Whole Breast + Lymph Node Irradiation: Prone Compared to Supine Position in 15 or 5 Fractions

Study Overview
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Brief Summary
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The goal of this trial is to evaluate the effect of the prone crawl treatment position and/or accelerated schedule on acute and late toxicities, as well as quality of life and time management for breast cancer patients receiving whole breast and regional nodal irradiation after breast conserving surgery.

Detailed Description
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Locoregional radiotherapy after lumpectomy and axillary node dissection diminishes the locoregional recurrence risk at 10 years by 21,2 % in women with pathologically confirmed lymph node involvement. Excess dose to organs at risk can lead to acute and late side effects, such as tissue damage, organ malfunction and secondary cancers. Radiotherapy in prone position has helped reduce these risks for whole breast radiotherapy only, but has not yet been adequately investigated for patients also requiring regional nodal irradiation. One of the reasons is that there is no optimal patient support device available to allow regional nodal irradiation in prone position. To this end, a novel positioning device was developed at our center, allowing regional nodal irradiation in prone position. It was called the crawl breast couch because the patient position resembles a phase from the crawl swimming technique. A previous planning study by Deseyne et al. using this device shows a benefit (i.e. reduced dose) for the ipsilateral lung, the thyroid, as well as a minor benefit for the right lung, and contralateral breast (which already receive very low relative doses) while maintaining similar target coverage when compared to supine positioning. Apart from the paradigm shift from supine to prone radiotherapy, in recent years, it has become clear that breast cancer cells are more sensitive to fraction dose than originally presumed. Large randomized trials confirm this hypothesis: moderate hypofractionation schemes in 15 or 16 fractions are at least equivalent in tumor control and toxicity although the total dose is lower than the traditional 50 Gy in 25 fractions. Further acceleration to 5 fractions is expected to have an even larger radiobiological advantage regarding tumor control. Additional advantages are patient comfort and a better use of radiotherapy resources. This randomized trial with 2 x 2 factorial design tests 2 interventions for patients with breast cancer requiring whole-breast and regional nodal irradiation: radiotherapy in prone position with a specifically designed patient support device called the crawl breast couch, and accelerated radiotherapy in 5 fractions. The standard arm in this trial is supine hypofractionated radiotherapy. The goal of this trial is to evaluate the effect of the prone crawl treatment position and/or accelerated schedule on acute and late toxicities, as well as quality of life and time management for breast cancer patients receiving whole breast and regional nodal irradiation after breast conserving surgery.

Official Title
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Whole Breast (WB) + Lymph Node Irradiation (LNI): Prone Compared to Supine Position in a Randomized Study With 15 or 5 Fractions

Conditions
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Breast Neoplasms, Radiotherapy, Lymph Node Metastases

Intervention / Treatment
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* Device: Prone Radiotherapy
* Radiation: Acceleration
* Device: Supine Radiotherapy
* Radiation: Hypofractionation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Breast conserving surgery AND Multidisciplinary decision of adjuvant whole breast + regional nodal irradiation AND Informed consent obtained, signed and dated before specific protocol procedures Exclusion Criteria: Mastectomy OR Bilateral breast irradiation OR Distant metastasis/metastases OR previous irradiation to the thoracic, cervical or axillary region and overlap of fields with current treatment OR life expectancy of less than 2 years OR pre-existing conditions or comorbidities making toxicity evaluation difficult, e.g. skin disorders OR pregnant or breast feeding OR mental condition rendering the patient unable to understand the nature, scope and possible consequences of the study OR patient unlikely to complete the study

Ages Eligible for Study
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Minimum Age: 18 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: Factorial Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Supine Hypofractionated Radiotherapy<br>Supine Radiotherapy and Hypofractionation: Whole breast + regional nodal irradiation in supine position with a median dose of 15 x 2.67 Gy prescribed to the whole breast and nodal regions. Median dose of the simultaneously integrated boost is 3.12 Gy per fraction. | Device: Supine Radiotherapy<br>* Supine positioning for regional nodal irradiation using breastboard.<br>* Other names: Supine regional nodal irradiation;Radiation: Hypofractionation<br>* Moderate hypofractionation in 15 fractions over 3 weeks with simultaneously integrated boost<br>* Other names: Moderate hypofractionation;|
| Experimental: Prone Hypofractionated Radiotherapy<br>Prone Radiotherapy and Hypofractionation: Whole breast + regional nodal irradiation in prone position with a 15 x 2.67 Gy dose prescription to the whole breast and nodal regions. Median dose of the simultaneously integrated boost is 3.12 Gy per fraction. | Device: Prone Radiotherapy<br>* Prone positioning for regional nodal irradiation using the crawl breast couch.<br>* Other names: Prone regional nodal irradiation;Radiation: Hypofractionation<br>* Moderate hypofractionation in 15 fractions over 3 weeks with simultaneously integrated boost<br>* Other names: Moderate hypofractionation;|
| Experimental: Supine Accelerated Radiotherapy<br>Supine Radiotherapy and Acceleration: Whole breast + regional nodal irradiation in supine position with a median dose of 5 x 5.7 Gy to the whole breast. Lymph node regions receive a median dose of 5 x 5.4 Gy. Median dose of the simultaneously integrated boost is 6.2 Gy per fraction. | Radiation: Acceleration<br>* Accelerated irradiation in 5 fractions over 12 days with simultaneously integrated boost<br>* Other names: 5 fractions;Device: Supine Radiotherapy<br>* Supine positioning for regional nodal irradiation using breastboard.<br>* Other names: Supine regional nodal irradiation;|
| Experimental: Prone Accelerated Radiotherapy<br>Prone Radiotherapy and Acceleration: Whole breast + regional nodal irradiation in prone position with a median dose of 5 x 5.7 Gy to the whole breast. Lymph node regions receive a median dose of 5 x 5.4 Gy. Median dose of the simultaneously integrated boost is 6.2 Gy per fraction. | Device: Prone Radiotherapy<br>* Prone positioning for regional nodal irradiation using the crawl breast couch.<br>* Other names: Prone regional nodal irradiation;Radiation: Acceleration<br>* Accelerated irradiation in 5 fractions over 12 days with simultaneously integrated boost<br>* Other names: 5 fractions;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Breast retraction | Rate of breast retraction or volume loss after radiotherapy | 2 years after radiotherapy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Acute toxicity - Dermatitis | Dermatitis measured by CTCAE v4.03 | Baseline and from radiation initiation until 8-16 days after radiation treatment | 
| Acute toxicity - Desquamation | Desquamation measured by CTCAE v4.03 | Baseline and from radiation initiation until 8-16 days after radiation treatment | 
| Acute toxicity - Breast oedema | Breast oedema measured by CTCAE v4.03 | Baseline and from radiation initiation until 8-16 days after radiation treatment | 
| Acute toxicity - Shoulder range of motion | Shoulder range of motion measured by maximal excursion in abduction-adduction and anteversion-retroversion, in degrees from anatomical reference position | Baseline and from radiation initiation until 8-16 days after radiation treatment | 
| Acute toxicity - Arm circumference | Arm circumference measured in cm 15 cm above and below medial epicondyle | Baseline and from radiation initiation until 8-16 days after radiation treatment | 
| Acute toxicity - Breast symptoms - pain | Breast pain measured on a scale: 0 (no pain) - 1 (pain on contact) - 2 (pain on contact and also occasionally spontaneous) - 3 (pain on contact and regularly spontaneous) - 4 (pain medication needed and specify which) | Baseline and from radiation initiation until 8-16 days after radiation treatment | 
| Acute toxicity - Breast symptoms - sense of heaviness | Sense of breast heaviness defined as present or absent. | Baseline and from radiation initiation until 8-16 days after radiation treatment | 
| Acute toxicity - Breast symptoms - itching | Itching in the breast on a scale: 0 (no itching) - 1 (occasional itching) - 2 (regular itching) | Baseline and from radiation initiation until 8-16 days after radiation treatment | 
| Acute toxicity - Arm Symptoms - Pain | Arm pain measured on a scale: 0 (no pain) - 1 (pain on contact) - 2 (pain on contact and also occasionally spontaneous) - 3 (pain on contact and regularly spontaneous) - 4 (pain medication needed and specify which) | Baseline and from radiation initiation until 8-16 days after radiation treatment | 
| Acute toxicity - Arm Symptoms - Sense of heaviness | Sense of arm heaviness defined as present or absent. | Baseline and from radiation initiation until 8-16 days after radiation treatment | 
| Acute toxicity - Shoulder symptoms - Pain | Pain in the irradiated shoulder as defined on a scale: 0 (no pain) - 1 (occasional pain) - 2 (regular pain) | Baseline and from radiation initiation until 8-16 days after radiation treatment | 
| Acute toxicity - Shoulder symptoms - Impaired shoulder mobility | Impaired shoulder mobility on the irradiated side defined as present or absent | Baseline and from radiation initiation until 8-16 days after radiation treatment | 
| Acute toxicity - Pain not in arm/shoulder/breast | Pain present in any other region than arm, shoulder or breast, defined on a scale: 0 (no pain) - 1 (occasional pain) - 2 (regular pain). Painful locations are indicated on a figure. | Baseline and from radiation initiation until 8-16 days after radiation treatment | 
| Acute toxicity - Dysphagia | Dysphagia measured according to CTCAE v4.03 | Baseline and from radiation initiation until 8-16 days after radiation treatment | 
| Acute toxicity - Dyspnea | Dyspnea measured according to CTCAE v4.03 | Baseline and from radiation initiation until 8-16 days after radiation treatment | 
| Acute toxicity - Cough | Cough measured according to CTCAE v4.03 | Baseline and from radiation initiation until 8-16 days after radiation treatment | 
| Acute toxicity - Cardiac toxicity | Troponin T value at last treatment session ± 1 day compared with baseline measurement. | Baseline and from radiation initiation until 8-16 days after radiation treatment | 
| Non-breast retraction late treatment related toxicity | breast oedema, telangiectasia, color changes, fibrosis, shoulder symptoms, breast symptoms, arm symptoms, brachial plexopathy, heart toxicity, dyspnea, thyroid function, pain, fatigue. | Baseline and from 6 months post radiotherapy until 5 years after radiotherapy | 
| Cosmesis | Photographic image analysis using BCCT.core using frontal images with different arm positions. Reported cosmetic outcome is evaluated with radiotherapy specific items of the Breast Q questionnaire | Baseline, 1st visit after radiotherapy and at year 1, 2 and 5 | 
| Quality of life - General | EORTC questionnaire QLQ-C30 | At baseline and at 1, 2 and 5 years after radiotherapy | 
| Quality of life - Breast specific questionnaire | Supplementing the general quality of life outcome (QLQ-C30) with breast specific questionnaire using the EORTC QLQ-BR23 tool | At baseline and at 1, 2 and 5 years after radiotherapy | 
| Locoregional and distant tumor control | Locoregional and distant tumor control | At 1, 2 and 5 years after radiotherapy | 
| Treatment duration | Time registration from the moment the patient climbs the treatment couch until end of radiation. The first fraction is not measured as unforeseen problems in the workflow, questions or difficulties might delay treatment and falsify the results. The moment the patient mounts the treatment couch as well as the moment she climbs down, will be registered using a remote sensor. The beam on time is automatically registered by the treatment software. | At 3 weeks | 
| Dose parameters of target tissues/organs at risk | Data extracted from dose-volume histograms (DVHs) and associated DVH planning files. the data are extracted from the developped treatment plan before treatment is initiated. Discrete values will be evaluated for all patients, more precisely the following: D02 as a surrogate for Dmax, D05, D50, D95, D100, mean dose. All these values are reported in Gray (Gy) Parameters evaluated for OARs: - Mean dose, D02, D05, all in Gray | After treatment planning (Week 1-2 after inclusion) | 
| Volume parameters of targets/organs at risk/hot spots - volume of the structures | Data extracted from dose-volume histograms (DVHs) and associated DVH planning files. the data are extracted from the developped treatment plan before treatment is initiated. Volume of the targets and organs at risk is measured in cubic centimeters (cm³). Hot spots are defined as regions receiving either 105 or 107 % of the prescribed dose or more. | After treatment planning (Week 1-2 after inclusion) | 
| Volume parameters of targets/organs at risk - relative volume receiving a certain dose | Data extracted from dose-volume histograms (DVHs) and associated DVH planning files. the data are extracted from the developped treatment plan before treatment is initiated. For Organs at risk, a V5, V10, V20, V30 will be calculated. This is the relative volume of a the structure receiving a dose of 5, 10, 20 or 30 Gy. The value is measured as a percentage (%) of the total structure volume. | After treatment planning (Week 1-2 after inclusion) | 
| Setup accuracy | Cone beam computed tomography verification directly prior to each scheduled radiation treatment session to determine shift between planned positioning and actual positioning. Shifts are performed and registered in laterolateral, craniocaudal and anteroposterior directions. No rotations are performed. | Before each scheduled radiation treatment session (every treatment day starting from radiotherapy start until ± 3 weeks later) | 
| Treatment cost | Cost-Utility Analysis (CUA) using the EuroQoL 5D tool. | Baseline, 1st visit after radiotherapy and at year 1, 2 and 5 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Prone position, Supine position, Hypofractionation, Accelerated radiotherapy, Regional nodal irradiation