Outcome of 15 Versus 5 Fractions in Adjuvant Breast Radiotherapy in Women Over 65 Years (HAI-5-III)

A Partially Randomized Patient Preference Trial, Comparing Adjuvant Hypofractionated Radiotherapy in 15 Versus 5 Fractions After Breast Conserving Surgery or Mastectomy for Early or Locally Advanced Breast Cancer in Women Above 65 Years

This study will evaluate the effect of highly accelerated external beam radiotherapy (EBRT) in 5 fractions over 10 days compared to 15 fractions over 3 weeks for early as well as locally-advanced stage breast cancer.

Primary endpoint will be chronic toxicity (breast deformation and retraction). Secondary endpoints are acute toxicity, loco-regional and distant tumor control, patient reported QoL and cosmetic satisfaction. Patients with lymph node irradiation will be closely monitored for radiation induced plexopathy.

Study Overview

• Status: Active, not recruiting
• Conditions: Breastcancer
• Intervention / Treatment: Radiation: WBI 5 fractions; Radiation: SIB 5 fractions if needed; Radiation: WBI 15 fractions; Radiation: SIB 15 fractions if needed; Radiation: LNI 5 fractions; Radiation: LNI 15 fractions; Radiation: TWI 5 fractions; Radiation: TWI 15 fractions

Detailed Description

Over the age of 65, uptake of adjuvant radiotherapy after surgery for breast cancer declines, even in women with poor prognostic stage or adverse tumor characteristics.

Lowering the number of fractions may reduce reluctancy for radiotherapy in this age group.

In a preceding prospective phase I-II trial, evaluating EBRT over 10 days, results on technical feasibility and acute toxicity were positively evaluated.

However, data on the chronic effects of breast irradiation using high doses per fraction are still sparse.

This trial is developed to compare standard hypo-fractionation in 15 fractions (if needed with simultaneously integrated boost - SIB) with highly accelerated radiotherapy in 5 fractions.

Patients referred for adjuvant radiotherapy after breast conserving surgery will preferably be randomized, depending on the indication, to a study-arm with whole breast irradiation (WBI) +/- SIB or to a study-arm with WBI+/- SIB and lymph node irradiation (LNI).

If patients after breast conserving surgery (BCS) have a strong preference for 5 or 15 fractions, they will be invited to enter the parallel observational arm (patient preference).

Patients referred for adjuvant radiotherapy after mastectomy +/- LNI accepting to participate, can choose a 5 or 15-fraction schedule. No randomization is foreseen in this last observational group.

• Study Type: Interventional
• Enrollment (Actual): 144
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Belgium
  • Ghent, Belgium, 9000
    • Ghent University Hospital, Dept. Radiotherapy-Oncology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 65 years and older (Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• breast conserving surgery or mastectomy for breast carcinoma
• multidisciplinary decision of adjuvant irradiation
• absence of distant metastases
• informed consent obtained, signed and dated before specific protocol procedures

Exclusion Criteria:

• History of previous radiation treatment to the same region
• Bilateral breast irradiation
• Life expectancy of less than 2 years
• Planned reconstructive breast surgery
• Condition making toxicity evaluation difficult, e.g. skin disorders, pre-existing brachial plexus injury, …
• Inability to respect constraints on skin, heart, lungs, esophagus, ribs, brachial plexus or any other organ at risk
• Mental condition rendering the patient unable to understand the nature, scope and possible consequences of the study
• Patient unlikely to comply with the protocol; i.e. uncooperative attitude, inability to return for follow-up visits or unlikely to complete the study

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

10

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: WBI - randomized - 5; WBI 5 fractions SIB 5 fractions if needed	Radiation: WBI 5 fractions; External beam radiotherapy in 5 fractions of 5,7Gy; Radiation: SIB 5 fractions if needed; Simultaneous boost of 5 x 6,2Gy (6,5Gy in case of involved resection margins) if needed
Active Comparator: WBI - randomized - 15; WBI 15 fractions SIB 15 fractions if needed	Radiation: WBI 15 fractions; External beam radiotherapy in 15 fractions of 2,67Gy; Radiation: SIB 15 fractions if needed; Simultaneous boost of 15x3,12Gy (3,33Gy in case of involved resection margins) if needed
Experimental: WBI - observational - 5; WBI 5 fractions SIB 5 fractions if needed	Radiation: WBI 5 fractions; External beam radiotherapy in 5 fractions of 5,7Gy; Radiation: SIB 5 fractions if needed; Simultaneous boost of 5 x 6,2Gy (6,5Gy in case of involved resection margins) if needed
Active Comparator: WBI - observational - 15; WBI 15 fractions SIB 15 fractions if needed	Radiation: WBI 15 fractions; External beam radiotherapy in 15 fractions of 2,67Gy; Radiation: SIB 15 fractions if needed; Simultaneous boost of 15x3,12Gy (3,33Gy in case of involved resection margins) if needed
Experimental: WBI + LNI - randomized - 5; WBI 5 fractions SIB 5 fractions if needed LNI 5 fractions	Radiation: WBI 5 fractions; External beam radiotherapy in 5 fractions of 5,7Gy; Radiation: SIB 5 fractions if needed; Simultaneous boost of 5 x 6,2Gy (6,5Gy in case of involved resection margins) if needed; Radiation: LNI 5 fractions; External beam radiotherapy in 5 fractions of 5,4Gy
Active Comparator: WBI + LNI - randomized - 15; WBI 15 fractions SIB 15 fractions if needed LNI 15 fractions	Radiation: WBI 15 fractions; External beam radiotherapy in 15 fractions of 2,67Gy; Radiation: SIB 15 fractions if needed; Simultaneous boost of 15x3,12Gy (3,33Gy in case of involved resection margins) if needed; Radiation: LNI 15 fractions; External beam radiotherapy in 15 fractions of 2,67Gy
Experimental: WBI with LNI - observational - 5; WBI 5 fractions SIB 5 fractions if needed LNI 5 fractions	Radiation: WBI 5 fractions; External beam radiotherapy in 5 fractions of 5,7Gy; Radiation: SIB 5 fractions if needed; Simultaneous boost of 5 x 6,2Gy (6,5Gy in case of involved resection margins) if needed; Radiation: LNI 5 fractions; External beam radiotherapy in 5 fractions of 5,4Gy
Active Comparator: WBI with LNI - observational - 15; WBI 15 fractions SIB 15 fractions if needed LNI 15 fractions	Radiation: WBI 15 fractions; External beam radiotherapy in 15 fractions of 2,67Gy; Radiation: SIB 15 fractions if needed; Simultaneous boost of 15x3,12Gy (3,33Gy in case of involved resection margins) if needed; Radiation: LNI 15 fractions; External beam radiotherapy in 15 fractions of 2,67Gy
Experimental: thoracic wall irradiation (TWI) +/- LNI - observational - 5; TWI 5 fractions SIB 5 fractions if needed LNI 5 fractions	Radiation: LNI 5 fractions; External beam radiotherapy in 5 fractions of 5,4Gy; Radiation: TWI 5 fractions; External beam radiotherapy in 5 fractions of 5,7Gy
Active Comparator: TWI +/- LNI - observational - 15; TWI 15 fractions SIB 15 fractions if needed LNI 15 fractions	Radiation: LNI 15 fractions; External beam radiotherapy in 15 fractions of 2,67Gy; Radiation: TWI 15 fractions; External beam radiotherapy in 15 fractions of 2,67Gy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Breast retraction (LENTSOMA)	Breast Cancer Conservative treatment.core (BCCT.core) objective measurement	2-5 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Acute toxicity: number of patients with clinical relevant dermatitis (CTCAE v. 4.0)	Assessment of grade of dermatitis	1-8 weeks
Acute toxicity: number of patients with moist desquamation	CTCAE v. 4.0 (grade 3)	1-8 weeks
Acute toxicity: number of patients with pain (CTCAE v. 4.0)	Grade 1: mild; Grade 2: moderate, limiting activity of daily living (ADL); grade 3: severe, limiting ADL	1-8 weeks
Acute toxicity: number of patients with pruritus (CTCAE v. 4.0)	Grade 1: mild, localized topical intervention; Grade 2: intense, oral intervention, skin changes	1-8 weeks
Acute toxicity: number of patients with fatigue (MFI-20)	Questionnaire (20 questions)	1-8 weeks
Chronic toxicity: measurement of patient satisfaction with breast esthetic outcome	BREAST-Q questionnaire: Patient reported outcome, evaluating satisfaction with esthetic outcome.	Before radiotherapy and after 2 and 5 years
Chronic toxicity: prevalence of fibrosis	LENT Soma: fibrosis (score 0-3)	2 and 5 years
Chronic toxicity: prevalence of pain	LENT Soma: score 0-4	2 and 5 years
Chronic toxicity: prevalence of telangiectasia	LENT Soma: Score 0-3	2 and 5 years
Chronic toxicity: prevalence of lymphedema	LENT Soma: score 0-4	2 and 5 years
Chronic toxicity: prevalence of fatigue (MFI-20)	Questionnaire (20 questions)	2 and 5 years
Chronic toxicity - prevalence of radiation induced brachial plexopathy (RIBP) (standardized screening questionnaire), confirmed by electromyogram (EMG)	If a screening reveals unilateral pain, loss of function or muscular atrophy in the ipsilateral arm, an EMG will be performed to confirm/exclude RIBP	2 and 5 years
Loco-regional tumor control	Ipsilateral or regional breast recurrence	2 and 5 years
Distant tumor control	Distant metastases free survival	2 and 5 years
Breast cancer specific survival	Number of patients alive and without breast cancer recurrence at 2 and 5 years after adjuvant radiotherapy	2 and 5 years
Overall survival	Number of patients alive, 2 and 5 years after adjuvant radiotherapy	2 and 5 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Patient preference	Patients can accept clinical trial but refuse randomization. In this case they will be allocated to a patient preference study arm, existing also of a 5 or 15 fraction-schedule. The choice of the patient: acceptance or non-acceptance of study, acceptance or non-acceptance of randomization, in case of patient preference arm: acceptance or 5 or 15 fractions.	Moment of intake, before allocation to study arm.
QoL within perspective of cancer patients	QLQ C30 - standardised questionnaire	4 weeks, 1, 2 and 5 years
QoL within perspective of breast cancer patients	QLQ BR23 - standardised questionnaire	4 weeks, 1, 2 and 5 years
QoL within perspective of healthy patients	EQ-D5: standardised questionnaire	4 weeks, 1, 2 and 5 years
Number of patients evolving to higher frailty score after radiotherapy	Measurement of frailty using G8 geriatric screening tool	4 weeks, 1, 2 and 5 years
Cost Effectiveness Analysis	Cost effectiveness analysis comparing 5 with 15 fractions	5 years
Technical feasibility of prone positioning	Percentage of patients able to perform prone positioning on new breast board: yes or no.	At the moment of simulation
Technical feasibility of deep inspirational breath-hold in prone position	Percentage of patients able to perform breath-hold procedure in prone position: yes or no.	At the moment of simulation

Collaborators and Investigators

• Sponsor: University Hospital, Ghent
• Investigators: Principal Investigator: Liv Veldeman, M.D., PhD, Ghent University Hospital, Dept. Radiotherapy-Oncology

Publications and helpful links

Helpful Links

• HAI-5 feasilibility trial: results acute toxicity

Study record dates

Study Major Dates

• Study Start (Actual): February 15, 2017
• Primary Completion (Actual): November 15, 2021
• Study Completion (Estimated): November 15, 2026

Study Registration Dates

• First Submitted: January 13, 2017
• First Submitted That Met QC Criteria: April 14, 2017
• First Posted (Actual): April 20, 2017

Study Record Updates

• Last Update Posted (Actual): December 22, 2023
• Last Update Submitted That Met QC Criteria: December 21, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Keywords: Accelerated radiotherapy; Older women; Hypo-fractonation
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms
• Other Study ID Numbers: EC/2016/1386

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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