Abstract OT3-6-01: The LORD trial: A randomized, non-inferiority trial, between active surveillance versus standard treatment in patients with low risk ductal carcinoma in situ
Authors: Elshof Lotte E , Tryfonidis Konstantinos , Slaets Leen , van Leeuwen-Stok A Elise , Dif Nicolas , Skinner Victoria P , Loo Claudette E , Warnars Gonneke , Bleiker Eveline , Pijnappel Ruud M , Bijker Nina , Rutgers Emiel JTh , Wesseling Jelle 
Published: May 2015

Background

The goal in treating patients with ductal carcinoma in situ (DCIS) is to prevent the development of invasive breast cancer (iBC). However, a substantial number of DCIS lesions will never form a health hazard, particularly if it concerns slow-growing, low-grade DCIS. The conventional treatment of low-grade DCIS is similar to that of early-stage iBC, i.e. breast-conserving surgery (BCS) often followed by radiotherapy (RT), or mastectomy, and possibly hormonal therapy (HT). This implies that many women might be unnecessarily going through intensive treatment resulting in a decrease in quality of life and an increase in health care costs, without any survival benefit.

Trial Design

LORD is a randomized, international, multicenter, phase III non-inferiority trial. Patients will be randomized between active surveillance and standard treatment according to local policy. Active surveillance comprises monitoring by annual mammography and treatment if there is progression to iBC or higher grade DCIS. Standard treatment encompasses BCS only, BCS + RT, or mastectomy, possibly followed by HT, and follow-up by annual mammography.

Eligibility criteria

• Women ≥49 years

• Referral to the hospital solely based on microcalcifications detected by population-based or opportunistic screening mammography

• Unilateral, pure DCIS grade I based on multiple vacuum assisted biopsies

• No prior history of iBC or DCIS

Specific Aims

Our aim is to investigate whether active surveillance of low-grade DCIS is as safe as the current standard treatment, and to study the effects on quality of life of these women by saving them from intensive treatment. The primary end-point is time to ipsilateral iBC (iiBC). Secondary end-points include rate of iBC at final pathology after standard treatment, radical intervention rate, and biopsy rate during follow-up. Tissue will be collected for genomic profiling and proteomics to detect iBC risk patterns in low-grade DCIS. Furthermore we aim to develop an online informational aid for clinicians and patients to facilitate the dissemination and understanding of information on low-grade DCIS and its treatment.

Statistical Methods

We apply a special type of non-inferiority design, where the alternative hypothesis corresponds to "minor inferiority". We assume that the iiBC-free rate in the standard arm at 5 years equals 97.6%. The hazard ratio under the null hypothesis is 3.4 and the hazard ratio under the alternative hypothesis is 2.1, corresponding to iiBC-free rates in the experimental arm of 92.0% and 95.0% respectively. With a one-sided log-rank test for non-inferiority with α=0.05 and β=0.2, 124 events are needed for which 1842 low-grade DCIS patients need to be randomized during an accrual period of 5.5 years, and the accrual period will be followed by a further follow-up period of 7.5 years.

Present Accrual and Target accrual

The LORD trial is endorsed by the Dutch Breast Cancer Research Group (BOOG 2014-04) and the European Organisation for Research and Treatment of Cancer (EORTC 1401). Participating sites will be identified mid-2014. Patient accrual is expected to start early 2015.

Citation Format: Lotte E Elshof, Konstantinos Tryfonidis, Leen Slaets, A Elise van Leeuwen-Stok, Nicolas Dif, Victoria P Skinner, Claudette E Loo, Gonneke Warnars, Eveline Bleiker, Ruud M Pijnappel, Nina Bijker, Emiel JTh Rutgers, Jelle Wesseling. The LORD trial: A randomized, non-inferiority trial, between active surveillance versus standard treatment in patients with low risk ductal carcinoma in situ [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr OT3-6-01.