Management of Low-risk (Grade I and II) DCIS (LORD)

Management of Low Risk Ductal Carcinoma in Situ (Low-risk DCIS): a Non-randomized, Multicenter, Non-inferiority Trial; Standard Therapy Approach Versus Active Surveillance

A substantial number of DCIS lesions will never form a health hazard, particularly if it concerns slow-growing low-risk DCIS (grade I and II). 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.

The LORD (LOw Risk DCIS) study is a non-randomized, international, multicenter, phase III non-inferiority trial, and aims to determine whether screen-detected low-risk DCIS can safely be managed by an active surveillance strategy or that the conventional treatment, being either WLE alone, WLE + RT, or mastectomy, and possibly HT, should remain the standard of care.

Study Overview

• Status: Recruiting
• Conditions: DCIS
• Intervention / Treatment: Other: Standard treatment; Radiation: radiotherapy; Device: digital mammography

Detailed Description

Background of the study:

The introduction of population-based breast cancer screening and implementation of digital mammography have led to an increased incidence of ductal carcinoma in situ (DCIS) without a decrease in the incidence of advanced breast cancer. This suggests DCIS overdiagnosis exists. We hypothesize that asymptomatic, low-risk DCIS (grade I and II DCIS) can safely be managed by active surveillance. If progression to invasive breast cancer would still occur, this will be lowgrade and hormone receptor positive with excellent survival rates. Also, breast-conserving treatment will still be an option, if no prior radiotherapy has been applied. It also may save many low-risk DCIS patients from intensive treatment.

Objective of the study:

The primary end-point is ipsilateral invasive breast tumor-free rate at 10 years.

Secondary end-points are among others: overall survival, breast cancer-specific survival, mastectomy rate and patient reported outcomes. To determine whether low- risk DCIS can safely (measured by ipsilateral invasive breast cancer rate at 10 years) be managed by an active surveillance strategy or if the conventional treatment, being either wide local excision (WLE) only, WLE plus radiotherapy or mastectomy, possibly followed by hormonal therapy, will remain the standard of care.

Study design:

Phase III, open-label, non-inferiority, multi-center, non-randomized clinical trial. By patient's preference, women will be included into one of the following arms: active surveillance or standard treatment according to local policy, being either WLE alone, WLE plus radiotherapy or mastectomy, possibly followed by hormonal therapy. The same follow-up scheme will be applied in both study arms, i.e. annual mammography for a period of five years and an additional two mammograms at year seven and ten.

• Study Type: Interventional
• Enrollment (Estimated): 2500
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Carine MT Sondermeijer, Bsc; Phone Number: +31634511549; Email: c.sondermeijer@nki.nl

Study Locations

• Netherlands
  • Alkmaar, Netherlands
    • Recruiting
    • Noordwest Ziekenhuisgroep- site Alkmaar
    • Principal Investigator: Gea Gooiker, PhD
  • Almere, Netherlands
    • Recruiting
    • Flevoziekenhuis
    • Principal Investigator: van der Meij
  • Amsterdam, Netherlands
    • Recruiting
    • The Netherlands Cancer Institute-Antoni Van Leeuwenhoekziekenhuis
    • Principal Investigator: Wesseling
  • Amsterdam, Netherlands
    • Recruiting
    • Onze Lieve Vrouwe Gasthuis
    • Principal Investigator: H Witjes, Dr
  • Arnhem, Netherlands
    • Recruiting
    • Rijnstate Ziekenhuis
    • Principal Investigator: Van Eekeren
  • Assen, Netherlands
    • Recruiting
    • Wilhelmina Ziekenhuis Assen
    • Principal Investigator: M Boskamp, Dr
  • Beverwijk, Netherlands
    • Recruiting
    • Rode Kruis Ziekenhuis
    • Principal Investigator: NJ Harlaar, Dr
  • Bilthoven, Netherlands
    • Recruiting
    • Alexander Monro Ziekenhuis
    • Principal Investigator: Veenendaal
  • Breda, Netherlands
    • Not yet recruiting
    • Amphia Ziekenhuis
    • Principal Investigator: Luiten
  • Delft, Netherlands
    • Recruiting
    • Reinier de Graaf Gasthuis
    • Contact: Janneke Immink, Dr
    • Principal Investigator: Janneke Immink, Dr
  • Den Haag, Netherlands
    • Recruiting
    • Hagaziekenhuis
    • Principal Investigator: I. Jannink
  • Deventer, Netherlands
    • Recruiting
    • Deventer Ziekenhuis
    • Principal Investigator: Torrenga
  • Doetinchem, Netherlands
    • Recruiting
    • Slingeland Ziekenhuis
    • Principal Investigator: Reijnders
  • Dordrecht, Netherlands
    • Recruiting
    • Albert Schweitzer Ziekenhuis
    • Principal Investigator: Westenend
  • Ede, Netherlands
    • Recruiting
    • Ziekenhuis Gelderse Vallei
    • Contact: A. Bosch, Dr
    • Principal Investigator: A. Bosch, Dr
  • Eindhoven, Netherlands
    • Recruiting
    • Máxima Medisch Centrum
    • Principal Investigator: Maaskant
  • Eindhoven, Netherlands
    • Recruiting
    • Catharina Ziekenhuis
    • Principal Investigator: van Riet
  • Enschede, Netherlands
    • Recruiting
    • Medisch Spectrum Twente Ariensplain
    • Principal Investigator: van Duyn
  • Gouda, Netherlands
    • Recruiting
    • Groene Hart Ziekenhuis
    • Principal Investigator: Linthorst
  • Groningen, Netherlands
    • Recruiting
    • Universitair Medisch Centrum Groningen
    • Contact: Monique Dorius, Dr
    • Principal Investigator: Monique Dorius, Dr
  • Groningen, Netherlands
    • Recruiting
    • Martini Ziekenhuis
    • Principal Investigator: W Kelder, Dr
  • Haarlem, Netherlands
    • Recruiting
    • Spaarne Gasthuis
    • Principal Investigator: Vuylsteke
  • Hardenberg, Netherlands
    • Recruiting
    • Saxenburgh Medisch Centrum
    • Principal Investigator: M.H. Raber, Dr
  • Harderwijk, Netherlands
    • Recruiting
    • Ziekenhuis St. Jansdal
    • Principal Investigator: Schouten van der Velden
  • Heerenveen, Netherlands
    • Recruiting
    • Tjongerschans Ziekenhuis
    • Principal Investigator: I. Kappers, Dr
  • Heerlen, Netherlands
    • Recruiting
    • Zuyderland Medisch Centrum
    • Principal Investigator: Vissers
  • Hengelo, Netherlands
    • Recruiting
    • Ziekenhuisgroep Twente
    • Principal Investigator: D. Evers, Dr
  • Hertogenbosch, Netherlands
    • Recruiting
    • Jeroen Bosch ziekenhuis
    • Principal Investigator: Bessems
  • Hilversum, Netherlands
    • Not yet recruiting
    • Ter Gooi
    • Principal Investigator: A. Hellingman, Dr
  • Hoofddorp, Netherlands
    • Recruiting
    • Spaarne ziekenhuis
    • Principal Investigator: Vuylsteke
  • Hoogeveen, Netherlands
    • Recruiting
    • Treant Zorggroep Bethesda
    • Contact: Leonie Smit, Dr
    • Principal Investigator: L. Smit, Dr
  • Hoorn, Netherlands
    • Recruiting
    • Dijklander
    • Principal Investigator: Govaert
  • Leeuwarden, Netherlands
    • Recruiting
    • Medisch Centrum Leeuwarden
    • Principal Investigator: Susanne H Estourgie, PhD
  • Leiden, Netherlands
    • Recruiting
    • Leids Universitair Medisch Centrum
    • Principal Investigator: Liefers
  • Leiderdorp, Netherlands
    • Recruiting
    • Alrijne Ziekenhuis
    • Principal Investigator: W. Van Gijn
  • Leidschendam, Netherlands
    • Recruiting
    • Haaglanden MC Antoniushove
    • Principal Investigator: Marieke Straver, Dr
  • Maastricht, Netherlands
    • Recruiting
    • Academisch Ziekenhuis Maastricht
    • Principal Investigator: Smidt
  • Nieuwegein, Netherlands
    • Recruiting
    • St. Antonius Ziekenhuis
    • Principal Investigator: Koelemij
  • Nijmegen, Netherlands
    • Recruiting
    • Canisius-Wilhelmina Ziekenhuis
    • Principal Investigator: Strobbe
  • Purmerend, Netherlands
    • Recruiting
    • Dijklander
    • Principal Investigator: De Widt-Levert
  • Rotterdam, Netherlands
    • Recruiting
    • Maasstad Ziekenhuis
    • Principal Investigator: A. Pieters, Dr
  • Rotterdam, Netherlands
    • Recruiting
    • Erasmus Medisch Centrum
    • Principal Investigator: Obdeijn
  • Schiedam, Netherlands
    • Recruiting
    • Franciscus Gasthuis en Vlietland
    • Principal Investigator: Taco Klem, dr
  • Sittard, Netherlands
    • Recruiting
    • Zuyderland Ziekenhuis
    • Contact: Y. Vissers, Dr
    • Principal Investigator: Y. Vissers, Dr
  • Sneek, Netherlands
    • Recruiting
    • Antonius Ziekenhuis
    • Principal Investigator: J. vd Zee, dr
  • Terneuzen, Netherlands
    • Recruiting
    • Zorgsaam Zeeuws-Vlaanderen
    • Principal Investigator: Els van Dessel, Drs
  • Terneuzen, Netherlands
    • Recruiting
    • Zorgsaam Ziekenhuis
    • Contact: Els v Dessel, Dr
    • Principal Investigator: Els v Dessel, Dr
  • Tiel, Netherlands
    • Recruiting
    • Ziekenhuis Rivierenland
    • Principal Investigator: Maartje Sier, Dr
  • Tilburg, Netherlands
    • Recruiting
    • St. Elisabeth Ziekenhuis
    • Principal Investigator: Jansen
  • Uden, Netherlands
    • Recruiting
    • Bernhoven Ziekenhuis
    • Principal Investigator: S Jeurriens, Dr
  • Utrecht, Netherlands
    • Recruiting
    • Universitair Medisch Centrum Utrecht
    • Principal Investigator: van der Pol
  • Utrecht, Netherlands
    • Recruiting
    • Diakonessenhuis
    • Principal Investigator: van Dalen
  • Veldhoven, Netherlands
    • Recruiting
    • Maxima Medisch Centrum - Locatie Veldhoven
    • Principal Investigator: Maaskant
  • Venlo, Netherlands
    • Recruiting
    • VieCuri - Medisch Centrum voor Noord-Limburg - Locatie Venlo
    • Principal Investigator: Aarts
  • Weert, Netherlands
    • Recruiting
    • St Jans Gasthuis
    • Principal Investigator: J.A. v Essen, Dr
  • Winterswijk, Netherlands
    • Recruiting
    • Streekziekenhuis Koningin Beatrix
    • Principal Investigator: L van Steensel, Dr
  • Zaandam, Netherlands
    • Recruiting
    • Zaans Medisch Centrum
    • Principal Investigator: Muller
  • Zoetermeer, Netherlands
    • Recruiting
    • Haga ziekenhuis loc Zoetermeer
    • Principal Investigator: I Jannink, Dr
  • Zutphen, Netherlands
    • Recruiting
    • Gelre Ziekenhuizen
    • Principal Investigator: Truin
  • Zwolle, Netherlands
    • Recruiting
    • Isala Klinieken
    • Principal Investigator: Noorda

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 43 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion criteria

• Written informed consent according to ICH GCP, and national andlocal regulations
• Women ≥ 45 years old, any menopausal status
• Unilateral DCIS grade I or II of any size
• American Society of Anesthesiologists (ASA) score 1-2 or 3, only if able to undergo surgery and yearly mammography
• Lesions of type 'calcifications only', detected by population-based or opportunistic screening mammography
• Within twelve weeks of detection, stereotactic biopsy has to be performed from the area of the calcifications. Preferably vacuum assisted biopsies. Alternatively, at least six 12 G needle biopsies (or the equivalent of six 12 G needles) may be used. ) . Whatever needle size is applied, it is essential to confirm that the biopsies contain representative calcifications via biopsy radiography, microscopy, or both.
• Estrogen receptor ≥ 80% positive and HER2 negative: 0 or 1+ or 2+ with negative ISH), analysed centrally by pathology at NKI-AVL
• In case of an extended lesion (> 5 cm): biopsies were taken from the center and the periphery of the lesion, or from two peripheral parts of the lesion
• In case of multiple lesions with calcifications biopsies have been taken from two, but not more, groups of calcifications
• Marker placement at biopsy site (s) in the breast
• FFPE tissue blocks from the biopsy and, if applicable, from the resection specimen, are available for translational research purposes. If no FFPE tissue blocks can be submitted, 10 unstained slides of 4-5 micrometer thickness from the lesion(s) are acceptable
• Good correlation between pathological and radiological findings i.e. both findings confirm low-risk DCIS and no suspicion of high- grade DCIS or invasive breast cancer
• The interval between histologic diagnosis of low-risk DCIS on biopsy and inclusion is ≤ 12 weeks

Exclusion criteria

• Estrogen receptor negative: <80% or HER2 positive: 3+, or 2+ with positive ISH
• Presence of either mass, increased focal density or architectural distortion around the calcifications on mammography (suspicious for invasive disease)
• Presence of Paget's disease, invasive breast cancer, or pleomorphic LCIS; Lobular neoplasia, referring to atypical lobular hyperplasia (ALH) and/or classic Lobular Carcinoma In Situ according to the WHO Classification of Tumours of the Breast, is no reason to exclude, whereas pleomorphic LCIS is
• Symptomatic DCIS e.g. DCIS detected by palpation or bloody nipple discharge
• Synchronous invasive carcinoma in the contralateral breast
• Prior history of invasive breast cancer or DCIS, prior surgery because of benign breast lesion (s) is allowed
• Prior history of other malignancy (except non-melanoma skin cancer and carcinoma in situ of the cervix) unless patient is discharged from follow-up for at least five years.
• Serious disease that precludes definitive surgical treatment (e.g cardiovascular/ pulmonary/ renal disease)
• Individual with a family member with a known gene mutation associated with increased risk of breast cancer, unless study participant is a proven non-carrier of mutation
• Pregnancy or breast-feeding. Contraceptive measures during the trial are mandatory for those patients that will participate in standard treatment arm and adequate counseling should be provided by the treating physician. The duration of contraception will be specified by the treating physician according to patient and treatment characteristics, standard clinical practice and national regulations
• Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Standard treatment; Standard treatment according to local policy. This can be either wide local excision only, wide local excision and radiotherapy, or mastectomy. Hormonal therapy is also allowed. Follow-up:by annual digital mammography for a period of 5 years and a digital mammography at 7 and 10 years.	Other: Standard treatment; wide local excision only or wide local excision and radiotherapy or mastectomy. +/- hormonal therapy; Radiation: radiotherapy; according local policy
Experimental: Active surveillance; Active surveillance : monitoring by annual digital mammography for a period of 5 years and a digital mammography at 7 and 10 years.	Device: digital mammography; annual mammography; Other Names: Active surveillance

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Ipsilateral invasive breast cancer-free rate at 10 years	Ipsilateral invasive breast cancer-free rate at 10 years (both therapeutic policies	10 years from inclusion

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to contralateral invasive breast cancer	Time to contralateral invasive breast cancer,, both therapeutic policies	from inclusion to the development of a contralateral invasive breast cancer, up to 10 years
Distant metastases free interval	Distant metastases free interval,both therapeutic policies	from inclusion to the time of invasive distant metastases or death due to breast cancer, up to 10 years
Overall survival	Overall survival,both therapeutic policies	from inclusion to the time of death, during 10 years at minimum
Rate of invasive disease at the final pathology specimen (standard arm only)	Rate of invasive disease at the final pathology specimen (standard arm only)	from inclusion till time of invasive disease during 10 years at minimum
Rate of grade III DCIS at the final pathology specimen (standard arm only)	Rate of grade III DCIS at the final pathology specimen (standard arm only)	from inclusion till time of invasive disease during 10 years at minimum
Biopsy rate for ipsilateral breast during follow-up	Biopsy rate for ipsilateral breast during follow-up (both therapeutic policies)	from inclusion to the time of death, during 10 years at minimum
Masectomy rate for ipsilateral breast	Masectomy rate for ipsilateral breast, baseline or subsequent ipsilateral DCIS or iBC (both therapeutic policies)	from inclusion to the time of ipsilateral breast cancer or death, during 10 years at minimum
Time to ipsilateral grade III DCIS	Time to ipsilateral grade III DCIS, both therapeutic policies	from inclusion to the development of a new ipsilateral DCIS of grade III, up to 10 years
Time to contralateral DCIS	Time to contralateral DCIS, both therapeutic policies	from inclusion to the development of a new contralateral DCIS I,II,III, up to 10 years
Time to failure of active surveillance strategy	Time to failure of active surveillance strategy, i.e. time to crossover to standard treatment, due to any cause	from inclusion to the time patients received standard treatment to the ipsilateral breast, up to 10 years
Health Related Quality of life	General QoL/global health perception, specific funcionalities, pain ( both therapeutic policies	6 times from inclusion to 10 yrs follow-up
Cost-effectiveness	Health economic evaluation (both therapeutic policies)	6 times from inclusion to 10 years follow-up

Collaborators and Investigators

• Sponsor: The Netherlands Cancer Institute
• Collaborators: European Organisation for Research and Treatment of Cancer - EORTC; Borstkanker Onderzoek Groep
• Investigators: Principal Investigator: Jelle Wesseling, PhD, The Netherlands Cancer Institute

Publications and helpful links

General Publications

• Elshof LE, Tryfonidis K, Slaets L, van Leeuwen-Stok AE, Skinner VP, Dif N, Pijnappel RM, Bijker N, Rutgers EJ, Wesseling J. Feasibility of a prospective, randomised, open-label, international multicentre, phase III, non-inferiority trial to assess the safety of active surveillance for low risk ductal carcinoma in situ - The LORD study. Eur J Cancer. 2015 Aug;51(12):1497-510. doi: 10.1016/j.ejca.2015.05.008. Epub 2015 May 26.

Study record dates

Study Major Dates

• Study Start (Actual): February 13, 2017
• Primary Completion (Estimated): February 1, 2034
• Study Completion (Estimated): February 1, 2034

Study Registration Dates

• First Submitted: June 24, 2015
• First Submitted That Met QC Criteria: July 7, 2015
• First Posted (Estimated): July 8, 2015

Study Record Updates

• Last Update Posted (Actual): April 5, 2024
• Last Update Submitted That Met QC Criteria: April 3, 2024
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Keywords: Women; Active surveillance; DCIS grade I and II; Standard treatment
• Other Study ID Numbers: M18LORD; 2014-04 (Other Identifier: BOOG); EORTC-1401 (Other Identifier: EORTC)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No