Hypofractionated LocoRegional Radiotherapy in Breast Cancer

Overview

The primary objective is to determine if hypofractionated radiotherapy (RT) delivered over 3 weeks to the breast and regional nodes (supraclavicular, axillary and internal mammary) following breast conserving surgery (BCS), or to the chest wall and regional nodes following mastectomy, is non-inferior to conventional fractionation delivered over 5 weeks in patients with node positive breast cancer.

Full Title of Study: “Randomized Trial of Hypofractionated LocoRegional Radiotherapy in Breast Cancer and Lymphedema (RHEAL)”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Treatment
    • Masking: None (Open Label)
  • Study Primary Completion Date: March 1, 2023

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.

Interventions

  • Radiation: Locoregional radiation treatment – Conventional fractionation
    • 50 Gray in 25 daily fractions over 5 weeks
  • Radiation: Locoregional radiation treatment – Hypofractionation
    • 42.5 Gray in 16 daily fractions over 3 weeks

Arms, Groups and Cohorts

  • Active Comparator: Control
    • Conventional fractionation for locoregional radiotherapy
  • Experimental: Experimental
    • Hypofractionation for locoregional radiotherapy

Clinical Trial Outcome Measures

Primary Measures

  • Lymphedema
    • Time Frame: 3 years post randomization
    • Lymphedema defined as relative volume change (RVC) >10%

Secondary Measures

  • Breast cancer recurrence
    • Time Frame: Annually for 5 years post randomization
    • Both locoregional and distant recurrence and second cancers
  • Mortality
    • Time Frame: Annually for 5 years post randomization
    • Survival
  • Radiation toxicity
    • Time Frame: During last week of radiotherapy, at 3 months post radiotherapy and annually for 5 years post randomization
    • Acute and late radiation toxicity
  • Arm mobility
    • Time Frame: 1 and 3 years post randomization
    • Assessed by measuring the straight lateral abduction of both the ipsilateral and contralateral arm
  • Patient Quality of Life with respect to daily health and activities
    • Time Frame: During last week of radiotherapy, at 3 months post radiotherapy and 1 and 3 years post randomization
    • 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.
  • Perception of lymphedema
    • Time Frame: During last week of radiotherapy, at 3 months post radiotherapy and 1 and 3 years post randomization
    • 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.
  • Health Care Resource Utilization
    • Time Frame: During radiotherapy, at 3 months post radiotherapy and annually for 5 years post randomization
    • Health Care Resource Utilization will be estimated using dates and duration of radiotherapy treatment and emergency department visits and hospitalizations.
  • Patient Costs
    • Time Frame: During last week of radiotherapy, at 3 months post radiotherapy and 1 and 3 years post randomization
    • Patient costs will be assessed using a Time Off Work Questionnaire to study the financial impact of breast cancer and its treatment

Participating in This Clinical Trial

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. Breast cancer stage after definitive surgery.

  • if neoadjuvant chemotherapy was not administered: pathologic stage T1-3, N1-2
  • if neoadjuvant chemotherapy was administered: clinical stage T1-3, N1-2 (histologically node positive) and pathologic stage T0-3, N0-2†

Note: †Patients who are histologically node positive prior to chemotherapy and who have complete response in the lymph nodes are eligible.

4. No evidence of metastatic disease.

5. Candidate for locoregional radiotherapy.

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. Synchronous or previous contralateral breast cancer.

5. Breast reconstruction.

6. History of non-breast malignancy within the last 5 years other than non-melanoma skin cancer or treated in-situ carcinoma.

7. 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.

8. Known pregnancy or currently lactating.

9. Geographic inaccessibility for follow-up.

10. Inability to provide informed consent.

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: N/A

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Ontario Clinical Oncology Group (OCOG)
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Timothy Whelan, Principal Investigator, Juravinski Cancer Centre, McMaster University, Hamilton
  • Overall Contact(s)
    • Kathryn Cline, BSc, 905-527-2299, clinek@mcmaster.ca

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