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.     

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.     

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.     

Comparative pathology of breast cancer in a randomised trial of screening.

In the Edinburgh Randomised Breast Screening Project (EBSP) to December 1988 there were 500 cancers in the study population invited to screening and 340 cancers identified in the control population. The size and negative lymph node status characteristics of invasive cancers from the two populations were significantly different (P less than 0.05). The cancers detected by screening were predominantly 'early stage', with 16% noninvasive (PTIS) and 42% invasive stage I (pT1 node negative), whereas cancers were frequently 'late stage' (more than pT2) and inoperable in nonattenders (44%) and controls (36%). Grouped according to customary size ranges of invasive cancers, the proportion of cases lymph node positive differed in those screen detected compared with controls, but the benefit in favour of screen detection was not constant. In comparisons of cancers detected at prevalence and incidence screens, as a test of conformity with screening theory, no significant differences were apparent according to size and lymph node status, yet the characteristics of histological type of cancer discriminated significantly (P less than 0.05). When these same histological characteristics were used to compare survival, the capacity to separate invasive cancers into two groups having good and poor survival probabilities was evident, with a significant improvement for the screen detected poor survival group compared with controls (P less than 0.05).     

Efficacy of communication skills training on colorectal cancer screening by GPs: a cluster randomised controlled trial

Colorectal cancer (CRC) mass screening has been implemented in France since 2008. Participation rates remain too low. The objective of this study was to test if the implementation of a training course focused on communication skills among general practitioners (GP) would increase the delivery of gaiac faecal occult blood test and CRC screening participation among the target population of each participating GP. A cluster randomised controlled trial was conducted with GP's practice as a cluster unit. GPs from practices in the control group were asked to continue their usual care. GPs of the intervention group received a 4‐h educational training, built with previous qualitative data on CRC screening focusing on doctor–patient communication with a follow‐up of 7 months for both groups. The primary outcome measure was the patients' participation rate in the target population for each GP. Seventeen GPs (16 practices) in intervention group and 28 GPs (19 practices) in control group participated. The patients' participation rate in the intervention group were 36.7% vs. 24.5% in the control group (P = 0.03). Doctor–patient communication should be developed and appear to be one of the possible targets of improvement patients adherence and participation rate in the target population for CRC mass screening.     

Clinical breast examination: preliminary results from a cluster randomized controlled trial in India

A cluster randomized controlled trial was initiated in the Trivandrum district (Kerala, India) on January 1, 2006, to evaluate whether three rounds of triennial clinical breast examination (CBE) can reduce the incidence rate of advanced disease incidence and breast cancer mortality. A total of 275 clusters that included 115,652 healthy women, aged 30-69 years, were randomly allocated to intervention (CBE; 133 clusters; 55,844 women) or control (no screening; 142 clusters; 59,808 women) groups. Performance characteristics (sensitivity, specificity, false-positive rate, and positive predictive value) of CBE were evaluated. An intention-to-treat analysis was performed for comparison of incidence rates between the intervention and control groups. Preliminary results for incidence are based on follow-up until May 31, 2009, when the first round of screening was completed. Of the 50,366 women who underwent CBE, 30 breast cancers were detected among 2880 women with suspicious findings in CBE screening that warranted further investigations. Sensitivity, specificity, false-positive rate, and positive predictive value of CBE were 51.7% (95% confidence interval [CI] = 38.2% to 65.0%), 94.3% (95% CI = 94.1% to 94.5%), 5.7% (95% CI = 5.5% to 5.9%), and 1.0% (95% CI = 0.7% to 1.5%), respectively. The age-standardized incidence rates for early-stage (stage IIA or lower) breast cancer were 18.8 and 8.1 per 100,000 women and for advanced-stage (stage IIB or higher) breast cancer were 19.6 and 21.7 per 100,000 women, in the intervention and control groups, respectively.     

Overdiagnosis and overtreatment of breast cancer: Overdiagnosis in randomised controlled trials of breast cancer screening

Data from randomised controlled trials of mammographic screening can be used to determine the extent of any overdiagnosis, as soon as either a time equivalent to the lead-time has elapsed after the final screen, or the control arm has been offered screening. This paper reviews those randomised trials for which breast cancer incidence data are available. In recent trials in which the control group has not been offered screening, an excess incidence of breast cancer remains after many years of follow-up. In those trials in which the control arm has been offered screening, although there is a possible shift from invasive to in situ disease, there is no evidence of overdiagnosis as a result of incident screens.     

The psychological impact of a specialist referral and telephone intervention on male cancer patients: a randomised controlled trial

Objective: To examine the psychological impact of a referral and telephone intervention, involving information and support, among men with colorectal cancer (CRC) and prostate cancer. Methods: 571 newly diagnosed male CRC (N=182) and prostate (N=389) cancer patients were block‐randomised into three arms. In the two intervention arms, the specialist actively referred men to a Cancer Helpline. In Active Referral—4 outcalls, men received calls from the Helpline within 1 week of diagnosis, and at 6 weeks, 3 months and 6 months post‐diagnosis. In Active Referral—1 outcall, men received one call within 1 week of diagnosis. In the control arm, Passive Referral, patients were referred to the Helpline, with contact at their initiative. Participants completed scales measuring cancer‐specific distress, anxiety and depression at study entry, then 4, 7 and 12 months post‐diagnosis. Random effects regression models compared rates of change in these outcomes between study arms. Results: At the first outcall, over 85% of participants in both intervention arms discussed treatment management and psychological/emotional issues. Among the Active Referral—4 outcalls arm, over 80% of participants discussed psychological/emotional issues at each call. Mean changes over time in cancer‐specific distress, anxiety and depression were similar between study arms. Conclusion: Although men were willing to discuss psychosocial issues via the telephone, we found no psychological impact. Further research is required to determine whether the intervention is more effective for patients who do not have psychosocial support or have unmet information needs. Copyright © 2009 John Wiley & Sons, Ltd.     

A randomised controlled trial of adjuvant hormono-chemotherapy in Stage II breast cancer

From 1979 to 1984 women with histologically proven Stage II breast cancer were entered into a randomised controlled trial of adjuvant hormono-chemotherapy following mastectomy. Adjuvant therapy was started within 2 weeks of surgery and was given for 6 months as continuous 'Tamoxifen' and 6-monthly cycles of vincristine, adriamycin and cyclophosphamide (VAC). Of the 157 women randomised 82 were assigned to the control group and 75 to the adjuvant group. Comparing the two groups by life table analysis the rate of recurrence was found to be significantly greater in the control group (n = 46) than in the adjuvant group (n = 25) (Peto log rank test chi 2 = 7.46 P less than 0.01). Although there were more deaths amongst the control patients (n = 31) than in those randomised to receive adjuvant therapy (n = 18), this difference did not achieve statistical significance (chi 2 = 2.80 P less than 0.1). This analysis has shown that although adjuvant hormono-chemotherapy may significantly delay recurrence the trial has failed to demonstrate any significant improvement in the survival of women with Stage II breast cancer following mastectomy.     

HPV self-sampling among long-term non-attenders to cervical cancer screening in Norway: a pragmatic randomised controlled trial

Background Cervical cancer screening participation is suboptimal in most settings. We assessed whether human papillomavirus (HPV) self-sampling may increase screening participation among long-term non-attenders in Norway.Methods A pragmatic randomised controlled trial with participation as the primary outcome was initiated in the national cervical screening programme in March 2019. A random sample of 6000 women aged 35–69 years who had not attended screening for at least 10 years were randomised 1:1:1 to receive either (i) a reminder to attend regular screening (control), (ii) an offer to order a self-sampling kit (opt-in) for HPV testing or (iii) a self-sampling kit unsolicited (send-to-all) for HPV testing.Results Total participation was 4.8%, 17.0% and 27.7% among control, opt-in and send-to-all (P < 0.0001; participation difference (%) send-to-all vs. control: 22.9 (95%CI: 20.7, 25.2); opt-in vs. control: 12.3 (95%CI: 10.3, 14.2); send-to-all vs. opt-in: 10.7 (95% CI: 8.0, 13.3)). High-risk HPV was detected in 11.5% of self-samples and 9.2% of clinician-collected samples (P = 0.40). Most women (92.5%) who returned a positive self-sample attended the clinic for triage testing. Of the 933 women screened, 33 (3.5%) had CIN2 + (1.1%, 3.7%, 3.8% among control, opt-in, and send-to-all, respectively), and 11 (1.2%) had cervical cancer (0%, 1.2%, 1.3% among control, opt-in, send-to-all, respectively).Conclusion Opt-in and send-to-all self-sampling increased screening participation among long-term, higher-risk non-attenders.Clinical trial registration ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT03873376","term_id":"NCT03873376"}}NCT03873376.Subject terms: Preventive medicine, Population screening, Epidemiology     

Determinants of participation of women in a cervical cancer visual screening trial in rural south India

The efficacy of a single round of screening of visual inspection with acetic acid (VIA) on cervical cancer incidence and mortality is investigated in a cluster randomized controlled trial in south India. Women aged 30-59 years in 113 clusters in Dindigul District were randomized to VIA screening by nurses (57 clusters, 48,225 eligible women) and to a control group (56 clusters, 30,167 women). 30,577 (63.4%) eligible women participated in screening. Younger, educated, married, multiparous, low-income women and those who have had tubal sterilization had a higher compliance with screening. Of the 2069 women diagnosed with CIN and invasive cancer, 1498 (72.4%) received treatment. Young women, those who practiced contraception and women with high-grade precursor lesions and invasive cancers were more likely to comply with treatment. In summary, our study indicates that women accept screening with VIA by nurses and a moderate level of compliance with screening and treatment can be reached through appropriate service delivery systems including health education activities, personal invitations, clinics in proximity to the target women, and testing and treatment in the same session. Our results imply that integration of screening activities with primary health services seems to have the potential to replicate most of these service delivery conditions in routine programs.     

The Edinburgh randomised trial of screening for breast cancer: description of method.

Edinburgh was selected as one of the centres in the UK Seven-year Trial of Breast Screening of women aged 45-65 which began in 1979. Subsequently, our study was extended to a randomised trial with its own control population within the city. Half the practices were randomly allocated for screening, giving a cluster sampling of women. The total number in the trial is 65,000. Women with previously diagnosed breast cancer are excluded. Women allocated for screening are invited to the clinic and screened according to the procedures specified in the U.K. protocol, having clinical examination every year and mammography on alternate years. The two modalities of screening are assessed independently and the role of nurses is being evaluated. Breast cancer incidence is monitored by pathology register and the local cancer registry office and deaths from the General Register office. Long-term follow-up will be obtained through flagging at NHS Central Register. To determine the value of screening, standard statistical methods will be used to compare breast cancer mortality rates in the whole of the screening population with that of the controls. This trial has a power of 83% of detecting a reduction in mortality of 35% after 7 years of follow-up and a power of 95% of detecting a similar reduction at 10 years (alpha = 0.05, one-sided test).     

TELEMAM: a cluster randomised trial to assess the use of telemedicine in multi-disciplinary breast cancer decision making

AimThe TELEMAM trial aimed to assess the clinical effectiveness and costs of telemedicine in conducting breast cancer multi-disciplinary meetings (MDTs).MethodsOver 12 months 473 MDT patient discussions in two district general hospitals (DGHs) were cluster randomised (2:1) to the intervention of telemedicine linkage to breast specialists in a cancer centre or to the control group of ‘in-person’ meetings. Primary endpoints were clinical effectiveness and costs. Economic analysis was based on a cost-minimisation approach.ResultsLevels of agreement of MDT members on a scale from 1 to 5 were high and similar in both the telemedicine and standard meetings for decision sharing (4.04 versus 4.17), consensus (4.06 versus 4.20) and confidence in the decision (4.16 versus 4.07). The threshold at which the telemedicine meetings became cheaper than standard MDTs was approximately 40 meetings per year.ConclusionTelemedicine delivered breast cancer multi-disciplinary meetings have similar clinical effectiveness to standard ‘in-person’ meetings.     

A randomised,controlled trial of the psychological effects of reflexology in early breast cancer

PurposeTo conduct a pragmatic randomised controlled trial (RCT) to evaluate the effects of reflexology on quality of life (QofL) in women with early breast cancer.Patients and methodsOne hundred and eighty-three women were randomised 6 weeks post-breast surgery to self-initiated support (SIS) (comparator intervention), SIS plus reflexology, or SIS plus scalp massage (control for physical and social contact). Reflexology and massage comprised eight sessions at weekly intervals. The primary end-point was 18 weeks post surgery; the primary outcome measure was the Trial Outcome Index (TOI) of the Functional Assessment of Cancer Therapy (FACT-B) – breast cancer version. The secondary end-point was 24 weeks post surgery. Secondary outcome measures were the Hospital Anxiety and Depression Scale (HADS) and the Mood Rating Scale (MRS).ResultsAt primary end-point, massage, but not reflexology, was significantly better than SIS on the TOI. Reflexology and massage were both better than SIS for MRS relaxation. Massage was better than reflexology and SIS for MRS easygoingness. At secondary end-point, reflexology, but not massage, was better than SIS on the TOI and MRS relaxation. There were no significant differences between reflexology or massage. There were no significant between group differences in HADS anxiety and depression.Self-reported use of out of study complementary therapies indicated that this was unlikely to have a significant effect on findings.ConclusionsWhen compared to SIS, reflexology and massage have statistically significant, and, for reflexology, clinically worthwhile, effects on QofL following surgery for early breast carcinoma.