Clinical trial NCT00470236: Radiation Doses and Fractionation Schedules in Non-low Risk Ductal Carcinoma In Situ (DCIS) of the Breast
Official title: A Randomised Phase III Study of Radiation Doses and Fractionation Schedules in Non-low Risk Ductal Carcinoma In Situ (DCIS) of the Breast
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: NA
Conditions: Carcinoma, Ductal, Breast
Keywords: Ductal carcinoma in-situ
Breast conserving therapy
Whole breast radiation therapy
Tumour bed boost
Fractionation schedules
Completely excised non-low risk DCIS
Lead sponsor: Trans Tasman Radiation Oncology Group
Sponsor class: OTHER
Collaborators: name: Breast International Group
name: NCIC Clinical Trials Group
name: Cancer Trials Ireland
name: Borstkanker Onderzoek Groep
name: ETOP IBCSG Partners Foundation
name: Scottish Cancer Trials Breast Group
name: European Organisation for Research and Treatment of Cancer - EORTC
First posted: 2007-05-07
Enrollment: 1608
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Hypotheses:

1. The addition of tumour bed boost after BCS in women with non-low risk DCIS reduces the risk of local recurrence (invasive or intraductal recurrence in the ipsilateral breast).
2. The risk of local recurrence in the shorter fractionation arm is not worse than that for the standard fractionation arm.
3. A molecular signature predictive of invasive recurrence of DCIS will be detectable and the molecular signature may eventually have clinical utility for therapy individualization.

Overall Objectives:

1. To improve the outcome of women with non-low risk DCIS treated with breast conserving therapy.
2. To individualize treatment selection for women with DCIS to achieve long term disease control with minimal toxicity.

Detailed description: Specific objectives:

1. To evaluate time to local recurrence in women with DCIS treated with breast conserving surgery followed by:

   * whole breast RT alone versus whole breast RT plus tumour bed boost;
   * RT using the standard fractionation schedule versus the shorter schedule.
2. To evaluate time to disease recurrence and overall survival in women with DCIS treated with breast conserving surgery followed by:

   * whole breast RT alone versus whole breast RT plus tumour bed boost;
   * RT using the standard fractionation schedule versus the shorter schedule.
3. To compare the toxicity of:

   * whole breast RT alone versus whole breast RT plus tumour bed boost;
   * RT using the standard fractionation schedule versus the shorter schedule.
4. To compare the cosmetic outcome of:

   * whole breast RT alone versus whole breast RT plus tumour bed boost;
   * RT using the standard fractionation schedule versus the shorter schedule.
5. To identify a molecular signature predictive of invasive recurrence of DCIS to facilitate therapy individualization.
6. To assess inter-relationship of biomarkers and relationship between biomarker expression and specific histopathologic features of DCIS.
7. To evaluate the quality of life of women treated with:

   * whole breast RT alone versus whole breast RT plus tumour bed boost;
   * RT using the standard fractionation schedule versus the shorter schedule.

Eligibility criteria: Inclusion Criteria:

Patients must fulfill all of the following criteria for admission to study:

* Women ≥ 18 years.
* Histologically proven DCIS of the breast without an invasive component.
* Bilateral mammograms performed within 6 months prior to randomization.
* Clinically node-negative.
* Treated by breast conserving surgery (primary excision or re-excision) with complete microscopic excision and clear radial margins of ≥1 mm\* (\*Patients with superficial or deep resection margin of \<1 mm are eligible if surgery has removed all of the intervening breast tissue from the subcutaneous tissue to the pectoralis fascia).
* Women who are at high risk of local recurrence due to:

  * Age \< 50 years; OR
  * Age ≥ 50 years plus at least one of the following:

    * Symptomatic presentation
    * Palpable tumour
    * Multifocal disease
    * Microscopic tumour size ≥ 1.5 cm in maximum dimension
    * Intermediate or high nuclear grade
    * Central necrosis
    * Comedo histology
    * Radial\* surgical resection margin \< 10 mm. (\*Patients with superficial or deep resection margin of \< 10 mm are eligible if surgery has not removed all of the intervening breast tissue from the subcutaneous tissue to the pectoralis fascia.)
* Assessed by surgeon and radiation oncologist to be suitable for breast conserving therapy including whole breast RT.
* Ability to tolerate protocol treatment.
* Protocol RT should preferably commence within 8 weeks but must commence no later than 12 weeks from the last surgical procedure.
* ECOG performance status 0, 1 or 2.
* Patient's life expectancy \> 5 years.
* Availability for long-term follow-up.
* Written informed consent.

Exclusion Criteria:

Patients who fulfill any of the following criteria are not eligible for admission to study:

* Multicentric disease or extensive microcalcifications that could not be completely excised by breast conserving surgery with radial margins of ≥1 mm\*.

  \*Patients with superficial and/or deep margin of \<1 mm are eligible if surgery has removed all of the intervening breast tissue from the subcutaneous tissue to the pectoralis fascia.
* Presence of tumour cells in lymph nodes detected using H\&E or immunohistochemical examination (if lymph node biopsy or dissection has been performed).
* Locally recurrent breast cancer.
* Previous DCIS or invasive cancer of the contralateral breast.

  * Bilateral DCIS of the breasts
  * Synchronous invasive carcinoma of the contralateral breast
* Other concurrent or previous malignancies except:

  * Non-melanomatous skin cancer;
  * Carcinoma in situ of the cervix or endometrium; and
  * Invasive carcinoma of the cervix, endometrium, colon, thyroid and melanoma treated at least five years prior to study admission without disease recurrence.
* Serious non-malignant disease that precludes definitive surgical or radiation treatment (e.g., scleroderma, systemic lupus erythematosus, cardiovascular/pulmonary/renal disease).
* ECOG performance status ≥ 3.
* Women who are pregnant or lactating.

Primary outcomes:
measure: Time to local recurrence, measured from the date of randomization to the date of first evidence of local recurrence.
timeFrame: Main analysis after all patients have completed 5 years of follow-up. Updated analysis after 10 years of follow-up.
Secondary outcomes:
measure: Overall survival
timeFrame: Measured from the date of randomization to the date of death from any cause. Main analysis of secondary outcomes after all patients have completed 5 years of follow-up. Updated analysis after 10 years of follow-up.
measure: Time to disease recurrence
timeFrame: Measured from the date of randomization to the date of first evidence of recurrent disease. Main analysis of secondary outcomes after all patients have completed 5 years of follow-up. Updated analysis after 10 years of follow-up.
measure: Cosmetic Outcome
timeFrame: Cosmetic assessment will take place at baseline, 12, 36 and 60 months post RT.
measure: Radiation toxicity
timeFrame: Assessed at baseline, last week of RT, 3, 6, and 12 months post RT and then yearly until year 10.
measure: Quality of Life change
timeFrame: Assessed at baseline, last week of RT, 6, 12, 24, 60 & 120 months post RT.
Other outcomes:
Locations:
city: Campbelltown
country: Australia
facility: Campbelltown Hospital
state: New South Wales
city: Kingswood
country: Australia
facility: Nepean Cancer Care Centre
state: New South Wales
city: Kogarah
country: Australia
facility: St George Hospital
state: New South Wales
city: Liverpool
country: Australia
facility: Liverpool Hospital
state: New South Wales
city: St Leonards
country: Australia
facility: Royal North Shore Hospital
state: New South Wales
city: Wagga Wagga
country: Australia
facility: Riverina Cancer Care Centre
state: New South Wales
city: Waratah
country: Australia
facility: Calvary Mater Newcastle
state: New South Wales
city: Wentworthville
country: Australia
facility: Westmead Hospital
state: New South Wales
city: Auchenflower
country: Australia
facility: Premion - Wesley
state: Queensland
city: Brisbane
country: Australia
facility: Royal Brisbane and Women's Hospital
state: Queensland
city: Brisbane
country: Australia
facility: Princess Alexandra Hospital
state: Queensland
city: Nambour
country: Australia
facility: Genesis Cancer Care (previously Premion) - Nambour
state: Queensland
city: South Brisbane
country: Australia
facility: Radiation Oncology - Mater Centre
state: Queensland
city: Toowoomba
country: Australia
facility: Toowoomba Cancer Research Centre
state: Queensland
city: Townsville
country: Australia
facility: North Queensland Oncology Service
state: Queensland
city: Tugun
country: Australia
facility: Genesis Cancer Care (previously Premion) - Tugun
state: Queensland
city: Adelaide
country: Australia
facility: Royal Adelaide Hospital
state: South Australia
city: Hobart
country: Australia
facility: Royal Hobart Hospital
state: Tasmania
city: Launceston
country: Australia
facility: Launceston General Hospital
state: Tasmania
city: Geelong
country: Australia
facility: Barwon Health - Andrew Love Cancer Care Centre, Geelong Hospital
state: Victoria
city: Melbourne
country: Australia
facility: Peter MacCallum Cancer Centre
state: Victoria
city: Melbourne
country: Australia
facility: Austin Hospital
state: Victoria
city: Melbourne
country: Australia
facility: William Buckland Radiotherapy Centre, Alfred Hospital
state: Victoria
city: Nedlands
country: Australia
facility: Sir Charles Gardiner Hospital
state: Western Australia
city: Perth
country: Australia
facility: Royal Perth Hospital
state: Western Australia
city: Perth
country: Australia
facility: Perth Radiation Oncology
state: Western Australia
city: Aalst
country: Belgium
facility: Onze Lieve Vrouw Ziekenhuis
city: Antwerpen
country: Belgium
facility: ZNA Middelheim
city: Brussel
country: Belgium
facility: Cliniques Univeritaires St Luc
city: Brussel
country: Belgium
facility: Universitair Zielenhusi
city: Haine St Paul
country: Belgium
facility: Hopital De Jolimont
city: Kortrijk
country: Belgium
facility: AZ Groeninghe - Campus Maria's Voorzienigheid
city: Wilrijk
country: Belgium
facility: Algemeen Ziekenhis Sint-Augustinus
city: Halifax
country: Canada
facility: Nova Scotia Cancer Centre
city: Hamilton
country: Canada
facility: Jurvanski Cancer Centre
city: Hearst
country: Canada
facility: Notre Dame Hospital
city: Kelowna
country: Canada
facility: BCCA Southern Interior - CAVK
city: London
country: Canada
facility: London Regional Cancer Program
city: Miramichi
country: Canada
facility: Saint John Regional Hospital
city: Moncton
country: Canada
facility: Leon Richard Oncology Centre
city: Montreal
country: Canada
facility: Hospital Maisonneuve-Rosemont
city: Oshawa
country: Canada
facility: Lakeridge Health
city: Quebec
country: Canada
facility: CHUQ L'Hotel-Dieu de Quebec
city: Sainte-Anne-de-Bellevue
country: Canada
facility: McGill University Department of Oncology
city: Saskatoon
country: Canada
facility: Allan Blair Cancer Centre
city: Saskatoon
country: Canada
facility: Saskatoon Cancer Centre
city: Sherbrooke
country: Canada
facility: Universite de Sherbrooke - CUGH
city: Thunder Bay
country: Canada
facility: Thunder Bay Regional Health Sciences Centre
city: Toronto
country: Canada
facility: Odette Cancer Centre
city: Toronto
country: Canada
facility: Princess Margaret Hospital
city: Victoria
country: Canada
facility: BCCA Vancouver Centre
city: Victoria
country: Canada
facility: Vancouver Island Cancer Centre
city: Winnipeg
country: Canada
facility: Cancer Care Manitoba
city: Grenoble
country: France
facility: Chr De Grenoble - La Tronche
city: Nice
country: France
facility: Centre Antine Lacassagne
city: Cork
country: Ireland
facility: Cork University Hospital
city: Galway
country: Ireland
facility: University Hospital Galway
city: Rathgar
country: Ireland
facility: SLRON (St Luke's Rad Onc Network)
city: Aviano
country: Italy
facility: Centro Di Riferimento Oncologico - Aviano
city: Pavia
country: Italy
facility: Fondazione Salvatore Maugeri
city: Amsterdam,
country: Netherlands
facility: Academisch Medisch Centrum
city: Amsterdam
country: Netherlands
facility: Cancer Institute Antoni Van Leeuwenhoekziekenhuis
city: Arnhem
country: Netherlands
facility: Arnhem 'S Radiotherapeutisch Instituut
city: Delft
country: Netherlands
facility: Reinier de Graaf Groep
city: Groningen
country: Netherlands
facility: University Medical Centre Groningen
city: Leiden
country: Netherlands
facility: Leiden University Medical Centre
city: Maastricht
country: Netherlands
facility: Maastricht Radiation Oncology Maastro Clinic
city: Westeinde
country: Netherlands
facility: Medisch Centrum Haaglanden
city: Zwolle
country: Netherlands
facility: ISALA Klinieken
city: Auckland
country: New Zealand
facility: Auckland Hospital
city: Christchurch
country: New Zealand
facility: Christchurch Hospital
city: Hamilton
country: New Zealand
facility: Waikato Hospital
city: Singapore
country: Singapore
facility: National University Hospital
city: Basel
country: Switzerland
facility: University Hospital Basel
city: Bellinzona
country: Switzerland
facility: IOSI
city: Bern
country: Switzerland
facility: Inselspital Bern
city: Chur
country: Switzerland
facility: Kantonsspital Graubunden
city: Munsterlingen
country: Switzerland
facility: Kantonsspital Munsterlingen
city: St. Gallen
country: Switzerland
facility: Kantonsspital St. Gallen
city: Zurich
country: Switzerland
facility: Brust-Zentrum Zurich-Seefeld
city: Zurich
country: Switzerland
facility: Klinik Hirslanden
city: Cheltenham
country: United Kingdom
facility: Gloucestershire Royal & Cheltenham General Hospitals
state: Gloucestershire
city: Oxford
country: United Kingdom
facility: Churchill Hospital
state: Headington
city: Boston
country: United Kingdom
facility: Pilgram Hospital
state: Lincolnshire
city: Northwood
country: United Kingdom
facility: Mount Vernon Cancer Centre
state: Middlesex
city: Southall
country: United Kingdom
facility: Ealing Hospital
state: Middlesex
city: Sutton-In-Ashfield
country: United Kingdom
facility: Kings Mill Hospital Nottingham
state: Nottinghamshire
city: Taunton
country: United Kingdom
facility: Musgrove Park Hospital
state: Somerset
city: Burton-On-Trent
country: United Kingdom
facility: Queens Hospital Burton
state: Staffordshire
city: Stoke-On-Trent
country: United Kingdom
facility: University of North Staffordshire
state: Staffordshire
city: Aberdeen
country: United Kingdom
facility: Aberdeen Royal Infirmary
city: Basildon
country: United Kingdom
facility: Basildon University Hospital
city: Belfast
country: United Kingdom
facility: Belfast City Hospital
city: Birmingham
country: United Kingdom
facility: Queen Elizabeth Hospital
city: Birmingham
country: United Kingdom
facility: Sandwell and West Birmingham Hospitals NHS Trust
city: Bristol
country: United Kingdom
facility: Bristol Haematology & Oncology
city: Colchester
country: United Kingdom
facility: Colchester Hospital
city: Coventry
country: United Kingdom
facility: Coventry Arden Cancer Centre
city: Derby
country: United Kingdom
facility: Royal Derby Hospital
city: Dumfries
country: United Kingdom
facility: Dumfries & Galloway Royal Infirmary
city: Dunfermline
country: United Kingdom
facility: Queen Margaret Hospital
city: Edinburgh
country: United Kingdom
facility: Edinburgh Western General Hospital
city: Glasgow
country: United Kingdom
facility: The Beatson West of Scotland Cancer Centre
city: Guildford
country: United Kingdom
facility: Royal Surrey County Hospital
city: Ipswich
country: United Kingdom
facility: Ipswich Hospital
city: Kidderminster
country: United Kingdom
facility: Kidderminster Hospital
city: Leicester
country: United Kingdom
facility: Leicester Royal Infirmary
city: Lincoln
country: United Kingdom
facility: Lincoln County Hospital
city: London
country: United Kingdom
facility: Imperial College Healthcare Charing Cross
city: Middlesborough
country: United Kingdom
facility: James Cook University Hospital
city: Nottingham
country: United Kingdom
facility: Nottingham University Hospitals
city: Paisley
country: United Kingdom
facility: Royal Alexandra Hospital
city: Redditch
country: United Kingdom
facility: Alexandra Hospital
city: Sheffield
country: United Kingdom
facility: Weston Park Hospital
city: Shrewsbury
country: United Kingdom
facility: The Shrewsbury and Telford Hospital NHS Trust
city: Southend
country: United Kingdom
facility: Southend University Hopstial
city: Stafford
country: United Kingdom
facility: Stafford Hospital
city: Sutton
country: United Kingdom
facility: Royal Marsden
city: Warwick
country: United Kingdom
facility: Warwick Hospital
city: Wolverhampton
country: United Kingdom
facility: New Cross Hospital
Study officials:
affiliation: Prince of Wales Hospital Randwick
name: Boon Chua
role: STUDY_CHAIR
References:
citation: Chua BH, Link EK, Kunkler IH, Whelan TJ, Westenberg AH, Gruber G, Bryant G, Ahern V, Purohit K, Graham PH, Akra M, McArdle O, O'Brien P, Harvey JA, Kirkove C, Maduro JH, Campbell ID, Delaney GP, Martin JD, Vu TTT, Muanza TM, Neal A, Olivotto IA; BIG 3-07/TROG 07.01 trial investigators. Radiation doses and fractionation schedules in non-low-risk ductal carcinoma in situ in the breast (BIG 3-07/TROG 07.01): a randomised, factorial, multicentre, open-label, phase 3 study. Lancet. 2022 Aug 6;400(10350):431-440. doi: 10.1016/S0140-6736(22)01246-6.
citation: King MT, Link EK, Whelan TJ, Olivotto IA, Kunkler I, Westenberg AH, Gruber G, Schofield P, Chua BH; BIG 3-07/TROG 07.01 trial investigators. Quality of life after breast-conserving therapy and adjuvant radiotherapy for non-low-risk ductal carcinoma in situ (BIG 3-07/TROG 07.01): 2-year results of a randomised, controlled, phase 3 trial. Lancet Oncol. 2020 May;21(5):685-698. doi: 10.1016/S1470-2045(20)30085-1. Epub 2020 Mar 20.