feasible options and relevant evidence for screening and early detection of common cancers in India. The evidence-based recommendations provided in this Review are intended to act as a guide for policy makers, clinicians, and public health practitioners who are developing and implementing strategies in cancer control for the three most common cancers in India.

Banning tobacco sales and advertisements near educational institutions may reduce students' tobacco use risk: evidence from Mumbai, India.

BACKGROUND: India's Cigarettes and Other Tobacco Products Act bans tobacco sales and advertisements within 100 yards of educational institutions. In school-adjacent neighbourhoods in Mumbai, we assessed adherence to these policies and whether tobacco vendor and advertisement densities were associated with students' tobacco use. METHODS: High school students' tobacco use was measured using a multistage cluster sampling survey (n=1533). Field geographic information systems data were obtained for all tobacco vendors and advertisements within 500 m of schools (n=26). Random-effects multilevel logistic regression was used to estimate associations of tobacco vendor and advertisement densities with ever tobacco use, current smokeless tobacco use and current tobacco use. RESULTS: There were 1741 tobacco vendors and 424 advertisements within 500 m of schools, with 221 vendors (13%) and 42 advertisements (10%) located within 100 m. School-adjacent tobacco vendor density within 100 m was not associated with the tobacco use outcomes, but tobacco advertisement density within 100 m was associated with all outcomes when comparing highest to lowest density tertiles: ever use (OR: 2.01; 95% CI 1.00 to 4.07), current use (2.23; 1.16, 4.28) and current smokeless tobacco use (2.01; 1.02, 3.98). Tobacco vendor density within 200, 300, 400 and 500 m of schools was associated with current tobacco use and current smokeless tobacco use, but not ever use. CONCLUSIONS: The tobacco sales ban near educational institutions could be expanded beyond 100 m. Greater enforcement is needed regarding the current bans, particularly because advertisement density within 100 m of schools was associated with all students' tobacco use outcomes.

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.

Evaluation of cytology and visual triage of human papillomavirus-positive women in cervical cancer prevention in India.

Although virtually all cervical cancers and most cervical intraepithelial neoplasia (CIN) are caused by persistent human papillomavirus (HPV) infection, only a small proportion of HPV-positive women have or will develop CIN. Triaging HPV-positive women has been suggested to reduce the false-positive rate and proportion of women referred for CIN confirmation and/or treatment. In two cross-sectional studies and one randomized trial in India, we evaluated the impact of using cytology or visual inspection with acetic acid (VIA) to triage HPV-positive women on the proportion of women who would be referred for CIN confirmation and on the detection rates of high-grade CIN. We present the numbers of HPV test-positive women found and the CIN detected among them. We further assess the proportions that would be referred for CIN confirmation with colposcopy/biopsy and CIN that would be detected if cytology triage or VIA triage were used. Using cytology triage at atypical squamous cells of undetermined significance threshold or VIA triage reduced referrals for colposcopy by about 62% and 59%, respectively (p-value = 0.012), but missed around 16% and 18%, respectively, of the high-grade CIN (p-value = 0.539) indicating similar performance of both triaging approaches. The choice of a triage test in different low- and middle-income countries (LMIC) would depend on the availability and affordability in the particular setting. Cytology triage may be considered in settings where adequate infrastructure exists, whereas VIA triage may be suitable in settings with limited or no cytology infrastructure.

Culturally Competent Education and Human Papillomavirus Self-Sampling Achieves Healthy People 2030 Cervical Screening Target Among Low-Income Non-Hispanic Black and Hispanic Women.

PURPOSE: Disparities in cervical cancer screening, incidence, and mortality exist in the United States. Cervical cancer incidence and mortality rates in Texas are 20% and 32% higher, respectively, than national averages. Within Texas, these rates are significantly higher among non-Hispanic (NH) Black and Hispanic women. Cervical cancer screening uptake is lower among NH Black and Hispanic women (72.9% and 75.9%, respectively) compared with White women (85.5%) in Texas. METHODS: During March-August 2023, we conducted a pilot study that offered culturally competent education and human papillomavirus (HPV) self-sampling kits to women in two public housing projects in Houston, TX, that have predominantly NH Black or Hispanic residents. Among those eligible for cervical cancer screening, 35% (n = 24) of the NH Black and 34% (n = 16) of the Hispanic women were found to be underscreened per the US Preventive Services Task Force Guideline. We recruited 40 (24 NH Black and 16 Hispanic) eligible women for our study. The study was approved by the MD Anderson institutional review board and registered with ClinicalTrials.gov (NCT04614155-March 11, 2020). RESULTS: Seventy-five percent of the NH Black and 87% of the Hispanic participants completed the HPV self-sampling procedures per protocol. Samples of 17% NH Black and 12% Hispanic participants showed a performance error. Overall, cervical cancer screening uptake improved from 65% to 91% among NH Black and from 66% to 96% among Hispanic participants. CONCLUSION: Culturally competent education and HPV self-sampling resulted in remarkable improvement in cervical cancer screening uptake among underscreened NH Black and Hispanic women residents of Houston public housing projects. Implementing this strategy could significantly reduce cervical cancer incidence and mortality among similar populations in the United States and globally.

Social Determinants of Health and Cancer Care: An ASCO Policy Statement.

ASCO's new policy statement on SDOH supports practices that sustain and advance cancer health equity.

Evaluation of immune response to single dose of quadrivalent HPV vaccine at 10-year post-vaccination.

BACKGROUND: The recent World Health Organization recommendation supporting single-dose of HPV vaccine will significantly reduce programmatic cost, mitigate the supply shortage, and simplify logistics, thus allowing more low- and middle-income countries to introduce the vaccine. From a programmatic perspective the durability of protection offered by a single-dose will be a key consideration. The primary objectives of the present study were to determine whether recipients of a single-dose of quadrivalent HPV vaccine had sustained immune response against targeted HPV types (HPV 6,11,16,18) at 10 years post-vaccination and whether this response was superior to the natural antibody titres observed in unvaccinated women. METHODS: Participants received at age 10-18 years either one, two or three doses of the quadrivalent HPV vaccine. Serology samples were obtained at different timepoints up to 10 years after vaccination from a convenience sample of vaccinated participants and from age-matched unvaccinated women at one timepoint. The evolution of the binding and neutralizing antibody response was presented by dose received. 10-year durability of immune responses induced by a single-dose was compared to that after three doses of the vaccine and in unvaccinated married women. RESULTS: The dynamics of antibody response among the single-dose recipients observed over 120 months show stabilized levels 18 months after vaccination for all four HPV types. Although the HPV type-specific (binding or neutralizing) antibody titres after a single-dose were significantly inferior to those after three doses of the vaccine (lower bounds of GMT ratios < 0.5), they were all significantly higher than those observed in unvaccinated women following natural infections (GMT ratios: 2.05 to 4.04-fold higher). The results correlate well with the high vaccine efficacy of single-dose against persistent HPV 16/18 infections reported by us earlier at 10-years post-vaccination. CONCLUSION: Our study demonstrates the high and durable immune response in single-dose recipients of HPV vaccine at 10-years post vaccination.

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.

Prevalence of human papillomavirus types in cervical lesions from women in rural Western India.

Cervical cancer is the most common cancer among women in many areas of India which contributes for a fifth of the global burden of disease. Persistent infection with one of the high-risk human papillomaviruses (HPV) has been established as the cause for cervical cancer and the documentation of the prevalence of HPV types in cervical cancer in different regions of India is useful for a prevention program combining both screening and vaccination. In this study, the HPV type distribution and the frequency of p16(INK4a) immunoexpression have been determined in 125 cases of inflammatory lesions or grade 1 cervical intraepithelial neoplasia, 74 cases of grade 2, 72 cases of grade 3, and 113 cervical cancer cases diagnosed among women from rural Solapur and Osmanabad districts, Maharashtra. The overall prevalence of high-risk HPV was 37.6% in inflammatory lesions or grade 1 cervical intraepithelial neoplasia, 63.5% in grade 2, 97.2% in grade 3 and 92% in cervical cancer cases. HPV 16 and HPV 18 were detected in 80.6% of grade 3 cervical intraepithelial neoplasia and 86.5% of cervical cancer cases. 94.7% of the cervical cancer and 84.4% of the high grade lesions with a strong and full thickness staining for p16(INK4a) were positive for HPV infection; p16(INK4a) immunoexpression increased with worsening grade of cervical intraepithelial neoplasia. The HPV genotyping data showing a high HPV 16 and 18 prevalence in cancer specimens indicate that prophylactic HPV 16/18 vaccination would have a significant impact on the prevention of cervical cancer in India.

Financial Toxicities Persist for Cancer Survivors Irrespective of Current Cancer Status: An Analysis of Medical Expenditure Panel Survey.

This study estimates the out-of-pocket (OOP) expenditures for different cancer types among survivors with current vs no current cancer condition and across sex, which is understudied in the literature. This is a cross-sectional study of Medical Expenditure Panel Survey data for 2009-2018 where the primary outcome was the average per year OOP expenditure incurred by cancer survivors. Of 189 285 respondents, 15 010 (7.93%) were cancer survivors; among them, 46.28% had a current cancer condition. Average per year OOP expenditure for female survivors with a current condition of breast cancer ($1730), lung cancer ($1679), colon cancer ($1595), melanoma ($1783), non-Hodgkin lymphoma ($1656), nonmelanoma/other skin cancer (NMSC, $2118) and two or more cancers ($2310) were significantly higher than that of women with no history of cancer ($853, all P < .05). Similarly, average per year OOP expenditure for male survivors with a current condition of prostate cancer ($1457), lung cancer ($1131), colon cancer ($1471), melanoma ($1474), non-Hodgkin's lymphoma ($1653), NMSC ($1789), and bladder cancer ($2157) were significantly higher compared with the men with no history of cancer ($621, all P < .05). These differences persisted in survivors with no current cancer condition for breast cancer among women; prostate, lung, colon, and bladder cancer among men; and melanoma, NMSC, and two or more cancers among both sexes. OOP expenditure varied across cancer types and by sex for survivors with and without a current cancer condition. These findings highlight the need for targeted interventions for cancer survivors.

Secondary Prevention of Cervical Cancer: ASCO Resource-Stratified Guideline Update.

PURPOSE: To update resource-stratified, evidence-based recommendations on secondary prevention of cervical cancer globally. METHODS: American Society of Clinical Oncology convened a multidisciplinary, multinational Expert Panel to produce recommendations reflecting four resource-tiered settings. A review of existing guidelines, formal consensus-based process, and modified ADAPTE process to adapt existing guidelines was conducted. Other experts participated in formal consensus. RESULTS: This guideline update reflects changes in evidence since the previous update. Five existing guidelines were identified and reviewed, and adapted recommendations form the evidence base. Cost-effectiveness analyses provided indirect evidence to inform consensus, which resulted in ≥ 75% agreement. RECOMMENDATIONS: Human papillomavirus (HPV) DNA testing is recommended in all resource settings; visual inspection with acetic acid may be used in basic settings. Recommended age ranges and frequencies vary by the following setting: maximal: age 25-65 years, every 5 years; enhanced: age 30-65 years, if two consecutive negative tests at 5-year intervals, then every 10 years; limited: age 30-49 years, every 10 years; basic: age 30-49 years, one to three times per lifetime. For basic settings, visual assessment is used to determine treatment eligibility; in other settings, genotyping with cytology or cytology alone is used to determine treatment. For basic settings, treatment is recommended if abnormal triage results are obtained; in other settings, abnormal triage results followed by colposcopy is recommended. For basic settings, treatment options are thermal ablation or loop electrosurgical excision procedure; for other settings, loop electrosurgical excision procedure or ablation is recommended; with a 12-month follow-up in all settings. Women who are HIV-positive should be screened with HPV testing after diagnosis, twice as many times per lifetime as the general population. Screening is recommended at 6 weeks postpartum in basic settings; in other settings, screening is recommended at 6 months. In basic settings without mass screening, infrastructure for HPV testing, diagnosis, and treatment should be developed.Additional information is available at www.asco.org/resource-stratified-guidelines.

Evaluating the Performance of Hybrid Capture 2 Test as a Primary Screening Test from Studies Conducted in Low and Middle-Income Country Settings- Special Focus India.

Among the screening tests for cervical cancer, advantages of screening with second generation molecular Hybrid Capture 2 (HC2) test is the high sensitivity and negative predictive value that makes it easy to implement as a cervical cancer screening policy necessitating less screening rounds. High income countries are now implementing HC2 test in their national cervical cancer screening program. Since the acceptance of any screening test depends on the sensitivity of the test, the current study was carried out to evaluate the sensitivity of HC2 test reported from Low- and Middle-income countries (LMIC) which share major burden of cervical cancer globally and to establish if HC2 test could be used as a primary screening test in India. MATERIALS AND METHODS: The population based cross sectional studies from LMICs which evaluated HC2 test as a primary screening modality to diagnose Cervical intraepithelial neoplasm grade 2 and above (CIN2+) lesions were included. RESULTS: A total of 18 studies from LMIC involving 1,13,086 women were reviewed for sensitivity of HC2 as a primary screening test. The overall average sensitivity and specificity to diagnose CIN2+ lesions were 79.84% (95% CI-71.01,86.73) and 85.63% (95% CI- 84.37,86.92) respectively. India demonstrated an average sensitivity and specificity of 65% (95% CI 57,77) and 93% (95% CI- 92,94) respectively. CONCLUSION: Results from LMIC demonstrate a comparably low sensitivity of HC2 test to diagnose CIN2+ lesions as compared to that reported from High income countries. Sensitivity of HC2 was substantially low for India. The current study discusses issues of HC2 assay and the role of untreated Reproductive tract infections as probable causes for low sensitivity of the test. This needs further research in an attempt to improve the sensitivity of the test in an era of self-sampling and low-cost HPV test on horizon to improve the coverage for cervical cancer.
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Effect of screening by clinical breast examination on breast cancer incidence and mortality after 20 years: prospective, cluster randomised controlled trial in Mumbai.

OBJECTIVE: To test the efficacy of screening by clinical breast examination in downstaging breast cancer at diagnosis and in reducing mortality from the disease, when compared with no screening. DESIGN: Prospective, cluster randomised controlled trial. SETTING: 20 geographically distinct clusters located in Mumbai, India, randomly allocated to 10 screening and 10 control clusters; total trial duration was 20 years (recruitment began in May 1998; database locked in March 2019 for analysis). PARTICIPANTS: 151 538 women aged 35-64 with no history of breast cancer. INTERVENTIONS: Women in the screening arm (n=75 360) received four screening rounds of clinical breast examination (conducted by trained female primary health workers) and cancer awareness every two years, followed by five rounds of active surveillance every two years. Women in the control arm (n=76 178) received one round of cancer awareness followed by eight rounds of active surveillance every two years. MAIN OUTCOME MEASURES: Downstaging of breast cancer at diagnosis and reduction in mortality from breast cancer. RESULTS: Breast cancer was detected at an earlier age in the screening group than in the control group (age 55.18 (standard deviation 9.10) v 56.50 (9.10); P=0.01), with a significant reduction in the proportion of women with stage III or IV disease (37% (n=220) v 47% (n=271), P=0.001). A non-significant 15% reduction in breast cancer mortality was observed in the screening arm versus control arm in the overall study population (age 35-64; 20.82 deaths per 100 000 person years (95% confidence interval 18.25 to 23.97) v 24.62 (21.71 to 28.04); rate ratio 0.85 (95% confidence interval 0.71 to 1.01); P=0.07). However, a post hoc subset analysis showed nearly 30% relative reduction in breast cancer mortality in women aged 50 and older (24.62 (20.62 to 29.76) v 34.68 (27.54 to 44.37); 0.71 (0.54 to 0.94); P=0.02), but no significant reduction in women younger than 50 (19.53 (17.24 to 22.29) v 21.03 (18.97 to 23.44); 0.93 (0.79 to 1.09); P=0.37). A 5% reduction in all cause mortality was seen in the screening arm versus the control arm, but it was not statistically significant (rate ratio 0.95 (95% confidence interval 0.81 to 1.10); P=0.49). CONCLUSIONS: These results indicate that clinical breast examination conducted every two years by primary health workers significantly downstaged breast cancer at diagnosis and led to a non-significant 15% reduction in breast cancer mortality overall (but a significant reduction of nearly 30%in mortality in women aged ≥50). No significant reduction in mortality was seen in women younger than 50 years. Clinical breast examination should be considered for breast cancer screening in low and middle income countries. TRIAL REGISTRATION: Clinical Trials Registry of India CTRI/2010/091/001205; ClinicalTrials.gov NCT00632047.

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.

Immunogenicity and safety of human papillomavirus-16/18 AS04-adjuvanted cervical cancer vaccine in healthy Indian women.

AIM: India has the highest number of annual incident cases and mortality rates for cervical cancer worldwide. This study was conducted to assess the immunogenicity and safety of human papillomavirus (HPV)-16/18 AS04-adjuvanted cervical cancer vaccine in healthy Indian women aged 18-35 years old. METHODS: This double-blind, randomized (1:1), controlled and multicenter trial with two parallel groups, the Vaccine and Placebo groups, included 354 subjects in four centers across India. Subjects were given GlaxoSmithKline's HPV-16/18 AS04-adjuvanted cervical cancer vaccine or aluminum hydroxide placebo according to a 0, 1 and 6 month schedule and followed up until month 7. Serum samples were drawn at pre-vaccination and at month 7. Safety data were collected throughout the study. RESULTS: A total of 330 subjects completed the study. One month post-Dose 3, all initially seronegative subjects in the Vaccine group had seroconverted for HPV-16 and HPV-18 antibodies with anti-HPV-16 and anti-HPV-18 geometric mean titer levels of 10226.5 EL.U/ml (95% confidence interval: 8847.1-11821.0) and 3953.0 EL.U/ml (95% confidence interval: 3421.8-4566.8), respectively. Initially seropositive subjects also showed an increase to similar geometric mean titer levels. Six serious adverse events (two in the Vaccine group and four in the Placebo group), all unrelated to vaccination, were reported. Commonly reported solicited local (injection-site pain) and general (fatigue, headache and fever) symptoms were similar in both groups. Compliance to the three-dose vaccination course was >97%. CONCLUSIONS: The AS04-adjuvanted HPV-16/18 cervical cancer vaccine was highly immunogenic and generally well-tolerated making it a potential tool for prevention and control of cervical cancer in India.