Dataset Information

Cancer prevention with aspirin in hereditary colorectal cancer (Lynch syndrome), 10-year follow-up and registry-based 20-year data in the CAPP2 study: a double-blind, randomised, placebo-controlled trial.

ABSTRACT: BACKGROUND:Lynch syndrome is associated with an increased risk of colorectal cancer and with a broader spectrum of cancers, especially endometrial cancer. In 2011, our group reported long-term cancer outcomes (mean follow-up 55·7 months [SD 31·4]) for participants with Lynch syndrome enrolled into a randomised trial of daily aspirin versus placebo. This report completes the planned 10-year follow-up to allow a longer-term assessment of the effect of taking regular aspirin in this high-risk population. METHODS:In the double-blind, randomised CAPP2 trial, 861 patients from 43 international centres worldwide (707 [82%] from Europe, 112 [13%] from Australasia, 38 [4%] from Africa, and four [<1%] from The Americas) with Lynch syndrome were randomly assigned to receive 600 mg aspirin daily or placebo. Cancer outcomes were monitored for at least 10 years from recruitment with English, Finnish, and Welsh participants being monitored for up to 20 years. The primary endpoint was development of colorectal cancer. Analysis was by intention to treat and per protocol. The trial is registered with the ISRCTN registry, number ISRCTN59521990. FINDINGS:Between January, 1999, and March, 2005, 937 eligible patients with Lynch syndrome, mean age 45 years, commenced treatment, of whom 861 agreed to be randomly assigned to the aspirin group or placebo; 427 (50%) participants received aspirin and 434 (50%) placebo. Participants were followed for a mean of 10 years approximating 8500 person-years. 40 (9%) of 427 participants who received aspirin developed colorectal cancer compared with 58 (13%) of 434 who received placebo. Intention-to-treat Cox proportional hazards analysis revealed a significantly reduced hazard ratio (HR) of 0·65 (95% CI 0·43-0·97; p=0·035) for aspirin versus placebo. Negative binomial regression to account for multiple primary events gave an incidence rate ratio of 0·58 (0·39-0·87; p=0·0085). Per-protocol analyses restricted to 509 who achieved 2 years' intervention gave an HR of 0·56 (0·34-0·91; p=0·019) and an incidence rate ratio of 0·50 (0·31-0·82; p=0·0057). Non-colorectal Lynch syndrome cancers were reported in 36 participants who received aspirin and 36 participants who received placebo. Intention-to-treat and per-protocol analyses showed no effect. For all Lynch syndrome cancers combined, the intention-to-treat analysis did not reach significance but per-protocol analysis showed significantly reduced overall risk for the aspirin group (HR=0·63, 0·43-0·92; p=0·018). Adverse events during the intervention phase between aspirin and placebo groups were similar, and no significant difference in compliance between intervention groups was observed for participants with complete intervention phase data; details reported previously. INTERPRETATION:The case for prevention of colorectal cancer with aspirin in Lynch syndrome is supported by our results. FUNDING:Cancer Research UK, European Union, MRC, NIHR, Bayer Pharma AG, Barbour Foundation.

SUBMITTER: Burn J

PROVIDER: S-EPMC7294238 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Cancer prevention with aspirin in hereditary colorectal cancer (Lynch syndrome), 10-year follow-up and registry-based 20-year data in the CAPP2 study: a double-blind, randomised, placebo-controlled trial.

Burn John J Sheth Harsh H Elliott Faye F Reed Lynn L Macrae Finlay F Mecklin Jukka-Pekka JP Möslein Gabriela G McRonald Fiona E FE Bertario Lucio L Evans D Gareth DG Gerdes Anne-Marie AM Ho Judy W C JWC Lindblom Annika A Morrison Patrick J PJ Rashbass Jem J Ramesar Raj R Seppälä Toni T Thomas Huw J W HJW Pylvänäinen Kirsi K Borthwick Gillian M GM Mathers John C JC Bishop D Timothy DT

Lancet (London, England) 20200601 10240

<h4>Background</h4>Lynch syndrome is associated with an increased risk of colorectal cancer and with a broader spectrum of cancers, especially endometrial cancer. In 2011, our group reported long-term cancer outcomes (mean follow-up 55·7 months [SD 31·4]) for participants with Lynch syndrome enrolled into a randomised trial of daily aspirin versus placebo. This report completes the planned 10-year follow-up to allow a longer-term assessment of the effect of taking regular aspirin in this high-ri ...[more]

PMID: 32534647

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Project description:AbstractThe CAPP2 trial investigated the long-term effects of aspirin and resistant starch on cancer incidence in patients with Lynch syndrome (LS). Participants with LS were randomized double-blind to 30 g resistant starch (RS) daily or placebo for up to 4 years. We present long-term cancer outcomes based on the planned 10-year follow-up from recruitment, supplemented by National Cancer Registry data to 20 years in England, Wales, and Finland. Overall, 463 participants received RS and 455 participants received placebo. After up to 20 years follow-up, there was no difference in colorectal cancer incidence (n = 52 diagnosed with colorectal cancer among those randomized to RS against n = 53 on placebo) but fewer participants had non-colorectal LS cancers in those randomized to RS (n = 27) compared with placebo (n = 48); intention-to-treat (ITT) analysis [HR, 0.54; 95% confidence interval (CI), 0.33-0.86; P = 0.010]. In ITT analysis, allowing for multiple primary cancer diagnoses among participants by calculating incidence rate ratios (IRR) confirmed the protective effect of RS against non-colorectal cancer LS cancers (IRR, 0.52; 95% CI, 0.32-0.84; P = 0.0075). These effects are particularly pronounced for cancers of the upper GI tract; 5 diagnoses in those on RS versus 21 diagnoses on placebo. The reduction in non-colorectal cancer LS cancers was detectable in the first 10 years and continued in the next decade. For colorectal cancer, ITT analysis showed no effect of RS on colorectal cancer risk (HR, 0.92; 95% CI, 0.62-1.34; P = 0.63). There was no interaction between aspirin and RS treatments. In conclusion, 30 g daily RS appears to have a substantial protective effect against non-colorectal cancer cancers for patients with LS.Prevention relevanceRegular bowel screening and aspirin reduce colorectal cancer among patients with LS but extracolonic cancers are difficult to detect and manage. This study suggests that RS reduces morbidity associated with extracolonic cancers. See related Spotlight, p. 557.

Project description:BackgroundA large, double-blind, randomised, placebo-controlled trial of repeat BCG found 49% efficacy against leprosy but no protection against tuberculosis after 6-9 years' follow-up in 1995. We report here additional follow-up, which resulted in greatly increased tuberculosis case numbers, and allowed subgroup analysis.MethodsNearly 47 000 individuals of all ages living in northern Malawi with a BCG vaccine scar were randomly assigned (1:1) between 1986 and 1989 to receive a second BCG or placebo. The investigators and project staff remained masked to all interventions. Enhanced passive surveillance ensured ascertainment of tuberculosis and leprosy to the end of 2018. Tuberculosis case definitions included rigorous microbiological or histological confirmation. Prespecified subgroup analyses were by tuberculosis type, age at vaccination, time since vaccination, previous tuberculin reactivity, HIV status and Mycobacterium tuberculosis lineage. The original trial is registered with ISRCTN registry, ISRCTN11311670.FindingsIn follow-up until Dec 31, 2018, 824 participants had developed tuberculosis, including 786 with pulmonary disease, of whom 383 (63%) of 607 with known HIV status were HIV positive. There was no effect of a second BCG overall (odds ratio [OR] 0·92; 95% CI 0·80-1·05), or for pulmonary (0·93; 0·81-1·07), or lymph node tuberculosis (0·60; 0·31-1·17). The OR was lower for those with known HIV-negative tuberculosis (0·77; 0·59-1·00), for those vaccinated as children (aged <5 years, 0·74; 0·41-1·35; aged 5-14 years, 0·77; 0·60-0·99), and for cases arising at least 20 years after vaccination (0·79; 0·63-1·01). There were no differences by tuberculin status at vaccination, or lineage. There was no evidence of protection against leprosy beyond 10 years after vaccination (although there have been only nine diagnostically certain cases since 1995).InterpretationThere was no evidence that repeat BCG vaccination provides appreciable protection against overall tuberculosis in this rural African population with a high prevalence of HIV. Subgroup effects should not be overinterpreted given the multiple analyses done. However, the evidence for modest protection against HIV-negative tuberculosis, and for a delayed benefit in those vaccinated as children, is consistent with other observations in the literature.FundingLEPRA, Wellcome Trust, Bill & Melinda Gates Foundation.

Project description:BackgroundBreast, colorectal, ovarian, and endometrial cancers constitute approximately 30% of newly diagnosed cancer cases in Switzerland, affecting more than 12,000 individuals annually. Hundreds of these patients are likely to carry germline pathogenic variants associated with hereditary breast ovarian cancer (HBOC) or Lynch syndrome (LS). Genetic services (counseling and testing) for hereditary susceptibility to cancer can prevent many cancer diagnoses and deaths through early identification and risk management.ObjectiveCascade screening is the systematic identification and testing of relatives of a known mutation carrier. It determines whether asymptomatic relatives also carry the known variant, needing management options to reduce future harmful outcomes. Specific aims of the CASCADE study are to (1) survey index cases with HBOC or LS from clinic-based genetic testing records and determine their current cancer status and surveillance practices, needs for coordination of medical care, psychosocial needs, patient-provider and patient-family communication, quality of life, and willingness to serve as advocates for cancer genetic services to blood relatives, (2) survey first- and second-degree relatives and first-cousins identified from pedigrees or family history records of HBOC and LS index cases and determine their current cancer and mutation status, cancer surveillance practices, needs for coordination of medical care, barriers and facilitators to using cancer genetic services, psychosocial needs, patient-provider and patient-family communication, quality of life, and willingness to participate in a study designed to increase use of cancer genetic services, and (3) explore the influence of patient-provider communication about genetic cancer risk on patient-family communication and the acceptability of a family-based communication, coping, and decision support intervention with focus group(s) of mutation carriers and relatives.MethodsCASCADE is a longitudinal study using surveys (online or paper/pencil) and focus groups, designed to elicit factors that enhance cascade genetic testing for HBOC and LS in Switzerland. Repeated observations are the optimal way for assessing these outcomes. Focus groups will examine barriers in patient-provider and patient-family communication, and the acceptability of a family-based communication, coping, and decision-support intervention. The survey will be developed in English, translated into three languages (German, French, and Italian), and back-translated into English, except for scales with validated versions in these languages.ResultsDescriptive analyses will include calculating means, standard deviations, frequencies, and percentages of variables and participant descriptors. Bivariate analyses (Pearson correlations, chi-square test for differences in proportions, and t test for differences in means) will assess associations between demographics and clinical characteristics. Regression analyses will incorporate generalized estimating equations for pairing index cases with their relatives and explore whether predictors are in direct, mediating, or moderating relationship to an outcome. Focus group data will be transcribed verbatim and analyzed for common themes.ConclusionsRobust evidence from basic science and descriptive population-based studies in Switzerland support the necessity of cascade screening for genetic predisposition to HBOC and LS. CASCADE is designed to address translation of this knowledge into public health interventions.Trial registrationClinicalTrials.gov NCT03124212; https://clinicaltrials.gov/ct2/show/NCT03124212 (Archived by WebCite at http://www.webcitation.org/6tKZnNDBt).

Dataset Information

Cancer prevention with aspirin in hereditary colorectal cancer (Lynch syndrome), 10-year follow-up and registry-based 20-year data in the CAPP2 study: a double-blind, randomised, placebo-controlled trial.

Publications

Cancer prevention with aspirin in hereditary colorectal cancer (Lynch syndrome), 10-year follow-up and registry-based 20-year data in the CAPP2 study: a double-blind, randomised, placebo-controlled trial.

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