Hypofractionated LocoRegional Radiotherapy in Breast Cancer (RHEAL)

Randomized Trial of Hypofractionated LocoRegional Radiotherapy in Breast Cancer and Lymphedema (RHEAL)

The primary objective of this study is to determine if hypofractionated RT delivered over 1 week to the breast or chest wall and regional nodes (26Gy in 5 daily fractions) following BCS or mastectomy, is non-inferior to conventional fractionation to the breast or chest wall and regional nodes delivered over 3 weeks (40Gy in 15 daily fractions) in patients with node-positive breast cancer.

Study Overview

• Status: Recruiting
• Conditions: Breast Neoplasms; Lymphedema; Radiotherapy
• Intervention / Treatment: Radiation: Locoregional radiation treatment - Conventional fractionation; Radiation: Locoregional radiation treatment - Hypofractionation

Detailed Description

A multi-centre, randomized, non-inferior, phase III study comparing two radiation treatment modalities, conventional fractionation with hypofractionation for locoregional RT. Eligible, consenting patients with newly diagnosed and histologically confirmed invasive carcinoma of the breast without evidence of metastatic disease; treated with definitive surgery [BCS or mastectomy with nodal staging using sentinel lymph node biopsy (SLNB) or axillary lymph node dissection (ALND)] will be randomized in a 1:1 fashion to either conventional locoregional RT (control group) or hypofractionated locoregional RT (experimental group). Stratification factors include: body mass index, the performance of ALND, type of surgery (BCS or mastectomy) and clinical centre.

Study participants will be assessed for lymphedema, the primary outcome, by measuring arm volume. Arm mobility will be assessed by measuring arm movement. Study participants will be assessed for acute and late radiation toxicities, during and post RT. Study participants will be followed and assessed annually for breast cancer recurrence (BCR), new second cancers, quality of life (QOL) and overall survival. Cost effectiveness and cost utility will also be determined. The planned sample size is 588 study participants. The study will be conducted at clinical centres throughout Canada.

• Study Type: Interventional
• Enrollment (Estimated): 588
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Brittany Speller; Phone Number: 42611 905-527-2299; Email: spelleb@mcmaster.ca
• Study Contact Backup: Name: Sharon Nason; Phone Number: 42622 905-527-2299; Email: nasons@mcmaster.ca

Study Locations

• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N 4N2
      • Recruiting
      • Tom Baker Cancer Centre
      • Contact: Marny Yar
      • Principal Investigator: Jeff Cao
    • Edmonton, Alberta, Canada, T6G 1Z2
      • Recruiting
      • Cross Cancer Institute
      • Contact: Juliette Jordan
      • Principal Investigator: Fleur Huang
  • British Columbia
    • Kelowna, British Columbia, Canada, V1Y 5L3
      • Recruiting
      • BC Cancer - Centre for the Southern Interior
      • Contact: Kiana Wong
      • Principal Investigator: Angela Lin
    • Victoria, British Columbia, Canada, V8R 6V5
      • Recruiting
      • BC Cancer - Vancouver Island Centre
      • Contact: Emily White
      • Principal Investigator: Tanya Berrang
  • Ontario
    • Hamilton, Ontario, Canada, L8V 5C2
      • Recruiting
      • Juravinski Cancer Centre
      • Contact: Brenda DeMedeiros
      • Principal Investigator: Tim Whelan
    • London, Ontario, Canada, N6A 5W9
      • Recruiting
      • London Regional Cancer Program
      • Principal Investigator: Francisco Perera
      • Contact: Alisha Moynahan
    • Ottawa, Ontario, Canada, K1H 8L6
      • Recruiting
      • The Ottawa Hospital Regional Cancer Centre
      • Principal Investigator: Lynn Chang
      • Contact: Krista Liimatainen
    • Sudbury, Ontario, Canada, P3E5J1
      • Recruiting
      • Northeast Cancer Centre, Health Sciences North
      • Contact: Amanda Snyder
      • Principal Investigator: Karan Paul Sanghera
    • Toronto, Ontario, Canada, M4N 3M5
      • Recruiting
      • Sunnybrook Health Sciences Centre - Odette Cancer Centre
      • Contact: Clarissa Chau
      • Principal Investigator: Eileen Rakovitch
    • Toronto, Ontario, Canada, M5G 1E0
      • Recruiting
      • Princess Margaret Cancer Centre - UHN
      • Contact: Vicky Gillman
      • Principal Investigator: Kathy Han
  • Quebec
    • Lévis, Quebec, Canada, G6V 3Z1
      • Recruiting
      • Hotel-Dieu de Lévis (CISSS CA)
      • Contact: Pierre Bedard
      • Principal Investigator: Anne Dagnault
    • Montreal, Quebec, Canada, H1T 2M4
      • Recruiting
      • CIUSSS de l'Est-de-l'Île de Montréal, Hôpital, Maisonneuve-Rosemont
      • Principal Investigator: Michael Yassa, MD
      • Contact: Lys Fernet
    • Montréal, Quebec, Canada, H4A 3J1
      • Recruiting
      • McGill University Health Centre-Cedars Cancer Centre
      • Principal Investigator: Tarek Hijal
      • Contact: Marianna Perna
    • Montréal, Quebec, Canada
      • Recruiting
      • CHUM - Centre Hospitalier de l'Universite de Montreal
      • Contact: Mom Phat
      • Principal Investigator: Pierre Rousseau
    • Quebec City, Quebec, Canada
      • Recruiting
      • CHU-de Québec-Université de Laval
      • Principal Investigator: Valerie Theberge
      • Contact: Josee Allard
    • Sherbrooke, Quebec, Canada, J1G 2E8
      • Active, not recruiting
      • Sherbrooke University Hospital Centre
  • Saskatchewan
    • Regina, Saskatchewan, Canada, S4T 7T1
      • Recruiting
      • Allan Blair Cancer Centre
      • Contact: Bernadette Procyk
      • Principal Investigator: Derek Suderman
    • Saskatoon, Saskatchewan, Canada, S7N 4H4
      • Recruiting
      • Saskatoon Cancer Centre
      • Contact: Shavaun Liss
      • Principal Investigator: Philip Wright

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Newly diagnosed invasive carcinoma of the breast.
2. Treated with definitive surgery (BCS or mastectomy with nodal staging using SLNB or ALND) with clear margins of excision.* Note: *Patients with limited positive posterior margin where disease is resected to chest wall or limited positive anterior margin where disease is resected to dermis are eligible.

3. Candidate for locoregional radiotherapy: breast cancer stage after definitive surgery:

   • Neoadjuvant chemotherapy was not administered: pathologic stage T3N0,T1-3 N1-2**

     ** patients with nodal micromets (N1mi) are eligible

   • Neoadjuvant chemotherapy was administered: clinical stage T3N0, T1-3, N1-2 and pathologic stage T0-3, N0-2†

     • Patients who are clinically N1-2 prior to chemotherapy should be confirmed histologically unless it is clear that they are node positive. Patients who are deemed node negative prior to chemotherapy but are node positive following chemotherapy are eligible. Patients who are node positive prior to chemotherapy and who have complete response in the lymph nodes are also eligible.
4. No evidence of metastatic disease.

Exclusion Criteria:

1. Age < 18 years.
2. Clinical stages T4 and/or N3.
3. Clinical lymphedema in the ipsilateral arm or breast/chest wall.
4. Any prior history, not including index cancer, of ipsilateral invasive breast cancer or ipsilateral DCIS treated with radiation therapy. (Patients with previous ipsilateral DCIS or LCIS not treated with radiation are eligible.)
5. Synchronous or previous contralateral breast cancer.(Patients with previous contralateral DCIS or LCIS not treated with radiation are eligible.)
6. History of non-breast malignancy within the last 5 years other than non-melanoma skin cancer or treated in-situ carcinoma.
7. Neoadjuvant endocrine therapy. (Extended neoadjuvant endocrine therapy is not permitted. Endocrine therapy exposure for 12 weeks or less prior to surgery is acceptable.)
8. Breast reconstruction.
9. Presence of known medical conditions that would preclude follow-up for 5 years.
10. Previous radiotherapy to the ipsilateral breast or chest wall or serious non-malignant disease e.g. scleroderma, severe lung or heart disease that would preclude radiotherapy.
11. Known pregnancy or currently lactating.
12. Geographic inaccessibility for follow-up.
13. Inability to provide informed consent.

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

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Control; Conventional fractionation for locoregional radiotherapy	Radiation: Locoregional radiation treatment - Conventional fractionation; 40 Gray in 15 daily fractions over 3 weeks
Experimental: Experimental; Hypofractionation for locoregional radiotherapy	Radiation: Locoregional radiation treatment - Hypofractionation; 26 Gray in 5 daily fractions over 1 week

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Lymphedema	Lymphedema defined as relative volume change (RVC) ≥10%	3 years post randomization

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Breast cancer recurrence	Both locoregional and distant recurrence and second cancers	Annually for 5 years post randomization
Mortality	Survival	Annually for 5 years post randomization
Radiation toxicity	Acute and late radiation toxicity	During last week of radiotherapy, at 3 months post radiotherapy and annually for 5 years post randomization
Arm mobility	Assessed by measuring the straight lateral abduction of both the ipsilateral and contralateral arm	1 and 3 years post randomization
Patient Quality of Life with respect to daily health and activities	Impact on quality of life will be assessed with the European Organization for Research in Treatment of Cancer and the Breast Cancer Specific Module 23. The scale is 1 to 4 where a higher score means a worse outcome.	During last week of radiotherapy, at 3 months post radiotherapy and 1 and 3 years post randomization
Perception of lymphedema	Impact of lymphedema on quality of life will be assessed with the National Surgical Adjuvant Breast and Bowel Project questionnaire. The scale is 1 to 5 where a higher score means a worse outcome.	During last week of radiotherapy, at 3 months post radiotherapy and 1 and 3 years post randomization
Perception of breast cosmesis	Patient-reported breast cosmesis using a Breast Cosmesis Questionnaire to study the late effects of radiation.	1 and 3 years post randomization
Health Care Resource Utilization	Health Care Resource Utilization will be estimated using dates and duration of radiotherapy treatment and emergency department visits and hospitalizations.	During radiotherapy, at 3 months post radiotherapy and annually for 5 years post randomization
Patient Costs	Patient costs will be assessed using a Time Off Work Questionnaire to study the financial impact of breast cancer and its treatment	During last week of radiotherapy, at 3 months post radiotherapy and 1 and 3 years post randomization

Collaborators and Investigators

• Sponsor: Ontario Clinical Oncology Group (OCOG)
• Investigators: Principal Investigator: Timothy Whelan, Juravinski Cancer Centre, McMaster University, Hamilton

Study record dates

Study Major Dates

• Study Start (Actual): February 10, 2021
• Primary Completion (Estimated): September 30, 2025
• Study Completion (Estimated): December 31, 2030

Study Registration Dates

• First Submitted: January 9, 2020
• First Submitted That Met QC Criteria: January 10, 2020
• First Posted (Actual): January 14, 2020

Study Record Updates

• Last Update Posted (Actual): March 8, 2024
• Last Update Submitted That Met QC Criteria: March 6, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: Lymphedema; Breast Cancer; Hypofractionated; Locoregional
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Lymphatic Diseases; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Lymphedema
• Other Study ID Numbers: OCOG-2019-RHEAL

Drug and device information, study documents

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