Outcome of 15 Versus 5 Fractions in Adjuvant Breast Radiotherapy in Women Over 65 Years

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Breastcancer

Intervention / Treatment
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* Radiation: WBI 5 fractions
* Radiation: WBI 15 fractions
* Radiation: LNI 5 fractions
* Radiation: LNI 15 fractions
* Radiation: SIB 5 fractions if needed
* Radiation: SIB 15 fractions if needed
* Radiation: TWI 5 fractions
* Radiation: TWI 15 fractions


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 65 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

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

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Accelerated radiotherapy, Older women, Hypo-fractonation