Radiation Doses and Fractionation Schedules in Non-low Risk Ductal Carcinoma In Situ (DCIS) of the Breast (DCIS)

A Randomised Phase III Study of Radiation Doses and Fractionation Schedules in Non-low Risk Ductal Carcinoma In Situ (DCIS) of the Breast

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Carcinoma, Ductal, Breast
• Intervention / Treatment: Radiation: Standard WB fractionation; Radiation: Shorter WB fractionation; Radiation: Standard WB fractionation+Boost; Radiation: Shorter WB fractionation + Boost

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.

• Study Type: Interventional
• Enrollment (Actual): 1608
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Campbelltown, New South Wales, Australia, 2560
      • Campbelltown Hospital
    • Kingswood, New South Wales, Australia
      • Nepean Cancer Care Centre
    • Kogarah, New South Wales, Australia, 2217
      • St George Hospital
    • Liverpool, New South Wales, Australia, 2170
      • Liverpool Hospital
    • St Leonards, New South Wales, Australia, 2065
      • Royal North Shore Hospital
    • Wagga Wagga, New South Wales, Australia, 2650
      • Riverina Cancer Care Centre
    • Waratah, New South Wales, Australia, 2298
      • Calvary Mater Newcastle
    • Wentworthville, New South Wales, Australia, 2145
      • Westmead Hospital
  • Queensland
    • Auchenflower, Queensland, Australia, 4006
      • Premion - Wesley
    • Brisbane, Queensland, Australia, 4102
      • Princess Alexandra Hospital
    • Brisbane, Queensland, Australia, 4006
      • Royal Brisbane and Women's Hospital
    • Nambour, Queensland, Australia
      • Genesis Cancer Care (previously Premion) - Nambour
    • South Brisbane, Queensland, Australia, 4101
      • Radiation Oncology - Mater Centre
    • Toowoomba, Queensland, Australia
      • Toowoomba Cancer Research Centre
    • Townsville, Queensland, Australia, 4810
      • North Queensland Oncology Service
    • Tugun, Queensland, Australia, 4224
      • Genesis Cancer Care (previously Premion) - Tugun
  • South Australia
    • Adelaide, South Australia, Australia, 5000
      • Royal Adelaide Hospital
  • Tasmania
    • Hobart, Tasmania, Australia, 7000
      • Royal Hobart Hospital
    • Launceston, Tasmania, Australia, 7250
      • Launceston General Hospital
  • Victoria
    • Geelong, Victoria, Australia, 3220
      • Barwon Health - Andrew Love Cancer Care Centre, Geelong Hospital
    • Melbourne, Victoria, Australia, 3002
      • Peter Maccallum Cancer Centre
    • Melbourne, Victoria, Australia, 3084
      • Austin Hospital
    • Melbourne, Victoria, Australia, 3181
      • William Buckland Radiotherapy Centre, Alfred Hospital
  • Western Australia
    • Nedlands, Western Australia, Australia, 6009
      • Sir Charles Gardiner Hospital
    • Perth, Western Australia, Australia, 6001
      • Royal Perth Hospital
    • Perth, Western Australia, Australia
      • Perth Radiation Oncology
• Belgium
  • Aalst, Belgium
    • Onze Lieve Vrouw Ziekenhuis
  • Antwerpen, Belgium
    • ZNA Middelheim
  • Brussel, Belgium
    • Cliniques Univeritaires St Luc
  • Brussel, Belgium
    • Universitair Zielenhusi
  • Haine St Paul, Belgium
    • Hôpital de Jolimont
  • Kortrijk, Belgium
    • AZ Groeninghe - Campus Maria's Voorzienigheid
  • Wilrijk, Belgium
    • Algemeen Ziekenhis Sint-Augustinus
• Canada
  • Halifax, Canada
    • Nova Scotia Cancer Centre
  • Hamilton, Canada
    • Jurvanski Cancer Centre
  • Hearst, Canada
    • Notre Dame Hospital
  • Kelowna, Canada
    • BCCA Southern Interior - CAVK
  • London, Canada
    • London Regional Cancer Program
  • Miramichi, Canada
    • Saint John Regional Hospital
  • Moncton, Canada
    • Leon Richard Oncology Centre
  • Montreal, Canada
    • Hospital Maisonneuve-Rosemont
  • Oshawa, Canada
    • Lakeridge Health
  • Quebec, Canada
    • CHUQ L'Hotel-Dieu de Quebec
  • Sainte-Anne-de-Bellevue, Canada
    • McGill University Department of Oncology
  • Saskatoon, Canada
    • Saskatoon Cancer Centre
  • Saskatoon, Canada
    • Allan Blair Cancer Centre
  • Sherbrooke, Canada
    • Universite de Sherbrooke - CUGH
  • Thunder Bay, Canada
    • Thunder Bay Regional Health Sciences Centre
  • Toronto, Canada
    • Princess Margaret Hospital
  • Toronto, Canada
    • Odette Cancer Centre
  • Victoria, Canada
    • BCCA Vancouver Centre
  • Victoria, Canada
    • Vancouver Island Cancer Centre
  • Winnipeg, Canada
    • Cancer Care Manitoba
• France
  • Grenoble, France
    • Chr De Grenoble - La Tronche
  • Nice, France
    • Centre Antine Lacassagne
• Ireland
  • Cork, Ireland
    • Cork University Hospital
  • Galway, Ireland
    • University Hospital Galway
  • Rathgar, Ireland
    • SLRON (St Luke's Rad Onc Network)
• Italy
  • Aviano, Italy
    • Centro di Riferimento Oncologico - Aviano
  • Pavia, Italy
    • Fondazione Salvatore Maugeri
• Netherlands
  • Amsterdam, Netherlands
    • Cancer Institute Antoni Van Leeuwenhoekziekenhuis
  • Amsterdam,, Netherlands
    • Academisch Medisch Centrum
  • Arnhem, Netherlands
    • Arnhem 'S Radiotherapeutisch Instituut
  • Delft, Netherlands
    • Reinier de Graaf Groep
  • Groningen, Netherlands
    • University Medical Centre Groningen
  • Leiden, Netherlands
    • Leiden University Medical Centre
  • Maastricht, Netherlands
    • Maastricht Radiation Oncology Maastro Clinic
  • Westeinde, Netherlands
    • Medisch Centrum Haaglanden
  • Zwolle, Netherlands
    • Isala Klinieken
• New Zealand
  • Auckland, New Zealand, 1001
    • Auckland Hospital
  • Christchurch, New Zealand, 8011
    • Christchurch Hospital
  • Hamilton, New Zealand, 3204
    • Waikato Hospital
• Singapore
  • Singapore, Singapore, 119074
    • National University Hospital
• Switzerland
  • Basel, Switzerland
    • University Hospital Basel
  • Bellinzona, Switzerland
    • IOSI
  • Bern, Switzerland
    • Inselspital Bern
  • Chur, Switzerland
    • Kantonsspital Graubünden
  • Munsterlingen, Switzerland
    • Kantonsspital Münsterlingen
  • St. Gallen, Switzerland
    • Kantonsspital St. Gallen
  • Zurich, Switzerland
    • Brust-Zentrum Zurich-Seefeld
  • Zurich, Switzerland
    • Klinik Hirslanden
• United Kingdom
  • Aberdeen, United Kingdom
    • Aberdeen Royal Infirmary
  • Basildon, United Kingdom
    • Basildon University Hospital
  • Belfast, United Kingdom
    • Belfast City Hospital
  • Birmingham, United Kingdom
    • Queen Elizabeth Hospital
  • Birmingham, United Kingdom
    • Sandwell and West Birmingham Hospitals NHS Trust
  • Bristol, United Kingdom
    • Bristol Haematology & Oncology
  • Colchester, United Kingdom
    • Colchester Hospital
  • Coventry, United Kingdom
    • Coventry Arden Cancer Centre
  • Derby, United Kingdom
    • Royal Derby Hospital
  • Dumfries, United Kingdom
    • Dumfries & Galloway Royal Infirmary
  • Dunfermline, United Kingdom
    • Queen Margaret Hospital
  • Edinburgh, United Kingdom
    • Edinburgh Western General Hospital
  • Glasgow, United Kingdom
    • The Beatson West of Scotland Cancer Centre
  • Guildford, United Kingdom
    • Royal Surrey County Hospital
  • Ipswich, United Kingdom
    • Ipswich Hospital
  • Kidderminster, United Kingdom
    • Kidderminster Hospital
  • Leicester, United Kingdom
    • Leicester Royal Infirmary
  • Lincoln, United Kingdom
    • Lincoln County Hospital
  • London, United Kingdom
    • Imperial College Healthcare Charing Cross
  • Middlesborough, United Kingdom
    • James Cook University Hospital
  • Nottingham, United Kingdom
    • Nottingham University Hospitals
  • Paisley, United Kingdom
    • Royal Alexandra Hospital
  • Redditch, United Kingdom
    • Alexandra Hospital
  • Sheffield, United Kingdom
    • Weston Park Hospital
  • Shrewsbury, United Kingdom
    • The Shrewsbury and Telford Hospital NHS Trust
  • Southend, United Kingdom
    • Southend University Hopstial
  • Stafford, United Kingdom
    • Stafford Hospital
  • Sutton, United Kingdom
    • Royal Marsden
  • Warwick, United Kingdom
    • Warwick Hospital
  • Wolverhampton, United Kingdom
    • New Cross Hospital
  • Gloucestershire
    • Cheltenham, Gloucestershire, United Kingdom
      • Gloucestershire Royal & Cheltenham General Hospitals
  • Headington
    • Oxford, Headington, United Kingdom
      • Churchill Hospital
  • Lincolnshire
    • Boston, Lincolnshire, United Kingdom
      • Pilgram Hospital
  • Middlesex
    • Northwood, Middlesex, United Kingdom
      • Mount Vernon Cancer Centre
    • Southall, Middlesex, United Kingdom
      • Ealing Hospital
  • Nottinghamshire
    • Sutton-In-Ashfield, Nottinghamshire, United Kingdom
      • Kings Mill Hospital Nottingham
  • Somerset
    • Taunton, Somerset, United Kingdom
      • Musgrove Park Hospital
  • Staffordshire
    • Burton-On-Trent, Staffordshire, United Kingdom
      • Queens Hospital Burton
    • Stoke-On-Trent, Staffordshire, United Kingdom
      • University of North Staffordshire

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Arm 1 (Standard WB Fractionation); Whole Breast RT alone - Standard fractionation schedule (50GY/25 Fractions/35days)	Radiation: Standard WB fractionation; A total dose of 50 Gy in 25 fractions in 2-Gy daily fractions, 5 fractions per week (at least 9 fractions per fortnight).; Other Names: Radiation
Experimental: Arm 2 (Shorter WB Fractionation); Whole Breast RT alone - Shorter fractionation schedule (42.5 Gy/16 fractions/22 days)	Radiation: Shorter WB fractionation; A total dose of 42.5 Gy in 16 fractions in 2.656-Gy daily fractions, 5 fractions per week (at least 9 fractions per fortnight).; Other Names: Radiation
Active Comparator: Arm 3 (Standard WB fractionation+Boost); Whole Breast RT + tumor bed boost - Standard fractionation schedule (50 Gy/25 fractions/35 days; Boost 16 Gy/8 fractions/10 days)	Radiation: Standard WB fractionation+Boost; Whole Breast: A total dose of 50 Gy in 25 fractions in 2-Gy daily fractions, 5 fractions per week (at least 9 fractions per fortnight). Tumour bed: A total dose of 10 Gy in 5 fractions in 2-Gy daily fractions, 5 fractions per week.; Other Names: Radiation
Experimental: Arm 4 (Shorter WB fractionation + Boost); Whole breast RT + tumour bed boost - Shorter fractionation schedule (42.5 Gy/16 fractions/22 days; Boost 16 Gy/8 fractions/10 days)	Radiation: Shorter WB fractionation + Boost; Whole breast: A total dose of 42.5 Gy in 16 fractions in 2.656-Gy daily fractions, 5 fractions per week (at least 9 fractions per fortnight). Tumour bed: A total dose of 10 Gy in 4 fractions in 2.5-Gy daily fractions, 4 fractions per week.; Other Names: Radiation

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Time to local recurrence, measured from the date of randomization to the date of first evidence of local recurrence.	Main analysis after all patients have completed 5 years of follow-up. Updated analysis after 10 years of follow-up.

Secondary Outcome Measures

Outcome Measure	Time Frame
Overall survival	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.
Time to disease recurrence	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.
Cosmetic Outcome	Cosmetic assessment will take place at baseline, 12, 36 and 60 months post RT.
Radiation toxicity	Assessed at baseline, last week of RT, 3, 6, and 12 months post RT and then yearly until year 10.
Quality of Life change	Assessed at baseline, last week of RT, 6, 12, 24, 60 & 120 months post RT.

Collaborators and Investigators

• Sponsor: Trans Tasman Radiation Oncology Group
• Collaborators: European Organisation for Research and Treatment of Cancer - EORTC; NCIC Clinical Trials Group; ETOP IBCSG Partners Foundation; Breast International Group; Borstkanker Onderzoek Groep; Cancer Trials Ireland; Scottish Cancer Trials Breast Group

Publications and helpful links

General Publications

• 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.
• 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.

Helpful Links

• Click here for more information about this study on the TROG official website

Study record dates

Study Major Dates

• Study Start: June 1, 2007
• Primary Completion (Anticipated): June 1, 2024
• Study Completion (Anticipated): June 1, 2024

Study Registration Dates

• First Submitted: May 3, 2007
• First Submitted That Met QC Criteria: May 4, 2007
• First Posted (Estimate): May 7, 2007

Study Record Updates

• Last Update Posted (Actual): March 22, 2023
• Last Update Submitted That Met QC Criteria: March 19, 2023
• Last Verified: March 1, 2023

More Information

Terms related to this study

• Keywords: Breast conserving therapy; Ductal carcinoma in-situ; Whole breast radiation therapy; Tumour bed boost; Fractionation schedules; Completely excised non-low risk DCIS
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Adenocarcinoma; Neoplasms, Glandular and Epithelial; Breast Diseases; Breast Neoplasms; Neoplasms, Ductal, Lobular, and Medullary; Breast Carcinoma In Situ; Carcinoma in Situ; Carcinoma; Carcinoma, Ductal; Carcinoma, Intraductal, Noninfiltrating; Carcinoma, Ductal, Breast
• Other Study ID Numbers: TROG 07.01; NHMRC 454390 (Other Grant/Funding Number: NHMRC); BIG 3-07 (Other Identifier: Collaborative Group); NCIC CTG MA.33 (Other Identifier: Collaborative Group); BOOG 2009-03 (Other Identifier: Collaborative Group); ICORG 10-06 (Other Identifier: Collaborative Group); EORTC 22085-10083 (Other Identifier: Collaborative Group); IBCSG 38-10 (Other Identifier: Collaborative Group); SCTBG 2009MayPR55 (Other Identifier: Collaborative Group)