Clinical trial NCT02492607: Management of Low-risk (Grade I and II) DCIS
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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: DCIS
Keywords: Women
DCIS grade I and II
Active surveillance
Standard treatment
Lead sponsor: The Netherlands Cancer Institute
Sponsor class: OTHER
Collaborators: name: Borstkanker Onderzoek Groep
name: European Organisation for Research and Treatment of Cancer - EORTC
First posted: 2015-07-08
Enrollment: 2500
Sex: FEMALE
Minimum age (years): 45
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Ipsilateral invasive breast cancer-free rate at 10 years
timeFrame: 10 years from inclusion
Secondary outcomes:
measure: Rate of invasive disease at the final pathology specimen (standard arm only)
timeFrame: from inclusion till time of invasive disease during 10 years at minimum
measure: Rate of grade III DCIS at the final pathology specimen (standard arm only)
timeFrame: from inclusion till time of invasive disease during 10 years at minimum
measure: Biopsy rate for ipsilateral breast during follow-up
timeFrame: from inclusion to the time of death, during 10 years at minimum
measure: Masectomy rate for ipsilateral breast
timeFrame: from inclusion to the time of ipsilateral breast cancer or death, during 10 years at minimum
measure: Time to ipsilateral grade III DCIS
timeFrame: from inclusion to the development of a new ipsilateral DCIS of grade III, up to 10 years
measure: Time to contralateral DCIS
timeFrame: from inclusion to the development of a new contralateral DCIS I,II,III, up to 10 years
measure: Time to contralateral invasive breast cancer
timeFrame: from inclusion to the development of a contralateral invasive breast cancer, up to 10 years
measure: Time to failure of active surveillance strategy
timeFrame: from inclusion to the time patients received standard treatment to the ipsilateral breast, up to 10 years
measure: Distant metastases free interval
timeFrame: from inclusion to the time of invasive distant metastases or death due to breast cancer, up to 10 years
measure: Overall survival
timeFrame: from inclusion to the time of death, during 10 years at minimum
measure: Health Related Quality of life
timeFrame: 6 times from inclusion to 10 yrs follow-up
measure: Cost-effectiveness
timeFrame: 6 times from inclusion to 10 years follow-up
Other outcomes:
Locations:
city: Alkmaar
country: Netherlands
facility: Noordwest Ziekenhuisgroep- site Alkmaar
city: Almere
country: Netherlands
facility: Flevoziekenhuis
city: Amsterdam
country: Netherlands
facility: Onze Lieve Vrouwe Gasthuis
city: Amsterdam
country: Netherlands
facility: The Netherlands Cancer Institute-Antoni Van Leeuwenhoekziekenhuis
city: Arnhem
country: Netherlands
facility: Rijnstate Ziekenhuis
city: Assen
country: Netherlands
facility: Wilhelmina Ziekenhuis Assen
city: Beverwijk
country: Netherlands
facility: Rode Kruis Ziekenhuis
city: Bilthoven
country: Netherlands
facility: Alexander Monro Ziekenhuis
city: Breda
country: Netherlands
facility: Amphia Ziekenhuis
city: Delft
country: Netherlands
facility: Reinier de Graaf Gasthuis
city: Den Haag
country: Netherlands
facility: HagaZiekenhuis
city: Deventer
country: Netherlands
facility: Deventer Ziekenhuis
city: Doetinchem
country: Netherlands
facility: Slingeland Ziekenhuis
city: Dordrecht
country: Netherlands
facility: Albert Schweitzer Ziekenhuis
city: Ede
country: Netherlands
facility: Ziekenhuis Gelderse Vallei
city: Eindhoven
country: Netherlands
facility: Catharina Ziekenhuis
city: Eindhoven
country: Netherlands
facility: Maxima Medisch Centrum
city: Enschede
country: Netherlands
facility: Medisch Spectrum Twente Ariensplain
city: Gouda
country: Netherlands
facility: Groene Hart Ziekenhuis
city: Groningen
country: Netherlands
facility: Martini Ziekenhuis
city: Groningen
country: Netherlands
facility: Universitair Medisch Centrum Groningen
city: Haarlem
country: Netherlands
facility: Spaarne Gasthuis
city: Hardenberg
country: Netherlands
facility: Saxenburgh Medisch Centrum
city: Harderwijk
country: Netherlands
facility: Ziekenhuis St. Jansdal
city: Heerenveen
country: Netherlands
facility: Tjongerschans Ziekenhuis
city: Heerlen
country: Netherlands
facility: Zuyderland Medisch Centrum
city: Hengelo
country: Netherlands
facility: Ziekenhuisgroep Twente
city: Hertogenbosch
country: Netherlands
facility: Jeroen Bosch Ziekenhuis
city: Hilversum
country: Netherlands
facility: Ter Gooi
city: Hoofddorp
country: Netherlands
facility: Spaarne ziekenhuis
city: Hoogeveen
country: Netherlands
facility: Treant Zorggroep Bethesda
city: Hoorn
country: Netherlands
facility: Dijklander
city: Leeuwarden
country: Netherlands
facility: Medisch Centrum Leeuwarden
city: Leiden
country: Netherlands
facility: Leids Universitair Medisch Centrum
city: Leiderdorp
country: Netherlands
facility: Alrijne Ziekenhuis
city: Leidschendam
country: Netherlands
facility: Haaglanden MC Antoniushove
city: Maastricht
country: Netherlands
facility: Academisch Ziekenhuis Maastricht
city: Nieuwegein
country: Netherlands
facility: St. Antonius Ziekenhuis
city: Nijmegen
country: Netherlands
facility: Canisius-Wilhelmina Ziekenhuis
city: Purmerend
country: Netherlands
facility: Dijklander
city: Rotterdam
country: Netherlands
facility: Erasmus Medisch Centrum
city: Rotterdam
country: Netherlands
facility: Maasstad Ziekenhuis
city: Schiedam
country: Netherlands
facility: Franciscus Gasthuis en Vlietland
city: Sittard
country: Netherlands
facility: Zuyderland Ziekenhuis
city: Sneek
country: Netherlands
facility: Antonius Ziekenhuis
city: Terneuzen
country: Netherlands
facility: Zorgsaam Zeeuws-Vlaanderen
city: Terneuzen
country: Netherlands
facility: Zorgsaam Ziekenhuis
city: Tiel
country: Netherlands
facility: Ziekenhuis Rivierenland
city: Tilburg
country: Netherlands
facility: St. Elisabeth Ziekenhuis
city: Uden
country: Netherlands
facility: Bernhoven Ziekenhuis
city: Utrecht
country: Netherlands
facility: Diakonessenhuis
city: Utrecht
country: Netherlands
facility: Universitair Medisch Centrum Utrecht
city: Veldhoven
country: Netherlands
facility: Maxima Medisch Centrum - Locatie Veldhoven
city: Venlo
country: Netherlands
facility: VieCuri - Medisch Centrum voor Noord-Limburg - Locatie Venlo
city: Weert
country: Netherlands
facility: St Jans Gasthuis
city: Winterswijk
country: Netherlands
facility: Streekziekenhuis Koningin Beatrix
city: Zaandam
country: Netherlands
facility: Zaans Medisch Centrum
city: Zoetermeer
country: Netherlands
facility: Haga ziekenhuis loc Zoetermeer
city: Zutphen
country: Netherlands
facility: Gelre ziekenhuizen
city: Zwolle
country: Netherlands
facility: Isala Klinieken
Study officials:
affiliation: The Netherlands Cancer Institute
name: Jelle Wesseling, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.