Every year, thousands of women diagnosed with low-risk ductal carcinoma in situ (DCIS) are offered surgery they may not need. This trial asks whether simply monitoring these patients with regular mammograms is as safe as operating. The problem is overtreatment. Breast screening saves lives by catching cancers early, but it also detects DCIS—abnormal cells that have not yet invaded breast tissue. Many of these cases will never become dangerous, yet current practice treats them as urgent cancer, leading to unnecessary surgery, radiotherapy, and psychological harm. No one knows which patients can safely skip treatment. If the trial succeeds, it could change clinical guidelines overnight. Women with low-risk DCIS would avoid hospital stays, mastectomies, and breast reconstruction, saving the NHS significant costs while maintaining long-term mammography. The study will also generate radiological and pathological data to identify biomarkers that predict which DCIS cases will progress, allowing future patients to make truly informed choices. This is not fundamental science—it is a direct, pragmatic test of whether less treatment can be better.
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BACKGROUND: The independent review of the UK National Health Service Breast Screening Programme reported recently on the benefits and harms of breast screening (The Lancet, Volume 380, Issue 9855, Pages 1778 - 1786, 17 November 2012). This concluded that breast screening saves lives but acknowledged the existence of overtreatment. Consequently, randomised trials were recommended to elucidate the appropriate treatment of screen-detected ductal carcinoma in situ (DCIS) and to gain a better understanding of its natural history. The LORIS trial aims to establish whether patients with newly diagnosed low risk DCIS can safely avoid surgery without detriment to their wellbeing (psychological and physical) and whether those patients who do require surgery can be identified by pathological and radiological means. DESIGN: LORIS is a multi-centre, randomised (1:1), controlled phase III trial of Surgery versus Active Monitoring in patients with low risk DCIS, incorporating a 2 year internal Feasibility Study. SETTING: NHS Breast Screening Clinics and Symptomatic Breast Clinics. TARGET POPULATION: Women with newly diagnosed, mammographically detected, asymptomatic, low risk DCIS (defined as low grade or low-intermediate grade, confirmed by Central Histopathology Review). HEALTH TECHNOLOGIES BEING ASSESSED: Effectiveness, cost effectiveness and acceptability to patients and clinicians of no surgical intervention for low risk DCIS. The trial addresses the possible current overtreatment of low risk DCIS. MEASUREMENT OF COST AND OUTCOMES: If non-inferiority of no surgery is shown, the trial will be immediately practice changing, saving hospital admission costs (breast conservation surgery, mastectomy, breast reconstruction, radiotherapy) but with minimal additional costs, as with or without surgery, long-term mammography is indicated. There are therefore clear potential healthcare savings to a non-surgical approach. It begins to address concerns aimed mainly at the breast screening service but applicable to equally to current treatments of asymptomatic mammogram-detected DCIS performed outside screening, where women are treated by target-driven surgery as urgent cancer patients. The radiological, pathological and translational data generated from this trial will assess the natural history of low risk DCIS and allow patients to make an informed choice and enable the selection of patients who can safely avoid surgery. The objective of the Feasibility Study is to demonstrate that enough eligible patients can be identified and recruited over the course of the trial to robustly answer the main trial objectives. The primary objective of the trial is ipsilateral invasive breast cancer free survival rate at 5 years. Secondary objectives are: time to development of ipsilateral invasive breast cancer, time to development of any invasive breast cancer, time to development of contralateral invasive breast cancer, overall survival, time to mastectomy, time to surgery, Quality of Life, Quality-Adjusted Life Years and assessment of predictive biomarkers. SAMPLE SIZE: The primary endpoint is ipsilateral invasive breast cancer free survival rate at 5 years. 932 patients are needed to show 2.5% non-inferiority. This includes the patients recruited during the Feasibility Study, plus a 10% allowance for non-adherence. The adherence rate will be reviewed following completion of the feasibility phase. The sample size will be adjusted accordingly should the drop-out rate be higher or lower than expected. The one-sided type I error is set at 5% and power is 80%. Assuming a 5 year ipsilateral invasive breast cancer free rate of 97.5% in the Surgery arm, to exclude a difference of less that 2.5% at 5 years. PROJECT TIMETABLE: Trial to open to recruitment in March 2014. Feasibility Study to complete by the end of Year 2 and any adjustments to patient information, recruitment strategy, trial processes to be made. Recruitment will continue until February 2020. Primary endpoint to be reported in 2025. Long term follow-up is essential, 10 years of annual mammograms are mandated or, inclusion within HTA mammographic follow-up trials.
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