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one of the following heart sparing techniques :

* DIBH radiotherapy
* IMRT

For all participants, myocardial perfusion SPECT will be performed :

at 3, 6 and 12 months (post irradiation)

myocardial perfusion SPECT

Valérie SARTORI

Manon VOEGELIN

Martin SCHMITT, MD

Breast irradiation is known to cause radiation-induced heart disease (RIHD) many years later after radiotherapy. Recent studies suggest that RIHD could be an earlier complication and that subclinical cardiac injury can be detected such as myocardial perfusion defects. Myocardial perfusion single photon emission computed tomography (SPECT) is a sensitive and specific technique able to detect perfusion abnormalities which are more frequent in left-sided breast cancer patients because of the cardiac exposure.

The most used technique for breast cancer irradiation is tangential opposed field, but this technique exposes the left anterior descending coronary artery to high dose during left breast irradiation.

There are different cardiac sparing techniques to reduce heart exposure such as:

* Deep inspiration breath-hold (DIBH) which displaces the heart out of the radiation beam
* Intensity-modulated radiation therapy (IMRT) which decreases heart exposure to high doses but changes the dose distribution in the heart and increases lower doses.

In breast radiotherapy, especially for left sides breast cancers, the heart is the organ-at-risk which whose dose constraints are source of controversies. Historically breast cancer radiation therapy was associated with a significantly increased cardiac mortality. Two meta-analyses founded that the cardiac mortality risk was increased by 27% to 38%. This result is linked to outdated 2-D treatment techniques causing massive cardiac overexposure (Clarke M et al. 2005, Cheng YJ et al. 2017).

Three dimensional conformational radiotherapy reduced mean heart dose but the link between heart irradiation and radiation-induced heart damages doesn't seem to have threshold therefore to RHID is still a matter of concern (Darby SC et al. 2013; Taylor C et al. 2017).

The most used technique for breast cancer irradiation is opposite tangential field radiotherapy, however, it exposes the anterior interventricular coronary artery to a high dose during left breast irradiation (Nieder C et al. 2007). Therefore, radiotherapy techniques have developed to reduce cardiac exposure such as deep inspiration breath hold (DBIH) and intensity modulated radiation therapy (IMRT).

DBIH "mechanically" moves the heart away from the radiation beam and IMRT the dose distribution in the heart and reduces its exposure to high doses (Boda-Heggemann J et al. 2016, Lauche O et al. 2016).

Nevertheless, recent studies suggest that even with this level of cardiac exposure subclinical cardiac alterations may be detected, such as myocardial perfusion deficit (Eber et al. 2022; Marks LB et al. 2005; Gyenes G et al. 1997; Sioka C et al. 2011; Seddon B et al. 2002; Eftekhari M et al. 2015).

The heart is a complex and heterogeneous organ, however it's mostly considered as an homogeneous organ-at-risk during treatment planning in daily practice. Dosimetric optimization is therefore mainly performed on the global cardiac structure and the mean cardiac dose (MHD). Dosimetric studies reported a poor correlation between MHD and mean doses to cardiac substructures questioning the relevance of the MHD as a reflection of the dose distribution to the heart (Jacob S et al. 2016).

Recent data suggested to take account of the histological diversity and the functional complexity of the cardiac substructure (Darby SC et al. 2010; Gillette EL et al. 1985; Ghita M et al. 2020; Eber J et al. 2021). This delineation is not performed in routine clinical practice due to the poorly reproducible and time-consuming manual contouring.

The development of auto-segmentation software can save time and improve the quality of the delineation process of these substructures in order to optimize dosimetry (Feng M et al. 2011; Maffei N et al. 2020).

The investigators propose a single-centre prospective study to evaluate the utility of deep inspiration breath hold using a surface monitoring technique (AlignRT, Vision RT Ltd., London, UK) and IMRT, as means to prevent the development of myocardial perfusional deficits in patients treated for left breast cancer, using stress and, if necessary, resting myocardial scintigraphy.

Before initiation of radiotherapy patients will performed a chest CT scan in the treatment position for 3D treatment planning and dose calculation; a chest CT angiography for delineation of cardiac substructures; and a myocardial perfusion SPECT imaging to provide a map of regional myocardial perfusion and determine left ventricle ejection fraction (LVEF).

Treatment phase will consist of the standard course of breast radiotherapy in our department. The main difference will be in the delineation of the organ at risk, cardiac substructures will be delineated to obtain the dosimetry During the follow up period, patient will be scheduled to undergo cardiac SPECT before and at 3-, 6-, and 12-month period post irradiation. Stress ECG-gated SPECT will be performed after infusion of 3 MBq/kg 99mTc-tetrofosmin (Myoview®, General Electrics Healthcare) at peak pharmacological stress with regadenoson, (single dosage: 400 µg; Rapiscan®, GE healthcare)

Efficacity of Deep Inspiration Breath Hold and Intensity-modulated Radiotherapy in Preventing PErfusion Defect for Left Sided Breast Cancer (EDIPE)

Incidence of perfusion defects on follow-up myocardial perfusion SPECT scans

Incidence of left ventricular wall motion disorder and LVEF quantification on follow-up myocardial perfusion SPECT scans.

Measurement of the doses delivered to the cardiac volumes and its substructures.

Anticancer therapy characteristics (type)

Anticancer therapy characteristics (dose)

Anticancer therapy characteristics (duration)

Institut de cancérologie Strasbourg Europe

Cohort 1 - No prior anthracycline-based chemotherapy or herceptin, deep inspiration breath hold breast radiation therapy

Cohort II - no prior Anthracycline based chemotherapy or Herceptin and (ii) to receive FB RT (not able to hold breath for at least 20 seconds or does not have a minimum of 1.0 cm of heart on at least 3 slices (3mm slices) on the FB scan)

Cohort III - Prior Anthracycline-based chemotherapy or Herceptin, and (ii) eligible to receive DIBH RT. (Patient has a minimum of 1.0 cm of heart on at least 3 slices (3mm slices) on the FB scan)

Radiation therapy

Kurian Joseph, MB, FFRRCSI, FRCR, FRCPC

The study hopes to determine whether patients with left-sided breast cancer are at an increased risk of cardiac changes due to radiation to the breast +/- Anthracycline-based chemotherapy +/- Herceptin and whether a deep inspiration breath hold (DIBH) technique during radiotherapy treatments would further reduce dosimetric dose to the heart as compared to the conventional free breathing (FB) technique thus reducing cardiac toxicity as measured by cardiac MRI using left ventricular end-diastolic volume (LVEDV) as a metric. Bio fluid samples will also be collected to investigate specific biomarkers of breast cancer: BNP, PIIINP and CITP

Patients with left-sided breast cancer who receive adjuvant breast or chest wall radiation have increased risk of treatment related cardiovascular morbidity. The risk of cardiac morbidity and mortality is increased when a patient receives radiation following adjuvant chemotherapy and Herceptin. The dose-volume histogram (DVH) parameters associated with increased cardiac toxicity include volume of heart irradiated, total radiation dose received by the left ventricle (LV), V25 and mean cardiac dose. Even though modern RT treatments like 3DCRT and IMRT can reduce the mean dose to the heart, the maximum dose to the left side of the heart/LV may not be reduced if the target is close to the heart. The hypothesis is that DIBH RT can safely and effectively reduce the heart dose, especially the dose to the LV, that could lead to reduction in the incidence of radiation induced cardiovascular morbidity and mortality.

Radiotherapy has detrimental effects on cardiac function due to remodeling of the cardiac tissue that receive radiation. We believe that the radiation related acute effects on heart tissue can be detected with cardiac functional MRI. The study will quantify the acute RT related effects. To our knowledge, cardiac MRI has not been explored as a non invasive technique to quantify RT +/- chemotherapy related effects.

Study to See Whether Breath-Hold Techniques During RT Are Effective in Helping to Improve Sparing of the Heart

A Cohort Study Assessing Cardiac Function With MRI in Left-Sided Breast Cancer Patients Treated With Deep Inspiration Breath Hold (DIBH) Technique to Improve Cardiac Sparing During Adjuvant Radiotherapy

Using MRI-based cardiac functional imaging to measure radiation-related acute and long term cardiac functional changes in patients treated with deep-inspiration breath-hold (DIBH) compared to free breathing (FB) treatment

Radiation dosimetry is the accurate calculation and measurement of radiation doses received by tissue resulting from the exposure to radiation. A radiation dosimetric comparison will be performed between the deep inspiration breath hold (DIBH) technique treatment plan and the free breathing (FB) technique treatment plan to explore sparing of cardiac sub-structures from radiation, if any

Cross Cancer Institute

AHS Cancer Control Alberta

Carcinoma

Carcinoma, Ductal

Carcinoma in Situ

Carcinoma, Intraductal, Noninfiltrating

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Adenocarcinoma

Breast Carcinoma In Situ

For prone positioning, patients will be positioned with alpha cradle casts, and a prone breast board.

For the supine positioning, patients will be positioned with the breast board currently in use in the Department of Radiation Oncology.

The DIBH technique involves the patient breathing to a specified threshold and then holding that level of inspiration during every radiation therapy field delivered.

Deep Inspiration Breath Hold during Radiation

The patient will be instructed to breathe freely.

Free breathing during radiation

Adam Currey, MD, PhD

This study aims to discover more about radiation techniques for people treated for left-sided breast cancer that minimizes exposure to the heart, as noted by mean heart dose.

This study aims to discover more about radiation techniques for people treated for left-sided breast cancer that minimizes exposure to the heart, as noted by mean heart dose. Both prone (lying face down) radiation and Deep Inspiration Breath Hold (DIBH) are more labor-intensive and usually require longer treatment times for patients than traditional supine (lying face up) free-breathing radiation treatments. Thus, identifying people that benefit most from these techniques can better utilize resources. This study compares supine and prone positioning, with or without DIBH, to further assess which positioning technique will achieve the lowest cardiac radiation doses.

The Use of Deep Inspiration Breath Hold and Prone Irradiation to Decrease Cardiac Radiation Exposure

A Phase II Study of the Use of Deep Inspiration Breath Hold and Prone Irradiation to Decrease Cardiac Radiation Exposure

Changes in QRS wave form will be categorized as 'present' or 'absent' based on the presentation (or lack) of a r' wave, or notched r or s wave on the EKG tracing. QRS-T angle will be measured in degrees.

Mitochondrial energy production will be measured by determining oxygen consumption rate (pmol of O2 consumed per second per·10\^6 cells).

This will be assessed by measuring the ascending aortic diameters 3 cm above the aortic valve at end-diastole and end-systole in the 2D parasternal view.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Efficacity of Deep Inspiration Breath Hold and Intensity-modulated Radiotherapy in Preventing PErfusion Defect for Left Sided Breast Cancer (EDIPE)	NCT05454553	Breast Cancer	myocardial perf...	18 Years -	Institut de cancérologie Strasbourg Europe
Study to See Whether Breath-Hold Techniques During RT Are Effective in Helping to Improve Sparing of the Heart	NCT02052102	Breast Cancer Adverse Effect ...	Radiation thera...	18 Years - 70 Years	AHS Cancer Control Alberta
The Use of Deep Inspiration Breath Hold and Prone Irradiation to Decrease Cardiac Radiation Exposure	NCT03375892	Breast Cancer Ductal Carcinom... Invasive Breast...	Deep Inspiratio... Free breathing ...	18 Years -	Medical College of Wisconsin

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