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

DCIS Clinical Trial

— LORD  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT02492607
• Other study ID #: M18LORD
• Secondary ID: 2014-04EORTC-140
• Status: Recruiting
• Phase: N/A
• Start date: February 13, 2017
• Est. completion date: February 1, 2034

Study information

• Verified date: September 2023
• Source: The Netherlands Cancer Institute
• Contact: Carine MT Sondermeijer, Bsc
• Phone: +31634511549
• Email: c.sondermeijer[@]nki.nl
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 2500
• Est. completion date: February 1, 2034
• Est. primary completion date: February 1, 2034
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 45 Years and older

Eligibility

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

Related Conditions & MeSH terms

• DCIS

Intervention

Other:
• Standard treatment
wide local excision only or wide local excision and radiotherapy or mastectomy. +/- hormonal therapy

Device:
• digital mammography
annual mammography

Radiation:
• radiotherapy
according local policy

Locations

Country	Name	City	State
Netherlands	Noordwest Ziekenhuisgroep- site Alkmaar	Alkmaar
Netherlands	Flevoziekenhuis	Almere
Netherlands	Onze Lieve Vrouwe Gasthuis	Amsterdam
Netherlands	The Netherlands Cancer Institute-Antoni Van Leeuwenhoekziekenhuis	Amsterdam
Netherlands	Rijnstate Ziekenhuis	Arnhem
Netherlands	Wilhelmina Ziekenhuis Assen	Assen
Netherlands	Rode Kruis Ziekenhuis	Beverwijk
Netherlands	Alexander Monro Ziekenhuis	Bilthoven
Netherlands	Amphia Ziekenhuis	Breda
Netherlands	Reinier de Graaf Gasthuis	Delft
Netherlands	HagaZiekenhuis	Den Haag
Netherlands	Deventer Ziekenhuis	Deventer
Netherlands	Slingeland Ziekenhuis	Doetinchem
Netherlands	Albert Schweitzer Ziekenhuis	Dordrecht
Netherlands	Ziekenhuis Gelderse Vallei	Ede
Netherlands	Catharina Ziekenhuis	Eindhoven
Netherlands	Maxima Medisch Centrum	Eindhoven
Netherlands	Medisch Spectrum Twente Ariensplain	Enschede
Netherlands	Groene Hart Ziekenhuis	Gouda
Netherlands	Martini Ziekenhuis	Groningen
Netherlands	Universitair Medisch Centrum Groningen	Groningen
Netherlands	Spaarne Gasthuis	Haarlem
Netherlands	Saxenburgh Medisch Centrum	Hardenberg
Netherlands	Ziekenhuis St. Jansdal	Harderwijk
Netherlands	Tjongerschans Ziekenhuis	Heerenveen
Netherlands	Zuyderland Medisch Centrum	Heerlen
Netherlands	Ziekenhuisgroep Twente	Hengelo
Netherlands	Jeroen Bosch Ziekenhuis	Hertogenbosch
Netherlands	Ter Gooi	Hilversum
Netherlands	Spaarne ziekenhuis	Hoofddorp
Netherlands	Treant Zorggroep Bethesda	Hoogeveen
Netherlands	Dijklander	Hoorn
Netherlands	Medisch Centrum Leeuwarden	Leeuwarden
Netherlands	Leids Universitair Medisch Centrum	Leiden
Netherlands	Alrijne Ziekenhuis	Leiderdorp
Netherlands	Haaglanden MC Antoniushove	Leidschendam
Netherlands	Academisch Ziekenhuis Maastricht	Maastricht
Netherlands	St. Antonius Ziekenhuis	Nieuwegein
Netherlands	Canisius-Wilhelmina Ziekenhuis	Nijmegen
Netherlands	Dijklander	Purmerend
Netherlands	Erasmus Medisch Centrum	Rotterdam
Netherlands	Maasstad Ziekenhuis	Rotterdam
Netherlands	Franciscus Gasthuis en Vlietland	Schiedam
Netherlands	Zuyderland Ziekenhuis	Sittard
Netherlands	Antonius Ziekenhuis	Sneek
Netherlands	Zorgsaam Zeeuws-Vlaanderen	Terneuzen
Netherlands	Zorgsaam Ziekenhuis	Terneuzen
Netherlands	Ziekenhuis Rivierenland	Tiel
Netherlands	St. Elisabeth Ziekenhuis	Tilburg
Netherlands	Bernhoven Ziekenhuis	Uden
Netherlands	Diakonessenhuis	Utrecht
Netherlands	Universitair Medisch Centrum Utrecht	Utrecht
Netherlands	Maxima Medisch Centrum - Locatie Veldhoven	Veldhoven
Netherlands	VieCuri - Medisch Centrum voor Noord-Limburg - Locatie Venlo	Venlo
Netherlands	St Jans Gasthuis	Weert
Netherlands	Streekziekenhuis Koningin Beatrix	Winterswijk
Netherlands	Zaans Medisch Centrum	Zaandam
Netherlands	Haga ziekenhuis loc Zoetermeer	Zoetermeer
Netherlands	Gelre ziekenhuizen	Zutphen
Netherlands	Isala Klinieken	Zwolle

Sponsors (3)

Lead Sponsor	Collaborator
The Netherlands Cancer Institute	Borstkanker Onderzoek Groep, European Organisation for Research and Treatment of Cancer - EORTC

Country where clinical trial is conducted

Netherlands, 

References & Publications (1)

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Overall survival	Overall survival,both therapeutic policies	from inclusion to the time of death, during 10 years at minimum
Secondary	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
Secondary	Cost-effectiveness	Health economic evaluation (both therapeutic policies)	6 times from inclusion to 10 years follow-up